Clinical trial NCT03301857
Conditions: Giant Cell Tumor of Bone
Sponsor: Amgen
Start date: 2017-11-13; Completion date: 2023-07-27
Enrollment: 85 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study 20140114 will continue to follow participants with GCTB who were treated in Study 20062004 and remained on the study at the completion of Study 20062004 for an additional 5 years on long-term safety follow up.

Detailed description:
Study 20140114 will continue to follow participants with GCTB who were treated in Study 20062004 and remained on the study at the completion of Study 20062004 for an additional 5 years on long-term safety follow up. Collection of long-term safety information will include adverse events of interest and all treatment-emergent adverse events and serious adverse events

Arms: arm 1: Participants who are still being treated with denosumab when 20062004 completes: 120 mg administered subcutaneously (SC) every 4 weeks (Q4W).

For participants undergoing retreatment with denosumab: 120 mg administered SC on Days 1, 8, 15 and 28 then every 4 weeks subsequently. arm 2: Participants who completed denosumab treatment and were in safety follow-up at the conclusion of 20062004 will have follow-up visits performed every 6 months via telephone or in-person clinic visit.
Interventions: intervention 1: Denosumab
Intervention descriptions: intervention 1: 120 mg administered subcutaneously (SC) every 4 weeks (Q4W).

Protocol documents:
Prot_000.pdf: 
Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 1 of 65 
 
 
CONFIDENTIAL 
 
 
Title Page 
Protocol Title: 
Long-term Safety Follow-up of Subjects With 
Giant Cell Tumor of Bone Treated With 
Denosumab in Study 20062004 
Short Protocol Title: 
Long-term Safety Follow-up of Subjects With 
Giant Cell Tumor of Bone Treated With 
Denosumab in Study 20062004 
Protocol Number: 
20140114 
Investigational Product: 
Denosumab 
Trade Name: 
XGEVA® 
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive, 
Thousand Oaks, CA  91320-1799  
United States 
Telephone 
Number: 
1-805-447-1000 
Key 
Sponsor 
Contact 
Name: 
Address: 
One Amgen Center Drive, 
Thousand Oaks, CA  91320-1799  
United States 
Telephone 
Number: 
Email Address: 
EudraCT Number: 
2017‐001758‐32 
NCT Number: 
NCT03301857 
Protocol Date: 
Document Version 
Date 
Original 
17 May 2017 
Amendment 1 
15 November 2017 
Superseding 
Amendment 1 
23 January 2018 
Amendment 2 
23 August 2018 
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 2 of 65 
 
 
CONFIDENTIAL 
 
 
Version/Date: 
Data Element 
Standards Version 
Date 
5.0  
20 March 2015 
 
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:  United States sites, 1- 800-77-AMGEN; 
Canadian sites, 1-866-50-AMGEN; Amgen’s general number in the United States, 
1-805-447-1000. 
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 3 of 65 
 
 
CONFIDENTIAL 
 
 
Investigator's Agreement: 
I have read the attached protocol entitled Long-term Safety Follow-up of Subjects With 
Giant Cell Tumor of Bone Treated With Denosumab in Study 20062004,  
dated 23 August 2018, 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) 
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 4 of 65 
 
 
CONFIDENTIAL 
 
 
Table of Contents 
Table of Contents ............................................................................................................ 4 
1. 
Protocol Synopsis ................................................................................................... 7 
2. 
Study Schema and Schedule of Activities ............................................................. 10 
2.1 
Study Schema ........................................................................................... 10 
2.2 
Schedule of Activities ................................................................................ 11 
3. 
Introduction ........................................................................................................... 13 
3.1 
Study Rationale ......................................................................................... 13 
3.2 
Background ............................................................................................... 13 
3.2.1 
Disease ..................................................................................... 13 
3.2.2 
Amgen Investigational Product Background:  
Denosumab ............................................................................... 13 
4. 
Objectives, Endpoints and Hypotheses ................................................................. 14 
4.1 
Objectives and Endpoints .......................................................................... 14 
4.2 
Hypotheses ............................................................................................... 14 
5. 
Study Design ........................................................................................................ 14 
5.1 
Overall Design .......................................................................................... 14 
5.2 
Number of Subjects ................................................................................... 17 
5.2.1 
Replacement of Subjects ........................................................... 17 
5.2.2 
Number of Sites ......................................................................... 17 
5.3 
End of Study ............................................................................................. 17 
5.3.1 
End of Study Definition .............................................................. 17 
5.3.2 
Study Duration for Subjects ....................................................... 18 
5.4 
Justification for Investigational Product Dose ............................................ 18 
6. 
Study Population .................................................................................................. 18 
6.1 
Inclusion Criteria ....................................................................................... 18 
6.2 
Exclusion Criteria ...................................................................................... 18 
6.3 
Subject Enrollment .................................................................................... 18 
6.4 
Screen Failures ......................................................................................... 19 
7. 
Treatments ........................................................................................................... 19 
7.1 
Treatment Procedures............................................................................... 19 
7.1.1 
Investigational Products ............................................................ 19 
7.1.2 
Non-investigational Products ..................................................... 21 
7.1.3 
Medical Devices ........................................................................ 21 
7.1.4 
Other Protocol-required Therapies ............................................ 21 
7.1.5 
Other Treatment Procedures ..................................................... 21 
7.1.6 
Product Complaints ................................................................... 21 
7.1.7 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 21 
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 5 of 65 
 
 
CONFIDENTIAL 
 
 
7.2 
Method of Treatment Assignment ............................................................. 22 
7.3 
Blinding ..................................................................................................... 22 
7.4 
Dose Modification ...................................................................................... 22 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 22 
7.4.1.1 
Amgen Investigational Product:  
Denosumab ............................................................. 22 
7.5 
Preparation/Handling/Storage/Accountability ............................................ 23 
7.6 
Treatment Compliance .............................................................................. 23 
7.7 
Treatment of Overdose ............................................................................. 23 
7.8 
Prior and Concomitant Treatment ............................................................. 23 
7.8.1 
Prior Treatment ......................................................................... 23 
7.8.2 
Concomitant Treatment ............................................................. 23 
8. 
Discontinuation Criteria ......................................................................................... 24 
8.1 
Discontinuation of Study Treatment........................................................... 24 
8.2 
Discontinuation From the Study ................................................................ 25 
8.2.1 
Reasons for Removal From Washout, Run-in or 
Invasive Procedures .................................................................. 25 
8.2.2 
Reasons for Removal From Study ............................................. 25 
8.3 
Lost to Follow-up ....................................................................................... 25 
9. 
Study Assessments and Procedures .................................................................... 26 
9.1 
General Study Periods .............................................................................. 26 
9.1.1 
Enrollment ................................................................................. 26 
9.1.2 
Treatment Period ....................................................................... 26 
9.1.3 
End-of-treatment Visit ................................................................ 27 
9.1.4 
Long-term Safety Follow-up ....................................................... 27 
9.1.5 
End of Study .............................................................................. 27 
9.2 
Description of General Study Assessments and Procedures ..................... 28 
9.2.1 
General Assessments ............................................................... 28 
9.2.1.1 
Informed Consent .................................................... 28 
9.2.1.2 
Demographics ......................................................... 28 
9.2.1.3 
Medical History ........................................................ 28 
9.2.1.4 
Physical Examination .............................................. 28 
9.2.1.5 
Physical Measurements .......................................... 28 
9.2.2 
Efficacy Assessments ................................................................ 28 
9.2.3 
Safety Assessments .................................................................. 29 
9.2.3.1 
Adverse Events ....................................................... 29 
9.2.3.2 
Vital Signs ............................................................... 32 
9.2.4 
Clinical Laboratory Assessments ............................................... 33 
9.2.4.1 
Pregnancy Testing .................................................. 33 
9.2.5 
Other Assessments ................................................................... 33 
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 6 of 65 
 
 
CONFIDENTIAL 
 
 
9.2.5.1 
Giant Cell Tumor of Bone Status 
Assessments ........................................................... 33 
10. 
Statistical Considerations ...................................................................................... 33 
10.1 
Sample Size Determination ....................................................................... 33 
10.2 
Analysis Sets, Subgroups, and Covariates ................................................ 34 
10.2.1 
Analysis Sets ............................................................................. 34 
10.2.2 
Covariates ................................................................................. 34 
10.2.3 
Subgroups ................................................................................. 34 
10.2.4 
Handling of Missing and Incomplete Data .................................. 34 
10.3 
Statistical Analyses ................................................................................... 34 
10.3.1 
Planned Analyses ...................................................................... 35 
10.3.1.1 
Primary Analysis ..................................................... 35 
10.3.2 
Methods of Analyses ................................................................. 35 
10.3.2.1 
General Considerations ........................................... 35 
10.3.2.2 
Efficacy Analyses .................................................... 35 
10.3.2.3 
Safety Analyses ...................................................... 35 
11. 
References ........................................................................................................... 37 
12. 
Appendices ........................................................................................................... 38 
Appendix 1.  List of Abbreviations and Definitions of Terms .................................. 39 
Appendix 2.  Clinical Laboratory Tests .................................................................. 41 
Appendix 3.  Study Governance Considerations ................................................... 42 
Appendix 4.  Safety Events:  Definitions and Procedures for Recording, 
Evaluating, Follow-up and Reporting ......................................................... 50 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and 
Lactation Information ................................................................................. 60 
 
List of Tables 
Table 2-1.  Schedule of Activities ................................................................................... 11 
Table 7-1.  Study Treatments ........................................................................................ 20 
Table 10-1.  Estimated 95% Confidence Interval for Example Adverse Event 
of Interest Incidence Rate ....................................................................... 34 
List of Figures 
Figure 2-1.  Study Schema ............................................................................................ 10 
Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form .................. 55 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet ...................................... 64 
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 7 of 65 
 
 
CONFIDENTIAL 
 
 
1. 
Protocol Synopsis 
Protocol Title:  Long-term Safety Follow-up of Subjects With Giant Cell Tumor of Bone 
Treated With Denosumab in Study 20062004 
Short Protocol Title:  Long-term Safety Follow-up of Subjects With Giant Cell Tumor of 
Bone Treated With Denosumab in Study 20062004 
Study Phase:  Phase 4 
Indication:  Giant Cell Tumor of Bone 
Rationale 
XGEVA (denosumab) was approved in the United States, Canada, European Union, 
Australia, and other countries for the treatment of giant cell tumor of bone (GCTB) 
largely based on results from ongoing Study 20062004.  Study 20062004 is an 
open-label, single-arm trial where subjects with GCTB are treated with denosumab 
120 mg every 4 weeks.  For subjects with surgically salvageable disease, treatment 
continued until surgery for complete resection and for approximately 6 months 
post-surgery.  For subjects with surgically unsalvageable disease, treatment continued 
as long as there was investigator-determined clinical benefit.  Study 20062004 will 
continue until all subjects enrolled in the initial phase of the study complete at least 
5 years of follow-up on study.  Enrollment in the initial phase of Study 20062004 
concluded in November 2012; therefore, the study ended in May 2018.   
Study 20140114 will continue to follow subjects with GCTB who were treated in 
Study 20062004 for an additional 5 or more years of long-term safety follow-up. 
Objectives/Endpoints 
 
Objectives 
Endpoints 
Primary 
• 
Evaluate adverse events of interest in 
subjects with GCTB treated with 
denosumab in Study 20062004 
• 
Rate of adverse events of interest in 
subjects with GCTB treated with 
denosumab in Study 20062004 
Secondary 
• 
Evaluate treatment-emergent adverse 
events for subjects who are receiving 
denosumab  
• 
Rate of treatment-emergent adverse 
events for subjects who are receiving 
denosumab 
• 
Evaluate serious adverse events for all 
subjects 
• 
Rate of serious adverse events for all 
subjects 
• 
Summarize the rate of disease 
progression or recurrence of GCTB for all 
subjects 
• 
Rate of disease progression or recurrence 
of GCTB for all subjects 
• 
Summarize the use of GCTB 
interventions for all subjects 
• 
Rate of GCTB interventions for all 
subjects 
 
Hypotheses 
This study is descriptive in nature and does not involve testing formal hypotheses.   
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 8 of 65 
 
