Clinical trial NCT01419717
Conditions: Bone Metastases in Men With Hormone-Refractory Prostate Cancer Bone Metastases in Subjects With Advanced Breast Cancer
Keywords: cancer bone metastases breast cancer prostate cancer
Sponsor: Amgen
Start date: 2011-11-22; Completion date: 2018-08-10
Enrollment: 129 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This trial will facilitate access to denosumab for adults with advanced cancer who have participated in a denosumab phase 3 study until denosumab is approved and available for sale.

Detailed description:

Arms: arm 1: Participants received 120 milligrams of denosumab injected subcutaneously every 4 weeks until denosumab was approved and available for sale.
Interventions: intervention 1: Denosumab
Intervention descriptions: intervention 1: Administered by subcutaneous injection every 4 weeks (Q4W)

Protocol documents:
Prot_000.pdf: 
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Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 2 of 42 
 
Investigator’s Agreement 
I have read the attached protocol entitled “Open-Label Access Protocol of Denosumab 
for Subjects with Advanced Cancer”, dated 22 February 2013, and agree to abide by all 
provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice and applicable FDA regulations/guidelines set forth 
in 21 CFR Parts 11, 50, 54, 56 and 312. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to 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 Principal Investigator 
 
Date (DD Month YYYY) 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 3 of 42 
 
Protocol Synopsis 
Title:  Open-Label Access Protocol of Denosumab for Subjects with Advanced Cancer 
Study Phase:  3b 
Indication:  Treatment of subjects with advanced cancer 
Primary Objective:  To facilitate the access of denosumab for subjects with advanced cancer 
who have participated in a denosumab phase 3 study until denosumab is approved and available 
for sale.  
Safety Objective:  To further assess the safety of denosumab for subjects who have participated 
in open label extensions of a denosumab advanced cancer phase 3 study. 
Hypotheses:  A formal statistical hypothesis will not be tested or estimated. 
Study Endpoints:  Subject incidence of treatment-emergent adverse events and anti-
denosumab antibodies. 
Study Design:  This is an open-label, single-arm access protocol for subjects with advanced 
cancer. 
Subjects will be offered open-label denosumab at a dose of 120 mg SC Q4W until denosumab is 
approved and available for sale.  Amgen may end this study prior to denosumab being approved 
and available for sale if another mechanism is identified to provide denosumab to ongoing 
subjects, or as otherwise stated in Section 12.1 of this protocol. 
Severe hypocalcemia can occur in subjects receiving denosumab.  Calcium levels should be 
monitored as part of routine clinical practice.  It is strongly recommended that all subjects receive 
daily supplements of at least 500 mg calcium and at least 400 IU of vitamin D, unless 
documented hypercalcemia (albumin-adjusted serum calcium > 2.9 mmol/L [11.5 mg/dL] or 
ionized calcium > 1.5 mmol/L [6.0 mg/dL]) develops on study.  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. 
Osteonecrosis of the jaw (ONJ) can occur in subjects receiving denosumab.  Subjects should be 
monitored for ONJ as part of routine clinical practice.  Subjects should be instructed to maintain 
good oral hygiene, and avoid invasive dental procedures, if possible.  
Sample Size:  The number of subjects will be determined by the number of subjects who qualify 
for the protocol.  It is estimated that up to approximately 400 subjects will participate in this 
protocol. 
Summary of Subject Eligibility Criteria:  Adults with advanced cancer and participating in an 
Amgen denosumab phase 3 study.  For a full list of eligibility criteria, please refer to Section 4.1 
and 4.2. 
Amgen Investigational Product Dosage and Administration:  Open-label denosumab at a 
dose of 120 mg SC Q4W until denosumab is approved and available for sale. 
Control Group:  None 
Procedures:  Informed consent must be obtained for all participating subjects.  At various times 
throughout this study adverse events, serious adverse events, and drug accountability will be 
collected for each subject.  A blood sample will be collected after the last dose of denosumab for 
anti-denosumab antibody testing. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and Appendix A. 
Statistical Considerations:  Adverse events, serious adverse events, deaths, and anti-
denosumab antibody status will be summarized.   
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen Inc. 


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Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 5 of 42 
 
Study Glossary 
Abbreviation/Terminology 
Definition 
CRF 
case report form 
CTCAE  
Common Terminology Criteria for Adverse Events 
GCP 
Good Clinical Practice 
FDA 
Food and Drug Agency 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
IRB 
institutional review board 
IV 
Intravenous 
IVRS 
interactive voice response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg/dL 
Milligrams per deciliter 
mmol/L 
Millimole per liter 
ONJ 
Osteonecrosis of the jaw 
Q4W 
Every 4 weeks 
SC 
Subcutaneous 
SRE 
Skeletal Related Events 
w/v 
Weight per volume 
Interactive Voice Response 
(IVR) 
Telecommunication technology that is linked to a central computer 
in real time as an interface to collect and process information.  
Source Data 
Information from an original record or certified a 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 ID, Randomization ID, and Stratification 
Value. 
study day 1 
The first day that protocol-specified investigational product is 
administered to the subject 
end of study for individual 
subject 
Approximately 30 days after the last dose of denosumab 
end of study (end of trial) 
Defined as when the last subject is assessed or receives an 
intervention for evaluation in the study 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 6 of 42 
 
Table of Contents 
 
Page 
Protocol Synopsis ............................................................................................................. 3 
Study Design and Treatment Schema .............................................................................. 4 
Study Glossary .................................................................................................................. 5 
1. 
OBJECTIVES ........................................................................................................... 9 
1.1 
Primary ......................................................................................................... 9 
1.2 
Safety ........................................................................................................... 9 
2. 
BACKGROUND AND RATIONALE .......................................................................... 9 
2.1 
Disease ......................................................................................................... 9 
2.2 
Denosumab Background ............................................................................ 11 
2.3 
Rationale .................................................................................................... 11 
2.4 
Clinical Hypotheses .................................................................................... 12 
3. 
EXPERIMENTAL PLAN ......................................................................................... 12 
3.1 
Study Design .............................................................................................. 12 
3.2 
Number of Centers ..................................................................................... 13 
3.3 
Number of Subjects .................................................................................... 13 
3.4 
Estimated Study Duration ........................................................................... 13 
3.4.1 
Study Duration for Participants ................................................... 13 
3.4.2 
End of Study ............................................................................... 14 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 14 
4.1 
Inclusion Criteria ......................................................................................... 14 
4.2 
Exclusion Criteria ........................................................................................ 14 
5. 
SUBJECT ENROLLMENT ..................................................................................... 14 
6. 
TREATMENT PROCEDURES ............................................................................... 15 
6.1 
Denosumab ................................................................................................ 15 
6.1.1 
Dosage, Administration, and Schedule ...................................... 16 
6.1.2 
Dose-cohort Study Escalation and Stopping Rules .................... 16 
6.1.3 
Dosage Adjustments .................................................................. 16 
6.2 
Concomitant Therapy ................................................................................. 16 
6.3 
Excluded Treatments During Study Period ................................................ 16 
6.4 
Other Treatment Procedures ...................................................................... 16 
7. 
STUDY PROCEDURES ......................................................................................... 16 
7.1 
General Study Procedures ......................................................................... 17 
7.2 
Adverse Events and Serious Adverse Events ............................................ 17 
7.3 
Antibody Testing Procedures ..................................................................... 17 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 7 of 42 
 
8. 
REMOVAL AND REPLACEMENT OF SUBJECTS ............................................... 17 
8.1 
Removal of Subjects ................................................................................... 17 
8.2 
Replacement of Subjects ............................................................................ 18 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 18 
9.1 
Adverse Events .......................................................................................... 18 
9.1.1 
Definition of Adverse Events ...................................................... 18 
9.1.2 
Reporting Procedures for Adverse Events ................................. 19 
9.2 
Serious Adverse Events ............................................................................. 20 
9.2.1 
Definition of Serious Adverse Events ......................................... 20 
9.2.2 
Reporting Procedures for Serious Adverse Events .................... 20 
9.3 
Pregnancy and Lactation Reporting ........................................................... 21 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 22 
10.1 
Study Endpoints ......................................................................................... 22 
10.2 
Sample Size Considerations ...................................................................... 22 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees .............................................................................................. 22 
10.4 
Interim Analysis and Early Stopping Guidelines ......................................... 22 
10.5 
Planned Methods of Analysis ..................................................................... 22 
10.5.1 
General Approach/Considerations ............................................. 22 
10.5.2 
Analysis of Key Study Endpoints ................................................ 22 
10.5.2.1 
Treatment-emergent Adverse Events ...................... 22 
10.5.2.2 
Anti-denosumab Antibodies ..................................... 23 
11. 
REGULATORY OBLIGATIONS ............................................................................. 23 
11.1 
Informed Consent ....................................................................................... 23 
11.2 
Independent Ethics Committee/Institutional Review Board ........................ 23 
11.3 
Subject Confidentiality ................................................................................ 24 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 24 
12.1 
Protocol Amendments and Study Termination ........................................... 24 
12.2 
Study Documentation and Archive ............................................................. 25 
12.3 
Study Monitoring and Data Collection ........................................................ 26 
12.4 
Language.................................................................................................... 27 
12.5 
Publication Policy ....................................................................................... 27 
12.6 
Compensation ............................................................................................ 28 
13. 
REFERENCES ....................................................................................................... 29 
14. 
APPENDICES ........................................................................................................ 32 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 8 of 42 
 
