Clinical trial NCT02791516
Conditions: Postmenopausal Osteoporosis
Keywords: Osteoporosis. Osteoporosis-Postmenopausal. Bone Diseases-Metabolic. Bone Diseases. Musculoskeletal Diseases.
Sponsor: Amgen
Start date: 2017-01-16; Completion date: 2018-12-21
Enrollment: 67 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to evaluate the effect of treatment with romosozumab for 6 months compared with placebo on percent changes in bone mineral density (BMD) at the lumbar spine as assessed by dual-energy X-ray absorptiometry (DXA) in postmenopausal women with osteoporosis.

Detailed description:

Arms: arm 1: Participants received placebo subcutaneous injection once a month for 6 months. arm 2: Participants received 210 mg romosozumab by subcutaneous injection once a month for 6 months.
Interventions: intervention 1: Romosozumab intervention 2: Placebo
Intervention descriptions: intervention 1: Administered by subcutaneous injection once a month (QM) intervention 2: Administered by subcutaneous injections once a month

Protocol documents:
Prot_000.pdf: 
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Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 2 of 74 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Multicenter, Randomized, Double-blind, 
Placebo-controlled, Study to compare the Efficacy and Safety of Romosozumab with 
placebo in postmenopausal South Korean women with osteoporosis, dated 
13 November 2017, and agree to abide by all provisions set forth therein.  
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 3 of 74 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Multicenter, Randomized, Double-blind, Placebo-controlled, Study to  
Compare the Efficacy and Safety of Romosozumab with Placebo in Postmenopausal 
South Korean women with Osteoporosis 
Study Phase:  3 
Indication:  Osteoporosis in postmenopausal women 
Primary Objective:  To evaluate the effect of treatment with romosozumab for 6 months 
compared with placebo on percent changes in bone mineral density (BMD) at the lumbar spine as 
assessed by dual-energy x-ray absorptiometry (DXA) in postmenopausal women with 
osteoporosis. 
Secondary Objective:  To evaluate the effect of treatment with romosozumab for 6 months 
compared with placebo on the percent changes in DXA BMD at the total hip and femoral neck. 
Exploratory Objective: To evaluate the effect of treatment with romosozumab for 6 months 
compared with placebo on percent changes in bone turnover markers (BTM): bone formation 
marker procollagen type 1 N-telopeptide (P1NP) and bone resorption marker serum type I 
collagen C-telopeptide (CTX). 
Safety Objective: To characterize the safety and tolerability of treatment with romosozumab for 
6 months compared with placebo as determined by a review of reported adverse events, 
laboratory data, vital signs, and the formation of anti-romosozumab antibodies over the 6-month 
treatment period, and adverse events and the formation of anti-romosozumab antibodies for the 
overall study period (6-month treatment period followed by the 3-month follow-up period). 
Pharmacokinetics (PK): To characterize the serum romosozumab concentration 
Hypotheses:  The primary clinical hypothesis is that in South Korean postmenopausal women 
with osteoporosis, the mean percent change in lumbar spine BMD in subjects receiving 
romosozumab will be superior to that of those receiving placebo at month 6.  It is hypothesized 
that changes in BMD at the lumbar spine in subjects receiving romosozumab will be at least 6.6% 
greater than in subjects receiving placebo.  The safety hypothesis is that romosozumab treatment 
for 6 months is well tolerated in South Korean women with osteoporosis. 
Primary Endpoint:  Percent change from baseline in DXA BMD at the lumbar spine at month 6 
Secondary Endpoint:  Percent change from baseline in DXA BMD at the femoral neck and total 
hip at month 6. 
Exploratory Endpoints:  Percent changes from baseline in bone turnover markers (BTM):  bone 
formation marker procollagen type 1 N-telopeptide (P1NP) and bone resorption marker serum 
type I collagen C-telopeptide (CTX) at months 1, 3, and 6 
Safety Endpoints: 
For the 6-month treatment period: 
• 
Subject incidence of adverse events by system organ class and preferred term 
• 
Changes from baseline in laboratory assessments (serum chemistry and hematology) and 
shifts from baseline to the worst value between baseline and month 6 
• 
Changes from baseline in vital signs 
• 
Incidence of subjects with anti-romosozumab antibodies at months 1, 3, and 6 
For the overall study period (6-month treatment period followed by the 3-month follow-up period): 
• 
Subject incidence of adverse events by system organ class and preferred term 
• 
Subject incidence of the formation of anti-romosozumab antibodies 
Pharmacokinetic Endpoint: Romosozumab serum concentration at months 1, 3, and 6 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 4 of 74 
CONFIDENTIAL 
 
 
Study Design:  This is a multicenter, randomized, double-blind, placebo-controlled study in 
approximately 60 South Korean postmenopausal women with osteoporosis.  The study is 
designed to evaluate if treatment with romosozumab once a month (QM) for 6 months compared 
with placebo is effective in increasing BMD at the lumbar spine.  In addition, the study will assess 
the effect of treatment with romosozumab QM for 6 months compared with placebo on BMD at 
the femoral neck and total hip. 
Approximately 60 subjects will be randomized in a 1:1 ratio to receive 210 mg romosozumab 
subcutaneous (SC) QM (approximately 30 subjects) or matched placebo SC QM (approximately 
30 subjects), respectively, in a blinded fashion for the duration of the 6-month treatment period. 
Upon completion of the 6-month treatment period, subjects will be followed for an additional 
3 months to ensure appropriate follow-up for anti-romosozumab antibody formation. 
From screening to end of study (EOS), subjects will receive daily calcium and vitamin D 
supplementation.  In addition, subjects with a serum 25 (OH) vitamin D level of ≥ 20 ng/mL and 
≤ 40 ng/mL at screening will receive an initial loading dose of vitamin D after randomization. 
Approximately 10 sites in South Korea will participate in this study.  Sites that do not enroll 
subjects within 2 months of site initiation may be closed. 
Sample Size:  Approximately 60 subjects will be enrolled in the study. 
Summary of Subject Eligibility Criteria:  The study will enroll ambulatory postmenopausal 
Korean women, ≥ 55 to ≤ 90 years of age at randomization with a DXA BMD T-score ≤ -2.50 at 
the lumbar spine, total hip or femoral neck.  Subjects must have at least 2 vertebrae in the L1 
through L4 region and at least 1 proximal femur evaluable by DXA.  Subjects with a BMD T-score 
≤ -4.0 at the lumbar spine, total hip or femoral neck and subjects with a history of hip fracture are 
ineligible for the study.  For a full list of eligibility criteria, please refer to Section 4.1.  
Investigational Product:  Romosozumab or matching placebo administered by prefilled 
syringe (PFS). 
Amgen Investigational Product Dosage and Administration:  Romosozumab 210 mg or 
matching placebo will be administered QM for 6 months as an SC injection via PFS at day 1, 
month 1, month 2, month 3, month 4, and month 5.  All dosing with be administered in-clinic. 
Non-Amgen Non-investigational Product Dosage and Administration:  From screening to 
EOS, subjects will receive daily calcium and vitamin D supplementation that at a minimum is in 
the range of 500 to 1 000 mg elemental calcium and 600 to 800 IU vitamin D.  In addition, 
subjects with a serum 25 (OH) vitamin D level of ≥ 20 ng/mL and ≤ 40 ng/mL at screening will 
receive an initial loading dose of 50 000 to 60 000 IU vitamin D after randomization, preferably by 
the oral route.  Subjects with a serum 25 (OH) vitamin D level of > 40 ng/mL at screening may 
also receive the vitamin D loading dose at the principal investigator’s discretion. 
Procedures:  Informed consent; demographics; medical, medication, fracture, tobacco, alcohol, 
and substance use history; physical examination; physical measurements (height and weight); 
vital signs (blood pressure, heart rate, respiratory rate, and temperature); concomitant 
medications; serious adverse event reporting; adverse event reporting; laboratory assessments 
(serum chemistry, hematology, serum protein electrophoresis, hepatitis B and C testing, serum 
25 (OH) vitamin D, intact parathyroid hormone (iPTH), pharmacokinetics, anti-romosozumab 
antibody, BTMs; DXA scan of the lumbar spine and proximal femur; IP administration; daily 
calcium and vitamin D supplementation; and if applicable, vitamin D loading dose administration. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 1). 
Statistical Considerations: 
Primary Efficacy Endpoint: 
The analysis to assess the percent change from baseline in lumbar spine DXA BMD at month 6 
will employ an analysis of covariance (ANCOVA) model.  The ANCOVA model will include 
treatment group, baseline value of BMD, machine type and interaction of baseline BMD value and 
machine type as independent variables.  Summaries for the results will include least-squares 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 5 of 74 
CONFIDENTIAL 
 
 
means point estimates of the percent change from baseline for each treatment arm.  The 
variance structure will allow for heterogeneity between treatments.  The 2-sided 95% confidence 
interval (CI) and associated p-value will be provided for the difference between the least-squares 
means for romosozumab and placebo. 
Conclusions for the primary efficacy hypothesis of different efficacy of romosozumab compared 
with placebo at lumbar spine BMD will be made using a 2-sided test with type 1 error rate of 0.05.  
Secondary Efficacy Endpoints: 
For the secondary efficacy BMD endpoints (total hip and femoral neck at month 6), the percent 
change from baseline in DXA BMD will employ an ANCOVA model.  The ANCOVA model will 
include treatment group, baseline value of BMD, machine type and interaction of baseline BMD 
value and machine type as independent variables.  Summaries for the results will include 
least-squares means point estimates of the percent change from baseline for each treatment arm.  
The variance structure will allow for heterogeneity between treatments.  The 2-sided 95% CI and 
associated p-value will be provided for the difference between the least-squares means for 
romosozumab and placebo.  
Exploratory Efficacy Endpoints: 
For P1NP and CTX, descriptive statistics will be presented by treatment group at each visit for 
both actual values and the percent change from baseline values.  Graphs depicting median and 
interquartile ranges by treatment group for percent change over time will be provided.  
Safety Endpoints: 
Safety analyses will include assessments of treatment-emergent adverse events, IP exposure, 
clinical laboratory assessments, vital signs, and anti-romosozumab antibodies.  The safety 
analysis set will be used for these analyses.  There is no planned inferential statistical testing in 
the safety analyses.  All categorical endpoints will be summarized using the number and percent 
of subjects.  All continuous endpoints will be summarized using descriptive statistics including 
mean, standard deviation, minimum, quartiles, maximum, and number of subjects. 
Pharmacokinetic Endpoint: 
Trough serum concentration values determined from subjects may be summarized in tabular form 
and presented graphically.  Additional pharmacokinetic analyses will be performed as 
appropriate. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen, Inc. 
Data Element Standards 
Version(s)/Date(s):  
Version 5/20 March 2015 
 


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Legend
Study visit with IP administration
Study visit without IP administration
RANDOMIZATION
SCREENING
PRIMARY ANALYSIS
FINAL ANALYSIS
D1
M1
M2
M3
M4
M5
M6
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210 mg Romosozumab SC QM
n = 30
Placebo SC QM
n = 30
Loading dose 50,000-60,000 IU vitamin D, if applicable
Screening period
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6 months
Follow-up period
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Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 7 of 74 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ALP 
alkaline phosphatase  
ALT 
alanine transferase  
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase  
BMD 
bone mineral density 
BMI 
body mass index 
BP 
blood pressure 
BTM 
bone turnover markers 
CI 
confidence interval 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTX 
collagen C-telopeptide 
DILI 
drug-induced liver injury  
DXA 
dual-energy x-ray absorptiometry  
EDC 
electronic data capture 
End of Study (end of trial) defined as when the last subject is assessed or receives an 
intervention for evaluation in the study 
End of Study (primary 
completion) 
defined as when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary 
endpoint 
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Treatment  
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
EOI 
Event of Interest 
EOS 
end of study 
ET 
early termination 
GCP 
Good Clinical Practice  
HepBcAb 
total hepatitis B core antibody 
HepBsAg 
Hepatitis B Surface Antigen  
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
INR 
international normalized ratio 
IVRS 
interactive voice response system, telecommunication technology 
that is linked to a central computer in real time as an interface to 
collect and process information.  