 
CONFIDENTIAL 
 
 
Overall Design 
This prospective study will provide long-term safety follow-up for subjects who complete 
Study 20062004 and consent to enroll in Study 20140114.  The subject’s follow-up 
begins after signing the informed consent form (ICF) and continues through the earliest 
date of:  5 years after the subject enrolled signs the ICF, death, withdrawal of consent, or 
lost to follow-up.  Study assessments are to be completed every 6 months (± 30 days).  
End of study (EOS) visits for all patients will be at 5 years; Cohort A subjects on 
investigational product will have an EOS visit conducted 30 days following the 
last dose of investigational product (end of treatment [EOT] visit) if receiving 
investigational product at the 5 year time point. 
Subjects who are still being treated with denosumab when 20062004 completes can 
continue receiving open-label denosumab at dose of 120 mg subcutaneously every 
4 weeks.  Collection of long-term safety information will include the following adverse 
events of interest:  osteonecrosis of the jaw, malignancy (including malignancy in 
GCTB), atypical femoral fracture, hypocalcemia, hypercalcemia following treatment 
discontinuation, and pregnancy and lactation (if occurring on treatment or within 
5 months of last dose of denosumab).  Additionally, all treatment-emergent adverse 
events and serious adverse events will be collected.   
Number of Subjects 
The number of subjects in this study will be determined by the number of subjects 
completing Study 20062004 who are willing to enroll in this study for long-term safety 
follow-up.  It is estimated that this will be approximately 100 to 300 subjects.   
Summary of Subject Eligibility Criteria 
All subjects from Study 20062004 who agree to participate in this study and sign the ICF 
will be considered enrolled.   
For a full list of eligibility criteria, please refer to Section 6.1 and Section 6.2. 
Treatments 
For subjects receiving denosumab: 
Denosumab will be supplied as a sterile, clear, colorless to slightly yellow, 
preservative-free liquid, in single-use 3.0 mL glass vials containing a deliverable dose of 
1.7 mL.  Denosumab will be administered as a subcutaneous (SC) injection 120 mg 
every 4 weeks.  A planned dose may be given up to 7 days before the scheduled visit, 
as long as there are at least 21 days between doses.  If a planned dose is delayed more 
than 7 calendar days, it will be considered a missed dose and recorded as such on the 
electronic case report form.  If a subject undergoes retreatment with denosumab, 
they will receive denosumab as a SC injection 120 mg on days 1, 8, 15, and 28, 
then every 4 weeks subsequently. 
All subjects receiving denosumab should be adequately supplemented with calcium and 
vitamin D (at least 500 mg of calcium and 400 IU of vitamin D), except in the case of 
pre-existing hypercalcemia. 
Procedures 
Written informed consent must be obtained from all subjects before any study-specific 
procedures are performed.  The following key procedures will occur per the Schedule of 
Activities (Table 2-1):  collection of disease status, GCTB interventions, review of 
adverse events of interest, serious adverse events, and treatment-emergent adverse 
events.   
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 9 of 65 
 
 
CONFIDENTIAL 
 
 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 9.2 and the Schedule of Activities in Table 2-1. 
Statistical Considerations 
The number of subjects in this study will be determined by the number of subjects 
completing Study 20062004 who are willing to enroll in this study for long-term safety 
follow-up.  It is estimated that this will be approximately 100 to 300 subjects. 
Treatment-emergent adverse event will be summarized for all subjects who receive at 
least 1 dose of denosumab during this study.  Serious adverse event and adverse event 
of interests will be summarized for all subjects who have signed the ICF and enrolled.  
Exposure-adjusted events of interest will be summarized. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor Name:  Amgen Inc. 
 
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 10 of 65 
 
CONFIDENTIAL 
 
 
2. 
Study Schema and Schedule of Activities 
2.1 
Study Schema 
Figure 2-1.  Study Schema 
Cohort A:
Subjects remaining on 
denosumab 120 mg SC 
Q4W in 20062004
Key Eligibility 
Criteria
20062004 
subjects 
Continued
Long-term safety 
follow-up
Denosumab
120 mg SC Q4W 
Cohort B:
Subjects in safety 
follow-up in 20062004
Long-term follow-up for up to 5 years 
END OF STUDY
Q6M        Q6M
Q6M
Q6M
Q6M
Q6M
Q6M
Q6M
Q6M
Q6M
(a)
ICF signed
EOS
 
EOS = end of study; GCTB = giant cell tumor of bone; ICF = informed consent form; SC = subcutaneous; Q4W = every 4 weeks; Q6M = every 6 months 
a Subjects in Cohort A who end denosumab for any reason will complete an end-of-treatment visit and move to safety follow-up.  Subjects who experience GCTB 
recurrence in Cohort B are eligible to resume denosumab at investigator’s discretion and would then be monitored as per Cohort A requirements.  See Section 5.1 for 
more detail. 
 
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 11 of 65 
 
CONFIDENTIAL 
 
 
2.2 
Schedule of Activities 
Table 2-1.  Schedule of Activities 
PROCEDURE 
Baseline
/Day 1a 
Long-term Follow-up 
M6 
M12 
M18 
M24 
M30 
M36 
M42 
M48 
M54 
M60b 
EOTc 
End of 
Studyd 
GENERAL ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographicse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyf  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Disease status and interventionh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapiesi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAFETY ASSESSMENTSj 
Adverse events of interest (serious or 
nonserious)k, l  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse eventsm  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Product complaintsn  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Other nonserious adverse eventso  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
STUDY TREATMENT 
Denosumab administrationp, q, r, s 
←←Subjects will be receiving denosumab 120 mg SC Q4W →→ 
 
 
eCRF = electronic case report form; EOS = end of study; EOT = end of treatment; GCTB = giant cell tumor of bone; ICF = informed consent form; IP = investigational 
product; M = months; Q4W = every 4 weeks; Q6M = every 6 months; SC = subcutaneous 
a Day 1 is defined as the date when the ICF is signed.  Baseline safety assessments (below) should include reporting of any events occurring between the end of the 
20062004 clinical study and 20140114 enrollment. 
b Subjects will continue to have in-person clinic visits every 6 months (± 30 days) until the last subject enrolled has had the opportunity to complete 5 years of follow-up, 
death, withdrawal of consent, or loss to follow-up, whichever comes first. 
c For subjects in Cohort A only and subjects from Cohort B who resume treatment with denosumab for disease recurrence:  EOT in-person clinic visit will occur 30 days 
(± 8 days) after the last dose of denosumab.   
d End of study will occur when one of the following happens: the last subject enrolled has had the opportunity to complete 5 years of follow-up, death, withdrawal of 
consent, or loss to follow-up, whichever comes first.   
e Review the following patient demographics:  sex, age, race, and ethnicity.   
f A complete medical and surgical history will be collected after signing of the ICF.   
 
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 12 of 65 
 
CONFIDENTIAL 
 
 
g For subjects in Cohort A only and subjects from Cohort B who resume treatment with denosumab for disease recurrence:  physical examination will be performed and 
will include disease assessment. 
h Disease status will be clinically accessed by the investigator.  GCTB interventions, including surgery, embolization, radiotherapy, and chemotherapy will be collected 
at each Q6M visit and recorded. 
i If denosumab treatment is discontinued or interrupted, the calcium and vitamin D supplementation should also be re-evaluated. 
j Any adverse event leading to study discontinuation (Cohort A and B) must be reported. 
k The following adverse events of interest will be collected at each Q6M visit and recorded from the signing of the ICF through the EOS visit: 
• osteonecrosis of the jaw  
• malignancy, including malignancy in GCTB 
• atypical femoral fracture  
• hypocalcemia 
• hypercalcemia following treatment discontinuation 
• pregnancy and lactation (if occurred on treatment or within 5 months of last dose of denosumab) 
l Investigators are advised to include assessment of serum calcium (eg, every 2 to 3 months for approximately 1 year) as clinically indicated following IP treatment 
discontinuation or interruption. 
m Serious adverse events will be collected at each Q6M visit and recorded from the signing of the ICF through the EOS visit. 
n For subjects in Cohort A only and subjects from Cohort B who resume treatment with denosumab for disease recurrence:  product complaints as defined in 
Section 7.1.6 will be collected at each Q6M visit and recorded from signing of the ICF through the EOT visit. 
o For subjects in Cohort A only and subjects from Cohort B who resume treatment with denosumab for disease recurrence: treatment-emergent adverse events will be 
collected at each Q6M visit and recorded from the first dose of denosumab through the last EOT visit. 
p For subjects in Cohort A only and subjects from Cohort B who resume treatment with denosumab for disease recurrence:  subjects will receive denosumab 120 mg 
subcutaneous Q4W until confirmation of disease progression, the subject’s decision to discontinue for any reason, or any other reason listed in Section 8.1.  The 
planned dose may be given up to 7 days before the scheduled visit, as long as there are at least 21 days between doses.  If a planned dose is delayed more than 
7 days, it will be considered a missed dose and recorded as such on the eCRF.  For subjects in Cohort A who were receiving denosumab in 20062004, and continue 
to receive denosumab in this study:  denosumab will commence at the next scheduled Q4W visit (with at least 21 days from the last dose of denosumab received in 
the 20062004 study).  Denosumab administration dates will be collected for all subjects receiving denosumab, including Cohort B subjects who resume treatment 
after disease recurrence.  If the subject has discontinued denosumab, stop date and reason for discontinuation will be documented. 
q All subjects receiving denosumab should be adequately supplemented with calcium and vitamin D (at least 500 mg of calcium and 400 IU of vitamin D), except in the 
case of pre-existing hypercalcemia. 
r Retreatment with denosumab is permitted for subjects who demonstrated a previous response to denosumab (eg, in the case of recurrent disease while subject is in 
the safety follow-up).  Eligibility criteria for retreatment are outlined in Section 7.4.1.  Refer to Section 7.1.1 for information on additional doses. 
s No study assessments are required during the Q4W dosing visits unless the visits coincide with the timing of the Q6M follow-up study visits.   
 
 
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 13 of 65 
 
CONFIDENTIAL 
 
 
3. 
Introduction 
3.1 
Study Rationale 
XGEVA® (denosumab) was approved in the United States, Canada, European Union, 
Australia, and other countries for the treatment of giant cell tumor of bone (GCTB) 
largely based on results from ongoing Study 20062004.  Study 20062004 is an 
open-label, single-arm trial where subjects with GCTB are treated with denosumab 
120 mg every 4 weeks.  For subjects with surgically salvageable disease, treatment 
continued until surgery for complete resection and for approximately 6 months 
post-surgery.  For subjects with surgically unsalvageable disease, treatment continued 
as long as there was investigator-determined clinical benefit.  Study 20062004 will 
continue until all subjects enrolled in the initial phase of the study complete at least 
5 years of follow-up on study.  Enrollment in the initial phase of Study 20062004 
concluded in November 2012; therefore, the study ended in May 2018.   
Study 20140114 will continue to follow subjects with GCTB who were treated in 
Study 20062004 for an additional 5 or more years of long-term safety follow-up.   
3.2 
Background 
3.2.1 
Disease 
Giant cell tumor of bone is a rare disease characterized clinically by relentlessly 
expansive osteolytic lesions usually located at the epiphyses of long bones.  GCTB has 
2 components:  a mononuclear stromal cell matrix and dispersed multinuclear giant 
cells.  The mononuclear stromal cells express receptor activator of nuclear factor 
kappa-B ligand (RANKL); its receptor, RANK, is expressed on the multinuclear giant 
cells.  The RANK/RANKL pathway is an essential mediator of osteoclast function, 
formation and survival.     
3.2.2 
Amgen Investigational Product Background:  Denosumab 
Denosumab, a fully human monoclonal antibody to RANKL, inhibits osteoclast‑mediated 
bone destruction and has been shown to provide therapeutic benefit for patients with 
GCTB.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of 
denosumab can be found in Denosumab Investigator’s Brochure/XGEVA package 
insert.   
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 14 of 65 
 
CONFIDENTIAL 
 
 
4. 
Objectives, Endpoints and Hypotheses 
4.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
• 
Evaluate adverse events of interest in 
subjects with GCTB treated with 
denosumab in Study 20062004 
 
• 
Rate of adverse events of interest in 
subjects with GCTB treated with 
denosumab in Study 20062004 
Secondary 
• 
Evaluate treatment-emergent adverse 
events for subjects who are receiving 
denosumab  
• 
Rate of treatment-emergent adverse 
events for subjects who are receiving 
denosumab 
• 
Evaluate serious adverse events for all 
subjects 
• 
Rate of serious adverse events for all 
subjects 
• 
Summarize the rate of disease 
progression or recurrence of GCTB for all 
subjects 
• 
Rate of disease progression or recurrence 
of GCTB for all subjects 
• 
Summarize the use of GCTB 
interventions for all subjects 
• 
Rate of GCTB interventions for all 
subjects 
  