List of Appendices 
Appendix A.  Schedule of Assessments ......................................................................... 33 
Appendix B.  Additional Safety Assessment Information ................................................ 34 
Appendix C.  Sample Serious Adverse Event Form ....................................................... 35 
Appendix D.  Pregnancy Notification Worksheet ............................................................ 37 
Appendix E.  Lactation Notification Worksheet ............................................................... 38 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 9 of 42 
 
1. 
OBJECTIVES   
1.1 
Primary  
To facilitate the access of denosumab for subjects with advanced cancer who have 
participated in a denosumab phase 3 study until denosumab is approved and available 
for sale. 
1.2 
Safety 
To further assess the safety of denosumab for subjects who have participated in open 
label extensions of a denosumab advanced cancer phase 3 study 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease  
Bone metastases occur in more than 1.5 million patients with cancer worldwide 
(Coleman and Brown, 2005) and are most commonly implicated in cancers of the 
prostate, lung, and breast, with incidence rates as high as 75% 
(Selvaggi and Scagliotti, 2005; Carlin and Andriole, 2000; Coleman, 1997; 
Viadana et al, 1973).  Bone metastases can result in incapacitating clinical sequelae 
(Coleman, 2006).  These complications include debilitating pain that often requires 
aggressive management with radiation therapy and narcotic analgesics, pathologic 
fractures that may impair ambulation, surgery to prevent or treat pathologic fractures or 
manage pain, and spinal cord compressions that can result in numbness or weakness, 
urinary or fecal incontinence, and paralysis.  Furthermore, skeletal complications of bone 
metastases have been associated with increased mortality (Lage et al, 2008; 
DePuy et al, 2007).   
The underlying pathophysiology of bone metastases, irrespective of primary tumor type 
and their radiographic appearance, is a locally increased pathologic rate of bone 
remodeling, including increased osteoclast activity (Roodman, 2004; Yonou et al, 2004).  
Increased osteoclast activity can be demonstrated on histology (Roudier et al, 2008) and 
by elevated levels of serum bone resorption markers (Demers et al, 2003).  Elevated 
levels of bone resorption, as measured by increases in bone resorption markers, have 
been associated with worse prognosis for significant skeletal morbidity 
(Coleman et al, 2005).   
As above, the clinical consequences of increased osteoclastic activity associated with 
pathological bone remodeling in the setting of bone metastases may lead to fracture, 
radiation therapy or surgery to bone to alleviate bone pain and/or prevent impending 
fracture, spinal cord or nerve compression, and hypercalcemia of malignancy.  As a 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 10 of 42 
 
composite, the local irreversible events (fractures, radiation to bone, spinal cord 
compression or surgery to bone) are defined as Skeletal Related Events (SREs), 
whereas Hypercalcemia of Malignancy is a systemic and potentially reversible event and 
is not considered to be a component of SREs.   
A key objective in managing the skeletal morbidity associated with bone metastases is to 
inhibit excessive osteolysis and interrupt the vicious cycle of bone destruction, tumor 
growth, and further bone destruction, thus preventing or delaying the complications from 
bone metastases.  The pharmacologic armamentarium for this indication is currently 
comprised of IV bisphosphonates (eg, zoledronic acid, pamidronate), which have been 
shown to reduce the incidence of SREs in patients with advanced cancer and bone 
metastases (Kohno et al, 2005; Saad et al, 2002; Rosen et al, 2003; Rosen et al, 2001; 
Theriault et al, 1999; Berenson et al, 1996; Hortobagyi et al, 1996) and act by reducing 
bone resorption through inhibition of mature osteoclast activity (Zometa, 2011 [United 
States prescribing information]).  Suppression of bone resorption and formation markers 
has been observed following bisphosphonate treatment (Body, 2003).  These data, as 
well as data from nonclinical models (Roodman and Dougall, 2008), suggest that 
inhibition of osteoclast activity leads to a reduction in cancer-induced bone destruction 
and support the use of antiresorptives as treatment for bone metastases.  Currently, in 
addition to systemic antitumor therapy, treatment with IV bisphosphonates 
(eg, zoledronic acid, pamidronate) is recommended for patients with bone metastases 
(Carlson et al, 2008; Theriault et al, 2006; Warr et al, 2004; Hillner et al, 2003).  Of the 
currently available IV bisphosphonates, zoledronic acid is considered the standard of 
care, with demonstrated efficacy across tumor types (Kohno et al, 2005; 
Saad et al, 2002; Rosen et al, 2004; Rosen et al, 2001) and greater potency compared 
to other bisphosphonates (Gutta and Louis, 2007). 
Despite the availability of bisphosphonate treatment, an opportunity exists to improve the 
management of skeletal complications in patients with bone metastases 
(Clark et al, 2008; Coleman et al, 2008).  A substantial proportion of patients (between 
approximately 30% to 50%) continue to experience these complications 
(Rosen et al, 2004; Rosen et al, 2001; Saad et al, 2002), indicating that additional 
treatment options are warranted.  In addition, bisphosphonates are not recommended for 
use in patients with severe renal impairment because this therapy has been associated 
with an increased risk of clinically significant deterioration in renal function 
(Zometa, 2011 [United States prescribing information]; Aredia, 2008 [United States 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 11 of 42 
 
prescribing information]).  Renal deterioration is a prevalent condition in patients with 
advanced cancer, with decreased renal function observed in approximately 50% to 60% 
of patients with solid tumors, including breast cancer (Launay-Vacher et al, 2008; 
Kleber et al, 2007).  Therefore, minimizing exposure to drugs that may increase the risk 
of nephrotoxicity, such as bisphosphonates, is an important consideration in the 
treatment of these patients.  Although bisphosphonates have proven to be efficacious 
inhibitors of bone resorption, it is now clear that their antiresorptive activity resides in 
their ability to inhibit osteoclast activity (Fleisch, 1998).  Denosumab, by virtue of its 
anti-osteoclastic properties, would be expected to be effective in reducing the 
occurrence of skeletal-related events in patients with bone lesions from solid tumors or 
multiple myeloma.  Denosumab may also have the potential for use in the pediatric 
oncology setting. 
2.2 
Denosumab Background  
Perturbations in the balance between bone formation and resorption can lead to 
generalized osteoporosis (resulting from estrogen deficiency and aging) or local bone 
lysis (resulting from rheumatoid arthritis and bone metastases).  The RANK-RANK 
ligand (RANKL) system has been identified as an essential mediator of osteoclast 
formation, function, and survival (Teitelbaum and Ross, 2003).  RANKL binds RANK on 
osteoclasts or osteoclast precursors to stimulate or promote differentiation into 
osteoclasts and activate mature osteoclasts to resorb bone.  Therefore, RANKL is a 
therapeutic target for diseases associated with increased bone resorption. 
Denosumab is a fully human monoclonal IgG2 antibody to RANKL that binds with high 
affinity (Kd 3 x 10-12 M) and specificity to the soluble and cell membrane-bound forms of 
human RANKL.  Denosumab is highly specific because it binds only to RANKL and not 
to other members of the TNF family, including TNFα, TNFβ, TNF-related 
apoptosis-inducing ligand (TRAIL), or CD40 ligand (Elliott et al, 2006; 
Kostenuik et al, 2009).  Denosumab binding prevents the activation of RANK and inhibits 
the formation, activation, and survival of osteoclasts.  As a consequence, bone 
resorption and cancer-induced bone destruction are reduced.   
Refer to the investigator’s brochure for additional information. 
2.3 
Rationale  
A positive benefit:risk was demonstrated in Amgen study 20050136 (treatment of SREs 
in advanced breast cancer with bone metastasis) when superiority was demonstrated for 
both delaying the time to the first on-study Skeletal Related Events (SREs)(fracture, 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 12 of 42 
 
