A Randomized, Multicenter, Open-label, Parallel Group Study in Postmenopausal Women With Osteoporosis to Evaluate the Noninferiority of Subject-administered Romosozumab Via Autoinjector/Pen vs Healthcare Provider-administered Romosozumab Via Prefilled Syringe
Phase: PHASE3
Conditions: Post-Menopausal Osteoporosis
Sponsor: Amgen

Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
Page 1 of 93 
Title Page 
Protocol Title: 
A Randomized, Multicenter, Open-label, Parallel 
Group Study in Postmenopausal Women With 
Osteoporosis to Evaluate the Noninferiority of 
Subject-administered Romosozumab via 
Autoinjector/Pen vs Healthcare 
Provider-administered Romosozumab via 
Prefilled Syringe 
Short Protocol Title: 
A Comparison of Subject-administered 
Romosozumab with Healthcare 
Provider-administered Romosozumab for 
Osteoporosis 
Protocol Number: 
20150120 
Investigational Product: 
Romosozumab 
Trade Name: 
Enter Trade Name 
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 USA 
Telephone Number: 
1-805-447-1000
Key 
Sponsor 
Contact 
Name: 
Address: 
One Amgen Center Drive, M/S 38-3-C 
Thousand Oaks, CA 91320 USA 
Telephone Number: 
Email Address: 
EudraCT Number: 
Enter EudraCT Number 
NCT Number: 
Unavailable for first version 
Protocol Date: 
Document Version 
Date 
Original 
10 August 2017 
Version/Date: 
Data Element 
Standards Version 
Date 
5.0 
20 March 2015 
CONFIDENTIAL 
NCT Number: NCT03432533 
This NCT number has been applied to the document 
for purposes of posting on clinicaltrials.gov

Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
Page 2 of 93 
 
Confidentiality Notice 
 
Investigator's Agreement: 
I have read the attached protocol entitled A Randomized, Multicenter, Open-label, 
Parallel Group Study in Postmenopausal Women With Osteoporosis to Evaluate the 
Noninferiority of Subject-administered Romosozumab via Autoinjector/Pen vs Healthcare 
Provider-administered Romosozumab via Prefilled Syringe, dated 10 August 2017, and 
agree to abide by all provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, 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) and my 
subinvestigators (including, if applicable, their spouses or legal partners and dependent 
children) at the start of the study and for up to 1 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) 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000. 
 
CONFIDENTIAL 
 

Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
Page 3 of 93 
 
Table of Contents 
Table of Contents ..................................................................................................... 3 
1. 
Protocol Synopsis..................................................................................................... 8 
2. 
Study Schema and Schedule of Activities .............................................................. 13 
2.1 
Study Schema ............................................................................................ 13 
2.2 
Schedule of Activities ................................................................................. 14 
3. 
Introduction ............................................................................................................ 17 
3.1 
Study Rationale .......................................................................................... 17 
3.2 
Background ................................................................................................ 17 
3.2.1 
Disease ....................................................................................... 17 
3.2.2 
Amgen Investigational Product Background:  
Romosozumab ........................................................................... 19 
4. 
Objectives, Endpoints and Hypotheses .................................................................. 21 
4.1 
Objectives and Endpoints ........................................................................... 21 
4.2 
Hypotheses ................................................................................................. 22 
5. 
Study Design .......................................................................................................... 22 
5.1 
Overall Design ............................................................................................ 22 
5.2 
Number of Subjects .................................................................................... 23 
5.2.1 
Replacement of Subjects ............................................................ 23 
5.2.2 
Number of Sites .......................................................................... 24 
5.3 
End of Study ............................................................................................... 24 
5.3.1 
End of Study Definition ............................................................... 24 
5.3.2 
Study Duration for Subjects ........................................................ 24 
5.4 
Justification for Investigational Product Dose ............................................. 24 
6. 
Study Population .................................................................................................... 25 
6.1 
Inclusion Criteria  ........................................................................................ 25 
6.2 
Exclusion Criteria ........................................................................................ 26 
6.3 
Subject Enrollment ..................................................................................... 29 
6.4 
Screen Failures .......................................................................................... 29 
7. 
Treatments ............................................................................................................. 30 
7.1 
Treatment Procedures ................................................................................ 30 
7.1.1 
Investigational Products ............................................................. 30 
7.1.2 
Medical Devices ......................................................................... 33 
7.1.3 
Other Protocol-required Therapies ............................................. 33 
7.1.4 
Other Treatment Procedures ...................................................... 34 
7.1.5 
Product Complaints .................................................................... 34 
7.1.6 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ................................................ 34 
7.2 
Method of Treatment Assignment .............................................................. 35 
 
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Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
Page 4 of 93 
 
7.3 
Blinding ....................................................................................................... 35 
7.4 
Dose Modification ....................................................................................... 35 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ...................................... 35 
7.4.1.1 
Amgen Investigational Product:  
Romosozumab ......................................................... 35 
7.4.2 
Hepatotoxicity Stopping and Rechallenge Rules ........................ 36 
7.5 
Preparation/Handling/Storage/Accountability ............................................. 36 
7.6 
Treatment Compliance ............................................................................... 36 
7.7 
Treatment of Overdose ............................................................................... 36 
7.8 
Prior and Concomitant Treatment .............................................................. 37 
7.8.1 
Prior Treatment ........................................................................... 37 
7.8.2 
Concomitant Treatment .............................................................. 37 
8. 
Discontinuation Criteria .......................................................................................... 37 
8.1 
Discontinuation of Study Treatment ........................................................... 37 
8.2 
Discontinuation From the Study ................................................................. 38 
8.2.1 
Reasons for Removal From Washout, Run-in, or 
Invasive Procedures ................................................................... 39 
8.2.2 
Reasons for Removal From Study ............................................. 39 
8.3 
Lost to Follow-up ........................................................................................ 39 
9. 
Study Assessments and Procedures ..................................................................... 40 
9.1 
General Study Periods ............................................................................... 40 
9.1.1 
Screening, Enrollment and/or Randomization ............................ 40 
9.1.1.1 
Screening Bone Mineral Density 
Assessment ............................................................. 41 
9.1.2 
Treatment Period ........................................................................ 41 
9.1.3 
Safety Follow-up ......................................................................... 42 
9.1.4 
End of Study ............................................................................... 42 
9.2 
Description of General Study Assessments and Procedures ..................... 42 
9.2.1 
General Assessments ................................................................ 42 
9.2.1.1 
Informed Consent .................................................... 42 
9.2.1.2 
Demographics .......................................................... 42 
9.2.1.3 
Medical History ........................................................ 42 
9.2.1.4 
Physical Examination ............................................... 42 
9.2.1.5 
Physical Measurements ........................................... 43 
9.2.1.6 
Substance Abuse History ......................................... 43 
9.2.2 
Efficacy Assessments ................................................................. 43 
9.2.2.1 
Dual-energy X-ray Absorptiometry ........................... 43 
9.2.3 
Safety Assessments ................................................................... 43 
9.2.3.1 
Adverse Events ........................................................ 44 
9.2.3.2 
Vital Signs ................................................................ 47 
9.2.4 
Clinical Laboratory Assessments ............................................... 47 
 
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Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
Page 5 of 93 
 
9.2.4.1 
Pregnancy Testing ................................................... 48 
9.2.4.2 
Hepatitis B and C Testing ........................................ 48 
9.2.4.3 
Prespecified Biomarker Assessments ..................... 48 
9.2.5 
Pharmacokinetic Assessments ................................................... 48 
9.2.6 
Antibody Testing Procedures ..................................................... 49 
10. 
Statistical Considerations ....................................................................................... 49 
10.1 
Sample Size Determination ........................................................................ 49 
10.2 
Analysis Sets, Subgroups, and Covariates ................................................ 50 
10.2.1 
Analysis Sets .............................................................................. 50 
10.2.1.1 
Full Analysis Set ...................................................... 50 
10.2.1.2 
Primary Efficacy Analysis Subset ............................ 50 
10.2.1.3 
Hip Bone Mineral Density Efficacy 
Analysis Subset ....................................................... 51 
10.2.1.4 
Safety Analysis Subset ............................................ 51 
10.2.1.5 
Per Protocol Analysis Subset ................................... 51 
10.2.2 
Covariates .................................................................................. 51 
10.2.3 
Subgroups .................................................................................. 51 
10.2.4 
Handling of Missing and Incomplete Data .................................. 51 
10.2.4.1 
DXA BMD Endpoints ................................................ 52 
10.2.4.2 
Bone Turnover Markers ........................................... 52 
10.2.4.3 
Laboratory Parameters ............................................ 52 
10.3 
Statistical Analyses ..................................................................................... 52 
10.3.1 
Planned Analyses ....................................................................... 52 
10.3.1.1 
Interim Analysis and Early Stopping 
Guidelines ................................................................ 52 
10.3.1.2 
Primary Analysis ...................................................... 52 
10.3.1.3 
Final Analysis ........................................................... 53 
10.3.2 
Methods of Analyses .................................................................. 54 
10.3.2.1 
General Considerations ........................................... 54 
10.3.2.2 
Efficacy Analyses ..................................................... 54 
10.3.2.3 
Safety Analyses ....................................................... 55 
11. 
References ............................................................................................................. 57 
12. 
Appendices ............................................................................................................ 60 
Appendix 1.  List of Abbreviations and Definitions of Terms .................................. 61 
Appendix 2.  Clinical Laboratory Tests ................................................................... 63 
Appendix 3.  Study Governance Considerations .................................................... 65 
Independent Adjudication Committee(s) for Osteonecrosis of the 
Jaw, Atypical Femoral Fracture, and Serious 
Cardiovascular Events  .............................................................. 65 
Regulatory and Ethical Considerations ...................................................... 65 
Informed Consent Process ......................................................................... 66 
Data Protection/Subject Confidentiality ...................................................... 68 
 
CONFIDENTIAL 
 

Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
Page 6 of 93 
 
Publication Policy ....................................................................................... 68 
Investigator Signatory Obligations .............................................................. 69 
Data Quality Assurance .............................................................................. 70 
Source Documents ..................................................................................... 71 
Study and Site Closure ............................................................................... 72 
Compensation ............................................................................................ 72 
Appendix 4.  Safety Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting .......................................................... 73 
Definition of Disease-related Event ............................................................ 73 
Definition of Adverse Event ........................................................................ 73 
Definition of Serious Adverse Event ........................................................... 74 
Definition of Adverse Device Effect ............................................................ 75 
Recording Adverse Events, Disease-related Events (if 
Applicable), and Serious Adverse Events .................................. 76 
Evaluating Adverse Events and Serious Adverse Events .......................... 77 
Reporting of Serious Adverse Event .......................................................... 78 
Adverse Device Effects:  Recording, Evaluating, and Reporting ................ 78 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information .................................................................................. 84 
Collection of Pregnancy Information ........................................................... 84 
Collection of Lactation Information ............................................................. 85 
Appendix 6.  Sample Storage and Destruction ...................................................... 88 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ................................................................................................... 90 
Criteria for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-
required Therapies Due to Potential Hepatotoxicity ................... 90 
Criteria for Rechallenge of Amgen Investigational Product and 
Other Protocol-required Therapies After Potential 
Hepatotoxicity ............................................................................. 91 
Drug-induced Liver Injury Reporting and Additional 
Assessments .............................................................................. 92 
 
CONFIDENTIAL 
 

Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
Page 7 of 93 
 
 
List of Tables 
Table 2-1.  Schedule of Activities .................................................................................... 14 
Table 7-1.  Study Treatments .......................................................................................... 31 
Table 12-1.  Analyte Listing ............................................................................................. 64 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................... 91 
 
List of Figures 
Figure 2-1.  Study Schema ............................................................................................. 13 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form .................. 79 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet ...................................... 86 
 
 
CONFIDENTIAL 
 

Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
Page 8 of 93 
 
1. 
Protocol Synopsis 
Protocol Title:  A Randomized, Multicenter, Open-label, Parallel Group Study in 
Postmenopausal Women With Osteoporosis to Evaluate the Noninferiority of 
Subject-administered Romosozumab via Autoinjector/Pen vs Healthcare 
Provider-administered Romosozumab via Prefilled Syringe 
Short Protocol Title:  A Comparison of Subject-administered Romosozumab with 
Healthcare Provider-administered Romosozumab for Osteoporosis 
Study Phase:  3 
Indication:  osteoporosis in postmenopausal women 
Rationale 
Amgen is developing a 90 mg/mL concentration of romosozumab in a 1.17 mL 
deliverable volume (ie, 105 mg romosozumab) to be administered using prefilled syringe 
(PFS), as well as autoinjector/pen (AI/Pen).  Both 90 mg/mL drug product presentations 
(PFS and AI/Pen) will use the same syringe with Crystal Zenith resin barrel as the 
primary container for the drug.  The AI/Pen is a single-use, disposable, handheld, 
“spring-based”, mechanical injection device that administers a fixed dose of 
romosozumab into the subcutaneous (SC) tissue.  Unlike the PFS, the AI/Pen is being 
developed for home use.  Designed with a hidden needle, the AI/Pen may alleviate 
anxiety in patients with needle phobia and potentially decrease the risk of accidental 
needle sticks.   
The purpose of this study is to demonstrate that postmenopausal women with 
osteoporosis can successfully self-administer 210 mg romosozumab at 90 mg/mL once 
a month (QM) with 2 AI/Pens, as measured objectively by the percent change from 
baseline in bone mineral density (BMD) at 6 months.  A comparison will be made with 
subjects receiving healthcare provider (HCP)-administered doses of 210 mg at 
90 mg/mL with 2 PFS. 
Data from this study is anticipated to support noninferiority of the 90 mg/mL 
concentration of romosozumab self-administered by the subject with AI/Pen compared to 
that administered by an HCP with PFS; it will additionally support global regulatory 
approval of the romosozumab AI/Pen. 
 