4.2 
Hypotheses 
This study is descriptive in nature and does not involve testing formal hypotheses.   
5. 
Study Design 
5.1 
Overall Design 
This prospective study will provide long-term safety follow-up for subjects who complete 
Study 20062004 and consent to enroll in Study 20140114.  As Study 20062004 nears its 
end of study (EOS) date, subjects in Study 20062004 will be offered to roll-over into 
Study 20140114.  Study assessments are to be completed every 6 months (± 30 days).  
The subject’s follow-up begins after signing the informed consent form (ICF) and 
continues through the earliest date of: 5 years after the last subject enrolled signs the 
ICF, death, withdrawal of consent, or lost to follow-up.  Study assessments are detailed 
in the Table 2-1.   
There will be 2 cohorts in this study: 
Cohort A:  subjects who were receiving denosumab at the conclusion of Study 20062004 
can continue receiving denosumab at the current dose and schedule at the investigator’s 
discretion.  All subjects should be adequately supplemented with calcium and vitamin D 
(at least 500 mg of calcium and 400 IU of vitamin D), except in the case of pre-existing 
hypercalcemia.  Follow-up study visits will be performed in clinic every 6 months 
(± 30 days) while receiving denosumab.  Subjects who discontinue denosumab will have 
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an end of treatment (EOT) in-person clinic visit approximately 30 days (± 8 days) after 
the last dose of denosumab.  Thereafter, they will enter the long-term safety follow-up 
and will be monitored as per Cohort B requirements.  In addition to the EOT, all subjects 
should be monitored for the development of signs and symptoms of hypercalcemia 
following discontinuation of investigational product (IP).  Investigators are advised to 
include assessment of serum calcium (eg, every 2 to 3 months for approximately 1 year) 
as clinically indicated following IP treatment discontinuation or interruption.  The calcium 
and vitamin D supplementation following discontinuation of IP should also be 
re-evaluated.  When investigational product is discontinued, the investigator 
should evaluate the individual subject’s risk for vertebral fragility fractures.  
Subjects with a high risk for fragility fracture (eg, history of osteoporosis, 
postmenopausal status, prior fracture history), should be monitored for the 
development of signs and symptoms of vertebral fractures following 
discontinuation of denosumab. 
Cohort B:  subjects who completed denosumab treatment in 20062004 and were in the 
safety follow-up at the conclusion of 20062004 will continue in long-term safety follow-up 
in this study.  Follow-up study visits will be done every 6 months (± 30 days) either via 
telephone or in-person clinic visit.  If subjects have completed denosumab treatment less 
than a year before enrolling in Study 20140114, they should be monitored for 
development of signs and symptoms of hypercalcemia. 
Retreatment with denosumab (120 mg subcutaneous [SC] on days 1, 8, 15, and 28, 
then every 4 weeks subsequently) is allowed for subjects who previously demonstrated 
a response to denosumab and have experienced disease recurrence while in long-term 
safety follow-up at the investigator’s discretion.  If more than 12 months have elapsed 
since the last denosumab therapy, biopsy confirmation of disease for further pathologic 
evaluation of the recurrence is required.  Once denosumab treatment is resumed, the 
investigator must follow the safety reporting requirements as outlined for Cohort A.   
For Cohorts A and B:  laboratory assessments are not mandated by the study and will 
be performed at the investigator’s discretion as part of the standard of care or as 
clinically indicated.  Investigators are advised to monitor all subjects for the development 
of signs and symptoms of hypercalcemia and to consider periodic assessment of serum 
calcium (eg, every 2 to 3 months for approximately 1 year) as clinically indicated 
following IP treatment discontinuation or interruption. 
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At each follow-up study visit, subjects will be assessed (for in-person clinic visit) or 
asked (for visit via telephone) for signs and symptoms of the following adverse events of 
interest: 
• 
osteonecrosis of the jaw (ONJ) 
• 
malignancy, including malignancy in GCTB 
• 
atypical femoral fracture (AFF) 
• 
hypocalcemia (assessed per Common Terminology Criteria for Adverse Events 
[CTCAE] criteria) 
• 
hypercalcemia following treatment discontinuation (assessed by CTCAE criteria)  
• 
pregnancy and lactation (if occurring on treatment or within 5 months of last dose of 
denosumab) 
Specific relevant additional information where available will be requested.  Additional 
information may include, but is not limited to: 
• 
ONJ:  dental records; information will be sent for adjudication by independent 
reviewers 
• 
malignancy, including malignancy in GCTB:  pathology reports, tumor slides or 
blocks, imaging studies, medical/surgical records 
• 
AFF:  X-ray or other imaging; medical/surgical records; information will be sent for 
adjudication by independent reviewers 
• 
hypocalcemia:  laboratory reports; medical records 
• 
hypercalcemia following treatment discontinuation:  laboratory reports; medical 
records 
• 
pregnancy and lactation (if occurring on treatment or within 5 months of last dose of 
denosumab):  pregnancy and lactation notification worksheets (Appendix 5). 
If the subject has experienced any other serious adverse event (Section 9.2.3.1.1.3) 
while on study, pertinent information is to be collected and reported.  Additionally, all 
treatment-emergent adverse events will be collected while the subject is receiving 
denosumab through the EOT visit. 
Information regarding GCTB disease status (investigator assessed) and previous or 
current treatments, including surgery, embolization, radiotherapy, and chemotherapy will 
be collected at each visit.  Embolization, chemotherapy, radiation therapy are permitted 
in accordance with local guidelines.  No investigational agents for GCTB are allowed on 
study.  Use of any unapproved (ie, no marketing authorization has been granted) 
investigational product or device is not allowed while the subject remains on study. 
Denosumab administration dates will be collected for all subjects receiving denosumab, 
including Cohort B subjects who resume treatment after disease recurrence.  If the 
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subject has discontinued denosumab, stop date and reason for discontinuation must be 
documented. 
The overall study design is described by a study schema in Section 2.1.  The endpoints 
are defined in Section 4.1. 
5.2 
Number of Subjects 
The number of subjects in this study will be determined by the number of subjects 
completing Study 20062004 who are willing to enroll in this study for long-term safety 
follow-up.  It is estimated that this will be approximately 100 to 300 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. 
5.2.2 
Number of Sites 
Approximately 25 sites will be enrolling subjects for this study.  Sites that do not enroll 
subjects within 3 months of site initiation may be closed. 
5.3 
End of Study 
5.3.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint, for the purposes of conducting the primary analysis, whether the study 
concluded as planned in the protocol or was terminated early. 
The primary completion date is the date when the last subject has completed the 
assessments for 5 years of follow-up.   
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
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. 
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5.3.2 
Study Duration for Subjects 
The duration of study for each subject is at least 5 years from the date of enrollment 
(ie, date of signing the ICF).   
5.4 
Justification for Investigational Product Dose 
Subjects in Cohort A will continue denosumab at the same dose and schedule as in the 
Study 20062004.  Denosumab will be dosed at 120 mg SC every 4 weeks. 
6. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).   
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Appendix 3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, will not be provided. 
6.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Subject was previously enrolled in Study 20062004. 
102 
Subject or subject’s legally acceptable representative has provided informed 
consent/assent prior to initiation of any study-specific activities/procedures.   
6.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply. 
201 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge.   
202 
Females of childbearing potential on denosumab and not willing to continue to 
use 1 highly effective method of contraception during treatment and for 5 months 
after the EOT 
6.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, ICF, and all other subject information 
and/or recruitment material, if applicable (see Appendix 3). 
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The subject or the subject’s legally acceptable representative must personally sign and 
date the IRB/IEC and Amgen approved informed consent before commencement of 
study-specific procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each enrolled subject receives a unique subject identification number before any 
study-related activities/procedures are performed.  The subject identification number will 
be assigned via Interactive Voice Response System (IVRS).  This number will be used 
to identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.   
6.4 
Screen Failures 
Not applicable.  
7. 
Treatments 
Study treatment is defined as any investigational product(s) intended to be administered 
to a study subject according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment shown in Table 7-1 below. 
7.1 
Treatment Procedures 
7.1.1 
Investigational Products 
 
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Table 7-1.  Study Treatments 
Study Treatment Name 
Amgen Investigational Product:a 
Denosumab (XGEVA) 
Dosage Formulation 
Denosumab will be supplied as a sterile, clear, colorless to slightly yellow, preservative-free liquid, in single-use 
3.0 mL glass vials containing a deliverable dose of 1.7 mL. 
Unit Dose Strength(s)/ 
Dosage Level(s) and Dosage 
Frequency 
120 mg every 4 weeks 
Route of Administration 
SC injection 
Accountability 
Administration dates, doses, and lot number of denosumab are to be recorded on each subject's eCRF(s). 
Dosing Instructions 
Denosumab is to be administered by a licensed healthcare professional at a dose of 120 mg SC Q4W with an 
additional dose of 120 mg SC on days 8 and 15 of treatment for subjects entering retreatment with 
denosumab  (subjects on continuous investigational product from Study 20062004, will not receive an 
additional dose of 120 mg on days 8 or 15).  If the doses on study days 8 and 15 are delayed more than 
8 calendar days, it will be considered a missed dose and recorded as such on the eCRF.  The next dose is 
to be given at the next scheduled visit date (based on study day 1).  There must be at least 4 days (ie, 
96 hours) between the study days 1, 8, and 15 doses (ie, ± 3 days from the scheduled visit date).  The 
planned dose may be given up to 7 days before the scheduled visit, as long as there are at least 21 days between 
doses.  If a planned dose is delayed more than 7 calendar days, it will be considered a missed dose and recorded 
as such on the eCRF. 
eCRF = electronic case report form; Q4W = every 4 weeks; 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 
Non-investigational products will not be used.  
7.1.3 
Medical Devices 
No medical devices are to be used in this study other than those considered to be 
standard.   
Non-investigational medical devices (eg, syringes, sterile needles), that are 
commercially available are not usually provided or reimbursed by Amgen (except, for 
example, if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these devices. 
7.1.4 
Other Protocol-required Therapies 
There are no other protocol-required therapies. 
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(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material. 
This includes any drug(s), device(s), or combination product(s) provisioned and/or 
repackaged/modified by Amgen.  Drug(s) or device(s) includes investigational product.   
Any product complaint(s) associated with an investigational product(s), 
non-investigational product(s), device(s), or combination product(s) supplied by Amgen 
are to be reported according to the instructions provided in the IPIM. 
7.1.7 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Concurrent treatment with bisphosphonates is not allowed while the subject is receiving 
denosumab.  Embolization, chemotherapy, and radiation therapy are permitted in 
accordance with local guidelines.  No investigational agents for GCTB are allowed on 
study.  Use of any unapproved (ie, no marketing authorization has been granted) 
investigational product or device is not allowed while the subject remains on study. 
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Invasive dental procedures should be avoided when possible and should be recorded in 
the electronic CRF.  Administration of denosumab is recommended to be withheld 
30 days prior to any elective invasive oral/dental procedure.  Denosumab administration 
is recommended to remain withheld until documented evidence of complete mucosal 
healing following any invasive oral/dental procedure.  Subjects with ONJ on study may 
temporarily or permanently discontinue investigational product at investigator discretion.  
Re-exposure to denosumab may occur if the investigator and sponsor agree subject’s 
safety will not be compromised.   
7.2 
Method of Treatment Assignment 
Not applicable. 
7.3 
Blinding 
This is an open-label study; blinding procedures are not applicable. 
7.4 
Dose Modification 
7.4.1 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
7.4.1.1 
Amgen Investigational Product:  Denosumab 
There will be no dose adjustments allowed in this study.   
Retreatment (restarting denosumab following discontinuation) may be allowed for 
subjects who demonstrated a response to denosumab and are currently not receiving 
denosumab treatment (eg, in the case of recurrent disease while subject is in the safety 
follow-up).  Pathological confirmation of GCTB is required prior to retreatment if more 
than 12 months have elapsed since the last denosumab dose to further evaluate disease 
recurrence and rule out malignancy.  Subjects will not be allowed retreatment if any of 
the following criteria apply: 
• 
Concurrent bisphosphonate treatment. 
• 
Known or suspected current diagnosis of underlying malignancy including high-grade 
sarcoma, osteosarcoma, fibrosarcoma, malignant giant cell sarcoma. 
• 
Active dental or jaw condition which requires oral surgery, including tooth extraction. 
• 
Non-healed dental/oral surgery.  
• 
Subject is receiving other investigational agent(s). 
• 
Subject has known sensitivity to denosumab.  
• 
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 should only be allowed retreatment 
after a confirmed menstrual period and a negative urine or serum pregnancy test.) 
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• 
Female subjects of childbearing potential unwilling to use 1 highly effective method 
of contraception during treatment and for an additional 5 months after the last dose 
of denosumab.   
• 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject and investigator’s knowledge. 
• 
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. 
7.5 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of denosumab during the study are provided in the IPIM. 
7.6 
Treatment Compliance 
Not applicable.   
7.7 
Treatment of Overdose 
The effects of overdose of denosumab are not known.  
7.8 
Prior and Concomitant Treatment 
7.8.1 
Prior Treatment 
Prior therapies that were being taken from the EOS visit for 20062004 study through the 
signing of the ICF for 20140114 should be collected.  For prior therapies, collect therapy 
name, indication, dose, unit, frequency, route, start date, and stop date. 
7.8.2 
Concomitant Treatment 
All subjects should be adequately supplemented with calcium and vitamin D (at least 
500 mg of calcium and 400 IU of vitamin D), except in the case of pre-existing 
hypercalcemia.  Due to differences in regional availability, a dosage form of vitamin D 
that gives an equivalent of at least 400 IU daily may be given.  If denosumab treatment 
is discontinued or interrupted, the calcium and vitamin D supplementation should also be 
re-evaluated. 
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. 
For concomitant therapies, collect therapy name, indication, dose, unit, frequency, route, 
start date, and stop date.   
Concomitant therapies are to be collected from signing of the ICF through the EOS.   
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8. 
Discontinuation Criteria 
Subjects have the right to withdraw from denosumab treatment, protocol procedures, or 
the study as a whole at any time and for any reason without prejudice to their future 
medical care by the physician or at the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from denosumab 
treatment, protocol procedures, or the study as a whole at any time prior to study 
completion for the reasons listed in Sections 8.1, 8.2.1, and 8.2.2. 
8.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
denosumab at any time during the study but continue participation in the study.  If this 
occurs, or if the subject discontinues denosumab treatment for any reason 
(eg, investigator decision or adverse event [AE]), the investigator is to discuss with the 
subject the appropriate processes for discontinuation from denosumab, including 
counseling the subject on signs and symptoms of hypercalcemia, and if clinically 
indicated, assessment of serum calcium, 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.  When investigational product 
is discontinued, the investigator should evaluate the individual subject’s risk for 
vertebral fragility fractures.  Subjects with a high risk for fragility fracture (eg, 
history of osteoporosis, postmenopausal status, prior fracture history), should be 
monitored for the development of signs and symptoms of vertebral fractures 
following discontinuation of denosumab.  Subjects who have discontinued 
denosumab should not be automatically removed from the study.  Whenever safe and 
feasible, it is imperative that subjects remain on-study to ensure safety surveillance 
and/or collection of outcome data. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with Appendix 3. 
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Reasons for removal from denosumab treatment or procedural assessments include any 
of the following: 
• 
decision by sponsor 
• 
lost to follow-up 
• 
death 
• 
ineligibility determined 
• 
protocol deviation 
• 
noncompliance  
• 
adverse event 
• 
subject request 
• 
disease progression  
• 
pregnancy 
8.2 
Discontinuation From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical records. 
Refer to the Schedule of Activities for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
8.2.1 
Reasons for Removal From Washout, Run-in or Invasive Procedures 
Not applicable.   
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.  
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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.  
 
9. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 2-1).  
As protocol waivers or exemptions are not allowed, if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
9.1 
General Study Periods 
9.1.1 
Enrollment 
Informed consent must be obtained before completing any assessments detailed in the 
Schedule of Activities (Table 2-1).  If subjects are continuing on denosumab from the 
Study 20062004 (Cohort A), the informed consent must be signed prior to administration 
of denosumab in this study.   
9.1.2 
Treatment Period  
Cohort A subjects can continue receiving denosumab at the investigator’s discretion.  
Denosumab will commence at the next scheduled every-4-week visit (with at least 
21 days from the last dose of denosumab received in the 20062004 study).  Cohort B 
subjects who enter retreatment only may also receive denosumab at the investigator’s 
discretion.  All dosing and follow-up study visits will be scheduled based on the day 1 
date defined as the date the ICF is signed.  Dosing visits will occur every 4 weeks, per 
the Schedule of Activities (Table 2-1).  Follow-up study visits will be performed in clinic 
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every 6 months (± 30 days).  No safety assessments are required during the 
every-4-week dosing visits unless the visits coincide with the timing of the follow-up 
study visit.  
9.1.3 
End-of-treatment Visit  
Cohort A and Cohort B subjects who enter retreatment only:  upon discontinuation from 
denosumab for any reason, an EOT in-person clinic visit will be performed approximately 
30 days (± 8 days) after the last dose of denosumab.   
Thereafter, they will enter the long-term safety follow-up. 
In addition to the EOT visit, all subjects stopping denosumab should be monitored for the 
development of signs and symptoms of hypercalcemia following discontinuation of IP.  
Investigators are advised to include assessment of serum calcium (eg, every 2 to 
3 months for approximately 1 year) as clinically indicated following IP treatment 
discontinuation or interruption.  If denosumab treatment is discontinued or interrupted, 
the calcium and vitamin D supplementation should also be re-evaluated. 
9.1.4 
Long-term Safety Follow-up 
Cohort B:  subjects who completed denosumab treatment in Study 20062004 and were 
in the safety follow-up at the conclusion of Study 20062004 will continue in long-term 
safety follow-up in this study.  If subjects have completed denosumab treatment less 
than a year before enrolling in Study 20140114, they should be monitored for the 
development of signs and symptoms of hypercalcemia with serum calcium assessments 
as clinically indicated.  Study assessments during follow-up study visits in long-term 
safety follow-up will be completed per the Schedule of Activities (Table 2-1) every 
6 months (± 30 days) either via telephone or in-person clinic visit.  An EOS visit should 
be performed 5 years after signing of the ICF. 
Cohort A and Cohort B subjects who enter retreatment only:  subjects will enter 
long-term safety follow-up after the EOT visit and will be monitored per Cohort B 
requirements.  Subjects receiving investigational product 5 years after signing of 
the ICF, should undergo an in-person clinic, combined EOT and EOS visit 30 days 
following the last dose of investigational product. 
9.1.5 
End of Study 
End of study will occur when one of the following happens: the last subject enrolled has 
had the opportunity to complete 5 years of follow-up, death, withdrawal of consent, or 
lost to follow-up, whichever comes first.   
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9.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
9.2.1 
General Assessments  
9.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
Institutional Review Boards/Independent Ethics Committee (IRB/IEC) approved informed 
consent before any study-specific procedures are performed. 
9.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety.  
9.2.1.3 
Medical History 
A complete medical and surgical history will be collected after signing of the ICF.  
Medical history will include information on the subject's concurrent medical conditions.  
Record all findings on the medical history CRF.  In addition to the medical history above, 
GCTB disease specific history must date back to the original diagnosis and reported to 
the GCTB Details page.  The current toxicity grade will be collected for each condition 
that has not resolved.   
9.2.1.4 
Physical Examination  
For subjects in Cohort A only and subjects from Cohort B who resume treatment with 
denosumab for disease recurrence:  physical examination will be performed.  Physical 
examination findings should be recorded on the appropriate CRF (eg, medical history, 
GCTB details). 
9.2.1.5 
Physical Measurements 
Not applicable. 
9.2.2 
Efficacy Assessments 
Not applicable.    
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9.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities. 
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 
Treatment-emergent Adverse Events 
The adverse event grading scale to be used for this study will be the CTCAE and is 
described in Appendix 4. 
For Cohort A and Cohort B subjects who enter retreatment only:  investigator is 
responsible for ensuring that all treatment-emergent adverse events observed by the 
investigator or reported by the subject that occur after the first dose of denosumab 
through the last EOT visit are reported using the Event CRF. 
9.2.3.1.1.2 
Adverse Events of Interest 
For all subjects (Cohorts A and B):  at each visit, subjects will be assessed for signs and 
symptoms of the following adverse events of interest: 
• 
ONJ 
• 
malignancy, including malignancy in GCTB 
• 
AFF 
• 
hypocalcemia (assessed per CTCAE criteria) 
• 
hypercalcemia following treatment discontinuation (assessed per CTCAE criteria) 
• 
pregnancy and lactation (if occurring on treatment or within 5 months of last dose of 
denosumab) 
If the subject has experienced any adverse events of interest (serious or nonserious) 
while in study, specific relevant additional information where available will be requested.  
Additional information may include, but is not limited to: 
• 
ONJ:  dental records; information will be sent for adjudication by independent 
reviewers 
• 
malignancy, including malignancy in GCTB:  pathology reports, tumor slides or 
blocks, imaging studies, medical/surgical records 
• 
AFF:  x-ray or other imaging; medical/surgical records; information will be sent for 
adjudication by independent reviewers 
• 
hypocalcemia:  laboratory reports; medical records 
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• 
hypercalcemia following treatment discontinuation:  laboratory reports; medical 
records 
• 
pregnancy and lactation (if occurring on treatment or within 5 months of last dose of 
denosumab):  pregnancy and lactation notification worksheets (Appendix 5) 
Adverse events of interest will be collected and recorded from the signing of the ICF 
through the EOS visit.   
9.2.3.1.1.3 
Serious Adverse Events 
For all subjects (Cohorts A and B): the investigator is responsible for ensuring that all 
serious adverse events observed by the investigator or reported by the subject that 
occur after signing of the informed consent through EOS visit are reported using the 
Event CRF. 
For all subjects who experienced a treatment gap of more than 30 days between 
the EOS visit of Study 20062004 and signing the ICF for Study 20140114, all 
serious adverse events and/or events of interest observed by the investigator or 
reported by the subject that occurred in that period must be reported using the 
electronic case report form (eCRF).  Events of interest include: 
• 
ONJ 
• 
malignancy, including malignancy in GCTB 
• 
AFF 
• 
hypocalcemia (assessed per CTCAE criteria) 
• 
hypercalcemia following treatment discontinuation (assessed per CTCAE 
criteria) 
• 
pregnancy and lactation (if occurring on treatment or within 5 months of last 
dose of denosumab) 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours, as indicated in Appendix 4.  The investigator will submit any 
updated serious adverse event data to the sponsor within 24 hours of it being available. 
9.2.3.1.1.4 
Serious Adverse Events After the Protocol-required Reporting 
Period 
There is no requirement to monitor study subjects for serious adverse events following 
the EOS (ie, the protocol-required reporting period).  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. 
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Serious adverse events reported after EOS will be captured within the safety database.  
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 Appendix 4. 
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 
otherwise explained, or the subject is lost to follow-up (as defined in Section 8.3).  
Further information on follow-up procedures is given in Appendix 4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
9.2.3.1.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from denosumab 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 toward 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. 
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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 female partners of 
male subjects will be collected after the start of denosumab and until 5 months after the 
last dose of 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 Appendix 5.  
Amgen Global Patient Safety will follow-up with the investigator regarding additional 
information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Appendix 5. 
9.2.3.1.6 
Adjudication Process for Suspected Osteonecrosis of the jaw and 
Suspected Atypical Femoral Fracture Adverse Events 
All subjects with an oral sign or symptom suspicious for ONJ should be examined by a 
dentist or other qualified oral specialist (eg, oral surgeon).  All subjects presenting with 
new or unusual thigh, hip, or groin pain should be evaluated for a suspected adverse 
event of AFF. 
Adverse events reported as ONJ or AFF as well as adverse events identified by Amgen 
as potentially representing ONJ or AFF will be reviewed by an independent adjudication 
panel of experts to determine whether the pre-defined criteria for ONJ or AFF are met.  
Amgen will request the investigating site to provide all available source documents 
surrounding that event to be reviewed by the blinded adjudication committee.   
9.2.3.2 
Vital Signs 
Not applicable.   
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9.2.4 
Clinical Laboratory Assessments 
Laboratory assessments, both on denosumab and following discontinuation of 
denosumab are not required and will be performed at the investigator’s discretion as part 
of the standard of care or as clinically indicated.  Investigators are advised to include 
assessments of serum calcium (eg, every 2 to 3 months for approximately 1 year) as 
clinically indicated following IP treatment discontinuation or interruption (Appendix 2). 
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Event CRF.  The investigator 
must determine whether an abnormal value in an individual study subject represents a 
clinically significant change from the subject’s baseline values (Appendix 4).  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.   
9.2.4.1 
Pregnancy Testing 
On-treatment pregnancy testing may be performed at the investigator’s discretion or as 
required per local laws and regulations. 
9.2.5 
Other Assessments  
9.2.5.1 
Giant Cell Tumor of Bone Status Assessments 
The following GCTB disease status assessments will be collected: 
• 
disease progression  
• 
disease recurrence  
• 
GCTB interventions, including surgery, embolization, radiotherapy, or chemotherapy  
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 20062004, and who are willing to enroll in this study for long-term 
safety follow-up.  It is estimated that this will be approximately 100 to 300 subjects. 
For the expected sample size of 100 to 300 subjects, the 95% confidence interval (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 more than 1.2% for 300 subjects 
is unlikely for that particular adverse event.   
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Table 10-1.  Estimated 95% Confidence Interval for Example Adverse Event 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) 
0/200 
0 
(0.0, 1.8) 
2/200 
1 
(0.1, 3.6) 
10/200 
5 
(2.4, 9.0) 
20/200 
10 
(6.2, 15.0) 
0/300 
0 
(0.0, 1.2) 
3/300 
1 
(0.2, 2.9) 
15/300 
5 
(2.8, 8.1) 
30/300 
10 
(6.8, 14.0) 
CI = confidence interval 
10.2 
Analysis Sets, Subgroups, and Covariates 
10.2.1 
Analysis Sets 
The analysis will be based on the full analysis set which includes all enrolled subjects 
who have provided informed consent and have a non-missing enrollment date. 
10.2.2 
Covariates 
Not applicable. 
10.2.3 
Subgroups 
Not applicable. 
10.2.4 
Handling of Missing and Incomplete Data 
Subjects may have missing data points for a variety of reasons.  In general, data may be 
missing due to subject’s early withdrawal from study, a missed visit, or non-evaluability 
of an endpoint at a particular point in time.  The detailed approach for handling missing 
data will be included in the statistical analysis plan. 
In general, analyses will be based on available data.   
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.   
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10.3.1 
Planned Analyses 
10.3.1.1 
Primary Analysis 
Primary analysis will occur upon completion of the study when all subjects have had the 
opportunity to complete 5 years of follow-up.   
10.3.2 
Methods of Analyses 
10.3.2.1 
General Considerations 
The statistical analysis in this long-term safety follow-up study will be descriptive in 
nature and no hypothesis testing will be performed.  In general, data summaries will be 
presented overall.  Categorical outcomes will be summarized by the number and 
percentage of subjects in each category.  Continuous outcomes will be summarized by 
the number of non-missing values, mean, standard deviation, median, lower and upper 
quartiles and minimum and maximum values.  For the incidence, 95% CI will be 
presented based on an exact method.  Kaplan-Meier estimates and their 95% CI will be 
provided for time to adverse event of interest.  The incidence rates (annual and 
cumulative) of adverse events of interest will be estimated.  The incidence of malignancy 
in GCTB will be compared with the historical control rates based on the published 
literature. 
10.3.2.2 
Efficacy Analyses 
No formal efficacy analysis is planned for this study.   
10.3.2.3 
Safety Analyses 
10.3.2.3.1 
Analyses of Safety Endpoints 
 
