Conditions: Breast Cancer
Keywords: Early Stage Breast Cancer Bone Metastasis Adjuvant treatment Neoadjuvant treatment Denosumab Stage II breast cancer Stage III breast cancer Stage IIA breast cancer Stage IIB breast cancer Stage IIIA breast cancer Stage IIIB breast cancer Stage IIIC breast cancer Early breast cancer Breast Tumors Breast Neoplasms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 4509
Healthy volunteers: no

Brief summary:
This randomized phase 3 trial is studying the effect of denosumab to see if it can prevent disease recurrence in the bone or in any other part of the body, when it is given as adjuvant therapy for women with early-stage breast cancer, who are at high risk of disease recurrence.

Detailed description:
Eligible participants were randomized in a 1:1 ratio to receive denosumab 120 mg or placebo subcutaneously (SC) for up to 5 years. Randomization was stratified based on:

1. Breast cancer therapy/lymph node (LN) status: neoadjuvant therapy/any LN status versus adjuvant therapy/LN negative (based on axillary LN dissection, or based on sentinel node status) versus adjuvant therapy/LN positive
2. Hormone receptor (estrogen receptor \[ER\]/progesterone receptor \[PR\]) status: ER and/or PR positive versus ER and PR negative
3. Human epidermal growth factor receptor 2 (HER-2) status: HER-2 positive versus HER-2 negative
4. Age: \< 50 years versus ≥ 50 years
5. Geographic Region: Japan versus Other regions.

The primary analysis was conducted after all enrolled participants had the opportunity to complete 5 years of treatment from study day 1.

Arms:
arm 1: Participants received placebo subcutaneous injections once every 4 weeks for 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years. arm 2: Participants received denosumab 120 mg subcutaneous injections once every 4 weeks for 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.

Interventions: intervention 1: Placebo intervention 2: Denosumab
Intervention descriptions: intervention 1: Administered subcutaneously for up to 5 years intervention 2: Administered subcutaneously for up to 5 years

Protocol document:
SAP_002.pdf: 
Product:  Denosumab 
Statistical Analysis Plan: 20060359
Version 3.0 Addendum Dated: 26 March 2018
Page 1
STATISTICAL ANALYSIS PLAN
A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase 3 Study of 
Denosumab as Adjuvant Treatment for Women with Early-Stage Breast Cancer at 
High Risk of Recurrence (D-CARE)
Protocol Number 20060359
Version:
3.0 Addendum
Date:
26 March, 2018
Authors:
PPD
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Product:  Denosumab 
Statistical Analysis Plan: 20060359
Version 3.0 Addendum Dated: 26 March 2018
Page 2
Table of Contents
Table of Abbreviations.....................................................................................................3
1.
Introduction.............................................................................................................4
2.
Study Endpoints .....................................................................................................4
2.1
Efficacy Endpoint ........................................................................................4
2.2
Safety Endpoints.........................................................................................5
3.
Statistical Methods of Analysis................................................................................5
3.1
Subject Accountability .................................................................................5
3.2
Efficacy Analyses........................................................................................5
3.3
Safety Analyses ..........................................................................................6


Product:  Denosumab 
Statistical Analysis Plan: 20060359
Version 3.0 Addendum Dated: 26 March 2018
Page 3
Table of Abbreviations
Abbreviation
Definition
AE
adverse event
AFF
atypical femoral fracture
CRF
case report form
CTCAE
common terminology criteria for adverse Events
EOI
event of interest
EOTP
end of treatment phase
IP
investigational product
LTFU
long-term follow-up
MedDRA
medical dictionary for regulatory activities
ONJ
osteonecrosis of the jaw
PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan


Product:  Denosumab 
Statistical Analysis Plan: 20060359
Version 3.0 Addendum Dated: 26 March 2018
Page 4
1.
Introduction
The primary analysis for Amgen protocol 20060359, entitled “A Randomized, 
Double-Blind, Placebo-Controlled, Multi-Center Phase 3 Study of Denosumab as 
Adjuvant Treatment for Women with Early-Stage Breast Cancer at High Risk of 
Recurrence (D-CARE)”, was performed based on data collected through the primary 
analysis data cut-off date, 31 August 2017, according to the statistical analysis plan 
(SAP) version 3.0 dated on 15 November 2017. According to the protocol amendment 4
dated on 17 October 2016, all subjects on study at the primary analysis data cut-off date 
completed the end of treatment phase (EOTP) visit and entered in the long-term 
follow-up (LTFU) phase after the primary analysis data cut-off date.
In early 2018, 
Amgen decided to close the study in April 2018 and carry out the final analysis, 
specifically the final database lock was planned on 12 April 2018.
This addendum to 
SAP version 3.0 describes the data analysis plan for conducting the final analysis. The 
efficacy and safety data collected through the final database lock are included in this 
analysis.
2.
Study Endpoints 
Per the study design (please refer to protocol amendment 4 Section 7.1.4.2 and 
SAP version 3.0 Section 3.1), following the primary analysis data cut-off date, all 
subjects should complete the EOTP visit and would be followed by clinic visit or 
telephone contact every 6 months (± 1 month) for survival only. Study endpoints to be 
analyzed in the final analysis are listed as follows.
2.1
Efficacy Endpoint
Endpoint
Analysis Time Period
Overall survival (determined by the time from 
randomization to death from any cause) 
Randomization through the final database 
lock


Product:  Denosumab 
Statistical Analysis Plan: 20060359
Version 3.0 Addendum Dated: 26 March 2018
Page 5
2.2
Safety Endpoints
Parameter
Analysis Time Period
Treatment-emergent adverse events (AEs):
Unless otherwise specified, the 
analysis time period is from study 
day 1 through 30 days after the 
last dose of IP or the final 
database lock, whichever is earlier
All AEs
Serious AEs (SAEs)
Fatal AEs
CTCAE Grade 3, 4, and 5 AEs
AEs leading to investigational product (IP)  
discontinuation 
AEs leading to study discontinuation
New AEs reported after the primary analysis
Changed AEs with changes in reported AE term 
and/or serious flag after the primary analysis
Adverse events of interest (EOIs)
Note: The Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 or higher will be used.
3.
Statistical Methods of Analysis
This section summarizes the analysis methods for the final analysis.
3.1
Subject Accountability
For all randomized subjects, the number and percentage achieving the planned 
assessments listed below will be tabulated by treatment arm: 

Subjects who enrolled study, subjects who discontinued study by their reasons 
for study discontinuation, subjects with complete follow-up (ie, dead, or known to 
be alive at the end of the study)

Important protocol deviations
In addition, listings will be provided for important protocol deviations and protocol 
inclusion/exclusion deviations.
3.2
Efficacy Analyses
Overall survival will be analyzed using the full analysis set (please refer to 
SAP version 3.0 Section 6.1.1 for the definition of full analysis set). 
Kaplan-Meier estimates of the survival functions will be graphically displayed for each 
treatment group.  Kaplan-Meier quartiles (25th percentile and median) with 2-sided 95% 
confidence intervals will be calculated if applicable. In addition, overall survival time will 
be summarized via displaying number of subjects at risk, the percent of subjects that 
died, and Kaplan-Meier survival rates with 2-sided 95% confidence intervals at year 1, 
year 2, year 3, year 4, and year 5.  


Product:  Denosumab 
Statistical Analysis Plan: 20060359
Version 3.0 Addendum Dated: 26 March 2018
Page 6
A log-rank test stratified by the randomization stratification factors (please refer to
SAP version 3.0 Section 3.1) will be used to compare overall survival of the two 
treatment groups.  The hazard ratio of denosumab compared with placebo and its 
corresponding 2-sided 95% confidence interval will be estimated using a Cox 
proportional hazards model with treatment group as the independent variable and 
stratified by the randomization stratification factors.  
3.3
Safety Analyses 
In safety analyses, the safety analysis set (please refer to SAP version 3.0 Section 6.1.3 
for its definition) will be used, and no statistical testing is planned.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 20.1 or higher. As defined in the SAP version 3.0 Section 9.4.1, 
treatment-emergent AEs are events occurred during the time period from the first dose 
date (AEs are excluded if the indicator of “Did event start before the first dose of 
investigational product?” is checked as “Yes” on Adverse Events Summary CRF pages) 
through 30 days after the last dose of IP.  Based on the AEs summary instructions, an 
AE that exists prior to the administration of IP and gets worse during the time period 
defined above will be included as a treatment-emergent AE. Unless otherwise specified, 
all AE related analyses are based on treatment-emergent AEs. 
For all AEs, SAEs, grade ≥ 3 (ie, CTCAE grade 3, 4, and 5) AEs, fatal AEs, AEs leading 
to discontinuation of IP or study, as listed in Section 2.2, subject incidence will be 
summarized. Subject incidence by system organ class, high level term and preferred 
term (PT) will be tabulated for all AEs, SAEs, and fatal AEs. In addition, listings will be 
provided for new AEs reported after the primary analysis, and the changed AEs with 
changes in reported AE term and/or serious flag after the primary analysis.
For EOIs, including AEs of hypocalcaemia, osteonecrosis of the jaw (ONJ), new primary 
malignancy, atypical femur fracture (AFF), cardiac/vascular disorders, infections and 
infestations, AEs potentially associated with hypersensitivity, osteonecrosis excluding 
the jaw, musculoskeletal pain, and hypercalcemia occurred after 30 days following 
discontinuation of IP, subject incidence of AEs and SAEs will be tabulated.


Product:  Denosumab 
Statistical Analysis Plan: 20060359
Version 3.0 Addendum Dated: 26 March 2018
Page 7

All adjudicated positive ONJ events with triggering AEs having onset dates up to
the final database lock will be included in the analysis. The proportion of 
subjects experiencing adjudicated positive ONJ will be summarized. Subject-year 
adjusted incidence rate of adjudicated positive ONJ by incremental time period 
(0-12 months, >12 - 24 months, >24 - 36 months, >36 - 48 months, >48 months) 
will be presented. A Kaplan-Meier plot for time to first adjudicated positive ONJ 
will be provided.

AEs that are adjudicated as positive for AFF and have onset dates up to the final
database lock will be included in the analysis. The proportion of subjects 
experiencing adjudicated positive AFF will be summarized. Subject-year adjusted 
incidence rate of adjudicated positive AFF by incremental time period 
(0-12 months, >12 - 24 months, >24 - 36 months, >36 - 48 months, >48 months) 
will be presented. A Kaplan-Meier plot for time to first adjudicated positive AFF 
will be provided.

Prot_000.pdf: 
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Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 1 of 56 
CONFIDENTIAL 
 
 
Amendment 4 
Protocol Title:  A Randomized, Double-Blind, Placebo-Controlled, Multi-Center 
Phase 3 Study of Denosumab as Adjuvant Treatment for Women with Early-Stage 
Breast Cancer at High Risk of Recurrence (D-CARE) 
 
Amgen Protocol Number (Denosumab) 20060359 
IND # 9838 
EudraCT number 2009-011299-32 
 
Amendment Date: 
17 October 2016 
Rationale: 
The D-CARE study has been ongoing since January 2010.  During the course of the 
study, a considerable gap developed between the expected and observed number of 
BMFS as well as DFS events (primary and secondary endpoints, respectively).  There 
are several reasons that may explain the divergence of the observed event rate from the 
expected event rate. 
Epidemiologic studies have demonstrated that the recurrence risk in breast cancer is 
highest during the first 3 to 5 years, with a peak at about 18 months after diagnosis 
(Cheng et al, 2012; Demicheli et al, 1996).  During initial protocol development, a linear 
event rate was assumed.  Furthermore, in recent years, the adoption of more effective 
therapies, including optimization of aromatase inhibitor therapy for hormone-positive 
disease and the widespread use of anti-HER2 therapy for HER2 positive breast cancer, 
may have contributed to lower disease recurrence overall. 
Based on the current BMFS event total and BMFS event rate, there will be a substantial 
delay in the time to reach the BMFS event target for the primary analysis, and there is 
considerable risk of continued delays.  Moreover, based on the DFS event total and 
event rate, it appears that the DFS event target required for the primary analysis will not 
be reached at all.  The D-CARE steering committee, an advisory group of key 
investigators participating in the study, recommended that a landmark primary analysis 
triggered when all enrolled subjects have the opportunity to complete 5 years of 
treatment on investigational product would be the best approach for the study analysis 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 2 of 56 
CONFIDENTIAL 
 
 
given the considerable challenges to achieving event targets.  The 5-year mark is also 
typically used in clinical trials. 
Therefore, this protocol is being amended to: 
• 
Change the primary analysis from an event-driven analysis to a landmark 
(time-based) analysis, triggered when all subjects have the opportunity to complete 
5 years treatment with investigational product. 
• 
Remove the second interim analysis from the study to avoid the situation whereby 
the primary analysis and second interim analysis occur within a short period of time. 
• 
Remove the open-label phase from the study.  The open-label period would only 
apply if during the course of the blinded treatment phase, denosumab was 
determined to be superior and have a positive benefit/risk profile compared to 
placebo.  The read-out would occur at the interim analyses.  Because the second IA 
was removed, the open-label period is also removed since all subjects will have 
completed the blinded study treatment prior to the primary analysis. 
• 
Redefine long-term follow-up visit frequency and assessments before and after the 
primary analysis cut-off date to avoid unnecessary data collection and burden to 
sites and subjects. 
• 
Update protocol to align with the current protocol template, such as, safety definition 
and reporting language (as well as pregnancy and lactation reporting forms), and 
publication policy. 
 
 
 


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Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 4 of 56 
CONFIDENTIAL 
 
 
Section:  Title Page 
Add: 
Amendment 4 Date: 
 
17 October 2016 
Section:  Investigator’s Agreement, For Japanese Sites Only 
Replace: Vice President,  
 
Clinical Development Department II 
 
R&D Division, Daiichi Sankyo Co., Ltd. 
With: 
Vice President,  
 
Oncology Clinical Development Department 
 
Daiichi Sankyo Co., Ltd. 
Section:  Synopsis, Study Design, Paragraph 2 
Add: 
Subjects who develop bone metastasis will permanently discontinue 
investigational treatment, complete the End of Treatment Phase (EOTP) visit, 
and enter long-term follow-up (LTFU) upon documented evidence (per 
central imaging analysis or biopsy).  For an individual subject, the 
maximum duration of LTFU after completing the EOTP visit is 5 years 
(total study duration for an individual subject is up to 10 years from the 
date of randomization). 
Section:  Synopsis, Study Design, Paragraph 3 
Delete: 
After completing the treatment phase of the study, subjects will be followed 
by clinic visit or telephone contact approximately monthly for 6 months to 
assess clinical outcomes, approximately every 3 months thereafter to assess 
SREs, hypercalcemia, disease recurrence status, and survival (until 
documented evidence of bone metastasis), and approximately every 6 
months thereafter to assess SREs, hypercalcemia, and survival, for up to 10 
years (120 months) from the date of randomization. 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 5 of 56 
CONFIDENTIAL 
 
 
Section:  Synopsis, Study Design, Paragraphs 4 and 5 
Replace: A data monitoring committee (DMC) external to Amgen and external to 
Daiichi Sankyo Co., Ltd. will review safety data at regular intervals, as 
outlined in the DMC charter (approximately twice yearly; the start date will 
depend on subject accrual rates), and will conduct two interim analyses of 
efficacy; the first after approximately 367 subjects have developed bone 
metastasis or died, and approximately 555 subjects have developed any 
disease recurrence or died, whichever comes last; and the second after 
approximately 551 subjects have developed bone metastasis or died, and 
approximately 833 subjects have developed any disease recurrence or died, 
whichever comes last.  The respective interim analyses may be conducted 
early, as soon as approximately 6 months after the sufficient event number 
has been reached for either BMFS or DFS in the full study population, even if 
the event number for the other endpoint has not been reached. 
 
The primary analysis will be conducted after approximately 735 subjects have 
developed bone metastasis or died, and approximately 1110 subjects in the 
full study population and 512 subjects in the postmenopausal subset have 
developed any disease recurrence or died, whichever comes last.  Subjects 
will remain on blinded treatment until the primary analysis is completed.  If 
denosumab is determined to be superior and have a positive benefit/risk 
profile compared with placebo, then all subjects, who remain on blinded study 
treatment, will be offered open-label denosumab 120 mg SC according to 
their scheduled study procedures, for a total treatment duration of 5 years 
from their date of first dose of investigational product (study day 1), or until 
documented evidence of bone metastasis (per investigator report), or until 
denosumab is commercially available for the treatment of early-stage breast 
cancer, whichever comes first.  If denosumab is not determined to have a 
positive benefit/risk profile compared with placebo, then all subjects will 
complete the EOTP visit and enter follow-up for survival (approximately every 
6 months for up to 10 years [120 months] from the date of randomization). 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 6 of 56 
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With: 
A data monitoring committee (DMC) external to Amgen and external to 
Daiichi Sankyo Co., Ltd. will review safety data at regular intervals, as 
outlined in the DMC charter (approximately twice yearly; the start date will 
depend on subject accrual rates), and will conduct 1 interim analysis of 
efficacy after approximately 367 subjects have developed bone metastasis or 
died, and approximately 555 subjects have developed any disease 
recurrence or died, whichever comes last.  This interim analysis may be 
conducted early, as soon as approximately 6 months after the sufficient event 
number has been reached for either BMFS or DFS in the full study 
population, even if the event number for the other endpoint has not been 
reached. 
 
The primary analysis will be conducted after all enrolled subjects have had 
the opportunity to complete 5 years of treatment from study day 1. 
Section:  Synopsis, Investigational Product Dosage and Administration, Paragraph 4 
Delete: 
Subjects will remain on blinded treatment until the primary analysis is 
completed.  If denosumab is determined to be superior and have a positive 
benefit/risk profile compared with placebo, then all subjects, who remain on 
blinded study treatment, will be offered open-label denosumab 120 mg SC 
according to their scheduled study procedures, for a total treatment duration 
of 5 years from their first dose of investigational product (study day 1), or until 
documented evidence of bone metastasis (per investigator report), or until 
denosumab is commercially available for the treatment of early-stage breast 
cancer, whichever is earlier.  If denosumab is not determined to have a 
positive benefit/risk profile compared with placebo, then all subjects will 
complete the EOTP visit and enter follow-up for survival (approximately every 
6 months for up to 10 years [120 months] from the date of randomization). 
Section:  Synopsis, Investigational Product Dosage and Administration, Paragraph 4 
Add: 
Administration of investigational products (denosumab or placebo) will be 
withheld for any subject who experiences a grade 3 or 4 adverse event per 
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 
reported by the investigator as related to investigational product, atypical 
femoral fracture (AFF) or osteonecrosis of the jaw (ONJ), as determined by 
the investigator or by an independent expert panel. 
 
 
 


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Protocol Number:  20060359 
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Section:  Synopsis, Key Study Procedures, Paragraph 4 
Replace: Treatment and Follow-up: Subjects will receive investigational product for up 
to 5 years from study day 1 (treatment period), and will then be followed by 
clinic visit or telephone contact approximately monthly (Q4W ± 7 days) for 
six months to assess clinical outcomes (SREs, hypercalcemia of malignancy, 
concomitant medications, breast cancer therapy, patient-reported outcomes 
[BPI-SF, EQ-5D], disease recurrence status [until documented evidence of 
bone metastasis], and survival), approximately every 3 months (every 
12 weeks ± 14 days) thereafter to assess SREs, hypercalcemia, disease 
recurrence status, and survival (until documented evidence of bone 
metastasis), and approximately every 6 months (± 1 month) thereafter to 
assess SREs, hypercalcemia, and survival, for up to 10 years (120 months) 
from the date of randomization. 
With: 
Treatment and Follow-up:  Subjects will receive investigational product for up 
to 5 years from study day 1 (treatment period), and will then enter LTFU for 
approximately 5 years (60 months) following the EOTP visit.  The 
expected total study duration for an individual subject is up to 10 years 
from the randomization date. 
Section:  Synopsis, Key Study Procedures, Paragraph 7 
Delete: 
Blinded Treatment Phase:  The following assessments will be performed at 
various visits (see Appendix A): 
Section:  Synopsis, Key Study Procedures, Paragraph 8 
Delete: 
Open-Label Treatment Phase: The following assessments will be performed 
at various visits (see Appendix A): ECOG performance status; physical 
examination including vital signs (temperature, pulse, blood pressure, 
respiratory rate) and weight; oral examination; clinical fractures and SREs; 
breast cancer therapy; concomitant medications; hematology; serum 
chemistry; denosumab PK (subjects participating in the PK substudy who 
received blinded denosumab on study); anti-denosumab antibodies.  Adverse 
events and concomitant medications will be recorded throughout the study. 
 
 
 


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Section:  Synopsis, Statistical Considerations, Paragraph 1 
Replace: The key secondary objective is to compare the treatment effect of 
denosumab with that of placebo on prolonging DFS in the full study 
population or in the postmenopausal subset. 
With: 
The key secondary objective is to compare the treatment effect of 
denosumab with that of placebo on prolonging DFS in the full study 
population and in the postmenopausal subset. 
Section:  Synopsis, Statistical Considerations, Paragraphs 2 to 3 
Replace: Key efficacy analyses: Two interim analyses of efficacy will be conducted; the 
first after approximately 367 subjects have developed bone metastasis or 
died, and approximately 555 subjects in the full study population have 
developed any disease recurrence or died, whichever comes last; and the 
second after approximately 551 subjects have developed bone metastasis or 
died, and approximately 833 subjects in the full study population have 
developed any disease recurrence or died, whichever comes last.  The 
respective interim analyses may be conducted early, as soon as 
approximately 6 months after the sufficient event number has been reached 
for either BMFS or DFS in the full study population, even if the event number 
for the other endpoint has not been reached. 
 
The primary analysis will be performed after approximately 735 subjects have 
developed bone metastasis or died, and approximately 1110 subjects in the 
full study population and approximately 512 subjects in the postmenopausal 
subset have developed any disease recurrence or died, whichever comes 
last. 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 9 of 56 
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With: 
Key efficacy analyses:  One interim analysis of efficacy will be conducted; 
after approximately 367 subjects have developed bone metastasis or died, 
and approximately 555 subjects in the full study population have developed 
any disease recurrence or died, whichever comes last.  This interim analysis 
may be conducted early, as soon as approximately 6 months after the 
sufficient event number has been reached for either BMFS or DFS in the full 
study population, even if the event number for the other endpoint has not 
been reached. 
 
The primary analysis will be conducted after all enrolled subjects have 
had the opportunity to complete 5 years of treatment from study day 1. 
 
 
 
 


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Section:  Study Schema 
Replace: 
 
 
 
 
 


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Protocol Number:  20060359 
Date:  17 October 2016 
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With: 
 
 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
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Section:  Study Glossary 
Add: 
EU 
European Union 
LTFU 
Long-term follow-up 
Section:  Study Glossary 
Replace: 
Primary Analysis Data 
Cut-off Date 
(primary completion) 
Amgen will set a primary analysis data cut-off date in anticipation of 
approximately 735 subjects having developed bone metastasis or 
died, and approximately 1110 subjects in the full study population 
and 512 subjects in the postmenopausal subset having developed 
any disease recurrence or died, whichever comes last.  The primary 
analysis will be based on the data from randomization through the 
primary analysis data cut-off date. 
With: 
Primary Analysis Data 
Cut-off Date 
(primary completion) 
Amgen will set a primary analysis data cut-off date in anticipation of 
all enrolled subjects having had the opportunity to complete 
5 years of treatment from study day 1.  The primary analysis will 
be based on the data from randomization through the primary 
analysis data cut-off date. 
Section:  Study Glossary 
Delete: 
End of Blinded Treatment 
Phase  
(for the clinical study) 
If denosumab is determined to be superior and have a positive 
benefit/risk profile compared with placebo, then the end of the 
blinded treatment phase is defined as approximately 12 weeks after 
the last dose of investigation product in the blinded treatment phase.  
If the benefit/risk profile is not positive, then the end of the blinded 
treatment phase is defined as approximately 4 weeks after the last 
dose of denosumab in the blinded treatment phase. 
Open-Label Treatment 
Phase 
If denosumab is determined to be superior and have a positive 
benefit/risk profile compared with placebo, then all subjects, who 
remain on blinded study treatment, will be offered open-label 
denosumab 120 mg SC according to their scheduled study 
procedures, for a total treatment duration of 5 years (approximately 
60 months) from their study day 1, or until documented evidence of 
bone metastasis (per investigator report), or until denosumab is 
commercially available for the treatment of early-stage breast 
cancer, whichever comes first. 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
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Page 13 of 56 
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Section:  Study Glossary 
Delete: 
End of Treatment Phase 
(EOTP)  
(for an individual 
participant) 
An individual subject may receive investigational product for up to 
5 years (ie, 60 months) from the day of first dose of investigational 
product (study day 1), or until documented evidence of bone 
metastasis (per central imaging analysis or biopsy), or (for subjects 
on open-label denosumab only) until documented evidence of bone 
metastasis (per investigator report), or until denosumab is 
commercially available for the treatment of early-stage breast 
cancer, whichever is earlier.  See Section 3.4.1. 
Section:  2.6.  Hypotheses, Paragraph 2 
Replace: It is anticipated that the true HR of denosumab compared with placebo is 
0.83 in the full study population or in the postmenopausal subset. 
With: 
It is anticipated that the true HR of denosumab compared with placebo is 
0.83 in the full study population and 0.76 in the postmenopausal subset. 
Section:  3.1.  Study Design, Paragraph 1 
Delete: 
Approximately 4,500 subjects will be randomized in a 1:1 ratio to receive 
denosumab 120 mg or matching placebo SC Q4W (± 7 days) for 
approximately 6 months followed by denosumab 120 mg or matching placebo 
SC every Q3M (ie, every 12 weeks ± 14 days) for 4½ years (approximately 
54 months), for a total treatment duration of 5 years (approximately 
60 months), or until the end of the blinded treatment phase, whichever is 
earlier. 
Section:  3.1.  Study Design, Paragraphs 3 to 4 
Replace: A data monitoring committee (DMC) external to Amgen and external to 
Daiichi Sankyo Co., Ltd. will review safety data at regular intervals, as 
outlined in the DMC charter (approximately twice yearly; the start date will 
depend on subject accrual rates).  This external DMC will conduct two interim 
analyses of efficacy; the first after approximately 367 subjects have 
developed bone metastasis or died, and approximately 555 subjects have 
developed any disease recurrence or died, whichever comes last; and the 
second after approximately 551 subjects have developed bone metastasis or 
died, and approximately 833 subjects have developed any disease 
recurrence or died, whichever comes last.  To ensure timely conduct of the 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
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respective interim analyses, the interim analyses may be conducted early, as 
soon as approximately 6 months after the sufficient event number has been 
reached for either BMFS or DFS in the full study population, even if the event 
number for the other endpoint has not been reached. 
 