 
 
CONFIDENTIAL 
 

Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
Page 9 of 93 
 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
• 
To evaluate the noninferiority of a 
6-month treatment with 210 mg 
romosozumab at 90 mg/mL 
administered subcutaneously (SC) 
once a month (QM) in 
postmenopausal women with 
osteoporosis either by healthcare 
provider (HCP) administration with 
prefilled syringe (PFS) or by subject 
self-administration with 
autoinjector/pen (AI/Pen) 
• 
Percent change from baseline in bone 
mineral density (BMD) at the lumbar 
spine, as assessed by dual-energy 
x-ray absorptiometry (DXA) 
Secondary 
Efficacy 
• 
To evaluate the efficacy of a 6-month 
treatment with 210 mg romosozumab 
at 90 mg/mL SC QM in 
postmenopausal women with 
osteoporosis either by HCP 
administration with PFS or by subject 
self-administration with AI/Pen 
 
• 
Percent changes from baseline in 
BMD at the total hip and femoral neck 
by DXA 
Safety 
• 
To evaluate the safety and tolerability 
of a 6-month treatment with 210 mg 
romosozumab at 90 mg/mL SC QM by 
HCP administration with PFS or by 
subject self-administration with AI/Pen 
• 
Incidence of treatment-emergent 
adverse events, serious adverse 
events, and adverse device effects 
• 
Incidence of subjects developing 
anti-romosozumab antibodies 
• 
Change from baseline in laboratory 
assessments and vital signs 
 
Hypotheses 
The primary hypothesis is that the mean percent change from baseline in lumbar spine 
DXA BMD at Month 6 in subjects (postmenopausal women with osteoporosis) 
self-administering 210 mg romosozumab QM with AI/Pen is not inferior to that in 
subjects receiving 210 mg romosozumab QM by HCP administration with PFS using a 
margin of -2 percentage points.  It is hypothesized that the mean percent change from 
baseline in lumbar spine DXA BMD at Month 6 in subjects who self-administer 210 mg 
romosozumab QM with AI/Pen is the same as that in subjects who receive 210 mg 
romosozumab QM by HCP administration with PFS. 
 
CONFIDENTIAL 
 

Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
Page 10 of 93 
 
Overall Design 
This is a phase 3 randomized, multicenter, open-label, noninferiority study of 
romosozumab in postmenopausal women with osteoporosis.  The study is designed to 
evaluate the noninferiority of a 6-month 210 mg romosozumab SC QM treatment by 
subject self-administration with AI/Pen to HCP administration with PFS. 
After signing the informed consent form (ICF), subjects will undergo the following 
periods: 
• 
Screening period (35 days) to complete eligibility assessments  
• 
Open-label treatment period (6 months)  
• 
Follow-up period (3 months) 
During the open-label treatment period, subjects will be randomized to receive 
romosozumab either via HCP administration with PFS or via self-administration with 
AI/Pen. 
During the follow-up period, subjects will be followed for an additional 3 months to 
ensure appropriate follow-up for anti-romosozumab antibody formation and adverse 
events.   
The primary analysis will be performed after all subjects have had the opportunity to 
complete the Month 6 visit.  The final analysis will be performed after all subjects have 
had the opportunity to complete the Month 9 visit. 
Number of Subjects 
Approximately 260 subjects will be enrolled in the study and randomized 1:1 into the 
following treatment arms to receive 210 mg romosozumab at 90 mg/mL SC QM: 
• 
HCP administration with PFS (approximately 130 subjects) 
• 
Subject self-administration with AI/Pen (approximately 130 subjects) 
Summary of Subject Eligibility Criteria 
The study will enroll ambulatory, postmenopausal women aged ≥ 55 to ≤ 90 years with a 
BMD T-score of ≤ -2.50 at the lumbar spine, total hip, or femoral neck and at least 
2 vertebrae in the L1-L4 region and at least 1 hip, evaluable by DXA.  Eligible subjects 
should also have a history of fragility or at least 2 clinical risk factors for fracture.  
Subjects who have a history of osteonecrosis of the jaw, atypical femoral fracture, or 
metabolic or bone disease (except for osteoporosis) that may interfere with the 
 
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Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
Page 11 of 93 
 
 
CONFIDENTIAL 
 
interpretation of the results will be excluded.  Subjects taking exclusionary medication 
affecting bone metabolism are also excluded.  Other disease-related exclusion criteria 
include vitamin D insufficiency, hyper- or hypothyroidism, or hyper- or 
hypoparathyroidism.   
For a full list of eligibility criteria, please refer to Section 6.1 to Section 6.2. 
Treatments 
During the open-label treatment period, subjects will receive 210 mg romosozumab SC 
QM either by HCP administration with 2 PFS or by self-administration with 2 AI/Pens. 
Procedures 
Written informed consent must be obtained from all subjects before any study‑specific 
screening procedures are performed.  Among the procedures performed, blood samples 
will be collected from subjects for serum chemistry, hematology, bone turnover markers, 
romosozumab levels, and anti-romosozumab antibodies.  Bone mineral density 
assessments will be obtained with DXA at the lumbar spine and proximal femur. 
Serious adverse events and concomitant therapies will be collected during the screening 
period.  During the treatment period through end of study, adverse events, adverse 
device effects, disease-related events, and concomitant therapies will be collected. 
Romosozumab will be administered to the subjects in the PFS arm as the last procedure 
of all applicable visits during the treatment period.  For subjects in the AI/Pen arm, the 
self-administration of the first dose will be performed under the supervision of an HCP as 
the last procedure; for all subsequent doses, AI/Pens will be dispensed to subjects for 
self-administration without HCP supervision and outside of a professional healthcare 
facility.  
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 9.2 and the Schedule of Activities in Table 2-1. 
Statistical Considerations 
The primary analysis to assess the treatment difference between the PFS and AI/Pen 
arms in the percent change from baseline in lumbar spine DXA BMD at Month 6 will 
employ an analysis of covariance model.  The model will have randomized treatment, 
baseline value of BMD, machine type, and interaction of baseline BMD value and 
machine type as prognostic variables.  The lower bound of the one-sided 97.5% CI from 
mean treatment difference for the treatment arms will be compared with the 
noninferiority margin of -2% for assessing noninferiority.  The analysis will include all 

Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
Page 12 of 93 
 
randomized subjects who have a baseline DXA BMD measurement and at least 
1 post-baseline DXA BMD measurement.  Subjects will be analyzed according to their 
randomized treatment assignment, regardless of treatment received. 
To assess the robustness of the analysis for the primary endpoint, a sensitivity analysis 
will be performed using the per protocol analysis subset.  
 
 
The subject incidence of treatment-emergent adverse events and adverse device effects 
will be summarized by actual treatment received.  Laboratory values over time will be 
summarized by actual treatment received.  Laboratory shift tables will be provided and 
will compare baseline laboratory values with most extreme post-baseline values.  
Subject incidence of anti-romosozumab antibodies formation will be tabulated.  These 
safety summaries will use the safety analysis subset, which will include all randomized 
subjects who receive at least 1 dose of investigational product.   
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor Name:  Amgen Inc. 
 
 
CONFIDENTIAL 
 

Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
Page 13 of 93 
 
2. 
Study Schema and Schedule of Activities 
2.1 
Study Schema 
Figure 2-1.  Study Schema 
Subject Self-administration with Autoinjector/Pen
n = 130
Screeninga
Randomization 1:1
Day 1
HCP Administration with Prefilled Syringe
n = 130
M6
Open-label Treatment Period
(210 mg romosozumab SC QM)
Final Analysis/EOS
Follow-up Period
M9
Day -35
Daily calcium and vitamin D supplementation
(at a minimum in the range of 500 to 1000 mg calcium and 600 to 800 IU vitamin D)
Screening 
Period
Site visits for romosozumab dose administration or Autoinjector/Pen dispensation
M1
M2
M3
M4
M5
Primary Analysis
 
EOS = end of study; HCP = healthcare provider; M = month; QM = once a month; SC = subcutaneous 
a Rescreening is permitted only once and only for subjects who fail the serum 25 (OH) vitamin D eligibility criterion. 
 
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Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
Page 14 of 93 
 
 
CONFIDENTIAL 
 
2.2 
Schedule of Activities 
Table 2-1.  Schedule of Activities 
PROCEDURE 
Screening 
Treatment Period 
Follow-up 
Notes 
up to 
35 days 
before 
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/ 
ET 
(-7/+3 days) 
Month 9/ 
EOS 
(-7/+3 days) 
 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical and fracture history  
X 
 
 
 
 
 
 
 
 
 
Medication history 
X 
 
 
 
 
 
 
 
 
 
Instructions for daily calcium 
and vitamin D supplementation 
X 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
 
 
 
X 
 
 
X 
 
 
Physical measurements 
X 
 
 
 
X 
 
 
X 
 
Height and weight 
Vital signs 
X 
 
 
 
X 
 
 
X 
 
BP, heart rate, respiratory 
rate, and temperature 
Substance use 
X 
 
 
 
 
 
 
 
 
Substances: alcohol, tobacco, 
caffeine, other 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serious adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse device effects 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Disease-related events 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant therapies review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Page 1 of 2 
Footnotes defined on last page of the table 
 

Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
Page 15 of 93 
 
 
CONFIDENTIAL 
 
Table 2-1.  Schedule of Activities 
PROCEDURE 
Screening 
Treatment Period 
Follow-up 
Notes 
up to 
35 days 
before 
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/ 
ET 
(-7/+3 days) 
Month 9/ 
EOS 
(-7/+3 days) 
 
LABORATORY ASSESSMENTS (CENTRAL) 
Hematology 
X 
X 
 
 
X 
 
 
X 
 
 
Serum chemistry 
X 
X 
X 
 
X 
 
 
X 
 
 
Serum 25 (OH) vitamin D 
X 
 
 
 
 
 
 
 
 
One rescreen allowed for 
vitamin D levels < 20 ng/mL  
Hepatitis B and C testing 
X 
 
 
 
 
 
 
 
 
 
Serum protein electrophoresis 
X 
 
 
 
 
 
 
 
 
 
Anti-romosozumab antibodya 
 
X 
X 
 
X 
 
 
X 
X 
Collect before romosozumab 
administration 
STUDY-SPECIFIC ASSESSMENTS  
DXA scan: lumbar spine 
X 
 
 
 
 
 
 
X 
 
Perform in duplicate 
DXA scan: proximal femur 
X 
 
 
 
 
 
 
X 
 
 
BIOMARKER ASSESSMENTS 
Bone Turnover Markers 
(sCTX/P1NP) 
 
X 
X 
 
 
 
 
X 
 
Obtain from subjects in fasting 
stageb and before noon  
PHARMACOKINETIC ASSESSMENTS 
Romosozumab levels 
 
X 
X 
 
X 
 
 
X 
 
 
STUDY TREATMENT 
Romosozumab administrationc 
 
PFS armd 
 
X 
X 
X 
X 
X 
X 
 
 
 
AI/Pen arme 
 
X 
X 
X 
X 
X 
X 
 
 
 
Inquiry on treatment 
compliance for previous dose 
 
 
 
X 
X 
X 
X 
X 
 
Collect only from AI/Pen arm 
Page 2 of 2 
Footnotes defined on next page of the table 

Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
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AI/Pen = autoinjector/pen; BP = blood pressure; DXA = dual-energy x-ray absorptiometry; EOS = end of study; ET = early termination; HCP = healthcare provider; 
P1NP = procollagen type 1 N-telopeptide; PFS = prefilled syringe; sCTX = serum type-1 collagen C-telopeptide 
 
a Subjects who test positive for neutralizing antibodies to romosozumab at the EOS or ET visit will be asked to return for anti-romosozumab antibody testing for up to 
1 year after the last investigational product administration.  A longer testing period may be requested in the event of safety concerns. 
b Fasting stage is defined as overnight or, if not possible, a minimum of 8 hours. 
c First dose should be given on day of randomization (or within 72 hours). 
d To be administered by site staff as last procedure of each applicable visit. 
e As last procedure of Day 1 visit, study staff will supervise self-administration of first dose.  At each dosing visit thereafter, the study staff will dispense a single dose 
(1 box of 2 AI/Pens) to each subject for self-administration without HCP supervision and outside of a professional healthcare facility. 
 