radiation to bone, surgery to bone, or spinal cord compression) (hazard ratio 0.82, 
95 percent CI: 0.71, 0.95), and delaying the time to the first-and-subsequent SREs 
(hazard ratio 0.77, 95 percent CI: 0.66, 0.89) (Stopeck et al, 2010).   
Amgen study 20050103 (treatment of SREs in advanced prostate cancer with bone 
metastasis) demonstrated superiority for both delaying the time to the first on-study 
Skeletal Related Events (SREs)(fracture, radiation to bone, surgery to bone, or spinal 
cord compression) (hazard ratio 0.82, 95 percent CI: 0.71, 0.95), and delaying the time 
to the first-and-subsequent SREs (hazard ratio 0.82, 95 percent CI: 0.71, 0.94) 
(Fizazi et al, 2011). 
Amgen study 20050147 (delay of bone metastasis-free survival in hormone-refractory 
[castrate-resistant] prostate cancer] demonstrated that denosumab significantly 
improved median bone metastasis-free survival by 4.2 months (HR= 0.85, 95 percent CI 
0.73-0.98, p=0.03 ie. 15% risk reduction) compared to placebo (primary endpoint), and 
significantly improved time to first occurrence of bone metastases (secondary endpoint).  
Overall survival was similar between the denosumab and placebo groups (secondary 
endpoint) (Amgen Press Release, 2010). 
After the above mentioned studies demonstrated a positive benefit:risk, subjects were 
offered access to denosumab in an open-label extension to the study for either up to 2 or 
3 years.  As these studies approach the end of the open-label extensions, subjects who 
are still on-study and receiving benefit from denosumab are not able to get access to 
denosumab.  This study will allow access to denosumab for subjects with advanced 
cancer who have participated in the Open-label Extension portion of a denosumab 
phase 3 study and will have access to denosumab until it is approved and available for 
sale.  
2.4 
Clinical Hypotheses 
A formal statistical hypothesis will not be tested or estimated. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is an open-label, single-arm access protocol for subjects with advanced cancer. 
Subjects will be offered open-label denosumab at a dose of 120 mg SC Q4W until 
denosumab is approved and available for sale.  Amgen may end this study prior to 
denosumab being approved and available for sale if another mechanism is identified to 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 13 of 42 
 
provide denosumab to ongoing subjects, or as otherwise stated in Section 12.1 of this 
protocol. 
Severe hypocalcemia can occur in subjects receiving denosumab.  Calcium levels 
should be monitored as part of routine clinical practice.  It is strongly recommended that 
all subjects receive daily supplements of at least 500 mg calcium and at least 400 IU of 
vitamin D, unless documented hypercalcemia (albumin-adjusted serum calcium 
> 2.9 mmol/L [11.5 mg/dL] or ionized calcium > 1.5 mmol/L [6.0 mg/dL]) develops on 
study.  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. 
Osteonecrosis of the jaw (ONJ) can occur in subjects receiving denosumab.  Subjects 
should be monitored for ONJ as part of routine clinical practice.  Subjects should be 
instructed to maintain good oral hygiene, and avoid invasive dental procedures, if 
possible.  
The overall study design is described by a study schema at the end of the protocol 
synopsis section. 
3.2 
Number of Centers 
This access protocol will be available to sites in countries in which Amgen has 
conducted phase 3 studies with denosumab in oncology.  The number of sites in this 
study will be determined by the number of sites requesting access to denosumab.   
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
The number of subjects will be determined by the number of subjects who qualify for the 
protocol.  It is estimated that up to approximately 400 subjects will participate in this 
protocol. 
3.4 
Estimated Study Duration 
3.4.1 
Study Duration for Participants 
The anticipated total duration for a subject enrolling in the study will be until denosumab 
is approved and available for sale. 
It is anticipated that the average treatment duration under this protocol will be 
approximately 1 year per subject. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 14 of 42 
 
3.4.2 
End of Study 
The end of study for an individual subject will occur approximately 30 days after the last 
dose of denosumab.  The end of the clinical study is defined as the time when the last 
subject is assessed or receives an intervention for evaluation in the study. 
4. 
SUBJECT ELIGIBILITY 
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 procedure, the appropriate written informed 
consent must be obtained (see Section 11.1).   
4.1 
Inclusion Criteria 
4.1.1 
Subjects was previously enrolled in a denosumab phase 3 study and 
participated in the Open-label Extension portion of that study. 
4.1.2 
Subject or subject’s legally acceptable representative has provided 
informed consent. 
4.2 
Exclusion Criteria 
4.2.1 
Subject is of child bearing potential and planning to become pregnant 
within 7 months after the end of treatment. 
4.2.2 
Subject is of child bearing potential and is not willing to use, in 
combination with her partner, two highly effective method of contraception 
during treatment and for 7 months after the end of treatment 
4.2.3 
Subject has known sensitivity to any of the products to be administered 
during dosing. 
4.2.4 
Subject will not be available for protocol-required study visits or 
procedures, to the best of the subject and investigator’s knowledge. 
4.2.5 
Subject has any kind of disorder that, in the opinion of the investigator, 
may compromise the ability of the subject to give written informed 
consent and/or to comply with all required study procedures. 
5. 
SUBJECT ENROLLMENT 
Before subjects may be entered into the study, Amgen Inc requires a copy of the site’s 
written Independent Ethics Committee/Institutional Review Board (IEC/IRB) approval of 
the protocol, informed consent form, and all other subject information if applicable 
(see Section 11.2).  All subjects or legally acceptable representatives must personally 
sign and date the consent form before any study-specific screening procedures.   
All subjects who enter into the screening period for the study (defined as the point at 
which the subject signs the informed consent) will receive a unique subject identification 
number before any study procedures are performed.  This number will be used to 
identify the subject throughout the clinical study and must be used on all study 


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Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 16 of 42 
 
6.1.1 
Dosage, Administration, and Schedule 
Each subject will receive a 120 mg SC injection of denosumab Q4W until denosumab is 
approved and available for sale. 
Amgen will notify investigators when denosumab is to become available (on a 
per-country basis) to discuss the timelines for stopping protocol treatment.  
6.1.2 
Dose-cohort Study Escalation and Stopping Rules 
There are no dose escalations or stopping rules in this study. 
6.1.3 
Dosage Adjustments  
There will be no dose adjustments for denosumab. 
6.2 
Concomitant Therapy  
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.3.   
6.3 
Excluded Treatments During Study Period  
Bisphosphonates (oral or intravenous [IV]) or commercial denosumab are not to be 
administered during the study treatment. 
6.4 
Other Treatment Procedures  
Severe hypocalcemia can occur in subjects receiving denosumab.  Calcium levels 
should be monitored as part of routine clinical practice.  It is strongly recommended that 
all subjects receive daily supplements of at least 500 mg calcium and at least 400 IU of 
vitamin D, unless documented hypercalcemia (albumin-adjusted serum calcium 
> 2.9 mmol/L [11.5 mg/dL] or ionized calcium > 1.5 mmol/L [6.0 mg/dL]) develops on 
study.  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.  
Osteonecrosis of the jaw (ONJ) can occur in subjects receiving denosumab.  Subjects 
should be monitored for ONJ as part of routine clinical practice.  Subjects should be 
instructed to maintain good oral hygiene, and avoid invasive dental procedures, if 
possible.   
7. 
STUDY PROCEDURES 
Study assessments will be performed only after written informed consent is obtained.  
The schedule of assessments is provided in Appendix A.   


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 17 of 42 
 
All tests and procedures scheduled for screening must be performed within 35 days 
before the planned first dose of investigational product (ie, study day 1).   
Study visits will occur Q4W (± 8 days).  Every effort should be made to keep subjects on 
the study schedule as planned from study day visit 1.   
Any missed visits, tests not done, or examinations that are not conducted must be 
reported as such on the CRF.   
7.1 
General Study Procedures  
7.2 
Adverse Events and Serious Adverse Events  
Adverse Events and Serious Adverse Events will be recorded starting at Study Day 1 
and will be followed through approximately 30 days after the last dose of denosumab.   
7.3 
Antibody Testing Procedures 
A blood sample at the end of study visit will be collected from all subjects for the 
measurement of anti-denosumab binding anti-bodies.  Samples testing positive for 
binding antibodies will also be tested for neutralizing antibodies and may be further 
characterized for quantity/titer, isotype, affinity and presence of immune complexes.  
Additional blood samples may be obtained to rule out anti-denosumab antibodies during 
the study.   
Subjects who test positive for neutralizing antibodies to denosumab at the final 
scheduled study visit will be asked to return for additional follow-up testing.  This testing 
should occur approximately every 3 months starting from when the site has been notified 
of the positive result, until:  (1) neutralizing antibodies are no longer detectable or (2) the 
subject has been followed for a period of at least 1 year (± 4 weeks).  More frequent 
testing (eg, every month) or testing for a longer period of time may be requested in the 
event of safety-related concerns. 
Subjects who test positive for binding, non-neutralizing antibodies and have clinical 
sequelae that are considered potentially related to an anti-denosumab antibody 
response may also be asked to return for additional follow-up testing. 
8. 
REMOVAL AND REPLACEMENT OF SUBJECTS 
8.1 
Removal of Subjects 
Subjects have the right to withdraw fully or partially from the study at any time and for 
any reason without prejudice to his or her future medical care by the physician or at the 
institution. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 18 of 42 
 
