Clinical trial NCT03638128
Conditions: Osteogenesis Imperfecta (OI)
Keywords: OI Bone.
Sponsor: Amgen
Start date: 2018-07-26; Completion date: 2022-03-28
Enrollment: 75 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate long-term safety of denosumab in children/young adults with pediatric osteogenesis imperfecta (OI) who completed the prior study 20130173 (NCT02352753).

Detailed description:
All participants who completed the prior denosumab study 20130173 (NCT02352753) were offered participation in this study (20170534). Participants could continue to receive denosumab once every 3 months (Q3M) or could receive denosumab once every 6 months (Q6M) or off-treatment observation only at the investigator's discretion. The study design allowed subjects to discontinue denosumab, resume denosumab, initiate alternative osteoporosis medication, discontinue alternative osteoporosis medication, or receive no treatment (observation only) at any time. Therefore results of this study were analyzed according to both baseline treatment and subsequent treatment trajectories.

Arms: arm 1: Participants who received non-denosumab alternative therapy during the study or who were not receiving any medication at baseline.

Alternative osteoporosis medication(s) were determined at the investigator's discretion and per standard of care and local guidelines. arm 2: Participants who received at least 1 dose of 1 mg/kg denosumab administered once every 6 months (Q6M) by subcutaneous injection, but no Q3M denosumab during this study. arm 3: Participants who received at least one dose of 1 mg/kg denosumab administered once every 3 months (Q3M) by subcutaneous injection during this study.
Interventions: intervention 1: Denosumab intervention 2: Alternative osteoporosis medications
Intervention descriptions: intervention 1: Solution for injection intervention 2: Alternative osteoporosis medication/s at the discretion of the investigator.

Protocol documents:
Prot_000.pdf: 
Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
Page 1 of 102 
CONFIDENTIAL  
 
 
Title Page 
Protocol Title: 
Multicenter, Single-arm Open-label Extension 
Study to Assess Long-term Safety and Efficacy 
of Current or Prior Treatment With Denosumab 
in Children/Young Adults With Osteogenesis 
Imperfecta 
Short Protocol Title: 
Open-label Extension of Study 20130173 of 
Denosumab in Children and Young Adults with 
Osteogenesis Imperfecta 
Protocol Number: 
20170534 
Investigational Product: 
Denosumab 
Trade Name: 
Prolia 
Sponsor 
Name of Sponsor: 
Amgen Inc.  
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone Number: 
805-447-1000 
Protocol 
Approver 
Name: 
 
Function: 
VP Global Development 
Key 
Sponsor 
Contact 
Name: 
 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone Number: 
 
Email Address: 
 
EudraCT Number: 
2018-000550-21 
NCT Number: 
NCT03638128 
Protocol Date: 
 
 
 
 
 
 
 
Document Version 
Date 
Original 
06 April 2018 
Amendment 1 
11 July 2019 
Amendment 2 
31 March 2020 
Superseding 
Amendment 2 
30 April 2020 
Amendment 3 
17 November 2020 
Superseding 
Amendment 3 
14 January 2021 
Amendment 4 
09 November 2021 
Amendment 5 
02 February 2022 
Version/Date: 
Data Element Standards Version 
Version 5.0; 20 March 2015 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
Page 2 of 102 
CONFIDENTIAL  
 
 
 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.  This format and content of this protocol is aligned with 
Good Clinical Practice:  Consolidated Guidance (International Council for Harmonisation 
[ICH] E6). 
Confidentiality Notice 
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; for all other countries, insert the local toll-free Medical Information 
number; Amgen’s general number in the US, 1-805-447-1000. 
 
 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
Page 3 of 102 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled Multicenter, Single-arm Open-label Extension 
Study to Assess Long-term Safety and Efficacy of Current or Prior Treatment With 
Denosumab in Children/Young Adults With Osteogenesis Imperfecta, dated 02 
February 2022, 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) 
 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
Page 4 of 102 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Synopsis ................................................................................................... 9 
2. 
Study Schema and Schedule of Activities ............................................................. 14 
2.1 
Study Schema ........................................................................................... 14 
2.2 
Schedule of Activities ................................................................................ 16 
3. 
Introduction ........................................................................................................... 20 
3.1 
Study Rationale ......................................................................................... 20 
3.2 
Background ............................................................................................... 20 
3.2.1 
Disease ..................................................................................... 20 
3.2.2 
Amgen Investigational Product Background:  
Denosumab ............................................................................... 21 
3.2.3 
Alternative Osteoporosis Medication/s Product 
Background ............................................................................... 22 
3.3 
Benefit/Risk Assessment ........................................................................... 22 
3.3.1 
Therapeutic Context .................................................................. 23 
3.3.2 
Key Benefits .............................................................................. 23 
3.3.3 
Key Risks .................................................................................. 23 
3.3.3.1 
Risks ....................................................................... 23 
3.3.3.2 
Hypocalcemia.......................................................... 25 
3.3.3.3 
Hypercalcemia ........................................................ 26 
3.3.3.4 
Osteopetrosis .......................................................... 27 
3.3.3.5 
Tooth Eruption ......................................................... 28 
3.3.3.6 
Multiple Vertebral Fractures Following 
Treatment Discontinuation....................................... 28 
3.3.3.7 
Osteonecrosis of the Jaw Events ............................ 29 
3.3.3.8 
Atypical Femoral Fracture Events ............................ 29 
4. 
Objectives, Endpoints and Hypotheses ................................................................. 30 
4.1 
Objectives and Endpoints .......................................................................... 30 
4.2 
Hypotheses ............................................................................................... 31 
5. 
Study Design ........................................................................................................ 31 
5.1 
Overall Design .......................................................................................... 31 
5.1.1 
All Dosing Stopped and Subjects on Denosumab 
Followed for Safety ................................................................... 33 
5.2 
Number of Subjects ................................................................................... 33 
5.2.1 
Replacement of Subjects ........................................................... 33 
5.2.2 
Number of Sites ......................................................................... 33 
5.3 
End of Study ............................................................................................. 34 
5.3.1 
End of Study Definition .............................................................. 34 
5.3.2 
Study Duration for Subjects ....................................................... 34 
5.4 
Justification for Investigational Product Dose ............................................ 34 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
Page 5 of 102 
CONFIDENTIAL  
 
 
5.5 
Patient Input on Study Design ................................................................... 35 
6. 
Study Population .................................................................................................. 35 
6.1 
Inclusion Criteria  ...................................................................................... 35 
6.2 
Exclusion Criteria  ..................................................................................... 36 
6.3 
Subject Enrollment .................................................................................... 36 
6.4 
Screen Failures ......................................................................................... 37 
7. 
Treatments ........................................................................................................... 38 
7.1 
Treatment Procedures............................................................................... 38 
7.1.1 
Investigational Products ............................................................ 38 
7.1.2 
Non-investigational Products ..................................................... 40 
7.1.3 
Medical Devices ........................................................................ 40 
7.1.4 
Other Protocol-required Therapies ............................................ 40 
7.1.5 
Other Treatment Procedures ..................................................... 41 
7.1.6 
Product Complaints ................................................................... 41 
7.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 41 
7.2 
Method of Treatment Assignment ............................................................. 42 
7.3 
Blinding ..................................................................................................... 43 
7.4 
Dose Modification ...................................................................................... 43 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 43 
7.4.1.1 
Amgen Investigational Product:  
Denosumab ............................................................. 43 
7.4.1.2 
Non-Amgen Non-Investigational 
Product(s):  Alternative Osteoporosis 
Medication/s ............................................................ 44 
7.4.1.3 
Additional Safety Monitoring of 
Hypocalcemia.......................................................... 45 
7.4.2 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 45 
7.5 
Preparation/Handling/Storage/Accountability ............................................ 45 
7.6 
Treatment Compliance .............................................................................. 45 
7.7 
Treatment of Overdose ............................................................................. 45 
7.8 
Prior and Concomitant Treatment ............................................................. 45 
7.8.1 
Prior Treatment ......................................................................... 45 
7.8.2 
Concomitant Treatment ............................................................. 45 
8. 
Discontinuation Criteria ......................................................................................... 45 
8.1 
Discontinuation of Study Treatment........................................................... 46 
8.2 
Discontinuation From the Study ................................................................ 47 
8.2.1 
Reasons for Removal From Washout, Run-in or 
Invasive Procedures .................................................................. 48 
8.2.2 
Reasons for Removal From Study ............................................. 48 
8.3 
Lost to Follow-up ....................................................................................... 48 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
Page 6 of 102 
CONFIDENTIAL  
 
 
9. 
Study Assessments and Procedures .................................................................... 49 
9.1 
General Study Periods .............................................................................. 49 
9.1.1 
Screening and Enrollment ......................................................... 49 
9.1.2 
Treatment Period ....................................................................... 49 
9.1.3 
Safety Follow-up/End of Study .................................................. 50 
9.1.4 
End of Study .............................................................................. 51 
9.2 
Description of General Study Assessments and Procedures ..................... 51 
9.2.1 
General Assessments ............................................................... 51 
9.2.1.1 
Informed Consent/Assent ........................................ 51 
9.2.1.2 
Demographics ......................................................... 51 
9.2.1.3 
Medical History ........................................................ 51 
9.2.1.4 
Physical Examination .............................................. 52 
9.2.1.5 
Physical Measurements .......................................... 52 
9.2.2 
Efficacy Assessments ................................................................ 52 
9.2.3 
Safety Assessments .................................................................. 53 
9.2.3.1 
Adverse Events ....................................................... 54 
9.2.3.2 
Vital Signs ............................................................... 57 
9.2.3.3 
Other Safety ............................................................ 57 
9.2.4 
Clinical Laboratory Assessments ............................................... 58 
9.2.4.1 
Pregnancy Testing .................................................. 59 
9.2.5 
Antibody Testing Procedures ..................................................... 59 
9.2.6 
Other Assessments ................................................................... 60 
9.2.6.1 
End of Study Visit .................................................... 60 
10. 
Statistical Considerations ...................................................................................... 61 
10.1 
Sample Size Determination ....................................................................... 61 
10.2 
Analysis Sets, Subgroups, and Covariates ................................................ 62 
10.2.1 
Analysis Sets ............................................................................. 62 
10.2.2 
Covariates ................................................................................. 62 
10.2.3 
Subgroups ................................................................................. 62 
10.2.4 
Handling of Missing and Incomplete Data .................................. 62 
10.3 
Statistical Analyses ................................................................................... 63 
10.3.1 
Planned Analyses ...................................................................... 63 
10.3.1.1 
Interim Analysis and Early Stopping 
Guidelines ............................................................... 63 
10.3.1.2 
Primary Analysis ..................................................... 63 
10.3.1.3 
Final Analysis .......................................................... 63 
10.3.2 
Methods of Analyses ................................................................. 63 
10.3.2.1 
General Considerations ........................................... 63 
10.3.2.2 
Efficacy Analyses .................................................... 63 
10.3.2.3 
Safety Analyses ...................................................... 64 
11. 
References ........................................................................................................... 66 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
Page 7 of 102 
CONFIDENTIAL  
 
 
12. 
Appendices ........................................................................................................... 68 
12.1 
Appendix 1.  List of Abbreviations and Definitions of Terms ...................... 69 
12.2 
Appendix 2.  Clinical Laboratory Tests ...................................................... 72 
12.3 
Appendix 3.  Study Governance Considerations ....................................... 74 
Independent Adjudication Committee(s) .................................................... 74 
Regulatory and Ethical Considerations ...................................................... 74 
Recruitment Procedures ............................................................................ 75 
Informed Consent/Assent Process ............................................................ 75 
Data Protection/Subject Confidentiality ..................................................... 77 
Publication Policy ...................................................................................... 78 
Investigator Signatory Obligations ............................................................. 78 
Data Quality Assurance ............................................................................. 79 
Source Documents .................................................................................... 80 
Study and Site Closure.............................................................................. 81 
Compensation ........................................................................................... 81 
12.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ....................................... 82 
Definition of Serious Adverse Event .......................................................... 83 
Recording Adverse Events and Serious Adverse Events .......................... 83 
Evaluating Adverse Events and Serious Adverse Events .......................... 84 
Reporting of Serious Adverse Event .......................................................... 85 
12.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ........................................................ 92 
Definition of Females of Childbearing Potential ......................................... 92 
Collection of Pregnancy Information .......................................................... 93 
Collection of Lactation Information ............................................................ 94 
12.6 
Appendix 6.  Sample Storage and Destruction .......................................... 97 
12.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ................................................................................................. 99 
Drug-induced Liver Injury Reporting and Additional 
Assessments ........................................................................... 101 
 
List of Tables 
Table 2-1.  Schedule of Activities for Investigational Product (3-Month Dosing 
Regimen), Alternative Therapies, and Observation ................................. 16 
Table 7-1.  Study Treatments ........................................................................................ 39 
Table 7-2.  List of Proscribed Therapy ........................................................................... 41 
Table 10-1.  Estimated 95% CI for Example Adverse Events of Interest 
Incidence Rate........................................................................................ 61 
Table 12-1.  Analyte Listing ........................................................................................... 72 
 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
Page 8 of 102 
CONFIDENTIAL  
 
 
List of Figures 
Figure 2-1.  Study Schema ............................................................................................ 14 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Report 
Form ....................................................................................................... 87 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet ...................................... 95 
 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
Page 9 of 102 
CONFIDENTIAL  
 
 
1. 
Protocol Synopsis 
Protocol Title:  Multicenter, Single-arm Open-label Extension Study to Assess 
Long-term Safety and Efficacy of Current or Prior Treatment With Denosumab in 
Children/Young Adults With Osteogenesis Imperfecta 
Short Protocol Title:  Open-label Extension of Study 20130173 of Denosumab in 
Children and Young Adults with Osteogenesis Imperfecta 
Study Phase:  3 
Indication:  Osteogenesis Imperfecta (OI) 
Rationale 
Study 20170534 was an open-label extension of Study 20130173 to assess long-term 
safety and efficacy of current or prior treatment with denosumab in children/young adults 
with osteogenesis imperfecta (OI).  This study was required for compliance with key 
binding elements from the denosumab Pediatric Investigational Plan (PIP) for 
Study 20130173.  All subjects who completed end of study (EOS) on Study 20130173, 
regardless of whether they received investigational product until the last 
protocol-specified dose on the 20130173 study or ended investigational product early, 
were offered participation in a long-term open-label follow-up study – where this protocol 
had been approved at the site.  Subjects who withdrew consent/assent to transition to 
3-Month Dosing Regimen on 20130173 were also offered participation in the study.  
When subjects in Study 20130173 neared the EOS visit (completion), subjects were 
offered participation in Study 20170534.  If a subject was rolled over into the 
20170534 study, they were offered to receive alternative treatment including commercial 
denosumab every 6 months (6-Month Dosing Regimen) or would be observed without 
any treatment or the investigational product given every 3 months (3-Month Dosing 
Regimen). 
Starting from 30 September 2021, due to the life-threatening events of hypercalcemia 
reported on denosumab use in the pediatric OI study, it was decided not to dose any 
subject further on Study 20170534 and to follow all subjects for safety for 24 weeks 
following the last dose of denosumab as part of an urgent safety measure.   
Rationale for Protocol Amendment 5 
Given the limited amount of available data for efficacy analysis, the analysis of the 
secondary endpoints is changed to ensure only quality data is presented as an 
endpoint.  The secondary efficacy endpoints of fracture and growth velocity are 
removed, and BMD Z-score is clarified given the multiple treatment sequences in 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
Page 10 of 102 
CONFIDENTIAL  
 
 
the trial.  Adverse events of fracture, including femur fractures, will be presented 
in the adverse event tables. 
The primary objective and endpoint is safety and is unchanged. 
Objective(s)/Endpoint(s) 
 
 
Hypotheses 
This study is descriptive in nature and does not involve testing formal hypotheses. 
Overall Design 
Recently, life-threatening events of hypercalcemia were reported on denosumab 
1 mg/kg Q3M regimen in the pediatric OI subjects within 20130173 study.  Amgen 
considers that the overall benefit:risk profile of Prolia (denosumab) (Q3M/Q6M) is not 
favorable in the OI pediatric patient population based on the data observed and decided 
to stop the 20170543 study for any further enrollment or dosing with denosumab.  
Per the 30 September 2021 Dear Investigator Letter (DIL), all investigators were notified 
to immediately stop denosumab treatment and continue the study as per the normal 
Schedule of Activities (without denosumab treatment).  All subjects participating in the 
study will be followed for 24 weeks after their last dose of denosumab.  At 24 weeks the 
EOS Assessments should be completed per the current Schedule of Activities 
(Table 2-1).  
Subjects who were on denosumab (3 months or every 6 months treatment) and stopped 
denosumab more than 24 weeks ago should be scheduled for their EOS Visit at the next 
Objectives 
Endpoints 
Primary 
 
To evaluate long-term safety of 
denosumab in subjects with 
pediatric osteogenesis imperfecta 
(OI) completing Study 20130173 
 
The primary endpoints are subject incidence of 
adverse events, serious adverse events, and 
adverse events of special interest, subject 
incidence of antidenosumab antibodies, changes 
from baseline in laboratory values and vital signs, 
and subject incidence of metaphyseal index 
Z-score above age-appropriate normal range, 
abnormal molar eruption, and mandibular 
shaping 
Secondary 
 
To describe changes in bone 
mineral density (BMD) of lumbar 
spine and proximal femur (total hip 
and femoral neck) from baseline to 
6, 12, and 24 months 
 
Actual values and changes in BMD Z-score of 
lumbar spine and proximal femur (total hip and 
femoral neck) from Study 20170534 baseline, as 
assessed by dual X-ray absorptiometry (DXA), at 
6, 12, and 24 months 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
Page 11 of 102 
CONFIDENTIAL  
 
 
scheduled visit and have their EOS Visit assessments conducted per the current 
Schedule of Activities (Table 2-1). 
Subjects on alternative or observational therapy that have never taken denosumab 
should complete the EOS assessments at the next scheduled visit (Table 2-1).  
Study 20170534 is an open-label, prospective, extension study of Study 20130173 to 
assess long-term safety and efficacy of current or prior treatment with denosumab in 
children/young adults with OI.  This study is required for compliance with key binding 
elements from the denosumab PIP for Study 20130173.  All subjects who complete EOS 
on Study 20130173, regardless of whether they received investigational product until the 
last protocol-specified dose on the 20130173 study or ended investigational product 
early, are offered participation in a long-term open-label follow-up study – where this 
protocol has been approved at the site.  Subjects who withdraw consent/assent to 
transition to 3-Month Dosing Regimen on 20130173 will also be offered participation in 
this study.  When subjects in Study 20130173 near the EOS visit (completion), subjects 
will be offered participation in Study 20170534.  If a subject is rolled over into the 
20170534 study, they will be offered to receive alternative treatment including 
commercial denosumab every 6 months (6-Month Dosing Regimen) or will be observed 
without any treatment or the investigational product given every 3 months (3-Month 
Dosing Regimen). 
Number of Subjects 
The number of subjects in this study will be determined by the number of subjects 
completing Study 20130173, and who are willing and able to participate in the long-term 
follow-up study. 
Summary of Subject Eligibility Criteria 
Any subject enrolled in Study 20130173 and completed the study, or EOS visit 
regardless of completing or ending investigational product early.   
For a full list of eligibility criteria, please refer to Section 6.1 and Section 6.2. 
Treatments 
On the 3-Month Dosing Regimen, calcium and vitamin D were dispensed as a protocol-
required therapy.  For subjects on alternative therapies including the 6-Month Dosing 
Regimen, calcium and vitamin D were not protocol-required therapies and used at the 
investigator’s discretion and local standard of care in pediatric OI.  After the Urgent 
Safety Measure, all subjects are on alternative therapy with the exclusion of the 6-Month 
Dosing Regimen and are to use calcium and vitamin D at the site’s discretion, and 
consistent with the local standard of care.   


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
Page 12 of 102 
CONFIDENTIAL  
 
 
Subjects may receive denosumab at a 3-Month Dosing Regimen, alternative 
osteoporosis medication/s of investigator’s choice administered per local standard of 
care (including commercial denosumab at a 6-Month Dosing Regimen) or observation 
only (no intervention).  Subjects on denosumab at a 3-Month Dosing Regimen will be 
dispensed calcium and vitamin D. 
Procedures 
After signing informed consent/assent for this study, demographics and all medical 
history (including medical history of fracture and OI, and resolved adverse events 
[including fractures]) will be carried over from Study 20130173.  Clinically relevant 
resolved adverse events will be manually added at investigator discretion into the 
medical history case report form (CRF) and resolved fracture events will also be added 
to fracture history.  Ongoing events (including fractures) at screening will be added to 
CRF pages for Study 20170534.  The standard assessments of physical examination 
and physical measurements of height and weight will be performed.  Assessment of 
safety (adverse events, serious adverse events, laboratory parameters) will also be 
performed.  Tanner stage will be conducted in female subjects to determine the need for 
pregnancy testing.  Highly sensitive pregnancy test will be performed and confirmed 
negative before each administration of denosumab at all scheduled visits in all female 
subjects who are at Tanner Stage 2 or (higher) or have had menarche. 
Study-specific assessments include laboratory assessments (25 [OH] vitamin D, 
 
, antidenosumab antibody), armspan, DXA (lumbar spine, proximal 
femur), x-rays (lateral thoracic, lumbar spine, anteroposterior knees), dental x-rays, oral 
visual inspection, and clinical fracture recording.  
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 
Statistical analysis in this study will be descriptive in nature and statistical inferences will 
be for guidance only.  Descriptive statistics will be provided for baseline demographics 
and subject characteristics based on FAS, and for all endpoints based on their 
respective analysis sets and within each pattern of treatment received during the study if 
data warrant.  Continuous outcomes will be summarized by the number of non-missing 
values, mean, SD, median, lower and upper quartiles and minimum and maximum 
values.  Nominal and ordinal categorical variables will be summarized using counts and 
percentages.  
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, 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
Page 13 of 102 
CONFIDENTIAL  
 
 
adverse events leading to withdrawal from investigational product (denosumab), and 
adverse events of special interest will also be provided.  The adverse events of special 
interest will include changes in growth plate morphology, severe or symptomatic 
hypocalcemia, osteonecrosis of the jaw (ONJ), abnormal molar eruption, hypercalcemia, 
and abnormal mandibular shaping. 
Details will be described in the Statistical Analysis Plan.  For a full description of 
statistical analysis methods, please refer to Section 10. 
Sponsor Name:  Amgen Inc.  