The primary analysis will be conducted after approximately 735 subjects have 
developed bone metastasis or died, and approximately 1110 subjects in the 
full study population and 512 subjects in the postmenopausal subset have 
developed any disease recurrence or died, whichever comes last. Subjects 
will remain on blinded treatment until the primary analysis is completed. If 
denosumab is determined to be superior and have a positive benefit/risk 
profile compared with placebo, then all subjects, who remain on blinded study 
treatment, will be offered open-label denosumab 120 mg SC according to 
their scheduled study procedures, for a total treatment duration of 5 years 
from their day of first dose of investigational product (study day 1), or until 
documented evidence of bone metastasis (per investigator report), or until 
denosumab is commercially available for the treatment of early-stage breast 
cancer, whichever comes first.  If denosumab is not determined to have a 
positive benefit/risk profile compared with placebo, then all subjects will 
complete the EOTP visit and enter follow-up for survival (approximately every 
6 months for up to 10 years [120 months] from the date of randomization). 
With: 
A data monitoring committee (DMC) external to Amgen and external to 
Daiichi Sankyo Co., Ltd. will review safety data at regular intervals, as 
outlined in the DMC charter (approximately twice yearly; the start date will 
depend on subject accrual rates).  This external DMC will conduct 1 interim 
analysis of efficacy after approximately 367 subjects have developed bone 
metastasis or died, and approximately 555 subjects have developed any 
disease recurrence or died, whichever comes last.  To ensure timely conduct 
of the interim analysis, the interim analysis may be conducted early, as 
soon as approximately 6 months after the sufficient event number has been 
reached for either BMFS or DFS in the full study population, even if the event 
number for the other endpoint has not been reached. 
 
The primary analysis will be conducted after all enrolled subjects have had 
the opportunity to complete 5 years of treatment from study day 1. 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
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Page 15 of 56 
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Section:  3.3.  Number of Subjects, Paragraph 1 
Delete: 
Participants in this clinical investigation shall be referred to as “subjects”. 
Approximately 2,250 subjects will be randomized to each treatment group, for 
a total planned sample size of approximately 4,500 subjects.  Amgen may 
choose to increase sample size to ensure timely completion of the study, e.g. 
if the event rate is lower than expected. Refer to Section 10.3 for details on 
the rationale for the number of subjects. 
Section:  3.4.1.  Study Duration for Individual Participants, Paragraph 1 
Delete: 
An individual subject may receive investigational product treatment for up to 
5 years (ie, 60 months) from the day of first dose of investigational product 
(study day 1), or until documented evidence of bone metastasis (per central 
imaging analysis or biopsy), or (for subjects on open-label denosumab only) 
until documented evidence of bone metastasis (per investigator report), or 
until denosumab is commercially available for the treatment of early-stage 
breast cancer, whichever is earlier (treatment phase). 
Section:  3.4.1.  Study Duration for Individual Participants, Paragraph 2 
Replace: After completing the treatment phase of the study, subjects will be followed 
by clinic visit or telephone contact approximately monthly (Q4W ± 7 days) for 
six months to assess clinical outcomes.  After the first six months, subjects 
will be followed approximately every 3 months (every 12 weeks ± 14 days) 
thereafter to assess SREs, hypercalcemia, disease recurrence status, and 
survival.  If there is documented evidence of bone metastasis, the frequency 
of follow-up visits will change to approximately every 6 months (± 1 month) to 
assess SREs, hypercalcemia, and survival for up to 10 years (120 months) 
from the date of randomization. 
With: 
After completing the treatment phase of the study, subjects will be followed 
by clinic visit or telephone contact for up to 5 years (60 months) from the 
EOTP visit (total study duration for an individual subject is up to 
10 years from the date of randomization).  Follow-up procedures are 
detailed in Section 7.1.4. 
 
 
 


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Section:  3.4.2.  Duration of the Clinical Study, Paragraph 1 
Replace: The anticipated duration of the blinded treatment phase is approximately 
93 months (ie 7 years and 9 months) from first subject enrolled.  This 
represents time to recruit approximately 4,500 subjects (approximately 
30 months) and time for approximately 735 subjects to experience bone 
metastasis or death, and for approximately 1110 subjects in the full study 
population and 512 subjects in the postmenopausal subset to experience any 
disease recurrence or death, whichever comes last, as well as continued 
blinded treatment until the primary analysis is complete and the benefit/risk 
profile of denosumab is determined.  Actual study duration may vary 
depending on observed event rates. 
With: 
The anticipated duration from first subject enrolled to the primary 
completion of the study is approximately 87 months (ie, 7 years and 
3 months).  This represents time to recruit approximately 4,500 subjects 
(approximately 27 months) and time for all subjects to have the 
opportunity to complete 5 years of blinded treatment. 
Section:  3.4.2.  Duration of the Clinical Study, Paragraph 2 
Delete: 
Amgen will monitor the overall event rate pooled by treatment group, and will 
set a data cut-off date for the primary analysis in anticipation of approximately 
735 subjects having experienced bone metastasis or death, and 
approximately 1110 subjects in the full study population and 512 subjects in 
the postmenopausal subset having experienced disease recurrence or death.  
Amgen may choose to increase the sample size in order to ensure timely 
completion of the study. 
Section:  3.4.2.  Duration of the Clinical Study, Paragraph 2 
Replace: The anticipated overall duration of the clinical study, including the recruitment 
period (approximately 2.5 years [30 months]), the treatment period 
(approximately 5 years [60 months], and the follow-up period (approximately 
5 years [60 months]), will be approximately 12.5 years or approximately 
150 months. 
 
 
 


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With: 
The anticipated overall duration of the clinical study, including the recruitment 
period (approximately 2.5 years [27 months]), the treatment period 
(approximately 5 years [60 months]), and the follow-up period (approximately 
5 years [60 months]), will be approximately 12.5 years or approximately 
150 months. 
Section:  3.4.3.  End of Study (End of the Clinical Study), Paragraph 1 
Replace: Amgen will set a primary analysis data cut-off date in anticipation of 
approximately 735 subjects having developed bone metastasis or died, and 
approximately 1110 subjects in the full study population and 512 subjects in 
the postmenopausal subset having developed any disease recurrence or 
died, whichever comes last.  The primary analysis will be based on the data 
from randomization through the primary analysis data cut-off date and is 
considered the primary completion of the study. 
With: 
The primary analysis will be conducted after all enrolled subjects have 
had the opportunity to complete 5 years of treatment from study day 1.  
The primary analysis will be based on the data from randomization through 
the primary analysis data cut-off date and is considered the primary 
completion of the study. 
Section:  3.4.3.  End of Study (End of the Clinical Study), Paragraph 2 
Replace: The End of Study (End of the Clinical Study) is defined as the date that the 
last subject is assessed in the follow-up phase.  With 30 months of enrollment 
and the last subject anticipated to be on study for 10 years (ie., 120 months), 
the end of study is anticipated to be approximately 12.5 years (ie., 
approximately 150 months) from the first subject enrolled. 
With: 
The End of Study (End of the Clinical Study) is defined as the date that the 
last subject is assessed in the follow-up phase.  With 27 months of enrollment 
and the last subject anticipated to be on study for up to 10 years (ie, 
120 months), the end of study is anticipated to be approximately 12.5 years 
(ie, approximately 150 months) from the first subject enrolled. 
 
 
 


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Section:  6.1.  Investigational Product Dosage, Administration, and Schedule, 
Paragraph 3 
Delete: 
The total treatment duration will be 5 years (approximately 60 months) or until 
the end of the blinded treatment phase, whichever is earlier. 
Section:  6.5.  Dose Escalation and Dose Stopping Rules, Paragraph 2 
Add: 
Administration of investigational product (denosumab or placebo) will be 
withheld for any subject who experiences a grade 3 or 4 adverse event per 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) version 3.0 reported by the investigator as related to 
investigational product, atypical femoral fracture (AFF), or osteonecrosis of 
the jaw (ONJ), as determined by the investigator or by an independent expert 
panel. 
Section:  7.1.2.1.  Study Treatment, Paragraph 1 
Delete: 
Blinded Treatment Phase 
 
Study treatment (investigational product:  denosumab at a dose of 120 mg or 
matching placebo) will be administered by a licensed healthcare professional 
SC Q4W (±7 days, at least 3 weeks apart; see Section 6.1) for approximately 
6 months, followed by investigational product SC Q3M (ie, every 
12 weeks ± 14 days) for 4½ years (approximately 54 months), for a total 
treatment duration of 5 years (approximately 60 months), or until documented 
evidence of bone metastasis (per central imaging analysis or biopsy), or until 
the end of the blinded treatment phase, whichever is earlier.  During the first 
approximate 6 months of treatment, investigational product may be 
administered Q3W to subjects receiving or scheduled to receive Q3W 
adjuvant/neoadjuvant chemotherapy (see Section 6.1).  There must be at 
least a 3-week interval between administrations of investigational product. 
 
Open-Label Treatment Phase 
 
Subjects will remain on blinded treatment until the primary analysis is 
completed.  If denosumab is determined to be superior and have a positive 
benefit/risk profile compared with placebo, then all subjects, who remain on 
blinded study treatment, will be offered open-label denosumab 120 mg SC 
according to their scheduled study procedures, for a total treatment duration 
 
 
 


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of 5 years from their date of first dose of investigational product (study day 1), 
or until documented evidence of bone metastasis (per investigator report), or 
until denosumab is commercially available for the treatment of early-stage 
breast cancer, whichever is earlier. 
Section:  7.1.3.  End of Treatment Phase (EOTP), Paragraphs 2 to 4 
Delete: 
If denosumab is not determined to have a positive benefit/risk profile 
compared with placebo, then all subjects will complete the EOTP visit 4 
weeks (+ 7 days) after their last dose of investigational product.  
 
All EOTP assessments must be completed (unless done within the prior 
4 weeks), except imaging assessments, which do not need to be repeated if 
completed within the prior 6 months (ie, 24 weeks).  
 
If denosumab is not determined to have a positive benefit/risk profile 
compared with placebo, then no imaging will be required at the EOTP visit. 
Section:  7.1.4.  Follow-up Procedures, entire section 
Replace: Blinded Treatment Phase 
 
After completing the treatment phase of the study, subjects will be followed 
by clinic visit or telephone contact approximately monthly (Q4W ± 7 days) for 
six months to assess clinical outcomes (SREs, hypercalcemia of malignancy, 
concomitant medications, breast cancer therapy, patient-reported outcomes 
[BPI-SF, EQ-5D], disease recurrence status [until documented evidence of 
bone metastasis {per central imaging analysis or biopsy}] and survival) and 
approximately every 3 months (every 12 weeks ± 14 days) thereafter to 
assess SREs, hypercalcemia, disease recurrence status, and survival (until 
documented evidence of bone metastasis [per central imaging analysis or 
biopsy]), and approximately every 6 months (± 1 month) thereafter to assess 
SREs, hypercalcemia, and, survival, for up to 10 years (120 months) from the 
date of randomization. 
 
Imaging assessments will continue during follow-up per the schedule of 
assessments (Appendix A), until documented evidence of disease recurrence 
in the bone (per central imaging analysis or biopsy).  See Section 7.2.9 for 
details. 
 
 
 


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One serum sample to evaluate for the presence of anti-denosumab 
antibodies will be collected approximately 6 months (24 weeks ± 14 days) 
after the last investigational product administration.  In addition, biomarker 
samples will be taken at the time of disease recurrence (including both first 
disease recurrence, and first disease recurrence in the bone, if applicable). 
 
Open-Label Treatment Phase 
 
After completing the open-label treatment phase of the study, subjects will be 
followed by clinic visit or telephone contact approximately every 3 months 
(every 12 weeks ± 14 days) to assess disease recurrence status and survival 
(until documented evidence of bone metastasis [per investigator report]), and 
approximately every 6 months (± 1 month) thereafter to assess survival, for 
up to 10 years (120 months) from the date of randomization. 
 
There will be no scheduled imaging assessments during the open-label 
treatment phase. 
 
One serum sample to evaluate for the presence of anti-denosumab 
antibodies will be collected approximately 6 months (24 weeks ± 14 days) 
after the last investigational product administration.  In addition, biomarker 
samples will be taken at the time of disease recurrence (including both first 
disease recurrence, and first disease recurrence in the bone, if applicable). 
 
Follow-up if Benefit/Risk Profile is Not Determined to be Positive 
 
If denosumab is not determined to have a positive benefit/risk profile 
compared with placebo, then all subjects will complete the EOTP visit and 
enter follow-up for survival (approximately every 6 months for up to 10 years 
[120 months] from the date of randomization).  
 
One serum sample to evaluate for the presence of anti-denosumab 
antibodies will be collected approximately 6 months (24 weeks ± 14 days) 
after the last investigational product administration. 
 
There will be no scheduled imaging assessments, and no other scheduled 
procedures. 
 
 
 


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With: 
After completing the treatment phase of the study, subjects will then enter 
LTFU for approximately 5 years (60 months) following the EOTP visit.  
The study requirements during LTFU are different before and after 
primary analysis data cut-off date and are detailed in Section 7.1.4.1 
(before primary analysis data cut-off date) and Section 7.1.4.2 (after 
primary analysis data cut-off date). 
 
7.1.4.1.  LTFU Requirements Prior to the Primary Analysis Data Cut-off 
Date 
 
All subjects (including subjects with documented evidence of bone 
metastasis) should be followed by clinic visit or telephone contact 
every 3 months (every 12 weeks ± 14 days) for approximately 6 months 
(ie, first 2 visits of LTFU following EOTP). 
• 
The following assessments are required: 
− 
clinical fractures/SREs  
− 
hypercalcemia of malignancy  
− 
breast cancer therapy  
− 
concomitant medications  
− 
patient-reported outcomes (BPI-SF, EQ-5D)  
− 
disease recurrence status (until documented evidence of bone 
metastasis [per central imaging analysis or biopsy]).  Not required 
for subjects with documented evidence of bone metastasis 
− 
survival 
All subjects without documented evidence of bone metastasis:  
following the completion of the initial 6 month LTFU period, subjects 
should be followed by clinic visit or telephone contact every 3 months 
(every 12 weeks ± 14 days). 
• 
The following assessments are required: 
− 
clinical fractures/SREs 
− 
hypercalcemia 
− 
disease recurrence status (until documented evidence of bone 
metastasis [per central imaging analysis or biopsy]) 
− 
survival 
Imaging assessments will continue during LTFU per the schedule of 
assessments (Appendix A), until documented evidence of disease recurrence 
 
 
 


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in the bone (per central imaging analysis or biopsy).  See Section 7.2.9 for 
details. 
Biomarker samples will be taken at the time of disease recurrence (including 
both first disease recurrence, and first disease recurrence in the bone, if 
applicable). 
Subjects with documented evidence of bone metastasis including 
subjects whose bone metastasis is confirmed after the initial 6 month 
(per central imaging analysis or biopsy):  following the completion of 
the initial 6 month LTFU period, subjects should be followed by clinic 
visit or telephone contact every 6 months (± 1 month). 
• 
The following assessments are required: 
− 
SREs 
− 
hypercalcemia 
− 
survival 
 
7.1.4.2.  LTFU Requirements After the Primary Analysis Data Cut-off 
Date 
 
Following the primary analysis data cut-off date, all subjects should 
complete the EOTP visit and will be followed by clinic visit or telephone 
contact every 6 months (± 1 month) for survival only.  All scheduled 
imaging and all other assessments (except survival) will cease after the 
primary analysis data cut-off date. 
Section:  7.2.5.  Adverse Event Collection 
Replace: Exceptions are hypercalcemia of malignancy, clinical fractures, and SREs, 
which will be followed until the End of Study (see Sections 7.2.5.1 and 7.2.6). 
With: 
Exceptions are hypercalcemia of malignancy, clinical fractures, and SREs, 
which will continue to be collected during LTFU prior to primary analysis 
data cut-off date (see Sections 7.2.5.1 and 7.2.6). 
 
 
 


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Section:  7.2.5.1.  Hypercalcemia of Malignancy 
Replace: Clinical events of hypercalcemia of malignancy will be collected on the eCRF 
throughout the study and during the follow-up. 
With: 
Clinical events of hypercalcemia of malignancy will be collected on the eCRF 
throughout the study and during LTFU prior to primary analysis data 
cut-off date. 
Section:  7.2.6.  Clinical Fracture and Skeletal-related Event Collection, 
Paragraphs 6 to 7 
Replace: Information about any new clinical fractures or SREs will be assessed and 
documented on the eCRF at each scheduled clinic visit and during the 
follow-up.  Copies of all radiographic assessments performed to diagnose 
clinical fractures and SREs must be submitted to the central imaging vendor.  
Copies of all screening and on-study radiology, surgery, or pathology reports 
should be kept in the subject’s records regardless if corresponding 
radiographs (or equivalent) are available. 
 
Open-Label Treatment Phase: Radiographic assessments of events incurred 
during the open-label treatment phase will not be submitted to the central 
imaging vendor. 
With: 
Information about any new clinical fractures (prior to the development of 
bone metastasis) or SREs will be assessed and documented on the eCRF 
at each scheduled clinic visit and during LTFU prior to primary analysis 
data cut-off date.  Copies of all radiographic assessments performed to 
diagnose clinical fractures and SREs must be submitted to the central 
imaging vendor.  Copies of all screening and on-study radiology, surgery, or 
pathology reports should be kept in the subject’s records regardless if 
corresponding radiographs (or equivalent) are available. 
 
Radiographic assessments for clinical fractures and SREs collected 
after primary analysis data cut-off date will not be submitted to the 
central imaging vendor. 
 
 
 


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Section:  7.2.8.  Patient Reported Outcomes, Paragraph 2 
Delete: 
Open-Label Treatment Phase: There will be no collection of patient reported 
outcomes during the open-label treatment phase. 
Section:  7.2.9.1.  Disease Assessments (Mammography, Bone Scan, CT/MRI), 
Paragraph 2 
Add: 
All scheduled on-study imaging must be performed within ± 6 weeks of the 
protocol-specified time point, unless performed within the previous 6 months.  
All scheduled imaging will cease after the primary analysis data cut-off 
date. 
Section:  7.2.9.1.  Disease Assessments (Mammography, Bone Scan, CT/MRI), 
Paragraph 3 
Delete: 
Open-Label Treatment Phase: There will be no protocol required imaging 
assessments during the open-label treatment phase. 
Section:  7.2.10.1.  Blood Assessments, Paragraphs 4-8 
Delete: 
Open-Label Treatment Phase: After subjects have been unblinded, there will 
be no scheduled collection of PK samples for subjects, who switch from 
placebo to open-label denosumab.  Subjects, who switch from blinded 
denosumab to open-label denosumab will continue PK sampling per the 
schedule of assessments. 
 
The centers that will participate in this part of the study will be determined at 
the time of site selection, on the basis of center interest, site ability to obtain 
and process serum denosumab concentration samples, and recruitment 
capacity.  A competitive enrollment strategy will be used.  Serum levels for 
denosumab will be obtained in randomized subjects at these centers until 
approximately 120 subjects have been enrolled into the PK portion of the trial 
(optional for subjects). 
 
Anti-denosumab antibodies: Serum for anti-denosumab antibody assay will 
be collected at baseline (prior to administration of the investigational products 
on study day 1), and on study as outlined in the schedule of assessments 
(Appendix A), and one sample during follow-up (approximately 6 months [24 
weeks ± 14 days] after the last investigational product administration). 
 
 
 


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Blood biomarkers and Bone Specific Alkaline Phosphatase (BSAP): Blood for 
biomarker assessments and BSAP will be obtained at baseline (prior to 
administration of the investigational products on study day 1), on study as 
outlined in the schedule of assessments (Appendix A), and upon disease 
recurrence (including both first disease recurrence, and first disease 
recurrence in the bone, if applicable). 
 
Open-Label Treatment Phase: There will be no scheduled biomarker 
assessments during the open-label treatment phase. 
Section:  7.2.10.2.  Urine Assessments, Paragraph 4 
Delete: 
Open-Label Treatment Phase: There will be no scheduled urine assessments 
during the open-label treatment phase. 
Section:  7.2.10.3.  Tumor Samples, Paragraph 2 
Delete: 
Open-Label Treatment Phase: There will be no scheduled tumor sample 
collection during the open-label treatment phase. 
Section:  7.3.1.  Biomarker Development, Paragraph 3 
Delete: 
Open-Label Treatment Phase: There will be no scheduled biomarker 
assessments during the open-label treatment phase. 
Section:  9.1.1.  Adverse Events, Paragraphs 2 to 7 
Replace: This definition of adverse events is broadened in this study to include any 
such occurrence (e.g., sign, symptom, or diagnosis) or worsening of a 
pre-existing medical condition from the time that a subject has signed 
informed consent to the time of randomization to or initiation of investigational 
product.  Worsening indicates that the pre-existing medical condition (e.g., 
diabetes, migraine headaches, gout) has increased in severity, frequency, or 
duration of the condition or an association with significantly worse outcomes. 
 
If infections occur, microbiological investigations (e.g. cultures) should be 
performed as clinically feasible to identify a causative organism, and specific 
data should be reported. 
 
Recurrence of breast cancer should not be reported as an adverse event.  
However, any specific symptoms or sequelae of the disease recurrence (e.g., 
 
 
 


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organ failure, respiratory distress, etc) will be considered adverse events and 
will be captured on the eCRF.   
 
Interventions for pretreatment conditions (e.g., elective surgery) or medical 
procedures that were planned before study enrollment are not considered 
adverse events.   
 
The investigator is responsible for reviewing laboratory test results and 
determining whether an abnormal value in an individual study subject 
represents a change from values before the study.  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 requiring therapy or adjustment in prior therapy are 
considered adverse events. 
With: 
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. 
 
This definition of adverse events is broadened in this study to include any 
such occurrence (eg, sign, symptom, or diagnosis) or worsening of a 
pre-existing medical condition from the time that a subject has signed 
informed consent to the time of randomization to or initiation of investigational 
product.  Worsening indicates that the pre-existing medical condition or 
underlying disease (eg, diabetes, migraine headaches, gout) has increased 
in severity, frequency, and/or duration more than would be expected, 
and/or has an association with a significantly worse outcome than 
expected. 
 
If infections occur, microbiological investigations (eg, cultures) should be 
performed as clinically feasible to identify a causative organism, and specific 
data should be reported. 
 
Recurrence of breast cancer should not be reported as an adverse event.  
However, any specific symptoms or sequelae of the disease recurrence (eg, 
organ failure, respiratory distress, etc) will be considered adverse events and 
will be captured on the eCRF.   
 
 
 


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Interventions for pretreatment conditions (eg, elective surgery) or, medical 
procedures that were planned before study enrollment, are not considered 
adverse events.   
 
The investigator’s clinical judgment is used to determine whether a 
subject is to be removed from treatment due to an adverse event.  In the 
event a subject, or subject’s legally acceptable representative requests 
to withdraw from protocol-required therapies or the study due to an 
adverse event, refer to Section 8.1 for additional instructions on the 
procedures recommended for safe withdrawal from protocol-required 
therapies or the study. 
 
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 requiring therapy or adjustment in 
prior therapy are considered adverse events.  Where applicable, clinical 
sequelae (not the laboratory abnormality) are to be recorded as the 
adverse event.  The investigator is expected to follow reported adverse 
events until stabilization or reversibility. 
Section:  9.1.2.  Serious Adverse Events, Paragraph 1 
Add: 
A serious adverse event is defined as an adverse event that meets at least 1 
of the following criteria: 
Section:  9.1.2.  Serious Adverse Events, Paragraph 3 
Add: 
Examples include allergic bronchospasm, convulsions, and blood dyscrasias, 
drug-induced liver injury, or events that necessitate an emergency room 
visit, outpatient surgery, or urgent intervention. 
Section:  9.2.  Safety Event Reporting Procedures, Section Title 
Replace: Reporting Procedures for All Adverse Events 
With: 
Safety Event Reporting Procedures 
 
 
 


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Section:  9.2.  Safety Event Reporting Procedures 
Add: 
9.2.1 
Adverse Events 
Section:  9.2.2.  Reporting Procedures for Serious Adverse Events, Paragraphs 1 to 4 
Replace: 
9.3 
Serious Adverse Event Reporting Procedures 
 
Serious adverse events will be collected and recorded at least throughout the 
study period, beginning with the signing of the informed consent until the 
EOTP, or for 30 days after the last dose of investigational product for subjects 
who discontinue investigational product before the EOTP.  All serious 
adverse events occurring after the above mentioned criteria will be collected 
and recorded. 
 
All serious adverse events that occur after the subject has signed the 
informed consent form must be submitted to Amgen within 24 hours following 
the investigator’s knowledge of the event via the applicable electronic Serious 
Adverse Event (eSAE) eCRF.  If the electronic data capture (EDC) system is 
unavailable to the site staff to report the Serious Adverse Event, the 
information is to be reported to Amgen via an electronic Serious Adverse 
Event (eSAE) Contingency Report Form within 24 hours of the Investigator’s 
knowledge of the event.  See Appendix G for a sample of the Serious 
Adverse Event Worksheet/electronic Serious Adverse Event Contingency 
Report Form. 
 
New information relating to a previously reported serious adverse event must 
be submitted to Amgen.  All new information for serious adverse events must 
be sent to Amgen within 24 hours following knowledge of the new 
information.  The Investigator may be asked to provide additional follow-up 
information, which may include a discharge summary or extracts from the 
medical record.  Information provided about the serious adverse event must 
be consistent with that recorded on the applicable eCRF (eg, Adverse Event 
Summary eCRF). 
 
 
 


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With: 
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 signing of the informed consent through the EOTP, or for 
30 days after the last dose of investigational product for subjects who 
discontinue investigational product before the EOTP, are recorded in the 
subject’s medical record and are submitted to Amgen.  All serious 
adverse events must be submitted to Amgen within 24 hours following 
the investigator’s knowledge of the event via the Adverse Event CRF.   
 
All serious adverse events that occur after the subject has signed the 
informed consent form must be submitted to Amgen within 24 hours following 
the investigator’s knowledge of the event via the applicable electronic Serious 
Adverse Event (eSAE) eCRF.  If the electronic data capture (EDC) system is 
unavailable to the site staff to report the Serious Adverse Event, the 
information is to be reported to Amgen via an electronic Serious Adverse 
Event (eSAE) Contingency Report Form within 24 hours of the Investigator’s 
knowledge of the event.  See Appendix G for a sample of the Serious 
Adverse Event Worksheet/electronic Serious Adverse Event Contingency 
Report Form.  For EDC studies where the first notification of a Serious 
Adverse Event is reported to Amgen via the eSAE Contingency Report 
Form, the data must be entered into the EDC system when the system is 
available again. 
 
