Conditions: Non-Small Cell Lung Cancer Anemia Cancer Lung Cancer
Keywords: darbepoetin alfa non-small cell lung cancer Aranesp chemotherapy chemotherapy induce anemia advanced lung cancer malignant pleural effusion metastatic lung cancer NSCLC anemia lung cancer pleural effusion Stage IIIB lung cancer Stage IV lung cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2549
Healthy volunteers: no

Brief summary:
This is a study in patients with chemotherapy induced anemia receiving multi-cycle chemotherapy for the treatment of stage IV non-small cell lung cancer (NSCLC). The primary objective of the study is to demonstrate that overall survival (OS) is not worse in participants on darbepoetin alfa treated to a hemoglobin ceiling of 12.0 g/dL compared to participants treated with placebo.

Detailed description:
Oversight Authorities continued: Colombia

Arms:
arm 1: Participants received placebo once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first. arm 2: Participants received darbepoetin alfa 500 µg once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.

Interventions: intervention 1: Darbepoetin alfa intervention 2: Placebo
Intervention descriptions: intervention 1: Administered subcutaneously once every 3 weeks intervention 2: Administered subcutaneously once every 3 weeks

Protocol document:
Prot_001.pdf: 
Product:  Darbepoetin alfa 
Protocol Number:  20070782 
Date:  13 November 2012 
Page 1 of 86 
 
Title:  A Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Long-term Safety and Efficacy of Darbepoetin Alfa Administered at 500 µg Once-
Every-3-Weeks in Anemic Subjects With Advanced Stage Non-small Cell Lung 
Cancer Receiving Multi-cycle Chemotherapy  
Darbepoetin alfa 
Amgen Protocol Number 20070782 
BB-IND 8223 
EudraCT number 2007-005792-34 
 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Tel: +1 (805) 447-1000 
Fax: +1 (805) 375-8546 
Key Sponsor Contact: 
 
Global Study Manager, Amgen Inc. 
One Amgen Center Drive. 
Thousand Oaks, CA 91320, USA 
 
 
Regional Study Manager, Amgen Ltd. 
 
   
 
Date: 
25 November 2008 
Amendment 1 
11 February 2009 
Amendment 2 
22 March 2009 
Amendment 3 
25 May 2010 
Superseding Amendment 3 13 November 2012 
 
Confidentiality Notice 
This document contains confidential information of Amgen Inc.  
This document must not be disclosed to anyone other than the study staff and members 
of the independent ethics committee/institutional review board.   
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc.  
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number: for US sites, 1- 800-77-AMGEN; for Canadian 
sites, 1-866-50-AMGEN.  For all other study-related questions, continue to contact the 
Key Sponsor Contact. 
PPD
PPD
PPD
PPD
PPD


Product:  Darbepoetin alfa 
Protocol Number:  20070782 
Date:  13 November 2012 
Page 2 of 86 
 
Investigator’s Agreement 
I have read the attached protocol entitled, “A Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Long-term Safety and Efficacy of Darbepoetin 
Alfa Administered at 500 Pg Once-Every-3-Weeks in Anemic Subjects With Advanced 
Stage Non-small Cell Lung Cancer Receiving Multi-cycle Chemotherapy” dated  
13 November 2012, and agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice and applicable regulations/guidelines. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
x 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
x 
my sub-investigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
Name of Principal or Coordinating 
Investigator 
 
Date (DD Month YYYY) 


Product:  Darbepoetin alfa 
Protocol Number:  20070782 
Date:  13 November 2012 
Page 3 of 86 
 
Protocol Synopsis 
Title:  A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Long-term Safety 
and Efficacy of Darbepoetin Alfa Administered at 500 µg Once-Every-3-Weeks (Q3W) in Anemic 
Subjects With Advanced Stage Non-small Cell Lung Cancer Receiving Multi-cycle Chemotherapy      
Study Phase:  3 
Indication:  Chemotherapy-induced Anemia (CIA) 
Primary Objective 
• To demonstrate non-inferiority of overall survival (OS) when comparing subjects on 
darbepoetin alfa treated to a hemoglobin ceiling of 12.0 g/dL to subjects treated with placebo 
Secondary Objectives 
• To demonstrate non-inferiority of progression-free survival (PFS) when comparing subjects 
on darbepoetin alfa treated to a hemoglobin ceiling of 12.0 g/dL to subjects treated with 
placebo 
• To demonstrate superiority in reducing the incidence of red blood cell (RBC) transfusions 
when comparing subjects on darbepoetin alfa treated to a hemoglobin ceiling of 12.0 g/dL to 
subjects treated with placebo 
• To assess other safety and efficacy parameters in subjects on darbepoetin alfa treated to a 
hemoglobin ceiling of 12.0 g/dL compared to subjects treated with placebo  
Hypothesis 
The primary hypothesis to be tested is that the OS of subjects with CIA with stage IV non-small 
cell lung cancer (NSCLC) receiving cyclic chemotherapy treated with darbepoetin alfa 500 µg 
Q3W to a hemoglobin ceiling of 12.0 g/dL will not be worse than the OS of anemic subjects 
treated with placebo.   
Study Design 
This is a double-blind, randomized, placebo-controlled phase 3 non-inferiority study in subjects 
with CIA receiving multi-cycle chemotherapy for the treatment of advanced stage NSCLC.   
Approximately 3000 subjects with stage IV NSCLC will be randomized in a 2:1 allocation to 
Groups A and B:  
• Group A: darbepoetin alfa 500 µg (Q3W) to a hemoglobin ceiling of 12.0 g/dL 
• Group B: placebo Q3W 
Section 6.1.2 describes the dosing algorithms. 
Randomization will be stratified by geographic region, histology, and screening hemoglobin (local 
laboratory hemoglobin; sample obtained within 7 days prior to randomization). 
The study consists of a screening period (up to 21 days), a treatment period, and a long-term 
follow up (LTFU) period.  Investigational Product (IP) will be given Q3W during the treatment 
period.  IP will be discontinued within 3 weeks after the completion of chemotherapy, or upon the 
determination of disease progression, whichever occurs first.  Study visits Q3W and imaging 
studies Q9W will occur during the treatment period until disease progression.  An end of 
treatment period (EOTP) visit will occur at the next Q3W visit after disease progression has been 
determined.  Subjects will then enter LTFU and will be followed with once-every-3-months (Q3M) 
study visits until death, or until approximately 2700 deaths have occurred (End of Study [EOS]).  
Adverse events and serious adverse events will be collected until 30 days after the last dose of 
IP.  Based on the estimated recruitment rate and the projected survival rate of metastatic NSCLC, 
the study duration is anticipated to take approximately 7 years for enrollment and 3 years follow 
up for a total of 10 years from first subject enrolled into study to EOS.   
Tumor Sample Banking:  If available and upon the consent of the subjects, archived paraffin 
embedded tumor tissue blocks or unstained tumor slides (from primary tumor or metastasis) will 
be collected during screening and submitted upon enrollment for erythropoietin receptor (EpoR) 
testing, tumor mutation analysis, and other biomarker evaluation.  There will not be an additional 


Product:  Darbepoetin alfa 
Protocol Number:  20070782 
Date:  13 November 2012 
Page 4 of 86 
 
procedure required but rather these tumor samples may be obtained from previous diagnostic 
biopsy.   
Primary and Secondary Endpoints 
Primary Endpoint 
• Overall survival (OS) 
Secondary Endpoints 
• Progression-free survival (PFS) 
• Incidence of at least 1 RBC transfusion or hemoglobin ≤ 8.0 g/dL from week 5 (day 29) to the 
end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of 
IP or the last dose of chemotherapy, whichever is later; the EOETP will be set to the EOTP if 
the EOETP exceeds the EOTP) 
Other Safety Endpoints 
• 
 
 
• 
 
• 
  
Other Efficacy Endpoints 
• 
 
 
• 
 
Sample Size:  Approximately 3000 subjects  
Summary of Subject Eligibility Criteria   
Inclusion Criteria 
• Subjects with stage IV NSCLC (not recurrent or re-staged)  
• Expected to receive at least 2 additional cycles (at least 6 total weeks) of first line 
myelosuppressive cyclic chemotherapy after randomization.  Subjects should not be 
expected to receive only maintenance chemotherapy.   
• Life expectancy > 6 months based on the judgment of the investigator and documented 
during screening 
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 as assessed 
within 21 days prior to randomization 
• 18 years of age or older at screening 
• Hemoglobin level ≤ 11.0 g/dL as assessed by the local laboratory; sample obtained within 7 
days prior to randomization (retest in screening is acceptable) 
• Subjects must have had a baseline scan (CT, MRI, or PET/CT) of the chest to assess 
disease burden before starting on first line chemotherapy for NSCLC and those images must 
have been reviewed by the investigator prior to randomization.  If the scan was performed 
more than 28 days prior to randomization, an additional scan must be performed and 
reviewed by the investigator to confirm that the patient has not progressed before 
randomization.       
• Adequate serum folate (≥ 2 ng/mL) and vitamin B12 (≥ 200 pg/mL) levels assessed by the 
central laboratory during screening (supplementation and retest acceptable) 
• Before any study specific procedure, the appropriate written informed consent must be 
obtained from the subject or legally accepted representative 
Exclusion Criteria 
•
CCI
 Known primary benign or malignant hematologic disorder which can cause anemia 
CCI
CCI
CCI
CCI


Product:  Darbepoetin alfa 
Protocol Number:  20070782 
Date:  13 November 2012 
Page 5 of 86 
 
x 
History of, or current active cancer other than NSCLC, with the exception of curatively 
resected non-melanomatous skin cancer, curatively treated cervical carcinoma in situ, or 
other primary solid tumors curatively treated with no known active disease present and no 
curative treatment administered for the last 3 years   
x 
Received any prior adjuvant or neoadjuvant therapy for NSCLC 
x 
Subjects with a history of brain metastasis 
x 
Uncontrolled hypertension (systolic blood pressure [BP] > 160 mmHg or diastolic BP 
> 100 mmHg), or as determined by the investigator during screening 
x 
History of neutralizing antibody activity to rHuEPO or darbepoetin alfa 
x 
Uncontrolled angina, uncontrolled heart failure, or uncontrolled cardiac arrhythmia as 
determined by the investigator at screening.  Subjects with known myocardial infarction within 
6 months prior to randomization.   
x 
Subjects with a history of seizure disorder taking anti-seizure medication within 30 days prior 
to randomization 
x 
Clinically significant systemic infection or uncontrolled chronic inflammatory disease (eg, 
rheumatoid arthritis, inflammatory bowel disease) as determined by the investigator during 
screening 
x 
Known seropositivity for human immunodeficiency virus (HIV) or diagnosis of acquired 
immunodeficiency syndrome (AIDS), positive for hepatitis B surface antigen, or seropositive 
for hepatitis C virus 
x 
History of pure red cell aplasia 
x 
History of deep venous thrombosis or embolic event (eg, pulmonary embolism) within 6 
months prior to randomization  
x 
Known previous treatment failure to ESAs (eg, rHuEPO, darbepoetin alfa) 
x 
ESA therapy within the 28 days prior to randomization 
x 
Known hypersensitivity to recombinant ESAs or the excipients contained within the 
investigational product 
x 
Transferrin saturation < 20% and ferritin < 50 ng/mL as assessed by the central laboratory 
during screening.  Subjects must have both to be excluded (supplementation and retest 
acceptable). 
x 
Abnormal renal function (serum creatinine level > 2 times [X] the upper limit of normal [ULN]) 
as assessed by the central laboratory during screening 
x 
Abnormal liver function (total bilirubin > 2X ULN or liver enzymes alanine aminotransferase 
[ALT] or aspartate aminotransferase [AST] > 2.5X ULN for subjects without liver metastasis 
or ≥ 5X ULN for subjects with liver metastasis) as assessed by the central laboratory during 
screening.  Subjects with documented Gilbert’s Disease may be eligible. 
x 
Received any RBC transfusion within 28 days prior to randomization 
x 
Plan to receive any RBC transfusion between randomization and study day 1 
x 
Less than 30 days since receipt of any investigational product or device.  Investigational 
use/receipt of a medicinal product or device that has been approved by the country’s local 
regulatory authority for any indication is permitted 
x 
Subjects of reproductive potential who are pregnant, breast feeding or not willing to use 
effective contraceptive precautions during the study and for at least one month after the last 
dose of investigational product in the judgment of the investigator (including females of 
childbearing potential who are partners of male subjects) 
x 
Previously randomized to this study 


Product:  Darbepoetin alfa 
Protocol Number:  20070782 
Date:  13 November 2012 
Page 6 of 86 
 
• Investigator has concerns regarding the ability of the subject to give written informed consent 
and/or to comply with study procedures (including availability for follow-up visits) 
Investigational Product Dosage and Administration 
Investigational product will be initiated on study day 1 and administered subcutaneously Q3W.  
The first dose of IP may be administered no earlier than on the same day that first line 
myelosuppressive cyclic chemotherapy is initiated.  Investigational product will be supplied in 
vials containing a human serum albumin free polysorbate formulation and darbepoetin alfa 
concentration of 500 µg, 300 µg, 200 µg or 100 µg per mL or placebo (without active drug).  Each 
box will contain a single vial of IP.  Investigational product will be blinded. 
Control Group:  Placebo Q3W 
Procedures 
See Section 7 and/or Appendix A (Schedule of Assessments) for a complete list of procedures. 
Statistical Considerations 
General Approach 
The analyses will be based on all randomized and consented subjects who receive at least one 
dose of IP.  Sensitivity analyses will be based on all randomized and consented subjects and on 
a prospectively defined per-protocol analysis set.  
To preserve the overall significance level for the study, statistical testing of the primary and 
secondary endpoints will follow a hierarchical structure.  First, the primary endpoint of OS will be 
tested.  If darbepoetin alfa is demonstrated to be non-inferior to placebo with respect to OS then 
PFS will be formally tested.  If darbepoetin alfa is demonstrated to be non-inferior to placebo with 
respect to PFS then the incidence of RBC transfusions or a hemoglobin ≤ 8.0 g/dL will be formally 
tested.  If non-inferiority is demonstrated for both OS and PFS and superiority is demonstrated for 
the transfusion endpoint, superiority will then be tested for both OS and PFS using the Hochberg 
procedure to adjust for multiplicity.  For endpoints that are not designated as primary or 
secondary, statistical testing will be considered descriptive and no adjustments will be made for 
multiplicity. 
Sample Size Considerations 
A total of 2700 deaths will be observed in order to exclude a hazard ratio (darbepoetin alfa to 
placebo) of 1.15 with a 1-sided significance level of 0.025.  With 2700 deaths, the study is 
powered at just over 90% if the true hazard ratio is 1.0 (approximately 93%).  To observe 2700 
deaths, the study will randomize a total of 3000 subjects which assumes a 7-year enrollment 
period, a 3-year follow-up after last subject enrolled, a 1-year survival rate of 51% 
(Sandler et al, 2006), and a common exponential drop-out rate of 0.0511. 
Excluding a hazard ratio of 1.15 corresponds to excluding a decrease in median survival of 
approximately 1.6 months in the darbepoetin alfa arm group compared to placebo.  This 
estimation assumes survival time is exponentially distributed which allows for a conversion from a 
hazard ratio to medians.  A median survival of 12.3 months (Sandler et al, 2006) was assumed as 
the median survival in the placebo arm in order to derive the difference in medians that 
correspond to a hazard ratio of 1.15. 
Analysis of Primary Endpoint 
The analysis of OS will use a Cox proportional hazards model, stratified by the randomization 
factors, with treatment group as the only covariate (a sensitivity analysis will include additional 
covariates potentially predictive of OS to assess the robustness of the primary approach).  
Subjects last known to be alive will be censored on date of last contact.  Non-inferiority will be 
declared if the upper confidence limit for the hazard ratio is less than 1.15 using a 1-sided 
significance level of 0.025. 
Analysis of Secondary Endpoints 
The same methods used to analyze OS will be used to analyze PFS.  Progression-free survival 
will be measured from randomization to disease progression (as defined by the version of 
RECIST specified in the protocol at the time of subject enrollment using investigator-assessed 
scans) or death from any cause; subjects without either event will be censored at the last disease 
assessment date.  Non-inferiority will be declared if the upper confidence limit for the hazard ratio 


Product:  Darbepoetin alfa 
Protocol Number:  20070782 
Date:  13 November 2012 
Page 7 of 86 
 
is less than 1.15 using a 1-sided significance level of 0.025.  This analysis will be performed on all 
subjects in the primary analysis set who have not had disease progression prior to randomization.   
To assess treatment group differences in the incidence of RBC transfusions or a hemoglobin 
≤ 8.0 g/dL, the Cochran-Mantel-Haenszel method will be used which will adjust for the 
stratification factors at randomization.  The incidence will be assessed from day 29 to the EOETP.  
This analysis will be performed on all subjects in the primary analysis set whose EOETP is 
≥ day 29. 
Interim Analysis and Early Stopping Guidelines 
An independent Data Monitoring Committee (DMC) will assess safety on a regular basis 
throughout the duration of the study.  The DMC will convene approximately once every 6 months 
for the first 2 years and once a year thereafter during the course of the trial.  In addition, the DMC 
will oversee 5 formal interim analyses to assess harm (ie, inferiority of darbepoetin alfa), which 
will occur when approximately 10%, 20%, 30%, 40%, and 60% of the planned total of 2700 
deaths have been observed.  If warranted from these reviews, the DMC may request additional 
safety data, recommend modifying or stopping the treatment, or recommend suspending 
randomization.  In addition, the DMC will review enrollment status and evaluate changes in the 
practice of medicine to make recommendations regarding the ongoing feasibility of the trial.  Prior 
to the completion of the recruitment period, the sponsor will re-assess the study assumptions (eg, 
recruitment rate and mortality rate) on a blinded basis, and may revise the sample size in order to 
ensure that the study completes. 
Sponsor/Licensee: Amgen Inc. 
 


Product:  Darbepoetin alfa 
Protocol Number:  20070782 
Date:  13 November 2012 
Page 8 of 86 
 
Study Design and Treatment Schema 
 
Q3W = once-every-3-weeks; Wk = Week; DP = disease progression 
a Screening assessments will be performed within 21 days prior to randomization.  The local laboratory hemoglobin sample to confirm eligibility must be obtained 
within 7 days prior to randomization.   
b Subjects will be randomized in a 2:1 allocation (Group A:Group B), stratified by geographic region, histology, and screening hemoglobin (local laboratory 
hemoglobin; sample obtained within 7 days prior to randomization). 
c Investigational product will be administered Q3W during the treatment period.  IP w
ill be discontinued within 3 weeks after the last dose of chemotherapy, or upon 
the determination of disease progression, whichever occurs first.  For subjects who end IP without disease progression, imaging studies will continue every 9 weeks 
and study visits will continue Q3W until progression, at which time they will complete EOTP and enter LTFU.  AEs and SAEs will be collected up to 30 days after the 
last dose of IP. 
d EOTP visit will occur at the next Q3W visit after disease progression has been determined.  Subjects who are unable to continue Q3W visits and Q9W imaging 
studies until disease progression should complete EOTP procedures at their next Q3W visit and will be asked to enter the LTFU period.  
e Imaging studies (CT scans, MRI, or PET/CT) of the chest will be performed during screening (if needed for eligibility) and every 9 weeks (or sooner if clinically 
indicated) from Week 1 until disease progression.  The same type of scan should be used throughout study.  Subjects must have had a baseline image performed 
prior to starting first line chemotherapy for NSCLC.  Bone scans, MRI, CT, PET, PET/CT, or X-ray should be performed when signs or symptoms suggestive of bone 
metastasis are present. 
f Subjects will be followed for survival until death, or until approximately 2700 deaths have occurred on the study. 


Product:  Darbepoetin alfa 
Protocol Number:  20070782 
Date:  13 November 2012 
Page 9 of 86 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ACS 
Acute coronary syndromes 
AE 
Adverse Event 
AGO 
Arbeitsgemeinschaft Gynaekologische Onkologie (German 
Gynecological Oncology Study Group) 
AHRQ 
Agency for Healthcare Research and Quality 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATE 
Arterial thromboembolic event 
Baseline Hemoglobin 
Screening hemoglobin (ie, local laboratory hemoglobin; sample 
obtained within 7 days prior to randomization) 
BEST 
Breast Cancer Erythropoietin Survival Trial 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CA 
Cancer 
CBC 
Complete blood count 
CDM 
Clinical Data Management 
CI 
Confidence interval 
CIA 
Chemotherapy-induced anemia 
CR 
Complete response 
CRF 
Case report form 
CRP 
C-reactive protein 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
dL 
Deciliter  
DMC 
Data monitoring committee 
DNA 
Deoxyribonucleic acid 
DP 
Disease progression 
DVT 
Deep vein thrombosis 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
Enroll, Enrolled, or 
Enrollment 
Enrollment is defined as the point in time when all required 
screening procedures have been completed, all eligibility criteria are 
met, and IVR/IWR System has been accessed to randomize the 
subject. 


Product:  Darbepoetin alfa 
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Date:  13 November 2012 
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Abbreviation or Term 
Definition/Explanation 
EOETP 
End of the Efficacy Treatment Period is defined as 21 days after 
either the last dose of IP or the last dose of chemotherapy, 
whichever is later; the EOETP will be set to the EOTP if the EOETP 
exceeds the EOTP. 
EOS 
End of Study is defined for a subject as either the date of death or 
the date when the long-term follow-up period ends (ie, when 2700 
deaths have occurred), whichever comes first. 
EOTP 
End of Treatment Period will occur at the next Q3W visit after 
disease progression has been determined. 
EPO 
Erythropoietin 
EpoR 
Erythropoietin receptor 
ESA 
Erythropoiesis stimulating agent 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose-PET 
g/dL 
Gram per deciliter 
GBG 
German Breast Group 
GGT 
Gamma-glutamyltransferase 
GOG 
Gynecologic Oncology Group 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
HSA-free 
Human serum albumin-free 
ICF 
Informed consent form 
ICH GCP 
International Conference on Harmonisation Tripartite Guideline on 
Good Clinical Practice 
ID 
Identification 
IEC/IRB 
Independent ethics committee/institutional review board 
IP 
Investigational product 
IV 
Intravenous 
IVR/IWR System 
Interactive Voice Response/Interactive Web Response System 
 
 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LTFU 
Long-term follow-up 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MDS 
Myelodysplastic syndromes 
mL 
Milliliter 
MRI 
Magnetic resonance imaging 
PPD


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Abbreviation or Term 
Definition/Explanation 
NA 
Not applicable 
NE 
Inevaluable 
ng 
Nanogram 
NSCLC 
Non-small cell lung cancer 
ODAC 
Oncologic Drug Advisory Committee 
OR 
Odds ratio 
OS 
Overall survival 
PD 
Progressive disease 
PE 
Physical examination or pulmonary embolism 
PET 
Positron emission tomography 
PET-CT 
Positron emission tomography-computer tomography 
PFS 
Progression-free survival 
pg 
Picogram 
PICC 
Peripherally-inserted central catheter 
PIN 
Personal identification number 
PR 
Partial response 
Q3M 
Once-every-3-months 
Q3W 
Once-every-3-weeks 
Q9W 
Once-every-9-weeks 
QW 
Once-weekly 
RBC 
Red blood cell 
RECIST 
Response evaluation criteria in solid tumors 
rHuEPO 
Recombinant human erythropoietin 
SAE 
Serious adverse events 
SAER 
Serious adverse event report 
SCLC 
Small cell lung cancer 
Screening hemoglobin 
Local laboratory hemoglobin; sample obtained within 7 days prior to 
randomization 
Screening period 
Starts when the subject signs and dates the informed consent form 
and ends when the subject is randomized or screen failed.  Must 
not exceed 21 days. 
SD 
Stable disease 
SUSAR 
Suspected unexpected serious adverse reactions 
TIA 
Transient ischemic attack 
TIBC 
Total iron binding capacity 
Tsat 
Transferrin saturation 


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Abbreviation or Term 
Definition/Explanation 
Treatment period 
Starts when the subject is randomized and ends at the next Q3W 
visit after disease progression has been determined (EOTP).  Note 
that EOTP is based on disease progression, not IP dosing.     
TVE 
Thrombovascular event 
Pg 
microgram 
ULN 
Upper limit of normal 
US 
Ultrasound 
VTE 
Venous thromboembolic event 
WBC 
White blood cell 
Wk 
Week 


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TABLE OF CONTENTS 
Page 
Protocol Synopsis ............................................................................................................. 3 
Study Design and Treatment Schema .............................................................................. 8 
Study Glossary 
.................................................................................................................. 9 
1. OBJECTIVES ......................................................................................................... 
17 
1.1 
Primary ....................................................................................................... 
17 
1.2 
Secondary .................................................................................................. 
17 
2. BACKGROUND AND RATIONALE 
........................................................................ 
17 
2.1 
Background ................................................................................................ 
17 
2.1.1 
Anemia ....................................................................................... 
17 
2.1.2 
Chemotherapy-induced Anemia 
................................................. 18 
2.1.3 
Darbepoetin alfa 
......................................................................... 
18 
2.2 
Safety Concerns of ESAs 
........................................................................... 
19 
2.2.1 
Non-small Cell Lung Cancer 
....................................................... 
22 
2.2.2 
Combined Analysis of Safety of ESAs in Lung Cancer 
.............. 
23 
2.3 
Rationale .................................................................................................... 
24 
2.4 
Hypothesis 
.................................................................................................. 
25 
3. EXPERIMENTAL PLAN 
......................................................................................... 
25 
3.1 
Study Design 
.............................................................................................. 
25 
3.2 
Number of Centers 
..................................................................................... 
26 
3.3 
Number of Subjects 
.................................................................................... 
26 
3.4 
Estimated Study Duration 
........................................................................... 
26 
3.4.1 
Study Duration for Subjects 
........................................................ 
26 
3.4.2 
End of Study 
............................................................................... 
27 
4. SUBJECT ELIGIBILITY 
.......................................................................................... 
27 
4.1 
Inclusion Criteria 
......................................................................................... 
27 
4.1.1 
Disease Related 
......................................................................... 
27 
4.1.2 
Demographic 
.............................................................................. 
27 
4.1.3 
Laboratory .................................................................................. 
27 
4.1.4 
Imaging 
....................................................................................... 
27 
4.1.5 
Ethical 
......................................................................................... 
27 
4.2 
Exclusion Criteria 
........................................................................................ 
28 
4.2.1 
Disease Related 
......................................................................... 
28 
4.2.2 
Laboratory .................................................................................. 
28 
4.2.3 
Medications ................................................................................ 
28 
4.2.4 
General 
....................................................................................... 
29 


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5. SUBJECT ENROLLMENT ..................................................................................... 
29 
5.1 
Screening ................................................................................................... 
29 
5.2 
Treatment Assignment ............................................................................... 
30 
5.3 
Randomization 
............................................................................................ 
30 
6. TREATMENT PROCEDURES 
............................................................................... 
31 
6.1 
Investigational Product Dosage, Administration, and Schedule 
................. 
31 
6.1.1 
Dose Escalation 
.......................................................................... 
31 
6.1.2 
Dosage Adjustments and Stopping Rules 
.................................. 
31 
6.1.3 
Missed or Delayed Doses 
........................................................... 
32 
6.2 
Concomitant Therapy 
................................................................................. 
33 
6.2.1 
RBC Transfusion 
........................................................................ 
33 
6.2.2 
Chemotherapy 
............................................................................ 
33 
6.2.3 
Supplementation 
......................................................................... 
34 
6.3 
Proscribed Therapy During the Treatment Period 
...................................... 
34 
7. STUDY PROCEDURES 
......................................................................................... 
34 
7.1 
General Study Procedures 
......................................................................... 
34 
7.1.1 
Medical and Medication History 
.................................................. 
35 
7.1.2 
Physical Examination ................................................................. 
35 
7.1.3 
Venous Catheter 
......................................................................... 
35 
7.1.4 
Vital Signs 
................................................................................... 
35 
7.1.5 
ECOG Performance Status 
........................................................ 
35 
7.1.6 
Imaging Studies 
.......................................................................... 
35 
7.1.7 
Disease Progression .................................................................. 
36 
7.1.8 
Thrombovascular Events 
............................................................ 
36 
7.1.9 
Concomitant Medication and Red Blood Cell 
Transfusion ................................................................................ 
37 
7.1.10 Adverse Events Reporting 
.......................................................... 
37 
7.1.11 Survival Status 
............................................................................ 
37 
7.1.12 Central Laboratory Assessments ............................................... 
38 
7.1.13 Local Laboratory Assessment 
.................................................... 
39 
7.1.14 Tumor Sample Banking (Optional) 
............................................. 
39 
7.2 
Screening ................................................................................................... 
40 
7.3 
Randomization 
............................................................................................ 
41 
7.4 
Study Day 1/Week 1 
................................................................................... 
41 
7.5 
Treatment Period (Q3W Visits) 
................................................................... 
42 
7.6 
End of Treatment Period ............................................................................ 
42 
7.7 
Long-term Follow-up Period 
....................................................................... 
43 
7.8 
End of Study 
............................................................................................... 
43 
7.9 
Tumor Sample for Future Biomarker Evaluation (Optional) ....................... 
44 
8. REMOVAL AND REPLACEMENT OF SUBJECTS ............................................... 
45 
8.1 
Removal of Subjects 
................................................................................... 
45 