 
 
 
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3. 
Introduction 
3.1 
Study Rationale 
Amgen is developing a 90 mg/mL concentration of romosozumab in a 1.17 mL 
deliverable volume (ie, 105 mg romosozumab) to be administered using prefilled syringe 
(PFS), as well as autoinjector/pen (AI/Pen).  Both 90 mg/mL drug product presentations 
(PFS and AI/Pen) will use the same syringe with Crystal Zenith resin barrel as the 
primary container for the drug.  The AI/Pen is a single-use, disposable, handheld, 
“spring-based”, mechanical injection device that administers a fixed dose of 
romosozumab into the subcutaneous (SC) tissue.  Unlike the PFS, the AI/Pen is being 
developed for home use.  Designed with a hidden needle, the AI/Pen may alleviate 
anxiety in patients with needle phobia and potentially decrease the risk of accidental 
needle sticks. 
The purpose of this study is to demonstrate that postmenopausal females with 
osteoporosis can successfully self-administer 210 mg romosozumab at 90 mg/mL once 
a month (QM) with 2 AI/Pens, as measured objectively by the percent change from 
baseline in bone mineral density (BMD) at 6 months.  A comparison will be made with 
subjects receiving healthcare provider (HCP)-administered doses of 210 mg at 
90 mg/mL with 2 PFS. 
Data from this study is anticipated to support noninferiority of the 90 mg/mL 
concentration of romosozumab self-administered by the subject with AI/Pen compared to 
that administered by an HCP with PFS; it will additionally support global regulatory 
approval of the romosozumab AI/Pen. 
3.2 
Background 
3.2.1 
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; according to the World Health Organization’s current definition of 
osteoporosis (BMD T-score ≥ 2.5 standard deviations below the mean for normal 
young 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 (US), Europe, and Japan 
(World Health Organization, 2007).  The morbidity and mortality associated with 
 
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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).  
Approved treatments for postmenopausal women with osteoporosis include inhibitors of 
bone resorption, such as selective estrogen receptor modulators (SERMs, 
eg, raloxifene), bisphosphonates (eg, alendronate [ALN], risedronate, ibandronate, and 
zoledronate), calcitonin, denosumab, or agents that stimulate bone formation like 
teriparatide (the 1‑34 fragment of intact parathyroid hormone [PTH]) (Greenblatt, 2005).  
Antiresorptive therapies prevent osteoclasts from resorbing bone, slowing the 
progression of bone breakdown, increasing BMD, and lowering the risk of vertebral 
fractures (relative risk reduction [RRR]:  40% to 70%) and, to a lesser extent, 
nonvertebral fractures (RRR:  20% to 25%) (Cummings et al, 2009; Black et al, 2007; 
Chestnut et al, 2004; McClung et al, 2001; Chestnut et al, 2000; Ettinger et al, 1999; 
Harris et al, 1999; Cummings et al, 1998; Black et al, 1996).  Osteoporosis is a chronic 
disease; and despite long‑term administration of bisphosphonates, the most commonly 
prescribed class of antiresorptives, postmenopausal women with severe 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.   
In contrast, bone-forming agents can promote larger improvements in bone mass and 
bone strength than 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).  Analogs of PTH (PTH 1-34 
[teriparatide] and PTH 1-84) increase bone remodeling by stimulating both bone 
formation and bone resorption with a net gain in bone mass.  As a result, there is a 
marked improvement in BMD, as well as indices of bone microstructure that are 
associated with improved mechanical strength (Borggrefe et al, 2010).  Teriparatide 
shows a RRR of nonvertebral fractures of approximately 35% to 50% and lowers the risk 
of one or more new vertebral fractures by 65% (Neer et al, 2001).   
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 
to increase bone strength and reduce the risk for fracture, would be a welcome new 
therapeutic option particularly for subjects with significantly compromised bone strength 
at high risk of fracture. 
 
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3.2.2 
Amgen Investigational Product Background:  Romosozumab 
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 (normal and osteoporotic rats, monkeys) (Ominsky et al, 2010a; 
Ominsky et al, 2010b; Li et al, 2009; Li et al, 2007a; Li et al, 2007b).   
Romosozumab is a humanized monoclonal antibody that is designed to bind and inhibit 
sclerostin, thereby promoting osteoblast differentiation and activity.  By inhibiting 
sclerostin, romosozumab has a dual effect on bone, increasing bone formation and 
decreasing bone resorption.  Romosozumab increases trabecular and cortical bone 
mass and improves bone structure and 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 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 markers Procollagen Type 1 
N-telopeptide (P1NP), Osteocalcin, and Bone-Specific Alkaline Phosphatase, and a 
decrease in the bone resorption marker serum type‑1 collagen C‑telopeptide (sCTX).  
Increases in BMD at the lumbar spine, total hip, and femoral neck have also been 
demonstrated by dual-energy x-ray absorptiometry (DXA) and quantitative computed 
tomography (QCT).   
Clinical studies that have been completed include the following:  
• 
A phase 1b ALN-to-romosozumab transition study in postmenopausal women with 
low bone mass who had been receiving ALN or were treatment naïve 
 
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• 
A phase 1b multiple-dose study using peripheral QCT to evaluate the effect of 
romosozumab on parameters of bone quality of the forearm in postmenopausal 
women with low bone mass 
• 
A phase 1 single-dose study in healthy postmenopausal Japanese women 
• 
A phase 1 bioequivalence study to evaluate delivering 90 mg/mL romosozumab SC 
by PFS or AI/Pen in healthy subjects 
• 
A phase 2a multiple-dose fracture-healing study in subjects with tibial diaphyseal 
fractures 
• 
A phase 2 multiple-dose fracture-healing study in subjects with proximal femur 
fractures 
• 
A phase 3 study in postmenopausal women with osteoporosis randomized to either 
12 months of romosozumab or placebo followed by denosumab for 24 months in 
each group  
• 
A phase 3 study in postmenopausal women with osteoporosis to evaluate the 
noninferiority of romosozumab at a 90 mg/mL concentration compared with a 
70 mg/mL concentration  
Ongoing clinical studies include the following: 
• 
A phase 3 fracture study in postmenopausal women with osteoporosis randomized to 
romosozumab for 12 months followed by ALN treatment compared to ALN treatment 
alone  
• 
A phase 3 study in postmenopausal Korean women with osteoporosis randomized to 
either romosozumab or placebo for 6 months  
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
romosozumab is provided in the Investigator’s Brochure. 
For additional information about the romosozumab nonclinical experience and clinical 
experience, refer to the Investigator’s Brochure.   
 
 
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4. 
Objectives, Endpoints and Hypotheses 
4.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
• 
To evaluate the noninferiority of a 
6-month treatment with 210 mg 
romosozumab at 90 mg/mL 
administered subcutaneously (SC) 
once a month (QM) in 
postmenopausal women with 
osteoporosis either by healthcare 
provider (HCP) administration with 
prefilled syringe (PFS) or by subject 
self-administration with 
autoinjector/pen (AI/Pen) 
• 
Percent change from baseline in bone 
mineral density (BMD) at the lumbar 
spine, as assessed by dual-energy 
x-ray absorptiometry (DXA) 
Secondary 
Efficacy 
• 
To evaluate the efficacy of a 6-month 
treatment with 210 mg romosozumab 
at 90 mg/mL SC QM in 
postmenopausal women with 
osteoporosis either by HCP 
administration with PFS or by subject 
self-administration with AI/Pen 
 
• 
Percent changes from baseline in 
BMD at the total hip and femoral neck 
by DXA 
Safety 
• 
To evaluate the safety and tolerability 
of a 6-month treatment with 210 mg 
romosozumab at 90 mg/mL SC QM by 
HCP administration with PFS or by 
subject self-administration with AI/Pen 
• 
Incidence of treatment-emergent 
adverse events, serious adverse 
events, and adverse device effects 
• 
Incidence of subjects developing 
anti-romosozumab antibodies 
• 
Change from baseline in laboratory 
assessments and vital signs 
 
 
 
 
 
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Exploratory 
  
4.2 
Hypotheses 
The primary hypothesis is that the mean percent change from baseline in lumbar spine 
DXA BMD at Month 6 in subjects (postmenopausal women with osteoporosis) 
self-administering 210 mg romosozumab QM with AI/Pen is not inferior to that in 
subjects receiving 210 mg romosozumab QM by HCP administration with PFS using a 
margin of -2 percentage points.  It is hypothesized that the mean percent change from 
baseline in lumbar spine DXA BMD at Month 6 in subjects who self-administer 210 mg 
romosozumab QM with AI/Pen is the same as that in subjects who receive 210 mg 
romosozumab QM by HCP administration with PFS. 
5. 
Study Design 
5.1 
Overall Design 
This is a phase 3 randomized, multicenter, open-label, noninferiority study of 
romosozumab in postmenopausal women with osteoporosis.  The study is designed to 
evaluate the noninferiority of a 6-month 210 mg romosozumab SC QM treatment by 
subject self-administration with AI/Pen to HCP administration with PFS. 
After signing the informed consent form (ICF), subjects will undergo the following 
periods: 
• 
Screening period (35 days) to complete eligibility assessments  
• 
Open-label treatment period (6 months)  
• 
Follow-up period (3 months) 
During the open-label treatment period, subjects will be randomized to receive 
romosozumab either via HCP administration with PFS or via self-administration with 
AI/Pen.  Subjects in the AI/Pen arm will self-administer the first dose on Day 1 under 
HCP supervision; at each dosing visit thereafter, a single dose (1 box of 2 AI/Pens) will 
 
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be dispensed to each subject for self-administration without HCP supervision and 
outside of a professional healthcare facility.   
The following events will be submitted to independent committees for adjudication: 
• 
potential osteonecrosis of the jaw (ONJ) events 
• 
potential cases of atypical femoral fracture (AFF) 
• 
all deaths and serious adverse events that are deemed by the investigator to be of 
potential cardiovascular origin or etiology and serious adverse events with terms 
mapping to a pre-defined preferred term list potentially indicative of cardiovascular 
etiology 
During the follow-up period, subjects will be followed for an additional 3 months to 
ensure appropriate follow-up for anti-romosozumab antibody formation (as detailed in 
Section 9.2.6) and adverse events.   
The primary analysis will be performed after all subjects have had the opportunity to 
complete the Month 6 visit.  The final analysis will be performed after all subjects have 
had the opportunity to complete the Month 9 visit.  
From screening to end of study (EOS), subjects will receive daily calcium and vitamin D 
supplementation that at a minimum should be in the range of 500 to 1000 mg elemental 
calcium and 600 to 800 IU vitamin D.   
The overall study design is described by a study schema in Section 2.1.  The endpoints 
are defined in Section 4.1. 
5.2 
Number of Subjects 
Approximately 260 subjects will be enrolled in the study and randomized 1:1 into the 
following treatment arms to receive 210 mg romosozumab at 90 mg/mL SC QM: 
• 
HCP administration with PFS (approximately 130 subjects) 
• 
Subject self-administration with AI/Pen (approximately 130 subjects) 
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 10.1. 
5.2.1 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
 