The investigator must assess whether the serious adverse event is 
possibly related to the investigational product and/or other 
protocol-required therapies.  This relationship is indicated by a “yes” or 
“no” response to the question:  Is there a reasonable possibility that the 
event may have been caused by the investigational product?  
Relatedness means that there are facts or reasons to support a 
relationship between investigational product and the event.  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 following knowledge of the new 
 
 
 


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information.  If specifically requested, 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 eCRF (eg, Adverse Event Summary eCRF). 
Section:  9.2.3.  Reporting Serious Adverse Events After the Protocol-required 
Reporting Period, (new section) 
Add: 
9.2.3 
Reporting Serious Adverse Events After the 
Protocol-required Reporting Period 
 
There is no requirement to monitor study subjects for serious adverse 
events following the protocol-required reporting period or after end of 
study.  However, these serious adverse events can be reported to 
Amgen.  In some countries (eg, European Union [EU] member states), 
investigators are required to report serious adverse events that they 
become aware of following the protocol-required reporting or after end 
of study.  If serious adverse events are reported, the investigator is to 
report them to Amgen within 24 hours following the investigator’s 
knowledge of the event. 
 
Serious adverse events reported outside of the protocol-required 
reporting period will be captured within the safety database as clinical 
trial cases for the purposes of expedited reporting. 
Section:  9.3.  Pregnancy and Lactation Reporting, Paragraphs 2 to 5 
Replace: In addition to reporting any pregnancies occurring during the study, 
Investigators should monitor for pregnancies that occur after the last dose of 
protocol-required therapies through 5 months after the end of treatment. 
 
The pregnancy should be reported to Amgen’s global Pregnancy Surveillance 
Program (PSP) within 7 business days of the site receiving notification of a 
pregnancy.  Report a pregnancy on the Pregnancy Notification Worksheet 
(Appendix F).  The Pregnancy Surveillance Program will seek to follow the 
pregnant woman throughout her pregnancy and her baby up to 12 months 
after birth. 
 
 
 


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With: 
In addition to reporting any pregnancies occurring during the study, 
investigators should report pregnancies that occur through 5 months after 
the last dose of protocol-required therapies. 
 
The pregnancy should be reported to Amgen Global Patient Safety within 
24 hours of the investigator’s knowledge of the event of a pregnancy.  
Report a pregnancy on the Pregnancy Notification Worksheet (Appendix F).  
Amgen Global Patient Safety will follow-up with the investigator 
regarding additional information that may be requested. 
 
If a female subject becomes pregnant during the study, the investigator 
should attempt to obtain information regarding the birth outcome and 
health of the infant.  
 
If the outcome of the pregnancy meets a criterion for immediate 
classification as a Serious Adverse Event (eg, female subject 
experiences a spontaneous abortion, stillbirth, or neonatal death or 
there is a fetal or neonatal congenital anomaly) the investigator will 
report the event as a Serious Adverse Event. 
Section:  9.3.  Pregnancy and Lactation Reporting, Paragraph 8 
Replace: Any lactation case should be reported to Amgen’s global Lactation 
Surveillance Program (LSP) within 7 business days of the site receiving 
notification. 
With: 
Any lactation case should be reported to Amgen Global Patient Safety within 
24 hours of the investigator’s knowledge of event. 
Section:  10.1.  Study Design, Paragraphs 2 to 3 
Replace: A DMC external to Amgen and external to Daiichi Sankyo Co., Ltd. will review 
safety data at regular intervals, as outlined in the DMC charter (approximately 
twice yearly; the start date will depend on subject accrual rates).  This 
external DMC will conduct two interim analyses of efficacy; the first after 
approximately 367 subjects have developed bone metastasis or died, and 
approximately 555 subjects have developed any disease recurrence or died, 
whichever comes last; and the second after approximately 551 subjects have 
developed bone metastasis or died, and approximately 833 subjects have 
developed any disease recurrence or died, whichever comes last.  To ensure 
 
 
 


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timely conduct of the respective interim analyses, the interim analyses may 
be conducted early, as soon as approximately 6 months after the sufficient 
event number has been reached for either BMFS or DFS in the full study 
population, even if the event number for the other endpoint has not been 
reached. 
 
The primary analysis will be conducted after approximately 735 subjects have 
developed bone metastasis or died, and approximately 1110 subjects in the 
full study population and 512 subjects in the postmenopausal subset have 
developed any disease recurrence or died, whichever comes last.  Subjects 
will remain on blinded treatment until the primary analysis is completed. 
With: 
An external DMC will monitor the study and conduct 1 interim analysis 
of efficacy.  Refer to Section 10.5 for details. 
 
The primary analysis will be conducted after all enrolled subjects have 
had the opportunity to complete 5 years of treatment from study day 1. 
Section:  10.3 Sample Size Considerations, entire section 
Replace: The sample size calculation is based on the primary endpoint, BMFS, and is 
estimated using EAST 5.2.  Estimates of the event rates for BMFS and DFS 
for the target population are based on (Colleoni et al., 2000) and on recent 
published and unpublished data, including (Francis et al., 2008; 
Martin et al., 2005) for the HER-2 negative population, (Romond et al., 2005; 
Slamon et al., 2006) for the HER-2 positive population, (Howell et al., 2005; 
Thurlimann et al., 2005) for the population receiving adjuvant hormonal 
therapy, and (Coleman et al., 2014) for the use of adjuvant zoledronic acid in 
stage II-III breast cancer.  Based on the reported event rates, and based on 
the event rate proportions for disease recurrence in the bone, the viscera, or 
death reported by (Colleoni et al., 2000) and (Coleman et al., 2014), the 
respective rates at three years of BMFS and DFS are expected to be 
approximately 89% and 83% in the control group. 
 
For BMFS, if the true hazard ratio is 0.8, 735 subjects with an event of bone 
metastasis or death among the 4,500 planned subjects, of whom about 47% 
were postmenopausal at enrollment, will provide 85% power to detect 
superiority of denosumab over placebo.  For DFS, assuming a true hazard 
ratio of 0.83, 1110 subjects in the full study population with an event of 
 
 
 


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disease recurrence or death, including approximately 512 subjects in the 
postmenopausal subset, will provide about 80% power to detect superiority of 
denosumab over placebo.  For DFS in the postmenopausal subset, assuming 
a true hazard ratio of 0.76, approximately 512 postmenopausal subjects with 
an event of disease recurrence or death will provide about 80% power to 
detect superiority of denosumab over placebo. 
 
The study will conclude when approximately 735 subjects have developed 
bone metastasis or died, and approximately 1110 subjects in the full study 
population and 512 subjects in the postmenopausal subset have developed 
any disease recurrence or died, whichever comes last.  With 4,500 subjects, 
an enrollment period of approximately 30 months, and a loss to follow-up rate 
of 6% per year, the study is estimated to reach the primary analysis data 
cut-off date in approximately 89 months (ie,  7 years and 5 months).  The rate 
of bone metastasis or death and the rate of disease recurrence or death of 
the pooled treatment groups will be monitored.  If the rates are lower than 
expected, then the sample size may be modified, or the study duration 
prolonged. 
With: 
The sample size calculation is based on the primary endpoint, BMFS, and is 
estimated using EAST 6.4.  Estimates of the event rates for BMFS and DFS 
for the target population are based on (Colleoni et al., 2000) and on recent 
published and unpublished data, including (Francis et al., 2008; 
Martin et al., 2005) for the HER-2 negative population, (Romond et al., 2005; 
Slamon et al., 2006) for the HER-2 positive population, (Howell et al., 2005; 
Thurlimann et al., 2005) for the population receiving adjuvant hormonal 
therapy, and (Coleman et al., 2014) for the use of adjuvant zoledronic acid in 
stage II-III breast cancer.  Based on the reported event rates, the event rate 
proportions for disease recurrence in the bone, the viscera, or death reported 
by (Colleoni et al., 2000) and (Coleman et al., 2014), and considering the 
availability of some breast cancer adjuvant therapies, the BMFS rate at 
three years is expected to be approximately 90.5% in the control group.  
Disease recurrence risk after primary breast cancer treatment can vary 
over time (Cheng et al, 2012).  For DFS, assume a piece-wise 
exponential distribution with a risk of about 5.5% per year for the first 
3 years and 3.2% per year afterwards in the control group. 
 
 
 


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The primary analysis will be conducted after all enrolled subjects have 
had the opportunity to complete 5 years of treatment from study day 1.  
With 4,500 subjects, an enrollment period of approximately 27 months, and a 
loss to follow-up rate of 6% per year, the study is estimated to reach the 
primary analysis data cut-off date in approximately 87 months (ie, 7 years 
and 3 months).  For BMFS, if the true hazard ratio is 0.8, the power to 
detect superiority of denosumab over placebo in the primary analysis is 
estimated to be approximately 80%.   
Section:  10.5.  Interim Analysis and Early Stopping Guidelines, Paragraph 2 
Replace: The DMC will review safety data at regular intervals, as outlined in the DMC 
charter (approximately twice yearly; the start date will depend on subject 
accrual rates), and will conduct two interim analyses of efficacy. 
With: 
The DMC will review safety data at regular intervals, as outlined in the DMC 
charter (approximately twice yearly; the start date will depend on subject 
accrual rates), and will conduct 1 interim analysis of efficacy. 
Section:  10.5.  Interim Analysis and Early Stopping Guidelines, Paragraph 2, Bullet 1 
Replace: There are two formal interim analyses; the first after approximately 
367 subjects have developed bone metastasis or died, and approximately 
555 subjects have developed any disease recurrence or died, whichever 
occurs last; and the second after approximately 551 subjects have developed 
bone metastasis or died, and approximately 833 subjects have developed 
any disease recurrence or died, whichever occurs last.  The respective 
interim analyses may be performed as soon as approximately 6 months after 
the sufficient event number has been reached for either BMFS or DFS in the 
full study population, even if the event number for the other endpoint has not 
been reached.  The critical p-values for rejecting the null or alternative 
hypothesis, as determined by the Lan-DeMets spending function with an 
O’Brien-Fleming approach for efficacy, and the Gamma Family with 
parameter -14 for futility (BMFS only), are listed in the following table.  The 
multiplicity from testing DFS in the full study population and in the 
postmenopausal subset simultaneously will be adjusted based on a 
Hochberg procedure (Sakamaki, 2013; Ye et al., 2012).  The study could 
potentially be stopped if both BMFS and DFS in the full study population 
 
 
 


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cross their corresponding efficacy boundaries, or if BMFS crosses the futility 
boundary at either interim analysis.  The other secondary endpoints OS and 
DRFS will only be tested when the study is stopped or at the final analysis; 
the same Lan-DeMats spending function with an O’Brien-Fleming approach 
as for BMFS will be used to adjust for multiplicity for each of these endpoints. 
With: 
There is 1 formal interim analysis after approximately 367 subjects have 
developed bone metastasis or died, and approximately 555 subjects have 
developed any disease recurrence or died, whichever occurs last.  This 
interim analysis may be performed as soon as approximately 6 months after 
the sufficient event number has been reached for either BMFS or DFS in the 
full study population, even if the event number for the other endpoint has not 
been reached.  The critical p-values for rejecting the null or alternative 
hypothesis are listed in the following table.  The multiplicity from testing DFS 
in the full study population and in the postmenopausal subset simultaneously 
will be adjusted based on a Hochberg procedure (Sakamaki, 2013; 
Ye et al., 2012).  The study could potentially be stopped if both BMFS and 
DFS in the full study population cross their corresponding efficacy 
boundaries, or if BMFS crosses the futility boundary at the interim analysis.  
The other secondary endpoints OS and DRFS will only be tested when the 
study is stopped or at the primary analysis; the same procedure as for 
BMFS will be used to adjust for multiplicity between the interim and primary 
analysis for each of these endpoints. 
 
 
 


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Section: 10.5.  Interim Analysis and Early Stopping Guidelines, Table 2 
Replace: Decision rule (1-sided) at interim/ final analyses 
Analysis 
Reject H0 
Reject H1 
Interim Analysis 1 
BMFS: P <0.0015 
DFS in the full study population:  
P <0.0004 or 
P<0.0015 for both the full study 
population and the subset 
DFS in the subset:  
P <0.0004 or 
P<0.0015 for both the full study 
population and the subset 
P >0.9333 for BMFS  
Interim Analysis 2 
BMFS: P < 0.0092 
DFS in the full study population:  
P < 0.0038; or  
P < 0.0092 for both the full study 
population and the subset; or 
P < 0.0092 if DFS in the subset was 
rejected at IA #1  
DFS in the subset:  
P < 0.0038; or  
P < 0.0092 for both the full study 
population and the subset; or  
P < 0.0092 if DFS in the full study 
population was rejected at IA #1  
P > 0.4969 for BMFS  
Final Analysis 
BMFS: P < 0.022 
DFS in the full study population:  
P < 0.0113; or  
P < 0.022 for both the full study 
population and the subset or 
P < 0.022 if DFS in the subset was 
rejected at any IA  
DFS in the subset:  
P < 0.0113; or  
P < 0.022 for both the full study 
population and the subset; or  
P < 0.022 if DFS in the full study 
population was rejected at any IA  
 
 
 
 


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With: 
Table 2.  Decision Rule (1-sided) at Interim/Primary Analyses 
Analysis 
Reject H0 
Reject H1 
Interim Analysis 
BMFS: P <0.0015 
DFS in the full study population:  
P <0.0004 or 
P<0.0015 for both the full study 
population and the subset 
DFS in the subset:  
P <0.0004 or 
P<0.0015 for both the full study 
population and the subset 
P >0.9333 for BMFS  
 
 
 
Primary Analysisa 
BMFS: P < 0.0247 
DFS in the full study population:  
P < 0.0125; or  
P < 0.0249 for the full study population 
and P < 0.0248 for the subset 
DFS in the subset:  
P < 0.0125; or  
P < 0.0249 for the full study population 
and P < 0.0248 for the subset 
 
a Boundaries are based on the estimated number of events and will be recalculated based on the 
actual observed number of events. 
Section:  10.5.  Interim Analysis and Early Stopping Guidelines, Paragraph 2, Bullet 3 
Add: 
3.  At the primary analysis that is time-driven, the exact number of 
events for the primary and secondary endpoints are not fixed and the 
final alpha boundaries can potentially vary.  Table 2 includes the 
boundaries calculated according to the estimated total numbers of 
events.  In order to strictly control the overall type I error rate, the final 
boundaries will be updated based on the actual number of events 
achieved and the alpha levels that have been spent at the interim 
analysis (Proschan et al, 2006). 
 
 
 


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Section:  10.6.1.  General Approach/Considerations, Paragraph 1 
Replace: Amgen will set a primary analysis data cut-off date in anticipation of 
approximately 735 subjects having developed bone metastasis or died, and 
approximately 1110 subjects in the full study population and 512 subjects in 
the postmenopausal subset having developed any disease recurrence or 
died, whichever comes last.  The primary analysis will be based on the data 
from randomization through the primary analysis data cut-off date. 
With: 
Amgen will set a primary analysis data cut-off date after all enrolled 
subjects have had the opportunity to complete 5 years of treatment 
from study day 1.  The primary analysis will be based on the data from 
randomization through the primary analysis data cut-off date. 
Section:  10.6.4.  Planned Methods of Analysis Through the End of the Blinded 
Treatment Phase (entire section deleted) 
Delete: 
10.6.4 
Planned Methods of Analysis Through the End of the Blinded 
Treatment Phase 
 
If appropriate, analyses described in Section 10.6 will be performed based on 
the data from randomization through end of the blinded treatment phase.  
These analyses will be supportive and exploratory in nature 
Section:  10.6.4.  Final Analysis of Data From Long-term Follow-up (entire section) 
Replace: 10.6.5 
Analysis of Data From Follow-up 
 
Selected safety data (including adverse events, laboratory assessments) and 
efficacy data (including disease recurrence, sites of recurrence, and death) 
will be summarized for the open-label treatment phase.  Events of disease 
recurrence, sites of recurrence, and deaths during the long-term survival 
follow-up, and from randomization through long-term follow-up, will also be 
summarized. 
With: 
10.6.4 
Final Analysis of Data From Long-term Follow-up 
 
Deaths during the long-term survival follow-up, and from randomization 
through long-term follow-up, will be summarized. 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 39 of 56 
CONFIDENTIAL 
 
 
Section:  13.5.  Publication Policy, Paragraph 2 and Bullet 1 
Replace: Authorship of any publications resulting from this study will be determined on 
the basis of the Uniform Requirement for Manuscripts Submitted to 
Biomedical Journals (International Committee of Medical Journal Editors, 
2005), 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. 
With: 
Authorship of any publications resulting from this study will be determined on 
the basis of the Recommendations for the Conduct, Reporting, Editing, 
and Publication of Scholarly Work in Medical Journals (International 
Committee of Medical Journal Editors 2013, updated 2014), which states: 
• 
Authorship credit should be based on (1) substantial contributions to 
conception and design, acquisition of data, or analysis and interpretation 
of data; (2) drafting the article or revising it critically for important 
intellectual content; (3) final approval of the version to be published; and 
(4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any 
part of the work are appropriately investigated and resolved.  
Authors should meet conditions 1, 2, 3, and 4. 
Section:  14.  References 
Add: 
Cheng L, Swartz MD, Zhao H, et al.  Hazard of recurrence among women 
after primary breast cancer treatment - a 10-year follow-up using data 
from SEER medicare.  Cancer Epidemiol Biomarkers Prev.  
2012;21(5):800-809. 
Section:  14.  References 
Add: 
Proschan MA, Lan KKG, Wittes JT.  Statistical Monitoring of Clinical 
Trials:  A Unified Approach.  Springer, New York; 2006. 
 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 40 of 56 
CONFIDENTIAL 
 
 
Section:  Appendix A.  Schedule of Assessments 
Replace: 
 
 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 41 of 56 
CONFIDENTIAL 
 
 
With: 
 
Treatment Period - Years 3, 4, and 5 (continued) 
 
Visit 
V16 
V17 
 
V18 
V19 
V20 
V21 
V22 
 
V23 
V24 
V25 
V26 
 
EOTP 
Week 
 
156 
Q3M (± 14 days) 
208 
Q3M (± 14 days) 
260 
265 
Year 
3 
3 
3 
4 
4 
4 
4 
4 
4 
5 
5 
5 
5 
5 
6 
Study Assessments 
Physical Examination, ECOG Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oral Examination 
X 
X 
X 
X 
X 
X 
Adverse Event Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Fracture / SRE Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hypercalcemia of Malignancy Collection 
X 
Breast Cancer Therapy Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PRO Questionnaires (BPI-SF, EQ-5D) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging Assessments 
Skeletal Scintigraphy 
- - - - - -X - - - - 
.- - - - - - X- - - -  
- - - - - -X - - - - - - X 
Mammography, CT/MRI Imaging 
- - - - - -X - - - - 
.- - - - - - X- - - -  
- - - - - -X - - - - - - X 
Investigational Product Administration 
Denosumab 120 mg or Placebo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Assessments 
Serum Albumin, Calcium 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other Serum Values (Mg, P) 
X 
 
 
 
X 
 
 
X 
 
 
 
X  
 
 
Vitamin D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Denosumab Antibody Collection 
X 
X 
X 
X 
Denosumab PK Sample Collection * 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Biomarker, BSAP Collection 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Collection 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Sample Collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Recurrence/Survival Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 42 of 56 
CONFIDENTIAL 
 
 
 
Long-term Follow-up 
 
Prior to primary analysis data cut-off date 
Post-primary 
analysis data cut-off 
date 
Visit 
All subjects, first 2 
visits 
All subjects without 
bone mets 
All subjects with 
documented bone mets 
Every 6M 
Notes 
Every 3M 
Every 3M 
Every 6M 
Year 
6 
6 to 10 
6 to 10 
6 to 10 
 
Study Assessments 
Clinical Fracture / SRE Collection 
X 
X 
X 
 
 
Hypercalcemia of Malignancy 
Collection 
X 
X 
X 
 
 
Breast Cancer Therapy Collection 
X 
 
 
Concomitant Medications Collection 
X 
 
 
PRO Questionnaires (BPI-SF, EQ-
5D) 
X 
 
 
 
 
Imaging Assessments 
Skeletal Scintigraphy 
Yearly 
 
 
See Section 7.2.9 
Mammography, CT/MRI Imaging 
Yearly 
 
 
See Section 7.2.9 
Laboratory Assessments 
Blood Biomarker, BSAP Collection 
X 
X 
 
As applicable, refer to 
Section 7.2.10.1 
Tumor Sample Collection 
X 
X 
 
As applicable, refer to 
Section 7.2.10.3 
Follow-up 
Disease Recurrence 
X 
X 
 
 
 
Survival 
X 
X 
X 
X 
 
 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 43 of 56 
CONFIDENTIAL 
 
 
Section:  Appendix A.  Schedule of Assessments 
Delete: 
OL1.  Open-Label Treatment Phase Schedule of Assessments – Years 1, 2, and 3 
 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 
V12 V13 
Week 
Q4W (+ 7 days) 
Year 
1 
1 
1 
1 
1 
1 
1 
1 
1 
2 
2 
2 
2 
Study Assessments 
Physical Examination,ECOG Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oral Examination 
X 
X 
X 
X 
Adverse Event Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Fracture I SRE Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hypercalcemia  of Malignancy Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Breast Cancer Therapy Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigational Product Administration 
Denosumab 120 mg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Assessments 
Serum Albumin,Calcium 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other Serum Values (Mg,P) 
X 
X 
X 
X 
X 
Hematology (CBC,Differential),Vitamin D 
X 
Denosumab Antibody Collection 
X 
X 
X 
X 
Denosumab PK Sample Collection • 
X 
X 
X 
X 
X 
X 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Recurrence/ Survival Follow-up 
 
 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 44 of 56 
CONFIDENTIAL 
 
 
OL1.  Open-Label Treatment Phase Schedule of Assessments – Years 3, 4, and 5 
Open Label Treatment Phase-  Years 3, 4, and 5 (continued) 
Follow-up 
Visit 
V16 V17 V18 V19 V20 V21 V22 V23 V24 V25 V26 
EOTP F/U 
Week 
Q3M (+ 14 days) 
Q3M (+ 14 days) 
265 
291 + 
Year 
3 
3 
4 
4 
4 
4 
4 
5 
5 
5 
5 
6 
6 to 10 
Study Assessments 
Physical Examination,ECOG Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Oral Examination 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Adverse Event Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Fracture I SRE Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hypercalcemia  of Malignancy Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Breast Cancer Therapy Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Investigational Product Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
Denosumab 120 mg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Albumin,Calcium 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Other Serum Values (Mg,P) 
X 
X 
X 
X 
 
Hematology (CBC,Differential),Vitamin D 
 
X 
Denosumab Antibody Collection 
 
X 
X 
 
X 
X 
 
Denosumab PK Sample Collection • 
 
X 
 
 
 
 
 
Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Recurrence/ Survival Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 45 of 56 
CONFIDENTIAL 
 
 
Section:  Appendix A.  Schedule of Assessments, Legend 
Delete: 
* at selected sites only; 6M F/U, first six months of follow-up period; CBC, 
complete blood cell count; EOTP, End of Treatment Phase Visit; F/U, 
Follow-up; Mg, magnesium; P, phosphorus; PRO, patient-reported outcomes; 
Q3M, every 3 months (every 12 weeks ± 14 days); Q4W, every 4 weeks 
(± 7 days); SRE, skeletal-related event; V, visit; W, week; wks, weeks. 
Section:  Appendix A.  Schedule of Assessments, Adverse Events Footnote 
Replace: Exceptions are hypercalcemia of malignancy, clinical fractures, and SREs, 
which will be followed until the End of Study (see Sections 7.2.5.1 and 7.2.6). 
With: 
Exceptions are hypercalcemia of malignancy, clinical fractures, and SREs, 
which will be followed during LTFU prior to primary analysis data cut-off 
date (see Sections 7.2.5.1 and 7.2.6). 
Section:  Appendix A.  Schedule of Assessments, Clinical Fractures / Skeletal-related 
Events Footnote 
Replace: Information about any new clinical fractures (prior to the development of bone 
metastasis) or skeletal-related events (SREs; defined as any pathologic 
fracture [vertebral or non-vertebral], radiation therapy to bone [including the 
use of radioisotopes], surgery to bone, or spinal cord compression following 
the development of bone metastasis) will be assessed and documented at 
each scheduled clinic visit and during the follow-up period.  Copies of all 
screening and on-study radiographic assessments performed to diagnose 
clinical fractures and SREs must be submitted to the central imaging vendor.  
Copies of all screening and on-study radiology, surgery, or pathology reports 
should be kept in the subject’s records regardless if corresponding 
radiographs (or equivalent) are available. See Section 7.2.6 for details. 
 