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 8 of 74 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
IP 
investigational product 
IPIM 
Investigational Product Instruction Manual  
iPTH 
intact parathyroid hormone 
IRB/IEC 
institutional review board/independent ethics committee 
IV 
intravenous  
NHANES 
National Health and Nutritional Examination Survey  
P1NP 
procollagen type 1 N-telopeptide 
PCR 
polymerase chain reaction 
PFS 
prefilled syringe  
PMO 
postmenopausal osteoporosis 
PTH 
parathyroid hormone  
QM 
once a month 
SC 
subcutaneous 
SERM 
selective estrogen receptor modulator 
Source Data 
information from an original record or certified copy of the original 
record containing patient information for use in clinical research.  
The information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies).  
(ICH Guideline (E6)).  Examples of source data include Subject 
identification, Randomization identification, and Stratification Value. 
T4 
thyroxine 
TBL 
total bilirubin  
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal  


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 9 of 74 
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 6 
Study Glossary ................................................................................................................ 7 
1. 
OBJECTIVES ....................................................................................................... 14 
1.1 
Primary ..................................................................................................... 14 
1.2 
Secondary ................................................................................................. 14 
1.3 
Exploratory ................................................................................................ 14 
1.4 
Safety ........................................................................................................ 14 
1.5 
Pharmacokinetics ...................................................................................... 14 
2. 
BACKGROUND AND RATIONALE ...................................................................... 14 
2.1 
Disease ..................................................................................................... 14 
2.2 
Amgen Investigational Product Background .............................................. 15 
2.3 
Calcium and Vitamin D Background .......................................................... 16 
2.4 
Rationale ................................................................................................... 17 
2.4.1 
Choice of Control Group ............................................................ 18 
2.4.2 
Study Population ....................................................................... 18 
2.5 
Clinical Hypotheses ................................................................................... 18 
3. 
EXPERIMENTAL PLAN ........................................................................................ 19 
3.1 
Study Design ............................................................................................. 19 
3.2 
Number of Sites ........................................................................................ 19 
3.3 
Number of Subjects ................................................................................... 19 
3.4 
Replacement of Subjects .......................................................................... 20 
3.5 
Estimated Study Duration .......................................................................... 20 
3.5.1 
Study Duration for Subjects ....................................................... 20 
3.5.2 
End of Study .............................................................................. 20 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 20 
4.1 
Inclusion and Exclusion Criteria ................................................................ 21 
4.1.1 
Inclusion Criteria ........................................................................ 21 
4.1.2 
Exclusion Criteria ...................................................................... 21 
5. 
SUBJECT ENROLLMENT .................................................................................... 23 
5.1 
Randomization/Treatment Assignment ...................................................... 24 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 25 
6. 
TREATMENT PROCEDURES .............................................................................. 25 
6.1 
Classification of Products and Medical Device .......................................... 25 
6.2 
Investigational Product .............................................................................. 25 
6.2.1 
Amgen Investigational Product .................................................. 25 
6.2.1.1 
Dosage, Administration, and Schedule .................... 26 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 10 of 74 
CONFIDENTIAL 
 
 
6.2.1.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 27 
6.2.2 
Non-Amgen Non-investigational Products ................................. 27 
6.2.2.1 
Calcium ................................................................... 27 
6.2.2.2 
Vitamin D ................................................................ 27 
6.2.2.3 
Non-Amgen Non-investigational Products 
Dose Adjustments ................................................... 28 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 28 
6.3.1 
Criteria for Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity ................................. 28 
6.3.2 
Criteria for Conditional Withholding of Amgen 
Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity ................................. 29 
6.3.3 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity ............................................................. 30 
6.4 
Concomitant Therapy ................................................................................ 30 
6.5 
Medical Devices ........................................................................................ 30 
6.6 
Product Complaints ................................................................................... 30 
6.7 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period .................................................................................. 31 
7. 
STUDY PROCEDURES ....................................................................................... 31 
7.1 
Schedule of Assessments ......................................................................... 31 
7.2 
General Study Procedures ........................................................................ 34 
7.2.1 
Screening Enrollment and/or Randomization ............................. 34 
7.2.2 
Rescreening .............................................................................. 35 
7.2.3 
Treatment Period ....................................................................... 36 
7.2.4 
End of Study Visit ...................................................................... 36 
7.3 
Description of Study Procedures ............................................................... 36 
7.3.1 
Informed Consent ...................................................................... 36 
7.3.2 
Demographics ........................................................................... 37 
7.3.3 
Medical History .......................................................................... 37 
7.3.4 
Fracture History ......................................................................... 37 
7.3.5 
Medication History ..................................................................... 37 
7.3.6 
Substance use History ............................................................... 37 
7.3.7 
Physical Examination ................................................................ 38 
7.3.8 
Height and Weight ..................................................................... 38 
7.3.9 
Vital Signs ................................................................................. 38 
7.3.10 
Concomitant Medications .......................................................... 38 
7.3.11 
Adverse Events, Serious Adverse Events, and 
Adverse Device Effects ............................................................. 38 
7.3.12 
Pharmacokinetic Assessment .................................................... 39 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 11 of 74 
CONFIDENTIAL 
 
 
7.3.13 
Dual-energy X-ray Absorptiometry ............................................. 39 
7.3.13.1 
Screening Bone Mineral Density 
Assessment ............................................................ 40 
7.3.13.2 
On-study Bone Mineral Density 
Assessments ........................................................... 40 
7.4 
Laboratory Assessments ........................................................................... 41 
7.5 
Antibody Testing Procedures .................................................................... 43 
7.6 
Biomarker Development ............................................................................ 43 
7.7 
Sample Storage and Destruction ............................................................... 44 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 45 
8.1 
Subjects’ Decision to Withdraw ................................................................. 45 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 45 
8.3 
Reasons for Removal From Treatment or Study ....................................... 46 
8.3.1 
Reasons for Removal From Treatment ...................................... 46 
8.3.2 
Reasons for Removal From Study ............................................. 46 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 46 
9.1 
Definition of Safety Events ........................................................................ 46 
9.1.1 
Disease-related Events ............................................................. 46 
9.1.2 
Adverse Events ......................................................................... 47 
9.1.3 
Serious Adverse Events ............................................................ 48 
9.2 
Safety Event Reporting Procedures .......................................................... 49 
9.2.1 
Reporting Procedures for Disease Related Events .................... 49 
9.2.2 
Adverse Events ......................................................................... 49 
9.2.2.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 49 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ..................................................................... 50 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 51 
9.3 
Pregnancy and Lactation Reporting .......................................................... 52 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 52 
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 52 
10.1.1 
Study Endpoints ........................................................................ 52 
10.1.1.1 
Primary Endpoint ..................................................... 52 
10.1.1.2 
Secondary Endpoint ................................................ 52 
10.1.1.3 
Exploratory Endpoints ............................................. 52 
10.1.1.4 
Safety Endpoints ..................................................... 53 
10.1.1.5 
Pharmacokinetic Endpoint ....................................... 53 
10.1.2 
Analysis Sets ............................................................................. 53 
10.1.3 
Covariates and Subgroups ........................................................ 54 
10.2 
Sample Size Considerations ..................................................................... 54 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 12 of 74 
CONFIDENTIAL 
 
 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees ............................................................................................. 54 
10.4 
Planned Analyses ..................................................................................... 54 
10.4.1 
Interim Analysis ......................................................................... 54 
10.4.2 
Primary Analysis ........................................................................ 55 
10.4.3 
Final Analysis ............................................................................ 55 
10.5 
Planned Methods of Analysis .................................................................... 56 
10.5.1 
General Considerations ............................................................. 56 
10.5.2 
Primary Efficacy Endpoint .......................................................... 56 
10.5.3 
Secondary Efficacy Endpoints ................................................... 57 
10.5.4 
Exploratory Efficacy Endpoints .................................................. 57 
10.5.5 
Safety Endpoints ....................................................................... 57 
10.5.5.1 
Adverse Events ....................................................... 57 
10.5.5.2 
Exposure to Investigational Product ........................ 58 
10.5.5.3 
Laboratory Assessments ......................................... 58 
10.5.5.4 
Vital Signs ............................................................... 58 
10.5.5.5 
Anti-romosozumab Antibodies ................................. 58 
10.5.6 
Pharmacokinetic Endpoint ......................................................... 58 
11. 
REGULATORY OBLIGATIONS ............................................................................ 59 
11.1 
Informed Consent ...................................................................................... 59 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 59 
11.3 
Subject Confidentiality ............................................................................... 60 
11.4 
Investigator Signatory Obligations ............................................................. 60 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 61 
12.1 
Protocol Amendments and Study Termination .......................................... 61 
12.2 
Study Documentation and Archive ............................................................ 61 
12.3 
Study Monitoring and Data Collection ....................................................... 62 
12.4 
Investigator Responsibilities for Data Collection ........................................ 63 
12.5 
Language .................................................................................................. 63 
12.6 
Publication Policy ...................................................................................... 64 
12.7 
Compensation ........................................................................................... 64 
13. 
REFERENCES ..................................................................................................... 65 
14. 
APPENDICES ...................................................................................................... 67 
 
List of Tables 
Table 1.  Schedule of Assessments ............................................................................... 32 
Table 2.  Analyte Listing ................................................................................................ 42 


Product:  Romosozumab 
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List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 68 
Appendix B.  Sample Serious Adverse Event Report Form ........................................... 70 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 73 
 


Product:  Romosozumab 
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1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the effect of treatment with romosozumab for 6 months compared with 
placebo on percent changes in bone mineral density (BMD) at the lumbar spine as 
assessed by dual-energy x-ray absorptiometry (DXA) in postmenopausal women with 
osteoporosis. 
1.2 
Secondary 
To evaluate the effect of treatment with romosozumab for 6 months compared with 
placebo on the percent changes in DXA BMD at the total hip and femoral neck. 
1.3 
Exploratory 
To evaluate the effect of treatment with romosozumab for 6 months compared with 
placebo on percent changes in bone turnover markers (BTM): bone formation marker 
procollagen type 1 N-telopeptide (P1NP) and bone resorption marker serum type I 
collagen C-telopeptide (CTX). 
1.4 
Safety 
To characterize the safety and tolerability of treatment with romosozumab for 6 months 
compared with placebo as determined by a review of reported adverse events, 
laboratory data, vital signs, and the formation of anti-romosozumab antibodies over the 
6-month treatment period, and adverse events and the formation of anti-romosozumab 
antibodies for the overall study period (6-month treatment period followed by the 
3-month follow-up period). 
1.5 
Pharmacokinetics 
To characterize the serum romosozumab concentration. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
Osteoporosis is defined as a skeletal disorder characterized by compromised bone 
strength predisposing to an increased risk of fracture (NIH Consensus Development 
Panel on Osteoporosis Prevention, Diagnosis, and Therapy, 2001).  Osteoporosis is a 
common disorder, based on the World Health Organization’s current definition of 
osteoporosis (BMD T-score ≥ 2.5 standard deviations below the mean for young healthy 
adults) (World Health Organization, 1994); the worldwide prevalence of osteoporosis has 
been estimated as 200 million people (Reginster and Burlet, 2006), including more than 
75 million people in the United States, Europe, and Japan 


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(World Health Organization, 2007).  In Korea, at the age of 50 years, the residual lifetime 
probabilities of osteoporosis-related fractures are 59.5% for women (Park, 2011).  The 
morbidity and mortality associated with osteoporotic-related fractures is significant in 
terms of disability to an individual and cost to the global economy (Cree et al, 2003; 
Kanis et al, 2001a; Kanis et al, 2001b). 
Osteoporosis is a chronic disease and despite long-term administration of 
bisphosphonates, the most commonly prescribed class of antiresorptives, some 
postmenopausal women with osteoporosis remain at increased risk of fracture and are in 
need of therapies with strong efficacy and the potential to reverse their disease condition 
by increasing bone formation and improving bone structure.  Bone forming agents can 
promote larger improvements in bone mass and bone strength compared with 
antiresorptives and restore bone architecture, thereby addressing the need for improved 
protection against fractures, in particular at nonvertebral sites (Canalis, 2010; 
Papapoulos and Makras, 2008).  A novel bone forming agent for the treatment of 
osteoporosis in postmenopausal women, with a different mechanism of action and the 
potential to reverse the features of osteoporosis by increasing bone volume and BMD 
and by improving bone architecture, ultimately resulting in increased bone strength and 
reduced risk for fracture, would be a welcome new therapeutic option particularly for 
subjects with significantly compromised bone strength at high risk of fracture. 
2.2 
Amgen Investigational Product Background 
Sclerostin, the protein product of SOST, produced by the osteocyte, is an inhibitor of 
osteoblast-mediated bone formation (Poole et al, 2005; Van Bezooijen et al, 2004; 
Winkler et al, 2003; Balemans et al, 2001; Brunkow et al, 2001).  Humans with inherited 
sclerostin deficiencies have high bone mass and BMD throughout the skeleton and are 
resistant to fractures (Hamersma et al, 2003; Vanhoenacker et al, 2003).  
Administration of a sclerostin antibody, resulting in the blocking of the inhibitory effect of 
sclerostin on bone formation, has been shown to increase bone formation, BMD, and 
bone strength in multiple animal models (non-osteopenic and osteopenic rats and 
monkeys) (Ominsky et al, 2015; Li et al, 2014; Li et al, 2010; Ominsky et al, 2010). 
Romosozumab is a humanized monoclonal antibody that is designed to bind and inhibit 
sclerostin, thereby promoting osteoblast differentiation and activity, leading to an 
increase in bone formation, BMD, and bone strength.  Proof of biological activity for 
romosozumab has been established in a first-in-human, ascending-single-dose study in 
healthy men and postmenopausal women, an ascending-multiple-dose study in healthy 


Product:  Romosozumab 
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men and postmenopausal women with low bone mass and a phase 2 dose-ranging 
study in postmenopausal women with low bone mass.  In all studies, treatment with 
romosozumab was generally well tolerated and resulted in a transient increase of the 
bone formation marker P1NP and a decrease in the bone resorption marker serum CTX.  
Increases in BMD at the lumbar spine, total hip and femoral neck have also been 
demonstrated, by DXA, and quantitative computed tomography. 
The ability of romosozumab to prevent fractures in postmenopausal women with 
osteoporosis is currently being evaluated in the following phase 3 studies: 
• 
Placebo-controlled study designed to evaluate if treatment with romosozumab for 
12 months is effective in reducing the risk of new vertebral and nonvertebral 
fractures 
• 
Alendronate-controlled study designed to evaluate if treatment with romosozumab for 
12 months followed by alendronate treatment, is effective in reducing the incidence 
of clinical fractures and new vertebral fractures 
Refer to the specific sections of the Romosozumab Investigator’s Brochure for additional 
information related to the physical, chemical, and pharmaceutical properties and 
formulation. 
For additional information about the romosozumab nonclinical experience and clinical 
experience, refer to the Investigator’s Brochure. 
2.3 
Calcium and Vitamin D Background 
Calcium and vitamin D are important in the formation of bone matrix and for its 
subsequent mineralization where calcium found as calcium hydroxyapatite 
(Ca10[PO4]6[OH]2) provides bones and teeth tissue with its strength.  Calcium and 
vitamin D are therefore considered key components of therapy in the management of 
postmenopausal osteoporosis (PMO) (Dawson-Hughes et al, 2010) and have been 
required as background therapies in all contemporary therapeutic trials in PMO.  
Because of the active bone formation and mineralization that is expected with 
romosozumab, calcium and vitamin D supplementation will be necessary in order to 
achieve and maintain positive bone balance.  The recommended dietary allowance and 
tolerable upper intake level of dietary calcium recommended by the United States 
Institutes of Medicine for women over the age of 50 years on a western diet is 1,200 mg 
and 2000 mg per day respectively.  The recommended dietary allowance and tolerable 
upper intake level of dietary vitamin D for women aged 51 to 70 years is 600 IU and 
4000 IU per day respectively while the recommended dietary allowance and tolerable 
upper intake level of dietary vitamin D for women over the age of 70 years is 800 IU and 