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5.2.2 
Number of Sites 
Approximately 30 investigative sites in the United States and Europe will be included in 
the study.  Sites that do not enroll subjects within 3 months of site initiation may be 
closed. 
5.3 
End of Study 
5.3.1 
End of Study Definition 
Primary Completion:  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 purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early. 
The primary completion date is the date when the last subject has completed the 
assessments for the Month 6 visit. 
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination [ET] 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). 
End of Study:  The EOS date is defined as the date when the last subject across all 
sites is assessed or receives an intervention for evaluation in the study (ie, last subject 
last visit).  
5.3.2 
Study Duration for Subjects 
After signing the informed consent, subjects must be randomized within 35 days (or 
within 70 days for subjects who are rescreened).   
After 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 ET visit will be asked to 
return for anti-romosozumab antibody testing for up to 1 year after the last 
investigational product administration.  A longer testing period may be requested in the 
event of safety concerns.   
5.4 
Justification for Investigational Product Dose 
The proposed treatment regimen of 210 mg romosozumab QM for 6 months is expected 
to achieve substantial increases in BMD in subjects who are treatment naïve.  This was 
demonstrated by the observation of substantial increases in BMD at the lumbar spine, 
 
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total hip, and femoral neck during 6 months of romosozumab administration in the 
phase 3 placebo-controlled fracture study, in which BMD increased from baseline of 
9.7 % with 95% CI (7.9%, 10.8%) at the lumbar spine and 4.7 % with 95% CI (3.2%, 
5.5%) at the total hip (Cosman et al, 2016).   
This 210-mg romosozumab QM dosing regimen was also used in another phase 3 
study, in which postmenopausal women with osteoporosis were randomized to either 
romosozumab for 12 months followed by ALN treatment or to ALN treatment alone.  
6. 
Study Population 
The population for the study is postmenopausal women with osteoporosis at high risk for 
fracture who are not currently taking any exclusionary medication affecting bone 
metabolism.  
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)/Interactive Web Response System (IWRS). 
Eligibility criteria will be evaluated during screening.   
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Appendix 3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
6.1 
Inclusion Criteria  
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Subject has provided informed consent/assent prior to initiation of any study-
specific activities/procedures, or subject’s legally acceptable representative has 
provided informed consent prior to any study-specific activities/procedures being 
initiated when the subject has any kind of condition that, in the opinion of the 
Investigator, may compromise the ability of the subject to give written informed 
consent. 
102 
Postmenopausal female (postmenopausal status is defined as no vaginal 
bleeding or spotting for 12 consecutive months prior to screening) 
103 
≥ 55 to ≤ 90 years of age at the time of informed consent 
104 
Ambulatory 
 
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105 
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  
106 
Subject has at least 2 vertebrae in the L1-L4 region evaluable by DXA, as 
assessed by the principal investigator or designee 
107 
Subject has at least 1 hip evaluable by DXA, as assessed by the principal 
investigator or designee 
108 
Subject has history of fragility (ie, osteoporosis-related fracture) or subject meets 
at least 2 of the following clinical risk factors for fracture 
• 
≥ 70 years of age at the time of informed consent 
• 
BMD T-score ≤ -3.00 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  
• 
current smoker   
• 
consumption of ≥ 3 glasses of alcohol a day 
• 
parental history of fragility (ie, osteoporosis-related) fracture 
• 
body weight ≤ 125 pounds/56 kilogram 
109 
Ability to follow and understand instructions and the ability to self-inject, per 
investigator judgement 
6.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply. 
Disease-Related 
201 
History of ONJ and/or AFF  
202 
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 
203 
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) 
204 
Vitamin D insufficiency [defined as serum 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. 
205 
Current hyperthyroidism (unless well controlled on stable antithyroid therapy) by 
subject report or by chart review, per principal investigator evaluation  
206 
Current clinical hypothyroidism (unless well controlled on stable thyroid 
replacement therapy) by subject report or by chart review, per principal 
investigator evaluation  
 
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207 
Current, uncontrolled hyper- or hypoparathyroidism, defined as PTH outside the 
normal range, per subject medical history.  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.   
208 
Current hyper- or hypocalcemia, defined as albumin-adjusted serum calcium 
outside the normal range, as assessed by the central laboratory.  Serum calcium 
levels may be retested once in case of an elevated serum calcium level within 
1.1x the ULN as assessed by the central laboratory 
Other Medical Conditions 
209 
Malignancy, except non-melanoma skin cancers or cervical or breast ductal 
carcinoma in situ within the last 5 years 
210 
Possible diagnosis of multiple myeloma or related lymphoproliferative disorder, 
as assessed by serum protein electrophoresis performed by the central 
laboratory and interpreted by the investigator  
211 
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. 
212 
Positive for Human Immunodeficiency Virus, per subject report or chart review 
Prior/Concomitant Therapy 
213 
Strontium ranelate or fluoride (for osteoporosis): more than 1 month of 
cumulative use within 5 years prior to randomization 
214 
Intravenous (IV) bisphosphonates 
Zoledronic acid:  
− 
any dose received within 3 years prior to randomization 
− 
more than 1 dose received within 5 years prior to randomization 
IV ibandronate or IV pamidronate: 
− 
any dose received within 12 months prior to randomization 
− 
more than 3 years of cumulative use, unless last dose received ≥ 5 years 
prior to randomization 
215 
Dose received within the past 18 months prior to randomization: denosumab or 
any cathepsin K inhibitor, such as odanacatib (MK-0822) 
216 
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 
 
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217 
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 
218 
Dose received within the past 6 months prior to randomization: systemic oral or 
transdermal estrogen or SERMs (up to 1 month of cumulative use is allowed) 
219 
More than 1 month of cumulative use of activated vitamin D3 or vitamin K2 within 
6 months prior to randomization 
220 
Dose received within the past 6 months prior to randomization: hormonal ablation 
therapy (up to 1 month of cumulative use is allowed) 
221 
Dose received within the past 3 months prior to randomization: tibolone, 
calcitonin, or cinacalcet 
222 
Dose received within the past 3 months prior to randomization: systemic 
glucocorticosteroids (≥ 5 mg prednisone equivalent per day for more than 
14 days 
223 
Subject has previously received a sclerostin antibody product within the past 
12 months prior to randomization 
Prior/Concurrent Clinical Study Experience 
224 
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).  
225 
Subject has previously entered this study 
226 
Other investigational procedures while participating in this study are excluded 
Other Exclusions 
227 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 3 months after the last dose of 
romosozumab.   
228 
Subject has known sensitivity to any of the products or components to be 
administered during dosing. 
229 
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. 
230 
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. 
 
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6.3 
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 
committee (IRB/IEC) approval of the protocol, ICF, and all other subject information 
and/or recruitment material, if applicable (see Appendix 3). 
The subject or the subject’s legally acceptable representative must personally sign and 
date the IRB/IEC and Amgen approved informed consent before commencement of 
study-specific 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 (which begins after the 
ICF is signed) receives a unique subject identification number before any study-related 
activities/procedures are performed.  The subject identification number will be assigned 
by the IVRS/IWRS.  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. 
6.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, medical history, prior therapies, and any serious adverse events. 
Individuals who fail to meet the vitamin D entry criteria, ie, subjects with a serum 
25 (OH) vitamin D level < 20 ng/mL may rescreen 1 time.  Subjects who fail any other 
eligibility criteria are not permitted to be rescreened.  
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 will be 
randomized.  While it is possible to repeat the serum 25 (OH) vitamin D test during the 
 
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rescreening period, vitamin D eligibility must be confirmed by the central laboratory and 
the subject must be randomized within the 35-day rescreening window. 
7. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to, or used by a 
study subject according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment shown in Table 7-1 below. 
7.1 
Treatment Procedures 
7.1.1 
Investigational Products 
 
 
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Table 7-1.  Study Treatments 
Study 
Treatment 
Name 
Amgen Investigational Product: 
Romosozumaba in PFS 
Amgen Investigational Product: 
Romosozumaba in AI/Pen 
Dosage 
Formulation 
Romosozumab will be presented in a box containing 2 PFS.  
Each PFS will contain 1.17 mL of 90 mg/mL romosozumab. 
Romosozumab will be presented in a box containing 2 AI/Pens.  
Each AI/Pen will contain 1.17 mL of 90 mg/mL romosozumab. 
Unit Dose 
Strength(s)/ 
Dosage 
Level(s) and 
Dosage 
Frequency 
210 mg QM (2 PFS) 
210 mg QM (2 AI/Pens) 
Route of 
Administration 
SC injection 
SC injection 
Accountability 
The amount administered, date and time of administration, and 
box number of romosozumab are to be recorded on each 
subject's CRF. 
 
The amount dispensed, amount returned, amount 
self-administered (ie, full, partial, none, unknown), date 
dispensed, date returned, the date of self-administration, and 
box number of romosozumab are to be recorded on each 
subject's CRF. 
 
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Product:  Romosozumab 
Protocol Number:  20150120 
Date:  10 August 2017 
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Study 
Treatment 
Name 
Amgen Investigational Product: 
Romosozumaba in PFS 
Amgen Investigational Product: 
Romosozumaba in AI/Pen 
Dosing 
Instructions 
Injections of romosozumab will be administered by an HCP into 
different sites on the subject’s anterior abdominal wall, thigh, or 
upper arm.  The injection should not be administered in the 
same arm from which blood is drawn.  The SC injection must 
be administered as the last procedure after all other study visit 
procedures have been completed.  A physician must be 
available during administration of romosozumab.  It is 
recommended that all subjects be closely observed for 
approximately 30 minutes after dosing.   
The first dose should be administered on the day of 
randomization.  If this is not possible, it must be administered 
within 72 hours of randomization.  All efforts should be made to 
administer romosozumab within the defined study visit 
windows (refer to Table 2-1).  In case of an out-of-window visit, 
romosozumab can be administered ± 2 weeks of the target visit 
date, ie, calculated from the Day 1 visit, as described in 
Section 9.1.2.  If romosozumab cannot be administered 
± 2 weeks of the target visit date, the dose is to be considered 
missed.   
The first dose will be self-administered into the subject’s 
anterior abdominal wall or thigh under the supervision of an 
HCP.  The SC injection must be administered as the last 
procedure after all other study visit procedures have been 
completed.  For all subsequent injections, the subjects will 
self-administer the dose into different sites on their anterior 
abdominal wall or thigh without HCP supervision and outside of 
a professional healthcare facility. 
The first dose should be self-administered on the day of 
randomization.  If this is not possible, it must be self-
administered within 72 hours of randomization.  All efforts 
should be made to dispense and self-administer the 
romosozumab AI/Pens within the defined study visit windows 
(refer to Table 2-1).  In case of an out-of-window visit, 
romosozumab can be dispensed and self-administered 
± 2 weeks of the target visit date, ie, calculated from the Day 1 
visit, as described in Section 9.1.2.  If the romosozumab 
AI/Pens cannot be dispensed and self-administered ± 2 weeks 
of the target visit date, the dose is to be considered missed.   
Device 
PFS 
AI/Pen 
AI/Pen = autoinjector/pen; CRF = case report form; HCP = healthcare provider; PFS = prefilled syringe; QM = once a month; SC = subcutaneous  
a Romosozumab will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug distribution procedures. 
 
 
 
 
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Date:  10 August 2017 
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7.1.2 
Medical Devices 
The investigational medical device(s) provided by Amgen for use in this study are the 
PFS and AI/Pen (Table 7-1). 
The romosozumab AI/Pen is a single-use disposable, handheld, “spring-based”, 
mechanical injection device for the SC injection of a fixed dose of 105 mg in a 1.17 mL 
deliverable volume.  A full dose of 210 mg comprises 2 AI/Pens. 
The romosozumab PFS is a single-use, disposable, handheld manual injection device 
for the SC injection of a fixed dose of 105 mg in a 1.17 mL deliverable volume.  A full 
dose of 210 mg comprises 2 PFS. 
Additional details are provided in the IPIM. 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
Non-investigational medical 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. 
7.1.3 
Other Protocol-required Therapies 
Other protocol-required therapies (calcium and vitamin D supplements) that are 
commercially available are not provided but will be reimbursed by Amgen.  The 
investigator will be responsible for obtaining supplies of these protocol-required 
therapies. 
From screening to EOS, subjects will receive daily calcium and vitamin D 
supplementation that, at a minimum, should be in the range of 500 to 1000 mg elemental 
calcium and 600 to 800 IU vitamin D.   
Where available, vitamin D3 preparations should be used; if vitamin D3 is not available, 
use of vitamin D2 preparations is acceptable. 
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.   
 