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
 
Page 14 of 102 
CONFIDENTIAL  
 
 
2. 
Study Schema and Schedule of Activities 
2.1 
Study Schema 
Figure 2-1.  Study Schema 
Denosumabb
1 mg/kg SC  at Day 1, Week 12, 24, 36, 48, 60, 72, and 84
Study  20130173 Month 36/Month 48 (Q3M dose)a
On Study Period
Calcium and vitamin D supplementation (as applicable)
Final Visit/ End of Study
Observation onlyc
Alternative Osteoporosis Medication/sc
Per local standard of care
(Week 12, 36, 60, and 84 if needed)
Baseline/Day 1
Week 48
Week 60*
Week 72
Week 96
Week 36*
Week 24
Week 12*
Week 84*
Follow up for safety 
(at least 24 weeks)
OR
OR
Urgent safety measure
Urgent safety measure
 
EOS  end of study; IP  investigational product; Q3M  3-Month Dosing Regimen; SC  subcutaneous 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
 
Page 15 of 102 
CONFIDENTIAL  
 
 
a Subjects who decline Q3M dose change in Study 20130173 may also be offered participation in Study 20170534.  All subjects already on study who consent to Q3M 
and have not had opportunity to complete 12 months of dosing will be allowed to continue until they have completed a minimum of 12 months (note:  subjects may 
continue up to week 96 on Q3M). 
b Following urgent safety measure, treatment with denosumab will be discontinued for all subjects and subjects will be followed for safety for 24 weeks following the last 
dose of denosumab.  Subjects who were on denosumab (every 3 months or every 6 months treatment) and stopped denosumab more than 24 weeks ago should be 
scheduled for their EOS Visit at the next scheduled visit and have their EOS Visit assessments conducted per the current Schedule of Assessments. 
c Subjects on alternative or observational therapy that have never taken denosumab should complete the EOS assessments at the next scheduled visit.   
* Quarterly visits:  These visits (week 12, 36, 60, 84) are only required for subjects receiving denosumab or if the subject is treated with alternative osteoporosis 
medication/s requiring quarterly administration.  Observation-only subjects should attend every 6 months.


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
 
Page 16 of 102 
CONFIDENTIAL  
 
 
2.2 
Schedule of Activities 
Table 2-1.  Schedule of Activities for Investigational Product (3-Month Dosing Regimen), Alternative Therapies, and 
Observation 
PROCEDURE 
Screening
a 
Treatment Period (24 Months) 
Final 
Visit 
Day 
1b 
Day 
10c 
Day 
30c 
Week 
12d 
Day 
10c 
Day 
30c 
Week 
24 
Day 
10c 
Day 
30c 
Week 
36d 
Week 
48 
Week 
60d 
Week 
72 
Week 
84d 
Additional 
12 weeks 
safety 
follow- up 
Week 
96/End 
of 
Study/ET 
Day visits have a  3 days window; week visits have a  7-day window 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationg 
Xh 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Tanner stagei 
Xh 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
Xh 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsj 
Xk 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant medicationj 
Xf 
Xf 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
LABORATORY ASSESSMENTS 
Pregnancy test (urine 
dipstick method)l 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Hematology 
Xh 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Chemistryc 
Xh,u 
 
Xu 
Xu 
Xu 
Xu,v 
Xu,v 
Xu 
Xu,v 
Xu,v 
Xu 
Xu 
Xu 
Xu 
Xu 
X 
Xu 
Urine calciumc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
25 OH)
tam n D 
Antidenosumab-antibodyn
Xh
X
 
 
X 
Page 1 of 2 
Abbreviations and footnotes are at the end of the table. 
 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
 
Page 17 of 102 
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Table 2-1.  Schedule of Activities for Investigational Product (3-Month Dosing Regimen), Alternative Therapies, and 
Observation 
PROCEDURE 
Screening
a 
Treatment Period (24 Months) 
Final 
Visit 
Day 
1b 
Day 
10c 
Day 
30c 
Week 
12d 
Day 
10c 
Day 
30c 
Week 
24 
Day 
10c 
Day 
30c 
Week 
36d 
Week 
48 
Week 
60d 
Week 
72 
Week 
84d 
Additional 
12 weeks 
safety 
follow- up 
Week 
96/End 
of 
Study/ET 
Day visits have a  3 days window; week visits have a  7-day window 
STUDY-SPECIFIC ASSESSMENTS  
Armspan 
Xh 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
DXA (AP lumbar spine)o 
Xh 
Xm 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
DXA (proximal femur – 
total hip and femoral neck 
in subjects  5 years of 
age)o 
Xh 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X-ray (lateral thoracic, 
lumbar spine)o 
Xh 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X-ray (AP knees)n,o 
Xh 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
Dental X-ray 
(cephalogram and 
panoramic radiograph)o 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Oral visual inspection 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Dental X-ray (molars)o,p 
Xp 
Clinical fracture 
recordingq 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
STUDY TREATMENTS 
Investigational product 
(denosumab)r 
 
Xs 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
Alternative osteoporosis 
medication/sr 
 
Continuously, as per local standard of care 
 
Dispensation of calcium 
and vitamin Dt 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Page 2 of 2 
AP  anteroposterior; 
 DXA  Dual-energy X-ray absorptiometry; EOS  end of study; ET  Early Termination; 
OI  osteogenesis imperfecta; 
 


Product:  Denosumab 
Protocol Number:  20170534 
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Page 18 of 102 
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a Screening and study day 1 may be combined and occur on the same day.  Study day 1 should occur within 7 days from Screening. 
b Screening should take place within 28 days of the Study 20130173 End of Study visit and may occur on the same day.  Completion of screening assessment occurs 
on study day 1 of study, which can also be combined with Study 20130173 End of Study and screening visit.  The 3-Month Dosing Regimen day 1 is defined as the 
date of reconsent/assent and the first dose of denosumab on the 3-Month Dosing Regimen.  All subjects previously enrolled into the study prior to this amendment 
will be eligible to transition to the 3-Month Dosing Regimen.  Study 20130173 subjects who do not consent/assent to transition to 3-Month Dosing Regimen will 
perform a 20130173 EOS prior to month 36 and be offered the opportunity to enroll into this study. 
C The assessments on day 10 and day 30 after day 1 and weeks 12 and 24 are only required for subjects who started on 3-Month Dosing Regimen for the first time 
( 3 days).  Urine calcium is needed on day 1 only if it was not collected at Screening.  Serum calcium to be performed on days 10 and 30 following week 12 and 
week 24 doses. 
d Quarterly visits:  These visits (week 12, 36, 60, and 84) are only required for subjects receiving denosumab or if the subject is treated with alternative osteoporosis 
medication/s requiring quarterly administration.  If alternative medication is given more frequently than at the scheduled quarterly visits, the interim dosing only visits 
could be administered by any health care provider (refer to Section 5.1).  Observation only subjects should attend every 6 months. 
e Demographic data (except age) will be carried over from Study 20130173.   
f Medical history:  all medical history including fracture history and OI history will be transferred from Study 20130173 to Study 20170534.  Resolved events (including 
fractures) on Study 20130173 should be entered in the appropriate medical history or subject fracture history forms at discretion of the investigator. 
g Physical examination includes height and weight.  
h Screening and study day 1 visit should coincide with Study 20130173 End of Study visit.  These assessments are expected to be performed at Study 20130173 End 
of Study visit and should not be duplicated.  All imaging and laboratory assessments should be conducted for Study 20130173 End of Study visit and data will be 
transferred to the Study 20170534 screening visit.  Physical examination, physical measurements, vital signs, Tanner stage, and pregnancy test should be conducted 
if Study 20130173 End of Study and screening visits do not occur on the same day. 
i Tanner stage to be conducted in female subjects to determine the need to perform a pregnancy urine dipstick test at these visits. 
j Data collected at supplemental visits includes adverse events, serious adverse events, and concomitant medications. 
k Ongoing events at screening and any new events since Study 20130173 End of Study visit will be entered into medical history.   
l To be performed in all female subjects who are at Tanner Stage 2 or (higher) or have had menarche.  Highly sensitive pregnancy test will be performed and confirmed 
negative before each administration of denosumab at all scheduled visits in all female subjects who are at Tanner Stage 2 or (higher) or have had menarche.  
Additional on-treatment pregnancy testing (urine) may be performed at the investigator’s discretion if there is suspicion that a female subject is pregnant or per local 
laws and regulations.  Pregnancy tests should be performed for subjects receiving alternative OI medications (alternative therapy includes the commercial 
denosumab 6-Month Dosing Regimen) as per label instructions.  
m See Section 9.2.2.  The DXA scan to be performed in duplicate at day 1.  Only required for subjects going onto denosumab 3-Month dosing for the first time. 
n Only for subjects who continue denosumab in this study.  For X-ray (AP knees):  Only in subjects with open growth plates who do not have bilateral hardware. 
o All images/reports (as applicable) to be sent to the central imaging vendor.  The panoramic radiogram is a panoramic scanning dental X-ray of the upper and lower 
jaw, which shows a 2-dimensional view of a half-circle from ear to ear.  Panoramic radiogram will be performed to monitor molar eruption at day 1, 3-Month Dosing 
Regimen day 1 visit, and end of the study. 
p To be performed only if a delay in molar eruption is suspected based on oral visual inspection (refer to Section 9.2.3.3; Oral Visual Inspection). 
q An X-ray should be sent to the central imaging vendor for all non-vertebral fractures occurring after enrollment. 
r Subjects will receive either denosumab 3-Month Dosing Regimen or alternative osteoporosis medication/s per local standard of care (including commercial 
denosumab at a 6-Month Dosing Regimen) or observation only (no intervention).  Changes to study treatment will occur only at the next scheduled visit for that 
therapy, either denosumab 3-Month Dosing Regimen or alternative osteoporosis medication/s. 
s Study day 1:  up to a 7-day window is allowed for administration of first dose of Amgen investigational product (denosumab). 
t Calcium and vitamin D are recommended for subjects receiving denosumab. 
u At all study visits, signs and symptoms of hypocalcemia will be assessed and subjects reminded of importance of taking calcium and vitamin D. 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
 
Page 19 of 102 
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v On days 10 and 30 following weeks 12 and 24, blood collection may be performed by a qualified individual at the subject’s home, in lieu of a site visit.   


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3. 
Introduction 
3.1 
Study Rationale 
Rationale for Stopping Denosumab Administration (Protocol Amendment 4) 
Recently, life-threatening events of hypercalcemia were reported on denosumab 
1 mg/kg Q3M regimen in the pediatric OI subjects in Study 20130173.  Amgen considers 
that the overall benefit:risk profile of Prolia (denosumab) (Q3M/Q6M) is not favorable in 
the OI pediatric patient population based on the data observed. 
As a result of the potentially life-threatening risk of hypercalcemia, starting from 
30 September 2021, all further dosing of denosumab in this study was stopped and 
enrollment was closed.  Refer to Section 5.1. 
Study 20170534 was an open-label extension of Study 20130173 to assess long-term 
safety and efficacy of current or prior treatment with denosumab in children/young adults 
with osteogenesis imperfecta (OI).  This study was required for compliance with key 
binding elements from the denosumab Pediatric Investigational Plan (PIP) for 
Study 20130173 whereby subjects were offered participation in a long-term open-label 
follow-up study. 
3.2 
Background 
3.2.1 
Disease 
Osteogenesis imperfecta is a group of genetic skeletal disorders characterized by 
increased bone fragility, low bone mass (Rauch and Glorieux, 2004), and increased 
bone turnover (Rauch et al, 2009).  Osteogenesis imperfecta is the most common form 
of primary osteoporosis in children with an estimated incidence of 1 per 25 000 live births 
(Byers, 2000). 
At least 12 types of OI have been identified based on clinical phenotype and underlying 
genetic defect (Forlino and Marini, 2016; Marini and Blissett, 2013).  The majority of 
individuals with OI are heterozygous for mutations in the type I collagen genes COL1A1 
or COL1A2 that lead to quantitative and/or qualitative defects in collagen synthesis and 
negatively impact bone strength (van Dijk et al, 2012). 
The clinical features of OI may include fractures, short stature, hyperlaxity of ligaments 
and skin, hearing loss, blue sclera, and dentinogenesis imperfecta (Marini et al 2017; 
Steiner et al, 2005).  The clinical severity of OI caused by dominantly inherited collagen 
mutations varies from mild, non-deforming to perinatal lethal; most children with OI 


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Page 21 of 102 
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experience recurrent fractures, with or without progressive deformity, disability, and pain 
(Rauch and Glorieux, 2004). 
The medical management of pediatric OI includes the orthopedic prevention and 
treatment of fractures, bowing, and scoliosis.  Currently, there are no approved 
medicinal products for the treatment of OI, except for neridronate, which is only 
approved for the treatment of OI in Italy.  Clinicians have been using bisphosphonates in 
children with moderate to severe OI to reduce osteoclast activity and increase bone 
mass (even though abnormal collagen is usually present [Byers, 2000]) with the aim of 
reducing fractures (Rauch and Glorieux, 2004).  Clinical trials of bisphosphonate have 
had variable effects on fracture reduction, bone pain and quality of life 
(Castillo et al, 2009).  Recent meta-analyses confirm the variable effect of 
bisphosphonates on fracture reduction (Dwan et al, 2016; Hald et al, 2015).  Thus, an 
unmet need remains in children with OI. 
3.2.2 
Amgen Investigational Product Background:  Denosumab 
Denosumab is a fully human monoclonal antibody that binds with high affinity 
(dissociation equilibrium constant [Kd] 3 x 10-12 M) and specificity to receptor activator of 
nuclear factor kappa-Β ligand (RANKL) and neutralizes the activity of RANKL, 
preventing activation of its receptor, receptor activator of nuclear factor kappa-Β (RANK), 
on the surface of osteoclast precursors and osteoclasts.  Denosumab has an 
approximate molecular weight of 147 kDa and is produced in genetically engineered 
mammalian Chinese hamster ovary cells.  It consists of 2 heavy chains of the 
immunoglobulin (Ig) G2 subclass and 2 light chains of the kappa subclass.  The heavy 
and light chains are covalently linked through disulfide bonds. 
Denosumab, by inhibiting RANK ligand, has the potential to treat diseases characterized 
by increased osteoclast-mediated bone loss and increased fracture risk.  In children with 
OI, denosumab may have benefit due to its unique mechanism of action, reversible 
pharmacokinetics (PK), and ease of administration.  In a mouse model of moderate to 
severe OI, both RANKL inhibition (via RANK-Fc) and alendronate significantly reduced 
fracture incidence when treatment was started in neonatal animals 
(Bargman et al, 2012). 
Denosumab is currently indicated for treatment of postmenopausal women with 
osteoporosis; treatment of men with osteoporosis; treatment of bone loss in men 
receiving androgen deprivation therapy (ADT) for prostate cancer, and treatment of bone 


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loss in women receiving aromatase inhibitor therapy for breast cancer, and treatment of 
adult glucocorticoid-induced osteoporosis. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
denosumab is provided in the Denosumab Investigator’s Brochure. 
3.2.3 
Alternative Osteoporosis Medication/s Product Background 
Initiation, selection, and dosing regimen of alternative osteoporosis medication/s 
including reduced dosing in subjects who discontinued denosumab prior to or upon 
entering study or who discontinue denosumab during the study is at investigator 
discretion, per local standard of care.  Refer to the regional manufacturer package insert 
for additional information. 
3.3 
Benefit/Risk Assessment 
This pediatric study involves greater than minimal risk in part due to the increased 
skeletal growth in this population.  OI is clinically associated with osteoporosis and 
fragility fractures, which may benefit from antiresorptives such as bisphosphonates or 
denosumab.  Use of denosumab in this population may present the prospect of direct 
benefit to the subject.  Pediatric subjects treated with denosumab in this study are 
expected to have a risk profile comparable to that observed in adults.  Although 
denosumab has been studied in an adolescent population in the oncology setting of 
giant cell tumor of bone, it has not been studied in the setting of skeletal fragility in 
children.  The potential benefit:risk assessment will be established in Study 
20130173 and this study.  Several aspects will be investigated and are further 
considered in Section 9.  Additional information on specific risks in this pediatric 
population for patients on denosumab are provided below and in Section 3.3.3.1 to 
Section 3.3.3.8. 
Preliminary study data indicate that after administration of 1 mg/kg denosumab, PK 
exposures are cleared within 3 months and 
 
levels recover back to near baseline by 3 months.  This is likely due to higher RANKL 
target expression levels and a faster rate of bone turnover in the pediatric OI population 
(Brunetti et al, 2016; Rauch et al, 2000; Baron et al, 1983).   
Recently, life-threatening events of hypercalcemia were reported on denosumab 
1 mg/kg Q3M regimen in the pediatric OI subjects in the 20130173 study.  Amgen 
considers that the overall benefit:risk profile of Prolia (denosumab) (Q3M/Q6M) is not 
favorable in the OI pediatric patient population based on the data observed.   


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Page 23 of 102 
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Refer to the Denosumab Investigator’s Brochure for further data on denosumab. 
3.3.1 
Therapeutic Context 
The extensive denosumab clinical development program includes pivotal phase 
3 studies in bone loss settings in adults, ie, postmenopausal women with osteoporosis 
(Study 20030216) or low bone mass (Study 20040132); bone loss associated with ADT 
for prostate cancer (Study 20040138) or aromatase inhibitor therapy for breast cancer 
(Study 20040135); men with osteoporosis (Study 20080098), and adult subjects with 
glucocorticoid-induced osteoporosis (GiOP) (Study 20101217), as well as ongoing 
studies in pediatric subjects with OI (Study 20130173) and GiOP (Study 20140444). 
In addition, denosumab also has been studied in adolescent subjects with giant cell 
tumor of bone at a dose of 120 mg every 4 weeks (Study 20062004). 
3.3.2 
Key Benefits 
The clinical benefits of denosumab treatment derive from its inhibition of RANKL binding 
to RANK, thereby inhibiting the formation, activation, and survival of osteoclasts, 
decreasing bone resorption, and increasing bone mass, volume, and strength 
(Brunetti et al, 2016; Kostenuik, 2005).  In children with OI, denosumab may have 
provided benefit due to its unique mechanism of action, reversible PK, and ease of 
administration (subcutaneous [SC] injection).  Given the life-threatening events of 
hypercalcemia reported in the 20130173 study, the hypercalcemia was identified as 
'important identified risk' of denosumab (Prolia) use in pediatric OI studies, and the 
benefit-risk profile of denosumab in the OI population is not considered positive. 
3.3.3 
Key Risks 
Key risks with denosumab in adult indications include hypocalcemia, hypercalcemia, 
osteopetrosis, tooth eruption, multiple vertebral fractures following discontinuation of 
denosumab treatment, osteonecrosis of the jaw (ONJ), and atypical femoral fracture 
(AFF), as detailed in Section 3.3.3.2 to Section 3.3.3.8. 
3.3.3.1 
Risks 
In clinical studies in adults to date, there has been a comparable incidence of adverse 
events overall between the denosumab and placebo or active-comparator treatment 
groups and a low incidence of treatment-related adverse events, serious adverse 
events, withdrawals due to adverse events, and deaths.  Most adverse events have 
been mild to moderate in severity, transient, and considered unrelated to denosumab.  
Adverse reactions to denosumab include hypocalcemia; hypersensitivity; skin infections, 


Product:  Denosumab 
Protocol Number:  20170534 
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CONFIDENTIAL  
 
 
predominantly cellulitis, leading to hospitalization; ONJ, AFF (reported rarely in patients 
treated with denosumab and not evaluable in subjects with OI); eczema (including 
dermatitis, allergic dermatitis, atopic dermatitis, and contact dermatitis), pain in the 
extremities, and musculoskeletal pain.  Multiple vertebral fractures and hypercalcemia 
(in subjects with growing skeletons) may occur following discontinuation of denosumab 
treatment.  Additionally, hypercalcemia following denosumab discontinuation is an 
important potential risk in patients with growing skeletons.  There is a possibility that 
hypercalcemia could occur at the end of the dosing interval when a subject is still 
receiving Investigational Product. 
As of 03 August 2021, 60 subjects had received at least 1 dose of Prolia at the 1 mg/kg 
Q3M dosing regimen.   
Of the 153 subjects who had received IP, 149 (97.4%) had at least 
1 treatment-emergent adverse event; 121 (79.1) subjects, 57 (37.3) subjects, and 1 
(0.7) subjects had grade 2, 3, and 4 adverse events, respectively.  A total of 47 
(30.7%) subjects had a serious adverse event, and 5 (3.3%)subjects had an adverse 
event leading to withdrawal of IP.  There were no fatal adverse events.   
In the Q6M dosing regimen, hypercalcemia events including events of calcium ionized 
increased and blood calcium increased have been reported in 24 (15.7) study 
subjects.  No serious adverse events of hypercalcemia have been reported.  The 
majority of hypercalcemia adverse events were grade 1 in severity.  Three subjects had 
events grade 2 in severity including the following verbatim events:  asymptomatic 
increased level of ionized calcium reported on day 29; calcium blood 
increased - nonsymptomatic, underlying diagnosis unknown on day 30; and a report of 
hypercalcemia (no clinical consequences) beginning as a grade 1 hypercalcemia 
12 days following the previous dose.  The severity grade was increased to 2 on day 85 
and the event resolved on day 180 following the previous dose.   
In the combined Q3M/Q6M dosing cohorts, treatment-emergent adverse events of 
hypocalcemia have been reported in 19 (12%) of study subjects.  There have been no 
serious adverse events of hypocalcemia reported.  There have been no cases of 
positively-adjudicated osteonecrosis of the jaw. 
In a substudy assessment of urine calcium, DPD/creat ratio, and NTX for each treatment 
cycle shows the following trends: 


Product:  Denosumab 
Protocol Number:  20170534 
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– Urine calcium/creatine ratio declines in first 2 weeks following 
investigational product administration and increases to slightly above 
baseline in weeks 12-18 
– Absolute value and DPD/creatine ratio decreases within the first 2 weeks 
following dosing and subsequently increases by week 8 and returns to or 
slightly above baseline between 12-18 weeks following investigational 
product administration 
– Urine N-telopeptide (NTX) similarly decreases within first 2 weeks, 
increasing by week 8 and is back to baseline levels by 18 weeks 
In the bone loss setting, denosumab use is contraindicated in pregnancy, in patients with 
hypocalcemia, and in patients with hypersensitivity to the active substance or to any of 
the excipients. 
Volumes of blood withdrawn for analysis in association with clinical monitoring will be 
minimized as appropriate for this pediatric population based on body weight 
(EU Ethical Considerations, 2008).  
3.3.3.2 
Hypocalcemia 
Skeletal turnover rates vary by age and are higher in children than adults.  These higher 
bone turnover rates expected at baseline in children may increase the risk for 
hypocalcemia and hypophosphatemia resulting from denosumab-mediated reduction of 
bone turnover.  In addition, clinical reports of denosumab administration in pediatric 
patients with disorders of high bone turnover (eg, fibrous dysplasia and juvenile Paget’s 
disease) have described disturbances in mineral metabolism, including hypocalcemia 
and hypophosphatemia (Grasemann et al, 2013; Boyce et al, 2012).  
To minimize such risk, the following strategies will be employed:   
 
Calcium and vitamin D supplementation will be given to all subjects receiving study 
medication (denosumab) 
 
Serum calcium and phosphorus concentrations will be monitored throughout the 
study on a regular basis 
 
At all study visits, signs and symptoms of hypocalcemia will be assessed and 
subjects reminded of importance of taking calcium and vitamin D 
 
Occurrence of severe or symptomatic hypocalcemia will prompt discontinuation of 
study medication (denosumab) and institution of appropriate medical treatment 


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3.3.3.3 
Hypercalcemia  
The higher bone turnover rates expected at baseline in children with OI may increase 
the risk for rebound hypercalcemia in the latter part of the dosing interval due to release 
of bone turnover inhibition.  In addition, clinical reports of denosumab administration in 
pediatric patients with disorders of high bone turnover other than OI (eg, fibrous 
dysplasia and juvenile Paget’s disease) have described the occurrence of rebound 
hypercalcemia (Grasemann et al, 2013; Boyce et al, 2012). 
To minimize such risk, the following strategies will be employed:   
 
If a subject becomes hypercalcemic during the course of denosumab treatment, the 
calcium and/or vitamin D supplementation may be discontinued or dose adjusted at 
site discretion until the serum or urine calcium concentration has returned to the 
normal range 
 
Serum and urine calcium will be measured routinely during 3-Month Dosing Regimen 
visits 
As of 07 September 2021, a total of 56 events of hypercalcemia were reported in the 
pediatric Studies 20130173 and 20170534.  Of these 56 events, 5 events of severe 
hypercalcemia grade 4 (n = 2) and grade 3 (n = 3) were reported in study 20130173.  
The remaining 51 hypercalcemia events were of grade 1 (n = 47) and grade 2 (n = 4).  
Thirteen events, including 5 events of severe hypercalcemia ( grade 3) occurred in 
subjects receiving Q3M dosing in studies 20130173 (n = 12) and 20170534 (n = 1).  
These events occurred in 12 subjects between age of 5 years and 13 years.  Three 
events were serious and the remaining 10 events were non serious.  Nine (69%) of 
these events occurred after the subjects had received 3 or 4 doses of denosumab.  
Twelve events occurred toward the end of dosing regimen between 60 and 99 days after 
the prior dose.  The severe life-threatening adverse events of hypercalcemia have been 
reported at or near the end of the denosumab 1 mg/kg Q3M dosing period (> 60 days 
from the previous dose) in Study 20130173.  Two subjects had hypercalcemia grade 4 
and both required hospitalization and are described below.  
 