Withdrawal of full consent for a study means that the subject does not wish to receive 
further investigational treatment and 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.  Any subject may withdraw full consent to participate in the study 
at any time during the study.  The investigator will discuss with the subject appropriate 
procedures for withdrawal from the study. 
Should a subject (or a legally acceptable representative) request or decide to withdraw 
from the study, all efforts will be made to complete and report the observations as 
thoroughly as possible up to the date of withdrawal.  All information should be reported 
on the applicable CRFs.   
Reasons for removal from protocol-required product(s) or observation might include: 
• 
withdrawal of full consent 
• 
administrative decision by the investigator or Amgen 
• 
pregnancy in a female subject (report on Pregnancy Notification Worksheet; see 
Appendix D).  
• 
ineligibility 
• 
significant protocol deviation 
• 
patient noncompliance 
• 
adverse event 
• 
disease progression 
• 
other safety concern by the investigator or Amgen  
• 
death 
• 
lost to follow-up 
8.2 
Replacement of Subjects 
Subjects will not be replaced. 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Adverse Events 
9.1.1 
Definition of Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates the pre-existing medical condition (eg, diabetes, migraine 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 19 of 42 
 
headaches, gout) has increased in severity, frequency, and/or duration, and/or has an 
association with a significantly worse outcome.  A pre-existing condition that has not 
worsened during the study, and involves an intervention such as elective cosmetic 
surgery or a medical procedure while on study is not considered an adverse event.  
The term “disease progression of the primary tumor” should not be captured as an 
adverse event (including fatal adverse event).  If there are signs and/or symptoms of 
disease progression (regardless of primary or secondary tumor) that are new or 
worsened from baseline signs and/or symptoms, these should be reported as adverse 
event(s).  If a new primary malignancy appears, it will be considered an adverse event. 
9.1.2 
Reporting Procedures for Adverse Events 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after Study Day 1 through 
approximately 30 days after the last dose of denosumab are reported using the 
applicable CRF (eg, Adverse Event Summary CRF).  
The investigator must assign the following adverse event attributes: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
Dates of onset and resolution, 
• 
Severity [and/or toxicity per protocol], 
• 
Assessment of relatedness to denosumab, and 
• 
Action taken. 
The adverse event toxicity grading scale used will be the Common Terminology Criteria 
for Adverse Events (CTCAE) version 3.0.  The toxicity grading scale used in this study is 
described in Appendix B. 
The investigator must assess whether the adverse event is possibly related to 
denosumab.  This relationship is indicated by a “yes” or “no” response to the question:  
Is there a reasonable possibility that the event may have been caused by the 
investigational product?   
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) should not be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 20 of 42 
 
clinical sequelae (not the laboratory abnormality) should be recorded as the adverse 
event. 
The investigator’s clinical judgment will be used to determine whether a subject should 
be removed from treatment or from the study due to an adverse event.  A subject, or 
subject’s parent/legal guardian, may also voluntarily withdraw from treatment due to an 
adverse event.  If the subject withdraws full consent, the subject should be encouraged 
to undergo, at a minimum, an end-of-study assessment.   
9.2 
Serious Adverse Events 
9.2.1 
Definition of Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).  
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, drug-induced liver injury, 
or events that necessitate an emergency room visit, outpatient surgery, or urgent 
intervention.  
9.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after Study Day 1 through 30 days 
after the last dose of denosumab are recorded in the subject’s medical record and are 
submitted to Amgen.  The serious adverse event must be submitted to Amgen within 
24 hours of discovery or notification of the event. 
The investigator must assess whether the serious adverse event is possibly 
related to any study-mandated activity or procedure.  This relationship is 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 21 of 42 
 
indicated by a “yes” or “no” response to the question:  “Is there a reasonable 
possibility that the event may have been caused by a study activity/procedure”?  
The investigator is expected to follow reported serious adverse events until 
stabilization or reversibility. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours of receipt.  The investigator may be asked to provide additional 
follow-up information, which may include a discharge summary or extracts from the 
medical record.  Information provided about the serious adverse event must be 
consistent with that recorded on the applicable CRF (eg, Adverse Event Summary CRF). 
If a subject is permanently withdrawn from the study because of a serious adverse 
event, this information must be submitted to Amgen. 
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IEC/IRB in 
compliance with all reporting requirements according to local regulations and good 
clinical practice.  
The investigator should notify the appropriate IEC/IRB of serious adverse events 
occurring at the site and other adverse event reports received from Amgen, in 
accordance with local procedures and statutes.   
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-specified product and for 7 months after end of treatment, the 
pregnancy should be reported to Amgen’s global Pregnancy Surveillance Program 
within 24 hours of the investigator’s knowledge of a pregnancy.  Report pregnancy 
on the Pregnancy Notification Worksheet (Appendix D).  The Pregnancy Surveillance 
Program (PSP) will seek to follow the pregnant woman throughout her pregnancy 
and her baby up to 12 months after birth. 
If a lactation case occurs while the female subject is taking protocol-required 
therapies report the lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should 
monitor for lactation cases that occur after the last dose of protocol-required 
therapies through 7 months after IP discontinuation.  


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 22 of 42 
 
Any lactation case should be reported to Amgen’s global Lactation Surveillance 
Program (LSP) within 24 hours of the investigator’s knowledge of event.  Report a 
lactation case on the Lactation Notification Worksheet (Appendix E). 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
Subject incidence of treatment-emergent adverse events and anti-denosumab 
antibodies. 
10.2 
Sample Size Considerations 
The statistical reporting of the safety outcomes will be entirely descriptive (summary 
statistics), with no formal statistical hypothesis tested or estimated.  The number of 
subjects will be determined by the number of subjects who qualify for the protocol.  It is 
estimated that up to approximately 400 subjects will participate in this protocol. 
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
All subjects will receive denosumab. 
10.4 
Interim Analysis and Early Stopping Guidelines 
There will be no interim analysis or early stopping rules. 
10.5 
Planned Methods of Analysis 
10.5.1 
General Approach/Considerations 
Descriptive statistics provided for categorical outcomes will include the frequency and 
percentage.  Continuous outcomes will include the number of subjects, mean, standard 
deviation, median, 25th and 75th percentiles, minimum, and maximum. 
Safety data will be summarized for all subjects who received at least 1 dose of 
investigational product. 
10.5.2 
Analysis of Key Study Endpoints 
10.5.2.1 
Treatment-emergent Adverse Events  
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The analysis of adverse events will be descriptive.  The subject incidence 
rates of treatment-emergent adverse events will be tabulated by system organ class and 
preferred term.  Additional summary tables will be provided separately for serious 
adverse events, Common Terminology Criteria for Adverse Events (CTCAE) grade 3, 4, 
or 5 adverse events, adverse events leading to investigational product discontinuation, 
and adverse events leading to study withdrawal.  Narratives of deaths and serious 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 23 of 42 
 
adverse events will also be provided.  All investigational product related adverse events, 
serious adverse events, CTCAE grade 3, 4 or 5 adverse events, adverse events leading 
to investigational product discontinuation, and adverse events leading to study 
withdrawal will be summarized in the same manner as treatment-emergent adverse 
events 
10.5.2.2 
Anti-denosumab Antibodies 
The incidence and percentages of subjects who develop anti-denosumab antibodies at 
any time will be tabulated. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial generic informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template will be 
communicated by letter from the Amgen to the investigator.  The written informed 
consent document should be prepared in the language(s) of the potential patient 
population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any investigational products are administered.   
The acquisition of informed consent should be documented in the subject’s medical 
records, and the informed consent form should be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  The original 
signed informed consent form should be retained in accordance with institutional policy, 
and a copy of the signed consent form should be provided to the subject. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  
11.2 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IEC/IRB for 
written approval.  A copy of the written approval of the protocol and informed consent 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 24 of 42 
 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IEC/IRB 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator should notify the IEC/IRB of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator will be responsible for obtaining annual IEC/IRB approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IEC/IRB continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained:   
• 
On the CRFs or other documents submitted to Amgen, subjects should be identified 
by a subject identification number only, with a complete and accurate date of birth on 
the demographics CRF.   
• 
For Serious Adverse Events reported to Amgen, subjects should be identified by 
their initials, date of birth, and a subject identification number.   
• 
Documents that are not for submission to Amgen (eg, signed informed consent 
forms) should be kept in strict confidence by the investigator. 
In compliance with Federal 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 IEC/IRB 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 named representatives to have access to 
his/her study-related records, including personal information, without violating the 
confidentiality of the subject. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the investigator must be obtained.  The 
IEC/IRB must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IEC/IRB to Amgen. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 25 of 42 
 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the investigator’s participation in the study 
according to the study contract.  The investigator should notify the IEC/IRB 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 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, and by what mechanism, after 
termination of the trial and before it is available commercially. 
12.2 
Study Documentation and Archive 
The investigator should maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  Elements should include: 
• 
Subject files containing completed CRF, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, investigator’s brochure, 
copies of prestudy documentation, and all correspondence to and from the IEC/IRB 
and Amgen 
• 
If kept, proof of receipt/delivery sheet, Investigational Product Accountability Record, 
Return of Investigational Product for Destruction, Final Investigational Product 
Reconciliation Statement (if applicable), and all drug-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 26 of 42 
 