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8.2 
Replacement of Subjects 
............................................................................ 
46 
9. SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
....................... 
46 
9.1 
Adverse Events .......................................................................................... 
46 
9.1.1 
Definition of Adverse Event 
........................................................ 
46 
9.1.2 
Reporting Procedures for Adverse Events 
................................. 
47 
9.2 
Serious Adverse Events 
............................................................................. 
48 
9.2.1 
Definition of Serious Adverse Event 
........................................... 
48 
9.2.2 
Reporting Procedures for Serious Adverse Events 
.................... 
49 
9.3 
Pregnancy and Lactation Reporting 
........................................................... 
50 
10. STATISTICAL CONSIDERATIONS 
....................................................................... 
51 
10.1 Study Design 
.............................................................................................. 
51 
10.2 Study Endpoints, Subsets, and Covariates 
................................................ 
51 
10.2.1 Study Endpoints ......................................................................... 
51 
10.2.2 Primary Analysis Set .................................................................. 
52 
10.2.3 Covariates .................................................................................. 
52 
10.3 Sample Size Considerations ...................................................................... 
52 
10.4 Access to Individual Subject Treatment Assignments 
................................ 
53 
10.5 Interim Analysis and Early Stopping Guidelines 
......................................... 
53 
10.6 Planned Methods of Analysis 
..................................................................... 
53 
10.6.1 General Approach/Considerations ............................................. 
53 
10.6.2 Analysis of Key Study Endpoints 
................................................ 
54 
10.6.3 Additional Analyses 
.................................................................... 
56 
11. INVESTIGATIONAL PRODUCT ............................................................................ 
57 
11.1 Darbepoetin alfa 
......................................................................................... 
57 
11.2 Access to Treatment Assignments 
............................................................. 
57 
12. REGULATORY OBLIGATIONS 
............................................................................. 
58 
12.1 Informed Consent 
....................................................................................... 
58 
12.2 Independent Ethics Committee/Institutional Review Board 
........................ 
59 
12.3 Pre-study Documentation Requirements 
.................................................... 
59 
12.4 Subject Confidentiality 
................................................................................ 
60 
12.5 Investigator Signatory Obligations 
.............................................................. 
60 
13. ADMINISTRATIVE AND LEGAL OBLIGATIONS 
................................................... 
60 
13.1 Protocol Amendments and Study Termination 
........................................... 
60 
13.2 Study Documentation and Archive 
............................................................. 
61 
13.3 Study Monitoring and Data Collection 
........................................................ 
62 
13.4 Language.................................................................................................... 
63 
13.5 Publication Policy ....................................................................................... 
63 
13.6 Compensation ............................................................................................ 
64 
14. REFERENCES ....................................................................................................... 
65 


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15. APPENDICES ........................................................................................................ 
68 
List of Tables 
Table 1.   
Studies That Have Raised Safety Concerns for ESA Use 
....................... 
20 
Table 2.   
Comparison of Meta-analyses of Overall Mortality 
.................................. 
22 
Table 3.   
Summary of Overall or On-study Death or Progression in Lung 
Cancer Studies ........................................................................................ 
24 
 
List of Appendices 
Appendix A.  Schedule of Assessments 
........................................................................ 
69 
Appendix B.   Adverse Event Severity Scoring System ................................................. 
71 
Appendix C.  Serious Adverse Event Contingency Reporting Form ............................. 
72 
Appendix D.   ECOG Performance Status Scale 
............................................................ 
75 
Appendix E.   Pharmacy Guide 
...................................................................................... 
76 
Appendix F.   Pregnancy Notification Worksheet 
........................................................... 
79 
Appendix G.   Lactation Notification Worksheet ............................................................. 
80 
Appendix H.   RECIST 1.1 With Modifications 
................................................................ 
81 
 


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1. 
OBJECTIVES  
1.1 
Primary  
The primary objective is: 
• To demonstrate non-inferiority of overall survival (OS) when comparing subjects on 
darbepoetin alfa treated to a hemoglobin ceiling of 12.0 g/dL to subjects treated with 
placebo 
1.2 
Secondary  
The secondary objectives are: 
• To demonstrate non-inferiority of progression free survival (PFS) when comparing 
subjects on darbepoetin alfa treated to a hemoglobin ceiling of 12.0 g/dL to subjects 
treated with placebo 
• To demonstrate superiority in reducing the incidence of red blood cell (RBC) 
transfusions when comparing subjects on darbepoetin alfa treated to a hemoglobin 
ceiling of 12.0 g/dL to subjects treated with placebo 
• To assess other safety and efficacy parameters in subjects on darbepoetin alfa 
treated to a hemoglobin ceiling of 12.0 g/dL compared to subjects treated with 
placebo  
2. 
BACKGROUND AND RATIONALE 
2.1 
Background 
2.1.1 
Anemia 
Anemia frequently develops in patients with neoplastic disease and is associated with 
mild to moderate erythroid hypoplasia, reduction in RBC survival and abnormal 
ferrokinetics (Quirt et al, 2002).  The etiology of anemia in cancer patients tends to be 
multifactorial including a direct inhibitory effect by various pro-inflammatory cytokines on 
the proliferation and differentiation of erythroid precursors within the bone marrow 
(Weiss and Goodnough, 2005) coupled with a blunted erythropoietic response to 
endogenous erythropoietin (Cazzola, 2000; Miller et al, 1990).  Additional etiologies of 
cancer related anemia include bone marrow infiltration by tumor, poor nutritional status, 
tumor related hemorrhage and myelotoxicity from systemic chemotherapy and/or 
radiotherapy (Ray-Coquard et al, 1999). 
The severity of cancer associated anemia depends in part on the extent of the 
underlying neoplastic disease as well as the regimen of cytotoxic treatments 
administered.  In a state of persistent anemia, compensatory mechanisms for the 
reversal of tissue hypoxia are instigated including shunting of blood from non-vital areas 
to more essential oxygen-sensitive organs (Vatner, 1974) along with compensatory 
cardiopulmonary hyperactivities resulting in increased cardiac work load 


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(Metivier et al, 2000; Hébert et al, 2004).  Symptoms of anemia may include fatigue, 
dyspnea on exertion, shortness of breath, decreased motivation, and impaired cognition 
and depression, with fatigue affecting greater than 65% of patients during their 
chemotherapy treatments.  Fatigue is regarded by patients as a symptom that has a 
greater negative impact on their daily lives than many other cancer or treatment related 
complications (Harper and Littlewood, 2005). 
2.1.2 
Chemotherapy-induced Anemia 
Myelosuppressive chemotherapy is a common cause of anemia in cancer patients with 
the degree of chemotherapy-induced anemia (CIA) dependent upon the type, schedule 
and intensity of the chemotherapy regimen.  For patients with non-myeloid malignancy, 
the highest frequency of anemia occurs among those undergoing systemic therapies for 
lymphoma, lung carcinoma, ovarian carcinoma or urothelial carcinoma (Ludwig and 
Fritz, 1998; Tas et al, 2002; Skillings et al, 1993).  In situations where rapid reversal of 
anemia is required RBC transfusion is indicated, although allogeneic blood product 
transfusion carries potential undesirable risks including subjecting the recipient to 
possible infection with viral agents such as hepatitis and human immunodeficiency virus 
(Barbara, 2004), acute hemolytic transfusion reaction (Sloop and Friedberg 1995), 
transfusion-related acute lung injury (Looney et al, 2004), allergic reactions (Gilstad, 
2003), iron overload (Franchini and Veneri, 2004) or hypervolemia-related exacerbation 
of congestive heart failure symptoms (Freudenberger and Carson, 2003).  As an 
alternative to blood product transfusion, erythropoiesis stimulating agents (ESAs) have 
been employed as a pharmacological measure to palliate and/or reverse the anemia 
associated with chemotherapy in non-emergent settings, effectively reducing a patient’s 
transfusion requirement as well as the number of RBC units required by those who do 
receive transfusions. 
2.1.3 
Darbepoetin alfa 
Darbepoetin alfa, a novel glycoengineered analog of rHuEpo with 2 additional extra 
consensus N-linked carbohydrate addition sites, has a longer mean residence time and 
a 3-fold longer serum half-life than rHuEpo in both dialysis and cancer patients as well 
as demonstrating augmented in vivo activity (Egrie et al, 2003; Macdougall et al, 1999; 
Elliott et al, 2004; Jung and Schwartz, 2002).  Darbepoetin alfa is manufactured by 
recombinant DNA technology using a Chinese hamster ovary mammalian cell line and is 
currently licensed in the United States, European Union, Australia, and Canada for the 
treatment of anemia associated with chronic renal failure (including patients who are and 


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are not on dialysis) and for the treatment of anemia in patients with non-myeloid 
malignancy where anemia is due to the effects of concomitantly administered 
chemotherapy.   
Details of the chemistry, preclinical pharmacology, pharmacokinetics, and toxicology of 
darbepoetin alfa are contained in the current version of the Investigator’s Brochure. 
2.2 
Safety Concerns of ESAs 
In the CIA setting, an increased risk of thromboembolic events associated with the use 
of ESAs is well documented and reflected in the current ESA label.  However, safety 
concerns regarding increased mortality or tumor progression with ESAs have also been 
raised by 8 of 59 studies conducted outside of the currently-approved treatment 
indication or recommended target hemoglobin range (Table 1).  Data from randomized, 
controlled studies evaluating mortality in subjects treated with ESAs in accordance with 
current labeling are not available.     


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Table 1.  Studies That Have Raised Safety Concerns for ESA Use 
Study 
Population 
Primary 
endpoint 
Hemoglobin 
target (g/dL) 
Key results for survival 
and/or disease progression 
Chemotherapy alone or chemoradiotherapy 
Leyland-Jones 
et al, 2005 
(BEST trial) 
Metastatic 
breast CA 
 
N = 939 
12-month OS 
12 – 14 
Shortened overall survival 
and increased deaths 
attributed to disease 
progression at 4 months in 
ESA group 
Higher 12-month mortality in 
ESA group: HR 1.37 (95% 
CI: 1.07, 1.75, p = 0.012)
a 
Long-term follow up OS 
similar between ESA and 
control groups: HR 1.04 
(95% CI: 0.90, 1.20; p=0.6)b 
Hedenus et al, 
2003 
Hedenus et al, 
2005 
Lymphoid 
malignancy 
 
N = 344 
hemoglobin 
response 
13 – 14 
(women); 13-
15 (men) 
Higher mortality in ESA 
group: HR: 1.36 (95% CI: 
1.02, 1.82) a 
PREPARE 
(AGO/GBG) 
Early breast 
cancer 
 
N = 733 
Relapse-free 
survival and 
OS 
12.5 – 13 
No significant difference in 
pathologic complete 
remission (final data) 
Lower survival rate in the 
ESA group (interim data) (HR 
1.42, 95% CI: 0.93, 2.18) a 
Lower relapse-free survival 
rate in the ESA group 
(interim data) (HR 1.33, 95% 
CI: 0.99, 1.79) a 
Thomas et al, 
2007 (GOG 
study) 
Cervical 
cancer 
 
N = 114 
PFS, OS and 
locoregional 
control 
12 – 14 
More frequent local 
recurrence (21% vs. 20%) 
and distant recurrence (12% 
vs. 7%) in ESA group 
Lower 3-year OS in ESA 
group HR 1.28, 95% CI: 0.68, 
2.42) a 
Lower 3-year PFS in ESA 
group HR 1.06, 95% CI: 0.58, 
1.91) a 
Page 1 of 2 
a Aranesp® Prescribing Information  
b Data on file 
c Cancer study 8 in Aranesp® Prescribing Information: Median survival was shorter in the ESA group 
(HR 1.30, 95% CI: 1.07, 1.57). 


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Table 1.  Studies That Have Raised Safety Concerns for ESA Use 
Study 
Population 
Primary 
endpoint 
Hemoglobin 
target (g/dL) 
Key results for survival 
and/or disease progression 
No radiotherapy or chemotherapy 
Smith et al, 
2008 
Mixed 
tumors 
 
N = 989 
RBC 
transfusions 
12–13 
Higher mortality in ESA 
group: HR 1.22 (95% CI: 
1.03, 1.45) c  
Wright et al, 
2007 
NSCLC 
 
N = 70 
Quality of life 
12–14 
Shorter survival duration  in 
the ESA group (HR 1.84; 
p = 0.04) a  
Deaths due to disease 
progression: 89% ESA, 91% 
control 
Radiotherapy only 
Henke et al, 
2003 
(ENHANCE 
study) 
Head and 
neck CA 
 
N = 351 
Locoregional 
PFS 
≥14 (women); 
≥15 (men) 
Shorter OS in ESA group: 
(HR 1.39, 95% CI: 1.05, 1.84; 
p = 0.02) a  
Locoregional PFS poorer in 
ESA group: HR 1.62 (95% 
CI: 1.22, 2.14; p = 0.0008)
 a 
Overgaard et 
al, 2007 
(interim data) 
(DAHANCA-10 
study) 
Head and 
neck CA 
 
N = 522 
Locoregional 
disease 
control 
14–15.5 
Higher 5- year mortality in 
ESA group: RR 1.28 (95% 
CI: 0.98, 1.68; p = 0.08)
 a 
5-year locoregional control 
poorer in ESA group: RR 
1.44 (95% CI: 1.06, 1.96; 
p = 0.02)
 a 
Page 2 of 2 
a Aranesp® Prescribing Information  
b Data on file 
c Cancer study 8 in Aranesp® Prescribing Information: Median survival was shorter in the ESA group 
(HR 1.30, 95% CI: 1.07, 1.57). 
Several study-level meta-analyses have been performed to examine the relationship of 
ESAs and overall mortality in patients with cancer (Table 2).  In addition, the EPO 
Individual Patient Data Meta-analysis Collaborative Group, a working group of the 
Cochrane Hematological Malignancies Group has recently completed and presented an 
analysis of overall mortality using patient-level data provided by ESA study sponsors and 
independent investigators (Bohlius et al, 2008).  It is important to note that these 
meta-analyses are comprised of studies that did not use ESAs in accordance with 
current FDA label, as they included patients without chemotherapy-induced anemia 
and/or treated to higher hemoglobin targets.  The results of these meta-analyses differ 
somewhat based on differences in the studies included and exact methodology used.  


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However, the hazard ratio estimates for meta-analyses limited to studies where patients 
are receiving chemotherapy are similar and do not indicate a statistically significant 
increase in mortality risk.  Although these results may be viewed as reassuring, 
well-designed, randomized, controlled clinical trials are needed to completely 
characterize the effects of ESAs on survival and tumor progression in 
chemotherapy-induced anemia. 
Table 2.  Comparison of Meta-analyses of Overall Mortality 
 
All Studies 
Chemotherapy Studies 
 
n 
(studies) Events 
Risk 
Estimate 
Survival 
95% CI 
n 
(studies) Events 
Risk 
Estimate* 
Survival 
95% CI 
Cochrane 
(Bohlius et 
al 2006) 
8167a 
(42) 
2234a 
1.08 
0.99, 
1.18 
6282 
(30) 
1743 
1.02 
0.90, 
1.15 
AHRQ 
(Seidenfeld 
et al 2006) 
7891 
(39) 
2202 
1.08 
0.98, 
1.18 
6704b 
(32) 
1759b 
1.03 
0.92, 
1.15 
Bennett et 
al, 2008 
>13122 
(51) 
>2632c 
1.10 
1.01, 
1.20 
>7670 
(41) 
>1940c 
1.03 
0.94, 
1.13 
ODAC 
2008 
(Amgen) 
15249 
(59) 
5340 
1.05 
0.97, 
1.14 
12034 
(46)
d 
4009 
1.02 
0.93, 
1.13 
Cochrane 
(Bohlius et 
al 2008) 
13933 
(53) 
4993 
1.06e 
1.00, 
1.12 
10441 
(38)
e 
3555 
1.04e 
0.97, 
1.11 
* Estimated by Amgen based on the reported original classification of studies 
a Cochrane included 1 MDS study (3 events/66 subjects); Chemotherapy excluded 5 CTxRTx studies and 
2 studies classified as “Unclear”; 3 chemotherapy studies had no deaths in either arm 
b Assume same classification as Cochrane since same studies and events were used but added in 2 studies 
classified as “Unclear” in Cochrane 
c Bennett did not report the number of events for 9 studies (7 chemotherapy studies) 
d Chemotherapy studies included studies where both chemotherapy and radiotherapy could be given 
concomitantly or sequentially 
e Patient-level meta-analysis; estimates based on Cox proportional hazards model stratified by study; 
Chemotherapy studies included were those where at least 70% of study subjects received 
myelosuppressive chemotherapy 
 
2.2.1 
Non-small Cell Lung Cancer 
In the setting of lung cancer, only the EPO-CAN-20 study has raised concerns regarding 
the effect of ESAs on overall survival.  The EPO-CAN-20 study (Wright et al, 2007) was 
a 12-week, randomized, double-blind, placebo-controlled study that was initially 
designed to examine the effect of epoetin alfa 40000 U once-weekly (QW) on 


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quality-of-life in subjects with advanced NSCLC and hemoglobin level ≤ 12.0 g/dL who 
neither received chemotherapy 2 months prior to the study nor were expected to receive 
chemotherapy during the study.  Study drug was withheld if hemoglobin level exceeded 
14.0 g/dL.   
Due to concerns regarding thromboembolic events in other ESA trials, an unplanned 
safety analysis of this study was conducted after the first 70 subjects (of a planned 
300 subjects) were randomized (33 epoetin alfa group, 37 placebo group).  In this 
analysis, OS in the subjects receiving epoetin alfa was worse than the subjects who 
received placebo (63 versus 129 days, p=0.04), leading to termination of the study.   
The majority of deaths in this study, 66 of 70 enrolled subjects, was reported to be due 
to underlying lung cancer; 28 of 32 subjects (87.5%) in the epoetin alfa group and 31 of 
34 subjects (91.2%) in the placebo group died.  Tumor progression was not assessed in 
this study.  Furthermore, the study was conducted in subjects not receiving 
chemotherapy and who were treated to higher hemoglobin levels than those 
recommended in the prescribing information.  Consequently no conclusions can be 
drawn regarding the safety of ESAs in lung cancer patients within the labeled indication 
of CIA when ESAs are used in accordance with current labeling. 
2.2.2 
Combined Analysis of Safety of ESAs in Lung Cancer 
Five randomized, controlled lung cancer studies in CIA (representing 1943 subjects) 
have collected long-term follow-up information [Pirker et al, 2007; Grote et al, 2005; 
Vansteenkiste et al, 2002; Milroy et al, 2003; and EPO-GER-22 (ODAC 2008)].  An 
additional two studies [EPO-CAN-15 (ODAC 2008) and Thatcher et al, 1999] reported 
deaths on study but did not collect long-term follow-up information.  In all studies in CIA, 
ESAs had a neutral effect on survival relative to the control group.  These studies, along 
with study EPO-CAN-20 which did not involve chemotherapy, are summarized in 
Table 3. 


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Table 3.  Summary of Overall or On-study Death or Progression in Lung Cancer 
Studies  
 
Tumor type 
HR or OR for OS (95% 
CI) 
Progression 
endpoints (95% CI) 
Study with negative signal (subjects not receiving chemotherapy) 
Wright et al, 2007 
(EPO-CAN-20) 
Advanced NSCLC 
HRb: 1.54 (0.94, 2.53) 
ORa 
death due to disease 
progression: 1.08 (0.30, 
3.95) 
Studies with neutral signal (subjects receiving chemotherapy) 
Pirker et al, 2007 
Extensive stage 
SCLC 
HR: 0.93 (0.78, 1.11) 
HR: 1.02 (0.86, 1.21) 
Vansteenkiste et al, 
2002 
NSCLC + SCLC 
HR: 0.78 (0.59, 1.01) 
HR: 0.77 (0.60, 0.99) 
NSCLC 
HR: 0.85 (0.62, 1.17) 
HR: 0.91 (0.68, 1.23) 
SCLC 
HR: 0.63 (0.38, 1.04) 
HR: 0.55 (0.34, 0.88) 
EPO-GER-22 
(ODAC 2008) 
NSCLC (stage 3, 
inoperable) 
HRb: 0.81 (0.64, 1.02) 
N/A 
Grote et al, 2005 
(N93-004) 
SCLC (all stages) 
HRb: 1.17 (0.89, 1.54) 
ORa
 (PD/EOS Tumor Response): 
0.85 (0.50, 1.44) 
Milroy et al, 2003 
(EPO-INT-49) 
NSCLC (stage 3B 
and 4) 
HRb: 1.13 (0.89, 1.44) 
ORa
 (PD/EOS Tumor Response): 
0.90 (0.57, 1.41) 
EPO-CAN-15 
(ODAC 2008) 
Limited stage 
SCLC 
ORa,c: 0.93 (0.43, 2.00) 
N/A 
Thatcher et al, 1999 
SCLC (all stages) 
ORa,c: 1.21 (0.30, 4.93) 
N/A 
a  Calculated by Amgen for ODAC 2008 
b: Calculated by J&JPRD for ODAC 2008 
c: Based on reported deaths on-study; long-term (>6 months after ESA use) was not evaluated 
HR: hazard ratio; J&JPRD: Johnson & Johnson Pharmaceutical Research & Development; OR: odds ratio; 
SCLC: small-cell lung cancer; N/A: not available 
 
When the study-level data from all controlled CIA studies in subjects with lung cancer 
(including those without long-term follow up) were meta-analyzed, the OR (ESA versus 
control; random effects model) for mortality was 0.85 (95% CI: 0.66, 1.04).  Given this 
continued uncertainty as to whether ESAs affect OS or PFS in NSCLC, particularly at a 
hemoglobin ceiling of 12.0 g/dL, this study is designed to address these questions. 
2.3 
Rationale  
The 20070782 study is a large, multi-national study intended to provide safety and 
efficacy data that are applicable to all regions where ESAs are approved for the 
treatment of chemotherapy-induced anemia.  


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The study design, including hemoglobin initiation and ceiling levels, and non-responder 
and dose reduction algorithms will allow sufficient exposure to study drug to evaluate 
safety outcomes while ensuring consistent dosing, minimizing risks and maintaining 
potential benefits to subjects.  While some design parameters are not consistent with the 
United States and other regional labels, Amgen intends for the results of this study to be 
directly extrapolated to corresponding product labeling and to risk: benefit decisions 
about the use of ESA in the oncology setting. 
The definition of non-inferiority in this study will be the exclusion of a hazard ratio 
(darbepoetin alfa to placebo) of 1.15 with a 1-sided significance level of 0.025 (ie, the 
upper limit of the 95% confidence interval is < 1.15).  This definition is derived from a 
benefit:risk assessment.  Excluding a hazard ratio of 1.15 corresponds to excluding a 
decrease in median survival of approximately 1.6 months in the darbepoetin alfa arm 
group compared to placebo.  The estimated decrease in survival has equipoise with the 
decreased risk of the need for RBC transfusions. 
2.4 
Hypothesis  
The primary hypothesis to be tested is that the OS of subjects with CIA with stage IV 
NSCLC receiving cyclic chemotherapy treated with darbepoetin alfa 500 µg Q3W to a 
hemoglobin ceiling of 12.0 g/dL will not be worse than the OS of anemic subjects treated 
with placebo.   
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a double-blind, randomized, placebo-controlled phase 3 non-inferiority study in 
subjects with CIA receiving multi-cycle chemotherapy for the treatment of stage IV 
NSCLC.  Approximately 3000 subjects with stage IV NSCLC receiving or about to 
receive first line chemotherapy will be enrolled into the study.  Subjects will be 
randomized in a 2:1 allocation (Group A: Group B): 
• Group A: darbepoetin alfa 500 µg Q3W to a hemoglobin ceiling of 12.0 g/dL 
• Group B: placebo Q3W 
Section 6.1.2 describes the dosing adjustment algorithms.  
Randomization for NSCLC will be stratified by geographic region, histology, and 
screening hemoglobin (local laboratory hemoglobin; sample obtained within 7 days prior 
to randomization). 


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The study consists of a screening period (up to 21 days), a treatment period, and a 
long-term follow up (LTFU) period.  IP will be administered Q3W during the treatment 
period.  IP will be discontinued within 3 weeks after the last dose of chemotherapy, or 
upon the determination of disease progression, whichever occurs first.  Study visits Q3W 
and imaging studies Q9W will occur during the treatment period until disease 
progression.  Once disease progression has been determined, subjects will complete the 
EOTP visit and then enter LTFU and will be followed for survival until death, or until 
approximately 2700 deaths have occurred in the study (End of Study [EOS]).   
Investigational product vials and boxes will be packaged in a blinded manner and 
identified by a unique box number for assignment via Interactive Voice Response/ 
Interactive Web System (IVR/IWR).  Darbepoetin alfa and placebo will be administered 
subcutaneously by a trained healthcare professional at the site.  
The overall study design is described in a study schema at the end of the protocol 
synopsis section and the Schedule of Assessments (Appendix A). 
The study endpoints are defined in Section 10.2. 
3.2 
Number of Centers 
Approximately 500 sites will participate in this study across the world (eg, North America, 
Europe, Asia, Africa, Australia, and Latin America).  Subject enrollment will be 
competitive and sites that do not enroll subjects within 6 months of site initiation may be 
closed.  
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects.”  This study will 
randomize approximately 3000 subjects with stage IV NSCLC in order to observe 2700 
death events.  For additional information on the sample size justification, please see 
Section 10.3.  
3.4 
Estimated Study Duration 
3.4.1 
Study Duration for Subjects 
Subject enrollment may occur over approximately a 7-year period.  The study will consist 
of a screening period (up to 21 days), a treatment period in which Q3W study visits and 
Q9W radiological assessments will continue until disease progression, the EOTP visit, 
and the LTFU period.  Once disease progression has been determined, subjects will 
complete the EOTP visit at their next Q3W visit and then enter the LTFU and will be 
followed for survival status every 3 months until their death or until approximately 2700 


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deaths have occurred.  Based on estimated recruitment rate and the estimated OS rate 
of patients with NSCLC, it is anticipated that the study duration may take approximately 
10 years from the first subject enrolled into study to EOS.   
3.4.2 
End of Study 
Since this is an event driven protocol, this study will end when approximately 2700 
deaths have occurred.   
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (ie, age, sex, 
race), date and outcome of the screening (eg, enrolled into study, reason for ineligibility, 
or refused to participate). 
4.1 
Inclusion Criteria 
4.1.1 
Disease Related 
• Subjects with stage IV NSCLC (not recurrent or re-staged)  
• Expected to receive at least 2 additional cycles (at least 6 total weeks) of first line 
myelosuppressive cyclic chemotherapy after randomization.  Subjects should not be 
expected to receive only maintenance chemotherapy.  
4.1.2 
Demographic 
• Eastern Cooperative Oncology Group performance status of 0 or 1 as assessed 
within 21 days prior to randomization 
• 18 years of age or older at screening 
• Life expectancy > 6 months based on the judgment of the investigator and 
documented during screening 
4.1.3 
Laboratory 
• Hemoglobin level ≤ 11.0 g/dL as assessed by the local laboratory; sample obtained 
within 7 days prior to randomization (retest in screening is acceptable) 
• Adequate serum folate (≥ 2 ng/mL) and vitamin B12 (≥ 200 pg/mL) levels assessed 
by central laboratory (supplementation and retest acceptable) during screening 
4.1.4 
Imaging 
• Subjects must have had a baseline scan (CT, MRI, or PET/CT) of the chest to 
assess disease burden before starting on first line chemotherapy for NSCLC and 
those images must have been reviewed by the investigator prior to randomization.  If 
the scan was performed more than 28 days prior to randomization, an additional 
scan must be performed and reviewed by the investigator to confirm that the patient 
has not progressed before randomization.       
4.1.5 
Ethical 
• Before any study-specific procedure, the appropriate written informed consent must 
be obtained from the subject or a legally accepted representative (see Section 12.1) 


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4.2 
Exclusion Criteria 
4.2.1 
Disease Related 
x 
Known primary benign or malignant hematologic disorder which can cause anemia 
x 
History of, or current active cancer other than NSCLC, with the exception of 
curatively resected non-melanomatous skin cancer, curatively treated cervical 
carcinoma in situ, or other primary solid tumors curatively treated with no known 
active disease present and no curative treatment administered for the last 3 years 
x 
Received any prior adjuvant or neoadjuvant therapy for NSCLC 
x 
Subjects with a history of brain metastasis  
x 
Uncontrolled hypertension (systolic BP > 160 mmHg or diastolic BP > 100 mmHg), or 
as determined by the investigator during screening 
x 
History of neutralizing antibody activity to rHuEPO or darbepoetin alfa 
x 
Uncontrolled angina, uncontrolled heart failure, or uncontrolled cardiac arrhythmia as 
determined by the investigator at screening.  Subjects with known myocardial 
infarction within 6 months prior to randomization. 
x 
Subjects with a history of seizure disorder taking anti-seizure medication within 
30 days prior to randomization 
x 
Clinically significant systemic infection or uncontrolled chronic inflammatory disease 
(eg, rheumatoid arthritis, inflammatory bowel disease) as determined by the 
investigator during screening 
x 
Known seropositivity for HIV or diagnosis of AIDS, positive for hepatitis B surface 
antigen, or seropositive for hepatitis C virus 
x 
History of pure red cell aplasia 
x 
History of deep venous thrombosis or embolic event (eg, pulmonary embolism)   
within 6 months prior to randomization  
4.2.2 
Laboratory 
x 
Transferrin saturation < 20% and ferritin < 50 ng/mL as assessed by the central 
laboratory during screening.  Subjects must have both to be excluded 
(supplementation and retest acceptable). 
x 
Abnormal renal function (serum creatinine level > 2X ULN) as assessed by the 
central laboratory during screening 
x 
Abnormal liver function (total bilirubin > 2X ULN or liver enzymes ALT or AST > 2.5X 
ULN for subjects without liver metastasis or ≥ 5X ULN for subjects with liver 
metastasis) as assessed by the central laboratory during screening.  Subjects with 
documented Gilbert’s Disease may be eligible. 
4.2.3 
Medications 
x 
Received any RBC transfusion within 28 days prior to randomization.   
x 
Plan to receive any RBC transfusion between randomization and study day 1 
x 
Known previous treatment failure to ESAs (eg, rHuEPO, darbepoetin alfa) 
x 
ESA therapy within the 28 days prior to randomization 


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• Known hypersensitivity to recombinant ESAs or the excipients contained within the 
investigational product 
4.2.4 
General 
• Less than 30 days since receipt of any investigational product or device.  
Investigational use/receipt of a medicinal product or device that has been approved 
by the country’s local regulatory authority for any indication is permitted 
• Subjects of reproductive potential who are pregnant, breast feeding or not willing to 
use effective contraceptive precautions during the study and for at least one month 
after the last dose of investigational product in the judgment of the investigator 
(including females of childbearing potential who are partners of male subjects) 
• Previously randomized to this study 
• Investigator has concerns regarding the ability of the subject to give written informed 
consent and/or to comply with study procedures (including availability for follow-up 
visits) 
5. 
SUBJECT ENROLLMENT 
Before subjects may be entered into the study, Amgen requires a copy of the site’s 
written independent ethics committee/institutional review board (IEC/IRB) approval of the 
protocol, informed consent form, and all other subject information and/or recruitment 
material, if applicable, and that the site undergoes a formal site initiation visit (see 
Section 12.3).  The written informed consent form (ICF) must be signed and personally 
dated by the subject or legally acceptable representatives and by the person who 
conducted the informed consent discussion before any study specific procedures are 
performed. 
5.1 
Screening 
The screening period, which starts when the subject signs and dates the ICF and ends 
when the subject is randomized or screen failed, must not exceed 21 days.  All subjects 
who enter into the screening period will receive a unique subject identification (ID) 
number, assigned by IVR/IWR System before any study procedures are performed.  The 
unique subject ID will be comprised of 9 digits (eg, 82-3456-789).  The first 2 digits 
represent the study code (82), 3 to 6 are for the site number, and 7 to 9 are for the 
subject number at the site.  This number will be used to identify the subject throughout 
the study and must be used on all study documentation related to that subject.  The 
subject identification number must remain constant throughout the entire clinical study; it 
must not be changed at the time of re-screening (if required) or randomization.  The 
subject identification number is not the same as the randomization number assigned for 
the study.  The randomization number will be assigned by the IVR/IWR System at the 
time of randomization. 