In one 13-year-old male subject, the grade 4 event occurred 77 days after the most 
recent dose and was life-threatening.  He was treated with intravenous normal 
saline.  The event resolved.  
 
In one 7-year old male subject, the grade 4 event occurred 91 days after the most 
recent dose.  The subject presented with severe dehydration, reduced glomerular 
filtration rate (GFR) and seizures resulting in sedation, intubation and assisted 
ventilation.  Rescue medication (IV Zoledronic Acid) was required to stabilize the 
subject. 


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There were 43 events reported in 31 subjects receiving Q6M dosing in the studies 
20130173 (n = 41) and 20170534 (n = 2).  These events occurred in subjects between 
the ages of 2 and 16 years.  There were 40 events of grade 1 hypercalcemia and 3 
events of grade 2 hypercalcemia. 
Therefore, hypercalcemia is a risk in this pediatric population receiving denosumab. 
Starting from 30 September 2021, due to the life-threatening events of hypercalcemia 
reported on denosumab use in the pediatric OI study, subjects will not receive any 
further dosing on 20170534 and will be followed for safety for 24 weeks following the last 
dose of denosumab. 
3.3.3.4 
Osteopetrosis 
In children, osteoclast activity is necessary to remove the cartilaginous anlagen of bone.  
Genetic deficiency in RANKL leads to osteopetrosis, a disorder of poor bone quality, 
retained cartilage, frequent fractures, and a high bone mass typified by poorly modelled 
bones with widened, club-shaped metaphyses.  Significant reduction of this resorption 
based modeling can lead to osteopetrosis-like changes with a similar abnormal 
geometry (Whyte et al, 2003).  In nonclinical studies of denosumab, the severity of 
phenotypic changes observed in the growth plate and bone was consistent with the rate 
of longitudinal growth in the bone, with limited and reversible effects in the adolescent 
monkey.  The most rapid increase in stature in humans occurs during the first 9 or 
12 months of life, and head circumference continues to increase sharply over the first 
2 years of life (Centers for Disease Control and Prevention, 2011).  Based on these 
data, the potential for significant alterations of skeletal growth and morphology is lower in 
children ≥ 5 years of age.  The limited and reversible bone effects of denosumab in the 
adolescent monkey (the second most rapid growth phase), lack of negative 
biomechanical consequences seen in the infant mice, and the radiographic monitorability 
minimize the risk of denosumab administration in pediatric patients whose growth rates 
approximate that of adolescent monkeys. 
Strategies to assess changes to the skeleton include the following:   
 
Physical examination and radiographic assessments will be performed on a regular 
basis throughout the study to monitor for possible detrimental skeletal changes in 
subjects receiving study medication (denosumab); such assessment will also include 
evaluation of metaphyseal index via knee X-ray to be performed every 6 months 
throughout the study in subjects with open growth plates only, as only in subjects 
with open growth plates does the potential risk exist of an abnormal rate of increase 
in metaphyseal width  


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 
Changes in growth plate morphology as observed in the 6 months monitoring 
considered by the investigator to be unexpected and having an adverse clinical 
impact for the subject consistent with local institutional guidelines will prompt 
discontinuation of study medication (denosumab) and institution of appropriate 
follow-up 
3.3.3.5 
Tooth Eruption 
In tooth eruption, RANKL plays an important role.  In nonclinical studies conducted in 
neonatal rats, osteoprotegerin-immunoglobulin Fc segment complex and alendronate 
administration impaired the eruption of second and third molars and also reduced incisor 
growth.  These findings were at least partially reversible within 10 weeks of discontinuing 
osteoprotegerin-immunoglobulin Fc segment complex.  In infant monkeys exposed in 
utero to denosumab, there was no effect on tooth eruption, although altered bone shape 
and jaw length led to tooth dysplasia and malalignment.  Such findings were not 
observed in adolescent cynomolgus monkeys.  These data suggest that the use of 
denosumab in the rapidly growing skeleton carries potential risk for impaired tooth 
eruption.  
To minimize this risk, the following strategies will be employed: 
 
Molar eruption and mandibular shaping will be monitored using visual inspection and 
X-ray assessments 
3.3.3.6 
Multiple Vertebral Fractures Following Treatment Discontinuation 
Multiple vertebral fractures may occur following discontinuation of denosumab treatment, 
particularly in adult subjects with a history of vertebral fracture.  Among postmenopausal 
women with osteoporosis who discontinued denosumab during the placebo-controlled 
Study 20030216 and its open-label active-treatment extension, the incidence of new 
vertebral fracture was higher than in subjects who remained on-treatment, but similar to 
the incidence in subjects who discontinued placebo, ie, had never been treated.  Among 
subjects who experienced off-treatment new vertebral fractures, a greater percentage of 
those who discontinued denosumab than placebo sustained multiple new vertebral 
fractures.  Prior vertebral fracture before or during treatment was the strongest predictor 
of off-treatment new vertebral fracture, including multiple vertebral fractures. 
During the 24-month study period, subjects may discontinue denosumab as study 
treatment at investigator discretion and either be treated with an alternative osteoporosis 
medication/s of investigator’s choice administered per local standard of care or followed 
on observation only (no intervention). 


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Given the identified risk for multiple vertebral fractures after denosumab cessation in 
study subjects at high risk for fracture, subjects who stop denosumab during the study or 
at the end of the study, and are judged by the investigator to be at high risk of multiple 
vertebral fractures following treatment discontinuation, should be considered for 
transition to an alternative osteoporosis medication/s per local standard of care. 
It is recognized that (with the exception of neridronate in Italy), no medications are 
approved for the treatment of pediatric OI, and antiresorptive use is considered off-label; 
however, local standard of care for pediatric subjects with OI may include 
bisphosphonate use.  Therefore, the decision to use an alternative osteoporosis 
medication/s and selection of the dose and regimen will be at investigator discretion. 
3.3.3.7 
Osteonecrosis of the Jaw Events 
Cases of ONJ have been reported in association with antiresorptive use.  ONJ may be 
associated with pain and/or infection of the jaw bone, teeth or gums resulting in a 
non-healing area of exposed bone in the mouth.  How this happens is poorly 
understood.  One hypothesized mechanism involves interference with bone remodeling 
as a result of decreased osteoclast activity.  In this study, all events reported as ONJ, or 
those coded to prespecified terms potentially indicative of ONJ, will be reviewed by an 
independent adjudication committee. 
To minimize this risk, the following strategies will be employed: 
 
Potential infection of jaw bone, tooth, or gum infections will be monitored with oral 
visual inspection (including after molar eruption) and x-ray assessments when 
indicated 
3.3.3.8 
Atypical Femoral Fracture Events 
Cases of AFF have been reported in patients with osteoporosis in association with 
antiresorptive use.  Some case series have reported a possible association between 
AFF and long-term alendronate therapy (Odvina et al, 2010; Lenart et al, 2008; 
Odvina et al, 2005), while others have not (Abrahamsen et al, 2009).  Osteogenesis 
imperfecta is characterized by increased bone fragility and resulting frequent fractures 
that are often precipitated by minimal trauma.  The most frequent fracture site in patients 
with OI includes the femur (Folkestad et al, 2017).  The major defining features of AFF 
include a fracture that is associated with minimal or no trauma, a subtrochanteric or 
femoral shaft location, and a fracture line that is transverse in orientation.  This definition 
however, does not apply to pathological fractures associated with primary or metastatic 


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bone tumors and certain bone diseases (eg, Paget’s disease, fibrous dysplasia) 
(Shane et al, 2014). 
The increased rate of femoral fractures in OI is likely related to the brittleness of bones 
and the femoral fractures in OI tend to resemble AFF.  Earlier data suggested an 
increased risk of AFF-like femur with antiresorptive (bisphosphonate) use 
(Nicolau et al, 2012), but more recent studies suggest that the atypical features of femur 
fractures were likely related to severity of OI and not bisphosphonate use 
(Trejo et al, 2017; Vuorimies et al, 2017). 
To minimize this risk, the following strategies will be employed: 
 
Subjects will be seen no less frequently than every 6 months and can have hip 
X-rays where clinically suspected.  All femur fractures will be reviewed by the study 
team and site investigator to determine if change in treatment is required.   
In alignment with the Study 20130173 data monitoring committee terminology, all femur 
fractures will be reviewed as typical OI femur fractures (TOIFF). 
4. 
Objectives, Endpoints and Hypotheses 
4.1 
Objectives and Endpoints 
 
 
 
Exploratory 
Objectives 
Endpoints 
Primary 
 
To evaluate long-term safety of 
denosumab in subjects with 
pediatric osteogenesis imperfecta 
(OI) completing Study 20130173 
 
The primary endpoints are subject incidence of 
adverse events, serious adverse events, and 
adverse events of special interest, subject 
incidence of antidenosumab antibodies, changes 
from baseline in laboratory values and vital signs, 
and subject incidence of metaphyseal index 
Z-score above age-appropriate normal range, 
abnormal molar eruption, and mandibular 
shaping 
Secondary 
 
To describe changes in bone 
mineral density (BMD) of lumbar 
spine and proximal femur (total hip 
and femoral neck) from baseline to 
6, 12, and 24 months 
 
Actual values and changes in BMD Z-score of 
lumbar spine and proximal femur (total hip and 
femoral neck) from Study 20170534 baseline, as 
assessed by dual X-ray absorptiometry (DXA), at 
6, 12, and 24 months 


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Rationale for Changing Study Endpoints (Protocol Amendment 5) 
Fracture and growth velocity efficacy endpoints have been deleted due to multiple 
treatment sequences during the trial and an urgent safety measure with early 
termination leading to a small number of subjects for quality statistical analysis.  
Adverse events of fracture, including femur fractures, will be presented in the 
adverse event tables. 
4.2 
Hypotheses 
This study is descriptive in nature and does not involve testing formal hypotheses.  
5. 
Study Design 
5.1 
Overall Design 
Starting from 30 September 2021, due to the life-threatening events of hypercalcemia 
reported on denosumab use in the pediatric OI study, it was decided that subjects 
would not receive any further dosing on 20170534 and would be followed for safety for 
24 weeks following the last dose of denosumab (see Section 5.1.1).  Study 
20170534 was an open-label, prospective, extension study of Study 20130173 to 
assess long-term safety and efficacy of current or prior treatment with denosumab in 
children/young adults with OI.  This study was required for compliance with key binding 
elements from the denosumab PIP for Study 20130173.  All subjects who completed 
EOS on Study 20130173, regardless of whether they received investigational product 
until the last protocol-specified dose on the 20130173 study or ended investigational 
product early, were offered participation in a long-term open-label follow-up study – 
where this protocol had been approved at the site.  Subjects who withdrew 
consent/assent to transition to 3-Month Dosing Regimen on 20130173 were also offered 
participation in this study.  When subjects in Study 20130173 neared the EOS visit 
(completion), subjects were offered participation in Study 20170534.  If a subject was 
rolled over into the 20170534 study, they were offered to receive alternative treatment 
including commercial denosumab every 6 months (6-Month Dosing Regimen) or would 
be observed without any treatment or the investigational product given every 3 months 
(3-Month Dosing Regimen). 
For subjects that consent/assent to participate in Study 20170534, Screening and study 
day 1 visit should coincide with Study 20130173 EOS visit.  Where this is not possible, 


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the screening visit should occur on or within 28 days of the Study 20130173 EOS visit.  
Study day 1 should occur within 7 days from Screening. 
Subjects enrolled in the study may be treated with denosumab or alternative 
osteoporosis medication/s at the discretion of the investigator, or may discontinue any 
osteoporosis medication for off-treatment observation.  At any time during the study 
subjects may (1) discontinue denosumab, (2) resume denosumab (3-Month Dosing 
Regimen), (3) initiate alternative osteoporosis medication/s, and (4) discontinue 
alternative osteoporosis medication/s, based on the medical judgment of the investigator 
and per local standard of care (as applicable).  In subjects who transition from 
denosumab to an alternative osteoporosis medication, the latter should be administered 
approximately 3 months after the last denosumab dose, ie, the next visit scheduled to 
receive study treatment, unless otherwise medically indicated.  Similarly, transition from 
1 standard of care osteoporosis medication to another or a reduced dose of denosumab 
should occur at the end of the dosing interval of the previous therapy.  For subjects 
electing alternative therapy, alternative therapy may be administered by any qualified 
healthcare provider (HCP).  The HCP must provide a written note to the subject 
describing the nature and date of alternative treatment to be documented by the 
investigative site.  Subjects on alternative regimens given by HCPs other than 
investigational product, will continue to attend the study site every 6 months (weeks 12, 
36, 60, and 84). 
Subjects should return to the study site every 12 weeks (± 7 days) for treatment with 
denosumab.  Subjects who are on observation only or on 6-Month dosing for alternative 
medications may attend scheduled visits every 24 weeks.  For subjects receiving 
alternative osteoporosis medication/s, dosing frequency will be determined by the 
treatment regimen selected by the investigator, subjects will attend scheduled study 
visits every 6 months as per the Schedule of Activities (Table 2-1).  In this case, where a 
dosing visit does not coincide with a scheduled study visit, additional collection of 
assessments is not required other than recording of the medication on the concomitant 
medication eCRF page under alternative osteoporosis medication.  All subjects should 
return for a final EOS/Early Termination visit.   
Samples will be collected for clinical laboratory testing, including assessment of BTM 
and antidenosumab antibodies.  Adverse events will be assessed throughout the study.  
Subjects will undergo DXA and radiographic assessments as detailed in the Schedule of 
Activities (Table 2-1).  


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The overall study design is described by a study schema in Figure 2.1.  The endpoints 
are defined in Section 4.1. 
5.1.1 
All Dosing Stopped and Subjects on Denosumab Followed for Safety 
Recently, life-threatening events of hypercalcemia were reported on denosumab 
1 mg/kg Q3M regimen in the pediatric OI subjects within 20130173 study.  Amgen 
considers that the overall benefit:risk profile of Prolia (denosumab) (Q3M/Q6M) is not 
favorable in the OI pediatric patient population based on the data observed and decided 
to stop the 20170543 study for any further enrollment or dosing with denosumab.  
Per the 30 September 2021 DIL, all investigators were notified to immediately stop 
denosumab treatment and continue the study as per the normal schedule of 
assessments (without denosumab treatment).  All subjects participating in the study will 
be followed for 24 weeks after their last dose of denosumab.  At 24 weeks the End of 
Study (EOS) Assessments should be completed per the current Schedule of Activities 
(Table 2-1).  
Subjects who were on denosumab (every 3 months or every 6 months treatment) and 
stopped denosumab more than 24 weeks ago should be scheduled for their EOS Visit at 
the next scheduled visit and have their EOS Visit assessments conducted per the 
current Schedule of Activities (Table 2-1). 
Subjects on observational or alternative therapies that have never taken denosumab 
should complete their EOS visit at the next scheduled visit (Table 2-1). 
5.2 
Number of Subjects 
The number of subjects in this study will be determined by the number of subjects 
completing Study 20130173, and who are willing and able to participate in the long-term 
follow-up study. 
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.  
Subjects may switch to an alternative osteoporosis medication/s, or, if they discontinue 
all treatment, they will be followed as off-treatment (observation only).  Subjects may 
resume/start denosumab 3-Month Dosing Regimen at any time during the study.  Any 
subject starting denosumab 3-Month Dosing Regimen for the first time will complete 
day 1 and continue for a minimum of 12 months. 


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5.2.2 
Number of Sites 
Approximately 40 investigative sites in North America, Europe, and Australia were 
planned in Study 20130173.  Any sites with subjects willing and able to participate in this 
study will be included.  Sites that do not enroll any subjects within 28 days of the last 
participant last visit of Study 20130173 will be closed as subjects would no longer be 
eligible for inclusion.  Subjects who were already taking denosumab 6-Month Dosing 
Regimen will be offered the opportunity to move to the 3-Month Dosing Regimen. 
5.3 
End of Study 
5.3.1 
End of Study Definition 
An individual subject is considered to have completed the study if he/she has completed 
week 96 visit, except for those subjects enrolled prior to the 6-Month Dosing Regimen of 
Protocol Amendment 1 and transitioning to a 3-Month Dosing Regimen.  Starting from 
30 September 2021, subjects on denosumab who had not completed their EOS were 
immediately discontinued from denosumab and will be followed for 24 weeks following 
the last dose of denosumab.  
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), following any additional parts in the study (eg, long-term follow-up), as applicable. 
5.3.2 
Study Duration for Subjects 
The duration of study for each subject that enrolls in this study is expected to be up to 
120 weeks, including treatment and final visit/EOS visit, whether or not they are 
receiving denosumab or alternative osteoporosis medication or off-treatment 
(observation only).  For subjects already enrolled on the 20170534 study on the 6-Month 
Dosing Regimen, regardless of the arm of the study they are on, that 
consents/assents/switches to denosumab investigational product 3-Month Dosing 
Regimen (for the first time) whom are expected to complete a minimum of 12 months on 
investigational product, may consequently exceed the expected 96 weeks on-study if 
they switch beyond week 48. 
5.4 
Justification for Investigational Product Dose 
Ongoing bone treatment will be at the discretion of the investigator, allowing 
denosumab, alternative osteoporosis medication/s per local standard of care, or 
off-treatment observation.  Subjects who continue denosumab on 3-Month Dosing 
Regimen from 20130173 will continue the dose (1 mg/kg, up to a maximum of 60 mg) 
used in Study 20130173, with appropriate adjustments made for change in body weight.  


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Dose and dosing regimen for alternative osteoporosis medication/s that may be used 
during the study at investigator’s discretion will be determined by local standard of care. 
5.5 
Patient Input on Study Design 
Not applicable. 
6. 
Study Population 
Eligibility will be evaluated at EOS visit of Study 20130173 based on assessments done 
at this visit including discussion with subject and willingness to participate within 
28 days.  Screening will occur on or within 28 days of the EOS visit of Study 20130173. 
Before any study-specific activities/procedures, the appropriate written informed 
consent/assent must be obtained (see Section 12.3). 
Subjects who were enrolled into this study under Protocol Amendment 1 will be 
reconsented/reassented at their next visit, and those receiving investigational product 
(denosumab) will transition to a 3-Month Dosing Regimen.  Subjects receiving 
alternative OI medication/s (alternative therapy includes the commercial denosumab 
6-Month Dosing Regimen) or off-treatment (observation only) may also consent/assent 
to resume denosumab 3-Month Dosing Regimen.  Subject eligibility will not be 
re-assessed at time of transition to 3-Month Dosing Regimen. 
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 20170534 specific activities/procedures. 
Subject’s legally acceptable representative has provided informed consent when 
the subject is legally too young to provide informed consent and the subject has 
provided written assent based on local regulations and/or guidelines prior to any 
study-specific activities/procedures being initiated. 
102. 
Subject was enrolled in Study 20130173 and: 
 completed the 20130173 EOS visit (regardless of completing or ending 
investigational product early).  
OR 
 Subjects who do not reconsent/reassent to transition to 3-Month Dosing 
Regimen on Study 20130173 are also eligible for enrollment 
OR 


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 Early terminated from Study 20130173 as a result of meeting BMD Z-score 
investigational product stopping criteria and was required to early terminate 
from the study  
6.2 
Exclusion Criteria  
Subjects are excluded from the study if any of the following criteria apply:   
Prior/Concomitant Therapy 
201. 
Treatment with any prohibited proscribed medications (see Section 7.1.7) while 
receiving denosumab.  Eligibility into study treatment with alternative 
osteoporosis medication/s of investigator’s choice, follow guidelines per the 
specific alternative osteoporosis medication/s selected.  For subjects off-
treatment (observation only), no prohibited medications apply. 
Prior/Concurrent Clinical Study Experience 
202. 
Subjects currently receiving treatment in another investigational device or drug 
study other than Study 20130173.  Other investigational procedures while 
participating in this study are excluded. 
Other Exclusions 
203. 
For subjects expected to receive investigational product (denosumab) at study 
day 1:  Female subject is pregnant or breastfeeding or planning to become 
pregnant or breastfeed during treatment and for an additional 5 months after the 
last dose of denosumab.  Females of childbearing potential (Tanner Stage ≥ 2) 
should only be included in the study after a negative highly sensitive urine 
pregnancy test.  For study treatment with alternative osteoporosis medication/s of 
investigator’s choice, follow guidelines per the specific alternative osteoporosis 
medication/s selected.  For subjects off-treatment (observation only), no 
exclusion applies. 
204. 
For subjects expected to receive investigational product (denosumab) at study 
day 1:  Female subjects of childbearing potential unwilling to practice true sexual 
abstinence (refrain from heterosexual intercourse) or use 1 highly effective 
method of contraception during treatment and for an additional 5 months after the 
last dose of investigational product (denosumab).  For study treatment with 
alternative osteoporosis medication/s of investigator’s choice, follow 
contraception guidelines per the specific alternative osteoporosis medication/s 
selected.  For subjects off-treatment (observation only), no contraception 
required.  Refer to Section 12.5 for additional contraceptive information. 
205. 
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.  
6.3 
Subject Enrollment 
Due to the life-threatening risk of hypercalcemia, an urgent safety measure has been 
implemented to stop all enrollment and treatment with denosumab with the EOS visit 24 
weeks after the last dose of denosumab.  See Section 5.1.1. 