Product:  Romosozumab 
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4000 IU per day respectively (Ross et al, 2011; IOM, 2010).  This is consistent with 2015 
Position Statement of the Korean Society for Bone and Mineral Research which 
recommends a daily calcium intake of 800 to 1 000 mg/day and a minimum intake of 
800 IU per day of vitamin D in South Korea (Kim, 2015).  The initial loading dose of 
50 000 to 60 000 IU of vitamin D for subjects with vitamin D levels of ≥ 20 ng/mL and 
≤ 40 ng/mL at screening is necessary to provide a sufficient calcium pool for the 
expected and significant increase in bone mass and needed for bone mineralization in 
the first several months after initiation of treatment with romosozumab.  This dose has 
been shown to be safe and well tolerated (Giusti et al, 2010; Tucci, 2009).  The daily 
supplementation required in this study, that at a minimum should be in the range of 
500 to 1 000 mg elemental calcium and 600 to 800 IU of vitamin D, is safe and 
represents commonly used and accepted doses for PMO clinical trials and are 
consistent with existing treatment practice and guidelines (Dawson-Hughes et al, 2010; 
IOM 2010). 
2.4 
Rationale 
A 6-month romosozumab treatment duration is supported by the following 
considerations: 
Substantial increases in BMD at the lumbar spine, total hip and femoral neck were 
observed during 6 months of romosozumab administration in the phase 2 dose-ranging 
study.  At 6 months, the 210 mg once a month (QM) dosing regimen resulted in a BMD 
increase from baseline of 8.2 % with 95% confidence interval (CI) (7.3%, 9.2%) at the 
lumbar spine and 2.9 % with 95% CI (2.3%, 3.4%) at the total hip. 
The 210-mg romosozumab QM dosing regimen is the same dosing regimen used in the 
other phase 3 trials including the 2 fracture trials mentioned above.  
In summary, the proposed treatment regimen of 210 mg romosozumab QM for 6 months 
is expected to achieve optimal increases in BMD and bone formation markers in 
subjects who are treatment-naïve and in those who have previously received 
alendronate without negatively impacting the safety profile of romosozumab.  Thus, a 
210 mg QM dosing regimen is expected to provide the best risk-benefit profile and 
enable evaluation of the safety, tolerability, and efficacy of romosozumab to prevent 
fractures in postmenopausal women with osteoporosis.  
Refer to the Investigator’s Brochure for a detailed description of data from the phase 2 
dose-ranging study. 


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2.4.1 
Choice of Control Group 
A placebo-controlled study was chosen because it permits a minimally confounded 
demonstration of efficacy and safety of romosozumab in the treatment of 
postmenopausal women with osteoporosis.  The use of a placebo control is also 
consistent with regulatory guidance in South Korea.  The following measures have been 
taken to minimize risk for subjects who will receive placebo: 
• 
Subjects with a history of hip fractures and those with BMD T-score ≤ -4.0 at the 
lumbar spine, total hip or femoral neck are excluded. 
• 
Subjects are eligible for a loading dose of vitamin D (50 000 to 60 000 IU) at the start 
of the study, and all subjects will receive supplemental vitamin D and calcium 
throughout the study.  These supplements have been shown to have a protective 
effect on the skeleton. 
• 
Exposure to placebo is minimized by the short study duration (6 months). 
2.4.2 
Study Population 
The target population for this study is postmenopausal South Korean women with 
osteoporosis, defined as: 
• 
BMD T-score ≤ -2.50 at the lumbar spine, total hip, or femoral neck. 
These inclusion criteria approximate those used in the romosozumab phase 3 global 
fracture studies in postmenopausal women with osteoporosis.  Key exclusion criteria are 
metabolic bone disease, uncorrected vitamin D insufficiency, current uncontrolled 
hyper-or hypoparathyroidism, current uncontrolled hyperparathyroidism or history of 
hypoparathyroidism, and current hyper- or hypocalcemia.  These and other criteria have 
been selected to align with the eligibility criteria used in the global romosozumab phase 
3 fracture studies in postmenopausal women with osteoporosis. 
2.5 
Clinical Hypotheses 
The primary clinical hypothesis is that in South Korean postmenopausal women with 
osteoporosis, the mean percent change in lumbar spine BMD at month 6 in subjects 
receiving romosozumab will be superior to that of those receiving placebo.  It is 
hypothesized that changes in BMD at the lumbar spine in subjects receiving 
romosozumab will be at least 6.6% greater than in subjects receiving placebo. 
The safety hypothesis is that romosozumab treatment for 6 months is well tolerated in 
South Korean women with osteoporosis. 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a multicenter, randomized, double-blind, placebo-controlled study in 
approximately 60 South Korean postmenopausal women with osteoporosis.  The study 
is designed to evaluate if treatment with romosozumab QM for 6 months compared with 
placebo is effective in increasing BMD at the lumbar spine.  In addition, the study will 
assess the effect of treatment with romosozumab QM for 6 months compared with 
placebo on BMD at the femoral neck and total hip. 
Approximately 60 subjects will be randomized in a 1:1 ratio to receive 210 mg 
romosozumab subcutaneous (SC) QM (approximately 30 subjects) or matched placebo 
SC QM (approximately 30 subjects), respectively, in a blinded fashion for the duration of 
the 6-month treatment period. 
Upon completion of the 6-month treatment period, subjects will be followed for an 
additional 3 months to ensure appropriate follow-up for anti-romosozumab antibody 
formation. 
The overall study design is described by a study schema at the end of the protocol 
synopsis section.  
From screening to end of study (EOS), subjects will receive daily calcium and vitamin D 
supplementation, which at a minimum should be in the range of 500 to 1000 mg 
elemental calcium and 600 to 800 IU vitamin D.  In addition, subjects with a serum 
25 (OH) vitamin D level of ≥ 20 ng/mL and ≤ 40 ng/mL at screening will receive an initial 
loading dose of 50 000 to 60 000 IU vitamin D after randomization (administered within 
1 week of the study day 1 visit), preferably by the oral route.  Subjects with a serum 
25 (OH) vitamin D level of > 40 ng/mL at screening may also receive the vitamin D 
loading dose at the principal investigator’s discretion. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
Approximately 10 sites in South Korea will participate in this study.  Sites that do not 
enroll subjects within 2 months of site initiation may be closed. 
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”.  Approximately 
60 South Korean postmenopausal women with osteoporosis will be enrolled, including 


Product:  Romosozumab 
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approximately 30 subjects randomized to receive 210 mg romosozumab SC QM and 
30 subjects randomized to receive matched placebo SC QM. 
The rationale for the number of subjects required is outlined in Section 10.2. 
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
After signing the informed consent form (ICF), subjects should be randomized within 
35 days. 
Following randomization, individual subjects will participate in the study for up to 
9 months, including a 6-month treatment period and a 3-month follow-up period. 
For individual subjects, the month 9 visit is the EOS visit.  Subjects who test positive for 
neutralizing antibodies to romosozumab at the EOS visit or the early termination (ET) 
visit will be asked to return for anti-romosozumab antibody testing after EOS for up to 
1 year after the last investigational product (IP) administration. 
3.5.2 
End of Study 
The primary completion date is defined as the date when the last subject is 
assessed or receives an intervention for the final collection of data for the primary 
endpoint(s), for the purpose of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early. 
Primary Completion:  the time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary analysis, ie, after 
all subjects have had the opportunity to complete the month 6 visit. 
End of Trial:  the time when the last subject is assessed or receives an intervention for 
evaluation in the study, ie, when the last subject completes the month 9 visit. 
If the study concludes prior to the primary completion date originally planned in 
the protocol (ie, early termination of the study), then the primary completion will 
be the date when the last subject is assessed or receives an intervention for 
evaluation in the study (ie, last subject last visit). 
4. 
SUBJECT ELIGIBILITY 
The study population is South Korean postmenopausal women with osteoporosis. 


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Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an interactive voice 
response system (IVRS). 
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1). 
4.1 
Inclusion and Exclusion Criteria 
4.1.1 
Inclusion Criteria 
101 
Subject has provided informed consent/assent prior to initiation of any 
study-specific activities/procedures. 
102 
Ambulatory postmenopausal Korean women, ≥ 55 to ≤ 90 years of age at 
enrollment. 
103 
Postmenopause is defined as no spontaneous vaginal bleeding or spotting for 
12 or more consecutive months prior to screening. 
104 
BMD T-score ≤ -2.50 at the lumbar spine, total hip or femoral neck, as assessed 
by the central imaging vendor at the time of screening, based on DXA scans and 
using data for Caucasian women from the National Health and Nutritional 
Examination Survey (NHANES) 1998. 
105 
At least 2 vertebrae in the L1 through L4 region and at least one hip are 
evaluable by DXA, as assessed by the principal investigator.  
4.1.2 
Exclusion Criteria 
201 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days since ending treatment on another investigational device or 
drug study(ies).  Other investigational procedures while participating in this study 
are excluded. 
202 
Subject has known sensitivity to any of the products to be administered during 
dosing (calcium supplements, vitamin D products, or mammalian cell derived 
products). 
203 
Subject likely to not be available to complete all protocol required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge. 
204 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures, or completion. 
205 
Subject is pregnant or breastfeeding or is planning to become pregnant or 
planning to breastfeed during treatment and within 3 months after the last dose of 
IP. 
206 
BMD T-score ≤ -4.0 at the lumbar spine, total hip, or femoral neck, as assessed 
by the central imaging vendor at the time of screening, based on DXA scans and 
using data for Caucasian women from the NHANES 1998. 


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207 
History of hip fracture. 
208 
History of metabolic or bone disease (except osteoporosis) that may interfere 
with the interpretation of the results, such as sclerosteosis, Paget’s disease, 
rheumatoid arthritis, osteomalacia, osteogenesis imperfecta, osteopetrosis, 
ankylosing spondylitis, Cushing’s disease, hyperprolactinemia, and 
malabsorption syndrome. 
209 
Subject with reported history of hearing loss associated with cranial nerve VIII 
compression due to excessive bone growth (eg, as seen in conditions such as 
Paget’s disease, sclerosteosis, and osteopetrosis). 
210 
History of solid organ or bone marrow transplant. 
211 
History of osteonecrosis of the jaw and/or atypical femoral fracture. 
212 
Vitamin D insufficiency (defined as 25 (OH) vitamin D levels < 20 ng/mL as 
determined by the central laboratory).  Vitamin D repletion will be permitted and 
subjects may be rescreened. 
213 
Current, uncontrolled hyper- or hypothyroidism, Uncontrolled hyperthyroidism is 
defined as thyroid stimulating hormone (TSH) and thyroxine (T4) outside the 
normal range.  Uncontrolled hypothyroidism is defined as TSH > 10. 
214 
Current, uncontrolled hyperparathyroidism or history of hypoparathyroidism, per 
subject report or chart review.  Uncontrolled hyperparathyroidism is defined as: 
parathyroid hormone (PTH) outside the normal range in subjects with concurrent 
hypercalcemia; or PTH values > 20% above the upper limit of normal (ULN) in 
normocalcemic subjects. 
215 
Current hyper- or hypocalcemia, defined as albumin-adjusted serum calcium 
outside the normal range, as assessed by the central laboratory.  
Albumin-adjusted serum calcium levels may be retested once in case of an 
elevated albumin-adjusted serum calcium level within 1.1 x the ULN as assessed 
by the central laboratory. 
216 
Subject previously has entered this study or has previously participated in a 
study with a sclerostin antibody product. 
217 
Malignancy within the last 5 years, except non-melanoma skin cancers, cervical 
or breast ductal carcinoma in situ. 
218 
Possible diagnosis of multiple myeloma or related lymphoproliferative disorder, 
as assessed by serum protein electrophoresis performed by the local laboratory 
(electrophoresis results within 6 months of signing consent will be acceptable). 
221 
Positive results for human immunodeficiency virus, per subject report or chart 
review. 
222 
Use of oral bisphosphonates: 
• 
any dose received within 3 months prior to randomization 
• 
more than 1 month of cumulative use between 3 and 12 months prior to 
randomization 
• 
more than 3 years of cumulative use, unless last dose received ≥ 5 years 
prior to randomization 