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Date:  10 August 2017 
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If a subject is unable to tolerate the daily calcium or vitamin D supplementation, the 
formulation may be changed or the dose lowered.  The intolerance as well as the 
resolution (ie, change in formulation or dosage) should be documented in the subject 
chart. 
Additional details regarding these protocol-required therapies are provided in the IPIM. 
7.1.4 
Other Treatment Procedures 
This is not applicable to this study.   
7.1.5 
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. 
This includes any drug(s), device(s) or combination product(s) provisioned and/or 
repackaged/modified by Amgen.  Drug(s) or device(s) include romosozumab, PFS, and 
AI/Pen.   
Any product complaint(s) associated with an investigational product(s), 
non-investigational product(s), device(s), or drug-device combination product(s) supplied 
by Amgen are to be reported according to the instructions provided in the IPIM. 
7.1.6 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Medications listed below will be proscribed during the study, as these medications are 
known or suspected to affect bone metabolism: 
• 
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) 
• 
IV 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) 
 
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Date:  10 August 2017 
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• 
SERMs (cumulative dosing regimens of ≤ 1 month are acceptable) 
• 
calcitonin (cumulative dosing regimens of ≤ 1 month are acceptable) 
• 
tibolone (cumulative dosing regimens of ≤ 1 month are acceptable) 
• 
cinacalcet 
• 
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) 
• 
hormonal ablation therapy 
If a subject discontinues the investigational product 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). 
7.2 
Method of Treatment Assignment 
Subjects will be randomized in a 1:1 allocation ratio to either the PFS or AI/Pen arm in 
an open-label manner on a randomization schedule prepared by the Amgen Global 
Randomization and Blinding Group before the start of the study.  
The randomization will be performed by IVRS/IWRS, and the randomization number will 
be provided through the IVRS/IWRS.   
A subject may only be randomized once, and each randomization number may only be 
assigned once.  A subject will be considered enrolled once a randomization number is 
assigned by the IVRS/IWRS. 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF. 
7.3 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
7.4 
Dose Modification 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
7.4.1.1 
Amgen Investigational Product:  Romosozumab 
No dosing adjustments for romosozumab will be permitted. 
For subjects in the PFS arm, all efforts should be made to administer romosozumab 
within the defined study visit windows (refer to Table 2-1).  In case of an out-of-window 
visit, romosozumab can be administered ± 2 weeks of the target visit date, ie, calculated 
 
CONFIDENTIAL 
 

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Date:  10 August 2017 
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from the Day 1 visit.  If romosozumab cannot be administered ± 2 weeks of the target 
visit date, the dose is considered missed. 
For subjects in the AI/Pen arm, all efforts should be made to dispense and 
self-administer the romosozumab AI/Pens within the defined study visit windows (refer to 
Table 2-1).  In case of an out-of-window visit, AI/Pens can be dispensed and 
self-administered ± 2 weeks of the target visit date, ie, calculated from the Day 1 visit.  If 
AI/Pens cannot be dispensed and self-administered ± 2 weeks of the target visit date, 
the dose is to be considered missed.  
7.4.2 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Appendix 7 for details regarding drug-induced liver injury (DILI) guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009.  
7.5 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product, other protocol-required therapies, or devices 
during the study are provided in the IPIM for site staff and the Instructions for Use (IFU) 
document for subjects. 
7.6 
Treatment Compliance 
Subjects in the AI/Pen arm will be asked to bring in all used and unused packages 
dispensed for their unsupervised self-administration at their next site visit (ie, Month 2, 3, 
4, 5, and 6 visits) in a plastic box provided by Amgen.  In the case that the subject 
forgets, he or she should be advised to bring them in at the following site visit.  The 
investigational site staff will count the number of used and unused AI/Pens.  The amount 
dispensed, amount returned, the amount self-administered (ie, full, partial, none, 
unknown), date dispensed, date returned, the date of self-administration, and box 
number of romosozumab are to be recorded on each subject's CRF.   
7.7 
Treatment of Overdose 
Overdose with this product has not been reported.  Neither the effects of overdose of 
romosozumab nor an antidote to overdose are 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 
 
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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.   
7.8 
Prior and Concomitant Treatment 
7.8.1 
Prior Treatment 
Prior therapies affecting bone metabolism that were being taken/used from 5 years prior 
to screening through randomization will be collected.  The therapy name, indication, 
dose, unit, frequency, start date, and stop date will be recorded.   
For the following prior therapies, collect whether the therapy was being taken before 
screening through randomization: therapies for cardiovascular conditions.  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.   
7.8.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 7.1.6. 
Concomitant therapies are to be collected from randomization through EOS.  For 
concomitant therapies, collect therapy name, indication, dose, unit, frequency, start date, 
and stop date.     
8. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Sections 8.1, 8.2.1, and 8.2.2. 
8.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
 
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Date:  10 August 2017 
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investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (see Table 2-1) 
including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints, adverse events, 
disease-related events, and device-related events, as applicable and must document 
this decision in the subject’s medical records.  Subjects who have discontinued 
investigational product and/or other protocol-required therapies or procedures should not 
be automatically removed from the study.  Whenever safe and feasible, it is imperative 
that subjects remain on-study to ensure safety surveillance and/or collection of outcome 
data. 
Subjects may be eligible for continued treatment with Amgen investigational product(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 Appendix 3. 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
• 
Decision by sponsor 
• 
Lost to follow-up 
• 
Death 
• 
Ineligibility determined 
• 
Protocol deviation 
• 
Non-compliance  
• 
Adverse event 
• 
Subject request 
• 
Requirement for alternative therapy 
• 
Pregnancy 
8.2 
Discontinuation From the Study 
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, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
 
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subject appropriate procedures for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical records.   
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Appendix 6 for further details).  Refer to the Schedule of Activities for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
8.2.1 
Reasons for Removal From Washout, Run-in, or Invasive 
Procedures 
This is not applicable to this study. 
8.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
Decision by sponsor 
• 
Withdrawal of consent from study 
• 
Death 
• 
Lost to follow-up 
8.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to and/or 
is able to continue in the study. 
• 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and, if necessary, a certified letter to the subject’s last 
known mailing address or local equivalent methods).  These contact attempts are 
to be documented in the subject’s medical record. 
• 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
• 
For subjects who are lost to follow-up, the investigator can search publicly 
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. 
 
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9. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 2-1).  
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
9.1 
General Study Periods 
9.1.1 
Screening, Enrollment and/or Randomization 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject has 
signed the ICF, the site will register the subject in the IVRS/IWRS and screen the subject 
in order to assess eligibility for participation.  Screening procedures may be performed 
on multiple days but must be completed within a 35-day screening window. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  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.  
Rescreen subjects must first be registered as screen failures in IVRS/IWRS and 
subsequently registered as rescreens on the same day.  Subjects not entered into the 
IVRS/IWRS as a rescreen will not be eligible for randomization.  Once the subject is 
registered as rescreened, a new 35-day screening window will begin.  Subjects will 
retain the same subject identification number assigned at the original screening.   
 
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9.1.1.1 
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 lumbar vertebrae and at least 
1 proximal femur, evaluable by DXA (as determined by the principal investigator or 
designee). 
9.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 2-1) during the treatment period 
from Day 1 through Month 6.   
Day 1 is defined as the date on which the first dose of romosozumab 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. 
For subjects in the PFS arm, romosozumab is to be administered as the last procedure 
during each dosing visit.  Subjects in the AI/Pen arm will self-administer their first dose 
under HCP supervision as the last procedure of their Day 1 visit; at each dosing visit 
thereafter, a single dose will be dispensed to each subject for self-administration without 
HCP supervision and outside of a professional healthcare facility.     
Subjects who discontinue the study before the Month 6 visit should undergo all the 
procedures for the Month 6 visit, as indicated in the Schedule of Activities (Table 2-1). 
 
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9.1.3 
Safety Follow-up 
Upon permanent discontinuation from the study treatment for any reason, a safety 
follow-up visit will be performed approximately 30 (+3) days after the end of the last 
dosing interval of investigational product. 
9.1.4 
End of Study 
The EOS visit is the Month 9 visit.  Subjects will return to the site for the EOS visit for the 
procedures specified in the Schedule of Activities (Table 2-1). 
9.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
9.2.1 
General Assessments  
9.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent before any study-specific procedures are 
performed. 
9.2.1.2 
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.   
9.2.1.3 
Medical History 
The Investigator or designee will collect a complete medical history that started prior to 
screening through administration of the first dose of romosozumab.  Medical history will 
include information on the subject's prior or current medical conditions.  Record all 
findings on the medical history CRF.  
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 romosozumab.  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. 
9.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
 
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9.2.1.5 
Physical Measurements 
Height in centimeters should be measured without shoes.  Weight in kilograms should 
be measured without shoes. 
9.2.1.6 
Substance Abuse History  
Obtain a detailed history of prior and/or concurrent use of alcohol, tobacco, caffeine, or 
other.  
9.2.2 
Efficacy Assessments 
9.2.2.1 
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 the 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 
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 CD or other media as 
specified in the DXA Procedural Manual, but electronic submission is preferred.   
After analysis by the central imaging vendor, the study site may be asked to re-acquire a 
scan due to malpositioning or other technical reasons.  The investigative sites must 
comply with the requests from the central imaging vendor.  Repeat scans must be 
performed as soon as possible after the request is received.   
9.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities. 
 
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9.2.3.1 
Adverse Events 
9.2.3.1.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
9.2.3.1.1.1 
Disease-related Events 
Disease-related events are defined in Appendix 4. 
The investigator is responsible for ensuring that all disease-related events observed by 
the investigator or reported by the subject that occur after the first dose of investigational 
product(s)/study treatment/protocol-required therapies through EOS are reported using 
the Event CRF.   
Disease-related events assessed by the investigator to be more severe than expected 
and/or related to the investigational product(s)/study treatment/protocol-required 
therapies, and determined to be serious, must be reported on the Event CRF as serious 
adverse events. 
Disease-related events pre-defined for this study include: fractures (serious or 
non-serious), as they are anticipated to occur in the study population due to the 
underlying disease. 
9.2.3.1.1.2 
Adverse Events 
The adverse event grading scale to be used for this study will be the Common 
Terminology Criteria for Adverse Events (CTCAE) and is described in Appendix 4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of investigational 
product(s) through EOS are reported using the Event CRF. 
9.2.3.1.1.3 
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 EOS, ET, or 30 days after the last dose of investigational product 
(whichever is longer) are reported using the Event CRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours, as indicated in Appendix 4.  The investigator will submit any 
updated serious adverse event data to the sponsor within 24 hours of it being available. 
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. 
 
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9.2.3.1.1.4 
Adverse Events and Serious Adverse Events Requiring Adjudication 
The following events will be submitted to independent committees for adjudication: 
• 
potential ONJ events 
• 
potential cases of AFF 
• 
all deaths and serious adverse events that are deemed by the investigator to be of 
potential cardiovascular origin or etiology and serious adverse events with terms 
mapping to a pre-defined preferred term list potentially indicative of cardiovascular 
etiology  
9.2.3.1.1.5 
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.  Per local requirements in some countries, 
investigators are required to report serious adverse events that they become aware of 
after EOS.  If serious adverse events are reported, the 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 and handled accordingly based 
on relationship to investigational product.  
The method of recording, evaluating, and assessing causality of adverse events, 
adverse device effects, disease-related events, and serious adverse events and the 
procedures for completing and transmitting serious adverse event reports are provided 
in Appendix 4. 
9.2.3.1.2 
Method of Detecting Adverse Events and Serious Adverse Events 
As a means to not introduce bias when detecting adverse events and/or serious adverse 
events, open-ended and non-leading verbal questioning of the subject is the preferred 
method to inquire about adverse event occurrence. 
9.2.3.1.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 8.3).  
Further information on follow-up procedures is given in Appendix 4. 
 