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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, informed consent/assent form, and all 
other subject information, if applicable (see Section 12.3). 
The subject or the subject’s legally acceptable representative must personally sign and 
date the IRB/IEC and Amgen approved informed consent/assent 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) and contact 
the Interactive Voice Response System/Interactive Web Response System (IVRS/IWRS) 
to enroll the subject. 
Each subject who signs the IRB/IEC-approved ICF will be assigned the same subject 
identification number as the parent study (Study 20130173) before any study-related 
activities/procedures are performed. 
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. 
Subjects enrolled prior to this Protocol Amendment will be reconsented/reassented.  
Subject eligibility will not be re-assessed at time of transition to 3-Month Dosing 
Regimen. 
 
Subjects who do not reconsent/assent to a 3-Month Dosing Regimen will be 
discontinued from investigational product (denosumab) but may switch to 
alternative OI medication or off-treatment (observation only).  
 
Subjects previously receiving alternative OI medication/s or off-treatment 
(observation only) may resume investigational product (denosumab) 3-Month 
Dosing Regimen. 
A subject call will be placed in the IVRS/IWRS at time of reconsent/assent and transition 
to the 3-Month Dosing Regimen.  The investigator is to document this decision, and date 
of dosing schedule change, in the subject’s medical record. 


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6.4 
Screen Failures 
The investigator will maintain a Screening and Enrollment log to document all eligible 
subjects from parent Study 20130173, that includes limited information about the 
potential candidate, such as date of informed consent/assent (if obtained) and screen fail 
reason. 
7. 
Treatments 
There is no protocol-required investigational product in this trial.  All treatment is at 
investigator discretion and not mandated by the protocol.  Subjects may continue to be 
treated with open-label denosumab at a 3-Month Dosing Regimen, which for the 
purposes of this study is defined as any investigational product.  Investigator may decide 
to treat with alternative osteoporosis medication/s or observation only (no intervention) 
rather than administer investigational product.  All subjects regardless of treatment with 
investigational product, alternative osteoporosis medication/s (denosumab at a 6-Month 
Dosing Regimen) or observation only (no intervention) may participate in this study. 
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 denosumab 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:   
Denosumaba 
Dosage Formulation 
70 mg/mL solution containing 1.7 mL in a 3 mL vial 
Unit Dose Strength(s)/ 
Dosage Level(s) and Dosage Frequency 
1 mg/kg body weight not to exceed 60 mg per subject at any visit 
day 1, at week 12, week 24, week 36, week 48, week 60, week 72, and week 
84 
Route of Administration 
SC injection 
Accountability 
The lot number(s), start date, start time, administration setting (in-clinic, 
non-clinic), total dose administered (quantity administered, and total 
administered) of investigational product are to be recorded on each subject's 
CRF. 
Dosing Instructions 
All SC injections must be administered by authorized site personnel.  The 
denosumab SC injection must be administered as the last procedure after all 
other study visit procedures have been completed.   
CRF = case report form; SC = subcutaneous 
a Denosumab will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug distribution procedures.  
 


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7.1.2 
Non-investigational Products 
Not applicable.  
7.1.3 
Medical Devices 
Non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not provided or reimbursed by Amgen (except, for example, if 
required by local regulation).  The investigator will be responsible for obtaining supplies 
of these devices.  
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care. 
7.1.4 
Other Protocol-required Therapies 
On the 3-Month Dosing Regimen, calcium and vitamin D were dispensed as a protocol-
required therapy.  For subjects on alternative therapies including the 6 Month Dosing 
Regimen, calcium and vitamin D were not protocol-required therapies and used at the 
investigator’s discretion and local standard of care in pediatric OI.  After the Urgent 
Safety Measure, all subjects are on alternative therapy with the exclusion of the 6 Month 
Dosing Regimen and are to use calcium and vitamin D at the site’s discretion, and 
consistent with the local standard of care.   
Protocol-required therapies, including calcium and vitamin D, that are commercially 
available and are not provided or reimbursed by Amgen (except if required by local 
regulation).  The investigator will be responsible for obtaining supplies of these 
protocol-required therapies. 
Subjects administered investigational product (denosumab) are recommended to take 
daily supplements of 30 to 50 mg/kg and not to exceed 1000 mg elemental calcium and 
at least 800 IU vitamin D while on denosumab during the study.  Dose and duration of 
daily calcium and vitamin D supplementation when subjects are administered alternative 
osteoporosis medication/s will be determined by the investigator, per local standard of 
care. 
If a subject becomes hypercalcemic, hypercalciuric, or has other intolerance over the 
course of the study, the calcium and/or vitamin D supplementation may be modified or 
discontinued at investigator discretion and site will manage supplementation to maintain 
normal serum and urine calcium.  Similarly, if a subject becomes hypocalcemic over the 
course of the study, the calcium and/or vitamin D supplementation may be increased, 
per medical judgment of the investigator. 


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Any vitamin D and calcium dose adjustments will be recorded on the CRF Concomitant 
Medication page. 
Alternative therapy for OI is at investigator discretion and consistent with local standard 
of care and clinical practice guidelines. 
Additional details regarding these protocol-required therapies are provided in the IPIM. 
7.1.5 
Other Treatment Procedures 
Not applicable. 
7.1.6 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product, or device after it is released for distribution 
to market or clinic by either (1) Amgen or (2) distributors and partners for whom Amgen 
manufactures the material.  This includes all components distributed with the drug, such 
as packaging drug containers, delivery systems, labeling, and inserts. 
This includes any investigational products described above provisioned and/or 
repackaged/modified by Amgen. 
Any product complaint(s) associated with products described above and supplied by 
Amgen are to be reported according to the instructions provided in the modular IPIM. 
7.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
All medications listed in the exclusion criteria, shown in Table 7-2 below, or any other 
medication that is known or suspected to have activity on bone metabolism (except, 
calcium and vitamin D) will not be allowed during the study.  Bisphosphonates or other 
osteoporosis medications listed below are allowed as alternative osteoporosis 
medication/s, at the investigators discretion, for the duration of the study. 
Table 7-2.  List of Proscribed Therapy 
Aluminum compounds used as 
phosphate binders 
Chronic heparin use 
(> 7 days) (low molecular 
weight heparin [LMWH] are 
permitted) 
 
Progestins, when used as 
monotherapy, including 
progestogens, pregnen(4) 
derivatives, and pregnadien 
derivatives 
(progestin monotherapy 
contraceptions are permitted) 
Androgensa/Anabolic steroids:  
Natural or synthetic androgens 
alone or in combination with 
Cinacalcet 
 


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progestogen and/or estrogen 
including androstan 
derivatives, estren derivatives, 
3-oxoandrosten(4) derivatives, 
and 5-androstandon 
derivatives 
Anticonvulsants not on stable 
dose and with difficulty 
regulation calcium and 
vitamin D:  Antiepileptics, 
barbiturates and derivatives, 
hydantoin derivatives, 
oxazolidine derivatives, 
succinimide derivatives, 
carboxamide derivatives, and 
valproic acid (gabapentin and 
benzodiazepines are allowed) 
Citrated products 
Protease inhibitors 
Any investigational agents for 
bone loss other than study 
drug 
Fluoride 
Strontium 
Aromatase inhibitors:  
Including aminoglutethimide, 
anastrazole, exemestane, 
fadrozole, formestane, 
letrozole, roglemtimide, and 
vorozole 
Gonadotropin-releasing 
hormone agonists 
 
Biologics:  including biological 
(monoclonal antibody) 
immunosuppressives and 
antineoplastic agents (insulins 
and vaccines are allowed) 
Growth hormone (unless 
stable for at least 3 months 
prior to screening) 
 
Calcitonin 
Non-biologic 
immunosuppressants:  
Including chloroquine, 
hydroxychloroquine, 
azathioprine, leflunamide, 
sulfasalazine, 
cyclophosphamide, 
methotrexate, 
mycophenolate mofetil, 
cyclosporine, tacrolimus, 
sirolimus, everolimus, and 
gold preparations 
Tibolone 
Calcium chelators 
Lithium 
 
Chemotherapeutics 
Parathyroid hormone (or a 
derivative), including 
semparatide, abaloparatide, 
and teriparatide 
 
a Androgen replacement therapy is not excluded. 
7.2 
Method of Treatment Assignment 
Subjects who meet eligibility criteria will be administered treatment at investigator 
discretion and not mandated by the protocol.  Subjects may continue to be treated with 
investigational product (denosumab) or alternative osteoporosis medication/s at the 


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discretion of the investigator, or may discontinue any osteoporosis medication for 
off-treatment observation. 
The treatment administration date is to be documented in the subject’s medical record 
and on the CRF. 
7.3 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
7.4 
Dose Modification 
Denosumab will be administered as a weight-based dose determined based on each 
subject’s weight assessed at the time of dosing.  There are no additional dose 
adjustments for the SC investigational product (denosumab). 
Alternative osteoporosis medication/s selected will be adjusted per standard of care and 
local guidelines. 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
7.4.1.1 
Amgen Investigational Product:  Denosumab 
Denosumab will be administered as a weight-based dose determined based on subject’s 
weight assessed at the time of dosing every 3 months.  There, dose reduction of 
denosumab is allowed.  If a subject misses a scheduled dose of denosumab during a 
study visit, then he/she should return to the clinic to receive the missed dose within the 
visit window allowed for that particular visit.  The clinical monitor should be contacted for 
specific instructions if a subject cannot receive his/her dose within the allowed window. 
Subjects who discontinue denosumab may continue on-study on an alternative 
osteoporosis medication/s of investigator’s choice or observation only (no intervention).  
Dosing with alternative osteoporosis medication should not be until the next scheduled 
dose (ie, 12 weeks from last dose of denosumab). 
Subjects may discontinue alternative osteoporosis medication at any time.  Subjects who 
discontinue from alternative osteoporosis medication may commence or re-start 
treatment with denosumab at the next scheduled study visit. 
Dosing may be delayed if a subject has bone surgery scheduled.  Dosing with 
denosumab can be continued after the surgery at the investigator’s discretion. 
See Section 12.7 for details on hepatotoxicity. 


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Administration of Amgen investigational product (denosumab) must be stopped for 
subjects in the following situations (in addition to reasons specified in Section 8.1).  
Subjects may continue on-study with alternative osteoporosis medication of 
investigator’s choice or observation only (no intervention):  
1. Severe or symptomatic hypocalcemia 
a Subjects who are removed from treatment as a result of severe or symptomatic 
hypocalcemia should receive treatment according to local standard of care, at the 
discretion of the treating physician and should be closely followed up until resolution 
of the adverse event 
2. Severe or symptomatic hypercalcemia, which requires the use of a rescue 
medication for management 
3. Osteonecrosis of the jaw 
4. Dental abnormalities requiring invasive dental procedures, as determined by 
Investigator and/or treating dentist and within the local institutional practice 
guidelines.  Denosumab administration should be withheld 30 days prior to an 
invasive dental procedure and until complete mucosal healing is observed and 
documented (see above for guidance on restarting denosumab). 
5. 4 or more new long bone and/or vertebral fractures in any 6-month period (additional 
spine x-rays should be obtained if clinically indicated) 
6. Decline in BMD Z-score by 0.5 units at any 6-month assessment compared to the 
3-Month baseline 
a. Subjects who are removed from treatment as a result of the above fracture 
thresholds or lumbar spine BMD Z-score decline (3, 4, and 5) should be followed 
up and treated, if applicable, according to local standard of care, at the discretion 
of the treating physician 
7. Changes in growth plate morphology, as observed in the 12-month monitoring, 
considered by the investigator to be unexpected and having an adverse clinical 
impact for the subject consistent with local institutional guidelines 
8. Pregnancy 
9. Severe hypersensitivity 
7.4.1.2 
Non-Amgen Non-Investigational Product(s):  Alternative 
Osteoporosis Medication/s 
The reason for dose change or change in alternative osteoporosis medication/s is to be 
recorded on each subject’s CRF (Concomitant Medications Form).  Dose changes are at 
the discretion of the investigator.  Alternative osteoporosis medication/s is reviewed if 
any of the above situations occur, and changes or cessation will be at investigator 
discretion consistent with local standard of care. 


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7.4.1.3 
Additional Safety Monitoring of Hypocalcemia 
Hypocalcemia will be monitored as indicated in the Schedule of Activities (Table 2-1) to 
ensure the subject is not experiencing signs and symptoms of hypocalcemia. 
7.4.2 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 12.7 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 Amgen investigational product (denosumab) during the study are 
provided in the IPIM. 
7.6 
Treatment Compliance 
Not applicable for this study. 
7.7 
Treatment of Overdose 
Overdose with this product (denosumab) has not been reported.  The highest dose 
tested in clinical trials is 210 mg SC once every 6 months (6-Month Dosing Regimen).  It 
is possible that an overdose may result in hypocalcemia. 
Hypocalcemia, if severe, should be managed by oral or parenteral calcium replacement, 
as clinically indicated. 
7.8 
Prior and Concomitant Treatment 
7.8.1 
Prior Treatment 
All concomitant medications ongoing at the time of informed consent/assent will be 
recorded on the concomitant medications CRF. 
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 7.1.7. 
Concomitant therapies are to be collected and entered on the CRF from signing of 
informed consent/assent through week 96 or EOS. 
8. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product (denosumab), and/or 
other protocol-required therapies, protocol procedures, or the study as a whole at any 


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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 (denosumab), 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. 
The investigator and/or sponsor must decide to withdraw a subject(s) from 
investigational product (denosumab) for any of the following: 
 
Adverse event as defined in Section 7.4.1.1 
 
Pregnancy 
The investigator may discontinue any alternative osteoporosis medication/s at any time 
based on clinical judgment. 
8.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product (denosumab), and/or other protocol-required therapies, 
alternative OI medications, or procedures at any time during the study but continue 
participation in the study.  If this occurs, the investigator is to discuss with the subject the 
appropriate processes for discontinuation from study treatment 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,  and must document this decision in the subject’s 
medical records.  Subjects who have been discontinued from investigational product 
(denosumab) as a result of the urgent safety measure, and subjects who have 
previously discontinued IP and/or other protocol-required therapies, alternative OI 
medications, or procedures should not be automatically removed from the study.  
Subjects may continue to off-treatment (observation only) at investigator’s discretion.  
Whenever safe and feasible, it is imperative that subjects remain on-study to ensure 
safety surveillance, collection/reporting of serious adverse events, and/or collection of 
outcome data and can use alternative osteoporosis medication/s or be followed 
off-treatment (observation only) at investigator discretion.  Following implementation of 
the Urgent Safety Measure, subjects who were receiving denosumab will be followed for 
24 weeks for safety following the last dose of denosumab.   


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Subjects on observational or alternative therapies that have never taken denosumab 
should complete their EOS visit at the next scheduled visit (Table 2-1). 
Reasons for removal from investigational product (denosumab), other protocol-required 
therapies, or procedural assessments include any of the following:   
 
Decision by Sponsor 
 
Lost to follow-up 
 
Death 
 
Ineligibility determined 
 
Protocol deviation 
 
Non-compliance  
 
Adverse event (including ONJ, and severe or symptomatic hypocalcemia; see 
Section 7.4.1.1) 
 
Subject request 
 
Pregnancy 
Reasons for removal from alternative osteoporosis medication/s is at investigator 
discretion consistent with local standard of care. 
8.2 
Discontinuation From the Study 
Withdrawal of consent/assent 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/assent will be included in the analysis of the study, and where permitted, 
publicly available data can be included after withdrawal of consent/assent.  The 
investigator is to discuss with the subject appropriate procedures for withdrawal from the 
study, and must document the subject’s decision to withdraw in the subject’s medical 
records. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product (denosumab) and/or procedures at any time during the study, but 
continue participation in the study.  If this occurs, the investigator is to discuss with the 
subject the appropriate processes for discontinuation from investigational product 
(denosumab) and must discuss with the subject the options for continuation of the 
Schedule of Activities (Table 2-1) and collection of data, including endpoints and 
adverse events.  The investigator must document the change to the Schedule of 
Activities (Table 2-1) and the level of follow-up that is agreed to by the subject (eg, in 


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person, by telephone/mail, through family/friends, in correspondence/communication 
with other physicians, or from review of the 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 
Section 12.6 for further details).  Refer to the Schedule of Activities (Table 2-1) 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 
Not applicable for 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 (Table 2-1), is essential and required for study conduct. 
9.1 
General Study Periods 
9.1.1 
Screening and Enrollment  
Informed consent/assent must be obtained before completing any study procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject has 
signed the informed consent/assent form, the site will register the subject in the 
IVRS/IWRS.  Screening and study day 1 visit should coincide with Study 20130173 EOS 
visit, however if not, subjects should screen within 28 days from the Study 
20130173 EOS visit.  Study day 1 should occur within 7 days from Screening. 
Data from Study 20130173 EOS visit will be used as baseline and assessments should 
not be duplicated.  All imaging and laboratory assessments should be conducted for 
Study 20130173 EOS visit and data will be transferred to the Study 20170534 screening 
visit.  Physical examination, physical measurements, vital signs, Tanner stage, and 
pregnancy test assessments should be conducted if Study 20130173 EOS and screening 
visits do not occur on the same day.  25 (OH) vitamin levels should be collected at 
Screening. 
The investigator will maintain a Screening and Enrollment log to document that all 
eligible subjects were offered participation.  The investigator should note the subject 
number, enrollment date, or reason that the subject screen failed or did not enroll. 
9.1.2 
Treatment Period 
As a result of the potentially life-threatening risk of hypercalcemia, starting from 
30 September 2021, all further dosing of denosumab in this study was stopped and 
enrollment was closed.  Refer to Section 5.1. 
Visits will occur per the Schedule of Activities (Table 2-1).  On-study visits may be 
completed within ± 7 days.  Study day 1 is the date of the first dose of investigational 


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product (denosumab) or alternative osteoporosis medication/s, or the date of informed 
consent/assent for observation only subjects.  All subsequent doses and study visits will 
be scheduled based on the Study day 1 date.  Administration of investigational product 
(denosumab) or alternative osteoporosis medication is to be administered by authorized 
site personnel only after all other study visit procedures have been completed. 
If the investigator has opted for No Study Treatment (observation only) for the subject, 
all study assessments will be performed as per the Schedule of Activities (Table 2-1).  
Subjects enrolled prior to this Protocol Amendment and receiving 6-Month Dosing 
Regimen will be reconsented/assented to the 3-Month Dosing Regimen.  Subjects will 
complete a Study day 1 assessments for 3-Month Dosing Regimen per Schedule of 
Activities (Table 2-1). 
Subjects who do not consent/assent to 3-Month Dosing Regimen may switch to an 
Alternative OI Medication/s or off-treatment (observation only).  Subjects may resume 
investigational product (denosumab 3-Month Dosing Regimen) at any time. 
9.1.3 
Safety Follow-up/End of Study 
Per the 30 September 2021 DIL, all investigators were notified to immediately stop 
denosumab treatment and continue the study as per the normal schedule of 
assessments (without denosumab treatment).  All subjects participating in the study will 
be followed for 24 weeks after their last dose of denosumab.  At 24 weeks the End of 
Study (EOS) Assessments should be completed per the current Schedule of Activities 
(Table 2-1).  
Subjects who were on denosumab (3 months or every 6 months treatment) and stopped 
denosumab more than 24 weeks ago should be scheduled for their EOS Visit at the next 
scheduled visit and have their EOS Visit assessments conducted per the current 
Schedule of Activities (Table 2-1). 
Subjects on alternative or observational therapy that have never taken denosumab 
should complete the EOS assessments at the next scheduled visit (Table 2-1).  
If possible, the procedures of the EOS visit should be completed at the time of 
withdrawal with the following exception:   
 
Procedures involving X-ray radiation exposure other than DXA assessment may not 
be performed if < 3 months have elapsed since the previous radiographic 
assessment. 
 
DXA scans will only be performed if > 30 days have elapsed since the previous 
assessment. 


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9.1.4 
End of Study 
The EOS visit will be performed during the safety follow-up as described in 
Section 9.1.3. 
9.2 
Description of General Study Assessments and Procedures 
As a result of the potentially life-threatening risk of hypercalcemia, starting from 
30 September 2021, all further dosing of denosumab in this study was stopped and 
enrollment was closed.  Refer to Section 5.1. 
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/Assent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent/assent before any study-specific procedures are 
performed.   
A child is defined as a person who has not attained the legal age for consent for 
treatments or procedures involved in clinical investigations, under the applicable law of 
the jurisdiction in which the clinical investigation will take place.  Country-specific 
requirements should be followed for specific local information. 
9.2.1.2 
Demographics 
Demographic data (except age) will be carried over from Study 20130173.  Demographic 
data collection, including sex, age, race, and ethnicity may be used to study their 
possible association with subject safety and treatment effectiveness.   
9.2.1.3 
Medical History 
All data entered in the 20130173 medical history, fracture history, and OI history will be 
transferred into the 20170534 database.  Resolved and ongoing adverse events 
(including fractures) on Study 20130173 will be entered into the medical history or 
subject fracture history forms at the investigator discretion. 
Events starting after the EOS visit of Study 20130173 but prior to the screening visit of 
this study will be entered in the Event CRF and flagged as adverse events occurring 
between last study visit of Study 20130173 and prior to informed consent/assent on 
Study 20170534.  


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9.2.1.4 
Physical Examination  
A pelvic, breast, or rectal examination is not required unless a specific evaluation is 
warranted.  Physical examination findings should be recorded on the appropriate CRF 
(eg, medical history, event).  
Where the screening visit coincides with the Study 20130173 EOS visit, the physical 
examination should not be repeated.  The physical examination should be conducted if 
the Study 20130173 EOS and screening visits do not occur on the same day. 
9.2.1.5 
Physical Measurements 
Height in centimeters should be measured without shoes.  Height measurements will be 
performed in the standing position unless it is not possible to do so.  In instances where 
standing height cannot be measured, measurement of recumbent height will be allowed. 
Weight in kilograms should be measured without shoes. 
Armspan is measured with the child leaning against a flat surface (eg, wall) with the 
arms outstretched (or extended to the best of the child’s ability) parallel to the ground at 
shoulder height, and between the tip of the middle fingers of the left and right hands.  
The flat surface should have a fixed point against which the child places 1 middle finger 
and a mark should be made on the surface for the opposite middle finger.  The child 
then steps away and the distance between the fixed point and the new mark is 
measured and recorded. 
Where the screening visit coincides with the Study 20130173 EOS visit, physical 
measurements should not be repeated.  Physical measurements should be assessed if 
the Study 20130173 EOS and screening visits do not occur on the same day. 
9.2.2 
Efficacy Assessments 
Radiographic Assessments 
Radiographic assessments should be conducted for the Study 20130173 EOS visit and 
data will be transferred to the Study 20170534 screening visit. 
All available radiographic assessments for evaluation of potential fracture from day 1 
until EOS, including any unscheduled assessments, will be submitted to central imaging 
vendor for final analysis. 
Dual-energy X-Ray Absorptiometry Assessments 
All subjects will undergo bone densitometry assessments of the lumbar spine and 
subjects 5 years of age or older at screening will undergo bone densitometry 


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assessments of the proximal femur (for total hip and femoral neck) performed by DXA 
per the schedule outlined in Table 2-1.  Scans will be performed at all applicable visits. 
A DXA should be performed as indicated in the Schedule of Activities (Section 2.2). 
Only General Electric Lunar or Hologic bone densitometers will be allowed for this study.  
The same DXA machine should be used for all study procedures for a particular subject.  
Any changes to DXA machines should follow the requirements specified in the Imaging 
Manual.  The left side should be used for proximal femur, unless prohibited (eg, hip 
implant).  If another side must be used or is inadvertently used during day 1, then it must 
be used consistently throughout the study.  Lumbar spine scans should include L1 
through L4. 
After analysis of the scans by the central imaging vendor, the study site may be asked to 
re-acquire a scan, because of poor positioning or other technical reasons.  The 
investigator sites must comply with the requests from the central imaging vendor. 
Detailed instructions for scan acquisition will be in a separate manual provided by the 
central imaging vendor. 
Spine Radiographs 
Lateral radiographs of the thoracic and lumbar spine will be obtained annually to 
determine vertebral fracture status. 
For the purposes of this study, fractures related to OI are not considered pathological 
fractures, however pathological will relate to fractures in this disease of interest. 
Blood and Serum Assessments 
 
All blood samples will be obtained by venipuncture before investigational product 
administration.  The average volume of blood drawn per visit will be approximately 
5.0 mL.  
 
Refer to Section 12.2 
9.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Table 2-1). 


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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 
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 Section 12.4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur from screening through week 96 or 
EOS: 
 
the EOS visit (week 96) for a completed subject, or  
 
for subjects receiving investigational product (denosumab) and who withdraw full 
consent/assent prior to EOS, 30 days after the last dose of investigational product 
(denosumab), or 
 
for subjects receiving alternative osteoporosis medication/s or observation only and 
who withdraw consent/assent prior to EOS, until consent/assent is withdrawn, are 
reported using the Event CRF. 
9.2.3.1.1.2 
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 
20170534 informed consent/assent through the EOS visit or for subjects who withdraw 
full consent/assent prior to EOS 30 days after the last day of treatment with 
investigational product (denosumab) are reported using the Event CRF.  Any serious 
adverse events that occur prior to signing the 20170534 informed consent/assent can be 
reported using the electronic Serious Adverse Contingency Report Form for 
20130173 as per 20130173 protocol Section 9.2.1.2. 
Adverse events that are adjudicated as positive for ONJ will be categorized as serious 
adverse events and will follow the serious adverse events reporting as noted above. 
There are no anticipated serious adverse events that are not planned to be reported 
individually in an expedited manner. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours, as indicated in Section 12.4.  The investigator will submit any 
updated serious adverse event data to the sponsor within 24 hours of it being available. 


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Since the criteria the CTCAE grading scale differs from the regulatory criteria for serious 
adverse events, if adverse events correspond to grade 4 CTCAE toxicity grading scale 
criteria (eg, laboratory abnormality reported as grade 4 without manifestation of life-
threatening status), it will be left to the investigator’s judgment to also report these 
abnormalities as serious adverse events.  For any adverse event that applies to this 
situation, comprehensive documentation of the event’s severity must be recorded in the 
subject medical records. 
9.2.3.1.1.3 
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 using the 
electronic Serious Adverse Event Contingency Report form. 
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 (denosumab).  
The method of recording, evaluating, and assessing causality of adverse events, and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Section 12.4. 
If further safety related data is needed to fulfill any regulatory reporting requirements for 
a reportable event, then additional information may need to be collected from the 
subject’s records after the subject ends the study. 
9.2.3.1.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to 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 


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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 Section 12.4. 
All new information for previously reported serious adverse events including those that 
initiated during Study 20130173 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 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 and, if indicated, female 
partners of male subjects, will be collected after the start of investigational product 
(denosumab) and until 5 months after the last dose of investigational product 
(denosumab). 
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 


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Section 12.5.  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. 
Further details regarding pregnancy and lactation are provided in Section 12.5. 
9.2.3.2 
Vital Signs 
The following measurements should be performed:  systolic and diastolic blood pressure 
(if clinically acceptable by the Investigator), heart rate, respiratory rate, and temperature.  
Subject should be in a supine position in a rested and calm state for at least 5 minutes 
before heart rate assessments are conducted.  If the subject is unable to be in the 
supine position, the subject should be in most recumbent position as possible.  The 
position selected for a subject should be the same that is used throughout the study and 
documented on the vital sign CRF.  The temperature location selected for a subject 
should be the same that is used throughout the study and documented on the vital signs 
CRF.  Record all measurements on the vital signs CRF. 
Where the screening visit coincides with the Study 20130173 EOS visit, vital signs 
should not be repeated.  Vital signs should be assessed if the Study 20130173 EOS and 
screening visits do not occur on the same day.  
9.2.3.3 
Other Safety 
Knee Radiograph Anteroposterior 
This will be performed only in subjects with open growth plates who do not have bilateral 
hardware.  Radiographs of the knee assessed in Study 20130173 should be obtained.  
The knee for assessment of metaphyseal index during the study should be the knee 
assessed in Study 20130173, unless prohibited by presence of hardware, in which case 
an anteroposterior radiograph of the contralateral knee may be obtained. 
Lateral Cephalogram 
The lateral cephalogram is a profile X-ray of the skull and soft tissues and is used to 
assess the relation of the teeth in the jaws, the relation of the jaws to the skull, and the 
relation of the soft tissues to the teeth and jaws.  Lateral cephalogram will be performed 
to enable assessment of mandibular shaping. 


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Panoramic Radiogram 
The panoramic radiogram is a panoramic scanning dental X-ray of the upper and lower 
jaw, which shows a 2-dimensional view of a half-circle from ear to ear.  Panoramic 
radiogram will be performed to monitor molar eruption at day 1, 3-Month Dosing 
Regimen day 1 visit, and end of the study. 
Other Dental Radiograms 
As indicated below (see “Oral Visual Inspection”), reflex radiographic assessment 
(eg, panoramic, bitewing, or periapical view) may be performed in the event a subject is 
referred to a dentist due to suspicion of unerupted molar(s), based on visual inspection.  
The choice of technique/view for this reflex radiographic assessment (eg, panoramic, 
bitewing, or periapical view) will be determined by the dentist based on his/her 
professional judgment.  All films resulting from these assessments should be submitted 
to the central imaging vendor. 
Oral Visual Inspection 
Each subject will undergo a visual inspection under natural light for the presence of 
molars.  Since third molar eruption normally occurs after age 21, evaluation of third 
molar eruption will not be carried out. 
Oral visual inspection should be performed at screening and at visits for the 3-Month 
Dosing Regimen to assess the risk for unerupted molars.  The subject should be 
referred to a dentist to perform radiographic assessment of the unerupted molar(s) (see 
“Other Dental Radiograms”) if:   
 
A subject is 7 years of age or older and appears to have an unerupted upper or 
lower first molar (ie, all 4 first molars should be visible/detectable). 
 
A subject is 13 years of age or older and appears to have an unerupted upper or 
lower (first or) second molar (ie, all 4 first molars and all 4 second molars should 
be visible/detectable).  
Any Other Safety procedures captured at EOS visit of Study 20130173 may be used as 
the baseline visit data for this study if the visit is combined. 
9.2.4 
Clinical Laboratory Assessments 
Refer to Section 12.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Table 2-1) 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 


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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) 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. 
All protocol-required laboratory assessments, as defined in Section 12.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Table 2-1).  
9.2.4.1 
Pregnancy Testing 
A highly sensitive (urine) pregnancy test should be completed within 7 days prior to 
initiation (day 1) and subsequent dosing of investigational product (denosumab) for 
female subjects who are at Tanner stage 2 (or higher) or have had menarche.  For these 
subjects, a negative pregnancy test must be confirmed prior to administration of 
denosumab at all scheduled visits.  Refer to Schedule of Activities (Table 2-1).  
Pregnancy tests should be performed for subjects receiving alternative OI medications 
as per label instructions. 
Additional on-treatment pregnancy testing (urine) may be performed at the investigator’s 
discretion if there is suspicion that a female subject is pregnant or per local laws and 
regulations. 
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Worksheet, see Figure 12-2).  Refer to Section 12.5 for contraceptive requirements. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
9.2.5 
Antibody Testing Procedures 
Blood sample(s) are to be collected (from denosumab treated subjects only) as specified 
in the Schedule of Activities (Table 2-1) for the measurement of antidenosumab binding 
antibodies.  Antibody testing should be conducted for the Study 20130173 EOS visit and 
data will be transferred to the Study 20170534 screening visit.  Samples testing positive 
for binding antibodies will also be tested for neutralizing antibodies and may be further 


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characterized.  Additional blood samples may be obtained to rule out antidenosumab 
antibodies during the study. 
Subjects who test positive for binding, non-neutralizing antibodies and have clinical 
sequelae that are considered potentially related to an antidenosumab antibody response 
may also be asked to return for additional follow-up testing.  This testing is to occur 
approximately every 3 months from the final scheduled antibody time point and continue 
until:  (1) 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 denosumab.  All follow-up 
results, both positive and negative will be communicated to the sites.  More frequent 
testing or testing for a longer period of time may be requested in the event of 
safety-related concerns. 
9.2.6 
Other Assessments  
9.2.6.1 
End of Study Visit 
Per the 30 September 2021 DIL, all investigators were notified to immediately stop 
denosumab treatment and continue the study as per the normal schedule of 
assessments (without denosumab treatment).  All subjects participating in the study will 
be followed for 24 weeks after their last dose of denosumab.  At 24 weeks the End of 
Study (EOS) Assessments should be completed per the current Schedule of Activities 
(Table 2-1).  
Subjects who were on denosumab (3 months or every 6 months treatment) and stopped 
denosumab more than 24 weeks ago should be scheduled for their EOS Visit at the next 
scheduled visit and have their EOS Visit assessments conducted per the current 
Schedule of Activities (Table 2-1).  
Subjects on alternative or observational therapy that never taken denosumab should 
complete the EOS assessment at the next schedule visit  s(Table 2-1)  
If possible, the procedures of the week 96 EOS visit should be completed at the time of 
withdrawal with the following exception:   
 
Procedures involving X-ray radiation other than DXA assessment may not be 
performed if less than 3 months have elapsed since the previous radiographic 
assessment. 
 
DXA scans will only be performed if more than 30 days have elapsed since the 
previous assessment.  


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10. 
Statistical Considerations 
10.1 
Sample Size Determination 
The number of subjects in this study will be determined by the number of subjects 
completing Study 20130173, and who are willing and able to participate in the long-term 
follow-up study.  All statistical analyses will only involve descriptive statistics, and no 
formal hypothesis testing will be done.  Therefore, no sample size calculation is 
necessary for this study. 
For sample sizes ranging from 100 to 150 subjects, the 95% CI based on exact method 
for the incidence rate of a particular adverse event is calculated below (Table 10-1).  If 
none of the subjects report a particular adverse event, then a true incidence rate of more 
than 3.6% for 100 subjects and 2.4% for 150 subjects is unlikely for that particular 
adverse event. 
Table 10-1.  Estimated 95% CI for Example Adverse Events of Interest Incidence 
Rate 
Number of Subjects 
Reporting Adverse Event 
Adverse Event Incidence Rate 
Estimate (%) 
95% CI (%) 
0/100 
0 
(0.0, 3.6) 
1/100 
1 
(0.0, 5.4) 
5/100 
5 
(1.6, 11.3) 
10/100 
10 
(4.9, 17.6) 
0/120 
0 
(0.0, 3.0) 
1/120 
0.8 
(0.0, 4.6) 
6/120 
5 
(1.9, 10.6) 
12/120 
10 
(5.3, 16.8) 
0/150 
0 
(0.0, 2.4) 
1/150 
0.7 
(0.0, 3.7) 
8/150 
5.3 
(2.3, 10.2) 
15/150 
10 
(5.7, 16.0) 
 


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10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
Full Analysis Set 
The full analysis set (FAS) includes all enrolled subjects who have provided informed 
consent/assent and have a non-missing enrollment date.  
Safety Analysis Set 
The safety analysis set includes all subjects in the FAS who received ≥ 1 dose of 
denosumab during Study 20130173. 
DXA Analysis Set 
The DXA analysis set includes all subjects in the FAS with baseline and ≥ 1 postbaseline 
valid DXA assessments for the endpoint of interest (lumbar spine, total hip or femoral 
neck) as provided by the central imaging vendor.  Note that this subset could potentially 
be different from endpoint to endpoint due to missing data. 
Metaphyseal Analysis Set 
This analysis set includes all subjects in the safety analysis set with open growth plates 
(and no hardware preventing accurate calculation of metaphyseal index) at baseline and 
X-ray of the knee at baseline and postbaseline. 
Details on analysis sets will be included in the Statistical Analysis Plan.  
10.2.2 
Covariates 
Not applicable for this study.  
10.2.3 
Subgroups 
Not applicable for this study.  
10.2.4 
Handling of Missing and Incomplete Data 
In general, analyses will be based on available data.  Missing outcomes of interest will 
not be imputed.  Missing dates will be imputed, the details of which will be included in 
the Statistical Analysis Plan. 


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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 the 
EOS, as defined in Section 5.3.1. 
10.3.1 
Planned Analyses 
10.3.1.1 
Interim Analysis and Early Stopping Guidelines 
Not applicable for this study. 
10.3.1.2 
Primary Analysis 
Primary analysis will occur upon completion of the study when the last subject 
completes the 24-week follow-up visit following the last dose of denosumab. 
10.3.1.3 
Final Analysis 
No final analysis is planned as the primary analysis will occur at the end of the study. 
10.3.2 
Methods of Analyses 
10.3.2.1 
General Considerations 
Statistical analysis in this study will be descriptive in nature and statistical inferences will 
be for guidance only.  Descriptive statistics will be provided for baseline demographics 
and subject characteristics based on the FAS, and for all endpoints based on their 
respective analysis sets and within each pattern of treatment received during the study if 
data warrant.  Continuous outcomes will be summarized by the number of non-missing 
values, mean, SD, median, lower and upper quartiles and minimum and maximum 
values.  Nominal and ordinal categorical variables will be summarized using counts and 
percentages.  All outcomes will be summarized for both the FAS and within each pattern 
of treatment received during the study, if warranted by the data.  Detailed definition of 
treatment patterns will be provided in the Statistical Analysis Plan. 
Details will be described in the Statistical Analysis Plan. 
10.3.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
The analysis of primary endpoints will be descriptive, and details will be 
provided in the SAP. 
Secondary 
The analysis of secondary endpoints will be descriptive, and details will be 
provided in the SAP. 


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Exploratory 
For each exploratory endpoint, descriptive statistics will be provided per 
described in Section 10.3.2.1 and details will be provided in the SAP. 
SAP = statistical analysis plan 
10.3.2.3 
Safety Analyses 
10.3.2.3.1 
Analyses of Primary Safety Endpoint(s) 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Descriptive statistics will be provided as described in Section 10.3.2.1 for both 
the FAS and within each pattern of treatment received during the study if data 
warrant for rate of adverse events, serious adverse events, and adverse 
events of special interest. 
 
10.3.2.3.2 
Adverse 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 (denosumab), and 
adverse events of special interest will also be provided.  The adverse events of special 
interest will include changes in growth plate morphology, severe or symptomatic 
hypocalcemia, ONJ, abnormal molar eruption, hypercalcemia, and abnormal mandibular 
shaping. 
10.3.2.3.3 
Laboratory Test Results 
Actual values and changes from baseline in each parameter will be descriptively 
summarized at each visit.  For serum calcium, phosphorus, and alkaline phosphatase 
(ALP), summary of the percent change from baseline also will be provided. 
Shifts in laboratory parameters between baseline and the most extreme postbaseline 
values will be assessed based on the CTCAE v4.03. 
All laboratory analyses will be done for both the FAS and within each pattern of 
treatment received during the study if data warrant.  Subjects with missing data for a 
scheduled visit will not contribute to the tabulation for that time point (no imputation). 
10.3.2.3.4 
Vital Signs 
Descriptive statistics of the actual values and changes from baseline in vital signs (heart 
rate, respiration rate, temperature) will be presented by visit for both the FAS and within 
each pattern of treatment received during the study if data warrant. 
Subjects with missing data for a scheduled visit will not contribute to the tabulation for 
that time point (no imputation). 


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10.3.2.3.5 
Antibody Formation 
Immunogenic response during the study will be described by tabulating the numbers and 
percentages of subjects who tested positive for (binding and neutralizing) 
antidenosumab antibodies based on subjects treated with denosumab in this study. 
10.3.2.3.6 
Exposure to Investigational Product 
Subjects are considered exposed to denosumab if they received at least 1 dose of 
denosumab during the study. 
Administration dates and doses of denosumab will be collected and cumulative 
denosumab exposure will be recorded and summarized using descriptive statistics. 
10.3.2.3.7 
Exposure to Non-Amgen Product:  Alternative Osteoporosis 
Medication/s 
Subjects are considered exposed to alternative osteoporosis medication/s if they 
received at least 1 dose of alternative osteoporosis medication/s during the study. 
Administration dates, routes, and doses of alternative osteoporosis medication/s will be 
collected and cumulative alternative osteoporosis medication/s will be recorded and 
summarized using descriptive statistics. 


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11. 
References 
Abrahamsen B, Eiken P, Eastell R.  Subtrochanteric and diaphyseal femural fractures in 
patients treated with alendronate:  a register-based national cohort study.  J Bone Miner 
Res. 2009;24:1095-1102. 
Bargman R, Posham R, Boskey AL, DiCarlo E, Raggio C, Pleshko N.  Comparable 
outcomes in fracture reduction and bone properties with RANKL inhibition and 
alendronate treatment in a mouse model of osteogenesis imperfecta.  Osteoporos Int. 
2012;23:1141-1150. 
Baron R, Gertner JM, Lang R, et al.  Increased Bone Turnover with Decreased Bone 
Formation by Osteoblasts in Children with Osteogenesis Imperfecta Tarda.  Pediatr Res.  
1983;17:204-207. 
Boyce AM, Chong WH, Yao J, et al.  Denosumab treatment for fibrous dysplasia.  J 
Bone Miner Res. 2012;27:1462-1470. 
Brunetti G, Papadia F, Tummola A, et al.  Impaired bone remodeling in children with 
osteogenesis imperfecta treated and untreated with bisphosphonates: the role of DKK1, 
RANKL, and TNF-α.  Osteoporos Int.  2016;27:2355-2365. 
Byers PH.  Osteogenesis imperfecta: perspectives and opportunities.  Curr Opin Pediatr. 
2000;12:603-609. 
Castillo H, Samson-Fang L.  American Academy for Cerebral P, Developmental 
Medicine Treatment Outcomes Committee Review P.  Effects of bisphosphonates in 
children with osteogenesis imperfecta:  an AACPDM systematic review.  Dev Med Child 
Neurol. 2009;51:17-29. 
Centers for Disease Control and Prevention. Overview of the CDC growth Charts. 2011. 
http://www.cdc.gov/nccdphp/dnpa/growthcharts/training/modules/module2/text/module2p
rint.pdf (website accessed 23 March 2014). 
Denosumab Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.  
Dwan K, Phillipi CA, Steiner RD, et al.  Bisphosphonate therapy for osteogenesis 
imperfecta.  Cochrane Database Syst Rev.  2016;10:CD005088. 
EU Ethical Considerations.  Ethical considerations for clinical trials on medicinal 
products conducted with the paediatric population. 2008.  
ftp://ftp.cordis.europa.eu/pub/fp7/docs/ethical-considerations-paediatrics_en.pdf (website 
accessed 23 March 2014). 
Folkestad L, Hald JD, Ersboll AK, et al.  Fracture rates and fracture sites in patients with 
osteogenesis Imperfecta:  a nationwide register-based cohort study.  J Bone Miner Res.  
2017;32:125–134. 
Forlino A and Marini JC.  Osteogenesis imperfecta.  Lancet.  2016;387:1657-1671. 
Grasemann Schundeln MM, Hovel M, Schweiger B, et al.  Effects of RANK-ligand 
antibody (denosumab) treatment on bone turnover markers in a girl with juvenile Paget's 
disease. J Clin Endocrinol Metab. 2013;98:3121-3126. 
Hald JD, Evangelou E, Langdahl BL, et al.  Bisphosphonates for the Prevention of 
Fractures in Osteogenesis Imperfecta: Meta-Analysis of Placebo-Controlled Trials.  J 
Bone Miner Res.  2015;5:929-933.  
Kostenuik PJ.  Osteoprotegerin and RANKL regulate bone resorption, density, geometry 
and strength.  Curr Opin Pharmacol.  2005; 5:618-625.   


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Lenart BA, Lorich DG, Lane JM.  Atypical fractures of the femoral diaphysis in 
postmenopausal women taking alendronate.  N Engl J Med.  2008; 358:1304-1306. 
Marini JC, Forlino A, Bachinger HP, et al.  Osteogenesis imperfecta.  Nat Rev Dis 
Primers.  2017;3:17052. 
Marini JC, Blissett AR.  New Genes in Bone Development:  What's New in Osteogenesis 
Imperfecta.  J Clin Endocrinol Metab. 2013;98:3095-3103. 
Nicolaou N, Agrawal Y, Padman M, Fernandes JA, Bell MJ.  Changing pattern of femoral 
fractures in osteogenesis imperfecta with prolonged use of bisphosphonates.  J Child 
Orthop.  2012;6:21-27. 
Odvina C, Zerwekh JE, Rao S, et al.  Severely suppressed bone turnover:  a potential 
complication of alendronate therapy.  J Clin Endocrinol Metab.  2005; 90:1294-1301. 
Odvina C, Zerwekh JE, Rao S, et al.  Unusual mid-shaft fractures during long term 
bisphosphonate therapy.  Clin Endocrinol.  2010; 72:161-168. 
Rauch F, Travers R, Parfitt AM, et al.  Static and dynamic bone histomorphometry in 
children with osteogenesis imperfecta.  Bone.  2000;26:581-589. 
Rauch F, Munns CF, Land C, Cheung M, Glorieux FH.  Risedronate in the Treatment of 
Mild Pediatric Osteogenesis Imperfecta:  A Randomized Placebo-Controlled Study.  
J Bone Miner Res. 2009;24:1282-1289. 
Rauch F, Glorieux FH.  Osteogenesis imperfecta.  Lancet. 2004;363:1377-1385. 
Shane E, Burr D, Abrahamsen B, et al.  Atypical subtrochanteric and diaphyseal femoral 
fractures:  second report of a task force of the American Society for Bone and Mineral 
Research.  J Bone Miner Res.  2014;29(1):1–23. 
Steiner RD, Adsit J, Basel D.  COL1A1/2-Related Osteogenesis imperfecta. In: Pagon 
RA, Adam MP, Bird TD, et al, ed. GeneReviews: University of Washington, Seattle; 
2005. 
Trejo P, Fassier F, Glorieux FH, Rauch F.  Diaphyseal femur fractures in osteogenesis 
imperfecta:  characteristics and relationship with bisphosphonate treatment.  J Bone 
Miner Res.  2017;32(5):1034-1039. 
van Dijk FS, Byers PH, Dalgleish R, et al.  EMQN best practice guidelines for the 
laboratory diagnosis of osteogenesis imperfecta.  Eur J Hum Genet. 2012;20:11-19. 
Vuorimies I, Mäyränpää MK, Valta H, Kröger H, Toiviainen-Salo S, Mäkitie O.  
Bisphosphonate treatment and the characteristics of femoral fractures in children with 
osteogenesis imperfecta.  J Clin Endocrinol Metab.  2017;173(3):806-808. 
Whyte RS, Wenkert D, Clements KL, McAlister WH, Mumm S.  Bisphosphonate-induced 
osteopetrosis.  N Engl J Med. 2003;349:457-463. 


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12. 
Appendices 
 


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12.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ADT 
androgen deprivation therapy 
AFF 
atypical femoral fractures 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BIL 
bilirubin 
BMC 
bone mineral content 
BMD 
bone mineral density 
BMI 
body mass index 
CFR 
U.S. Code of Federal Regulations 
CRF 
case report form 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DIL 
Dear Investigator Letter 
DILI 
drug-induced liver injury 
DXA 
dual X-ray absorptiometry 
Early Termination 
defined as the date when a subject decides to end study early 
EDC 
electronic data capture 
End of Study 
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), following any additional parts in the 
study (eg, long-term follow-up), as applicable 
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 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GiOP 
glucocorticoid-induced osteoporosis 
HCP 
healthcare provider 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
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Abbreviation or Term 
Definition/Explanation 
ID 
identification 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
Interactive Voice Response 
System (IVRS) 
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 
Kd 
dissociation equilibrium constant 
NCT 
National Clinical Trials 
OI 
osteogenesis imperfecta 
ONJ 
osteonecrosis of the jaw 
PIP 
Pediatric Investigational Plan 
PK 
pharmacokinetics 
RANK 
receptor activator of nuclear factor kappa-Β 
RANKL 
receptor activator of nuclear factor kappa-Β ligand 
Q3M 
every 3 months 
Q6M 
every 6 months 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
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. 
Study day 1 
defined as the day of the first dose of investigational product 
(denosumab) on the 3-Month dosing schedule for subjects: 
      –that transition from 20130173 EOS to investigational         
product 3-Month Dosing Regimen 
      –or currently enrolled on any arm of the 20170534 PA1 that 
consent/assent to investigational product 3-Month dosing 
schedule for the first time 
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Abbreviation or Term 
Definition/Explanation 
TBL 
total bilirubin 
TOIFF 
typical OI femur fractures 
ULN 
upper limit of normal 
Page 3 of 3 


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12.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 12-1 will be performed by the central laboratory and/or by 
Amgen.  Highly sensitive urine pregnancy test will be performed locally.  Additional 
analyte test results may be reported by the local or central laboratory, in accordance with 
standard laboratory procedures (eg, components of a hematology panel).  Under 
exceptional circumstances (eg, pandemic), scheduled study clinical laboratory tests may 
be performed by the investigative site; this should be agreed with the study team in 
advance.  Data will be entered into Rave by the site.  Blood collection may be performed 
by a qualified individual at the subject’s home, in lieu of a site visit, on days 10 and 30 
following visits at week 12 and week 24. 
The central laboratory will be responsible for all serum chemistry, hematology as well as 
serology assessments.  The central laboratory will also conduct assessments of 
vitamin D, 
 
  The central laboratory (PPD) will perform the antidenosumab 
antibody assay.  Amgen will be responsible for performing the neutralizing 
antidenosumab antibody assay on binding positive samples (if necessary).  The central 
laboratory will provide a study manual that outlines handling, labeling, and shipping 
procedures for all serum samples. 
All samples will be non-fasting and obtained by venipuncture before investigational 
product (denosumab) or alternative osteoporosis medication administration, when 
applicable.  The date and time of blood collection will be recorded in the subject’s 
medical record. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Table 12-1.  Analyte Listing 
Central Laboratory:  
Chemistry 
Central Laboratory:  
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin-corrected calcium 
Calcium 
Magnesium 
Phosphorus 
Glucose 
RBC 
Hemoglobin 
Platelets 
WBC 
Differential 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes  
Central Laboratory:   
25 (OH) vitamin D 
Ur ne calcium 
 
Local Laboratory 
Urine pregnancy 
 
Central Laboratory (PPD) 


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Central Laboratory:  
Chemistry 
Central Laboratory:  
Hematology 
Other Labs 
BUN  
Creatinine 
Total bilirubin 
ALP 
AST (SGOT) 
ALT (SGPT)  
GFR 
Antidenosumab antibody assay 
 
Amgen 
Antidenosumab neutralizing 
antibody assay (if necessary) 
 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase;  
; BUN = blood urea nitrogen; GFR = glomerular filtration rate; 
RBC = red blood cell count; 
; SGOT = serum 
glutamic-oxaloacetic transaminase; SGPT - serum glutamic-pyruvic transaminase; WBC = white blood cell 
count 
 


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12.3 
Appendix 3.  Study Governance Considerations 
Independent Adjudication Committee(s) 
Potential events of ONJ will be adjudicated by an independent adjudication committee. 
Typical osteogenesis imperfecta femur fractures will be read by central imaging vendor 
providing standard description of all fractures. 
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 International Ethical Guidelines 
 
Applicable International Council on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent/assent form, Investigator’s 
Brochure, and other relevant documents (eg, subject recruitment advertisements) must 
be submitted to an Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)] by the investigator and reviewed and approved by the IRB/IEC.  A copy of the 
written approval of the protocol and informed consent/assent form must be received by 
Amgen before recruitment of subjects into the study and shipment of Amgen 
investigational product (denosumab). 
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/assent document that Amgen distributes to the 
site.  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 
 
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 


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 
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 U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
Recruitment Procedures 
Subjects completing Study 20130173 and are willing to enroll in this study will be 
included. 
Informed Consent/Assent Process 
Investigators should have communicated the Urgent Safety Measure findings and 
actions to all ongoing subjects by phone or in-person within 3 days of the receipt of the 
Dear Investigator letter and documented this contact in the subject’s medical records.  A 
written consent/assent will be provided to subjects, following approval by the IRB/IEC, 
and subjects will be asked to sign this written consent/assent. 
An initial sample informed consent/assent form is provided for the investigator to prepare 
the informed consent/assent 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 Trial 
Manager to the investigator.  The written informed consent/assent 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 (denosumab) is 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/assent, 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/assent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act requirements, where 
applicable, and the IRB/IEC or study site.  
The medical record must include a statement that written informed consent/assent was 
obtained before the subject was enrolled in the study and the date the written 


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consent/assent was obtained.  The authorized person obtaining the informed 
consent/assent must also sign the informed consent/assent 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 
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/assent and the subject’s agreement or refusal of 
his/her notification of the primary care physician is to be documented in the subject’s 
medical records, and the informed consent/assent 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/assent discussion.  Subject withdrawal of 
consent/assent 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 reconsented/assented to the most current version of the informed 
consent/assent form(s) during their participation in the study.  If the subject reaches the 
age of consent during the duration of the study, once the subject reaches the age of 
maturation (usually 18); the previously acquired parental consent is no longer applicable 
and the participants consent must be taken.  Per ICH E11 (R1), during clinical studies 
there is a requirement for obtaining adequate informed consent for continued 
participation from pediatric participants once a child reaches the age of legal consent.  
Local regulations related to confidentiality and privacy of pediatric participants must be 
followed. 
The original signed informed consent/assent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent/assent form(s) must be provided 
to the subject or the subject’s legally authorized representative.  
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent/assent 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 


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informed consent/assent was freely given and understood.  (Refer to ICH GCP 
guideline, Section 4.8.9). 
The informed consent form (ICF) will contain a separate section that addresses the use 
of remaining mandatory samples for optional future research.  The investigator or 
authorized designee will explain to each subject the objectives of the future 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 future research.  Subjects who decline to participate will not 
provide this separate signature. 
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 Case Report Form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent/assent forms) 
are to be kept in confidence by the investigator, except as described below. 
In compliance with governmental regulations/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/assent of the subject to 
permit such individuals to have access to his/her study-related records, including 
personal information. 


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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. 
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 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:   


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 
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 
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 and Development 
Compliance and Audit function (or designees).  Inspection of site facilities (eg, 
pharmacy, protocol-required therapy storage areas, laboratories) and review of 


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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. 
Case report forms (CRF) must be completed in English.  TRADENAMES® (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 
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) 
system (if used, such as subject identification [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. 
Elements to include:   


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 
Subject files containing completed CRFs, informed consent/assent 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, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
 
Non-investigational product(s), and/or 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 
(denosumab) 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 (denosumab) 
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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12.4 
Appendix 4.  Safety Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
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, 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 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. 


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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. 
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 1 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. 
Recording Adverse Events and Serious Adverse Events 
Adverse Event, and Serious Adverse Event Recording 
 
When an adverse 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 /serious adverse event 
information in the Event case report form (CRF). 


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 
The investigator must assign the following adverse event attributes:   
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
 
Dates of onset and resolution (if resolved); 
 
Severity (or toxicity defined below); 
 
Assessment of relatedness to denosumab; and 
 
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 Events 
CRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to sponsor/responsible contact research organization (CRO) in 
lieu of completion of the Events 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 Amgen Global Patient Safety. 
 
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. 
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, version 4.03 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 (denosumab) and other antiresorptive therapy 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 (denosumab) and the event. 
 
The investigator will use clinical judgment to determine the relationship. 


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 
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. 
 
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 
Amgen Global Patient Safety 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. 
 
For all deaths, available autopsy reports and relevant medical reports should be 
provided to Amgen Global Patient Safety] 
 
New or updated information will be recorded in the originally completed Events 
CRF. 
 
The investigator will submit any updated serious adverse event data to Amgen 
Global Patient Safety 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 electronic 
data capture (EDC) system. 
 
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 Contingency 
Report Form (see Figure 12-1) within 24 hours of the investigator’s knowledge of 
the event. 


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 
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 the 
20170534 eSAE Contingency Report Form (see Figure 12-1). 
• Once the study has ended, serious adverse event(s) will be reported to Amgen 
(regardless of causality) if the investigator becomes aware of a serious adverse 
event.  The investigator should use the paper-based Serious Adverse Event 
Contingency Report Form to report the event. 


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Date:  02 February 2022 
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Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Report Form 
 


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12.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for female of childbearing potential OR who 
have reached puberty are outlined in Section 6.2. 
Female subjects of childbearing potential who have reached puberty must receive 
pregnancy prevention counseling and be advised of the risk to the fetus if they become 
pregnant during treatment and for 5 months after the last dose of denosumab.  Subjects 
receiving alternative osteoporosis medication/s of the investigator’s choice should be 
counseled per specific drug requirements.  Subjects not receiving any treatment 
(observation only) are not required to use contraception. 
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:   
 
Documented hysterectomy; 
 
Documented bilateral salpingectomy; or 
 
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 
 
Tanner grade  2 
Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
Note:  Failure rate of < 1% per year when used consistently and correctly. 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
Intrauterine device  
 
Intrauterine hormonal-releasing system  
 
Bilateral tubal ligation/occlusion 


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 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject) 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include:   
 
Periodic abstinence (calendar, symptothermal, postovulation methods) 
 
Withdrawal (coitus interruptus) 
 
Spermicides only 
 
Lactational amenorrhea method 
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 5 months after the last 
dose of denosumab. 
 
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). 
 
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 5 months after 
the last dose of denosumab.  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. 


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Date:  02 February 2022 
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 
Any serious adverse event occurring as a result of a poststudy pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 12.4.  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). 
Male Subjects With Partners Who Become Pregnant  
 
In the event a male subject fathers a child during treatment, the information will be 
recorded on the Pregnancy Notification Worksheet.  The worksheet (see 
Figure 12-2) must be submitted to Amgen Global Patient Safety within 24 hours of 
the site’s awareness of the pregnancy.  (Note:  Sites are not required to provide any 
information on the Pregnancy Notification Worksheet that violates the country or 
regions local privacy laws). 
 
The investigator will attempt to obtain a signed authorization for release of pregnancy 
and infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
 
After obtaining the female partner’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome and 
infant health information on the pregnant partner and her baby and complete the 
pregnancy questionnaires.  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 the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 5 months after the last dose of 
denosumab. 
 
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 203. 
 
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 5 months after the last dose of 
denosumab after discontinuing protocol-required therapies. 


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Protocol Number:  20170534 
Date:  02 February 2022 
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Figure 12-2.  Pregnancy and Lactation Notification Worksheet 
 


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Protocol Number:  20170534 
Date:  02 February 2022 
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12.6 
Appendix 6.  Sample Storage and Destruction 
Any blood 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/assent is provided by the subject, Amgen can do additional testing 
on remaining samples (ie, residual and back-up) to investigate and better understand the 
osteogenesis imperfecta, the dose response and/or prediction of response to 
denosumab, 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, 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/assent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
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appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 12.3 for subject confidentiality. 
 


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12.7 
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 (denosumab) 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, Other Antiresorptive Therapies, and Other 
Protocol-required Therapies Due to Potential Hepatotoxicity 
Denosumab and other protocol-required therapies (including other antiresorptive 
therapies), as appropriate, should be discontinued permanently and the subject should 
be followed according to the recommendations in Section 12.3 (Additional Safety 
Assessment Information) for possible drug-induced liver injury (DILI), if ALL of the 
criteria below are met:   
 
TBL > 2 x upper limit of normal (ULN) or INR > 1.5 
 
AND increased AST or ALT from the relevant baseline value as specified below:   
Baseline AST or ALT value 
AST or ALT elevation 
< ULN 
> 3x ULN 
 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
TBL values include, but are not limited to:   
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr virus, cytomegalovirus, 
herpes simplex virus, varicella, toxoplasmosis, and parvovirus) 
 
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 BIL glucuronidation (eg, indinavir, 
atazanavir) 
 
Alpha-one antitrypsin deficiency 
 
Alcoholic hepatitis 


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 
Autoimmune hepatitis  
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis (e)  
 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
Criteria for Conditional Withholding of Amgen Investigational Product, Other 
Antiresorptive Therapies, and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
The following rules are recommended for withholding of denosumab and other 
protocol-required therapies (including antiresorptives):   
 
Elevation of either AST or ALT according to the following schedule:   
Baseline AST or ALT value 
AST or ALT elevation  
Any 
> 8x ULN at any time 
Any 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
Any 
> 5x ULN but < 8x ULN and unable to adhere to enhanced 
monitoring schedule 
Any 
> 3x ULN with clinical signs or symptoms that are 
consistent with hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, vomiting, jaundice).   
 
OR:  TBL > 3x ULN at any time 
 
OR:  ALP > 8x ULN at any time 
Denosumab, antiresorptive therapies, and other protocol-required therapies, as 
appropriate, should be withheld pending investigation into alternative causes of DILI.  If 
investigational product(s) is withheld, the subject is to be followed according to 
recommendations in Section 12.3 for possible DILI.  Rechallenge may be considered if 
an alternative cause for impaired liver tests (ALT, AST, ALP) and/or elevated TBL, is 
discovered and the laboratory abnormalities resolve to normal or baseline (See:  Criteria 
for Rechallenge of Amgen Investigational Product, Other Antiresorptive Therapies, and 
Other Protocol-required Therapies After Potential Hepatotoxicity).   
Criteria for Rechallenge of Amgen Investigational Product, Other Antiresorptive 
Therapies, and Other Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, the subject’s legally acceptable representative, investigator, 
and Amgen. 


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If signs or symptoms recur with rechallenge, then denosumab, other antiresorptive 
therapies, and other protocol-required therapies, as appropriate should be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in “Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product, Other Antiresorptive Therapies, and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity”) should never be rechallenged.  
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 Case Report Form (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 Section 12.4. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product (denosumab) or protocol-required therapies 
is/are withheld (either permanently or conditionally) due to potential DILI or who 
experience AST or ALT elevations  3 x  ULN or 2-fold increases above baseline values 
for subjects with elevated values before drug 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, ALPBIL (total and direct), and INR within 24 hours  
 
In cases of TBL  2 x ULN or INR  1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product (denosumab) or protocol-required therapies 
has/have been discontinued AND the subject is asymptomatic. 


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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:   
 
Complete blood count with differential to assess for eosinophilia 
 
Serum total immunoglobulin (Ig)G, antinuclear antibody antismooth muscle antibody, 
and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 
 
A more detailed history of:   
 
Prior and/or concurrent diseases or illness 
 
Exposure to environmental and/or industrial chemical agents  
 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Viral serologies 
 
Creatine phosphokinase, haptoglobin, lactate dehydrogenase and peripheral blood 
smear 
 
Appropriate liver imaging if clinically indicated 
 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected 
 
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
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 investigational product (denosumab) 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. 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
Page 1 of 11 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 5 
Protocol Title:  Multicenter, Single-arm Open-label Extension Study to Assess 
Long-term Safety and Efficacy of Current or Prior Treatment With Denosumab in 
Children/Young Adults With Osteogenesis Imperfecta 
 
Amgen Protocol Number 20170534 
 
 
Amendment Date: 
02 February 2022 
 
Rationale: 
The intent of study 20170534 was a safety extension after treatment with denosumab for 
36 months on a 6-month dosing regimen and where there was no protocol mandated 
treatment.  This would allow for the collection of longer-term safety data on denosumab 
as well as an assessment of the impact of stopping denosumab and switching to an 
alternative treatment on efficacy.   
In protocol amendment 3, a 3-month dosing regimen was introduced given the less than 
expected increase in bone mineral density (BMD) on 6-month dosing and 
pharmacokinetics/pharmacodynamics (PK/PD) data showing low denosumab levels at 
3 months.  Starting from 30 September 2021, due to the life-threatening events of 
hypercalcemia reported on denosumab use in the pediatric osteogenesis imperfecta (OI) 
study, further dosing on 20170534 was stopped, and subjects were to be followed for 
safety for 24 weeks following the last dose of denosumab.  This urgent safety measure 
resulted in early trial termination for severe and serious hypercalcemia on a 3-month 
dosing regimen.   
Given the limited amount of available data for efficacy analysis, the analysis of the 
secondary endpoints is changed in this protocol amendment to ensure that only quality 
data is presented as an endpoint.  The secondary efficacy endpoints of fracture and 
growth velocity are removed, and BMD Z-score is clarified given the multiple treatment 
sequences in the trial.  Adverse events of fracture, including femur fractures, will be 
presented in the adverse event tables. 
The primary objective and endpoint in this study is safety and is unchanged. 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  02 February 2022 
Page 2 of 11 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendments to the protocol include: 
 
Deletion of secondary efficacy endpoints of fracture and growth velocity 
 
Clarification of the secondary endpoint of bone mineral density (BMD) Z-score 
assessed at 6, 12, and 24 months 
 
Deletion of the exploratory endpoint for BMD and bone mineral content 
 
Clarif cation of the exploratory endpoint of 
 
 
 
Deletion of investigational product administration from additional 12-week safety 
follow-up column in the Schedule of Activities 
 
Deletion of the growth velocity and vertebral fracture analysis sets as a result of the 
deletion of the corresponding endpoints 
 
Deletion of subgroups analysis information from the protocol 
 
Administrative and typographical updates for consistency and clarity 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  09 November 2021 
Page 1 of 24 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 4 
Protocol Title:  Multicenter, Single-arm Open-label Extension Study to Assess 
Long term Safety and Efficacy of Current or Prior Treatment With Denosumab in 
Children/Young Adults With Osteogenesis Imperfecta 
 
Amgen Protocol Number 20170534 
NCT Number NCT03638128 
 
Amendment Date: 
09 November 2021 
 
Rationale: 
This protocol is being amended to: 
 
Address Risk Level 1 safety concern of hypercalcemia.  The protocol has been 
updated to stop all dosing of denosumab due to Data Monitoring Committee 
(DMC) decision.  
 
Implement a safety follow-up period for 24 months following the last dose of 
denosumab 
 
Stop enrollment to the study 
 
Update risks and benefits to reflect that the benefit of denosumab does not 
outweigh the risks 
 
Update safety language per newest protocol template 
 
Administrative and editorial updates 
 
 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  14 January 2021 
Page 1 of 51 
Amgen Proprietary - Confidential 
FORM-492529,  Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 3 
Protocol Title:  Multicenter, Single-arm Open-label Extension Study to Assess 
Long-term Safety and Efficacy of Current or Prior Treatment With Denosumab in 
Children/Young Adults With Osteogenesis Imperfecta 
 
Amgen Protocol Number Denosumab 20170534 
 
Superseding Amendment Date: 
14 January 2021 
 
Superseding Amendment 3 Summary of Changes: 
Rationale: 
Additional updates were made to harmonize content with protocol 20130173 and remove 
a reference to the Safety Report Form since reporting will now be collected on the 
Events electronic case report form, and the Safety Report Form will be retired. 
Changes include, but are not limited to: 
 
Updates to Schedule of Activities including: 
 
Link chemistry activity to footnote letter u (At all study visits signs and symptoms 
of hypocalcemia will be assessed and subjects reminded of importance of taking 
calcium and vitamin D.) 
 
Link chemistry activity on days 10 and 30 after weeks 12 and 24 to footnote letter 
v (On days 10 and 30, blood collection may be performed by a qualified 
individual at the subject’s home, in lieu of a site visit.) 
 