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223 
Use of intravenous (IV) bisphosphonates 
• 
Zoledronic acid: 
o any dose received within 3 years prior to randomization 
o more than 1 dose received within 5 years prior to randomization 
• 
IV ibandronate, IV pamidronate, or IV alendronate: 
o any dose received within 12 months prior to randomization 
o more than 3 years of cumulative use, unless last dose received 
≥ 5 years prior to randomization 
224 
Use of teriparatide or any PTH analogs: 
• 
any dose received within 3 months prior to randomization 
• 
more than 1 month of cumulative use between 3 and 12 months prior to 
randomization 
225 
Use of strontium ranelate, or fluoride (for osteoporosis): 
• 
more than 1 month of cumulative use within 5 years prior to 
randomization 
226 
Use of denosumab or any cathepsin K inhibitor, such as odanacatib (MK-0822): 
• 
any dose received within 18 months prior to randomization 
227 
Use of tibolone, cinacalcet or calcitonin: 
• 
any dose received within 3 months prior to randomization 
228 
Use of systemic oral or transdermal estrogen or selective estrogen receptor 
modulators (SERMs): 
• 
more than 1 month of cumulative use within 6 months prior to 
randomization 
229 
Use of activated vitamin D3, vitamin K2, more than 1 month of cumulative use 
within 6 months prior to randomization 
230 
Use of hormonal ablation therapy: 
• 
more than 1 month of cumulative use within 6 months prior to 
randomization 
231 
Use of systemic glucocorticosteroids: ≥ 5 mg prednisone equivalent per day for 
more than 14 days within 3 months prior to randomization 
232 
Evidence of acute or chronic hepatitis B or hepatitis C virus.  Hepatitis status will 
be evaluated by testing for hepatitis B surface antigen (HepBsAg), total hepatitis 
B core antibody (HepBcAb) and hepatitis C antibody by the central laboratory at 
initial screening.  Polymerase chain reaction (PCR) should be performed to 
confirm active disease only if total HepBcAb is positive and HepBsAg is negative 
or if C antibody is positive.   
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 


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committee (IRB/IEC) approval of the protocol, ICF, and all other subject information 
and/or recruitment material, if applicable (see Section 11.2).  All subjects must 
personally sign and date the ICF before commencement of study specific 
activities/procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (defined as the point at 
which the subject signs the ICF) receives a unique subject identification number before 
any study-related activities/procedures are performed.  The subject identification number 
will be assigned by the IVR/IWR.  This number will be used to identify the subject 
throughout the clinical study and must be used on all study documentation related to that 
subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the study. 
Only subjects who do not meet the serum 25 (OH) vitamin D eligibility criterion 
(ie, subjects with a serum 25 (OH) vitamin D level < 20 ng/mL) (see Section 4.1.1) will be 
permitted to rescreen one time. 
5.1 
Randomization/Treatment Assignment 
Subjects who meet all eligibility requirements (Section 4.1) will be randomly assigned in 
a 1:1 allocation ratio to the 2 treatment groups (romosozumab and placebo) in a 
double-blind manner. 
Randomization will be based on a schedule prepared by the Amgen Central 
Randomization Group before the start of the study.  Randomization will be performed by 
IVRS, and the randomization number will be provided through the IVRS.  A subject may 
be randomized only once, and each randomization number will be assigned only once. 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF. 


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Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 26 of 74 
CONFIDENTIAL 
 
 
6.2.1.1 
Dosage, Administration, and Schedule 
The IP will be administered in accordance with instructions in the IPIM.  
The IP (romosozumab/placebo) will be administered SC via PFS on day 1, month 1, 
month 2, month 3, month 4, and month 5.  All doses will be administered at the study 
site.  
Subjects will receive 3 SC injections of romosozumab (ie, 3 injections of 70 mg 
romosozumab for a total dose of 210 mg) or matching placebo QM.  A separate PFS will 
be used for each injection; however, all 3 PFS to be used at a specific visit will be 
supplied in a single box, as assigned by the IVRS. 
Injections will be administered by a healthcare professional into different sites on the 
subject’s anterior abdominal wall, upper thigh, or upper arm.  The injection should not be 
administered in the same arm from which blood is drawn.  The romosozumab/placebo 
SC injection must be administered as the last procedure after all other study visit 
procedures have been completed. 
The volume, start date/time, each administration site, and box number of 
romosozumab/placebo are to be recorded on each subject’s CRF. 
A physician must be available during administration of romosozumab/placebo.  It is 
recommended that all subjects be closely observed for approximately 30 minutes after 
dosing with IP. 
The first dose of IP should be administered on the day of randomization.  If this is not 
possible, it must be administered within 72 hours of randomization. 
Refer to specific instructions provided by the IVRS vendor for additional information on 
box assignment and to the IPIM for additional information regarding storage and 
preparation of IP. 
Overdose with this product has not been reported.  The effects of overdose of this 
product are not known.  An antidote to overdose of this product is not known.  The 
maximum amount of romosozumab that can be safely administered in a single dose has 
not been determined, and there is currently insufficient information to draw any 
conclusions about the safety of doses higher than those studied in clinical trials.  The 
highest single dose of romosozumab tested in clinical trials is 10 mg/kg SC.  Subjects 
who have received higher than protocol-defined doses should be carefully monitored for 
adverse events. 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 27 of 74 
CONFIDENTIAL 
 
 
6.2.1.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
No dosing adjustments for romosozumab/placebo will be permitted. 
All efforts should be made to administer romosozumab/placebo within the defined study 
visit windows (refer to Section 7).  In case of an out-of-window visit, 
romosozumab/placebo can be administered within ± 2 weeks of the target visit date 
(ie, calculated from the day 1 visit as described in Section 7).  If romosozumab/placebo 
cannot be administered within ± 2 weeks of the target visit date, the dose has to be 
considered missed. 
6.2.2 
Non-Amgen Non-investigational Products 
The non-Amgen non-IPs (vitamin D and calcium) that are commercially available are not 
provided by Amgen.  The investigator will be responsible for obtaining supplies of these 
protocol-required therapies and will be reimbursed for those supplies.  
The dose, start date, stop date, and frequency for calcium and vitamin D are to be 
recorded on each subject’s CRF.  At screening, the investigator or designee will instruct 
subjects on daily calcium and vitamin D supplementation. 
Additional details regarding the non-Amgen non-IPs are provided in the IPIM. 
6.2.2.1 
Calcium 
Subjects will receive daily calcium supplementation orally from screening to EOS, which 
at a minimum should be in the range of 500 to 1 000 mg elemental calcium. 
6.2.2.2 
Vitamin D 
Where available, vitamin D3 preparations should be used; if vitamin D3 is not available, 
use of vitamin D2 preparations is acceptable. 
Subjects will receive daily vitamin D supplementation orally from screening to EOS, 
which at a minimum should be in the range of 600 to 800 IU vitamin D.  In addition, 
subjects with a serum 25 (OH) vitamin D level of ≥ 20 ng/mL and ≤ 40 ng/mL at 
screening will receive an initial loading dose of 50 000 to 60 000 IU of vitamin D after 
randomization, preferably by the oral route.  Subjects with a serum 25 (OH) vitamin D 
level of > 40 ng/mL at screening may also receive the vitamin D loading dose at the 
principal investigator’s discretion. 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 28 of 74 
CONFIDENTIAL 
 
 
6.2.2.3 
Non-Amgen Non-investigational Products Dose Adjustments 
If a subject develops hypercalcemia over the course of the study, the principal 
investigator may use his/her medical judgment and reduce the calcium and/or vitamin D 
supplementation to maintain serum calcium concentration within the normal range. 
If a subject develops hypocalcemia over the course of the study, appropriate additional 
supplementation should be instituted as deemed acceptable by local guidelines, to 
maintain serum calcium concentration within the normal range. 
If a subject is unable to tolerate the daily calcium or vitamin D supplementation, the 
formulation may be changed or the dosage lowered.  The intolerance as well as the 
resolution (ie, change in formulation or dosage) should be documented in the subject 
chart. 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio [INR] and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen IP or other protocol-required therapies as specified in the Guidance for Industry 
Drug-Induced Liver Injury (DILI):  Premarketing Clinical Evaluation, July 2009). 
6.3.1 
Criteria for Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
Amgen IP (romosozumab/placebo) should be discontinued permanently and the subject 
should be followed according to the recommendations in Appendix A (Additional Safety 
Assessment Information) for possible DILI, if ALL of the criteria below are met:  
• 
TBL > 2x ULN or INR > 1.5 
• 
AND increased AST or ALT from the relevant baseline value as specified below:  
Baseline AST or ALT value 
AST or ALT elevation 
< ULN 
> 3x ULN 
• 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
TBL values include, but are not limited to: 
− 
Hepatobiliary tract disease 
− 
Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, 
Herpes Simplex Virus, Varicella, toxoplasmosis, and Parvovirus) 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 29 of 74 
CONFIDENTIAL 
 
 
− 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia  
− 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms   
− 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir) 
− 
Alpha-one antitrypsin deficiency 
− 
Alcoholic hepatitis 
− 
Autoimmune hepatitis 
− 
Wilson’s disease and hemochromatosis 
− 
Nonalcoholic Fatty Liver Disease including Steatohepatitis 
− 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
6.3.2 
Criteria for Conditional Withholding of Amgen Investigational 
Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of Amgen IP 
outlined above and have no underlying liver disease, and eligibility criteria requiring 
normal transaminases and TBL at baseline or subjects with underlying liver disease and 
baseline abnormal transaminases, the following rules are recommended for withholding 
of Amgen IP and other protocol-required therapies:  
• 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation  
Any 
> 8x ULN at any time 
Any 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
Any 
> 5x ULN but < 8x ULN and unable to adhere to enhanced 
monitoring schedule 
Any 
> 3x ULN with clinical signs or symptoms that are 
consistent with hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, vomiting, jaundice). 
• 
OR: TBL > 3x ULN at any time 
• 
OR: ALP > 8x ULN at any time 
Romosozumab/placebo should be withheld pending investigation into alternative causes 
of DILI.  If IP(s) is withheld, the subject is to be followed according to recommendations 
in Appendix A for possible DILI.  Rechallenge may be considered if an alternative cause 
for impaired liver tests (ALT, AST, ALP) and/or elevated TBL, is discovered and the 
laboratory abnormalities resolve to normal or baseline (Section 6.3.3). 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 30 of 74 
CONFIDENTIAL 
 
 
6.3.3 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then romosozumab/placebo should be 
permanently discontinued.  Subjects who clearly meet the criteria for permanent 
discontinuation (as described in Section 6.3.1) should never be rechallenged. 
6.4 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.7. 
Concomitant therapies are to be collected in the CRF from the signing of the ICF through 
the EOS visit.  For concomitant therapies affecting bone metabolism, collect therapy 
name, indication, dose, unit, frequency, start date, and stop date.  For all other 
concomitant therapies, collect therapy name, indication, start date, and stop date. 
6.5 
Medical Devices 
The PFS used in this study will be provided by Amgen.  The PFS will be used for 
administration of IP for all subjects.  Additional details for the PFS is to be provided in 
the IPIM. 
Other medical devices (eg, syringes, sterile needles, alcohol prep pads), which are not 
considered test articles, may be used in the conduct of this study as part of standard 
care.  These devices that are commercially available are not usually provided or 
reimbursed by Amgen (except, for example, if required by local regulation).  The 
investigator will be responsible for obtaining supplies of these devices. 
6.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  Drugs or devices include romosozumab/placebo and PFS. 
This includes any drug(s) or device(s) provisioned and/or repackaged /modified by 
Amgen.  Drug(s) or device(s) includes IP.  Any product complaint(s) associated with an 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 31 of 74 
CONFIDENTIAL 
 
 
IP(s) or non-IP(s) or device(s) supplied by Amgen are to be reported according to the 
instructions provided in the IPIM. 
6.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following treatments are not permitted during the study: 
• 
Strontium (including strontium ranelate and over-the-counter strontium preparations) 
• 
Fluoride (for treatment of osteoporosis) 
• 
Vitamin K and vitamin K analogs (for treatment of osteoporosis) 
• 
Activated vitamin D (1,25-di(OH) vitamin D, or 1 (OH) vitamin D) 
• 
Intravenous bisphosphonates  
• 
Oral bisphosphonates (cumulative dosing regimens of ≤ 1 month are acceptable) 
• 
Denosumab  
• 
Teriparatide or any PTH analogs 
• 
Systemic oral or transdermal estrogen (cumulative dosing regimens of ≤ 1 month are 
acceptable, vaginal preparations and estrogen creams will be allowed at any time) 
• 
SERMs (cumulative dosing regimens of ≤ 1 month are acceptable) 
• 
Calcitonin (cumulative dosing regimens of ≤ 1 month are acceptable) 
• 
Tibolone 
• 
Prolonged (ie, > 3 months) oral glucocorticoid therapy at a prednisone equivalent 
dose of ≥ 5.0 mg/day (tapering glucocorticoid courses of ≤ 1 month duration are 
permitted regardless of dose; inhaled or topical glucocorticoids are permitted) 
• 
Any cathepsin K inhibitor, such as odanacatib (MK-0822):  
• 
Hormonal ablation therapy 
• 
Cinacalcet 
If a subject discontinues IP and begins an approved alternative osteoporosis therapy, 
every effort should be made to have the subject continue participation in the study and 
complete all scheduled assessments (ie, withdrawal of partial consent, see Section 8.1). 
7. 
STUDY PROCEDURES 
Screening assessments and study procedures outlined in this section and in Table 1 can 
only be performed after obtaining informed consent.  Refer to the applicable 
supplemental laboratory manuals for detailed collection and handling procedures. 
7.1 
Schedule of Assessments 
 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 32 of 74 
CONFIDENTIAL 
 
 
Table 1.  Schedule of Assessments 
Period 
Screening 
Treatment Period 
Follow-up 
Period 
Visit 
1 
2 
3 
4 
5 
6 
7 
8/ET 
9/EOS 
Day/Month 
Within 35 days 
of Day 1 
Day 1 
Month 1 
± 7 days 
Month 2 
± 7 days 
Month 3 
± 7 days 
Month 4 
± 7 days 
Month 5 
± 7 days 
Month 6 
-7/+3 days 
Month 9 
-7/+3 days 
General and safety assessments 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Fracture history 
X 
Medication history 
X 
 
 
 
 
 
 
 