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Subjects determined to be screen failures (based on laboratory or any other 
assessment) will not be eligible for immediate participation and must be registered as a 
screen failure in IVR/IWR System.  Laboratory assessments used to determine subject 
eligibility may be repeated during the screening period before the subject is considered a 
screen failure.  Screen-failed subjects may be re-screened at the investigator’s 
discretion (the subject will maintain the same subject ID number provided at the initial 
screening).  Subjects who are determined not eligible after re-screen must be registered 
as a screen fail in IVR/IWR System.  Subjects must be re-consented if more than 30 
days have elapsed between date of informed consent and date of randomization.   
5.2 
Treatment Assignment 
The site will obtain the subject’s treatment group randomization prior to or at the first 
dosing visit via IVR/IWR System.  At each dosing visit the site will access IVR/IWR 
System and enter the last hemoglobin value and, if applicable, any transfusion 
information in order to obtain the appropriate treatment assignment for each subject.  
The appropriate volume and box number of the vial of IP to be administered to each 
subject will be provided by IVR/IWR System.   
5.3 
Randomization 
Randomization may occur on the same day as the first dose of IP (ie, study day 1), or it 
may occur up to 4 days prior to study day 1.   
Eligible subjects will be randomized in a 2:1 allocation (Group A: Group B): 
• Group A: darbepoetin alfa 500 µg Q3W to a hemoglobin ceiling of 12.0 g/dL 
• Group B: placebo Q3W 
Randomization will be stratified by: 
• Histology (squamous versus other) 
• Screening hemoglobin (local laboratory hemoglobin value; sample obtained within 7 
days prior to randomization) (< 10.0 g/dL versus ≥ 10.0 g/dL) 
• Geographic region 
Randomization will be based on a schedule generated by Amgen before the start of the 
study and will be centrally executed using IVR/IWR System.  The subject, site personnel, 
and Amgen study personnel and designees will be blinded to the randomization 
treatment group assignment, with the exception of those circumstances where the 
investigator deems it necessary to break the blind in order to provide appropriate 
medical treatment for the subject.  Refer to Section 10.4 for details on when and how the 
randomization code may be broken. 


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6. 
TREATMENT PROCEDURES 
Darbepoetin alfa and placebo will be considered investigational products for the 
purposes of maintaining the blind to treatment groups in this study. 
6.1 
Investigational Product Dosage, Administration, and Schedule 
Investigational product will be provided as a human serum albumin free polysorbate 
formulation that is a clear, colorless, sterile, preservative-free protein solution containing 
500 µg, 300 µg, 200 µg, and 100 µg of darbepoetin alfa per mL or placebo (without the 
active drug).  For dose adjustment and stopping rules, refer to Section 6.1.2.  
Investigational product administration including date of dosing will be recorded on the 
case report forms (CRFs). 
The day of the first dose of IP (darbepoetin alfa or placebo) will be considered study 
day 1 and may occur up to 4 days after randomization.  The first dose of IP must be 
administered no earlier than on the same day that first line myelosuppressive cyclic 
chemotherapy is initiated.  Investigational product should be administered 
subcutaneously by the appropriately trained and designated study personnel at the 
dosing schedule outlined in the Schedule of Assessment (Appendix A).  The correct box 
number of IP to be administered will be assigned via IVR/IWR System.  It is important 
that the correct hemoglobin value and transfusion information are entered into IVR/IWR 
System for each dosing visit.  Failure to comply with IVR/IWR System dosing 
instructions may result in the removal of the subject from the study and possible 
suspension of further enrollment activities at the site. 
Investigational product should be stored, prepared and administered according to the 
instructions in the Pharmacy Guide (Appendix E). 
6.1.1 
Dose Escalation 
No dose escalation will be allowed in this study.   
6.1.2 
Dosage Adjustments and Stopping Rules 
Dose adjustments will be based on the most recent local laboratory hemoglobin value 
(obtained on the day of the dosing visit or 1 day prior to the dosing visit), incidence of 
RBC transfusion in the last 21 days prior to the dosing visit, disease and chemotherapy 
status.  An RBC transfusion includes either whole blood or packed RBC transfusion.  
Before the subject can be dosed, the site personnel will enter the relevant information 
into IVR/IWR System during a medication assignment call.   


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Automated programming in IVR/IWR System will determine if dose adjustment or 
withholding is required based on the dosing rules listed below.  If dose adjustment 
occurs, all subsequent adjustments will be relative to the new dose.  Rate of rise 
calculations will be based on the subject’s hemoglobin value at the time of the last dose 
or for the last 3 weeks of study if more than 3 weeks have passed since the last dose.   
If a subject stops myelosuppressive chemotherapy completely, IP will be discontinued 
within 3 weeks after the last dose of chemotherapy.     
At any time during the study, the investigator may withhold or discontinue IP 
administration for any subject who experiences a severe or life-threatening adverse 
event reported by the investigator to be related to IP.  The Common Toxicity Criteria for 
Adverse Events (CTCAE) grading scale will be used as a guide for grading the adverse 
events.  Refer to Section 9 for more detail on adverse event reporting.  If an investigator 
decides to discontinue IP (regardless of whether the subject will continue in the study), 
the site personnel are to enter this information into the IVR/IWR System.       
IVR/IWR System will instruct investigators to withhold IP or to reduce the dose of IP 
according to the following criteria, which include non-responsiveness, rapid rate of rise of 
hemoglobin, and high hemoglobin value.  These criteria are described as follows: 
• A non-responder is defined as a subject who, after study day 35, receives 2 or more 
transfusions that are ≥ 21 days apart and ≤ 42 days apart.  Non-responders will be 
discontinued from darbepoetin alfa if they are on the darbepoetin alfa treatment arm 
and will be switched to placebo (by IVR/IWR System).     
• If hemoglobin increases by > 1.5 g/dL in any 21 day period in the absence of RBC 
transfusion, the IVR/IWR System will reduce the dose of IP by approximately 40% of 
the previous dose (ie, 500 µg to 300 µg; 300 µg to 200 µg, 200 µg to 100 µg) for a 
maximum of 3 dose reductions.  Investigational product will be discontinued after 
3 dose reductions. 
• If hemoglobin > 12.0 g/dL, the IVR/IWR System will instruct the investigator that IP 
will be temporarily withheld until hemoglobin falls to ≤ 12.0 g/dL at which time 
treatment will be restarted at a dose which is reduced by approximately 40% of the 
previous dose (ie, 500 µg to 300 µg; 300 µg to 200 µg, 200 µg to 100 µg) for a 
maximum of 3 dose reductions.  Investigational product will be discontinued after 
3 dose reductions. 
6.1.3 
Missed or Delayed Doses 
Investigational product should be administered on the same day Q3W throughout the 
study.  However, if IP cannot be administered as scheduled, every attempt should be 
made to administer the IP within ± 6 days of the Q3W schedule.  If a dosing visit does 
not occur within this window, then it is considered a missed dose.  No 2 separate IP 
administrations should occur within a 14-day interval.  After a missed or delayed dose, 


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every attempt should be made to resume dosing according to the original dosing 
schedule.   
6.2 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care, except for those 
listed in Section 6.3.  Selected medications administered while the subject is on study 
must be recorded on the CRF. 
6.2.1 
RBC Transfusion 
Subjects may receive RBC (whole blood or packed red blood cell) transfusion if 
medically indicated.  Documentation of RBC transfusions received while on study will 
include date of transfusion and number of units and volume, reason for transfusion, any 
associated AEs including VTE, the associated pre-transfusion hemoglobin value and any 
AEs as a result of the transfusion.  Red blood cell transfusion is recommended when 
hemoglobin level decreases to ≤ 8.0 g/dL.  Subjects may also require a RBC transfusion 
when hemoglobin level is > 8.0 g/dL if clinically indicated (eg, subject is symptomatic).  
Administration of a RBC transfusion when the hemoglobin level is > 8.0 g/dL, in the 
absence of accompanying signs and/or symptoms, is not recommended.   
6.2.2 
Chemotherapy 
Subjects should be expected to receive at least 2 additional cycles (at least 6 total 
weeks) of first line myelosuppressive cyclic chemotherapy (eg, standard doublet 
chemotherapy) after randomization.  Subjects should not be expected to receive only 
maintenance chemotherapy.   First line chemotherapy in combination with other targeted 
therapy (eg, biologics) that is considered acceptable standard for first line treatment of 
NSCLC is allowed.  Chemotherapy regimens or combination therapies including 
chemotherapy will be dependent upon local standard and practices, however, 
chemotherapy regimens containing investigational agents (ie, not approved for any 
indication by the applicable regulatory authority) will not be allowed.  If the first line 
chemotherapy regimen changes at any time during the study (eg, due to toxicity) or if 
optional myelosuppressive maintenance therapy is initiated, then the subject may 
receive IP as scheduled as long as the subject continues to receive myelosuppressive 
chemotherapy and does not have disease progression.  If a subject stops 
myelosuppressive chemotherapy completely, IP will be discontinued within 3 weeks after 
the last dose of chemotherapy.     


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Chemotherapy regimen including date of administration will be recorded in the subject’s 
CRF. 
6.2.3 
Supplementation 
Iron supplementation is recommended for subjects with transferrin saturation < 20% at 
any point during the study.  Iron supplementation may be administered according to the 
local practice or institution guidelines. 
Folate and vitamin B12 supplementation are recommended if vitamin B
12 is < 200 pg/mL 
or serum folate is < 2 ng/mL.  Supplementation should be administered in accordance 
with local practice or institution guidelines. 
6.3 
Proscribed Therapy During the Treatment Period 
During the treatment period of the study and prior to EOTP, subjects should not receive 
an ESA (other than IP as defined in this protocol), or any investigational agents/devices 
not currently approved by the country’s regulatory authority for any indication.  The dose 
and date of dosing information will be collected on the CRFs for any extra darbepoetin 
alfa or ESA administration during the study.  Subjects who receive additional IP or other 
ESA therapy during the treatment period may be discontinued from IP at Amgen’s 
discretion, but will be followed for progression and survival.   
There is no proscribed therapy during the LTFU period.   
7. 
STUDY PROCEDURES 
Refer to the Schedule of Assessments (Appendix A) for an outline of the procedures 
required at each study visit.  The investigator at each site is responsible for ensuring that 
all study procedures are performed as specified in the protocol. 
For each study visit, all assessments should be performed prior to the administration of 
IP or chemotherapy. 
Sites must utilize local laboratory hemoglobin for subject eligibility and for dosing 
decisions/adjustments during the treatment period on study.  A central laboratory will be 
utilized for parameters detailed in Section 7.1.12. 
7.1 
General Study Procedures  
All subjects or the legally authorized representative must personally sign and date the 
Amgen/IEC/IRB approved ICF before any study specific procedures are performed.  All 
study procedures should be performed prior to the administration of IP, chemotherapy 
and prior to initiation of intravenous hydration for chemotherapy.  Please refer to the 


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Schedule of Assessments (Appendix A) for details on study procedures and on-study 
visit schedule. 
7.1.1 
Medical and Medication History 
A review of targeted medical history, including tumor details (primary malignancy type, 
tumor staging, metastasis), RBC transfusion, anti-cancer therapy, radiotherapy, anti-
cancer surgery, medication, including ESA use will be performed by the investigator 
during screening. 
7.1.2 
Physical Examination  
A complete physical examination (PE) including weight and height will be performed on 
all subjects within 21 days prior to randomization.  The subject’s weight will be collected 
Q3W during the treatment period.   
7.1.3 
Venous Catheter 
The presence of an existing central venous line, peripherally-inserted central catheter 
(PICC), or mid-line venous catheter will be reported at baseline; the presence of new / 
replaced central or mid-line venous catheters will be reported on the CRF at subsequent 
study visits during the treatment period. 
7.1.4 
Vital Signs  
Vital signs will include pulse, temperature and resting blood pressure (systolic and 
diastolic blood pressures in mmHg). 
7.1.5 
ECOG Performance Status 
Subject’s Eastern Cooperative Oncology Group (ECOG) performance status will be 
assessed within 21 days prior to randomization and Q3W during the treatment period.  
Subjects must have ECOG of 0 or 1 to be eligible for the study.  The subject’s ECOG 
performance status will be assessed by the investigator.  See Appendix D for a complete 
description of the scale.   
7.1.6 
Imaging Studies 
Subjects must have had a pre-chemotherapy scan (computed tomography [CT], 
magnetic resonance imaging [MRI] or positron emission tomography-computer 
tomography [PET/CT with diagnostic quality CT]) of the chest to assess disease burden 
at baseline.  The scan must include the chest and is expected to include the adrenal 
glands.  The scan(s) must be reviewed by the investigator prior to randomization.  If the 
scan was performed more than 28 days prior to randomization, an additional scan must 
be performed and reviewed by the investigator to confirm that the patient has not 


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progressed before randomization.  Subjects who have progressed are not eligible for 
randomization.     
Throughout the study, a subject will be followed by the same method of assessment that 
was used at baseline to ensure consistency and comparability of images.  When 
possible, similar scanning techniques and equipment, including level and thickness 
should be used as at baseline for a subject.  Tumor assessments will be performed 
according to the modified RECIST 1.1 criteria (Appendix H) and must be conducted 
according to protocol specified techniques.   
After randomization, imaging studies will be performed every 9 weeks (± 7 days) from 
study day 1/week 1 or sooner if clinically indicated until disease progression as defined 
by modified RECIST 1.1 criteria.  Once disease progression has been determined, 
imaging studies are no longer required.   
Additional CT scans of other body regions (eg, brain, bone) may be acquired in the 
event of a suspected metastasis as clinically appropriate for evaluation and 
management.  If there are signs or symptoms suggestive of bone metastasis, a bone 
scan, MRI, CT, PET, PET/CT, or X-ray will be performed.  For subjects with a positive 
bone scan or PET scan, the bone metastasis must be confirmed with another method of 
imaging (ie, X-ray, CT or MRI).  Evidence of suspected disease progression must be 
recorded in source documents at the site.   
Images from the imaging studies will be collected and stored in a central location by the 
imaging vendor.  Refer to the imaging manual for additional information and instructions 
on the handling and shipping of the images to the imaging vendor. 
7.1.7 
Disease Progression 
Disease progression will be based on imaging studies assessed by the investigator 
using modified RECIST 1.1; if imaging cannot be performed, disease progression should 
be based on clinical signs and symptoms.  Imaging studies to evaluate disease 
progression will be performed within 7 days of the study-specified visit and at any time 
symptoms suggestive of disease progression occur.  Subjects who discontinue 
chemotherapy or IP should continue to be evaluated radiographically Q9W until disease 
progression.  
7.1.8 
Thrombovascular Events 
All subjects will be monitored closely for clinical signs and symptoms of thrombovascular 
events (TVE) (arterial thromboembolic events [ATE]: stroke, transient ischemic attack 


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[TIA], acute coronary syndromes [ACS], other arterial thrombosis/embolism; venous 
thromboembolic events [VTE]: deep vein thrombosis [DVT], pulmonary embolism [PE], 
other venous thrombosis excluding superficial venous thrombosis).  If any signs or 
symptoms are present, the subject will undergo specific laboratory and medical imaging 
studies to confirm VTEs.  The medical imaging study or studies selected will depend on 
the anatomic site of the suspected VTE or organ of involvement (eg, Doppler ultrasound, 
venography, ventilation perfusion lung scan, angiography, MRI).  If a VTE is confirmed, 
appropriate medical care according to standard local clinical practice should be initiated 
immediately.   
TVEs will be documented in the CRF through the EOTP or 30 days after the last dose of 
IP, whichever occurs later.      
7.1.9 
Concomitant Medication and Red Blood Cell Transfusion 
Concomitant medications, procedures of interests (eg, radiotherapy, anti-cancer 
surgery), and RBC transfusion details will be collected from screening to EOTP.  The 
reason for the RBC transfusion and any adverse events (including VTE) associated with 
RBC transfusion will be recorded on the CRFs.  Concomitant medications include, but 
are not limited to, the use of any prohibited ESA or non-protocol specified dose of IP, 
hematopoietic growth factor, iron supplement, anti-hypertensive agent, anti-cancer 
therapy including chemotherapeutic agents, and anticoagulation therapy.  Collection of 
information on ESA usage and anti-cancer therapy will be continued at pre-specified 
intervals during the LTFU period. 
7.1.10 
Adverse Events Reporting 
Adverse events starting at randomization through 30 days after last dose of IP will be 
reported to Amgen.  All serious adverse events (SAEs) occurring from the date the 
subject signs the ICF through 30 days after the last dose of IP will be reported to Amgen.  
All TVEs, and adverse events associated with RBC transfusions administered during the 
treatment period, will be reported through the EOTP or 30 days after the last dose of IP, 
whichever occurs later.  Refer to Section 9 for more detail on adverse events reporting. 
7.1.11 
Survival Status 
Survival status will be assessed by the investigator or qualified site personnel at the 
pre-specified intervals throughout the study.  If the subject has died, the date of death 
and the primary cause of death will be collected on the CRF.  If available, death 
certificates may be used by the monitors to confirm the date and cause of death.  Site 


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staff can access publicly available records to determine survival status where 
permitted by law.  
7.1.12 
Central Laboratory Assessments 
Laboratory data from the central laboratory will be used for analysis purposes and for 
determination of eligibility within 21 days prior to randomization.  (Exception: The 
hemoglobin sample obtained within 7 days prior to randomization to confirm eligibility 
must be assessed by a local laboratory.)  During the treatment period, the sample may 
be obtained on the day of IP dosing or up to 1 day prior to the day of IP dosing.  
Laboratory samples during the screening and treatment periods will be processed and 
sent to the central laboratory which is responsible for either completing the assessment 
or shipping the samples to Amgen for assay depending on the assessment.  The central 
laboratory will be utilized for parameters such as: complete blood count (CBC) with 
differential (including hemoglobin for statistical analyses), serum chemistry, serum 
pregnancy test (for female subjects of reproductive potential), vitamin B12, serum folate, 
C-reactive protein (CRP), reticulocyte count, soluble transferrin receptor, iron, ferritin, 
Tsat, and TIBC.  Samples for darbepoetin alfa antibody and endogenous EPO testing 
will be sent to the central laboratory and the central laboratory will forward the samples 
to Amgen (or designee) for analyses.   


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The central laboratory will analyze the following list of analytes with the exception of the 
darbepoetin alfa antibody and endogenous EPO: 
Chemistry  
CBC 
Folate and 
Vitamin B12 
Iron Studies 
Other Labs 
Total bilirubin 
Hemoglobin 
Serum folate 
Iron 
Darbepoetin alfa antibody 
Direct bilirubin 
Hematocrit  
Vitamin B12 
Ferritin 
Serum pregnancy 
Alkaline  
RBC 
 
TIBC 
Endogenous EPO 
Phosphatase 
MCV  
 
Tsat 
CRP 
ALT(SGPT) 
MCH 
 
Soluble transferrin 
receptor  
Reticulocyte count 
AST (SGOT) 
MCHC 
 
 
 
GGT 
RBC 
morphology 
 
 
 
LDH 
WBC 
 
 
 
BUN 
Neutrophils 
 
 
 
Creatinine 
Lymphocytes 
 
 
 
Glucose 
Monocytes 
 
 
 
Uric Acid 
Eosinophils 
 
 
 
Sodium 
Basophils 
 
 
 
Potassium 
Platelets 
 
 
 
Chloride 
 
 
 
 
Bicarbonate 
 
 
 
 
Calcium 
 
 
 
 
Phosphorus 
 
 
 
 
Total protein 
 
 
 
 
Albumin 
 
 
 
 
 
7.1.13 
Local Laboratory Assessment 
Sites will utilize a local laboratory for assessing a subject’s hemoglobin level to confirm 
eligibility (the sample must be obtained within 7 days prior to randomization) and for 
dosing decisions / adjustments during the treatment period (the sample may be obtained 
on the day of IP dosing or up to 1 day prior to the day of IP dosing).  
7.1.14 
Tumor Sample Banking (Optional) 
If available, archived paraffin embedded tumor tissue blocks or unstained tumor slides 
(from primary tumor or metastasis) will be collected during screening and submitted 
upon enrollment to the central lab, along with the associated pathology report for 
erythropoietin receptor (EpoR) testing, tumor mutation analysis, and other biomarker 
evaluation.  There will not be an additional procedure required but rather these tumor 
samples may be obtained from previous diagnostic biopsy.   
Tumor sample blocks may be returned to an investigational site upon request by the 
investigator. 


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7.2 
Screening 
The screening period, which starts when the subject signs and dates the ICF and ends 
when the subject is randomized or screen failed, must not exceed 21 days.  Study-
specific screening tests and procedures must be performed and results obtained within 
the screening period.  Certain procedures that are considered by the investigational site 
to be standard of care, such as imaging studies, the complete physical exam, local 
laboratory hemoglobin testing, and ECOG performance status assessment, may be 
performed prior to the start of screening.     
Laboratory assessments used to determine subject eligibility may be repeated during the 
screening period before the subject is considered a screen failure.  Subjects determined 
to be screen failures (based on laboratory or any other assessment) will not be eligible 
for immediate participation and must be registered as a screen failure in IVR/IWR 
System, but may be re-screened at the investigator’s discretion (the subject will maintain 
the same subject ID number provided at the initial registration).  Subjects who are 
determined not eligible after re-screen must be screen failed through IVR/IWR System.  
Subjects must be re-consented if more than 30 days have elapsed between date of 
informed consent and date of randomization. 
The following assessments will be completed as part of screening: 
• Informed consent (marks the beginning of the screening period) 
• Access IVR/IWR System to obtain subject ID number 
• Medical history including tumor diagnosis and staging, and pre-chemotherapy tumor 
evaluation 
• Complete physical examination including height and weight (exam may be performed 
up to 21 days prior to randomization) 
• Vital signs 
• ECOG performance status (assessment may be performed up to 21 days prior to 
randomization)    
• The presence of a central or mid-line venous catheter 
• Imaging studies (if required; see Section 7.1.6) 
• Serious Adverse Events (collected beginning from the date informed consent is 
signed) 
• Concomitant medications, radiotherapy and RBC transfusion history 
• Central laboratory tests: serum chemistries, CBC with differential (including 
hemoglobin), reticulocyte count, serum folate, vitamin B12,  and iron studies 
• Central laboratory serum pregnancy testing for women of child bearing potential 
according to investigator’s judgment 


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x 
Local laboratory hemoglobin to determine eligibility (sample may be obtained up to 
7 days prior to randomization)  
x 
If available, paraffin embedded tumor tissue blocks or unstained tumor slides will be 
submitted along with associated pathology report 
7.3 
Randomization  
Once all screening procedures are complete and all eligibility criteria have been met, the 
subject may be randomized into the study by calling IVR/IWR system.  Before 
randomizing a subject, site staff should prospectively assess scheduling conflicts with 
the subject for the study from screening through EOTP.   
Randomization may occur on the same day as the first dose of IP (ie, study day 1) or it 
may occur up to 4 days prior to the first dose of IP.  Adverse events will be reported 
beginning from the date of randomization. 
7.4 
Study Day 1/Week 1 
Study day 1 (ie, week 1) is the first day IP (darbepoetin alfa or placebo) is administered.   
The day 1 / week 1 study procedures (eg, ECOG, laboratory sample draws) may be 
performed up to 1 day prior to IP dosing.   
The following assessments and procedures will be completed on study day 1 (week 1): 
x 
Vital signs and weight 
x 
The presence of a central or mid-line venous catheter 
x 
ECOG performance status 
x 
Assess for signs and symptoms of clinically relevant TVE.  If present, perform 
appropriate laboratory, diagnostic, and medical imaging for suspected TVE 
x 
Darbepoetin alfa antibody collection 
x 
Endogenous EPO level 
x 
Adverse events  
x 
Concomitant medications, radiotherapy, anti-cancer therapy, anti-cancer surgery, 
and RBC transfusions 
x 
Central laboratory tests: clinical chemistries and CBC with differential (including 
hemoglobin for statistical analyses), CRP, and soluble transferrin receptor 
x 
Local laboratory hemoglobin for dosing determination 
x 
Access IVR/IWR system for medication assignment 
x 
Subcutaneous administration of IP 


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7.5 
Treatment Period (Q3W Visits) 
Study visits will occur every 3 weeks ± 6 days with subcutaneous IP administration Q3W 
during the treatment period.  IP will be discontinued within 3 weeks after the last dose of 
chemotherapy, or upon the determination of disease progression, whichever occurs first.  
For all study visits during the treatment period, study procedures (eg, ECOG, laboratory 
sample draws) may be performed up to 1 day prior to IP dosing.  
The following assessments and procedures will be performed during the treatment 
period: 
• Vital signs and weight 
• The presence of a central or mid-line venous catheter 
• ECOG performance status  
• Assessment of disease progression 
• Assess for signs and symptoms of clinically relevant TVE.  If present, perform 
appropriate laboratory, diagnostic, and medical imaging for suspected TVE 
• Imaging studies Q9W (or earlier if clinically indicated) until documented disease 
progression (see Section 7.1.6)     
• Central laboratory tests: clinical chemistries and CBC with differential (including 
hemoglobin for statistical analyses), Tsat, ferritin, iron, and TIBC.  Central laboratory 
tests will continue until the next Q3W study visit that occurs after the last dose of IP 
• Local laboratory hemoglobin for IP dosing determination.  Local laboratory 
hemoglobin testing will continue until the next Q3W study visit that occurs after the 
last dose of IP 
• Access IVR/IWR system for medication assignment or to register a subject’s 
discontinuation from IP (if applicable) 
• Subcutaneous Q3W administration of IP 
• Subjects who discontinued IP but have not had disease progression will continue 
Q3W visits and Q9W imaging studies until disease progression has been 
determined.   Subjects who are unable to continue Q3W visits and Q9W imaging 
studies until disease progression should complete EOTP procedures at no later than 
their next Q3W visit and will be asked to enter the LTFU period 
Concomitant medications, radiotherapy, anti-cancer therapy, anti-cancer surgery, and 
RBC transfusion information will be collected throughout the treatment period.  AEs and 
SAEs will be collected up to 30 days after the last dose of IP.    
7.6 
End of Treatment Period 
Subjects will complete the EOTP visit at the next Q3W visit (± 6 days) after disease 
progression has been determined either by imaging studies or by clinical assessments in 
the absence of imaging confirmation.  Subjects who are unable to continue Q3W visits 
and Q9W imaging studies until disease progression should complete EOTP procedures 


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at no later than their next Q3W visit (± 6 days).  At the time of the EOTP visit, any 
subject who has experienced a serious and treatment related adverse event during the 
study, as determined by the investigator, will continue to be followed for that event, until 
the event is resolved or considered stable; all EOTP visit procedures may still be 
conducted prior to resolution. 
The following EOTP assessments and procedures will be required for all subjects:  
x 
Vital signs and weight 
x 
The presence of a central or mid-line venous catheter 
x 
ECOG performance status 
x 
Assess for signs and symptoms of clinically relevant TVE.  If present, perform 
appropriate laboratory, diagnostic, and medical imaging for suspected TVE 
x 
Adverse events, concomitant medications, radiotherapy, anti-cancer therapy, anti-
cancer surgery, and RBC transfusions 
x 
Central laboratory serum chemistries and CBC with differential (including hemoglobin 
for statistical analyses) (except if EOTP visit occurs following the Q3W visit after the 
last dose of IP) 
x 
Local laboratory hemoglobin (except if EOTP visit occurs following the Q3W visit 
after the last dose of IP)  
x 
Darbepoetin alfa antibody  
7.7 
Long-term Follow-up Period 
After the EOTP visit, subjects will enter the LTFU period and will visit the clinic at 
3-month intervals (± 2 weeks).  For subjects who are unable to come to the clinic, site 
staff should contact the subjects by phone to ascertain survival status.   
The following data will be collected by the investigator or site personnel and forwarded to 
Amgen or designee:  
x 
Overall survival status 
x 
ESA administration (eg, date of administration, type, and dose) 
x 
Anti-cancer therapy (eg, date of administration, type and dose) 
x 
Anti-cancer surgery 
x 
Radiotherapy 
7.8 
End of Study 
The EOS for a subject is when the subject has died or when approximately 2700 deaths 
have occurred.  For any subjects still receiving IP when the 2700th death occurs, these 
subjects may continue to receive IP per protocol. 