Remove separate serious adverse event assessment since this is included in the 
adverse event assessment 
 
Replace assessment of clinical fracture recording continuously throughout study 
with an assessment at visit day 1, days 10 and 30 after day 1, and at every 
12 week visit including the final visit 
 
Clarify that blood collection on days 10 and 30 after week 12 and 24 visit can be 
performed by a qualified individual at the subject’s home 
 
Update timing of activities in the protocol to be consistent with the schedule of 
activities table 
 
Remove serum as a type of pregnancy test to be used 
 
Remove the reference to the Safety Report Form from Appendix 4 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  17 November 2020 
Page 1 of 39 
Amgen Proprietary - Confidential 
FORM-492529,  Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 3 
Protocol Title:  Multicenter, Single-arm Open-label Extension Study to Assess 
Long-term Safety and Efficacy of Current or Prior Treatment With Denosumab in 
Children/Young Adults With Osteogenesis Imperfecta 
 
Amgen Protocol Number Denosumab 20170534 
 
Amendment Date: 
17 November 2020 
 
Rationale: 
The protocol is being amended to harmonize content with protocol 20130173 and to 
address Food and Drug Administration (FDA) feedback received.  In addition, this 
amendment is intended to optimize study procedures to improve the operational 
efficiency of the protocol following team feedback.   
Changes include, but are not limited to: 
-Additional blood samples at days 10 and 30 following investigational product dosing at 
weeks 12 and 24. 
-Add the assessment of signs and symptoms of hypocalcemia to be assessed at 
days 10 and 30 following investigational product dosing at weeks 12 and 24. 
-Administrative changes from previously written memos. 
-Analyte table updated. 
-Statistical Analysis section updated. 
-Administration, typographical and formatting changes were made throughout the 
protocol.  Updates have been implemented to align with the current template.   


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SAP_001.pdf: 
Product:  Denosumab 
Protocol Number:  20170534 
Date:  27 APR 2022 
Page 1 of 38 
CONFIDENTIAL  
 
 
Statistical Analysis Plan 
 
Protocol Title: 
Multicenter, Single-arm Open-label Extension Study to 
Assess Long term Safety and Efficacy of Current or Prior 
Treatment With Denosumab in Children/Young Adults 
With Osteogenesis Imperfecta 
Short Protocol Title: 
Open-label Extension of Study 20130173 of Denosumab 
in Children and Young Adults with Osteogenesis 
Imperfecta 
Protocol Number: 
20170534 
NCT Number: 
NCT03638128 
Authors: 
 
Sponsor: 
Amgen, Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
SAP Date: 
Document Version 
Date 
Amendment 2 (v[3.0]) 
27 APR 2022 
 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  27 APR 2022 
Page 2 of 38 
CONFIDENTIAL  
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
10 October 2019 
Not applicable  
Amendment 1 (v2.0) 
11 March 2022 
This statistical analysis plan (SAP) is updated 
based on the protocol amendment 5 for 
Denosumab study 20170534 dated 02 
February 2022 and the German country 
specific substudy protocol supplement dated 
11 January 2022 to perform final analysis.  
Amendment 2 
(v3.0) 
27 Apr 2022 
This statistical analysis plan (SAP) is updated 
to add the definition for German substudy 
safety analysis set. 
Added the visit window for renal laboratory. 
Added the imputation rules for concomitant 
medications. 
 


Product:  Denosumab 
Protocol Number:  20170534 
Date:  27 APR 2022 
Page 3 of 38 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents .......................................................................................................................... 3 
1. 
Introduction ........................................................................................................................... 8 
2. 
Objectives, Endpoints and Hypotheses ........................................................................... 8 
2.1 
Objectives and Endpoints ..................................................................................... 8 
2.2 
Hypotheses and/or Estimations ......................................................................... 10 
3. 
Study Overview .................................................................................................................. 10 
3.1 
Study Design ......................................................................................................... 10 
3.2 
Sample Size .......................................................................................................... 12 
3.3 
Adaptive Design ................................................................................................... 12 
4. 
Covariates and Subgroups .............................................................................................. 12 
4.1 
Planned Covariates .............................................................................................. 12 
4.2 
Subgroups ............................................................................................................. 12 
5. 
Definitions ........................................................................................................................... 12 
5.1 
Study points of Reference ................................................................................... 12 
5.1.1 
Baseline ............................................................................................... 12 
5.2 
General Study Periods ........................................................................................ 14 
5.2.1 
Screening Period ................................................................................ 14 
5.2.2 
Treatment Period ................................................................................ 14 
5.2.3 
End of Study/Safety Follow-up Period ............................................ 14 
5.3 
Subject Disposition............................................................................................... 14 
5.4 
Arithmetic Calculations ........................................................................................ 15 
5.5 
Study Endpoints ................................................................................................... 16 
5.5.1 
DXA Assessments .............................................................................. 16 
5.5.2 
Metaphyseal Index Z-score of the Distal Femur ............................ 17 
5.5.3 
Dental Radiograms (Mandibular Shaping) ..................................... 17 
5.5.4 
Molar Eruption ..................................................................................... 18 
6. 
Analysis Sets ...................................................................................................................... 18 
6.1 
Full Analysis Set ................................................................................................... 18 
6.2 
Safety Analysis Set .............................................................................................. 18 
6.3 
Study-specific Analysis Sets ............................................................................... 18 
6.3.1 
DXA Analysis Set ............................................................................... 18 
............................................................................... 18 
6.3.3 
Metaphyseal Analysis Set ................................................................. 19 
6.3.4 
German Substudy Safety Analysis Set ........................................... 19 
7. 
Planned Analyses .............................................................................................................. 19 
7.1 
Interim Analysis and Early Stopping Guidelines .............................................. 19 


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7.2 
Primary Analysis ................................................................................................... 19 
7.3 
Final Analysis ........................................................................................................ 19 
8. 
Data Screening and Acceptance .................................................................................... 19 
8.1 
General Principles ................................................................................................ 19 
8.2 
Data Handling and Electronic Transfer of Data ............................................... 19 
8.2.1 
Rollover of 20130173 CRF Data to 20170534  .............................. 20 
8.3 
Handling of Missing and Incomplete Data ........................................................ 20 
8.4 
Detection of Bias .................................................................................................. 20 
8.5 
Outliers ................................................................................................................... 21 
8.6 
Distributional Characteristics .............................................................................. 21 
8.7 
Validation of Statistical Analyses ....................................................................... 21 
9. 
Statistical Methods of Analysis ........................................................................................ 21 
9.1 
General Considerations ....................................................................................... 21 
9.2 
Subject Accountability ......................................................................................... 22 
9.3 
Important Protocol Deviations ............................................................................ 22 
9.4 
Demographic and Baseline Characteristics ..................................................... 22 
9.5 
Efficacy Analyses ................................................................................................. 23 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) ....................................... 23 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) ................................. 24 
9.5.2.1 
BMD Z score of lumbar spine and proximal 
femur ................................................................................ 24 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ................................ 24 
........................... 24 
........................... 24 
9.6 
Safety Analyses .................................................................................................... 24 
9.6.1 
Analyses of Primary Safety Endpoint(s) ......................................... 24 
9.6.2 
Adverse Events ................................................................................... 25 
9.6.2.1 
Adverse Events of Special Interest ............................. 26 
9.6.3 
Laboratory Test Results .................................................................... 27 
9.6.4 
Vital Signs ............................................................................................ 27 
9.6.5 
Physical Measurements .................................................................... 27 
9.6.6 
Antibody Formation ............................................................................ 27 
9.6.7 
Exposure to Investigational Product ................................................ 27 
9.7 
Other Analyses ..................................................................................................... 27 
9.7.1 
Metaphyseal Index Z-Scores and Oral Hygiene ............................ 27 
.......................................... 28 
10. 
Changes From Protocol-specified Analyses ................................................................. 29 
11. 
Literature Citations / References .................................................................................... 30 


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12. 
Data Not Covered by This Plan....................................................................................... 31 
13. 
Appendices ......................................................................................................................... 32 
 


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List of Tables 
Table 1.  Treatment Headers/ Definitions for Study 20170534 ............................................ 16 
Table 2.  Treatment Headers/ Definitions for Study 20170534 ............................................ 16 
Table 3.  Primary Efficacy Endpoint Summary Table ............................................................ 24 
Table 4.  Secondary Efficacy Endpoint Summary Table ....................................................... 24 
Table 5.  Exploratory Efficacy Endpoint Summary Table ..................................................... 24 
Table 6.  Primary Safety Endpoint Summary Table ............................................................... 25 
 


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List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse Event 
AFF 
Atypical femoral fractures 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BMC 
Bone mineral content 
BMD 
Bone mineral density 
BMDS 
Biomedical Data Stewardship Standard 
BMI 
Body mass index 
CRF 
Case report form 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DXA 
Dual X-ray absorptiometry 
EDC 
Electronic data capture 
ET 
End of treatment 
FAS 
Full analysis set 
GSO-DM 
Global Study Operations-Data Management 
ICH 
International Council on Harmonisation 
IP 
Investigational product 
IPD 
Important protocol deviations   
IVRS 
Interactive voice response system  
MI 
Metaphyseal index 
MRI 
Magnetic resonance imaging 


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Abbreviation or Term 
Definition/Explanation 
OI 
Osteogenesis imperfecta 
ONJ 
Osteonecrosis of the jaw 
PIP 
Pediatric Investigational Plan 
PK 
Pharmacokinetics 
Q6M 
Once every 6 months 
Q3M 
Once every 3 months 
SAP 
Statistical Analysis Plan 
SAS 
Safety analysis set / Statistical Analysis System 
SC 
Subcutaneous 
SQ 
Genant semiquantitative scoring system 
 
 


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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within protocol amendment 5 for study 20170534, 
AMG 162 Denosumab dated 02 February 2022. The scope of this plan includes the Final 
analyses and will be executed by the Amgen Global Biostatistical Science department 
unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To evaluate long-term safety of denosumab in 
subjects with pediatric osteogenesis 
imperfecta (OI) completing Study 20130173 
The primary endpoints are subject incidence 
of adverse events, serious adverse events, 
and adverse events of special interest, subject 
incidence of anti-denosumab antibodies, 
changes from baseline in laboratory values 
and vital signs, and subject incidence of 
metaphyseal index Z score above 
age-appropriate normal range, abnormal 
molar eruption, and mandibular shaping 
Secondary 
 
To describe changes in bone mineral density 
(BMD) of lumbar spine and proximal femur 
(total hip and femoral neck) from baseline to 
6, 12, and 24 months. 
Actual values and changes in BMD Z score of 
lumbar spine and proximal femur (total hip 
and femoral neck) from Study 20170534 
baseline, as assessed by dual X-ray 
absorptiometry (DXA), at 6,12 and 24 months. 
  
Exploratory 


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Objectives 
Endpoints 
 
2.2 
Hypotheses and/or Estimations 
This study is descriptive in nature and does not involve testing formal hypotheses. 
3. 
Study Overview 
3.1 
Study Design 
Starting from 30 September 2021, due to the life-threatening events of hypercalcemia 
reported on denosumab use in the pediatric OI study, subjects will not receive any 
further dosing on 20170534 and will be followed for safety for 24 weeks following the last 
dose of denosumab. Study 20170534 is an open-label, prospective, extension study of 
Study 20130173 to assess long-term safety and efficacy of current or prior treatment 
with denosumab in children/young adults with OI. This study is required for compliance 
with key binding elements from the denosumab PIP for Study 20130173. All subjects 
who complete EOS on Study 20130173, regardless of whether they received 
investigational product until the last protocol-specified dose on the 20130173 study or 
ended investigational product early, are offered participation in a long-term open-label 
follow-up study – where this protocol has been approved at the site. Subjects who 
withdraw consent/assent to transition to 3-Month Dosing Regimen on 20130173 will also 
be offered participation in this study. When subjects in Study 20130173 near the EOS 
visit (completion), subjects will be offered participation in Study 20170534. If a subject is 
rolled over into the 20170534 study, they will be offered to receive alternative treatment 
including commercial denosumab every 6 months (6-Month Dosing Regimen) or will be 
observed without any treatment or the investigational product given every 3 months (3-
Month Dosing Regimen). For subjects that consent/assent to participate in Study 
20170534, Screening and study day 1 visit should coincide with Study 20130173 EOS 


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visit. Where this is not possible, the screening visit should occur on or within 28 days of 
the Study 20130173 EOS visit.  Study day 1 should occur within 7 days from Screening. 
Subjects enrolled in the study may be treated with denosumab or alternative 
osteoporosis medication/s at the discretion of the investigator, or may discontinue any 
osteoporosis medication for off-treatment observation.  At any time during the study 
subjects may (1) discontinue denosumab, (2) resume denosumab (3-Month Dosing 
Regimen), (3) initiate alternative osteoporosis medication, and (4) discontinue alternative 
osteoporosis medication, based on the medical judgment of the investigator and per 
local standard of care (as applicable).  In subjects who transition from denosumab to an 
alternative osteoporosis medication, the latter should be administered approximately 3 
months after the last denosumab dose, ie, the next visit scheduled to receive study 
treatment, unless otherwise medically indicated.  Similarly, transition from one standard 
of care osteoporosis medication to another or a reduced dose of denosumab should 
occur at the end of the dosing interval of the previous therapy. For subjects electing 
alternative therapy, alternative therapy may be administered by any qualified healthcare 
provider (HCP).  The HCP must provide a written note to the subject describing the 
nature and date of alternative treatment to be documented by the investigative site.  
Subjects on alternative regimens given by HCPs other than investigational product, will 
continue to attend the study site every 6 months (weeks 12, 36, 60, and 84). 
Subjects should return to the study site every 12 weeks (± 7 days) for treatment with 
denosumab. Subjects who are on observation only or on 6-Month dosing for alternative 
medications may attend scheduled visits every 24 weeks.  For subjects receiving 
alternative osteoporosis medication/s, dosing frequency will be determined by the 
treatment regimen selected by the investigator, subjects will attend scheduled study 
visits every 6 months as per the Schedule of Activities.  In this case, where a dosing visit 
does not coincide with a scheduled study visit, additional collection of assessments is 
not required other than recording of the medication on the concomitant medication eCRF 
page under alternative osteoporosis medication.  All subjects should return for a final 
EOS/Early Termination visit.   
Samples will be collected for clinical laboratory testing, including assessment of 
and antidenosumab antibodies.  Adverse events will be assessed throughout the study.  
Subjects will undergo annual DXA and radiographic assessments.  


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3.2 
Sample Size 
The number of subjects in this study will be determined by the number of subjects 
completing Study 20130173, and who are willing and able to participate in the long-term 
follow-up study.     
3.3 
Adaptive Design 
Not applicable for this study. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
Not applicable for this study. 
4.2 
Subgroups 
Not applicable for this study. 
5. 
Definitions 
5.1 
Study points of Reference 
5.1.1 
Baseline 
Study 20170534 baseline 
For a given variable, the last measured value prior to administration of the first dose of 
denosumab or alternative osteoporosis medication/s in study 20170534 for subjects who 
will continue to receive denosumab or switch to alternative osteoporosis medication/s at 
start of 20170534, respectively, or the last measured value at Study 20130173 end of 
study visit for subjects who are observational only. Data collected after these specified 
timepoints will not be used for baseline. 
The following study 20170534 baseline assessments will be conducted as part of the 
20130173) end of study visit. 
 
Physical examination 
 
Tanner stage 
 
Vital signs 
 
Pregnancy test 
 
Hematology 
 
Chemistry 
 
Antidenosumab-antibody 
 
Armspan 


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 
DXA (AP lumbar spine) 
 
DXA (proximal femur – total hip and femoral neck in subjects ≥ 5 years of age) 
 
X-ray (lateral thoracic, lumbar spine) 
 
X-ray (AP knees) 
 
Dental X-ray (cephalogram and panoramic radiograph) 
 
Adverse events collection including clinical fracture recording 
 
Serious adverse events 
 
Concomitant medications 
Above assessments from 20130173 end of study will be rolled-over as 20170534 
screening assessments. Detailed roll-over procedures for adverse events, serious 
adverse events or concomitant medications are described in Section 8.2.1. 
More generally, references to a study 20130173 measurement or milestone will always 
include the term “study 20130173”; therefore, any references to a timepoint without a 
study designation always refer to study 20170534.  
Study Day 1 
Study day 1 is defined as date of enrollment. 
Study Day 
The number of days from Study Day 1, inclusive: 
Study Day = (Date of Interest – Date of Study Day 1 in 20170534 study) + 1 
Visit Windows 
See details in Appendix C Analytical Windows 
Study dates 
Informed Consent (IC) Date 
The date on which the study informed consent form, and subject assent form if 
applicable, for study 20170534 is signed. 
Screening Date 
The screening date is the IC date of study 20170534. 
Enrollment Date 
The date on which the enrollment call for study 20170534 is made using IVRS. 


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End of Study Date 
The date recorded on the End of Study eCRF. 
5.2 
General Study Periods 
5.2.1 
Screening Period 
The time between date of informed consent and the enrollment date, inclusive. Subjects 
should enroll within 28 days from the Study 20130173 end of study visit, otherwise they 
will not be included in this study. 
5.2.2 
Treatment Period 
The time between study day 1 and the date of month 24/ end of study visit, inclusive.  
5.2.3 
End of Study/Safety Follow-up Period 
For subjects who discontinue study prior to month 24 visit, time between date of last 
protocol-required therapy or assessment visit and the safety follow-up date, inclusive.  
5.3 
Subject Disposition 
Enrolled 
Individuals are considered enrolled when an enrollment call is made using IVRS. 
Enrolled individuals are referred to as ‘subjects’. 
Exposed to IP 
Subjects are defined as exposed to IP if the total amount of IP volume received during 
the study is greater than zero. 
Exposed to alternative osteoporosis medication/s 
Subjects are defined as exposed to alternative osteoporosis medication/s if the total 
amount of any alternative osteoporosis medication volume received during the study is 
greater than zero. 
Treatment Headers/ Definitions 
Because of the study design that allows subjects at any time to discontinue denosumab, 
resume denosumab, initiate alternative osteoporosis medication, discontinue alternative 
osteoporosis medication or receive no treatment (observation only), the analysis of the 
20170534 study will be based upon the respective baseline treatment and subsequent 
treatment paradigms (ie, it will be based on the subjects’ entire dosing trajectory). These 
groups are therefore not “as-randomized” and are not suitable for between-group formal 
statistical comparisons. Baseline/demog and safety data for the 20170534 study will be 


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summarized using the treatment headers and definitions as defined in Table 1. 
BMD, protocol deviations, and antibody data will be summarized using any treatment 
defined in Table 2  
Table 1.  Treatment Headers/ Definitions for Study 20170534 
Analysis Description 
Treatment Header 
Definition 
Denosumab 
1. Q3M Denosumab  
Includes subjects who received at least 
one dose of Q3M denosumab in study 
20170534 
2. Q6M Denosumab 
Includes subjects who received at least 
one dose of denosumab, but no Q3M 
denosumab in study 20170534 
 
Non-Denosumab 
Alternative medications 
only / Observational 
Includes subjects who received non-
denosumab alternative therapy during 
study 20170534 or subjects who are 
not receiving any medication at 
20170534 baseline. 
Table 2.  Treatment Headers/ Definitions for Study 20170534 
Analysis Description 
Treatment Header 
Definition 
Any Treatment 
Q3M Denosumab / Q6M 
Denosumab / Alternative 
medications  / 
Observational 
 
Includes all subjects 
 
5.4 
Arithmetic Calculations 
Age at Enrollment (Years) 
Number of whole years from a subject’s birth date to enrollment date as recorded on the 
study 20130173 eCRF if date is provided as DD/MM/YYYY or MM/YYYY, or number of 
years from a subject’s birth year to the year of the enrollment date as recorded on the 
eCRF if date is provided as YYYY.  
Age at Enrollment (Months) 
Age in months is derived as collected age on screening period in years multiplied by 
number of months in year.  
Age at Visit  
Age at visit in years is derived as –  


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((visit date - Date of Birth) +1) / 365.25 
If Date of birth is incomplete then use below formula, 
Collected age at screening period in years + (visit date - screening date)+1 / 365.25 
Age at visit in months is derived as –  
((visit date - Date of Birth)+1) / 30.4375 
If Date of birth is incomplete then use below formula, 
Collected age at screening period in months + (visit date - screening date)+1 / 30.4375 
Change from baseline 
For a given variable, study baseline of interest, and timepoint of interest, subtract the 
endpoint value at the timepoint of interest minus the corresponding baseline value. 
Percent Change from baseline 
The change from baseline divided by study baseline value of interest and multiplied by 
100: 
(Change from Baseline/ Baseline) * 100 
Subject Incidence Rate 
The subject incidence rate for a given event in a given time period is defined as the 
number of subjects with ≥ 1 reported occurrence of the event divided by the number of 
subjects who are at risk for having the event at the beginning of the given time period. 
For subjects with multiple occurrences of the same event, the event will be counted once 
per subject.   
5.5 
Study Endpoints 
5.5.1 
DXA Assessments 
All subjects will undergo bone densitometry assessments of the lumbar spine and 
subjects 5 years of age or older at screening will undergo bone densitometry 
assessments of the proximal femur (for total hip and femoral neck) performed by DXA.  
Scans will be performed at all applicable visits. Only GE Lunar or Hologic bone 
densitometers will be allowed for this study. The same DXA machine must be used for 
all DXA assessments for a particular subject. The left side should be used for proximal 
femur, unless prohibited (eg, hip implant). If another side must be used or is 


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inadvertently used during Screening, then the same side must be used consistently 
throughout the study. 
Lumbar spine scans should include L1 through L4. Individual vertebral levels may be 
excluded due to artifact. A vertebral level excluded from one visit will be excluded from 
all visits with the total lumbar spine BMD calculated based on the evaluable vertebral 
levels. Baseline DXAs will be performed as duplicate scans; DXA assessments at all 
other visits will be performed as single scans. After analysis of the scans by the central 
imaging vendor, the study site may be asked to re-acquire a scan, because of poor 
positioning or other technical reasons. 
5.5.2 
Metaphyseal Index Z-score of the Distal Femur 
To assess a subject’s eligibility at screening, anteroposterior radiographs of both knees 
(unless prohibited by the presence of hardware such as implants) is to be used to 
calculate the metaphyseal index Z-score of each knee; the knee for assessment during 
the study at 6,12,18 and 24 months should be the one with the higher Z-score at 
baseline, unless prohibited by presence of hardware, in which case an anteroposterior 
radiograph of the contralateral knee may be obtained. Subject incidences of 
metaphyseal index Z-score above age-appropriate normal range (ie, metaphyseal index 
Z-score > +2) will be provided at each timepoint. The metaphyseal index (MI) will be 
calculated by the central imaging vendor as the ratio of the femoral width (W) over the 
distal femoral growth plate width (GPW), and the Z-score for each subject, relative to the 
subject’s age as: 
MI Z-score = (subject value – mean)/ SD, 
where mean and standard deviation (SD) are the corresponding values based on Ward 
et al database, (Ward, 2005), for the subject’s age group at the time of the assessment. 
5.5.3 
Dental Radiograms (Mandibular Shaping) 
Lateral cephalogram will be performed to enable assessment of mandibular shaping at 
Screening and 24 months. The lateral cephalogram is a profile X-ray of the skull and soft 
tissues and is used to assess the relation of the teeth in the jaws, the relation of the jaws 
to the skull, and the relation of the soft tissues to the teeth and jaws. 
The following anatomical angles and dimensions will be measured to evaluate the 
correct proportions of the mandible and its position relative to the skull/maxilla: 
 
Gonial angle 
 
SNA angle 


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 
SNB angle 
 
ANB Angle = SNA - SNB. 
5.5.4 
Molar Eruption 
Radiographic assessment of molars will be performed at all visits. In addition, each 
subject will undergo a visual inspection under natural light for the presence of the first 
and second molars. Oral visual inspection should be performed at every 3 months to 
assess the risk for unerupted molars. The subject should be referred to a dentist to 
perform radiographic assessment of the unerupted molar(s) if: 
 
A subject is age 7 to 12 years and appears to have an unerupted upper or lower 
first molar (ie, not all 4 first molars are visible/detectable). 
 