 
Smoking and ethanol use history 
X 
Substance use history 
X 
Instructions for daily vitamin D & calcium 
supplementation 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
Physical measurements  
X 
X 
Vital signs 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record serious adverse events 
X--------------------------------------------------------------------------------------------------------------------------------------X 
Record adverse events 
X--------------------------------------------------------------------------------------------------------------------X 
Record disease-related events 
 
X--------------------------------------------------------------------------------------------------------------------X 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
Serum chemistry 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
Serum protein electrophoresis 
X 
Hepatitis B & Hepatitis C testing 
X 
Serum 25 (OH) vitamin D 
X 
X 
iPTH 
X 
X 
X 
X 
Pharmacokinetics 
X 
X 
X 
X 
Anti-romosozumab antibody 
X 
X 
X 
X 
X 
Bone turnover markers 
X 
X 
X 
X 
Page 1 of 2 
Footnotes defined on next page of the table 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 33 of 74 
CONFIDENTIAL 
 
 
Table 1.  Schedule of Assessments 
Period 
Screening 
Treatment Period 
Follow-up 
Period 
Visit 
1 
2 
3 
4 
5 
6 
7 
8/ET 
9/EOS 
Day/Month 
Within 35 days 
of Day 1 
Day 1 
Month 1 
± 7 days 
Month 2 
± 7 days 
Month 3 
± 7 days 
Month 4 
± 7 days 
Month 5 
± 7 days 
Month 6 
-7/+3 days 
Month 9 
-7/+3 days 
Imaging Assessments 
 
 
 
 
 
 
 
 
 
DXA scan - Lumbar spine 
X 
X 
DXA scan - Proximal femur 
X 
X 
IP Administration 
 
 
 
 
 
 
 
 
 
In-clinic IP injectiona 
X 
X 
X 
X 
X 
X 
vitamin D loading doseb 
X 
Page 2 of 2 
DXA = dual-energy x-ray absorptiometry; EOS = end of study; ET = early termination; iPTH = Intact Parathyroid Hormone. 
a Must be the last procedure at each dosing visit. 
b Vitamin D loading dose of at least 50 000 to 60 000 IU, preferably by oral route is required for all subjects with a serum 25 (OH) vitamin D level of ≥ 20 ng/mL and 
≤ 40 ng/mL at screening.  Subjects with a serum 25 (OH) vitamin D level of > 40 ng/mL at screening may also receive the vitamin D loading dose at the principal 
investigator’s discretion. 
 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 34 of 74 
CONFIDENTIAL 
 
 
7.2 
General Study Procedures 
Study assessments and procedures will be performed only after written informed 
consent is obtained.  During the study, every effort should be made to keep subjects on 
the study schedule of procedures. 
The procedures performed at each study visit are outlined Table 1. 
Details regarding each type of procedure are provided in subsequent sub-sections.  
Refer to the applicable supplemental central laboratory, IVRS, IPIM, and study manuals 
for detailed collection and handling procedures. 
IP administration must be the last procedure after all other study visit procedures have 
been completed at each applicable visit. 
7.2.1 
Screening Enrollment and/or Randomization 
Informed consent must be obtained before completing any other screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After signing the written 
ICF, site will register the subject in the IVRS and screen the subject in order to assess 
eligibility for participation.  Screening procedures may be performed on multiple days but 
must be completed within the 35-day screening window.  If a subject has not met all 
eligibility criteria at the end of the 35-day window, the subject will be registered as a 
screen fail.  Subjects who screen fail only the serum 25 (OH) vitamin D eligibility criterion 
may be eligible for rescreening once as described in Section 7.2.2. 
The screening procedures to be completed are designated in the Schedule of 
Assessments (Table 1). 
During the screening period, albumin-adjusted serum calcium levels may be retested 
once in case of an elevated albumin-adjusted serum calcium level within 1.1x ULN as 
assessed by the central laboratory.  To enroll subjects after retesting of 
albumin-adjusted serum calcium levels, an eligible albumin-adjusted serum calcium level 
must be confirmed by the central laboratory, and the subject must be randomized within 
the original 35-day screening window.  These subjects should not be screen failed. 
A blood sample will be collected during the screening period for serum protein 
electrophoresis to assess possible diagnosis of multiple myeloma or related 
lymphoproliferative disorder; the analysis will be performed by the local laboratory.  
Electrophoresis results within 6 months prior to signing informed consent will be 
acceptable. 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 35 of 74 
CONFIDENTIAL 
 
 
At screening, laboratory assessments will be conducted to determine hepatitis B and C 
status as follows: 
• 
If hepatitis B and/or hepatitis C status is known to be positive by serology, no 
additional laboratory testing procedures are required  
• 
If hepatitis B and/or hepatitis C status is not known to be positive by serology, the 
following laboratory testing is required: 
− 
Hepatitis B Surface Antigen (HepBsAg) and total hepatitis B core antibody 
(HepBcAb) 
− 
If results are HepBcAb positive and HepBsAg positive, no additional testing is 
necessary 
−If results are HepBcAb positive and HepBsAg negative, additional testing for 
Hepatitis B virus DNA by polymerase chain reaction (PCR) is necessary 
− 
Hepatitis C virus antibody  
− 
If results are hepatitis C virus antibody positive, additional testing for 
hepatitis C virus RNA by PCR is necessary.  
7.2.2 
Rescreening 
Rescreening is permitted only once, and only for subjects who fail the serum 25 (OH) 
vitamin D eligibility criterion (ie, subjects with a serum 25 (OH) vitamin D level 
< 20 ng/mL).  Subjects who fail any other eligibility criteria are not permitted to be 
rescreened.  To initiate rescreening, subjects must first be registered as screen failed in 
IVRS and subsequently registered as rescreened.  Subjects will retain the same subject 
identification number assigned at the original screening.  Subjects not entered into IVRS 
as a rescreen will not be eligible for randomization.  Rescreening date is defined as the 
date of IVRS entry, and a 35-day rescreening window will commence at this time.  
Subjects are not required to reconsent for the rescreening period. 
During the rescreening period, the subject should receive vitamin D repletion following a 
protocol defined by the principal investigator.  A serum 25 (OH) vitamin D level 
≥ 20 ng/mL must be confirmed by the central laboratory before the subject can be 
randomized.  While it is possible to repeat the serum 25 (OH) vitamin D test during the 
rescreening period, vitamin D eligibility must be confirmed by the central laboratory and 
the subject must be randomized within the 35-day rescreening window. 
The following procedures are to be completed during the rescreening period as 
designated in the Schedule of Assessments (Table 1): 
• 
Laboratory assessments (vitamin D only) 
• 
Serious adverse event reporting 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 36 of 74 
CONFIDENTIAL 
 
 
• 
Documentation of concomitant medications  
• 
Registration in IVRS 
• 
Randomization via IVRS 
Any other procedures already performed during the screening period (eg, imaging 
assessments, or laboratory assessments other than vitamin D status) do not need to be 
repeated during the rescreening period. 
7.2.3 
Treatment Period 
Visits will occur per the Schedule of Assessments (Table 1) during the treatment period 
from day 1 through month 6.  Romosozumab is to be administered as the last procedure 
of each applicable visit. 
Day 1 is defined as the day the first dose of IP is administered.  All on-study visits 
(ie, visits after day 1) are calculated from the day 1 visit.  If a subject’s visit is delayed, 
their subsequent visit date is not to be shifted, and is always to be calculated from the 
day 1 visit. Month is defined as a calendar month.  
If a subject withdraws from the study early, all efforts should be made to complete and 
report the observations as thoroughly as possible up to the date of withdrawal.  The 
procedures for the month 6/ET visit should be completed at the time of withdrawal 
(Table 1). 
7.2.4 
End of Study Visit 
At month 9, subjects will return to the site for the EOS visit for the procedures specified 
in the Schedule of Assessments (Table 1). 
Subjects who test positive for neutralizing antibodies to romosozumab at the EOS visit or 
the ET visit will be asked to return for anti-romosozumab antibody testing after EOS for 
up to 1 year after the last IP administration. 
7.3 
Description of Study Procedures 
The sections below provide a description of the individual study procedures, which are 
conducted at the timepoints specified in the Schedule of Assessments (Table 1). 
7.3.1 
Informed Consent 
All subjects must sign and personally date the IRB/IEC-approved informed consent 
before any study specific procedures are performed. 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 37 of 74 
CONFIDENTIAL 
 
 
7.3.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally demographic data may be used to study the impact on BTMs variability and 
pharmacokinetics of the protocol-required therapies. 
7.3.3 
Medical History 
The investigator or designee will collect a complete medical history starting within 
5 years prior to screening through administration of the first dose of IP.  In addition, 
osteoporosis history must date back to the original diagnosis.  Medical history will 
include information on the subject’s concurrent medical conditions.  All findings are to be 
recorded on the medical history CRF. 
Detailed information will also be collected about the history of hearing disorders and 
cancer history. 
In addition to the medical history above, osteoporosis history must date back to the 
original diagnosis.  Fracture history will be collected from the age of 45 through 
administration of the first dose of IP.  Fracture history will include date of fracture, 
anatomical site(s) of fracture(s), and degree of trauma involved.  Record all findings on 
the fracture history CRF. 
7.3.4 
Fracture History 
will be collected from the age of 45 through administration of the first dose of IP.  
Fracture history will include date of fracture, anatomical site(s) of fracture(s), and degree 
of trauma involved.  All findings are to be recorded on the fracture history CRF. 
7.3.5 
Medication History 
The investigator or designee will collect a detailed history of prior therapies affecting 
bone metabolism that were taken from 5 years prior to screening through randomization.  
The therapy name, indication, dose, unit, frequency, start date and stop date will be 
recorded. 
A detailed history will also be collected of other prior therapies taken from 30 days prior 
to study enrollment through randomization.  The therapy name, indication, start date and 
stop date will be recorded. 
7.3.6 
Substance use History 
The investigator or designee will collect information about the prior and/or current use of 
tobacco and alcohol and substance use.  All findings are to be recorded on the CRF. 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 38 of 74 
CONFIDENTIAL 
 
 
7.3.7 
Physical Examination 
A physical examination will be conducted as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
7.3.8 
Height and Weight 
Body weight should be measured in kilograms without shoes, and height should be 
measured in centimeters without shoes.  
7.3.9 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure (BP), 
heart rate, respiratory rate, and temperature.  Subject must be in a supine position in a 
rested and calm state for at least 5 minutes before BP assessments are conducted.  If 
the subject is unable to be in the supine position, the subject should be in most 
recumbent position possible.  The position selected for a subject should be the same 
throughout the study and documented on the vital sign CRF.  The arm with the highest 
systolic reading at screening will then be used for further BP readings throughout study.  
The appropriate sized cuff should be used. 
The temperature location selected for a subject should be the same that is used 
throughout the study and documented on the vital signs CRF. 
If abnormalities are found and they are considered an adverse event, they are to be 
recorded on the Event CRF. 
7.3.10 
Concomitant Medications 
Concomitant therapies are to be collected in the CRF from the signing of the ICF through 
the EOS visit.  For concomitant therapies affecting bone metabolism, collect therapy 
name, indication, dose, unit, frequency, start date, and stop date.  For all other 
concomitant therapies, collect therapy name, indication, start date, and stop date. 
7.3.11 
Adverse Events, Serious Adverse Events, and Adverse Device 
Effects 
Any serious adverse events occurring after the signing of the ICF through the EOS visit, 
ET visit, or 30 days after the last dose of IP (whichever period is longer) will be recorded.  
Any adverse events, adverse device effects, and disease-related events observed by the 
investigator or reported by the subject occurring after randomization through the EOS 
visit, ET visit, or 30 days after the last dose of IP (whichever period is longer) will be 
recorded in the subjects’ records and on the appropriate CRFs.  Refer to Section 9.2 for 
more details. 


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In order to fully evaluate certain events of interest during the study, the following events 
will be submitted to an independent committee for adjudication: 
• 
potential osteonecrosis of the jaw events 
• 
potential atypical femoral fracture events 
• 
injection site reaction 
• 
potential events of serious cardiovascular adverse events 
Further, in order to carefully evaluate cardiovascular events during the trials, all deaths 
and serious adverse events that are deemed by the investigator to be of potential 
cardiovascular origin or etiology will be submitted to an independent committee for 
adjudication, as described in the Clinical Events Classification Charter for Study 
20150242.  Serious adverse events with terms mapping to a pre-defined preferred term 
list potentially indicative of cardiovascular etiology will also be adjudicated. 
7.3.12 
Pharmacokinetic Assessment 
Samples for pharmacokinetic assessments will be collected from all subjects enrolled. 
Blood samples for pharmacokinetic testing are to be collected at the time points outlined 
in the Schedule of Assessments (Table 1).  At study visits where pharmacokinetic 
samples are to be collected and IP is also to be administered, blood samples for 
pharmacokinetic testing are to be collected prior to administration of IP. 
Results from pharmacokinetic assays are considered potentially unblinding and will not 
be reported to study-related personnel. 
7.3.13 
Dual-energy X-ray Absorptiometry 
Bone density measurements will be performed by DXA.  Only Lunar or Hologic bone 
densitometers will be allowed for the study.  The same DXA machine must be used for 
all study procedures for a particular subject for the duration of the study.  All DXA scans 
will be submitted to and analyzed by the central imaging vendor.  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. 
Bone density will be measured at the lumbar spine and proximal femur.  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.  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 


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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.  Sites unable to submit data electronically can submit on compact disc 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 
scan due to malpositioning or other technical reasons.  The study site must comply with 
the requests from the central imaging vendor.  Repeat scans must be performed as soon 
as possible after the request is received. 
7.3.13.1 
Screening Bone Mineral Density Assessment 
To determine eligibility based on BMD T-score, lumbar spine and proximal femur DXA 
scans will be analyzed by the central imaging vendor. 
For screening purposes, DXA scans of the lumbar spine and proximal femur taken up to 
35 days prior to the beginning of the screening period may be used if all of the following 
criteria are met: 
• 
Images were obtained as part of the routine standard of care, or following 
appropriate informed consent procedures 
• 
Images were obtained by a trained technician, using the parameters specified by 
the central imaging vendor for this study (refer to the appropriate imaging 
manuals provided by the central imaging vendor)  
• 
DXA images were obtained using the same DXA scanner that will be used for 
this study 
To be eligible for the study, subjects must have at least 2 evaluable lumbar vertebrae 
and at least 1 evaluable proximal femur (as determined by the principal investigator or 
designee). 
7.3.13.2 
On-study Bone Mineral Density Assessments 
DXA BMD data are considered potentially unblinding.  In order to maintain the blind, all 
DXA scans performed after the screening assessment must not be analyzed by site 
staff.  DXA BMD data obtained after screening will not be reported to study-related 
personnel, including sites.  The results from the central imaging vendor will be used as 
the final data for statistical analysis. 