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7.9 
Tumor Sample for Future Biomarker Evaluation (Optional) 
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Tumor Sample Storage and Destruction 
 
  
 
 
 
 
 
 
 
 
 
   
8. 
REMOVAL AND REPLACEMENT OF SUBJECTS 
8.1 
Removal of Subjects 
CCI
Subjects have the right to withdraw fully or partially from the study at any time and for 
any reason without prejudice to his or her future medical care by the physician or at the 
institution. 
Withdrawal of full consent for a study means that the subject does not wish to receive 
further investigational treatment and does not wish to or is unable to continue further 
study participation.  Any subject may withdraw full consent to participate in the study at 
any time during the study.  The investigator will discuss with the subject the most 
appropriate way to withdraw to ensure the subject’s health.   
Withdrawal of partial consent means that the subject does not wish to take IP any longer 
but is still willing to collaborate in providing further data by continuing on study (eg, 
participate in all subsequent imaging visits until disease progression and/or to be 
followed during the LTFU period).  Withdrawal of partial consent also means that the 
subject, although having completed IP or stopped receiving IP for other reasons, is still 
willing to collaborate in providing further data by continuing on study (eg, participate in all 
subsequent imaging visits until disease progression and/or to be followed during the 
LTFU period).   
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Reasons for discontinuation of IP or study visits or procedures might include: 
• withdrawal of full consent 
• withdrawal of partial consent 
• administrative decision by the investigator or Amgen 
• pregnancy (report on Pregnancy Notification Worksheet, see Appendix F)  
• ineligibility 
• lost to follow up 
• significant protocol deviation 
• subject non-compliance 
• adverse event  
8.2 
Replacement of Subjects 
Subjects who prematurely discontinue following randomization will not be replaced. 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Adverse Events 
9.1.1 
Definition of Adverse Event  
An adverse event is defined as any untoward medical occurrence in a clinical 
investigation subject occurring from the time that the subject has signed informed 
consent through 30 days after last dose of IP and does not necessarily have a causal 
relationship with study treatment.  The investigator is responsible for ensuring that any 
adverse events observed by the investigator or reported by the subject are recorded in 
the subject’s medical record.  These records are the source documents from which data 
are extracted and reported to Amgen per the reporting procedures (Section 9.1.2). 
The definition of adverse event includes worsening of a pre-existing medical condition.  
Worsening indicates the pre-existing medical condition (eg, cancer, diabetes, migraine 
headache, gout) has increased in severity, frequency, and/or duration, and/or has an 
association with a significantly worse outcome.  A pre-existing condition that has not 
worsened during the study, but involves an intervention such as elective cosmetic 
surgery or a routine standard of care medical procedure while on study, is not 
considered an adverse event.  
Disease progression (ie, progression of cancer) will not be considered an adverse event, 
nor a serious adverse event if International Conference for Harmonization (ICH) criteria 
for seriousness are met.  Disease progression will instead be documented on a specific 
case report form and analyzed separately as a key secondary study endpoint.  Similarly, 


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disease progression as a cause of death will be captured on a Death Summary case 
report form. 
There are several well documented adverse events in oncology subjects that are known 
to occur during chemotherapy treatment such as nausea, vomiting, diarrhea, 
constipation, anorexia, and fatigue.  These symptoms should not be considered adverse 
events, unless: 
• Severity, frequency, or duration of the symptom(s) has increased from baseline 
• Symptom(s) meets a serious criterion (report as AE and SAE) 
• Symptom(s) is considered possibly related to investigational product 
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a change from the 
subject’s baseline values.  In general, an abnormal laboratory finding without clinical 
significance (based on the investigator
's judgment) should not be considered adverse 
events.  However, a laboratory value change that requires treatment or adjustment in 
current therapy would be considered an adverse event.  Where applicable, clinical 
sequelae, and not the laboratory abnormality, should be considered an adverse event. 
9.1.2 
Reporting Procedures for Adverse Events 
All adverse events occurring after randomization through 30 days after last dose of IP as 
recorded in the subject’s medical record, will be reported to Amgen via the Adverse 
Event Summary CRF.  TVEs, and adverse events associated with RBC transfusions 
administered during the treatment period, that occur through the EOTP or 30 days after 
the last dose of IP, whichever occurs later, also will be documented in the CRF.  VTEs 
are captured on a specific CRF page. 
The investigator must assign the following adverse event attributes: 
• Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms) 
• Event description (with detail appropriate to the event) 
• Dates of onset and resolution 
• Severity 
• Assessment of relatedness to IP 
• Assessment of relatedness to transfusion 
• Assessment of relatedness to chemotherapy 
• Action taken 
The adverse event severity grading scale used will be the CTCAE.  The severity grading 
scale used in this study is described in Appendix B. 


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The investigator must assess whether the adverse event is possibly related to the IP.  
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 IP?” 
The investigator must assess whether the adverse event is possibly related to 
transfusion.  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 RBC 
transfusion?” 
The investigator must assess whether the adverse event is possibly related to 
chemotherapy.  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 
chemotherapy?”  
Medically significant adverse events considered related to the IP by the investigator will 
be followed until resolved or considered stable. 
The investigator’s clinical judgment will be used to determine whether a subject should 
be removed from treatment or from the study due to an adverse event.  A subject may 
also voluntarily withdraw from treatment due to an adverse event.  If the subject is 
withdrawn, the subject should be strongly encouraged to undergo at a minimum an 
end-of-treatment assessment.  The subject should be followed until symptoms cease or 
the condition becomes stable. 
9.2 
Serious Adverse Events 
9.2.1 
Definition of Serious Adverse Event 
A serious adverse event (SAE) is an adverse event that meets at least one of the 
following serious criteria: 
x 
fatal 
x 
life threatening (places the subject at immediate risk of death) 
x 
requires in-patient hospitalization or prolongation of existing hospitalization 
x 
results in persistent or significant disability/incapacity 
x 
congenital anomaly/birth defect, and/or 
x 
other significant medical hazard 
The investigator is responsible for ensuring, for all subjects who have signed an 
informed consent, that all serious adverse events occurring from signing of informed 
consent (inclusive of the screening phase) through 30 days after last dose of IP are 
recorded in the subject’s medical record.  This includes serious adverse events 


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observed by the investigator or reported by the subject.  These records are the source 
documents from which data are extracted and reported to Amgen per the reporting 
procedures (Section 9.2.2). 
An adverse event meets the serious criterion of “requires hospitalization”, if the event 
necessitates an admission that includes a minimum of an overnight stay in a health care 
facility.  
If an investigator considers an event to be clinically important, but it does not meet any 
other serious criteria, the event could be reported under the criterion of “other significant 
medical hazard”.  Examples of such events include allergic bronchospasm, convulsions, 
and blood dyscrasias, which result in an emergency room visit, outpatient surgery, or 
other urgent intervention. 
If the following interventions are performed as standard of care and not associated with 
a new health issue or worsening of a pre-existing health issue, the health issue for which 
the intervention is performed will not be considered an adverse event, nor a serious 
adverse event.   
• Insertion of a central line as an outpatient or associated with hospitalization 
• Blood transfusion(s) 
• Hospitalization for the purpose of chemotherapy administration 
If there is a health complication as a result of the intervention, the complication would be 
reported as an adverse event; if the complication meets at least 1 serious criterion, the 
complication would be also reported as a serious adverse event. 
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 
informed consent through 30 days after last dose of IP as recorded in the subject’s 
medical record and are submitted to Amgen.  Serious TVEs, and SAEs associated 
with RBC transfusions administered during the treatment period, that occur through the 
EOTP or 30 days after the last dose of IP, whichever occurs later, also will be reported 
to Amgen.  During long-term follow-up period, SAEs will not be reported to Amgen, 
except for SAEs occurring after 30 days post last dose of IP AND thought to be possibly 
related to IP.  These events are to be submitted to Amgen. 
The serious adverse event must be submitted to Amgen within 24 hours following 
the Investigator’s knowledge of the event via the applicable CRF.  If the electronic 


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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 a Serious Adverse 
Event (SAE) Contingency Reporting Form within 24 hours of the Investigator’s 
knowledge of the event.  See Appendix C for a sample of the Serious Adverse 
Event Contingency Reporting Form.  If the first notification of a Serious Adverse 
Event is reported to Amgen via the Serious Adverse Event Contingency Reporting 
Form, the data must be entered into the EDC system when the system is again 
available. 
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; autopsy reports should be 
provided for deaths, if available.  Information provided about the serious adverse 
event must be consistent with that recorded on the applicable CRF (eg, Adverse 
Event Summary CRF).  If a subject is permanently withdrawn from the study because of 
a serious adverse event, this information must be submitted to Amgen. 
The investigator should notify the appropriate IRB, ethics committee, or head of the 
medical institution, when applicable, of serious adverse events occurring at the site and 
other adverse event reports received from Amgen, in accordance with local procedures 
and statutes. 
To comply with worldwide reporting regulations for serious adverse events, the 
treatment assignment of subjects who develop serious, unexpected, and related adverse 
events may be unblinded by Amgen before submission to regulatory authorities.  
Investigators will receive notification of related serious adverse events reports 
sent to regulatory authorities in accordance with local requirements. 
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and 
good clinical practice.  
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, 
while the subject is taking protocol-specified product and for 1 month after end of 


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IP, the pregnancy should be reported to Amgen’s global Pregnancy Surveillance 
Program using the Pregnancy Notification Worksheet (Appendix F). 
If a lactation case occurs in a female subject, while the subject is taking protocol-
specified product and for 1 month after the end of IP, the lactation case should be 
reported to Amgen’s global Lactation Surveillance Program within 7 business 
days of the site receiving notification using the Lactation Notification Worksheet 
(Appendix G). 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Design 
This is a double-blind, randomized, placebo-controlled, phase 3 non-inferiority study in 
CIA subjects receiving multi-cycle chemotherapy for the treatment of stage IV NSCLC 
cancer.  Randomization will occur in a 2 to 1 ratio (darbepoetin alfa to placebo) and will 
be stratified by geographic region, histology (squamous versus other), and screening 
hemoglobin (< 10.0 g/dL versus ≥ 10.0 g/dL).  Subjects will receive IP Q3W during the 
treatment period.  IP will be discontinued within 3 weeks after the last dose of 
chemotherapy, or upon the determination of disease progression, whichever occurs first.  
Study visits Q3W and imaging studies Q9W will occur during the treatment period until 
disease progression.  The EOTP visit will occur at the next Q3W visit after disease 
progression has been determined.  Subjects will then enter long-term follow-up and will 
be followed for survival until death, or until approximately 2700 deaths have occurred. 
The primary objective of the study is to demonstrate that subjects treated with 
darbepoetin alfa to a hemoglobin ceiling of 12 g/dL is non-inferior to subjects on placebo 
with respect to survival.  Key secondary objectives include demonstrating that subjects 
treated with darbepoetin alfa to a hemoglobin ceiling of 12 g/dL is non-inferior to subjects 
on placebo with respect to PFS and demonstrating that darbepoetin alfa is superior to 
placebo with respect to transfusions.   
10.2 
Study Endpoints, Subsets, and Covariates 
10.2.1 
Study Endpoints 
Primary Endpoint 
• Overall survival 
Secondary Endpoint 
• Progression-free survival 
• Incidence of at least 1 RBC transfusion or hemoglobin ≤ 8.0 g/dL from week 5 
(day 29) to EOETP 


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Other Safety Endpoints 
• 
 
 
• 
 
• 
  
Other Efficacy Endpoints 
• 
  
 
• 
 
10.2.2 
Primary Analysis Set 
The primary analysis set will include all randomized and consented subjects who receive 
at least 1 dose of IP.  Subjects will be analyzed according to their randomized treatment 
assignment.  Sensitivity analyses will be based on all randomized and consented 
subjects and a prospectively defined per-protocol analysis set.   
10.2.3 
Covariates 
The analysis of the primary and secondary endpoints will be stratified by the stratification 
factors at randomization.  Additional analyses may include the following baseline factors 
as covariates: age, sex, planned on study treatment for NSCLC (eg, chemotherapy with 
or without any anti-EGFR or anti-angiogenic agents), time from start of chemotherapy to 
anemia, stage, pre-chemotherapy weight loss, race, smoking status, past medical 
history (eg, VTEs, ATEs, diabetes), pre-chemotherapy hemoglobin, and baseline serum 
erythropoietin level.  Pre-specified analyses of additional covariates may be performed if 
other prognostic factors emerge in this population during the time it takes to complete 
this study. 
10.3 
Sample Size Considerations 
A total of 2700 deaths will be observed in order to exclude a hazard ratio (darbepoetin 
alfa to placebo) of 1.15 with a 1-sided significance level of 0.025.  With 2700 deaths, the 
study is powered at just over 90% if the true hazard ratio is 1.0 (approximately, 93%).  
To observe 2700 deaths, the study will randomize a total of 3000 subjects which 
assumes a 7-year enrollment period, a 3-year follow-up after last subject enrolled, a 
1-year survival rate of 51% (Sandler et al, 2006
CCI
), and a common exponential drop-out 
rate of 0.0511. 
Excluding a hazard ratio of 1.15 corresponds to excluding a decrease in median survival 
of approximately 1.6 months in the darbepoetin alfa arm group compared to placebo.  
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This estimation assumes survival time is exponentially distributed which allows for a 
conversion from a hazard ratio to medians.  A median survival of 12.3 months 
(Sandler et al, 2006) was assumed as the median survival in the placebo arm in order to 
derive the difference in medians that correspond to a hazard ratio of 1.15. 
10.4 
Access to Individual Subject Treatment Assignments 
A subject’s treatment assignment should only be unblinded when this knowledge is 
essential for the further management of the subject.  Unblinding for any other reason will 
be considered a protocol violation. 
The principal investigator is strongly encouraged to contact Amgen or its designee 
before unblinding any subject’s treatment assignment, and must do so within 1 working 
day after the event.   
For the review of unblinded safety data by the Data Monitoring Committee (DMC), an 
independent biostatistics group will be responsible for analyzing the unblinded data.  The 
study personnel will remain blinded to the individual subject treatment assignments. 
10.5 
Interim Analysis and Early Stopping Guidelines 
An independent Data Monitoring Committee (DMC) will assess safety on a regular basis 
throughout the duration of the study.  The DMC will convene approximately once every 
6 months for the first 2 years and once a year thereafter during the course of the trial.  In 
addition, the DMC will oversee 5 formal interim analyses to assess harm (ie, inferiority of 
darbepoetin alfa), which will occur when approximately 10%, 20%, 30%, 40%, and 60% 
of the planned total of 2700 deaths have been observed.  If warranted from these 
reviews, the DMC may request additional safety data, recommend modifying or stopping 
the treatment, or recommend suspending randomization.  In addition, the DMC will 
review enrollment status and assess changes in the practice of medicine to make 
recommendations regarding the ongoing feasibility of the trial.  Prior to the completion of 
the recruitment period, the sponsor will re-assess the study assumptions (eg, 
recruitment rate and mortality rate) on a blinded basis, and may revise the sample size 
in order to ensure that the study completes. 
10.6 
Planned Methods of Analysis 
10.6.1 
General Approach/Considerations 
The primary analysis will be triggered by the date when the 2700th death is reported in 
the clinical trial database.  Once this death is reported, sites will be instructed to enter all 
outstanding data into the clinical trial database, the database will be cleaned, a snapshot 


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will be taken, the database will be locked, and the primary analysis will be performed.  
Any additional deaths reported during the entry of outstanding data which occur on or 
prior to the termination date will be counted in the primary analysis.  The timing of the 
interim analyses is described in Section 10.6.2.  
Continuous variables will be summarized by the mean, standard deviation, median, and 
range.  Categorical variables will be summarized by the number and percentage in each 
category.  Time to event variables will be summarized with hazard ratios, Kaplan-Meier 
curves, Kaplan-Meier quartiles, the number of subjects censored, and the number of 
subjects with events.  Point estimates will be accompanied by 2-sided 95% confidence 
intervals.  Overall survival and PFS will be assessed using a 1-sided significance level of 
0.025; all other statistical hypothesis testing will use a 2-sided significance level of 0.05 
unless otherwise specified. 
For stratified analyses, the value for the stratification factors will be taken from IVR/IWR 
System rather than the case report form; a cross-tabulation of the values recorded in the 
IVR/IWR System and CRF will be generated to assess the potential impact of 
misspecifications of the stratification factors at randomization. 
To preserve the overall significance level for the study, statistical testing of the primary 
and secondary endpoints will follow a hierarchical structure.  First, the primary endpoint 
of OS will be tested.  If darbepoetin alfa is demonstrated to be non-inferior to placebo 
with respect to OS then PFS will be formally tested.  If darbepoetin alfa is demonstrated 
to be non-inferior to placebo with respect to PFS then the incidence of RBC transfusions 
or a hemoglobin ≤ 8.0 g/dL will be formally tested.  If non-inferiority is demonstrated for 
both OS and PFS and superiority is demonstrated for the transfusion endpoint, 
superiority will then be tested for both OS and PFS using the Hochberg procedure to 
adjust for multiplicity.  For endpoints that are not designated as primary or secondary, 
statistical testing will be considered descriptive and no adjustments will be made for 
multiplicity. 
10.6.2 
Analysis of Key Study Endpoints 
10.6.2.1 
Analysis of Primary Endpoint 
The analysis of OS will use a Cox proportional hazards model, stratified by the 
randomization factors, with treatment group as the only covariate (a sensitivity analysis 
will include additional covariates described in Section 10.2.3 to assess the robustness of 
the primary approach).  Subjects last known to be alive will be censored on date of last 


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contact.  Non-inferiority will be declared if the upper confidence limit for the hazard ratio 
is less than 1.15 using a 1-sided significance level of 0.025.  
10.6.2.2 
Analysis of Secondary Endpoints 
The same method used to analyze OS will be used to analyze PFS.  Progression-free 
survival will be measured from randomization to disease progression (as defined by the 
version of RECIST specified in the protocol at the time of subject enrollment using 
investigator-assessed scans) or death from any cause; subjects without either event will 
be censored at the last disease assessment date.  Non-inferiority will be declared if the 
upper confidence limit for the hazard ratio is less than 1.15 using a 1-sided significance 
level of 0.025.  This analysis will be performed on all subjects in the primary analysis set 
who have not had disease progression prior to randomization. 
If non-inferiority is declared for both OS and PFS, then the effectiveness of darbepoetin 
alfa in reducing the incidence of RBC transfusions or a hemoglobin ≤ 8.0 g/dL will be 
formally tested.  To assess treatment group differences, a 2-sided Cochran-Mantel-
Haenszel test at a significance level of 0.05 will be used which will adjust for the 
stratification factors at randomization.  The incidence will be assessed from day 29 to the 
EOETP.  This analysis will be performed on all subjects in the primary analysis set 
whose EOETP is ≥ day 29. 
10.6.2.3 
Analysis of Other Safety Endpoints 
CCI
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.6.2.4 
Analysis of Other Efficacy Endpoints 
 
 
 
 
 
 
 
  
 
 
 
10.6.3 
Additional Analyses 
The number and percentage of subjects screened, randomized, and received at least 
one dose of IP will be presented.  The number and percentage of subjects who withdrew 
prematurely will be tabulated by the reason for withdrawal. 
The following demographic characteristics and baseline variables will be summarized by 
treatment group: 
• Age, sex, and race 
• Weight, body mass index, ECOG performance status, stage of disease, histology, 
and pre-chemotherapy weight loss 
• Extent of pre-treatment chemotherapy and time from start of chemotherapy to 
anemia  
• Smoking status and past medical history including hypertension, prior VTEs, prior 
ATEs, and diabetes 
•
CCI
 Hemoglobin value, platelet count, WBC, ferritin level, and serum erythropoietin level 
The total number of doses of darbepoetin alfa, the cumulative dose of darbepoetin alfa 
administered, and the average total weekly dose will be summarized by treatment group 
using mean, standard deviation, median, and range.  In addition, the number and 
proportion of subjects with dose adjustments in each treatment group will be tabulated. 
Use of selected concomitant medications, including chemotherapy, other erythropoietic 
agents, anti-hypertensives, anti-anginals and anticoagulants will be grouped according 
CCI


Product:  Darbepoetin alfa 
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to medication class.  The number and proportion of subjects receiving each medication 
will be summarized by medication class for each treatment group. 
11. 
INVESTIGATIONAL PRODUCT 
11.1 
Darbepoetin alfa 
Darbepoetin alfa will be manufactured and packaged by Amgen and distributed 
according to Amgen’s clinical trial drug procedures.  Darbepoetin alfa will be provided in 
single dose vials of human serum albumin free (HSA-free) polysorbate solution.  Four 
vial concentrations will be available:  500 µg, 300 µg, 200 µg, and 100 µg, each 
containing a 1.0 ml withdrawable volume of solution (ie, 500, 300, 200 and 100 µg per 
ml).  Placebo will be provided in similar single dose vials as a clear, colorless, sterile, 
protein-free solution containing a 1.0 ml withdrawable volume.  Vials will be packed and 
shipped in boxes.  Each box of investigational product will have a unique number and 
will contain one vial.  The box number with the corresponding vial strength and identity of 
investigational product will be available to IVR/IWR system. 
The box number of investigational product administered is to be recorded on each 
subject’s Drug Administration case report form for each dose.  This must be done in 
such a manner that a subject’s treatment assignment will not be unblinded during the 
trial. 
The vials of investigational product must be stored in a secured location and refrigerated 
at a temperature of 2°C to 8°C and protected from light. 
Initial shipments of drug and ongoing re-supply will be conducted through the IVR/IWR 
system.  For more detail refer to the IVR/IWR system manual and study guide. 
Investigational product details including labeling, storage, preparation, etc are provided 
in the Pharmacy Guide Appendix E. 
11.2 
Access to Treatment Assignments 
In this study, the identity of IP assigned to subject numbers or to individual boxes of IP 
will be contained in IVR/IWR system.  Authorized site staff will be provided with a unique 
Personal Identification Number (PIN) to access IVR/IWR system to obtain unblinding 
information.  This PIN is unique to the individual and must not be shared. 
Since all subjects will be given investigational product, a subject’s treatment assignment 
should only be unblinded when knowledge of the treatment is essential for the further 
management of the subject.  Unblinding at the study site for any other reason will be 
considered a protocol deviation. 


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The principal investigator is strongly encouraged to contact the Amgen study manager
before unblinding any subject’s treatment assignment, but must do so within 1 working 
day after the event and must document the unblinding in the subject’s case report form.  
12.
REGULATORY OBLIGATIONS
12.1
Informed Consent
An initial generic informed consent form is provided to the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template will be 
communicated by letter from the clinical study manager to the investigator.  The written 
informed consent document should be prepared in the language(s) of the potential 
patient population.
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol-specific screening procedures or any IP is 
administered.  A legally acceptable representative is an individual or other body 
authorized under applicable law to consent, on behalf of a prospective subject, to the 
subject’s participation in the clinical study.  The investigator is also responsible for 
asking the subject if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator shall inform the subject’s primary care physician of the 
subject’s participation in the clinical study. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician should be documented in the subject’s medical 
records, and the ICF should be signed and personally dated by the subject or a legally 
acceptable representative and by the person who conducted the informed consent 
discussion (not necessarily an investigator).  The original signed ICF should be retained 
in accordance with institutional policy, and a copy of the signed consent form should be 
provided to the subject or legally acceptable representative.
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  


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12.2
Independent Ethics Committee/Institutional Review Board
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IEC/IRB for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of IP.
The investigator must submit and, where necessary, obtain approval from the IEC/IRB
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator should notify the IEC/IRB of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures.
The investigator will be responsible for obtaining annual IEC/IRB approval and IRBs
renewal throughout the duration of the study.  Copies of the investigator’s reports and 
the IEC/IRB’s continuance of approval must be sent to Amgen.
12.3
Pre-study Documentation Requirements
The investigator is responsible for forwarding the following documents to Amgen or 
designee for review before study initiation can occur:
x
Signed and dated protocol signature page (Investigator’s Agreement)
x
Copy of approved informed consent form and subject information sheet, if applicable
x
Copy of the IEC/IRB approval of the protocol, consent form, and subject information 
sheet
x
Up-to-date curricula vitae of principal investigator and all co/sub-investigators
x
IEC/IRB composition and/or written statement that IEC/IRB is in compliance with 
regulations
x
Laboratory normal ranges and documentation of laboratory certification (or 
equivalent)
x
Current subject/investigator indemnity insurance
x
Signed study contract
x
Completed FDA form 1572 (or equivalent).  Central and local laboratories for the 
study must be listed on the form.
x
Other country-specific forms, as defined in the country-specific requirements such as 
completed Financial Disclosure statements for the principal investigator, all 
sub-investigators, and their spouses (legal partners) and dependent children


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12.4
Subject Confidentiality
The investigator must ensure that the subject’s confidentiality is maintained:  
x
On the case report forms or other documents submitted to Amgen, subjects should 
be identified by a subject identification number only.  
x
On Serious Adverse Event forms submitted to Amgen, subjects should be identified 
by their initials and a subject identification number only.  
x
Documents that are not for submission to Amgen (eg, signed informed consent 
forms) should be kept in strict confidence by the investigator.
In compliance with Federal regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IEC/IRB direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.  The investigator is obligated to inform and 
obtain the consent of the subject to permit named representatives to have access to 
his/her study-related records without violating the confidentiality of the subject.
12.5
Investigator Signatory Obligations
Each clinical study report should be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator.
The coordinating investigator, identified by Amgen, will either be:
x
a recognized expert in the therapeutic area
x
an investigator who provided significant contributions to either the design or 
interpretation of the study
x
an investigator contributing a high number of eligible subjects
13.
ADMINISTRATIVE AND LEGAL OBLIGATIONS
13.1
Protocol Amendments and Study Termination
Protocol amendments, except where necessary to eliminate an immediate hazard to 
subjects, must be made only with the prior approval of Amgen.  Agreement from the 
investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The IEC/IRB must be informed of all amendments and 
give approval.  The investigator must send a copy of the approval letter from the IEC/IRB
to Amgen.
Both Amgen and the investigator reserve the right to terminate the study according to 
the study contract.  The investigator should notify the IEC/IRB in writing of the study’s 
completion or early termination and send a copy of the notification to Amgen.


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Subjects may be eligible for continued treatment with investigational product by 
extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply the investigational product, and by what mechanism, after termination 
of the trial and before it is available commercially. 
13.2 
Study Documentation and Archive 
The investigator should maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on case report forms will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
case report form data are obtained.  These include but are not limited to hospital 
records, clinical and office charts, laboratory and pharmacy records, diaries, microfiches, 
radiographs, and correspondence.  Case report form entries may be considered source 
data if the case report form is the site of the original recording (ie, there is no other 
written or electronic record of data).   
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  Elements should include: 
• Subject files containing completed case report forms, informed consent forms, and 
subject identification list 
• Study files containing the protocol with all amendments, investigator’s brochure, 
copies of prestudy documentation (see Section 12.3), and all correspondence to and 
from the IEC/IRB and Amgen 
• If kept, proof of receipt, Investigational Product Accountability Record, Return of 
Investigational Product for Destruction, Final Investigational Product Reconciliation 
Statement, and all drug-related correspondence 
In addition, all original source documents supporting entries in the case report forms 
must be maintained and be readily available. 
No study document should be destroyed without prior written agreement between 
Amgen and the investigator.  Should the investigator wish to assign the study records to 
another party or move them to another location, he/she must notify Amgen in writing of 
the new responsible person and/or the new location. 


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13.3
Study Monitoring and Data Collection
The Amgen representative and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, case report forms 
and other pertinent data) provided that subject confidentiality is respected.
The Amgen monitor is responsible for verifying the case report forms at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The monitor should have access to subject medical records and other study-
related records needed to verify the entries on the case report forms.
The investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits, including delays in completing case 
report forms, are resolved.
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Clinical Quality Assurance Department (or 
designees).  Inspection of site facilities (eg, pharmacy, drug storage areas, laboratories) 
and review of study-related records will occur to evaluate the study conduct and 
compliance with the protocol, ICH GCP, and applicable regulatory requirements.
Data capture for this study is planned to be electronic:
x
Updates to electronic case report forms (eCRF) will be automatically documented 
through the software’s “audit trail”.
x
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review will be performed on subject data received at Amgen.  During 
this review, subject data will be checked for consistency, omissions, and any 
apparent discrepancies.  In addition, the data will be reviewed for adherence to the 
protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or site notifications will be created in 
the electronic data capture (EDC) system database for site resolution and closed by 
Amgen reviewer.
x
The principal investigator signs only the Investigator Verification Form for this 
electronic data capture study.  This signature will indicate that the principal 
investigator inspected or reviewed the data on the case report form, the data queries, 
and the site notifications, and agrees with the content.
x
Amgen’s clinical data management department will correct the database for the 
following eCRF issues without notification to site staff:

deletion of obvious duplicate data (eg, same results sent twice with the same 
date but different clinical planned events—week 4 and early termination)

clarifying “other, specify” if data are provided (eg, race, physical examination)


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
addition of a leading zero to date and/or time entries if necessary

deletion of leading and/or trailing spaces to adverse event or concomitant 
medication terms to facilitate uploading of coded files

where query responses confirm worsening of a baseline/previous condition but 
the data field was not updated accordingly by the site, CDM will update AE 
terms/entries with “worsening”
13.4
Language
Case report forms must be completed in English. Generic names for concomitant 
medications may be entered in the local language.
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.  Consult the country-
specific requirements for language requirements.
13.5
Publication Policy
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several principal investigators and appropriate 
Amgen staff.  The committee is expected to solicit input and assistance from other 
investigators and Amgen staff as appropriate.  Membership on the committee (both for 
investigators and Amgen staff) does not guarantee authorship—the criteria described 
below should be met for every publication.
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors, 2005), which states:
x
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.
x
When a large, multi-center group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above.
x
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship.
x
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed.
x
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content.
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for corporate review.  The Clinical 


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Study Agreement among the institution, principal investigator, and Amgen will detail the 
procedures for, and timing of, Amgen’s review of publications.
13.6
Compensation 
Subject will be treated and/or compensated for any study-related illness/injury pursuant 
to the information provided in the Compensation for Injury section of the Informed 
Consent.  Subjects may be compensated for other inconveniences not associated with 
study-related injuries (eg, travel costs, child care costs).