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All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
9.2.3.1.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
9.2.3.1.5 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects will be collected after the 
start of study treatment and until 3 months after the end of treatment with romosozumab. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in Appendix 5.  
Amgen Global Patient Safety will follow-up with the investigator regarding additional 
information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
 
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Further details regarding pregnancy and lactation are provided in Appendix 5. 
9.2.3.1.6 
Adverse Device Effects 
In order to fulfill regulatory reporting obligations worldwide, the investigator is 
responsible for the detection and documentation of any adverse device effects that occur 
during the study with such devices.  
An adverse device effect is any adverse event related to the use of a combination 
product or medical device.  Adverse device effects include adverse events resulting from 
insufficient or inadequate 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. 
All adverse device effects are to be reported as adverse events following the same 
reporting periods and procedures in the event CRF. 
Product complaints are described in Section 7.1.5. 
Further details regarding adverse device effects can be found in Appendix 4. 
9.2.3.2 
Vital Signs 
The following measurements must be performed: systolic/diastolic blood pressure, 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 blood pressure assessments are conducted.  
If the subject is unable to be in the supine position, the subject should be in the most 
recumbent position as possible.  The position selected for a subject should be the same 
as that is used throughout the study and documented on the vital sign CRF.  
The temperature location selected for a subject should be the same as that is used 
throughout the study and documented on the vital signs CRF.  Record all measurements 
on the vital signs CRF. 
9.2.4 
Clinical Laboratory Assessments 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities for the timing and frequency.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.  The investigator 
must determine 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) 
 
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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 in the event CRF. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities.  
9.2.4.1 
Pregnancy Testing 
Pregnancy testing is not relevant to this study because the study population is 
postmenopausal women with osteoporosis. 
9.2.4.2 
Hepatitis B and C Testing 
Hepatitis testing will be performed at initial screening to confirm subject eligibility.  
Subjects should be excluded if they have a positive HepBsAg or if PCR is positive for 
hepatitis B or hepatitis C virus.  Hepatitis testing will be performed by the central 
laboratory. 
The following laboratory testing will be performed: 
• 
HepBsAg and total HepBcAb 
• 
Hepatitis B Virus DNA Real-Time PCR will be only performed if total HepBcAb is 
positive and HepBsAg is negative 
• 
Hepatitis C virus antibody 
• 
Hepatitis C Virus RNA Real-Time PCR will be only performed if hepatitis C virus 
antibody is positive 
9.2.4.3 
Prespecified Biomarker Assessments 
Subjects will have blood drawn at visits specified in the Schedule of Activities (Table 2-1) 
for analysis of bone turnover markers (BTMs), P1NP and sCTX.   
Blood draws for BTMs must be obtained from subjects in fasting stage and before noon.  
Fasting stage is defined as overnight fasting.  If overnight fasting is not feasible, a 
minimum of 8 hours fasting is required. 
9.2.5 
Pharmacokinetic Assessments 
All subjects will have pharmacokinetic samples assessed. 
Whole blood samples of approximately 5 mL per each applicable visit will be collected 
for measurement of serum concentrations of romosozumab as specified in the Schedule 
of Activities (Table 2-1).  Instructions for the collection and handling of biological 
samples will be provided by the sponsor.  The actual date and time (24-hour clock time) 
of each sample will be recorded.   
 
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9.2.6 
Antibody Testing Procedures 
Blood sample(s) for antibody testing are to be collected according to the time points 
specified in the Schedule of Activities (Table 2-1) 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.  
Additional blood samples may be obtained to rule out anti-romosozumab antibodies 
during the study. 
Subjects who test positive for neutralizing antibodies to romosozumab at the final 
scheduled study visit defined as the EOS 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, every month) 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 Activities (Table 2-1), as applicable, for specific time points, and the 
laboratory manual for detailed collection and handling instructions. 
10. 
Statistical Considerations 
10.1 
Sample Size Determination 
The noninferiority margin is calculated on the basis of the comparison of 210 mg QM 
romosozumab at a 90 mg/mL concentration administered by an HCP using PFS with 
placebo on percent change from baseline in lumbar spine at Month 6 in postmenopausal 
women with low bone mass (Study 20120156). 
 
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  This result assumes a 5% dropout 
rate during the 6-month treatment period, no expected difference in mean percent 
changes in lumbar spine DXA BMD from baseline at Month 6 between the 2 groups, and 
a common standard deviation of 4.3 percentage points.   
10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
10.2.1.1 
Full Analysis Set 
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.   
10.2.1.2 
Primary Efficacy Analysis Subset 
The primary efficacy analysis subset will include all randomized subjects who have a 
baseline lumbar spine DXA BMD measurement and at least 1 post-baseline lumbar 
spine DXA BMD measurement.  Data from subjects in this subset will be analyzed 
according to randomized treatment groups, regardless of treatment received. 
 
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10.2.1.3 
Hip Bone Mineral Density Efficacy Analysis Subset 
The hip BMD analysis subset will include all randomized subjects who have a baseline 
hip DXA BMD measurement and at least 1 post-baseline hip DXA BMD measurement.  
Data from subjects in this subset will be analyzed according to randomized treatment 
groups, regardless of treatment received. 
10.2.1.4 
Safety Analysis Subset 
The safety analysis subset will include all randomized subjects who receive at least 
1 dose of investigational product.  These subjects will be analyzed according to their 
actual treatment received, such that subjects who received at least 1 dose of the 
romosozumab self-administration by AI/Pen will be analyzed in the romosozumab 
self-administration by AI/Pen treatment group, regardless of the randomized treatment. 
10.2.1.5 
Per Protocol Analysis Subset 
A per protocol analysis for the primary efficacy endpoint will also be implemented and be 
considered supportive to the primary analysis based on the primary efficacy analysis 
subset.  The per protocol analysis subset will include all subjects in the primary efficacy 
analysis subset who received 5 of the 6 planned doses and who had no important 
protocol deviations through Month 6.  Subjects who received the incorrect treatment 
(compared to their randomized treatment) at any time point will be excluded from this 
subset.  The important protocol deviations will be defined in the Statistical Analysis Plan 
and will be identified prior to the primary analysis.  Subjects will be analyzed according 
to their randomized treatment group.   
10.2.2 
Covariates 
All analyses assessing treatment effect of BMD will include randomized treatment, 
baseline BMD at the same body site as the endpoint, machine type, and interaction 
between baseline BMD and machine type as prognostic variables in the model.   
10.2.3 
Subgroups 
No subgroups will be evaluated in this study.   
10.2.4 
Handling of Missing and Incomplete Data 
Subjects may have missing specific data points for a variety of causes.  In general, data 
may be missing due to a subject’s early withdrawal from study, a missed visit, or 
non-evaluability of a specific clinical measurement at its planned clinical visit.  Unless 
specified, no imputation will be used.  The general procedures outlined below describe 
the procedures when a data point is missing.   
 
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10.2.4.1 
DXA BMD Endpoints 
Missing baseline values for endpoints by DXA at any anatomical site will not be imputed.  
Sensitivity analysis accounting for missing data will be described in the statistical 
analysis plan.   
10.2.4.2 
Bone Turnover Markers 
Missing bone turnover maker (either baseline or post-baseline values) will not be 
imputed.  Any values below the lower limit of quantification (LLOQ) will be imputed using 
the LLOQ for analysis.  
10.2.4.3 
Laboratory Parameters 
Lab parameters with values below the LLOQ or above the upper limit of quantification 
(ULOQ) will be imputed as the LLOQ or ULOQ value, respectively 
10.3 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock.  Below 
is a summary of the timing and methods for the planned statistical analyses.  To 
preserve study integrity, the final analysis will be conducted and reported following EOS, 
as defined in Section 5.3.1. 
10.3.1 
Planned Analyses 
10.3.1.1 
Interim Analysis and Early Stopping Guidelines 
No interim analyses or sample size re-estimation are planned for this study.   
10.3.1.2 
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 noninferiority of the effect of self-administering 210 mg romosozumab QM via AI/Pen 
compared with the effect of 210 mg romosozumab QM administered by HCP via PFS in 
postmenopausal women with osteoporosis with respect to percent change from baseline 
in DXA BMD of lumbar spine at Month 6.  Formal statistical testing will be conducted to 
evaluate the following hypothesis: the mean percent change from baseline in lumbar 
spine DXA BMD at Month 6 in subjects self-administering 210 mg romosozumab QM 
with AI/Pen is not inferior to that in subjects receiving 210 mg romosozumab QM by HCP 
administration with PFS using a margin of -2 percentage points.  The lower bound of the 
one-sided 97.5% CI from mean treatment difference for the treatment arms will be 
compared with the noninferiority margin of -2% for assessing noninferiority. 
 
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Secondary objectives of the primary analysis include the evaluation of the efficacy of 
self-administration of 210 mg romosozumab QM by AI/Pen and HCP administration of 
210 mg romosozumab QM by PFS on the following: 
• 
percent change from baseline in DXA BMD of total hip and femoral neck at 
Month 6 
 
 
Safety objectives of the primary analysis include the comparison of safety and tolerability 
of self-administration of 210 mg romosozumab QM by AI/Pen and HCP administration of 
210 mg romosozumab QM by PFS on the following: 
• 
subject incidence of treatment-emergent adverse events 
• 
subject incidence of the formation of anti-romosozumab antibodies 
• 
change from baseline in laboratory assessments and vital signs 
The focus of the safety statistical analyses will be estimation.  No formal statistical 
testing will be performed.  
10.3.1.3 
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. 
The primary objective of the final analysis is the safety objective, ie, the comparison of 
the safety and tolerability of a 6-month treatment with 210 mg romosozumab at 
90 mg/mL QM by HCP administration with PFS or by subject self-administration with 
AI/Pen. 
The focus of the safety statistical analyses will be estimation.  No formal statistical 
testing will be performed.  
 
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10.3.2 
Methods of Analyses 
10.3.2.1 
General Considerations 
For computation of change from baseline endpoints, baseline will be taken as the 
observation recorded just prior to first dose of investigational product.  In the case in 
which 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.   
10.3.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
The primary analysis to assess the percent change from baseline in 
dual-energy x-ray absorptiometry (DXA) bone mineral density (BMD) 
at lumbar spine at Month 6 will employ an analysis of covariance 
(ANCOVA) model.  The ANCOVA model will include randomized 
treatment, baseline value of BMD, machine type, and interaction of 
baseline BMD value and machine type as prognostic 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 HCP-administered 
210 mg romosozumab by PFS and self-administered 210 mg 
romosozumab by AI/Pen.   
Conclusions for the primary efficacy hypothesis of efficacy of 
self-administration of romosozumab by AI/Pen compared with 
HCP-administered romosozumab by PFS at lumbar spine BMD at 
Month 6 will be made using a 1-sided test with type 1 error rate of 
0.025 and noninferiority margin of -2.0%.  The primary efficacy 
analysis set will be used to for the primary analysis.  A sensitivity 
analysis using the per protocol analysis subset will be performed. 
 
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Secondary 
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 prognostic 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 self-administration of 
romosozumab by AI/Pen and HCP-administered romosozumab by 
PFS.  The hip BMD efficacy analysis subset will be used to for these 
analyses. 
 
10.3.2.3 
Safety Analyses 
10.3.2.3.1 
Adverse Events and Disease-related Events 
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, 
adverse events leading to withdrawal from investigational product or other protocol-
required therapies, and significant treatment-emergent adverse events will also be 
provided.  Subject incidence of disease-related events, fatal disease-related events, and 
adverse device effects, if applicable, will be tabulated by system organ class and 
preferred term.  The subject incidence of treatment-emergent adverse events and 
adverse device effects will be summarized by actual treatment received.   
10.3.2.3.2 
Laboratory Test Results 
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.   
10.3.2.3.3 
Vital Signs 
The analyses of vital signs will include summary statistics over time by treatment group.   
 