Endpoint 
Statistical Analysis Methods 
Primary 
• 
Rate of adverse events of interest in subjects with GCTB treated with 
denosumab in Study 20062004 
Secondary 
• 
Rate of treatment-emergent adverse events for subjects who are 
receiving denosumab  
• 
Rate of serious adverse events for all subjects 
• 
Rate of disease progression or recurrence of GCTB for all subjects  
• 
Rate of GCTB interventions for all subjects 
 
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10.3.2.3.2 
Adverse Events  
The incidence of adverse events of interest will be summarized by system organ class 
and by preferred term per the current Medical Dictionary for Regulatory Activities.  The 
proportion of subjects with adverse events of interest will be estimated for all subjects 
with 95% CI based on an exact method. 
Exposure-adjusted incidence rates will be summarized for adverse events of interest.  
For the ONJ, AFF, and malignancy, including malignancy in GCTB events of interest, 
analyses will be performed by pooling data from Study 20062004 and this study based 
on all subjects who received at least 1 dose of denosumab.  The incidence of 
malignancy in GCTB will be compared with the historical control rates based on the 
published literature. 
The incidence of treatment-emergent adverse events will be summarized by system 
organ class and by preferred term per the current Medical Dictionary for Regulatory 
Activities for subjects who are receiving denosumab.  The proportion of subjects with 
serious adverse events will be estimated.   
10.3.2.3.3 
Exposure to Investigational Product 
Subjects are considered exposed 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.  
Similar analysis will be performed for the time period starting from the first denosumab 
dose in Study 20062004 to the last denosumab dose date (in either Study 20140114 or 
Study 20062004) plus 28 days, whichever is later.   
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11. 
References 
Denosumab Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.   
XGEVA [package insert].  Thousand Oaks, CA:  Amgen, Inc.; March 2016 
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12. 
Appendices 
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Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
AFF 
atypical femur fracture 
CI 
confidence interval 
CRF 
case report form 
CTCAE  
Common Terminology Criteria for Adverse Events 
EDC 
electronic data capture 
End of Study (end of trial) 
defined as the date when the last subject is assessed or 
receives an intervention for evaluation in the study (ie, last 
subject last visit), following any additional parts in the study 
(eg, long-term follow-up), as applicable 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary 
analysis, whether the study concluded as planned in the protocol 
or was terminated early  
End of Study for Individual 
Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Treatment 
defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
EOS 
end of study 
EOT 
end of treatment 
GCP 
Good Clinical Practice 
GCTB 
giant cell tumor of bone 
HRT 
hormonal replacement therapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
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   
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Boards 
ONJ 
osteonecrosis of the jaw 
RANKL 
receptor activator of nuclear factor kappa-B ligand 
Page 1 of 2 
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Abbreviation or Term 
Definition/Explanation 
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 
Page 2 of 2 
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Appendix 2.  Clinical Laboratory Tests 
No laboratory tests are required by this study while subjects are receiving denosumab or 
following discontinuation of denosumab.  Investigators are advised in include 
assessment of serum calcium (eg, every 2 to 3 months for approximately 1 year) as 
clinically indicated following IP treatment discontinuation or interruption. 
Any laboratory tests performed as standard of care will be performed by the local 
laboratory. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
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Appendix 3.  Study Governance Considerations 
Adjudication Committees 
The Osteonecrosis of the Jaw Adjudication Committee and the Atypical Femur Fracture 
Adjudication Committee will independently adjudicate potential osteonecrosis of the jaw 
(ONJ) and atypical femur fracture (AFF) events identified in this clinical trial.  The 
respective processes are described in the ONJ and AFF Manuals of Operations. 
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 for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
• 
applicable laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), Investigator’s 
Brochure, and other relevant documents (eg, subject recruitment advertisements) must 
be submitted to an Institutional Review Boards/Independent Ethics Committee (IRB/IEC) 
by the investigator and reviewed and approved by the IRB/IEC.  A copy of the written 
approval of the protocol and ICF must be received by Amgen before recruitment of 
subjects into the study and shipment of Amgen investigational product. 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
• 
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 United States Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
and all other applicable local regulations. 
Recruitment Procedures 
This is a roll-over study, and no specific recruitment procedures are required.  
Informed Consent Process 
An initial sample ICF is provided for the investigator to prepare the informed consent 
document to be used at his or her site.  Updates to the sample ICF are to be 
communicated formally in writing from the Amgen Trial Manager to the investigator.  The 
written ICF 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 procedures or any investigational 
product(s) is/are administered, and answer all questions regarding the study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
The 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 was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the ICF. 
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 
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physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the ICF is to be signed and personally dated by the subject or a legally 
acceptable representative and by the person who conducted the informed consent 
discussion.  Subject withdrawal of consent or discontinuation from study treatment 
and/or procedures must also be documented in the subject’s medical records; refer to 
Section 8. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
The original signed ICF is to be retained in accordance with institutional policy, and a 
copy of the ICF(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 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF to attest that informed consent was freely given and 
understood.  (Refer to ICH GCP guideline, Section 4.8.9.) 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the CRF demographics page, in addition to the unique subject identification number, 
include the age at time of 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). 
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Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in 
confidence by the investigator, except as described below. 
In compliance with 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 of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
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. 
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Acquisition of funding, collection of data, or general supervision of the research group, 
alone, does not justify authorship. 
All persons designated as authors must qualify for authorship, and all those who qualify 
are to be listed. 
Each author must have participated sufficiently in the work to take public responsibility 
for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
• 
A recognized expert in the therapeutic area 
• 
An investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
An investigator contributing a high number of eligible subjects 
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 
Approved 
 
 


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Protocol Number:  20140114 
Date:  23 August 2018 
Page 47 of 65 
 
CONFIDENTIAL 
 
 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research & Development Compliance 
and Audit function (or designees).  Inspection of site facilities (eg, pharmacy, 
protocol-required therapy storage areas, laboratories) and review of study-related 
records will occur to evaluate the study conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Amgen (or designee) will perform Self-Evident Corrections to obvious data errors in the 
clinical trial database.  Self-Evident Corrections will be documented in the CRF Standard 
Instructions and the CRF Specific Instructions, both of these will be available through the 
electronic data capture (EDC) system.  Examples of obvious data errors that may be 
corrected by Amgen (or designee) include deletion of obvious duplicate data (ie, the 
same results sent twice with the same date with different visit) and updating a specific 
response if the confirming datum is provided in the “other, specify” field (eg, for race, 
reason for ending study). 
CRFs 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. 
Approved 
 
 


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Page 48 of 65 
 
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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) system (if used, such as subject 
identification 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. 
• 
subject files containing completed CRFs, ICFs, and subject identification list 
• 
study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
• 
investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Approved 
 
 


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Date:  23 August 2018 
Page 49 of 65 
 
CONFIDENTIAL 
 
 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the investigator reserve the right to terminate the investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
Approved 
 
 


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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, electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from prior results, 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. 
• 
For situations when an adverse event or serious adverse event is due to giant cell 
tumor of bone, report all known signs and symptoms.  Death due to disease 
progression in the absence of signs and symptoms should be reported as the 
primary tumor type (eg, metastatic pancreatic cancer).  Note: the term “disease 
progression” should not be used to describe the disease-related event or adverse 
event. 
• 
“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. 
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Events NOT Meeting the Adverse Event Definition 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the adverse event. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that 
meets at least 1 of the following serious criteria: 
• 
Results in death (fatal) 
• 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are an adverse 
event.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event is to be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an adverse event. 
• 
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. 
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• 
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). 
• 
The investigator must assign the following adverse event attributes: 
o adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms) 
o dates of onset and resolution (if resolved) 
o severity (or toxicity defined below) 
o assessment of relatedness to denosumab 
o action taken. 
• 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Event CRF. 
• 
It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to Amgen in lieu of completion of the Event CRF page. 
• 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to Amgen. 
• 
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. 
Approved 
 
 


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CONFIDENTIAL 
 
 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on:  
The Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 which is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between denosumab and 
each occurrence of each adverse event/serious adverse event. 
• 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each adverse event/serious adverse event, the investigator must document in 
the medical notes that he/she has reviewed the adverse event/serious adverse 
event and has provided an assessment of causality. 
• 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
• 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
Approved 
 
 


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CONFIDENTIAL 
 
 
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 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 denosumab 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.   
• 
New or updated information will be recorded in the originally completed Event 
CRF. 
• 
The investigator will submit any updated serious adverse event data to Amgen 
within 24 hours of receipt of the information. 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
• 
The primary mechanism for reporting serious adverse event will be the electronic 
data capture (EDC) system via the Safety Report Form.  
• 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using an electronic Serious Adverse Event Contingency 
Report Form (see Figure 12-1) within 24 hours of the investigator’s knowledge of 
the event. 
• 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
• 
After the study is completed at a given site, the EDC system will be taken off-line 
to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC has been taken off-line, then the site can report this information on a paper 
Serious Adverse Event Report Form (see Figure 12-1). 
Approved 
 
 


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Figure 12-1.  Sample Electronic Serious Adverse Event Contingency Form 
 
Approved 
 
 


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CONFIDENTIAL 
 
 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy and Lactation 
Information 
Study-specific contraception requirements for female of childbearing potential are 
outlined in Section 6.2. 
Female subjects of childbearing potential 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. 
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception and for an increased length of time.  In addition, male subjects 
may also be required to use contraception.  The investigator must discuss these 
contraceptive changes with the subject. 
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 
• 
postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single follicle 
stimulating hormone measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
Approved 
 
 


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CONFIDENTIAL 
 
 
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 
• 
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, post-ovulation methods) 
• 
withdrawal (coitus interruptus) 
• 
spermicides only 
• 
lactational amenorrhoea method 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
• 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking denosumab through 5 months of 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 denosumab 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). 
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• 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
• 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 
complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
• 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
• 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Appendix 4.  While the 
investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting.  
• 
Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 8.1 for details). 
Male Subjects With Partners Who Become Pregnant or Were Pregnant at the Time of 
Enrollment 
• 
In the event a male subject fathers a child during treatment, and for an additional 
5 months after discontinuing denosumab, 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. 
Approved 
 
 


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Collection of Lactation Information 
• 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking denosumab through 5 months after 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.  
• 
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 denosumab through 5 months after discontinuing denosumab. 
Approved 
 
 


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CONFIDENTIAL 
 
 
Figure 12-2.  Pregnancy and Lactation Notification Worksheet 
 
Approved 
 
 


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Date:  23 August 2018 
Page 1 of 8 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  Long-term Safety Follow up of Subjects With Giant Cell Tumor of 
Bone Treated With Denosumab in Study 20062004 
 
Amgen Protocol Number (Denosumab) 20140114 
NCT Number NCT03301857 
EudraCT Number 2017-001758-32 
 
Amendment Date: 
23 August 2018 
Rationale: 
This protocol is being amended to: 
• 
change the interval between last dose of denosumab and the end of treatment 
(EOT) in-person clinic visit.  The current 6 month safety follow-up visit following 
investigational product discontinuation, is not in line with the historical 
denosumab clinical trial program.  To align with previous standards established in 
the denosumab clinical program, this visit will be changed to 30 days (± 8) 
following investigational product discontinuation.  This change will not alter the 
safety or physical or mental integrity of the clinical trial participants, or the 
scientific value of the trial. 
• 
add detail to denosumab dosing instructions.  This is to ensure subjects entering 
retreatment with denosumab, follow the approved labelled dosing instructions by 
including additional 120 mg doses on days 8 and 15. 
• 
clarify procedure for reporting serious adverse events and/or events of interest 
for subjects who experience a treatment gap of more than 30 days between the 
end of study (EOS) visit of Study 20062004 and signing the informed consent 
form (ICF) for Study 20140114. 
• 
clarify that Study 20062004 ended in May 2018, as the study was extended by a 
year. 
Approved 
 
 


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• 
clarify that the EOS visit for all subjects will be at 5 years.  Cohort A subjects on 
investigational product will have an EOS visit conducted 30 days following the 
last dose of investigational product (EOT visit) if receiving investigational product 
at the 5 year time point.   
• 
clarify that subjects with surgically salvageable disease, treatment continued until 
surgery for complete resection and for approximately 6 months post-surgery, as 
aligned to the 20062004 study. 
• 
clarify that investigators will not search publicly available records to ascertain 
survival status when a subject is lost to follow-up. 
• 
clarify that upon discontinuation, subject’s risk for vertebral fragility fractures 
should be evaluated.  This language is being added in order to align language 
with the core data sheet. 
• 
make editorial, typographical, and formatting changes throughout the document 
Approved 
 