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14. 
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Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in solid 
tumours: Revised RECIST guidelines (version 1.1).  Eur J Cancer. 2009;45:228-247.
Elliott S, Egrie J, Browne J, et al.  Control of rHuEpo biological activity: The role of 
carbohydrate.  Exp Hematol. 2004;32:1146-1155.
Franchini M, Veneri D.  Iron-chelation therapy: an update.  Hematol J. 2004;5:287-292.
Freudenberger RS, Carson JL.  Is there an optimal hemoglobin value in the cardiac 
intensive care unit? Curr Opin Crit Care. 2003;9:356-361.
Gilstad CW.  Anaphylactic transfusion reactions.  Curr Opin Hematol. 2003;10:419-423.
Grote T, Yeilding AL, Castillo R, et al.  Efficacy and safety analysis of epoetin alfa in 
patients with small-cell lung cancer: a randomized, double-blind, placebo-controlled trial.  
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Harper P, Littlewood T.  Anaemia of cancer: impact on patient fatigue and long-term 
outcome.  Oncology. 2005;69(Suppl 2):2-7.
Hébert PC, Van der Linde P, Biro G, et al.  Physiologic aspects of anemia.  Crit Care 
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Hedenus M, Adriansson M, San Miguel J, et al.  Efficacy and safety of darbepoetin alfa 
in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, 
placebo-controlled study.  Br J Haematol. 2003;122:394-403.
Hedenus M, Vansteenkiste J, Kotasek D, et al.  Darbepoetin alfa for the treatment of 
chemotherapy-induced anemia: Disease progression and survival analysis from four 
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Date: 13 November 2012
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Henke M, Laszig R, Rube C, et al.  Erythropoietin to treat head and neck cancer patients 
with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled 
trial. Lancet. 2003;362:1255-1260.
Jung LL, Schwartz RN.  Darbepoetin alfa.  Cancer Practice. 2002;10:327-330.
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levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer 
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Erythropoiesis Stimulating Protein (Aranesp) for the effect of radiotherapy in patients 
with primary squamous cell carcinoma of the head and neck (HNSCC) – the Danish 
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Pirker R, Ramlau R, Schuette W, et al.  A phase 3 randomized, double blind, placebo-
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Sandler A, Gray R, et al.  Paclitaxel-Carboplatin Alone or with Bevacizumab for Non-
Small Cell Lung Cancer. N Engl J Med. 2006;355:2542-2550.
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in Patients With Active Cancer Not Receiving Chemotherapy or Radiotherapy: Results of 
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Thomas G, Ali S, Hoebers FJP, et al.  Phase III trial to evaluate the efficacy of 
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randomized phase III trial of darbepoetin alfa in lung cancer patients receiving 
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Vatner SF.  Effects of hemorrhage on regional blood flow distribution in dogs and 
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Oncol. 2007;25:1027-1032.


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15.
APPENDICES


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Appendix A.  Schedule of Assessments
Screening 
a
Treatment Period 
n
EOTP Visit
LTFU 
m 
Study Week 
-3 
Day 
1 /
Wk 
1
Q3W (± 6 days)  
(eg, Wk 4, 7, 10, 13, 16, 19, 22, 25, 28...) 
Last 
dose 
of IP 
Next Q3W visit after 
disease progression 
Every 3 
months 
(± 2 
weeks)
Informed consent, medical history, and complete physical 
exam
X 
 
Vital signs; other
b
X
X
X
X
X
ECOG performance status 
X 
X 
X 
X 
X 
Adverse events 
c, concomitant meds and RBC transfusions 
 
 
 
 
 
 
 
Tumor evaluation and assessment of disease progression 
 
 
Investigational product administration 
d
X
X
X
Lab testing
Central lab clinical chemistries 
e
X
X
X
X
X
o
Central lab CBC 
f
X
X
X
X
X
o
Local lab hemoglobin 
g
X
X
X
X
X
o
Central lab serum folate and vitamin B12
X
Central lab iron studies 
h
X
X
X
X
Tumor samples 
i
X 
 
Darbepoetin alfa antibody 
j
 
X 
X 
Endogenous erythropoietin level
X
Central lab pregnancy test 
k
X
Imaging studies
CT scan, MRI, or PET-CT 
l 
X
Every 9 weeks until disease progression (eg, Wk 10, 19, 28...) 
LTFU
Collect information on survival, ESA usage, anti-cancer 
therapy, radiotherapy, anti-cancer surgery
 
 
X 


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a.
The screening period, which starts when the subject signs and dates the ICF and ends when the subject is randomized or screen failed, must not exceed 21 days.  The local 
laboratory hemoglobin sample to confirm the eligibility hemoglobin value ≤ 11.0 g/dL must be obtained within 7 days prior to randomization.  If the pre-chemotherapy baseline scan 
was performed more than 28 days prior to randomization, an additional scan must be performed and reviewed by the investigator to confirm that the patient has not progressed 
before randomization.   
b. 
Vital signs include temperature and resting BP (systolic and diastolic).  Weight, presence of new / replaced central or mid-line venous catheters, and radiotherapy information will be 
collected during screening and during the treatment period.  Anti-cancer therapy and anti-cancer surgery information will be collected during the treatment period. 
c. 
All SAEs that occur after the subject signed the ICF through 30 days post last dose of IP will be collected.  All AEs will be collected after randomization until 30 days post last dose of 
IP.  Signs and symptoms of clinically relevant TVEs will be assessed at each visit during the treatment period.  If present, appropriate labs, diagnostic, and imaging will be performed.  
All TVEs, and adverse events associated with RBC transfusions occurring during the treatment period, will be documented in the CRF through the EOTP or until 30 days after the last 
dose of IP, whichever occurs later. 
d. 
IP will be administered SC Q3W during the treatment period.  IP will be discontinued within 3 weeks after the last dose of chemotherapy, or upon the determination of disease 
progression, whichever occurs first.  Subjects who discontinued IP but have not had disease progression will continue Q3W visits and Q9W imaging studies until progression has 
been determined.  Subjects who are unable to continue Q3W visits and Q9W imaging studies until disease progression should complete EOTP procedures at their next Q3W visit and 
will be asked to enter the LTFU period. 
e. 
Central lab clinical chemistries includes creatinine, bilirubin, ALT, AST.  CRP will be performed at Day 1 only. 
f. 
Central lab CBC includes WBC with differential, hemoglobin, hematocrit, platelet count.  
g. 
The hemoglobin sample to confirm eligibility must be obtained within 7 days prior to randomization.  During the treatment period, the hemoglobin sample for dosing decisions / 
adjustments may be obtained on the day of IP dosing or up to 1 day prior to the day of IP dosing.   
h. 
Central lab iron studies consist of serum iron, ferritin, TIBC, and Tsat%.  Only soluble transferrin receptor will be performed at Day 1.  Iron, ferritin, Tsat%, and TIBC will be 
performed Q3W. 
i. 
If available, paraffin embedded tumor block or unstained slides from previous biopsy, along with the matching pathology report will be collected during screening  
j. 
Serum antibody samples must be collected pre-dose. 
k. 
Central lab pregnancy testing performed for all female subjects of reproductive potential. 
l. 
Subjects must have had a baseline scan (CT, MRI, or PET-CT) of the chest to assess disease burden before starting on first line chemotherapy for NSCLC and the images must be 
reviewed by the investigator prior to randomization. Images to assess disease status will be obtained Q9W (or sooner if clinically indicated) from Week 1 until disease progression 
using the same type of scan as at baseline.  Bone scans, MRI, CT, PET, PET/CT, or X-ray will be performed when signs or symptoms suggestive of bone metastasis are present, and 
positive bone scans or PET scans must be confirmed by another imaging method (ie, X-ray, CT or MRI).  Once disease progression has been determined, imaging studies are no 
longer required. 
m. Subjects will be followed in LTFU for survival until death, or until approximately 2700 deaths have occurred on the study (End of Study).
n. 
The treatment period starts when the subject is randomized and ends at the next Q3W visit after disease progression has been determined (EOTP).  Note that EOTP is based on 
disease progression, not IP dosing.  All study visits during the treatment period may occur over a 2 consecutive day period.  Study procedures (eg, ECOG, laboratory sample draws) 
may be performed up to 1 day prior to IP dosing.  
o. 
Central lab clinical chemistries, central lab CBC and local lab hemoglobin tests are not performed if the EOTP visit occurs following the Q3W visit after the last dose of IP.      


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Date: 13 November 2012 
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Appendix B.  Adverse Event Severity Scoring System
The Common Terminology Criteria for Adverse Events (CTCAE) is available at the 
following link:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm


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Appendix C.  Serious Adverse Event Contingency Reporting Form 
  
 


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Appendix D.  ECOG Performance Status Scale
ECOG PERFORMANCE STATUS
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, (eg, light house work, office work)
2
Ambulatory and capable of all self care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self care. Totally confined to bed or 
chair


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Appendix E.  Pharmacy Guide
Darbepoetin alfa
Packaging and Formulation
Human serum albumin-free (HSA-free) polysorbate darbepoetin alfa will be 
manufactured and packaged by Amgen Inc and distributed using Amgen clinical IP 
distribution procedures.  Darbepoetin alfa will be presented as a clear, colorless, 
preservative-free, sterile protein solution in vials containing 500, 300, 200 or 100 Pg of 
darbepoetin alfa per ml.  The vials supplied will contain 1.0 ml of study drug and are for 
single-dose use only.  Placebo will be provided in similar vials as a clear, colorless, 
sterile protein-free solution.  Each box of IP will contain a single vial.
The identity of investigational product assigned to subject numbers or to individual boxes 
of IP will be maintained by the IVR/IWR system.  Authorized Amgen (for safety reporting) 
and site staff will be provided with a unique Personal Identification Number (PIN) to 
access the IVR/IWR system to obtain unblinding information.  This PIN is unique to the 
individual and must not be shared.
A subject’s treatment assignment should only be unblinded by the site when knowledge 
of the treatment is essential for the further management of the subject, or is needed for 
safety reporting to regulatory authorities.  Unblinding at the study site for any other 
reason will be considered a protocol deviation.    
The principal investigator is strongly encouraged to contact the Amgen study manager 
before unblinding any subject’s treatment assignment, but must do so within 1 working 
day after the even and must document the unblinding in the subject’s CRF.
Labeling
Information provided on the labels will comply with ICH GCP and local regulatory 
requirements.
Storage
The supplied darbepoetin alfa and placebo must be stored in a secured location and 
refrigerated at a temperature of 2 to 8o C, protected from light.  The stability of 
darbepoetin alfa and placebo have been demonstrated for at least 24 months when 
stored at a temperature between 2°C and 8°C, and further stability testing is ongoing.  
Vials may be allowed to warm to room temperature immediately before use, but should 
not be left unrefrigerated for more than 30 minutes before use.  If vials are left out for 
more than 30 minutes, the study monitor should be contacted and the darbepoetin alfa 


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should not be administered to any subjects until further notice.  Exposure to 
temperatures above or below this range should be avoided, as should vigorous shaking, 
as this may denature the protein.
Investigational product must not be used if the contents freeze in transit or in storage, or 
if any particulate matter or discoloration is observed.
Records of actual storage conditions during the period of the study must be maintained 
(eg, records of the date and time, and the initials of persons checking, and the “working 
day” temperatures of the refrigerator used for storage of trial supplies, continuous 
temperature recordings, or regularly maintained temperature alarm systems used in 
conjunction with temperature recording).  
Preparation
Doses are to be administered SC with an appropriate syringe and hypodermic needle.  
Each vial is designed to be used only once, with the rest of the content kept until 
reconciled by Amgen or its designee. The site is to assess the IVR/IWR system prior to 
each dosing visit to determine the box number and volume of investigational product to 
administer to a subject.  
Supply and Return of Drug
At study initiation and as needed thereafter, investigation product (darbepoetin alfa and 
placebo) will be shipped to a responsible person (eg, a pharmacist) at the investigator’s 
institution, who will check the amount and condition of the drug and enter these data on 
the Investigational Product Accountability Record and via the electronic Proof of Receipt 
during the medication arrival call into IVR/IWR system.  Initial supply and subsequent re-
supply of darbepoetin alfa will be managed by the IVR/IWR system.  Medication 
assignment calls must be made to the IVR/IWR system in a timely manner to ensure 
proper inventory control.  At the end of the study, or as directed, all IP supplies, including 
used vials will be returned to Amgen’s designated vendor for destruction.
Investigational Product Accountability
An Investigational Product Accountability Record for the investigational products 
mandated by the protocol must be kept current and should contain:
x
the dates and quantities of investigational product received from Amgen  
x
fill lot numbers or box numbers for product received
x
subject’s identification number 
x
date and quantity of investigational product dispensed 


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x
the initials of the dispenser
x
date and quantity of drug returned to the investigator/pharmacy, if appropriate
The Return of Investigational Product for Destruction Form must be completed and 
included in the shipment of used and unused IP to Amgen or designee.  At the end of 
the study, the Final Investigational Product Reconciliation Statement must be completed 
and provided to Amgen.  These inventories must be made available for inspection by an 
authorized Amgen representative or designee and regulatory agency inspectors.  The 
investigator is responsible for the accountability of all used and unused clinical study 
supplies.


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Appendix F.  Pregnancy Notification Worksheet 
 
 
 
 


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Appendix G.  Lactation Notification Worksheet 
 


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Appendix H.  RECIST 1.1 With Modifications 
These guidelines describe a standard approach to solid tumor measurement and 
definitions for objective assessment of change in tumor size and are based on guidelines 
developed and published by Eisenhauer et al (2009). 
 
Methods 
• CT and MRI are the best currently available and reproducible methods to 
measure target lesions selected for response assessment.  Measurability of 
lesions on CT scan is based on the assumption that CT slice thickness is 5 mm 
or less.  When CT scans have a slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be the greater of either at least 10 mm or 
twice the slice thickness.  MRI is acceptable to assess disease extent if used 
throughout the study.     
• The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion throughout the trial.  
• Ultrasound (US) cannot be used to measure objective tumor response or 
progression.  For this protocol, a response of complete response, partial 
response or stable disease will be determined as assessed by cross-sectional 
imaging techniques (CT or MRI).  FDG-PET will not contribute to the assessment 
of response.  It is sometimes reasonable to incorporate the use of FDG-PET 
scanning to complement CT scanning in assessment of progression.  For the 
determination of progressive disease (PD), FDG-PET could be used to identify 
new lesions as follows:  
 
1) Negative PET at baseline, with a positive PET at follow-up is a sign of PD 
based on a new lesion 
2) No PET at baseline and a positive PET at follow-up:  If the positive PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine if 
there is truly progression occurring at that site (if so, the date of PD will be 
the date of the initial abnormal PET can).  If the positive PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing 
on the basis of the anatomic images, this is not PD. 
 
If a combined PET-CT scan is performed at the discretion of the investigator the 
CT portion of that exam should not be substituted for the dedicated CT exams 
required by this protocol for RECIST measurements unless the site can 
document that the CT performed as part of the PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast). 
 
Cytology and histology can be used to differentiate between partial response and 
complete response in rare cases (eg, after treatment to differentiate between 
residual benign lesions and residual malignant lesions in tumor types).  When 
effusions are known to be a potential adverse effect of treatment (eg, with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment can be 
considered if the measurable tumor has met criteria for response or stable 
disease in order to differentiate between response (or stable disease) and PD.  
 


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Definitions of “Measurable” and “Non-Measurable”
All measurements should be taken and recorded in metric notation, using a ruler or 
calipers.  Measurements should be recorded unidimensionally.  At baseline, tumor 
lesions/pathologic lymph nodes are categorized as measurable or non-measurable 
according to the following definitions:  
o
Measurable: Measurable lesions are defined at baseline as lesions that can 
be accurately measured in at least one dimension (longest diameter to be 
recorded) ≥10 mm by CT scan (CT scan slice thickness no greater than 5 
mm).  When CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be the greater of either at least 10 mm or 
twice the slice thickness.  Malignant lymph nodes: To be considered 
pathologically enlarged and measurable a lymph node must be ≥15 mm in 
short axis when assessed by CT scan.  
o
Non-measurable: All other lesions, including small lesions (longest diameter 
< 10 mm or pathological lymph nodes with ≥ 10 or < 15 mm short axis) and 
other truly non-measurable lesions are considered non-measurable and 
characterized as non target lesions.  Other examples of non-measurable 
lesions include some bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusion, and lymphangitic involvement of skin or lung, 
abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques.  Nodes that have a short axis < 10 mm 
are considered non-pathological and should not be recorded or followed. 
Clinical lesions will only be considered measurable when they are superficial (eg, 
skin nodules and palpable lymph nodes) and measure ≥10 mm by calipers.  For the 
case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.  Lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable. 
Special considerations:
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross sectional imaging techniques such 
as CT or MRI can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability described above.  Blastic bone 
lesions are non-measurable. 
Cystic lesions:  Lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions.  Cystic lesions thought to 
represent cystic metastases can be considered as measurable lesions, if they 
meet the definition of measurability described above.  However, if non-cystic 
lesions are present in the same patients these are preferred for selection as 
target lesions. 
Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there 
has been demonstrated progression in the lesion. 
Baseline (ie, Pre-chemotherapy) Identification of “Target” and “Non-Target” Lesions
Up to 5 target lesions (a maximum of 2 per organ) will be chosen to measure over 
the course of therapy.  Target lesions should be selected on the basis of their size 


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and their suitability for accurate repeated measurements by imaging techniques or 
clinically. 
A sum of the diameter (longest for non-nodal lesions, short axis for nodal lesions) for 
all target lesions will be calculated and reported as the baseline sum diameters. The
baseline sum diameters will be used as reference by which to characterize the 
objective tumor response.
x
All other lesions (or sites of disease) including any measurable lesions or 
pathological lymph nodes that were not chosen as target lesions, should be 
identified as non-target lesions.  Non-target lesions should be recorded and 
assessed qualitatively over the course of therapy.  These non-measurable, 
non target lesions should be followed as ‘present,’ ‘absent,’ or in rare cases, 
‘unequivocal progression.’  
x
Bone lesions: Bone scan, PET scan or plain films are not considered 
adequate imaging techniques to measure bone lesions.  If there are signs or 
symptoms suggestive of bone metastasis, a bone scan, MRI, CT, PET, 
PET/CT, or X-ray will be performed. For subjects with a positive bone scan 
or PET scan, the bone metastasis must be confirmed with another method of 
imaging (ie, X-ray, CT or MRI).  
Response Criteria
The subject’s tumor response will be assessed based on the response of the target 
lesions, the response of the non-target lesions, and the presence or absence of new 
lesions. 


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Evaluation of Target Lesions
* Complete Response (CR):
Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm. 
* Partial Response (PR):
At least a 30% decrease in the sum of the diameters* 
of the target lesions, taking as reference the baseline 
sum diameters.  
* Progressive Disease (PD):
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum of 
all target lesions recorded since the treatment started.  
The sum must also demonstrate an absolute increase 
of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progression). 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference 
the smallest sum of diameters while on study. 
Not Applicable (NA):
No target lesions were identified at baseline. 
Inevaluable (NE):
Scans were not performed, were incomplete, or were 
inevaluable due to poor scan quality at this time point 
to evaluate target lesions.
*Diameters used:
For nodal disease: shortest axis
For non-nodal disease: sum of longest diameters
Once on study, the convention will be used that if a lesion being measured decreases to 
the point that it is faintly seen and/or too small to measure a value of 5 mm will be 
assigned.  If the lesion subsequently increases in size to greater than or equal to 5 mm 
in one dimension, its true size will be recorded.  Nodal disease should always have the 
actual short axis measurement recorded even if the nodes regress to below 10 mm on 
study.  When lymph nodes are included as target lesions, the ‘sum’ of target lesions may 
not be zero even if CR criteria are met, since a normal lymph node is defined as having 
a short axis of < 10 mm.  For CR, each node must achieve a short axis < 10 mm.  For 
PR, SD and PD, the actual short axis measurement of the nodes is to be included in the 
sum of target lesions. 


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Date: 13 November 2012 
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Evaluation of Non-Target Lesions
Complete Response (CR):
Disappearance of all non-target lesions.  All lymph 
nodes must be non-pathological in size (< 10 mm short 
axis)
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s)
Progressive Disease (PD):
Not Applicable (NA):
Inevaluable (NE):
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions  
No non-target lesions identified at baseline
Scans were not performed, were incomplete or were 
inevaluable due to poor scan quality at this time point 
to
evaluate non-target lesions. 
When the patient also has measurable disease, to achieve an unequivocal progression 
there must be an overall level of substantial worsening in non-target disease such that 
even in the presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy.  When the patient has only non-
measurable disease, the increase of non-measurable disease should be comparable in 
magnitude to the increase required to declare PD for measurable disease (eg, 
equivalent to a 20% increase in sum of diameters of all measurable lesions). 
Evaluation of Best Overall Response
The overall response status is calculated at each time point for subjects as follows: 
Target lesions
Non-Target lesions
New Lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
PR
SD
NE
Non-PD or NE
Non-PD or NE   
No
No
No
PR
PR
SD
NE
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
PR      
CR
SD
NE
Any
NA
NA
NA
NA
Yes
No
No
No
No
PD
PR
CR
SD
NE


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Date: 13 November 2012 
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Time Point Response in Subjects with Non-target Disease Only
Non-target Lesions
(response)
New Lesions
(Yes or No)
Overall Response
CR
Non-CR/non-PD 
NE
Unequivocal PD
Any
No
No
No
Yes or No
Yes
CR
Non-CR/non-PD 
NE
PD 
PD
Non-CR/non-PD is preferred over ‘stable disease’ for non-target disease since SD is  
increasingly used as an endpoint of efficacy in some trials so to assign this category 
when no lesions can be measured is not advised. 
Special Notes on Response Assessment
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at the time should be
classified as “symptomatic deterioriation.”  In this case “progressive disease” cannot be 
assigned at the time as the overall objective tumor response.  Every effort should be 
made to document the objective progression even after discontinuation of treatment.
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends on this determination, the 
residual lesion may be further investigated (fine needle aspirate/biopsy) at investigator 
discretion to confirm the complete response status. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are 
met for complete response or partial response (whichever status is recorded first) until 
the first date that recurrence or PD is objectively documented, taking as reference for PD 
the smallest measurements recorded since the treatment started.
Duration of Stable Disease
SD is measured from the start of the treatment until the criteria for disease progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started. 


Product:  Darbepoetin alfa 
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Date:  13 November 2012 
Page 1 of 10 
 
Superseding Amendment 3 
Protocol Title:  A Randomized, Double-blind, Placebo-controlled Study to Evaluate 
the Long-term Safety and Efficacy of Darbepoetin Alfa Administered at 500 µg 
Once-Every-3-Weeks in Anemic Subjects With Advanced Stage Non-small Cell 
Lung Cancer Receiving Multi-cycle Chemotherapy 
 
Amgen Protocol Number Darbepoetin alfa 20070782 
 
Superseding Amendment Date: 
13 November 2012 
 
Rationale: 
This superseding amendment is necessary to comply with recent European Medicines 
Agency (EMA) guidance that revised the Serious Adverse Event (SAE) reporting 
requirements from 1 business day to 24 hours.  Additionally, in order to address findings 
from a recent Medicines and Healthcare products Regulatory Agency (MHRA) 
inspection, language describing the assessment of expectedness for expedited reporting 
of safety events was also updated.  Amgen will continue to utilize Core Safety 
Information in Appendix A of the Investigator’s Brochure (IB) to assess expectedness for 
applicable expedited reporting of safety events.   
A correction was made to the testing frequency for the TIBC iron performed by the 
central laboratory to remove the Q9W reference.  Additionally, a minor revision was 
made to move the collection and analyses for C-reactive protein (CRP) and soluble 
transferrin receptor from Screening to Day 1, since these laboratory tests are not used 
for eligibility.  Other updates to Key Sponsor Contacts, updated sample forms 
(Appendices C, F, and G), and corrections to typographical errors were also completed. 


Product:  Darbepoetin alfa 
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Date:  13 November 2012 
Page 2 of 10 
 
Specific Changes for this Superseding Amendment are outlined below: 
Section:  Header 
Replace:   
Date: 25 May 2010 
With:  
Date: 13 November 2012 
 
Section: Cover page; Key Sponsor Contact 
Replace: 
Key Sponsor Contact: 
 
Global Study Manager, Amgen Ltd. 
 
   
 
 
 
Regional Study Manager, Amgen Inc. 
One Amgen Center Drive. 
Thousand Oaks, CA 91320, USA 
 
 
 
Regional Study Manager, Amgen Ltd. 
 
   
 
With: 
Key Sponsor Contact: 
 
Global Study Manager, Amgen Inc. 
One Amgen Center Dr. 
Thousand Oaks, CA 91320, USA    
 
 
 
Regional Study Manager, Amgen Ltd. 
 
 
 
 
 
 
Section: Cover page, date 
Add: 
Superseding Amendment  3  
13 November 2012 
PPD
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Section:  Investigator Agreement 
Paragraph 1 
Replace: 
I have read the attached protocol entitled, “A Randomized, Double-blind, Placebo-
controlled Study to Evaluate the Long-term Safety and Efficacy of Darbepoetin Alfa 
Administered at 500 µg Once-Every-3-Weeks in Anemic Subjects With Advanced Stage 
Non-small Cell Lung Cancer Receiving Multi-cycle Chemotherapy”, dated  
25 May 2010, and agree to abide by all provisions set forth therein 
With: 
I have read the attached protocol entitled, “A Randomized, Double-blind, Placebo-
controlled Study to Evaluate the Long-term Safety and Efficacy of Darbepoetin Alfa 
Administered at 500 µg Once-Every-3-Weeks in Anemic Subjects With Advanced Stage 
Non-small Cell Lung Cancer Receiving Multi-cycle Chemotherapy”, dated  
13 November 2012, and agree to abide by all provisions set forth therein. 
 
Section:  5.1 Screening 
Paragraph 2, line 7 
Delete: 
Screen failed subjects may be re-screened at the investigator’s discretion (the subject 
will maintain the same subject ID number provided at the initial screening). 
 
Section:  6.1 Investigational Product Dosage, Administration, and Schedule 
Paragraph 3 
Replace: 
Investigational product should be stored, prepared and administered according to the 
instructions in the Pharmacy Guide (Appendix D). 
With: 
Investigational product should be stored, prepared and administered according to the 
instructions in the Pharmacy Guide (Appendix E). 
 
Section:  7.1.6 Imaging Studies 
Paragraph 2, line 4 
Replace: 
Tumor assessments will be performed according to the modified RECIST 1.1 criteria 
(Appendix F) and must be conducted according to protocol specified techniques. 
With: 
Tumor assessments will be performed according to the modified RECIST 1.1 criteria 
(Appendix H) and must be conducted according to protocol specified techniques. 
 


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Section:  7.1.11 Survival Status 
Line 4 
Add: 
Site staff can access publicly available records to determine survival status where 
permitted by law. 
 
Section: 7.1.12 Central Laboratory Assessments 
Analyte Table 
Replace: 
Chemistry  
CBC 
Folate and 
Vitamin B12 
Iron Studies 
Other Labs 
Total bilirubin Hemoglobin Serum folate Iron 
Darbepoetin alfa 
antibody 
Direct bilirubin Hematocrit  Vitamin B12 Ferritin 
Serum pregnancy 
Alkaline  
RBC 
 
TIBC 
Endogenous EPO 
Phosphatase MCV  
 
Tsat 
CRP (screening only) 
ALT(SGPT) 
MCH 
 
Soluble transferrin 
receptor 
(screening only) 
Reticulocyte count 
AST (SGOT) 
MCHC 
 
 
 
GGT 
RBC 
morphology 
 
 
 
LDH 
WBC 
 
 
 
BUN 
Neutrophils   
 
 
Creatinine 
Lymphocytes  
 
 
Glucose 
Monocytes  
 
 
Uric Acid 
Eosinophils   
 
 
Sodium 
Basophils 
 
 
 
Potassium 
Platelets 
 
 
 
Chloride 
 
 
 
 
Bicarbonate 
 
 
 
 
Calcium 
 
 
 
 
Phosphorus 
 
 
 
 
Total protein 
 
 
 
 
Albumin 
 
 
 
 


Product:  Darbepoetin alfa 
Protocol Number:  20070782 
Date:  13 November 2012 
Page 5 of 10 
 
With: 
Chemistry  
CBC 
Folate and 
Vitamin B12 
Iron Studies 
Other Labs 
Total bilirubin Hemoglobin Serum folate Iron 
Darbepoetin alfa 
antibody 
Direct bilirubin Hematocrit  Vitamin B12 Ferritin 
Serum pregnancy 
Alkaline  
RBC  
 
TIBC 
Endogenous EPO 
Phosphatase MCV  
 
Tsat 
CRP 
ALT(SGPT) 
MCH 
 
Soluble 
transferrin 
receptor 
Reticulocyte count 
AST (SGOT) 
MCHC 
 
 
 
GGT 
RBC 
morphology 
 
 
 
LDH 
WBC 
 
 
 
BUN 
Neutrophils  
 
 
Creatinine 
Lymphocytes  
 
 
Glucose 
Monocytes  
 
 
Uric Acid 
Eosinophils  
 
 
Sodium 
Basophils 
 
 
 
Potassium 
Platelets  
 
 
 
Chloride 
 
 
 
 
Bicarbonate 
 
 
 
 
Calcium  
 
 
 
 
Phosphorus 
 
 
 
 
Total protein 
 
 
 
 
Albumin  
 
 
 
 
 
Section:  7.2 Screening 
Bullet 11 
Replace: 
• Central laboratory tests: serum chemistries, CBC with differential (including 
hemoglobin), reticulocyte count, serum folate, vitamin B12, CRP, and iron studies 
With: 
• Central laboratory tests: serum chemistries, CBC with differential (including 
hemoglobin), reticulocyte count, serum folate, vitamin B12, and iron studies 
 
Section:  7.4 Study Day 1/Week1 
Bullet 9 
Replace: 
• Central laboratory tests: clinical chemistries and CBC with differential (including 
hemoglobin for statistical analyses) 
With: 
• Central laboratory tests: clinical chemistries and CBC with differential (including 
hemoglobin for statistical analyses), CRP, and soluble transferrin receptor 


Product:  Darbepoetin alfa 
Protocol Number:  20070782 
Date:  13 November 2012 
Page 6 of 10 
 
Section:  7.5 Treatment Period (Q3W Visits) 
Bullet 7 
Replace: 
Central laboratory tests: clinical chemistries and CBC with differential (including 
hemoglobin for statistical analyses), Tsat, ferritin, iron, and TIBC (Q9W).  Central 
laboratory tests will continue until the next Q3W study visit that occurs after the last dose 
of IP 
With: 
Central laboratory tests: clinical chemistries and CBC with differential (including 
hemoglobin for statistical analyses), Tsat, ferritin, iron, and TIBC.  Central laboratory 
tests will continue until the next Q3W study visit that occurs after the last dose of IP 
 
Section:  8.1 Removal of Subjects 
Paragraph 4, bullet 4 
Replace: 
• pregnancy (report on Pregnancy Notification Worksheet, see Appendix E) 
With: 
• pregnancy (report on Pregnancy Notification Worksheet, see Appendix F) 
 
Section:  9.2.2 Reporting Procedures for Serious Adverse Events 
Paragraph 1 
Replace:   
All SAEs occurring after signing of informed consent through 30 days after last dose of 
IP as recorded in the subject’s medical record will be reported to Amgen via a Serious 
Adverse Event Report (SAER) form.  Serious TVEs, and SAEs associated with RBC 
transfusions administered during the treatment period, that occur through the EOTP or 
30 days after the last dose of IP, whichever occurs later, also will be reported to Amgen 
via a SAER form.  These events must be faxed to Amgen within 1 working day of 
discovery or notification of the event.  During long-term follow-up period, SAEs will not 
be reported to Amgen.  
With: 
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 
informed consent through 30 days after last dose of IP as recorded in the subject’s 
medical record and are submitted to Amgen.  Serious TVEs, and SAEs associated 
with RBC transfusions administered during the treatment period, that occur through the 
EOTP or 30 days after the last dose of IP, whichever occurs later, also will be reported 
to Amgen.  During long-term follow-up period, SAEs will not be reported to Amgen, 
except for SAEs occurring after 30 days post last dose of IP AND thought to be possibly 
related to IP.  These events are to be submitted to Amgen. 
 