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10.3.2.3.4 
Physical Measurements 
The analyses of physical measurements will include summary statistics over time by 
treatment group.   
10.3.2.3.5 
Antibody Formation 
The incidence and percentage of subjects who develop anti-romosozumab antibodies 
(binding and, if positive, neutralizing) at any time will be tabulated by treatment group. 
10.3.2.3.6 
Exposure to Investigational Product 
Compliance with investigational product will be summarized for each subject using 
descriptive statistics 
 
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11. 
References 
Balemans W, Ebeling M, Patel N, et al.  Increased bone density in sclerosteosis is due 
to the deficiency of a novel secreted protein (SOST).  Hum Mol Genet.  
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Black DM, Delmas PD, Eastell R, et al.  Once-yearly zoledronic acid for treatment of 
postmenopausal osteoporosis.  N Engl J Med.  2007;356(18):1809-1822. 
Black DM, Cummings SR, Karpf DB, et al.  Randomised trial of effect of alendronate on 
risk of fracture in women with existing vertebral fractures.  Fracture Intervention Trial 
Research Group.  Lancet.  1996;348:1535-1541. 
Borggrefe J, Graeff C, Nickelsen TN, Marin F, Glüer CC.  Quantitative computed 
tomographic assessment of the effects of 24 months of teriparatide treatment on 3D 
femoral neck bone distribution, geometry, and bone strength: results from the 
EUROFORS study.  J Bone Miner Res.  Mar 2010;25(3):472-481. 
Brunkow ME, Gardner JC, Van Ness J, et al.  Bone dysplasia sclerosteosis results from 
loss of the SOST gene product, a novel cystine knot-containing protein.  Am J Hum 
Genet.  2001;68(3):577-589. 
Canalis E.  Update in new anabolic therapies for osteoporosis.  J Clin Endocrinol Metab.  
2010;95(4):1496-1504. 
Chestnut III CH, Skag A, Christiansen C, et al.  Effects of oral Ibandronate administered 
daily or intermittently on fracture risk in postmenopausal Osteoporosis.  J Bone Miner 
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Chestnut III CH, Silverman S, Andriano K, et al.  A randomized trial of nasal spray 
salmon calcitonin in postmenopausal women with established osteoporosis: the prevent 
recurrence of osteoporotic fractures study (PROOF).  PROOF Study Group.  Am J Med.  
2000;109:267-276. 
Cosman F, Crittenden DB, Adachi JD, et al.  Romosozumab Treatment in 
Postmenopausal Women with Osteoporosis.  N Engl J Med. 
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Cree MW, Juby AG, Carriere KC.  Mortality and morbidity associated with osteoporosis 
drug treatment following hip fracture.  Osteoporos Int.  2003;14(9):722-727. 
Cummings SR, San Martin J, McClung MR, et al.  Denosumab for prevention of 
fractures in postmenopausal women with osteoporosis.  N Engl J Med.  
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Cummings SR, Black DM, Thompson DE, et al.  Effect of alendronate on risk of fracture 
in women with low bone density but without vertebral fractures: results from the Fracture 
Intervention Trial.  JAMA.  1998;280(24):2077-2082. 
Ettinger B, Black DM, Mitlak BH, et al.  Reduction of vertebral fracture risk in 
postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year 
randomized clinical trial.  Multiple Outcomes of Raloxifene Evaluation (MORE) 
Investigators.  JAMA.  1999;282(7):637-645. 
Greenblatt D.  Treatment of postmenopausal osteoporosis.  Pharmacotherapy.  
2005;25(4):574-584. 
Hamersma H, Gardner J, Beighton P.  The natural history of sclerosteosis.  Clin Genet.  
2003;63(3):192-197. 
 
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Harris ST, Watts NB, Genant HK, et al.  Effects of risedronate treatment on vertebral and 
nonvertebral fractures in women with postmenopausal osteoporosis: a randomized 
controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group.  
JAMA.  1999;282(14):1344-1352. 
Kanis JA, Dawson A, Oden A, Johnell O, De Laet C, Jonsson B.  Cost-effectiveness of 
preventing hip fracture in the general female population.  Osteoporosis Int.  
2001a;12;356-362. 
Kanis JA, Oden A, Johnell O, Jonsson B, de Laet C, Dawson A.  The burden of 
osteoporotic fractures: a method for setting intervention thresholds.  Osteoporosis Int.  
2001b;12;417-427. 
Li X, Ominsky MS, Warmington KS, et al.  Sclerostin antibody treatment increases bone 
formation, bone mass, and bone strength in a rat model of postmenopausal 
osteoporosis.  J Bone Miner Res.  2009;24(4):578-588. 
Li X, Warmington KS, Niu Q, et al.  Bone formation without increasing bone resorption in 
aged male rats.  J Bone and Mineral Res.  2007a;22(suppl.1):S36.   
Li X, Warmington KS, Niu QT, et al.  Treatment with an anti-sclerostin antibody directly 
stimulates bone formation in a dose-dependent manner in ovariectomized rats with 
established osteopenia.  J Bone Miner Res.  2007b;22(Suppl 1):S65. 
McClung MR, Geusens P, Miller PD, et al.  Effect of risedronate on the risk of hip 
fracture in elderly women (HIP Study).  Hip Intervention Program Study Group.  N Engl J 
Med.  2001;344(5):333-340. 
Neer RM, Arnaud CD, Zanchetta JR, et al.  Effect of parathyroid hormone (1-34) on 
fractures and bone mineral density in postmenopausal women with osteoporosis.  
N Engl J Med.  2001;344(19):1434-1441. 
NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and 
Therapy.  Osteoporosis prevention, diagnosis, and therapy.  JAMA.  2001;285:785-795. 
Ominsky MS, Li CY, Li X, et al.  Inhibition of sclerostin by monoclonal antibody enhances 
bone healing and improves bone density and strength of non-fractured bones.  J Bone 
Miner Res.  Published online December 2, 2010a;doi:10.1002/jbmr.307. 
Ominsky MS, Niu QT, Kurimoto P, Ke HZ.  Tissue level mechanism of increased bone 
formation by sclerostin antibody in male cynomolgus monkeys.  J Bone Miner Res.  
2010b:25(Suppl 1):S53. 
Papapoulos S, Makras P.  Selection of antiresorptive or anabolic treatments for 
postmenopausal osteoporosis.  Nature Clin Practice Endocrinology & Metabolism.  
2008;4(9) 514-523. 
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.  2006;38(2 
suppl 1):S4-S9. 
Romosozumab (AMG 785) Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc. 
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. 
 
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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.  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. 
World Health Organization.  Assessment of fracture risk and its application to screening 
for postmenopausal osteoporosis.  World Health Organization.  Geneva, Switzerland.  
1994:1-129. 
 
 
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12. 
Appendices 
 
 
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Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
AI/Pen 
Autoinjector/pen  
ALN 
alendronate 
ALP 
alkaline phosphatase  
ALT 
alanine aminotransferase  
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase  
BMD 
bone mineral density 
BTM 
bone turnover marker 
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 the date when the last subject is assessed or 
receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study (eg, 
long-term follow-up), as applicable 
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 
EOS 
end of study 
ET 
early termination 
GCP 
Good Clinical Practice  
HCP 
Healthcare provider 
HepBcAb 
total hepatitis B core antibody 
HepBsAg 
Hepatitis B Surface Antigen  
HRT 
hormonal replacement therapy 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
INR 
international normalized ratio 
 
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Abbreviation or Term 
Definition/Explanation 
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.  
Interactive Web Response 
System (IWRS) 
web based technology that is linked to a central computer in real 
time as an interface to collect and process information  
IPIM 
Investigational Product Instruction Manual  
IRB/IEC 
institutional review board/independent ethics committee 
IV 
intravenous  
LLOQ 
lower limit of quantitation 
P1NP 
procollagen type 1 N-telopeptide 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic 
PFS 
prefilled syringe  
PTH 
parathyroid hormone  
QM 
once a month 
RRR 
relative risk reduction 
SC 
subcutaneous 
sCTX 
serum type-1 collagen C-telopeptide 
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. 
TBL 
total bilirubin  
ULN 
upper limit of normal  
 
 
 
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Appendix 2.  Clinical Laboratory Tests 
The tests for all applicable screening and all on-study blood samples detailed in 
Table 12-1 will be performed by the central laboratory.  Depending on the assessment, 
the central laboratory will be responsible for either performing the assays or shipping 
samples to Amgen or a specialty laboratory for assay.  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 will 
either 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 investigative product 
administration, when applicable, at the time points outlined in the Schedule of Activities 
(Table 2-1).  Blood samples for the assessments of BTMs must be obtained from 
subjects in fasting state, as indicated in Section 9.2.4.3.  The date and time of blood 
collection will be recorded in the subject’s medical record.   
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 6.1 to 6.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
 
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Table 12-1.  Analyte Listing 
Central Laboratory 
Serum Chemistry 
Hematology 
BTM 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Albumin-adjusted calcium 
Magnesium 
Phosphorus 
Glucose 
Blood urea nitrogen 
Creatinine 
TBL 
ALP 
ALT (SGPT) 
AST (SGOT) 
Red blood cell 
Hemoglobin 
Platelets 
White blood cell 
Differential 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
P1NP 
CTX 
Romosozumab levels 
25 (OH) vitamin D 
Anti-romosozumab 
antibody 
HepBsAg 
HepBcAb 
Hepatitis C virus antibody 
PCR for hepatitis Ba 
PCR for hepatitis Cb 
Serum protein 
electrophoresis 
ALP = alkaline phosphatase; ALT (SGOT) = alanine aminotransferase (serum glutamic pyruvic 
transaminase); AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
BTM = bone turnover marker; CTX = serum type-I collagen C-telopeptide; HepBsAg = hepatitis B surface 
antigen; HepBcAb = total hepatitis B core antibody; PCR = polymerase chain reaction; P1NP = procollagen 
type 1 N-telopeptide; TBL = total bilirubin 
 
a Hepatitis B Virus DNA Real-Time PCR will be only performed if total HepBcAb is positive and HepBsAg is 
negative. 
b Hepatitis C Virus RNA Real-Time PCR will be only performed if hepatitis C virus antibody is positive.    
 
 
 
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Appendix 3.  Study Governance Considerations 
Independent Adjudication Committee(s) for Osteonecrosis of the Jaw, Atypical 
Femoral Fracture, and Serious Cardiovascular Events  
The Osteonecrosis of the Jaw Adjudication Committee and the Atypical Femur Fracture 
Adjudication Committee will independently adjudicate potential osteonecrosis of the jaw 
(ONJ) and atypical femur fracture (AFF) events identified in this clinical trial.  The 
respective processes are described in the ONJ and AFF Manuals of Operations. 
The Duke Clinical Research Institute Clinical Events Classification (CEC) group will 
independently adjudicate potential serious cardiovascular adverse events identified in 
this clinical trial.  The processes are described in the CEC Charter for romosozumab 
protocol 20150120. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
• 
Applicable International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines 
• 
Applicable laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), 
Investigator’s Brochure, and other relevant documents (eg, subject recruitment 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC.  A copy of the written approval of the protocol and informed 
consent form must be received by Amgen before recruitment of subjects into the study 
and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  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 must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
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• 
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 
• 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations 
from the protocol or other adverse event reports received from Amgen, in 
accordance with local procedures 
• 
Overall conduct of the study at the site and adherence to requirements of Title 21 
of the US Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and 
all other applicable local regulations 
Informed Consent Process 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any 
investigational product(s) is/are administered, and answer all questions regarding the 
study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative, defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study, will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 
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 unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
 
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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 is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  Subject withdrawal of consent or discontinuation from 
study treatment and/or procedures must also be documented in the subject’s medical 
records; refer to Section 8. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject or the subject’s legally authorized representative.  
If a potential subject is illiterate and does not have a legally acceptable representative, 
the investigator must provide an impartial witness to read the informed consent form to 
the subject and must allow for questions.  Thereafter, both the subject and the witness 
must sign the informed consent form to attest that informed consent was freely given 
and understood.  (Refer to ICH GCP guideline, Section 4.8.9.) 
A subject who is rescreened for vitamin D is not required to sign another informed 
consent form if the rescreening occurs within 35 days from the previous informed 
consent form signature date.  Rescreening for any other reason is not permitted.  
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research.  The investigator or authorized designee will 
explain to each subject the objectives of the exploratory research.  Subjects will be told 
that they are free to refuse to participate and may withdraw their specimens at any time 
and for any reason during the storage period.  A separate signature will be required to 
document a subject’s agreement to allow any remaining specimens to be used for 
exploratory research.  Subjects who decline to participate will not provide this separate 
signature. 
 