A subject is age 13 years or older and appears to have an unerupted upper or 
lower (first or) second molar (ie, not all 4 first molars and all 4 second molars are 
visible/detectable). 
For subjects 7 to 12 years of age, the number of 1st unerupted or partially erupted molars 
will be reported by visit. Likewise, for subjects 13 years of age or older, the number of 
2nd unerupted or partially erupted molars will be reported by visit. Please note that the 
molars status refers to permanent molars only and age refers to age at visit. 
6. 
Analysis Sets 
6.1 
Full Analysis Set 
The full analysis set (FAS) includes all enrolled subjects who have provided informed 
consent/assent and have a non-missing enrollment date.  
6.2 
Safety Analysis Set 
The safety analysis set (SAS) includes all subjects in the FAS who received ≥ 1 dose of 
denosumab during study 20130173.  
6.3 
Study-specific Analysis Sets 
6.3.1 
DXA Analysis Set 
The DXA analysis set includes all subjects in the FAS with baseline and ≥ 1 postbaseline 
valid DXA assessments for the endpoint of interest (lumbar spine, total hip or femoral 
neck) as provided by the central imaging vendor. Note that this subset could potentially 
be different from endpoint to endpoint due to missing data. 


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6.3.3 
Metaphyseal Analysis Set 
This metaphyseal analysis set includes all subjects in the SAS with open growth plates 
(and no hardware preventing accurate calculation of metaphyseal index) at baseline and 
X-ray of the knee at baseline and postbaseline. 
6.3.4 
German Substudy Safety Analysis Set 
The subset includes all subjects in the SAS who enroll in the German substudy. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
Not applicable for this study. 
7.2 
Primary Analysis 
Primary analysis will occur upon completion of the study when the last subject completes 
the 24-week follow-up visit following the last dose of denosumab. 
7.3 
Final Analysis 
No final analysis is planned as the primary analysis will occur at the end of the study. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses, except for the imaging and 
laboratory data. This study will use the RAVE database. The central imaging vendor will 
provide DXA scans, and X-ray (lateral thoracic, knees, lateral cephalogram, and 
panoramic radiograms or radiographic assessment) data to Amgen cumulatively.  
The central laboratory vendor will provide all lab-related data, except for the samples 
analyzed at local laboratories. All laboratory values will be transferred cumulatively from 
the central laboratory.  
Data screening will be performed periodically during the conduct of the study. The 
objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. Any 
questionable values or situations will be reported to GSO-DM for review or confirmation.  


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As part of the data acceptance procedure, all datasets, planned tables, listings, and 
graphs will be generated and reviewed to identify any additional data issues. Any critical 
issues identified must be resolved with GSO-DM before final acceptance of the data. 
8.2.1 
Rollover of 20130173 CRF Data to 20170534  
Rollover program from 20130173 occurs only once for a patient when they complete 
20130173 end of study visit, and are ready to be enrolled in 20170534 study. Site calls 
IVRS to get patient created in RAVE for 20170534 study and provide 20130173 patient 
number to have same patient number in 20170534 eCRF.  
The following eCRF forms/ variables will be rolled over from 20130173 to 20170534 at 
time of enrollment via IVRS, 
 
Sex, Ethnicity, Race 
 
Medical History  
 
Subject Fracture History  
 
Type and features of OI  
 
Concomitant Medications 
 
Adverse events 
 
SAEs  
 
Adjudication data 
 
Clinical Fracture Summary 
Not all AEs from 20130173 study are expected to be recorded as medical history. It is 
investigator’s decision on what events to enter onto medical history. Ongoing AEs/SAEs, 
ongoing concomitant medications and unresolved fractures at the time of Study 
20170534 enrollment will be rolled over to 20170534. Resolved AEs, SAEs from Study 
20130173 will be entered into Study 20170534 Medical History by site at the discretion 
of investigator. Adjudication data will only be transferred if an event is ongoing or if 
entered by site.  
8.3 
Handling of Missing and Incomplete Data 
 Missing and incomplete dates will be imputed as outlined in Appendix B. 
8.4 
Detection of Bias 
Given the open-label nature of the study, changes to the study conduct and statistical 
analyses should be kept to a minimum to avoid undermining the study credibility. Any 
change to the protocol that is data driven should be avoided, except for safety related 


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events and changes related to inclusion/exclusion criteria to speed up enrollment, if 
needed. 
Important protocol deviations likely to impact the analysis and interpretation of the 
endpoints will be tabulated in the Clinical Study Report (CSR).   
If any sensitivity analyses are required to evaluate potential biases in the study’s 
conclusions, the sources of the potential biases and results of the sensitivity analyses 
will be documented in the CSR.  
8.5 
Outliers 
Scatter plots will be examined to identify outliers in continuous variables. Frequencies of 
the categorical data will be examined to identify questionable values. Outliers resulting 
from data entry error will be corrected in the database. Outliers that are not due to data 
entry error will be included in the analysis. The validity of any questionable values or 
outliers will be confirmed. No valid measurement will be excluded from analyses.  
8.6 
Distributional Characteristics 
Not applicable for the study. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics will be provided for demographics and subject characteristics, 
efficacy, and safety data . Descriptive statistics of continuous measurements will include 
mean, standard deviation, minimum, 25th percentile, median (50th percentile), 75th 
percentile, maximum and number of nonmissing observations (n). Nominal and ordinal 
categorical variables will be summarized using counts and percentages. 


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Visit based on the observed values, with no imputation for missing values. 
9.2 
Subject Accountability 
The disposition of all enrolled subjects will be tabulated. Disposition for number of 
enrolled subjects, successfully completing IP administration, and completing the study 
will be included. The disposition of subjects will also include the number of subjects who 
withdrew from the IP and their reasons for withdrawal and the number of subjects who 
withdrew from study and their reasons for withdrawal. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock. These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study. Eligibility deviations are defined 
in the protocol. 
Descriptive summary and listing of the IPDs will be generated for all the subjects during 
entire study. 
9.4 
Demographic and Baseline Characteristics 
Subject demographic and baseline disease characteristics will be summarized based on 
FAS.They include the following endpoints: 
 
Race 
 
Ethnicity 
 
Age (in years) 
 
Age (in months) 
 
Age cohorts (2 to 6, 7 to 10, 11 to 17 years, as observed at screening in 20130173 
study) 
 
Gender 
 
Body composition (height [cm], weight [kg], and BMI [kg/m2]) 
 
Armspan 
 
Vital signs (pulse, respiration rate, temperature) 
 
Select laboratory assessments  
 
DXA assessments of the lumbar spine and proximal femur (these DXAs will be 
performed as duplicate scans at 20170534 baseline only) 


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9.5 
Efficacy Analyses 
Table 3.  Primary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method (Specify Analysis Set if FAS 
is Not Used) 
Sensitivity Analysis 
Not applicable 
 
 
Table 4.  Secondary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method (Specify Analysis Set if FAS 
is Not Used) 
Sensitivity 
Analysis 
Actual values and changes in BMD Z 
score of lumbar spine and proximal 
femur (total hip and femoral neck) from 
Study 20170534  baseline, as 
assessed by dual X-ray absorptiometry 
(DXA), at 6, 12 and 24 months 
Summary statistics will be provided 
for actual and change from Study 
20170534  baseline in  
BMD Z-score per skeletal site (lumbar 
spine, total hip and femoral neck), 
and by visit (6, 12 and 24 months).  
Analysis will be based on DXA 
analysis set.  
 
Not 
applicable 
for this 
study. 
Table 5.  Exploratory Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method (Specify Analysis Set if 
FAS is Not Used) 
Sensitivity 
Analysis 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
Not applicable for the study. 


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9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
Summaries for each secondary efficacy endpoints will be provided by time points of 
interest and treatment headers/definitions as applicable.  
9.5.2.1 
BMD Z score of lumbar spine and proximal femur 
Summary statistics will be provided for actual values and change from study 20170534 
baseline in BMD Z-score per skeletal site (lumbar spine, total hip and femoral neck) at 
6,12 and 24 months. All analyses will be based on the site-specific DXA analysis set. 
Missing baseline and post-baseline BMD Z-scores will not be imputed. 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
Summaries for each exploratory efficacy endpoints will be provided by visit as 
applicable.  
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
Descriptive statistics will be provided for each safety endpoint by treatment category if 
data warrants. 
Table 6.  Primary Safety Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method 
(Specify Analysis Set if FAS is Not Used) 
Sensitivity Analysis 
Subject incidence of 
adverse events and 
serious adverse events 
Subject incidence of  any AEs, serious AEs, 
AEs leading to withdrawal of investigational 
product, AEs of special interest and fatal 
AEs will be tabulated by system organ class 
and preferred term in descending order of 
frequency using SAS and Overall summary 
of AE’s using German substudy safety 
analysis set. 
Not applicable for 
this study. 


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Subject incidence of anti-
denosumab antibodies 
Percentages of subjects who tested positive 
(binding or neutralizing) for antidenosumab 
antibodies will be descriptively summarized 
by visit for subjects in SAS and German 
substudy safety analysis set who continued 
with denosumab. 
Not applicable for 
this study. 
Changes from baseline 
in laboratory values and 
vital signs 
Actual values and changes from baseline in 
each laboratory and vital signs parameter 
will be summarized at each visit. For serum 
calcium, phosphorus, and alkaline 
phosphatase (ALP), summary of the percent 
change from baseline will be provided for 
subjects in SAS and German substudy 
safety analysis set. 
Shifts in laboratory parameters between 
baseline and the most extreme post baseline 
values will be provided based on the SAS. 
Not applicable for 
this study. 
Subject incidence of 
metaphyseal index Z 
score above age-
appropriate normal range 
Subject incidence of the metaphyseal index 
Z-score above age-appropriate normal range 
safety events will be tabulated for subjects in 
SAS and German substudy safety analysis 
set  
Not applicable for 
this study. 
Subject incidence of 
abnormal molar eruption, 
and mandibular shaping 
Subject incidence of the abnormal molar 
eruption safety events will be tabulated for 
subjects in SAS and German substudy 
safety analysis set and descriptive 
summary statistics for mandibular 
shaping parameters will be tabulated for 
subjects in SAS and German substudy 
safety analysis set. 
Not applicable for 
this study. 
 
Page 2 of 2 


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9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version [25.0] or later will be 
used to code all events categorized as adverse events, to a system organ class and a 
preferred term. All adverse event tables will be summarized using the treatment headers 
as defined Table 1. 
The subject incidence of adverse events will be summarized for adverse events, serious 
adverse events, adverse events leading to withdrawal of denosumab, fatal adverse 
events , and adverse events of special interest.   
Subject incidence of all adverse events, serious adverse events, adverse events leading 
to withdrawal of denosumab, and fatal adverse events will be tabulated by system organ 
class and preferred term in descending order of frequency.  
Subject incidence of events of interest (standardized MedDRA queries and/or Amgen 
customized queries) will also be summarized according to their categories and preferred 
term. 
In addition, summaries of all adverse events and serious adverse events occurring in at 
least 5% of the subjects by preferred term in any treatment arm will be provided in 
descending order of frequency.   
Summaries of adverse events and serious adverse events will be tabulated by system 
organ class, preferred term, and grade. 
9.6.2.1 
Adverse Events of Special Interest 
This tentative list of adverse events of special interest has been based on the events of 
interest (EOI) identified for denosumab in the osteoporosis indication, and may be 
revised and changed later on to better reflect the OI population. 
Event of Special Interest 
Search Strategy 
Narrow or Broad Search? 
Hypocalcemia 
Hypocalcemia AMQ 
Narrow 
Hypercalcemia 
Hypercalcemia AMQ 
Narrow 
Positively adjudicated 
osteonecrosis of the jaw 
(ONJ) 
Positively adjudicated cases 
in the database 
NA 
Hypersensitivity 
Hypersensitivity SMQ 
Narrow  
Bacterial Cellulitis (skin 
infection) 
Bacterial cellulitis AMQ with 
serious criteria of 
“hospitalization” 
Narrow 
Typical OI Femur Fractures 
(TOIFF) 
Atypical femoral fractures 
AMQ 
Narrow 


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In addition, Subject incidence for each adverse event of interest (EOI) will be presented 
by PT except for Positively adjudicated ONJ. Listing of Positively adjudicated ONJ and 
typical OI femur fractures (TOIFF) will be presented. 
9.6.3 
Laboratory Test Results 
Actual values and changes from baseline in each parameter will be descriptively 
summarized at each visit. For serum calcium, phosphorus, and alkaline phosphatase 
(ALP), summary of the percent change from baseline also will be provided. 
Shifts in laboratory parameters between baseline and the most extreme post baseline 
values will be assessed based on the CTCAE v4.03.  
See details in Appendix A. 
All laboratory analyses will be based on the safety analysis set and based on the 
German substudy safety analysis set. Subjects with missing data for a scheduled visit 
will not contribute to the tabulation for that time point (no imputation). Visit windows will 
be used for these summaries as described in Appendix C Analytical Windows 
9.6.4 
Vital Signs 
Descriptive statistics of the actual values and changes from baseline in vital signs (heart 
rate, respiration rate, temperature) will be presented by visit for the SAS and based on 
the German substudy safety analysis set.  
9.6.5 
Physical Measurements 
Physical measurements of height, weight and armspan will be summarized based on 
SAS. 
9.6.6 
Antibody Formation 
Subjects receiving at least 1 dose of denosumab in 20170534 will be tested for 
antidenosumab antibodies. The numbers and percentages of subjects who tested 
positive (binding or neutralizing) for antidenosumab antibodies will be descriptively 
summarized.  
9.6.7 
Exposure to Investigational Product 
Descriptive statistics ( for number of injections) will be produced to describe the 
exposure to investigational product. 


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9.7 
Other Analyses 
9.7.1 
Metaphyseal Index Z-Scores and Oral Hygiene  
The subject incidence of the following safety events will be tabulated based on the SAS 
and German substudy safety analysis set. 
 
Metaphyseal index Z-score above age-appropriate normal range (ie, 
metaphyseal index Z-score > +2) 
 
Abnormal molar eruption of the first or second molars 
Descriptive statistics (actual value, change from baseline, percent change from 
baseline ) will be provided for the continuous endpoints of mandibular anatomical 
angles. 


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10. 
Changes From Protocol-specified Analyses 
 Removed the German substudy analysis set from section 6.3.4 as this definition 
was applicable to efficacy endpoints considering baseline and post baseline 
information for endpoint of interest. However to analyze the safety endpoints 
related German substudy the new definition is added as below in section 6.3.4, 
German substudy safery analysis set - “The subset includes all subjects in the 
SAS who enroll in the German substudy.” 
Instead of Subject incidence of abnormal mandibular shaping, we will provide 
descriptive summary statistics for mandibular shaping parameters 


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11. 
Literature Citations / References 
Ward K, Cowell CT and Little DG. Quantification of metaphyseal modeling in children 
treated with bisphosphonates. Bone 2005; 36: 999-1002 
 


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12. 
Data Not Covered by This Plan 
Not applicable 


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13. 
Appendices 
Appendix A Reference Values/Toxicity Grades 
The Common Terminology Criteria for Adverse Events (CTCAE) are available at the 
following link:  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf 
 


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Appendix B Incomplete Dates and Missing Dates 
The following data will be imputed using the following algorithm:  
 
Concomitant Medications  
Imputation Rules for Partial or Missing Start Dates 
     
 
1Impute the date of first dose; 2Impute the first of the month; 3Impute January 1 of the year; 
4Impute January 1 of the stop year 
Note: For subjects who were never treated (first dose date is missing), partial start dates will be set 
to the first day of the partial month or first day of year if month is also missing. 
Imputation Rules for Partial or Missing Stop Dates 
Initial imputation 
 
If the month and year are present, impute the last day of that month. 
 
If only the year is present, impute December 31 of that year. 
 
If the stop date is entirely missing, assume the event or medication is ongoing. 
If the imputed stop date is before the start date, set stop date to missing. 
If the imputed stop date is after the death date, impute as death date. 
      


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Appendix C Analytical Windows 
Per protocol, all tests and procedures scheduled for Screening and Day 1 visit must be 
performed within 28 calendar days of the Study 20130173 End of Study visit. As 
specified in the protocol, all tests and procedures scheduled to occur at Months 3, 6, 9, 
12, 15, 18, 21, and 24 should be performed within  7 days of the scheduled day. 
However, for analysis purposes the analysis visit windows defined below will be used to 
assign evaluations to the most appropriate nominal visit. Regardless of the width of the 
visit window, if more than 1 visits falls within the defined window, the results from visit 
closest to the target day will be used. If 2 evaluations are the same distance from the 
target day, the result from the later visit will be used. If the 2 evaluations have the same 
assessment dates, the first evaluation with the expected clinical planned event will be 
used.  
Table C-1. Vital signs, Pregnancy Test (urine dipstick method), Physical 
Examination, Tanner Stage and Hematology, Urine calcium 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline* 
1 
Last evaluation prior to or on Study day 1  
Month 3 
92 
Study Day 2 to 138 
Month 6 
183 
Study Day 139 to 229 
Month 9 
275 
Study Day  230 to 321 
Month 12 
366 
Study Day 322 to 412 
Month 15 
458 
Study Day 413 to 504 
Month 18 
549 
Study Day 505 to 595 
Month 21 
641 
Study Day 596 to 687 
Month 24 
732 
After Study Day of 687 
Table C-2. Chemistry 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline* 
1 
Last evaluation prior to or on Study day 1 
Day 10 
10 
Study Day 2 to 20 
Day 30 
30 
Study Day 21 to 61 
Month 3 
92 
 Study Day 62 to 97 
Month 3 Day 10 
102 
Study Day 98 to 112 
Month 3 Day 30 
122 
Study Day 113 to 153 


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Month 6 
183 
Study Day 154 to 188 
Month 6 Day 10 
193 
Study Day 189 to 203 
Month 6 Day 30 
213 
Study Day 204 to 244 
Month 9 
275 
Study Day 245 to  321 
Month 12 
366 
Study Day 322 to  412 
Month 15 
458 
Study Day 413 to 504 
Month 18 
549 
Study Day 505 to 595 
Month 21 
641 
Study Day 596 to 687 
Month 24 
732 
After Study Day of 687 
Table C-4. Antidenosumab-antibody, Armspan 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline* 
1 
Last evaluation prior to or on Study day 1 
Month 12 
366 
Study Day 2 to 549 
Month 24 
732 
After Study Day of 549 
Table C-5. DXA 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline* 
1 
Last evaluation prior to or on Study day 1 
Month 6 
183 
Study Day 2 to 275 


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Month 12 
366 
Study Day 276 to 549  
Month 24 
732 
After Study Day of 549  
Table C-6. X-ray(AP knees) 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline* 
1 
Last evaluation prior to or on Study day 1 
Month 6 
183 
Study Day 2 to 275 
Month 12 
366 
Study Day 276 to 458 
Month 18 
549 
Study Day 459 to 641 
Month 24 
732 
After Study Day of 641 
Table C-7. Dental X-ray (cephalogram and panoramic radiograph), Dental X-ray 
(molars) 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Baseline* 
1 
Last evaluation prior to or on Study day 1 
Month 6 
183 
Study Day of 2 to 275 
Month 12 
366 
Study Day 276 to 458 
Month 18 
549 
Study Day 459 to 641 
Month 24 
732 
After Study Day of 641 
Table C-8. Denosumab Administration, Dispensation of calcium and vitamin D, 
Alternative osteoporosis medications 
Nominal Visit 
Target Day 
Window Definition (Study Day) 
Day 1 
1 
Last evaluation prior to or on Study day 1 
Month 3 
92 
Study Day 2 to 138 
Month 6 
183 
Study Day 139 to 229 
Month 9 
275 
Study Day  230 to 321 
Month 12 
366 
Study Day 322 to 412 
Month 15 
458 
Study Day 413 to 504 
Month 18 
549 
Study Day 505 to 595 
Month 21 
641 
Study Day 596 to 687 
Month 24 
732 
After Study Day of 687 
 


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Table C-9. Visit window for Renal Laboratory Value 
Nominal Visit                               
Target Day           Window Definition (Study Day) 
Baseline 
1 
Study Day 1 
Week 6 
42 
Study Day 2 to 49 
Week 8 
56 
Study Day 50 to 63 
Week 10 
70 
Study Day 64 to 77  
Week 12 
84 
Study Day 78 to 109  
Month 3 Week 6                             
134 
Study Day 110 to 141 
Month 3 Week 8 
148 
Study Day 142 to 155 
Month 3 Week 10 
162 
Study Day 156 to 169 
Month 3 Week 12 
176 
Study Day 170 to 201 
Month 6 Week 6 
225 
Study Day 202 to 232 
Month 6 Week 8 
239 
Study Day 233 to 246 
Month 6 Week 10 
253 
Study Day 247 to 260 
Month 6 Week 12 
267 
Study Day 261 to 292 
Month 9 Week 6 
317 
Study Day 293 to 324 
Month 9 Week 8 
331 
Study Day 325 to 338 
Month 9 Week 10 
345 
Study Day 339 to 352 
Month 9 Week 12 
359 
Study Day 353 to 384 
Month 12 Week 6 
408 
Study Day 385 to 415 
Month 12 Week 8 
422 
Study Day 416 to 429 
Month 12 Week 10 
436 
Study Day 430 to 443 
Month 12 Week 12 
450 
Study Day 444 to 475 
Month 15 Week 6 
500 
Study Day 476 to 507 
Month 15 Week 8 
514 
Study Day 508 to 521 
Month 15 Week 10 
528 
Study Day 522 to 535 
Month 15 Week 12 
542 
Study Day 536 to 567 
Month 18 Week 6 
591 
Study Day 568 to 598 
Month 18 Week 8 
605 
Study Day 599 to 612 
Month 18 Week 10 
619 
Study Day 613 to 626 
Month 18 Week 12 
633 
Study Day 627 to 683 
Month 24 
732 
After Study Day of 683 
* Baseline refers to Study 20170534 baseline as defined in this section 5.2.1 above