 


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Description of Changes: 
Section:  Global 
Change: 
Version dates updated throughout document from 23 January 2018 to 23 August 2018. 
Section:  Global 
Change:  Made editorial (formatting, typographical, and grammatical) corrections 
throughout the ICF. 
Section:  Title Page, Key Sponsor Contact, Name 
Replace: 
 
With: 
 
Section:  Title Page 
Add: 
Amendment 2 
23 August 2018 
Section:  1, Protocol Synopsis, Rationale 
Add: 
For subjects with surgically salvageable disease, treatment continued until surgery for 
complete resection and for approximately 6 months post-surgery. 
Section:  1, Protocol Synopsis, Rationale 
Replace: 
Enrollment in the initial phase of Study 20062004 concluded in November 2012; 
therefore, the study is anticipated to end in November 2017.   
With: 
Enrollment in the initial phase of Study 20062004 concluded in November 2012; 
therefore, the study ended in May 2018.   
Approved 
 
 


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CONFIDENTIAL 
 
 
Section:  1, Protocol Synopsis, Overall Design, Paragraph 1 
Delete: 
The subject’s follow up begins after signing the informed consent form (ICF) and 
continues through the earliest date of:  5 years after the last subject enrolled signs the 
ICF, death, withdrawal of consent, or lost to follow up. 
Section:  1, Protocol Synopsis, Overall Design, Paragraph 1 
Add: 
End of study (EOS) visits for all patients will be at 5 years; Cohort A subjects on 
investigational product will have an EOS visit conducted 30 days following the 
last dose of investigational product (end of treatment [EOT] visit) if receiving 
investigational product at the 5 year time point. 
Section:  1, Protocol Synopsis, Treatments, Paragraph 1 
Add: 
If a subject undergoes retreatment with denosumab, they will receive denosumab 
as a SC injection 120 mg on days 1, 8, 15, and 28, then every 4 weeks 
subsequently. 
Section:  2.2, Table 2-1, Schedule of Activities, Footnote c 
Replace: 
For subjects in Cohort A only and subjects from Cohort B who resume treatment with 
denosumab for disease recurrence:  EOT in-person clinic visit will occur 6 months 
(± 30 days) after the last dose of denosumab. 
With: 
For subjects in Cohort A only and subjects from Cohort B who resume treatment with 
denosumab for disease recurrence:  EOT in-person clinic visit will occur 30 days 
(± 8 days) after the last dose of denosumab. 
Section:  2.2, Table 2-1, Schedule of Activities, Footnote r 
Add: 
Retreatment with denosumab is permitted for subjects who demonstrated a previous 
response to denosumab (eg, in the case of recurrent disease while subject is in the 
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 5 of 8 
CONFIDENTIAL 
 
 
safety follow-up).  Eligibility criteria for retreatment are outlined in Section 7.4.1.  Refer 
to Section 7.1.1 for information on additional doses. 
Section:  3.1 Study Rationale, Paragraph 1 
Add: 
For subjects with surgically salvageable disease, treatment continued until surgery for 
complete resection and for approximately 6 months post-surgery. 
Section:  3.1 Study Rationale, Paragraph 1 
Replace: 
Enrollment in the initial phase of Study 20062004 concluded in November 2012; 
therefore, the study is anticipated to end in November 2017.   
With: 
Enrollment in the initial phase of Study 20062004 concluded in November 2012; 
therefore, the study to ended in May 2018.   
Section:  5.1 Overall Design, Paragraph 3 
Replace: 
Subjects who discontinue denosumab will have an end-of-treatment (EOT) in-person 
clinic visit approximately 6 months (± 30 days) after the last dose of denosumab.   
With: 
Subjects who discontinue denosumab will have an end of treatment (EOT) in-person 
clinic visit approximately 30 days (± 8 days) after the last dose of denosumab.   
Section:  5.1 Overall Design, Paragraph 3 
Add: 
When investigational product is discontinued, the investigator should evaluate the 
individual subject’s risk for vertebral fragility fractures.  Subjects with a high risk 
for fragility fracture (eg, history of osteoporosis, postmenopausal status, prior 
fracture history), should be monitored for the development of signs and 
symptoms of vertebral fractures following discontinuation of denosumab. 
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 6 of 8 
CONFIDENTIAL 
 
 
Section:  5.1 Overall Design, Paragraph 5 
Add: 
Retreatment with denosumab (120 mg subcutaneous [SC] on days 1, 8, 15, and 28, 
then every 4 weeks subsequently) is allowed for subjects who previously demonstrated 
a response to denosumab and have experienced disease recurrence while in long-term 
safety follow-up at the investigator’s discretion. 
Section:  7.1.1, Table 7-1, Study Treatments, Dosing Instructions 
Add: 
Study Treatment Name 
Amgen Investigational Product:a 
Denosumab (XGEVA) 
Dosing Instructions 
Denosumab is to be administered by a licensed healthcare 
professional at a dose of 120 mg SC Q4W with an additional 
dose of 120 mg SC on days 8 and 15 of treatment for 
subjects entering retreatment with denosumab  (subjects 
on continuous investigational product from 
Study 20062004, will not receive an additional dose of 
120 mg on days 8 or 15).  If the doses on study days 8 
and 15 are delayed more than 8 calendar days, it will be 
considered a missed dose and recorded as such on the 
eCRF.  The next dose is to be given at the next scheduled 
visit date (based on study day 1).  There must be at least 
4 days (ie, 96 hours) between the study days 1, 8, and 
15 doses (ie, ± 3 days from the scheduled visit date).  The 
planned dose may be given up to 7 days before the scheduled 
visit, as long as there are at least 21 days between doses.  If a 
planned dose is delayed more than 7 calendar days, it will be 
considered a missed dose and recorded as such on the eCRF. 
eCRF = electronic case report form; Q4W = every 4 weeks; SC = subcutaneous 
Section:  8.1 Discontinuation of Study Treatment, Paragraph 1 
Add: 
When investigational product is discontinued, the investigator should evaluate the 
individual subject’s risk for vertebral fragility fractures.  Subjects with a high risk 
for fragility fracture (eg, history of osteoporosis, postmenopausal status, prior 
fracture history), should be monitored for the development of signs and 
symptoms of vertebral fractures following discontinuation of denosumab.   
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 7 of 8 
CONFIDENTIAL 
 
 
Section:  8.3 Lost to Follow-up, Paragraph 2, Bullet 4 
Delete: 
• 
For subjects who are lost to follow-up, the investigator can search publically available 
records (where permitted) to ascertain survival status.  This ensures that the data 
set(s) produced as an outcome of the study is/are as comprehensive as possible. 
Section:  9.1.3 End-of-treatment Visit 
Replace: 
Cohort A and Cohort B subjects who enter retreatment only:  upon discontinuation from 
denosumab for any reason, an EOT in-person clinic visit will be performed approximately 
6 months (± 30 days) after the last dose of denosumab. 
With: 
Cohort A and Cohort B subjects who enter retreatment only:  upon discontinuation from 
denosumab for any reason, an EOT in-person clinic visit will be performed approximately 
30 days (± 8 days) after the last dose of denosumab.   
Section:  9.1.4 Long-term Safety Follow-up, Paragraph 1 
Add: 
An EOS visit should be performed 5 years after signing of the ICF. 
Section:  9.1.4 Long-term Safety Follow-up, Paragraph 2 
Add: 
Subjects receiving investigational product 5 years after signing of the ICF, should 
undergo an in-person clinic, combined EOT and EOS visit 30 days following the 
last dose of investigational product. 
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 August 2018 
Page 8 of 8 
CONFIDENTIAL 
 
 
Section:  9.2.3.1.1.3 Serious Adverse Events 
Add: 
For all subjects who experienced a treatment gap of more than 30 days between 
the EOS visit of Study 20062004 and signing the ICF for Study 20140114, all 
serious adverse events and/or events of interest observed by the investigator or 
reported by the subject that occurred in that period must be reported using the 
electronic case report form (eCRF).  Events of interest include: 
• 
ONJ 
• 
malignancy, including malignancy in GCTB 
• 
AFF 
• 
hypocalcemia (assessed per CTCAE criteria) 
• 
hypercalcemia following treatment discontinuation (assessed per CTCAE 
criteria) 
• 
pregnancy and lactation (if occurring on treatment or within 5 months of last 
dose of denosumab) 
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  23 January 2018  
Page 1 of 2 
CONFIDENTIAL 
Superseding Amendment 1 
Protocol Title:  Long-term Safety Follow-up of Subjects With Giant Cell Tumor of 
Bone Treated With Denosumab in Study 20062004 
Amgen Protocol Number Denosumab 20140114 
NCT Number:  NCT03301857 
Amendment Date: 
23 January 2018 
Rationale: 
This superseding amendment is being done to clarify inclusion criterion 101.  The 
objective of Study 20140114 is to continue to follow subjects with GCTB who were 
treated in Study 20062004.  A minor language update to inclusion criterion 101 clarifies 
that 1) to be considered potentially eligible for this study, a subject must have 
participated in the parent 20062004 study and have completed participation in that study 
and 2) a subject cannot be concurrently enrolled to Study 20062004 and 
Study 20140114; which is not clear according to the original protocol inclusion 
criterion 101. 
Approved 
 
 


Product:  Denosumab 
Protocol Number:  20140114 
Date:  15 November 2017 
Page 1 of 17 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  Long-term Safety Follow up of Subjects With Giant Cell Tumor of 
Bone Treated With Denosumab in Study 20062004 
 
Amgen Protocol Number Denosumab 20140114 
NCT Number:  NCT03301857 
 
Amendment Date: 
15 November 2017 
Rationale: 
This protocol is being amended to: 
• 
Clarify guidance to investigators about monitoring subjects for hypercalcemia upon 
discontinuation or interruption of IP 
• 
Add Month 60 to the Schedule of Assessments for clarity 
• 
Make editorial changes and corrections throughout the document 
Approved 
 
 

SAP_001.pdf: 
Product:  Denosumab  
Protocol Number:  20140114 
Date:  04 Sep 2023 
Page 1 of 26 
CONFIDENTIAL  
 
 
Statistical Analysis Plan 
Protocol Title: 
Long term Safety Follow up of Subjects With Giant 
Cell Tumor of Bone Treated With Denosumab in 
Study 20062004 
Short Protocol Title: 
Long term Safety Follow up of Subjects With Giant 
Cell Tumor of Bone Treated With Denosumab in 
Study 20062004 
Protocol Number: 
20140114 
NCT Number: 
NCT03301857 
Authors: 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive, 
Thousand Oaks, CA 91320-1799 
United States 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
30 July 2017 
Amendment 1 
(V2.0)                
04 Sep 2023 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
30 July 2017 
Not applicable 
Amendment 1 (v2.0) 
11 August 2023 
1. Used the new SAP template. 
2. Incorporated updates in Protocol 
Amendment 2 (dated 23Aug2018) 
3. Added/removed and updated 
some definitions in Section 5.  
4. Clarified the summary/analysis 
methods for IPDs, disease 
progression or recurrence, and 
GCTB interventions in Sections 
9.3, 9.5, and 9.6.9, respectively. 
5. Detailed the summary/analysis 
methods for safety endpoints in 
Section 9.6.2.  