12.3 
Study Monitoring and Data Collection 
The Amgen representative and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen monitor is responsible for verifying the CRFs at regular intervals throughout 
the study to verify adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research.  The 
monitor should have access to subject medical records and other study-related records 
needed to verify the entries on the CRFs. 
The investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits, including delays in completing CRFs, 
are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function 
(or designees).  Inspection of site facilities (eg, pharmacy, drug 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. 
Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the electronic CRFs must be 
maintained and readily available. 
• 
Updates to electronic CRFs will be automatically documented through the software’s 
“audit trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review will be performed on subject data received at Amgen.  During 
this review, subject data will be checked for consistency, omissions, and any 
apparent discrepancies.  In addition, the data will be reviewed for adherence to the 
protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or site notifications will be created in 
the Electronic Data Capture system database for site resolution and closed by 
Amgen reviewer. 
• 
The principal investigator signs only the Investigator Verification Form for this 
electronic data capture study.  This signature will indicate that the principal 
investigator inspected or reviewed the data on the CRF, the data queries, and the 
site notifications, and agrees with the content. 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self Evident Corrections 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 27 of 42 
 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit—week 4 and early termination) and clarifying “other, specify” if 
data are provided (eg, race, physical examination).  Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the trial 
and at study closeout.   
12.4 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.  Consult the 
country-specific requirements for language requirements. 
12.5 
Publication Policy 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several principal 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 should 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), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published.  Authors should meet conditions 1, 2, and 3. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 28 of 42 
 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for corporate review.  The Clinical 
Study Agreement among the institution, principal investigator, and Amgen will detail the 
procedures for, and timing of, Amgen’s review of publications. 
12.6 
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.  
Depending on the type of study, and if permitted under applicable regional laws or 
regulatory guidelines, subjects may be compensated for other inconveniences not 
associated with study-related injuries (eg, travel costs). 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 29 of 42 
 
13. 
REFERENCES  
Amgen Press Release. XGEVA(TM) (Denosumab) Significantly Improved Bone 
Metastasis-Free Survival in Men With Prostate Cancer; Pivotal Phase 3 '147 Study 
Meets Primary Endpoint First Bone-Targeted Therapy to Delay the Onset of Bone 
Metastases in Patients with Prostate Cancer. Available at:  www.amgen.com  2010 
Aredia (pamidronate disodium) Prescribing Information, Novartis Pharmaceuticals 
Corporation, East Hanover, NJ, 2008. 
Berenson JR, Lichtenstein A, Porter L, et al.  Efficacy of pamidronate in reducing 
skeletal events in patients with advanced multiple myeloma.  N Engl J Med.  
1996;334:488-493. 
Body J-J.  Rationale for the use of bisphosphonates in osteoblastic and osteolytic bone 
lesions.  The Breast.  2003;Suppl 2:S37-S44. 
Carlin BI, Andriole GL. The natural history, skeletal complications, and management of 
bone metastases in patients with prostate carcinoma. Cancer. 2000;88 
(12 Suppl):2989-2994. 
Carlson RW, Anderson BO, Edge SB, et al.  NCCN Clinical Practice Guidelines in 
Oncology, Breast Cancer, V.I.2009.  2008.  National Comprehensive Cancer Network, 
Inc.  Available at:  www.nccn.org. 
Clark JCM, Dass CR, Choong PFM.  Current and future treatments of bone metastases.  
Expert Opin Emerging Drugs.  2008;13(4):609-627. 
Coleman RE, Guise TA, Lipton A, et al.  Advancing treatment for metastatic bone 
cancer:  consensus recommendations from the second cambridge conference.  
Clin Cancer Res.  2008;14(20):6387-6395. 
Coleman RE.  Clinical features of metastatic bone disease and risk of skeletal morbidity.  
Clin Cancer Res.  2006;12(20 Suppl):6243s-6249s. 
Coleman RE, Brown JE.  Monitoring Response to Treatment – the Role of Biomarkers.  
In: Jasmin C, Coleman RE, Coia L, et al, eds.  Textbook of Bone Metastases.  Hoboken, 
NJ: John Wiley and Sons; 2005;105. 
Coleman RE, Major P, Lipton A, et al.  Predictive value of bone resorption and formation 
markers in cancer patients with bone metastases receiving the bisphosphonate 
zoledronic acid.  J Clin Oncol.  2005;23(22):4925-4935.   
Coleman R.  Skeletal complications of malignancy.  Cancer. 1997;80:1588-1594. 
Demers L, Costa L, Lipton A.  Biochemical markers and skeletal metastases.  Clin 
Orthop.  2003;(415 Suppl):S138-47. 
DePuy V, Anstrom KJ, Castel LD, Schulman KA, Weinfurt KP, Saad F.  Effects of 
skeletal morbidities on longitudinal patient-reported outcomes and survival in patients 
with metastatic prostate cancer.  Support Care Cancer.  2007;15:869-876. 
Elliott R, Kostenuik P, Chen C, et al.  Denosumab is a selective inhibitor of human 
receptor activator of NF- ligand that blocks osteoclast formation in vitro and in vivo.  
Eur J Ca Suppl.  2006;4:62. 
International Conference on Harmonisation (ICH) Tripartite Guideline; Guideline for 
Good Clinical Practice – (E6); www.ich.org 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 30 of 42 
 
Fizazi K, Carducci M, Smith M, et al.  Denosumab versus zoledronic acid for treatment 
of bone metastases in men with castration-resistant prostate cancer: a randomised, 
double-blind study.  Lancet.  2011; 377: 813–22 
Fleisch H.  Bisphophonates: mechanisms of action.  Endocrine Rev.  1998:19:80-100. 
Gutta R, Louis PJ.  Bisphosphonates and osteonecrosis of the jaws:  science and 
rationale.  Oral Surg Oral Med Oral Pathol Oral Radiol Endod.  2007;104(2):186-193. 
Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 
update on the role of bisphosphonates and bone health issues in women with breast 
cancer. J Clin Oncol.  2003;21:4042–4057. 
Hortobagyi GN, Theriault RL, Porter L, et al.  Efficacy of pamidronate in reducing 
skeletal complications in patients with breast cancer and lytic bone metastases. N Engl J 
Med.  1996;335:1785-1789. 
Kleber M, Cybulla M, Bauchmüller K, Ihorst G, Koch B, Engelhardt M.  Monitoring of 
renal function in cancer patients:  an ongoing challenge for clinical practice.  Ann Oncol.  
2007;18:950-958. 
Kohno N, Aogi K, Minami H, et al.  Zoledronic acid significantly reduces skeletal 
complications compared with placebo in Japanese woman with bone metastases from 
breast cancer: a randomized placebo-controlled trial.  J Clin Oncol.  2005;23:3314-3321. 
Kostenuik PJ, Nguyen HQ, McCabe J, et al.  Denosumab, a Fully Human Monoclonal 
Antibody to RANKL, Inhibits Bone Resorption and Increases BMD in Knock-In Mice That 
Express Chimeric (Murine/Human) RANKL.  J Bone Miner Res.  2009;24:182-195. 
Lage MJ, Barber BL, Harrison DJ, Jun S.  The Cost of Treating Skeletal-Related Events 
in Patients With Prostate Cancer.  Am J Manag Care.  2008;14:317-322. 
Launay-Vacher V, Gligorov J, Le Tourneau C, et al.  Prevalence of renal insufficiency in 
breast cancer patients and related pharmacological issues.  Breast Cancer Res Treat.  
2008;124(3):745-753.   
Roodman GD.  Mechanisms of bone metastasis.  N Engl J Med.  2004;350:1655-1664. 
Roodman GD, Dougall WC.  RANK ligand as a therapeutic target for bone metastases 
and multiple myeloma.  Cancer Treat Rev.  2008;34:92-101. 
Rosen LS, Gordon DH, Dugan W, et al.  Zoledronic acid is superior to pamidronate for 
the treatment of bone metastases in breast carcinoma patients with at least one 
osteolytic lesion.  Cancer.  2004;100:36-43. 
Rosen LS, Gordon D, Tchekmedyian S, et al.  Zoledronic acid versus placebo in the 
treatment of skeletal metastases in patients with lung cancer and other solid tumors:  a 
phase III, double-blind, randomized trial - The Zoledronic Acid Lung Cancer and Other 
Solid Tumors Study Group.  J Clin Oncol.  2003;21(16):  3150-3157 
Rosen LS, Gordon D, Kaminski M et al.  Zoledronic acid versus pamidronate in the 
treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of 
multiple myeloma:  a phase III, double-blind, comparative trial.  Cancer.  
2001;7(5):377-387. 
Roudier MP, Morrissey C, True LD, Higano CS, Vessella RL, Ott SM.  Histopathological 
assessment of prostate cancer bone osteoblastic metastases.  J Urol.  
2008;180(3):1154-1160. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 31 of 42 
 