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7.4 
Laboratory Assessments 
All screening and on-study laboratory samples will be processed and sent to the local 
and central laboratories, as applicable.  Depending on the assessment, the central 
laboratory will be responsible either for performing the assays, or for shipping samples to 
Amgen or a specialty laboratory for assay. 
The central laboratory will be responsible for all screening and on-study serum 
chemistry, hematology, hepatitis B and C, serum 25 (OH) vitamin D, and 
intact-parathyroid (iPTH) tests.  The central laboratory will provide a study manual that 
outlines handling, labeling, and shipping procedures for all serum samples.  
Blood samples for BTMs, romosozumab levels, and anti-romosozumab antibodies either 
will be processed by the central laboratory, sent to an appropriate secondary laboratory 
or sent to Amgen for analysis or further distribution to other laboratories. 
All blood samples will be obtained by venipuncture before IP administration.  Blood 
samples for the assessments of BTMs must be obtained from subjects in fasting state 
and before noon.  Fasting state is defined as overnight fasting.  If overnight fasting is not 
feasible, a minimum 8 hours of fasting is required.  The date and time of sample 
collection will be recorded in the source documents at the site.  
Specific analytes for serum chemistry, hematology, and other testing to be conducted on 
blood and urine samples are shown in Table 2.  Although not specifically listed, 
additional components, abnormal, and/or atypical cells will also be reported if present. 


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Table 2.  Analyte Listing 
Serum chemistry 
Hematology  
BTM 
Other analytes 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calciuma 
Albumin-adjusted calciuma 
Magnesium 
Phosphorusa 
Glucose 
Blood urea nitrogen 
Creatinine 
TBL 
ALPa 
ALT (SGPT) 
AST (SGOT) 
TSH 
Free T4 
Red blood cell 
Hemoglobin 
Platelets 
White blood cell 
-Differential 
-Neutrophils 
-Eosinophils 
-Basophils 
-Lymphocytes 
-Monocytes 
CTXa 
P1NPa 
Romosozumab levelsa 
25 (OH) vitamin D 
iPTHa 
Anti-romosozumaba 
antibody 
HepBsAg 
HepBcAb 
Hepatitis C virus 
antibody 
ALP = alkaline phosphatase; ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic 
transaminase); AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
BTM = bone turnover marker; HepBsAg = hepatitis B surface antigen; HepBcAb = total hepatitis B core 
antibody; iPTH = intact-parathyroid hormone; T4 = thyroxine; TBL = total bilirubin; TSH=thyroid stimulating 
hormone. 
a Results of post-day 1 assessments will be blinded to any study-related personnel (including the sites) 
except for serum calcium, albumin-adjusted calcium, phosphorus, or ALP in the event of a panic value. 
Results of laboratory assessments for serum calcium, albumin-adjusted calcium, 
phosphorus, ALP, P1NP, CTX, iPTH, romosozumab levels, and anti-romosozumab 
antibodies are considered potentially unblinding and will not be reported to any 
study-related personnel after day 1 in order to maintain the integrity of the study blind.  
However, in the event of an abnormal value of clinical relevance (panic value) for serum 
calcium, albumin-adjusted calcium, phosphorus, or ALP, sites will be notified of the 
unblinded value by the central laboratory.  After such notification is issued, the sites may 
perform additional follow-up blood draws for local analysis as required to support subject 
medical care.  Notifications will also be issued for subjects who test positive for 
neutralizing anti-romosozumab antibodies at the final scheduled study visit (refer to 
Section 7.3 for details). 


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7.5 
Antibody Testing Procedures 
All subjects will have samples assayed for binding, and if positive, neutralizing 
antibodies.  Blood samples for antibody testing are to be collected at the timepoints 
indicated in the Schedule of Assessments (Table 1) for the measurement of 
anti-romosozumab binding antibodies.  Samples testing positive for binding antibodies 
will also be tested for neutralizing antibodies and may be further characterized for 
quantity/titer, isotype, affinity and presence of immune complexes.  Additional blood 
samples may be obtained to rule out anti-romosozumab antibodies during the study.  
Sites will be notified of any positive neutralizing antibody results to romosozumab 
detected at the final scheduled visit.  If results are not provided, no neutralizing 
antibodies to romosozumab have been detected at the final scheduled study visit. 
Subjects who test positive for neutralizing antibodies to romosozumab at the final 
scheduled study visit will be asked to return for additional follow-up testing.  This testing 
is to occur approximately every 3 months starting from when the site has been notified of 
the positive result, until:  (1) neutralizing antibodies are no longer detectable or (2) the 
subject has been followed for a period of at least 1 year (± 4 weeks) post administration 
of romosozumab.  All follow-up results, both positive and negative will be communicated 
to the sites.  More frequent testing (eg, QM) or testing for a longer period of time may be 
requested in the event of safety-related concerns.  Follow-up testing is not required 
where it is established that the subject did not receive romosozumab. 
Subjects who test positive for binding, non-neutralizing antibodies and have clinical 
sequelae that are considered potentially related to an anti-romosozumab antibody 
response may also be asked to return for additional follow-up testing.  Refer to the 
Schedule of Assessments (Table 1), as applicable, for specific time points and the 
laboratory manual for detailed collection and handling instructions. 
7.6 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  Biomarker development can be useful in developing markers to identify 
disease subtypes, guide therapy, and/or predict disease severity.  Amgen may attempt 
to develop test(s) designed to identify subjects most likely to respond positively or 
negatively to romosozumab. 


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For all subjects in the study, blood samples will be collected according to the Schedule 
of Assessments (Table 1) for determination of BTMs (CTX and P1NP). 
7.7 
Sample Storage and Destruction 
Any blood sample collected according to the Schedule of Assessments (Table 1) can be 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality. 
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand 
osteoporosis, the dose response and/or prediction of response to romosozumab, 
characterize antibody response, and characterize aspects of the molecule 
(eg, mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years. 
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, biomarker development, or other exploratory studies are not placed in 
the subject’s medical record and are not to be made available to the subject, members 
of the family, the personal physician, or other third parties, except as specified in the 
informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 


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The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving IP 
and/or other protocol-required therapies or procedures at any time during the study but 
continue participation in the study.  If this occurs, the investigator is to discuss with the 
subject the appropriate processes for discontinuation from IP or other protocol-required 
therapies and must discuss with the subject the options for continuation of the Schedule 
of Assessments (Table 1) and collection of data, including endpoints and adverse 
events.  The investigator must document the change to the Schedule of Assessments 
(Table 1) and the level of follow-up that is agreed to by the subject (eg, in person, by 
telephone/mail, through family/friends, in correspondence/communication with other 
physicians, from review of the medical records).  
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.  
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from IP and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
prior to study completion.   


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Subjects may be eligible for continued treatment with Amgen IP(s) and/or other 
protocol-required therapies by a separate protocol or as provided for by the local 
country’s regulatory mechanism, based on parameters consistent with Section 12.1. 
8.3 
Reasons for Removal From Treatment or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required IP or procedural assessments might include 
any of the following: 
• 
subject request 
• 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, protocol-specified 
criteria, pregnancy) 
• 
death 
• 
lost to follow-up 
• 
decision by sponsor or investigator (other than subject request, safety concern, lost 
to follow-up) 
In the event a subject experiences a clinical fracture during the study period, the 
investigator is required to discuss the subject’s individual fracture risk and alternative 
treatment options with the subject and to note the discussion in the subject’s records.  If 
a decision is made to begin an alternative approved therapy, the subjects must 
discontinue IP and every effort should be made to have the subject complete the 
remaining study visits and assessments, regardless of the alternative therapy chosen by 
the subject. 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study might include: 
• 
decision by sponsor or investigator 
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Disease-related Events 
Disease-related events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease.  Fractures (serious or non-serious) are 


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anticipated to occur in the study population due to the underlying disease.  Such events 
do not meet the definition of an adverse event unless: 
• 
assessed to be more severe than expected for the subject’s condition or  
• 
if the investigator believes there is a causal relationship between the IP(s)/study 
treatment protocol required therapies and disease worsening. 
If one of these criteria are met, the disease-related event must be reported as an 
adverse event or serious adverse event; otherwise, it will be reported as a 
disease-related event.  
Disease-related events and/or disease-related outcomes that do not qualify as serious 
adverse events:  
• 
An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be 
reported as a Disease Related Event.  
• 
Death due to the disease under study is to be recorded on the Event CRF. 
If the outcome of the underlying disease is worse than that which would normally be 
expected for the subject, or if the investigator believes there is a causal relationship 
between the IP(s)/study treatment protocol required therapies and disease worsening, 
this must be reported as an adverse event or serious adverse event. 
9.1.2 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.  
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event.  
An adverse device effect is any adverse event related to the use of a medical device.  
Adverse device effects include adverse events resulting from insufficient or inadequate 


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instructions for use, adverse events resulting from any malfunction of the device, or 
adverse events resulting from use error or from intentional misuse of the device. 
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.  
9.1.3 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a disease-related event as 
defined in Section 9.1.1): 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
A disease-related event is to be reported as a serious adverse event if:  
• 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, or 
• 
if the investigator believes a causal relationship exists between the investigational 
medicinal product(s)/protocol-required therapies and the event,  
• 
and the event meets at least 1 of the serious criteria above. 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).  
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A for 
DILI reporting criteria), or events that necessitate an emergency room visit, outpatient 
surgery, or urgent intervention. 


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The criteria for grade 4 in the CTCAE grading scale differs from the regulatory criteria for 
serious adverse events.  It is left to the investigator’s judgment to report these grade 4 
abnormalities as serious adverse events. 
9.2 
Safety Event Reporting Procedures 
9.2.1 
Reporting Procedures for Disease Related Events 
The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur after first dose of IP through the 
EOS visit, ET visit, or 30 days after the last dose of IP (whichever period is longer) are 
reported using the Event CRF.  Additionally, the investigator is required to report a fatal 
disease-related event on the Event CRF.  
Events assessed by the investigator to be related to the IP/study treatment/protocol-
required therapies, and determined to be serious, require reporting of the event on the 
Event CRF.  
9.2.2 
Adverse Events 
9.2.2.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after enrollment through the EOS visit, 
ET visit, or 30 days after the last dose of IP (whichever period is longer) are reported 
using the Event CRF. 
The investigator must assign the following adverse event attributes: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
Dates of onset and resolution (if resolved), 
• 
Severity (or toxicity defined below), 
• 
Assessment of relatedness to IP (romosozumab/placebo and/or the PFS), or other 
protocol-required therapies/protocol-required procedure or activity, and 
• 
Action taken. 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE).  The grading scale used in this study is described in 
Appendix A.   
The investigator must assess whether the adverse event is possibly related to the IP 
and/or other protocol-required therapies.  This relationship is indicated by a “yes” or “no” 
response to the question:  Is there a reasonable possibility that the event may have been 
caused by the IP and/or other protocol-required therapies? 


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The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of IP, protocol-required therapies, device[s] 
and/or procedure including any screening procedure[s]).  This relationship is indicated by 
a “yes” or “no” response to the question:  “Is there a reasonable possibility that the event 
may have been caused by a study activity (eg, administration of IP, protocol-required 
therapies, device[s]), and/or procedure?” 
If the severity of an adverse event worsens from the date of onset to the date of 
resolution, record a single event for each increased level of severity on the Event CRF. 
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through the EOS visit, ET visit, or 30 days after the last dose of IP (whichever 
period is longer) are recorded in the subject’s medical record and are submitted to 
Amgen.  All serious adverse events must be submitted to Amgen within 24 hours 
following the investigator’s knowledge of the event via the Event CRF.  
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event Contingency Report Form within 24 hours of the investigator’s 
knowledge of the event.  See Appendix B for a sample of the Serious Adverse Event 
Worksheet/electronic Serious Adverse Event Contingency Report Form.  For EDC 
studies where the first notification of a Serious Adverse Event is reported to Amgen via 
the eSerious Adverse Event Contingency Report Form, the data must be entered into 
the EDC system when the system is again available. 