Product:  Denosumab  
Protocol Number:  20140114 
Date:  04 Sep 2023 
Page 2 of 26 
CONFIDENTIAL  
 
 
Table of Contents 
Table of Contents ............................................................................................................ 2 
1. 
Introduction ............................................................................................................. 7 
2. 
Objectives, Endpoints/Estimands and Hypotheses ................................................. 7 
2.1 
Objectives and Endpoints/Estimands .......................................................... 7 
2.2 
Hypotheses and/or Estimations ................................................................... 8 
3. 
Study Overview ...................................................................................................... 8 
3.1 
Study Design ............................................................................................... 8 
3.2 
Sample Size ................................................................................................ 9 
3.3 
Adaptive Design ........................................................................................ 10 
4. 
Covariates and Subgroups ................................................................................... 10 
4.1 
Planned Covariates ................................................................................... 10 
4.2 
Subgroups ................................................................................................. 10 
5. 
Definitions ............................................................................................................. 10 
6. 
Analysis Sets ........................................................................................................ 12 
6.1 
Full Analysis Set........................................................................................ 12 
6.1.1 
Adolescent Analysis Set ............................................................ 12 
6.2 
Safety Analysis Set ................................................................................... 13 
6.3 
Per Protocol Set(s) .................................................................................... 13 
6.4 
Health-related Quality-of-Life or Health Economics Analyses 
Set(s) ........................................................................................................ 13 
6.5 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) ................................ 13 
6.6 
Interim Analyses Set(s) ............................................................................. 13 
6.7 
Study-specific Analysis Set(s) ................................................................... 13 
7. 
Planned Analyses ................................................................................................. 13 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 13 
7.2 
Primary Analysis ....................................................................................... 13 
7.3 
Final Analysis ............................................................................................ 13 
8. 
Data Screening and Acceptance ........................................................................... 13 
8.1 
General Principles ..................................................................................... 13 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 13 
8.3 
Handling of Missing and Incomplete Data ................................................. 14 
8.4 
Detection of Bias ....................................................................................... 14 
8.5 
Outliers ..................................................................................................... 14 
8.6 
Distributional Characteristics ..................................................................... 14 
8.7 
Validation of Statistical Analyses ............................................................... 14 
9. 
Statistical Methods of Analysis.............................................................................. 15 
9.1 
General Considerations ............................................................................. 15 


Product:  Denosumab  
Protocol Number:  20140114 
Date:  04 Sep 2023 
Page 3 of 26 
CONFIDENTIAL  
 
 
9.2 
Subject Accountability ............................................................................... 15 
9.3 
Important Protocol Deviations ................................................................... 15 
9.4 
Demographic and Baseline Characteristics ............................................... 15 
9.5 
Efficacy Analyses ...................................................................................... 17 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) .............. 17 
9.5.2 
Analyses of Secondary Efficacy 
Endpoint(s)/Estimand(s) ............................................................ 17 
9.5.3 
Analyses of Exploratory Efficacy 
Endpoint(s)/Estimand(s) ............................................................ 17 
9.6 
Safety Analyses ........................................................................................ 17 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 17 
9.6.2 
Adverse Events ......................................................................... 17 
9.6.3 
Laboratory Test Results ............................................................ 19 
9.6.4 
Vital Signs ................................................................................. 19 
9.6.5 
Physical Measurements ............................................................ 19 
9.6.6 
Electrocardiogram ..................................................................... 19 
9.6.7 
Antibody Formation ................................................................... 19 
9.6.8 
Exposure to Investigational Product .......................................... 19 
9.6.9 
Exposure to Non-investigational Product ................................... 20 
9.6.10 
Exposure to Other Protocol-required Therapy ........................... 20 
9.6.11 
Exposure to Concomitant Medication ........................................ 20 
9.7 
Other Analyses ......................................................................................... 20 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 20 
9.7.2 
Analyses of Clinical Outcome Assessments .............................. 20 
9.7.3 
Analyses of Health Economic Endpoints ................................... 20 
9.7.4 
Analyses of Biomarker Endpoints .............................................. 20 
10. 
Changes From Protocol-specified Analyses.......................................................... 20 
11. 
Literature Citations / References ........................................................................... 20 
12. 
Prioritization of Analyses....................................................................................... 20 
13. 
Data Not Covered by This Plan............................................................................. 20 
14. 
Appendices ........................................................................................................... 21 
Appendix A.  Reference Values/Toxicity Grades ................................................... 21 
Appendix B.  Concomitant Medications ................................................................. 22 
Appendix C.  Clinical Outcome Assessment Forms/Instruments ........................... 23 
Appendix D.  Health Economic Forms/Instruments ............................................... 24 
Appendix E.  Details of PK or PK/PD Methods for Modeling ................................. 25 
Appendix F.  Analytical Windows .......................................................................... 26 
Appendix G.  Handling of Dates, Incomplete Dates and Missing Dates ................ 27 
Table 2.  Imputation Rules for Incomplete Dates .................................................. 27 


Product:  Denosumab  
Protocol Number:  20140114 
Date:  04 Sep 2023 
Page 4 of 26 
CONFIDENTIAL  
 
 
 


Product:  Denosumab  
Protocol Number:  20140114 
Date:  04 Sep 2023 
Page 5 of 26 
CONFIDENTIAL  
 
 
List of Tables 
Table 1.  Estimated 95 Confidence Interval for Example Adverse Event 
of Interest Incidence Rate ...................................................................... 9 
Table 2.  Imputation Rules for Incomplete Dates ...................................................... 26 
 
List of Figures 
No table of figures entries found. 
 
 


Product:  Denosumab  
Protocol Number:  20140114 
Date:  04 Sep 2023 
Page 6 of 26 
CONFIDENTIAL  
 
 
List of Abbreviations 
 
Abbreviation  
Explanation 
AFF 
atypical femur fracture 
AE 
adverse event 
CI 
confidence interval 
CR 
complete response 
CRF 
case report form 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
EOS 
end of study  
EOT 
end of treatment  
GCTB 
giant cell tumor of bone 
ICF 
informed consent form 
IP 
investigational product 
IPD 
Important protocol deviation 
MedDRA  
medical dictionary for regulatory activities  
ONJ 
osteonecrosis of the jaw 
PD 
progressive disease 
PR 
partial response 
PT 
preferred term 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
stable disease 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
 
 


Product:  Denosumab  
Protocol Number:  20140114 
Date:  04 Sep 2023 
Page 7 of 26 
CONFIDENTIAL  
 
 
1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol for study 20140114, Denosumab 
dated 23 August 2018 .The scope of this plan includes the primary analysis that is 
planned for long-term safety follow-up of subjects with giant cell tumor of bone treated 
with denosumab in study 20062004 and will be executed by the Amgen Global 
Biostatistical Science department unless otherwise specified. 
 
2. 
Objectives, Endpoints/Estimands and Hypotheses 
2.1 
Objectives and Endpoints/Estimands 
 
Objectives 
Endpoints 
Primary 
 
Evaluate adverse events of 
interest in subjects with GCTB 
treated with denosumab in Study 
20062004 
 
Rate of adverse events of interest 
in subjects with GCTB treated with 
denosumab in Study 20062004 
 
Secondary 
 
Evaluate treatment-emergent 
adverse events for subjects who 
are receiving denosumab 
 
Rate of treatment-emergent 
adverse events for subjects who 
are receiving denosumab 
 
Evaluate serious adverse events 
for all subjects 
 
Rate of serious adverse events for 
all subjects 
 
 
Summarize the rate of disease 
progression or recurrence of 
GCTB for all subjects 
 
Rate of disease progression or 
recurrence of GCTB for all subjects 
 
Summarize the use of GCTB 
interventions for all subjects 
 
Rate of GCTB interventions for all 
subjects 
 
 
 
Estimand(s) for Primary Objective(s) 


Product:  Denosumab  
Protocol Number:  20140114 
Date:  04 Sep 2023 
Page 8 of 26 
CONFIDENTIAL  
 
 
Not Applicable 
Estimand(s) for Secondary Objective(s) 
Not Applicable 
 
Exploratory 
Not Applicable 
 
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 
This prospective study will provide long-term safety follow up for subjects who complete 
Study 20062004 and consent to enroll in Study 20140114.  The subject’s follow up begins 
after signing the informed consent form (ICF) and continues through the earliest date of:  
5 years after the last subject enrolled signs the ICF, death, withdrawal of consent, or 
lost to follow up.  
Study assessments are to be completed every 6 months (± 30 days).  End of study (EOS) 
visits for all patients will be at 5 years. 
There will be 2 cohorts in this study: 
Cohort A - subjects who were receiving denosumab at the conclusion of Study 20062004 
can continue receiving denosumab at the current dose and schedule (Q4W) at the 
investigator’s discretion. Follow-up study visits will be performed in clinic every 6 
months (± 30 days) while receiving denosumab. Cohort A subjects on 
investigational product will have an EOS visit conducted 30 days following the last 
dose of investigational product (end of treatment [EOT] visit) if receiving 
investigational product at the 5 year time point. Subjects who discontinue 
denosumab will have an EOT in-person clinic visit approximately 30 days (± 8 days) 
after the last dose of denosumab. Thereafter, they will enter the long-term safety 
follow-up and will be monitored as per Cohort B requirements. 
Cohort B - subjects who completed denosumab treatment in 20062004 and were in the 
safety follow-up at the conclusion of 20062004 will continue in long-term safety follow-up 
in this study. Follow-up study visits will be done every 6 months (± 30 days) either via 
telephone or in-person clinic visit. 


Product:  Denosumab  
Protocol Number:  20140114 
Date:  04 Sep 2023 
Page 9 of 26 
CONFIDENTIAL  
 
 
Retreatment with denosumab (120 mg subcutaneous [SC] on days 1, 8, 15, and 28, 
then every 4 weeks subsequently) is allowed for subjects who previously demonstrated 
a response to denosumab and have experienced disease recurrence while in long-term 
safety follow-up at the investigator’s discretion. 
For Cohorts A and B - laboratory assessments are not mandated by the study and will be 
performed at the investigator’s discretion as part of the standard of care or as clinically 
indicated. 
At each follow-up study visit, subjects will be assessed (for in-person clinic visit) or 
asked (for visit via telephone) for signs and symptoms of the following events of interest: 
osteonecrosis of the jaw (ONJ), malignancy (including malignancy in GCTB), atypical 
femoral fracture (AFF), hypocalcemia (assessed per Common Terminology Criteria 
for Adverse Events [CTCAE] criteria), hypercalcemia following treatment 
discontinuation (assessed by CTCAE criteria), and pregnancy and lactation (if 
occurring on treatment or within 5 months of last dose of denosumab).  Additionally, all 
treatment emergent adverse events and serious adverse events will be collected 
3.2 
Sample Size 
The number of subjects in this study will be determined by the number of subjects 
completing Study 20062004, and who are willing to enroll in this study for long-term safety 
follow-up.  It is estimated that this will be approximately 100 to 300 subjects. 
For the expected sample size of 100 to 300 subjects, the 95% confidence interval (CI) 
based on exact method for the incidence rate of a particular adverse event is calculated 
below Table 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 1.2% for 300 subjects is unlikely 
for that particular adverse event.  
 


Product:  Denosumab  
Protocol Number:  20140114 
Date:  04 Sep 2023 
Page 10 of 26 
CONFIDENTIAL  
 
 
Table 1.  Estimated 95% Confidence Interval for Example Adverse Event 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) 
0/200 
0 
(0.0, 1.8) 
2/200 
1 
(0.1, 3.6) 
10/200 
5 
(2.4, 9.0) 
20/200 
10 
(6.2, 15.0) 
0/300 
0 
(0.0, 1.2) 
3/300 
1 
(0.2, 2.9) 
15/300 
5 
(2.8, 8.1) 
30/300 
10 
(6.8, 14.0) 
CI = confidence interval 
 
3.3 
Adaptive Design 
Not Applicable 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
Not applicable 
4.2 
Subgroups 
Treatment-emergent adverse events, overall serious adverse events and adverse 
events of interest will be summarized using adolescent analysis set. 
5. 
Definitions 
 
Investigational Product (IP)  
IP for this study refers to denosumab. 
 
Study Day 1 
The date on which the subject signs the informed consent for this study. 


Product:  Denosumab  
Protocol Number:  20140114 
Date:  04 Sep 2023 
Page 11 of 26 
CONFIDENTIAL  
 
 
 
Study Day 
The number of days from study day 1 to a date of interest, inclusive: Study day = 
(date of interest – study day 1) + 1. 
 
Treatment Emergent Adverse Event (TEAE) 
An adverse event is considered as treatment emergent if the adverse event occurs 
during the time period from the first dose of IP in this study through last dose of IP plus 
30 days. For subject without retreatment, this is 30 days after the last dose of IP in the 
treatment phase, for subject with retreatment(s), this is 30 days after the last dose of 
IP in the last retreatment phase. 
 
Original First Dose of IP 
The first dose of IP taken by the subject in study 20062004  
 
First Dose of IP in Study 20140114 
The first dose of IP after the subject enrolled on study 20140114. 
 
Exposed to IP in Study 20140114 
A subject is considered as exposed to IP if the subject has received one or more doses 
of IP in study 20140114. 
 
  IP Exposure Time in Study 20140114 
IP exposure is considered from the first dose of IP to the last dose of IP plus 28 days 
in study 20140114. If subject has retreatment(s), IP exposure will be the total 
exposure time over each treatment phase(s).  
 
End of Study (EOS) Date for an Individual Subject 
The EOS date is recorded on the End of Study page of the Case Report Form 
(CRF) for an enrolled subject.  
 
Gap Period 
Gap period is defined as after the end of study 20062004 to before the study Day 
1 of study 20140114.  
 Events of Interest  
 
Adverse events of interest include: 


Product:  Denosumab  
Protocol Number:  20140114 
Date:  04 Sep 2023 
Page 12 of 26 
CONFIDENTIAL  
 
 
1. Osteonecrosis of the Jaw 
2.  Malignancy, including malignancy in GCTB 
3.  Atypical femur fracture 
4. Hypocalcemia (assessed per Common Terminology Criteria for Adverse Events 
[CTCAE] criteria)  
5.  Hypercalcemia following treatment discontinuation (assessed by CTCAE criteria) 
6. pregnancy and lactation (if occurring on treatment or within 5 months of last dose 
of denosumab) 
 
Time to osteonecrosis of the Jaw (ONJ) 
Time to ONJ is defined as the time interval (in days) from the original first dose of IP 
to the date of first adverse event of adjudicated positive ONJ. For Kaplan-Meier 
estimates, subjects without adjudicated positive ONJ will be censored at EOS 
date of study 20140114 (for subjects entered into study 20140114), or censored 
at the latest date of end of initial treatment phase, end of retreatment phase, 
and end of safety follow-up phase of Study 20062004 (for subject who didn't 
enroll in study 20140114). 
 
Progressive Disease (PD)  
It is defined as the response of progressive disease, locally recurrent disease 
or distant recurrence as captured in the Disease Status page of the CRF. 
 
Disease Progression or Recurrence 
It is defined as the best post-baseline response of PD in study 20140114 
without any post-baseline complete response (CR) /partial response (PR) 
/stable disease(SD) or a post-baseline response of PD following a post-
baseline CR/PR/SD. 
6. 
Analysis Sets 
6.1 
Full Analysis Set 
Full analysis set includes all enrolled subjects (from 20062004) who have provided 
informed consent and have a non-missing enrollment date in this study. 
6.1.1 
Adolescent Analysis Set 
Adolescent analysis set includes all enrolled subjects in this study who were younger 
than 18 years when enrolled in 20062004. 


Product:  Denosumab  
Protocol Number:  20140114 
Date:  04 Sep 2023 
Page 13 of 26 
CONFIDENTIAL  
 
 
6.2 
Safety Analysis Set 
In this study, safety analysis will be conducted in the Full Analysis Set and Adolescent 
Analysis Set. Safety Analysis Set is not defined separately then. 
6.3 
Per Protocol Set(s) 
Not Applicable 
6.4 
Health-related Quality-of-Life or Health Economics Analyses Set(s) 
Not Applicable 
6.5 
Pharmacokinetic/Pharmacodynamic Analyses Set(s) 
Not Applicable 
6.6 
Interim Analyses Set(s) 
There is no interim analysis planned for this study. 
6.7 
Study-specific Analysis Set(s) 
Not Applicable 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
Not Applicable 
7.2 
Primary Analysis 
The primary analysis is the only planned analysis for this study. It will occur upon 
completion of the study when all subjects have had the opportunity to complete 5 years 
of follow-up in this study. 
7.3 
Final Analysis 
Not Applicable 
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.  This study will use the RAVE and 
ARGUS database 


Product:  Denosumab  
Protocol Number:  20140114 
Date:  04 Sep 2023 
Page 14 of 26 
CONFIDENTIAL  
 
 
8.3 
Handling of Missing and Incomplete Data 
Subjects may have missing data points for a variety of reasons.  In general, data may be 
missing due to subject’s early withdrawal from study, a missed visit, or non-evaluability of 
an endpoint at a particular point in time. The procedures outlined in Appendix G  
describing what will be done when data are missing . 
  
8.4 
Detection of Bias 
Not Applicable 
8.5 
Outliers 
Descriptive statistics will be used to identify outliers in applicable key variables for 
analysis.  For continuous variables, the univariate analyses will be conducted and 
scatter plots will be generated to identify outliers.  For discrete variables, frequency 
summary will be examined to identify questionable values. 
Outliers due to data entry error will be corrected in the database before the database 
freeze.  Outliers that are not due to data entry error will be included in the primary 
analysis, unless there is sufficient clinical justification obtained prior to analysis snapshot 
and database lock to exclude them. The validity of any questionable values or outliers 
will be confirmed.  No valid measurement may be excluded from descriptive or inferential 
analyses 
8.6 
Distributional Characteristics 
No assumption will be checked. Primary analyses are descriptive in nature. 
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 
The statistical analysis in this long-term safety follow up study will be descriptive in 
nature and no hypothesis testing will be performed. The analysis will be based on the full 


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analysis set defined in Section 6. In general, data summaries will be presented by the 
condition whether subjects were exposed to IP during 20140114. Categorical outcomes 
will be summarized by the number and percentage of subjects in each category.  
Continuous outcomes will be summarized by the number of non missing values, mean, 
standard deviation, median, lower and upper quartiles and minimum and maximum 
values. 
9.2 
Subject Accountability 
For the full analysis set and adolescent analysis set, the numbers and percentages 
of subjects who discontinued from investigational product by reason will be provided. 
Similarly, the numbers and percentages of subjects who discontinued the study by 
reason will be summarized. 
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. 
The number and percentage of subjects with IPD and covid-19 related IPD/PD will 
be summarized by protocol deviation category. IPDs will also be listed. 
9.4 
Demographic and Baseline Characteristics 
The following descriptive summaries of the demographic and baseline characteristics will 
be produced for the full analysis set: 
 
Subjects enrollment by country and investigator 
 
Subjects disposition includes discontinued IP/study, and reason for IP/study 
discontinuation 
 
Summary of demographics will include: age, sex, race, and geriatric age group (if 
applicable).   
 
Summary of medical history by preferred term. 
 
Summary of baseline disease classification and status. 
In addition, subject disposition, demographics, and baseline disease classification 
and status will also be summarized for the adolescent analysis set. 


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9.5 
Efficacy Analyses 
For the full analysis set and adolescent analysis set, the rate of disease progression or 
recurrence of GCTB and GCTB disease status with best 
response will be summarized by exposed to IP in 20140114 and not  
exposed to IP in 20140114. 
9.5.1 
Analyses of Primary Efficacy Endpoint(s)/Estimand(s) 
Not Applicable 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s)/Estimand(s) 
Not Applicable 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s)/Estimand(s) 
Not Applicable 
9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
 
Safety Endpoints 
Primary Summary and Analysis 
Method 
Primary 
 
Rate of adverse events of 
interest in subjects with 
GCTB treated with 
denosumab in 
Study 20062004 
 
Subject incidence of adverse 
events of interest will be 
summarized. Subject-year 
adjusted rate of certain adverse 
events of interest will also be 
summarized. The detailed 
summary and analysis methods 
are specified in Section 9.6.2 
below. 
 
9.6.2 
Adverse Events 
The current Medical Dictionary for Regulatory Activities (MedDRA) version will be used to 
code all adverse events (AEs) and adverse events of interest to a system organ class 
(SOC) and a preferred term (PT). For AE tables, all subjects in full analysis set will be 
analyzed and separately summarized in two groups, namely, subjects exposed to IP in 
20140114 and subjects never exposed to IP in 20140114. 
For treatment-emergent adverse events, subject incidence will be tabulated for the 
categories listed below by SOC, high level term and PT; by SOC and PT; and by PT 
only, respectively.  
 
All treatment-emergent adverse events  


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 
Treatment-emergent serious adverse events  
 
Treatment-emergent fatal adverse events  
 
CTCAE grade 3, 4, or 5 treatment-emergent adverse events  
 
Treatment-emergent adverse events leading to IP discontinuation  
Subject incidence of IP related treatment-emergent adverse events will be summarized 
by PT only. Subject-year adjusted event rate of all treatment-emergent adverse events 
and treatment-emergent serious adverse events will also be produced. 
For all SAEs and SAEs in follow up period, subject incidence will be tabulated by SOC 
and PT, and by PT only. Subject-year adjusted event rate for all SAEs will be produced. 
The SAEs collected in study 20140114 that started during the gap period  will also be 
listed. 
For adverse event of interest, i.e., adjudicated positive osteonecrosis of the jaw (ONJ), 
malignancy (including malignancy in GCTB), adjudicated positive atypical femoral 
fracture (AFF), hypocalcemia, and hypercalcemia following treatment discontinuation, 
subject incidence will be tabulated by PT. The proportion of subjects with adverse events 
of interest will be estimated with 95% CI based on an exact method i.e. Clopper-Pearson 
method for proportion and CI calculations. The adjudicated positive ONJ, malignancy 
and adjudicated positive AFF collected in study 20140114 that started during the gap 
period will also be listed. 
In addition, for adjudicated positive ONJ, malignancy (including malignancy in GCTB), 
and adjudicated positive AFF, the safety analysis will also be conducted based on 
combined data from studies 20062004 and 20140114 by the enrollment cohorts in study 
20062004. 
• 
Osteonecrosis of the Jaw 
Combining data from studies 20062004 and 20140114, the subject incidence of 
adjudicated positive ONJ will be summarized. Subject-year adjusted rate of adjudicated 
positive ONJ starting from original first dose of IP in 20062004 will be tabulated by PT and 
by time period. Time to first positive ONJ will be analyzed using Kaplan-Meier estimates 
with 95% CI. A KM plot for time to first adjudicated positive ONJ will be provided for 
combined cohorts.  
• 
Malignancy 


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The incidence of malignancy in GCTB will be summarized to compare with the historical 
control rates based on the published literature. Combining data from studies 20062004 
and 20140114, the proportion of subjects who have malignancy (including malignancy in 
GCTB) will be summarized. Subject-year adjusted rate of malignancy starting from original 
first dose of IP in 20062004 will be tabulated by PT and by time period. 
• 
Atypical Femur Fracture  
Combing data from studies 20062004 and 20140114, subject incidence of 
adjudicated positive AFF will be summarized. Listing of adjudicated positive AFF 
events will be provided.  
Safety analysis will be repeated for adolescent subjects as applicable. For subjects in the 
adolescent analysis set of study 20140114, subject incidence of treatment-emergent 
adverse events and adverse events of interest will be summarized. Subject listing of 
adverse events (including treatment-emergent adverse events, all serious adverse events, 
and adverse events of interest) will be provided. Combining data from studies 20062004 
and 20140114, subject incidence of adjudicated position ONJ, malignancy, and 
adjudicated positive AFF will be tabulated for adolescent subjects in the safety analysis 
set of study 20062004. 
9.6.3 
Laboratory Test Results 
Not Applicable. 
9.6.4 
Vital Signs 
Not Applicable 
9.6.5 
Physical Measurements 
Not Applicable 
9.6.6 
Electrocardiogram 
Not Applicable 
9.6.7 
Antibody Formation 
Not Applicable  
9.6.8 
Exposure to Investigational Product 
Administration dates and doses of IP will be collected and cumulative IP exposure will be 
summarized using descriptive statistics for study 20140114.  Similar analysis for doses 
of IP will be performed for studies 20062004 and 20140114 combined starting from 
the original first IP dose in Study 20062004.  


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9.6.9 
Exposure to Non-investigational Product  
Embolization, radiotherapy, interferon, chemotherapy or other therapeutic agents, 
and surgery for GCTB since last contact were collected on CRF page of GCTB 
Intervention. For full analysis set and adolescent analysis set, rate of those GCTB 
interventions (Yes/No) will be summarized by exposed to IP and not exposed to IP 
in study 20140114.  
9.6.10 
Exposure to Other Protocol-required Therapy 
Not Applicable 
9.6.11 
Exposure to Concomitant Medication 
 Prior concomitant medication and concurrent concomitant medication will be 
summarized by preferred term coded by the World Health Organization Drug (WHO 
DRUG) dictionary for the full analysis set. 
9.7 
Other Analyses 
Not Applicable 
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
Not Applicable 
9.7.2 
Analyses of Clinical Outcome Assessments 
Not Applicable 
9.7.3 
Analyses of Health Economic Endpoints 
Not Applicable 
9.7.4 
Analyses of Biomarker Endpoints 
Not Applicable 
10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 
11. 
Literature Citations / References 
Denosumab Investigator’s Brochure.  Thousand Oaks, CA.  Amgen Inc.   
XGEVA® [package insert].  Thousand Oaks, CA:  Amgen, Inc.; March 2016. 
12. 
Prioritization of Analyses 
Not Applicable 
13. 
Data Not Covered by This Plan 
Not Applicable 


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14. 
Appendices 
Appendix A.  Reference Values/Toxicity Grades 
Not Applicable 


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Appendix B.  Concomitant Medications 
Not Applicable 
 


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Appendix C.  Clinical Outcome Assessment Forms/Instruments 
Not Applicable 
 


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Appendix D.  Health Economic Forms/Instruments 
Not Applicable 
 


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Appendix E.  Details of PK or PK/PD Methods for Modeling 
Not Applicable 
 


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Appendix F.  Analytical Windows 
Not Applicable 
 


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Appendix G.  Handling of Dates, Incomplete Dates and Missing Dates 
 Imputation Rules for Partial or Missing Start/Stop Dates 
Incomplete event start dates and concomitant medications start or stop dates will be 
imputed as described in the table below. If the start date is missing, assume the event or 
medication started before enrollment; if the stop date and the flag for medication 
continuing are both missing for an on-study event or medication, assume the event or 
medication stopped after the end of study date. Partial dates will be listed as is on the 
listings. 
14.1 
Table 2.  Imputation Rules for Incomplete Dates 
  
Missing 
Imputation 
Exception 
Start date 
(AE, 
concomitant 
medication) 
Day 
01 
Default to study day 1 if an event 
starts the same year and month as 
study day 1 
Day / Month 
01JAN 
Default to study day 1 if an event 
started the same year as study day 1 
Stop date 
(concomitant 
medication 
only) 
Day 
Last day of the 
month 
Default to the End of Study (EOS) 
date if the concomitant medication 
stopped the same year and month as 
the EOS date  
 
Day / 
Month 
31DEC 
Default to the EOS date if the 
concomitant medication stopped the 
same year as the EOS date