Open-Label Treatment Phase: Radiographic assessments of events incurred 
during the open label treatment phase will not be submitted to the central 
imaging vendor. 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 46 of 56 
CONFIDENTIAL 
 
 
With: 
Information about any new clinical fractures (prior to the development of bone 
metastasis) or skeletal-related events (SREs; defined as any pathologic 
fracture [vertebral or non-vertebral], radiation therapy to bone [including the 
use of radioisotopes], surgery to bone, or spinal cord compression following 
the development of bone metastasis) will be assessed and documented at 
each scheduled clinic visit and during LTFU prior to primary analysis data 
cut-off date.  Copies of all screening and on-study radiographic assessments 
performed to diagnose clinical fractures and SREs must be submitted to the 
central imaging vendor.  Copies of all screening and on-study radiology, 
surgery, or pathology reports should be kept in the subject’s records 
regardless if corresponding radiographs (or equivalent) are available. See 
Section 7.2.6 for details.  After primary analysis data cut-off date:  
Radiographic assessments of events incurred after primary analysis 
data cut-off date will not be submitted to the central imaging vendor. 
Section:  Appendix A.  Schedule of Assessments, PRO Questionnaires (BPI-SF and 
EQ-5D) Footnote 
Delete: 
Open-Label Treatment Phase: There will be no
Section:  Appendix A.  Schedule of Assessments, Imaging Assessments Footnote 
 PRO assessments during the 
open-label treatment phase. 
Add: 
Copies of all screening and on-study radiology, surgery, or pathology reports 
should be kept in the subject’s records regardless if corresponding 
radiographs (or equivalent) are available.  All scheduled imaging will cease 
after the primary analysis data cut-off date. 
Section:  Appendix A.  Schedule of Assessments, Imagine Assessments Footnote 
Delete: 
Open-Label Treatment Phase: There will be no
Section:  Appendix A.  Schedule of Assessments, Urine Collection Footnote 
 scheduled imaging 
assessments during the open-label treatment phase. 
Delete: 
Open-Label Treatment Phase: There will be no scheduled urine collection 
during the open-label treatment phase. 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 47 of 56 
CONFIDENTIAL 
 
 
Section:  Appendix A.  Schedule of Assessments, Anti-denosumab antibodies Footnote 
Replace: Serum for anti-denosumab antibody assay will be collected at baseline (prior 
to administration of the investigational products on study day 1), on study as 
outlined in the schedule of assessments, at the EOTP visit, and 
approximately 6 months (24 weeks ± 14 days) after the last investigational 
product administration. 
With: 
Serum for anti-denosumab antibody assay will be collected at baseline (prior 
to administration of the investigational products on study day 1) and on study 
as outlined in the schedule of assessments. 
Section:  Appendix A.  Schedule of Assessments, Blood Biomarkers and BSAP 
Footnote 
Delete: 
Open-Label Treatment Phase: There will be no scheduled biomarker and 
BSAP collection during the open-label treatment phase. 
Section:  Appendix A.  Schedule of Assessments, Pharmacokinetics (PK) Footnote 
Delete: 
Open-Label Treatment Phase: After subjects have been unblinded, there will 
be no scheduled collection of PK samples for subjects, who switch from 
placebo to open-label denosumab in the open-label treatment phase.  
Subjects, who switch from blinded denosumab to open-label denosumab will 
continue PK sampling per the Schedule of Assessments. 
Section:  Appendix A.  Schedule of Assessments, Tumor Samples Footnote 
Delete: 
Open-Label Treatment Phase: There will be no tumor sample collection 
during the open-label treatment phase. 
Section:  Appendix A.  Schedule of Assessments, End of Treatment Phase (EOTP) Visit 
Footnote 
Delete: 
will be completed per Schedule of Assessments (± 14 days), or at any time 
once an individual subject discontinues study participation (4 weeks 
[+ 7 days] after the last dose of investigational product).  If denosumab is not 
determined to have a positive benefit/risk profile compared with placebo, then 
all subjects will complete the EOTP visit 4 weeks (+ 7 days) after their last 
dose of investigational product. 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 48 of 56 
CONFIDENTIAL 
 
 
 
All EOTP assessments must be completed (unless done within the prior 
4 weeks), except imaging assessments, which do not need to be repeated if 
completed within the prior 6 months (ie, 24 weeks).  If denosumab is not 
determined to have a positive benefit/risk profile compared with placebo, then 
no imaging will be required at the EOTP visit. 
Section:  Appendix A.  Schedule of Assessments, Long-term Follow-up Footnote 
Replace: Follow-up 
 
Blinded Treatment Phase 
 
After completing the treatment phase of the study (60 months from study day 
1; or as specified in Section 7.1.2.3 and Section 7.1.3), subjects will be 
followed by clinic visit or telephone contact approximately monthly 
(Q4W ± 7 days) for six months to assess clinical outcomes (SREs, 
hypercalcemia of malignancy, concomitant medications, breast cancer 
therapy, patient-reported outcomes [BPI-SF, EQ-5D], disease recurrence 
status [until documented evidence of bone metastasis] and survival), 
approximately every 3 months (every 12 weeks ± 14 days) thereafter to 
assess SREs, hypercalcemia, disease recurrence status and survival (until 
documented evidence of bone metastasis), and approximately every 
6 months (± 1 month) thereafter to assess SREs, hypercalcemia, and 
survival, for up to 10 years (120 months) from the date of randomization.  
 
Imaging assessments will continue during follow-up per the Schedule of 
Assessments, until documented evidence of disease recurrence in the bone 
(per central imaging analysis or biopsy).  See Section 7.2.9 for details.  
Copies of all radiographic assessments documenting first evidence of 
disease recurrence and first evidence of disease recurrence in the bone, 
respectively, will be submitted to the central imaging vendor. 
 
One serum sample to evaluate for the presence of anti-denosumab 
antibodies will be collected approximately 6 months (24 weeks ± 14 days) 
after the last investigational product administration.  In addition, a biomarker 
sample will be taken at the time of disease recurrence (including both first 
disease recurrence, and first disease recurrence in the bone, if applicable). 
 
Open-Label Treatment Phase 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 49 of 56 
CONFIDENTIAL 
 
 
 
After completing the open-label treatment phase of the study, subjects will be 
followed by clinic visit or telephone contact approximately every 3 months 
(every 12 weeks ± 14 days) to assess disease recurrence status, and survival 
(until documented evidence of bone metastasis), and approximately every 
6 months (± 1 month) thereafter to assess survival, for up to 10 years 
(120 months) from the date of randomization. 
 
There will be no scheduled imaging assessments during the open-label 
treatment phase. 
 
One serum sample to evaluate for the presence of anti-denosumab 
antibodies will be collected approximately 6 months (24 weeks ± 14 days) 
after the last investigational product administration.  In addition, biomarker 
samples will be taken at the time of disease recurrence (including both first 
disease recurrence, and first disease recurrence in the bone, if applicable). 
 
Follow-up if Positive Benefit/Risk is Not Determined 
 
If denosumab is not determined to have a positive benefit/risk profile 
compared with placebo, then all subjects will complete the EOTP visit and 
enter follow-up for survival (approximately every 6 months for up to 10 years 
[120 months] from the date of randomization).  
 
One serum sample to evaluate for the presence of anti-denosumab 
antibodies will be collected approximately 6 months (24 weeks ± 14 days) 
after the last investigational product administration. 
 
There will be no scheduled imaging assessments, and no other scheduled 
procedures. 
With: 
Long-term Follow-up: 
 
After completing the treatment phase of the study (60 months from study 
day 1; or as specified in Section 7.1.2.3 and Section 7.1.3), subjects will be 
enter LTFU for approximately 5 years (total study duration for an 
individual subject is up to 10 years from the date of randomization).  
The study requirements during LTFU are determined by the primary 
analysis data cut-off date, refer to Section 7.1.4.1 for assessments prior 
to primary analysis data cut-off date and Section 7.1.4.2 for 
assessments required after primary analysis data cut-off date. 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 50 of 56 
CONFIDENTIAL 
 
 
Section:  Appendix F.  Pregnancy Notification Worksheet 
Replace: 
 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 51 of 56 
CONFIDENTIAL 
 
 
With: 
 
 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 52 of 56 
CONFIDENTIAL 
 
 
Section:  Appendix G.  Serious Adverse Event Worksheet/Electronic Serious Adverse 
Event Contingency Report Form 
Delete: 
 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 53 of 56 
CONFIDENTIAL 
 
 
 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 54 of 56 
CONFIDENTIAL 
 
 
Section:  Appendix K.  Lactation Notification Worksheet 
Replace: 
 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 55 of 56 
CONFIDENTIAL 
 
 
With: 
 
 
 
 


Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  17 October 2016 
Page 56 of 56 
CONFIDENTIAL 
 
 
REFERENCES 
Cheng L, Swartz MD, Zhao H, et al.  Hazard of recurrence among women after primary 
breast cancer treatment - a 10-year follow-up using data from SEER-medicare.  Cancer 
Epidemiol Biomarkers Prev.  2012;21(5):800-809. 
Demicheli R, Abbattista A, Miceli R, Valagussa P, Bonadonna G.  Time distribution of 
the recurrence risk for breast cancer patients undergoing mastectomy:  further support 
about the concept of tumor dormancy.  Breast Cancer Res Treat.  1996;41(2):177-185.  
 
 
 


 
 
 
Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  18 March 2015 
Page 1 of 31 
CONFIDENTIAL 
 
 
Amendment # 3 
Protocol Title:  A Randomized, Double-Blind, Placebo-Controlled, Multi-Center 
Phase 3 Study of Denosumab as Adjuvant Treatment for Women with Early-Stage 
Breast Cancer at High Risk of Recurrence (D-CARE) 
 
Amgen Protocol Number (Denosumab) 20060359 
IND # 9838 
EudraCT number 2009-011299-32 
 
Amendment Date: 
18 March 2015 
 
Rationale: 
The main purpose of this protocol amendment is to add disease-free survival (DFS) in 
the postmenopausal subset as a secondary endpoint based on recently published data 
supporting an enhanced treatment effect of adjuvant bisphosphonates in 
postmenopausal subjects with early breast cancer.  
Additional changes to the study protocol are summarized below: 
 
A summary of recent literature was included in the background section to support 
adding DFS in postmenopausal women as a secondary endpoint. 
 
The hazard ratio of denosumab compared with placebo was added for the 
postmenopausal subset. 
 
Pathological variables in tumor tissue from neoadjuvant subjects after surgery 
was added as an exploratory objective, as a large proportion of the enrolled 
subjects are neoadjuvant, where pathologic evaluation after surgery is of 
importance. 
 
The numbers of subjects with events (any disease recurrence or died, whichever 
comes last) required for the interim and final analyses was updated to account 
for event rates. 
 
The period of time for which subjects must not become pregnant or breastfeed 
following the end of treatment was changed from 7 months to 5 months, in 
accordance with Investigator’s Brochure and Informed Consent Form updates.   
 
Clarification was made in the language describing study duration for individual 
participants, frequency of follow-up visits, and visit windows, to facilitate study 
conduct. 


 
 
 
Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 
Date:  18 March 2015 
Page 2 of 31 
CONFIDENTIAL 
 
 
 
The duration of the study was changed based on the change in the 
expected/projected time to primary analysis. 
 
Section 9.1.3 was updated to also include atypical femoral fracture along with 
osteonecrosis of the jaw as adverse events of interest which should undergo 
adjudication by an independent panel of experts.   
 
Covariates which may be explored in relation to the primary and secondary 
efficacy endpoints were updated, and primary tumor size and lymph node status 
were added to the list of covariates, as these are important prognostic factors.  
 
The expected event rates at 3 years for bone metastasis-free survival (BMFS) 
and DFS were updated. 
 
The Key Sponsor Contact (Global) information was updated 
 
Minor editorial changes or clarifications were made throughout the protocol for 
consistency between sections, to facilitate study conduct, or to correct 
typographical errors. 


 
 
 
Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 (D-CARE) – Amendment 2 
Date:  15 August 2012 
Page 116 of 142 
 
Amendment 2 
Protocol Title:  A Randomized, Double-Blind, Placebo-Controlled, Multi-Center 
Phase 3 Study of Denosumab as Adjuvant Treatment for Women with Early-Stage 
Breast Cancer at High Risk of Recurrence (D-CARE) 
Denosumab (AMG 162) 
 
Amgen Protocol Number (Denosumab) 20060359  
IND # 9838 
 
EudraCT number 2009-011299-32 
 
Amendment Date: 
15 August 2012 
Rationale: 
The purpose of this amendment is to extend the collection of skeletal related event 
(SRE) information through the long-term follow-up.  Objectives and endpoints for SREs 
and bone metastasis were also modified. 
Additional changes to the study are summarized below: 
 
The fasting requirement has been removed from the urine collection for uNTx 
 
The reporting timeframe for Serious Adverse Events (SAE) has been changed from 
1 day to 24 hours 
 
The SAE reporting section has been updated to reflect the use of electronic SAE 
reporting 
 
Pregnancy and Lactation Surveillance Programs have been added to section 9 
 
Typographic and formatting errors, redundancies, and inconsistencies were 
corrected. 


 
 
 
Product:  Denosumab (AMG 162) 
Protocol Number:  20060359 (D-CARE) – Amendment 1 
Date:  05 May 2011 
Page 112 of 174 
 
Amendment 1 
Protocol Title:  A Randomized, Double-Blind, Placebo-Controlled, Multi-Center 
Phase 3 Study of Denosumab as Adjuvant Treatment for Women with Early-Stage 
Breast Cancer at High Risk of Recurrence (D-CARE) 
Denosumab (AMG 162) 
 
Amgen Protocol Number (Denosumab) 20060359  
IND # 9838 
 
EudraCT number 2009-011299-32 
 
Amendment Date: 
05 May 2011 
 
Rationale: 
The purpose of this amendment is to increase the window for screening imaging 
assessments to document disease extent from 12 weeks to 24 weeks.  This increase in 
the screening window will allow subjects additional time to complete all screening 
imaging assessments required for participation in the study.   
Additionally, in consideration of the length of time anticipated to reach the primary 
analysis date, a second formal interim analysis is being added. 
The amount of time expected to reach the primary analysis data cut-off date has been 
modified from 75 months to 77 months resulting in a change in the overall event rate 
from approximately 730 subjects to 735 subjects who have developed bone metastasis 
or died, and approximately 910 subjects to 922 subjects who have developed any 
disease recurrence or died, whichever comes last. 
Additional changes to the study are summarized below: 
• 
The number of centers is being increased from 400 to 500 sites globally 
• 
Breast density measurements have been included as an exploratory outcome 
(objective and endpoint) for the study. These assessments will be performed by the 
central imaging laboratory based on protocol-specified annual mammograms. No 
additional imaging will be required. 
• 
Certain study-related definitions have been clarified including a change to the end of 
study from the end of the treatment phase to the last assessment by the last subject.  
This change in definition does not affect the overall timing or conduct of the study.  
• 
Appendix C from the original protocol has been removed and replaced with an 
Investigational Product Instruction Manual.  Other appendices have been adjusted to 
accommodate this change. 
• 
Typographic and formatting errors, redundancies, and inconsistencies were 
corrected. 

SAP_001.pdf: 
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Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 2 
 
Table of Contents 
Table of Abbreviations ...................................................................................................... 6 
1. 
Introduction .............................................................................................................. 8 
2. 
Objectives ................................................................................................................ 8 
2.1 
Primary Objective ......................................................................................... 8 
2.2 
Secondary Objectives ................................................................................... 8 
2.3 
Exploratory Objectives .................................................................................. 8 
3. 
Study Overview ........................................................................................................ 9 
3.1 
Study Design ................................................................................................ 9 
3.2 
Sample Size ............................................................................................... 11 
4. 
Study Endpoints and Covariates ............................................................................ 12 
4.1 
Primary and Secondary Efficacy Endpoints ............................................... 12 
4.2 
Safety Endpoints ........................................................................................ 13 
4.2.1 
Adverse Events (AEs) ................................................................ 13 
4.2.2 
Laboratory Values ...................................................................... 14 
4.2.2.1 
Serum Chemistry ..................................................... 14 
4.2.2.2 
Hematology .............................................................. 14 
4.2.3 
Anti-denosumab Antibody .......................................................... 14 
4.2.4 
Vital Signs ................................................................................... 14 
4.2.5 
Performance Status .................................................................... 15 
4.3 
Exploratory Endpoints ................................................................................ 15 
4.3.1 
Efficacy Exploratory Endpoints ................................................... 15 
4.3.2 
Patient Reported Outcome (PRO) Endpoints ............................. 16 
4.3.3 
Denosumab Serum Concentration Levels .................................. 16 
4.3.4 
Bone Turnover Markers .............................................................. 17 
4.4 
Covariates .................................................................................................. 17 
5. 
Definitions .............................................................................................................. 18 
5.1 
Basic Definition ........................................................................................... 18 
5.2 
Study Points of Reference .......................................................................... 18 
5.3 
Study Dates ................................................................................................ 18 
5.4 
Study Time Intervals ................................................................................... 19 
5.5 
Subject Dispositions ................................................................................... 19 
5.6 
Study-specific Definitions ........................................................................... 20 
5.7 
Derived Variables ....................................................................................... 25 
6. 
Analysis Data Sets ................................................................................................. 31 
6.1 
Data Subsets .............................................................................................. 31 
6.1.1 
Full Analysis Set (FAS) ............................................................... 31 
6.1.2 
Per Protocol Set ......................................................................... 31 
6.1.3 
Safety Analysis Set ..................................................................... 33 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 3 
 
6.1.4 
Pharmacokinetic (PK) Analysis Set ............................................ 33 
6.2 
Subset for Interim Analysis ......................................................................... 33 
6.3 
Subgroup Analyses .................................................................................... 34 
7. 
Interim Analysis and Early Stopping Guidelines ..................................................... 34 
8. 
Data Screening and Acceptance ............................................................................ 37 
8.1 
General Principles ...................................................................................... 37 
8.2 
Data Handling and Electronic Transfer of Data .......................................... 37 
8.3 
Handling of Missing and Incomplete Data .................................................. 37 
8.3.1 
Missing Dates ............................................................................. 37 
8.3.2 
Assayed Values Below or Above Quantifiable Limits of 
Bone Turnover Marker (BTM) .................................................... 39 
8.3.3 
Missing / Unknown Values of Covariates ................................... 39 
8.3.4 
Missing PRO data ....................................................................... 39 
8.3.5 
Missing Pathological Complete Response ................................. 39 
8.4 
Assessment of Outliers ............................................................................... 39 
8.5 
Distributional Characteristics ...................................................................... 40 
8.6 
Validation of Statistical Analysis ................................................................. 40 
9. 
Statistical Methods of Analysis ............................................................................... 40 
9.1 
General Principles ...................................................................................... 40 
9.2 
Subject Accountability ................................................................................ 41 
9.3 
Demographic and Baseline Characteristics ................................................ 41 
9.3.1 
Demographics ............................................................................ 42 
9.3.2 
Baseline Characteristics ............................................................. 42 
9.3.3 
Bone-specific Medication History ............................................... 43 
9.3.4 
Fracture History .......................................................................... 43 
9.3.5 
Baseline PRO Characteristics and Analgesic Use ..................... 43 
9.4 
Safety Analyses .......................................................................................... 44 
9.4.1 
Adverse Events (AEs) ................................................................ 44 
9.4.1.1 
Events of Interests (EOIs) ........................................ 44 
9.4.1.2 
Osteonecrosis of the Jaw ......................................... 45 
9.4.1.3 
Atypical Femoral Fracture ........................................ 45 
9.4.2 
Investigational Product Exposure ............................................... 45 
9.4.3 
Concomitant Medications and Anti-neoplastic 
Therapies/Surgeries ................................................................... 46 
9.4.4 
ECOG Performance Status ........................................................ 46 
9.4.5 
Vital Signs ................................................................................... 46 
9.4.6 
Immunogenic Response ............................................................. 46 
9.4.7 
Clinical Laboratory Results ......................................................... 46 
9.5 
Efficacy Analyses ....................................................................................... 47 
9.5.1 
Primary and Secondary Efficacy Endpoints ............................... 48 
9.5.1.1 
Estimation of Outcomes ........................................... 48 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 4 
 
9.5.1.2 
Hypotheses to Be Tested ......................................... 48 
9.5.1.3 
Primary Analysis ...................................................... 49 
9.5.1.4 
Supportive Analyses ................................................ 50 
9.5.1.5 
Subgroup Analyses .................................................. 51 
9.5.1.6 
Analysis of Covariates ............................................. 52 
9.5.2 
Exploratory Endpoints ................................................................ 52 
9.5.2.1 
Time to Event Exploratory Endpoints ....................... 52 
9.5.2.2 
Analgesic Score ....................................................... 53 
9.5.2.3 
PRO Analysis ........................................................... 53 
9.5.2.4 
Breast Density .......................................................... 55 
9.5.2.5 
Pathological Complete Response ............................ 55 
9.5.2.6 
Residual Invasive Tumor Size ................................. 55 
9.5.2.7 
Serum Denosumab Trough 
Concentrations ......................................................... 55 
9.5.2.8 
Blood Biomarkers and Bone Turnover 
Markers .................................................................... 55 
10. 
Final Analysis of Data From Ltfu ............................................................................ 56 
11. 
Literature Citations  References ............................................................................ 57 
12. 
Appendices ............................................................................................................ 59 
12.1 
Technical Detail/Supplemental Information Regarding Statistical 
Procedures and Programs .......................................................................... 59 
12.1.1 
Dates .......................................................................................... 59 
12.1.2 
Visit Windows ............................................................................. 59 
12.2 
Reference Values / Toxicity Grades ........................................................... 63 
12.3 
Patient Report Outcome Forms/Instruments .............................................. 64 
12.3.1 
Patient Report Outcome Forms .................................................. 64 
12.3.2 
Patient Report Outcome Instruments ......................................... 64 
12.3.2.1 
Reliability and Validity of PRO Instruments ............. 64 
12.3.2.2 
PRO Question Mapping ........................................... 64 
12.3.2.3 
Scoring Algorithm for PROs ..................................... 65 
List of Tables 
Table 1.  Primary and Secondary Efficacy Endpoints ..................................................... 13 
Table 2.  Adverse Event .................................................................................................. 13 
Table 3.  Serum Chemistry ............................................................................................. 14 
Table 4.  Hematology ...................................................................................................... 14 
Table 5.  Anti-denosumab Antibody ................................................................................ 14 
Table 6.  Vital Signs ........................................................................................................ 14 
Table 7.  Performance Status ......................................................................................... 15 
Table 8.  Efficacy Exploratory Endpoints ........................................................................ 15 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 5 
 
Table 9.  PRO Endpoints ................................................................................................ 16 
Table 10.  Bone Turnover Markers ................................................................................. 17 
Table 11.  Decision Rule (1-sided) at Interim/Primary Analyses ..................................... 36 
Table 12.  Imputation Rules for Incomplete Dates .......................................................... 38 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 6 
 
Table of Abbreviations 
Abbreviation 
Definition 
AE 
adverse events 
AFF  
atypical femoral fracture 
AJCC 
American Joint Committee on Cancer 
αCTx 
C-telopeptide of type I collagen 
AQL 
above quantifiable level 
BMFS 
Bone metastasis-free survival 
BPI-SF 
Brief Pain Inventory – Short Form 
BQL 
below quantifiable level 
BI-RADS 
Breast Imaging-Reporting and Data System 
BSAP 
bone specific alkaline phosphatase 
BTM 
bone turnover marker 
CDM 
clinical data management 
CI 
confidence interval 
CRF 
case report form 
CRO 
clinical research organization 
CT 
computed tomography 
CTCAE  
common terminology criteria for adverse events 
DBP  
diastolic blood pressure  
DMC 
data monitoring committee 
DFS 
disease-free survival 
DRFS 
distant recurrence-free survival 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EOD 
extraosseous disease 
EOI 
event of interest 
EOS 
end of study 
EQ-5D 
EuroQol –5 Dimensions 
FAS 
full analysis set 
GEE 
generalized estimating equation 
HLT 
high level term 
IP 
investigational product 
LTFU 
Long-term follow-up 
MRI 
magnetic resonance imaging 
OME 
morphine equivalent 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 7 
 
Abbreviation 
Definition 
ONJ 
osteonecrosis of the jaw 
OS 
overall survival 
PRO 
patient reported outcomes 
RITS 
residual invasive tumor size 
SBP 
systolic blood pressure 
SPECT 
single-photon emission CT 
SRE(s) 
skeletal-related event(s) 
uNTx 
Urinary N-telopeptide of type I collagen 
VAS 
visual analogue scale 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 8 
 
1. 
Introduction 
This document outlines the planned statistical analyses for data collected within the 
scope of Amgen denosumab protocol 20060359, entitled “A Randomized, Double-Blind, 
Placebo-Controlled, Multi-Center Phase 3 Study of Denosumab as Adjuvant Treatment 
for Women with Early-Stage Breast Cancer at High Risk of Recurrence (D-CARE)”.  This 
statistical analysis plan (SAP) applies to the protocol amendment 4 dated on 
October 17, 2016.  The purpose of this plan is to provide general, and in some 
instances, specific guidelines from which the analysis will proceed.   
The primary analysis will include efficacy and safety data up to the primary analysis data 
cut-off date. The analysis time period/point for each endpoint is specified in Section 4. 
Final analysis will be conducted at the end of the long-term follow-up (LTFU) phase 
(Section 10). 
2. 
Objectives 
2.1 
Primary Objective 
To compare the treatment effect of denosumab with that of placebo on prolonging bone 
metastasis-free survival (BMFS) in subjects with early-stage breast cancer at high risk of 
disease recurrence.   
2.2 
Secondary Objectives 
To compare the treatment effect of denosumab with that of placebo on: 
• 
Disease-free survival (DFS) in the full study population 
• 
DFS in the postmenopausal subset  
• 
Overall survival (OS) 
• 
Distant recurrence-free survival (DRFS)  
Safety Objectives 
• 
To assess the safety and tolerability of denosumab compared with placebo 
2.3 
Exploratory Objectives 
To evaluate the treatment effect of denosumab compared with placebo on: 
• 
Time to first bone metastasis (excluding deaths) 
• 
Time to bone metastasis as site of first recurrence 
• 
Time to disease recurrence  
• 
Time to distant recurrence 
• 
Time to first on-study fracture (vertebral or non-vertebral fracture) 
• 
Time to first on-study skeletal-related event (SRE; following the development of bone 
metastasis) 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 9 
 
• 
Time to first on-study SRE or hypercalcemia (following the development of bone 
metastasis) 
• 
Time to first on-study symptomatic bone metastasis 
• 
Brief Pain Inventory - Short Form (BPI-SF) ‘worst’ pain score 
• 
BPI-SF pain severity and pain interference scales 
• 
EQ-5D health index and visual analogue scale (VAS) scores  
• 
Analgesic use 
• 
Breast density 
• 
Pathological variables in tumor tissue from neoadjuvant subjects after surgery 
• 
Pharmacokinetics 
− 
Serum trough levels of denosumab 
• 
Pharmacodynamic response 
− 
Levels and dynamics of bone turnover markers and potential other 
pharmacodynamic markers 
To investigate other potential biomarker development (eg, biochemical levels and 
abundance of drug targets) by biochemical analysis of blood and/or tumor tissue, and 
correlate with treatment outcomes 
To investigate the association of tumor genetic variations in cancer genes, drug/pathway 
target genes, and/or other biomarker genes with treatment outcomes 
To investigate the genetic variation in cancer genes, drug/pathway target genes, and/or 
other biomarker genes, and correlate with treatment outcomes (optional; requires 
separate informed consent) 
3. 
Study Overview 
3.1 
Study Design 
This is an international, phase 3, randomized, double-blind, placebo-controlled study in 
women with early-stage (stage II or III) breast cancer at high risk of disease recurrence. 
Approximately 4,500 subjects will be randomized in a 1:1 ratio to receive denosumab 
120 mg or matching placebo. Randomization will be stratified based on the following 
criteria at the time of study entry: 
• 
Breast cancer therapy / Lymph node (LN) status:  neo-adjuvant therapy / any LN 
status versus [vs] adjuvant therapy / LN negative (based on axillary LN dissection, or 
based on sentinel node [SN] status) vs adjuvant therapy / LN positive 
• 
Hormone receptor (estrogen receptor [ER] / progesterone receptor [PR]) status:  
ER and/or PR positive vs ER and PR negative 
• 
Human epidermal growth factor receptor 2 (HER-2) status:  HER-2 positive 
vs HER-2 negative 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 10 
 