Saad F, Gleason DM, Murray R et al.  A randomized, placebo-controlled trial of 
zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma.  
J Natl Cancer Inst.  2002;94:1458-68. 
Selvaggi G, Scagliotti GV,  Management of bone metastases in cancer: A review.  Crit 
Rev Oncol Hematol.  2005;56:365-378. 
Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the 
treatment of bone metastases in patients with advanced breast cancer: a randomized, 
double-blind study. J Clin Oncol. 2010; 28: 5132–39 
Teitelbaum SL, Ross FP.  Genetic regulation of osteoclast development and function. 
Nat Rev Genet.  2003;4:638-649. 
Theriault RL, Biermann JS, Brown E, et al.  NCCN task force report:  Bone health and 
cancer care.  J Natl Compr Canc Netw.  2006;4 Suppl 2:S1-S20. 
Theriault RL, Lipton A, Hortobagyi GN, et al.  Pamidronate reduces skeletal morbidity in 
women with advanced breast cancer and lytic bone lesions:  a randomized, 
placebo-controlled trial.  J Clin Oncol.  1999;17(3):846-854. 
Viadana E, Cotter R, Pickren JW, Bross IDJ.  An autopsy study of metastatic sites of 
breast cancer.  Cancer Res.  1973;33:179-181. 
Warr D, Johnston M, Breast Cancer Disease Site Group.  Use of bisphosphonates in 
women with breast cancer:  practice guideline report #1-11 (version 2.2002).  Hamilton, 
ON: Cancer Care Ontario, Program in Evidence-based Care; 2004.  Available at:  
http://www.cancercare.on.ca/toolbox/qualityguidelines/diseasesite/breast-ebs/. 
Yonou H, Ochiai A, Goya M, et al.  Intraosseous growth of human prostate cancer in 
implanted adult human bone: relationship of prostate cancer cells to osteoclasts in 
osteoblastic metastatic lesions.  Prostate.  2004;58:406-413. 
Zometa [zoledronic acid] Prescribing Information.  Novartis Pharmaceuticals 
Corporation, East Hanover, NJ, 2011. 
Denosumab Investigator’s Brochure, Thousand Oaks, CA:  Amgen Inc. 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 32 of 42 
 
14. 
APPENDICES  


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 33 of 42 
 
Appendix A.  Schedule of Assessments 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 34 of 42 
 
Appendix B.  Additional Safety Assessment Information 
Adverse Event Toxicity Grading Scale 
The Common Terminology Criteria for Adverse Events (CTCAE) is available at the 
following link:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm] 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 35 of 42 
 
Appendix C.  Sample Serious Adverse Event Form 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 36 of 42 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 37 of 42 
 
Appendix D.  Pregnancy Notification Worksheet 
 
 
PREGNANCY NOTIFICATION WORKSHEET
Sex
SEX CODES:
1
Female subject
0
Male subject partner
Estimated Date of Conception
Day
Month
Year
Investigational Product Administration
Start Date
Investigational Product Administration
Stop Date
Day
Month
Year
Day
Month
Year
The investigator will be contacted for further information.
Fax to:
Date Faxed
Day
Month
Year


Did subject withdraw from the study?
Yes
1
No
    0
Site No.
Subject ID No.
Subject Initials
Study No.:
Please provide the following information:
Investigator Name:
Telephone:
Institution:
Site No:
Address:
(              )
v4 14Apr04sb
Form Completed By:
Date:


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 38 of 42 
 
Appendix E.  Lactation Notification Worksheet 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 39 of 42 
 
Superseding Original 
Protocol Title:  Open-Label Access Protocol of Denosumab for Subjects with 
Advanced Cancer 
 
Amgen Protocol Number denosumab 20110113 
 
Amendment Date: 
22 February 2013 
Rationale: 
The purpose of this amendment is to clarify the serious adverse event reporting process 
and timelines and provide a mechanism for reporting of lactation events should they 
occur in female subjects who are receiving or have received denosumab within 7 months 
prior. 
Summary of changes: 
• 
Clarify that serious adverse events must be reported within 24 hours 
• 
Clarify how serious adverse events reported to Amgen will be reported to regulators 
and investigators 
• 
Provide lactation notification worksheet in the protocol 


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Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 41 of 42 
 
With: 
The serious adverse event must be submitted to Amgen within 24 hours of discovery or 
notification of the event. 
Section 9.2.2 Reporting Procedures for Serious Adverse Events 
Add: 
The investigator must assess whether the serious adverse event is possibly 
related to any study-mandated activity or procedure.  This relationship is 
indicated by a “yes” or “no” response to the question:  “Is there a reasonable 
possibility that the event may have been caused by a study activity/procedure”?  
The investigator is expected to follow reported serious adverse events until 
stabilization or reversibility. 
Section 9.2.2 Reporting Procedures for Serious Adverse Events 
Replace: 
All new information for serious adverse events must be sent to Amgen within 1 working 
day of receipt. 
With: 
All new information for serious adverse events must be sent to Amgen within 24 hours 
of receipt.   
Section 9.2.2 Reporting Procedures for Serious Adverse Events 
Delete: 
Serious adverse events deemed possibly related to investigational product by the 
investigator occurring more than 30 days after the last dose of investigational product 
will be submitted to Amgen within 1 working day of discovery or notification of the event. 
Section 9.2.2 Reporting Procedures for Serious Adverse Events 
Delete: 
Determination of expectedness for Amgen products will be based on the contents of the 
Investigator’s Brochure (Appendices A and/or B when available) for investigational 
products and the regional prescribing information for products being studied for an 
approved use.  Expectedness assessments will be made for all investigational products 
(Amgen and non-Amgen) using the appropriate reference safety information per local 


Product:  Denosumab (AMG 162) 
Protocol Number:  20110113 
Date:  22 February 2013 
Page 42 of 42 
 
regulatory reporting requirements.  Suspected unexpected serious adverse reactions 
reported for subjects receiving a non-Amgen investigational product will be expedited 
according to local requirements.  
Section 9.3 Pregnancy and Lactation Reporting 
Replace: 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-specified product and for 7 months after end of treatment, the 
pregnancy should be reported to Amgen’s global Pregnancy Surveillance Program.  
Report pregnancy on the Pregnancy Notification Worksheet (Appendix D). 
With: 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-specified product and for 7 months after end of treatment, the 
pregnancy should be reported to Amgen’s global Pregnancy Surveillance Program within 
24 hours of the investigator’s knowledge of a pregnancy.  Report pregnancy on the 
Pregnancy Notification Worksheet (Appendix D).  The Pregnancy Surveillance 
Program (PSP) will seek to follow the pregnant woman throughout her pregnancy 
and her baby up to 12 months after birth. 
If a lactation case occurs while the female subject is taking protocol-required 
therapies report the lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should 
monitor for lactation cases that occur after the last dose of protocol-required 
therapies through 7 months after IP discontinuation.  
Any lactation case should be reported to Amgen’s global Lactation Surveillance 
Program (LSP) within 24 hours of the investigator’s knowledge of event.  Report a 
lactation case on the Lactation Notification Worksheet (Appendix E). 
Section:  Appendix C Serious Adverse Event Form has been updated 
Section:  Appendix E Lactation Notification Worksheet has been added 

SAP_001.pdf: 
Product:  Denosumab
Protocol Number:  20110113
Date:  27 August 2018
Page 1 of 18
CONFIDENTIAL
Statistical Analysis Plan
Protocol Title:
Open-Label Access Protocol of Denosumab for
Subjects with Advanced Cancer
Short Protocol Title:
Protocol Number:
20110113
Authors:
Sponsor:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
Telephone: + 1-805-447-1000
SAP Date:
Document Version
Date
Version 2.0
27 August 2018
PPD
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Product:  Denosumab
Protocol Number:  20110113
Date:  27 August 2018
Page 2 of 18
CONFIDENTIAL
Table of Contents
Table of Contents ...................................................................................................2
1.
Introduction.............................................................................................................5
2.
Objectives, Endpoints and Hypotheses...................................................................5
2.1
Objectives and Endpoints............................................................................5
2.2
Hypotheses and/or Estimations...................................................................5
3.
Study Overview ......................................................................................................5
3.1
Study Design...............................................................................................5
3.2
Sample Size................................................................................................6
3.3
Adaptive Design..........................................................................................6
4.
Covariates and Subgroups .....................................................................................6
4.1
Planned Covariates.....................................................................................6
4.2
Subgroups...................................................................................................6
5.
Definitions...............................................................................................................6
6.
Analysis Sets..........................................................................................................9
6.1
Full Analysis Set..........................................................................................9
6.2
Safety Analysis Set .....................................................................................9
6.3
Per Protocol Set(s)......................................................................................9
6.4
Health-related Quality-of-Life or Health Economics Analyses 
Set(s) ..........................................................................................................9
6.5
Pharmacokinetic/Pharmacodynamic Analyses Set(s)..................................9
6.6
Interim Analyses Set(s) ...............................................................................9
7.
Planned Analyses...................................................................................................9
7.1
Interim Analysis and Early Stopping Guidelines ..........................................9
7.2
Primary Analysis .........................................................................................9
7.3
Final Analysis..............................................................................................9
8.
Data Screening and Acceptance...........................................................................10
8.1
General Principles.....................................................................................10
8.2
Data Handling and Electronic Transfer of Data..........................................10
8.3
Handling of Missing and Incomplete Data .................................................10
8.4
Detection of Bias.......................................................................................10
8.5
Outliers .....................................................................................................11
8.6
Distributional Characteristics.....................................................................11
8.7
Validation of Statistical Analyses...............................................................11
9.
Statistical Methods of Analysis..............................................................................11
9.1
General Considerations.............................................................................11
9.2
Subject Accountability ...............................................................................11
9.3
Important Protocol Deviations ...................................................................12