Product:  Darbepoetin alfa 
Protocol Number:  20070782 
Date:  13 November 2012 
Page 7 of 10 
 
Section:  9.2.2 Reporting Procedures for Serious Adverse Events 
New Paragraph 2 
Add: 
The serious adverse event must be submitted to Amgen within 24 hours following 
the Investigator’s knowledge of the event via the applicable CRF.  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 a Serious Adverse 
Event (SAE) Contingency Reporting Form within 24 hours of the Investigator’s 
knowledge of the event.  See Appendix C for a sample of the Serious Adverse 
Event Contingency Reporting Form.  If the first notification of a Serious Adverse 
Event is reported to Amgen via the Serious Adverse Event Contingency Reporting 
Form, the data must be entered into the EDC system when the system is again 
available. 
 
Section:  9.2.2 Reporting Procedures for Serious Adverse Events 
Paragraph 3 
Replace: 
All amendments or additions to any serious adverse event data must be recorded on a 
SAER form and faxed to Amgen.  The investigator may be asked to provide follow-up 
information, discharge summaries, and extracts from medical records or CRFs.  
Relevant medical records should be faxed to Amgen as soon as they become available; 
autopsy reports should be provided for deaths if available.  Information provided on the 
SAER form must be consistent with that recorded for the same event on the Adverse 
Event Summary CRF.  SAEs for screen-failed subjects will not be collected on the CRF 
and only collected on the SAER form submitted to Amgen.  If a subject is permanently 
withdrawn from the study because of a serious adverse event, this information must be 
reported via a SAER form. 
With: 
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; autopsy reports should be 
provided for deaths, if available.  Information provided about the serious adverse 
event must be consistent with that recorded on the applicable CRF (eg, Adverse 
Event Summary CRF).  If a subject is permanently withdrawn from the study because of 
a serious adverse event, this information must be submitted to Amgen. 
 
Section:  9.2.2 Reporting Procedures for Serious Adverse Events 
Paragraph 5 
Replace: 
To comply with local or regional serious adverse event reporting regulations, the 
treatment assignment of subjects who develop serious, unexpected, and related adverse 
events may be unblinded before submission to regulatory authorities by Amgen.  
Investigators will receive notification of related serious adverse event reports sent to 
regulatory authorities in accordance with local requirements.  Determination of 


Product:  Darbepoetin alfa 
Protocol Number:  20070782 
Date:  13 November 2012 
Page 8 of 10 
 
expectedness for Amgen products will be based on the contents of Appendix A and B in 
the Investigator’s Brochure for pre-approval investigational products and the regional 
prescribing information for products being studied for an approved use. 
With: 
To comply with worldwide reporting regulations for serious adverse events, the 
treatment assignment of subjects who develop serious, unexpected, and related adverse 
events may be unblinded by Amgen before submission to regulatory authorities.  
Investigators will receive notification of related serious adverse events reports 
sent to regulatory authorities in accordance with local requirements. 
 
Section:  9.2.2 Reporting Procedures for Serious Adverse Events 
Paragraph 6 
Replace: 
Amgen will report serious adverse events (SAEs) and/or suspected unexpected serious 
adverse reactions (SUSARs) as required to regulatory authorities, investigators/ 
institutions and ethics committees in compliance with all applicable regulatory 
requirements and ICH GCP guidelines.  
With: 
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and 
good clinical practice.  
 
Section:  9.2.2 Reporting Procedures for Serious Adverse Events 
Paragraph 6 
Delete: 
Serious adverse events occurring after 30 days post last dose of IP AND thought to be 
possibly related to IP will be recorded on an SAER form and faxed to Amgen within 
1 working day of discovery or notification of the event. 
 
Section:  Insert New Section 9.3 Pregnancy and Lactation Reporting 
Add: 
If a pregnancy occurs in a female subject, or female partner of a male subject, 
while the subject is taking protocol-specified product and for 1 month after end of 
IP, the pregnancy should be reported to Amgen’s global Pregnancy Surveillance 
Program using the Pregnancy Notification Worksheet (Appendix F). 
If a lactation case occurs in a female subject, while the subject is taking protocol-
specified product and for 1 month after the end of IP, the lactation case should be 
reported to Amgen’s global Lactation Surveillance Program within 7 business 
days of the site receiving notification using the Lactation Notification Worksheet 
(Appendix G). 
 


Product:  Darbepoetin alfa 
Protocol Number:  20070782 
Date:  13 November 2012 
Page 9 of 10 
 
Section:  Appendix A 
Footnote e 
Replace: 
e Central lab clinical chemistries includes creatinine, bilirubin, ALT, AST.  CRP will be performed during 
screening only. 
With: 
e Central lab clinical chemistries includes creatinine, bilirubin, ALT, AST.  CRP will be performed at Day 1 
only. 
 
Section:  Appendix A 
Line: Central lab iron studiesh 
Column: Day 1 / Wk 1 
Add: 
X 
 
Section:  Appendix A 
Footnote h 
Replace: 
h Central lab iron studies consist of serum iron, ferritin, TIBC, and Tsat%.  Soluble transferrin receptor will be 
performed during screening only.  Iron, ferritin, and Tsat% will be performed Q3W and TIBC Q9W on 
study. 
With: 
h Central lab iron studies consist of serum iron, ferritin, TIBC, and Tsat%.  Only soluble transferrin receptor 
will be performed at Day 1.  Iron, ferritin, Tsat%, and TIBC will be performed Q3W. 
 
Section: Appendix C.  Serious Adverse Event Contingency Reporting Form 
Section caption updated 
Replace: 
Appendix C.  ECOG Performance Status Scale 
With: 
Appendix C.  Serious Adverse Event Contingency Reporting Form 
 
Section:  Appendix C.  Serious Adverse Event Contingency Reporting Form 
Insert new sample reporting form 
 
Section:  Appendix D.  ECOG Performance Status Scale 
Section caption updated 
Replace: 
Appendix D.  Pharmacy Guide 
With: 
Appendix D.  ECOG Performance Status Scale 


Product:  Darbepoetin alfa 
Protocol Number:  20070782 
Date:  13 November 2012 
Page 10 of 10 
 
Section:  Appendix E.  Pharmacy Guide 
Section caption updated 
Replace: 
Appendix E.  Pregnancy Notification Worksheet 
With: 
Appendix E.  Pharmacy Guide 
 
Section: Appendix F.  Pregnancy Notification Worksheet 
Section caption updated 
Replace: 
Appendix F.  RECIST 1.1 With Modifications 
With: 
Appendix F.  Pregnancy Notification Worksheet 
 
Section:  Appendix F.  Pregnancy Notification Worksheet 
Updated worksheet 
 
Section:  Appendix G.  Lactation Notification Worksheet 
New Section and sample worksheet 
Add: 
Appendix G.  Lactation Notification Worksheet  
 
Section:  Appendix H.  RECIST 1.1 With Modifications 
New Section 
Add: 
Appendix H.  RECIST 1.1 With Modifications  
 

SAP_000.pdf: 
Product: darbepoetin alfa
Protocol Number:  20070782
Date:  14 September 2017
Page 1 of 52
CONFIDENTIAL
Statistical Analysis Plan
Protocol Title:
A Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Safety and Efficacy of 
Darbepoetin alfa Administered at 500 μg Once-
Every-3-Weeks in Anemic Subjects With Advanced 
Stage Non-small Cell Lung Cancer Receiving Multi-
cycle Chemotherapy
Short Protocol Title:
Placebo-controlled Non-inferiority Study in CIA 
NSCLC Subjects
Protocol Number:
20070782
Authors:
 (Versions 1-4), 
Sponsor:
Amgen
1 Amgen Center Drive
Thousand Oaks, CA 91301
Report Date:
Document Version
Date
V5.0
14 September 2017
1&71XPEHU
7KLV1&7QXPEHUKDVEHHQDSSOLHGWRWKHGRFXPHQW
IRUSXUSRVHVRISRVWLQJRQFOLQLFDOWULDOVJRY
PPD
PPD


Product: darbepoetin alfa
Protocol Number:  20070782
Date:  14 September 2017
Page 2 of 52
CONFIDENTIAL
Table of Contents
Table of Contents................................................................................................... 2
1.
Introduction............................................................................................................ 8
2.
Objectives, Endpoints and Hypotheses.................................................................. 9
2.1
Objectives and Endpoints........................................................................... 9
2.2
Hypotheses and/or Estimations ................................................................ 10
3.
Study Overview.................................................................................................... 11
3.1
Study Design............................................................................................ 11
3.2
Sample Size ............................................................................................. 11
4.
Covariates and Subgroups................................................................................... 13
4.1
Planned Covariates .................................................................................. 13
4.2
Subgroups................................................................................................ 13
5.
Definitions............................................................................................................ 15
6.
Analysis Sets ....................................................................................................... 19
6.1
Primary Analysis Set ................................................................................ 19
6.1.1
Transfusion from Week 5 to EOETP Primary Analysis Set ....... 19
6.1.2
Full Analysis Set ....................................................................... 19
6.1.3
Radiographic Endpoint Primary Analysis Set............................ 19
6.1.4
Radiographic Endpoint Full Analysis Set .................................. 19
6.2
Safety Analysis Set................................................................................... 19
6.3
Per Protocol Set ....................................................................................... 20
6.4
Interim Analyses Set(s) ............................................................................ 20
7.
Planned Analyses ................................................................................................ 21
7.1
Interim Analysis and Early Stopping Guidelines........................................ 21
7.2
Primary Analysis....................................................................................... 21
8.
Data Screening and Acceptance.......................................................................... 22
8.1
General Principles .................................................................................... 22
8.2
Data Handling and Electronic Transfer of Data......................................... 22
8.3
Handling of Missing and Incomplete Data................................................. 22
8.3.1
Missing Survival Data ............................................................... 22
8.3.2
Missing Progression Data......................................................... 22
8.3.3
Missing Transfusion Data ......................................................... 22
8.3.4
Missing Hemoglobin Data......................................................... 22
8.3.5
Missing Adverse Event and Concomitant Medication Data ....... 22
8.4
Detection of Bias ...................................................................................... 23
8.5
Outliers..................................................................................................... 24
8.6
Distributional Characteristics .................................................................... 24
8.7
Validation of Statistical Analyses .............................................................. 24


Product: darbepoetin alfa
Protocol Number:  20070782
Date:  14 September 2017
Page 3 of 52
CONFIDENTIAL
9.
Statistical Methods of Analysis............................................................................. 25
9.1
General Considerations............................................................................ 25
9.2
Subject Accountability .............................................................................. 25
9.3
Important Protocol Deviations................................................................... 26
9.4
Demographic and Baseline Characteristics .............................................. 26
9.5
Efficacy Analyses ..................................................................................... 27
9.5.1
Analyses of Primary Efficacy Endpoint(s).................................. 29
9.5.2
Analyses of Secondary Efficacy Endpoint(s)............................. 29
9.5.3
Analyses of Exploratory Efficacy Endpoint(s)............................ 30
9.6
Safety Analyses........................................................................................ 30
9.6.1
Primary Safety Endpoints ......................................................... 37
9.6.2
Secondary Safety Endpoint ...................................................... 39
9.6.3
Other Safety Endpoints............................................................. 40
9.6.4
Adverse Events and Disease-related Events ............................ 40
9.6.5
Laboratory Test Results............................................................ 41
9.6.6
Vital Signs................................................................................. 42
9.6.7
Physical Measurements............................................................ 42
9.6.8
Electrocardiogram..................................................................... 42
9.6.9
Antibody Formation................................................................... 42
9.6.10
Exposure to Investigational Product.......................................... 42
9.6.11
Exposure to Other Protocol-specified Treatment....................... 43
9.6.12
Exposure to Concomitant Medication........................................ 43
10.
Changes From Protocol-specified Analyses......................................................... 45
11.
Literature Citations / References.......................................................................... 46
12.
Prioritization of Analyses...................................................................................... 47
13.
Data Not Covered by This Plan............................................................................ 48
14.
Appendices.......................................................................................................... 49
Appendix A.  Technical Detail and Supplemental Information Regarding Statistical 
Procedures and Programs........................................................................ 49
Appendix B.  Concomitant Medications................................................................ 52
List of Table
Table 9-1.   Efficacy Endpoint Summary Table ............................................................. 25
Table 9-2.  Safety Endpoint Summary Table................................................................. 30


Product: darbepoetin alfa
Protocol Number:  20070782
Date:  14 September 2017
Page 4 of 52
CONFIDENTIAL
List of Abbreviations and Definition of Terms
Abbreviation or Term
Definition/Explanation
AE
Adverse Event
ATE
Arterial thromboembolic event
Baseline Value
The baseline value is the value measured on study day 1 
before the first dose of investigational product.  If such a 
measurement is not available, the closest value measured 
within 7 days before randomization/study day 1 will be 
used as the baseline value.  For assessments not 
scheduled to be performed on study day 1, the baseline 
value is the value from the screening period measured 
closest to study day 1.  
The definition above will be used to derive “baseline” 
hemoglobin but it should be noted that the “screening” 
hemoglobin is the value taken just prior to randomization 
to determine eligibility and randomization stratum; and the 
“pre-chemotherapy” hemoglobin is the value taken just 
prior to the start of first line chemotherapy for NSCLC.  It 
should also be noted that “baseline” in terms of imaging 
studies will be defined as the imaging studies performed 
just prior to the start of first line chemotherapy for NSCLC.
CIA
Chemotherapy-induced anemia
CTCAE
Common Toxicity Criteria for Adverse Events
DMC
Data monitoring committee
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
End of the Efficacy 
Treatment Period 
End of the efficacy treatment period is defined as 21 days 
after either the last dose of IP or the last dose of 
chemotherapy, whichever is later; the EOETP will be set to 
the EOTP if the EOETP exceeds the EOTP
End of Study (EOS)
The end of study is defined for a subject as either the date 
of death or the date when the long term follow-up period 
ends (i.e., when 2700 deaths have occurred) or early 
study termination, whichever comes first.  For subjects 
lost to follow-up, this will be the date of last contact


Product: darbepoetin alfa
Protocol Number:  20070782
Date:  14 September 2017
Page 5 of 52
CONFIDENTIAL
Abbreviation or Term
Definition/Explanation
End of Treatment Period
The treatment period ends at the end of treatment period 
visit which is scheduled to occur at the next Q3W visit 
following disease progression.  Subjects who are unable to 
continue Q3W visits and Q9W imaging studies until 
progression should complete EOTP procedures no later 
than their next Q3W visit (± 6 days).  The date captured on 
the end of treatment period electronic case report form 
(eCRF) will not be used in determining time to disease 
progression; time to disease progression will be derived 
from the dates of imaging studies.
EOETP
End of the Efficacy Treatment Period
EOI
Event of Interest
EOS
End of Study
EOTP
End of Treatment Period
ESA
Erythropoiesis stimulating agent
First-line chemotherapy
Initial (first) chemotherapy given for a disease.
g/dL
Gram per deciliter
IBG
Independent Biostatistics Group.  This group provides 
statistical support to a data monitoring committee 
(DMC) but is not a voting member of the DMC.
IP
Investigational Product
IVRS
Interactive Voice Response System
Kg
Kilogram
LTFU
Long term follow-up
MedDRA
Medical Dictionary for Regulatory Activities
µg
Microgram
MOI
Medication of Interest
NSCLC
Non-small cell lung cancer
ORR
Objective (tumor) response rate
OS
Overall survival


Product: darbepoetin alfa
Protocol Number:  20070782
Date:  14 September 2017
Page 6 of 52
CONFIDENTIAL
Abbreviation or Term
Definition/Explanation
PFS
Progression-free survival
Pre-chemotherapy” 
Hemoglobin
The hemoglobin value taken just prior to the start of first-
line chemotherapy for NSCLC
Q3W
Once-every-3-weeks
Randomization Day
This is the day subjects are randomized (enrolled) into the 
study through the interactive voice response system 
(IVRS).  The randomization day may occur on the same 
day as the first dose of investigational product or it may 
occur up to 4 days before the first dose of investigational 
product.
RBC
Red blood cell
RECIST
Response evaluation criteria in solid tumors
SAE
Serious adverse event
Screening Hemoglobin
The local laboratory hemoglobin value obtained within 7 
days prior to randomization; this is used to confirm 
eligibility and randomization stratum and will be used as a 
stratification factor for overall survival, progression-free 
survival, and incidence of transfusions from weeks 5 (ie, 
day 29) to end of treatment
Study Day 1.
This is the first day of investigational product 
administration.  All laboratory assessments on study day 1 
are to be completed before study drug administration and 
will be used as baseline measurements.  The 
randomization day may occur on the same day as the first 
dose of investigational product or it may occur up to 4 days 
before the first dose of investigational product
Study Entry Hemoglobin
The hemoglobin value obtained closest to the date 
when the subject signs and dates the informed 
consent form (ICF).  This may be a central or local 
laboratory hemoglobin value.


Product: darbepoetin alfa
Protocol Number:  20070782
Date:  14 September 2017
Page 7 of 52
CONFIDENTIAL
Abbreviation or Term
Definition/Explanation
Study Termination Date
The planned study termination date will be the date when 
the 2700th death is reported in the clinical trial database or
at an early termination date, if applicable.  Once this 
death is reported or the early termination date is 
reached, sites will be instructed to enter all outstanding 
data into the clinical trial database, the database will be 
cleaned, a snapshot will be taken, the database will be 
locked, and the primary analysis will be performed.  Any 
additional deaths reported during the entry of outstanding 
data which occur on or prior to the termination date will be 
counted in the primary analysis.  
Study Week 1
The 7-day period beginning with study day 1 is considered 
study week 1.
Treatment Period
The treatment period begins on study day 1 and ends at 
the next Q3W visit following disease progression.  
Subjects who are unable to continue Q3W visits and Q9W 
imaging studies until progression should complete EOTP 
procedures no later than their next Q3W visit (± 6 days).
TVE
Thrombovascular event
VTE
Venous thromboembolic event


Product: darbepoetin alfa
Protocol Number:  20070782
Date:  14 September 2017
Page 8 of 52
CONFIDENTIAL
1.
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical analyses 
that have been outlined within the protocol for study 20070782, darbepoetin alfa dated 14 
September 2017. The scope of this plan includes the planned final analysis and will be executed by 
the Amgen Global Biostatistics department unless otherwise specified.
This SAP does not cover the planned interim analyses; these are outlined in the Data 
Monitoring Committee charter and maintained by the Independent Biostatistics Group (IBG;
PRA Health Sciences, Charlottesville, Virginia).  The SAP also does not cover the unplanned 
interim analysis performed in Q4 2016.  
The SAP was amended on 30 June 2017 to reflect a recommendation by the independent 
Data Monitoring Committee to terminate the study early and incorporates the current SAP 
Template and Tables, Figures, and Listing guidance.


Product: darbepoetin alfa
Protocol Number:  20070782
Date:  14 September 2017
Page 9 of 52
CONFIDENTIAL
2.
Objectives, Endpoints and Hypotheses
2.1
Objectives and Endpoints
Objectives
Endpoints
Primary

To demonstrate non-inferiority of 
overall survival (OS) when 
comparing subjects on darbepoetin 
alfa treated to a hemoglobin ceiling 
of 12.0 g/dL to subjects treated with 
placebo

Overall survival
Secondary

To demonstrate non-inferiority of 
progression-free survival (PFS) when 
comparing subjects on darbepoetin 
alfa treated to a hemoglobin ceiling 
of 12.0 g/dL to subjects treated with 
placebo

To demonstrate superiority in 
reducing the incidence of red blood 
cell (RBC) transfusions when 
comparing subjects on darbepoetin 
alfa treated to a hemoglobin ceiling of 
12.0 g/dL to subjects treated with 
placebo

If non-inferiority hypotheses are 
confirmed for both OS and PFS and 
the superiority hypothesis is 
confirmed for the transfusion 
endpoint, a superiority hypothesis will 
then be tested for both OS and PFS.  
Progression-free survival

Incidence of at least 1 RBC 
transfusion or hemoglobin 8.0 g/dL 
from week 5 (day 29) to end of the 
efficacy treatment period (EOETP; 
defined as 21 days after either the 
last dose of IP or the last dose of 
chemotherapy, whichever is later; the 
EOETP will be set to the EOTP if the 
EOETP exceeds the EOTP)
Overall all and progression-free 
survival
Other Endpoints

To assess other safety and 
efficacy parameters in subjects on 
darbepoetin alfa treated to a 
hemoglobin ceiling of 12.0 g/dL 
compared to subjects treated with 
placebo

Incidence of adverse events such as
thrombovascular events (TVE), 
venous thromboembolic events 
(VTE), and AEs associated with RBC 
transfusions 

Objective tumor response rate

Incidence of neutralizing antibody 
formation to darbepoetin alfa 


Product: darbepoetin alfa
Protocol Number:  20070782
Date:  14 September 2017
Page 10 of 52
CONFIDENTIAL

Incidence of at least 1 RBC
transfusion or hemoglobin 8.0 g/dL
from study day 1 to EOETP

Change in hemoglobin from 
baseline to EOETP
2.2
Hypotheses and/or Estimations
The primary hypothesis to be tested is that the OS of subjects treated with darbepoetin alfa is not
worse than the OS of subjects treated with placebo.  The hypothesis for OS will be confirmed if the 
upper confidence limit for the hazard ratio (darbepoetin alfa to placebo) is less than 1.15 using a 1-
sided significance level of 0.025.  
If the primary hypothesis is confirmed, the secondary hypothesis that PFS is not worse in subjects 
treated with darbepoetin alfa than the PFS in subjects treated with placebo will be tested.  The 
hypothesis for PFS will be confirmed if the upper confidence limit for the hazard ratio is less than 
1.15 using a 1-sided significance level of 0.025.
If both the OS and PFS hypotheses are confirmed, the hypothesis that the incidence of RBC
transfusions is less in subjects treated with darbepoetin alfa than in subjects treated with placebo 
will be tested.  This hypothesis will be confirmed if the p-value is < 0.05 from a two-sided Cochran-
Mantel-Haenszel test comparing darbepoetin alfa to placebo with respect to the incidence of at least 
1 RBC transfusion or hemoglobin 8.0 g/dL from day 29 to EOETP.
If non-inferiority hypotheses are confirmed for both OS and PFS and the superiority hypothesis is 
confirmed for the transfusion endpoint, a superiority hypothesis will then be tested for both OS and 
PFS.  These hypotheses will be confirmed by examining the p-values associated with hazard ratios 
from both OS and PFS; the Hochberg procedure will adjust for multiplicity and maintain an overall 
two-sided significance level of 0.05.


Product: darbepoetin alfa
Protocol Number:  20070782
Date:  14 September 2017
Page 11 of 52
CONFIDENTIAL
3.
Study Overview
3.1
Study Design
This is a double-blind, randomized, placebo-controlled, phase 3 study in CIA subjects receiving 
multi-cycle chemotherapy for the treatment of advanced stage NSCLC cancer.  Randomization will 
occur in a 2 to 1 ratio (darbepoetin alfa to placebo) and will be stratified by histology (squamous 
versus other), screening hemoglobin (< 10.0 g/dL versus ≥10.0 g/dL), and geographic region (see 
Section 4.1 for regions).
Subjects will receive IP Q3W during the treatment period.  IP will be discontinued within 3 weeks 
after the completion of chemotherapy, or upon the determination of disease progression, whichever 
occurs first. Study visits Q3W and imaging studies Q9W will occur during the treatment period until 
disease progression. 
An end of the treatment period visit will occur at the next Q3W visit after disease progression has 
been determined. Hemoglobin and other hematology and chemistry values collected beyond 
this period (ie, beyond 3 weeks after disease progression) will be excluded from analysis.  
Subjects will then enter long term follow-up and will be followed for survival until death, until 
approximately 2700 deaths have occurred or until early study termination.  
3.2
Sample Size
A total of 2700 deaths were planned to be observed in order to exclude a hazard ratio (darbepoetin 
alfa to placebo) of 1.15 with a 1-sided significance level of 0.025.  With 2700 deaths, the study is 
powered at just over 90% if the true hazard ratio is 1.0 (approximately 93%).  To observe 2700 
deaths, the study planned to randomize a total of 3000 subjects which assumes a 7-year 
enrollment period, a 3-year follow-up after last subject enrolled, a 1-year survival rate of 51% 
(Sandler et al, 2006), and a common exponential drop-out rate of 0.0511.
Excluding a hazard ratio of 1.15 corresponds to excluding a decrease in median survival of 
approximately 1.6 months in the darbepoetin alfa arm group compared to placebo.  The estimated 
decrease in survival has equipoise with the decreased risk of the need for RBC transfusions.  This 
estimation assumes survival time is exponentially distributed which allows for a conversion from a 
hazard ratio to medians (i.e., hazard ratio = medianplacebo/mediandarbepoetin alfa).  A median survival of 
12.3 months (Sandler et al, 2006) was assumed in the placebo arm in order to derive the difference 
in medians that corresponds to a hazard ratio of 1.15.
The study was terminated early based on a recommendation by the independent Data 
Monitoring Committee with a sample size of 2549 subjects. The study was closed to further 


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enrollment as of 8 May 2017 and the last data are anticipated to be collected as of 7 June 
2017.


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4.
Covariates and Subgroups
4.1
Planned Covariates

Stratification factors:
o
Geographic region (some regions may be combined for analysis):

Region 1: Belgium, Germany, Israel, Italy, Luxembourg, Netherlands, Spain, 
Switzerland, South Africa, UK

Region 2: Bulgaria, Czech Republic, Greece, Poland, Romania, Russia, Serbia, 
Slovenia, Ukraine 

Region 3: Argentina, Brazil, Chile, Hong Kong, South Korea, Malaysia, Mexico, 
Philippines, Taiwan

Region 4: India

Region 5: Canada, United States (reference group)

Region 6: China

Region 7: Japan (analyzed as part of Region 3)
o
Histology: Squamous vs non-squamous cell (reference group)
o
Screening hemoglobin level: <10 g/dL vs >=10 g/dL (reference group)

Potentially clinically important covariates:
o
NSCLC platinum-based chemotherapy vs. other chemotherapy (reference
group)
o
NSCLC Targeted therapy (anti-EGFr or anti-angiogenic agents or other) vs. none 
(reference group)
o
Baseline serum erythropoietin: ≤100 mU/mL vs >100 mU/mL (reference group)
o
History of VTEs: yes vs. no (reference group)
Note that the reference group will be coded a “0” in any statistical modeling including 
stratification factors and/or covariates.
4.2
Subgroups
The subgroup of subjects who were not impacted by the early study closure to may be 
analyzed as a sensitivity analysis for the primary and secondary endpoints (overall survival, 
progression-free survival and incidence of transfusion or hemoglobin ≤ 8 g/dL) as well as the 
analyses of investigational product dosing and changes in dosing.  For the analysis of 
overall survival, this would include subjects who were lost to follow-up or who died prior to 8 
June 2017.  For progression-free survival, this would include subjects who were withdrawn,
lost to follow-up or who died or had radiographic progression prior to 8 June 2017.  For 
incidence of transfusion or hemoglobin ≤ 8 g/dL, investigational product dosing and changes 
in dosing, this would include subjects who were withdrawn, lost to follow-up or completed 
chemotherapy prior to 8 June 2017.


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These subgroups and planned covariates will be re-examined and appropriately re-
categorized before the analysis. If a subgroup only contains less than 10% of the total study 
population, it will be combined with another subgroup in the analysis.