• 
Age:  < 50 vs ≥ 50 
• 
Region:  Japan vs Other 
Subjects will receive denosumab 120 mg or matching placebo subcutaneously (SC) 
every 4 weeks (Q4W; ± 7 days) for approximately 6 months followed by denosumab 
120 mg or matching placebo SC every 3 months (Q3M; ie, every 12 weeks ± 14 days) for 
4½ years (approximately 54 months), for a total treatment duration of 5 years 
(approximately 60 months). As there are approved bone-targeted therapies for the 
treatment of bone metastasis, subjects who develop bone metastasis will permanently 
discontinue investigational treatment, complete the End of Treatment Phase (EOTP) 
visit, and enter LTFU upon documented evidence of bone metastasis (per central 
imaging analysis or biopsy). For an individual subject, the maximum duration of LTFU 
after completing the EOTP visit is 5 years (total study duration for an individual subject is 
up to 10 years from the date of randomization). During the first approximate 6 months of 
treatment, investigational product (denosumab or matching placebo) may be 
administered Q3W to subjects receiving or scheduled to receive Q3W 
adjuvant/neoadjuvant chemotherapy, to minimize patient clinic visits and enhance 
adherence to treatment. There must be at least a 3-week interval between 
administrations of investigational product. All subjects will be required to receive vitamin 
D and calcium supplementation at standard doses (at least 500 mg calcium and 
at least 400 IU of vitamin D), unless documented hypercalcemia develops on study.  
After completing the treatment phase of the study, subjects will then enter LTFU for 
approximately 5 years (60 months) following the EOTP visit. The study requirements 
during LTFU are different before and after primary analysis data cut-off date. 
Specifically, before the primary analysis data cut-off date, all subjects (including subjects 
with documented evidence of bone metastasis) should be followed by clinic visit or 
telephone contact every 3 months (every 12 weeks ± 14 days) for approximately 
6 months (ie, first 2 visits of LTFU following EOTP) to assess clinical fractures/SREs, 
hypercalcemia of malignancy, breast cancer therapy, concomitant medications, 
patient-reported outcomes [BPI-SF, EQ-5D], disease recurrence status 
(until documented evidence of bone metastasis  [per central imaging analysis or biopsy], 
not required for subjects with documented evidence of bone metastasis), and survival. 
All subjects without documented evidence of bone metastasis following the completion 
of the initial 6 month LTFU period should be followed by clinic visit or telephone contact 
every 3 months (every 12 weeks ± 14 days) to assess clinical fractures/SREs, 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 11 
 
hypercalcemia, disease recurrence status (until documented evidence of 
bone metastasis [per central imaging analysis or biopsy]), and survival. Subjects with 
documented evidence of bone metastasis including subjects whose bone metastasis is 
confirmed after the initial 6 month (per central imaging analysis or biopsy): following the 
completion of the initial 6 month LTFU period should be followed by clinic visit or 
telephone contact every 6 months (± 1 month) to assess SREs, hypercalcemia, and 
survival. Following the primary analysis data cut-off date, all subjects should complete 
the EOTP visit and will be followed by clinic visit or telephone contact every 6 months 
(± 1 month) for survival only. 
A data monitoring committee (DMC) external to Amgen and external to Daiichi Sankyo 
Co., Ltd. will review safety data at regular intervals, as outlined in the DMC charter 
(approximately twice yearly; the start date will depend on subject accrual rates). This 
external DMC will conduct 1 interim analysis of efficacy after approximately 367 subjects 
have developed bone metastasis or died, and approximately 555 subjects have 
developed any disease recurrence or died, whichever comes last. To ensure timely 
conduct of the interim analysis, the interim analysis may be conducted early, as soon as 
approximately 6 months after the sufficient event number has been reached for either 
BMFS or DFS in the full study population, even if the event number for the other 
endpoint has not been reached.  
The primary analysis will be conducted after all enrolled subjects have had the 
opportunity to complete 5 years of treatment from study day 1. 
3.2 
Sample Size 
The sample size calculation is based on the primary endpoint, BMFS, and is estimated 
using EAST 6 or above.  Estimates of the event rates for BMFS and DFS for the target 
population are based on (Colleoni et al., 2000) and on recent published and unpublished 
data, including (Francis et al., 2008, Martin et al., 2005) for the HER-2 negative 
population, (Romond et al., 2005, Slamon et al, 2006) for the HER-2 positive population, 
(Howell et al., 2005, Thurlimann et al., 2005) for the population receiving adjuvant 
hormonal therapy, and (Coleman et al., 2014) for the use of adjuvant zoledronic acid in 
stage II-III breast cancer.  Based on the reported event rates, the event rate proportions 
for disease recurrence in the bone, the viscera, or death reported by (Colleoni et 
al., 2000) and (Coleman et al. 2014), and considering the availability of some breast 
cancer adjuvant therapies, the BMFS rates at three years is expected to be 
approximately 90.5% in the control group. Disease recurrence risk after primary breast 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 12 
 
cancer treatment can vary over time (Cheng et al, 2012). For DFS, it is assumed that the 
time to event (death or disease recurrence) in the control group follows a piece-wise 
exponential distribution with a risk of about 5.5% per year for the first 3 years and 
3.2% per year afterwards in the full study population, and a piece-wise exponential 
distribution with a risk of about 5.6% per year for the first 3 years and 3.7% per year 
afterwards in the postmenopausal subset. It is anticipated that the true hazard ratio of 
denosumab compared with placebo is 0.83 in the full study population and 0.76 in the 
postmenopausal subset. 
The primary analysis will be conducted after all enrolled subjects have had the 
opportunity to complete 5 years of treatment from study day 1. With 4,500 subjects, an 
enrollment period of approximately 27 months, the study is estimated to reach the 
primary analysis data cut-off date in approximately 87 months (ie, 7 years and 3 months) 
from the start of enrollment.  
With a loss to follow-up rate of 6% per year, for BMFS, if the true hazard ratio is 0.8, the 
power to detect superiority of denosumab over placebo in the primary analysis is 
estimated to be approximately 80%. 
4. 
Study Endpoints and Covariates 
4.1 
Primary and Secondary Efficacy Endpoints 
The primary and secondary efficacy endpoints are listed in Table 1.   


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 13 
 
Table 1.  Primary and Secondary Efficacy Endpoints  
 
Endpoints 
Analysis Time Period 
Primary 
Bone metastasis-free survival (determined by 
the time from randomization to the 
first observation of bone metastasis or death 
from any cause) 
Randomization through the 
primary analysis data cut-off 
date 
Secondary 
 
Disease-free survival in the full study 
population (determined by the time from 
randomization to the first observation of 
disease recurrence or death from any 
cause)  
 
Disease-free survival in the 
postmenopausal subset (determined by the 
time from randomization to the first 
observation of disease recurrence or death 
from any cause) 
 
Overall survival (determined by the time 
from randomization to death from any 
cause)  
 
Distant recurrence-free survival 
(determined by the time from 
randomization to the first observation of 
distant metastasis or death from any 
cause) 
4.2 
Safety Endpoints 
4.2.1 
Adverse Events (AEs) 
Table 2.  Adverse Event 
Parameter 
Analysis Time Period 
Treatment-emergent adverse events: 
 
Study day 1 through 30 
days after the last dose for 
subjects who 
discontinued/completed IP 
or the primary analysis data 
cut-off date, whichever is 
earlier. 
 
All AEs 
 
AEs leading to investigational product (IP)  discontinuation  
 
AEs leading to study discontinuation 
 
Serious AEs 
 
Serious AEs leading to IP discontinuation 
 
Serious AEs leading to study discontinuation 
 
CTCAE Grade 3, 4, and 5 AEs 
 
Fatal AEs 
 
All AEs related to IP  
 
Adverse events of interest (EOIs) 
Note: The Common Terminology Criteria for Adverse Events (CTCAE Version 3.0 or higher) will be used. 


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Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 16 
 
4.3.2 
Patient Reported Outcome (PRO) Endpoints 
Recorded values and changes from baseline will be provided using descriptive statistics 
for each PRO parameter. 
Table 9.  PRO Endpoints 
Parameter 
Analysis Time Point 
Analgesic Use 
Baseline through the primary 
analysis data cut-off date 
(details in Section 9.5.2.2) 
   Analgesic score  
   Proportion of subjects with analgesic score ≥ 3 (in 
subjects with baseline scores 0-2) 
 
 
 
BPI-SF 
Baseline through the primary 
analysis data cut-off date 
(details in Section 9.5.2.3) 
 
 
“Worst” pain score 
 
Pain severity score 
Pain interference score 
 
Time to  2-point increase from baseline in “Worst” 
pain score (in subjects with baseline scores 0-8) 
 
Time to > 4-point in “Worst” pain score (in subjects 
with baseline scores 0-4) 
 
Proportion of subjects with  2-point increase from 
baseline in “Worst” pain score (in subjects with 
baseline scores 0-8) 
 
Proportion of subjects with “Worst” 
 pain score > 4-point  (in subjects with baseline scores 
0-4) 
 
 
EQ-5D 
Baseline through the primary 
analysis data cut-off date 
(details in Section 9.5.2.3) 
 
Health Index score 
 
Visual Analogue Scale (VAS) 
 
 
4.3.3 
Denosumab Serum Concentration Levels 
Serum denosumab concentration levels will be obtained from a subset of subjects prior 
to administration of the investigational products and on study. For the primary analyses, 
serum denosumab concentration levels will be summarized by visit up to the primary 
analysis data cut-off date. 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 17 
 
4.3.4 
Bone Turnover Markers 
Table 10.  Bone Turnover Markers 
Parameter 
Analysis Time Point 
BTMs (Recorded values, change and percent change from 
baseline): 
Urinary N-telopeptide corrected by urine   creatinine 
(uNTx/Cr) 
Urinary C-telopeptide corrected by urine creatinine 
(αCTx/Cr) 
Bone specific alkaline phosphatase (BSAP) 
Study day 1 and then by visit  
4.4 
Covariates 
The relationship of the following covariates to the primary and key secondary efficacy 
endpoints may be explored:  
 
Breast cancer therapy / Lymph node status (neo-adjuvant therapy / any LN status, 
adjuvant therapy / LN negative, and adjuvant therapy / LN positive) 
 
Hormone receptor (ER/PR) status (positive, negative) 
 
HER-2 status (positive, negative) 
 
Age (continuous) 
 
Menopausal status (premenopausal, postmenopausal)  
 
Postmenopausal status (>5 years since menopause, other [including premenopause, 
≤5 years since menopause, and unknown]) 
 
Breast cancer AJCC stage (IA or IB or IIA, IIB, IIIA, IIIB and above) 
 
Primary tumor size (T stage: T0 or T1 or T1a -T1c or T1mi or Tis, T2, T3, T4 or 
T4a-T4d) 
 
Lymph node status (N-stage: N0 or pN0 or pN0 (i-) or pN0 (i+) or pN0 (mol-) or 
pN0 (mol+) or pN1mi,  N1 or pN1 or pN1a - pN1c,  N2 or N2a or N2b or pN2 or pN2a 
or pN2b,   N3 or N3a - N3c or pN3 or pN3a - pN3a).  
 
Breast cancer histopathologic grade (G1=low, G2=intermediate, G3=high, not 
evaluable/missing)  
 
Region (Japan, Other)  
 
Global Region (North America, Eastern Europe, Western Europe and Australia, Asia, 
and Other) 
Other covariates reported in the literature or from other ongoing Amgen studies may be 
considered in the analysis as appropriate at the time of analysis. 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 18 
 
5. 
Definitions 
5.1 
Basic Definition 
Investigational Product (IP) 
IP for this study refers to denosumab or placebo. 
IVRS 
An IVRS (interactive voice response system) will be used in this study to assign eligible 
subjects to randomized treatment, manage IP supply at the site, and unblind subjects as 
needed. 
Postmenopausal Subset 
This subset includes all randomized subjects who were postmenopausal at enrollment. 
In this study, postmenopausal status is defined as follows: 
• 
Having undergone a bilateral oophorectomy 
• 
Age ≥ 60 years 
• 
Age 45 to 59 years meeting one of the criteria, ie, either amenorrhea 
> 12 months with an intact uterus and ≥ 1 intact ovary(ies); or amenorrhea for 
≤ 12 months and FSH and estradiol in the postmenopausal range 
Note that patients who have received adjuvant or neoadjuvant chemotherapy must have 
met at least 1 of the above criteria for postmenopausal status prior to that 
chemotherapy. 
5.2 
Study Points of Reference 
Study Day 1 
The date of the first IP administration or the date of enrollment for subjects who are not 
administrated any dose of IP. 
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. 
Analysis Visit Window 
Per protocol, all tests and procedures will be performed within a time window to allow for 
variations in scheduling. The analysis visit windows defined in Section 12.1.2 will be 
used to assign measurements to the appropriate nominal visit for the analyses. 
5.3 
Study Dates 
Informed Consent Date 
The informed consent date is the date on which the subject signs the informed consent. 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 19 
 
Enrollment (Randomization) Date 
The date on which a subject is assigned to one of the treatment arms through the IVRS 
system. 
First Dose Date 
The first dose date is the date on which a subject is administered the first non-zero dose 
of IP, required by protocol to be ≤ 8 calendar days after randomization to the study. 
Last Dose Date 
The date on which a subject is administered her final non-zero dose of IP.   
Primary Analysis Data Cut-off Date 
The date, defined by Amgen, on which all enrolled subjects would have had the 
opportunity to complete 5 years of treatment from study day 1. The primary analysis data 
cut-off date for this study is assigned to August 31, 2017. 
End of Treatment Phase (EOTP) Date for a Subject 
The end of treatment phase date is the date recorded on the End of Treatment Phase 
page of the Case Report Form (CRF) for an enrolled subject.  
End of Study Date for a Subject 
The end of study date is the date recorded on the End of Study page of the CRF for an 
enrolled subject.  
5.4 
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. This period is required by protocol to be ≤ 4 weeks.  
On-Study Period (up to the primary analysis data cut-off date) 
For the primary analyses, 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 (for subjects who 
terminated study before the primary analysis data cut-off date) or the primary analysis 
data cut-off date, whichever is earlier.   
5.5 
Subject Dispositions 
Enrolled 
Individuals are considered enrolled if they have been assigned a randomization number 
and they have a non-missing date of randomization.  Enrolled individuals are referred to 
as “subjects”. 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 20 
 
On-Study (up to the primary data cut-off date) 
For the primary analyses, subjects are considered on-study during the period between 
the date of enrollment and the end of study date on the CRF or the primary data analysis 
cut-off date, whichever comes first.   
Exposed to Investigational Product 
Subjects are considered as exposed to IP if they have received one or more non-zero 
doses of IP.  
5.6 
Study-specific Definitions 
Onsite Clinical Visit  
In the treatment phase, onsite clinical visits are determined as the visits at which 
physical exam and/or vital signs and/or ECOG have been assessed or IP dosing was 
performed. During LTFU, onsite clinical visits are determined as the visits at which the 
type of contact is documented as Clinical Visit or Another Physician on the Follow-up 
Survival Status CRF page.   
Solitary Lesion (Via Central Imaging Analysis) 
Subjects are considered to have a solitary lesion if there is only a single lesion, 
bone metastasis or extraosseous disease (EOD) lesion, identified by the central imaging 
vendor across all body sites. If the single lesion is inside the bone, the subject is 
considered to have a solitary bone metastasis lesion. Otherwise, the subject is 
considered to have a solitary EOD lesion.  
Bone Metastasis  
Bone metastasis must be confirmed by central imaging analysis or by biopsy, and it 
includes any of the following: 
• 
Bone metastasis lesion that is confirmed via central imaging analysis and is not a 
solitary lesion  
• 
Solitary bone metastasis lesion via central imaging analysis [see definition of 
“solitary lesion (via central imaging analysis)” above] confirmed by the 
investigator with a positive biopsy unless biopsy is medically contra-indicated  
• 
Bone metastasis determined by the investigator and confirmed via positive 
biopsy  
Any positive skeletal scintigraphy (‘bone scan’) (per central imaging analysis) must be 
confirmed using X-ray, computerized tomography (CT), magnetic resonance imaging 
(MRI), or biopsy evidence of lesions consistent with bone metastasis. Evidence of 
disseminated tumor cells in bone marrow is not sufficient for determination of disease 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 21 
 
recurrence. Development of new primary malignancy in bone will not be considered as 
bone metastasis. 
Extraosseous Disease (EOD)  
EOD must be confirmed by the central imaging analysis or by biopsy/cytology, and it 
includes any of the following  
• 
EOD lesion that is confirmed via central imaging analysis and is not a solitary 
lesion 
• 
Solitary EOD lesion via central imaging analysis [see definition of “solitary lesion 
(via central imaging analysis)” above] confirmed by the investigator with a 
positive biopsy or cytology unless biopsy/cytology is medically contra-indicated 
• 
EOD determined by the investigator and confirmed via positive biopsy or 
cytology. Cytology or biopsy is required for diagnosis of malignant effusion 
(eg, pleural effusion, pericardial effusion, or ascites) or meningeal carcinomatosis 
(cerebrospinal fluid).  
Local-regional findings (see definition below) prior to surgical (± radiation) treatment with 
curative intent are not considered as EOD.  For a subject with local-regional findings 
after the surgical (± radiation) treatment with curative intent, these findings will be 
considered as EOD (local-regional disease recurrence) if at least one of them is 
confirmed by positive biopsy or cytology. For a neoadjuvant subject without surgical 
(± radiation) treatment with curative intent, all her local-regional findings will be 
considered as EOD (local-regional disease recurrence) if at least one of these findings is 
confirmed by positive biopsy or cytology.  
Development of non-breast cancer new primary malignancy will not be considered as 
EOD. 
Local-Regional Findings  
Defined as potential development of breast cancer in any soft tissue or skin of the 
ipsilateral chest wall; or in the regional lymph nodes, including ipsilateral axillary, 
ipsilateral internal mammary, ipsilateral supraclavicular, and/or ipsilateral infraclavicular 
lymph nodes, and/or in the soft tissue of the ipsilateral axilla. Specifically, the local body 
sites include breast and non-bone chest wall. The regional body sites include axillary 
node, axillary non-nodal, infraclavicular nodes, internal mammary node, intramammary 
node, supraclavicular nodes, and subpectoral node. 
Distant Disease Recurrence 
Distant disease recurrence is defined as the development of breast cancer in any distant 
site (including the skin, subcutaneous tissue [other than skin or subcutaneous tissue 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 22 
 
areas identified above], and the contralateral breast, within others) and/or distant lymph 
nodes (ie, any lymph nodes other than local or regional lymph nodes as defined above). 
In a word, distant disease recurrence includes all bone metastasis as well as any EOD 
other than local-regional disease recurrence defined above. Development of non-breast 
cancer new primary malignancy will not be considered as distant disease recurrence.  
Breast Cancer Disease Recurrence  
Breast cancer disease recurrence includes bone metastasis and EOD defined above.  
Bone Metastasis [including investigator reported events] 
Bone metastasis [including investigator reported events] includes bone metastasis 
defined above and clinically diagnosed breast cancer recurrence in bone, specifically 
includes any of the following 
• 
Bone metastasis lesion that is confirmed via central imaging analysis and is not a 
solitary lesion  
• 
Solitary bone metastasis lesion via central imaging analysis [see definition of 
“solitary lesion (via central imaging analysis)” above] confirmed by the 
investigator with a positive biopsy unless biopsy is medically contra-indicated  
• 
Bone metastasis determined by the investigator via any diagnostic procedure 
Any positive skeletal scintigraphy (‘bone scan’) (per central imaging analysis) must be 
confirmed using X-ray, CT, or MRI. Evidence of disseminated tumor cells in bone 
marrow is not sufficient for determination of disease recurrence. Development of new 
primary malignancy in bone will not be considered as bone metastasis. 
Extraosseous Disease (EOD) [including investigator reported events] 
EOD [including investigator reported events] includes EOD defined above and clinically 
diagnosed breast cancer recurrence at a body location outside the bone, specifically 
includes any of the following  
• 
EOD lesion that is confirmed via central imaging analysis and is not a solitary 
lesion 
• 
Solitary EOD lesion via central imaging analysis [see definition of “solitary lesion 
(via central imaging analysis)” above] confirmed by the investigator with a 
positive biopsy or cytology unless biopsy/cytology is medically contra-indicated 
• 
EOD determined by the investigator via any diagnostic procedure 
Local-regional findings (see definition above) prior to surgical (± radiation) treatment with 
curative intent are not considered as EOD [including investigator reported events]. For a 
subject with local-regional findings after the surgical (± radiation) treatment with curative 
intent, these findings will be considered as EOD (local-regional disease recurrence) 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 23 
 
[including investigator reported events] if at least one of them is determined by the 
investigator via any diagnostic procedure. For a neoadjuvant subject without surgical 
(± radiation) treatment with curative intent, all her local-regional findings will be 
considered as EOD (local-regional disease recurrence) [including investigator reported 
events] if at least one of these findings is determined by the investigator via any 
diagnostic procedure.  
Development of non-breast cancer new primary malignancy will not be considered as 
EOD [including investigator reported events] 
Breast Cancer Disease Recurrence [including investigator reported events] 
Breast cancer disease recurrence [including investigator reported events] includes bone 
metastasis [including investigator reported events] and EOD [including investigator 
reported events] defined above. 
Fracture (Vertebral or Non-vertebral Fracture, Prior to Bone Metastasis)   
Only fractures occurring before 12 weeks prior to the first bone metastasis are 
considered. Fractures (vertebral or non-vertebral) includes fractures, which are 
confirmed by central imaging analysis, occurring at any site except skull, facial, 
mandible, metacarpus, finger phalanges, and toe phalanges. In addition, fractures 
associated with high trauma severity (ie, fall from higher than about 20 inches, or severe 
trauma other than a fall) will be excluded.  
Skeletal Related Event (SRE) 
A SRE is defined as one of the following: pathologic fracture, radiation therapy to bone, 
surgery to bone, or spinal cord compression. All such events that occur from 12 weeks 
prior to the first confirmed bone metastasis are considered SRE in this study. 
Pathologic Fracture  
Pathologic fractures are those new bone fractures that occur spontaneously in subjects 
with bone metastases and are not a result of severe trauma (ie, fall from higher than 
about 20 inches, or severe trauma other than a fall).  Pathologic fractures are identified 
or confirmed by the central imaging vendor. The severity of the trauma will be 
determined by the investigator on the CRF. If a fracture is reported by central imaging 
vendor but not in the CRF it will be considered as not due to severe trauma.   
Radiation Therapy to Bone 
Radiation therapy to bone in subjects with bone metastases includes radiation for pain 
control (including use of radioisotopes), to treat or prevent pathologic fractures, or to 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 24 
 
treat or prevent spinal cord compression.  These events will be captured on the CRF.  
Radiation may be administered over a period of time. Only the start date of radiation will 
be relevant when counting skeletal events.   
Surgery to Bone 
Surgery to bone in subjects with bone metastases includes procedures to set or stabilize 
a pathologic fracture, or to prevent an imminent pathologic fracture or spinal cord 
compression.  These events will be captured on the CRF. 
Spinal Cord Compression 
Spinal cord compression events in subjects with bone metastases must be confirmed by 
the central imaging vendor using appropriate radiographic imaging (eg, myelogram, MRI 
or CT scans), and not due to trauma per investigator’s evaluation. 
Hypercalcemia of Malignancy 
Clinical events of hypercalcemia of malignancy will be collected on the CRF throughout 
the study and during LTFU prior to primary analysis data cut-off date.  Hypercalcemia of 
malignancy is defined in this study as a serum calcium value (albumin-adjusted if 
necessary) of CTCAE version 3.0 grade 2 or greater (ie, > 11.5 mg/dL) during the 
treatment phase, and CTCAE grade 2 or greater events recorded on the 
Calcium Abnormalities CRF page during LTFU.   
Breast Density 
Breast density will be determined based on standard mammography imaging, and 
assessed according to the Breast Imaging-Reporting and Data System (BI-RADS) 
classification of overall breast composition as follows: 
• 
The breast is almost entirely fat (< 25% glandular) 
• 
There are scattered fibroglandular densities (approximately 25 – 50% glandular)  
• 
The breast tissue is heterogeneously dense, which could obscure detection of 
small masses (approximately 51 – 75% glandular) 
• 
The breast tissue is extremely dense. This may lower the sensitivity of 
mammography (> 75% glandular). 
Pathological Complete Response  
There has not been a uniform definition of pathological complete response. In this study, 
pathological complete response following the completion of surgery for breast cancer for 
neo-adjuvant subjects is assessed per investigators’ justification based on the evaluation 
performed by the local pathologist. A complete pathologic response is considered if no 
invasive or noninvasive residual disease was found in the breast or axillary lymph nodes. 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 25 
 
Residual Invasive Tumor Size (RITS) 
There has not been a uniform definition of RITS. In this study, RITS following the 
completion of surgery for breast cancer for neo-adjuvant subjects is assessed per 
investigators’ justification based on the evaluation performed by the local pathologist. A 
RITS “0 mm” is considered if no residual invasive tumor was recorded in the breast or 
axillary lymph nodes. 
5.7 
Derived Variables 
Baseline Value 
Baseline value is the latest recorded measurement on or prior to the day of the first dose 
of IP. If a subject doesn’t receive IP, baseline is the latest recorded measurement on or 
prior to the enrollment date. 
Change from Baseline Value 
The arithmetic difference between a value of interest and a baseline value: Change from 
baseline value = (value of interest - baseline value) 
Percent Change from Baseline Value 
The ratio of the arithmetic difference between a value of interest and the baseline value 
to the baseline value multiplied by 100: Percent change from baseline value = [(value of 
interest - baseline value) / baseline value] * 100. 
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 EDC RAVE database. 
Time to Event for Efficacy 
Time interval (days) from the randomization date to the date of occurrence of the event 
or censorship during the given period: 
Time interval = (date of occurrence of the event or 
censorship –  randomization date) +1 


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 26 
 
Time to Event for Safety 
Time interval (days) from the first dose date to the date of occurrence of the event or 
censorship during the given period: 
Time interval = (date of occurrence of the event or censorship – first dose date) +1 
Last Assessment Date (Via Central Imaging Analysis) for Bone Metastasis 
Defined as the exam date of the latest imaging record among all the following imaging 
records from the central imaging analysis. If no such record exists on study, the 
last assessment date (via central imaging analysis) for bone metastasis is defined as the 
randomization date. 
• 
Whole-body planar radioisotope bone scan  
• 
Whole-body single-photon emission CT (SPECT) scan  
Last Assessment Date (Via Central Imaging Analysis) for Disease Recurrence 
Defined as the exam date of the latest imaging record among all the following imaging 
records from the central imaging analysis. If no such record exists on study, the 
last assessment date (via central imaging analysis) for disease recurrence is defined as 
the randomization date.  
• 
Whole-body planar radioisotope bone scan  
• 
Whole-body single-photon emission CT (SPECT) scan  
• 
CT of the chest  
• 
CT of the abdomen 
• 
MRI of the chest  
• 
MRI of the abdomen 
Bone Metastasis-free Survival (BMFS) Time 
Time interval (days) from the randomization date to the date of first occurrence of bone 
metastasis (ie, first documented evidence per central imaging analysis or per the 
investigator via confirmation procedure of biopsy) or death from any cause, whichever 
comes first.  Subjects last known to be alive, who have not experienced bone metastasis, 
are censored at their last assessment date (via central imaging analysis) for bone 
metastasis defined above, or at the primary analysis data cut-off date, whichever comes 
first. Subjects who had first occurrence of bone metastasis before randomization will be 
censored at their randomization date.  


