Strategies Using Darbepoetin Alfa to Avoid Transfusions in Chronic Kidney Disease
Phase: PHASE3
Conditions: Anemia in Chronic Kidney Disease Patients Not on Dialysis
Sponsor: Amgen

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Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 2 of 67 
 
Investigator’s Agreement 
I have read the attached protocol entitled START-CKD:  Strategies Using 
Darbepoetin alfa to Avoid Transfusions in Chronic Kidney Disease, dated 
16 December 2013 and agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice. 
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my subinvestigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
 
 
Signature 
 
 
Name of Principal Investigator 
 
Date (DD Month YYYY) 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 3 of 67 
 
The START-CKD study is designed to describe the benefits and potential risks of a new 
treatment strategy using a fixed dose of darbepoetin alfa in subjects with chronic kidney disease 
and not on dialysis (ND-CKD).  Subjects will be randomly allocated to treatment with a fixed dose 
of darbepoetin alfa or to treatment with darbepoetin alfa using a hemoglobin (Hb)-based titration 
strategy, which has been the conventional dosing strategy.  This study aims to estimate the 
incidence of red blood cell (RBC) transfusions (administered as deemed clinically necessary) in 
each group and the difference in incidence of RBC transfusions between the 2 groups.  In 
addition, multiple aspects, such as cumulative darbepoetin alfa dose, total number of units of 
transfusions, Hb concentration, Hb-related parameters (eg, Hb variability, excursions, rate of 
change), and adverse (eg, cardiovascular) events, will also be considered in order to determine a 
preferred dosing regimen. 
Protocol Synopsis 
Title:  START-CKD: Strategies Using Darbepoetin alfa to Avoid Transfusions in Chronic Kidney 
Disease 
Study Phase:  3 
Indication:  Management of anemia in chronic kidney disease patients not on dialysis. 
Primary Objective:  To evaluate the incidence of RBC transfusions in ND-CKD subjects using 
either a Hb-based titration algorithm or a weight-based dose that will not be titrated (fixed dose), 
and to evaluate the difference in the incidence of RBC transfusions between the 2 groups.   
Secondary Objective(s) 
To summarize the following for each dosing strategy: 
• 
Transfusion burden  
• 
Time to first RBC transfusion 
• 
Achieved Hb concentration  
• 
Cumulative dose of darbepoetin alfa 
To describe the difference in each of the above between the two dosing strategies. 
Safety Objective: To describe the safety profile of darbepoetin alfa, including adverse events 
and the occurrence of adjudicated clinical events of interest. 
Exploratory Objective(s) 
To describe with each dosing strategy: 
• 
Dose and Hb-related parameters  
• 
Initial Hb response and resulting dose and achieved Hb 
• 
Duration of hospitalization 
• 
Allosensitization over time 
Hypotheses:  The incidence of RBC transfusions in each treatment group (Hb-based titration 
group and fixed dose group) and their difference will be estimated, and no formal hypothesis will 
be tested.  The width of the 95% confidence interval (CI) of the transfusion incidence rate is 
expected to be < 10% (ie, ± 5% around the point estimate) in each group and the width of the 
95% CI of the difference in transfusion incidence rates is expected to be < 14% (ie, ± 7% around 
the point estimate).  The efficacy and safety of each treatment group will be described, as these 
aspects will assist in the determination of a preferred dosing regimen. 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 4 of 67 
 
Primary Endpoint:  Receipt of 1 or more RBC transfusion 
Secondary Endpoint(s)   
• 
Total number of units of RBC transfused 
• 
Time to first RBC transfusion 
• 
Average achieved Hb concentration while receiving investigational product 
• 
Cumulative dose of darbepoetin alfa 
Safety Endpoint(s) 
• 
Time to major clinical events: 
− 
Composite of all-cause mortality and the occurrence of major cardiovascular events 
(stroke, myocardial infarction, and decompensated heart failure) 
− 
Composite of all-cause mortality, stroke or myocardial infarction, ie, major adverse 
cardiovascular events (MACE) 
− 
All-cause mortality 
− 
Cardiovascular mortality 
− 
Stroke 
− 
Myocardial infarction 
− 
Decompensated heart failure 
− 
Thromboembolic events 
− 
Vascular access thrombosis 
• 
Adverse events 
• 
Blood pressure and pulse 
• 
Anti-erythropoietic protein antibodies 
Exploratory Endpoint(s) 
• 
Darbepoetin alfa dose received at each study visit 
• 
Hb concentration at each study visit 
• 
Hb concentration change from baseline at each study visit 
• 
Time to first Hb concentration ≥ 10.0 g/dL 
• 
Proportion of Hb measurements ≥ 10.0 g/dL 
• 
Hb rate of change in a 4 week interval at each study visit 
• 
Hb variability, defined as the intrasubject standard deviation over a 6 month rolling window 
• 
Initial Hb response, defined as the change of Hb concentration from baseline at week 5 
• 
Darbepoetin alfa dose over time by initial Hb response 
• 
Hb over time by initial Hb response 
• 
Number of days hospitalized 
• 
Anti-human leukocyte antigen (HLA) antibodies 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 5 of 67 
 
Study Design:  This is a phase 3, multicenter, randomized, double-blind, parallel group study.  
Anemic, ND-CKD subjects, without recent ESA use, will be randomized to 1 of 2 dosing 
strategies.  In the Hb-based titration group, darbepoetin alfa doses will be titrated to maintain 
Hb ≥ 10.0 g/dL.  In the other group, subjects will receive a fixed dose of darbepoetin alfa.  All 
subjects will receive investigational product (IP) as a subcutaneous injection every 4 weeks 
(Q4W).  Treatment group, darbepoetin alfa doses, and protocol specified Hb concentrations will 
be blinded to the investigator, subjects and study team.  Subjects will be followed for 
approximately 2 years from the date of randomization.  
Sample Size:  A total of approximately 750 subjects (approximately 375 per treatment group) will 
be randomized. 
Summary of Subject Eligibility Criteria   
Anemic ND-CKD subjects: 
• 
Age 18 or older 
• 
Two Hb concentrations < 10.0 g/dL at least 2 weeks apart  
• 
Not currently receiving dialysis with an estimated glomerular filtration rate of 
< 45.0 mL/min/1.73m2 during screening 
• 
Iron replete, defined as a transferrin saturation (TSAT) ≥ 20% and a ferritin ≥ 100 ng/mL  
• 
Clinically stable by the investigator  
Who have not: 
• 
Received erythropoiesis stimulating agents (ESAs) within 4 weeks of screening 
• 
Received  an RBC transfusion within 8 weeks of screening  
• 
Received intravenous iron or had changes to oral iron therapy within 4 weeks of screening  
For a full list of eligibility criteria, please refer to Section 4. 
Amgen Investigational Product Dosage and Administration 
Investigational product (darbepoetin alfa or placebo) will be administered subcutaneously every 
4 weeks.  Darbepoetin alfa will be supplied as a clear, colorless, sterile protein solution in single 
use prefilled syringes (PFS) at concentrations of 10, 20, 30, 40, 50, 60, 80, 100, 150, 200 and 
300 µg.  Placebo will be provided in similar PFS as a clear, colorless, sterile solution. 
The protocol specified doses (PSD) for use in this study are 10, 20, 30, 40, 50, 60, 80, 100, 120, 
150, 200, 250, and 300 µg.   
Every 4 weeks a protocol specified Hb will be measured using an modified Hb point of care 
(POC) device and the results will be blinded.  The codes provided by the modified Hb POC 
device and the mean systolic blood pressure (SBP) will be entered into the interactive voice 
response/interactive web response (IVR/IWR) system at each dosing visit. The mean SBP 
obtained from additional blood pressure monitoring visits will also be entered into the IVR/IWR 
system. 
In both dosing groups, the dose of investigational product will be withheld if the subject’s mean 
SBP is ≥ 160 mmHg for three consecutive visits (including blood pressure monitoring visits).  
Investigational product will be restarted at the dosing visit when the mean SBP is ≤ 140 mmHg. 
Subjects randomized to the Hb-based titration group will receive an initial dose of 
darbepoetin alfa of 0.45 µg/kg, based on the subject’s screening weight, rounded down to the 
next lower PFS strength.  Subsequently, the dose of darbepoetin alfa will be titrated based on the 
Hb concentration at the current visit and rate of rise (ROR) as outlined in the table below.  The Hb 
ROR will be determined by the protocol specified Hb concentrations obtained from the previous 
dose to the current dose.  An IVR/IWR system will be used to determine and assign each dose. 
Subjects may be assigned 2 injections to ensure they receive the dose assigned for that visit.   

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 6 of 67 
 
Dosing Algorithm for Hb-based Titration Group 
Hb (g/dL) 
Hb ROR (g/dL/4W) 
≤ 1.0 
> 1.0 and ≤ 2.0 
> 2.0 
<10.0 
↑ to next higher PSDa  
Maintain 
↓ to next lower PSDb 
10.0-10.5 
Maintain 
↓ to next lower PSDb 
↓ to next lower PSDb 
>10.5 -11.0 
↓ to next lower PSDb 
↓ to next lower PSDb 
Placeboc 
>11.0 
Placeboc 
Placeboc 
Placeboc 
a Subjects receiving 300 µg who require a dose increase will continue to receive 300 µg 
b Subjects receiving 10 µg who require a dose reduction will receive placebo 
c Restart darbepoetin alfa when Hb < 10.0 g/dL, at next lower PSD 
Subjects randomized to the fixed dose group will receive a fixed dose of darbepoetin alfa 
throughout the study of 0.45 µg/kg, based on the subject’s screening weight, rounded down to the 
next lower PFS strength.  The same dose of darbepoetin alfa will then be administered Q4W for 
the duration of the study, with 1 exception: if the Hb is > 12.0 g/dL, the darbepoetin alfa dose will 
be withheld and placebo will be administered until the Hb falls below 10.0 g/dL, at which time the 
darbepoetin alfa dose will be restarted.  In order to maintain the blind when a subject in the 
Hb-based titration group is assigned 2 injections of investigational product, subjects in the fixed 
dose group will be assigned at random to receive 2 injections of investigational product.  
Throughout the study, investigators should provide adequate supportive care.  It is recommended 
that iron be administered to ensure TSAT levels of ≥ 20% and serum ferritin ≥ 100 ng/mL and 
blood pressure be monitored and managed as appropriate, such as to target a SBP < 130 mmHg 
and a diastolic blood pressure (DBP) < 80 mmHg.  Subjects should not receive any other ESAs 
while receiving investigational product during the study. 
Procedures   
Informed consent will be obtained prior to the execution of any study procedures.  Subject visits 
and assessments will occur from the time of screening through the end of study.  At the 
conclusion of the screening period, eligible subjects will be randomized in a 1:1 ratio to 1 of 
2 dosing strategies: 
• 
Hb-based titration group:  Darbepoetin alfa titrated to maintain Hb ≥ 10.0 g/dL  
• 
Fixed dose group:  Weight-based dose of darbepoetin alfa that will not be titrated 
Randomization will be stratified by RBC transfusion received within 12 months prior to 
randomization (yes/no) and site practice setting (nephrology/non-nephrology).  
Assessments during the study visits may include: 
• 
Recording of transfusions, adverse events, concomitant medications, hospitalizations and 
collection of study endpoint data for adjudication 
• 
Physical assessments (eg, blood pressure) 
• 
Collection of laboratory samples for evaluation of blood chemistry, hematology and iron 
status 
• 
Collection of blood samples for biomarkers 
Subjects ending investigational product prior to week 97 will be asked to complete 
scheduled visits and study procedures.  At a minimum, subjects must be followed for 
the collection of RBC transfusions and endpoint data for adjudication.  
 
RBC transfusions should be performed as deemed necessary by the treating physician and 
criteria are not stipulated by this study protocol.  Information regarding the context surrounding 
RBC transfusions will be collected throughout the study including units of RBCs transfused, the 
transfusion setting (eg, dialysis center, intensive care unit, emergency department) and clinical 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 7 of 67 
 
events (eg, bleeding, surgery).  This information will be reviewed by an independent Clinical 
Endpoint Committee (CEC). 
Events of death, myocardial infarction, stroke, decompensated heart failure and 
thromboembolism, including vascular access thrombosis, will also be collected from 
randomization through the end of the study and adjudicated in a blinded fashion by the 
independent CEC.  
Adverse events (AEs) will be collected from the time of randomization through 4 weeks following 
the last dose of investigational product.  Serious adverse events will be collected from the date of 
consent.  Any serious adverse events with a fatal outcome (regardless of possible relationship to 
investigational product) occurring through the end of the subject’s participation on the study are to 
be reported to Amgen.   
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and Appendix A. 
Statistical Considerations  
Subjects who receive at least 1 dose of investigational product will be included in the primary 
analysis.  The evaluation period will begin at the date of randomization and subjects will be 
censored at the last administration of investigational product plus 3 months or end of study, 
whichever is earlier (on-treatment approach).  
For the primary endpoint, the proportion of subjects in each treatment group receiving at least 
1 RBC transfusion during the evaluation period will be presented with 2-sided 95% CIs.  The 
difference in proportions between treatment groups and the relative risk ratio will be described 
with 2-sided 95% CIs.  Confidence intervals will be derived using normal approximation.  The 
primary analysis will be repeated by subgroups of interest. 
As a sensitivity analysis, the primary analysis will be repeated using all randomized subjects with 
the evaluation period beginning at the date of randomization and subjects will be censored at the 
end of study (on-study approach).  
Sensitivity analyses will also be performed to assess the impact of potential differential follow-up 
on the primary endpoint.  Exposure-adjusted subject incidence of receiving at least 1 RBC 
transfusion will be calculated with 95% CI using Chi-square approximation to the Poisson 
distribution for both on-treatment and on-study approaches. 
For the analyses of the secondary endpoints: total number of units of RBC transfused per subject 
will be summarized for each treatment group.  Time to first RBC transfusion using both 
on-treatment and on-study approaches will be described for each treatment group.  Average 
achieved Hb concentration while receiving investigational product will be analyzed as average Hb 
using the area under the curve (AUC) method.  Cumulative doses of darbepoetin alfa adjusted for 
investigational product exposure time will also be described. 
Safety endpoints will include the descriptive summary of the time to adjudicated event endpoint 
by treatment group, using Kaplan-Meier curves, Kaplan-Meier percentiles, the number of subjects 
censored, and the number of subjects with events.  Subject incidence of adverse events will be 
tabulated by system organ class, high level group term, and preferred term by treatment group.  
Adverse events of interest will be tabulated by treatment group.  Subgroup analyses will be 
presented for all adverse events. 
An independent Data Monitoring Committee (DMC) will review unblinded study data on a regular 
basis throughout the duration of the study.  The DMC may recommend modifying or stopping the 
study, or suspending enrollment.  This recommendation can be based on any safety concerns, 
lack of efficacy/futility, or preponderance of early evidence of efficacy.  The DMC will conduct an 
interim analysis, which will occur when approximately 33% of subjects have completed 12 months 
of planned study follow-up.   
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen Inc. 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 8 of 67 
 