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The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure?” 
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility. 
In addition to the attributes listed in Section 9.2.2.1, the investigator must also complete 
the serious adverse event section of the Event CRF. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Investigators 
will receive notification of related serious adverse events reports sent to regulatory 
authorities in accordance with local requirements.  
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and GCP.  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 
9.2.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after EOS.  However, these serious adverse 
events can be reported to Amgen.  If serious adverse events are reported, the 


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investigator is to report them to Amgen within 24 hours following the investigator’s 
knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting. 
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a subject, while the subject is taking protocol-required 
therapies, report the pregnancy to Amgen as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of protocol-required therapies 
through 3 months after the end of treatment with romosozumab/placebo. 
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  
If a lactation case occurs while the subject is taking protocol-required therapies report 
the lactation case to Amgen as specified below.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C). 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
• 
Percent change from baseline in DXA BMD at the lumbar spine at month 6 
10.1.1.2 
Secondary Endpoint 
• 
Percent change from baseline in DXA BMD at the femoral neck and total hip at 
month 6 
10.1.1.3 
Exploratory Endpoints 
• 
Percent changes from baseline in BTMs: P1NP and CTX at months 1, 3, and 6 


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10.1.1.4 
Safety Endpoints 
For the 6-month treatment period: 
• 
Subject incidence of adverse events by system organ class and preferred term 
• 
Changes from baseline in laboratory assessments (serum chemistry and 
hematology) and shifts from baseline to the worst value between baseline and 
month 6 
• 
Changes from baseline in vital signs 
• 
Incidence of subjects with anti-romosozumab antibodies at months 1, 3, and 6 
For the overall study period (6-month treatment period followed by the 3-month follow-up 
period): 
• 
Subject incidence of adverse events by system organ class and preferred term 
• 
Subject incidence of the formation of anti-romosozumab antibodies 
10.1.1.5 
Pharmacokinetic Endpoint 
• 
Romosozumab serum concentration at months 1, 3, and 6 
10.1.2 
Analysis Sets 
The full analysis set includes all randomized subjects.  Subjects in this set will be 
analyzed according to their randomized treatment assignment, regardless of treatment 
received. 
The BMD efficacy analysis set for each BMD endpoint will include all randomized 
subjects who have a baseline DXA BMD measurement and at least 1 postbaseline DXA 
BMD measurement for the skeletal site (lumbar spine, femoral neck, or total hip) being 
evaluated.  Data from subjects in this set will be analyzed according to randomized 
treatment groups, regardless of actual treatment received. 
The BTM efficacy analysis set will include all randomized subjects who have a baseline 
measurement and at least 1 postbaseline measurement for the endpoint of interest 
(CTX, P1NP).  Data from subjects in this set will be analyzed according to randomized 
treatment groups, regardless of actual treatment received. 
The safety analysis set will include all randomized subjects who receive at least 1 dose 
of IP.  These subjects will be analyzed according to their actual treatment received. 
The pharmacokinetic set will include all subjects in the safety set who have evaluable 
serum romosozumab concentration.  This set will be used in all PK analyses. 


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10.1.3 
Covariates and Subgroups 
All analyses assessing BMD endpoints at the lumbar spine, femoral neck, and total hip 
will include treatment group, baseline value of BMD, machine type and interaction of 
baseline BMD value, and machine type as independent covariates. 
No subgroup analysis is planned.  
10.2 
Sample Size Considerations 
The sample size is based on comparison of romosozumab to placebo on percent 
change in lumbar spine BMD at month 6.  From earlier Study 20060326, the estimated 
mean percentage differences in lumbar spine BMD between romosozumab versus 
placebo at month 6 were 7.9 with 95% CI (6.6, 9.3).  The standard deviations 
(romosozumab vs. placebo) of mean percentage change in lumbar spine BMD at 
month 6 were 3.9 vs. 3.8.  A sample size of 30 subjects per treatment arm will provide 
>99% power to detect significant treatment difference (romosozumab vs. placebo) in  
percent change in lumbar spine BMD at month 6 assuming a mean percent difference of 
6.6 and a standard deviation of 3.9 with two-sided type 1 error of 5% and 10% dropout 
rate under the two sample t-test. 
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information should not be 
distributed to the study team, investigators, or subjects prior to the study being formally 
unblinded (eg, the formal unblinding at the final analysis) except as specified 
(eg, Section 5.2 and Section 9.2.2.2). 
In order to perform limited planned analyses (eg, exposure-response analyses, PK 
analyses) or other key evaluations, certain functions may be unblinded to individual 
treatment assignments prior to the formal unblinding of the study.  If such analyses will 
be performed during the conduct of the study, consider listing the functions and when 
they will become unblinded (eg, study milestone, percentage of study data availability). 
10.4 
Planned Analyses 
10.4.1 
Interim Analysis 
No interim analyses or sample size re-estimation are planned for this study. 


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10.4.2 
Primary Analysis 
The primary analysis will be performed after all subjects have had the opportunity 
to complete the month 6 visit.   
The primary objective of the primary analysis is to evaluate the effect of treatment 
with romosozumab for 6 months compared with placebo on percent changes in 
BMD at the lumbar spine as assessed by DXA in South Korean women with 
osteoporosis. Formal statistical testing will be conducted to evaluate the following 
hypothesis: in South Korean women with osteoporosis, the mean percent change 
in lumbar spine BMD in subjects receiving romosozumab will be different to that 
of those receiving placebo at month 6. 
Secondary objectives of the primary analysis include the evaluation of the effect 
of treatment with romosozumab compared with placebo on the following: 
• 
Percent change from baseline in DXA BMD at the femoral neck and total hip 
at month 6 
Exploratory objectives of the primary analysis include the evaluation of the effect 
of treatment with romosozumab for 6 months compared with placebo on the 
following: 
• 
Percent changes from baseline in BTMs P1NP and CTX 
For the exploratory objectives, all inferential statistics will be considered 
exploratory in nature. 
Safety objectives of the primary analysis include the comparison of the safety and 
tolerability for 6-month treatment with 210 mg romosozumab QM to placebo in 
South Korean women with osteoporosis on the following: 
• 
Subject incidence of adverse events, including Event of Interest (EOI) 
• 
Changes from baseline in laboratory assessments (serum chemistry and 
hematology) and shifts from baseline to the worst value 
• 
Changes from baseline in vital signs 
• 
Incidence of subjects with anti-romosozumab antibodies 
10.4.3 
Final Analysis 
The final analysis will be performed after all subjects have had the opportunity to 
complete the month 9 visit (ie, after all subjects have had the opportunity to complete the 
3-month follow-up study period).  The 3-month follow-up period will provide the 


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opportunity to monitor all subjects for adverse events and formation of 
anti-romosozumab antibodies.   
Final analysis will include the analysis of primary, secondary, exploratory efficacy 
endpoints, as well as the safety endpoints through 6-month treatment period and 
the analysis of safety endpoints (adverse events and formation of 
anti-romosozumab antibodies) for the 9-month study period. 
The primary objective of the final analysis is the safety objective (ie, the comparison of 
the safety and tolerability following 9-month treatment with 210 mg romosozumab QM to 
placebo in South Korean women with osteoporosis). 
In the final analysis, data from the overall 9-month study period (6-month 
treatment period plus 3-month follow-up period) will be analyzed. 
10.5 
Planned Methods of Analysis 
10.5.1 
General Considerations 
For computation of change from baseline endpoints, baseline will be taken as the 
observation recorded just prior to first dose of IP.  In the case where the protocol 
specifies multiple baseline measurements to be taken, the mean of the baseline records 
will be used for analysis. 
Continuous variables will be summarized descriptively using mean, median, standard 
deviation, 25th percentile, 75th percentile, minimum, maximum, and the number of 
nonmissing observations.  Frequencies and percentages will be presented for nominal 
categorical variables. 
10.5.2 
Primary Efficacy Endpoint 
The analysis to assess the percent change from baseline in lumbar spine DXA BMD at 
month 6 will employ an analysis of covariance (ANCOVA) model.  The ANCOVA model 
will include treatment group, baseline value of BMD, machine type and interaction of 
baseline BMD value and machine type as independent variables.  Summaries for the 
results will include least-squares means point estimates of the percent change from 
baseline for each treatment arm.  The variance structure will allow for heterogeneity 
between treatments.  The 2-sided 95% CI and associated p-value will be provided for 
the difference between the least-squares means for romosozumab and placebo. 
Conclusions for the primary efficacy hypothesis of different efficacy of romosozumab 
compared with placebo at lumbar spine BMD will be made using a 2-sided test with 


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type 1 error rate of 0.05.  The BMD efficacy analysis set will be used to for these 
analyses. 
10.5.3 
Secondary Efficacy Endpoints 
For the secondary efficacy BMD endpoints (total hip and femoral neck at month 6), the 
percent change from baseline in DXA BMD will employ an ANCOVA model.  The 
ANCOVA model will include treatment group, baseline value of BMD, machine type and 
interaction of baseline BMD value and machine type as independent variables.  
Summaries for the results will include least-squares means point estimates of the 
percent change from baseline for each treatment arm.  The variance structure will allow 
for heterogeneity between treatments.  The 2-sided 95% CI and associated p-value will 
be provided for the difference between the least-squares means for romosozumab and 
placebo.  The BMD efficacy analysis set will be used for these analyses. 
10.5.4 
Exploratory Efficacy Endpoints 
For P1NP and CTX, descriptive statistics will be presented by treatment group at each 
visit for both actual values and the percent change from baseline values.  Graphs 
depicting median and interquartile ranges by treatment group for percent change over 
time will be provided.  The BTM efficacy analysis set will be used for these analyses. 
10.5.5 
Safety Endpoints 
Safety analyses will include assessments of treatment-emergent adverse events, IP 
exposure, clinical laboratory assessments, vital signs, and anti-romosozumab 
antibodies.  
The safety analysis set will be used for these analyses. 
There is no planned inferential statistical testing in the safety analyses.  All categorical 
endpoints will be summarized using the number and percent of subjects.  All continuous 
endpoints will be summarized using descriptive statistics including mean, standard 
deviation, minimum, quartiles, maximum, and number of subjects. 
10.5.5.1 
Adverse Events 
For the 6-month treatment period, subject incidence of all treatment-emergent adverse 
events will be tabulated by system organ class and preferred term.  Tables of fatal 
adverse events, serious adverse events, events of interest (including positively 
adjudicated osteonecrosis of the jaw, positively adjudicated atypical femoral 
fracture, injection site reaction, and positively adjudicated serious cardiovascular 
adverse events), adverse events leading to withdrawal from IP or other 


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protocol-required therapies, and treatment-emergent adverse events will also be 
provided.  Subject incidence of disease-related events and fatal disease-related events 
will be tabulated by system organ class and preferred term.  The treatment-emergent 
adverse events in the overall 9-month study period (6-month treatment period followed 
by a 3-month follow-up period) will be summarized using the same approach as for the 
6-month treatment period.  In addition, adverse events reported between month 6 and 
month 9 (no treatment phase) will be listed by subject number and treatment received in 
the first 6 months. 
10.5.5.2 
Exposure to Investigational Product 
The exposure to IP will be summarized using descriptive statistics. 
10.5.5.3 
Laboratory Assessments 
The analyses of safety laboratory endpoints will include summary statistics (actual value 
and change or percent change from baseline for each laboratory parameter) over time 
by visit for the 6-month treatment period.  Shifts in grades of safety laboratory values 
between the baseline and the worst on-study value will be tabulated.  Graphical 
representation of aggregate data may also be presented. 
10.5.5.4 
Vital Signs 
The analyses of vital signs will include summary statistics (actual value and change from 
baseline for blood pressure, pulse and temperature) over time by visit for the 6-month 
treatment period. 
10.5.5.5 
Anti-romosozumab Antibodies 
The incidence and percentage of subjects who develop anti-romosozumab antibodies 
(binding, and if positive, neutralizing) at months 1, 3, 6 and 9 will be tabulated by 
treatment group.  For subjects who develop anti-romosozumab antibodies, 
romosozumab serum concentrations may also be analyzed.  Additionally, exploratory 
analyses may be performed to assess any impact on safety or efficacy. 
10.5.6 
Pharmacokinetic Endpoint 
Trough serum concentration profiles determined from subjects may be summarized in 
tabular form and presented graphically.  Additional pharmacokinetic analyses will be 
performed as appropriate.  The pharmacokinetic set will be used for these analyses. 


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11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample ICF is provided for the investigator to prepare the informed consent 
document to be used at his or her site.  Updates to the template are to be communicated 
formally in writing from the Amgen Clinical Study Manager to the investigator.  The 
written informed consent document is to be prepared in the language(s) of the potential 
patient population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any IP is administered.  
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.  
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the ICF is to be signed and personally dated by the subject and by the 
person who conducted the informed consent discussion.  The original signed ICF is to 
be retained in accordance with institutional policy, and a copy of the signed consent form 
is to be provided to the subject. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF to attest that informed consent was freely given and 
understood.  
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed ICF, other written subject information, and any 
proposed advertising material must be submitted to the IRB/IEC for written approval.  A 


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copy of the written approval of the protocol and ICF must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen IP. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.  
• 
Subjects are to be identified by a unique subject identification number.  
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.  
• 
On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.  
• 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
• 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in 
confidence by the investigator, except as described below. 
In compliance with ICH GCP Guidelines, it is required that the investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the 
IRB/IEC direct access to review the subject’s original medical records for verification of 
study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of 
the study.  The investigator is obligated to inform and obtain the consent of the subject to 
permit such individuals to have access to his/her study-related records, including 
personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 


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The coordinating investigator, identified by Amgen, will be any or all of the following: 
• 
a recognized expert in the therapeutic area 
• 
an Investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an Investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the Investigator must be obtained.  The 
IRB/IEC must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IRB/IEC to Amgen. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
Investigator reserve the right to terminate the Investigator’s participation in the study 
according to the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study’s completion or ET and send a copy of the notification to Amgen.  
Subjects may be eligible for continued treatment with Amgen IP(s) by an extension 
protocol or as provided for by the local country’s regulatory mechanism.  However, 
Amgen reserves the unilateral right, at its sole discretion, to determine whether to supply 
Amgen IP(s) and by what mechanism, after termination of the study and before the 
product(s) is/are available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
In this study, the IVR/IWR system captures the following data points and these are 
considered source data:  subject identification number, randomization date, 
randomization number, and treatment group assignment. 
CRF entries may be considered source data if the CRF is the site of the original 
recording (ie, there is no other written or electronic record of data. 