Product:  Denosumab 
Statistical Analysis Plan:  20060359 
Date:  15 November 2017 
Page 27 
 
Disease-free Survival (DFS) Time 
Time interval (days) from the randomization date to the date of first observation of 
disease recurrence (ie, first documented evidence per central imaging analysis or 
per the investigator via confirmation procedure of biopsy or cytology) or death from any 
cause, whichever comes first.  Subjects last known to be alive, who have not 
experienced recurrence of disease, are censored at their last assessment date (via 
central imaging analysis) for disease recurrence defined above, or at the primary 
analysis data cut-off date, whichever comes first. Subjects who had first disease 
recurrence before randomization will be censored at their randomization date. 
Overall Survival (OS) Time 
Time interval (days) from the randomization date to the date of death from any cause.  
Subjects last known to be alive are censored at their last contact date, or at the primary 
analysis data cut-off date, whichever comes first. 
Distant Recurrence-free Survival (DRFS) Time 
Time interval (days) from the randomization date to the date of first observation of 
distant disease recurrence or death from any cause, whichever comes first.  
Subjects last known to be alive, who have not experienced distant disease recurrence, 
are censored at their last assessment date (via central imaging analysis) for disease 
recurrence defined above, or at the primary analysis data cut-off date, whichever comes 
first. Subjects who had first distant recurrence before randomization will be censored at 
their randomization date. 
Time to First Bone Metastasis (excluding death) 
Time interval (days) from the randomization date to the date of first observation of bone 
metastasis (ie, first documented evidence per central imaging analysis or per the 
investigator via confirmation procedure of biopsy).  Subjects, who have not experienced 
bone metastasis, are censored at their last assessment date (via central imaging 
analysis) for bone metastasis defined above, or at the primary analysis data cut-off date, 
whichever comes first. Subjects who had first occurrence of bone metastasis before 
randomization will be censored at their randomization date. 
Time to Bone Metastasis as Site of First Recurrence (excluding death) 
Time interval (days) from the randomization date to the date of first observation of bone 
metastasis as site of first disease recurrence. Subjects, who have not experienced bone 
metastasis as site of first recurrence, are censored at the time of first EOD recurrence 
(for cause-specific analysis), or at their last assessment date (via central imaging 


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analysis) for bone metastasis defined above, or at the primary analysis data cut-off date, 
whichever comes first. Subjects who had first disease recurrence before randomization 
will be censored at their randomization date. 
Time to Disease Recurrence 
Time interval (days) from the randomization date to the date of first observation of 
disease recurrence, excluding death.  Subjects, who have not experienced recurrence of 
disease, are censored at their last assessment date (via central imaging analysis) for 
disease recurrence defined above, or at the primary analysis data cut-off date, 
whichever comes first. Subjects who had first disease recurrence before randomization 
will be censored at their randomization date. 
Time to Distant Recurrence 
Time interval (days) from the randomization date to the date of first observation of 
distant recurrence, excluding death.  Subjects, who have not experienced distant 
recurrence, are censored at their last assessment date (via central imaging analysis) for 
disease recurrence defined above, or at the primary analysis data cut-off date, 
whichever comes first. Subjects who had first distant recurrence before randomization 
will be censored at their randomization date.  
Time to First On-study Fracture (Prior to Bone Metastasis) 
Time interval (days) from the randomization date to the date of first fracture (vertebral or 
non-vertebral fracture) prior to the development of bone metastasis (up to 12 weeks prior 
to the date of first diagnosis of bone metastasis).  Subjects, who have not experienced a 
fracture on study, are censored at 12 weeks before the time of development of bone 
metastasis, at their last contact date, or at the primary analysis data cut-off date, 
whichever comes first. 
Time to First SRE  
Time interval (days) from the randomization date to the date of first on-study SRE 
(pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord 
compression) following the development of bone metastasis (including 12 weeks prior to 
the date of first diagnosis of bone metastasis). Subjects who have not experienced an 
SRE on study are censored at their last contact date, or at the primary analysis data 
cut-off date, whichever comes first.  


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Time to First SRE or Hypercalcemia  
Time interval (days) from the randomization date to the date of first on-study SRE 
(pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord 
compression) or hypercalcemia following the development of bone metastasis (including 
12 weeks prior to the date of first diagnosis of bone metastasis).  Subjects, who have not 
experienced a SRE or hypercalcemia on study, are censored at their last contact date, 
or at the primary analysis data cut-off date, whichever comes first. 
Time to First On-study Symptomatic Bone Metastasis  
Time interval (days) from the randomization date to the date of first on-study observation 
of bone metastasis which is accompanied by symptom at the time of detection. Subjects 
who have not experienced symptomatic bone metastasis are censored at their 
first on-study asymptomatic bone metastasis date (for cause-specific analysis), at their 
last assessment date (via central imaging analysis) for bone metastasis defined above, 
or at the primary analysis data cut-off date, whichever comes first. Subjects who had 
first symptomatic bone metastasis before randomization will be censored at their 
randomization date. 
Time to ≥ 2-point Increase from Baseline in “Worst” Pain Score 
Time interval (days) from the randomization date to the date of first observation of 
≥ 2-point increase from baseline in “Worst” pain score.  Subjects, who have not 
experienced the event of interest, are censored at the later of the randomization date 
and the last BPI-SF assessment date, or at the primary analysis data cut-off date, 
whichever comes first.  
Time to ≥ 2-point Increase from Baseline in “Worst” Pain Score (After 6 Months 
Post Randomization) 
Time interval (days) from the randomization date to the date of first observation of 
≥-2-point increase from baseline in “Worst” pain score occurred after 6 months 
post randomization.  Subjects, who have not experienced the event of interest after 
6 months post randomization, are censored at the later of 6 months post randomization 
and the last BPI-SF assessment, or at the primary analysis data cut-off date, whichever 
comes first. 
Time to > 4-point in “Worst” Pain Score 
Time interval (days) from the randomization date to the date of first observation of 
> 4-point in “Worst” pain score.  Subjects, who have not experienced the event of 


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interest, are censored at the later of the randomization date and the last BPI-SF 
assessment, or at the primary analysis data cut-off date, whichever comes first. 
Time to > 4-point in “Worst” Pain Score (After 6 Months Post Randomization) 
Time interval (days) from the randomization date to the date of first observation of 
> 4-point in “Worst” pain score occurred after 6 months post randomization.  Subjects, 
who have not experienced the event of interest after 6 months post randomization, are 
censored at the later of 6 months post randomization and the last BPI-SF assessment, 
or at the primary analysis data cut-off date, whichever comes first. 
Analgesic Score 
Analgesic score is defined as follows. 
0 = No analgesics 
1 = Non-opioid analgesics  
2 = Weak opioids (eg, meperidine, codeine, tramadol) 
3 = Strong opioids ≤ 75 mg oral morphine equivalent (OME) per day 
4 = Strong opioids with > 75 - 150 mg OME per day  
5 = Strong opioids with > 150 - 300 mg OME per day  
6 = Strong opioids with > 300 - 600 mg OME per day  
7 = Strong opioids with > 600 mg OME per day  
Analgesic score will be used as numerical value.  For guidance on analgesic scoring 
derivation process and analgesic assumptions, please refer to User Manual, Opiod 
Analgesic Quantification Algorithm for Denosumab Oncology Skeletal Related Event 
Clinical Studies. The User Manual will be updated before unblinding of the study for 
primary analysis, and kept on file at Amgen.  
Subject Years on Study for Safety Analysis  
The sum of days on study ([30 days after the last dose of IP for subjects who 
discontinued/completed IP or the primary analysis data cut-off date, whichever comes 
first] – first dose date +1) divided by 365.25. 
Subject year-adjusted Adverse Event Rate 
The number of adverse events reported in the given time period divided by total subject 
years on study during the period. 


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The visit when ≥ 30% of subjects dropped out due to death, disease progression 
or consent withdrawn  
This is used in some PRO analyses and is defined as the first visit when ≥ 30% of 
subjects dropped out due to death, disease progression or consent withdrawn among 
those who have had an opportunity to reach that visit. 
6. 
Analysis Data Sets 
6.1 
Data Subsets  
6.1.1 
Full Analysis Set (FAS) 
The FAS includes all subjects who are randomized. Subjects in the FAS will be analyzed 
according to their original treatment assignment, regardless of treatment received.  Data 
collected on subjects in this subset during the period from randomization to the primary 
analysis data cut-off date will be included, regardless of compliance with the protocol. 
6.1.2 
Per Protocol Set 
The per protocol set is defined as all subjects with a protocol-defined diagnosis, no 
major protocol violations, no disease recurrence before study day 1, and who received at 
least 1 dose of investigational product. Subjects with deviations from the following 
protocol-specified eligibility criteria will be excluded from the per-protocol set: 
1. Inclusion criteria:  
• 
Histologically confirmed, AJCC stage II or III breast cancer  
• 
High risk of breast cancer recurrence, defined as documented evidence of one or 
more of the following criteria: 
− 
Biopsy evidence of breast cancer in regional LN (node positive disease) 
− 
Nodal micrometastases only are not considered node positive 
− 
Tumor size > 5 cm (T3) or locally advanced disease (T4) 
• 
Documented pathological evaluation of the breast cancer for hormone receptor 
(estrogen receptor [ER] and progesterone receptor [PR]) status and HER-2 status  
• 
For subjects receiving adjuvant therapy only: 
− 
If the subject did not have complete resection of the primary tumor by the time of 
randomization, definitive treatment must be planned to be completed within 
approximately 12 months of randomization 
− 
Time between definitive surgery and randomization must be ≤ 12 weeks 
− 
If the subject had node-positive disease but did not undergo treatment of axillary 
LN with curative intent prior to randomization, definitive treatment must be 
planned to be completed within approximately 12 months of randomization 
− 
Subjects must not have received prior neoadjuvant treatment 
− 
Endocrine treatment for less than 30 days prior to surgery is not considered prior 
neoadjuvant treatment 


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 
For subjects receiving neoadjuvant therapy only: 
 
Time between start of neoadjuvant treatment and randomization must be 
 8 weeks 
 
Subjects must be scheduled to undergo definitive treatment (including surgery 
and/or radiotherapy) with curative intent within approximately 12 months of 
starting neoadjuvant treatment 
 
Serum calcium or albumin-adjusted serum calcium not less than 1.75 mmol/L 
(7.0 mg/dL)  
 
Eastern Cooperative Oncology Group (ECOG) performance status of  0 or 1 
 
Written informed consent before any study-specific procedure is performed  
2. Exclusion criteria:  
 
Prior or current evidence of any metastatic involvement of any distant site 
 
History of breast cancer (other than ductal carcinoma in situ [DCIS] or lobular 
carcinoma in situ [LCIS]) prior to the current diagnosis  
 
Osteoporosis requiring treatment at the time of randomization or treatment 
considered likely to become necessary within the subsequent six months 
 
Any prior or synchronous malignancy (other than breast cancer), except: 
 
Malignancy treated with curative intent and with no evidence of disease for  
 5 years prior to enrollment and considered to be at low risk for recurrence by 
the treating physician 
 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease 
 
Active infection with Hepatitis B virus or Hepatitis C virus  
 
Known infection with human immunodeficiency virus (HIV)  
 
Prior history or current evidence of osteomyelitis/ osteonecrosis of the jaw 
 
Active dental or jaw condition which requires oral surgery 
 
Non-healed dental or oral surgery 
 
Prior or current IV bisphosphonate administration 
 
Prior administration of denosumab 
 
Subject currently is enrolled in or has not yet completed at least 30 days since 
ending other investigational device or investigational drug study(s), or subject is 
receiving other investigational agent(s) 
 
Subject has known sensitivity to any of the products to be administered during the 
study (eg, mammalian derived products, calcium, or vitamin D)  
Time to event endpoints will be defined from the 1st dose date to the event of interest or 
censoring time. For a subject who has not experienced the event of interest, she is 
censored at the last assessment date (per definition of the time to event endpoint in 
Section 5.7), at the earliest violation date (if she has experienced any of the following 
violations), or at the primary analysis data cut-off date, whichever comes first. For a 


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subject who has experienced the event of interest after any of the following violations, 
they will be censored at the earliest violation date, or at the primary analysis data cut-off 
date, whichever comes first. 
• 
Receiving a dose(s) of investigational product not matching the subject’s 
randomized treatment group. The violation date is the first date that the incorrect 
investigation product was administered.  
• 
Receiving one treatment regimen of proscribed medication or therapy on study. 
Proscribed therapy includes administration of IV bisphosphonates, denosumab 
available through commercial sources (eg, XGEVA™, Prolia®) or oral 
bisphosphonates for the adjuvant/neoadjuvant treatment of breast cancer, or any 
unapproved investigational product(s) or investigational device(s) while subject 
are on study treatment. The violation date is the first date that proscribed 
medication or therapy was received. 
• 
Not receiving investigational product for 3 consecutive doses due to reasons 
other than investigational product related CTCAE grade 3 or 4 adverse event, or 
suspected atypical femoral fracture (AFF) or osteonecrosis of the jaw (ONJ), or 
planned invasive dental procedure /healing from invasive dental procedure. The 
violation date is 98 days after the time of last previously received dose. 
Subjects in the per-protocol subset will be analyzed according to the randomized 
treatment assignment and the actual stratum. 
6.1.3 
Safety Analysis Set 
This subset includes all subjects who are randomized and receive ≥ 1 dose of 
investigational product. Subjects in this subset will be analyzed according to their actual 
treatment received; subjects who received ≥ 1 dose of denosumab will be analyzed in 
the denosumab treatment group regardless of the randomized treatment assigned.   
6.1.4 
Pharmacokinetic (PK) Analysis Set 
The PK analysis set is the subset for analyses of denosumab serum concentration 
levels. This subset includes subjects who enrolled into the pharmacokinetics portion of 
the trial and who also received at least one dose of denosumab. 
6.2 
Subset for Interim Analysis 
There is 1 formal interim analysis after approximately 367 subjects have developed bone 
metastasis or died, and approximately 555 subjects have develop any disease 
recurrence or died, whichever occurs last. This interim analysis may be conducted as 
soon as approximately 6 months after the sufficient event number has been reached for 
either BMFS or DFS in the full study population, even if the event number for the other 
endpoint has not been reached. All subjects enrolled by the time of the interim analysis 
data cut-off dates will be included in the interim analysis.  


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6.3 
Subgroup Analyses  
The primary and key secondary efficacy endpoints will be analyzed in the following 
subgroups:  
• 
Breast cancer therapy / Lymph node status (neo-adjuvant therapy / any LN status, 
adjuvant therapy / LN negative, and adjuvant therapy / LN positive) 
• 
Breast cancer therapy (neo-adjuvant, adjuvant) 
• 
Hormone receptor (ER/PR) status (positive, negative) 
• 
HER-2 status (positive, negative) 
• 
Molecular subtypes of breast cancer (hormone receptor positive and HER-2 positive, 
hormone receptor positive and HER-2 negative, hormone receptor negative and 
HER-2 positive, hormone receptor negative and HER-2 negative)  
• 
Age (<50 years , ≥ 50 years) 
• 
Menopausal status (premenopausal, postmenopausal) 
• 
Postmenopausal  status (>5 years since menopause, other [including 
premenopause, ≤5 years since menopause, and unknown]) 
• 
Region (Japan, Other) 
• 
Global Region (North America, Eastern Europe, Western Europe and Australia, Asia, 
and Other) 
• 
Race (Caucasian, or Non-Caucasian)  
These subgroups, except for stratification variables, will be re-examined and 
appropriately re-categorized before unblinding. The treatment by subgroup interaction 
will be examined and tested as described in Section 9.5.1.5.  
The safety endpoints including all AEs and SAEs, will be analyzed in the following 
subgroup:  
• 
Menopausal status (premenopausal, postmenopausal) 
7. 
Interim Analysis and Early Stopping Guidelines 
A DMC external to Amgen and external to Daiichi Sankyo Co., Ltd. will be formed with 
members consisting of individuals chosen for their expertise in oncology, bone disease, 
and in statistical methods in clinical trials.  The primary role of the external DMC is to 
protect the safety of the study participants throughout the study duration.  They will 
accomplish this by periodically reviewing safety and efficacy analysis results in order to 
assess the risk-benefit profile for subjects enrolled in this study.  Access to both safety 
and efficacy data will provide the DMC a broad perspective with which to generate 
recommendations for appropriate actions. The external individuals serving on the DMC 
will have access to subjects’ individual treatment assignments. To minimize the potential 


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introduction of bias, these individuals will not have direct contact with the study site 
personnel or subjects. Selected Amgen staff may serve as liaisons to the external DMC, 
but will not be voting members, and will not be unblinded to the results. Members of this 
external DMC will include, at a minimum, physicians external to Amgen and Daiichi 
Sankyo Co., Ltd., and appropriate statistical representation external to Amgen and 
Daiichi Sankyo Co., Ltd.  
The data for review are outlined in the DMC charter and agreed to in advance by the 
DMC members.  Unblinded reports for review will be generated by an independent CRO 
that is external to Amgen as well. The external DMC will convene approximately 
twice yearly, and the start date will depend on subject accrual rates.  It is recognized that 
the DMC may feel ethically compelled to recommend early stopping in the event of 
overwhelming efficacy.  The stopping rules are defined as follows:  
1. There is 1 formal interim analysis after approximately 367 subjects have 
developed bone metastasis or died, and approximately 555 subjects have 
developed any disease recurrence or died, whichever occurs last.  This analysis 
may be performed as soon as approximately 6 months after the sufficient event 
number has been reached for either BMFS or DFS in the full study population, 
even if the event number for the other endpoint has not been reached.  The 
critical p-values for rejecting the null or alternative hypothesis are listed in 
Table 11.  The multiplicity from testing DFS in the full study population and in the 
postmenopausal subset simultaneously will be adjusted based on a Hochberg 
procedure (Sakamaki, 2013; Ye et al., 2012). The study could potentially be 
stopped if both BMFS and DFS in the full study population cross their 
corresponding efficacy boundaries, or if BMFS crosses the futility boundary at the 
interim analysis.  The other secondary endpoints OS and DRFS will only be 
tested when the study is stopped or at the primary analysis; the same procedure 
as for BMFS will be used to adjust for multiplicity between the interim and primary 
analysis for each of these endpoints. 


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Table 11.  Decision Rule (1-sided) at Interim/Primary Analyses 
Analysis 
Reject H0 
Reject H1 
Interim Analysis 1* 
BMFS: P <0.0015                                 
DFS in the full study population:  
P > 0.9333 for BMFS  
•   P <0.0004 or     
•    P<0.0015 for both the full study 
population and the subset 
DFS in the subset:  
•    P <0.0004 or     
•    P<0.0015 for both the full study 
population and the subset 
  
Primary Analysis** 
BMFS: P < 0.0247 
  
DFS in the full study population:  
•    P < 0.0125; or  
•    P < 0.0249 for the full study 
population and P < 0.0248 for the 
subset 
DFS in the subset:  
        •    P < 0.0125; or  
•    P < 0.0249 for the full study 
population and P < 0.0248 for the 
subset  
 
 
*At the interim analysis 1, the study could potentially be stopped if both BMFS and DFS in the full study 
population cross their corresponding efficacy boundaries, or if BMFS crosses the futility boundary as 
shown in the table 
 **Boundaries are based on the estimated number of events and will be recalculated based on the actual 
observed number of events. 
2. At other interim evaluations, the DMC will focus on safety, and will review efficacy 
data only to balance the risk-benefit assessment.  At these analyses, the 
guideline is that p-values for both BMFS and DFS of less than 0.0005 will be used 
as evidence of overwhelming efficacy to stop the study. 
3. At the primary analysis that is time-driven, the exact number of events for the 
primary and secondary endpoints are not fixed and the final alpha boundaries can 
potentially vary. Table 11 includes the boundaries calculated according to the 
estimated total numbers of events. In order to strictly control the overall 
type I error rate, the final boundaries will be updated based on the actual number 
of events achieved and the alpha levels that have been spent at the interim 
analysis (Proschan et al, 2006). 


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As described in the DMC charter, recommendations of the DMC will be communicated 
by the DMC Chair to senior management at Amgen for discussion on how to proceed.  
Amgen senior management will be responsible for making decisions for further 
dissemination of the recommendations at that time. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of 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 (CDM) 
for review or confirmation. 
8.2 
Data Handling and Electronic Transfer of Data 
Amgen’s Data Management department will provide all data to be used in the planned 
analyses. This study will use the Electronic Data Capture (EDC) database, RAVE. All 
laboratory values will be electronically transferred from the central laboratory to the 
Amgen database. The central imaging vendor will assess the images submitted by 
investigators (eg, Mammography, Bone Scan, CT/MRI) and electronically transfer the 
data to Amgen.  
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.  For the study of time-to-event endpoints, 
subjects completing the study and not experiencing an event of interest are considered 
censored to the event (see Section 5.7).  The procedures outlined below describing what 
will be done when data are missing may be refined during the blind review of the data.   
8.3.1 
Missing Dates 
Incomplete event start dates and concomitant medications start or stop dates will be 
imputed as described in Table 12.  If the start date is complete missing, for AE, default to 
study day 1 if the indicator of “Did event start before the first dose of investigational 
product” is checked as “No”; for concomitant medication, assume it started before 
enrollment. If the stop date and the flag for continuing are both missing for an on-study 
event or medication, assume the event or medication stopped after the end of 
study date.  Partial dates will be listed as is on the listings.  


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Table 12.  Imputation Rules for Incomplete Dates 
 
Missing 
Imputation 
Exception 
Start date (AE, 
and 
concomitant 
medication) 
Day 
01 
Default to Study Day 1 if an event starts 
the same year and month as Study Day 1 
Day / Month 
01JAN 
Default to Study Day 1 if an event started 
the same year as Study Day 1 
Start date 
(disease 
recurrence, 
and 
SRE) 
Day 
01 
Default to randomization date if an event 
starts the same year and month as 
randomization date 
Day / Month 
01JAN 
Default to randomization date if an event 
started the same year as randomization 
date 
Stop date 
(concomitant 
medication 
only) 
Day 
Last day of the 
month 
 
 
 
 
 
 
Default to the End of Study Date or the 
primary analysis data cut-off date for 
ongoing subjects if the concomitant 
medication stopped the same year and 
month as the End of Study Date or 
primary analysis data cut-off date for 
ongoing subjects respectively  
  
Stop date 
(concomitant 
medication 
only) 
Day / Month 
31DEC 
Default to the End of Study Date or the 
primary analysis data cut-off date for 
ongoing subjects if the concomitant 
medication stopped the same year as the 
End of Study Date or primary analysis 
data cut-off date for ongoing subjects 
respectively 
For historical events (eg, date of initial diagnosis of breast cancer, date of last menstrual 
period) that will be used to derive baseline covariates, the imputation rules are as 
follows: if the day is missing, default to day 15; if both month and day are missing, 
default to July 1.  If the imputed date is on or after the randomization date, default to 
randomization date minus 1.  Missing years will not be imputed under any conditions.  
If a death date is incomplete and missing only the day field, the partial death date (also 
end of treatment phase or end of study date if death is the end-of-treatment-phase or 
end-of-study reason) 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. 
For PRO analysis, if the date on the PRO administration page is missing, the date of IP 
administration at the corresponding visit with the same FOLDER will be used.  


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8.3.2 
Assayed Values Below or Above Quantifiable Limits of Bone 
Turnover Marker (BTM) 
BTM measurements that are below quantifiable limit (BQL) or above quantifiable limit 
(AQL) will be considered equal to the limits of quantification for numerical analyses 
unless explicitly noted otherwise. 
8.3.3 
Missing / Unknown Values of Covariates 
For continuous covariates, the missing / unknown values will be imputed using the mean 
of the pooled observed data.  For categorical covariate, the missing / unknown values 
will be combined with the category with the most subjects if the missing / unknown rate 
is <=2% of the pooled observed data or they will be classified into a separate category if 
the missing/unknown rate is > 2% of the pooled observed data.  If the covariates are 
also used as subgroup variables, the imputed values of subgroup variables will not be 
used for subgroup categorization. 
8.3.4 
Missing PRO data  
Multiple imputation is used as the imputation method for missing PRO data in this study. 
The imputation model includes the corresponding PRO assessments up to the visit when 
≥ 30% subjects have ended treatment phase due to death, disease progression or 
consent withdrawn, and the covariates used in the Cox proportional hazards model 
described in Section 9.5.2.3. 
8.3.5 
Missing Pathological Complete Response  
For neo-adjuvant subjects without receiving primary breast cancer surgery, the missing 
pathological completed response will be imputed as “No”. 
8.4 
Assessment of Outliers 
Descriptive statistics will be used to identify outliers in any key variables defined in 
Section 4.  For continuous variables, the univariate analysis will be conducted and box 
plots will be generated to identify outliers.  For discrete variables, frequency summaries 
will be examined to identify questionable values.  
Outliers due to data entry error will be corrected in the database before the before 
analysis snapshot and database lock.  Outliers that are not due to data entry error will be 
included in the primary analysis, unless there is sufficient clinical justification obtained 
prior to unblinding to exclude them.  The validity of any questionable values or outliers 
will be confirmed.  No valid measurement may be excluded from descriptive or inferential 
analyses.  However, sensitivity analyses may be conducted to evaluate the impact of 
extreme values on the data.  


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8.5 
Distributional Characteristics  
The assumption of proportional hazards for proportional hazards models (Lawless, 
1982) will be examined by visualizing plots of log (-log (survival function)) versus time 
and plots of Schoenfeld residuals versus time (Schoenfeld, 1982). When there is modest 
deviation from the assumption, inferences in proportional hazards models are generally 
fairly robust. 
The normality assumptions in the parametric models analyzed for continuous data will 
be checked. If the assumptions for the distributional characteristics of endpoints are not 
met, these will be described and further analyses may be carried out using 
transformations of endpoint values. 
8.6 
Validation of Statistical Analysis 
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 analysis consists of Amgen-supported 
versions of statistical analysis software, for example, the SAS System 9.4. 
9. 
Statistical Methods of Analysis 
9.1 
General Principles 
The analyses of efficacy and safety endpoints will be based on the analysis sets defined 
in Section 6.1.  Sensitivity analyses for primary and key secondary efficacy endpoints 
will be performed as described in Section 9.5.1.4 to test the robustness of the treatment 
effects observed. Two-sided p-values will be presented for all the statistical testing.  
Continuous variables will be summarized using descriptive statistics, which includes 
n (number of non-missing observations), the mean, median, 25th and 75th percentiles, 
standard deviation, 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.  For categorical variables, 
descriptive statistics include frequency and percentage. 
For time to event variables, the Kaplan-Meier method will be used to estimate the 
quartiles (25th percentile and median) of time to event variable for each treatment group, 
along with 95% confidence intervals (Kaplan and Meier, 1958).  Kaplan-Meier estimates 


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will be presented graphically for each treatment group approximately up to the time point 
where there are less than 50 subjects in the risk set for both treatment groups combined.  
Kaplan-Meier event rates with 2-sided 95% confidence intervals at year 1, year 2, year 
3, year 4 and year 5 will also be estimated. The hazard ratio and its 2-sided 95% CI will 
be estimated using Cox proportional hazards model (Cox, 1972) with treatment group as 
the independent variable and stratified by the randomization stratification factors.  
For analyses where stratification needs to be adjusted for, the following general 
principles will be followed: 
• 
Primary analyses, which are intended to evaluate treatment effects and are using 
stratified models, will be based on the randomized stratum, regardless of the 
subject’s actual value.  If > 5% of all randomized subjects were stratified incorrectly 
for 1 or more factors, then a sensitivity analysis using the actual value should also be 
performed for the primary and key secondary endpoints.      
• 
Covariate analyses, where covariates are stratification factors, will be based on 
subject’s actual value, regardless of the stratum that they were randomized to.  
• 
For subgroup analyses,  
− 
Analyses will be based on the randomized stratum. 
− 
If the subgroup variable is a stratification factor, sensitivity analyses according to 
actual value may be needed. 
9.2 
Subject Accountability 
For all randomized subjects, the number and percentage achieving the planned 
assessments listed below will be tabulated by treatment arm:   
• 
Subject enrollment by region, country and site 
• 
Subjects who enrolled, who discontinued study, and their reasons for study 
discontinuation 
• 
Subjects who never received IP, who received IP, who discontinued IP, and their 
reasons for IP discontinuation  
• 
Subjects in each key analysis set 
• 
Screening disposition and reasons for screen failure    
• 
Important protocol deviations 
In addition, listings will be provided for randomization assignment, important protocol 
deviations, protocol inclusion/exclusion deviations, manufacturing lot numbers and 
manufacturing lot numbers used for all enrolled subjects.   
9.3 
Demographic and Baseline Characteristics  
Descriptive statistics will be tabulated for demographics, baseline characteristics and 
disease history as listed below by randomized treatment group using FAS.  


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9.3.1 
Demographics  
• 
Gender 
• 
Age at study entry (year) 
• 
Age group (18 - 64 years, 65 - 74 years, 75 - 84 years, ≥ 85 years) 
• 
Age group 2 (<50 versus ≥ 50) 
• 
Ethnic group/race  
• 
Global Region (North America, Eastern Europe, Western Europe and Australia, Asia, 
and Other) 
• 
Menopausal status (postmenopausal, premenopausal) 
9.3.2 
Baseline Characteristics  
Baseline Characteristics and Disease History 
• 
Weight (kg) 
• 
Height (cm) 
• 
Body mass index (kg/m2) 
• 
ECOG performance status at study entry (0, 1) 
• 
Breast cancer therapy (neoadjuvant, adjuvant) 
• 
Hormone receptor (ER/PR) status (positive, negative) 
• 
HER-2 status (positive, negative) 
• 
Molecular subtypes of breast cancer (hormone receptor positive and HER-2 positive, 
hormone receptor positive and HER-2 negative, hormone receptor negative and 
HER-2 positive, hormone receptor negative and HER-2 negative) 
• 
Breast cancer AJCC stage (IA, IB, IIA, IIB, IIIA, IIIB, IIIC, IV) 
• 
Primary tumor size (T-stage: T0, T1 or T1a-T1c or T1mic, T2, T3, T4 or T4a-T4d, Tx, 
Tis) 
• 
Lymph node status (N-stage: N0 or pN0 or pN0 (i-) or pN0 (i+) or pN0 (mol-) or 
pN0 (mol+) or pN1mi,  N1 or pN1 or pN1a - pN1c,  N2 or N2a or N2b or pN2 or pN2a 
or pN2b,  N3 or N3a - N3c or pN3 or pN3a - pN3a,  Nx or pNx).  
• 
Breast cancer histopathologic grade (G1=low, G2=intermediate, G3=high, not 
evaluable/missing) 
• 
Time from initial breast cancer diagnosis to randomization (in months) 
Other Cancers Disease History 
• 
History of Other Cancers (yes, no)  
Substance Use History 
• 
Alcoholic beverages (none, <=2 per day, >= 3 per day) 
• 
Tobacco use (never, former, current) 


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 Baseline Labs and Bone Turnover Markers (BTMs): 
• 
Calcium/ Albumin-adjusted calcium  
• 
Magnesium 
• 
Phosphorus  
• 
Serum 25 (OH) Vitamin D 
• 
Hematology 
• 
Bone-specific alkaline phosphatase (BSAP) 
• 
uNTx corrected for creatinine (uNTx/Cr) 
• 
αCTx corrected for creatinine (αCTx/Cr) 
Previous Anti-neoplastic Treatment and Surgical Procedure for Neoadjuvant / 
Adjuvant Subjects 
• 
Chemotherapy  
• 
Anti-HER2 therapy 
• 
Hormonal therapy  
• 
Radiotherapy 
• 
Breast cancer surgery  
9.3.3 
Bone-specific Medication History 
• 
Subject incidence of historical bone-specific medication usage by preferred term  
9.3.4 
Fracture History  
• 
Any historical fracture  
• 
Historical osteoporotic fracture 
• 
Historical vertebral fracture 
• 
Historical non-vertebral fracture 
• 
Parental hip facture 
9.3.5 
Baseline PRO Characteristics and Analgesic Use 
• 
Analgesic use  
• 
BPI-SF  
− 
“Worst” pain score 
− 
Pain severity scale 
− 
Pain interference score 
• 
EQ-5D 
− 
Health index scores 
− 
VAS 


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9.4 
Safety Analyses 
Safety analyses in this study will evaluate the safety profile of denosumab as compared 
with placebo. This will include assessments of treatment-emergent adverse events and 
adverse events of interest, investigational product exposure, concomitant medication 
usage, ECOG performance status, vital signs, immunogenic response, and clinical 
laboratory results. No statistical testing is planned in the safety analysis. 
9.4.1 
Adverse Events (AEs) 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 20.1 or higher.  Treatment-emergent adverse events are events 
occurred during the time period from the first dose date (AEs are excluded if the 
indicator of “Did event start before the first dose of investigational product?” is checked 
as “Yes” on Adverse Events Summary CRF pages) through 30 days after the last dose 
of IP.  Based on the AEs summary instructions, an AE that exists prior to the 
administration of IP and gets worse during the time period defined above will be included 
as a treatment emergent adverse event. Unless otherwise specified, all AE related 
analyses are based on treatment-emergent adverse events.  
For all AEs, SAEs, grade ≥ 3 (ie, CTCAE grade 3, 4, and 5) AEs, fatal AEs, AEs leading 
to discontinuation of IP or study, as listed in Section 4.2.1, subject incidence will be 
summarized by system organ class (SOC), high level term (HLT) and preferred term 
(PT), and by PT only. Subject incidence of AEs by SOC, HLT, PT, and worst grade will 
be tabulated. Subject-year adjusted incidence rates will be summarized for all AEs, 
SAEs, and grade ≥ 3 AEs by SOC, HLT and PT, and by PT only.  A summary table for 
investigator determined IP related AEs will be provided by PT.  In addition, subject 
incidence for all AEs and SAEs by SOC, HLT and PT will be tabulated by incremental 
time period (0 - 12 months, >12– 24 months, >24 - 36 months, >36 - 48 months, 
>48 months). 
9.4.1.1 
Events of Interests (EOIs) 
Events of interests (EOIs), including adverse events of hypocalcaemia, osteonecrosis of 
the jaw (ONJ), new primary malignancy, atypical femur fracture (AFF), cardiac/vascular 
disorders, infections and infestations, adverse events potentially associated with 
hypersensitivity, osteonecrosis excluding the jaw, musculoskeletal pain, and 
hypercalcemia occurred after 30 days following discontinuation of IP will be summarized. 
Subject incidence of AEs and SAEs of these EOIs will be tabulated at the EOI level and 
PT level.  


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9.4.1.2 
Osteonecrosis of the Jaw 
All subjects with an oral adverse event suspicious of osteonecrosis of the jaw (ONJ) 
should be examined by a dentist or other qualified oral specialist (eg, 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 
osteonecrosis of jaw; 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 dates prior to the primary analysis 
cut-off date will be included. The proportion of subjects experiencing adjudicated positive 
ONJ will be summarized by PT. In addition, subject-year adjusted incidence rate of 
adjudicated positive ONJ by incremental time period (0 - 12 months, >12 – 24 months, 
>24-36 months, >36-48 months, >48 months) will be presented. A KM plot for time to 
first adjudicated positive ONJ will be provided. 
9.4.1.3 
Atypical Femoral Fracture 
All subjects presenting with new or unusual thigh, hip, or groin pain should be evaluated 
for a suspected adverse event of atypical femoral fracture (AFF). Adverse events 
reported as AFF as well as adverse events identified by Amgen as potentially 
representing AFF will be reviewed by an independent adjudication panel 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 blinded adjudication committee. Adverse events that are adjudicated as 
positive for AFF and have onset dates prior to the primary analysis cut-off date will be 
included.  The proportion of subjects experiencing adjudicated positive AFF will be 
summarized by PT. In addition, subject-year adjusted incidence rate of adjudicated 
positive AFF by incremental time period (0 - 12 months, >12 – 24 months, 
>24-36 months, >36-48 months, >48 months) will be presented. A KM plot for time to 
first adjudicated positive AFF will be provided. 
9.4.2 
Investigational Product Exposure 
The number of months on study, number of doses received, and cumulative 
investigational product exposure will be summarized using descriptive statistics. FAS will 
be used for this summary. 


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9.4.3 
Concomitant Medications and Anti-neoplastic Therapies/Surgeries 
Subject incidence of bone-specific medications, and calcium and vitamin D medications 
will be summarized by medication preferred term. Safety analysis set will be used in the 
analysis. 
On-study anti-neoplastic therapy (eg, chemotherapy, anti-HER-2 therapy, and hormonal 
therapy), radiotherapy and surgery for breast cancer will be summarized for subjects in 
the FAS. In case that there is a large imbalance on the use of on-study anti-neoplastic 
therapy between treatment groups, sensitivity analysis may be performed to adjust for 
the use for primary and key secondary endpoints. 
9.4.4 
ECOG Performance Status 
The recorded value and change from baseline of ECOG performance status will be 
summarized by treatment group and visit using safety analysis set.  
9.4.5 
Vital Signs  
Summary statistics for recorded values for systolic blood pressure (SBP), diastolic blood 
pressure (DBP), pulse, respiration rate, and temperature will be displayed by visit using 
safety analysis set.  Subjects with missing data for a clinical planned event will not 
contribute to the tabulations for that time point.  
9.4.6 
Immunogenic Response 
Immunogenic response will be described by tabulating the numbers and percentages of 
subjects who tested positive (binding, neutralizing) for anti-denosumab antibodies in the 
subjects receiving at least one dose of denosumab.  If a subject tests positive for 
neutralizing antibodies against denosumab, the relationship between the presence of 
neutralizing antibodies, adverse events, and bone turnover will be evaluated.  
Immunogenic response will be listed by subject and visit date for subjects that test 
positive to either binding or neutralizing antibodies.   
9.4.7 
Clinical Laboratory Results 
Only central lab parameters will be used for analysis.  Laboratory parameters will be 
summarized over time via shift tables, in which the incidence of shifts of toxicity grade 
(CTCAE version 3.0 or higher) in recorded values from baseline to ‘Worst’ on-study 
value, are displayed by treatment group.   
Laboratory parameters will also be summarized using descriptive statistics for recorded 
values and changes from baseline.  Lab parameters will be summarized using 


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International System (SI) units. The following parameters: serum calcium adjusted for 
albumin, and phosphorus will also be summarized using conventional units. 
In addition, the proportion of subjects who have grade shifts of at least 2 grades from 
baseline and the proportion of subjects who have CTCAE grade decrease of at 
least 2 grades in albumin-adjusted calcium at any time during the study will be 
summarized. The subject incidence of lab grade ≥ 3 (CTCAE grade 3 and 4) will also be 
tabulated. 
Missing laboratory data are generally not imputed.  If multiple laboratory records for a 
parameter are available on a day, the sample that is the closest to the scheduled time 
will be used.  Laboratory data within a pre-specified window around a scheduled visit are 
considered valid.  Pre-specified windows for each scheduled visit are supplied in the 
Appendix.  In cases where multiple records exist within a window, the record that is the 
closest to the target day will be used.  If 2 evaluations are the same distance from the 
target day, the later visit will be used. 
9.5 
Efficacy Analyses  
Efficacy analyses of the primary and secondary endpoints will determine the treatment 
effects of denosumab on bone metastasis-free survival (BMFS), disease-free survival 
(DFS) in the full study population, disease-free survival (DFS) in the postmenopausal 
subset, overall survival (OS), and distant recurrence-free survival (DRFS) compared with 
placebo.  
The primary efficacy endpoint, BMFS, will be compared between denosumab and 
placebo using a log-rank test stratified by the randomization stratification factors.  If 
denosumab is determined to be superior to placebo with respect to the primary efficacy 
endpoint, the secondary efficacy endpoints including 
• 
Step 1: DFS in the full study population and DFS in the postmenopausal subset 
• 
Step 2: OS  
• 
Step 3: DRFS 
will be tested in a stepwise fashion over 3 steps; ie, the treatment effect with respect to 
the secondary endpoints at the subsequent step will be tested only when denosumab is 
determined to be superior to placebo with respect to all the secondary endpoints at 
previous steps. At Step 1, DFS in the full study population and DFS in the 
postmenopausal subset will be tested simultaneously using Hochberg procedure to 


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adjust for multiplicity (Sakamaki, 2013; Ye et al, 2011).  The secondary endpoints will be 
analyzed using a similar stratified log-rank test.  
In the interim / primary analysis, the primary and secondary endpoints will be tested in a 
stepwise fashion as described above with the critical p-values listed in Table 11. In the 
interim analysis, the study could potentially be stopped if both BMFS and DFS in the full 
study population cross their corresponding efficacy boundaries, or if BMFS crosses the 
futility boundary.  The other secondary endpoints OS and DRFS will only be tested 
hierarchically when denosumab is determined to be superior to placebo with respect to 
all three efficacy endpoints BMFS, DFS in the full study population and DFS in the 
postmenopausal subset in the interim /primary analysis. In order to strictly control the 
overall type I error rate, the final critical p-values will be updated based on the actual 
number of events achieved and the alpha levels that have been spent at the interim 
analysis (Proschan et al, 2006). If the tests on BMFS, DFS in the full study population 
and DFS in the postmenopausal subset are all successful at the primary analysis, similar 
procedure will be used to adjust for multiplicity between interim and primary analysis for 
OS and DRFS. Namely, the final critical p-values will be based on the actual numbers of 
events achieved at the interim and primary analysis, and the alpha levels that have been 
spent at the interim analysis using O’Brien Fleming spending function with information 
fraction based on actual numbers of events. 
9.5.1 
Primary and Secondary Efficacy Endpoints 
9.5.1.1 
 Estimation of Outcomes  
The primary efficacy endpoint is BMFS, and the secondary efficacy endpoints are DFS 
in the full study population, DFS in the postmenopausal subset, OS, and DRFS.  
9.5.1.2 
Hypotheses to Be Tested 
At the interim and primary analyses, the primary and secondary null hypotheses will be 
tested in a stepwise fashion (as described in Section 9.5), where the hypothesis of 
secondary endpoints will be tested only when the null hypothesis of BMFS is rejected at 
the designed significance level, and the secondary endpoints at the subsequent step will 
be tested only when the null hypothesis of all the secondary endpoints at previous steps 
is rejected. 
• 
Primary null hypothesis: The overall risk of developing bone metastasis or death for 
the denosumab treated group is no less than that of the placebo treated group.  
• 
Primary alternative hypothesis: The overall risk of developing bone metastasis or 
death for the denosumab treated group is less than that of the placebo treated 


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group.  It is anticipated that the true hazard ratio of denosumab compared with 
placebo will be 0.8.  
• 
Secondary null hypothesis for DFS in the full study population: The overall risk of 
disease recurrence or death for the denosumab treated group is no less than that of 
the placebo treated group.  
• 
Secondary alternative hypothesis for DFS in the full study population: The overall 
risk of disease recurrence or death for the denosumab treated group is less than that 
of the placebo treated group.  It is anticipated that the true hazard ratio of 
denosumab compared with placebo will be 0.83.  
• 
Secondary null hypothesis for DFS in the postmenopausal subset: The risk of 
disease recurrence or death in the denosumab treated group is no less than that of 
the placebo treated group for subjects who have been postmenopausal at 
enrollment. 
• 
Secondary alternative hypothesis for DFS in the postmenopausal subset: The risk of 
disease recurrence or death in the denosumab treated group is less than that of the 
placebo treated group for subjects who have been postmenopausal at enrollment.  It 
is anticipated that the true hazard ratio of denosumab compared with placebo will be 
0.76.  
• 
Secondary null hypotheses for OS and DRFS:  
− 
The overall risk of all cause death for the denosumab treated group is no less 
than that of the placebo treated group. 
− 
The overall risk of distant recurrence or death for the denosumab treated group is 
no less than that of the placebo treated group. 
• 
Secondary alternative hypotheses for OS and DRFS:  
− 
The overall risk of all cause death for the denosumab treated group is less than 
that of the placebo treated group.  
− 
The overall risk of distant recurrence or death for the denosumab treated group is 
less than that of the placebo treated group.  
9.5.1.3 
Primary Analysis 
Bone Metastasis-free Survival  
Kaplan-Meier estimates of the survival functions will be graphically displayed for each 
treatment group.  Kaplan-Meier quartiles (25th percentile and median) with 2-sided 
95% confidence intervals will be calculated if applicable.  In addition, BMFS time will be 
summarized via displaying number of subjects at risk, the percent of subjects that are 
censored, and Kaplan-Meier event rates with 2-sided 95% confidence intervals at year 1, 
year 2, year 3, year 4 and year 5.   
A log-rank test stratified by the randomization stratification factors (defined in Section 3) 
will be used to compare the BMFS of the two treatment groups.  The hazard ratio of 
denosumab compared with placebo and its corresponding 2-sided 95% confidence 
interval will be estimated using a Cox proportional hazards model with treatment groups 


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as the independent variable and stratified by the randomization stratification factors.  
FAS will be used in the primary analysis.  
Disease-free Survival in the full study population, Disease-free Survival in the 
postmenopausal subset, Overall Survival and Distant Recurrence-free Survival  
If superiority of denosumab over placebo for BMFS is established, the key secondary 
endpoints of DFS in the full study population and DFS in postmenopausal subset will be 
tested simultaneously based on a Hochberg procedure. If denosumab is determined to 
be superior to placebo with respect to both of the key secondary efficacy endpoints, OS 
and DRFS will be tested hierarchically. If superiority is not demonstrated for an endpoint, 
analyses will be provided for subsequent endpoints (following the order as described 
above) using similar methods that are used for the primary endpoint. The analyses will 
be considered descriptive in nature.  FAS will be used in the analysis.  
9.5.1.4 
 Supportive Analyses 
To demonstrate the robustness of the results for BMFS, DFS in the full study population, 
and DFS in the postmenopausal subset in the primary analysis, supportive analysis will 
be conducted in the following aspects: 
• 
Analyses will be performed using the per protocol set.  
• 
Analyses will be performed using the FAS and the actual strata. 
• 
Analyses will be performed using the FAS without censoring subjects who had the 
first occurrence of event before randomization [ie, including baseline events]. For 
these subjects, they will have their event date default to their randomization date. 
• 
Analysis will be performed for BMFS (based on the definition of bone metastasis 
[including investigator reported events]), DFS in the full study population (based on 
the definition of breast cancer disease recurrence [including investigator reported 
events]), and DFS in the postmenopausal subset (based on the definition of 
breast cancer disease recurrence [including investigator reported events]) using the 
FAS. For BMFS [including investigator reported events], subjects who have not 
experienced event will be censored at the later of the last onsite clinical visit date and 
the last assessment date (via central imaging analysis) for bone metastasis, or at the 
primary analysis data cut-off date, whichever comes first. Subjects who had 
first occurrence of bone metastasis [including investigator reported events] before 
randomization will be censored at their randomization date. For DFS in the full study 
population [including investigator reported events] and DFS in the postmenopausal 
subset [including investigator reported events], subjects who have not experienced 
event will be censored at the later of the last onsite clinical visit date and the 
last assessment date (via central imaging analysis) for disease recurrence, or at the 
primary analysis data cut-off date, whichever comes first. Subjects who had 
first disease recurrence [including investigator reported events] before randomization 
will be censored at their randomization date. 


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The following analysis will be performed for BMFS, DFS in the full study population, and 
DFS in postmenopausal subset using FAS to explore the potential informative censoring 
due to drop-out: 
• 
Missing data subsequent to censoring will be imputed using the following 
two parameters: 
o The hazard rate subsequent to censoring in the control group is assumed 
to be varied from half to twice of the observed hazard rate before 
imputation  
o The hazard ratio for denosumab relative to control is assumed to be 
varied from half to twice of the observed hazard ratio before imputation. 
o The presentation of the ranges for assumed hazard rate in the control 
group and assumed hazard ratio may be reassessed based on the event 
distribution of observed data. 
• 
For each combination of the two parameters: 
o Event status between censoring and primary data cut-off date for the 
control group will be randomly imputed using the hazard rate based on 
exponential distribution for BMFS and piece-wise exponential distribution 
for DFS. Similarly, event status between censoring and primary data 
cut-off date for the denosumab group will be randomly imputed using the 
hazard rate for the control group times the hazard ratio.  
o Repeat the imputation many times. The hazard ratio after imputation will 
be estimated for each repetition. The overall estimate of the hazard ratio 
will be calculated using the multiple imputation procedure (Little and 
Rubin, 1987). 
9.5.1.5 
Subgroup Analyses 
BMFS, DFS in the full study population, DFS in the postmenopausal subset will be 
analyzed within each of the subgroups indicated in Section 6.3, except for 
age (<50 years, ≥ 50 years) and menopausal status (premenopause, postmenopause) 
for DFS in the postmenopausal subset. 
For each category of a subgroup, the following analyses will be performed using the 
FAS:  
• 
Kaplan-Meier quartiles (25th percentile and median) with 2-sided 95% confidence 
intervals, and Kaplan-Meier event rates with 2-sided 95% confidence intervals at 
year 1, year 2, year 3, year 4 and  year 5  will be calculated if applicable.   
• 
A log-rank test stratified by the randomization stratification factors (defined in 
Section 3) will be used to compare the two treatment groups.  Hazard ratio of 
denosumab compared with placebo and its corresponding 2-sided confidence 
interval will be estimated using a Cox proportional hazards model with treatment 
groups as the independent variable and stratified by the randomization stratification 
factors.  


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• 
A Cox proportional hazards model with treatment groups, indicator variable of 
subgroups, the interaction between the treatment and indicator variable, as the 
independent variables, and stratified by the randomization stratification factors will be 
used.  If the p-value of the interaction term is less than 0.05, then the interaction is 
significant, and the Gail and Simon test (Gail and Simon, 1985) will be used to test 
for qualitative interaction.  The nature of the interaction will be investigated.   
9.5.1.6 
Analysis of Covariates 
The covariates in Section 4.4 will be analyzed for BMFS, DFS in the full study 
population, and DFS in the postmenopausal subset, except for age (<50 years, 
≥ 50 years) and menopausal status (premenopause, postmenopause) for DFS in the 
postmenopausal subset.  The 95% 2-sided confidence interval of the hazard ratio of 
denosumab compared with placebo, adjusted for each covariate separately and all 
covariates simultaneously from the Cox proportional hazards model will be obtained.  
FAS will be used. These covariates, except for the stratification variables, will be 
re-examined and appropriately re-categorized (due to small sample size) before 
unblinding for the interim and primary analyses. 
9.5.2 
Exploratory Endpoints 
All analyses of exploratory efficacy endpoints listed in Section 4.3 will be performed as 
follows: 
9.5.2.1 
Time to Event Exploratory Endpoints  
For each of the time to event endpoint, ie, time to first bone metastasis (excluding 
death), time to first bone metastasis as site of first recurrence, time to disease 
recurrence, time to distant recurrence, time to first on-study fracture (vertebral or 
non-vertebral fracture), time to first on-study SRE, time to first on-study SRE or 
hypercalcemia, and time to on-study symptomatic bone metastasis,  
• 
Kaplan-Meier method will be used to estimate the survival function by treatment 
group.  
• 
A log-rank test stratified by the randomization stratification factors will be used to 
compare the two treatment groups.   
• 
Hazard ratio of denosumab compared with placebo and its 2-sided 95% confidence 
interval will be estimated using a Cox proportional hazards model with treatment 
groups as the independent variable and stratified by the randomization stratification 
factors. 
• 
In addition, for time to first bone metastasis as site of first recurrence and time to 
first symptomatic bone metastasis, cumulative incidence function (CIF) (Kalbfleisch 
and Prentice, 2002) will be estimated with non-bone site of first recurrence and with 
first asymptomatic bone metastasis as a competing event respectively. Comparison 
of the CIF between denosumab and placebo will be based on Gray (1988) and 
Zhou et al (2011) stratified by the randomization stratification factors.  


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FAS will be used in the analysis. It should be note that in the analysis of time to 
first bone metastasis as site of first recurrence and time to on-study symptomatic bone 
metastasis, subjects who developed the first recurrence outside the bone and subjects 
who developed bone metastases that were not asymptomatic are censored respectively. 
The censorship could be potentially informative, thus the results should be interpreted 
with caution. 
9.5.2.2 
Analgesic Score  
Descriptive statistics for recorded values and changes from baseline will be displayed by 
visit. Proportion of subjects with AQA score ≥ 3 in subjects with baseline AQA score of 
0-2  will be summarized at year 1, year 2,  year 3, year 4 and year 5, and compared 
between  two treatment groups using chi-square test at each year. FAS will be used in 
the analysis. 
9.5.2.3 
PRO Analysis  
BPI-SF 
For each of the BPI endpoint (“Worst” pain score, pain severity score and pain 
interference score) listed in Section 4.3.2, descriptive statistics for recorded values and 
changes from baseline will be displayed by visit using the FAS.  
The survival function of time to 1) ≥ 2-point increase from baseline in “Worst”  pain 
score, and 2) > 4-point in “Worst”  pain score in subjects with baseline “Worst”  pain 
score of 0-4 for each treatment group will be estimated using Kaplan-Meier method.  The 
analyses will be based on the observed data.  Analyses will include subjects who have 
an opportunity to meet the response criteria described above.  For example, subjects 
with baseline score ≤ 8-point will be considered in time to ≥ 2-point increase analysis. 
The hazard ratio of denosumab compared with placebo and its corresponding 2-sided 
95% CI will be estimated based on a Cox proportional hazards model adjusting the 
applicable covariates below and stratified by the randomization stratification factors 
(defined in Section 3). 
• 
Treatment group (denosumab,  placebo)  
• 
Age (continuous)  
• 
Race (Caucasian, non-Caucasian)  
• 
Menopausal status (premenopause, postmenopause) 
• 
Baseline ECOG=0 (yes, no) 
• 
Time from breast cancer diagnosis to randomization  
• 
Baseline pain at worst score  


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• 
Baseline analgesic score  
• 
Breast cancer AJCC stage  
• 
Global Region (North America, Eastern Europe, Western Europe and Australia, Asia, 
and Other) 
The analysis described above will be repeated for the following two endpoints defined in 
Section 5.7. 
• 
Time to ≥ 2-point increase score from baseline in ’Worst’ pain score (after 6 months 
post randomization) 
• 
Time to 4-point in “Worst”  pain score (after 6 months post randomization) 
The proportions of subjects who meet the following criteria for response will be 
summarized by visit.  
• 
≥ 2-point increase in ’Worst’ pain score from baseline at each visit  
• 
 ’Worst’ pain score > 4-point at each visit in subjects with baseline ‘Worst’ pain score 
of 0-4 
The overall treatment effect will be tested based on all data and the data after 6 months 
post randomization respectively using Generalized Estimating Equations (GEEs) 
adjusting treatment, study visit, the interaction between treatment and study visit, 
baseline worst pain score, baseline analgesic score, IP dosing schedule (Q3W/Q3M IP 
dosing schedule, Q4W/Q3M IP dosing schedule) and randomized stratification factors. 
The analyses will be based on the observed data, and the imputed data using the PRO 
multiple imputation method. If the baseline score limits the response (eg, subject with 
baseline score ≥ 9- point cannot reach ≥ 2-point increase), subject is categorized as 
non-responder, and will be excluded from the analysis. 
In addition, the proportions of subjects who meet the criteria for response above at 
year 1, year 2, year 3, year 4 and year 5 will be compared between the two treatment 
groups using a logistic regression model adjusting the same covariates listed above, IP 
dosing schedule (Q3W/Q3M IP dosing schedule, Q4W/Q3M IP dosing schedule), and 
randomization stratification factors.  The odds ratio and the corresponding 95% 2-sided 
confidence interval and p-values will be provided.  In case that the logistic regression 
model does not converge due to sparse data or separation, a conditional logistic 
regression stratified by randomization stratification factors may be used. The analyses 
will be based on the imputed data using the PRO multiple imputation method.  If the 
baseline score limits the response (eg, subject with baseline score ≥ 9-points cannot 


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reach a ≥ 2-point increase), subject is categorized as non-responder, and will be 
excluded from the analysis. 
EQ-5D 
Descriptive statistics for recorded values and changes from baseline for the EQ-5D 
health index and EQ-5D VAS will be displayed by visit using the FAS. 
9.5.2.4 
Breast Density  
The distribution of breast density level and the shift of breast density from baseline will 
be summarized by visit. The change from baseline in breast density will be summarized 
descriptively by visit. The comparison of the change in breast density from baseline 
between treatment groups at each visit will be based on a van Elteren stratified rank test 
(van Elteren, 1960) stratified by the randomization stratification factors.  
9.5.2.5 
Pathological Complete Response 
For neo-adjuvant subjects, pathological complete response will be compared between 
treatment groups using a logistic regression model adjusting the randomization 
stratification factors.  
9.5.2.6 
Residual Invasive Tumor Size 
For neo-adjuvant subjects, descriptive statistics for the residual invasive tumor size will 
be summarized, which includes n (number of non-missing observations), the mean, 
median, 25th and 75th percentiles, standard deviation, minimum, and maximum. The 
residual invasive tumor size between treatment groups will be compared using a van 
Elteren rank test (van Elteren, 1960) stratified by the randomization stratification factors. 
All neo-adjuvant subjects who are randomized and have observed values of residual 
invasive tumor size will be used in the analysis. 
9.5.2.7 
Serum Denosumab Trough Concentrations  
Summary statistics will be calculated for serum denosumab trough concentrations.  The 
PK analysis set defined in Section 6.1.4 will be used in the analysis.  For serum 
denosumab concentrations below the lower limit of quantification, a value of zero will be 
assigned for calculation of summary statistics. 
9.5.2.8 
Blood Biomarkers and Bone Turnover Markers 
Blood biomarkers and bone turnover markers (BTMs; including uNTx/Cr, α-CTx/Cr and 
BSAP), will be analyzed for all randomized subjects, as measured at baseline, and at 
each visit.  Recorded values, change from baseline and percent change from baseline 
will be presented.  Percent change in BTMs will be analyzed using non-parametric 


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methodology since it is anticipated that the distribution of these parameters will deviate 
from normality.  A van Elteren stratified rank test (van Elteren, 1960) will be used to 
compare treatment groups with stratification factors.  All the subjects who are 
randomized and have observed values of the endpoints at the time of interest will be 
used in the analysis.   
10. 
Final Analysis of Data From Ltfu 
Deaths during the long-term survival follow-up, and from randomization through LTFU 
will be summarized. 


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11. 
Literature Citations / References 
Denosumab Investigator’s Brochure.  Thousand Oaks, CA: Amgen Inc. 
Brooks R (1996) EuroQol: the current state of play.  Health Police, 37(1): 53-72. 
Cleeland CS. (1991) Research in cancer pain:  what we know and what we need to 
know.  Cancer, 67 (suppl 3):  823-7 
Coleman, R., Cameron, D., Dodwell, D., Bell, R., Wilson, C., Rathbone, E., Keane, M., 
Gil, M., Burkinshaw, R., Grieve, R., Barrett-Lee, P., Ritchie, D., Liversedge, V., Hinsley, 
S., Marshall, H., on behalf of the AZURE investigators (2014). Adjuvant zoledronic acid 
in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) 
randomised open-label phase 3 trial. Lancet Oncol, 15(9), 997-1006. 
Colleoni, M., O'Neill, A., Goldhirsch, A., Gelber, R.  D., Bonetti, M., Thurlimann, B., Price, 
K.  N., Castiglione-Gertsch, M., Coates, A.  S., Lindtner, J., Collins, J., Senn, H.  J., 
Cavalli, F., Forbes, J., Gudgeon, A., Simoncini, E., Cortes-Funes, H., Veronesi, A., Fey, 
M., & Rudenstam, C.  M. (2000).  Identifying breast cancer patients at high risk for bone 
metastases.  J Clin Oncol, 18(23), 3925-3935. 
Cheng L, Swartz MD, Zhao H, et al (2012). Hazard of recurrence among women after 
primary breast cancer treatment - a 10-year follow-up using data from SEER-medicare. 
Cancer Epidemiol Biomarkers Prev. 21(5): 800-809.  
Cox, D.R. (1972) Regression models and life tables (with discussion).  Journal of Royal 
Statistical Society, Series B, 34: 187-220. 
Fairclough, D.L. (2002) Design and Analysis of Quality of Life Studies in Clinical Trials 
Chapman & Hall/CRC.  
Francis, P., Crown, J., Di Leo, A., Buyse, M., Balil, A., Andersson, M., Nordenskjold, B., 
Lang, I., Jakesz, R., Vorobiof, D., Gutierrez, J., van Hazel, G., Dolci, S., Jamin, S., 
Bendahmane, B., Gelber, R.  D., Goldhirsch, A., Castiglione-Gertsch, M., & 
Piccart-Gebhart, M. (2008).  Adjuvant chemotherapy with sequential or concurrent 
anthracycline and docetaxel: Breast International Group 02-98 randomized trial.  J Natl 
Cancer Inst, 100(2), 121-133. 
Gail, M.  H., and Simon, R (1985)  Testing for qualitative interactions between treatment 
effects and patients subsets.  Biometrics, 41: 361-372. 
Gray RJ (1988) A class of K-sample tests for comparing the cumulative incidence of a 
competing risk, Annals of Statistics, 16:1141-1154. 
Howell, A., Cuzick, J., Baum, M., Buzdar, A., Dowsett, M., Forbes, J.  F., Hoctin-Boes, 
G., Houghton, J., Locker, G.  Y., & Tobias, J.  S. (2005).  Results of the ATAC (Arimidex, 
Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment 
for breast cancer.  Lancet, 365(9453), 60-62. 
Kalbfleisch, J. D., and R. L. Prentice (2002) The statistical analysis of failure time data 
(Second Edition). John Wiley & Sons, New York. 
Kaplan, E.L., and Meier, P. (1958) Nonparametric estimation from incomplete 
observation.  Journal of the American Statistical Association, 53:  457-481. 
Lawless, J. F. (1982) Statistical Models and Methods for Lifetime Data, New York: John 
Wiley and Sons, Inc.  
Little, R.J.A. and Rubin, D.B. (1987) Statistical Analysis with Missing Data. J. Wiley & 
Sons, New York. 


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Martin, M., Pienkowski, T., Mackey, J., Pawlicki, M., Guastalla, J.  P., Weaver, C., 
Tomiak, E., Al-Tweigeri, T., Chap, L., Juhos, E., Guevin, R., Howell, A., Fornander, T., 
Hainsworth, J., Coleman, R., Vinholes, J., Modiano, M., Pinter, T., Tang, S.  C., Colwell, 
B., Prady, C., Provencher, L., Walde, D., Rodriguez-Lescure, A., Hugh, J., Loret, C., 
Rupin, M., Blitz, S., Jacobs, P., Murawsky, M., Riva, A., & Vogel, C. (2005).  Adjuvant 
docetaxel for node-positive breast cancer.  N Engl J Med, 352(22), 2302-2313. 
Proschan MA, Lan KKG, Wittes JT (2006). Statistical Monitoring of Clinical Trials: A 
Unified Approach. Springer, New York.  
Romond, E.  H., Perez, E.  A., Bryant, J., Suman, V.  J., Geyer, C.  E., Jr., Davidson, N.  
E., Tan-Chiu, E., Martino, S., Paik, S., Kaufman, P.  A., Swain, S.  M., Pisansky, T.  M., 
Fehrenbacher, L., Kutteh, L.  A., Vogel, V.  G., Visscher, D.  W., Yothers, G., Jenkins, R.  
B., Brown, A.  M., Dakhil, S.  R., Mamounas, E.  P., Lingle, W.  L., Klein, P.  M., Ingle, J.  
N., & Wolmark, N. (2005).  Trastuzumab plus adjuvant chemotherapy for operable 
HER2-positive breast cancer.  N Engl J Med, 353(16), 1673-1684. 
Schoenfeld, D. (1982) Partial Residuals for the Proportional Hazards Regression Model. 
Biometrika, 69, 239 -241.  
Sakamaki K (2013). A group sequential method using Hochberg procedure for clinical 
trials with multiple primary endpoints. Activity number 599, Presented at American 
Statistical Association Joint Statistical Meeting, Montreal, Canada, August 7, 2013. 
Slamon, D., Eiermann, W., Robert, N., Pienkowski, T., Martin, M., Pawlicki, M., Chan, A., 
Smylie, M., Liu, M., Falkson, C., Pinter, T., Fornander, T., Shiftan, T., Valero, V., 
Mackey, J., Tabah-Fisch, I., Buyse, M., Lindsay, M., Riva, A., Bee, V., Pegram, M., 
Press, M., & Crown, J. (2006).  BCIRG 006: 2nd interim analysis phase III randomized 
trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACT) with 
doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) with 
docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer 
patients.  SABCS (Abstract #52). 
Thurlimann, B., Keshaviah, A., Coates, A.  S., Mouridsen, H., Mauriac, L., Forbes, J.  F., 
Paridaens, R., Castiglione-Gertsch, M., Gelber, R.  D., Rabaglio, M., Smith, I., Wardley, 
A., Price, K.  N., & Goldhirsch, A. (2005).  A comparison of letrozole and tamoxifen in 
postmenopausal women with early breast cancer.  N Engl J Med, 353(26), 2747-2757. 
Van Elteren P.H. (1960).  On the combination of independent two-sample test of 
Wilcoxon, Bulletin of the International Statistical Institute, 37, 351-361. 
Ye Y., Li A., Liu L., Yao B. (2012). A group sequential Holm procedure with multiple 
primary endpoints. Statistics in medicine, 32: 1112-1124.  
Zhou B, Latouche A, Rocha V, Fine J. (2011). Competing Risks Regression for Stratified 
Data. Biometrics. 67(2):661-70. 


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12. 
Appendices  
12.1 
Technical Detail/Supplemental Information Regarding Statistical 
Procedures and Programs 
12.1.1 
Dates 
All dates should be converted to SAS dates prior to its use in any calculation. 
12.1.2 
Visit Windows  
Per protocol, post baseline study visits are to be performed ± 7 days from the scheduled 
Q4W and Q3W visit dates, and ± 14 days from the scheduled Q3M visit dates. To allow 
for variations in scheduling, the following visit windows will be used to assign evaluations 
to a most appropriate nominal visit for analysis and summarization.   


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For Subjects on the Q4W/Q3M Schedule: 
Frequency of 
Assessments 
Endpoint 
Nominal 
Visit 
Window Definition 
(Study Day) 
Q4W up to week 25 
followed by Q12W 
up to week 253 
Serum albumin, calcium and 
calcium (corrected)  
Baseline 
Week 5 
Week 9  
Week 13  
Week 17 
Week 21  
Week 25  
Week 37 
 … 
Week 241 
Week 253 
≤1 
2 – 42 
43 – 70 
71 – 98 
99 – 126 
127 – 154 
155 – 182 
183 – 294 
… 
1639 – 1722 
≥1723  
Q12W up to 
week 25 followed by 
Q36W up to week 
241 
Magnesium, and 
phosphorus  
Baseline 
Week 13 
Week 25  
Week 61  
Week 97 
Week 133  
Week 169 
Week 205 
Week 241 
≤1 
2 – 126 
127 – 210 
211 – 546 
547 – 798 
799 – 1050 
1051 – 1302 
1303 – 1554 
≥1555 
Multiple frequencies 
Hematology, and vitamin D 
Baseline 
EOTP 
≤1 
≥2 
Q12W 
ECOG assessment, vital 
signs, and physical exam 
Baseline 
Week 13  
Week 25 
Week 37 
Week 49 
… 
≤1 
2 – 126 
127 – 210 
211 – 294 
295 – 378 
… 
Q12W up to 
week 277 
PRO 
Baseline 
Week 13  
Week 25 
Week 37 
Week 49 
… 
Week 265 
Week 277 
≤1 
2 – 126 
127 – 210 
211 – 294 
295 – 378 
… 
1807 – 1890 
≥1891 
Q24W 
Oral exam 
Baseline 
Week 25  
Week 49  
Week 73 
Week 97 
… 
≤1 
2 – 252 
253 – 420 
421 – 588 
589 – 756 
… 


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Frequency of 
Assessments 
Endpoint 
Nominal 
Visit 
Window Definition 
(Study Day) 
Multiple frequencies 
PK, BTMs and blood 
biomarkers  
Baseline 
Week 13  
Week 25  
Week 37 
Week 49  
Week 61  
Week 145 
≤1 
2 – 126 
127 – 210 
211 – 294 
295 – 378 
379 –  462 
≥463 
Multiple frequencies 
Anti-denosumab antibodies  
 
Baseline 
Week 25  
Week 49  
Week 97 
Week 145  
Week 205  
Week 253 
Week 277 
≤1 
2 – 252 
253 – 420 
421 – 840 
841 – 1176 
1177 – 1638 
1639 – 1932 
≥1933 
Yearly 
Breast density and PRO  
Baseline 
Year 1  
Year 2  
Year 3 
Year 4 
Year 5 
≤1 
2 – 548 
549 –  913 
914 – 1278 
1279 – 1643 
≥1644 


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For Subjects on the Q3W/Q3M Schedule:  
Frequency of 
Assessments 
Endpoint 
Nominal 
Visit 
Window Definition 
(Study Day) 
Q3W up to week 19 
followed by Q12W 
up to week 247 
Serum albumin, calcium and 
calcium (corrected)  
Baseline 
Week 4 
Week 7  
Week 10  
Week 13 
Week 16  
Week 19  
Week 31 
 … 
Week 235 
Week 247 
≤1 
2 – 31 
32 – 52 
53 – 73 
74 – 94 
95 – 115 
116 – 136 
137 – 252 
… 
1597 – 1680 
≥1681  
Q9W up to week 19 
followed by Q36W 
up to week 235 
Magnesium, and 
phosphorus  
Baseline 
Week 10 
Week 19  
Week 55  
Week 91 
Week 127  
Week 163 
Week 199 
Week 235 
≤1 
2 – 94  
95 – 157 
158 – 504 
505 – 756 
757 – 1008 
1009 – 1260 
1261 – 1512 
≥1513 
Multiple frequencies 
Hematology, and vitamin D 
Baseline 
EOTP 
≤1 
≥2 
Q9W up to week 19 
followed by Q12W  
ECOG assessment, vital 
signs, and physical exam 
Baseline 
Week 10  
Week 19 
Week 31 
Week 43 
… 
≤1 
2 – 94 
95 – 157 
158 – 252 
253 – 336 
… 
Q9W up to week 19 
followed by Q12W 
up to week 271 
PRO 
Baseline 
Week 10  
Week 19 
Week 31 
Week 43 
… 
Week 259 
Week 271 
≤1 
2 – 94 
95 – 157 
158 – 252 
253 – 336 
… 
1765 – 1848 
≥1849 
Q18W up to 
week 19 followed by 
Q24W 
Oral exam 
Baseline 
Week 19  
Week 43  
Week 67 
Week 91 
… 
≤1 
2 – 189 
190 – 378 
379 – 546 
547 – 714 
… 


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Frequency of 
Assessments 
Endpoint 
Nominal 
Visit 
Window Definition 
(Study Day) 
Multiple frequencies 
PK, BTMs and blood 
biomarkers  
Baseline 
Week 10  
Week 19  
Week 31 
Week 43  
Week 55  
Week 139 
≤1 
2 – 94 
95 – 157 
158 – 252 
253 – 336 
337 – 420 
≥421 
Multiple frequencies 
Anti-denosumab antibodies  
 
Baseline 
Week 19  
Week 43  
Week 91 
Week 139  
Week 199 
Week 247 
Week 271 
≤1 
2 – 189 
190 – 378 
379 – 798 
799 – 1134 
1135 – 1596 
1597 – 1890 
≥1891 
Yearly 
Breast density and PRO 
Baseline 
Year 1  
Year 2  
Year 3 
Year 4 
Year 5 
≤1 
2 – 548 
549 –  913 
914 – 1278 
1279 – 1643 
≥1644 
For urine and serum samples, the baseline sample time must be on or before the 
1st dose time.  If there are multiple records within a Baseline (BL) window, the record that 
is the closest to and prior to and including Study Day 1 will be considered as the 
baseline value.  If there are multiple records within the subsequent visit window, the 
record that is closest to the day of the planned visit (eg, target day for visit  
“Week 5” = 7 * 5 – 7 + 1; target day for EOTP visit is the end of treatment phase date on 
the CRF) will be used as the measurement for this planned visit (the nominal visit).  If 
two observations are the same distance from the target day, use the later one.  
For samples that are assessed with different frequencies, a mixture of the windows 
given in Visit Table will be used. For example, if a parameter is evaluated every 4 week 
up to week 25 and then every 12 week thereafter, the window of Q4W will be used up to 
week 25. The window for week 37 will cover study day 183 to 294. From week 49 and 
onwards, the Q12W window will be used. 
12.2 
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. 


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12.3 
Patient Report Outcome Forms/Instruments 
12.3.1 
Patient Report Outcome Forms 
In this study, the PRO measurements are: the BPI-SF and the EQ-5D.  
12.3.2 
Patient Report Outcome Instruments 
12.3.2.1 
Reliability and Validity of PRO Instruments 
The BPI-SF is a questionnaire specifically designed to assess pain in cancer.  The 
BPI-SF captures information on the intensity of pain (pain severity) as well as the degree 
to which pain interferes with function (pain interference).  The single item, which asks 
patients to rate their pain ‘at its worst’, is an exploratory endpoint in this study.  The 
severity scale, which is comprised of 4 items, and the pain interference scale, which is 
comprised of 7 items, are also exploratory endpoints in this study.  Evidence for 
reliability and validity of the BPI-SF has been well documented in cancer patients 
(Cleeland CS, 1991). 
The EQ-5D, developed in 1990, is a widely used generic HRQOL instrument that allows 
for estimation of Quality Adjusted Life Years (QALY), a requirement for reimbursement 
dossiers and formulary submissions.  The EQ-5D is comprised of 6 questions.  The 
first 5 questions address the following quality of life dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety /depression.  Each of these questions has a 
simple three-category response scale.  The last question is represented by a 20-cm 
vertical VAS, scored from 0 to 100 asking the patient to “mark your own health state 
today” (Brooks, 1996). 
12.3.2.2 
PRO Question Mapping 
Question mapping for the PROs are outlined in the table below. 
MEASURES (scale) 
QUESTIONS 
BPI-SF 
 
Pain Severity 
3-6 
Pain Interference 
9A-9G 
EQ-5D 
 
Mobility 
8a 
Self-Care 
8b 
Usual Activities 
8c 
Pain Discomfort 
8d 
Anxiety/Depression 
8e 
Vertical VAS 
9 


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12.3.2.3 
Scoring Algorithm for PROs 
12.3.2.3.1 
BPI-SF Scoring 
Raw scores (0-10) for single item question will be used for each item.  The scoring for 
composite pain severity and pain interference base on the developer approved 
algorithm. 
12.3.2.3.2 
EQ-5D Scoring 
The EQ-5D instrument yields two measures: health state index value and health state 
visual analog scale score.  The scoring of each is detailed below.  
12.3.2.3.2.1 
Health State Index Value 
Question 8, a-e, asks the subject to describe his/her present health state on 
five dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression.  Each question has 3 response choices, listed in order of increasing 
severity.  The first response choice (“no problems”) is coded as a 1; the second 
(“moderate problems”) is coded as a 2; the third (“extreme problems”) is coded as a 3, 
as indicated on the questionnaire.  In addition to the five variables representing these 
items, a string variable formed by concatenating the values for the five dimension 
variables should be included in the database.  For example, if a subject reports as,  
2.a. = 2, 2.b. = 1, 2.c. = 1, 2.d = 1, and 2.e. = 2, then string variable “Health State” would 
be “21112”.  In total, there are 243 health states.   
Value classification for the 243 health states has been calculated in previous studies 
using regression models.  Parameters estimated by the previous models can be applied 
to estimate a health state index value for this study using the dimension scores from 
question 8 a-e and the following set of IF / THEN statements: 
Calculation of Health State Index  
Generalized least-squares (GLS) regression techniques in which the functional form was 
additive were used to estimate health state index scores from the EQ-5D questionnaire.  
The dependent variable Y was defined as 1 –S where “S” is the health state index score.  
Besides the intercept, the specification of the remaining independent variables was 
derived from the ordinal nature of items in the EQ-5D.  
Since there are three response choices for each dimension, there are two dummy 
variables for each dimension.  For example, there are two dummy variables for mobility 
(MO2, MO3), two dummy variables for self-care (SC2, SC3), two dummy variables for 
usual activities (UA2, UA3), two dummy variables for pain / discomfort (PD2, PD3), and 


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two dummy variables for anxiety/ depression (AD2, AD3).  The table below shows the 
independent variables specified in the model.  There is one dummy variable N3 
represents whether any of the dimensions is at level 3.  Dummy variable D23 represents 
whether any of the dimensions is not “1”.  D23 variable will equal to 0 only for health 
state “11111” (when a patient marks “1” to all questions). 
Y = β1D23 +β2MO2 + β3SC2 + β4UA2 + β5PD2 + β6AD2 + β7MO3 + β8SC3 + β9UA3 
+ β10PD3 + B11AD3 +B12N3 
EuroQoL 
dimension 
Patient Response 
Parameters 
D23 
D23=1 if a patient marks “2” or “3” to ANY question 
D23=0, otherwise (Note: D23=0 only for health state 
“11111”) 
0.081 
MO2 
MO2= 1 if patient marks “2” to Mobility question 
MO2= 0, otherwise  
0.069 
SC2 
 SC2=1 if patient marks “2” to Self-Care question 
SC2=0, otherwise 
0.104 
UA2 
UA2=1 if patient marks “2” to Usual Activities question 
UA2=0, otherwise 
0.036 
PD2 
PD2=1 if patient marks “2” to Pain/Discomfort question 
PD2=0 otherwise 
0.123 
AD2 
AD2=1 if patient marks “2” to Anxiety/Depression 
question AD2=0 otherwise 
0.071 
MO3 
MO3=1 if patient marks “3” to Mobility question MO3=0 
otherwise 
  0.314 
SC3 
SC3=1 if patient marks “3” to Self-Care question 
SC3=0 otherwise 
  0.214 
UA3 
UA3=1 if patient marks “3” to Usual Activities question 
UA3=0 otherwise 
  0.094 
PD3 
PD3=1 if patient marks “3” to Pain/Discomfort question 
PD3=0 otherwise 
  0.386 
AD3 
AD3=1 if patient marks “3” to Anxiety/Depression 
question 
  0.236 
N3 
N3=1 if patient marks “3” to any question N3=0 
otherwise 
0.269 
The resulting scores can range between 1.0 and -0.594; scores less than 0.0 are 
included because a number of states were rated as worse than death.  A higher score 
indicates a more preferred health status.  


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12.3.2.3.2.2 
Health State Visual Analog Scale  
Questionnaire Question 9 asks respondents to rate their present health status on a 
vertical 0 to 100 visual analog scale of 20 cm, with 0 labeled as “Worst imaginable health 
state” and 100 labeled as “Best imaginable health state.” The scale is marked in 
increments of “1,” with values labeled at each decile. The person scoring this question 
must observe the point at which the subject’s hand- drawn line intersects the scale and 
enter the closest integer.