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5.
Definitions
Best Overall Response
A subject’s best overall response during the study will be categorized in the following order: 
complete response, partial response, stable disease, disease progression, not evaluable, missing 
due to clinical progression, and missing for reasons other than clinical progression.
Change in hemoglobin from baseline to EOETP
The change score is the difference between the baseline hemoglobin value and the EOETP value 
(i.e., EOETP value – baseline value).  Post-baseline hemoglobin values within 28 days after a RBC 
transfusion will not be used in the calculation of change.  The last available post-baseline 
hemoglobin, not occurring in the 28 days after a RBC transfusion, will be used to calculate change 
in the event that the EOETP value is missing or occurred in the 28 days after a RBC transfusion.  
Subjects without a post-baseline value that did not occur in the 28 days after a RBC transfusion and 
subjects missing a baseline hemoglobin will be excluded from the analysis.  Only central laboratory 
values will be used.  Because the EOETP will vary by subject, the change in hemoglobin from 
baseline will also be summarized at specific time points of week 13 and week 16.
Events of Interest (EOI):  EOIs for Aranesp are as follows:
Event of Interest
Search Strategy
Scope
Ischaemic Heart Disease, including 
MI
Ischaemic Heart Disease SMQ
Narrow
Mortality and/or Tumor 
Progression
Malignancies SMQ
Narrow
Cerebrovascular disorders
Central nervous system vascular 
disorders SMQ 
Narrow
Hypertension
Hypertension SMQ
Narrow
Cardiac failure
Cardiac failure SMQ
Narrow
Thromboembolic events, venous
Embolic and thrombotic events, 
venous
Narrow
Convulsions
Convulsions SMQ
Narrow & Broad
Severe cutaneous reactions
Severe cutaneous reactions SMQ
Narrow & Broad
Hypersensitivity
Hypersensitivity SMQ
Narrow & Broad
PRCA
Antibody-mediated Pure Red Cell 
Aplasia AMQ
Hemoglobin Threshold
A hemoglobin that increases to >12 g/dL at any time during the treatment period is considered to 
have exceeded the threshold.  This increase will be summarized both by including and excluding 
hemoglobin values that occurred in the 28-day period following an RBC transfusion.


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Medications of Interest (MOI): MOIs for Aranesp Oncology are as follows based on values as of 
Q2 2017 or later:
Antihypertensives
Antimicrobials
Antithrombotic agents
Colony stimulating factors
Epoetins
Histone deacylating inhibitors
Hypomethylating agents
Iron
Iron chelating agents
Lenalidomide
Methotrexates
Platelets
Thalidomide
Thrombopoesis stimulating factors
Non-response (to investigational product)
A non-responder is a subject who, after study day 35, received two transfusions that are ≥21 days 
apart and ≤42 days apart.
Objective tumor response rate (ORR)
The incidence of a complete or partial response at any time during the study.  Response will be 
determined by the investigator’s assessment of the scans using the version of RECIST specified in 
the protocol at the time of subject enrollment.
Overall survival (OS)
Time from randomization to date of death.  Subjects will be censored on the date of last contact (ie, 
the date the subject was last known to be alive) if they are not known to be dead.
Progression-free survival (PFS)
Time from randomization to date of radiographic disease progression or death from any cause, 
whichever event occurs first.  Subjects without either event will be censored on the date of their last 
disease assessment.  Disease progression will be based on the investigator’s assessment of scans 
using the version of RECIST specified in the protocol at the time of subject enrollment.  
Rate of rise in hemoglobin >1.5 g/dL in 21 days
The occurrence of a hemoglobin that increases by >1.5 g/dL in any 21-day period in the treatment 


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period.  This will be summarized both by keeping a 21-day window after each RBC transfusion and 
excluding a 21-day window after each RBC transfusion.
RBC transfusion or hemoglobin 8.0 g/dL from week 5 (day 29) to EOETP
Any RBC transfusion (packed RBCs or whole blood) given or a hemoglobin ≤8.0 g/dL on or after 
study day 29 until the EOETP, inclusive. 
RBC transfusion or hemoglobin 8.0 g/dL from week 1 (day 1) to EOETP
Any RBC transfusion (packed RBCs or whole blood) given or a hemoglobin ≤8.0 g/dL on or after 
study day 1 until the EOETP, inclusive. 
RBC transfusion from week 5 (Day 29) to EOETP
Any RBC transfusion (packed RBCs or whole blood) given on or after study day 29 until the EOETP, 
inclusive. 
RBC transfusion from week 1 (Day 1) to EOETP
Any RBC transfusion (packed RBCs or whole blood) given on or after study day 1 until the EOETP, 
inclusive. 
Thrombovascular event (TVE)
Thrombovascular events are adverse events that include arterial thromboembolic events (ATEs), 
venous thromboembolic events (VTEs), and unspecified/mixed thromboembolic events.  These 
events will be coded using MedDRA version 20.0 (or higher) and identified using a Standardized 
MedDRA Query (SMQ 20000081, “embolic and thrombotic events”) or more appropriate query 
available at the time of analysis.  Arterial thromboembolic event (ATEs), Venous 
thromboembolic event (VTEs) and Unspecified/mixed thromboembolic events are described 
below:

ATE
ATEs include stroke, transient ischemic attack (TIA), acute coronary syndromes (ACS), and 
other arterial thrombosis/embolism.  These events will be coded using MedDRA version 20.0 (or 
higher) and identified using the sub-SMQ 20000082 (“embolic and thrombotic events, arterial”) 
or more appropriate query available at the time of analysis.

VTE
VTEs include deep vein thrombosis (DVT), pulmonary embolism (PE), and other venous 
thrombosis excluding superficial venous thrombosis.  These events will be coded using 
MedDRA version 20.0 (or higher) and identified using the sub-SMQ 20000084 (“embolic and 
thrombotic events, venus”) or more appropriate query available at the time of analysis.  In 


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addition, VTEs will be distinguished by whether or not they were confirmed by imaging.  The 
primary analysis of VTEs will include fatal VTEs and VTEs confirmed by imaging; a sensitivity 
analysis will summarize all VTEs regardless of severity or confirmation. 

Unspecified/mixed thromboembolic event
Unspecified/mixed thromboembolic events include thromboembolic events where the vessel 
type is either unspecified or a mix of arterial and venous.  These events will be coded using 
MedDRA version 20.0 (or higher) and identified using the sub-SMQ 20000083 (“embolic and 
thrombotic events, vessel type unspecified and mixed arterial and venous”) or more appropriate 
query available at the time of analysis. 
Time to Progression (TTP)
Time from randomization to date of radiographic disease progression.  Subjects without progression 
will be censored on the date of their last disease assessment.  Disease progression will be based on 
the investigator’s assessment of scans using the version of RECIST specified in the protocol at the 
time of subject enrollment.
Treatment Group
Subjects were randomized to 1 of 2 treatment groups: darbepoetin alfa (500 µg) Q3W or placebo 
Q3W in a 2:1 allocation.
Treatment-emergent Adverse Event
A treatment-emergent adverse event is an adverse reported via the adverse event summary eCRF 
with an onset date between study day 1 and 30 days after the last dose of IP, inclusive, with one 
exception: VTEs and adverse events associated with RBC transfusions can have an onset date of 
30 days after the last dose of IP or the EOTP visit, whichever is later.


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6.
Analysis Sets
6.1
Primary Analysis Set
The primary analysis set will include all randomized and consented subjects with non-small 
cell lung cancer who receive at least one dose of investigational product. Subjects will be
analyzed according to their randomized treatment group. The analysis of overall survival, 
progression-free survival, time to progression, response-related endpoints, serious 
AEs, events of interest, VTE and all efficacy endpoints (except for the endpoint of
transfusion or hemoglobin 8.0 g/dL from day 29 to EOETP) will be performed using the
primary analysis set.
6.1.1
Transfusion from Week 5 to EOETP Primary Analysis Set
The transfusion from week 5 to EOETP primary analysis set will include all subjects in the
primary analysis set whose EOETP is ≥day 29. The analysis of the endpoint of transfusion or
hemoglobin 8.0 g/dL from day 29 to EOETP will be performed using this primary analysis
set.
6.1.2
Full Analysis Set
The full analysis set will include all randomized and consented subjects. Subjects will be analyzed
according to their randomized treatment group. A sensitivity analysis of overall survival will be
performed using the full analysis set.
6.1.3
Radiographic Endpoint Primary Analysis Set
The radiographic endpoint primary analysis set will include all randomized and consented
subjects who have not had disease progression prior to randomization and who received at 
least one dose of investigational product. Subjects will be analyzed according to their
randomized treatment group.
6.1.4
Radiographic Endpoint Full Analysis Set
The radiographic endpoint full analysis set will include all randomized and consented subjects
who have not had disease progression prior to randomization. Subjects will be analyzed
according to their randomized treatment group.  This data set will be used as a sensitivity 
analysis for progression-free survival.
6.2
Safety Analysis Set
The safety analysis set will include all randomized and consented subjects who receive at
least one dose of investigational product. Subjects will be analyzed according to their actual
treatment group.  If a subject is randomized to placebo but receives at least 1 dose of 
darbepoetin alfa, then that subject will be analyzed as a darbepoetin alfa subject.  If a subject 


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is randomized to darbepoetin alfa but only receives placebo, then that subject will be
analyzed as a placebo subject.  The safety analysis set will be used to analyze adverse 
events, VTEs, hematologies, chemistries, dosing, vital signs, and antibody data.
6.3
Per Protocol Sets
Since poor adherence to the protocol could have the potential to bias the results towards a
conclusion of non-inferiority, a sensitivity analysis will be performed on a per protocol set to
confirm results from the primary analysis set. The sensitivity analysis using this per protocol set
will be performed for overall survival and progression free survival. The per protocol set will
include subjects in the primary analysis set who meet all of the following additional criteria (also 
see Appendix A):

had metastatic (Stage IV) or advanced stage IIIB with malignant pleural effusion (prior to 
Amendment 3) NSCLC

no disease progression prior to study day 1

no history of or current cancer diagnosis other than NSCLC

had baseline pre-chemo scan prior to randomization (for PFS only)

had an ECOG performance status of 0 or 1 at screening

had a life expectancy > 6 months based on the judgment of the investigator at 
screening

did not receive erythropoiesis stimulating agents within the 28 days prior to screening

did not have a documented history of pure red cell aplasia

dosed per protocol through week 7 with the correctly assigned investigational product (this
includes receiving planned doses and dose adjustments per section 6.1.2 of the protocol)

received first-line cyclic chemotherapy for NSCLC during the treatment period

did not receive erythropoiesis stimulating agents, other than investigational product as defined in
the protocol, during the treatment period.
6.4
Interim Analyses Set(s)
The interim analyses will be conducted on subjects in primary analysis set who are in the 
clinical trial database at the time of the interim analyses. The interim analysis may include 
subjects with only partial data (eg, a subject may have only been on study through week 3).


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7.
Planned Analyses
7.1
Interim Analysis and Early Stopping Guidelines
An Independent Biostatistics Group (IBG) will perform regular safety and interim analyses for an 
independent Data Monitoring Committee (DMC).  The DMC will review all available safety data 
regularly; once every 6 months for the first 2 years and once a year thereafter.  In addition, the IBG 
will conduct 5 formal interim analyses to assess harm (ie, inferiority of darbepoetin alfa relative to 
placebo) which will occur when approximately 10%, 20%, 30%, 40% and 60% of the planned total of 
2700 deaths have been observed.  If warranted from these reviews, the DMC may request 
additional safety data, recommend modifying or stopping the treatment, or recommend suspending 
randomization.  In addition, the DMC will review enrollment status and assess changes in the 
practice of medicine to make recommendations regarding the ongoing feasibility of the trials.  
The IBG and DMC will have access to subjects’ individual treatment assignments.  To minimize the
potential introduction of bias to the conduct of the study, members of the DMC and will not have any 
direct contact with study center personnel or subjects.  The DMC will communicate major safety 
concerns and recommendations regarding study modification or termination based on the safety 
parameters to Amgen in accordance with the DMC charter.
Records of all meetings will be approved by the DMC and maintained by the IBG on behalf of the 
DMC Chair for the duration of the study.  Records of all meetings will be transferred and archived in 
the eTMF (in accordance with SOP-024846) at the conclusion of the study.  Further details are 
provided in the DMC charter.
7.2
Primary Analysis
The primary analysis will be triggered by the study termination date. The planned study termination
date will be the date when the 2700th death is reported in the clinical trial database or the study is 
otherwise stopped.  The study was terminated early based on an independent Data 
Monitoring Committee recommendation.  The study was closed to further enrollment as of 8 
May 2017.  Sites were instructed to enter all outstanding data into the clinical trial database as of 7 
June2017, the database will be cleaned, a snapshot will be taken, the database will be locked, and
the primary analysis will be performed. Any additional deaths reported during the entry of
outstanding data which occur on or prior to the termination date will be counted in the primary
analysis.  The primary analysis will also serve as the final analysis for this study.


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8.
Data Screening and Acceptance
8.1
General Principles
The objective of the data screening is to assess the quantity, quality, and statistical characteristics of 
the data relative to the requirements of the planned analyses.
8.2
Data Handling and Electronic Transfer of Data
The Amgen Global Study Operations-Data Management (GSO-DM) department will provide all data 
to be used in the planned analyses.  This study uses the RAVE database.
8.3
Handling of Missing and Incomplete Data
8.3.1
Missing Survival Data
Subjects who did not die on study and are lost to follow-up will be censored on the date last known 
to be alive.
8.3.2
Missing Progression Data
In order to minimize missing progression data, the study is designed to follow subjects until 
documented radiographic disease progression.  If radiographic disease progression is not observed, 
the primary analysis of progression-free survival and time to progression will censor subjects at 
their last on-study disease assessment date.
8.3.3
Missing Transfusion Data
Subjects who withdraw from study prior to day 29 will have missing data for the secondary endpoint, 
“RBC transfusion or hemoglobin 8.0 g/dL from week 5 (day 29) to EOETP”; these subjects will be 
excluded from the analysis of this endpoint. 
8.3.4
Missing Hemoglobin Data
For the endpoint “Change in hemoglobin from baseline to EOETP”, the last available post-baseline 
hemoglobin, not occurring in the 28 days after a RBC transfusion, will be used to calculate change 
in the event that the EOETP value is missing or occurred within 28 days after a RBC transfusion.  
Subjects without a post-baseline value that did not occur in the 28 days after a RBC transfusion and 
subjects with a missing baseline hemoglobin will be excluded from the analysis of this endpoint.  
8.3.5
Missing Adverse Event and Concomitant Medication Data
Missing data for adverse events and concomitant medication will not be imputed.  Adverse event 
and concomitant medication data will be analyzed as observed with the exception of missing dates.  
Missing or incomplete dates for adverse event or concomitant medication data will be handled 
according to the following rules in order to estimate when the event occurred/medication was taken 
and the duration:


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8.3.5.1
Imputing Partial or Missing Start Dates

If the year is unknown, then the date will not be imputed and will be assigned a missing value.

If the month is unknown, then:

If the year matches the first dose date, then impute the month and day of the first dose date.

Otherwise, assign January.

If the day is unknown, then:

If the month and year match the first dose date, then impute the day of the first dose date.

Otherwise, assign ‘01’.
8.3.5.2
Imputing Partial or Missing Stop Dates

If the year is unknown or “ongoing” is indicated, then the date will not be imputed and will be 
assigned a missing value.

If the month is unknown, then assign December.

If the day is unknown, then assign the last day of the month.
In no case will the stop date be later than the EOS date
8.4
Detection of Bias
To check for the introduction of bias, the following analyses will be performed:

Comparing the percentage of subjects between treatment groups who withdraw from the 
treatment prematurely (e.g., withdrawing before completion of chemotherapy or radiographic 
disease progression)

Calculating the rate of cross-in (subjects randomized to placebo who receive erythropoiesis 
stimulating agents at any point after randomization) in the placebo arm (if applicable)

Comparing the percentage of subjects between treatment groups who receive an RBC 
transfusion when the hemoglobin value at the time of transfusion was 8.0 g/dL (number of 
subjects transfused is the denominator)

Cross-tabulating the values of the stratification factors recorded in the IVRS versus the case 
report forms to assess the degree of misspecifications of the stratification factors at 
randomization.


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Analyses that examine the impact of these potential sources of bias will be described in the sections 
that describe the analyses for the primary and secondary endpoints; however, these tables may 
not be included in the clinical study report.
8.5
Outliers
Potential data outliers will be identified during the analysis dataset programming process and 
queried as appropriate.  Any data points that are identified as possible outliers, but are subsequently 
verified through the query process, will be treated as valid data and analyzed accordingly.
8.6
Distributional Characteristics
The statistical assumptions for each method of inferential testing or estimation will be assessed.  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 or 
alternative inferential or estimation methods.  The use of transformations or alternative analysis 
methods will be fully justified in the final study report.
8.7
Validation of Statistical Analyses
Programs will be developed and maintained, and output will be verified in accordance with current 
risk-based quality control procedures.  
Tables, figures, and listings will be produced with validated standard macro programs where 
standard macros can produce the specified outputs.  
The production environment for statistical analyses consists of Amgen-supported versions of 
statistical analysis software; for example, the SAS System version 9.4 or later or using R.


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9.
Statistical Methods of Analysis
9.1
General Considerations

Continuous variables will be summarized by the mean, standard deviation, median, and
range. The confidence interval and standard error for the mean will also be summarized
for efficacy variables that are continuous.

Categorical variables will be summarized by the number and percentage in each 
category.

Time to event variables will be summarized with hazard ratios, Kaplan-Meier curves, 
Kaplan-Meier quartiles, the number of subjects per treatment group, the number of subjects
censored, and the number & percent of subjects with events.

For stratified analyses, the value for the stratification factors will be taken from IVRS rather
than the case report forms; a cross-tabulation of the values recorded in the IVRS versus
the case report forms will be generated to assess degree of misspecifications of the
stratification factors at randomization.

To preserve the overall significance level for the study, statistical testing of the primary and
secondary endpoints will follow a hierarchical structure. First, the primary endpoint of OS
will be tested. If darbepoetin alfa is demonstrated to be non- inferior to placebo with respect
to OS, PFS will be formally tested. If darbepoetin alfa is demonstrated to be non-inferior to
placebo with respect to PFS then the incidence of RBC transfusions or a hemoglobin ≤8.0
g/dL will be formally tested. If non- inferiority is demonstrated for both OS and PFS and
superiority is demonstrated for the transfusion endpoint, superiority will then be tested for
both OS and PFS using the Hochberg procedure to adjust for multiplicity. For endpoints
that are not designated as primary or secondary, statistical testing will be considered
descriptive and no adjustments will be made for multiplicity.

Where confidence intervals are provided, these will be 2-sided at the 95% level, unless otherwise
specified
9.2
Subject Accountability
The number and percentage of subjects screened, randomized, and who received at least one dose 
of investigational product will be presented (a footnote will include the date of first subject 
randomized and the end of study date). The number and percentage of subjects who withdrew 
prematurely will be tabulated by the reason for withdrawal.  Since the study was terminated early, 


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the number of subjects who were still on-study as of the termination date (dosing terminated 
8 May 2017; data collection terminated 7 June 2017) will be tabulated by treatment group.
The number and percentage of subjects in the primary analysis set, the radiographic endpoint 
primary analysis set, the transfusion from week 5 to EOETP primary analysis set, full analysis set, 
and the safety analysis set will be presented.  The number and percentage excluded from the 
analysis sets will be tabulated by the reason for exclusion.  
A cumulative distribution plot will depict subject randomization over time; this will include a footnote 
of the number of subjects randomized but not dosed.  In addition, the number and percentage of 
subjects randomized will be tabulated by study site and by the stratification factors (ie, geographic 
region, tumor histology and screening hemoglobin value).
A cumulative distribution plot will depict subject discontinuation from the treatment period over time.  
Each reason for ending the treatment period will be depicted by a line with separate plots for each 
treatment group
9.3
Important Protocol Deviations
Important Protocol Deviations (IPDs) categories are defined by the study team before the first 
subject’s initial visit and updated during the IPD reviews throughout the study prior to database lock.  
These definitions of IPD categories, subcategory codes, and descriptions will be used during the 
course of the study.  Eligibility deviations are defined in the protocol. The final IPD list is used to 
produce the Summary of IPDs table and the List of Subjects with IPDs.
9.4
Demographic and Baseline Characteristics
The following demographic and baseline characteristics will be summarized by treatment group and 
for both treatment groups combined:

Age, age group (18-64, 65-74, 75-84, ≥85 as well as ≥65 and ≥75), sex, and race

Weight, height and body mass index (BMI)

Stratification factors (geographic region, tumor histology, screening hemoglobin). A
cross tabulation of stratification factors according to the IVRS compared to the case 
report form values will be generated.  If there are major differences between the IVRS and 
case report form stratification factors, then a sensitivity analysis of the primary and 
secondary endpoints (overall survival, progression-free survival and incidence of 
transfusion or hemoglobin ≤8 g/dL) may be done.

ECOG performance status, tumor histology, and presence of measurable disease


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
Smoking status and significant medical history including hypertension, prior VTEs, prior ATEs, 
and diabetes 

Type of therapy for NSCLC used prior to randomization (chemotherapy, targeted therapy and/or 
radiotherapy) and on study day 1 (eg, chemotherapy with or without any anti-EGFr or anti-
angiogenic agents)

Baseline hematology values for hemoglobin level (at start of chemotherapy, at 
screening/randomization and at baseline), platelet count, absolute neutrophil count, white blood 
cell count, and baseline laboratory values for serum iron, serum ferritin, transferrin saturation
(TSAT), total iron binding capacity, creatinine, total bilirubin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST) and serum erythropoietin (EPO) level.
These characteristics will be summarized for the primary analysis set.
9.5
Efficacy Analyses
The following table summarizes the planned efficacy analyses:
Table 9-1. Efficacy Endpoint Summary Table
Endpoint
Primary Summary and Analysis 
Method (Specify Analysis Set)
Sensitivity Analysis
Primary Efficacy Endpoint – n/a (primary endpoint is a safety endpoint)
Secondary Efficacy Endpoints


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Endpoint
Primary Summary and Analysis 
Method (Specify Analysis Set)
Sensitivity Analysis
Transfusion or 
Hemoglobin 8.0 g/dL 
from Week 5 (day 29) 
to EOTP– Transfusion 
from Week 5 to EOETP 
Summarize the number and 
percent of subjects who are 
transfused or have hemoglobin 
8.0 g/dL, the difference in 
percent transfused between 
treatment groups; the common 
odds ratio; and the Cochran-
Mantel-Haenszel statistic and p-
value in the primary analysis set; 
calculate odds ratio of the 
treatment effect 
Dataset: Transfusion from Week 
5 to EOETP Primary Analysis 
Set

Transfusion from Week 5 
(day 29) to EOETP
Dataset: Transfusion from 
Week 5 to EOETP 

Transfusion or Hemoglobin 
8.0 g/dL from Week 5 (day 
29) to EOETP by 
stratification factors
Dataset: Transfusion from 
Week 5 to EOETP 

Transfusion or Hemoglobin 
8.0 g/dL from Week 5 (day 
29) to EOETP adjusted for
stratification factors [logistic 
regression model(s)]
Dataset: Transfusion from 
Week 5 to EOETP

Repeat analysis for 
subjects impacted vs not 
impacted by early study 
termination
Dataset: Transfusion from 
Week 5 to EOETP 

Repeat analysis for 
targeted study day 1 for 
subjects who delayed start 
of investigational product
Dataset: Week 5 to EOETP 
using the Full Analysis Set 
(starting from targeted day 
1)
Transfusion from Week 
5 (day 29) to EOETP
when Hemoglobin is 
8.0 g/dL at the Time of 
Transfusion
Summarize the number and 
percent of subjects with a 
transfusion when the hemoglobin 
is 8.0 g/dL at the time of 
transfusion by treatment group; 
the common odds ratio; and the 
Cochran-Mantel-Haenszel 
statistic and p-value in the 
primary analysis set; calculate
odds ratio of the treatment effect
Dataset: Transfusion from Week 
5 to EOETP Primary Analysis 
Set
N/A


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Endpoint
Primary Summary and Analysis 
Method (Specify Analysis Set)
Sensitivity Analysis
Transfusion or 
Hemoglobin 8.0 g/dL 
from Week 1 (day 1) to 
EOETP 
Summarize the number and 
percent of subjects with a 
transfusion or hgb8.0 g/dL by 
treatment group by treatment 
group; the difference in percent 
transfused between treatment 
groups; the common odds ratio; 
and the Cochran-Mantel-
Haenszel statistic and p-value
Dataset: Primary Analysis Set

Transfusion from Week 1 
(day 1) to EOETP
Dataset: Primary Analysis 
Set

Transfusion from Week 1 
(day 1) to EOETP when
hemoglobin is 8.0 g/dL at 
the Time of Transfusion
Dataset: Primary Analysis 
Set
Change in Hemoglobin 
from Baseline
Summarize the change in 
hemoglobin from baseline to 
Week 13, Week 16 and EOETP 
by treatment group and provide 
t-test p-value.
Dataset: Primary Analysis set; 
use central laboratory 
hemoglobin values

Box plot of median, mean 
25th and 75th percentiles, 
minimum and maximum over 
time by randomized 
treatment group
Dataset: Primary Analysis 
set; use central laboratory 
hemoglobin values

Plot change in hemoglobin 
values from baseline over 
time by randomized 
treatment group
Dataset: Primary Analysis 
set; use central laboratory 
hemoglobin values

Repeat analysis for 
targeted study day 1 for 
subjects who delayed start 
of investigational product
Dataset: Full analysis set 
using targeted day 1 as the 
baseline use central 
laboratory hemoglobin 
values
9.5.1
Analyses of Primary Efficacy Endpoint(s)
Not applicable
9.5.2
Analyses of Secondary Efficacy Endpoint(s)
The primary analysis of the incidence of a transfusion or hemoglobin 8.0 g/dL from day 29 to
EOETP will be based on the Cochran-Mantel-Haenszel method which will test for treatment group
differences while adjusting for the stratification factors at randomization. In addition, the Mantel-


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Haenszel estimate of the common odds ratio across strata will be estimated with a 95% confidence
interval. This analysis will be performed on all subjects in the transfusion from week 5 to EOETP
primary analysis set. If non-inferiority has been declared for OS and PFS, superiority will be declared
for the transfusion endpoint if the p-value from a two-sided test of significance using the Cochran-
Mantel-Haenszel method is less than 0.05 in favor of the darbepoetin alfa group.
The following sensitivity analyses will be performed:

An analysis will be performed that removes the “hemoglobin 8.0 g/dL” from the definition
of the endpoint in order to examine the treatment effect on the incidence of transfusion only
from day 29 to EOETP.

An analysis of transfusions when “hemoglobin 8.0 g/dL”.

To assess the impact of the early termination of the study, the analysis will be
repeated for subjects who were still on-study or in long-term follow-up as of June 7
and for subjects who were not impacted by the early study termination.
9.5.3
Analyses of Exploratory Efficacy Endpoint(s)
An analysis similar to the analysis for transfusion or hemoglobin 8.0 g/dL from week 5 to EOETP 
will be done for transfusion or hemoglobin 8.0 g/dL from day 1 to EOETP (with a sensitivity 
analysis of incidence of a transfusion from day 1 to EOETP).  These will be based on the Primary 
Analysis Set.
Descriptive statistics for change in hemoglobin from baseline will be provided at weeks 13 and 16 
and graphs will be provided for hemoglobin over time (box plot) and change in hemoglobin from 
baseline over time (line plot) by treatment group.  These will all be based on the Primary Analysis 
Set.
9.6
Safety Analyses
The following table summarizes the safety endpoints in this study, including the primary endpoint, 
overall survival, and the key secondary endpoint, progression-free survival.
Table 9-1.  Safety Endpoint Summary Table
Endpoint
Primary Summary and Analysis Method 
(Specify Analysis Set if FAS is Not 
Used)
Sensitivity Analysis

Primary Safety Endpoint (primary endpoint of the study)
Overall 
Survival
Summarize the number of subjects with 
events and numbers of subjects 
censored, Kaplan-Meier quartiles, KM 
estimates of 1-year, 2-year, and 3-year 

Overall survival using: Full
Analysis Set

Overall survival using: Per-
protocol Analysis Set


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survival by treatment group.  Present 
the hazard ratio with 95% confidence 
interval
Dataset: Primary Analysis Set

KM time-to-event plots using
the Primary Analysis Set, Full
Analysis Set and Per-protocol
Analysis Set

Repeat analysis by
stratification factors
Dataset: Primary Analysis Set

Repeat analysis for subjects
impacted vs not impacted
by early study termination
Dataset: Primary Analysis Set

Repeat analysis based on
study day 1 rather than date
of randomization
Dataset: Full analysis set
using targeted day 1 as the
baseline use central laboratory
hemoglobin values
Overall 
Survival
Cox proportional hazards regression 
modelling with treatment group in the 
model, stratified by the stratification 
factors.  This will include the p-value 
testing for an interaction between
treatment group and each stratification 
factor 
Dataset: Primary Analysis Set

Cox proportional hazards
regression modelling including
treatment group only.
Dataset: Primary Analysis Set

Cox proportional hazards
regression modelling including
the stratification factors and
other clinically important
covariates
Dataset: Primary Analysis Set

Results for stratification factors
and covariates may be
provided as a forest plot.
Dataset: Primary Analysis Set
Overall 
Survival
Overall Survival with Adjustment for 
Cross-in using a Cox regression that 
estimates the hazard ratio with 
treatment group treated as a time-
dependent covariate to account for 
cross-in of erythropoietic agent use by 
placebo
Dataset: Primary Analysis Set

Secondary Safety Endpoint
Progression-
free Survival
Summarize the number of subjects with 
events and numbers of subjects 
censored, Kaplan-Meier quartiles, KM 
estimates of 1-year, 2-year, and 3-year 
survival by treatment group.  Present 
the hazard ratio with 95% confidence 
interval
Dataset: Radiographic Endpoint 
Primary Analysis Set

KM time-to-event plots using
the Radiographic Endpoint
Dataset: Radiographic
Endpoint Primary Analysis Set

Repeat analysis by
stratification factors
Dataset: Radiographic
Endpoint Primary Analysis Set


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
Repeat analysis using 
Radiographic Endpoint Full 
Analysis set

Repeat analysis using Per 
Protocol Analysis set

Repeat analysis for subjects 
impacted vs not impacted 
by early study termination
Dataset: Radiographic 
Endpoint Primary Analysis Set
Progression-
free Survival
Cox proportional hazards regression 
modelling with treatment group in the 
model, stratified by the stratification 
factors.  This will include the p-value 
testing for an interaction between 
treatment group and each stratification 
factor 
Dataset: Radiographic Endpoint 
Primary Analysis Set

Cox proportional hazards 
regression modelling including 
treatment group only.
Dataset: Radiographic 
Endpoint Primary Analysis Set 

Cox proportional hazards 
regression modelling including 
the stratification factors and 
other clinically important 
covariates
Dataset: Radiographic 
Endpoint Primary Analysis Set
Progression-
free Survival 
with 
Adjustment for 
Cross-in
Summarize the results of a Cox 
regression that estimates the hazard 
ratio with treatment group treated as a 
time-dependent covariate to account for 
cross-in of erythropoietic agent use by 
placebo
Dataset: Radiographic Endpoint 
Primary Analysis Set
Progression-
free Survival 
to account for
RECIST 
version
Summarize the results of a Cox 
regression that estimates the hazard 
ratio with treatment group treated and 
RECIST version as covariates
Dataset: Radiographic Endpoint 
Primary Analysis Set
Other Safety Endpoint
Time to 
disease 
progression
Summarize the number of subjects with 
events and numbers of subjects 
censored, Kaplan-Meier quartiles, KM 
estimates of 1-year, 2-year, and 3-year 
survival by treatment group. Present the 
hazard ratio with 95% confidence 
interval.
Dataset: Radiographic Endpoint 
Primary Analysis Set

Repeat analysis by 
stratification factors
Dataset: Radiographic 
Endpoint Primary Analysis Set

KM time-to-event plots using 
the Radiographic Endpoint
Dataset: Radiographic 
Endpoint Primary Analysis Set
Summary of 
Objective 
Tumor 
Summarize the number and percent of 
subjects with an objective tumor 
response by treatment group; the 

Repeat analysis stratified by 
RECIST version


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Response
Rate
difference in percent between treatment 
groups; the common odds ratio; and the 
Cochran-Mantel-Haenszel statistic and 
p-value
Dataset: Radiographic Endpoint 
Primary Analysis Set
Summary of 
Best Overall 
Objective 
Tumor 
Response
Summarize the number and percentage 
of subjects whose best overall response 
during the treatment period falls into 
each of the following categories: 
complete response, partial response, 
stable disease, disease progression, 
not evaluable, missing due to clinical 
progression, and missing for reasons 
other than clinical progression by 
treatment group 
Dataset: Radiographic Endpoint 
Primary Analysis set, 

Repeat analysis stratified by 
RECIST version

Stratified by non-response 
to investigation product 
category
Dataset: Safety Analysis Set
Product Dosing and Medications
Exposure to 
Investigational
Product 
Summarize the number and percent of 
subjects exposed to investigational 
product, and the dose and duration 
measures described.
Dataset: Safety Analysis Set

Subgroup of subjects 
impacted or not impacted by 
early study termination
Dose 
Changes to 
Investigational 
Product
Summarize the number and percent of 
subjects with dose reductions, dose 
withholdings, dose discontinuations, 
and switches to placebo for non-
response 
Dataset: Safety Analysis Set

Subgroup of subjects 
impacted or not impacted by 
early study termination
Summary of 
Concomitant 
Medications
Tabulation of subjects receiving 
concomitant medication by WHODRUG 
preferred term by treatment group
Dataset: Safety Analysis Set

Repeat for MOIs
Summary of 
Treatment for 
NSCLC
Summarize the type and exposure 
NSCLC treatment by treatment group 
Dataset: Safety Analysis Set

Dataset: Primary Analysis Set
Summary of 
Erythropoiesis 
Stimulating 
Agents use 
Outside of 
Investigational
Product
Summarize the amount of exposure to 
erythropoiesis stimulating agent use 
outside of investigational product by 
treatment group 
Dataset: Safety Analysis Set
Adverse Events
Overall 
Summary of  
Treatment-
emergent 
Tabulation of subjects experiencing the 
following types of summary of 
treatment-emergent adverse events:  
all, serious, those leading to withdrawal 


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Adverse 
Events
of investigational product, and fatal by 
treatment group in the primary analysis 
set.
Safety Analysis Set
Treatment-
emergent 
Adverse 
Events by 
SOC and 
Preferred 
Term
Tabulation of subjects experiencing any 
treatment-emergent adverse events by 
system organ class and preferred term 
in alphabetical order by treatment group
Dataset: Safety Analysis Set
.
Serious 
Treatment-
emergent 
Adverse 
Events by 
SOC and 
Preferred 
Term
Tabulation of subjects experiencing 
serious treatment-emergent adverse 
events by system organ class and 
preferred term in alphabetical order by 
treatment group 
Dataset: Safety Analysis Set

Dataset: Primary Analysis Set
Summary of 
Treatment-
emergent 
Adverse 
Events 
Leading to 
Withdrawal of 
Investigational 
Product by 
SOC and 
Preferred 
Term
Tabulation of subjects experiencing 
treatment-emergent adverse events 
leading to withdrawal of investigational 
product by system organ class and 
preferred term by treatment group in 
alphabetical order
Dataset: Safety Analysis Set
Summary of 
Fatal 
Treatment-
emergent 
Adverse 
Events by 
SOC and 
Preferred 
Term
Tabulation of subjects experiencing 
fatal treatment-emergent adverse 
events by system organ class and 
preferred term by treatment group in 
alphabetical order
Dataset: Safety Analysis Set
.
Treatment-
emergent 
Adverse 
Events of 
Interest by 
Category
Tabulation of subjects experiencing 
treatment-emergent adverse events of 
special interest by category (which 
include TVEs, VTEs and AEs 
associated with RBC transfusions) by 
treatment group in alphabetical order
Dataset: Safety Analysis Set

Dataset: Primary Analysis Set
Treatment-
emergent 
Serious 
Tabulation of subjects experiencing 
treatment-emergent serious adverse 
events of special interest by category

Dataset: Primary Analysis Set


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Adverse 
Events of 
Interest by 
Category
(which include TVEs, VTEs and AEs 
associated with RBC transfusions) by 
treatment group in alphabetical order 
Dataset: Safety Analysis Set
Treatment-
emergent 
Adverse 
Events of 
Interest by 
Category and 
Preferred 
Term
Tabulation of subjects experiencing 
treatment-emergent adverse events of 
special interest by category (which 
include TVEs, VTEs and AEs 
associated with RBC transfusions) and 
preferred term by treatment group in 
descending order of frequency
Dataset: Safety Analysis Set
.
Treatment-
emergent
Serious
Adverse 
Events of 
Interest by 
Category and 
Preferred 
Term
Tabulation of subjects experiencing 
treatment-emergent adverse events of 
special interest by category (which 
include TVEs, VTEs and AEs 
associated with RBC transfusions) and 
preferred term by treatment group in 
alphabetical order
Dataset: Safety Analysis Set
Treatment 
emergent 
VTEs
VTEs confirmed and not confirmed 
by imaging, including fatal and non-
fatal VTEs.  Subjects with or without 
a history of VTE will also be included
Dataset: Safety Analysis Set

Dataset: Primary Analysis 
Set
Treatment 
emergent 
Serious VTEs
Serious VTEs confirmed and not 
confirmed by imaging, including fatal 
and non-fatal VTEs.  Subjects with or 
without a history of VTE will also be 
included
Dataset: Safety Analysis Set

Dataset: Primary Analysis 
Set
Treatment-
emergent 
Adverse 
Events 
Occurring in ≥ 
5% of All 
Subjects in 
Descending 
Order of 
Frequency 
Tabulation of subjects experiencing any 
treatment-emergent adverse events by 
treatment group in descending order of 
frequency in the total column and coded 
by preferred term Dataset: Safety 
Analysis Set
Treatment-
emergent 
Serious 
Adverse 
Events 
Occurring in ≥ 
5% in 
Descending 
Tabulation of subjects experiencing any 
treatment-emergent adverse events by 
treatment group in descending order of 
frequency in the total column and coded 
by preferred term Dataset: Safety 
Analysis Set


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Order of 
Frequency 
Treatment-
emergent 
Adverse 
Events in 
Descending 
Order of 
Frequency by 
SOC, 
Preferred 
Term and 
Grade
Tabulation of subjects experiencing any 
treatment-emergent adverse events by 
treatment group in descending order of 
frequency and coded by preferred term 
and grade
Dataset: Safety Analysis Set
.
Treatment-
emergent 
Serious 
Adverse 
Events in 
Descending 
Order of 
Frequency by 
SOC, 
Preferred 
Term and 
Grade
Tabulation of subjects experiencing any 
treatment-emergent adverse events by 
treatment group in descending order of
frequency and coded by preferred term 
and grade
Dataset: Safety Analysis Set
.
Laboratory Results
Clinical 
Laboratory
Summary statistics for baseline, 
minimum on study, maximum on study, 
EOTP, and change from baseline to 
EOTP by treatment group will be
provided for:

Hemoglobin

Platelets

White blood cell count

Serum ferritin

Serum iron

Transferrin saturation level 
(TSAT)

Total iron binding capacity

Creatinine

Total bilirubin

Alanine aminotransferase 
(ALT), and 

Aspartate aminotransferase 
(AST)
Dataset: Safety Analysis Set
N/A
Note: data for all other analytes 
will be provided in an electronic 
format
Summary of 
Hemoglobin 
Summarize the number and percent of 
subjects who had hemoglobin > 12.0 


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Threshold –
Primary 
Analysis Set
g/dL at any time in the treatment period 
(both adjusting and not adjusting for 
RBC transfusions) by treatment group 
Dataset: Safety Analysis Set
Summary of 
Rapid Rate of 
Rise in 
Hemoglobin –
Primary 
Analysis Set
Summarize the number and percent of 
subjects who had a rapid rate of rise in 
hemoglobin (> 1.5 g/dL in 21 days) at 
any time in the treatment period (both 
adjusting and not adjusting for RBC 
transfusions) by treatment group 
Dataset: Safety Analysis Set
Summary of 
Non-response 
to 
Investigational 
Product –
Primary 
Analysis Set
Summarize the number and percent of 
subjects who were non-responders by 
treatment group 
Dataset: Safety Analysis Set
.
Antibody Results, Vital Signs, ECOG
Summary of 
Antibody 
Results –
Summarize antibody results for 
darbepoetin alfa by treatment group 
Dataset: Safety Analysis Set

Summarize antibody results 
for erythropoetin by treatment 
group 
Dataset: Safety Analysis Set
Summary of 
Vital Signs
Summarize weight, systolic blood 
pressure, diastolic blood pressure, 
pulse by treatment group 
Dataset: Safety Analysis Set
.
Summary of 
ECOG 
Performance 
Status
Summarize ECOG by treatment group 
Dataset: Safety Analysis Set
.
9.6.1
Primary Safety Endpoints
The primary analysis of OS will be based on the primary analysis set and will use a Cox 
regression model, stratified by the randomization factors, with treatment group as the 
only covariate. Subjects last known to be alive will be censored on date of last contact. 
Non-inferiority will be declared if the upper confidence limit for the hazard ratio 
(darbepoetin alfa to placebo) is less than 1.15 using a 1-sided significance level of
0.025.
The following sensitivity analyses will be performed as further exploratory analyses for 
the primary endpoint:


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
To provide a completely unadjusted analysis, a hazard ratio with 95% confidence 
interval will be estimated from an unstratified Cox regression with treatment group as 
the only covariate.
To support the results obtained from the primary analysis set, analyses will be 
performed using the overall survival per protocol set.

To explore the consistency of the treatment effect, Cox regression models will be
generated including the stratification variables and covariates listed in Section 4.1.  
These models will include any interaction terms with treatment group where nominal
p-values of <0.10.

In addition, a hazard ratio with 95% confidence interval will be generated from an 
unstratified Cox regression for each stratum formed from the combination of 
randomization factors (e.g., subjects from North America with squamous cell and 
who have a screening hemoglobin < 10.0 g/dL) and for each level of a given 
stratification factor (e.g., subjects from North America).

To explore the impact of cross-in (placebo subjects who begin erythropoiesis 
stimulating agents at any point after randomization), an analysis will be performed 
that models erythropoiesis stimulating agent use as a time-dependent covariate in the
stratified Cox regression. For subjects randomized to the darbepoetin alfa arm, the
time-dependent covariate will be coded “1” throughout the time course (with the 
exception of subjects randomized to darbepoetin alfa who mistakenly receive 
placebo; they will be coded “0” throughout the time course unless they begin use of 
any erythropoiesis stimulating agent). For subjects randomized to the placebo arm, 
the time-dependent covariate will initially be coded “0” and change to “1” if and when 
they begin use of any erythropoiesis stimulating agent. Because the time-dependent 
covariate is based on information post-randomization, the results of this analysis will 
be interpreted with caution.

To assess the impact of misspecifications of the stratification factors at randomization,
a hazard ratio with 95% confidence interval will be estimated from an unstratified Cox
regression with treatment group as a covariate along with covariates that represent
the stratification factors. The values of the stratification factors will be determined
from the case report forms rather than the IVRS.  This analysis will only be done if 
there is evidence that there were errors in the IVRS stratification factors.

To assess the impact of the early termination of the study, the primary analysis 
will be repeated for subjects who were still on-study or in long-term follow-up 


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as of June 7 and for subjects who were not impacted by the early study 
termination.
9.6.2
Secondary Safety Endpoint
The primary analysis of PFS will be based on the radiographic endpoint primary analysis
set and will use a Cox regression model, stratified by the randomization factors, with
treatment group as the only covariate. PFS will be measured from randomization to 
disease progression (as defined by the version of RECIST specified in the protocol at the
time of subject enrollment) or death from any cause; subjects without either event will be
censored at the last disease assessment date. If non-inferiority has been declared for
OS, non-inferiority will be declared for PFS if the upper confidence limit for the hazard
ratio is less than 1.15 using a 1-sided significance level of 0.025.
Sensitivity analyses for PFS will be done similar to those for the primary endpoint, OS, 
as further exploratory analyses for the secondary endpoint:  However, the sensitivity 
analyses will be largely limited to the Radiographic Endpoint Primary Analysis Set
(ie, few sensitivity analyses using the Per Protocol Analysis Set or any other data 
set are planned).  In addition, a sensitivity analysis may be performed that examines the
treatment effect by subgroups formed on the basis of which version of RECIST was used
to evaluate the subject. If this analysis is performed, however, the results will need to be
interpreted cautiously since the version of RECIST will be confounded with time of
enrollment (RECIST 1.0 subjects will be enrolled first, RECIST 1.1 subjects second) and
it is anticipated that less than 10% of the subjects will be evaluated with RECIST 1.0.


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9.6.3
Other Safety Endpoints
The number and percentage of subjects with a confirmed objective tumor
response rate (as defined by the version of RECIST specified in the protocol at
the time of subject enrollment) will be presented by treatment group. Subjects
without any post-baseline tumor assessments will be considered non-responders.
Subjects without measurable disease at baseline will be excluded from the
analysis. To assess treatment group differences, the Cochran-Mantel-Haenszel
method will be used which will adjust for the stratification factors at randomization.
In addition, a more detailed classification of response will be presented by
summarizing the number and percentage of subjects whose best overall response
during the study falls into each of the following categories: complete response,
partial response, stable disease, disease progression, not evaluable, missing due
to clinical progression, and missing for reasons other than clinical progression. 
Non-response will also be summarized.  These analyses will be performed for
the radiographic endpoint primary analysis set.
9.6.4
Adverse Events and Disease-related Events
The Medical Dictionary for Regulatory Activities (MedDRA) version 20.0 or later
will be used to code all adverse events to a system organ class and a preferred
term.  Treatment-emergent adverse events are events with an onset after 
the administration of the first dose of investigational product.  The subject 
incidence of adverse events will be summarized for all treatment emergent 
adverse events, serious adverse events, adverse events leading to withdrawal of 
investigational product, fatal adverse events and adverse events of interest
using the safety analysis set.  Subject incidence of all treatment-emergent 
adverse events, serious adverse events, adverse events leading to 
withdrawal of investigational product, and fatal adverse events will be 
tabulated by system organ class and preferred term in alphabetical order.  
Subject incidence of events of interest will also be summarized according to their 
categories and preferred term within category.  Special interest adverse events
include TVEs, VTEs and AEs associated with RBC transfusions. All three sub-
categories of TVEs (VTEs, ATEs, and unspecified/mixed thromboembolic events)


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will be summarized in order to present the complete decomposition of TVEs.
However, ATEs alone are not of special interest. The primary analysis of VTEs
will include fatal VTEs and VTEs confirmed by imaging; a sensitivity analysis will
summarize all VTEs regardless of severity or confirmation.
In addition, summaries of treatment emergent and serious adverse events 
occurring in at least 5% of the subjects by preferred term in any treatment 
arm will be provided in descending order of frequency in the darbepoetin alfa 
arm.  Summaries of treatment-emergent and serious adverse events will 
also be tabulated by system organ class, preferred term and grade.
All adverse event tables will be summarized by treatment group using the
safety analysis set. In addition, serious adverse events, events of interest 
and VTE data will be analyzed using the primary analysis set.
9.6.5
Laboratory Test Results
Summary statistics for baseline, minimum on study, maximum on study, EOTP, and 
change from baseline to EOTP by treatment group will be provided for:

Hemoglobin

Platelets

White blood cell count

Serum ferritin

Serum iron

Transferrin saturation level (TSAT)

Total iron binding capacity

Creatinine

Total bilirubin

Alanine aminotransferase (ALT), and 

Aspartate aminotransferase (AST).  
Summary statistics will not be generated for the other hematology or analytes reported 
by the central laboratory but the data will be captured in the electronic line listings.
In addition, summary statistics for the average of all post-baseline hemoglobin values 
will be provided by treatment group (summarized both by keeping and excluding
hemoglobin values that occurred within 28 days following a RBC transfusion).


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Date:  14 September 2017
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9.6.6
Vital Signs
Summary statistics for baseline, minimum on study, maximum on study, EOTP, and 
change from baseline to EOTP by treatment group will be limited to:

Systolic blood pressure, 

Diastolic blood pressure, and;

Pulse
No other vital signs data will be summarized but the data will be captured in the 
electronic line listings.
Eastern Cooperative Oncology Group (ECOG) performance status scores will be 
summarized for each treatment group at baseline, EOTP and change from baseline to 
EOTP.
9.6.7
Physical Measurements
Summary statistics for baseline, minimum on study, maximum on study, EOTP, and 
change from baseline to EOTP by treatment group will be provided for:

Weight
No other physical measurements will be summarized but the data will be captured 
in the electronic line listings.
9.6.8
Electrocardiogram
The electrocardiogram (ECG) measurements from this clinical study were 
performed as per standard of care for routine safety monitoring, rather than for 
purposes of assessment of potential QT interval corrected (QTc) effect.  Because 
these evaluations may not necessarily be performed under the rigorous 
conditions expected to lead to meaningful evaluation of QTc data; neither 
summaries nor statistical analyses will be provided, and these data would not be 
expected to be useful for meta-analysis with data from other trials.
9.6.9
Antibody Formation
The number and percentage of subjects with confirmed neutralizing antibody formation to
darbepoetin alfa and erythropoietin will be presented.
9.6.10
Exposure to Investigational Product
Exposure to investigational product endpoints will include dose duration in weeks 
(the study week of last dose plus 3), the number of doses, the cumulative dose 


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administered (g), the weight-adjusted cumulative dose administered (cumulative dose 
divided by the baseline weight), the average weekly dose (cumulative dose divided by 
the dose duration), the average dose administered (cumulative dose divided by the 
number of doses), the weight-adjusted average weekly dose (weight-adjusted 
cumulative dose divided by the dose duration), and the weight-adjusted average dose 
administered (weight-adjusted cumulative dose divided by the number of doses).
Change in dosing will include the number and percent of subjects who had a dose 
reduction because of a fast rate of hemoglobin rise, had a dose withheld because the 
hemoglobin threshold was surpassed, had dose discontinued because of a severe or 
life-threatening adverse event reported by the investigator to be related to investigational 
product, and subjects switched to placebo because of non-response (darbepoetin alfa 
group only). 
Descriptive statistics will be produced to describe the exposure to investigational product 
by treatment group (only the dose duration and the numbers doses will be summarized 
for the placebo group).  

To assess the impact of the early termination of the study, the analysis of 
exposure to investigational product endpoints and change in dosing will 
be repeated for subjects who were still on-study or in long-term follow-up 
as of June 7 and for subjects who were not impacted by the early study 
termination.
9.6.11
Exposure to Other Protocol-specified Treatment
Not applicable
9.6.12
Exposure to Concomitant Medication
Medications of Interest
The concomitant medications of interest will be summarized by preferred term for each 
treatment group as coded by the World Health Organization Drug (WHODRUG) 
dictionary as of Q2 2017.  The number and proportion of subjects receiving 
therapies of interest, including erythropoiesis stimulating agents other than 
investigational product (as defined in the protocol), will be summarized by 
preferred term or category for each treatment group as coded by the WHODRUG
dictionary. For erythropoiesis stimulating agents, summary statistics will be provided to 


Product: darbepoetin alfa
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Date:  14 September 2017
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describe the amount of exposure received by treatment group. See Appendix B for a 
list of selected medications and their groupings. 
Concomitant Chemotherapy
Treatment(s) for NSCLC (including chemotherapy, anti-EGF-R, anti-angiogenic agents, 
or other anti-cancer treatments) both during the treatment period and until the first
disease progression will be summarized, including the amount of exposure 
received by treatment group.


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Date:  14 September 2017
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10.
Changes From Protocol-specified Analyses
The following changes to the analysis will be done due to changes in analysis 
practices during the study duration but are not specified in the protocol:
Summarization of demographic and baseline characteristics will be limited to the 
primary analysis set; analysis of these data using the radiographic endpoint 
primary analysis set, transfusion from week 5 to EOTP primary analysis set, full 
analysis and radiographic endpoint full analysis set will not be done
Sensitivity analyses are limited to the primary and secondary safety and efficacy 
endpoints
Stratified analyses are reduced to only the primary dataset per current practice
Subset analyses were limited per current practice
Analysis of safety data (adverse events, vital signs, hematology and chemistry 
data, study drug dosing, other medications, concomitant medications of interest,
and antibodies) using a Safety Set and subjects as treated (rather than as 
randomized) replaced the analysis in the primary data set by randomized 
treatment group for consistency with the analyses for other clinical trials in the 
darbepoetin alfa program.
Analysis of adverse events is limited to current Amgen standard adverse events 
tables (eg, summaries of treatment-related adverse events and treatment-related 
serious adverse events have been excluded)
Changes from the protocol will also be documented in the Clinical Study Report.


Product: darbepoetin alfa
Protocol Number:  20070782
Date:  14 September 2017
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11.
Literature Citations / References
Sandler A, Gray, R, et al.  Paclitaxel-Carboplatin Alone or with Bevacizumab for Non-
Small Cell Lung Cancer. N Engl J Med 2006; 355:2542-50.


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12.
Prioritization of Analyses
First priority analyses (due within 2-3 business days following database lock):

Demographics, baseline characteristics, baseline disease characteristics, 
subject disposition, IPDs (to assess imbalances between treatment 
groups); cross tabulation of stratification factors in IVRS vs reported using 
case report forms

Overall Survival (primary analysis set by randomized treatment group; all 
subjects and stratified by geographic region, histology and screening 
hemoglobin) including Kaplan-Meier plot

Progression-free survival (all subjects in the primary analysis set by 
randomized treatment group) including Kaplan-Meier plot

Objective response rate (all subjects in the primary analysis set by 
randomized treatment group)

Incidence of RBC transfusions from Week 5 to EOTP or hemoglobin ≤8 
g/dL (all subjects in the primary analysis set by randomized treatment 
group)

Adverse Events (AEs; safety analysis set by actual treatment group; all 
subjects)

Serious AEs (AEs; safety analysis set by actual treatment group; all 
subjects)

Events of interest (AEs; safety analysis set by actual treatment group; all 
subjects)

AEs leading to study drug discontinuation (AEs; safety analysis set by 
actual treatment group; all subjects)

Fatal AEs (AEs; safety analysis set by actual treatment group; all subjects)

VTEs (AEs; safety analysis set by actual treatment group and primary 
analysis set by randomized treatment group; all subjects)

Line graph of mean (with 95% confidence limits) hemoglobin values over 
time (all subjects in the primary analysis set by randomized treatment 
group)

Box plot of median hemoglobin values (with 25th and 75th percentiles, 
minimum and maximum) over time (all subjects in the primary analysis set 
by randomized treatment group)


Product: darbepoetin alfa
Protocol Number:  20070782
Date:  14 September 2017
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13.
Data Not Covered by This Plan
Paraffin embedded tumor tissue blocks or unstained tumor slides collected in this study
will not be described or analyzed directly and are not included in this plan.
Details of analyses provided to the Data Monitoring Committee, including the 
planned interim analyses, are not described or analyzed directly under this plan.  
These analyses were generated by PRA Health Sciences, Charlottesville, Virginia.  
An unplanned interim analysis conducted by an independent group at Amgen in 
Q4 2016 is also not covered in this plan.


Product: darbepoetin alfa
Protocol Number:  20070782
Date:  14 September 2017
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14.
Appendices
Appendix A.  Technical Detail and Supplemental Information Regarding Statistical 
Procedures and Programs
Visit
Study 
day(s)
Window Definition
Interval 
(days)
Screening 
period
“-1”
Evaluation(s) within 21 days prior to the 
randomization date
Note: these should be on or after the date of 
consent, and should include history, vital sign, 
ECOG and other protocol specified 
measurements
21 to day -1
Randomization
-4 to 1
Randomization may occur on study day 1 or up 
to 4 day prior to study day 1.
Note: Adverse events will be reported beginning 
from the data of randomization
Note: Subjects who progressed in the screening 
period (or prior to the screening period) are not 
eligible for randomization (protocol Section 
7.1.6)
1 day
Baseline/Study 
Day 1
1
Evaluation on Study Day 1 or last evaluation 
prior to Study Day 1 (if no value is available on 
Study Day 1).  The first dose of study drug 
should be given on study day 1
Note: Baseline hemoglobin value should be a 
central laboratory value.  Note that a local 
laboratory hemoglobin value may be present in 
the database; this is used to confirm study 
eligibility and should not be used a the baseline 
hemoglobin value
1
Treatment 
Period (Q3W 
visits)
Every 21 
days (+/- 6 
days)
Dose 1: study day 1 (1-7)
Dose 2: study day 22 (15-27)
Dose 3: study day 43 (37-49)
Dose 4: study day 64 (58-70)
Dose 5: study day 85 (79-91)
Dose 6: study day 106 (100-112)
Dose 7: study day 127 (121-133)
Dose 8: study day 141 (135-147)
Dose 9: study day 162 (156-168)
Dose 10: study day 183 (177-189)
Every 21 
days(15-27
days); 
duration is 
n/d


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etc
Note: The treatment period, including study 
drug administration should last until disease 
progression
Note: Per protocol, study procedures (eg, 
ECOG, laboratory sample draws) may be 
performed up to 1 day prior to IP dosing
Imaging studies will be performed every 9 
weeks (± 7 days) or at any time symptoms 
suggestive of disease progression occur.  
Subjects who discontinue chemotherapy or IP 
should continue to be evaluated 
radiographically Q9W until disease progression.
Every 8-10 
weeks until 
progression
EOTP
The EOTP visit is the next Q3W visit (± 6 days) 
after disease progression
n/d
Long-term 
follow-up 
(LTFU)
…
LTFU begins after disease progression.  Visits 
should occur at 3-month intervals (± 2 weeks).  
and 
n/d
EOS
EOS is when a subject dies or is lost to follow-
up or withdrawal or until 22 June 2017
n/d
n/d Not determinable – since many of these are event driven, the period for an individual subject cannot be 
determined apriori
Additional description of per protocol analysis 

Exclude subjects with EN 111 or EN 101 or OT 903
This excludes: 
a) subjects that did not have NSCLC (OT 903)
b) subjects that did not have metastatic (Stage IV) or advanced stage IIIB with
malignant pleural effusion NSCLC (prior to Amendment 3) (ie, subjects that had a 
lower grade tumor)
Exclude subjects with EN 117A
This excludes subjects with disease progression prior to study day 1
Exclude subjects with EN 202
This excludes subjects with a history of or current cancer diagnosis of a cancer 
type other than NSCLC
Exclude subjects with EN 109 or EN 117 B
This excludes subject who did not have a baseline pre-chemo scan prior to 
randomization
Exclude subjects with an ECOG performance status > 1 at screening (EN 113 or EN 103)
Exclude subjects with EN 114 or EN 105


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This should exclude subjects that had a life expectancy < 6 months based on the
judgment of the investigator at screening
Exclude subjects who received any erythropoiesis stimulating agents within the 28 days
prior to screening (EN 223 or 218)
Exclude subjects with EN 210
This should exclude subjects with a documented history of pure red cell aplasia
Exclude subjects who are not dosed per protocol through week 7 (however, include 
subjects who received a planned dose adjustment per section 6.1.2 of the protocol)
Exclude subjects who did not receive first line chemotherapy with an initial start date on 
or before Study day 1 and an end date after Study day 1 
Exclude subjects who received ≥ 1 dose of an erythropoiesis stimulating agent(s) other
than investigational product as defined in the protocol [eg, epoetin alfa (Procrit, Eprex or 
Epogen), epoetin beta (Micera), epoetin zeta (Retacrit)] during the treatment period (TA 
507)
Exclude subjects who received the incorrect investigational product (ie, randomized to 
placebo and received ≥ 1 dose of darbepoetin alfa; or, randomized to darbepoetin alfa 
and received ≥ 1 dose of placebo


Product: darbepoetin alfa
Protocol Number:  20070782
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Appendix B.  Concomitant Medications
The following are the Concomitant Medications of Interest for this study:

Antihypertensives

Antimicrobials

Antithrombotic agents

Colony stimulating factors

Epoetins

Histone deacylating inhibitors

Hypomethylating agents

Iron

Iron chelating agents

Lenalidomide

Methotrexates

Platelets

Thalidomide

Thrombopoesis stimulating factors
Source: aranesp_oncology_moi.sas7bdat in: \\filesrv09\gsb\moi\statdata\products\2016Q4