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The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  
Elements to include: 
• 
Subject files containing completed CRFs, ICFs, and subject identification list 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
• 
Investigational product-related correspondence including Proof of Receipts, IP 
Accountability Record(s), Return of IP for Destruction Form(s), Final IP 
Reconciliation Statement, as applicable. 
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen Clinical Monitor is responsible for verifying the CRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The Clinical Monitor is to have access to subject medical records and other 
study-related records needed to verify the entries on the CRFs. 
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study-related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 


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Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the CRFs must be maintained and 
readily available. 
• 
Updates to CRFs will be automatically documented through the software’s “audit 
trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
• 
The investigator signs only the Investigator Verification Form for this EDC study or 
the investigator applies an electronic signature in the EDC system if the study is set 
up to accept an electronic signature.  This signature indicates that investigator 
inspected or reviewed the data on the CRF, the data queries, and agrees with the 
content. 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit-week 4 and ET) and clarifying “other, specify” if data are provided 
(eg, race, physical examination).  Each investigative site will be provided a list of the 
types of corrections applied to study data at the initiation of the trial and at study 
closeout.  
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 1), the investigator can search publically available 
records (where permitted) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.  
12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.  


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12.6 
Publication Policy 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published, and (4) agreement to be accountable for all aspects of 
the work in ensuring that questions related to the accuracy or integrity of any 
part of the work are appropriately investigated and resolved.  Authors need to 
meet conditions 1, 2, 3, and 4. 
• 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals 
must fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify are to be listed. 
• 
Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 


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13. 
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Hamersma H, Gardner J, Beighton P. The natural history of sclerosteosis. Clin Genet. 
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Papapoulos S, Makras P. Selection of antiresorptive or anabolic treatments for 
postmenopausal osteoporosis. Nature Clin Practice Endocrinology & Metabolism. 
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Poole KE, van Bezooijen RL, Loveridge N, et al. Sclerostin is a delayed secreted product 
of osteocytes that inhibits bone formation. FASEB J. 2005;19(13):1842-1844.  
Reginster JY, Burlet N. Osteoporosis: a still increasing prevalence. Bone. 
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Ross AC, Taylor CL, Yaktine AL, Del Valle HB. (Editors)/Committee to Review Dietary 
Reference Intakes for vitamin D and Calcium. Dietary Reference Intakes for Calcium and 
vitamin D: The National Academies Press; 2011. 
Tucci JR. Vitamin D therapy in patients with primary hyperparathyroidism and 
hypovitaminosis D. Europ J Endocr. 2009;161:189-193. 
van Bezooijen RL, Roelen BA, Visser A, et al. Sclerostin is an osteocyte-expressed 
negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med. 
2004;199(6):805-814. 
Vanhoenacker FM, Balemans W, Tan GJ, et al. Van Buchem disease: lifetime evolution 
of radioclinical features. Skeletal Radiol. 2003;32(12):708-718. 
Winkler DG, Sutherland MK, Geoghegan JC, et al. Osteocyte control of bone formation 
via sclerostin, a novel BMP antagonist. EMBO J. 2003;22(23):6267-6276. 
World Health Organization. Assessment of fracture risk and its application to screening 
for postmenopausal osteoporosis. World Health Organization. Geneva, Switzerland. 
1994:1-129. 
World Health Organization. WHO Scientific Group on the Assessment of Osteoporosis at 
Primary Health Care Level (Summary Meeting Report, Brussels, Belgium, 5-7 May 
2004). Geneva, Switzerland: WHO Press; 2007.  


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 67 of 74 
CONFIDENTIAL 
 
 
14. 
APPENDICES 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 68 of 74 
CONFIDENTIAL 
 
 
Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
For grading of adverse events, CTCAE version 3.0 is to be used.  The CTCAE 
version 3.0 is available at the following link:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.3 require 
the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate CRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to the Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.2.2. 
Additional Clinical Assessments and Observation 
All subjects in whom IP(s) or protocol-required therapies is/are withheld (either 
permanently or conditionally) due to potential DILI as specified in Sections 6.3.1 and 
6.3.2 or who experience AST or ALT elevations > 3 x ULN are to undergo a period of 
“close observation” until abnormalities return to normal or to the subject’s baseline 
levels.  Assessments that are to be performed during this period include:  
• 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
• 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the IP(s) or protocol-required therapies has/have been discontinued AND the 
subject is asymptomatic. 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 69 of 74 
CONFIDENTIAL 
 
 
• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL: 
− 
Obtain complete blood count with differential to assess for eosinophilia 
− 
Obtain serum total immunoglobulin IgG, Anti-nuclear antibody, Anti Smooth 
Muscle Antibody, and Liver Kidney Microsomal antibody 1 to assess for 
autoimmune hepatitis 
− 
Obtain serum acetaminophen (paracetamol) levels 
− 
Obtain a more detailed history of:  
• 
Prior and/or concurrent diseases or illness 
• 
Exposure to environmental and/or industrial chemical agents  
• 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
• 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
• 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
− 
Obtain viral serologies 
− 
Obtain creatine phosphokinase, haptoglobin, lactate dehydrogenase, and 
peripheral blood smear 
− 
Perform appropriate liver imaging if clinically indicated 
• 
Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected  
• 
Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
• 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal.  The “close observation period” is to 
continue for a minimum of 4 weeks after discontinuation of all IP(s) and 
protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 70 of 74 
CONFIDENTIAL 
 
 
Appendix B.  Sample Serious Adverse Event Report Form 
 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 71 of 74 
CONFIDENTIAL 
 
 
 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 72 of 74 
CONFIDENTIAL 
 
 
 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 73 of 74 
CONFIDENTIAL 
 
 
Appendix C.  Pregnancy and Lactation Notification Worksheets 
 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 74 of 74 
CONFIDENTIAL 
 
 
 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 1 of 7 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Multicenter, Randomized, Double-blind, Placebo-controlled, 
Study to Compare the Efficacy and Safety of Romosozumab With Placebo in 
Postmenopausal South Korean Women With Osteoporosis 
 
Amgen Protocol Number Romosozumab (AMG 785) 20150242 
 
Amendment Date: 
13 November 2017 
 
Rationale: 
This study is being conducted to support registration of romosozumab in Korea.   
A primary analysis at 6 months is being added in this protocol amendment.  Conducting 
a primary analysis in addition to a final analysis allows evalalution of the efficacy and 
safety data in the most expedited manner to support registrational activities.   
Importantly, the primary analysis is being added to maintain consistency with what was 
done in previous studies with a similar design in the romosozumab development 
program. 
Additional updates include: 
• 
Align End of Study and Publication Policy language to new template text 
• 
Update schema to include primary and final analysis, and add month 5 visit to 
align with protocol 
• 
Clarify adverse events of interest to include injection site reactions and potential 
events of serious cardiovascular adverse events 
• 
Make editorial and administrative edits 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 2 of 7 
CONFIDENTIAL 
 
 
Description of Changes: 
Section:  Global 
Change:  Date updated throughout from 09 June 2017 to 13 November 2017. 
Section:  Title Page 
Add: 
Amendment 02 Date 
13 November 2017 
Section:  Study Design and Treatment Schema 
Replace: 
 


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Legend
Study visit with IP administration
Study visit without IP administration
RANDOMIZATION
SCREENING
PRIMARY ANALYSIS
FINAL ANALYSIS
D1
M1
M2
M3
M4
M5
M6
M9
210 mg Romosozumab SC QM
n = 30
Placebo SC QM
n = 30
Loading dose 50,000-60,000 IU vitamin D, if applicable
Screening period
чϯϱĚĂǇƐ
Treatment period 
6 months
Follow-up period
3 months
Daily calcium (at a minimum in the range of 500 to 1,000 mg) and vitamin D (at a minimum in the range of 600 to 800 IU)
b
0
C
s
o
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c
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HYDOXDWLRQLQWKHVWXG\LHODVWVXEMHFWODVWYLVLW


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 4 of 7 
CONFIDENTIAL 
 
 
Section: 7.3.11 Adverse Events, Serious Adverse Events, and Adverse Device Effects 
Replace: 
• 
potential osteonecrosis of the jaw events 
• 
potential cases of atypical femoral fracture 
With: 
• 
potential osteonecrosis of the jaw events 
• 
potential atypical femoral fracture events 
• 
injection site reactions 
• 
potential events of serious cardiovascular adverse events 
Section:  10.4.1 Interim Analysis 
Add: 
10.4.1 Interim Analysis 
No interim analyses or sample size re-estimation are planned for this study. 
Section:  10.4.2 Primary Analysis 
Add: 
10.4.2 Primary Analysis  
The primary analysis will be performed after all subjects have had the opportunity 
to complete the month 6 visit.   
The primary objective of the primary analysis is to evaluate the effect of treatment 
with romosozumab for 6 months compared with placebo on percent changes in 
BMD at the lumbar spine as assessed by DXA in South Korean women with 
osteoporosis. Formal statistical testing will be conducted to evaluate the following 
hypothesis: in South Korean women with osteoporosis, the mean percent change 
in lumbar spine BMD in subjects receiving romosozumab will be different to that 
of those receiving placebo at month 6. 
Secondary objectives of the primary analysis include the evaluation of the effect 
of treatment with romosozumab compared with placebo on the following: 
• 
Percent change from baseline in DXA BMD at the femoral neck and total hip 
at month 6 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 5 of 7 
CONFIDENTIAL 
 
 
Exploratory objectives of the primary analysis includes the evaluation of the effect 
of treatment with romosozumab for 6 months compared with placebo on the 
following: 
• 
Percent changes from baseline in BTMs P1NP and CTX 
For the exploratory objectives, all inferential statistics will be considered 
exploratory in nature. 
Safety objectives of the primary analysis include the comparison of the safety and 
tolerability for 6-month treatment with 210 mg romosozumab QM to placebo in 
South Korean women with osteoporosis on the following: 
• 
Subject incidence of adverse events, including Event of Interest (EOI) 
• 
Changes from baseline in laboratory assessments (serum chemistry and 
hematology) and shifts from baseline to the worst value 
• 
Changes from baseline in vital signs 
• 
Incidence of subjects with anti-romosozumab antibodies 
Section:  10.4.3 Final Analysis 
Replace: 
10.4.1 Final Analysis 
The final analysis will be performed after all subjects have had the opportunity to 
complete the month 9 visit (ie, after all subjects have had the opportunity to complete the 
3-month follow-up period).  The 3-month follow-up period will provide the opportunity to 
monitor all subjects for adverse events and formation of anti-romosozumab antibodies.  
The primary objective of the additional 3 months is the safety objective (ie the 
comparison of the safety and tolerability following 6 -month treatment with 210 mg 
romosozumab QM to placebo in postmenopausal women with osteoporosis)  
With: 
10.4.3 Final Analysis 
The final analysis will be performed after all subjects have had the opportunity to 
complete the month 9 visit (ie, after all subjects have had the opportunity to complete the 
3-month follow-up study period).  The 3-month follow-up period will provide the 
opportunity to monitor all subjects for adverse events and formation of 
anti-romosozumab antibodies.   


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 6 of 7 
CONFIDENTIAL 
 
 
Final analysis will include the analysis of primary, secondary, exploratory efficacy 
endpoints, as well as the safety endpoints through 6-month treatment period and 
the analysis of safety endpoints (adverse events and formation of 
anti-romosozumab antibodies) for the 9-month study period. 
The primary objective of the final analysis is the safety objective (ie, the comparison of 
the safety and tolerability following 9-month treatment with 210 mg romosozumab QM to 
placebo in South Korean women with osteoporosis). 
In the final analysis, data from the overall 9-month study period (6-month 
treatment period plus 3-month follow-up period) will be analyzed. 
Section:  10.5.5.1 Adverse Events 
Add: 
For the 6-month treatment period, subject incidence of all treatment-emergent adverse 
events will be tabulated by system organ class and preferred term.  Tables of fatal 
adverse events, serious adverse events, events of interest (including positively 
adjudicated osteonecrosis of the jaw, positively adjudicated atypical femoral 
fracture, injection site reaction, and positively adjudicated serious cardiovascular 
adverse events), adverse events leading to withdrawal from IP or other protocol-
required therapies, and treatment-emergent adverse events will also be provided.   
Section:  12.6 Publication Policy 
Replace: 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published.  Authors should meet conditions 1, 2, and 3. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  13 November 2017 
Page 7 of 7 
CONFIDENTIAL 
 
 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
With: 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published, and (4) agreement to be accountable for all aspects of 
the work in ensuring that questions related to the accuracy or integrity of any 
part of the work are appropriately investigated and resolved.  Authors need to 
meet conditions 1, 2, 3, and 4. 
• 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals 
must fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify are to be listed. 
• 
Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
 


Product:  Romosozumab 
Protocol Number:  20150242 
Date:  09 June 2017 
Page 1 of 4 
Amendment 1 
Protocol Title:  A Multicenter, Randomized, Double-blind, Placebo-controlled, 
Study to Compare the Efficacy and Safety of Romosozumab With Placebo in 
Postmenopausal South Korean Women With Osteoporosis 
 
Romosozumab (AMG 785) 20150242 
 
Amendment Date: 
09 June 2017 
 
Rationale: 
The protocol is amended to: 
• 
Add independent committee adjudication for deaths and serious adverse events 
to be of potential cardiovascular origin or etiology  
• 
Revise Hepatitis B and C exclusion criteria to clarify the circumstances under 
which PCR should be performed to determine active disease 
• 
Add a superscript “a” to CTX and P1NP in Table 2 (Analyte Listing) to indicate 
that post-day 1 assessments are blinded 
• 
Make minor administrative changes and edits throughout the protocol 
CONFIDENTIAL 
 
 

SAP_001.pdf: 
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