Product:  Denosumab
Protocol Number:  20110113
Date:  27 August 2018
Page 3 of 18
CONFIDENTIAL
9.4
Demographic and Baseline Characteristics...............................................12
9.5
Efficacy Analyses......................................................................................12
9.5.1
Analyses of Primary Efficacy Endpoint(s) ..................................12
9.5.2
Analyses of Secondary Efficacy Endpoint(s)..............................12
9.5.3
Analyses of Exploratory Efficacy Endpoint(s).............................12
9.6
Safety Analyses ........................................................................................12
9.6.1
Analyses of Safety Endpoints....................................................12
9.6.2
Adverse Events .........................................................................12
9.6.3
Laboratory Test Results.............................................................14
9.6.4
Vital Signs .................................................................................14
9.6.5
Physical Measurements.............................................................14
9.6.6
Electrocardiogram .....................................................................14
9.6.7
Antibody Formation ...................................................................15
9.6.8
Exposure to Investigational Product ..........................................15
9.6.9
Exposure to Other Protocol-specified Treatment .......................15
9.6.10
Exposure to Concomitant Medication ........................................15
9.7
Other Analyses..........................................................................................15
9.7.1
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints.........................15
9.7.2
Analyses of Clinical Outcome Assessments ..............................15
9.7.3
Analyses of Health Economic Endpoints ...................................15
9.7.4
Analyses of Biomarker Endpoints..............................................15
10.
Changes From Protocol-specified Analyses..........................................................15
11.
Literature Citations / References...........................................................................16
12.
Prioritization of Analyses.......................................................................................16
13.
Data Not Covered by This Plan.............................................................................16
14.
Appendices...........................................................................................................17
Appendix A.  Reference Values/Toxicity Grades...................................................18
List of Tables
Table 1.  Imputation Rules for Incomplete Dates ...........................................................10
Table 2.  Safety Endpoints for Treatment-emergent Adverse Events.............................14
Table 3.  Anti-denosumab Antibody...............................................................................15


Product:  Denosumab
Protocol Number:  20110113
Date:  27 August 2018
Page 4 of 18
CONFIDENTIAL
List of Abbreviations and Definition of Terms
Abbreviation or Term
Definition/Explanation
AE
Adverse event
AFF
Atypical femoral fracture
CRF
Case report form
CTCAE
Common Terminology Criteria for Adverse Events
EDC
Electronic data capture
GSO-DM
Global Study Operations-Data Management
IP
Investigational product
IPD
Important protocol deviation
IVRS
Interactive voice response system
MedDRA
Medical Dictionary for Regulatory Activities 
mg/dL
Milligrams per deciliter
mmol/L
Millimole per liter
ONJ
Osteonecrosis of the jaw
Q4W
Every 4 weeks
SAP
Statistical analysis plan
SC
Subcutaneous
SOC
System organ class


Product:  Denosumab
Protocol Number:  20110113
Date:  27 August 2018
Page 5 of 18
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 20110113, Denosumab
dated 22 February 2013. The scope of this plan includes the final analysis that is
planned and will be executed by the Amgen Global Biostatistical Science department 
unless otherwise specified.
2.
Objectives, Endpoints and Hypotheses
2.1
Objectives and Endpoints
Objectives
Endpoints
Primary

To facilitate the access of denosumab 
for subjects with advanced cancer 
who have participated in a 
denosumab phase 3 study until 
denosumab is approved and available 
for sale.
Secondary Safety

To further assess the safety of 
denosumab for subjects who have 
participated in open label extensions 
of a denosumab advanced cancer 
phase 3 study.

Subject incidence of treatment-
emergent adverse events (AEs)

Subject incidence of anti-denosumab
antibody (binding and neutralizing) 
formation
2.2
Hypotheses and/or Estimations
A formal statistical hypothesis will not be tested or estimated.
3.
Study Overview
3.1
Study Design
This is an open-label, single-arm access protocol for subjects with advanced cancer.
Subjects will be offered open-label denosumab at a dose of 120 mg SC Q4W until 
denosumab is approved and available for sale.
Amgen may end this study prior to 
denosumab being approved and available for sale if another mechanism is identified to
provide denosumab to ongoing subjects, or as otherwise stated in Section 12.1 of the
protocol 20110113.
Severe hypocalcemia can occur in subjects receiving denosumab. Calcium levels should 
be monitored as part of routine clinical practice. It is strongly recommended that all 
subjects receive daily supplements of at least 500 mg calcium and at least 400 IU of


Product:  Denosumab
Protocol Number:  20110113
Date:  27 August 2018
Page 6 of 18
CONFIDENTIAL
vitamin D, unless documented hypercalcemia (albumin-adjusted serum calcium
> 2.9 mmol/L [11.5 mg/dL] or ionized calcium > 1.5 mmol/L [6.0 mg/dL]) develops on 
study. 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.
Osteonecrosis of the jaw (ONJ) can occur in subjects receiving denosumab. Subjects
should be monitored for ONJ as part of routine clinical practice. Subjects should be
instructed to maintain good oral hygiene, and avoid invasive dental procedures, if
possible.
3.2
Sample Size
The statistical reporting of the study endpoints will be entirely descriptive (summary 
statistics), with no formal statistical hypothesis tested or estimated. The number of
subjects will be determined by the number of subjects who qualify for the protocol. It is
estimated that up to approximately 400 subjects will participate in this study.
3.3
Adaptive Design
Not applicable.
4.
Covariates and Subgroups
4.1
Planned Covariates
Not applicable.
4.2
Subgroups
Not applicable.
5.
Definitions
Basic Definitions

Investigational Product (IP)
IP for this study refers to denosumab.

IVRS
An IVRS (interactive voice response system) will be used in this study to assign eligible 
subjects to IP as well as to manage IP supply at the site and track subject study
termination data.


Product:  Denosumab
Protocol Number:  20110113
Date:  27 August 2018
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Study Points of Reference

Study Day 1
The date of the first IP administration after enrollment or the date of enrollment for
subjects who are not administrated any dose of IP during this study.

Study Day
The number of days from the study day 1 to a date of interest, inclusive: Study day =
(date of interest – study day 1) + 1.
Study Dates

Informed Consent Date
The informed consent date is the date on which the subject signs the informed consent
for this study.

Enrollment Date
The enrollment date is the date on which a subject is registered as enrolled in the study
through the IVRS system.

First Dose Date
The first dose date is the date on which a subject is administered the first dose of the IP
in this study.

Last Dose Date
The last dose date is the date on which a subject is administered the final dose of the IP 
in this study.

End of Study Date for a Subject
The end of study date is the date recorded on the End of Study page of the Case Report
Form (CRF) for an enrolled subject.
Study Time Intervals

Screening period
The screening period for a subject is defined as the time from the informed consent date
to the day of enrollment.


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Protocol Number:  20110113
Date:  27 August 2018
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
On-Study Period
For the final analysis, the on-study period for an enrolled subject is defined as the time
from the day of enrollment to the end of study date on the CRF.
Subject Dispositions

Enrolled
Individuals are considered enrolled if they have a non-missing date of enrollment.
Enrolled individuals are referred to as “subjects”.

On-Study
Subjects are considered on-study during the period between the date of enrollment and
the end of study date on the CRF.

Exposed to Investigational Product
Subjects are considered as exposed to IP if they have received one or more non-zero
doses of IP in this study.
Derived Variables

Subject Incidence Rate
The subject incidence rate for a given event is defined as the number of subjects with 
one or more reported occurrence of the event divided by the number of subjects who 
have the opportunity to report the event.

Subject Age at Study Entry
Age at study entry is defined as the number of whole years from a subject’s birth date to
the enrollment date as calculated in the Electronic Data Capture (EDC) RAVE 
database.

Subject-years on Study for Safety Analysis
The sum of days on study (the end of study date on the CRF – first dose date +1) for all 
subjects in the safety analysis set divided by 365.25.

Subject-year Adjusted Adverse Event Rate
The number of AEs reported in the given time period divided by total subject-years
on study during the period. 