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Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the CRF demographics page, in addition to the unique subject identification number, 
include the age at time of signing of informed consent. 
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 age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) 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. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
 
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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 (ICMJE) Recommendations for the 
Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical Journals, 
which states: 
Authorship credit is to 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 must 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. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
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 
 
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Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  
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. 
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. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research & Development Compliance 
and Audit 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. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
 
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Amgen (or designee) will perform Self-Evident Corrections (SEC) to obvious data errors 
in the clinical trial database.  SECs will be documented in the CRF Standard Instructions 
and the CRF Specific Instructions, both of these will be available through the electronic 
data capture (EDC) system.  Examples of obvious data errors that may be corrected by 
Amgen (or designee) include deletion of obvious duplicate data (ie, the same results 
sent twice with the same date with different visit, and updating a specific response if the 
confirming datum is provided in the “other, specify” field (eg, for race, reason for ending 
study). 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
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 provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
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.  Source documents may also include data captured in the 
Interactive Voice Response System (IVRS)/Interactive Web Response System (IWRS) 
(if used, such as subject ID and randomization number) and CRF entries if the CRF is 
the site of the original recording (ie, there is no other written or electronic record of data, 
such as paper questionnaires for a clinical outcome assessment). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The Investigator 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.  These include: 
 
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• 
Subject files containing informed consent forms 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 
(POR), Investigational Product Accountability Record(s), Return of Investigational 
Product for Destruction Form(s), Final Investigational Product Reconciliation 
Statement, as applicable 
• 
Medical device(s) or combination product(s) documentation, as applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(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 investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
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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Appendix 4.  Safety Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up and Reporting 
Definition of Disease-related Event 
Disease-related Event Definition 
• 
Disease-related events are events (serious or non-serious) anticipated to occur in 
the study population due to the underlying disease.  See Section 9.2.3.1.1.1 for the 
list of disease-related events.   
• 
Disease-related events that would qualify as an adverse event or serious adverse 
event: 
o An event based on the underlying disease that is worse than expected as 
assessed by the investigator for the subject’s condition or if the investigator 
believes there is a causal relationship between the investigational 
product(s)/study treatment/protocol-required therapies and disease worsening, 
this must be reported as an adverse event or serious adverse event. 
• 
Disease-related events that do not qualify as adverse events or serious adverse 
events:  
o 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.   
Definition of Adverse Event 
Adverse Event Definition 
• 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.   
• 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a treatment, combination 
product, medical device or procedure. 
 
Events Meeting the Adverse Event Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram [ECG], radiological scans, vital 
signs measurements), including those that worsen from baseline, that are 
considered clinically significant in the medical and scientific judgment of the 
investigator (ie, not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
 
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adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported 
regardless of sequelae. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be 
captured in the efficacy assessments.  However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as adverse event or 
serious adverse event if they fulfill the definition of an adverse event or serious 
adverse event.   
 
Events NOT Meeting the Adverse Event Definition 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that 
leads to the procedure is the adverse event. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence 
that, meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are an adverse event.  If a complication prolongs hospitalization or 
fulfills any other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the adverse event is to be considered 
serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an adverse event. 
 
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Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious 
adverse event reporting is appropriate in other situations such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition.  
These events are typically to be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
Definition of Adverse Device Effect 
The detection and documentation procedures for adverse device effects described in 
this protocol apply to all Amgen medical devices or combination products provided for 
use in the study (see Section 7.1.2 for the list of Amgen medical devices). 
Adverse Device Effect Definition 
An adverse device effect is any adverse event related to the use of a combination 
product or medical device.  Adverse device effects include adverse events resulting 
from insufficient or inadequate 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. 
 
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Recording Adverse Events, Disease-related Events (if applicable), and Serious 
Adverse Events 
Adverse Event, Disease-related Event (if applicable) and Serious Adverse Event 
Recording 
• 
When an adverse event, disease-related event or serious adverse event occurs, it 
is the responsibility of the investigator to review all documentation (eg, hospital 
progress notes, laboratory, and diagnostics reports) related to the event. 
• 
The investigator will then record all relevant adverse event/disease-related 
event/serious adverse event information in the Event CRF. 
o Additionally, the investigator is required to report a fatal disease-related event 
on the Event CRF. 
• 
The investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
o Dates of onset and resolution (if resolved); 
o Severity (or toxicity defined below); 
o Assessment of relatedness to investigational product, other protocol-required 
therapies, or devices; and 
o Action taken. 
• 
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.   
• 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to the sponsor in lieu of completion of the Event CRF page. 
• 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to the sponsor. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 
 
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Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on: 
The Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 
which is available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between investigational 
product, protocol-required therapies, device(s), and/or study-mandated procedure 
and each occurrence of each adverse event/serious adverse event. 
• 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
• 
Relatedness must also be assessed between the combination product device and 
any event 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each adverse event/serious adverse event, the investigator must document in 
the medical notes that he/she has reviewed the adverse event/serious adverse 
event and has provided an assessment of causality. 
• 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
• 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 
 
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Follow-up of Adverse Event and Serious Adverse Event 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
• 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
• 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor with a copy of any post-mortem 
findings including histopathology. 
• 
New or updated information will be recorded in the originally completed Event 
CRF. 
• 
The investigator will submit any updated serious adverse event data to Amgen 
within 24 hours of receipt of the information. 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
• 
The primary mechanism for reporting serious adverse event will be the EDC 
system via the Safety Report Form.  
• 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using an Electronic Serious Adverse Event (eSAE) 
Contingency Form (paper form; see Figure 12-1) within 24 hours of the 
investigator’s knowledge of the event. 
• 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
• 
After the study is completed at a given site, the EDC system will be taken off-line to 
prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC has been taken off-line, then the site can report this information on an 
Electronic Serious Adverse Event Contingency Form (paper form; see 
Figure 12-1). 
Adverse Device Effects:  Recording, Evaluating, and Reporting 
• 
Any adverse event resulting from an adverse device effect that occur during the 
study will be documented in the subject’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the Event CRF page. 
• 
It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by Amgen) at the time of the initial 
report and describes any corrective or remedial actions taken to prevent recurrence 
of the incident. 
 
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Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form 
 
 
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Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and Lactation 
Information 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
• 
Premenopausal female with 1 of the following: 
o Documented hysterectomy; 
o Documented bilateral salpingectomy; or 
o Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject’s medical records; 2) subject’s medical examination; or 
3) subject’s medical history interview. 
• 
Premenarchal female 
• 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause.  A high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT).  However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be 
required to use 1 of the non-hormonal highly effective contraception 
methods if they wish to continue their HRT during the study.  Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment. 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
• 
Investigator will collect pregnancy information on any female subject who 
becomes pregnant while taking protocol-required therapies through 3 months 
after the last dose of investigational product. 
• 
Information will be recorded on the Pregnancy Notification Worksheet (see 
Figure 12-2).  The worksheet must be submitted to Amgen Global Patient Safety 
within 24 hours of learning of a subject’s pregnancy.  (Note: Sites are not 
required to provide any information on the Pregnancy Notification Worksheet that 
violates the country or regions local privacy laws.) 
 
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• 
After obtaining the female subject’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy and infant 
health information and complete the pregnancy questionnaire for any female 
subject who becomes pregnant while taking protocol-required therapies through 
3 months after the last dose of investigational product of the study drug.  This 
information will be forwarded to Amgen Global Patient Safety.  Generally, infant 
follow-up will be conducted up to 12 months after the birth of the child (if 
applicable). 
• 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
• 
While pregnancy itself is not considered to be an adverse event or serious 
adverse event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate 
will be reported as an adverse event or serious adverse event.  Note that an 
elective termination with no information on a fetal congenital malformation or 
maternal complication is generally not considered an adverse event, but still must 
be reported to Amgen as a pregnancy exposure case. 
• 
If the outcome of the pregnancy meets a criterion for immediate classification as 
a serious adverse event (eg, female subject experiences a spontaneous 
abortion, stillbirth, or neonatal death or there is a fetal or neonatal congenital 
anomaly) the investigator will report the event as a serious adverse event. 
• 
Any serious adverse event occurring as a result of a post-study pregnancy which 
is considered reasonably related to the study treatment by the investigator, will 
be reported to Amgen Global Patient Safety as described in Appendix 4.  While 
the investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting.  
• 
Any female subject who becomes pregnant while participating will discontinue 
study treatment (see Section 8.1 for details). 
Collection of Lactation Information 
• 
Investigator will collect lactation information on any female subject who 
breastfeeds while taking protocol-required therapies through 3 months after the 
last dose of investigational product. 
• 
Information will be recorded on the Lactation Notification Worksheet (see below) 
and submitted to Amgen Global Patient Safety within 24 hours of the 
investigator’s knowledge of event. 
• 
Study treatment will be discontinued if female subject breastfeeds during the 
study as described in exclusion criterion 227. 
• 
With the female subjects signed authorization for release of mother and infant 
health information, the investigator will collect mother and infant health 
information and complete the lactation questionnaire on any female subject who 
breastfeeds while taking protocol-required therapies through 3 months after the 
last dose of investigational product after discontinuing protocol-required 
therapies. 
 
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Figure 12-2.  Pregnancy and Lactation Notification Worksheet 
 
 
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Appendix 6.  Sample Storage and Destruction 
Any blood, pharmacokinetic (PK), anti-drug antibody, or biomarker sample collected 
according to the Schedule of Activities (Table 2-1) 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 the 
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, the results of pharmacogenetic, 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 
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. 
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 
 
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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 
Appendix 3 for subject confidentiality. 
 
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Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and Follow-up 
Assessments and Study Treatment Rechallenge Guidelines 
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 investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR, and transaminases) has not been 
identified.  
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) 
• 
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-1 antitrypsin deficiency 
• 
Alcoholic hepatitis 
• 
Autoimmune hepatitis 
• 
Wilson’s disease and hemochromatosis 
• 
Nonalcoholic fatty liver disease including steatohepatitis (NASH) 
• 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
If investigational product(s) is/are withheld, the subject is to be followed for possible DILI 
according to recommendations in the last section of this appendix.  
 
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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 (see next section in this appendix). 
Table 12-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3x ULN  
at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5x ULN (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
> 5x ULN but < 8x ULN and unable to 
adhere to enhanced monitoring schedule 
> 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
> 3x ULN (when baseline was < ULN) 
 
OR 
ALP 
> 8x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then romosozumab is to be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Table 12-2) are never to be rechallenged. 
 
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Drug-induced Liver Injury Reporting and 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 the above, 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 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 Appendix 4. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 12-2 or who experience AST or ALT elevations > 3x upper limit of normal (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 to 48 hours  
• 
In cases of TBL > 2x ULN or AST/ALT much greater than 3x ULN, retesting 
should be performed within 24 hours; subjects should be monitored at least twice 
weekly.   
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
• 
PT/INR, fractionated bilirubin, and any other potentially relevant laboratory 
evaluations of liver function or disease 
• 
Complete blood count (CBC) with differential to assess for eosinophilia 
 
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• 
A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting, and fever 
o Prior and/or concurrent use of alcohol, recreational drugs, and special 
diets 
o Concomitant use of medications (including non-prescription medicines 
and herbal and dietary supplements), plants, and mushrooms 
• 
Full viral and autoimmune hepatitis evaluation (serologies for hepatitis A, B, C, D, 
E, Epstein-Barr Virus, Herpes Simplex Virus, etc.); evaluate for other potential 
causes of DILI, including but not limited to: Nonalcoholic Steatohepatitis, 
hypoxic/ischemic hepatopathy, and biliary tract disease 
• 
Creatine phosphokinase (CPK), haptoglobin, lactate dehydrogenase (LDH), and 
peripheral blood smear 
• 
Appropriate liver imaging or biopsy if clinically indicated; strongly consider these 
tests in cases of concurrent transaminase and TBL elevation that require 
permanent withholding of investigational product 
• 
Appropriate blood sampling for pharmacokinetic analysis if this has not already 
been collected 
• 
Gastroenterology or hepatology consult  
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all investigational product(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 the corresponding CRFs.  
 
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