Study Design and Treatment Schema 
Written Informed Consent 
Hb-Based Titration 
• N = 375 
• Initiate at 0.45 µg/kg darbepoetin alfa Q4W 
• Titrate to maintain Hb ≥ 10.0 g/dL 
Fixed Dose 
• 
N = 375 
• 
0.45 µg/kg darbepoetin alfa Q4W 
• 
No titration 
Screening Period 
2-4 weeks 
Eligible subjects 
randomized in 1:1 ratio 
(N=750) 
Treatment Period 
Approximately 2 years 
End of Study Visit 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 9 of 67 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse Event 
AUC 
Area Under the Curve 
CBC 
Complete Blood Count 
CEC 
Clinical Endpoint Committee 
CHOIR 
Correction of Hemoglobin and Outcomes in Renal Insufficiency 
CI 
Confidence Interval 
CKD 
Chronic Kidney Disease   
CRP 
C-Reactive Protein 
CV 
Cardiovascular 
DBP 
Diastolic Blood Pressure 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
eGFR 
estimated Glomerular Filtration Rate 
Electronic Source Data 
(eSource)  
Source data captured initially into a permanent electronic 
record used for the reconstruction and evaluation of a trial. 
Electronic Trial Operations 
(ETO) System 
An electronic system that is used to facilitate the operations of 
a clinical trial through the collection of study related data.  Most 
common applications of an ETO system within a clinical trial 
are: subject randomization and product management.  Term 
synonymous with the industry term IVR or IVRS.  Note: An 
individual can interface with an ETO system by using either an 
IVR or IWR interface.  See definitions of IVR and IWR below.  
End of Study for individual 
subject (EOS) 
Defined as the last day that protocol specified procedures are 
conducted for an individual subject 
End of Study  
(primary completion) 
Defined as the date when the last subject is assessed or 
receives an intervention for the purposes of final collection of 
data for the primary endpoint  
Enrollment 
Defined as the date the subject is randomly assigned to a 
treatment group or "randomized" 
EPO 
Erythropoietin 
ESA 
Erythropoiesis Stimulating Agent 
ET 
Early Termination 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
Hb 
Hemoglobin 
HBV 
Hepatitis B Virus 
Page 1 of 3 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 10 of 67 
 
Abbreviation or Term 
Definition/Explanation 
HCT 
Hematocrit 
HCV 
Hepatitis C Virus 
HemoCue 
Modified hemoglobin point of care device 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HTLV 
Human T-Lymphotropic Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Interactive Voice Response 
(IVR) 
Telecommunication technology that is linked to a central 
computer in real time as an interface to collect and process 
information.  
Interactive Web Response 
(IWR) 
Web based technology that is linked to a central computer in 
real time as an interface to collect and process information.  
IP 
Investigational Product 
IRB 
Institutional Review Board 
IV 
Intravenous 
KDOQI 
The National Kidney Foundation Kidney Disease Outcomes 
Quality Initiative 
MACE 
Major Adverse Cardiovascular Events 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration  
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
MPV 
Mean Platelet Volume 
ND-CKD 
Chronic Kidney Disease Not on Dialysis  
PFS 
Prefilled Syringe 
PIN 
Personal Identification Number 
POC 
Point of Care 
PSD 
Protocol Specified Dose 
PTCA 
Percutaneous Transluminal Coronary Angioplasty 
Q4W 
Every 4 Weeks 
Randomization 
Defined as the date the IVR/IWR system is contacted to 
randomize a subject to a treatment group.  Randomization 
occurs only after the subject has successfully met all screening 
eligibility criteria. 
Page 2 of 3 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 11 of 67 
 
Abbreviation or Term 
Definition/Explanation 
RBC 
Red Blood Cell 
RDW 
Red Cell Distribution Width  
rHuEPO 
recombinant Human Erythropoietin 
ROR 
Rate of Rise 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SC 
Subcutaneous 
SD 
Standard Deviation 
SE 
Standard Error 
Source Data 
Information from an original record or certified a copy of the 
original record containing patient information for use in clinical 
research.  The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original 
records or certified copies). (ICH Guideline (E6)).  Examples of 
source data include Subject ID, Randomization ID, and 
Stratification Value. 
Study week 
7 calendar days 
TACO 
Transfusion Associated Cardiac Overload 
Target visit date 
The calculated date for study visits based on the date of 
randomization 
TIA 
Transient Ischemic Attack 
TIBC 
Total Iron Binding Capacity 
TRALI 
Transfusion-Related Acute Lung Injury 
TREAT 
Trial to Reduce Cardiovascular Events with Aranesp® Therapy  
TSAT 
Transferrin Saturation 
WBC 
White Blood Cell 
Page 3 of 3 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 12 of 67 
 
Table of Contents 
 
Page 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 8 
Study Glossary ................................................................................................................ 9 
1. 
OBJECTIVES ....................................................................................................... 16 
1.1 
Primary ..................................................................................................... 16 
1.2 
Secondary ................................................................................................. 16 
1.3 
Safety ........................................................................................................ 16 
1.4 
Exploratory ................................................................................................ 16 
2. 
BACKGROUND AND RATIONALE ...................................................................... 16 
2.1 
Disease ..................................................................................................... 16 
2.2 
Darbepoetin alfa Background .................................................................... 17 
2.3 
Rationale ................................................................................................... 18 
2.4 
Clinical Hypotheses ................................................................................... 20 
3. 
EXPERIMENTAL PLAN ........................................................................................ 20 
3.1 
Study Design ............................................................................................. 20 
3.2 
Number of Centers .................................................................................... 20 
3.3 
Number of Subjects ................................................................................... 20 
3.4 
Estimated Study Duration .......................................................................... 21 
3.4.1 
Study Duration for Participants .................................................. 21 
3.4.2 
End of Study .............................................................................. 21 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 21 
4.1 
Inclusion Criteria ....................................................................................... 21 
4.2 
Exclusion Criteria ...................................................................................... 22 
5. 
SUBJECT ENROLLMENT .................................................................................... 24 
5.1 
Screening .................................................................................................. 24 
5.2 
Randomization .......................................................................................... 25 
5.3 
Site Personnel Access to Individual Treatment Assignments .................... 25 
6. 
TREATMENT PROCEDURES .............................................................................. 26 
6.1 
Classification of Products and Medical Devices......................................... 26 
6.2 
Darbepoetin alfa ........................................................................................ 26 
6.3 
Placebo ..................................................................................................... 26 
6.4 
Dosage, Administration, and Schedule ...................................................... 26 
6.4.1 
Dosage Adjustments ................................................................. 27 
6.4.1.1 
Dosage Adjustments Based on Systolic 
Blood Pressure Values ............................................ 27 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 13 of 67 
 
6.4.1.2 
Dosage Adjustments Based on Hb 
Parameters ............................................................. 28 
6.4.1.3 
Missed Doses.......................................................... 28 
6.5 
Concomitant Therapy ................................................................................ 29 
6.6 
Medical Devices ........................................................................................ 29 
6.6.1 
Modified HemoCue Hb 201+ System Hemoglobin 
Analyzer .................................................................................... 29 
6.6.2 
Other Medical Devices Provided................................................ 29 
6.7 
Product Complaints ................................................................................... 30 
6.8 
Excluded Treatments During Study Period ................................................ 30 
7. 
STUDY PROCEDURES ....................................................................................... 30 
7.1 
General Study Procedures ........................................................................ 30 
7.1.1 
Screening Evaluations ............................................................... 31 
7.1.2 
Rescreening Evaluations ........................................................... 32 
7.1.3 
Study Day 1 Evaluations ........................................................... 32 
7.1.4 
Treatment Period Evaluations ................................................... 33 
7.1.4.1 
Routine Study Visits ................................................ 33 
7.1.4.2 
Additional Visits for Blood Pressure 
Monitoring ............................................................... 34 
7.1.5 
Evaluations After End of Investigational Product ....................... 34 
7.1.6 
Early Termination ...................................................................... 34 
7.1.7 
End of Study Evaluations .......................................................... 34 
7.2 
Description of General Study Procedures ................................................. 35 
7.2.1 
Informed Consent ...................................................................... 35 
7.2.2 
Medical and Surgical History ..................................................... 35 
7.2.3 
Physical Examination ................................................................ 35 
7.2.4 
Blood Pressure and Pulse ......................................................... 35 
7.2.5 
Hemoglobin ............................................................................... 36 
7.2.6 
RBC Transfusions ..................................................................... 36 
7.2.7 
Hospitalizations and Emergency Department Visits ................... 36 
7.2.8 
Adverse Events ......................................................................... 37 
7.2.9 
Concomitant Medications .......................................................... 37 
7.2.10 
Electrocardiogram (ECG) .......................................................... 37 
7.2.11 
Endpoint Collection for Adjudication .......................................... 37 
7.2.12 
Laboratory Assessments ........................................................... 38 
7.3 
Antibody Testing Procedures .................................................................... 38 
7.3.1 
Anti-Erythropoietic Antibodies .................................................... 38 
7.3.2 
Anti-HLA Antibodies .................................................................. 39 
7.4 
Biomarker Development ............................................................................ 39 
8. 
REMOVAL AND REPLACEMENT OF SUBJECTS ............................................... 40 
8.1 
Removal of Subjects ................................................................................. 40 
8.2 
Replacement of Subjects .......................................................................... 41 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
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9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 41 
9.1 
Adverse Events ......................................................................................... 41 
9.1.1 
Definition of Adverse Events ...................................................... 41 
9.1.2 
Reporting Procedures for Adverse Events ................................. 42 
9.2 
Serious Adverse Events ............................................................................ 43 
9.2.1 
Definition of Serious Adverse Events ......................................... 43 
9.2.2 
Reporting Procedures for Serious Adverse Events .................... 44 
9.3 
Pregnancy and Lactation Reporting .......................................................... 45 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 46 
10.1 
Study Endpoints, Subsets, and Covariates ................................................ 46 
10.1.1 
Study Endpoints ........................................................................ 46 
10.1.2 
Full Analysis Set ........................................................................ 47 
10.1.3 
Subgroups and Covariates ........................................................ 47 
10.2 
Sample Size Considerations ..................................................................... 47 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees ............................................................................................. 48 
10.4 
Interim Analysis and Early Stopping Guidelines ........................................ 48 
10.5 
Planned Methods of Analysis .................................................................... 49 
10.5.1 
General Approach/Considerations ............................................. 49 
10.5.2 
Analysis of Key Study Endpoints ............................................... 49 
10.5.2.1 
Efficacy Endpoints ................................................... 49 
10.5.2.2 
Secondary Endpoints .............................................. 50 
10.5.2.3 
Safety Endpoints ..................................................... 50 
10.5.2.4 
Exploratory Endpoints ............................................. 51 
10.5.3 
Additional Analyses ................................................................... 51 
11. 
REGULATORY OBLIGATIONS ............................................................................ 52 
11.1 
Informed Consent ...................................................................................... 52 
11.2 
Independent Ethics Committee/Institutional Review Board ........................ 53 
11.3 
Subject Confidentiality ............................................................................... 53 
11.4 
Investigator Signatory Obligations ............................................................. 54 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 54 
12.1 
Protocol Amendments and Study Termination .......................................... 54 
12.2 
Study Documentation and Archive ............................................................ 54 
12.3 
Study Monitoring and Data Collection ....................................................... 55 
12.4 
Language .................................................................................................. 56 
12.5 
Publication Policy ...................................................................................... 56 
13. 
REFERENCES ..................................................................................................... 58 
14. 
APPENDICES ...................................................................................................... 60 
 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
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List of Tables 
Table 1.  Dosing Algorithm for Hb-based Titration Group .............................................. 28 
Table 2.  Analyte Listing ................................................................................................ 38 
 
List of Appendices 
Appendix A.  Schedule of Assessments ........................................................................ 61 
Appendix B.  Additional Safety Assessment Information ................................................ 62 
Appendix C.  Sample of the Serious Adverse Event Worksheet/electronic 
Serious Adverse Event (eSAE) Contingency Report Form...................... 63 
Appendix D.  Pregnancy Notification Worksheet ............................................................ 66 
Appendix E.  Lactation Notification Worksheet .............................................................. 67 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
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1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the incidence of red blood cell (RBC) transfusions in chronic kidney disease 
subjects not on dialysis (ND-CKD) using either a hemoglobin (Hb)-based titration 
algorithm or a weight-based dose that will not be titrated (fixed dose), and to evaluate 
the difference in the incidence of RBC transfusions between the 2 groups.   
1.2 
Secondary 
To summarize the following for each dosing strategy: 
• 
Transfusion burden  
• 
Time to first RBC transfusion 
• 
Achieved Hb concentration  
• 
Cumulative dose of darbepoetin alfa 
To describe the difference in each of the above between the two dosing strategies. 
1.3 
Safety 
To describe the safety profile of darbepoetin alfa, including adverse events and the 
occurrence of adjudicated clinical events of interest. 
1.4 
Exploratory 
To describe with each dosing strategy: 
• 
Dose and Hb-related parameters  
• 
Initial Hb response and resulting dose and achieved Hb 
• 
Duration of hospitalization 
• 
Allosensitization over time 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease  
Anemia is a common and debilitating complication of chronic kidney disease (CKD).  
It results primarily from decreased production of erythropoietin by the kidney 
(Eschbach and Adamson, 1985) and becomes increasingly prevalent and severe as 
kidney function declines (Moranne et al, 2009; Astor et al, 2002; Kazmi et al, 2001).  
This renal anemia itself may be severe enough to require RBC transfusions or may 
contribute to the need for a RBC transfusion in patients who experience a clinical event 
which worsens the anemia (eg, bleeding, infection, or inflammation).   
Avoidance of RBC transfusions is desirable due to the association of transfusions with 
a number of risks as well as because of blood inventory constraints 

 
 
 
Product:  Darbepoetin alfa 
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Page 17 of 67 
 
(Goodnough and Shander, 2007).  Some risks, including transfusion-related acute lung 
injury (TRALI), transfusion associated cardiac overload (TACO), hemolytic reactions, 
and bacterial sepsis, have been associated with transfusion-related death 
(Leo and Pedal, 2010; Eder and Chambers, 2007).  Transmission of blood-borne viral 
pathogens such as human immunodeficiency virus (HIV), human T-lymphotropic virus 
(HTLV), hepatitis B (HBV) or hepatitis C (HCV) is a lesser risk of RBC transfusions due 
to contemporary screening practices, but the risk has not been completely eliminated.  
Concerns remain regarding transmission of pathogens such as West Nile virus for which 
blood products are not routinely screened (Busch et al, 2003).  The possibility for RBC 
transfusions to transmit Creutzfeldt-Jakob disease is also a concern (Busch et al, 2003).  
Chronic transfusions can also lead to iron overload and its complications 
(Despotis et al, 2007; Goldman and Vanherweghem, 1987).   
CKD patients are at higher risk for specific complications of transfusions.  These include 
volume overload and hyperkalemia (Despotis et al, 2007; Simon and Bove, 1971).  
In addition, transfusions may lead to allosensitization (Murphey and Forsthuber, 2008).  
Allosensitization can increase the time a patient spends on the kidney transplant wait-list 
or even preclude transplant eligibility (Susal et al, 2009), and has also been associated 
with shorter graft survival (Seetharam et al, 2010; Opelz, 2005) and accelerated 
atherosclerosis (Hill et al, 2011). 
2.2 
Darbepoetin alfa Background  
Erythropoiesis stimulating agents (ESAs) bind to the erythropoietin receptor and 
stimulate erythropoiesis by the same mechanism as endogenous erythropoietin (EPO).  
They have been shown to effectively elevate and maintain Hb concentrations in patients 
with renal anemia and reduce transfusion requirements. 
Darbepoetin alfa is an ESA produced in Chinese hamster ovary cells as a secreted 
glycoprotein by recombinant DNA technology.  It is a 165 amino acid protein that 
contains 5 N-linked oligosaccharide chains, rather than the 3 contained in human EPO.  
The additional carbohydrate chains increase the molecular weight and carbohydrate 
content of the glycoprotein, which gives darbepoetin alfa an approximately 3-fold longer 
serum half-life and mean residence time than recombinant human erythropoietin 
(rHuEPO) in animal models and subjects with CKD, allowing extended administration 
dosing intervals (Macdougall, 2000; Egrie et al, 1993).  Details of the chemistry, 
preclinical pharmacology, pharmacokinetics, toxicology, and clinical experience with 
darbepoetin alfa are contained in the Investigator’s Brochure.  

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 18 of 67 
 
Darbepoetin alfa is licensed and approved in the United States, Europe, Canada, 
Australia and a number of other countries for the treatment of anemia in patients with 
CKD, including patients on dialysis and patients not on dialysis, and for the treatment of 
anemia in patients with non-myeloid malignancies when anemia is due to concomitantly 
administered chemotherapy.   
2.3 
Rationale  
Since their approval, ESAs have been in wide use in CKD patients both on dialysis and 
not on dialysis to raise Hb concentrations and reduce the need for RBC transfusions.  
Because observational studies had shown an association between anemia and 
increased cardiovascular (CV) morbidity and mortality in ND-CKD patients 
(Collins, 2003; McClellan et al, 2002; Sarnak et al, 2002; Al Ahmad et al, 2001; 
Mann, 1999; Levin et al, 1999), clinical trials were conducted in this population to 
evaluate potential CV benefits of ESAs.  Contrary to the hypothesis, 2 large clinical trials 
did not demonstrate a CV benefit when anemia was treated.  The Correction of 
Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) study evaluated outcomes in 
subjects with moderate anemia treated with epoetin alfa to Hb concentrations of 
13.5 g/dL vs 11.3 g/dL (Singh et al, 2006).  The CHOIR study identified an increased risk 
for death and serious CV events in the higher Hb target arm (hazard ratio 1.34; 
95% confidence interval [CI] 1.03 to 1.74), the imbalance being mostly for death and 
hospitalization for heart failure.  The Trial to Reduce Cardiovascular Events with 
Aranesp® Therapy (TREAT) evaluated ND-CKD subjects with moderate anemia and 
type 2 diabetes who were randomized to receive either treatment with darbepoetin alfa 
to a target Hb concentration of 13 g/dL or placebo with rescue darbepoetin alfa therapy if 
Hb concentration fell < 9 g/dL (Pfeffer et al, 2009).  The TREAT study did not 
demonstrate a benefit on the primary composite CV endpoint of all cause mortality or CV 
event (hazard ratio 1.05; 95% CI 0.94 to 1.17), however, an increased risk of stroke was 
observed when compared to the placebo group (hazard ratio 1.92; 95% CI 1.38 to 2.68).  
The mechanism for the increased risk observed when targeting high Hb concentrations 
has not been determined.  It has been suggested that exposure to high doses, high 
cumulative dose of ESA, Hb excursions, and rapid Hb rises might contribute to these 
risks.  Thus, there is a desire to define a dosing regimen that can retain the transfusion 
benefits of ESA treatment while minimizing potential contributing factors listed above.  
Although in CKD patients ESAs have historically been titrated to achieve a predefined 
Hb concentration, this may not be the only possible dosing strategy.  In particular, a 

 
 
 
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Date:  16 December 2013 
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dosing strategy using a fixed dose could mitigate some of the potential contributing 
factors of increased risk while effectively avoiding RBC transfusions.  A fixed dose 
strategy will avoid exposure to high doses entirely and could decrease the cumulative 
dose exposure.  Additionally, by not increasing doses, the occurrence of Hb excursions 
and rapid Hb rises may be minimized.  A fixed dose may also reduce Hb cycling, which 
may be associated with frequent dose changes, which has been associated with worse 
outcomes in some observational studies of dialysis patients (Gilbertson et al, 2008; 
Weinhandl et al, 2011).  A consistent, fixed dosing strategy, without titration, may also 
simplify therapy for patients and providers, which may potentially improve compliance 
and minimize dosing errors. 
The ability of treatment with a fixed dose to effectively reduce the need for transfusions 
is unknown.  One prospective single arm study designed to use primarily 1 fixed dose of 
epoetin alfa has suggested that such a strategy can reduce RBC transfusions in anemic 
ND-CKD patients (Provenzano et al, 2004).  During the short 16-week study, 3.7% of 
patients were transfused compared to 11.1% of patients within 6 months prior to 
enrollment.  However, this study enabled the “fixed dose” to be increased or decreased, 
and less than half the patients were maintained on the original 10,000 unit per week 
fixed dose of epoetin alfa throughout the study.  
This START-CKD study is designed to describe the benefits and potential risks of a new 
treatment strategy using a fixed dose of darbepoetin alfa.  Anemic ND-CKD subjects, 
without recent ESA use, will be randomly allocated to treatment with a fixed dose of 
darbepoetin alfa or to treatment with darbepoetin alfa using a Hb-based titration strategy, 
which has been the conventional dosing strategy.  This study will estimate the subject 
incidence of RBC transfusions (administered as deemed clinically necessary) in each 
group and the difference in incidence of RBC transfusions between the 2 groups.  
However, determining a preferred dosing regimen will also be based on multiple 
considerations, such as cumulative darbepoetin alfa dose, total number of units of 
transfusions, Hb concentration, Hb-related parameters (eg, Hb variability, excursions, 
rate of change), and adverse (eg, CV) events.  Given these considerations, an 
estimation approach was chosen for this study. 
The dosing algorithm that will be used in the Hb-based titration group is intended to 
maintain Hb concentration ≥ 10.0 g/dL, with a starting dose of 0.45 µg/kg, to be 
administered every 4 weeks (Q4W).  Model-based simulations were used to select a 
fixed dose that would achieve approximately the same population mean 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 20 of 67 
 
Hb concentration at the end of the study.  The simulations, conducted in a similar 
fashion as previously published (Doshi et al, 2010), predicted that a darbepoetin alfa 
dose of 0.45 µg/kg/Q4W should be used.  
The starting dose is the same for both of the dosing algorithms.  Thus it will be possible 
to analyze the dose received and achieved Hb concentrations by subgroups of initial 
Hb response using the same definition of Hb response for both treatment groups. 
2.4 
Clinical Hypotheses 
The incidence of RBC transfusions in each treatment group (Hb-based titration group 
and fixed dose group) and their difference will be estimated, and no formal hypothesis 
will be tested.  The width of the 95% CI of the transfusion incidence rate is expected to 
be < 10% (ie, ± 5% around the point estimate) in each group and the width of the 
95% CI of the difference in transfusion incidence rates is expected to be 
< 14% (ie, ± 7% around the point estimate).  The efficacy and safety of each treatment 
group will be described, as these aspects will assist in the determination of a preferred 
dosing regimen. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 3, multicenter, randomized, double-blind, parallel group study.  Anemic, 
ND-CKD subjects, without recent ESA use, will be randomized to 1 of 2 dosing 
strategies.  In the Hb-based titration group, darbepoetin alfa doses will be titrated to 
maintain Hb ≥ 10.0 g/dL.  In the other group, subjects will receive a fixed dose of 
darbepoetin alfa.  All subjects will receive investigational product (IP) as a subcutaneous 
injection Q4W.  Treatment group, darbepoetin alfa doses, and protocol specified Hb 
concentrations will be blinded to the investigator, subjects and study team.  The overall 
study design is described by a study schema at the end of the protocol synopsis section. 
The study endpoints are defined in Section 10.1. 
3.2 
Number of Centers 
The study will be conducted in approximately 350 sites in North America.  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”. 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
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Approximately 750 subjects in total will be enrolled into this study, with approximately 
375 per treatment group.  Refer to Section 10.2 for additional information regarding the 
calculation of the sample size. 
3.4 
Estimated Study Duration 
3.4.1 
Study Duration for Participants 
The total duration on-study for an individual subject is approximately 2 years, which 
includes the following: 
• 
2- to 4-week screening period 
• 
100-week on-study period including 
− 
96-week treatment period 
− 
4-week follow-up period, after final dose of investigational product for collection 
of RBC transfusions and safety information (eg, adverse events) 
3.4.2 
End of Study 
The end of study is defined as the date on which the last subject is assessed or receives 
an intervention for the purposes of final collection of data for the primary endpoint.   
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, sex, age, 
race), date and outcome of the screening process (eg, enrolled into the study, reason for 
ineligibility, or refused to participate).  This log may be completed and updated via an 
Electronic Trial Operations (ETO) System (eg, interactive voice response system).  
Before any study specific procedure, the appropriate written informed consent must be 
obtained (see Section 11.1).  For purposes of eligibility, screening is defined as the first 
screening procedure following signing of the informed consent. 
4.1 
Inclusion Criteria 
4.1.1 
Age 18 or older 
4.1.2 
Clinical history of advanced CKD not on dialysis with at least 1 historic 
estimated glomerular filtration rate (eGFR) < 45.0 mL/min/1.73m2 at least 
12 weeks prior to screening 
4.1.3 
Not currently receiving dialysis with an eGFR < 45.0 mL/min/1.73m2, per 
the central laboratory during screening 
4.1.4 
Chronic anemia due to renal failure  
4.1.5 
Two Hb concentrations < 10.0 g/dL, at least 2 weeks apart during screening 
using the modified Hb point of care (POC) device  

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 22 of 67 
 
4.1.6 
Iron replete, defined as a transferrin saturation (TSAT) ≥ 20% and a ferritin 
≥ 100 ng/mL, per the central laboratory during screening 
4.1.7 
Vitamin B12 and folate replete, defined as a vitamin B12 level > 180 pg/mL 
and a folate concentration > 7 nmol/L, per the central laboratory during 
screening 
4.1.8 
Clinically stable in the opinion of the investigator 
4.1.9 
Subject has provided written informed consent 
4.2 
Exclusion Criteria 
General 
4.2.1 
Systemic hematologic disease (eg, sickle cell anemia, myelodysplastic 
syndrome, hematologic malignancy) 
4.2.2 
Current or prior malignancy within 5 years of screening, with the exception of 
non-melanoma skin cancers and cervical intraepithelial neoplasia  
4.2.3 
Treatment for any malignancy (eg, radiation, chemotherapy, hormone 
therapy, or biologics) within 5 years of screening, with the exception of locally 
excised non-melanoma skin cancer or cervical intraepithelial neoplasia  
4.2.4 
Female subject not willing to use highly effective methods of birth control 
during treatment and for 4 weeks after the end of treatment 
4.2.5 
Subject is pregnant or breast feeding, or might become pregnant during the 
study or within 4 weeks after the end of treatment 
4.2.6 
Currently receiving intravenous antibiotics for treatment of an active infection 
4.2.7 
Known HIV positive 
4.2.8 
Currently receiving systemic immunosuppressive therapy with the exception 
of prednis(ol)one ≤ 10 mg per day (or the steroid equivalent) 
4.2.9 
History of any organ transplant  
4.2.10 
Currently enrolled in another interventional study (eg, studies which require 
medical device use or drug therapy or with protocol required procedures), or 
less than 4 weeks since ending another interventional study(s) or receiving 
investigational agent(s) 
4.2.11 
Known neutralizing anti-erythropoietic protein antibodies 
4.2.12 
Known sensitivity to any of the products to be administered during dosing  
4.2.13 
Previously enrolled in this study 
4.2.14 
Not expected to be available for protocol required study visits or procedures 
to the best of the subject and investigator’s knowledge 
4.2.15 
Subject has any kind of disorder that, in the opinion of the investigator, may 
compromise the ability of the subject to give written informed consent and/or 
comply with all required study procedures 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 23 of 67 
 
Within 24 weeks of screening 
4.2.16 
Occurrence of any of the following: 
• 
Stroke 
• 
Myocardial Infarction (MI) 
Within 8 weeks of screening 
4.2.17 
Receipt of any of the following: 
• 
RBC transfusion 
4.2.18 
Occurrence of any of the following: 
• 
Seizure 
• 
Clinically relevant active bleeding (eg, gastrointestinal [GI] bleed)  
• 
Any hospitalization  
Within 4 weeks of screening 
4.2.19 
Receipt of any intravenous (IV) iron therapy 
4.2.20 
Changes in oral iron therapy 
4.2.21 
Receipt of ESA therapy 
During screening 
4.2.22 
Diagnosis or treatment of malignancy, with the exception of non-melanoma 
skin cancers and cervical intraepithelial neoplasia  
4.2.23 
Receipt of any of the following: 
• 
ESA therapy 
• 
RBC transfusions 
• 
IV iron therapy 
4.2.24 
Changes in oral iron therapy 
4.2.25 
Occurrence of any of the following: 
• 
Stroke  
• 
MI  
• 
Seizure 
• 
Clinically relevant active bleeding (eg, GI bleed)  
• 
Any hospitalization 
• 
Any outpatient surgery 

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Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 25 of 67 
 
minimum of 14 days and must not exceed 28 days.  Eligibility criteria will be evaluated 
throughout the screening period.  
Screening procedures are described in Section 7.1.1.  Upon either completion of the 
final screening procedure or determination of ineligibility, the investigator or designee 
must contact the IVR/IWR system.   
If subjects are confirmed as eligible, the IVR/IWR system will continue to the 
randomization call and assign the investigational product.  Subjects must have their first 
dose of investigational product administered on this date.  At the completion of the call, a 
confirmation fax and/or e-mail will be sent to the site to verify that the correct information 
has been entered and to confirm the randomization. 
If subjects are not eligible for the study due to: 
• 
the screening Hb concentration only, the IVR/IWR system will notify the investigator 
or designee that the subject is not eligible and record the date of the screen failure 
• 
reasons other than the screening Hb concentration, the investigator or designee will 
enter the date and reason for screen failure   
Subjects who fail screening may be rescreened as described in Section 7.1.2 beginning 
14 days after the date of the last screening procedure. 
5.2 
Randomization 
Randomization by the IVR/IWR system will be done in a 1:1 ratio to 1 of the 2 treatment 
groups (Hb-based titration group or fixed dose group) based on the following 
stratification factors at the time of study entry: 
• 
Receipt of any RBC transfusion within the 12 months prior to randomization (yes/no) 
• 
Site practice setting (nephrology/non-nephrology), pre-specified by the specialty of 
the principal investigator at the time of site initiation  
Randomization will be based on a schedule generated before the start of the study by an 
Amgen representative not involved in the conduct of the study.   
5.3 
Site Personnel Access to Individual Treatment Assignments 
The identity of the treatment group assigned to the subject, the protocol specified Hb 
measurements, and the dose of investigational product assigned will be maintained by 
the IVR/IWR system.  The investigator will be provided with a unique personal 
identification number (PIN) to access the IVR/IWR system in the event that they need to 
unblind the subject treatment assignment. 

 
 
 
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The subject, site personnel, and Amgen study personnel and designees will be blinded 
to the 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.  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 is required to do so within 
1 working day after the event and must document the unblinding in the subject’s 
electronic case report form (eCRF). 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Products and Medical Devices 
The Amgen Investigational Products used in this study include:  Darbepoetin alfa and 
placebo in a prefilled syringe (PFS). 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, and 
administration of darbepoetin alfa and placebo. 
The medical devices that are provided by Amgen for use in this study include:  A 
modified HemoCue Hb 201+ system hemoglobin analyzer and an auto inflate Blood 
Pressure Monitor. 
6.2 
Darbepoetin alfa 
Darbepoetin alfa will be manufactured and packaged by Amgen Inc. and distributed 
using Amgen clinical study drug distribution procedures.  Darbepoetin alfa will be 
presented as a clear, colorless, sterile protein solution in single use PFS in the following 
strengths:  10, 20, 30, 40, 50, 60, 80, 100, 150, 200, and 300 µg.  
6.3 
Placebo 
Placebo will be provided as a clear, colorless, sterile solution in PFS identical to those 
containing the active drug. 
6.4 
Dosage, Administration, and Schedule 
Subjects’ Hb will be measured Q4W using an modified Hb POC device provided by 
Amgen.  The device will provide coded values that will be entered into IVR/IWR system 
at each scheduled dosing visit.  The IVR/IWR system will determine and assign the 
appropriate dose and individual box(es) of investigational product (darbepoetin alfa or 
placebo) for that specific visit based on the Hb concentration and the dosing algorithms 

 
 
 
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in Section 6.4.1 below.  Each box of investigational product will contain only 1 PFS that 
is to be administered at the study visit for which it has been assigned.  
The protocol specified doses (PSD) for use in this study are 10, 20, 30, 40, 50, 60, 80, 
100, 120, 150, 200, 250, and 300 µg.  Subjects who require either a 120 or 250 µg dose 
will require the administration of 2 injections.  When this occurs, in order to maintain the 
blind, a subject in the fixed dose arm will be assigned at random to receive 2 injections 
of investigational product by the IVR/IWR system.  When this is required, the IVR/IWR 
will assign 2 boxes of investigational product for administration during the study visit. 
Investigational product will be administered subcutaneously (SC) by appropriately 
trained medical personnel Q4W for the duration of the treatment period.  The starting 
dose of investigational product will be 0.45 µg/kg for both groups, using the subject’s 
body weight at screening Visit 1.  The dose obtained from this calculation will be 
rounded down to the next lower PFS strength.    
6.4.1 
Dosage Adjustments  
All dose adjustments will be managed using the IVR/IWR system.  In order to maintain 
the blind, subjects will receive a placebo injection in place of darbepoetin alfa therapy 
when the dose of study drug is to be withheld per the dosing algorithm, for reasons other 
than elevated SBP.   
The maximum dose of darbepoetin alfa administered at any time during the study will be 
300 µg. 
The dose of investigational product may be adjusted based on Hb parameters and SBP 
values. 
6.4.1.1 
Dosage Adjustments Based on Systolic Blood Pressure Values 
If the subject’s mean SBP is ≥ 160 mmHg for two consecutive visits (including blood 
pressure monitoring visits), the dose of investigational product will be withheld.   
If the subject’s dose is withheld for ≤ 2 consecutive dosing visits, the investigational 
product will be restarted at the subject’s previous dose at the dosing visit when the mean 
SBP is ≤ 140 mmHg. 
If the subject’s dose is withheld for > 2 consecutive dosing visits, the investigational 
product will be restarted on the initial study dose at the dosing visit when the mean SBP 
is ≤ 140 mmHg.  

 
 
 
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6.4.1.2 
Dosage Adjustments Based on Hb Parameters 
6.4.1.2.1 
Hb-based Titration Group 
Subjects randomized to the Hb-based titration group will have their dose of 
investigational product titrated based on the Hb concentration on the date of the visit, the 
corresponding Hb rate of rise (ROR), and the previously assigned dose, as outlined in 
Table 1 below.  The Hb ROR will be determined by the protocol specified 
Hb concentrations obtained from the previous dose to the current dose.  
Table 1.  Dosing Algorithm for Hb-based Titration Group  
Hb (g/dL) 
Hb ROR (g/dL/4W) 
≤ 1.0 
> 1.0 and ≤ 2.0 
> 2.0 
<10.0 
↑ to next higher PSDa  
Maintain 
↓ to next lower PSDb 
10.0-10.5 
Maintain 
↓ to next lower PSDb 
↓ to next lower PSDb 
>10.5 -11.0 
↓ to next lower PSDb 
↓ to next lower PSDb 
Placeboc 
>11.0 
Placeboc 
Placeboc 
Placeboc 
a Subjects receiving 300 µg who require a dose increase will continue to receive 300 µg 
b Subjects receiving 10 µg who require a dose reduction will receive placebo 
c Restart darbepoetin alfa when Hb < 10.0 g/dL, at next lower PSD 
When darbepoetin alfa therapy is withheld per the dosing algorithm, placebo will be 
administered.  Once the Hb falls to < 10.0 g/dL, darbepoetin alfa therapy will be resumed 
at the next lower PSD. 
6.4.1.2.2 
Fixed Dose Group 
Subjects randomized to the fixed dose group will receive the same dose as the 
one assigned at the time of randomization for the duration of the treatment period with 
1 exception:  if the Hb is > 12.0 g/dL, darbepoetin alfa therapy will be withheld and 
placebo administered.  Once the Hb falls to < 10.0 g/dL, darbepoetin alfa therapy will 
resume at the same dose.   
6.4.1.3 
Missed Doses 
If a subject in either group misses a scheduled dose of investigational product (defined 
as Q4W ± 5 days), this dose will not be administered off schedule.  The missed dose 
and reason should be entered into the eCRF.  For the next dosing visit, the subject 
should return to their original visit schedule. 
If a subject misses > 2 consecutive dosing visits, they will be restarted at their initial 
study dose at the next dosing visit. 

 
 
 
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6.5 
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 6.8.   
It is recommended that all subjects be iron replete during the study.  Supplemental iron 
therapy should be administered as needed and as tolerated.  The National Kidney 
Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend 
that TSAT be maintained ≥ 20% and ferritin ≥ 100 ng/mL. 
Blood pressure should be monitored and managed as appropriate.  The KDOQI 
guidelines recommend to target a SBP < 130 mmHg and a DBP < 80 mmHg. 
6.6 
Medical Devices 
The following medical devices will be used in this study and provided by Amgen: 
• 
Modified HemoCue Hb 201+ system hemoglobin analyzer 
• 
Auto inflate blood pressure monitor 
Medical devices (eg, syringes, sterile needles, alcohol prep pads), that are commercially 
available are not usually provided or reimbursed by Amgen.  The investigator will be 
responsible for obtaining supplies of these devices. 
6.6.1 
Modified HemoCue Hb 201+ System Hemoglobin Analyzer 
The HemoCue Hb 201+ system hemoglobin analyzer is a Hb POC device manufactured 
by HemoCue AB.  The device has been modified by HemoCue for the purpose of this 
trial to provide study specific coded hemoglobin values.  The modified HemoCue will be 
provided by Amgen for use in this study to determine protocol specified hemoglobin 
values while maintaining the blind. 
Additional details for the modified HemoCue Hb POC device may be found in the study 
specific user manual that accompanies the device. 
6.6.2 
Other Medical Devices Provided 
Amgen will also provide an auto inflate blood pressure monitor to be used throughout 
the trial for protocol specified blood pressure measurements.  The blood pressure will be 
measured as described in Section 7.2.4. 
Additional details for the automated blood pressure monitor may be found in the 
user manual that accompanies the device. 

 
 
 
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6.7 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution to market or clinic by 
either Amgen or by distributors and partners for whom Amgen manufactures the 
material. 
Any product complaint(s) associated with an investigational product or device supplied 
by Amgen are to be reported according to the instructions provided in the IPIM. 
6.8 
Excluded Treatments During Study Period  
Subjects are prohibited from participating in other interventional studies (eg, studies 
which require medical device use or drug therapy or with protocol required procedures) 
while participating in this study. 
Subjects should not receive commercial ESAs while receiving investigational product 
during the study. 
7. 
STUDY PROCEDURES 
Screening assessments and study procedures are outlined in this section and in 
Appendix A.  The informed consent must be obtained prior to performing any screening 
or study procedures.   
All on-study visits and dosing should be scheduled from Study Day 1.  It is important to 
perform study procedures and obtain samples at the time points outlined in the protocol.  
When it is not possible to perform the study visit at the specified time point, the visit may 
be performed within the acceptable visit window as defined in Section 7.1.  If a study 
visit is missed, subsequent study visits should resume on the original visit schedule.  
Missed assessments at prior visits should not be duplicated at subsequent visits. 
With the exception of the screening and rescreen visits, all study procedures for a visit 
must be completed on the same day. 
It is the responsibility of the investigator to ensure all procedures are performed 
according to the protocol. 
7.1 
General Study Procedures  
Any blood or serum sample collected according to the Schedule of Assessments 
(Appendix A) may be analyzed for any of the tests outlined in the protocol and for any 
tests necessary to ensure subject safety.  This includes testing to ensure analytical 

 
 
 
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methods produce reliable and valid data throughout the course of the study.  This may 
also include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability. 
If informed consent is provided by the subject, Amgen may do additional testing on 
remaining samples (ie, residual and back-up) as well as those collected for biomarker 
development as described in Section 7.4.  These samples may be used to investigate 
and better understand CKD, the dose response and/or prediction of response to 
darbepoetin alfa, characterize antibody response, and characterize aspects of the 
molecule (eg, metabolites).  Results from this analysis will be documented and 
maintained, but may not be reported as part of this study. 
The procedures performed at each study visit are outlined below and in Appendix A. 
Details regarding each type of procedure are provided in Section 7.2.  
7.1.1 
Screening Evaluations 
Informed consent must be obtained before completing any other screening procedures.  
After signing the informed consent form, subjects will be screened in order to assess 
eligibility for study participation.  The screening window is up to 28 days; subjects must 
complete 2 visits at least 14 days apart during this period.  If a subject has not met all 
eligibility criteria during or by the end of the 28-day window, the subject will be registered 
as a screen failure.  Subjects who screen fail may be eligible to rescreen per 
Section 7.1.2.   
The following procedures will be completed for all subjects during the first screening 
visit: 
• 
Informed consent 
• 
Blood pressure and pulse 
• 
Weight 
• 
eGFR, serum creatinine  
• 
Hb, using the modified Hb POC device 
• 
Serum pregnancy test for all women (except for women who are surgically sterile or 
are at least 1 year postmenopausal) 
• 
TSAT, ferritin, iron, total iron binding capacity (TIBC) 
• 
Serum vitamin B12 and folate 
Serious adverse events will be collected from the time the informed consent is signed. 

 
 
 
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The second screening visit will take place at least 14 days but no more than 28 days 
after the first screening visit.  The following procedures will be performed during the 
second screening visit: 
• 
Blood pressure and pulse 
• 
Serious adverse event assessment 
• 
Hb, using the modified Hb POC device 
7.1.2 
Rescreening Evaluations 
Subjects who do not meet eligibility criteria during the initial screening attempt will be 
permitted to rescreen 4 times, for a total of 5 screening attempts.  Rescreen subjects 
must first be registered as screen failed in the IVR/IWR system and subsequently 
registered as a rescreen subject.  Once the subject is registered as rescreened, a new 
28-day screening window will begin.  All screening procedures will need to be repeated. 
7.1.3 
Study Day 1 Evaluations 
The Day 1 visit will be the same day as screening Visit 2.  After completion of the 
screening period, when the subject has met all eligibility criteria, sites will need to 
complete the randomization call in the IVR/IWR system prior to beginning the Day 1 
evaluations.  All subsequent doses and study visits will be scheduled based on the 
Day 1 date. 
The following procedures will be completed on Day 1: 
• 
Medical and surgical history, including history of transfusions 
• 
Physical exam, including height and weight 
• 
Electrocardiogram 
• 
Concomitant medications (as specified in Section 7.2.9) 
• 
eGFR, serum creatinine 
• 
Complete blood count (CBC; results will remain blinded) 
• 
TSAT, ferritin, iron, TIBC 
• 
Troponin-T 
• 
Serum albumin, high sensitivity C-reactive protein (CRP) 
• 
Reticulocytes (results will remain blinded) 
• 
Blood samples for biomarkers 
• 
Spot urine albumin and creatinine 
• 
Anti-erythropoietic protein antibodies 
• 
Anti-human leukocyte antigen (HLA) antibodies 
• 
Investigational product administered 

 
 
 
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Once the subject is enrolled, collection of the following will begin: 
• 
RBC transfusions, as well as transfusions of other blood-derived products 
• 
Endpoint data for adjudication 
• 
Hospitalizations, including observational stays, and emergency department visits 
• 
Adverse events 
7.1.4 
Treatment Period Evaluations 
7.1.4.1 
Routine Study Visits 
Routine study visits will occur Q4W, as noted in the Schedule of Assessments 
(Appendix A), during the treatment period beginning at week 5 through the week 97 visit.  
On-study visits may be completed within ± 5 days of the target visit date.  The following 
procedures and data collection will be completed: 
• 
At Week 5  
− 
CBC (results will remain blinded) 
− 
TSAT, ferritin, iron, TIBC 
• 
At Week 5 and every 4 weeks thereafter 
− 
Blood pressure and pulse 
− 
Concomitant medications (as specified in Section 7.2.9) 
− 
RBC transfusions, as well as transfusions of other blood-derived products 
− 
Endpoint data for adjudication 
− 
Hospitalizations, including observational stays, and emergency department visits 
− 
Adverse event and serious adverse event assessment 
− 
Hb, using the modified Hb POC device 
− 
Investigational product administration 
• 
Every 12 weeks 
− 
CBC (results will remain blinded) 
− 
TSAT, ferritin, iron, TIBC 
− 
Anti-HLA antibodies 
• 
Every 24 weeks 
− 
eGFR, serum creatinine 
− 
Blood samples for biomarkers 

 
 
 
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7.1.4.2 
Additional Visits for Blood Pressure Monitoring 
For any subject with a mean SBP ≥ 160 mmHg measured during a routine study visit, an 
additional blood pressure monitoring visit is required 2 weeks later.  This visit may be 
completed within ± 5 days of the scheduled visit date.   
For subjects with mean SBP < 160 mmHg an additional study visit for blood pressure 
monitoring may also be scheduled 2 weeks after a routine study visit at the discretion of 
the investigator.  This visit may be completed within ± 5 days of the scheduled visit date. 
The procedures and data collected at blood pressure monitoring visits will include: 
• 
Blood pressure and pulse 
• 
Concomitant antihypertensive medications 
• 
Adverse event and serious adverse event assessment 
The SBP obtained during these visits will be entered into the IVR/IWR system. 
7.1.5 
Evaluations After End of Investigational Product 
Subjects ending investigational product prior to week 97 will be asked to continue to 
complete scheduled visits and study procedures outlined in Section 7.1.4 for the 
remainder of the treatment period.  At a minimum, subjects must be followed for the 
collection of RBC transfusions and endpoint data for adjudication.  Refer to Section 8.1 
for additional information.  In addition, serum for anti-erythropoietic protein antibody 
testing will be collected at the scheduled visit that occurs closest to the receipt of the last 
dose of investigational product.  Adverse events and serious adverse events will be 
collected as described in Section 9. 
7.1.6 
Early Termination 
Subjects who choose not to continue in the study prior to week 97 will be asked to 
complete an early termination visit and should have all End of Study (EOS) evaluations 
performed as outlined in Section 7.1.7 below. 
7.1.7 
End of Study Evaluations 
Subjects will complete an EOS visit at week 101 within ± 5 days of the target visit date or 
at early termination.  The following procedures apply to the EOS visit: 
• 
Physical examination 
• 
Blood pressure and pulse 
• 
Weight 
• 
Concomitant medications (as specified in Section 7.2.9) 
• 
RBC transfusions, as well as transfusions of other blood-derived products 

 
 
 
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• 
Endpoint data for adjudication 
• 
Hospitalizations, including observational stays, and emergency department visits 
• 
Adverse event and serious adverse event assessment 
• 
eGFR, serum creatinine 
• 
Hb, using the modified Hb POC device 
• 
Blood samples for biomarkers 
• 
Anti-erythropoietic protein antibodies 
• 
Anti-HLA antibodies 
7.2 
Description of General Study Procedures 
7.2.1 
Informed Consent 
All subjects must sign and personally date the IRB approved informed consent before 
any study specific procedures are performed.  See Section 11.1 for further details. 
7.2.2 
Medical and Surgical History 
The subject’s complete medical and surgical history will be obtained on Day 1 and 
recorded in the eCRF. 
7.2.3 
Physical Examination 
A physical exam will be performed on Day 1.  Breast, genital, and rectal examinations 
are not required for any study visit unless specific evaluation is warranted.  Weight and 
height should be measured with the subject wearing light clothing and with shoes 
removed. 
The physical examination, including weight, at EOS visit will consist of a follow-up 
examination to monitor for any changes from the Day 1 physical examination.  Any 
clinically significant changes in physical examination per the investigator’s opinion 
should be recorded on the adverse event eCRF. 
7.2.4 
Blood Pressure and Pulse 
Blood pressure and pulse will be obtained using an automated blood pressure machine 
provided by Amgen for purposes of this study.   
Blood pressure measurements should follow the recommended technique from the 
American Heart Association (Pickering et al, 2005).  The blood pressure should be taken 
with the subject’s arm supported at heart level using the appropriate sized cuff with the 
subject seated comfortably in a chair with their back supported and both feet on the 
ground.  Subjects should be resting quietly for at least 5 minutes before taking blood 
pressure measurements.  At the first screening visit, blood pressure will be taken in each 

 
 
 
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arm in triplicate at least 1 minute apart, except when there is a contraindication, such as 
a dialysis vascular access.  The arm with the higher mean blood pressure 
measurements will be recorded and then used at each of the visits for the duration of the 
study unless there is a contraindication, such as a dialysis vascular access.  Three 
successive measurements will be taken in the noted arm at least 1 minute apart during 
subsequent visits.  
If the mean SBP is > 140 mmHg or the mean DBP is > 90 mmHg at any study 
visit, additional information regarding the management of hypertension (eg, modification 
of antihypertensive medications) will be collected in the eCRF. 
7.2.5 
Hemoglobin 
All Hb measurements specified by the protocol for determination of eligibility, dosing, 
and as instructed by Amgen, will be blinded and obtained using an modified Hb POC 
device provided by Amgen.  All measurements should occur on the day of the study visit 
prior to the administration of investigational product.  The blood sample to be used for 
the Hb measurement will be obtained by venipuncture.  The utilization of blood obtained 
by a finger stick for Hb evaluations is not permitted. 
If a subject’s Hb is < 8.0 g/dL or > 13.0 g/dL, the investigator will be notified by the 
IVR/IWR system so that he/she may follow-up as clinically indicated. 
In addition, CBCs will be collected as specified in the Schedule of Assessments 
(Appendix A).  The results of the CBC will remain blinded. 
7.2.6 
RBC Transfusions 
RBC transfusions should be performed as deemed necessary by the treating physician 
and criteria are not stipulated by this study protocol.  All RBC transfusions received while 
the subject is on-study will be recorded on the RBC transfusion eCRF.  Information 
regarding the context surrounding transfusions will be collected at each study visit 
including units of RBCs transfused, the transfusion setting (eg, dialysis center, intensive 
care unit, emergency department), and clinical events (eg, bleeding, surgery).  This 
information will be reviewed by an independent Clinical Endpoint Committee (CEC). 
7.2.7 
Hospitalizations and Emergency Department Visits 
All hospitalizations, including observational stays, and emergency department visits that 
occur while the subject is on-study will be recorded on the eCRF, including the primary 
reason for the visit/stay. 

 
 
 
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7.2.8 
Adverse Events 
The incidence of adverse events will be collected for each subject at all study visits.  A 
serious adverse event that occurs in a subject after signing the informed consent but 
prior to randomization will be recorded on the screening serious adverse event eCRF.  
All adverse events that occur after randomization through 4 weeks after the last dose of 
investigational product will be recorded on the adverse event eCRF and on the serious 
adverse event eCRF if they are serious.  See Section 9 for additional information. 
7.2.9 
Concomitant Medications 
Concomitant medications will be collected beginning on Day 1 and recorded on the 
eCRF for this study as described below.  
The usage of concomitant medications will be collected every 4 weeks for the duration of 
the study.   
The administration of antihypertensive medications, including the name of the 
medication, dose, route, frequency, and dates of administration will be collected at every 
study visit, including any additional visits for blood pressure management. 
The administration of iron, including the name of the medication, dose, route and dates 
of administration, will be collected.   
The use of commercial ESAs in subjects who are no longer receiving investigational 
product is permitted in this study.  Administration of commercial ESAs while receiving 
investigational product will be documented as a protocol deviation.  For subjects who 
receive commercial ESAs, the name of the medication, dose, route and dates of 
administration will be collected. 
7.2.10 
Electrocardiogram (ECG) 
A standard 12-lead ECG will be obtained after the subject has been supine for at least 
5 minutes and prior to blood samples being drawn.  The investigator or designated 
physician will review and sign the ECG.  Once signed, the original ECG tracing will be 
retained with the subject’s source documents.  At the request of the sponsor, the original 
ECG tracing may be made available to Amgen.  
7.2.11 
Endpoint Collection for Adjudication 
Data for the specified endpoints will be collected for adjudication as outlined in the 
endpoint manual that will be provided to the study sites.  Data will be transferred to a 
CEC for analysis per Amgen instructions.  The original potential endpoint data package 
will be retained with the subject’s source documents. 

 
 
 
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Clinical events to be collected for adjudication include: 
• 
All-cause mortality 
• 
Stroke, TIA, MI, decompensated heart failure, thromboembolism, and vascular 
access thrombosis 
• 
The clinical context surrounding RBC transfusions 
7.2.12 
Laboratory Assessments 
All screening and on-study laboratory samples, with the exception of Hb samples 
utilizing the modified Hb POC device, will be processed and sent to the central 
laboratory.  The central laboratory will be responsible for all screening and on-study 
hematology, serum chemistry, iron, serum pregnancy, spot urine albumin and creatinine, 
and other laboratory tests required.  Amgen or designee will be responsible for 
anti-erythropoietic protein antibody and anti-HLA antibody assessments, and the central 
laboratory will ship the samples to Amgen or a specialty laboratory for assay testing. 
The central laboratory will provide a study manual that outlines handling, labeling, and 
shipping procedures for all blood and urine samples.  All blood samples will be obtained 
by venipuncture before investigational product administration.  The date and time of 
blood and urine collection will be recorded in the source documents at the site. 
Table 2 below outlines the specific analytes for serum chemistry, iron and other testing 
to be conducted on blood and urine samples. 
Table 2.  Analyte Listing 
Chemistry 
Urine 
Hematology 
Other 
Creatinine  
Spot albumin 
White blood cell count (WBC) 
Serum pregnancy test 
Albumin 
Spot creatinine 
RBC 
eGFR  
  
 
Hb 
High sensitivity CRP 
Iron 
 
Hematocrit (HCT) 
Folate  
TSAT  
 
Platelets 
Vitamin B12  
Ferritin  
 
Mean corpuscular hemoglobin (MCH) 
Troponin-T 
Iron 
 
Mean corpuscular hemoglobin 
concentration (MCHC) 
Anti-erythropoietic 
protein antibodies 
TIBC 
 
Mean corpuscular volume (MCV) 
Anti-HLA antibodies 
 
 
Red cell distribution width (RDW) 
 
  
 
Mean platelet volume (MPV)  
 
  
 
Reticulocytes  
 
7.3 
Antibody Testing Procedures 
7.3.1 
Anti-Erythropoietic Antibodies 
Blood samples will be collected from all subjects for the measurement of 
anti-erythropoietic protein antibodies.  Samples testing positive for binding antibodies 

 
 
 
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will also be tested for neutralizing antibodies and may be further characterized for 
quantity/titer, isotype, affinity and presence of immune complexes.  Additional blood 
samples may be obtained to rule out anti-erythropoietic protein antibodies during the 
study.   
Subjects who test positive for neutralizing antibodies at the final scheduled study visit will 
be asked to return for additional follow-up testing.  This testing should occur 
approximately every 12 weeks starting from when the site has been notified of the 
positive result, until:  (1) neutralizing antibodies are no longer detectable or (2) the 
subject has been followed for a period of at least 1 year (± 4 weeks).  More frequent 
testing (eg, Q4W) or testing for a longer period of time may be requested in the event of 
safety-related concerns.  Follow-up testing will not be required where it is established 
that the subject did not receive darbepoetin alfa. 
Subjects who test positive for binding, non-neutralizing antibodies and have clinical 
sequelae that are considered potentially related to an anti-erythropoietic protein antibody 
response may also be asked to return for additional follow-up testing. 
7.3.2 
Anti-HLA Antibodies 
Samples for assessment of allosensitization will be collected.  Allosensitization is the 
development of an immune response against foreign antigens, and in particular foreign 
HLA.  The detection of anti-HLA antibodies (allosensitization) has changed dramatically 
over the last few years, becoming much more sensitive and more specific 
(Murphey and Forsthuber, 2008).  Given the rapid innovation in the determination of 
allosensitization, samples collected for anti-HLA antibodies during the course of the trial 
will be stored until the completion of the study.  Anti-HLA antibodies will then be 
measured using the state-of-the-art and accepted methods at that time. 
7.4 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  Amgen may attempt to develop blood tests designed to identify subjects 
most likely to respond positively or negatively to darbepoetin alfa.  These samples may 
also be used to investigate and better understand CKD and characterize aspects of 
darbepoetin alfa.  Biomarker development may be pursued by use of advanced 
biochemical analyses, such as proteomic methods.  If informed consent is provided by 
the subject, blood samples will be collected for biomarker development on Day 1 and 

 
 
 
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every 24 weeks thereafter for the duration of the study.  Refer to the laboratory manual 
for detailed collection and handling procedures for all biomarker development samples. 
Sample Storage and Destruction  
These biomarker development samples and any other components from the cells may 
be stored for up to 20 years from the end of the study to research scientific questions 
related to nephrology and/or darbepoetin alfa.  The subject retains the right to request 
that the sample material be destroyed at any time by contacting the principal 
investigator.  The sponsor will be the exclusive owner of any data, discoveries, or 
derivative materials from the sample materials and is responsible for the destruction of 
the sample(s) at the request of the subject through the principal investigator or at the 
end of the storage period or as appropriate (eg, the scientific rationale for 
experimentation with a certain sample type no longer justifies keeping the sample).  
Following the request from the subject, the principal investigator will provide the sponsor 
with the required study and subject numbers so that any remaining serum samples and 
any other components from the cells can be located and destroyed.  If a commercial 
product is developed from this research project, the sponsor will own the commercial 
product.  The subject will have no commercial rights to such product and will have no 
commercial rights to the data, information, discoveries, or derivative materials gained or 
produced from the sample.  
8. 
REMOVAL AND REPLACEMENT OF SUBJECTS 
8.1 
Removal of Subjects 
Subjects have the right to withdraw 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. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product at any time during the course of the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate procedures for discontinuation 
from investigational product and must discuss with the subject the options for 
continuation of the schedule of assessments and collection of data, including endpoints 
and adverse events.  These subjects, as well as those who have stopped receiving 
investigational product for other reasons (eg, initiation of dialysis), are encouraged to 
continue the schedule of study visits.  If the subject is unable or unwilling to continue the 
schedule of visits: 
• 
At a minimum, subjects should be followed for the occurrence of RBC transfusions 
and collection of endpoint data for adjudication 

 
 
 
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• 
The investigator must document the change in schedule of assessments and the 
level of follow-up the subject is permitting:  in person, by telephone/mail, through 
family/friends, in correspondence/communication with other physicians, and/or from 
review of the medical records 
Withdrawal of consent for a study means that the subject does not wish to receive 
further investigational treatment and does not wish to or is unable to continue further 
study participation; subject data up to withdrawal of consent will be included in the 
analysis of the study, and where permitted, publically available data can be included 
after withdrawal of consent.  The investigator will discuss with the subject appropriate 
procedures for withdrawal from the study.   
Should a subject (or a legally acceptable representative) request or decide to withdraw 
from the study, all efforts will be made to complete and report the observations as 
thoroughly as possible up to the date of withdrawal.  All information should be reported 
on the applicable eCRFs.   
Reasons for removal from protocol-required investigational product or procedural 
assessments include: 
• 
subject request to end investigational product administration  
• 
pregnancy in a female subject (report on Pregnancy Notification Worksheet; 
see Appendix D) 
• 
safety concern (eg, due to an adverse event) 
• 
initiation of dialysis or receipt of a kidney transplant 
• 
lack of efficacy (eg, need for a commercial ESA regularly) 
Reasons for removal of a subject from the study include: 
• 
withdrawal of consent from the study 
• 
death 
• 
lost to follow-up 
• 
administrative decision by Amgen 
8.2 
Replacement of Subjects 
Subjects who withdraw from this study or are removed will not be replaced. 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Adverse Events 
9.1.1 
Definition of Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  

 
 
 
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The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates the pre-existing medical condition (eg, diabetes, migraine 
headaches, gout) has increased in severity, frequency, and/or duration, and/or has an 
association with a significantly worse outcome.  A pre-existing condition that has not 
worsened during the study and involves an intervention while on-study, such as elective 
cosmetic surgery or a medical procedure, is not considered an adverse event.  
An adverse device effect is any adverse event related to the use of a medical device.  
Adverse device effects include adverse events resulting from insufficient or inadequate 
instructions for use, adverse events resulting from any malfunction of the device(s), or 
adverse events resulting from use error or from intentional misuse of the device(s). 
9.1.2 
Reporting Procedures for Adverse Events 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after randomization through 4 weeks 
after the last dose of investigational product are reported using the applicable eCRF 
(eg, Adverse Event Summary eCRF).  
The investigator must assign the following adverse event attributes: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
Dates of onset and resolution, 
• 
Severity [and/or toxicity per protocol], 
• 
Assessment of relatedness to darbepoetin alfa, and 
• 
Action taken 
The adverse event toxicity grading scale used will be the Amgen adverse event standard 
grading score.  The toxicity grading scale used in this study is described in Appendix B. 
The investigator must assess whether the adverse event is possibly related to 
darbepoetin alfa.  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 
darbepoetin alfa? 
The investigator must assess whether the adverse event is possibly related to a device.  
This relationship is indicated by a “yes” or “no” response to the question:  Is there a 
reasonable possibility that the event may have been caused by a device? 

 
 
 
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The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated screening procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may be 
related to screening procedures?” 
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity or procedure.  This relationship is indicated by a “yes” or “no” 
response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure?” 
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) should not be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) should be recorded as the adverse 
event. 
The investigator’s clinical judgment will be used to determine whether a subject should 
be removed from treatment or from the study due to an adverse event.  A subject, or 
subject’s parent/legal guardian, may also voluntarily withdraw from treatment due to an 
adverse event.  If the subject requests to withdraw consent for further participation in the 
study, the subject should be encouraged to undergo, at a minimum, an end-of-study 
assessment.   
9.2 
Serious Adverse Events 
9.2.1 
Definition of Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   

 
 
 
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If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, or events that necessitate 
an emergency room visit, outpatient surgery, or urgent intervention. 
9.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 4 weeks after the last dose of investigational product are recorded in 
the subject’s medical record and are submitted to Amgen.  Any serious adverse events 
with a fatal outcome (regardless of possible relationship to investigational product) 
occurring through the end of the subject’s participation on the study are to be reported to 
Amgen.  This would include subjects who have been removed from investigational 
product and continued on-study.   
After the protocol-required reporting period defined above, the investigator does not 
need to actively monitor subjects for serious adverse events.  However, if the 
investigator becomes aware of a serious adverse event after this protocol-required 
reporting period, the investigator will report the event to Amgen within 24 hours following 
the investigator’s knowledge of the event.  Serious adverse events reported outside of 
the protocol-required reporting period will be captured within the safety database as 
clinical trial cases for the purposes of expedited reporting. 
The serious adverse event must be submitted to Amgen within 24 hours following the 
investigator’s knowledge of the event via the applicable eCRF.  If the electronic data 
capture (EDC) system is unavailable to the site staff to report the Serious Adverse 
Event, the information is to be reported to Amgen via an electronic Serious Adverse 
Event (eSAE) Contingency Report Form within 24 hours of the investigator’s knowledge 
of the event.  See Appendix C for a sample of the Serious Adverse Event 
Worksheet/eSAE Contingency Report Form.  When the first notification of a Serious 
Adverse Event is reported to Amgen via the eSAE Contingency Report Form, the data 
must be entered into the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”? 

 
 
 
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The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility. 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the applicable eCRF 
(eg, Adverse Event Summary eCRF). 
If a subject is permanently withdrawn from the study because of a serious adverse 
event, this information must be submitted to Amgen. 
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 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. 
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes.   
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol specified product and for 4 weeks after end of treatment, the 
pregnancy should be reported to Amgen’s global Pregnancy Surveillance Program within 
24 hours of the investigator’s knowledge of the event of a pregnancy.  Report a 
pregnancy on the Pregnancy Notification Worksheet (Appendix D).  The Pregnancy 
Surveillance Program will seek to follow the pregnant woman throughout her pregnancy 
and her baby up to 12 months after birth. 
If a lactation case occurs while the female subject is taking protocol-required therapies 
and for 4 weeks after end of treatment, the lactation case should be reported to Amgen’s 

 
 
 
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global Lactation Surveillance Program (LSP) within 24 hours of the investigator’s 
knowledge of the lactation case.  Report a lactation case on the Lactation Notification 
Worksheet (Appendix E). 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Subsets, and Covariates 
10.1.1 
Study Endpoints 
Primary endpoint 
• 
Receipt of 1 or more RBC transfusion 
Secondary endpoints 
• 
Total number of units of RBC transfused 
• 
Time to first RBC transfusion 
• 
Average achieved Hb concentration while receiving investigational product 
• 
Cumulative dose of darbepoetin alfa 
Safety endpoints 
• 
Time to major clinical events: 
− 
Composite of all-cause mortality and the occurrence of major cardiovascular 
events (stroke, myocardial infarction, and decompensated heart failure) 
− 
Composite of all-cause mortality, stroke or myocardial infarction, ie, major 
adverse cardiovascular events (MACE) 
− 
All-cause mortality 
− 
Cardiovascular mortality 
− 
Stroke 
− 
Myocardial infarction 
− 
Decompensated heart failure 
− 
Thromboembolic events 
− 
Vascular access thrombosis 
• 
Adverse events 
• 
Blood pressure and pulse 
• 
Anti-erythropoietic protein antibodies 
Exploratory endpoints 
• 
Darbepoetin alfa dose received at each study visit 
• 
Hb concentration at each study visit 
• 
Hb concentration change from baseline at each study visit 
• 
Time to first Hb concentration ≥ 10.0 g/dL 
• 
Proportion of Hb measurements ≥ 10.0 g/dL 

 
 
 
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• 
Hb rate of change in a 4 week interval at each study visit 
• 
Hb variability, defined as the intrasubject standard deviation over a 6 month rolling 
window 
• 
Initial Hb response, defined as the change of Hb concentration from baseline at 
week 5 
• 
Darbepoetin alfa dose over time by initial Hb response 
• 
Hb over time by initial Hb response 
• 
Number of days hospitalized 
• 
Anti-HLA antibodies 
10.1.2 
Full Analysis Set 
The full analysis set will include all randomized subjects who receive at least 1 dose of 
investigational product.  Subjects will be analyzed according to their randomized 
treatment assignment. 
10.1.3 
Subgroups and Covariates 
Subgroups and covariates to be considered include the stratification factors used 
at randomization, and the following baseline factors: age, sex, race, baseline 
Hb concentration and baseline eGFR.  Subgroups are defined as  
• 
Age: < 65, ≥ 65 and < 75, ≥ 75 years 
• 
Gender: Female, Male 
• 
Race: White, Black, Other 
• 
Baseline Hb concentrations: <9.0, 9.0 – < 9.5, 9.5 – < 10.0 g/dL 
• 
Baseline eGFR: < 30.0, ≥ 30.0 mL/min/1.73m2 
Additional analyses may be performed if other prognostic factors emerge in this study or 
in this population. 
10.2 
Sample Size Considerations 
The objective of the study is to provide estimations with acceptable precision.  Thus, the 
sample size is chosen to ensure that the width of the 95% confidence interval (CI) for the 
proportion of subjects who receive at least 1 RBC transfusion in each treatment group 
will be ≤ 10% (ie, ± 5% around the point estimate), assuming the proportion to be 25%.  
The choice of the precision of the estimated transfusion rate is based on clinical 
relevance and experience.  The estimated proportion of 25% of subjects receiving at 
least 1 RBC transfusion is based on post hoc analyses in both treatment groups of 
TREAT of subjects who met the eligibility criteria for this study (Amgen data on file) and 
transfusion rates observed in other studies (Provenzano et al, 2004; Lawler et al, 2010).  

 
 
 
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To ensure the 95% CI with a width of ≤ 10%, 300 subjects per group will be needed to 
enroll into the study.  In order to ensure this precision can be maintained for sensitivity 
analyses, 20% drop out is accounted for, and enrollment of 375 subjects per treatment 
group is planned.  This total sample size of 750 subjects will also ensure that the width 
of the 95% CI of the difference in transfusion incidence rates will be ≤ 14% 
(ie, ± 7% around the point estimate), assuming the proportion of subjects receiving at 
least 1 RBC transfusion during the study in both treatment groups is 25%.  All 
confidence intervals are derived using normal approximation. 
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Individual subject treatment assignments will be maintained by the IVR/IWR system.  
Only the Data Monitoring Committee (DMC) and the supporting independent biostatistics 
group will have access to unblinded data.  Members of the Amgen study team will not 
have access to unblinded data until the study is unblinded for the final analysis.   
The external, independent biostatistics group will provide unblinded results, including 
aggregate and subject level data, to the DMC for regular data reviews.  The role of the 
DMC is discussed in Section 10.4.  Any unplanned unblinding occurring during the study 
period will be documented and reported in the final clinical study report. 
Amgen staff from the Clinical Supply Chain Management and Biological Sample 
Management departments will not be blinded to the treatment assignments in this study. 
10.4 
Interim Analysis and Early Stopping Guidelines 
Prior to the completion of the recruitment period, the sponsor may conduct a 
reassessment of the study assumptions (eg, transfusion rate) based on blinded 
aggregated data and revise the sample size in order to ensure that the desired precision 
of transfusion rate estimates can be achieved. 
An independent, external DMC will review unblinded study data throughout the duration 
of the study and may request additional data.  If warranted, the DMC can recommend 
modifying or stopping the study, or suspending enrollment.  This recommendation can 
be based on any safety concerns, lack of efficacy/futility, or preponderance of early 
evidence of efficacy.  The DMC will convene approximately once every 3-6 months.  The 
DMC will oversee an interim analysis to assess the totality of the data , which will occur 
when approximately 33% of subjects have completed 12 months of planned study 
follow-up.   

 
 
 
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10.5 
Planned Methods of Analysis 
10.5.1 
General Approach/Considerations 
Descriptive statistics will be presented for all endpoints by treatment group.  For 
continuous variables, these include number of observations, mean, standard error (SE) 
and/or standard deviation (SD), median, 25th percentile (Q1), 75th percentile (Q3), 
minimum and maximum.  For categorical variables, the frequency and percentage are 
presented.  For time to event endpoints: Kaplan-Meier curves, Kaplan-Meier percentiles, 
the number of subjects censored, and the number of subjects with events will be 
summarized.  Confidence intervals will be constructed as 2-sided at the 95% level.  
Summaries of laboratory data, Hb and dose related parameters, and vital signs will be 
completed using the full analysis set, limited to measurements obtained while the subject 
is receiving the investigational product. 
10.5.2 
Analysis of Key Study Endpoints 
10.5.2.1 
Efficacy Endpoints 
The primary analysis of the primary endpoint will be conducted using the full analysis 
set.  The evaluation period will begin from the date of randomization and subjects will be 
censored at the last dose of investigational product plus 3 months or end of study, 
whichever is earlier (on-treatment approach).  For the primary endpoint, the proportion of 
subjects in each treatment group receiving at least 1 RBC transfusion during the 
evaluation period will be presented with 2-sided 95% CIs.  The difference in proportions 
between treatment groups and the relative risk ratio will be described with 2-sided 
95% CIs.  Confidence intervals will be derived using normal approximation. 
The primary analysis will be repeated by subgroups of stratification factors used at 
randomization, and also by subgroups of age, gender, race, baseline Hb concentrations 
and baseline eGFR. 
Sensitivity analyses of the primary endpoint will be repeated using all randomized 
subjects with the evaluation period beginning at the date of randomization and subjects 
will be censored at the end of study (on-study approach).   
Sensitivity analyses will be performed to assess the impact of potential differential follow 
up on the primary endpoint.  Exposure-adjusted subject incidence of receiving at least 
1 RBC transfusion will be calculated with 95% CI using Chi-square approximation to the 
Poisson distribution for both on-treatment and on-study approaches.  Other sensitivity 
analyses, such as completer analyses for investigational product and study, may be 
performed as appropriate. 

 
 
 
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The reason for investigational product discontinuation will be reviewed to evaluate its 
relationship and potential impact on the primary endpoint.  Additional transfusion related 
information collected will be summarized descriptively by treatment group using both on 
treatment approach and on study approach.  These include the transfusion setting and 
clinical context surrounding transfusions.  These summaries will be of transfusion event 
incidence instead of subject incidence. 
10.5.2.2 
Secondary Endpoints 
Total number of units of RBC transfused per subject will be described for each treatment 
group, and will be analyzed using a negative binomial regression model which will 
include the stratification factors used at randomization.  As a sensitivity analysis, 
exposure adjusted event incidence of total number of units RBC transfused will be 
presented with 95% CI using Chi-square approximation to the Poisson distribution.  
These analyses will be performed using both on-treatment and on-study approaches. 
Time to first RBC transfusion using both on-treatment and on-study approaches will be 
analyzed by each treatment group with Kaplan-Meier curves, Kaplan-Meier percentiles, 
the number of subjects censored, and the number of subjects transfused.  A supportive 
analysis will be performed using Cox proportional hazards model (Cox, 1972) stratified 
by the stratification factors used at randomization to evaluate the difference between the 
treatment groups.  The hazard ratio and its corresponding 95% CI will be estimated. 
Average achieved Hb concentration while receiving investigational product will be 
described as average Hb using the area under the curve (AUC) method.  The median of 
the difference in achieved Hb concentration (Hodges–Lehmann estimate) between 
treatment groups will be calculated and 2-sided 95% confidence limits will be derived by 
using a nonparametric Wilcoxon rank-sum statistic (Holander and Wolfe, 1973). 
Cumulative doses of darbepoetin alfa adjusted for investigation product exposure time 
will also be summarized, and the median of the difference (Hodges–Lehmann estimate) 
between treatment groups will be calculated and 2-sided 95% confidence limits will be 
derived by using a nonparametric Wilcoxon rank-sum statistic. 
10.5.2.3 
Safety Endpoints 
Time to adjudicated event endpoints, such as composite endpoints of mortality and CV 
morbidity, all-cause mortality, and fatal and non-fatal CV events, will be summarized by 
each treatment group with Kaplan-Meier curves, Kaplan-Meier percentiles, the number 
of subjects censored, and the number of subjects with events. 

 
 
 
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Adverse events will be coded using the most current version of MedDRA.  Subject 
incidence of all treatment-emergent adverse events will be tabulated by system organ 
class, high level group term, and preferred term by randomized treatment group.  Tables 
of fatal adverse events, serious adverse events, adverse events leading to withdrawal 
from investigational product or from study, and significant treatment-emergent adverse 
events, will also be provided.  Adverse events of interest will be tabulated by each 
randomized treatment group.  Subgroup analyses (by age group, race, and gender) will 
be presented for all adverse events. 
Vital signs at each study visit will be summarized descriptively by treatment group.  
Average blood pressure on treatment will be described as average value using the 
AUC method, and medication changes secondary to elevated blood pressure will be 
summarized descriptively in each treatment group. 
The incidence and percentage of subjects who develop anti-erythropoietic protein 
antibodies (binding and if positive, neutralizing) at any time will be tabulated by treatment 
group. 
10.5.2.4 
Exploratory Endpoints 
All exploratory endpoints, except otherwise mentioned in this section, will be described 
by each treatment group.  In addition to Hb concentration and change from baseline at 
each study visit, the subgroups of Hb concentrations, will also be presented. 
Number of days hospitalized will be summarized by treatment group using the 
on-treatment approach. 
Achieved Hb concentration and cumulative dose over time will be summarized by the 
initial Hb responsiveness and treatment group. 
Anti-HLA antibodies over time will be tabulated by each treatment group. 
10.5.3 
Additional Analyses 
The number and percentage of subjects screened, randomized, and received at least 
1 dose of investigational product will be presented.  The study disposition and 
investigational product disposition will be tabulated by the reason for ending study and 
ending investigational product respectively for each treatment group. 
Demographic, medical history and baseline characteristics will be described by 
treatment group.  Use of selected concomitant medications at baseline and on-study, 
such as iron therapies and other erythropoietic agents, will be summarized by treatment 

 
 
 
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group.  The analyses of laboratory parameters will include summary statistics at the 
scheduled visit by treatment group.  
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial generic informed consent form (ICF) is provided for the investigator to prepare 
the informed consent document to be used at his or her site.  Updates to the template 
will be communicated by letter from the Amgen 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 after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol specific screening procedures or any investigational products are administered.   
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  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.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator should 
document such in the subject’s medical record.  The acquisition of informed consent and 
the subject’s agreement or refusal of his/her notification of the primary care physician 
should be documented in the subject’s medical records, and the informed consent form 
should be signed and personally dated by the subject and by the person who conducted 
the informed consent discussion.  The original signed informed consent form should be 
retained in accordance with institutional policy, and a copy of the signed consent form 
should be provided to the subject. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.   

 
 
 
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11.2 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IEC/IRB for 
written approval.  A copy of the written approval of the protocol and ICF must be 
received by Amgen before recruitment of subjects into the study and shipment of Amgen 
investigational product. 
The investigator must submit and, where necessary, obtain approval from the IEC/IRB 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator should notify the IEC/IRB of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator will be responsible for obtaining annual IEC/IRB approval /renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IEC/IRB continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained:   
• 
On the eCRFs or other documents submitted to Amgen, subjects should be identified 
by a subject identification number only, with a complete and accurate date of birth on 
the demographics eCRF.   
• 
For Serious Adverse Events reported to Amgen subjects should be identified by their 
initials, date of birth, and a subject identification number.   
• 
Documents that are not for submission to Amgen (eg, signed informed consent 
forms) should be kept in strict confidence by the investigator. 
In compliance with Federal regulations/International Conference on Harmonisation (ICH) 
Good Clinical Practice (GCP) Guidelines, it is required that the investigator and 
institution permit authorized representatives of the company, of the regulatory agency(s), 
and the IEC/IRB direct access to review the subject’s original medical records for 
verification of study related procedures and data.  Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are important to the 
evaluation of the study.  The investigator is obligated to inform and obtain the consent of 
the subject to permit named representatives to have access to his/her study related 
records, including personal information, without violating the confidentiality of the 
subject. 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 54 of 67 
 
11.4 
Investigator Signatory Obligations 
Each clinical study report should be signed by the investigator or, in the case of 
multicenter studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will either be: 
• 
a recognized expert in the therapeutic area 
• 
an investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an investigator contributing a high number of eligible subjects 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the investigator must be obtained.  The 
IEC/IRB must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IEC/IRB to Amgen. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
investigator reserve the right to terminate the investigator’s participation in the study 
according to the study contract.  The investigator should notify the IEC/IRB in writing of 
the study’s completion or early termination and send a copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product by 
an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product, and by what mechanism, after 
termination of the trial and before it is available commercially. 
12.2 
Study Documentation and Archive 
The investigator should maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on eCRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
eCRF 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. 
In this study, the ETO System captures the following data points and these are 
considered source data:  hemoglobin. 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 55 of 67 
 
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 eCRF, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, investigator’s brochure, 
copies of prestudy documentation, and all correspondence to and from the IEC/IRB 
and Amgen 
• 
If kept, proof of receipt/delivery sheet, Investigational Product Accountability Record, 
Return of Investigational Product for Destruction, Final Investigational Product 
Reconciliation Statement (if applicable), and all drug related correspondence 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen monitor is responsible for verifying the eCRFs 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 eCRFs. 
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 eCRFs, 
are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function (or 
designees).  Inspection of site facilities (eg, pharmacy, drug storage areas, laboratories) 
and review of study related records will occur to evaluate the study conduct and 
compliance with the protocol, ICH GCP, and applicable regulatory requirements. 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 56 of 67 
 
Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the eCRFs must be maintained and 
readily available. 
• 
Updates to eCRFs will be automatically documented through the software’s “audit 
trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review will be performed on subject data received at Amgen.  During 
this review, subject data will be checked for consistency, omissions, and any 
apparent discrepancies.  In addition, the data will be reviewed for adherence to the 
protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries will be created in the EDC system 
database for site resolution and closed by Amgen reviewer. 
• 
The principal investigator signs only the Investigator Verification Form for this 
electronic data capture study.  This signature will indicate that the principal 
investigator inspected or reviewed the data on the eCRF, the data queries, and the 
site notifications, and agrees with the content. 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit—week 4 and early termination) and clarifying “other, specify” if 
data are provided (eg, race, physical examination).  Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the trial 
and at study closeout.   
12.4 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.  Consult the country 
specific requirements for language requirements. 
12.5 
Publication Policy 
To coordinate dissemination of data from this study, a publication committee consisting 
of members of the executive committee and appropriate Amgen staff will be formed, the 
governance and responsibilities of which are set forth in a Publication Charter.  The 
committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for executive committee members and 
Amgen staff) does not guarantee authorship—the criteria described below should be met 
for every publication. 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 57 of 67 
 
Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors (ICMJE) 
Recommendations for the Conduct, Reporting, Editing and Publication of 
Scholarly Work in Medical Journals, which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; (4) and agreement to be accountable for all aspects of 
the work in ensuring that questions related to the accuracy or integrity of any 
part of the work are appropriately investigated and resolved.  Authors should 
meet conditions 1, 2, 3, and 4. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for corporate review.  The Clinical 
Study Agreement among the institution, principal investigator, and Amgen will detail the 
procedures for, and timing of, Amgen’s review of publications. 

 
 
 
Product:  Darbepoetin alfa 
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Date:  16 December 2013 
Page 58 of 67 
 
13. 
REFERENCES  
Al Ahmad A, Rand WM, Manjunath G, et al.  Reduced kidney function and anemia as 
risk factors for mortality in patients with left ventricular dysfunction.  J Am Coll Cardiol.  
2001;38:955-962. 
Astor BC, Muntner P, Levin A, Eustace JA, Coresh J.  Association of kidney function 
with anemia.  Arch Intern Med.  2002;162:1401-4018. 
Busch MP, Kleinman SH, Nemo GJ.  Current and emerging infectious risks of blood 
transfusions.  JAMA.  2003;289:959-962. 
Cox DR.  Regression models and life-tables (with discussion).  Journal of Royal 
Statistical Society.  1972;B,34:187-220. 
Collins AJ.  The hemoglobin link to adverse outcomes.  Adv Stud Med.  
2003;3:S194-S197. 
Darbepoetin alfa Investigator’s Brochure.  Thousand Oaks, CA:  Amgen Inc. 
Despotis GJ, Zhang L, Lublin DM.  Transfusion risks and transfusion-related 
proinflammatory responses.  Hematol Oncol Clin North Am.  2007;21:147-161.   
Doshi S, Chow A, Perez Ruixo JJ.  Exposure-response modeling of darbepoetin alfa in 
anemic patients with chronic kidney disease not receiving dialysis.  J Clin Pharmacol.  
2010,50:75S-90S. 
Eder AF, Chambers LA.  Noninfectious complications of blood transfusion.  Arch Pathol 
Lab Med.  2007;131:708-718. 
Egrie JC, Grant JR, Gillies DK, Aoki KF, Strickland TW.  The role of carbohydrate on the 
biological activity of erythropoietin [abstract].  Glycoconj J.  1993;10:263. 
Eschbach JW, Adamson JW.  Anemia of end-stage renal disease (ESRD).  Kidney Int.  
1985;28:1-5. 
Gilbertson DT, Ebben JP, Foley RN, et al.  Hemoglobin level variability: associations 
with mortality.  Clin J Am Soc Nephrol.  2008;3:133–138. 
Goodnough LT, Shander A.  Blood Management.  Arch Pathol Lab Med.  
2007;131:695-701. 
Goldman M, Vanherweghem JL.  Multiple blood transfusions and iron overload in 
patients receiving haemodialysis.  Nephrol DialTransplant.  1987;2:205-207. 
Hill GS, Nochy D, Bruneval P, et al.  Donor-specific antibodies accelerate 
arteriosclerosis after kidney transplantation.  J Am Soc Nephrol.  2011;22:975-983.  
Holander M, Wolfe DA. Nonparametric Statistical Methods. New York: Wiley; 
1973:67-79. 
International Committee of Medical Journal Editors, Recommendations for the 
Conduct, Reporting, Editing and Publication of Scholarly Work in Medical 
Journals.  2013.  http://www.icmje.org/ 
Kazmi WH, Kausz AT, Kahn S, et al.  Anemia:  An early complication of chronic renal 
insufficiency.  Am J Kidney Dis.  2001;38:803-812. 
Lawler EV, Bradbury BD, Fonda JR, et al.  Transfusion burden among patients with 
chronic kidney disease and anemia.  Clin J Am Soc.  2010;5:667-672. 
Leo A, Pedal I.  Diagnostic approaches to acute transfusion reactions.  Forensic Sci Med 
Pathol.  2010;6:135-145. 

 
 
 
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Date:  16 December 2013 
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Levin A, Thompson CR, Ethier J, et al.  Left ventricular mass index increase in early 
renal disease:  impact of decline in hemoglobin.  Am J Kidney Dis.  1999;34:125-134. 
Macdougall I.  Novel erythropoiesis stimulating protein.  Sem Nephrol.  
2000;20:375-381. 
Mann JFE.  What are the short-term and long-term consequences of anaemia in CRF 
patients?  Nephrol Dial Transplant.  1999;14[Suppl 2]:29-36. 
McClellan WM, Flanders WD, Langston RD, Jurkovitz C, Presley R.  Anemia and renal 
insufficiency are independent risk factors for death among patients with congestive heart 
failure admitted to community hospitals:  A population-based study.  J Am Soc Nephrol.  
2002;13:1928-1936. 
Moranne O, Froissart M, Rossert J, et al.  Timing of onset of CKD-related metabolic 
complications.  J Am Soc Nephrol.  2009;20:164-171. 
Murphey CL, Forsthuber TG.  Trends in HLA antibody screening and identification and 
their role in transplantation.  Expert Rev Clin Immunol.  2008; 4:391-399. 
Opelz G, Collaborative Transplant Study.  Non-HLA transplantation immunity revealed 
by lymphocytotoxic antibodies.  Lancet.  2005;365:1570-1576. 
Pfeffer MA, Burdmann EA, Chen C-Y, et al.  A trial of darbepoetin alfa in type 2 diabetes 
and chronic kidney disease.  N Engl J Med.  2009;361:2019-2032. 
Pickering TG, Hall JE, Appel AJ, et al.  Recommendations for blood pressure 
measurements in humans and experimental animals. Part 1: Blood Pressure 
Measurement in Humans: A Statement for Professionals From the Subcommittee of 
Professional and Public Education of the American Heart Association Council on High 
Blood Pressure Research.  Circulation.  2005;111:697-716. 
Provenzano R, Garcia-Mayol L, Suchinda P, et al.  Once-weekly epoetin alfa for treating 
the anemia of chronic kidney disease.  Clin Nephrol.  2004;61:392-405. 
Sarnak MJ, Tighiouart H, Manjunath G, et al.  Anemia as a risk factor for cardiovascular 
disease in The Atherosclerosis Risk in Communities (ARIC) study.  J Am Coll Cardiol.  
2002;40:27-33. 
Seetharam A, Tiriveedhi V, Mohanakumar T.  Alloimmunity and autoimmunity in chronic 
rejection.  Curr Opin Organ Transplant.  2010;15:531-536. 
Simon GE, Bove JR.  The potassium load from blood transfusion.  Postgrad Med.  
1971;49:61-64. 
Singh AK, Szczech L, Tang KL, et al.  Correction of anemia with epoetin alfa in chronic 
kidney disease.  N Engl J Med.  2006;355:2085-2098. 
Susal C, Dohler B, Sadeghi M, Ovens J, Opelz G.  HLA Antibodies and the Occurrence 
of Early Adverse Events in the Modern Era of Transplantation: A Collaborative 
Transplant Study Report.  Transplantation.  2009;87:1367–1371. 
Weinhandl ED, Peng Y, Gilbertson DT, Bradbury BD, Collins AJ.  Hemoglobin variability 
and mortality: confounding by disease severity.  Am J Kidney Dis.  2011;57:255-265. 
 

 
 
 
Product:  Darbepoetin alfa 
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Date:  16 December 2013 
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14. 
APPENDICES  
 

 
 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 61 of 67 
 
Appendix A.  Schedule of Assessments 
Treatments and Procedures 
Screening  
 
Visit Frequency  
 
Visit 1 Visit 2 (g) Day 1 Week 5 
Q4W 
Q2W (i) 
Q12W 
Q24W 
EOS/ET 
Week 101 
General and Safety Assessments 
Informed consent (a) 
X 
 
 
 
Medical/surgical history , including history of transfusions  
X 
 
 
 
Physical exam and height (b) 
X 
 
 
X 
Electrocardiogram  
X 
 
 
 
Blood pressure, pulse 
X 
X 
X 
X 
X 
 
X 
Weight  
X 
X 
 
 
X 
Concomitant medications including iron, and commercial ESAs 
X 
X 
X 
 
 
X 
Concomitant medications – antihypertensive medications  
X 
X 
X 
X 
 
X 
RBC transfusions and transfusions of other blood-derived products (c)  
Record continuously 
Endpoint data collection for adjudication (c) 
Record continuously 
Hospitalizations, including observational stays, and emergency 
department visits (c) 
 
 
Record continuously 
Adverse events/serious adverse events (d, e) 
                               Record continuously 
Laboratory Assessments (f) 
eGFR, serum creatinine (h) 
X 
X 
 
X 
X 
Complete blood count (CBC) 
X 
X 
 
X 
 
Hb, using modified Hb point of care device  
X 
X 
X 
X 
 
X 
TSAT, ferritin, iron, TIBC  
X 
X 
X 
 
X 
 
Vitamin B12, folate 
X 
 
 
Serum pregnancy test (all women of child bearing potential)  
X 
 
 
Blood samples for biomarkers 
X 
 
X 
X 
Anti-HLA antibodies 
X 
 
X 
X 
Spot urine albumin and creatinine  
X 
 
 
Troponin-T, serum albumin, high sensitivity CRP  
X 
 
 
Reticulocytes  
X 
 
 
Anti-erythropoietic protein antibodies  
X 
 
X 
Dosing 
Investigational product administration  
X 
X 
X 
 
 
a) 
To occur before any study procedure  
 
 
 
                  f)  Samples should be drawn before investigational product administration  
b) 
 Rectal and gynecological not required  
 
 
 
                 g)  Eligible subjects must have Visit 2 and Day 1 completed on the same date  
c) 
 Record continuously throughout duration of study  
 
 
                 h)  eGFR and serum creatinine will not be performed on subjects who require renal replacement therapy  
d) 
 Serious adverse events collected from date of consent through 4 weeks after final dose of IP      i)  Required if SBP ≥ 160 mmHg during routine study visit, at investigator discretion if SBP < 160 mmHg 
(see Section 9.2.2 for) additional details 
 
Adverse events, collected  from Day 1 through 4 weeks after final dose of IP 

 
 
 
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Appendix B.  Additional Safety Assessment Information 
Adverse Event Toxicity Grading Scale 
Grade 
Amgen Standard Adverse Event Toxicity Grading Scale 
1 
MILD:  Aware of sign or symptom, but easily tolerated 
2 
MODERATE:  Discomfort enough to cause interference with usual activity 
3 
SEVERE:  Incapacitating with inability to work or do usual activity 
4 
LIFE-THREATENING:  Refers to an event in which the patient was, in the view of the 
investigator, at risk of death at the time of the event.  (This category is not to be used 
for an event that hypothetically might have caused death if it were more severe.) 
5 
FATAL 

 
 
 
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Appendix C.  Sample of the Serious Adverse Event Worksheet/electronic Serious 
Adverse Event (eSAE) Contingency Report Form 
 

 
 
 
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Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
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Protocol Number:  20110226 
Date:  16 December 2013 
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Appendix D.  Pregnancy Notification Worksheet 
 

 
 
 
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Appendix E.  Lactation Notification Worksheet 
 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 1 of 9 
 
 
 
Amendment 3 
Protocol Title:  START-CKD:  Strategies Using Darbepoetin alfa to Avoid 
Transfusions in Chronic Kidney Disease 
 
Amgen Protocol Number (Darbepoetin alfa) 20110226 
 
Amendment Date: 
16 December 2013 
Rationale: 
The purpose of this amendment is to address challenges with enrollment into the trial 
and potentially reduce the screen failure rate.   
The following eligibility criteria have been modified to have a positive impact on 
enrollment without a significant impact on the population being studied: 
• 
Removal of lower limit for eGFR required for inclusion 
• 
Modification of time required between events and screening including : 
o Receipt of a red blood cell transfusion 
o Occurrence of: 
 
Seizure 
 
Clinically relevant active bleeding 
 
Hospitalization 
 
Receipt of erythropoiesis stimulating agents 
Minor administrative changes and clarifications have also been incorporated. 
Additions are noted in bold text.  

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 2 of 9 
 
 
 
Description of Changes: 
Section: Global 
Replace date of protocol: 
25 June 2013 
With: 
16 December 2013 
Section: Global 
Replace: 
Investigational Hb point of care (POC) device 
With: 
Modified Hb point of care (POC) device 
Page 1, Title Page 
 
Add: 
Amendment 3 
Page 5, Synopsis 
Replace:   
• 
Estimated glomerular filtration rate of ≥ 15 to < 45 ml/min/1.73m2 
With: 
• 
Not currently receiving dialysis with an estimated glomerular filtration rate of 
< 45.0 mL/min/1.73m2 during screening 
Page 5, Synopsis 
Replace: 
• 
Received erythropoiesis stimulating agents (ESAs) within 12 weeks of screening 
• 
Received an RBC transfusion within 12 weeks of screening 
With: 
• 
Received erythropoiesis stimulating agents (ESAs) within 4 weeks of screening 
• 
Received an RBC transfusion within 8 weeks of screening 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 3 of 9 
 
 
 
Page 6, Synopsis 
Add: 
Subjects ending investigational product prior to week 97 will be asked to complete 
scheduled visits and study procedures.  At a minimum, subjects must be followed 
for the collection of RBC transfusions and endpoint data for adjudication. 
Page 21, Section 4.1, Inclusion Criteria 
Replace: 
4.1.3 eGFR ≥ 15.0 and < 45.0 mL/min/1.73m2, per the central laboratory during 
screening  
With: 
4.1.3 Not currently receiving dialysis with an eGFR < 45.0 mL/min/1.73m2, per the 
central laboratory during screening  
Page 22, Section 4.2, Exclusion Criteria 
Replace: 
4.2.6 Currently receiving systemic antibiotics for treatment of an active infection 
With: 
4.2.6 Currently receiving intravenous antibiotics for treatment of an active infection 
Page 23, Section 4.2, Exclusion Criteria 
Replace: 
Within 12 weeks of screening 
4.2.17 Receipt of any of the following: 
• 
RBC Transfusion 
• 
ESA Therapy 
With: 
Within 8 weeks of screening 
4.2.17 Receipt of any of the following: 
• 
RBC Transfusion 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 4 of 9 
 
 
 
Page 23, Section 4.2, Exclusion Criteria 
Replace: 
Within 4 weeks of screening 
4.2.19 Receipt of any intravenous (IV) iron therapy 
4.2.20 Changes in oral iron therapy 
4.2.21 Any outpatient surgery 
With: 
Within 4 weeks of screening 
4.2.19 Receipt of any intravenous (IV) iron therapy 
4.2.20 Changes in oral iron therapy 
4.2.21 Receipt of ESA therapy 
Page 24, Section 5.1, Screening 
Replace: 
Subjects who fail screening may be rescreened as described in Section 7.1.2 beginning 
28 days after the date of the last screening procedure. 
With: 
Subjects who fail screening may be rescreened as described in Section 7.1.2 beginning 
14 days after the last screening procedure. 
Page 26, Section 6.1, Classification of Products and Medical Devices 
Replace: 
The medical devices that are provided by Amgen for use in this study include:  A 
modified HemoCue Hb 201+ system hemoglobin analyzer (investigational) and an 
Omron HEM 705 CP Auto Inflate Blood Pressure Monitor (commercially available).   
With: 
The medical devices that are provided by Amgen for use in this study include:  A 
modified HemoCue Hb 201+ system hemoglobin analyzer and an auto inflate Blood 
Pressure Monitor. 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 5 of 9 
 
 
 
Page 27, Section 6.4.1.1, Dosage Adjustments Based on Systolic Blood Pressure 
Values 
Replace: 
If the subject’s mean SBP is ≥ 160 mmHg for three consecutive visits (including blood 
pressure monitoring visits), the dose of investigational product will be withheld. 
With: 
If the subject’s mean SBP is ≥ 160 mmHg for two consecutive visits (including blood 
pressure monitoring visits), the dose of investigational product will be withheld. 
Page 29, Section 6.6, Medical Devices 
Replace: 
6.6 
Investigational Medical Devices 
The following investigational medical devices will be used in this study and provided by 
Amgen: 
• 
Modified HemoCue Hb 201+ system hemoglobin analyzer 
With: 
6.6 
Medical Devices 
The following medical devices will be used in this study and provided by Amgen: 
• 
Modified HemoCue Hb 201+ system hemoglobin analyzer 
• 
Auto inflate blood pressure monitor 
Page 29, Section 6.6.1, Modified HemoCue Hb 201+ System Hemoglobin Analyzer 
Replace: 
The modified HemoCue is an investigational device provided by Amgen for use in this 
study to determine protocol specified hemoglobin values. 
With: 
The modified HemoCue will be provided by Amgen for use in this study to determine 
protocol specified hemoglobin values while maintaining the blind. 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 6 of 9 
 
 
 
Page 29, Other Medical Devices Provided 
Replace: 
6.7 
Other Medical Devices Provided 
Amgen will also provide the Omron HEM 705 CP Auto inflate blood pressure monitor to 
be used throughout the trial for protocol specified blood pressure measurements.  The 
blood pressure will be measured as described in section 7.2.4. 
With: 
6.6.2 Other Medical Devices Provided 
Amgen will also provide an auto inflate blood pressure monitor to be used throughout 
the trial for protocol specified blood pressure measurements.  The blood pressure will be 
measured as described in section 7.2.4. 
Additional details for the automated blood pressure monitor may be found in the 
user manual that accompanies the device. 
Page 30, Section 6.7.1, Omron HEM 705 CP Auto Inflate Blood Pressure Monitor 
Remove: 
6.7.1 Omron HEM 705 CP Auto Inflate Blood Pressure Monitor 
The Omron HEM 705 CP auto inflate blood pressure monitor is an automated blood 
pressure device manufactured by Omron Healthcare, Inc. and provided by Amgen for 
use in this trial.  A printer is also provided to document the blood pressure readings.  The 
printed blood pressure results should be placed with the subject’s source documents. 
Additional details for the Omron automated blood pressure monitor may be found in the 
user manual that accompanies the device. 
Page 32, Section 7.1.2, Rescreening Evaluations 
Replace: 
Subjects who do not meet eligibility criteria during the initial screening attempt will be 
permitted to rescreen twice, for a total of 3 screening attempts. 
With: 
Subjects who do not meet eligibility criteria during the initial screening attempt will be 
permitted to rescreen 4 times, for a total of 5 screening attempts. 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 7 of 9 
 
 
 
Page 34, Section 7.1.5, Evaluations After End of Investigational Product 
Replace: 
At a minimum, subjects must be followed for the collection of RBC transfusions and 
endpoint data for adjudication.  In addition, serum for anti-erythropoietic protein antibody 
testing will be collected at the scheduled visit that occurs closest to the receipt of the last 
dose of investigational product.   
With: 
At a minimum, subjects must be followed for the collection of RBC transfusions and 
endpoint data for adjudication.  Refer to Section 8.1 for additional information.  In 
addition, serum for anti-erythropoietic protein antibody testing will be collected at the 
scheduled visit that occurs closest to the receipt of the last dose of investigational 
product. 
Page 41, Section 9.1.1, Definition of Adverse Events 
Replace: 
An adverse device effect is any adverse event related to the use of an investigational 
medical device.  Adverse device effects include adverse events resulting from 
insufficient or inadequate instructions for use, adverse events resulting from any 
malfunction of the investigational device(s), or adverse events resulting from use error or 
from intentional misuse of the investigational device(s) 
With: 
An adverse device effect is any adverse event related to the use of a medical device.  
Adverse device effects include adverse events resulting from insufficient or inadequate 
instructions for use, adverse events resulting from any malfunction of the device(s), or 
adverse events resulting from use error or from intentional misuse of the device(s) 
Page 42, Section 9.1.2, Reporting Procedures for Adverse Events 
Replace: 
The investigator must assess whether the adverse event is possibly related to the 
investigational device.  This relationship is indicated by a “yes” or “no” response to the 
question:  Is there a reasonable possibility that the event may have been caused by the 
investigational device? 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 8 of 9 
 
 
 
With: 
The investigator must assess whether the adverse event is possibly related to a device.  
This relationship is indicated by a “yes” or “no” response to the question:  Is there a 
reasonable possibility that the event may have been caused by a device? 
Page 56, Section 12.5, Publication Policy 
Replace: 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors) which states: 
With: 
Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors (ICMJE) 
Recommendations for the Conduct, Reporting, Editing, and Publication of 
Scholarly Work in Medical Journals which states: 
Page 56, Section 12.5, Publication Policy 
Replace: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published.  Authors should meet conditions 1, 2, and 3. 
With: 
• 
Authorship 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; (4) and agreement to be accountable for all aspects of 
the work in ensuring that questions related to the accuracy or integrity of any 
part of the work are appropriately investigated and resolved.  Authors should 
meet conditions 1, 2, 3, and 4. 
Page 58, Section 13, References 
Replace: 
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals:  Writing and Editing for Biomedical 
Publication.  2006.  http://www.icmje.org/ 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  16 December 2013 
Page 9 of 9 
 
 
 
With: 
International Committee of Medical Journal Editors, Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical 
Journals.  2013.  http://www.ismje.org/ 
 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  25 June 2013 
Page 1 of 2 
 
Amendment 2 
Protocol Title:  START-CKD:  Strategies Using Darbepoetin alfa to Avoid 
Transfusions in Chronic Kidney Disease 
 
Amgen Protocol Number (Darbepoetin alfa) 20110226 
 
Amendment Date: 
25 June 2013 
 
Rationale: 
The purpose of this amendment is to further limit the potential for subjects with elevated 
blood pressure to be exposed to investigational product in the START-CKD study. 
Therefore, the exclusion criteria for uncontrolled hypertension has been modified. 
 
Additions are noted in bold text.  
 

 
 
 
Product:  Darbepoetin alfa 
Protocol Number:  20110226 
Date:  03 April 2013 
Page 1 of 18 
 
 
 
Amendment 1 
Protocol Title:  START-CKD:  Strategies Using Darbepoetin alfa to Avoid 
Transfusions in Chronic Kidney Disease 
 
Amgen Protocol Number (Darbepoetin alfa) 20110226 
 
Amendment Date: 
03 April 2013 
 
Rationale: 
The key purpose of this amendment is to provide additional measures to improve blood 
pressure control in subjects enrolled in the START-CKD study who are receiving 
investigational product.  
The following changes have been made throughout the protocol:   
• 
The protocol eligibility criteria have been modified and subjects with a mean systolic 
blood pressure > 140 mmHg or a mean diastolic blood pressure > 90 mmHg at both 
screening visits will be excluded 
• 
Additional visits have been added for subjects with elevated blood pressures.  These 
blood pressure monitoring visits will be required for subjects with a mean systolic 
blood pressure ≥ 160mmHg and may be conducted at the investigators discretion for 
those whose mean systolic blood pressure is < 160 mmHg   
• 
The dosing algorithm has been modified such that investigational product will be 
withheld if a subject’s mean systolic blood pressure is ≥ 160 mmHg for 3 consecutive 
visits (including blood pressure monitoring visits) and restarted only when the mean 
systolic blood pressure is ≤ 140 mmHg 
• 
Additional information regarding antihypertensive medication use will be collected at 
each study visit 
• 
Additional information regarding the investigational hemoglobin point of care device 
for the collection of study specific hemoglobin concentrations and the automated 
blood pressure monitor for the collection of blood pressure measurements has been 
provided. Both of these devices are provided by Amgen for use in this trial and the 
results obtained are incorporated into the dosing algorithm. 
Additional clarifications and administrative changes have also been made.  
Additions are noted in bold text.