Product:  Denosumab
Protocol Number:  20110113
Date:  27 August 2018
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6.
Analysis Sets
Subjects will be excluded from all analyses and all data subsets if properly 
documented informed consent was not obtained. These subjects will be 
identified, and safety data for these subjects will be provided separately in the 
clinical study report.
6.1
Full Analysis Set
This subset includes all subjects who are enrolled in this study, except for data 
collected from subjects without properly documented informed consent as 
described above.
6.2
Safety Analysis Set
This subset includes all subjects who are enrolled and received at least one dose of 
IP in this study, except for data collected from subjects without properly documented 
informed consent as described above.
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)
Not applicable.
7.
Planned Analyses
Only final analysis will be conducted.
7.1
Interim Analysis and Early Stopping Guidelines
No interim analysis is planned for this study.
7.2
Primary Analysis
No primary analysis is planned for this study.
7.3
Final Analysis
Final analysis will be conducted after all subjects complete/discontinue the study.


Product:  Denosumab
Protocol Number:  20110113
Date:  27 August 2018
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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. Any
questionable values or situations will be reported to Clinical Data Management for review
or confirmation.
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 EDC RAVE
database.
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 below describing what
will be done when data are missing may be refined during the review of the data.
Incomplete AE start dates will be imputed as described in Table 1. If the start date is
completely missing, default to study day 1 if the indicator of “Did event start before 
the first dose of investigational product” is checked as “No”. Partial dates will be 
listed as is on the listings.
Table 1. Imputation Rules for Incomplete Dates
Missing
Imputation
Exception
AE start
date
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
If a death date is incomplete and missing only the day field, the partial death date (also 
end of IP or end of study date if death is the reason for discontinuation) will be 
imputed as follows: if the latest assessment for this subject is before the month of the 
death, it will be imputed as the first day of the month; if the latest assessment is within 
the same month as the death, it will be imputed using this latest assessment date.
8.4
Detection of Bias
Not applicable.


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Protocol Number:  20110113
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8.5
Outliers
Not applicable.
8.6
Distributional Characteristics
Not applicable.
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.
9.
Statistical Methods of Analysis
9.1
General Considerations
The statistical analysis in this study will be entirely descriptive. Continuous variables will 
be summarized using descriptive statistics, which includes the number of non-missing
observations (n), the mean, standard deviation, median, 25th and 75th percentiles, 
minimum, and maximum. The minimum and maximum will be reported using the same
precision as the original measurement. The mean, median, other selected percentiles
and standard deviation will be reported to one decimal place more than the precision of
the original measurement. Descriptive statistics provided for categorical outcomes will 
include the frequency and percentage.
The analyses of safety endpoints will be based on the safety analysis set defined in
Section 6.2.
9.2
Subject Accountability
For all enrolled subjects, the number and percentage achieving the planned 
assessments listed below will be tabulated:

Subject enrollment by geographic region, country and site

Number and percentage exposed to IP

Number and percentage enrolled, but not exposed to IP

Number and percentage discontinuing IP administration by reason

Number and percentage of subjects discontinuing study by reason

Important on-study protocol deviations
Listings will be provided for important protocol deviations for all enrolled subjects.


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Protocol Number:  20110113
Date:  27 August 2018
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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.  The final IPD list is used to
produce the Summary of IPDs table and the List of Subjects with IPDs. 
9.4
Demographic and Baseline Characteristics
Descriptive statistics will be tabulated for demographics as listed below on all enrolled 
subjects in this study.

Gender

Age at study entry (year)

Age group (18 - 64 years, 65 - 74 years, 75 - 84 years, ≥ 85 years)

Ethnic group/Race
9.5
Efficacy Analyses
Not applicable.
9.5.1
Analyses of Primary Efficacy Endpoint(s)
Not applicable.
9.5.2
Analyses of Secondary Efficacy Endpoint(s)
Not applicable.
9.5.3
Analyses of Exploratory Efficacy Endpoint(s)
Not applicable.
9.6
Safety Analyses
9.6.1
Analyses of Safety Endpoints
Safety analyses in this study will include assessments of treatment-emergent
AEs, AEs of interest, and immunogenic response. The following sections
summarize the analysis methods for these safety endpoints. The safety
analysis set defined in Section 6.2 will be used in these analyses.
In addition, IP exposure will also be summarized.
9.6.2
Adverse Events
The Medical Dictionary for Regulatory Activities (MedDRA) version 20 or later will be 
used to code all AEs. Treatment-emergent AEs are events with an onset after the 
administration of the first dose of IP in this study. Based on the AE summary 


Product:  Denosumab
Protocol Number:  20110113
Date:  27 August 2018
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instructions, an AE that exists prior to the administration of IP and gets worse after the
first dose of IP will be included as a treatment-emergent AE.
The analysis of AEs will be descriptive. For treatment-emergent AEs, serious AEs, 
CTCAE grades 3, 4, and 5 AEs, fatal AEs, AEs leading to IP discontinuation or 
study discontinuation,  and serious AEs leading to IP discontinuation or study 
discontinuation listed in Table 2, subject incidence will be summarized by system
organ class (SOC) and preferred term, and by preferred term only. Subject 
incidence for treatment-emergent AEs by SOC, preferred term and worst grade 
will be tabulated. Subject-year adjusted adverse event rates will be summarized for
treatment-emergent AEs, serious AEs, and CTCAE grades 3, 4, and 5 AEs by SOC 
and preferred term, and by preferred term only. Summary tables for investigator
determined IP related treatment-emergent AEs will be provided by preferred term 
only. In addition, subject incidence for treatment-emergent AEs and serious AEs by
SOC and preferred term will be summarized by time period (e.g., 0 - 6 months, >6 –
12 months, >12 months). 
Events of interest (EOIs), including AEs of hypocalcaemia, infections and 
infestations, ONJ, osteonecrosis excluding the jaw, new primary malignancy, 
cardiac/vascular disorders, atypical femur fracture (AFF), musculoskeletal pain,
and AEs potentially associated with hypersensitivity will be summarized. Subject 
incidence of treatment-emergent AEs and SAEs of these EOIs will be tabulated 
at the EOI level and preferred term level.
Osteonecrosis of the Jaw Adjudication
All subjects with an oral AE suspicious of ONJ should be examined by a 
dentist or other qualified oral specialist (e.g., oral surgeon). Potential events of 
ONJ are identified by: a) obtaining the available information from investigators 
on pre-specified oral event terms including those specifically reported as 
ONJ; b) regular assessment of the clinical trial database to detect 
maxillofacial events which might be indicative of ONJ; c) review and 
assessment of all these events by an independent adjudication committee.  
All adjudicated positive ONJ events with triggering adverse events having 
onset after the administration of the first dose of IP in this study (i.e., the 
treatment-emergent adjudicated positive ONJ) will be included in the analysis 
of EOIs. Subject-year adjusted rate of treatment-emergent adjudicated 


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positive ONJ by time period (e.g., 0 – 12 months, >12 – 24 months, >24 –
36 months, >36 months) will also be presented.
Atypical Femoral Fracture Adjudication
All subjects presenting with new or unusual thigh, hip, or groin pain should be 
evaluated for a suspected AE of AFF. AEs reported as AFF as well as AEs
identified by Amgen as potentially representing AFF will be reviewed by an 
independent adjudication committee of experts to determine whether the 
pre-defined criteria for AFF are met. Amgen will request the investigating site to 
provide all available source documents surrounding that event to be reviewed by 
the adjudication committee. The treatment-emergent adjudicated positive AFF 
events will be included in the analysis of EOIs.
Table 2. Safety Endpoints for Treatment-emergent Adverse Events
Parameter
Time Point
Subject incidence of the following treatment-emergent AEs:
Study day 1 through the 
end of study
All AEs
All investigator determined IP related AEs
CTCAE Grade 3, 4, and 5 AEs
Serious AEs
Fatal AEs
AEs leading to IP discontinuation 
AEs leading to study discontinuation 
Serious AEs leading to IP discontinuation
Serious AEs leading to study discontinuation
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.


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Protocol Number:  20110113
Date:  27 August 2018
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9.6.7
Antibody Formation
Immunogenic response will be described by tabulating the numbers and percentages of 
subjects who tested positive (binding, neutralizing) for anti-denosumab antibodies in 
subjects receiving at least one dose of IP. If a subject tests positive for neutralizing 
antibodies against denosumab, the relationship between the presence of neutralizing 
antibodies and AEs will be evaluated.
Table 3. Anti-denosumab Antibody
Parameter
Time Point
Anti-denosumab Antibody (binding/neutralizing)
End of study visit
9.6.8
Exposure to Investigational Product
Descriptive statistics will be produced to describe the exposure to IP. The number 
of months on study, number of doses received, and cumulative IP exposure will be 
summarized.
9.6.9
Exposure to Other Protocol-specified Treatment
Not applicable.
9.6.10
Exposure to Concomitant Medication
Not applicable.
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.


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Protocol Number:  20110113
Date:  27 August 2018
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11.
Literature Citations / References
None.
12.
Prioritization of Analyses
None.
13.
Data Not Covered by This Plan
None.


Product:  Denosumab
Protocol Number:  20110113
Date:  27 August 2018
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14.
Appendices


Product:  Denosumab
Protocol Number:  20110113
Date:  27 August 2018
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Appendix A.  Reference Values/Toxicity Grades
The Common Terminology Criteria for Adverse Events (CTCAE) are available at the
following link: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf.