Phase 3, Randomized, Open-label, Active-controlled Study Evaluating the Efficacy and Safety of Oral Vadadustat for the Maintenance Treatment of Anemia in Subjects With Non-dialysis-dependent Chronic Kidney Disease (NDD-CKD) (PRO2TECT-CONVERSION)
Phase: PHASE3
Conditions: Anemia, Non-Dialysis-Dependent Chronic Kidney Disease
Sponsor: Akebia Therapeutics

AKB-6548-CI-0015 (ClinicalTrials.gov Identifier: NCT02680574; EudraCT Number: 2015-004774-14)
1. Original Protocol
2. Final Protocol
3. Rationale for Change for Protocol Amendments
AKB-6548-CI-0015 
This Supplement Contains: 
Date: 26 Feb 2019 

Protocol No.  AKB-6548-CI-0015 
Akebia — Company Confidential 
Page 1 of 80 
CLINICAL PROTOCOL 
PHASE 3, RANDOMIZED, OPEN-LABEL, ACTIVE-CONTROLLED STUDY 
EVALUATING THE EFFICACY AND SAFETY OF ORAL VADADUSTAT FOR THE 
MAINTENANCE TREATMENT OF ANEMIA IN SUBJECTS WITH NON-DIALYSIS-
DEPENDENT CHRONIC KIDNEY DISEASE (NDD-CKD) 
(PRO2TECT - CONVERSION) 
Compound: 
Vadadustat (AKB-6548) 
Protocol Number: 
AKB-6548-CI-0015 
US IND Number: 
102,465 
EudraCT Number 
2015-004774-14 
Phase: 
Phase 3 
Status/Date: 
Version 1.0/
 
Sponsor: 
Akebia Therapeutics, Inc. 
245 First Street 
Suite 1100 
Cambridge, MA 02142 
United States of America 
This document contains information that is confidential and proprietary to the Sponsor, Akebia Therapeutics, Inc.  
This information is being provided to you solely for the purpose of evaluating and/or conducting a clinical study 
for the Sponsor.  You may disclose the contents of this document only to study personnel under your supervision, 
the Institutional Review Board, the United States Food and Drug Administration, or duly authorized 
representatives of regulatory agencies for this purpose under the condition that they maintain confidentiality.  The 
contents of this document may not be used in any other clinical study, disclosed to any other person or entity, 
and/or published without the prior written permission of the Sponsor.  The foregoing shall not apply to disclosure 
required by any regulations; however, you will give prompt notice to the Sponsor of any such disclosure. 

Protocol No. AKB-6548-CI-0015 
CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title: 
Compound: 
Protocol N um her: 
Status/Date: 
Sponsor Approval: 
Phase 3, Randomized, Open-Label, Active-Controlled Study 
Evaluating the Efficacy and Safety of Oral Vadadustat for 
the Maintenance Treatment of Anemia in Subjects with 
Non-Dialysis-Dependent Chronic Kidney Disease (NDD­
CKD) (PRO2TECT- Conversion) 
Vadadustat (AKB-6548) 
AKB-6548-CI-0015 
Version 1.0/10 November 2015 
By signing this form, I confirm that I have read and that I approve this protocol and that this 
document has been prepared in accordance with the principles of Good Clinical Practices, as 
outlined by the International Conference on Harmonization, and applicable regional regulations. 
Signature: 
Akebia Therapeutics, Inc. 
Akebia - Company Confidential 
Date 

Protocol No.  AKB-6548-CI-0015 
Akebia — Company Confidential 
Page 3 of 80 
1.2 Investigator Agreement 
I confirm that I have read and that I understand this protocol, the Investigator Brochure, and 
other product information provided by the Sponsor.  I agree to conduct this study in accordance 
with the requirements of this protocol and also protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following: 

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonization Guidance for Industry, Good Clinical Practice
E6.

All applicable laws and regulations, including, without limitation, data privacy laws and
regulations.

Regulatory requirements for reporting serious adverse events defined in this protocol.

Terms outlined in the Clinical Study Site Agreement.
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Phone Number 
Full Address 

Protocol No.  AKB-6548-CI-0015 
Akebia — Company Confidential 
Page 4 of 80 
TABLE OF CONTENTS 
1 
SIGNATURE PAGES .................................................................................................. 2 
1.1 
Protocol Approval .................................................................................................... 2 
1.2 
Investigator Agreement ............................................................................................ 3 
2 
PROTOCOL SYNOPSIS .............................................................................................. 9 
3 
LIST OF ABBREVIATIONS ..................................................................................... 19 
4 
BACKGROUND INFORMATION ........................................................................... 22 
4.1 
Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors ..................................... 24 
4.2 
Summary of Clinical Experience ........................................................................... 24 
4.3 
Potential Benefits and Risks ................................................................................... 25 
5 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 26 
5.1 
Primary Objective .................................................................................................. 26 
5.2 
Primary Efficacy Endpoint ..................................................................................... 26 
5.3 
Secondary Efficacy Endpoints ............................................................................... 26 
5.4 
Safety Endpoints .................................................................................................... 27 
6 
STUDY DESIGN ........................................................................................................ 27 
6.1 
Study Design .......................................................................................................... 27 
6.2 
Rationale for Study Design .................................................................................... 29 
6.3 
Dose Justification ................................................................................................... 30 
6.4 
Independent Data Monitoring Committee .............................................................. 30 
6.5 
Endpoint Adjudication Committee ......................................................................... 30 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 30 
7.1 
General Criteria ...................................................................................................... 30 
7.2 
Inclusion Criteria .................................................................................................... 31 
7.3 
Exclusion Criteria ................................................................................................... 31 
7.4 
Retesting and Rescreening ..................................................................................... 32 
7.4.1 
Retesting ............................................................................................................ 32 
7.4.2 
Rescreening ....................................................................................................... 32 
7.5 
Subject Completion, Study Discontinuation, and Withdrawal of Subjects ............ 33 
7.5.1 
Subject Completion ........................................................................................... 33 
7.5.2 
Entire Study Termination .................................................................................. 33 
7.5.3 
Individual Study Site Termination .................................................................... 33 
7.5.4 
Individual Subject Discontinuation ................................................................... 33 
7.5.4.1 
Temporary Interruption of Study Medication ............................................... 34 
7.5.4.2 
Permanent Discontinuation of Study Medication ......................................... 34 
7.5.4.3 
Complete Withdrawal from Further Study Visits/Assessments ................... 34 
7.5.4.4 
Procedures to Encourage Continued Study Participation ............................. 35 

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7.5.4.5 
Procedures to Prevent “Lost to Follow-up” .................................................. 35 
8 
STUDY PRODUCT AND TREATMENT OF SUBJECTS ....................................... 36 
8.1 
Study Product, Supplies, and Storage .................................................................... 36 
8.1.1 
Vadadustat ......................................................................................................... 36 
8.1.2 
Darbepoetin Alfa ............................................................................................... 37 
8.2 
Dispensing Procedures ........................................................................................... 37 
8.2.1 
Dispensing of Vadadustat .................................................................................. 37 
8.2.2 
Dispensing of Darbepoetin Alfa ........................................................................ 37 
8.3 
Product Accountability and Destruction ................................................................ 37 
8.4 
Treatment of Subjects ............................................................................................. 38 
8.4.1 
Treatment Group Assignments .......................................................................... 38 
8.4.2 
Randomization ................................................................................................... 38 
8.4.3 
Blinding ............................................................................................................. 39 
8.4.4 
Dosing and Dose Adjustment Guidelines .......................................................... 39 
8.4.4.1 
Vadadustat Dosing and Dose Adjustment Guidelines .................................. 40 
8.4.4.2 
Darbepoetin Alfa Dosing and Dose Adjustment Guidelines ........................ 41 
8.4.5 
Late or Missed Doses ........................................................................................ 41 
8.4.6 
Iron Supplementation ........................................................................................ 41 
8.4.7 
Rescue Therapy ................................................................................................. 41 
8.4.7.1 
ESA Rescue (Optional) ................................................................................. 42 
8.4.7.2 
Red Blood Cell Transfusion ......................................................................... 42 
8.4.8 
Phlebotomy ........................................................................................................ 42 
8.4.9 
Treatment Compliance ...................................................................................... 43 
8.4.10 
Continuation of Treatment ................................................................................ 43 
8.5 
Prior and Concomitant Therapy ............................................................................. 43 
8.5.1 
General .............................................................................................................. 43 
8.5.2 
Investigational Medications ............................................................................... 43 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES ................................ 43 
9.1 
Administrative Procedures ..................................................................................... 44 
9.1.1 
Informed Consent .............................................................................................. 44 
9.1.2 
Documentation of Screen Failures .................................................................... 44 
9.1.3 
Contraception and Pregnancy Avoidance Measures ......................................... 44 
9.1.4 
Laboratory Accreditation and Reference Ranges .............................................. 45 
9.2 
Study Procedures and Evaluations ......................................................................... 45 
9.2.1 
Clinical Evaluations ........................................................................................... 45 
9.2.2 
Laboratory Evaluations ..................................................................................... 46 
9.3 
Schedule of Activities ............................................................................................ 49 
9.3.1 
Pre-Screening Visit ............................................................................................ 49 

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9.3.2 
Screening Visits ................................................................................................. 49 
9.3.2.1 
Screening Visit 1 (SV1) ................................................................................ 49 
9.3.2.2 
Screening Visit 2 (SV2) ................................................................................ 50 
9.3.2.3 
Subject Retesting .......................................................................................... 50 
9.3.3 
Subject Rescreening .......................................................................................... 50 
9.3.4 
Baseline Visit (Day 1) ....................................................................................... 50 
9.3.5 
Year 1 Treatment Period Visits (Day 2 through Week 52) ............................... 51 
9.3.6 
Year 2 Treatment Period Visits (Weeks 53 through 104) ................................. 52 
9.3.7 
Year 3/4 Treatment Period Visits (Weeks 116 through 208) ............................ 53 
9.3.8 
End of Treatment Visit ...................................................................................... 53 
9.3.9 
Follow-Up Visit ................................................................................................. 54 
10 
ADVERSE EVENTS .................................................................................................. 54 
10.1 
Definitions .............................................................................................................. 54 
10.1.1 
Adverse Events .................................................................................................. 54 
10.1.2 
Serious Adverse Events ..................................................................................... 57 
10.2 
Eliciting Adverse Event Information ..................................................................... 58 
10.3 
Reporting ................................................................................................................ 58 
10.3.1 
Reporting Period ................................................................................................ 58 
10.3.2 
Reporting AEs ................................................................................................... 58 
10.3.3 
Reporting SAEs ................................................................................................. 58 
10.3.4 
Reporting Study Endpoints ................................................................................ 59 
10.3.5 
Relationship to Study Medication ..................................................................... 59 
10.3.6 
Severity .............................................................................................................. 60 
10.3.7 
Follow-Up of Unresolved Events ...................................................................... 60 
10.4 
Exposure In Utero .................................................................................................. 60 
10.5 
Special Situations ................................................................................................... 61 
11 
DATA ANALYSIS ..................................................................................................... 62 
11.1 
Sample Size Determination .................................................................................... 62 
11.1.1 
Sample Size for the Primary Efficacy Endpoint ................................................ 62 
11.1.2 
Sample Size for the Primary Safety Endpoint ................................................... 63 
11.2 
Study Analysis Populations .................................................................................... 63 
11.3 
Analysis of Demographic and Pretreatment Variables .......................................... 63 
11.4 
Disposition of Subjects ........................................................................................... 64 
11.5 
Missing Data .......................................................................................................... 64 
11.6 
Efficacy Analyses ................................................................................................... 64 
11.6.1 
Analysis of Primary Efficacy Endpoint ............................................................. 65 
11.6.1.1 
Primary Analysis of Primary Efficacy Endpoint .......................................... 65 
11.6.1.2 
Sensitivity Analyses of Primary Efficacy Endpoint ..................................... 65 

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11.6.2 
Analysis of Key Secondary Efficacy Endpoints ............................................... 66 
11.6.2.1 
Analysis of Mean Change in HGB Value between Baseline (Mean 
Pretreatment HGB) and the Secondary Evaluation Period (Weeks 40-52) .. 66 
11.6.2.2 
Analysis of Proportion of Subjects with Mean HGB within the Target Range 
during the Primary Evaluation Period (Weeks 24-36) ................................. 66 
11.6.2.3 
Analysis of Mean Weekly Dose of IV Elemental Iron Administered from 
Baseline to Week 52 ..................................................................................... 66 
11.6.2.4 
Analysis of Proportion of Subjects Receiving RBC Transfusion(s) from 
Baseline to Week 52 ..................................................................................... 66 
11.6.3 
Analysis of Additional Secondary Efficacy Endpoints ..................................... 66 
11.7 
Safety Analyses ...................................................................................................... 67 
11.7.1 
Analysis of MACE ............................................................................................ 67 
11.7.2 
Analysis of Adverse Events ............................................................................... 67 
11.7.3 
Remaining Safety Endpoints ............................................................................. 67 
11.8 
Additional Assessments ......................................................................................... 68 
11.8.1 
Concomitant Medications .................................................................................. 68 
11.8.2 
Biomarkers ........................................................................................................ 68 
11.8.3 
Pharmacokinetics ............................................................................................... 69 
12 
DATA HANDLING AND RECORD KEEPING ...................................................... 69 
12.1 
Case Report Forms/Electronic Data Capture ......................................................... 69 
12.2 
Record Retention .................................................................................................... 69 
13 
QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) ....................... 70 
13.1 
Investigative Site Monitoring Visits ...................................................................... 70 
13.2 
Protocol Deviations ................................................................................................ 70 
14 
STUDY DISCONTINUATION/INVESTIGATIVE STUDY SITE TERMINATION
 ..................................................................................................................................... 70 
14.1 
Criteria for Premature Termination or Suspension of the Study ............................ 70 
14.2 
Criteria for Premature Termination or Suspension of Investigational Study Sites 71 
14.3 
Procedures for Premature Termination or Suspension of the Study or 
Investigational Sites ............................................................................................... 71 
15 
ETHICS ....................................................................................................................... 71 
15.1 
Ethical Conduct of the Study ................................................................................. 71 
15.2 
Institutional Review Board/Independent Ethics Committee .................................. 71 
15.3 
Subject Information and Consent ........................................................................... 71 
15.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .... 72 
15.5 
Subject Confidentiality ........................................................................................... 72 
16 
PUBLICATION OF STUDY RESULTS ................................................................... 72 
17 
REFERENCES ............................................................................................................ 73 
APPENDIX A:  SCHEDULE OF ACTIVITIES ................................................................... 75 

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APPENDIX B:  CKD-EPI CREATININE EQUATION ...................................................... 79 
APPENDIX C:  ACTH (COSYNTROPIN) STIMULATION TEST FOR ADRENAL 
FUNCTION MONITORING ...................................................................................... 80 

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2 PROTOCOL SYNOPSIS 
Study Title 
Phase 3, Randomized, Open-Label, Active-Controlled Study Evaluating the Efficacy 
and Safety of Oral Vadadustat for the Maintenance Treatment of Anemia in Subjects 
with Non-Dialysis-Dependent Chronic Kidney Disease (NDD-CKD) 
(PRO2TECT - CONVERSION) 
Protocol Number 
AKB-6548-CI-0015 
Study Phase 
Phase 3 
Investigational 
Product 
Vadadustat; 150 mg tablets 
Reference Medicinal 
Product 
Darbepoetin alfa (Aranesp™); Amgen Inc. 
Study Population 
The study population will consist of subjects ≥18 years of age with NDD-CKD, 
estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, and hemoglobin 
(HGB) between 8.0 and 11.0 g/dL (inclusive) in the United States (US) and between 
9.0 and 12.0 g/dL (inclusive) outside of the US, who are currently treated with an 
erythropoiesis-stimulating agent (ESA) for anemia. 
Investigative Sites 
Approximately 450 investigative sites in North America, Latin America, Europe, and 
Asia Pacific. 
Planned Number of 
Subjects 
Approximately 2100 subjects. 
Primary Objective 
Demonstrate the efficacy and safety of vadadustat compared with darbepoetin alfa for 
the maintenance treatment of anemia in subjects with NDD-CKD after conversion 
from current ESA therapy. 
Study Design 
Overview 
Phase 3, randomized, open-label, active-controlled study of the efficacy and safety of 
vadadustat versus darbepoetin alfa for the maintenance treatment of anemia after 
conversion from current ESA therapy.  Following a Screening period of up to 4 weeks, 
subjects who meet all inclusion and no exclusion criteria will be randomized 1:1 to 
vadadustat or darbepoetin alfa. 
Randomization will be stratified by: 

Geographic region (US versus European Union [EU] versus Rest of World
[ROW])

New York Heart Association congestive heart failure (CHF) Class 0 or I
versus II or III

Study entry HGB (<10.0 versus ≥10.0 g/dL).
Following randomization, there will be 3 periods during the study: 

Conversion and Maintenance Period (Weeks 0-52):  conversion to study
treatment for maintaining HGB (Weeks 0-23), primary efficacy evaluation
(Weeks 24-36), and secondary efficacy evaluation (Weeks 40-52)

Long-Term Treatment Period (Weeks 53-End of Treatment [EOT]):
continued study medication to assess long-term safety

Follow-Up Period (EOT + 4 weeks):  post-treatment visit (either in person or
via telephone) for safety.

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Study Duration 
Estimated time to full enrollment of approximately 2100 randomized subjects is 
20 months, and average follow-up duration is expected to be 1.8 years.  All subjects 
will remain in the study until approximately 631 major adverse cardiovascular events 
(MACE) occur across 2 separate NDD-CKD studies, at which time subjects will be 
scheduled for a final visit and the study will close.  Sites will be notified of the global 
study end date approximately 3 months prior to study closure (based on accrual of 
MACE across the 2 studies) and should inform active subjects of the global study end 
date thereafter. 
Inclusion Criteria 
1.
≥18 years of age
2.
Diagnosis of CKD with an eGFR ≤60 mL/min/1.73 m2 using the 2009
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine
equation at Screening and not expected to start dialysis within 6 months of
Screening
3.
Currently maintained on ESA therapy, with the last dose received within
8 weeks prior to Screening
4.
Mean Screening HGB between 8.0 and 11.0 g/dL (inclusive) in the US and
between 9.0 and 12.0 g/dL (inclusive) outside of the US, as determined by the
average of 2 HGB values measured by the central laboratory during Screening
5.
Serum ferritin ≥100 ng/mL and transferrin saturation (TSAT) ≥20% at
Screening
6.
Folate and vitamin B12 measurements ≥lower limit of normal at Screening
7.
Understands the procedures and requirements of the study and provides
written informed consent and authorization for protected health information
disclosure.
Exclusion Criteria 
1.
Anemia due to a cause other than CKD or subjects with active bleeding or
recent blood loss
2.
Subjects with sickle cell disease, myelodysplastic syndromes, bone marrow
fibrosis, hematologic malignancy, myeloma, hemolytic anemia, thalassemia,
or pure red cell aplasia
3.
Red blood cell (RBC) transfusion within 4 weeks prior to or during Screening
4.
Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase
(SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic
transaminase (SGPT), or total bilirubin >2.0 x upper limit of normal (ULN) at
Screening.  Subjects with a history of Gilbert’s syndrome are not excluded.
5.
Uncontrolled hypertension (confirmed diastolic blood pressure >110 mmHg
or systolic blood pressure >180 mmHg) at Screening
6.
Severe heart failure at Screening (New York Heart Association Class IV)
7.
Acute coronary syndrome (hospitalization for unstable angina or myocardial
infarction), urgent coronary revascularization, hospitalization for CHF, or
stroke within 12 weeks prior to Screening
8.
History of active malignancy within 2 years prior to Screening, except for
curatively resected basal cell carcinoma of skin, squamous cell carcinoma of
skin, cervical carcinoma in situ, or resected benign colonic polyps
9.
History of deep vein thrombosis (DVT) or pulmonary embolism (PE)
requiring active treatment within 8 weeks prior to Screening
10. History of hemosiderosis or hemochromatosis
11. History of prior organ transplantation or scheduled organ transplant (subjects
on kidney transplant wait-list are not excluded), or prior stem cell or bone
marrow transplant (corneal transplants are not excluded)
12. Use of an investigational medication or participation in an investigational

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study within 30 days or 5 half-lives of the investigational medication 
(whichever is longer), prior to the Screening visit 
13. Previous participation in this study, receipt of vadadustat in another study, or
previous participation in a study with another hypoxia-inducible factor
prolyl-hydroxylase inhibitor (HIF-PHI)
14. Females who are pregnant or breast-feeding.  Women of childbearing
potential who are unable or unwilling to use an acceptable method of
contraception
15. Non-vasectomized male subjects who are unable or unwilling to use an
acceptable method of contraception
16. Any other reason that in the opinion of the Investigator would make the
subject not suitable for participation in the study.
Retesting/Rescreening 
Subjects who initially fail to qualify for the study based on laboratory test results may 
be retested once within the 28-day Screening period, per Investigator discretion. 
Subjects who fail to meet the qualifying criteria for HGB or eGFR during a Screening 
period may be considered for rescreening at the discretion of the Investigator if it is felt 
that the subject’s status has progressed and that the subject may now qualify for the 
study.  Additionally, subjects who fail to qualify for the study based on low TSAT, 
ferritin, folate, or B12 values may be considered for rescreening after receiving 
replacement therapy.  Screening is limited to 3 attempts (initial Screening and 
2 additional rescreening attempts). 
Efficacy Endpoints 
Primary 

Mean change in HGB between Baseline (mean pretreatment HGB) and the
primary evaluation period (mean HGB from Weeks 24-36)
Key Secondary 

Mean change in HGB value between Baseline (mean pretreatment HGB) and
the secondary evaluation period (Weeks 40-52)

Proportion of subjects with mean HGB within the target range during the
primary evaluation period (Weeks 24-36)

Mean weekly dose of intravenous (IV) elemental iron administered from
Baseline to Week 52

Proportion of subjects receiving RBC transfusion(s) from Baseline to
Week 52.
Other Secondary 

Progression of CKD

Proportion of HGB values within the target range during the maintenance
period (Weeks 24-52)

Confirmed HGB values <10.0 or >12.0 g/dL

ESA rescue

Dose adjustments

Maintenance of iron sufficiency (defined as ferritin ≥100 ng/mL and
TSAT ≥20%)

Receiving IV iron therapy.

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Safety Endpoints 

MACE, defined as all-cause mortality, non-fatal myocardial infarction, or
non-fatal stroke

Individual components of MACE:
o
All-cause mortality
o
Non-fatal myocardial infarction
o
Non-fatal stroke

Thromboembolic events:  arterial thrombosis, DVT, PE, or vascular access
thrombosis

HGB >12.0 g/dL, >13.0 g/dL, or >14.0 g/dL

HGB increase >1.0 g/dL within any 2-week interval or >2.0 g/dL within any
4-week interval

Adverse events (AEs) and serious adverse events (SAEs)

Vital signs and clinical laboratory values.
Study Procedures and 
Assessments 
See Appendix A:  Schedule of Activities. 
Dosage and Regimens 
Subjects will be randomized 1:1 to either: 
Vadadustat starting dose:  2 tablets once daily (300 mg/day) 
Darbepoetin alfa subcutaneous (SC):  initial dose as follows 

For subjects already on darbepoetin, the initial dosing regimen in the study
should be based on the prior dosing regimen.

For subjects taking other ESAs, the initial dose of darbepoetin should be
based on the approved local product label.
For all subjects, it is recommended that no additional ESA doses be administered after 
Screening visit 2 (SV2) and prior to the Randomization visit. 
Dose Adjustment Guidelines – All Treatment Groups 
Dosing will be initiated at the Baseline visit, and the first dose of study medication 
(vadadustat or darbepoetin alfa) will be administered at the investigative site after other 
Baseline procedures have been completed.  For all subjects, it is recommended that no 
additional ESA doses be administered after SV2 and prior to the Randomization visit. 
Hemoglobin will be monitored via HemoCue® point of care device throughout the 
study to determine if the dose of study medication (vadadustat or darbepoetin alfa) will 
be adjusted or suspended.  From Weeks 0 to 12, HGB will be measured via HemoCue® 
every 2 weeks for monitoring for dose adjustment.  From Week 12 to Week 52, HGB 
via HemoCue® will be monitored every 4 weeks.  From Week 53 through the end of 
the study, HGB will continue to be monitored via HemoCue® to determine if the dose 
of study medication will be adjusted or suspended.  Hemoglobin will also be assessed 
with a complete blood count (CBC) through the central laboratory for efficacy and 
safety evaluations; however, dose adjustments should be based on the local HemoCue® 
HGB value. 
The aim is to maintain a HGB level of 10-11 g/dL in the US and 10-12 g/dL outside 
the US throughout the study. 
Adjustments to doses will be guided by an interactive web response (IWR) system 
based on HGB concentration and programmed Dose Adjustment Algorithms.  The 
programmed Dose Adjustment Algorithm for vadadustat will follow the Dose 
Adjustment Guidelines (see below).  The programmed Dose Adjustment Algorithm for 
darbepoetin alfa will be based on the local product label. 
When adjusting therapy, consider HGB rate of rise, rate of decline, and variability as 
well as the subject’s clinical condition (ie, recent illness, volume depletion, volume 
overload, etc).  In cases of extenuating clinical circumstances, the Investigator may 

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elect to dose outside the IWR system dosing recommendation to maintain the HGB 
within the target range.  In such cases, the clinical circumstances must be documented 
in the subject’s record and collected in the case report form (CRF). 
Vadadustat 
Vadadustat should be dosed according to the following Dose Adjustment Guidelines. 
US 

Do not increase the dose more frequently than once every 4 weeks.  Decreases
in dose can occur more frequently.  Avoid frequent dose adjustments.

If a dose adjustment is required to maintain HGB at the desired level, the
vadadustat dose is adjusted by 1 tablet (minimum dose of vadadustat is
150 mg/day [1 tablet]; maximum dose of vadadustat is 600 mg/day
[4 tablets]).

If the HGB rises rapidly (eg, >1 g/dL in any 2-week period), reduce the dose
of vadadustat by 1 tablet.

If the HGB falls below 10.0 g/dL, increase the dose of vadadustat by 1 tablet.

If the HGB exceeds 11.0 g/dL, interrupt vadadustat until HGB decreases to
10.5 g/dL or less then resume dosing of vadadustat with 1 fewer tablet.
Non-US 

Do not increase the dose more frequently than once every 4 weeks.  Decreases
in dose can occur more frequently.  Avoid frequent dose adjustments.

If a dose adjustment is required to maintain HGB at the desired level, the
vadadustat dose is adjusted by 1 tablet (minimum dose of vadadustat is
150 mg/day [1 tablet]; maximum dose of vadadustat is 600 mg/day
[4 tablets]).

If the HGB rises rapidly (eg, >1 g/dL in any 2-week period), reduce the dose
of vadadustat by 1 tablet.

If the HGB falls below 10.0 g/dL, increase the dose of vadadustat by 1 tablet.

If the HGB level exceeds 12.0 g/dL, reduce the dose of vadadustat by 1 tablet.
If the HGB level exceeds 13.0 g/dL, interrupt vadadustat until HGB decreases
to 12.5 g/dL or less then resume dosing of vadadustat with 1 fewer tablet.
Darbepoetin alfa 
For subjects randomized to darbepoetin alfa, the initial dose will be determined as 
follows: 

For subjects already on darbepoetin, the initial dosing regimen in the study
should be based on the prior dosing regimen.

For subjects taking other ESAs, the initial dose of darbepoetin should be
based on the approved local product label.
Following the dose conversion, darbepoetin alfa will be dosed SC, with dose 
adjustments guided by an IWR system implementing a Dose Adjustment Algorithm 
based on the approved darbepoetin alfa local product label.  Darbepoetin alfa dosing is 
independent of the visit schedule, and the dosing schedule may shift per local standard 
of care and country-specific darbepoetin dosing guidelines. 

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Dosing Instructions 
Vadadustat 
All subjects will start with 2 tablets daily (300 mg/day).  Dose levels of vadadustat 
include 150, 300, 450, and 600 mg (available tablet strength is 150 mg).  Each subject 
will take his/her first dose of vadadustat at the investigative site at the Baseline visit.  
Thereafter, vadadustat will be taken once daily on an outpatient basis.  Subjects may 
take vadadustat with or without food.  The dose should be taken at approximately the 
same time each day, preferably between 7 AM and 2 PM.  The subject should be 
instructed to take any oral iron supplements at least 2 hours before or 2 hours after the 
dose of vadadustat. 
Darbepoetin alfa 
Darbepoetin alfa will be administered, stored, and dispensed according to the approved 
local product label. 
Iron Supplementation 
Investigators should prescribe iron supplementation as needed during the study to 
maintain ferritin ≥100 ng/mL and TSAT ≥20%.  In general, only oral iron should be 
used for therapy.  Intravenous iron use is restricted and should only be administered to 
subjects who have documented intolerance to oral iron and iron deficiency (eg, ferritin 
<100 ng/mL and/or TSAT <20%).  Discontinuation of IV iron is required once the 
subject is no longer iron deficient (ferritin ≥100 ng/mL and TSAT ≥20%). 
Important:  Because of the potential for oral iron to reduce the bioavailability of 
vadadustat, the study medication should not be administered concurrently with an oral 
iron supplement (including multivitamins containing iron).  The subject should be 
instructed to take any oral iron supplements at least 2 hours before or 2 hours after the 
dose of vadadustat. 
Rescue Therapy 
Guidelines 
To ensure the safety of study subjects and to standardize the use of rescue in the study, 
rescue therapy guidelines are provided. 
1. ESA Rescue:  Starting at Week 6, subjects in both treatment arms will be allowed
(although will not be required) to have their HGB rescued with ESA therapy, per the
local standard of care.  When possible, a subject on vadadustat should be on the
maximum dose of vadadustat for 2 weeks prior to ESA rescue.  A subject on
darbepoetin alfa may rescue with another ESA per the standard of care.  To qualify for
ESA rescue, a subject must fulfill ALL of the following:

The subject has experienced a clinically significant worsening of their anemia
or symptoms of anemia (eg, fatigue, weakness, shortness of breath, chest
pain, confusion, or dizziness) compared with Baseline

The subject’s HGB is <9.0 g/dL

Reducing the risk of alloimmunization and/or other RBC transfusion-related
risks is a goal.
The ESA rescue therapy should be administered as per the local institution’s guidelines 
and per the approved local product label.  While receiving ESA rescue therapy, 
subjects must temporarily discontinue taking study medication (vadadustat or 
darbepoetin alfa).  Hemoglobin will be monitored throughout the study at scheduled 
visits as defined in the Schedule of Activities using a HemoCue® point of care device, 
and ESA rescue treatment should be stopped when HGB is ≥9.0 g/dL.  A minimum 
interval must be observed prior to restarting vadadustat after the last dose of rescue 
medication, and treatment may be resumed after the following intervals: 

2 days after last dose of epoetin rescue

7 days after last dose of darbepoetin alfa rescue

14 days after last dose of methoxy polyethylene glycol-epoetin beta rescue.
Following ESA rescue, the study medication should be resumed and adjusted 
according to the Dose Adjustment Guidelines. 

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2. RBC Transfusion:  Investigators should use their local institution’s transfusion
guidelines when determining whether to transfuse a study subject.  In general, in the
event of an acute or severe loss of blood, a RBC transfusion should be administered as
clinically indicated.  In less severe instances but where there may be worsening of
anemia or moderate to severe symptoms of anemia, RBC transfusions are permitted at
the discretion of the Investigator given the medical necessity.  Study medication
(vadadustat or darbepoetin alfa) may be continued during the transfusion period.
Phlebotomy 
If a subject’s HGB exceeds 14.0 g/dL or the rate of rise of HGB raises concern to the 
Investigator, the subject may be phlebotomized based on the Investigator’s judgment.  
The method of phlebotomy will be in accordance with the investigative site’s standard 
clinical practice. 
Subject Completion, 
Premature 
Termination of Study 
Medication, or 
Withdrawal from the 
Study 
Subject Completion 
A subject will be considered as having completed the study, regardless of whether the 
subject is on or off study medication, if the subject is followed until the global study 
end date as determined by the accrual of MACE.  Subjects who continue on the study 
medication up to the global study end date will continue receiving vadadustat or 
darbepoetin alfa until the EOT visit.  A post-treatment follow-up either in person or via 
telephone will occur approximately 4 weeks after the EOT visit.  The need for rescue 
therapy or the occurrence of safety endpoints do not constitute study completion and 
are not criteria for subject withdrawal from the study or study medication (vadadustat 
or darbepoetin alfa). 
Discontinuation of Study Medication Treatment 
During the course of this long-term study, it is anticipated that subjects may 
temporarily interrupt or permanently discontinue study medication (vadadustat or 
darbepoetin alfa) for any of the following reasons: 

Unacceptable toxicity or drug intolerability

Investigator discretion

Subject withdrawal of consent

Subject becomes pregnant

Development of end-stage kidney disease and initiation of ongoing chronic
hemodialysis or peritoneal dialysis or receipt of a kidney transplant.  (Note
that a subject who receives transient acute dialysis may still continue study
medication per Investigator discretion.)

Other reasons.
Subjects who either temporarily interrupt or permanently discontinue study 
medication (vadadustat or darbepoetin alfa) after randomization and prior to 
completion of the study should continue with study visits and assessments through 
Week 52 and should be followed for safety assessments after Week 52 (see 
“Procedures to Avoid Withdrawal or Lost to Follow-Up” below).  Unless 
contraindicated, treatment should be resumed wherever possible and routinely 
considered at every visit following study medication interruption/discontinuation. 
Receipt of rescue therapy is not a reason for permanent study medication 
discontinuation.  While receiving ESA rescue, subjects must temporarily discontinue 
study medication, but should resume study medication following the end of rescue 
therapy. 
Complete Withdrawal from Study Visits/Assessments 
Subjects may request to be withdrawn or may be withdrawn from the study prior to 
completion only for the following reasons:  

Death

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
Withdrawal of informed consent (complete withdrawal of consent requires a
subject’s refusal of ALL methods of follow-up noted in the informed consent
form:  procedures, participation in reduced procedures/study visits, telephone
contact only or alternative contact only, source document or designated
alternative contact, or access to medical records from alternative sources)

Lost to follow-up (detailed procedures to prevent subjects from becoming
“lost to follow-up” are provided below and these procedures must be followed
by the Investigators, their staff, and all designated study personnel).
Procedures to Avoid 
Withdrawal or Lost to 
Follow-Up 
Avoiding Study Discontinuation 
As part of the informed consent process, only subjects who fully understand and agree 
to full participation and long-term follow-up should be consented to participate. 
In all cases of impending study medication discontinuation, subject request for 
withdrawal from study visits, or consent withdrawal, Investigators should discuss with 
the subject their options of continuing in the study. 
The Investigator should ensure understanding and documentation of the reasons for a 
subject’s desire to stop study procedures or stop study medication. 
Minimizing Lost to Follow-Up 
The Investigator must make every effort to contact subjects who fail to return for 
scheduled visits so that they will not be declared “lost to follow-up.”  These actions 
must include, but are not limited to, the following: 
1. Contact all telephone numbers for the subject and his/her listed contacts (to be
collected in the source at the subject’s entry into the study), as applicable.  This
includes making phone calls after normal business hours or on holidays or weekends.
2. Contact the subject’s primary care physician, referring specialist, pharmacist, or
other healthcare professional, as applicable.
3. Send email, text, and postal mail with certified letters to all of the subject’s
addresses and contacts, as applicable.
4. Review available medical records/notes for details of hospitalizations, clinic visits,
or other procedures that may indicate the status of the subject, as applicable.
5. Utilize the internet to search for additional contact information, as applicable.
6. Check local, regional, and national public records to locate the subject or search for
mortality status as allowed by law, as applicable.
Once all of these actions have been exhausted and documented then the Sponsor or 
Sponsor representative should be contacted for additional guidance. 
Study Termination/ 
Individual Study Site 
Termination 
The entire study may be suspended or terminated by the Sponsor for safety or other 
unanticipated reasons or upon request of regulatory agencies.  If this occurs, prompt 
notification will be given to Investigators, Institutional Review Boards 
(IRBs)/Institutional Ethics Committees (IECs), and regulatory authorities in 
accordance with regulatory requirements. 
The Investigator must notify the Sponsor if the study is terminated by the Investigator 
or the IRB/IEC at the investigative site.  If the Investigator, IRB/IEC, or Sponsor 
decides to terminate or suspend the study conducted at a particular investigative site for 
safety, non-enrollment, non-compliance with the protocol, or other unanticipated 
reasons, the above parties will be promptly notified. 

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Statistical 
Considerations 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is defined as the mean HGB change from Baseline 
(mean pretreatment HGB) to the mean HGB from Weeks 24-36 (inclusive). 
The primary analysis will use an analysis of variance (ANOVA), stratified by the 
randomization strata with strata weighted by the stratum size. 
A 2-sided, 95% confidence interval will be calculated for the difference between the 
vadadustat group and control group.  Noninferiority of vadadustat will be established if 
the lower limit of this confidence interval is ≥-0.5 g/dL. 
MACE Analysis 
The MACE endpoint (adjudicated result) will be analyzed as the time from first dose of 
study medication to first MACE.  Subjects who have not experienced an adjudicated 
MACE by study closure will be censored as of their last assessment time. 
Major adverse cardiovascular events will be analyzed using a stratified Cox 
proportional hazards model with a model containing treatment group.  The 
randomization strata will be used in this analysis.  The primary MACE analysis will 
take place at study conclusion and will be based upon all subjects in the safety 
population.  The hazard ratio (vadadustat/control) will be estimated, together with its 
95% confidence interval.  As this individual study has not been powered to provide a 
stand-alone estimate of the hazard ratio for MACE, this interval will be considered as 
descriptive.  The time to first MACE will also be graphically presented using 
Kaplan-Meier curves. 
The primary analysis for MACE will be performed using the safety population.  These 
analyses will be repeated with censoring occurring 4 weeks following early 
discontinuation of study medication. 
An independent statistical analysis center will perform analyses in support of the 
Independent Data Monitoring Committee (IDMC). 
Sample Size 
Estimation 
For the primary efficacy analysis in this study, it will be assumed that the difference in 
mean change in HGB for vadadustat will be the same as the active control, darbepoetin 
alfa, and the common standard deviation for the mean change will be assumed to be 
1.5 g/dL.  The noninferiority margin of -0.5 g/dL will be used.  With these assumptions 
and approximately 1050 subjects per treatment group, the noninferiority evaluation 
will have >99% power. 
The primary MACE analysis will be based upon all events that accrue over 
2 separately planned NDD-CKD studies (Studies AKB-6548-CI-0014 and 
AKB-6548-CI-0015).  It has been calculated that 631 events will be required overall to 
have 80% power to establish noninferiority with a margin of 1.25, and >90% power to 
establish noninferiority with a margin of 1.3, evaluated with a 2-sided 95% confidence 
interval assuming no difference between the treatments.  The power is >90% to 
establish a noninferiority margin of 1.25 if the hazard ratio is 0.95 favoring vadadustat.  
A MACE rate of 10% annually is anticipated in both treatment arms based on a 
comprehensive review of available epidemiology and prospective clinical studies in the 
field.  With 1050 subjects per treatment group enrolled in this study, approximately 
20 months for accrual, and up to 36 months of follow-up, approximately 68% of the 
needed MACE (429) would be captured. 
Independent Data 
Monitoring 
Committee 
An IDMC will be established to review and discuss the available study safety data as 
subjects are enrolled and followed.  The team will meet approximately twice per year 
throughout the course of the study.  The IDMC will be unblinded and will include, at a 
minimum, a nephrologist, a cardiologist, and a biostatistician.  The discussions of the 
IDMC will include a review of key safety data (ie, AEs, vital signs measurements, and 
laboratory assessments). 

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Endpoint 
Adjudication 
Committee (EAC) 
An independent safety EAC, blinded to treatment group, will be formed prior to study 
commencement to adjudicate the components of the primary safety endpoints (eg, 
death, myocardial infarction, and stroke).  Thromboembolic events will also be 
adjudicated by the EAC. 

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3 LIST OF ABBREVIATIONS 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
ALT 
alanine aminotransferase (SGPT) 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase (SGOT) 
BUN 
blood urea nitrogen 
C 
Celsius 
CBC 
complete blood count 
CHF 
congestive heart failure 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CMH 
Cochran-Mantel-Haenszel 
CPK 
creatine phosphokinase 
CRF 
case report form 
CRO 
contract research organization 
CS 
clinically significant 
CV 
cardiovascular 
CVD 
cardiovascular disease 
dL 
deciliter 
DVT 
deep venous thrombosis 
EAC 
Endpoint Adjudication Committee 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOT 
end of treatment 
EPO 
erythropoietin 
ESA 
erythropoiesis-stimulating agent 
ESRD 
end-stage renal disease 
EU 
European Union 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
g 
gram 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GMP 
Good Manufacturing Practice 
HA 
health authority 
HDL 
high-density lipoprotein 
HGB 
hemoglobin 
HIF 
hypoxia-inducible factor 
HIFPH 
hypoxia-inducible factor prolyl-hydroxylase 
HIF-PHI 
hypoxia-inducible factor prolyl-hydroxylase inhibitor 
IC50 
50% inhibitory concentration 
ICH 
International Conference on Harmonization 

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IDMC 
Independent Data Monitoring Committee 
IDMS 
isotope dilution mass spectrometry 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
IV 
intravenous(ly) 
IWR 
interactive web response 
JSDT 
Japanese Society for Dialysis Therapy 
JSN 
Japanese Society of Nephrology 
KDIGO 
Kidney Disease:  Improving Global Outcomes 
kg 
kilogram 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LLN 
lower limit of normal 
MACE 
major adverse cardiovascular events 
MCH 
mean corpuscular (cell) hemoglobin 
MCHC 
mean corpuscular (cell) hemoglobin concentration 
MCV 
mean corpuscular (cell) volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
µM 
micromolar 
mg 
milligram 
mL 
milliliter 
mRNA 
messenger ribonucleic acid  
MTD 
maximum tolerated dose 
NDD-CKD 
non-dialysis dependent chronic kidney disease 
ng 
nanogram 
PD 
pharmacodynamics(s) 
PE 
pulmonary embolism 
PHD 
prolyl 4-hydroxylase domain 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QA 
quality assurance 
QC 
quality control 
RBC 
red blood cell 
RDW 
red cell distribution width 
ROW 
rest of world 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous(ly) 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
SmPC 
summary of product characteristics 
SV 
Screening visit 
TIBC 
total iron binding capacity 

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TREAT 
Trial to Reduce Cardiovascular Events with Aranesp Therapy 
TSAT 
transferrin saturation 
uACR 
urine albumin-to-creatinine ratio 
ULN 
upper limit of normal 
US 
United States 
VEGF 
vascular endothelial growth factor 
WBC 
white blood cell 
WHO 
World Health Organization 

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4 BACKGROUND INFORMATION 
Chronic kidney disease (CKD), defined as the presence of kidney damage or a decreased level of 
kidney function, is a major public health problem worldwide.  Globally, CKD is estimated to 
affect between 8-16% of the population (Jha et al. 2013; KDIGO 2013).  At the most advanced 
stages of CKD, end-stage renal disease (ESRD), patients require chronic dialysis or kidney 
transplantation to sustain life.  Chronic kidney disease is not only a cause of ESRD, but is also a 
significant risk factor for cardiovascular disease (CVD), infection, cancer, and mortality (Iseki 
and Kohagura 2007). 
Renal anemia often develops during the progression of CKD and is present in almost all patients 
with ESRD.  Anemia is defined as a decrease in circulating red blood cell (RBC) mass that is 
usually detected by low hemoglobin (HGB) concentration.  The causes of anemia in CKD 
include blood loss, shortened RBC lifespan, iron deficiency, erythropoietin (EPO) deficiency, 
and inflammation (Nurko 2006).  Although many factors contribute to anemia in CKD, it occurs 
primarily due to an inadequate synthesis of EPO by the kidneys, leading to a deficiency in the 
production of RBC progenitor cells by the bone marrow.  Also contributing to anemia in CKD 
are impaired iron homeostasis and iron loss, which often necessitate iron supplementation 
(Nurko 2006).  Anemia in CKD patients usually occurs when the glomerular filtration rate 
(GFR) falls below 60 mL/min/1.73 m2, and is present in >90% of the patients undergoing 
dialysis (CKD Stage 5) (Goodkin et al. 2011). 
The main impact of anemia on organ function is reduced oxygen delivery to tissues leading to a 
constellation of symptoms including fatigue, shortness of breath, and exercise intolerance 
(Stauffer and Fan 2014).  In patients with anemia related to CKD, compensatory changes occur 
in cardiac structure and function, including an increase in cardiac output, the development of left 
ventricular hypertrophy, and, eventually, the development of heart failure (Metivier et al. 2000).  
Risk of stroke also increases with anemia, which may be an underlying mechanism leading to 
stroke in CKD (Abramson et al., 2003; Iseki and Kohagura 2007).  Other consequences from 
anemia in CKD patients include impaired cognitive function, sleep disorders, and depressed 
immune function, which can impact the quality of life in these patients (Iseki and 
Kohagura 2007; NICE 2011).  Overall, anemia contributes to a poorer prognosis in patients with 
CKD (Nurko 2006; Iseki and Kohagura 2007). 
Erythropoiesis-stimulating agents (ESAs) administered either intravenously (IV) or 
subcutaneously (SC), along with oral or IV iron therapy, are currently the cornerstones for 
treating anemia in patients with CKD.  Treatment with exogenous recombinant ESAs can raise 
HGB levels, relieve symptoms, and reduce the complications of anemia, including RBC 
transfusions which carry the risks of infection, iron overload, and impact candidacy for kidney 
transplantation. 
Clinical practice guidelines and prescribing information for approved ESAs and guidelines 
provided by the United States (US) Food and Drug Administration (FDA), the European Union 
(EU), the Japanese Society of Nephrology, and the Japanese Society for Dialysis Therapy 
Guideline Committee differ slightly in their recommendations for treatment of renal anemia, as 
summarized in Table 1. 

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Table 1 
Treatment Guidelines and Prescribing Information for Renal Anemia in 
NDD-CKD 
KDIGO guidelines 
Treatment should occur in symptomatic patients and when HGB generally falls below 
10 g/dL (Kidney Disease:  Improving Global Outcomes [KDIGO] 2012). 
US darbepoetin alfa 
label 
Same as other approved ESAs, but also recommend that if HGB exceeds 10 g/dL in adults 
not on dialysis, the dose of ESA should be reduced or interrupted (Aranesp® US Package 
Insert 2015). 
EU practice 
guidelines 
Recommend that in high-risk patients with NDD-CKD, treatment with ESAs should be 
initiated when the HGB levels are between 9 g/dL and 10 g/dL, although in low-risk 
patients and those in whom a clear benefit of quality of life can be foreseen, the initiation 
of ESA therapy could be considered at higher HGB levels (Locatelli 2013). 
Japan practice 
guidelines 
JSDT recommends that ESA treatment be initiated when HGB is below 11 g/dL following 
a diagnosis of renal anemia in NDD-CKD.  JSN 2013 does not provide a clear 
recommendation or maintenance range for HGB.  Both guidelines recommend that if the 
HGB exceeds 13 g/dL, the dose of ESA should be reduced or interrupted.  In patients with 
CVD or complications, ESA treatment should be reduced or interrupted if the HGB 
exceeds 12 g/dL (Tsubakihara 2010; Japanese Society of Nephrology 2014). 
Abbreviations:  CVD = cardiovascular disease; ESA = erythropoietin stimulating agent; EU = European Union; 
HGB = hemoglobin; JSDT = Japanese Society for Dialysis Therapy; JSN = Japanese Society of Nephrology; 
KDIGO = Kidney Disease Improving Global Outcomes; NDD-CKD = non-dialysis dependent chronic kidney disease; 
US = United States. 
The majority of patients with CKD currently receives interventional therapy in the form of iron 
therapy, and may initiate therapy with an ESA if other interventions fail and HGB levels fall 
below 9 to 11 g/dL, dependent upon local clinical practice guidelines. 
A number of large, prospective, randomized controlled trials in CKD (Stages 3 to 5) have 
explored the potential benefit of ESAs in patients with CKD with respect to overall mortality, 
cardiovascular (CV) events, and progression of CKD with higher HGB targets (≥13 g/dL) 
(Besarab et al. 1998; Drüeke et al. 2006; Singh et al. 2006; Pfeffer et al. 2009a; Pfeffer 
et al. 2009b).  These trials did not demonstrate the expected beneficial effects of correcting 
anemia on these outcomes, but suggested an increased risk of death and CV events when 
targeting higher HGB levels (Besarab et al. 1998; Drüeke et al. 2006; Singh et al. 2006; Pfeffer 
et al. 2009a; Pfeffer et al. 2009b).  Additional analyses from these trials suggest that the risk of 
death or CV events appears to be highest in CKD patients who fail to respond to ESAs, as 
indicated by lower achieved HGB levels and higher average ESA dose requirements (Szczech 
et al. 2008; Solomon et al. 2010).  This suggests that in some subjects the ESAs themselves, and 
not the HGB level, may be causative of the increase in events.  This is supported by studies in 
CKD patients on dialysis with naturally high HGB levels and no increase in CV events (Goodkin 
et al. 2011). 
The risks identified with ESAs from these trials have led to changes in prescribing information 
and practice guidelines in the US, the EU, and Japan that guide clinicians toward more cautious 
use of ESAs and targeting lower HGB levels.  In the US, the mortality and CV risks associated 
with ESAs are outlined in a black-box warning in the prescribing information of ESAs with a 
recommendation to use the lowest dose possible to avoid transfusions.  While no similar major 
warnings exist in the EU Summary of Product Characteristics (SmPC) or on the approved 
labeling for ESAs in Japan, the EU SmPCs for ESAs do suggest caution with the use of these 

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drugs, with a recommendation to keep HGB levels below 12 g/dL, while the Japanese practice 
guidelines recommend ESA treatment be reduced or interrupted if the HGB exceeds 12 g/dL in 
patients with CVD or complications.  Further, recent EU clinical practice guidelines (Locatelli et 
al. 2013) recommend that risk factors for stroke (including a past history of stroke) and the 
presence of active malignancy or a past history of malignancy should be taken into account when 
making decisions to use ESAs for the treatment of anemia. 
The risks associated with ESAs, including an increased risk of death and CV events, highlight 
the need for additional therapies that might minimize or avoid these risks when compared to 
currently available recombinant protein-based ESAs.  Therefore, the unmet medical need for the 
treatment of anemia in non-dialysis dependent CKD (NDD-CKD) patients remains high, 
especially from a CV safety perspective.  To fulfill this unmet need, the vadadustat clinical 
program is focused on developing an orally active therapeutic for the treatment of anemia in 
patients with CKD. 
4.1 Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors 
Please see the vadadustat Investigator Brochure for additional discussion and information for 
the following section. 
Vadadustat is a novel, synthetic, orally bioavailable, small molecule being developed as an 
inhibitor of hypoxia-inducible factor prolyl-hydroxylases (HIFPHs) for the treatment of anemia 
associated with CKD.  Hypoxia-inducible factor prolyl-hydroxylase enzymes are also referred to 
as prolyl 4-hydroxylase domains (PHDs), of which the 2 most commonly expressed are PHD2 
and PHD3.  Vadadustat is a slightly more potent inhibitor of PHD3 (50% inhibitory 
concentration [IC50] = 0.08 µM) than of PHD2 (IC50 = 0.19 µM).  The inhibition of PHD3 and 
PHD2 stabilizes hypoxia-inducible factor (HIF)-2α and HIF-1α, which in turn stimulates the 
production of EPO.  In vivo animal efficacy and messenger ribonucleic acid (mRNA) data 
indicate that vadadustat induces the production of EPO from both renal and extra-renal sites 
(liver and brain), and this increase in EPO results in an increase in RBC production in the bone 
marrow.  In clinical trials, vadadustat has been shown to facilitate iron homeostasis by 
decreasing hepcidin and increasing transferrin levels in healthy adult male volunteers and male 
and female CKD patients.  This enables iron transport mechanisms that should enhance the 
terminal steps of erythropoiesis.  Vadadustat offers the potential of flexible oral dosing that 
provides a more gradual and reliable means of titration than injectable hormones.  Therefore, 
vadadustat is being developed as an alternative to the existing protein hormone ESAs. 
4.2 Summary of Clinical Experience 
Please see the vadadustat Investigator Brochure for additional discussion and information for 
the following section. 
To date, the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of 
vadadustat have been characterized in 6 completed Phase 1 studies in healthy volunteers, 
1 completed Phase 1 study in subjects undergoing chronic hemodialysis, 3 completed Phase 2a 
studies in NDD-CKD subjects, and 1 completed Phase 2b study in NDD-CKD subjects.  The 
Phase 2a studies evaluated Stages 3, 4, and 5 CKD (not on dialysis) subjects in a single-dose PK 
study, a multi-dose, 28-day, open-label, dose escalation pilot study, and a randomized, 
placebo-controlled study with 5 different dose groups dosed for 42 days.  The Phase 2b study 
evaluated Stages 3, 4, and 5 CKD (pre-dialysis).  A total of 379 subjects have received 

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vadadustat, including 125 healthy volunteers and 254 subjects with CKD (242 subjects with 
Stage 3, 4, or 5 not on dialysis and 12 subjects with ESRD or Stage 5 on dialysis).  An additional 
94 subjects have been dosed with vadadustat in a recently completed open-label, dose range 
finding efficacy study in subjects with ESRD on dialysis for 16 weeks of dosing. 
Overall, vadadustat has been well-tolerated and has demonstrated consistent, dose proportionate 
PK and PD.  Vadadustat has demonstrated the desired and anticipated effects of raising EPO 
concentrations in a dose-dependent manner in Phase 1 and Phase 2a studies.  The changes in 
EPO have been accompanied by dose responsive increases in iron mobilization (increased total 
iron binding capacity [TIBC] and transferrin and decreased hepcidin and ferritin).  Together, 
these effects have stimulated an increase in reticulocytes and HGB.  Vadadustat has generally 
been well-tolerated with limited adverse events (AEs) and serious adverse events (SAEs) 
observed to date.  The urinary excretion of the compound has been shown to be less than 50% in 
healthy human volunteers, which makes the compound appropriate for use in subjects with CKD. 
A recently completed Phase 2b, randomized, double-blind, placebo-controlled study to assess the 
hematologic PD response, safety, and tolerability of oral vadadustat for 20 weeks was performed 
in 210 subjects with anemia associated with NDD-CKD.  Subjects were assigned to a study 
group based on their ESA status at Screening (naïve, previously treated, or actively treated) and 
were randomized 2:1 to receive either vadadustat at a starting dose of 450 mg/day or placebo.  
The dose of vadadustat was adjusted based on HGB levels and changes in HGB.  A significantly 
higher proportion of subjects with a successful HGB response at the end of treatment was 
observed with vadadustat treatment when compared with placebo.  The dosing algorithm was 
effective in minimizing excessive HGB levels (>13.0 g/dL) and a consistent and sustained 
improvement in iron mobilization was observed with treatment with vadadustat.  The safety 
profile of vadadustat in this study was generally consistent with that observed in prior studies. 
Based on the Phase 1 and Phase 2 study results, vadadustat appears to be a suitable candidate for 
continued development as a treatment for anemia in patients with CKD. 
4.3 Potential Benefits and Risks 
Please see the vadadustat Investigator Brochure for additional discussion and information for 
the following section. 
Vadadustat offers the potential of flexible oral dosing that is easier to titrate than injectable 
hormone ESAs.  This alternate therapeutic approach may avoid the overshoots and fluctuations 
in HGB levels seen with currently available injectable ESAs and provide for a controlled, steady 
rise in HGB concentration.  This less aggressive approach to modifying the HGB concentration 
may be of benefit based on the FDA’s suggestion that fluctuations in HGB concentrations, 
rapidly increasing HGB levels, and overshoots of the target level are associated with an 
increased risk of CV events (Unger 2007; Unger et al. 2010). 
In addition, since HIFs downregulate the iron absorption regulator hepcidin, and upregulate the 
iron-mobilizing regulators ferroportin and transferrin (and its receptor) (Peyssonnaux et al. 
2007), vadadustat will likely enhance iron metabolism and transport, thereby enhancing EPO 
responsiveness.  In the Phase 1b multiple ascending dose study, a prominent effect on iron 
metabolism was noted with the dosing of vadadustat, including a rapid increase in iron uptake, a 
dose responsive increase in TIBC, decreases in hepcidin and ferritin, and an increase in 

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transferrin.  A similar pattern was observed in the Phase 2a and 2b studies, with dose responsive 
increases in TIBC and decreases in ferritin and hepcidin. 
To date, all of the acute findings observed at doses less than the maximum tolerated dose (MTD) 
in animals have been shown to be reversible and dose-related.  In addition, most of the findings 
have followed a pattern that would have been predicted based on the known HIF and HIFPH 
biochemistry, pharmacology, and human genetic variations (Chuvash polycythemia, etc).  In the 
completed clinical studies, vadadustat has been generally well-tolerated. 
5 STUDY OBJECTIVES AND ENDPOINTS 
5.1 Primary Objective 
The primary objective of this study is to demonstrate the efficacy and safety of vadadustat 
compared with darbepoetin alfa for the maintenance treatment of anemia in subjects with 
NDD-CKD after conversion from current ESA therapy. 
5.2 Primary Efficacy Endpoint 
The primary endpoint used to assess the efficacy objective will be the mean change in HGB 
between Baseline (mean pretreatment HGB) and the primary evaluation period (mean HGB from 
Weeks 24-36). 
5.3 Secondary Efficacy Endpoints 
Key secondary efficacy endpoints include the following: 

Mean change in HGB value between Baseline (mean pretreatment HGB) and the
secondary evaluation period (Weeks 40-52)

Proportion of subjects with mean HGB within the target range during the primary
evaluation period (Weeks 24-36)

Mean weekly dose of IV elemental iron administered from Baseline to Week 52

Proportion of subjects receiving RBC transfusion(s) from Baseline to Week 52.
Other secondary efficacy endpoints include: 

Progression of CKD

Proportion of HGB values within the target range during the maintenance period
(Weeks 24-52)

Confirmed HGB values <10.0 or >12.0 g/dL

ESA rescue

Dose adjustments

Maintenance of iron sufficiency (defined as ferritin ≥100 ng/mL and transferrin
saturation [TSAT] ≥20%)

Receiving IV iron therapy.

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5.4 Safety Endpoints 
Safety endpoints in this study include the following: 

Major adverse cardiovascular events (MACE), defined as all-cause mortality, non-fatal
myocardial infarction, or non-fatal stroke

Individual components of MACE:

All-cause mortality

Non-fatal myocardial infarction

Non-fatal stroke

Thromboembolic events:  arterial thrombosis, deep vein thrombosis (DVT), pulmonary
embolism (PE), or vascular access thrombosis

HGB >12.0 g/dL, >13.0 g/dL, or >14.0 g/dL

HGB increase >1.0 g/dL within any 2-week interval or >2.0 g/dL within any 4-week
interval

AEs and SAEs

Vital signs and clinical laboratory values

Adrenal function assessment in a subset of subjects (see Appendix C:  ACTH
(Cosyntropin) Stimulation Test for Adrenal Function Monitoring).
6 STUDY DESIGN 
6.1 Study Design 
This is a Phase 3, randomized, open-label, active-controlled study of the efficacy and safety of 
vadadustat versus darbepoetin alfa for maintenance treatment of anemia after conversion from 
current ESA therapy in subjects with NDD-CKD.  Target enrollment in this study is 
approximately 2100 subjects at approximately 450 investigative sites in North America, Latin 
America, Europe, and Asia Pacific. 
Subjects will be randomized at the Baseline visit using an Interactive Web Response (IWR) 
system to receive either vadadustat or darbepoetin alfa.  For all subjects, it is recommended that 
no additional ESA doses be administered after Screening visit 2 (SV2) and prior to the 
Randomization visit. 
To monitor adrenal function, a subset of 100 subjects per treatment arm (200 subjects total) in 
the EU will also undergo sequential adrenocorticotropic hormone (ACTH [cosyntropin]) adrenal 
stimulation tests at Baseline (predose), as well as at the Week 12 and Week 52 study visits, or at 
the end of treatment (EOT) visit if the subject permanently discontinues study medication early 
prior to the Week 52 study visit (Appendix C:  ACTH (Cosyntropin) Stimulation Test for 
Adrenal Function Monitoring). 
Randomization will be stratified by geographic region (US versus EU versus rest of world 
[ROW]), New York Heart Association congestive heart failure (CHF) Class 0 or I versus II or 
III, and study entry HGB level (<10.0 g/dL versus ≥10.0 g/dL based on the most recent central 
laboratory HGB measurement prior to the Baseline/Randomization visit).  Following 
randomization, there will be 3 periods during the study: 

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
Conversion and Maintenance Period (Weeks 0-52):  conversion to study medication for
maintaining HGB (Weeks 0-23), primary efficacy evaluation (Weeks 24-36), and
secondary efficacy evaluation (Weeks 40-52)

Long-term Treatment Period (Week 53-EOT):  continued study medication to assess
long-term safety

Follow-up Period (EOT + 4 weeks):  post-treatment visit for safety (either in person or
via telephone).
A HemoCue® point of care device will be used throughout the study to monitor HGB to 
determine if the dose of study medication (vadadustat or darbepoetin alfa) will be adjusted.  
From Weeks 0 to 12, HemoCue® will be used to monitor HGB every 2 weeks for dose 
adjustment.  From Week 12 to Week 52, HGB will be monitored via HemoCue® every 4 weeks.  
From Week 53 through the end of study, HGB will continue to be monitored via HemoCue® to 
determine if the dose of study medication will be adjusted or suspended.  Hemoglobin will also 
be assessed with a complete blood count (CBC) through the central laboratory for efficacy and 
safety evaluations; however, dose adjustments should be based on the HemoCue® HGB value. 
The aim of the dosing strategy is to maintain HGB levels of 10.0 g/dL to 11.0 g/dL in the US 
and 10.0 g/dL to 12.0 g/dL outside of the US throughout the study. 
Subjects assigned to vadadustat will initiate dosing at 2 tablets once daily at the Baseline visit.  
Adjustments to doses for vadadustat will be guided by an IWR system based on HGB 
concentration and a programmed Dose Adjustment Algorithm (Section 8.4.4.1, Vadadustat 
Dosing and Dose Adjustment Guidelines).  Dosing will be suspended if HGB rises to >11.0 g/dL 
(US investigative sites) or >13.0 g/dL (non-US investigative sites), and will not be restarted until 
HGB levels are reduced to ≤10.5 g/dL (US investigative sites) or ≤12.5 g/dL (non-US 
investigative sites) (see Section 8.4.4.1, Vadadustat Dosing and Dose Adjustment Guidelines for 
details regarding dose suspension). 
Subjects assigned to darbepoetin alfa will be dosed SC at the Baseline visit and the initial dose 
will be determined based on the approved local product label.  Dose adjustments will be guided 
by an IWR system implementing a programmed Dose Adjustment Algorithm based on the local 
product label (Section 8.4.4.2, Darbepoetin Alfa Dosing and Dose Adjustment Guidelines).  
Darbepoetin alfa dosing is independent of the visit schedule, and the dosing schedule may shift 
per local standard of care and country specific dosing guidelines. 
Investigators should prescribe iron supplementation as needed during the study to maintain 
ferritin ≥100 ng/mL and TSAT ≥20% (see Section 8.4.6, Iron Supplementation for details 
regarding iron supplementation during the study). 
Clinical and safety assessments (including laboratory assays, PK evaluations [both vadadustat 
parent compound and metabolites], MACE endpoint data, vital sign measurements, and AEs) 
will be performed as indicated at Screening, during the Conversion and Maintenance Period 
(Weeks 0-52), during the Long-term Treatment Period (visits approximately every 3 months), 
and during the Follow-up Period (4 weeks after the EOT).  Refer to Section 9, Study Procedures 
and Schedule of Activities and Appendix A:  Schedule of Activities for additional details. 
All subjects will remain in the study until approximately 631 MACE occur across 2 separately 
planned NDD-CKD studies (Studies AKB-6548-CI-0014 and AKB-6548-CI-0015), at which 

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time subjects will be scheduled for a final visit and the study will close (see Section 11.1.2, 
Sample Size for the Primary Safety Endpoint). 
6.2 Rationale for Study Design 
During prior clinical trials, vadadustat has been well-tolerated, and has demonstrated consistent, 
dose proportionate PK and PD.  Vadadustat has demonstrated the desired and anticipated effects 
of raising EPO concentrations in a dose-dependent manner in Phase 1 and Phase 2 studies.  The 
changes in EPO have been accompanied by dose responsive increases in iron mobilization 
(increased TIBC and transferrin and decreased hepcidin and ferritin).  Together, these effects 
have stimulated an increase in reticulocytes and HGB.  Vadadustat has generally been 
well-tolerated with limited AEs.  Finally, the urinary excretion of vadadustat has been shown to 
be less than 50% in humans which makes the compound appropriate for evaluation in subjects 
with CKD.  Based on the Phase 1 and Phase 2 study results, continued development of 
vadadustat as a treatment for anemia in patients with CKD is warranted. 
In this study, darbepoetin alfa was chosen as an active comparator as it has a longer half-life than 
epoetin alfa and, therefore, requires less frequent dosing visits.  Selection of a comparator is 
challenging in the current medical and regulatory climate given the accumulating trial findings 
that resulted in the FDA revising the prescribing information for the currently marketed ESAs.  
These trial results indicate an increased risk of death and adverse CV events, such as stroke and 
heart failure, particularly when using ESAs to achieve a higher HGB concentration.  In the US, 
the mortality and CV risks associated with ESAs are outlined in a black-box warning in the 
prescribing information of ESAs, with a recommendation to use the lowest dose possible to 
avoid transfusions.  While no similar major warnings exist in the EU SmPC or on the approved 
labeling for ESAs in Japan, the EU SmPCs for ESAs do suggest caution with the use of these 
drugs, with a recommendation to keep HGB levels below 12 g/dL.  Recent clinical practice 
guidelines (Locatelli et al. 2013) recommend that risk factors for stroke and malignancy should 
also be taken into account when making treatment decisions to use ESAs for the treatment of 
anemia. 
Given the concerns associated with marketed ESAs, a goal of this study will be to evaluate the 
CV events during the treatment of anemia with vadadustat.  The inclusion of a MACE endpoint 
in this study will allow for a statistical comparison of the rates of CV events between vadadustat 
and darbepoetin alfa treatment groups when used to treat anemia associated with NDD-CKD.  
While the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) (Pfeffer et 
al 2009b) compared different HGB targets, the present study will have similar HGB targets 
between treatment arms.  Importantly, the HGB goals for this study are lower than those used in 
TREAT and are consistent with practice guidelines and prescribing information for approved 
ESAs. 
This study will be performed as an open-label study.  Because HGB values are objective and will 
be measured via a central laboratory for all efficacy endpoints, efficacy assessments are not 
considered to be subject to bias with an open-label design.  Blinding of this study presented 
inherent practical problems, including potential dosing errors, inappropriate dose adjustments, 
and delays in dosing, which may also increase the safety risk to study participants.  Given the 
differing dosing regimens and routes for vadadustat (oral) and darbepoetin alfa (SC injection), a 
double-dummy design would have been required which also created ethical concerns and 
required extensive coordination to maintain the blind.  The Sponsor and contract research 

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organization (CRO) study teams will remain blinded to the randomization codes.  In addition, the 
study will involve blinded adjudication of MACE, the use of an independent data monitoring 
committee (IDMC), and an identical schedule of visits, procedures, and assessments for both 
treatment groups in order to reduce the potential for bias.  However, certain personnel directly 
involved in medical oversight of the study, regulatory reporting of safety information, and 
on-site monitoring activities may become unblinded to the treatment assignments of individual 
subjects during the course of the study. 
6.3 Dose Justification 
The starting dose and the proposed dosing algorithm in this study are designed to increase and 
maintain HGB in a predictable and controlled manner while minimizing abrupt increases or 
excessive rises in HGB levels.  Based on plasma concentrations and PD measures from 
previously conducted clinical studies with vadadustat, a population PK/PD model was 
developed.  Using this model and the proposed dosing algorithm, simulations were carried out to 
evaluate the effects of different starting doses and the resulting HGB responses to support the 
dosing rationale.  Results of the simulations indicated that a starting dose regimen of 300 mg 
once daily along with the proposed dosing algorithm are optimal to increase and maintain HGB 
levels of 10.0 to 11.0 g/dL in the US and 10.0 to 12.0 g/dL outside of the US while minimizing 
excessive rises. 
6.4 Independent Data Monitoring Committee 
An IDMC will be established to review and discuss study safety data as subjects are enrolled and 
followed.  The team will meet approximately twice per year throughout the course of the study.  
The IDMC will be unblinded and will include, at a minimum, a nephrologist, a cardiologist, and 
a biostatistician.  The discussions of the IDMC will include a review of key safety data (ie, AEs, 
vital signs, and laboratory assessments).  Written records of the IDMC meetings, the materials 
reviewed, and the decisions made will be maintained.  Details on the roles and responsibilities of 
the IDMC and guidelines for monitoring study safety data will be described further in the IDMC 
charter. 
6.5 Endpoint Adjudication Committee 
An independent safety endpoint adjudication committee (EAC) will be formed prior to study 
commencement to adjudicate the primary safety endpoints (death, myocardial infarction, and 
stroke).  Thromboembolic events will also be adjudicated by the EAC.  The committee will be 
blinded throughout the course of the study.  The EAC will be composed of independent experts 
with experience and training appropriate for adjudication of MACE and thromboembolic events. 
Details on the responsibilities of the EAC will be described further in the EAC charter. 
7 SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 General Criteria 
To be eligible for this study, a subject or their legally acceptable representative must provide 
valid informed consent and must meet all of the following criteria.  No study procedures 
(including Screening tests) may be performed until after the informed consent has been legally 
signed. 

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An optional Pre-Screen visit can be used to perform initial testing of the HGB level using a local 
point of care device to evaluate whether a subject should progress to full Screening procedures.  
A separate Pre-Screen informed consent (distinct from the full protocol informed consent) will 
be implemented for the Pre-Screen visit.  To be eligible for the Pre-Screen HGB measurement, a 
study subject or their legally acceptable representative must provide valid informed consent prior 
to the Pre-Screen procedure.  For a better understanding of the Pre-Screening visit, please see 
Section 9.3.1, Pre-Screening Visit. 
7.2 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible: 
1. At least 18 years of age
2. Diagnosis of CKD with an estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2
using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine
equation at Screening (see Appendix B:  CKD-EPI Creatinine Equation) and not expected to
start dialysis within 6 months of Screening
3. Currently maintained on ESA therapy with the last dose received within 8 weeks prior to
Screening
4. Mean Screening HGB between 8.0 and 11.0 g/dL (inclusive) in the US and between 9.0 and
12.0 g/dL (inclusive) outside of the US, as determined by the average of 2 HGB values
measured by the central laboratory during Screening
5. Serum ferritin ≥100 ng/mL and TSAT ≥20% at Screening
6. Folate and vitamin B12 measurements ≥lower limit of normal (LLN) at Screening
7. Understands the procedures and requirements of the study and provides written informed
consent and authorization for protected health information disclosure.
7.3 Exclusion Criteria 
Subjects presenting with any of the following will not qualify for entry into the study: 
1. Anemia due to a cause other than CKD or subjects with active bleeding or recent blood loss
2. Subjects with sickle cell disease, myelodysplastic syndromes, bone marrow fibrosis,
hematologic malignancy, myeloma, hemolytic anemia, thalassemia, or pure red cell aplasia
3. RBC transfusion within 4 weeks prior to or during Screening
4. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine
aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total bilirubin
>2.0 x upper limit of normal (ULN) at Screening.  Subjects with a history of Gilbert’s
syndrome are not excluded.
5. Uncontrolled hypertension (confirmed diastolic blood pressure >110 mmHg or systolic blood
pressure >180 mmHg) at Screening
6. Severe heart failure at Screening (New York Heart Association Class IV)
7. Acute coronary syndrome (hospitalization for unstable angina or myocardial infarction),
urgent coronary revascularization, hospitalization for CHF, or stroke within 12 weeks prior to
Screening
8. History of active malignancy within 2 years prior to Screening, except for curatively resected
basal cell carcinoma of skin, squamous cell carcinoma of skin, cervical carcinoma in situ, or
resected benign colonic polyps
9. History of DVT or PE requiring active treatment within 8 weeks prior to Screening

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10. History of hemosiderosis or hemochromatosis
11. History of prior organ transplantation or scheduled organ transplant (subjects on kidney
transplant wait-list are not excluded), or prior stem cell or bone marrow transplant (corneal
transplants are not excluded)
12. Use of an investigational medication or participation in an investigational study within
30 days or 5 half-lives of the investigational medication (whichever is longer), prior to the
Screening visit
13. Previous participation in this study, receipt of vadadustat in another study, or previous
participation in a study with another hypoxia-inducible factor prolyl-hydroxylase inhibitor
(HIF-PHI)
14. Females who are pregnant or breast-feeding.  Women of childbearing potential who are
unable or unwilling to use an acceptable method of contraception (refer to Section 9.1.3,
Contraception and Pregnancy Avoidance Measures)
15. Non-vasectomized male subjects who are unable or unwilling to use an acceptable method of
contraception (refer to Section 9.1.3, Contraception and Pregnancy Avoidance Measures)
16. Any other reason that in the opinion of the Investigator would make the subject not suitable
for participation in the study.
7.4 Retesting and Rescreening 
Subjects who fail to qualify for the study based on certain laboratory parameters may be retested 
and/or rescreened at the discretion of the Investigator. 
7.4.1 Retesting 
Subjects who initially fail to qualify for the study based on laboratory test results may have their 
laboratory value retested 1 time within the 28-day Screening period at the discretion of the 
Investigator.  Retesting within the 28-day Screening period does not constitute rescreening; 
however, if retesting falls outside of the 28-day Screening period, it should be considered a 
rescreen.  All Screening laboratories, including any repeat measurements, must be performed 
within the 28-day Screening window with a minimum of 4 days between the last qualifying 
repeat measurement and the Baseline visit. 
For eligibility purposes, if HGB at SV1 is 11.1-11.5 g/dL in the US or 12.1-12.5 g/dL outside of 
the US, 1 retest CBC should be performed prior to SV2.  If retest HGB is >11.0 g/dL in the US 
or >12.0 g/dL outside the US, the subject should not proceed with SV2.  If the HGB at SV1 is 
>11.5 g/dL in the US or >12.5 g/dL outside of the US, the subject should not proceed with any
further Screening at this time.
7.4.2 Rescreening 
Subjects who fail to meet the qualifying criteria for HGB or eGFR during a Screening period 
may be considered for rescreening at the discretion of the Investigator if it is felt that the 
subject’s status has progressed and that the subject may now qualify for the study.  Additionally, 
subjects who fail to qualify for the study based on low TSAT, ferritin, folate, or B12 values may 
be considered for rescreening after receiving replacement therapy. 
Screening is limited to 3 attempts (Screening and 2 additional rescreening attempts).  If IV iron 
is used to replete iron stores, the last dose of IV iron must be administered at least 4 weeks prior 
to rescreening. 

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Subjects who fail to qualify for the study at the initial Screening visit will receive a new subject 
number for each rescreening attempt.  If rescreened, the subject will also sign a new informed 
consent form and will repeat all Screening procedures for each rescreening attempt. 
7.5 Subject Completion, Study Discontinuation, and Withdrawal of Subjects 
7.5.1 Subject Completion 
A subject will be considered as having completed the study, regardless of whether they are on or 
off study medication (vadadustat or darbepoetin alfa), if the subject is followed until the global 
study end date as determined by the accrual of MACE (see Section 11.1.2, Sample Size for the 
Primary Safety Endpoint).  A post-treatment follow-up either in person or via telephone should 
occur approximately 4 weeks after the EOT visit.  The need for rescue therapy does not 
constitute study completion and is not a criterion for subject withdrawal from the study.  The 
occurrence of a safety endpoint also does not constitute study completion and is not a criterion 
for subject withdrawal from the study or study medication (vadadustat or darbepoetin alfa). 
7.5.2 Entire Study Termination 
The entire study may be suspended or terminated by the Sponsor for safety or other 
unanticipated reasons or upon request of regulatory agencies.  Criteria for premature study 
termination or suspension are detailed in Section 14.1, Criteria for Premature Termination or 
Suspension of the Study. 
7.5.3 Individual Study Site Termination 
Study participation may be suspended or terminated at an individual investigational site for 
various reasons.  Criteria and procedures for premature termination or suspension of an 
investigational site are detailed in Section 14.2, Criteria for Premature Termination or 
Suspension of Investigational Study Sites and Section 14.3, Procedures for Premature 
Termination or Suspension of the Study or Investigational Sites. 
7.5.4 Individual Subject Discontinuation 
During the course of this long-term study, it is anticipated that subjects may temporarily interrupt 
or permanently discontinue study medication (vadadustat or darbepoetin alfa) or study 
participation for any of the following reasons: 

Unacceptable toxicity or drug intolerability

Investigator discretion

Subject withdrawal of consent

Subject becomes pregnant

Development of end-stage kidney disease and initiation of ongoing chronic hemodialysis,
peritoneal dialysis, or receipt of a kidney transplant.  (Note that a subject who receives
transient acute dialysis may still continue study medication per Investigator discretion.)

Other reasons.
Subjects who temporarily interrupt or permanently discontinue study medication (vadadustat or 
darbepoetin alfa) early or are withdrawn from the study prior to Week 52 should continue with 
the Schedule of Activities and safety assessments through Week 52 and should be followed for 
safety assessments only after Week 52.  Subjects who stop study medication after Week 52 

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should be followed for safety assessments only for the remainder of the study (See 
Sections 7.5.4.1, Temporary Interruption of Study Medication and 7.5.4.2, Permanent 
Discontinuation of Study Medication, and Appendix A:  Schedule of Activities). 
Receipt of rescue therapy is not a reason for permanent study medication discontinuation.  While 
receiving ESA rescue, subjects must temporarily discontinue study medication (vadadustat or 
darbepoetin alfa), but should resume study medication once rescue therapy has ended, as detailed 
in Section 8.4.7, Rescue Therapy. 
As part of the informed consent process, only subjects who fully understand and agree to full 
participation and long-term follow-up should be consented to participate. 
7.5.4.1 Temporary Interruption of Study Medication 
Subjects who temporarily interrupt study medication (vadadustat or darbepoetin alfa) treatment 
after the first dose and prior to completion of the study will continue with study visits and 
assessments.  Unless contraindicated, treatment should be resumed wherever possible and 
routinely considered at every visit following study medication discontinuation.  If a subject does 
not return for a scheduled visit, every effort should be made to contact the subject. 
7.5.4.2 Permanent Discontinuation of Study Medication 
If a subject wishes to discontinue study medication (vadadustat or darbepoetin alfa) or withdraw 
from the study, the Investigator should encourage continued study participation, as described in 
Section 7.5.4.4, Procedures to Encourage Continued Study Participation.  A subject who 
permanently discontinues treatment will be recorded as a discontinuation on the case report form 
(CRF), and the Investigator must document the primary reason for the discontinuation. 
Subjects who permanently discontinue study medication early or are withdrawn from the study 
prior to Week 52 should continue with the Schedule of Activities and safety assessments through 
Week 52 and should be followed for safety assessments only after Week 52.  Subjects who stop 
study medication after Week 52 should be followed for safety assessments only for the 
remainder of the study (See Appendix A:  Schedule of Activities). 
For subjects who permanently discontinue study medication, the Investigator should resume 
standard of care treatment, including ESAs and iron therapy, as deemed appropriate. 
7.5.4.3 Complete Withdrawal from Further Study Visits/Assessments 
Subjects may request to be withdrawn from the study or may be withdrawn prior to completion 
only for the following reasons of: 

Death

Withdrawal of informed consent (complete withdrawal of consent requires a subject’s
refusal of ALL methods of follow-up noted in the informed consent form:  procedures,
participation in reduced procedures/study visits, telephone contact only or alternative
contact only, source document or designated alternative contact, or access to medical
records from alternative sources)

Lost to follow-up (detailed procedures to prevent subjects from becoming lost to
follow-up are provided in Section 7.5.4.5, Procedures to Prevent “Lost to Follow-up”,

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and these procedures must be followed by the Investigators, their staff, and all designated 
study personnel). 
7.5.4.4 Procedures to Encourage Continued Study Participation 
In all cases of impending study drug discontinuation or subject request for withdrawal, the 
Investigator should discuss with the subject their options of continuing in the study.  If a subject 
wishes to discontinue study medication (vadadustat or darbepoetin alfa) or to withdraw from the 
study, the following procedures should take place: 
1. The Investigator should understand the subject’s motivation to discontinue or withdraw (eg,
study visit fatigue, study medication intolerability, etc) and wherever possible make
accommodations to prevent treatment discontinuation or complete withdrawal of consent and
to maintain the fullest compliance with the protocol assessments (eg, provide necessary
travel reimbursement, in-home visits, alternate visit scheduling, including during weekends).
If the subject’s wish is to discontinue study medication only, proceed to Step 2.
2. Ask the subject, “Would you be willing to continue if your dose of medication was
lowered?”  If the answer is “Yes”, titrate the subject’s dose down 1 level for vadadustat or
reduce the dose or dosing frequency for darbepoetin alfa.  Repeat this step if the subject
continues to request withdrawal of consent.  If the answer is “No” or if, once the lowest dose
is reached, the subject continues to request discontinuation from study medication, proceed to
Step 3.
3. Ask the subject, “If we temporarily interrupt your study medication would you be willing to
later resume medication and continue with all visits and sample collections?”  If the answer
is “Yes”, interrupt study medication but continue to follow all other study procedures for the
subject until they restart treatment.  If the answer is “No”, proceed to Step 4.
4. Ask the subject, “If we discontinue your study medication permanently, would you continue
with all visits and sample collections?”  If the answer is “Yes”, discontinue study medication,
continue with all other assessments until Week 52, and then continue with safety assessments
only for the remainder of the study after Week 52.  If the answer is “No”, proceed to Step 5.
5. If further study support, interruption, or permanent discontinuation of study medication does
not resolve the subject’s issues, further accommodations such as less frequent visits or blood
draws may be used, so long as adequate safety monitoring can be ensured for those
continuing study medication treatments.  Less frequent visits or procedures should be offered
only if they are required to maintain access to the subject’s medical information and/or to
encourage the subject to continue in the study.  For subjects who are no longer on study
medication after Week 52, study visits can be reduced to every 24 weeks for safety
assessments only either in person or via telephone.
7.5.4.5 Procedures to Prevent “Lost to Follow-up” 
The Investigator must make every effort to contact subjects who fail to return for scheduled 
visits so that they will not be declared “lost to follow-up.”  These actions must include, but are 
not limited to, the following: 

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1. Contact all numbers for the subject and their listed contacts (to be collected in source at the
subject’s entry into the study), as applicable.  This includes making calls after normal
business hours or on holidays and weekends.
2. Contact the subject’s primary care physician, referring specialist, pharmacist, and/or other
healthcare professional (using the contacts provided by the subject at entry into the study), as
applicable
3. Send a text, email, and postal mail with certified (return-receipt requested) letters to the
subject’s addresses and all contacts, as applicable
4. Review available medical records/notes for details of hospitalizations, clinic visits, or other
procedures which may indicate the status of the subject (as allowed through release of
medical record forms to be completed by the subject at study entry), as applicable
5. Utilize the internet to search for additional contact information (eg, reverse directory for
phone numbers or new address information, Facebook, LinkedIn, or other social media for
status updates), as applicable
6. Check local, regional, and national public records to locate the subject or search for mortality
status as allowed by law, as applicable.
Once these actions have been exhausted and documented, the Sponsor’s clinical research 
associate or Medical Monitor should be contacted for additional guidance. 
8 STUDY PRODUCT AND TREATMENT OF SUBJECTS 
8.1 Study Product, Supplies, and Storage 
Oral vadadustat and darbepoetin alfa for injection will be provided and shipped by the Sponsor 
or its designated supplier/distributor.  Both vadadustat and darbepoetin alfa will be supplied as 
open-label supplies.  All study medication supplies must be kept in a temperature-controlled, 
locked facility, accessible only to authorized study personnel. 
Cosyntropin for the adrenal function substudy will be sourced by the investigative site. 
The Investigator or designated study personnel will be responsible for preparing study 
medication for dispensing to the subject (Section 8.2, Dispensing Procedures) and for study 
medication supply accountability (Section 8.3, Product Accountability and Destruction). 
8.1.1 Vadadustat 
Vadadustat will be provided as 150 mg white to off-white, round, bi-convex film-coated tablets 
for oral administration.  The tablets will be packaged in high-density polyethylene bottles with 
child-resistant closures, polypropylene liner, and induction seal.  Labeling will be in accordance 
with current Good Manufacturing Practices (GMP) and local regulatory requirements. 
Dose levels utilized in this study will include:  150 mg (1 tablet), 300 mg (2 tablets), 450 mg 
(3 tablets), and 600 mg (4 tablets) per day. 
Vadadustat should be stored at a controlled room temperature of 15°-30°C (59°-86°F). 

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8.1.2 Darbepoetin Alfa 
Darbepoetin alfa will be provided in its commercially-approved primary packaging and stored 
per the local product label. 
See the approved darbepoetin alfa local product label for further description and detail. 
8.2 Dispensing Procedures 
The Investigator will maintain record of all vadadustat tablets and darbepoetin alfa injections 
dispensed to and returned from each subject during the study.  Subjects will receive either 
vadadustat tablets or darbepoetin alfa according to the randomization assignments provided via 
the IWR system (see Section 8.4.2, Randomization). 
8.2.1 Dispensing of Vadadustat 
Subjects will be provided with a supply of vadadustat at the Baseline visit according to the IWR 
system assignment.  Resupply of additional vadadustat at subsequent visits will be managed via 
the IWR system and will be dependent on the current dose level of vadadustat and the number of 
tablets remaining in the subject’s current vadadustat supply at a given study visit 
(Section 8.4.4.1, Vadadustat Dosing and Dose Adjustment Guidelines).  Subjects will be 
instructed to finish 1 bottle before opening a new bottle. 
At the Baseline visit, study subjects will be provided with 1 bottle of vadadustat.  Each bottle of 
vadadustat will contain 100 tablets of vadadustat (150 mg tablets). 
Subjects should be instructed to bring unused vadadustat and empty bottles to each study visit for 
product accountability.  Empty bottles will be collected at these study visits.  Previously 
dispensed bottles (whether opened or unopened) with remaining tablets may be redispensed to 
the subject during the dosing phase of the study. 
8.2.2 Dispensing of Darbepoetin Alfa 
The initial darbepoetin alfa dose will be determined as follows: 

For subjects already on darbepoetin, the initial dosing regimen in the study should be
based on the prior dosing regimen.

For subjects taking other ESAs, the initial dose of darbepoetin should be based on the
approved local product label.
Dispensing of additional darbepoetin alfa at subsequent dosing visits will be managed by the 
IWR system (Section 8.4.4.2, Darbepoetin Alfa Dosing and Dose Adjustment Guidelines). 
8.3 Product Accountability and Destruction 
Product accountability should be an ongoing process throughout the study.  All study medication 
(vadadustat and darbepoetin alfa) must be accounted for and any discrepancies explained.  The 
Investigator or designated study personnel are responsible for keeping accurate records of the 
clinical supplies received from the Sponsor, all supplies retained in inventory at the investigative 
site, and study medication dispensed to or returned from each subject.  Records will be 
maintained that accurately reflect the drug accountability of vadadustat and darbepoetin alfa at 
all times. 

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Proper drug accountability includes, but is not limited to: 

Continuously monitoring expiration dates if expiry date or retest date is provided to the
Investigator

Frequently verifying that actual inventory matches documented inventory

Verifying that the log is completed for all drug received and that all required fields are
complete, accurate, and legible.
If any dispensing errors or discrepancies are discovered, the Sponsor must be notified 
immediately. 
During the study, the Investigator will be notified of any expiry dates or retest date extensions of 
clinical study material.  If an expiry date notification is received during the study, the 
investigative site must complete all instructions outlined in the notification, including 
segregation of expired clinical study material for return to the Sponsor or its designee for 
destruction. 
Prior to investigative site closure and at appropriate intervals during the study, a representative 
from the Sponsor will perform clinical study material accountability and reconciliation. 
At the end of the study, the Investigator will retain all original documentation regarding clinical 
study material accountability, return, and/or destruction, and copies will be sent to the Sponsor. 
All unused and/or partially used vadadustat or darbepoetin alfa should be returned to the Sponsor 
or destroyed at the investigational site, as specified by the Sponsor.  Appropriate records of the 
disposal will be documented and maintained.  No unused vadadustat or darbepoetin alfa may be 
disposed of until fully accounted for by the Sponsor’s monitor (or designee).  Empty containers 
may be disposed of according to local procedures. 
8.4 Treatment of Subjects 
8.4.1 Treatment Group Assignments 
Subjects will be randomized in a 1:1 ratio via the IWR system to either: 

Vadadustat (starting dose of 2 tablets once daily [300 mg/day])

Darbepoetin alfa (starting dose based on the approved local product label)
For all subjects, it is recommended that no additional ESA doses be administered after SV2 and 
prior to the Randomization visit. 
Target enrollment for each treatment group is approximately 1050 subjects. 
8.4.2 Randomization 
This study will be open to approximately 2100 subjects with NDD-CKD with an eGFR 
≤60 mL/min/1.73 m2 (pre-dialysis). 
Using an IWR system, eligible subjects will be assigned using permuted block randomization 
and a 1:1 ratio to either vadadustat or darbepoetin alfa during their Baseline visit. 
To maintain balance between vadadustat-treated and darbepoetin alfa-treated subjects, 
randomization will be stratified with respect to:  1) geographic region (US versus EU versus 

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ROW); 2) New York Heart Association CHF Class (0 or I versus II or III); and 3) study entry 
HGB level (<10.0 versus ≥10.0 g/dL, based on the most recent central laboratory HGB 
measurement prior to the Baseline/Randomization visit). 
8.4.3 Blinding 
This will be an open-label study.  Treatment assignment will be done through the IWR system 
and the Investigator will not be aware of which treatment will be assigned next.  Treatments will 
be administered in an open-label fashion; however, the Sponsor and CRO study teams will be 
blinded to the randomization codes.  In addition, the study will involve blinded adjudication of 
MACE, the use of an IDMC, and an identical schedule of visits, procedures, and assessments for 
both treatment groups in order to reduce the potential for bias.  However, certain personnel 
directly involved in medical oversight of the study, regulatory reporting of safety information, 
and on-site monitoring activities may become unblinded to the treatment assignments of 
individual subjects during the course of the study. 
In geographies where regulatory approval does not require a formal analysis of MACE, efficacy 
and safety analyses may be performed upon the completion of 52 weeks of post-randomization 
follow-up in a sufficient number of subjects to support registration in that geography.  The 
unblinding of the treatment assignments for this analysis will be detailed in the Statistical 
Analysis Plan (SAP).  The EAC will remain blinded throughout the full course of the study. 
8.4.4 Dosing and Dose Adjustment Guidelines 
Dosing will be initiated at the Baseline visit, and the first dose of study medication (vadadustat 
or darbepoetin alfa) will be administered at the investigative site after other Baseline visit 
procedures have been completed.  For all subjects, it is recommended that no additional ESA 
doses be administered after SV2 and prior to the Randomization visit. 
Hemoglobin will be monitored via HemoCue® throughout the study to determine if the dose of 
study medication (vadadustat or darbepoetin alfa) will be adjusted.  From Weeks 0 to 12, HGB 
will be obtained via HemoCue® every 2 weeks for monitoring for dose adjustment.  From 
Week 12 to Week 52, HGB will be monitored every 4 weeks via HemoCue®.  From Week 53 
through the study end, HGB will continue to be monitored via HemoCue® to determine if the 
dose of study medication will be adjusted or suspended.  Hemoglobin will also be assessed with 
a CBC through the central laboratory for efficacy and safety evaluations; however, dose 
adjustments should be based on the HemoCue® HGB value. 
The aim is to maintain a HGB level of 10-11 g/dL in the US and 10-12 g/dL outside of the US 
throughout the study. 
Adjustments to doses for vadadustat and darbepoetin alfa will be guided by an IWR system 
based on HGB concentration and programmed Dose Adjustment Algorithms.  The programmed 
Dose Adjustment Algorithm for vadadustat will follow the Dose Adjustment Guidelines (see 
below).  The programmed Dose Adjustment Algorithm for darbepoetin alfa will be based on the 
local product label. 
When adjusting therapy, consider HGB rate of rise, rate of decline, and variability, as well as the 
subject’s clinical condition (ie, recent illness, volume depletion, volume overload, etc).  In cases 
of extenuating clinical circumstances, the Investigator may elect to dose outside the IWR system 

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dosing recommendation to maintain the HGB within the target range.  In such cases, the clinical 
circumstances must be documented in the subject’s record and collected in the CRF. 
8.4.4.1 Vadadustat Dosing and Dose Adjustment Guidelines 
Subjects assigned to vadadustat will initiate dosing at 2 tablets once daily (300 mg/day).  Dose 
levels of vadadustat utilized in this study include 150, 300, 450, and 600 mg (available tablet 
strength is 150 mg). 
Dosing will be initiated at the Baseline visit and the first dose of vadadustat will be administered 
at the investigative site (study physician’s clinic) after other Baseline visit procedures have been 
completed.  Thereafter, vadadustat will be taken once daily on an outpatient basis.  Subjects may 
take vadadustat with or without food and should be instructed to swallow the tablet(s) whole.  
Subjects should be instructed to take vadadustat at roughly the same time each day, preferably 
between 7 AM and 2 PM. 
During the study, vadadustat should be dosed according to the following Dose Adjustment 
Guidelines. 
For subjects enrolled in a US investigative site, the following guidelines should be followed: 

Do not increase the dose more frequently than once every 4 weeks.  Decreases in dose
can occur more frequently.  Avoid frequent dose adjustments.

If a dose adjustment is required to maintain HGB at the desired level, the vadadustat dose
is adjusted by 1 tablet (minimum dose of vadadustat is 150 mg/day [1 tablet]; maximum
dose of vadadustat is 600 mg/day [4 tablets]).

If the HGB rises rapidly (eg, >1.0 g/dL in any 2-week period), reduce the dose of
vadadustat by 1 tablet.

If the HGB falls below 10.0 g/dL, increase the dose of vadadustat by 1 tablet.

If the HGB level exceeds 11.0 g/dL, interrupt vadadustat until the HGB decreases to
10.5 g/dL or less then resume dosing of vadadustat with 1 fewer tablet.
For subjects enrolled in investigative sites outside of the US (non-US), the following guidelines 
should be followed: 

Do not increase the dose more frequently than once every 4 weeks.  Decreases in dose
can occur more frequently.  Avoid frequent dose adjustments.

If a dose adjustment is required to maintain HGB at the desired level, the vadadustat dose
is adjusted by 1 tablet (minimum dose of vadadustat is 150 mg/day [1 tablet]; maximum
dose of vadadustat is 600 mg/day [4 tablets]).

If the HGB rises rapidly (eg, >1.0 g/dL in any 2-week period), reduce the dose of
vadadustat by 1 tablet.

If the HGB falls below 10.0 g/dL, increase the dose of vadadustat by 1 tablet.

If the HGB level exceeds 12.0 g/dL, reduce the dose of vadadustat by 1 tablet.  If the
HGB level exceeds 13.0 g/dL, interrupt vadadustat until the HGB decreases to 12.5 g/dL
or less then resume dosing of vadadustat with 1 fewer tablet.

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8.4.4.2 Darbepoetin Alfa Dosing and Dose Adjustment Guidelines 
For subjects randomized to receive darbepoetin alfa, the initial dose will be determined as 
follows: 

For subjects already on darbepoetin, the initial dosing regimen in the study should be
based on the prior dosing regimen.

For subjects taking other ESAs, the initial dose of darbepoetin should be based on the
approved local product label.
Each subject will receive their first dose of darbepoetin alfa at the Baseline visit.  Subsequent 
administration of darbepoetin alfa may occur at the clinic or may be self-administered at home 
per regional standard of care.  Darbepoetin alfa dosing is independent of the visit schedule, and 
the dosing schedule may shift per local standard of care and country-specific darbepoetin alfa 
dosing guidelines. 
8.4.5 Late or Missed Doses 
Subjects on vadadustat should be instructed to take the study medication at roughly the same 
time each day, preferably between 7 AM and 2 PM.  If a dose is forgotten, subjects should be 
instructed to take the dose as soon as they remember during the same day.  If a forgotten dose is 
not remembered on the same day, the subject should skip the dose and resume the normal dosing 
schedule the following day.  Subjects should not double-up on missed doses. 
Subjects on darbepoetin alfa should be instructed to take the study medication, including 
handling of late or missed dosed, as described in the approved local product label. 
Subjects should be questioned regarding dosing compliance and whether they have questions or 
have experienced any problems related to the dosing of study medication (vadadustat or 
darbepoetin alfa). 
8.4.6 Iron Supplementation 
Investigators should prescribe iron supplementation as needed during the study to maintain 
ferritin ≥100 ng/mL and TSAT ≥20%.  In general, only oral iron should be used for therapy.  
Intravenous iron use is restricted and should only be administered to subjects who have 
documented intolerance to oral iron and are iron deficient (eg, ferritin <100 ng/mL and/or 
TSAT <20%).  Discontinuation of IV iron is required once the subject is no longer iron deficient 
(ie, ferritin ≥100 ng/mL and TSAT ≥20%). 
Important:  Because of the potential for iron to reduce the bioavailability of vadadustat, the 
study medication should not be administered concurrently with an oral iron supplement 
(including multivitamins containing iron).  The subject should be instructed to take any oral iron 
supplement at least 2 hours before or 2 hours after the dose of vadadustat. 
8.4.7 Rescue Therapy 
To ensure the safety of study subjects and to standardize the use of rescue in the study, rescue 
therapy guidelines are provided. 

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8.4.7.1 ESA Rescue (Optional) 
Starting at Week 6, subjects in both treatment arms will be allowed (although will not be 
required) to have their HGB rescued with ESA therapy per the local standard of care.  Drug 
product and supplies for ESA rescue will not be provided by the Sponsor. 
If possible, a subject on vadadustat should be on a maximum dose of vadadustat for 2 weeks 
prior to ESA rescue.  A subject on darbepoetin alfa may rescue with another ESA per the 
standard of care.  To qualify for ESA rescue, a subject must fulfill ALL of the following: 

The subject has experienced a clinically significant worsening of their anemia or
symptoms of anemia (eg, fatigue, weakness, shortness of breath, chest pain, confusion, or
dizziness) compared with Baseline

The subject’s HGB is <9.0 g/dL

Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a
goal.
The ESA rescue therapy should be administered as per the local institution’s guidelines and per 
the approved local product label.  While receiving ESA rescue therapy, subjects must 
temporarily discontinue taking study medication (vadadustat or darbepoetin alfa).  Hemoglobin 
will be monitored throughout the study at scheduled visits as defined in the Schedule of 
Activities using HemoCue®, and ESA rescue treatment should be stopped when HGB is 
≥9.0 g/dL.  A minimum interval must be observed prior to restarting vadadustat after the last 
dose of rescue medication, and treatment may be resumed after the following intervals: 

2 days after last dose of epoetin rescue

7 days after last dose of darbepoetin alfa rescue

14 days after last dose of methoxy polyethylene glycol-epoetin beta rescue.
Following ESA rescue, the study medication should be resumed at the same dose as previously 
used and adjusted according to the Dose Adjustment Guidelines (Section 8.4.4, Dosing and Dose 
Adjustment Guidelines). 
8.4.7.2 Red Blood Cell Transfusion 
Investigators should use their local institution’s transfusion guidelines when determining whether 
to transfuse a study subject.  In general, in the event of an acute or severe loss of blood, a RBC 
transfusion should be administered as clinically indicated.  In less severe instances but where 
there may be worsening of anemia or moderate to severe symptoms of anemia, RBC transfusions 
are permitted at the discretion of the Investigator given the medical necessity.  Study medication 
(vadadustat or darbepoetin alfa) may be continued during the RBC transfusion period. 
8.4.8 Phlebotomy 
If a subject’s HGB exceeds 14.0 g/dL or the rate of rise of HGB raises concern to the 
Investigator, the subject may be phlebotomized based on the Investigator’s judgment.  The 
method of phlebotomy will be in accordance with the local institution’s guidelines and standard 
clinical practice. 

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8.4.9 Treatment Compliance 
Subjects will be questioned regarding dosing compliance and whether they have questions or 
have experienced any problems related to the dosing of study medication (vadadustat or 
darbepoetin alfa).  The Investigator will also maintain drug accountability logs itemizing all 
study medications dispensed to and returned from each subject during the study.  Treatment 
compliance will be determined from these forms along with the subject questioning and the study 
medication dispensing CRFs. 
Subjects who miss doses will be counseled on the importance of compliance. 
Subjects will also be questioned regarding the timing of their last dose of vadadustat prior to the 
PK samples at the Week 4, 12, 28, and 52 study visits.  The date and time of these doses will be 
recorded on the CRF. 
8.4.10 Continuation of Treatment 
Subjects may receive study medication (vadadustat or darbepoetin alfa) up until the EOT visit. 
8.5 Prior and Concomitant Therapy 
8.5.1 General 
All medications taken within 30 days prior to the start of study medication and during the study 
should be recorded on the appropriate CRF.  In addition, the ESA and iron treatment regimen 
prior to randomization and the date of last dose will be recorded. 
8.5.2 Investigational Medications 
Study subjects should not have received any investigational medications or participated in an 
investigational study within 30 days or 5 half-lives of the investigational medication, whichever 
is longer, prior to the Screening visit.  In addition, subjects should not have participated in a 
study with another HIF-PHI. 
Additionally, subjects should not take another investigational medication while participating in 
this study. 
9 STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES 
Please see Appendix A:  Schedule of Activities for a detailed table of the Schedule of Activities. 
This study includes the following visits: 

Optional Pre-Screening

Two Screening visits (SV1 and SV2)

Baseline/Randomization visit (Week 0/Day 1)

Year 1 Treatment Period Study Visits/Evaluations while receiving study medication:
Weeks 2, 4, 6, 8, 10, 12, and every 4 weeks thereafter until Week 52

Year 2 Treatment Period Study Visits/Evaluations while receiving study medication:
Weeks 64, 76, 88, and 104

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
Year 3 Treatment Period Study Visits/Evaluations while receiving study medication:
Weeks 116, 128, 140, and 156

Year 4 Treatment Period Study Visits/Evaluations while receiving study medication:
Weeks 168, 180, 192, and 208

EOT visit

Follow-up visit:  4 weeks after the EOT.
The following sections describe the procedures to be completed during the study.  Subjects are to 
be assessed by the same Investigator or investigative site personnel whenever possible. 
9.1 Administrative Procedures 
9.1.1 Informed Consent 
Informed consent must be obtained prior to the subject entering into the study and before any 
protocol-directed procedures are performed (including Screening activities).  Subjects 
participating in the optional Pre-Screening visit must sign an abbreviated consent form or full 
consent form prior to Pre-Screening and, if eligible, may proceed with the Screening visit after 
full consent has been obtained (see Section 9.3.1, Pre-Screening Visit and Section 15.3, Subject 
Information and Consent for additional details).  Additionally, subjects may be asked to provide 
a separate, optional consent to obtain and store a blood sample(s) for future genetic analyses. 
A subset of 200 subjects (100 subjects per treatment arm) in the EU will be selected to undergo 
sequential ACTH (cosyntropin) stimulation testing to monitor adrenal function (see Appendix C: 
ACTH (Cosyntropin) Stimulation Test for Adrenal Function Monitoring).  A separate optional 
informed consent form must be signed at SV1 prior to participation in this substudy. 
9.1.2 Documentation of Screen Failures 
Investigators will maintain documentation of Pre-Screening activities, to include information on 
potential study candidates evaluated and reasons that subjects considered for the study did not 
qualify. 
Investigators must account for all subjects who sign informed consent and will maintain a log of 
subjects screened and indicate who was randomized or excluded.  If the subject is found not to be 
eligible for randomization, the reason(s) for ineligibility must be documented by the Investigator. 
Screening numbers assigned to subjects who fail Screening will not be re-used. 
9.1.3 Contraception and Pregnancy Avoidance Measures 
In nonclinical animal embryo-fetal development and fertility studies, there was no evidence of 
teratogenicity, no skeletal or visceral malformations, and no changes in male or female 
reproductive and fertility indices, or in sperm parameters.  In rats, decreased fetal body weight 
and reduced skeletal ossification were noted at the highest dose tested of 160 mg/kg/day.  
Peri-postnatal development studies have not yet been conducted with vadadustat, and there are 
no data on the transmission of vadadustat in breast milk or the effect of vadadustat on infants. 

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Although the potential risk of vadadustat on the developing fetus is limited based on studies to 
date, the study requires that all subjects must agree to use adequate contraception throughout the 
study and for 30 days after the last dose of study medication. 
Adequate contraception is defined as follows: 
Female subjects must be surgically sterile, postmenopausal (no menses for at least one year), or 
have negative pregnancy test results at Screening (serum). 
Female subjects not surgically sterile or postmenopausal (no menses for at least one year) and 
non-vasectomized male subjects must practice at least 1 of the following methods of birth 
control: 

Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior
to Screening visit, throughout the study, and for 30 days after the last dose of study
medication)

A vasectomized partner

Hormonal contraceptives (oral, parenteral, or transdermal) for at least 3 months prior to
study drug administration or intrauterine contraception/device

Double-barrier method (such as male condom, female condom, diaphragm, sponge, or
cervical cap together with spermicidal foam/gel/film/suppository).
9.1.4 Laboratory Accreditation and Reference Ranges 
The Investigator and the Sponsor will maintain a copy of the laboratory accreditation and the 
reference ranges for the central laboratory used for clinical laboratory evaluations.  Additionally, 
other accreditation(s) will be collected as required. 
9.2 Study Procedures and Evaluations 
9.2.1 Clinical Evaluations 
The following clinical evaluations will be conducted during the course of the study: 

Medical history, demographics, and physical examination:  Medical history, demographic
information, and physical examination (including height) will be collected at SV2.
Relevant medical history (with particular emphasis on previous medical conditions that
may lead to exclusion) and significant ongoing medical conditions or diseases should be
documented.  After SV2, an abbreviated, symptom-directed physical examination should
be performed at the discretion of the Investigator as clinically indicated.

Vital signs:  Vital signs will include heart rate and blood pressure.  Heart rate and blood
pressure will be assessed in the seated position after 5 minutes of rest.  Vital signs will be
collected at SV1, SV2, Baseline, during study visits, and EOT and should be taken prior
to blood draws when possible.

Weight:  Weight will be collected for all subjects at SV2, at Weeks 12, 24, 36, and 52,
yearly thereafter, and at the EOT visit.  For subjects on darbepoetin alfa, subjects will be
weighed for dosing as per the local standard of care.

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
12-Lead electrocardiogram (ECG):  A standard 12-lead ECG will be performed at
Baseline.  The ECG should be obtained after the subject has been resting comfortably in a
supine position for approximately 5 minutes and should be taken prior to vital sign
assessments and blood draws when possible.  With the subject in a supine position, obtain
the 12-lead tracing.  All ECGs will be reviewed by the Investigator for the presence of
rhythms of potential clinical concern.  A record of the tracing(s) will be made and
retained with other source documents.

Completion of MACE Endpoint Questionnaire:  At each post-randomization study visit,
the subject must specifically be questioned regarding the occurrence of any potential
MACE endpoint event since the last study visit.  IMPORTANT:  The endpoint
questionnaire electronic CRF must be completed in full at each visit even if no
potential MACE endpoints have occurred.  If a potential endpoint event is reported,
the date of the event should be recorded and the appropriate source documents should be
collected according to the endpoint packet checklist.

AE Assessments:  Beginning with the first dose of study medication (vadadustat or
darbepoetin alfa) and through the global study end (Follow-up visit), the Investigator and
study personnel will review each subject’s laboratory and clinical evaluation findings and
query the subject directly regarding AEs (see Section 10, Adverse Events).  Subjects
must be followed for AEs until the final required protocol visit (global study end date) or
until all drug-related toxicities and SAEs have resolved (or are considered
chronic/stable), whichever is later.

Concomitant Medication Recording:  All medications (both prescription and
non-prescription, and including vitamins, herbals, topicals, inhaled, and intranasal) taken
within 30 days prior to the start of study medication (vadadustat or darbepoetin alfa) and
through the EOT visit should be recorded on the appropriate CRF.  At each study visit,
subjects will be asked whether they have started or discontinued any medication since
their previous study visit.  This includes single-use or as-needed medication use.  All
medications and treatments, including vitamin supplements, over-the-counter
medications, and oral herbal preparations must be recorded in the CRFs.  In addition, the
ESA and iron treatment regimen prior to randomization and date of last dose will be
recorded.
9.2.2 Laboratory Evaluations 
Samples for laboratory assays will be sent to a central laboratory for analysis.  Detailed 
instructions for the collection, processing, and shipment of laboratory samples will be provided 
by the Sponsor and the central laboratory.  The Investigator is responsible for reviewing 
laboratory results for clinical significance. 
The following laboratory evaluations will be conducted during the course of the study: 

Pregnancy test:  A serum pregnancy test will be performed at SV2 for females of
childbearing potential.  Additional serum or local urine pregnancy tests may be
conducted throughout the study in sufficient number, as determined by the Investigator or
required by local regulations, to establish the absence of pregnancy during the study.  The
SV2 results must be available and must be negative before the subject takes the first dose
of study medication.

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
CBC:  A CBC with differential will be performed at Baseline and twice annually at
Weeks 28, 52, 76, 104, 128, 156, 180, 208.  At all other noted visits in Appendix A:
Schedule of Activities, including SV1 and SV2, a CBC without differential will be
performed.  The CBC with differential will include:  HGB, hematocrit, RBCs, mean
corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular
hemoglobin concentration (MCHC), red cell distribution width (RDW), white blood cell
(WBC) count with differential (neutrophils, lymphocytes, monocytes, eosinophils,
basophils), and platelets.
Hemoglobin assessed by central laboratory CBC will be used for evaluations of efficacy
and safety, but should not be used for dose adjustments.  Rather, HGB levels assessed by
HemoCue® should be used for dose adjustments, as described in Section 8.4.4, Dosing
and Dose Adjustment Guidelines.
For eligibility purposes, if HGB at SV1 is 11.1-11.5 g/dL in the US or 12.1-12.5 g/dL
outside of the US, 1 retest CBC should be performed prior to SV2.  If retest HGB is
>11.0 g/dL in the US or >12.0 g/dL outside the US, the subject should not proceed with
SV2.  If the HGB at SV1 is >11.5 g/dL in the US or >12.5 g/dL outside of the US, the
subject should not proceed with any further Screening at this time.  Refer to
Sections 7.4.1, Retesting and 7.4.2, Rescreening for further details regarding repeating
laboratory measurements during the Screening period.

Point of care HGB:  Using HemoCue®, HGB will be monitored throughout the study to
determine if the dose of study medication (vadadustat or darbepoetin alfa) will be
adjusted or suspended as described in Section 8.4.4, Dosing and Dose Adjustment
Guidelines.

Reticulocyte count:  An automated reticulocyte count (both absolute and percent) will be
performed at Baseline and at Weeks 4, 12, 28, and 52.

Coagulation tests:  Blood samples will be drawn at Baseline to assess the prothrombin
time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR).

Folate and Vitamin B12:  A blood sample will be drawn at SV2 to assess the folate and
Vitamin B12 levels. 

Urine albumin-to-creatinine ratio (uACR):  A random urine spot sample should be
collected at the investigative site during the Baseline visit to provide the uACR.  Subjects
should refrain from heavy exercise 24 hours before the test.

C-reactive protein:  A blood sample for C-reactive protein will be collected at the
Baseline visit. 

Serum Chemistry:  Blood samples to assess serum chemistry will be collected at SV2,
Baseline, and twice annually at Weeks 28, 52, 76, 104, 128, 156, 180, 208.  At all other
noted visits in Appendix A:  Schedule of Activities, serum creatinine and eGFR will be
performed.  The serum chemistry will include the following assays:  sodium, potassium,
bicarbonate, chloride, calcium, magnesium, phosphorus, glucose, creatinine, blood urea
nitrogen (BUN), creatine phosphokinase (CPK), uric acid, albumin, and total protein.

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Note:  When a ≥50% decline in eGFR from the Baseline value is observed, a repeat 
central laboratory measure should be performed within 30 to 60 days. 

Liver Function Tests:  Blood samples to assess liver function will be collected at SV2,
Baseline, every 4 weeks through Week 28, every 8 weeks from Week 28 to Week 52, and
twice annually from Week 53 through the end of the study.  Blood samples will also be
collected at the EOT visit.  Liver function tests will include: total bilirubin, alkaline
phosphatase, ALT/SGPT, AST/SGOT, and lactate dehydrogenase (LDH).

Iron indices:  Blood samples to assess the iron indices will be collected at SV1, Baseline,
every 4 weeks through Week 12, every 8 weeks from Week 12 to Week 52, and every
12 weeks from Week 53 through the end of the study.  Blood samples will also be
collected at the EOT visit.  Assessments will include the following indices:  ferritin, iron,
TIBC, and TSAT.

Lipid Profile:  Blood samples will be collected at the Baseline, Week 28, and Week 52
visits to assess the cholesterol levels and will be tested for the following types of lipids:
total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and
triglycerides.

Biomarkers (hepcidin, vascular endothelial growth factor [VEGF]):  Samples for
biomarker analysis will be drawn at the Baseline, Week 12, Week 28, and EOT visits.

EPO:  Blood samples for EPO analysis will be obtained at Baseline and at Weeks 4, 12,
28, and 52.

PK Evaluations (samples to be drawn only for subjects randomized to vadadustat):
Plasma samples for PK evaluation will be collected to analyze for both the parent
compound (vadadustat) and its metabolites.  Collection time points for PK will include
Weeks 4, 12, 28, and 52.
Samples should be collected along with the other laboratory samples being collected at
the study visit.  Subjects will be questioned regarding the timing of their last dose of
vadadustat prior to the collection of PK samples.  The date and time of these doses will
be recorded by the sites.

Exploratory Samples:  Additional blood and urine samples will be collected at Baseline
and Week 28 which may be used for exploratory measurement of biomarkers (eg, factors
relating to the activation of the HIF pathway).  Subjects will also be asked to provide
optional consent to obtain and store a blood sample for future genetic analyses (eg, DNA,
mRNA).

ACTH (Cosyntropin) Stimulation Test:  An ACTH (cosyntropin) stimulation test will be
performed at Baseline and at Weeks 12 and 52 (or at the EOT visit if the subject
permanently discontinues study medication early prior to the Week 52 study visit) in a
subset of 200 subjects in the EU.  During the stimulation test, serum cortisol will be
measured prior to cosyntropin administration, and again 30 and 60 minutes after
cosyntropin administration.  Cosyntropin will be administered 0.25 mg (full vial) IV
push.  Depending on the results of the test, early morning cortisol and ACTH
measurements may be required to confirm the clinical significance of the results in

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individual subjects (see Appendix C:  ACTH (Cosyntropin) Stimulation Test for Adrenal 
Function Monitoring). 
9.3 Schedule of Activities 
The Schedule of Activities (see Appendix A:  Schedule of Activities) shows the timing of 
planned study procedures.  Every effort should be made to adhere to this procedure schedule and 
all assessments should be completed at each study visit. 
9.3.1 Pre-Screening Visit 
To minimize Screen failures, there will be an optional Pre-Screening visit which will enable the 
subject to have a HemoCue® HGB prior to proceeding with full Screening.  Subjects will need to 
sign an abbreviated Pre-Screening informed consent form or full consent form prior to 
Pre-Screening.  If the Pre-Screen HemoCue® HGB is between 8.0 and 11.0 g/dL (inclusive) in 
the US or between 9.0 and 12.0 g/dL (inclusive) outside the US, the investigative site may 
proceed with SV1, which preferably will occur on the same day as Pre-Screening. 
9.3.2 Screening Visits 
Subjects will need to sign a full consent form prior to Screening.  The Screening period is a 
maximum of 28 days in duration.  Two Screening visits (SV1 and SV2) must be performed 
within 28 days prior to dosing (Baseline visit or Day 1).  There must be a minimum of 4 days 
between the 2 Screening visits and a minimum of 4 days between SV2 and the Baseline visit. 
The Investigator will maintain a log of subjects (both Pre-Screened and Screened) and indicate 
who of the Pre-Screened subjects were brought in for informed consent and Screening and who 
of the Screened subjects were enrolled or excluded and the reason for exclusion. 
After obtaining informed consent and receiving a unique subject identification number, subjects 
will undergo a number of Screening activities. 
9.3.2.1 Screening Visit 1 (SV1) 
At SV1, the following activities/procedures will be performed: 

Informed consent (including an additional optional consent for blood samples for future
genetic analyses.  Also includes an additional optional consent for a substudy of adrenal
function in a subset of 200 subjects in the EU.)

Review of eligibility criteria

Vital signs including heart rate and blood pressure (assessed in seated position after
5 minutes of rest and prior to blood draws)

Laboratory procedures:
o
CBC (without differential)
o
Iron indices.
If the HGB at SV1 is 11.1-11.5 g/dL in the US or 12.1-12.5 g/dL outside of the US, 1 retest CBC 
should be performed prior to SV2.  If the retest HGB is >11.0 g/dL in the US or >12.0 g/dL 
outside the US, the subject should not proceed with SV2.  If the HGB at SV1 is >11.5 g/dL in the 
US or >12.5 g/dL outside of the US, the subject should not proceed with any further Screening at 
this time.  Refer to Sections 7.4.1, Retesting and 7.4.2, Rescreening for further details regarding 
repeating laboratory measurements during the Screening period. 

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9.3.2.2 Screening Visit 2 (SV2) 
At SV2, the following activities/procedures will be performed: 

Review of eligibility criteria

Physical examination

Demographics and medical history

Vital signs including heart rate and blood pressure (assessed in seated position after
5 minutes of rest and prior to blood draws), as well as height and weight

Laboratory procedures:
o
Folate and vitamin B12 levels
o
CBC (without differential)
o
Serum chemistry including serum creatinine and eGFR
o
Liver function tests
o
Serum pregnancy test for females of childbearing potential (eligible subjects will
be advised to use an adequate contraceptive method)

Prior and current medication use.
The mean of 2 HGB values from the central laboratory must be between 8.0 and 11.0 g/dL 
(inclusive) in the US or between 9.0 and 12.0 g/dL (inclusive) outside the US to qualify for 
inclusion into the trial.  If the subject’s HGB does not qualify after SV1 and/or SV2 +/- 1 retest 
HGB, the subject should be considered a Screen failure. 
9.3.2.3 Subject Retesting 
Subjects who initially fail to qualify for the study based on laboratory test results may be retested 
once within the 28-day Screening period, per Investigator discretion (Section 7.4.1, Retesting). 
9.3.3 Subject Rescreening 
Subjects who fail to meet the qualifying criteria for HGB or eGFR during the Screening period 
may be considered for rescreening at the discretion of the Investigator if it is felt that the 
subject’s status has progressed and that the subject may now qualify for the study.  Additionally, 
subjects who fail to qualify for the study based on low TSAT, ferritin, folate, or B12 values may 
be considered for rescreening after receiving replacement therapy.  Screening is limited to 
3 attempts (Screening and 2 additional rescreening attempts) (Section 7.4.2, Rescreening). 
9.3.4 Baseline Visit (Day 1) 
The Baseline visit must be performed within 28 days of the 2 Screening visits (SV1 and SV2) 
and a minimum of 4 days must elapse between the last Screening visit (SV2) and the Baseline 
visit. 
At the Baseline visit, the following activities/procedures will be performed: 

Randomization

12-lead ECG (prior to vital sign assessments and blood draws)

Vital signs including heart rate and blood pressure (assessed in seated position after
5 minutes of rest and prior to blood draws)

Laboratory Procedures:
o
Random spot urine sample for uACR

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o
Coagulation Tests
o
C-reactive protein
o
CBC (including differential)
o
Reticulocyte count
o
Serum chemistry including serum creatinine and eGFR
o
Liver function tests
o
Iron indices
o
Lipid profile
o
EPO
o
Biomarkers (hepcidin, VEGF)
o
Exploratory samples
o
ACTH (cosyntropin) stimulation test (for a subset of subjects in the EU)

Review of medical history for new conditions since Screening visit

Medication use since Screening visit

Study medication assessments and procedures:
o
Subject will take their first dose of study medication at the investigative site
during the Baseline visit
o
HGB by HemoCue® for dose initiation
o
Vadadustat dispensing
o
Darbepoetin alfa dispensing (per local product label)
o
Oral iron supplementation as needed to maintain ferritin ≥100 ng/mL and
TSAT ≥20% (per local product label; see Section 8.4.6, Iron Supplementation)

AE assessment as needed (after receiving the first dose of study medication).
9.3.5 Year 1 Treatment Period Visits (Day 2 through Week 52) 
During the Year 1 Treatment Period visits at Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 
44, 48, and 52, the following activities/procedures will be performed: 

Vital signs including heart rate and blood pressure (assessed in seated position after
5 minutes of rest and prior to blood draws)

Weight (Weeks 12, 24, 36, and 52)

Laboratory procedures:
o
CBC (Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52;
differential at Weeks 28 and 52)
o
Reticulocyte count (Weeks 4, 12, 28, and 52)
o
Serum chemistry (Weeks 28 and 52)
o
Serum creatinine and eGFR (Weeks 4, 8, 12, 20, 36, and 44; also at Weeks 28
and 52 as part of the serum chemistry)
o
Liver function tests (Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44, and 52)
o
Iron indices (Weeks 4, 8, 12, 20, 28, 36, 44, and 52)
o
Lipid profile (Weeks 28 and 52)
o
EPO (Weeks 4, 12, 28, and 52)
o
Biomarkers (Weeks 12 and 28)
o
PK (Weeks 4, 12, 28, and 52; see Section 9.2.2, Laboratory Evaluations; samples
to be drawn only for subjects randomized to vadadustat)
o
Exploratory samples (Week 28)

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o
ACTH (cosyntropin) stimulation test (Weeks 12 and 52 for a subset of subjects in
the EU)

Record date and time of subject’s last dose of vadadustat prior to the PK sample
(Weeks 4, 12, 28, and 52)

Safety assessments:
o
AE assessment
o
RBC transfusions and ESA rescue collection
o
Therapeutic phlebotomy collection
o
MACE endpoint questionnaire

Medication assessments and procedures:
o
Review of concomitant medications
o
HGB by HemoCue® for dose adjustment
o
Drug reconciliation:  Study medication (vadadustat or darbepoetin alfa)
reconciliation will be conducted per the pharmacy manual instructions.
o
Vadadustat dispensing as needed per Section 8.2.1, Dispensing of Vadadustat
o
Darbepoetin alfa dispensing (per local product label)
o
Iron supplementation as needed to maintain ferritin ≥100 ng/mL and TSAT ≥20%
(per local product label; see Section 8.4.6, Iron Supplementation)
o
Question subject regarding dosing compliance and whether they have questions or
have experienced any problems related to the dosing of study medication
(vadadustat or darbepoetin alfa).
9.3.6 Year 2 Treatment Period Visits (Weeks 53 through 104) 
During the Year 2 Treatment Period visits at Weeks 64, 76, 88, and 104, the following 
activities/procedures will be performed: 

Vital signs including heart rate and blood pressure (assessed in seated position after
5 minutes of rest and prior to blood draws)

Weight (Week 104)

Laboratory Procedures:
o
CBC (Weeks 64, 76, 88, and 104; differential at Weeks 76 and 104)
o
Serum chemistry including serum creatinine and eGFR (Weeks 76 and 104)
o
Liver function tests (Weeks 76 and 104)
o
Iron indices (Weeks 64, 76, 88, and 104)

Safety assessments:
o
AE assessment
o
RBC transfusions and ESA rescue collection
o
Therapeutic phlebotomy collection
o
MACE endpoint questionnaire

Medication assessments and procedures:
o
Review of concomitant medications
o
HGB by HemoCue® for dose adjustment
o
Drug reconciliation:  Study medication (vadadustat or darbepoetin alfa)
reconciliation will be conducted per the pharmacy manual instructions.
o
Vadadustat dispensing as needed per Section 8.2.1, Dispensing of Vadadustat
o
Darbepoetin alfa dispensing (per local product label)

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o
Iron supplementation to maintain ferritin ≥100 ng/mL and TSAT ≥20% (per local
product label; see Section 8.4.6, Iron Supplementation)
o
Question subject regarding dosing compliance and whether they have questions or
have experienced any problems related to the dosing of study medication
(vadadustat or darbepoetin alfa).
9.3.7 Year 3/4 Treatment Period Visits (Weeks 116 through 208) 
During the Year 3/4 Treatment Period visits at Weeks 116, 128, 140, 156, 168, 180, 192, 
and 208, the following activities/procedures will be performed: 

Vital signs including heart rate and blood pressure (assessed in seated position after
5 minutes of rest and prior to blood draws)

Weight (Weeks 156 and 208)

Laboratory Procedures:
o
CBC (Weeks 116, 128, 140, 156, 168, 180, 192, and 208; differential at
Weeks 128, 156, 180, and 208)
o
Serum chemistry including serum creatinine and eGFR (Weeks 128, 156, 180,
and 208)
o
Liver function tests (Weeks 128, 156, 180, and 208)
o
Iron indices (Weeks 116, 128, 140, 156, 168, 180, 192, and 208)

Safety assessments:
o
AE assessment
o
RBC transfusions and ESA rescue collection
o
Therapeutic phlebotomy collection
o
MACE endpoint questionnaire

Medication assessments and procedures:
o
Review of concomitant medications
o
HGB by HemoCue® for dose adjustment
o
Drug reconciliation:  Study medication (vadadustat or darbepoetin alfa)
reconciliation will be conducted per the pharmacy manual instructions.
o
Vadadustat dispensing as needed per Section 8.2.1, Dispensing of Vadadustat
o
Darbepoetin alfa dispensing (per local product label)
o
Iron supplementation to maintain ferritin ≥100 ng/mL and TSAT ≥20% (per local
product label; see Section 8.4.6, Iron Supplementation)
o
Question subject regarding dosing compliance and whether they have questions or
have experienced any problems related to the dosing of study medication
(vadadustat or darbepoetin alfa).
9.3.8 End of Treatment Visit 
End of treatment evaluations will be performed when the study is ended.  Subjects who 
prematurely discontinue study medication for any reason should attend all subsequent 
protocol-defined study visits and be continually monitored according to the Schedule of 
Activities for the duration of the study. 

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At the EOT visit, the following activities/procedures will be performed: 

Vital signs including heart rate and blood pressure (assessed in seated position after
5 minutes of rest and prior to blood draws), as well as weight

Laboratory Procedures:
o
CBC (without differential)
o
Serum creatinine and eGFR
o
Liver function tests
o
Iron indices
o
Biomarkers (hepcidin, VEGF)
o
ACTH (cosyntropin) stimulation test (the test will only be performed at the EOT
visit for subjects who are part of the adrenal function substudy and who have
permanently discontinued study medication early prior to the Week 52 study
visit.)

Safety assessments:
o
AE assessment
o
RBC transfusions and ESA rescue collection
o
Therapeutic phlebotomy collection
o
MACE endpoint questionnaire

Recording of concomitant medications

Drug reconciliation:  Study medication (vadadustat or darbepoetin alfa) reconciliation
will be conducted per the pharmacy manual instructions.

Question subject regarding dosing compliance and whether they have experienced any
problems related to the dosing of study medication (vadadustat or darbepoetin alfa).
9.3.9 Follow-Up Visit 
The Follow-up visit will be conducted in person or via the telephone 4 weeks after the EOT visit. 
The following activities/procedures will be performed: 

AE assessment

RBC transfusions and ESA rescue collection

Therapeutic phlebotomy collection

MACE endpoint questionnaire.
10 ADVERSE EVENTS 
10.1 Definitions 
10.1.1 Adverse Events 
For the purposes of this study, an AE is any untoward medical occurrence that occurs in the 
protocol-specified AE reporting period; the event does not necessarily have a causal relationship 
with that treatment or usage.  
An AE includes medical conditions, signs, and symptoms not previously observed in the subject 
that emerge during the protocol-specified AE reporting period, including signs or symptoms 
associated with pre-existing underlying conditions that were not present prior to the AE reporting 
period. 

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Adverse events therefore include the following: 

All AEs, whether suspected to be causally related to study drug or otherwise

All AEs secondary to any medication overdose, abuse, withdrawal, sensitivity, or toxicity

Illnesses apparently unrelated to study drug, including the worsening of a pre-existing
illness (see paragraph below on Pre-existing Conditions)

Injury or accidents.  Note that if a medical condition is known to have caused the injury
or accident (eg, a fall secondary to dizziness), the medical condition (dizziness) and the
accident (fall) should be reported as 2 separate AEs.

Abnormalities in physiological testing or physical examination findings that require
clinical intervention or further investigation (beyond ordering a repeat [confirmatory]
test)

Laboratory abnormalities that require clinical intervention or further investigation
(beyond ordering a repeat [confirmatory] test) unless they are associated with an already
reported clinical event.  Laboratory abnormalities associated with a clinical event
reported as an AE (eg, elevated liver enzymes in a subject with jaundice) should be
described under ‘Comments’ on the report of the clinical event rather than reported as
separate AEs.
The following guidelines are to be used when reporting AEs for this study: 
Medical Diagnoses – Whenever possible, a medical diagnosis term should be used to report AEs 
instead of signs and symptoms due to a common etiology, as determined by qualified medical 
study staff.  For example, pneumonia should be the reported AE term, instead of fever, dyspnea, 
etc, when the diagnosis has been established.  Signs and symptoms should be reported as event 
terms only when the medical diagnosis remains unknown, and revised to a medical diagnosis 
term once it has been established. 
Procedures – Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as AEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE.  For example, an acute 
appendicitis that begins during the AE reporting period should be reported as the AE and the 
resulting appendectomy noted under ‘Comments’. 
Pre-planned therapeutic procedures not associated with a new medical condition or worsening 
pre-existing condition should not be reported as AEs (with the exception of kidney transplant, 
see below). 
Pre-existing Conditions – In this study, a pre-existing condition (ie, a disorder present before 
the AE reporting period started and noted on the pretreatment medical history/physical 
examination form) should not be reported as an AE unless the condition worsens or episodes 
increase in frequency during the AE reporting period. 
Abnormal Test Findings – All laboratory test results will be reviewed by the Investigator.  The 
Investigator will utilize his/her judgment in determining if out of range laboratory values are 
clinically significant and will denote this using the abbreviation “CS” on the laboratory report for 
source documentation.  Laboratory tests that are labeled as clinically significant should be 
reported as AEs, either separately or as part of a description of a symptomatic AE.  If there are 

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significant changes in a laboratory report from a previous visit that are determined to be 
clinically significant, these should also be reported as AEs.  Any abnormal laboratory value 
which requires treatment or further diagnostic testing and/or results in discontinuation from study 
should be reported as an AE.  An expected laboratory abnormality from a condition that is part of 
the medical history is not considered clinically significant for the purposes of the study unless it 
represents a worsening of the condition. 
Worsening of Anemia – In this study, it is possible that some subjects may experience a 
worsening of anemia.  As the primary endpoint of this study assesses HGB response, worsening 
of anemia is captured as part of this efficacy parameter.  Worsening of anemia should not be 
considered an AE unless the worsening of anemia is associated with a cause other than the 
subject’s CKD. 
Renal-Related Events - Some subjects will experience a progression of their CKD over the 
course of this study as part of the natural course of the disease.  In addition, the study population 
is prone to experience acute, transient loss of kidney function of different etiologies, sometimes 
concomitantly complicated by progression of CKD. 
To ensure valid and consistent reporting of renal events, the following guidelines are to be used 
when reporting a renal-related AE: 

Acute kidney injury – If a decline and recovery of renal function has occurred, the
reported AE term should reflect whether the renal event was of a prerenal, intrarenal, or
postrenal etiology (see below).  Non-specific terms such as decreased eGFR or increased
creatinine should be avoided whenever the underlying etiology is known.
o
Examples of AE terms for a prerenal etiology include:  hypovolemia, hepatorenal
syndrome, and heart failure
o
Examples of AE terms for an intrarenal etiology include:  acute tubular necrosis,
acute interstitial nephritis, and glomerulonephritis
o
Examples of AE terms for a postrenal etiology include:  hydronephrosis,
pelvicaliectasis, and urinary tract obstruction.

Progression of CKD – If permanent loss of renal function due to underlying CKD has
occurred, the reported AE term should reflect the underlying etiology of the pre-existing
CKD.  Non-specific terms such as decreased eGFR or increased creatinine should be
avoided whenever the underlying etiology is known.
o
Examples of AE terms include:  lupus nephritis, diabetic kidney disease, and
glomerulonephritis

Progression of CKD Associated with Chronic Dialysis – Subjects who undergo transition
to chronic maintenance dialysis should have the event recorded as an AE and classified as
serious (refer to Section 10.1.2, Serious Adverse Events); the verbatim AE term should be
“progression of CKD” with the outcome denoted as “Chronic Dialysis”.

Transient Acute Dialysis - Subjects who undergo transient acute dialysis should have the
event recorded as an AE and classified as serious (refer to Section 10.1.2, Serious
Adverse Events); the verbatim AE term should reflect the indication requiring dialysis
(eg, hyperkalemia, volume overload, acute kidney injury, etc.).

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
Transplantation – During this long-term study, it is possible that some subjects may
receive a kidney transplant.  Subjects should have these events recorded as AEs and
classified as serious (refer to Section 10.1.2, Serious Adverse Events).  The verbatim AE
term should be “progression of CKD” with the outcome denoted as “Kidney
Transplantation”.

Medical conditions related to kidney disease but without loss of renal function – In these
cases the complication should be reported instead of progression of CKD or acute kidney
injury.
o
Examples of AE terms include:  edema and hyperkalemia.
10.1.2 Serious Adverse Events 
Each AE is to be classified by the Investigator as SERIOUS or NONSERIOUS.  An AE that 
meets 1 or more of the following criteria/outcomes is classified as serious: 

Death

Life-threatening (see paragraph below on life-threatening)

In-patient hospitalization or prolongation of existing hospitalization (see paragraph below
on hospitalization)

Persistent or significant disability/incapacity (see paragraph below on disability)

Congenital anomaly/birth defect

Is considered a medically important event not meeting the above criteria, but which may
jeopardize a subject, or may require medical or surgical intervention to prevent one of the
criteria listed in this definition.
In addition to the above criteria for classifying AEs as serious, the following situations will also 
be classified as serious for purposes of this study: 

Dialysis or Transplantation-Events requiring transition to chronic, ongoing dialysis, or
requiring an acute transient course of dialysis, or requiring an immediate kidney
transplantation (ie, not pre-planned) will be classified as serious.  Guidance for the
reporting of these events is provided in Section 10.1.1, Adverse Events.
Serious also includes any other event that the Investigator or Sponsor judges to be serious.  If 
there is any doubt whether the information constitutes an AE or SAE, the information is to be 
treated as an SAE. 
Life-threatening – Any AE that places the subject at immediate risk of death from the event as 
it occurred.  A life-threatening event does not include an event that might have caused death had 
it occurred in a more severe form but that did not create an immediate risk of death as it actually 
occurred.  For example, drug-induced hepatitis that resolved without evidence of hepatic failure 
would not be considered life threatening, even though drug-induced hepatitis of a more severe 
nature can be fatal. 
Hospitalization – Hospitalization is defined as an overnight admission with observation of a 
minimum of 24 hours.  A hospitalization planned before the start of the study for a pre-existing 
condition that has not worsened does not constitute an SAE unless an untoward event occurs 

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related to the procedure (eg, elective hospitalization for a total knee replacement due to a 
preexisting condition of osteoarthritis of the knee that has not worsened during the course of the 
study). 
Disability – Defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
10.2 Eliciting Adverse Event Information 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study subject.  In addition, each study subject will be questioned about AEs at each visit 
following the initiation of treatment. 
10.3 Reporting 
Each AE is to be classified by the Investigator as SERIOUS or NONSERIOUS. 
All AEs that occur in study subjects during the AE reporting period specified in the protocol 
must be reported, whether or not the event is considered related to study medication (vadadustat 
or darbepoetin alfa). 
10.3.1 Reporting Period 
The AE reporting period for this study begins upon receiving the first dose of study medication 
(vadadustat or darbepoetin alfa) and ends at the final protocol-required visit. 
In addition, any AE that occurs subsequent to the AE reporting period that the Investigator 
assesses as possibly or probably related to the study medication should also be reported as an 
AE. 
10.3.2 Reporting AEs 
NONSERIOUS AEs are to be reported on the AE CRFs. 
10.3.3 Reporting SAEs 
Any SAE, regardless of causal relationship, must be reported to the Sponsor’s Medical Monitor 
or CRO designee within 24 hours after the Investigator becomes aware of the SAE.  Compliance 
with this time requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
The initial SAE report should be completed as fully as possible but should contain, at a 
minimum: 

Subject number/ID, sex, and age/date of birth

The date of report

Name of the reporter

A description of the event, including event term(s), seriousness criteria, and a clinical
summary of the event

Causality assessment.

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Information about all SAEs (either initial or follow-up information) should be collected and 
recorded in English on the electronic SAE Report Form within the electronic data capture (EDC) 
system.  The Investigator must assess the relationship to each specific component of the study 
treatment.  When the form is completed, CRO personnel will be notified electronically and will 
retrieve the form.  If the event meets serious criteria and it is not possible to access the internet, a 
paper SAE Report Form should be sent to the CRO via email or fax or the Investigator should 
call the CRO SAE hotline within 24 hours of being made aware of the SAE (reference the site 
manual for contact information).  When the EDC system becomes available, the SAE 
information must be entered within 24 hours of the system becoming available. 
Follow-up information relating to an SAE must be reported to the Sponsor’s Medical Monitor or 
CRO designee within 24 hours of receipt by the Investigator by updating the electronic CRF with 
the new information or by submitting a paper SAE Report Form in the event that the EDC is not 
available.  When the EDC system becomes available, the SAE information must be entered 
within 24 hours.  The subject should be observed and monitored carefully until the condition 
resolves or stabilizes. 
All deaths are to be thoroughly investigated and reported.  Autopsy reports and death certificates 
are to be obtained, if possible. 
The Sponsor and/or its designee are responsible for reporting SAEs to all applicable regulatory 
agencies and the central ethics committees within the required timeline. 
The Investigators are responsible for submitting required safety information to their local 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC).  This information 
includes, but is not limited to, any safety alert letter received from the Sponsor and any SAEs 
occurring at their investigative site. 
10.3.4 Reporting Study Endpoints 
Investigators will be counseled to report any event that they assess as potentially being a study 
endpoint requiring adjudication (death, myocardial infarction, stroke, and thromboembolic 
events).  All study endpoint events will be submitted blinded to the EAC for adjudication.  To 
protect the integrity of the trial, these events that are adjudicated will not be unblinded or 
reported to either Health Authorities (HAs) or Investigators as safety reports unless otherwise 
requested by HAs or Ethics Committees.  After study completion, these events will be included 
in the final analysis which will be unblinded and submitted to HAs with the study report. 
10.3.5 Relationship to Study Medication 
The causal relationship of the AE to study medication (vadadustat or darbepoetin alfa) will be 
assessed by both the Investigator and the Sponsor.   
The assessment of causal relationship to study drug should be evidence-based, and not based on 
the premise that all AEs are possibly causally related to study medication until proven otherwise.  
Examples of evidence that would suggest a causal relationship between the study medication and 
the AE include the occurrence of an AE that is uncommon and known to be strongly associated 
with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson syndrome) or an AE that is 
uncommon in the population exposed to the drug. 
The following definitions will be used for the assessment of relationship to study medication: 

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Probably Related:  There is strong evidence to support a causal association between the AE and 
study medication (eg, the event occurred after the first dose, the characteristics of the AE are 
typical of a drug toxicity, and there is recurrence after rechallenge) and the AE cannot be 
reasonably explained by other factors such as the subject’s clinical state, therapeutic 
interventions, or concomitant drugs. 
Possibly Related:  There is some evidence to support a causal association between the AE and 
the study medication (eg, the AE resolved after study medication interruption and the 
characteristics of the AE are unusual for the study population) and alternative explanations, such 
as the subject’s clinical state, other therapeutic interventions, or concomitant drugs, are less 
likely than study medication. 
Unrelated:  There is currently no evidence to support a causal association with study medication 
and the AE is clearly related to other factors such as the subject’s clinical state, other therapeutic 
interventions, or concomitant drugs administered to the subject. 
Default assessments using the “possibly related” category without supportive evidence for a 
causal relationship to study medication are generally uninformative and do not contribute 
meaningfully to the development of the safety profile of the drug or to subject protection. 
10.3.6 Severity 
The Investigator will assess each AE as either MILD, MODERATE, or SEVERE using the 
following guidelines to describe the maximum severity of the AE: 
MILD:  Does not interfere with subject's usual function 
MODERATE:  Interferes to some extent with subject's usual function 
SEVERE:  Interferes significantly with subject's usual function 
Note that a severe AE is not necessarily a serious AE.  For example, a headache may be severe 
in intensity, but would not be classified as serious unless it met 1 of the criteria for serious events 
listed above. 
10.3.7 Follow-Up of Unresolved Events 
All AEs should be followed until they are resolved or the Investigator assesses them as chronic 
or stable or the subject’s participation in the trial ends (ie, until a final report is completed for 
that subject). 
In addition, all SAEs and those nonserious events assessed by the Investigator as possibly or 
probably related to the study medication should continue to be followed even after the subject's 
participation in the trial is over.  Such events should be followed until they resolve or until the 
Investigator assesses them as “chronic” or “stable”.  Resolution of such events is to be 
documented on the appropriate CRF. 
10.4 Exposure In Utero 
A pregnancy in a female subject must be confirmed by a positive serum β human chorionic 
gonadotropin (β-HCG) test. 

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If any study participant becomes or is found to be pregnant while receiving a study medication 
(vadadustat or darbepoetin alfa) or within 30 days of discontinuing the study medication, the 
pregnancy must be recorded on the Pregnancy Reporting Form/Exposure in Utero Form in the 
EDC within 24 hours of awareness of the pregnancy or the Investigator should call the CRO 
SAE hotline within 24 hours of being made aware of the pregnancy. 
Pregnancy during this time frame of the female partner of a male subject should also be reported. 
The Pregnancy Reporting Form/Exposure in Utero Form must be completed with all known 
information regarding the pregnancy at the time of reporting.  Investigative site personnel will 
update the form with additional information regarding the pregnancy and the outcome of the 
pregnancy as it becomes available until the outcome of the pregnancy is reported. 
The study medication should be immediately discontinued once the pregnancy of a female study 
participant has been confirmed. 
The Investigator will follow the subject (or female partner of a male subject) until completion of 
the pregnancy.  If the outcome of the pregnancy meets the criteria for classification as a SAE (ie, 
spontaneous abortion, stillbirth, neonatal death within 1 month of birth, or congenital anomaly 
[including that in an aborted fetus]), the Investigator should also follow the procedures for 
reporting a SAE within 24 hours of awareness.  A pregnancy in itself is not considered an AE; 
however, unexpected complications are considered AEs. 
Additional information about pregnancy outcomes follows: 

Note that “spontaneous abortion” includes miscarriage and missed abortion.

All neonatal deaths that occur within 1 month of birth should be reported, without regard
to causality, as SAEs.  In addition, any infant death after 1 month that the Investigator
assesses as possibly or probably related to the in utero exposure to the study medication
should also be reported.

In the case of a live birth, the “normality” of the newborn can be assessed at time of birth.

The “normality” of an aborted fetus can be assessed by gross visual inspection unless
there are pre-abortion laboratory findings suggestive of a congenital anomaly.
10.5 Special Situations 
Certain safety events, called ‘Special Situations’, that occur in association with study 
medication(s) may require reporting.  These Special Situations include, but are not limited to, the 
following: 

Overdose of the medicinal product

Suspected abuse/misuse of the medicinal product

Inadvertent or accidental exposure to the medicinal product

Medication error involving the medicinal product (with or without subject/patient
exposure to the Sponsor medicinal product, eg, name confusion)

Drug-drug interaction.
The Investigator should follow SAE criteria reporting guidelines for reporting Special Situations. 

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11 DATA ANALYSIS 
Data collected throughout the study will be summarized using descriptive statistics and listed in 
by-subject listings.  Continuous variables will be summarized using number of subjects with 
data, mean, standard deviation, median, minimum, and maximum.  For categorical variables, the 
number and percentage of subjects in each category will be tabulated.  Summaries will be 
provided by treatment group within appropriate analysis populations (as defined in Section 11.2, 
Study Analysis Populations) and by time point/time period as appropriate. 
For HGB, Baseline will be defined as the mean of all qualifying HGB values collected prior to 
the first dose of study medication (vadadustat or darbepoetin alfa).  For subjects rescreened, only 
values for the last Screening period will be used for establishing the Baseline.  For other 
parameters, unless otherwise specified, Baseline will be defined as the last available value prior 
to the first dose of study medication. 
Hemoglobin values as assessed through the central laboratory will be used for efficacy and safety 
evaluations; local HemoCue® HGB values will be used only for dose adjustments. 
In geographies where regulatory approval does not require a formal analysis of MACE, efficacy 
and safety analyses may be performed upon the completion of 52 weeks of post-randomization 
follow-up in a sufficient number of subjects to support registration in that geography.  Such 
analysis will be documented in a geography-specific SAP. 
11.1 Sample Size Determination 
The goal of this study is to demonstrate the efficacy and safety of vadadustat compared with 
darbepoetin alfa for the maintenance treatment of anemia in subjects with anemia secondary to 
NDD-CKD after conversion from current ESA therapy.  The sample size is calculated to ensure 
sufficient power for testing both efficacy in this trial and the primary safety endpoints as part of a 
pooled analysis. 
11.1.1 Sample Size for the Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the mean change in HGB from Baseline (mean 
pretreatment HGB) to the average HGB over the primary evaluation period (mean HGB from 
Weeks 24-36). 
The primary efficacy objective of this study is to show that vadadustat is noninferior to 
darbepoetin alfa within the noninferiority margin.  Noninferiority will be established based on a 
margin of -0.5 g/dL (for vadadustat minus darbepoetin alfa). 
For the primary efficacy analysis in this study, it is assumed that the mean change from Baseline 
in HGB for vadadustat will be the same as for darbepoetin alfa, and the common standard 
deviation for the mean change from Baseline is assumed to be 1.5 g/dL.  Noninferiority will be 
established based on a 2-sided 95% confidence interval for the difference between the vadadustat 
group and darbepoetin alfa and using a noninferiority margin of -0.5 g/dL.  With these 
assumptions and approximately 1050 subjects per treatment group for the primary efficacy 
analysis, the noninferiority assessment will have >99% power. 

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11.1.2 Sample Size for the Primary Safety Endpoint 
The primary safety endpoint is the time from first dose of study medication to the first 
(adjudicated) MACE (defined as all-cause mortality, non-fatal myocardial infarction, or non-fatal 
stroke). 
The primary safety analysis will be based upon all events that accrue over 2 planned NDD-CKD 
studies (Studies AKB-6548-CI-0014 and AKB-6548-CI-0015).  The sample size with respect to 
the MACE endpoint has been determined based on the number of events needed to demonstrate 
noninferiority of the 2-sided 95% confidence interval for the hazard ratio 
(vadadustat/darbepoetin alfa).  It has been calculated that 631 events will be required overall to 
have 80% power to establish noninferiority with a margin of 1.25, and >90% power to establish 
noninferiority with a margin of 1.3, assuming no difference between treatment groups.  The 
power is >90% to establish a noninferiority margin of 1.25 if the hazard ratio is 0.95 favoring 
vadadustat.  A MACE rate of 10% annually is anticipated in both treatment arms based on a 
comprehensive review of available epidemiology and prospective clinical studies in the field.  
With 1050 subjects per treatment group enrolled in this study, approximately 20 months for 
accrual, and up to 36 months of follow-up, approximately 68% of the needed MACE would be 
captured, assuming the dropout rate is negligible.  The remaining 32% of the needed MACE 
would be captured in Study AKB-6548-CI-0014. 
11.2 Study Analysis Populations 
The following analysis populations will be used in this study: 

Randomized population:  defined as all randomized subjects

Full analysis population:  defined as randomized subjects receiving 1 or more doses of
therapy

Per protocol (PP) population:  defined as all randomized subjects who received study
medication (vadadustat or darbepoetin alfa) during the primary evaluation period, had at
least 2 HGB assessments during the primary evaluation period, and received no rescue
therapy in the 8 weeks prior to the evaluation period

Safety population:  defined as all subjects who received at least 1 dose of study
medication
Efficacy analyses will utilize the randomized, full analysis, and PP populations while safety 
analyses will utilize the safety population. 
11.3 Analysis of Demographic and Pretreatment Variables 
Descriptive statistics will be generated for demographic and pretreatment variables for each 
analysis population defined in Section 11.2, Study Analysis Populations. 
Medical history terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by System Organ Class and Preferred Term for each treatment 
group based on the safety population. 

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11.4 Disposition of Subjects 
The number and percentage of subjects randomized and included in each analysis population will 
be summarized by treatment and overall.  Reasons for excluding subjects from the analysis 
populations will be presented in a by-subject listing. 
The number of randomized subjects who completed each period of study medication treatment 
(maintenance and long-term treatment), discontinued from study medication early, and 
completed or discontinued from the study and reasons for discontinuation will be summarized by 
treatment group and overall. 
11.5 Missing Data 
Subjects who stop study medication treatment after randomization and prior to completion of the 
study should continue with planned study visits and assessments unless they withdraw consent 
for participation in the study.  Similarly, subjects will continue with study medication and study 
procedures following the initiation of rescue therapy, with the exception that the subjects must 
discontinue taking study medication while receiving an ESA rescue therapy.  Treatment with 
study medication should be resumed after an appropriate interval following the ESA rescue 
therapy as described in Section 8.4.7, Rescue Therapy.  Data will continue to be collected 
following initiation of the rescue therapy as per the study Schedule of Activities. 
All data collected during the study, including at any point after the initiation of rescue therapy as 
well as after early discontinuation of study medication treatment, will be used for the primary 
analysis as well as main analyses of all efficacy endpoints.  Sensitivity analyses, as described 
below, will be performed to assess an impact of rescue therapy on study conclusions. 
In the primary analysis of the primary efficacy endpoint, all available qualifying HGB 
measurements during the pretreatment period and during the primary evaluation period 
(Weeks 24-36) will be used to calculate an average HGB during each period respectively.  For 
any subject with no available HGB measurements during the primary evaluation period, the 
value (central laboratory data only) closest in time to the evaluation period will be used for the 
change from Baseline.  Given the design of this study where the subjects will continue to be 
assessed after early study medication discontinuation, it is expected that only a minimal amount 
of missing data will be present and the primary analysis should not be substantially affected by 
the imputation. 
All data pertaining to the MACE endpoint collected at any point during the study, both during 
study medication treatment and post study medication treatment discontinuation, and regardless 
of the rescue therapy, will be used for the primary analysis of the MACE endpoint and its 
individual components. 
Unless stated otherwise, missing data for all other secondary efficacy and safety endpoints will 
not be imputed and the analysis will be based on observed data.  For certain responder-type 
binary endpoints, subjects with no available data will be classified into one of the categories as 
described in the relevant sections below. 
11.6 Efficacy Analyses 
The primary efficacy endpoint as well as all key and other secondary endpoints will be 
summarized using descriptive statistics by treatment group, as well as by study visit and/or 

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analysis period as appropriate.  Mean values of HGB as well as selected other efficacy 
parameters will be plotted across study visits/periods by treatment group. 
11.6.1 Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the mean HGB change from Baseline (mean 
pretreatment HGB) to the mean HGB from Weeks 24-36 (inclusive). 
11.6.1.1 Primary Analysis of Primary Efficacy Endpoint 
The primary analysis will use an analysis of variance (ANOVA) stratified by the randomization 
strata.  Within this model the strata-specific differences between the treatments will be combined 
using weights proportionate to the stratum size.  A 2-sided 95% confidence interval for the 
difference between the vadadustat group and the darbepoetin alfa group will be obtained from 
this model. 
Noninferiority of vadadustat to darbepoetin alfa will be established by comparing the lower limit 
of the 95% confidence interval for the difference between treatment groups (vadadustat minus 
darbepoetin alfa) obtained from this model to the noninferiority margin of -0.5 g/dL. 
The primary analysis will be performed using the full analysis population and the assigned 
treatment as described in Section 11.2, Study Analysis Populations.  All data collected during the 
study for subjects included in the full analysis population at the time of analysis, including data 
collected at any point after the initiation of rescue therapy as well as after early discontinuation 
of study medication treatment, will be used for the primary analysis.  Missing data will be 
handled by using the HGB data closest to the evaluation period, as described in Section 11.5, 
Missing Data. 
In geographies where regulatory approval does not require a formal analysis of MACE, efficacy 
and safety analyses may be performed upon the completion of 52 weeks of post-randomization 
follow-up in a sufficient number of subjects to support registration in that geography.  Details 
will be provided in a geography-specific SAP. 
11.6.1.2 Sensitivity Analyses of Primary Efficacy Endpoint 
The following sensitivity analyses will be conducted to investigate the impact of missing data 
and rescue treatment. 

Primary analysis will be repeated with change from Baseline to the primary evaluation
period in HGB based upon the last HGB value before rescue for subjects receiving any
form of rescue (transfusion or ESA) prior to the primary evaluation period (ie, during the
conversion period Weeks 0-23).

Primary analysis will be repeated using all randomized subjects.

Primary analysis will be repeated using only subjects with available HGB data during the
primary evaluation period, ie, excluding subjects with no available data during the
primary evaluation period.

Primary analysis will be repeated using the PP population with the actual treatment
received.

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11.6.2 Analysis of Key Secondary Efficacy Endpoints 
Secondary efficacy endpoints analyses will be performed using the randomized and full analysis 
populations and the assigned treatment as described in Section 11.2, Study Analysis Populations.  
Analysis for the key secondary efficacy endpoints will be repeated using the PP population with 
the actual treatment received. 
In order to control the overall Type I error rate, hierarchical testing procedures will be applied to 
the primary and secondary efficacy endpoints, and details will be provided in the SAP. 
11.6.2.1 Analysis of Mean Change in HGB Value between Baseline (Mean Pretreatment HGB) 
and the Secondary Evaluation Period (Weeks 40-52) 
This endpoint will be analyzed using the same methodology as specified for the primary efficacy 
endpoint, including the same method of imputation in absence of any measurements during the 
secondary evaluation period (Weeks 40-52). 
Sensitivity analyses similar to those of the primary efficacy endpoint will be performed and 
details will be provided in the SAP. 
11.6.2.2 Analysis of Proportion of Subjects with Mean HGB within the Target Range during the 
Primary Evaluation Period (Weeks 24-36) 
Each subject will be classified using a binary variable (“yes”/”no”) for the analysis of this 
endpoint.  A classification of “yes” will be assigned to any subject with a mean HGB within the 
target range during the primary evaluation period (Weeks 24-36).  All other subjects, including 
those with no available values during the primary evaluation period, will be classified to the “no” 
category.  The between-treatment difference will be summarized with a confidence interval 
which uses Cochran-Mantel-Haenszel (CMH) weighting. 
11.6.2.3 Analysis of Mean Weekly Dose of IV Elemental Iron Administered from Baseline to 
Week 52 
For each subject a mean weekly dose (mg) of IV elemental iron administered at any time starting 
on Day 1 through Week 52 will be calculated based upon observed data.  It will be calculated as 
a total cumulative dose (mg) of IV elemental iron administered from Day 1 through Week 52 
divided by the number of weeks the subject remained in the study up to the Week 52 visit.  The 
between-treatment difference will be summarized with a confidence interval similar to those 
used for the primary endpoint. 
11.6.2.4 Analysis of Proportion of Subjects Receiving RBC Transfusion(s) from Baseline to 
Week 52 
Each subject will be classified using a binary variable (“yes”/”no”) for the analysis of this 
endpoint.  A classification of “yes” will be assigned to any subject receiving RBC transfusion(s) 
at any time starting on Day 1 through Week 52.  All other subjects will be classified to the “no” 
category.  The between-treatment difference will be summarized with a confidence interval 
which uses CMH weighting.  Time to first RBC transfusion will also be summarized. 
11.6.3 Analysis of Additional Secondary Efficacy Endpoints 
Descriptive summaries of all secondary efficacy endpoints will be presented using observed data 
without imputation.  Analyses will consist of the presentation of descriptive statistics by 

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treatment group along with the presentation of 2-sided 95% confidence intervals for the 
treatment differences.  The descriptive summaries of the secondary endpoints will be made 
without stratification. 
11.7 Safety Analyses 
11.7.1 Analysis of MACE 
The primary safety endpoint, time to the first adjudicated MACE, will be analyzed as [date of the 
first MACE – the date of first dose of study medication].  A MACE is defined as all-cause 
mortality, non-fatal myocardial infarction, or non-fatal stroke.  Subjects who have not 
experienced a MACE by study closure will be censored on the date of their last study 
assessment.  The hazard ratio (vadadustat/darbepoetin alfa) and its 95% confidence interval will 
be obtained from a stratified Cox proportional hazards model.  As this study has not been 
designed to provide a stand-alone assessment of MACE, this analysis will be considered a 
descriptive analysis.  A similar analysis as described for the primary analysis of the MACE 
endpoint will be performed with censoring of subjects 4 weeks following discontinuation of 
study treatment if they did not have a MACE prior to that time. 
The primary MACE analysis will be based upon all events that accrue over 2 separately planned 
NDD-CKD studies (Studies AKB-6548-CI-0014 and AKB-6548-CI-0015) (see Section 11.1.2, 
Sample Size for the Primary Safety Endpoint). 
11.7.2 Analysis of Adverse Events 
Adverse events will be summarized using the number and percentage of subjects with AEs for 
all subjects in the safety population. 
All AEs will be coded using MedDRA.  Treatment-emergent and post-treatment AEs will be 
summarized by System Organ Class and Preferred Term for each treatment group.  Adverse 
events will also be summarized by their maximum severity. 
Summaries will also be provided for the following types of AEs: 

SAEs

Related AEs (including all categories for relationship to study medication other than
“Unrelated”, as determined by the Investigator)

AEs leading to early discontinuation of study medication.
11.7.3 Remaining Safety Endpoints 
The following safety endpoints will be analyzed using time to event methods: 
1) Individual components (death, myocardial infarction, stroke) of MACE
2) Thromboembolic events (defined as arterial thrombosis, DVT, PE, or vascular access
thrombosis).
For these endpoints the incidence ("yes"/"no") of the endpoint will be presented for each 
treatment arm.  Kaplan-Meier curves will be presented for each endpoint as the time of endpoint 
free survival (ie, time until endpoint or death). 

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The analysis of proportion of subjects with HGB >12.0 g/dL, >13.0 g/dL, or >14.0 g/dL 
post-Baseline will classify a subject as a “yes” if: 

Any value HGB >12.0 g/dL at any time after Day 1

Any confirmed value HGB >12.0 g/dL at any time after Day 1

Any value HGB >13.0 g/dL at any time after Day 1

Any confirmed value HGB >13.0 g/dL at any time after Day 1

Any value HGB >14.0 g/dL at any time after Day 1

Any confirmed value HGB >14.0 g/dL at any time after Day 1.
A HGB value above a set threshold will be considered as confirmed if there are 2 consecutive 
values above that threshold.  The second of the 2 consecutive assessments should be done at 
most 12 weeks after the first assessment.  Subjects with no available data post-Baseline will be 
excluded from this analysis.  All other subjects will be classified to the “no” category. 
The analysis of proportion of subjects with any HGB increase >1.0 g/dL within any 2-week 
interval or >2.0 g/dL within any 4-week interval post-Baseline will classify a subject as a “yes” 
if at least 1 of the following criteria at any point after Day 1 is met: 

HGB increase >1.0 g/dL within any 2-week interval

HGB increase >2.0 g/dL within any 4-week interval.
Subjects with no available data post-Baseline will be excluded from this analysis.  All 
other subjects will be classified to the “no” category. 
Observed values of continuous and categorical parameters and changes from Baseline for 
continuous parameters to each study visit will be summarized descriptively for vital signs and 
clinical laboratory results.  Graphical displays of selected laboratory parameters will also be 
provided. 
11.8 Additional Assessments 
11.8.1 Concomitant Medications 
Prior and concomitant medications will be coded using World Health Organization (WHO) Drug 
dictionary. 
Prior medications will be defined as any medications that were taken before the date of the first 
dose of study medication.  Concomitant medications will be defined as any medications taken at 
any time from the date of the first dose of study medication through the date of the last dose of 
the study medication. 
The total number of transfusions, ESA rescue therapies, and therapeutic phlebotomy collections 
will be summarized by period as well as post-Baseline overall. 
11.8.2 Biomarkers 
Biomarkers (hepcidin and VEGF) will be summarized descriptively at Baseline and by visit 
post-Baseline.  

Protocol No.  AKB-6548-CI-0015 
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11.8.3 Pharmacokinetics 
Descriptive and graphical summaries will be generated for PK measurements. 
12 DATA HANDLING AND RECORD KEEPING 
12.1 Case Report Forms/Electronic Data Capture 
This study will utilize an EDC system to manage data collection during this trial.  The system is 
fully Code of Federal Regulations 21 part 11 compliant.  An EDC system contains certain 
functionality including, but not limited to, a graphical user interface to help facilitate data entry, 
a data validation element to check user data, and a reporting function to assist with the review 
and analysis of data.  Case report forms available through this system are required and should be 
completed for each randomized subject. 
Any form of data from the electronic system are the sole property of the Sponsor and should not 
be made available in any form to third parties, except for authorized representatives of the 
Sponsor or appropriate regulatory authorities, without written permission from the Sponsor. 
The Investigator has ultimate responsibility for the accuracy, authenticity, and timely collection 
and reporting of all clinical, safety, and laboratory data entered in the EDC or any other data 
collection forms.  The CRFs must be signed electronically by the Investigator to attest that the 
data contained on the CRFs is true. 
In most cases, the source documents are contained in the subject’s chart at the hospital or the 
physician's office.  In these cases, data collected on the CRFs must match the data in those 
charts. 
12.2 Record Retention 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, eg, CRFs and hospital records), all original signed informed consent forms, 
copies of all CRFs, SAE forms, source documents, detailed records of drug disposition, and 
adequate documentation of relevant correspondence (eg, letters, meeting minutes, telephone calls 
reports).  The records should be retained by the Investigator according to the International 
Conference on Harmonization (ICH), local regulations, or as specified in the Clinical Study 
Agreement, whichever is longer. 
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), the Sponsor should be prospectively notified.  The 
study records must be transferred to a designee acceptable to the Sponsor, such as another 
Investigator, another institution, or to the Sponsor.  The Investigator must obtain Sponsor’s 
written permission before disposing of any records, even if retention requirements have been 
met. 

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13 QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) 
13.1 Investigative Site Monitoring Visits 
During study conduct, the Sponsor or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practice (GCP) are being followed.  The monitors will 
review source documents to confirm that the data recorded on the CRFs is accurate.  The 
Investigator/institution will allow the Sponsor’s monitors or designees and appropriate regulatory 
authorities direct access to source documents to perform this verification. 
The investigative site may also be subject to QA audits performed by the Sponsor or companies 
working with or on behalf of the Sponsor, and/or review by the IRB/IEC, and/or to inspection by 
appropriate regulatory authorities. 
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
13.2 Protocol Deviations 
The Investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects.  Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the Investigator should consult with the 
Sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
The investigative site should document all protocol deviations in the subject’s source documents.  
In the event of a significant deviation, the investigative site should notify the Sponsor or its 
designee (and IRB or IEC, as required).  Significant deviations include, but are not limited to, 
those that involve fraud or misconduct, increase the health risk to the subject, or confound 
interpretation of primary study assessments. 
14 STUDY DISCONTINUATION/INVESTIGATIVE STUDY SITE 
TERMINATION 
The Sponsor reserves the right to discontinue the study prior to inclusion of the intended number 
of subjects, but intends only to exercise this right for valid scientific or administrative reasons.  
After such a decision, the Investigator must contact all participating subjects within a time period 
specified by the Sponsor to inform them of the decision to discontinue the study. 
14.1 Criteria for Premature Termination or Suspension of the Study 
The following criteria may result in either temporary suspension or early termination of the 
study: 

New information regarding the safety or efficacy of the study medication that indicates a
change in the known risk/benefit profile for the compound, such that the risk/benefit is no
longer acceptable for subjects participating in the study

Significant violation of GCP that compromises the ability to achieve the primary study
objectives or compromises subject safety.
The Sponsor reserves the right to discontinue the study for other valid administrative reasons. 

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14.2 Criteria for Premature Termination or Suspension of Investigational Study 
Sites 
A study site may be terminated prematurely or suspended if the study site (including the 
Investigator) is found to be in significant violation of GCP, protocol, contractual agreement, or is 
unable to ensure adequate performance of the study. 
14.3 Procedures for Premature Termination or Suspension of the Study or 
Investigational Sites 
In the event that the Sponsor elects to terminate or suspend the study or the participation of an 
investigational study site, a study-specific procedure for early termination or suspension will be 
provided by the Sponsor; the procedure will be followed by applicable investigational study sites 
during the course of termination or study suspension. 
15 ETHICS 
15.1 Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical Principles 
for Medical Research Involving Human Subjects, adopted by the General Assembly of the World 
Medical Association (1996). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws. 
15.2 Institutional Review Board/Independent Ethics Committee 
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, (eg, recruitment 
advertisements, if applicable) from the IRB/IEC.  All correspondence with the IRB/IEC should 
be retained in the Investigator File.  Copies of IRB/IEC approvals should be forwarded to the 
Sponsor or its designee. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In that 
event, the Investigator must notify the IRB/IEC and the Sponsor in writing immediately after the 
implementation. 
15.3 Subject Information and Consent 
It is the responsibility of the Investigator to give each subject (or the subject’s acceptable 
representative), prior to inclusion in the study, full and adequate verbal and written information 
regarding the objective and procedures of the study and the possible risks involved.  The subjects 
must be informed about their right to withdraw from the study at any time. 
Furthermore, it is the responsibility of the Investigator, or a person designated by the 
Investigator, to obtain signed informed consent from each subject or the subject’s legally 
acceptable representative prior to inclusion in the study.  The Investigator will retain the original 
of each subject's signed consent form. 

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The informed consent forms will be in compliance with ICH GCP, local regulatory requirements, 
and legal requirements.  The informed consent forms used in this study, and any changes made 
during the course of the study, must be prospectively approved by both the IRB/IEC and the 
Sponsor before use. 
15.4 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority, or if the Investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of the investigational product, the Sponsor 
should be informed immediately. 
In addition, the Investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the Investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP, defined as a breach that will likely affect the 
safety or physical or mental integrity of subjects or the scientific value of the trial, that comes to 
the attention of the Investigator. 
15.5 Subject Confidentiality 
All parties will ensure protection of subject personal data and will not include subject names on 
any Sponsor forms, reports, publications, or in any other disclosures, except where required by 
law.  In case of data transfer, the Sponsor will maintain high standards of confidentiality and 
protection of subject personal data. 
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy.  Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number.  As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH guidelines for GCP and to verify compliance with this protocol, the 
Sponsor requires the Investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, FDA), the Sponsor’s designated auditors, and the appropriate 
IRBs and IECs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports.  Access to a subject’s original medical records requires the specific authorization of 
the subject as part of the informed consent process. 
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s CRF). 
16 PUBLICATION OF STUDY RESULTS 
No publication or disclosure of study results will be permitted, except under the terms and 
conditions of a separate, written agreement between Sponsor and the Investigator and/or the 
Investigator’s institution.  The Sponsor must have the opportunity to review and approve all 

Protocol No.  AKB-6548-CI-0015 
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proposed abstracts, manuscripts, or presentations regarding this study prior to submission for 
publication/presentation.  Any information identified by the Sponsor as confidential must be 
deleted prior to submission. 
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including:  Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors. 
17 REFERENCES 
Abramson JL, Jurkovitz CT, Vaccarino V et al. Chronic kidney disease, anemia, and incident 
stroke in a middle-aged, community-based population: the ARIC study.  Kidney Int (2003) 
64(2): 610-615. 
Aranesp (package insert). Thousand Oaks, CA: Amgen, Inc.; 2015. 
Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, et al.  The effects 
of normal as compared with low hematocrit values in patients with cardiac disease who are 
receiving hemodialysis and epoetin.  N Engl J Med (1998) 339(9):584-590. 
Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al.  Normalization 
of hemoglobin level in patients with chronic kidney disease and anemia.  N Engl J Med (2006) 
355(20):2071-2084. 
Goodkin DA, Fuller DS, Robinson BM, Combe C, Fluck R, Mendelssohn D, et al.  Naturally 
occurring higher hemoglobin concentration does not increase mortality among hemodialysis 
patients.  J Am Soc Nephrol (2011) 22(2):358-365. 
Iseki K and Kohagura K.  Anemia as a risk factor for chronic kidney disease.  Kidney Int (2007) 
Suppl 72:S4-9. 
Japanese Society of Nephrology.  Evidence-based clinical practice guideline for CKD 2013. Clin 
Exp Nephrol (2014) 18(3):346-423. 
Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and 
perspectives. Lancet (2013) 382(9888): 260-272.  
KDIGO CKD Working Group. KDIGO clinical practice guideline for the evaluation and 
management of chronic kidney disease. Kidney Int Suppl (2013) 3(1): 1-150. 
KDIGO.  KDIGO clinical practice guideline for anemia in chronic kidney disease.  Kidney Int 
(2012) 2(4):1-64.  Available at: 
http://www2.kidney.org/professionals/kdoqi/guidelines_ckd/p4_class_g1.htm 
Levey AS, Stevens LA, Schmid CH, et al.  A new equation to estimate glomerular filtration rate.  
Ann Intern Med (2009) 150(9):604-612. 
Locatelli F, Bárány P, Covic A, De Francisco A, Del Vecchio L, Goldsmith D, et al.  Kidney 
Disease: Improving Global Outcomes guidelines on anaemia management in chronic kidney 
disease: a European Renal Best Practice position statement.  Nephrol Dial Transplant (2013) 
28(6):1346-1359. 

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Metivier F, Marchais SJ, Guerin AP, Pannier B, London GM.  Pathophysiology of anaemia: 
focus on the heart and blood vessels.  Nephrol Dial Transplant (2000) 15 Suppl 3: 14-18. 
National Institute for Health and Care Excellence (NICE).  Anaemia management in people with 
chronic kidney disease.  NICE clinical guideline (2011) 114:1-39. 
Nurko S.  Anemia in chronic kidney disease: causes, diagnosis, treatment.  Cleve Clin J Med 
(2006) 73(3):289-297. 
Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, Nizet V, and 
Johnson RS.  Regulation of iron homeostasis by the hypoxia-inducible transcription factors 
(HIFs).  J Clin Invest (2007) 117(7):1926-1932. 
Pfeffer MA, Burdmann EA, Chen CY, et al.  A trial of darbepoetin alfa in type 2 diabetes and 
chronic kidney disease.  N Engl J Med (2009a) 361(21):2019-2032. 
Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al.  Baseline 
characteristics in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).  
Am J Kidney Dis (2009b) 54(1):59-69. 
Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al.  Correction of anemia 
with epoetin alfa in chronic kidney disease.  N Engl J Med (2006) 355(20):2085-2098. 
Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA, et al.  Erythropoietic 
response and outcomes in kidney disease and type 2 diabetes.  N Engl J Med (2010) 363(12): 
1146-1155. 
Stauffer ME and Fan T.  Prevalence of anemia in chronic kidney disease in the United States.  
PLoS One (2014) 9(1): e84943. 
Szczech LA, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, et al.  Secondary analysis 
of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes.  Kidney Int (2008) 
74(6):791-798. 
Tsubakihara Y, Nishi S, Akiba T, et al.  2008 Japanese Society for Dialysis Therapy:  Guidelines 
for renal anemia in chronic kidney disease.  Ther Apher and Dial (2010) 14(3):240-275. 
Unger EF.  FDA perspectives on erythropoiesis-stimulating agents (ESAs) for anemia of chronic 
renal failure: Hemoglobin target and dose optimization (Slide presentation from the Sep 11, 2007 
Joint Meeting of the Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety 
and Risk Management Advisory Committee).  Retrieved from 
http://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4315s1-10-FDA-Unger.ppt. 
Unger EF, Thompson AM, Blank MJ, and Temple R.  Erythropoiesis-stimulating agents - Time 
for a reevaluation.  N Engl J Med (2010) 362(3):189-92. 

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APPENDIX A:  SCHEDULE OF ACTIVITIES 
Study Period 
Optional 
Pre-
Screen 
Screening 
Treatment Period 
Post 
Treatment 
BL/ 
rand. [a] 
Year 1 
Year 2 
Year 3/Year 4 
Visit 
PS 
SV1 SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22/ 
26 
23/ 
27 
24/ 
28 
25/ 
29 
End of 
Trtmt 
Follow-
up [b] 
Week 
-4 to 0
0 
2 
4 
6 
8 
10 12 16 20 24 28 32 36 40 44 48 52 64 76 88 104 116/ 
168 
128/ 
180 
140/ 
192 
156/ 
208 
EOT [c] 
EOT 
+4
wks
Procedures/Assessments 
Informed Consent 
X [d] 
X [d] 
Pre-Screening Local 
HGB [e] 
X 
I/E Criteria [f] 
X 
X 
X 
Vital Signs [g] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics, Med 
History 
X 
Physical Exam [h] 
X 
12-Lead ECG [i]
X 
Randomization 
X 
Laboratory Procedures 
Pregnancy Test [j] 
X 
Folate and Vitamin B12 
X [k] 
Coagulation Tests [l] 
X 
C-Reactive Protein
X 
Urine Albumin: 
Creatinine (uACR) 
X 
CBC [m] with periodic 
diff  
X 
[k,n] X [k] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Iron Indices [o] 
X [k] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chem and 
eGFR [p] 
X [k] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Function Tests [q] 
X [k] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipid Panel [r] 
X 
X 
X 

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Study Period 
Optional 
Pre-
Screen 
Screening 
Treatment Period 
Post 
Treatment 
BL/ 
rand. [a] 
Year 1 
Year 2 
Year 3/Year 4 
Visit 
PS 
SV1 SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22/ 
26 
23/ 
27 
24/ 
28 
25/ 
29 
End of 
Trtmt 
Follow-
up [b] 
Week 
-4 to 0
0 
2 
4 
6 
8 
10 12 16 20 24 28 32 36 40 44 48 52 64 76 88 104 116/ 
168 
128/ 
180 
140/ 
192 
156/ 
208 
EOT [c] 
EOT 
+4
wks
Biomarkers [s] 
X 
X 
X 
X 
Reticulocyte Count 
X 
X 
X 
X 
X 
Erythropoietin 
X 
X 
X 
X 
X 
PK [t] 
X 
X 
X 
X 
Exploratory Samples [u] 
X 
X 
ACTH (Cosyntropin) 
Stimulation Test [v] 
X 
X 
X 
X [w] 
Safety Assessments 
MACE Endpoint 
Questionnaire [x] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessment [y] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transfusions and ESA 
Rescue Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Therapeutic 
Phlebotomy Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Assessments and Procedures 
Concomitant Med 
Review [z] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vadadustat Medication 
Dispensing [aa] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Reconciliation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visit Registration in 
IWR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HGB via HemoCue® for 
Dose Adjustment [bb] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Darbepoetin Alfa 
Dosing per approved local product label [cc] 
Vadadustat Dose 
Adjustments [dd] 
Start at 300 mg once daily, then adjust dose as per Dose Adjustment Guidelines 

Protocol No.  AKB-6548-CI-0015 
 
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Study Period 
Optional 
Pre-
Screen 
Screening 
Treatment Period 
Post 
Treatment 
BL/ 
rand. [a] 
Year 1 
Year 2 
Year 3/Year 4 
Visit 
PS 
SV1 SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22/ 
26 
23/ 
27 
24/ 
28 
25/ 
29 
End of 
Trtmt 
Follow-
up [b] 
Week 
-4 to 0
0 
2 
4 
6 
8 
10 12 16 20 24 28 32 36 40 44 48 52 64 76 88 104 116/ 
168 
128/ 
180 
140/ 
192 
156/ 
208 
EOT [c] 
EOT 
+4
wks
Oral Iron 
Supplementation [ee] 
As needed to maintain ferritin ≥100 ng/mL and TSAT ≥20% 
Abbreviations:  ACTH = adrenocorticotropic hormone; AE = adverse event; ALT/SGPT = alanine aminotransferase/serum glutamic-pyruvic transaminase; AST/SGOT = aspartate 
aminotransferase/serum glutamic oxaloacetic transaminase; BUN = blood urea nitrogen; CBC = complete blood count; CPK = creatine phosphokinase; CRF = case report form; diff = differential; 
ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; EOT = end of treatment; ESA = erythropoiesis-stimulating agent; HDL = high density lipoprotein; HGB = hemoglobin; 
HIF = hypoxia inducible factor; ICF = informed consent form; I/E = inclusion/exclusion; INR = international normalized ratio; IWR = interactive web response; LDH = lactate dehydrogenase; 
LDL = low density lipoprotein; MACE = major adverse cardiovascular event; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular 
volume; med = medication; PK = pharmacokinetic; PS = Pre-Screening; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cell; RDW = red cell distribution width; 
SV1 = Screening visit 1; SV2 = Screening visit 2; TIBC = total iron binding capacity; Trtmt = treatment; TSAT = transferrin saturation; uACR = urine albumin to creatinine ratio; VEGF = vascular 
endothelial growth factor; WBC = white blood cell; wks = weeks. 
[a] The Screening period is a maximum of 28 days in duration.  The Baseline visit must be performed within 28 days of the 2 Screening visits and a minimum of 4 days must elapse between the 
2 Screening visits (SV1 and SV2) and between SV2 and the Baseline visit.
[b] The Follow-up visit can be performed either in person OR via the telephone.
[c] EOT will be performed when the study is ended.  Subjects who prematurely discontinue study medication (vadadustat or darbepoetin alfa) for any reason should attend all subsequent study visits 
and be continually monitored according to the Schedule of Activities for the duration of the study.
[d] An abbreviated ICF will be used for Pre-Screening.  If the subject is eligible for Screening, a separate full ICF will be used.  An optional consent form for collection of blood samples for future 
genetic analysis will be provided at SV1.  An additional optional consent form for participation in an adrenal function substudy in 200 subjects in the EU will also be provided at SV1. 
[e] If the Pre-Screen HemoCue® HGB is between 8.0 and 11.0 g/dL (inclusive) within the US or between 9.0 and 12.0 g/dL (inclusive) outside of the US, the investigative site may proceed with
Screening Visit 1 (SV1), preferably on the same day as Pre-Screening. 
[f] Inclusion/Exclusion criteria will be reviewed at the Pre-Screening and Screening visits (SV1 and SV2).  Final eligibility determination will occur following the Screening visits when all data are 
available.
[g] Vitals: Heart rate and blood pressure to be assessed in the seated position after 5 minutes of rest.  Height (SV2 only) and weight (SV2, Weeks 12, 24, 36, and 52, yearly thereafter, and at the EOT 
visit) will also be measured.
[h] Physical exam:  a physical exam is required at SV2 as outlined in the protocol.  Thereafter, an abbreviated symptom-directed physical exam should be performed at the discretion of the Investigator 
as clinically indicated.
[i] ECG should be performed prior to blood draws when possible and obtained after the subject has been resting comfortably in a supine position for approximately 5 minutes.
[j]
Serum pregnancy will be tested in women of childbearing potential at SV2.  (Eligible subjects will be advised to use an adequate contraceptive method.)  Additional serum or local urine pregnancy 
tests should be conducted throughout the study in sufficient number, as determined by the Investigator or required by local regulations, to establish the absence of pregnancy during the study.  If 
positive at SV2, the subject is not eligible to enter the study.  If a subject becomes pregnant during the study, the subject must permanently discontinue study medication and should attend all 
subsequent study visits and be continually monitored according to the Schedule of Activities for the duration of the study.
[k] Subjects may be retested and/or rescreened as detailed in Sections 7.4.1, Retesting and 7.4.2, Rescreening. 
[l]
Coagulation tests:  prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR).
[m] A CBC with differential will be performed at Baseline and twice annually at Weeks 28, 52, 76, 104, 128, 156, 180, 208.  At all other noted visits, a CBC without differential will be performed.
CBC:  hemoglobin, hematocrit, red blood cells (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell 
distribution width (RDW), white blood cell (WBC) count with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), and platelets.
[n] If HGB at SV1 is 11.1-11.5 g/dL in the US or 12.1-12.5 g/dL outside the US, a single retest CBC should be performed prior to SV2.  If retest HGB is >11.0 g/dL in the US or >12.0 g/dL outside the 
US, the subject should not proceed with SV2.  If the HGB at SV1 is >11.5 g/dL in the US or >12.5 g/dL outside of the US, the subject should not proceed with any further Screening at this time.
[o] Iron indices:  ferritin, iron, total iron binding capacity (TIBC), and transferrin saturation (TSAT).

Protocol No.  AKB-6548-CI-0015 
 
Akebia — Company Confidential 
Page 78 of 80 
[p] A full serum chemistry panel will be performed at SV2, Baseline, and twice annually at Weeks 28, 52, 76, 104, 128, 156, 180, 208.  At all other noted visits, serum creatinine and eGFR will be 
performed.  Serum chemistry:  sodium, potassium, bicarbonate, chloride, calcium, magnesium, phosphorus, glucose, creatinine, blood urea nitrogen (BUN)/urea, creatine phosphokinase (CPK), uric
acid, albumin, and total protein.
[q] Liver function tests:  total bilirubin, alkaline phosphatase, alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), and lactate dehydrogenase (LDH).
[r] Lipids:  total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides.
[s] Hepcidin and vascular endothelial growth factor (VEGF) will be analyzed at Baseline and at Weeks 12, 28, and EOT.
[t]
PK samples are to be drawn only for subjects randomized to vadadustat.  Subjects will be questioned regarding the timing of their last dose of vadadustat. 
[u] Additional blood and urine samples will be collected at Baseline and Week 28 which may be used for exploratory measurement of biomarkers (eg, factors relating to the activation of the HIF 
pathway).  Subjects will also be asked to provide optional consent to obtain and store a blood sample for future genetic analyses (eg, DNA, mRNA, etc).
[v] The ACTH (cosyntropin) stimulation test will be performed on a subset of 100 subjects per treatment arm (200 subjects total) in the EU as part of a substudy on adrenal function.
[w]  The ACTH (cosyntropin) stimulation test will only be performed at the EOT visit for subjects who are part of the adrenal function substudy and who have permanently discontinued study 
medication early prior to the Week 52 study visit. 
[x] At each post-randomization study visit, the subject must specifically be questioned regarding the occurrence of any potential MACE endpoint events since the last study visit.  If a potential endpoint
event is reported, the date of the event should be recorded and the appropriate source documents should be collected according to the endpoint packet checklist. 
[y] Adverse events should be documented and recorded at each visit.  All adverse events (serious and non-serious, and related and non-related) will be documented and recorded through the follow-up
visit.  Subjects must be followed for adverse events until the final required protocol visit or until all drug-related toxicities and serious adverse events have resolved (or are considered
chronic/stable).
[z] Concomitant medications should be collected and recorded at each visit as noted.  All concomitant medications received up to and including 30 days prior to the start of study medication through the 
EOT visit will be recorded.
[aa] Subjects will be provided with a supply of vadadustat at the Baseline visit and will be resupplied at subsequent visits as needed.  Subjects will be instructed to complete 1 bottle prior to opening the 
next bottle.  The dose should be taken at approximately the same time each day, preferably between 7 AM and 2 PM. 
[bb]Hemoglobin will be monitored via local HemoCue® throughout the study to determine if the dose of study medication will be adjusted or suspended. 
[cc] Refer to the approved local product label.  Vital signs and weight should be obtained prior to dosing per the local product label.
[dd] The dose will be adjusted in accordance with the Dose Adjustment Guidelines.  Changes to dose will be accomplished by changing the number of tablets to be taken per day.
[ee] Iron supplementation should be prescribed as needed during the study to maintain ferritin ≥100 ng/mL and TSAT ≥20%.  In general, only oral iron should be used for therapy.  Vadadustat should
not be administered concurrently with the oral iron supplement (including multivitamins containing iron).  Oral iron supplement should be taken at least 2 hours before or 2 hours after the dose of 
study medication.  (See study protocol for further details regarding iron administration and potential intravenous therapy). 

Protocol No.  AKB-6548-CI-0015 
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APPENDIX B:  CKD-EPI CREATININE EQUATION 
The estimated glomerular filtration rate (eGFR) will be calculated from serum creatinine (isotope 
dilution mass spectrometry [IDMS] calibrated in mg/dL) using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) creatinine equation (Levey et al. 2009). 
The CKD-EPI creatinine equation is: 
eGFR = 141 x min(SCr/k,1)α x max(SCr/k,1)-1.209 x 0.993Age x [1.018 if female] x [1.159 if 
black] 
where: 
SCr is serum creatinine (in mg/dL) 
k = 0.7 for females 
k = 0.9 for males 
α = -0.329 for females 
α = -0.411 for males 
min = the minimum of SCr/k or 1 
max = the maximum of SCr/k or 1 

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APPENDIX C:  ACTH (COSYNTROPIN) STIMULATION TEST FOR 
ADRENAL FUNCTION MONITORING 
The adrenocorticotropic hormone (ACTH) stimulation test assesses the function of the adrenal 
glands and their ability to respond to ACTH.  Adrenocorticotropic hormone is a hormone 
produced in the pituitary gland that stimulates the adrenal glands to release cortisol.  Cosyntropin 
is a synthetic form of ACTH.  The ACTH stimulation test is recognized as the gold standard 
assay of adrenal insufficiency. 
Sequential ACTH (cosyntropin) stimulation tests will be conducted at European Union (EU) 
sites in the first 200 subjects randomized and who agree to participate in the testing 
(approximately 100 subjects per treatment arm).  Testing will be performed at the Baseline 
(predose), Week 12, and Week 52 study visits, or at the end of treatment (EOT) visit if the 
subject permanently discontinues study medication early prior to the Week 52 study visit. 
Female subjects who have taken estrogens within 30 days of the first dose of study medication 
should be excluded from the adrenal function monitoring substudy. 
Test details: 

Obtain blood sample for pretest serum cortisol measurement (collected prior to
administering cosyntropin)

Administer 0.25 mg cosyntropin via intravenous (IV) push

Obtain blood samples for serum cortisol measurements at 30 minutes and 60 minutes
after dosing of cosyntropin
Samples for cortisol measurements will be sent to the central laboratory for analysis. 

Protocol No. AKB-6548-CI-0015 
Amendment 7-COL 
Akebia — Company Confidential 
Page 1 of 105 
CLINICAL PROTOCOL 
PHASE 3, RANDOMIZED, OPEN-LABEL, ACTIVE-CONTROLLED STUDY 
EVALUATING THE EFFICACY AND SAFETY OF ORAL VADADUSTAT FOR THE 
MAINTENANCE TREATMENT OF ANEMIA IN SUBJECTS WITH NON-DIALYSIS-
DEPENDENT CHRONIC KIDNEY DISEASE (NDD-CKD) 
(PRO2TECT - CONVERSION) 
Compound: 
Vadadustat (AKB-6548) 
Protocol Number: 
AKB-6548-CI-0015 
US IND Number: 
102,465 
EudraCT Number 
2015-004774-14 
Phase: 
Phase 3 
Status/Date: 
Amendment 7-COL (
 Colombia-specific 
protocol amendment) 
Amendment 6-COL (
; Colombia-specific 
protocol amendment) 
Amendment 5-COL (
; Colombia-specific 
protocol amendment) 
Amendment 4-COL (
;  
Colombia-specific protocol amendment) 
Amendment 3-COL (
; 
Colombia-specific protocol amendment) 
Amendment 2-COL (
;  
Colombia-specific protocol amendment) 
Amendment 2 (
) 
Amendment 1 (
) 
Original protocol (
) 
Sponsor: 
Akebia Therapeutics, Inc. 
245 First Street  
Cambridge, MA 02142 
United States of America 
This document contains information that is confidential and proprietary to the Sponsor, Akebia Therapeutics, Inc.  This 
information is being provided to you solely for the purpose of evaluating and/or conducting a clinical study for the Sponsor.  You 

Protocol No. AKB-6548-CI-0015 
Amendment 7-COL 
may disclose the contents of this document only to study personnel under your supervision, the Institutional Review Board, the 
United States Food and Drug Administration, or duly authorized representatives of regulatory agencies for this purpose under the 
condition that they maintain confidentiality. The contents of this document may not be used in any other clinical study, disclosed 
to any other person or entity, and/or published without the prior written permission of the Sponsor. The foregoing shall not apply 
to disclosure required by any regulations; however, you will give prompt notice to the Sponsor of any such disclosure. 
1 
SIGNATURE PAGES 
1.1 
Protocol Approval 
Signature 
Clinical Development 
 
Biostatis
ty and Pharmacovigilance 
, Clinical 
  
Date 
Date 
Akebia - Company Confidential 
Page 2 of 105 

Protocol No. AKB-6548-CI-0015 
Amendment 7-COL 
Akebia — Company Confidential 
Page 3 of 105 
 
Investigator Agreement 
I confirm that I have read and that I understand this protocol, any amendments to the protocol (if 
applicable, a history of protocol changes are appended at the end of this document), the 
Investigator’s Brochure, and other product information provided by the Sponsor.  I agree to 
conduct this study in accordance with the requirements of this protocol and also protect the 
rights, safety, privacy, and well-being of study subjects in accordance with the following: 
•
The ethical principles that have their origin in the Declaration of Helsinki.
•
International Conference on Harmonisation Guidance for Industry, Good Clinical Practice E6.
•
All applicable laws and regulations, including, without limitation, data privacy laws and
regulations.
•
Regulatory requirements for reporting serious adverse events defined in this protocol.
•
Terms outlined in the Clinical Study Site Agreement.
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Phone Number 
Full Address 

Protocol No. AKB-6548-CI-0015 
Amendment 7-COL 
Akebia — Company Confidential 
Page 4 of 105 
TABLE OF CONTENTS 
1 
SIGNATURE PAGES .................................................................................................. 2 
Protocol Approval .................................................................................................... 2 
Investigator Agreement ............................................................................................ 3 
TABLE OF CONTENTS ......................................................................................................... 4 
2 
PROTOCOL SYNOPSIS .............................................................................................. 9 
3 
LIST OF ABBREVIATIONS ..................................................................................... 21 
4 
BACKGROUND INFORMATION ........................................................................... 24 
Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors ..................................... 26 
Summary of Clinical Experience ........................................................................... 26 
Potential Benefits and Risks ................................................................................... 27 
5 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 28 
Primary Objective .................................................................................................. 28 
Primary Efficacy Endpoint ..................................................................................... 28 
Secondary Efficacy Endpoints ............................................................................... 28 
Safety Endpoints .................................................................................................... 29 
Exploratory Endpoints ............................................................................................ 29 
6 
STUDY DESIGN ........................................................................................................ 30 
Study Design .......................................................................................................... 30 
Rationale for Study Design .................................................................................... 31 
Dose Justification ................................................................................................... 32 
Executive Steering Committee and Independent Data Monitoring Committee ..... 32 
6.4.1 
Executive Steering Committee .......................................................................... 32 
6.4.2 
Independent Data Monitoring Committee ......................................................... 33 
Endpoint Adjudication Committee ......................................................................... 33 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 33 
General Criteria ...................................................................................................... 33 
Inclusion Criteria .................................................................................................... 33 
Exclusion Criteria ................................................................................................... 34 
Retesting and Rescreening ..................................................................................... 35 
7.4.1 
Retesting ............................................................................................................ 35 
7.4.2 
Rescreening ....................................................................................................... 35 
Study Completion, Subject Completion, Study Discontinuation, and 
Withdrawal of Subjects .......................................................................................... 35 
7.5.1 
Study Completion .............................................................................................. 35 
7.5.2 
Subject Completion ........................................................................................... 36 
7.5.3 
Entire Study Termination .................................................................................. 37 

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7.5.4 
Individual Study Site Termination .................................................................... 37 
7.5.5 
Individual Subject Discontinuation ................................................................... 37 
7.5.5.1 
Temporary Interruption of Study Medication ............................................... 38 
7.5.5.2 
Permanent Discontinuation of Study Medication ......................................... 38 
7.5.5.3 
Complete Withdrawal from Further Study Visits/Assessments ................... 38 
7.5.5.4 
Procedures to Support Continued Study Participation ................................. 39 
7.5.5.5 
Procedures to Prevent “Lost to Follow-up” .................................................. 40 
8 
STUDY PRODUCT AND TREATMENT OF SUBJECTS ....................................... 40 
Study Product, Supplies, and Storage .................................................................... 40 
8.1.1 
Vadadustat ......................................................................................................... 41 
8.1.2 
Darbepoetin Alfa ............................................................................................... 41 
Dispensing Procedures ........................................................................................... 41 
8.2.1 
Dispensing of Vadadustat .................................................................................. 41 
8.2.2 
Dispensing of Darbepoetin Alfa ........................................................................ 41 
Product Accountability and Destruction ................................................................ 42 
Treatment of Subjects ............................................................................................. 43 
8.4.1 
Treatment Group Assignments .......................................................................... 43 
8.4.2 
Randomization ................................................................................................... 43 
8.4.3 
Blinding ............................................................................................................. 43 
8.4.4 
Dosing and Dose Adjustment Guidelines .......................................................... 44 
8.4.4.1 
Vadadustat Dosing and Dose Adjustment Algorithms ................................. 45 
8.4.4.2 
Darbepoetin Alfa Dosing and Dose Adjustment Algorithms ....................... 45 
8.4.5 
Late or Missed Doses ........................................................................................ 46 
8.4.6 
Iron Supplementation ........................................................................................ 46 
8.4.7 
Rescue Therapy ................................................................................................. 46 
8.4.7.1 
ESA Rescue (Optional) ................................................................................. 46 
8.4.7.2 
Red Blood Cell Transfusion (Optional) ........................................................ 47 
8.4.8 
Phlebotomy (Optional) ...................................................................................... 47 
8.4.9 
Treatment Compliance ...................................................................................... 47 
8.4.10 
Continuation of Treatment ................................................................................ 48 
Prior and Concomitant Therapy ............................................................................. 48 
8.5.1 
General .............................................................................................................. 48 
8.5.2 
Erythropoiesis-stimulation Agents .................................................................... 48 
8.5.3 
Transfusions ...................................................................................................... 48 
8.5.4 
Investigational Medications ............................................................................... 48 
8.5.5 
HMG-CoA Reductase Inhibitors (Statins) ........................................................ 49 
8.5.6 
Sulfasalazine and Other BCRP Substrates ........................................................ 50 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES ................................ 50 

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Administrative Procedures ..................................................................................... 50 
9.1.1 
Informed Consent .............................................................................................. 50 
9.1.2 
Documentation of Screen Failures .................................................................... 51 
9.1.3 
Contraception and Pregnancy Avoidance Measures ......................................... 51 
9.1.4 
Laboratory Accreditation and Reference Ranges .............................................. 51 
Study Procedures and Evaluations ......................................................................... 52 
9.2.1 
Clinical Evaluations ........................................................................................... 52 
9.2.2 
Laboratory Evaluations ..................................................................................... 53 
Schedule of Activities ............................................................................................ 55 
9.3.1 
Pre-Screening Visit ............................................................................................ 55 
9.3.2 
Screening Visits ................................................................................................. 55 
9.3.2.1 
Screening Visit 1 (SV1) ................................................................................ 56 
9.3.2.2 
Screening Visit 2 (SV2) ................................................................................ 56 
9.3.2.3 
Subject Retesting .......................................................................................... 56 
9.3.3 
Subject Rescreening .......................................................................................... 56 
9.3.4 
Baseline Visit (Day 1) ....................................................................................... 57 
9.3.5 
Year 1 Treatment Period Visits (Day 2 through Week 52) ............................... 57 
9.3.6 
Year 2-4 Monthly Hb Monitoring ..................................................................... 58 
9.3.7 
Year 2 Treatment Period Visits (Weeks 53 through 104) ................................. 59 
9.3.8 
Year 3/4 Treatment Period Visits (Weeks 116 through 208) ............................ 59 
9.3.9 
End of Treatment (EOT) Visit ........................................................................... 60 
9.3.10 
Follow-Up Visit ................................................................................................. 61 
9.3.11 
Unscheduled Visits ............................................................................................ 61 
9.3.12 
End of Study Subject Status .............................................................................. 61 
Study Medication Stopping Rules .......................................................................... 62 
10 
ADVERSE EVENTS .................................................................................................. 63 
Definitions .............................................................................................................. 63 
10.1.1 
Adverse Events .................................................................................................. 63 
10.1.2 
Serious Adverse Events ..................................................................................... 66 
Eliciting Adverse Event Information ..................................................................... 67 
Reporting ................................................................................................................ 67 
10.3.1 
Reporting Period ................................................................................................ 67 
10.3.2 
Reporting AEs ................................................................................................... 67 
10.3.3 
Reporting SAEs ................................................................................................. 68 
10.3.4 
Reporting Study Endpoints ................................................................................ 68 
10.3.5 
Relationship to Study Medication ..................................................................... 69 
10.3.6 
Severity .............................................................................................................. 69 
10.3.7 
Follow-Up of Unresolved Events ...................................................................... 70 

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Amendment 7-COL 
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Exposure In Utero .................................................................................................. 70 
Special Situations ................................................................................................... 71 
11 
DATA ANALYSIS ..................................................................................................... 71 
Sample Size Determination .................................................................................... 72 
11.1.1 
Sample Size for the Primary Efficacy Endpoint ................................................ 72 
11.1.2 
Sample Size for the Primary Safety Endpoint ................................................... 72 
Study Analysis Populations .................................................................................... 73 
Analysis of Demographic and Pretreatment Variables .......................................... 73 
Disposition of Subjects ........................................................................................... 73 
Missing Data .......................................................................................................... 74 
Efficacy Analyses ................................................................................................... 74 
11.6.1 
Analysis of Primary Efficacy Endpoint ............................................................. 74 
11.6.1.1 
Primary Analysis of Primary Efficacy Endpoint .......................................... 75 
11.6.1.2 
Sensitivity Analyses of Primary Efficacy Endpoint ..................................... 75 
11.6.2 
Secondary Efficacy Analyses ............................................................................ 75 
11.6.2.1 
Key Secondary Efficacy Analyses ................................................................ 75 
11.6.3 
Subgroups .......................................................................................................... 76 
Safety Analyses ...................................................................................................... 76 
11.7.1 
Analysis of MACE and Expanded MACE Components ................................... 76 
11.7.2 
Analysis of Adverse Events ............................................................................... 77 
11.7.3 
Remaining Safety Endpoints ............................................................................. 77 
Additional Assessments ......................................................................................... 78 
11.8.1 
Concomitant Medications .................................................................................. 78 
11.8.2 
Biomarkers ........................................................................................................ 78 
11.8.3 
Pharmacokinetics ............................................................................................... 78 
12 
DATA HANDLING AND RECORD KEEPING ...................................................... 78 
Case Report Forms/Electronic Data Capture ......................................................... 78 
Record Retention .................................................................................................... 79 
13 
QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) ....................... 79 
Investigative Site Monitoring Visits ...................................................................... 79 
Protocol Deviations ................................................................................................ 79 
14 
STUDY DISCONTINUATION/INVESTIGATIVE STUDY SITE 
TERMINATION ......................................................................................................... 80 
Criteria for Premature Termination or Suspension of the Study ............................ 80 
Criteria for Premature Termination or Suspension of Investigational Study Sites 80 
Procedures for Premature Termination or Suspension of the Study or 
Investigational Sites ............................................................................................... 80 
15 
ETHICS ....................................................................................................................... 80 

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Ethical Conduct of the Study ................................................................................. 80 
Institutional Review Board/Independent Ethics Committee .................................. 81 
Subject Information and Consent ........................................................................... 81 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .... 81 
Subject Confidentiality ........................................................................................... 81 
16 
PUBLICATION OF STUDY RESULTS ................................................................... 82 
17 
REFERENCES ............................................................................................................ 82 
APPENDIX A:  SCHEDULE OF ACTIVITIES ................................................................... 85 
APPENDIX B:  CKD-EPI CREATININE EQUATION ...................................................... 89 
APPENDIX C:  VADADUSTAT DOSING AND DOSE ADJUSTMENT 
ALGORITHMS .......................................................................................................... 90 
APPENDIX D:  DARBEPOETIN ALFA DOSING AND DOSE ADJUSTMENT 
ALGORITHMS .......................................................................................................... 94 
APPENDIX E:  END OF TREATMENT AND GLOBAL STUDY COMPLETION 
SUBJECT FLOW ....................................................................................................... 98 
APPENDIX F:  HISTORY OF AMENDMENTS TO THE PROTOCOL ........................... 99 

Protocol No. AKB-6548-CI-0015 
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Page 9 of 105 
2 
PROTOCOL SYNOPSIS 
Study Title 
Phase 3, Randomized, Open-Label, Active-Controlled Study Evaluating the Efficacy 
and Safety of Oral Vadadustat for the Maintenance Treatment of Anemia in Subjects 
with Non-Dialysis-Dependent Chronic Kidney Disease (NDD-CKD) 
(PRO2TECT - CONVERSION) 
Protocol Number 
AKB-6548-CI-0015 
Study Phase 
Phase 3 
Investigational 
Product 
Vadadustat; 150 mg tablets 
Reference Medicinal 
Product 
Darbepoetin alfa; Amgen, Inc. 
Study Population 
The study population will consist of subjects ≥18 years of age with NDD-CKD, 
estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, and hemoglobin (Hb) 
between 8.0 and 11.0 g/dL (inclusive) in the United States (US) and between 9.0 and 
12.0 g/dL (inclusive) outside of the US, who are currently treated with an 
erythropoiesis-stimulating agent (ESA) for anemia. 
Investigative Sites 
Approximately  480 investigative sites in North America, Latin America, Europe, and 
Asia Pacific. 
Planned Number of 
Subjects 
Approximately 1850 subjects. 
Primary Objective 
Demonstrate the efficacy and safety of vadadustat compared with darbepoetin alfa for 
the maintenance treatment of anemia in subjects with NDD-CKD after conversion 
from current ESA therapy. 
Study Design 
Overview 
Phase 3, randomized, open-label, active-controlled study of the efficacy and safety of 
vadadustat versus darbepoetin alfa for the maintenance treatment of anemia after 
conversion from current ESA therapy.  Following a Screening period of up to 8 weeks 
(56 days), subjects who meet all inclusion and no exclusion criteria will be randomized 
1:1 to vadadustat or darbepoetin alfa. 
Randomization will be stratified by: 
•
Geographic region (US versus European Union [EU] versus Rest of World
[ROW])
•
New York Heart Association congestive heart failure (CHF) Class 0 (no CHF)
or I versus II or III
•
Study entry Hb (<10.0 versus ≥10.0 g/dL).
Following randomization, there will be 3 periods during the study: 
•
Conversion and Maintenance Period (Weeks 0-52):  conversion to study
treatment for maintaining Hb (Weeks 0-23), primary efficacy evaluation
(Weeks 24-36), and secondary efficacy evaluation (Weeks 40-52)
•
Long-Term Treatment Period (Weeks 53-End of Treatment [EOT]):
continued study medication to assess long-term safety
•
Follow-Up Period (EOT + 4 weeks):  post-treatment visit (either in person or
via telephone) for safety.

Protocol No. AKB-6548-CI-0015 
Amendment 7-COL 
Akebia — Company Confidential 
Page 10 of 105 
Study Duration 
The study will be considered completed (end of trial) when approximately 631 major 
adverse cardiovascular events (MACE) have accrued over the 2 NDD-CKD studies 
(Studies AKB-6548-CI-0014 and AKB-6548-CI-0015) and all enrolled subjects have 
had the the opportunity to have their Visit 13 (+/- 5 days). All subjects will remain in 
the study until the global study completion (end of trial) at which time subjects will be 
scheduled for a final visit and the study will close.  Sites will be notified of global 
study completion date approximately 3 months prior to study closure (based on accrual 
of MACE across the 2 studies) and will have any subject that is active complete the 
EOT visit and Follow-Up visit, as applicable, and confirm the End of Study (EOS) 
status. 
Inclusion Criteria 
1.
≥18 years of age
2.
Diagnosis of CKD with an eGFR ≤60 mL/min/1.73 m2 using the 2009
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine
equation during Screening and not expected to start dialysis within 6 months
of Screening
3.
Currently maintained on ESA therapy, with a dose received within 6 weeks
prior to or during Screening
4.
Mean Screening Hb between 8.0 and 11.0 g/dL (inclusive) in the US and
between 9.0 and 12.0 g/dL (inclusive) outside of the US, as determined by the
average of 2 Hb values measured by the central laboratory during Screening
5.
Serum ferritin ≥100 ng/mL and transferrin saturation (TSAT) ≥20% during
Screening
6.
Folate and vitamin B12 measurements ≥lower limit of normal during
Screening
7.
Understands the procedures and requirements of the study and provides
written informed consent and authorization for protected health information
disclosure.
Exclusion Criteria 
1.
Anemia due to a cause other than CKD or subjects with active bleeding or
recent blood loss
2.
Subjects with sickle cell disease, myelodysplastic syndromes, bone marrow
fibrosis, hematologic malignancy, myeloma, hemolytic anemia, thalassemia,
or pure red cell aplasia
3.
Red blood cell (RBC) transfusion within 8 weeks prior to randomization.
4.
Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase
(SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic
transaminase (SGPT), or total bilirubin >2.0 x upper limit of normal (ULN)
during Screening.  Subjects with a history of Gilbert’s syndrome are not
excluded.
5.
Uncontrolled hypertension (confirmed diastolic blood pressure >110 mmHg
or systolic blood pressure >180 mmHg) during Screening
6.
Severe heart failure during Screening (New York Heart Association Class IV)
7.
Acute coronary syndrome (hospitalization for unstable angina or myocardial
infarction), surgical or percutaneous intervention for coronary,
cerebrovascular, or peripheral artery disease (aortic or lower extremity),
surgical or percutaneous valvular replacement or repair, sustained ventricular
tachycardia, hospitalization for HF, or stroke within 12 weeks prior to or
during Screening
8.
History of active malignancy within 2 years prior to or during Screening,
except for treated basal cell carcinoma of skin, curatively resected squamous
cell carcinoma of skin, or cervical carcinoma in situ
9.
History of deep vein thrombosis (DVT) or pulmonary embolism (PE) within

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12 weeks prior to randomization 
10. History of hemosiderosis or hemochromatosis
11. History of prior organ transplantation or scheduled organ transplant (subjects
on kidney transplant wait-list are not excluded), or prior hematopoietic stem
cell or bone marrow transplant (corneal transplants and stem cell therapy for
knee arthritis are not excluded)
12. Use of an investigational medication or participation in an investigational
study within 30 days or 5 half-lives of the investigational medication
(whichever is longer), prior to the Screening visit
13. Previous participation in this study, or previous participation in a study with a
hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) other than
vadadustat
14. Females who are pregnant or breast-feeding.  Women of childbearing
potential who are unable or unwilling to use an acceptable method of
contraception
15. Non-vasectomized male subjects who are unable or unwilling to use an
acceptable method of contraception
16. Any other reason that in the opinion of the Investigator would make the
subject not suitable for participation in the study
17. Hypersensitivity to darbepoetin or vadadustat, or to any of their excipients
Retesting/Rescreening 
Retesting is defined as repeating laboratory tests within the same Screening period. 
Subjects who initially fail to qualify for the study based on laboratory test results may 
be retested once for each laboratory parameter within the 8-week Screening period, per 
Investigator discretion. Subjects who fail to qualify for the study based on low TSAT, 
ferritin, folate, or B12 values may receive replacement therapy based on the 
investigative sites’ standard of care during the screening period and retest the 
laboratory parameter(s).  Subjects who receive iron replacement may retest screening 
Hb a minimum of 3 weeks after completion of iron replacement therapy.    
Subjects who fail to meet the qualifying criteria for Hb or eGFR during a Screening 
period may be considered for rescreening at the discretion of the Investigator if it is felt 
that the subject’s status has progressed and that the subject may now qualify for the 
study.  Additionally, subjects who fail to qualify for the study based on low TSAT, 
ferritin, folate, or B12 values may be considered for rescreening after receiving 
replacement therapy.  Screening is limited to 3 attempts (initial Screening and 
2 additional rescreening attempts). 
Efficacy Endpoints 
Primary 
•
Mean change in Hb between Baseline (mean pretreatment Hb) and the
primary evaluation period (mean Hb from Weeks 24-36)
Key Secondary 
•
Mean change in Hb value between Baseline (mean pretreatment Hb) and the
secondary evaluation period (Weeks 40-52)
•
Proportion of subjects with Hb values within the target range during the
primary evaluation period (Weeks 24-36)
•
Proportion of subjects with Hb values within the target range during the
secondary evaluation period (Weeks 40-52)
Other Secondary 
•
Proportion of time with Hb values within the target range during the primary
evaluation period (Weeks 24-36)
•
Proportion of time with Hb values within the target range during the
secondary evaluation period (Weeks 40-52)

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•
Proportion of subjects with Hb increase of >1.0g/dL from Baseline
•
Time to achieve Hb increase of  >1.0g/dL from Baseline
•
Mean change in Hb value between Baseline (mean pretreatment Hb) and the
primary evaluation period (mean Hb from Weeks 24-36) stratified by pre-
baseline ESA exposure
•
Progression of CKD
•
Proportion of subjects receiving IV iron therapy from Baseline  to Week 52
•
• 
Mean monthly dose of IV elemental iron administered from Baseline to Week 
52 in subjects who have received IV iron 
•
Proportion of subjects receiving RBC transfusion(s) from Baseline to Week
52
•
ESA rescue
•
Dose adjustments from Baseline to Week 52
Safety Endpoints 
•
MACE, defined as all-cause mortality, non-fatal myocardial infarction (MI),
or non-fatal stroke
•
Individual components of MACE:
o
All-cause mortality
o
Non-fatal myocardial infarction
o
Non-fatal stroke
•
Thromboembolic events:  arterial thrombosis, DVT, PE, or vascular access
thrombosis
•
Hospitalization for heart failure (HF)
•
Expanded MACE, defined as all-cause mortality, non-fatal myocardial
infarction, non-fatal stroke, hospitalization for HF, or thromboembolic event
•
Fatal/non-fatal MI
•
Fatal/non-fatal stroke
•
Sudden death
•
Cardiovascular death
•
Non-cardiovascular death
•
Hospitalization
•
Hb >12.0 g/dL, >13.0 g/dL, or >14.0 g/dL
•
Hb < 8.0 g/dL
•
Hb increase >1.0 g/dL within any 2-week interval or >2.0 g/dL within any
4-week interval
•
Adverse events (AEs) and serious adverse events (SAEs)
•
Vital signs and clinical laboratory values.
•
Adrenal function assessment in a subset of subjects
Exploratory 
Endpoints 
•
Biomarkers (including, but not limited to, hepcidin and vascular endothelial
growth factor [VEGF]
•
Time to achieve stable Hb values within the target range
•
Proportion of subjects with Hb values within target range without evidence of
iron overload
Dosage and Regimens 
Subjects will be randomized 1:1 to either: 

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Vadadustat starting dose:  2 tablets once daily (300 mg/day) 
Darbepoetin alfa subcutaneous (SC):  initial dose as follows 
•
For subjects already on darbepoetin, the initial dosing regimen in the study
should be based on the prior dosing regimen.
•
For subjects taking other ESAs, the initial dose of darbepoetin should be
based on the current. Package Insert (PI) for investigational sites in the US,
and the European Summary of Product Characteristics (SmPC) for all other
investigational sites (non-US) for adult patients with CKD not on dialysis.
For all subjects, it is recommended that no additional ESA doses be administered after 
Screening visit 2 (SV2) and prior to the Randomization visit. 
Dose Adjustment Guidelines – All Treatment Groups 
Dosing will be initiated at the Baseline visit, and the first dose of study medication 
(vadadustat or darbepoetin alfa) will be administered at the investigative site after other 
Baseline procedures have been completed. The investigator may elect to postpone the 
initial dose of study medication until a subsequent visit based on the subject’s Hb level 
or Hb trajectory assessed at the Baseline visit,  or based on timing of the last ESA dose 
given during screening. 
For all subjects, it is recommended that no additional ESA doses be administered after 
SV2 and prior to the Randomization visit. 
Hemoglobin will be monitored via HemoCue® point of care device throughout the 
study to determine if the dose of study medication (vadadustat or darbepoetin alfa) will 
be adjusted, interrupted, or maintained.  
Year 1-4 Treatment Period Visits 
From Weeks 0 to 12, Hb will be measured via HemoCue every 2 weeks for monitoring 
for dose adjustment.  From Week 12 to Week 52, Hb via HemoCue will be monitored 
every 4 weeks.  
From Week 53 through the end of the study, Hb will continue to be monitored via 
HemoCue to determine if the dose of study medication will be adjusted,interrupted, or 
maintained.  Hemoglobin will also be assessed with a complete blood count (CBC) 
through the central laboratory for efficacy and safety evaluations; however, dose 
adjustments should be based on the local HemoCue Hb value. If the Investigator has an 
immediate clinical concern about a subject's HemoCue value, the Investigator may use 
clinical judgment and repeat the HemoCue Hb, use local lab values or wait for central 
lab results. The test method utilized to inform the treatment decision must be recorded 
in the appropriate CRF  and the subject’s source. 
Year 2-4 Monthly Hb Monitoring 
Additionally, after Week 52 visit, the Hb drawn as part of the local standard of care 
labs must be monitored monthly for dosing oversight. Per the vadadustat or 
darbepoetin alfa dosing algorithms, if the Hb value suggests a dose adjustment is 
needed, an unscheduled visit must be performed.  
If monthly standard of care labs are not available, a study unscheduled visit must be 
performed. This visit will include, at minimum, the Hb measurement via HemoCue 
dose adjustment assessment, and adverse events assessment. 
The monthly Hb monitoring method is flexible between study visits after Week 52 to 
minimize unnecessary travel or redundant blood sampling for the subject. 
The aim is to maintain a Hb level of 10.0-11.0 g/dL in the US and 10.0-12.0 g/dL 
outside the US throughout the study. 

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Dose adjustments will be guided by  Hb concentration and the Dose Adjustment 
Algorithms.  The Dose Adjustment Algorithm for darbepoetin alfa will follow the 
Package Insert (PI) for investigational sites in the US, and the European Summary of 
Product Characteristics (SmPC) for all other investigational sites (non-US).  
. This protocol provides guidance for the treatment of subjects with anemia associated 
with CKD in order to achieve and maintain Hb levels within the target Hb range. Dose 
adjustment should be based on the investigator’s clinical discretion, incorporating the 
protocol guidance and considering the subject’s clinical condition, Hb rate of rise, Hb 
rate of decline, Hb variability, and ESA responsiveness.  
In cases where the Investigator does not follow the dosing algorithm, the clinical 
circumstances must be documented in the subject’s source. 
For subjects who progress to dialysis dependent – chronic kidney disease (DD-CKD), 
and remain on study treatment, the dose adjustment should be based on the Dose 
Adjustment Algorithms (Appendix C & D)  
Vadadustat 
Vadadustat should be dosed according to the Dose Adjustment Algorithms in 
Appendix C 
Darbepoetin alfa 
Subjects who are randomized to receive darbepoetin alfa, the initial dose will be 
according to the Dose Adjustment Algorithm (Appendix D).    
•
For subjects already on darbepoetin, the initial dosing regimen in the study
should be based on the prior dosing regimen.
For subjects taking other ESAs, the initial dose of darbepoetin should be based on the 
Package Insert (PI) for investigational sites in the US, and the European Summary of 
Product Characteristics (SmPC) for all other investigational sites (non-US). Following 
the dose conversion, darbepoetin alfa will be dosed SC, with dose adjustments 
according to  the Dose Adjustment Algorithm. Darbepoetin alfa dosing is independent 
of the visit schedule, and the dosing schedule may shift per local standard of care and 
per Investigator discretion. 
Dosing Instructions 
Vadadustat 
All subjects will start with 2 tablets daily (300 mg/day).  Dose levels of vadadustat 
include 150, 300, 450, and 600 mg (available tablet strength is 150 mg).  Each subject 
will take his/her first dose of vadadustat at the investigative site at the Baseline visit.  
Thereafter, vadadustat will be taken once daily on an outpatient basis.  Subjects may 
take vadadustat with or without food.  The full dose should be taken at approximately 
the same time each day.   The subject should be instructed to take any oral iron 
supplements (including multivitamins containing iron), iron containing phosphate 
binders, or any medications containing iron at least 2 hours before or 2 hours after the 
dose of vadadustat. 
Darbepoetin alfa 
Darbepoetin alfa will be administered, stored, and dispensed based on the Dosing 
Algorithms, and Package Insert (PI) for investigational sites in the US, and the 
European Summary of Product Characteristics (SmPC) for all other investigational 
sites (non-US).  
Iron Supplementation 
Investigators will prescribe iron supplementation during the study to maintain ferritin 
≥100 ng/mL or TSAT ≥20%.  In general, oral iron should be considered before 
initiating IV iron. Subjects already receiving oral iron supplementation as part of their 
treatment plan may continue their current treatment regimen.   
Important:  Because of the potential for oral iron to reduce the bioavailability of 
vadadustat, the study medication is not to be administered concurrently with an oral 

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iron supplement (including multivitamins containing iron), iron containing phosphate 
binders, or any medications containing iron.  The subject should be instructed to take  
these medications at least 2 hours before or 2 hours after the dose of vadadustat. 
Rescue Therapy 
Guidelines 
To ensure the safety of study subjects and to standardize the use of rescue in the study, 
rescue therapy guidelines are provided.  
1. ESA Rescue:  Starting at Week 6, subjects in both treatment arms will be allowed
(although will not be required) to have their Hb rescued with ESA therapy, per the
local standard of care.  If possible, a subject on vadadustat should be on the maximum
dose of vadadustat for 2 weeks prior to ESA rescue.  A subject on darbepoetin alfa
may rescue with another ESA per the standard of care.  To qualify for ESA rescue, a
subject must fulfill BOTH of the following:
•
The subject has experienced worsening of symptoms of anemia (eg, fatigue,
weakness, shortness of breath, chest pain, confusion, or dizziness) compared
with Baseline
•
The subject’s Hb is <9.0 g/dL
However, in the event the subject does not meet the above criteria for ESA rescue, 
ESA rescue is permitted when medically necessary at the discretion of the investigator. 
Reasons for ESA use will be captured in the appropriate CRF. 
The ESA rescue therapy should be administered as per the local institution’s guidelines 
and per the approved local product label.  While receiving ESA rescue therapy, 
subjects must temporarily discontinue taking study medication (vadadustat or 
darbepoetin alfa).  Hemoglobin will be monitored throughout the study at scheduled 
visits as defined in the Schedule of Activities using a HemoCue point of care device, 
and ESA rescue treatment should be stopped when Hb is ≥9.5 g/dL.  A minimum 
interval must be observed prior to restarting vadadustat after the last dose of rescue 
medication, and treatment may be resumed after the following intervals: 
•
2 days after last dose of epoetin rescue
•
7 days after last dose of darbepoetin alfa rescue
•
14 days after last dose of methoxy polyethylene glycol-epoetin beta rescue.
Following ESA rescue, the study medication should be resumed at the same dose as 
previously used or one dose higher and adjusted according to the Dose Adjustment  
Algorithms. 
2. RBC Transfusion:  Investigators will use their local institution’s transfusion
guidelines when determining whether to transfuse a study subject.  In general, in the
event of an acute or severe loss of blood, a RBC transfusion should be administered as
clinically indicated.  In less severe instances but where there may be worsening of
anemia or moderate to severe symptoms of anemia, RBC transfusions are permitted at
the discretion of the Investigator given the medical necessity. Reasons for RBC use
will be captured in the appropriate CRF.  Study medication (vadadustat or darbepoetin
alfa) may be continued during the transfusion period.

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Phlebotomy 
If a subject’s Hb exceeds 14.0 g/dL or the rate of rise of Hb raises concern to the 
Investigator, the subject may be phlebotomized based on the Investigator’s judgment.  
The method of phlebotomy will be in accordance with the investigative site’s standard 
clinical practice. 
Study Medication 
Stopping Rules 
Study medication must be permanently discontinued if a subject meets one of the 
criteria.  
•
ALT or AST >3x Upper Limit of Normal (ULN) and total bilirubin >2x ULN
•
ALT or AST >3x ULN and INR >1.5
•
ALT or AST >8x ULN
•
ALT or AST remains >5x ULN over 2 weeks*
•
ALT or AST >3x ULN with symptoms (e.g., fatigue, nausea, vomiting, right
upper quadrant pain, fever, rash) or eosinophilia
*Re-challenge generally should be avoided with ALT or AST >5x ULN unless there are
no other good therapeutic options.
Study Completion, 
Subject Completion, 
Premature 
Termination of Study 
Medication, or 
Withdrawal from the 
Study 
Study Completion 
The study will be considered completed (end of trial) when approximately 631 MACE 
events have accrued across the 2 NDD-CKD studies (Studies AKB-6548-CI-0014 and 
AKB-6548-CI-0015), and all enrolled subjects in this study have had the opportunity to 
have their Visit 13 (+/- 5 days).  
Subject Completion 
A subject will be considered as having completed the study, regardless of whether the 
subject is on or off study medication, and the subject is followed until global study end 
date as determined by the accrual of MACE.   
Subjects who continue on the study medication up to global study completion will 
complete the EOT visit, followed by the Follow-up visit, which will include recording 
the end of study (EOS) status.  
It is important to note that a subject’s need for rescue therapy or initiation of dialysis, 
or the occurrence of MACE event(s):  
•
Does not constitute study completion and
•
Is not criteria for subject withdrawal from the study or
•
Is not a requirement for permanent discontinuation of study medication
(vadadustat or darbepoetin alfa).
Discontinuation of Study Medication Treatment 
Subjects who discontinue study medication prior to global study completion are 
expected to continue to be followed post discontinuation of study medication. These 
subjects are to have their EOT visit at the time of discontinuing study medication, have 
the Follow-up visit and continue to be followed through global study completion. At 
the time of global study completion, each subject will have an EOS assessment to 
complete participation in the study.  
Receipt of rescue therapy is not a reason for permanent study medication 
discontinuation. While receiving ESA rescue, subjects must temporarily discontinue 
study medication, but are to resume study medication following the end of rescue 
therapy. 
During this study, it is anticipated that some subjects may permanently discontinue 
study medication (vadadustat or darbepoetin alfa) for any of the following reasons: 
•
Unacceptable toxicity or drug intolerability
•
Investigator discretion

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•
Subject withdrawal of consent
•
Subject becomes pregnant
•
Receipt of a kidney transplant
•
Lack of efficacy
•
Other reasons.
Subjects who undergo a solid organ (including kidney), hematopoietic stem cell, or 
bone marrow transplantation will have their study medication (vadadustat or 
darbepoetin alfa) permanently discontinued.   
It is important to continue to follow subjects that permanently discontinue study 
medication  through global study completion. Please, see “Procedures to Avoid 
Withdrawal or Lost to Follow-Up” for options to maintain subjects in the study. 
Complete Withdrawal from Study Visits/Assessments 
A subject has the right to withdraw consent for participation in the study at any time. 
Withdrawal of consent is a subject’s refusal of ALL methods of follow-up noted in the 
informed consent form:  procedures, participation in reduced procedures/study visits, 
telephone contact only or alternative contact only, source document or designated 
alternative contact, or access to medical records from alternative sources.It is important 
for the Investigator to review options with a subject that would allow follow-up 
through global study completion before the subject withdraws consent. For patients 
considering withdrawal of consent, the Investigator should consult with the Medical 
Monitor to ensure all options have been explored and that there is complete 
understanding by the subject for what withdrawal of consent constitutes. 
Procedures to Avoid 
Withdrawal or Lost to 
Follow-Up 
Avoiding Withdrawal of Consent or Lost to Follow-Up 
As part of the informed consent process, only subjects who fully understand and agree 
to full participation and long-term follow-up should be consented to participate. 
It is important that subjects understand the long-term duration and purpose of a 
cardiovascular outcome trial and that the subject (or designee) continue to allow 
follow-up through global study completion which could be several years, even post 
subject’s permanent discontinuation of study medication. 
In all cases of impending study medication discontinuation or subject request for  
stopping study visits, Investigators will discuss with the subject their options of 
continuing in the study. It is important to continue to follow subjects that discontinue 
study medication through global study completion at a frequency and approach that is 
agreed to between the Investigator and subject. Visit schedule and assessments are 
flexible and at the discretion of the Investigator and subject and will be clearly 
documented in the medical chart. Optimal data collection would include the following 
assessments through global study completion. 
•
EOS subject status (must collect at minimum)
•
MACE Endpoint Questionnaire
•
AE Assessment
Alternative options to support continued follow-up include but are not limited to the 
following: 
1.
Reduced frequency of on-site visits
2.
Telephone visits in lieu of on-site visits
3.
Telephone or any contact method

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4.
Telephone or any contact method with an alternative person (family member
or medical designee)
5.
Study team access to medical records for reporting MACE data or vital status
6.
Reporting of vital status at the EOS visit which will occur at global study
completion
In the most extreme case, the protocol will accommodate minimal contact with a 
subject or alternative method to obtain vital status at the global study completion. The 
objective is to keep a subject’s study status active to ascertain, at a minimum, vital 
status (alive or deceased) even if study medication is permanently discontinued 
(Section 7.5.5.2) or there is a significant change in a subject’s personal or medical 
situation (i.e., home move, dialysis unit/provider change, kidney transplant, long-term 
care facility admission). 
The Investigator will ensure understanding and documentation of the reasons for a 
subject’s desire to stop study procedures or stop study medication. 
Minimizing Lost to Follow-Up 
The Investigator must make every effort to contact subjects who fail to return for 
scheduled visits so that they will not be declared “lost to follow-up” (LFTU). These 
actions must include, but are not limited to, the following: 
1. Contact all telephone numbers for the subject and his/her listed contacts (to be
collected in the source at the subject’s entry into the study), as applicable.  This
includes making phone calls after normal business hours or on holidays or weekends.
2. Contact the subject’s primary care physician, referring specialist, pharmacist, or
other healthcare professional, as applicable.
3. Send email, text, and postal mail with registered (traceable or trackable) letters to
all the subject’s addresses and contact persons, as applicable. Registered (traceable or
trackable) letters need to be returned with a copy of the signature from whomever
signed, which can be compared to the ICF for vital status data. If undeliverable, then
send non-registered standard letters, which may be forwarded to a new address if the
subject has moved.
4. Review available medical records/notes for details of hospitalizations, clinic visits,
or other procedures that may indicate the status of the subject, as applicable.
5. Utilize the internet to search for additional contact information, as applicable.
6. Check local, regional, and national public records to locate the subject or search for
mortality status as allowed by law, as applicable.
It is important to obtain vital status at the global study completion for subjects that 
have been LTFU during the study. The Sponsor may utilize a third-party provider in 
accordance with all applicable guidelines and legislation to assist the site in locating 
contact information for all subjects during the study or in locating the vital status for all 
of their randomized subjects in anticipation of global study completion (end of trial). 
Study Termination/ 
Individual Study Site 
Termination 
The entire study may be suspended or terminated by the Sponsor for safety or other 
unanticipated reasons or upon request of regulatory agencies.  If this occurs, prompt 
notification will be given to Investigators, Institutional Review Boards 
(IRBs)/Institutional Ethics Committees (IECs), and regulatory authorities in 
accordance with regulatory requirements. 
The Investigator must notify the Sponsor if the study is terminated by the Investigator 
or the IRB/IEC at the investigative site.  If the Investigator, IRB/IEC, or Sponsor 
decides to terminate or suspend the study conducted at a particular investigative site for 
safety, non-enrollment, non-compliance with the protocol, or other unanticipated 
reasons, the above parties will be promptly notified. 

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Statistical 
Considerations 
Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is defined as the mean Hb change from Baseline (mean 
pretreatment Hb) to the mean Hb from Weeks 24-36 (inclusive). 
The primary analysis will use an analysis ofcovariance (ANCOVA) with multiple 
imputation, stratified by the randomization strata  and using Baseline Hb as the 
covariate.  
A 2-sided, 95% confidence interval will be calculated for the difference between the 
vadadustat group and control group.  Noninferiority of vadadustat will be established if 
the lower limit of this confidence interval is ≥-0.75 g/dL. 
Analysis of MACE and Expanded MACE Components 
The MACE endpoint (adjudicated result) will be analyzed as the time (days) from 
randomization dateto first MACE +1.   Subjects who have not experienced an 
adjudicated MACE by study closure will be censored as of their last assessment time. 
Major adverse cardiovascular events will be analyzed using a stratified Cox 
proportional hazards model with a model containing treatment group.  The 
randomization strata will be used in this analysis.  The primary MACE analysis will 
take place at study conclusion and will be based upon all subjects in the randomized 
population.  The hazard ratio (vadadustat/control) will be estimated, together with its 
95% confidence interval.  As this individual study has not been powered to provide a 
stand alone assesment of MACE, this interval will be considered as descriptive.  The 
time to first MACE will also be graphically presented using Kaplan-Meier curves. 
These analyses will be repeated with censoring occurring 4 weeks following early 
discontinuation of study medication. 
The following safety endpoints will also be summarized using time to event methods 
as for MACE: 
1)
Individual components (all-cause mortality, non-fatal myocardial infarction,
non-fatal stroke) of MACE
2)
Thromboembolic events (defined as arterial thrombosis, DVT, PE, or vascular
access thrombosis)
3)
Hospitalization for heart failure
4)
Expanded MACE, defined as all-cause mortality, non-fatal myocardial
infarction, non-fatal stroke, hospitalization for HF, or thromboembolic event
For these endpoints the incidence ("yes"/"no") of the endpoint will be presented for 
each treatment arm.  Kaplan-Meier curves will be presented for each endpoint as the 
time of endpoint free survival (ie, time until endpoint or death). 
An independent statistical analysis center will perform analyses in support of the 
Independent Data Monitoring Committee (IDMC). 
Sample Size 
Estimation 
For the primary efficacy analysis in this study, it will be assumed that the difference in 
mean change in Hb for vadadustat will be the same as the active control, darbepoetin 
alfa, and the common standard deviation for the mean change will be assumed to be 
1.5 g/dL.  The noninferiority margin of -0.75 g/dL will be used.  With these 
assumptions and approximately 925 subjects per treatment group, the noninferiority 
evaluation will have > 90% power. 
The primary MACE analysis will be based upon all events that accrue across the 2 
NDD-CKD studies (Studies AKB-6548-CI-0014 and AKB-6548-CI-0015).  It has been 
calculated that 631 events will be required overall to have 80% power to establish 
noninferiority with a margin of 1.25, when evaluated with a 2-sided 95% confidence 
interval assuming no difference between the treatments.  The power is >90% to 
establish a noninferiority margin of 1.25 if the hazard ratio is 0.95 favoring vadadustat.  

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A MACE rate of 10% annually is anticipated in both treatment arms based on a 
comprehensive review of available epidemiology and prospective clinical studies in the 
field.   
Independent Data 
Monitoring 
Committee 
An IDMC will be established to review and discuss the available study safety data as 
subjects are enrolled and followed.  The team will meet approximately twice per year 
throughout the course of the study.  The IDMC will be unblinded and will include, at a 
minimum, a nephrologist, a cardiologist, and a biostatistician.  The discussions of the 
IDMC will include a review of key safety data (ie, AEs, vital signs measurements, and 
laboratory assessments). 
Endpoint 
Adjudication 
Committee (EAC) 
An independent safety EAC, blinded to treatment group, will be formed prior to study 
commencement to adjudicate the components of the primary safety endpoints (eg, all-
cause mortality, non-fatal myocardial infarction, and non-fatal stroke).  
Thromboembolic events and hospitalization for HF will also be adjudicated by the 
EAC. 

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3 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase (SGPT) 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase (SGOT) 
β-HCG 
beta human chorionic gonadotropin 
BCRP 
breast cancer resistance protein 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CHF 
congestive heart failure 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CMH 
Cochran-Mantel-Haenszel 
CPK 
creatine phosphokinase 
CRF 
case report form 
CRO 
contract research organization 
CRP 
C-reactive protein
CS 
clinically significant
CV 
cardiovascular
CVD 
cardiovascular disease
DD-CKD
dialysis-dependent chronic kidney disease
DILI
Drug-Induced Liver Injury
dL
deciliter
DNA
deoxyribonucleic acid
DVT
deep venous thrombosis
EAC
Endpoint Adjudication Committee
ECG
electrocardiogram
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EOS
end of study
EOT
end of treatment
EPO
erythropoietin
ESC
Executive Steering Committee
ESA
erythropoiesis-stimulating agent
ESRD
end-stage renal disease
EU
European Union
FDA
Food and Drug Administration
g
gram
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GMP
Good Manufacturing Practice
HA
health authority
Hb
hemoglobin
HDL
high-density lipoprotein

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HF 
heart failure 
HIF 
hypoxia-inducible factor 
HIFPH 
hypoxia-inducible factor prolyl-hydroxylase 
HIF-PHI 
hypoxia-inducible factor prolyl-hydroxylase inhibitor 
IC50 
50% inhibitory concentration 
ICH 
International Conference on Harmonization 
ID 
identification 
IDMC 
Independent Data Monitoring Committee 
IDMS 
isotope dilution mass spectrometry 
IEC 
independent ethics committee 
IMP 
Investigational Medicinal Product  
INR 
international normalized ratio 
IRB 
institutional review board 
IV 
intravenous(ly) 
IWR 
interactive web response 
JSDT 
Japanese Society for Dialysis Therapy 
JSN 
Japanese Society of Nephrology 
KDIGO 
Kidney Disease:  Improving Global Outcomes 
kg 
kilogram 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein  
LLN 
lower limit of normal 
LTFU 
Lost to Follow Up 
MACE 
major adverse cardiovascular events 
MCH 
mean corpuscular (cell) hemoglobin 
MCHC 
mean corpuscular (cell) hemoglobin concentration 
MCV 
mean corpuscular (cell) volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
µM 
micromolar 
mg 
milligram 
mL 
milliliter 
mmhg 
millimeters of mercury 
mRNA 
messenger ribonucleic acid  
NDD-CKD 
non-dialysis dependent chronic kidney disease 
ng 
nanogram 
NYHA 
New York Heart Association 
PD 
pharmacodynamics(s) 
PE 
pulmonary embolism 
PHD 
prolyl 4-hydroxylase domain 
PI 
 package insert 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QA 
quality assurance 

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QC 
quality control 
RBC 
red blood cell 
RDW 
red cell distribution width 
ROW 
rest of world 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous(ly) 
SCr 
serum creatinine 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
SmPC 
summary of product characteristics 
SV 
Screening visit 
TIBC 
total iron binding capacity 
TREAT 
Trial to Reduce Cardiovascular Events with Aranesp Therapy 
TSAT 
transferrin saturation 
uACR 
urine albumin-to-creatinine ratio 
ULN 
upper limit of normal 
US 
United States 
VEGF 
vascular endothelial growth factor 
VHP 
Voluntary Harmonisation Procedures 
WBC 
white blood cell 
WHO 
World Health Organization 

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4 
BACKGROUND INFORMATION 
Chronic kidney disease (CKD), defined as the presence of kidney damage or a decreased level of 
kidney function, is a major public health problem worldwide.  Globally, CKD is estimated to 
affect between 8-16% of the population (Jha et al. 2013; KDIGO 2013).  At the most advanced 
stages of CKD, end-stage renal disease (ESRD), patients require chronic dialysis or kidney 
transplantation to sustain life.  Chronic kidney disease is not only a cause of ESRD, but is also a 
significant risk factor for cardiovascular disease (CVD), infection, cancer, and mortality (Iseki 
and Kohagura 2007). 
Renal anemia often develops during the progression of CKD and is present in almost all patients 
with ESRD.  Anemia is defined as a decrease in circulating red blood cell (RBC) mass that is 
usually detected by low hemoglobin (Hb) concentration.  The causes of anemia in CKD include 
blood loss, shortened RBC lifespan, iron deficiency, erythropoietin (EPO) deficiency, and 
inflammation (Nurko 2006).  Although many factors contribute to anemia in CKD, it occurs 
primarily due to an inadequate synthesis of EPO by the kidneys, leading to a deficiency in the 
production of RBC progenitor cells by the bone marrow.  Also contributing to anemia in CKD 
are impaired iron homeostasis and iron loss, which often necessitate iron supplementation 
(Nurko 2006).  Anemia in CKD patients usually occurs when the glomerular filtration rate 
(GFR) falls below 60 mL/min/1.73 m2, and is present in >90% of the patients undergoing 
dialysis (CKD Stage 5) (Goodkin et al. 2011). 
The main impact of anemia on organ function is reduced oxygen delivery to tissues leading to a 
constellation of symptoms including fatigue, shortness of breath, and exercise intolerance 
(Stauffer and Fan 2014).  In patients with anemia related to CKD, compensatory changes occur 
in cardiac structure and function, including an increase in cardiac output, the development of left 
ventricular hypertrophy, and, eventually, the development of heart failure (Metivier et al. 2000).  
Risk of stroke also increases with anemia, which may be an underlying mechanism leading to 
stroke in CKD (Abramson et al., 2003; Iseki and Kohagura 2007).  Other consequences from 
anemia in CKD patients include impaired cognitive function, sleep disorders, and depressed 
immune function, which can impact the quality of life in these patients (Iseki and 
Kohagura 2007; NICE 2011).  Overall, anemia contributes to a poorer prognosis in patients with 
CKD (Nurko 2006; Iseki and Kohagura 2007). 
Erythropoiesis-stimulating agents (ESAs) administered either intravenously (IV) or 
subcutaneously (SC), along with oral or IV iron therapy, are currently the cornerstones for 
treating anemia in patients with CKD.  Treatment with exogenous recombinant ESAs can raise 
Hb levels, relieve symptoms, and reduce the complications of anemia, including RBC 
transfusions which carry the risks of infection, iron overload, and impact candidacy for kidney 
transplantation. 
Clinical practice guidelines and prescribing information for approved ESAs and guidelines 
provided by the United States (US) Food and Drug Administration (FDA), the European Union 
(EU), the Japanese Society of Nephrology, and the Japanese Society for Dialysis Therapy 
Guideline Committee differ slightly in their recommendations for treatment of renal anemia, as 
summarized in Table 1. 

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Table 1 
Treatment Guidelines and Prescribing Information for Renal Anemia in 
NDD-CKD 
KDIGO guidelines 
Treatment should occur in symptomatic patients and when Hb generally falls below 
10 g/dL (Kidney Disease:  Improving Global Outcomes [KDIGO] 2012). 
US darbepoetin alfa 
label 
Same as other approved ESAs, but also recommend that if Hb exceeds 10 g/dL in adults 
not on dialysis, the dose of ESA should be reduced or interrupted (darbepoetin alfa 
[Aranesp®] US Package Insert 2017). 
EU practice 
guidelines 
Recommend that in high-risk patients with non-dialysis dependent CKD (NDD-CKD), 
treatment with ESAs should be initiated when the Hb levels are between 9 g/dL and 
10 g/dL, although in low-risk patients and those in whom a clear benefit of quality of life 
can be foreseen, the initiation of ESA therapy could be considered at higher Hb levels 
(Locatelli 2013). Detailed information on darbepoetin alfa in the EU is available on the 
European Medicines Agency web site. 
Japan practice 
guidelines 
JSDT recommends that ESA treatment be initiated when Hb is below 11 g/dL following a 
diagnosis of renal anemia in NDD-CKD.  JSN 2013 does not provide a clear 
recommendation or maintenance range for Hb.  Both guidelines recommend that if the Hb 
exceeds 13 g/dL, the dose of ESA should be reduced or interrupted.  In patients with CVD 
or complications, ESA treatment should be reduced or interrupted if the Hb exceeds 
12 g/dL (Tsubakihara 2010; Japanese Society of Nephrology 2014). 
Abbreviations:  CVD = cardiovascular disease; ESA = erythropoietin stimulating agent; EU = European Union; 
Hb = hemoglobin; JSDT = Japanese Society for Dialysis Therapy; JSN = Japanese Society of Nephrology; KDIGO = Kidney 
Disease Improving Global Outcomes; NDD-CKD = non-dialysis dependent chronic kidney disease; US = United States. 
The majority of patients with CKD currently receive interventional therapy in the form of iron 
therapy, and may initiate therapy with an ESA if other interventions fail and Hb levels fall below 
9 to 11 g/dL, dependent upon local clinical practice guidelines. 
A number of large, prospective, randomized controlled trials in CKD (Stages 3 to 5) have 
explored the potential benefit of ESAs in patients with CKD with respect to overall mortality, 
cardiovascular (CV) events, and progression of CKD with higher Hb targets (≥13 g/dL) (Besarab 
et al. 1998; Drüeke et al. 2006; Singh et al. 2006; Pfeffer et al. 2009a; Pfeffer et al. 2009b).  
These trials did not demonstrate the expected beneficial effects of correcting anemia on these 
outcomes, but suggested an increased risk of death and CV events when targeting higher Hb 
levels (Besarab et al. 1998; Drüeke et al. 2006; Singh et al. 2006; Pfeffer et al. 2009a; Pfeffer et 
al. 2009b).  Additional analyses from these trials suggest that the risk of death or CV events 
appears to be highest in CKD patients who fail to respond to ESAs, as indicated by lower 
achieved Hb levels and higher average ESA dose requirements (Szczech et al. 2008; Solomon et 
al. 2010).  This suggests that in some subjects the ESAs themselves, and not the Hb level, may 
be causative of the increase in events.  This is supported by studies in CKD patients on dialysis 
with naturally high Hb levels and no increase in CV events (Goodkin et al. 2011). 
The risks identified with ESAs from these trials have led to changes in prescribing information 
and practice guidelines in the US, the EU, and Japan that guide clinicians toward more cautious 
use of ESAs and targeting lower Hb levels.  In the US, the mortality and CV risks associated 
with ESAs are outlined in a black-box warning in the prescribing information of ESAs with a 
recommendation to use the lowest dose possible to avoid transfusions.  While no similar major 
warnings exist in the EU Summary of Product Characteristics (SmPC) or on the approved 
labeling for ESAs in Japan, the EU SmPCs for ESAs do suggest caution with the use of these 
drugs, with a recommendation to keep Hb levels below 12 g/dL, while the Japanese practice 

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guidelines recommend ESA treatment be reduced or interrupted if the Hb exceeds 12 g/dL in 
patients with CVD or complications.   Further, recent EU clinical practice guidelines (Locatelli et 
al. 2013) recommend that risk factors for stroke (including a past history of stroke) and the 
presence of active malignancy or a past history of malignancy should be taken into account when 
making decisions to use ESAs for the treatment of anemia. 
The risks associated with ESAs, including an increased risk of death and CV events, highlight 
the need for additional therapies that might minimize or avoid these risks when compared to 
currently available recombinant protein-based ESAs.  Therefore, the unmet medical need for the 
treatment of anemia in non-dialysis dependent CKD (NDD-CKD) patients remains high, 
especially from a CV safety perspective.  To fulfill this unmet need, the vadadustat clinical 
program is focused on developing an orally active therapeutic for the treatment of anemia in 
patients with CKD. 
 
Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors 
Please see the vadadustat Investigator’s Brochure for additional discussion and information for 
the following section. 
Vadadustat is a synthetic, orally bioavailable, small molecule being developed as an inhibitor of 
hypoxia-inducible factor prolyl-hydroxylases (HIFPHs) for the treatment of anemia associated 
with CKD.  Hypoxia-inducible factor prolyl-hydroxylase enzymes are also referred to as prolyl 
4-hydroxylase domains (PHDs), of which the 2 most commonly expressed are PHD2 and PHD3.
Vadadustat is a slightly more potent inhibitor of PHD3 (50% inhibitory concentration
[IC50] = 0.08 µM) than of PHD2 (IC50 = 0.19 µM).  The inhibition of PHD3 and PHD2 stabilizes
hypoxia-inducible factor (HIF)-2α and HIF-1α, which in turn stimulates the production of EPO.
In vivo animal efficacy and messenger ribonucleic acid (mRNA) data indicate that vadadustat
induces the production of EPO from both renal and extra-renal sites (liver and brain), and this
increase in EPO results in an increase in RBC production in the bone marrow.  In clinical trials,
vadadustat has been shown to facilitate iron homeostasis by decreasing hepcidin and increasing
transferrin levels in healthy adult male volunteers and male and female CKD patients.  This
enables iron transport mechanisms that should enhance the terminal steps of erythropoiesis.
Vadadustat offers the potential of flexible oral dosing that provides a more gradual and reliable
means of titration than injectable hormones.  Therefore, vadadustat is being developed as an
alternative to the existing protein hormone ESAs.
 
Summary of Clinical Experience 
Please see the vadadustat Investigator’s Brochure for additional discussion and information for 
the following section. 
To date, the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of 
vadadustat have been characterized in  9 completed Phase 1 studies in healthy volunteers, 
including 1 ethno-bridging study in Caucasian and Japanese subjects, 1 completed Phase 1 study 
in subjects undergoing chronic hemodialysis, 3 completed Phase 2a studies in NDD-CKD 
subjects, 1 completed Phase 2b study in NDD-CKD subjects, and 1 completed Phase 2 study in 
DD-CKD subjects.  The Phase 2a studies evaluated Stages 3, 4, and 5 CKD (not on dialysis)
subjects in a single-dose PK study, a multi-dose, 28-day, open-label, dose escalation pilot study,
and a randomized, placebo-controlled study with 5 different dose groups dosed for 42 days.  The
Phase 2b study evaluated Stages 3, 4, and 5 CKD (pre-dialysis) dosed for 20 weeks.  The phase 2

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study evaluated DD-CKD subjects on chronic hemodialysis dosed for 16 weeks.  In the studies 
completed to date, a total of  548 subjects have received vadadustat, including 200 healthy 
volunteers and 348 subjects with CKD.   
Vadadustat showed dose-dependent increases in EPO concentrations in Phase 1 and Phase 2a 
studies. The changes in EPO have been accompanied by an increase in reticulocytes as well as 
dose responsive increases in  total iron binding capacity [TIBC] and decreases in hepcidin and 
ferritin.  Overall, the safety profile for vadadustat has been acceptable and has supported further 
development. Vadadustat  has demonstrated dose proportional PK and dose-dependent PD 
(changes in serum EPO and/or Hb) in Phase 1 and Phase 2 studies covering the dose range of 80 
mg to 1200 mg after single administration and 500 to 900 mg after repeated daily administration. 
The plasma half-life of vadadustat was about 4 – 5 hours, 7 – 8 hours, and 9 to 10 hours in 
healthy subjects, NDD-CKD patients, and DD-CKD patients, respectively.  
Vadadustat is extensively metabolized. Vadadustat and its metabolites are eliminated from the 
body by dual routes of elimination,  renal and fecal. The urinary excretion of vadadustat and its 
metabolites  has been shown to be less than 60% in healthy human volunteers. In a clinical study 
conducted to evaluate the effect of hemodialysis on the exposures to vadadustat, hemodialysis 
did not have an effect on the exposures of vadadustat or its metabolites. Given its short half-life 
and the dual routes of elimination, vadadustat is unlikely to accumulate in patients with CKD.  
The completed Phase 2b, randomized, double-blind, placebo-controlled study to assess the 
hematologic PD response, safety, and tolerability of oral vadadustat for 20 weeks was performed 
in 210 subjects with anemia associated with NDD-CKD.  Subjects were assigned to a study 
group based on their ESA status at Screening (naïve, previously treated, or actively treated) and 
were randomized 2:1 to receive either vadadustat at a starting dose of 450 mg/day or placebo.  
The dose of vadadustat was adjusted based on Hb levels and changes in Hb.  Compared with the 
placebo group, the vadadustat-treated group demonstrated a significantly higher proportion of 
responders, defined as subjects achieving a Hb≥11.0 g/dL or an increase ≥1.2 g/dL from baseline 
(54.9% versus 10.3%). Few vadadustat subjects exhibited Hb excursions >13.0 g/dL (4.0%), and 
favorable changes in iron mobilization and utilization were observed with treatment with vadadustat. 
The safety profile of vadadustat in this study supported further development. 
Based on the Phase 1 and Phase 2 study results, vadadustat appears to be a suitable candidate for 
continued development as a treatment for anemia in patients with CKD. 
 
Potential Benefits and Risks 
Please see the vadadustat Investigator’s Brochure for additional discussion and information for 
the following section. 
Trials of injectable erythropoiesis-stimulating agents (ESAs) in patients with anemia secondary 
to NDD-CKD or DD-CKD have demonstrated an increased risk of cardiovascular events 
associated with higher Hb targets (Besarab 1998; Singh 2006; Pfeffer 2009). Post-hoc analyses 
performed by the FDA and others have shown an association between these adverse outcomes 
and supraphysiologic serum EPO levels and/or Hb oscillations and overshoots (McCullough 
2013, Unger 2010). In studies to date, oral vadadustat daily increased mean Hb with few 
excursions above the target range. In addition, serum EPO levels remained well below those 

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reported with ESAs in the literature. As a result, there is the potential for the investigational drug 
vadadustat to provide an effective and safe therapeutic option for the treatment of renal anemia. 
In addition, vadadustat may enhance iron metabolism and transport. Phase 1 and Phase 2 trials 
have demonstrated a consistent dose-dependent increase in TIBC and decrease in ferritin and 
hepcidin. Mechanistic studies have demonstrated that HIF stabilization downregulates the iron 
absorption regulator hepcidin, and upregulates the iron-mobilizing regulators ferroportin and 
transferrin (and its receptor) (Peyssonnaux et al. 2007). Potential clinical benefits include 
enhanced erythropoiesis and decreased exogenous iron requirements. 
The toxicological profile of vadadustat supports continued development in the ongoing Phase 3 
clinical trials.  Dose-limiting toxicity noted in the exploratory toxicology studies was due to 
hemoglobinuric nephropathy (rat) and emesis associated with body weight loss (dog).  Dose-
limiting toxicity noted in the sub-chronic and chronic toxicology studies was due to exaggerated 
pharmacology and the sequelae of events related to polycythemia (increased RBC mass, blood 
hyperviscosity and fibrin thrombi); polycythemia-related toxicity was consistent across species, 
monitorable and reversible.  In the completed clinical studies, vadadustat has had an acceptable 
safety profile to support further development. 
5 
STUDY OBJECTIVES AND ENDPOINTS 
 
Primary Objective 
The primary objective of this study is to demonstrate the efficacy and safety of vadadustat 
compared with darbepoetin alfa for the maintenance treatment of anemia in subjects with 
NDD-CKD after conversion from current ESA therapy. 
 
Primary Efficacy Endpoint 
The primary endpoint used to assess the efficacy objective will be the mean change in Hb 
between Baseline (mean pretreatment Hb) and the primary evaluation period (mean Hb from 
Weeks 24-36). 
 
Secondary Efficacy Endpoints 
The key secondary efficacy endpoints include the following: 
•
Mean change in Hb value between Baseline (mean pretreatment Hb) and the secondary
evaluation period (Weeks 40-52)
•
Proportion of subjects with Hb values within the target range during the primary
evaluation period (Weeks 24-36)
•
Proportion of subjects with Hb values within the target range during the secondary
evaluation period (Weeks 40-52)
Other secondary efficacy endpoints include: 
•
Proportion of time with Hb values within the target range during the primary evaluation
period (Weeks 24-36)
•
Proportion of time with Hb values within the target range during the secondary
evaluation period (Weeks 40-52)
•
Proportion of subjects with Hb increase of >1.0 g/dL from Baseline

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•
Time to achieve Hb increase of >1.0 g/dL from Baseline
•
Mean change in Hb between Baseline (mean pretreatment Hb) and the primary evaluation
period (mean Hb from Weeks 24-36) stratified by pre-baseline ESA exposure
•
Progression of CKD
•
Proportion of subjects receiving IV iron therapy from Baseline visit to Week 52
•
Mean monthly dose of IV elemental iron administered from Baseline to Week 52 in
subjects who have received IV iron
•
Proportion of subjects receiving RBC transfusion(s) from Baseline to Week 52
•
ESA rescue
•
Dose adjustments from Baseline  to Week 52
•
 
Safety Endpoints 
Safety endpoints in this study include the following: 
•
Major adverse cardiovascular events (MACE), defined as all-cause mortality, non-fatal
myocardial infarction, or non-fatal stroke
•
Individual components of MACE:
o
All-cause mortality
o
Non-fatal myocardial infarction
o
Non-fatal stroke
•
Thromboembolic events:  arterial thrombosis, deep vein thrombosis (DVT), pulmonary
embolism (PE), or vascular access thrombosis
•
Hospitalization for heart failure (HF)
•
Expanded MACE, defined as all-cause mortality, non-fatal myocardial infarction, non-
fatal stroke, hospitalization for HF, or thromboembolic event
• Fatal/non-fatal MI
• Fatal/non-fatal stroke
• Sudden death
• Cardiovascular death
• Non-cardiovascular death
• Hospitalization
•
Hb >12.0 g/dL, >13.0 g/dL, or >14.0 g/dLHb < 8.0 g/dL
•
Hb increase >1.0 g/dL within any 2-week interval or >2.0 g/dL within any 4-week
interval
•
AEs and SAEs
•
Vital signs and clinical laboratory values
Exploratory Endpoints
•
Biomarkers (including by not limiter to hepcidin, and vascular endothelial growth factor
[VEGF])
•
Time to achieve stable Hb values within the target range
•
Proportion of subjects with Hb values within the target range without evidence of iron
overload

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6 
STUDY DESIGN 
 
Study Design  
This is a Phase 3, randomized, open-label, active-controlled study of the efficacy and safety of 
vadadustat versus darbepoetin alfa for maintenance treatment of anemia after conversion from 
current ESA therapy in subjects with NDD-CKD.  Target enrollment in this study is 
approximately 1850 subjects at approximately 480 investigative sites in North America, Latin 
America, Europe, and Asia Pacific. 
Subjects will be randomized at the Baseline visit using an Interactive Web Response (IWR) 
system to receive either vadadustat or darbepoetin alfa (based on the current PI for 
investigational sites in the US, and the SmPC for all other investigational sites (non-US) for adult 
patients with CKD not on dialysis).  For all subjects, it is recommended that no additional ESA 
doses be administered after Screening visit 2 (SV2) and prior to the Randomization visit. 
Randomization will be stratified by geographic region (US versus EU versus rest of world 
[ROW]), New York Heart Association congestive heart failure (CHF) Class 0 (no CHF) or I 
versus II or III, and study entry Hb level (<10.0 g/dL versus ≥10.0 g/dL based on the most recent 
central laboratory Hb measurement prior to the Baseline/Randomization visit).  Following 
randomization, there will be 3 periods during the study: 
•
Conversion and Maintenance Period (Weeks 0-52):  conversion to study medication for
maintaining Hb (Weeks 0-23), primary efficacy evaluation (Weeks 24-36), and secondary
efficacy evaluation (Weeks 40-52)
•
Long-term Treatment Period (Week 53-EOT):  continued study medication to assess
long-term safety
•
Follow-up Period (EOT + 4 weeks):  post-treatment visit for safety (either in person or
via telephone).
A HemoCue® point of care device will be used throughout the study to monitor Hb to determine 
if the dose of study medication (vadadustat or darbepoetin alfa) will be adjusted.  From Weeks 0 
to 12, HemoCue will be used to monitor Hb every 2 weeks for dose adjustment.  From Week 12 
to Week 52, Hb will be monitored via HemoCue every 4 weeks.  From Week 53 through the end 
of study, Hb will continue to be monitored via HemoCue to determine if the dose of study 
medication will be adjusted, interrupted, or maintained.  Hemoglobin will also be assessed with a 
complete blood count (CBC) through the central laboratory for efficacy and safety evaluations; 
however, dose adjustments should be based on the HemoCue Hb value. 
The aim of the dosing strategy is to maintain Hb levels of 10.0 g/dL to 11.0 g/dL in the US 
and 10.0 g/dL to 12.0 g/dL outside of the US throughout the study. 
Subjects assigned to vadadustat will initiate dosing at 2 tablets once daily at the Baseline visit.  
Adjustments to doses for vadadustat will be guided by  Hb concentration and Dose Adjustment 
Algorithms (Section 8.4.4.1, Vadadustat Dosing and Dose Adjustment Algorithms).   
Subjects assigned to darbepoetin alfa will be dosed SC at the Baseline visit and the initial dose 
will be determined based on the current PI for investigational sites in the US, and the SmPC for 
all other investigational sites (non-US) for adult patients with CKD not on dialysis.  Dose 
adjustments will be based on Hb concentration and Dose Adjustment Algorithms  (Section 

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8.4.4.2, Darbepoetin Alfa Dosing and Dose Adjustment Algorithms). Darbepoetin alfa dosing is 
independent of the visit schedule, and the dosing schedule may shift per local standard of care 
and per Investigator discretion. 
Investigators will  prescribe iron supplementation during the study to maintain ferritin 
≥100 ng/mL or TSAT ≥20% (see Section 8.4.6, Iron Supplementation for details regarding iron 
supplementation during the study). Subjects already receiving oral iron supplementation as part 
of their treatment plan may continue their current treatment regimen. 
Clinical and safety assessments (including laboratory assays, PK evaluations [both vadadustat 
parent compound and metabolites], MACE endpoint data, vital sign measurements, and AEs) 
will be performed as indicated at Screening, during the Conversion and Maintenance Period 
(Weeks 0-52), during the Long-term Treatment Period (visits approximately every 3 months), 
and during the Follow-up Period (4 weeks after the EOT).  Refer to Section 9, Study Procedures 
and Schedule of Activities and Appendix A:  Schedule of Activities for additional details. 
The study will be considered completed (end of trial) when  approximately 631 major adverse 
cardiovascular events (MACE) have accrued over  the 2- NDD-CKD studies (Studies 
AKB-6548-CI-0014 and AKB-6548-CI-0015), and all enrolled subjects have had the opportunity 
to have their Visit 13 (+/- 5 days). All subjects will remain in the study until the global study 
completion (end of trial), at which time subjects will be scheduled for a final visit, and the study 
will close (see Section 11.1.2, Sample Size for the Primary Safety Endpoint). 
 
 Rationale for Study Design 
During prior clinical trials, vadadustat has demonstrated  dose proportionate PK and dose-
dependent PD.  Vadadustat  showed dose-dependent increases in EPO concentrations in Phase 1 
and Phase 2 studies.  The changes in EPO have been accompanied by an increase in reticulocytes 
as well as dose responsive increases in TIBC and decreases in hepcidin and ferritin.  Overall, the 
safety profile for vadadustat has been acceptable and has supported further development.  
Finally, the urinary excretion of vadadustat and its metabolites has been shown to be less than 
60% in humans.Given its short half life and the dual routes of elimination, vadadustat is unlikely 
to accumulate in patients with CKD. Based on the Phase 1 and Phase 2 study results, continued 
development of vadadustat as a treatment for anemia in patients with CKD is warranted. 
In this study, darbepoetin alfa was chosen as an active comparator as it has a longer half-life than 
epoetin alfa and, therefore, requires less frequent dosing visits.  Selection of a comparator is 
challenging in the current medical and regulatory climate given the accumulating trial findings 
that resulted in the FDA revising the prescribing information for the currently marketed ESAs.  
These trial results indicate an increased risk of death and adverse CV events, such as stroke and 
heart failure, particularly when using ESAs to achieve a higher Hb concentration.  In the US, the 
mortality and CV risks associated with ESAs are outlined in a black-box warning in the 
prescribing information of ESAs, with a recommendation to use the lowest dose possible to 
avoid transfusions.  While no similar major warnings exist in the EU SmPC or on the approved 
labeling for ESAs in Japan, the EU SmPCs for ESAs do suggest caution with the use of these 
drugs, with a recommendation to keep Hb levels below 12 g/dL.  Recent clinical practice 
guidelines (Locatelli et al. 2013) recommend that risk factors for stroke and malignancy should 
also be taken into account when making treatment decisions to use ESAs for the treatment of 
anemia. 

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Given the concerns associated with marketed ESAs, a goal of this study will be to evaluate the 
CV events during the treatment of anemia with vadadustat.  The inclusion of a MACE endpoint 
in this study will allow for a statistical comparison of the rates of CV events between vadadustat 
and darbepoetin alfa treatment groups when used to treat anemia associated with NDD-CKD.  
While the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) (Pfeffer et 
al 2009b) compared different Hb targets, the present study will have similar Hb targets between 
treatment arms.  Importantly, the Hb goals for this study are lower than those used in TREAT 
and are consistent with practice guidelines and prescribing information for approved ESAs. 
This study will be performed as an open-label study.  Because Hb values are objective and will 
be measured via a central laboratory for all efficacy endpoints, efficacy assessments are not 
considered to be subject to bias with an open-label design.  Blinding of this study presented 
inherent practical problems, including potential dosing errors, inappropriate dose adjustments, 
and delays in dosing, which may also increase the safety risk to study participants.  Given the 
differing dosing regimens and routes for vadadustat (oral) and darbepoetin alfa (SC injection), a 
double-dummy design would have been required which also created ethical concerns and 
required extensive coordination to maintain the blind.   
To minimize bias, Sponsor and contract research organization (CRO) study teams will remain 
blinded to ‘by treatment’ aggregated analyses, except for the unblinded statistician.  In addition, 
the study will involve blinded adjudication of MACE, the use of an independent data monitoring 
committee (IDMC), and an identical schedule of visits, procedures, and assessments for both 
treatment groups in order to reduce the potential for bias.  However certain personnel directly 
involved in medical oversight of the study, regulatory reporting of safety information, and 
on-site monitoring activities may become unblinded to the treatment assignments of individual 
subjects during the course of the study.  
In addition, to reduce subjectivity of dose adjustment, adjustments to doses for vadadustat and 
darbepoetin alfa will be guided by Hb concentration and the Dose Adjustment Algorithms. 
 
Dose Justification 
The starting dose and the proposed dosing algorithm in this study are designed to increase and 
maintain Hb in a predictable and controlled manner while minimizing abrupt increases or 
excessive rises in Hb levels.  Based on plasma concentrations and PD measures from previously 
conducted clinical studies with vadadustat, a population PK/PD model was developed.  Using 
this model and the proposed dosing algorithm, simulations were carried out to evaluate the 
effects of different starting doses and the resulting Hb responses to support the dosing rationale.  
Results of the simulations indicated that a starting dose regimen of 300 mg once daily along with 
the proposed dosing algorithm are optimal to increase and maintain Hb levels of 10.0 to 
11.0 g/dL in the US and 10.0 to 12.0 g/dL outside of the US while minimizing excessive rises. 
Executive Steering Committee and Independent Data Monitoring Committee 
6.4.1 Executive Steering Committee 
An Executive Steering Committee (ESC) will be established, which will be blinded to the 
randomization, and will oversee the study and provide expert input to assure a high scientific 
standard. The ESC may function as the Publication Committee.  The ESC membership will 
comprise recognized academic leaders, including those from the field of nephrology and 

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cardiology.  Details on the roles and responsibilities of the ESC will be described further in the 
ESC charter. 
6.4.2 Independent Data Monitoring Committee 
An IDMC will be established to review and discuss study safety data as subjects are enrolled and 
followed.  The team will meet approximately twice per year throughout the course of the study.  
The IDMC will be unblinded and will include, at a minimum, a nephrologist, a cardiologist, and 
a biostatistician.  The discussions of the IDMC will include a review of key safety data (ie, AEs, 
vital signs, and laboratory assessments).  Written records of the IDMC meetings, the materials 
reviewed, and the decisions made will be maintained.  Details on the roles and responsibilities of 
the IDMC and guidelines for monitoring study safety data will be described further in the IDMC 
charter. 
 
Endpoint Adjudication Committee 
An independent safety endpoint adjudication committee (EAC) will be formed prior to study 
commencement to adjudicate the primary safety endpoints (all-cause mortality, non-fatal 
myocardial infarction, and non-fatal stroke).  Thromboembolic events and hospitalization for HF 
will also be adjudicated by the EAC.  The committee will be blinded throughout the course of the 
study.  The EAC will be composed of independent experts with experience and training 
appropriate for adjudication of MACE, thromboembolic events, and hospitalization for HF.  
Details on the responsibilities of the EAC will be described further in the EAC charter. 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
 
General Criteria 
To be eligible for this study, a subject or their legally acceptable representative must provide 
valid informed consent and must meet all of the following criteria.  No study procedures 
(including Screening tests) may be performed until after the informed consent has been legally 
signed. 
An optional Pre-Screen visit can be used to perform initial testing of the Hb level using a  
HemoCue point of care device to evaluate whether a subject should progress to full Screening 
procedures.  A separate Pre-Screen informed consent (distinct from the full protocol informed 
consent) will be implemented for the Pre-Screen visit.  To be eligible for the Pre-Screen Hb 
measurement, a study subject or their legally acceptable representative must provide valid 
informed consent prior to the Pre-Screen procedure.  For a better understanding of the 
Pre-Screening visit, please see Section 9.3.1, Pre-Screening Visit. 
 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible: 
1. At least 18 years of age
2. Diagnosis of CKD with an estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2
using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine
equation during Screening (see Appendix B:  CKD-EPI Creatinine Equation) and not
expected to start dialysis within 6 months of Screening

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3. Currently maintained on ESA therapy with a dose received within 6 weeks prior to or during
Screening
4. Mean Screening Hb between 8.0 and 11.0 g/dL (inclusive) in the US and between 9.0 and
12.0 g/dL (inclusive) outside of the US, as determined by the average of 2 Hb values
measured by the central laboratory during Screening
5. Serum ferritin ≥100 ng /mL and TSAT ≥20% during Screening
6. Folate and vitamin B12 measurements ≥lower limit of normal (LLN) during Screening
7. Understands the procedures and requirements of the study and provides written informed
consent and authorization for protected health information disclosure.
 
Exclusion Criteria 
Subjects presenting with any of the following will not qualify for entry into the study: 
1. Anemia due to a cause other than CKD or subjects with active bleeding or recent blood loss
2. Subjects with sickle cell disease, myelodysplastic syndromes, bone marrow fibrosis,
hematologic malignancy, myeloma, hemolytic anemia, thalassemia, or pure red cell aplasia
3. RBC transfusion within 8 weeks prior to randomization
4. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine
aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total bilirubin
>2.0 x upper limit of normal (ULN) during Screening.  Subjects with a history of Gilbert’s
syndrome are not excluded.
5. Uncontrolled hypertension (confirmed diastolic blood pressure >110 mmHg or systolic blood
pressure >180 mmHg) during Screening
6. Severe heart failure during Screening (New York Heart Association Class IV)
7. Acute coronary syndrome (hospitalization for unstable angina or myocardial infarction),
surgical or percutaneous intervention for coronary, cerebrovascular, or peripheral artery
disease (aortic or lower extremity), surgical or percutaneous valvular replacement or repair,
sustained ventricular tachycardia, hospitalization for HF, or stroke within 12 weeks prior to
or during Screening
8. History of active malignancy within 2 years prior to or during Screening, except for treated
basal cell carcinoma of skin, curatively resected squamous cell carcinoma of skin, or cervical
carcinoma in situ
9. History of DVT or PE within 12 weeks prior to randomization
10. History of hemosiderosis or hemochromatosis
11. History of prior organ transplantation or scheduled organ transplant (subjects on kidney
transplant wait-list are not excluded), or prior hematopoietic stem cell or bone marrow
transplant (corneal transplants and stem cell therapy for knee arthritis are not excluded)
12. Use of an investigational medication or participation in an investigational study within
30 days or 5 half-lives of the investigational medication (whichever is longer), prior to the
Screening visit
13. Previous participation in this study, or previous participation in a study with a hypoxia-
inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) other than vadadustat
14. Females who are pregnant or breast-feeding.  Women of childbearing potential who are
unable or unwilling to use an acceptable method of contraception (refer to Section 9.1.3,
Contraception and Pregnancy Avoidance Measures)
15. Non-vasectomized male subjects who are unable or unwilling to use an acceptable method of
contraception (refer to Section 9.1.3, Contraception and Pregnancy Avoidance Measures)

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16. Any other reason that in the opinion of the Investigator would make the subject not suitable
for participation in the study
17. Hypersensitivity to darbepoetin or vadadustat, or to any of their excipients
 
Retesting and Rescreening 
Subjects who fail to qualify for the study based on certain laboratory parameters may be retested 
and/or rescreened at the discretion of the Investigator. 
7.4.1 Retesting 
Retesting is defined as repeating laboratory tests within the same Screening Period.  
Subjects who initially fail to qualify for the study based on laboratory test results may have any 
individual laboratory parameter retested 1 time within the 8-week Screening period at the 
discretion of the Investigator.  Retesting within the 8-week Screening period does not constitute 
rescreening; however, if retesting falls outside of the 8-week Screening period, it should be 
considered a rescreen.  All Screening laboratories, including any repeat measurements, must be 
performed within the 8-week Screening window with a minimum of 4 days between the last 
qualifying repeat measurement and the Baseline visit. 
For eligibility, the average of 2 Hb values measured by the central laboratory during Screening 
(SV1, SV2, or retest) must be < 11.0 g/dl in the US or < 12.0 g/dl outside the US.  
Subjects who fail to qualify for the study based on low TSAT, ferritin, folate, or B12 values may 
receive replacement therapy based on the investigative sites’ standard of care during the 
screening period and retest the laboratory parameter(s).  Subjects who receive iron replacement 
may retest screening Hb a minimum of 3 weeks after completion of iron replacement therapy.    
7.4.2 Rescreening 
Subjects who fail to meet the qualifying criteria for Hb or eGFR during a Screening period may 
be considered for rescreening at the discretion of the Investigator if it is felt that the subject’s 
status has progressed and that the subject may now qualify for the study.  Additionally, subjects 
who fail to qualify for the study based on low TSAT, ferritin, folate, or B12 values may be 
considered for rescreening after receiving replacement therapy. 
Screening is limited to 3 attempts (Screening and 2 additional rescreening attempts). 
Subjects who fail to qualify for the study at the initial Screening visit will receive a new subject 
number for each rescreening attempt.  If rescreened, the subject will also sign a new informed 
consent form and will repeat all Screening procedures for each rescreening attempt. 
Study Completion, Subject Completion, Study Discontinuation, and Withdrawal of 
Subjects 
7.5.1 Study Completion 
The study will be considered completed (end of trial) when approximately 631 MACE events 
have accrued across the 2 NDD-CKD studies (Studies AKB-6548-CI-0014 and AKB-6548-CI-
0015), and all enrolled subjects have had the opportunity to have their Visit 13 (+/- 5 days). 
These 2 NDD-CKD studies were sized based on power considerations for the primary safety 
analysis of MACE events, and thus each study is highly powered (>90%) for the primary and 

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key secondary efficacy analysis. Thus, primary efficacy analyses will be based on the 
randomized population and every subject will have completed (or had the opportunity to 
complete) the primary evaluation period (Weeks 24-36). 
7.5.2 Subject Completion 
A subject will be considered as having completed the study, regardless of whether they are on or 
off study medication (vadadustat or darbepoetin alfa), if the subject is followed until global study 
completion (end of trial).  The table outlines the different categories of subjects and handling the 
global study completion activities. 
Subject Status at time of 
Global Study Completion 
End of Treatment (EOT) 
End of Study (EOS) 
Subject on study medication 
(includes those on temporary 
interruption) 
After announcement of global 
study completion: 
•
Perform EOT visit
•
Perform the Follow-
up visit 4 weeks after
EOT visit and include
End of Study (EOS)
subject status
Not applicable 
The EOS subject status will 
be captured as part of the 
Follow-up visit 
Subject permanently 
discontinued study 
medication and continues to 
be followed in the study 
At time of permanent 
discontinuation of study 
medication: 
•
Perform EOT visit
•
Perform the Follow-
up visit 4 weeks after
EOT visit
Optimal data collection 
would include the following 
assessments:  
•
EOS subject status
(must collect at
minimum)
•
MACE Endpoint
Questionnaire
•
AE Assessment
Subject Lost to Follow-up 
Not applicable 
Work with third party vendor 
to ascertain vital status and 
complete EOS subject status  
If subject-site contact is 
reestablished and possible, 
collect available information 
for EOS subject status  
Subject Withdrawn Consent 
Not applicable 
Complete the EOS subject 
status form at time of 
withdrawal of consent, 
absolute refusal of ALL 
methods of MACE and health 
status follow-up 

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Subject Death 
Not applicable 
Complete the EOS subject 
status form at the time of 
death (see Section 10 
Adverse Events for more 
details on other actions 
related to reporting a death) 
The need for rescue therapy does not constitute study completion and is not a criterion for 
subject withdrawal from the study.  Also, the occurrence of a safety endpoint, or if a subject 
progressed to chronic dialysis dependent CKD (DD-CKD), does not constitute study completion 
and is not a criterion for subject withdrawal from the study or study medication (vadadustat or 
darbepoetin alfa). 
7.5.3 Entire Study Termination 
The entire study may be suspended or terminated by the Sponsor for safety or other 
unanticipated reasons or upon request of regulatory agencies.  Criteria for premature study 
termination or suspension are detailed in Section 14.1, Criteria for Premature Termination or 
Suspension of the Study. 
7.5.4 Individual Study Site Termination 
Study participation may be suspended or terminated at an individual investigational site for 
various reasons.  Criteria and procedures for premature termination or suspension of an 
investigational site are detailed in Section 14.2, Criteria for Premature Termination or 
Suspension of Investigational Study Sites and Section 14.3, Procedures for Premature 
Termination or Suspension of the Study or Investigational Sites. 
7.5.5 Individual Subject Discontinuation 
During this study, it is anticipated that some subjects may permanently discontinue study 
medication (vadadustat or darbepoetin alfa) for any of the following reasons: 
•
Unacceptable toxicity or drug intolerability
•
Investigator discretion
•
Subject withdrawal of consent
•
Subject becomes pregnant
•
Receipt of a kidney transplant
•
Lack of efficacy
•
Other reasons.
Lack of efficacy is defined as inadequate response to darbepoetin alfa or vadadustat in the 
investigator’s opinion. 
Subjects who undergo a solid organ (including kidney), hematopoietic stem cell, or bone marrow 
transplantation will have their study medication (vadadustat or darbepoetin alfa) permanently 
discontinued. 
See Section 9.4, Study Medication Stopping Rules for additional details on the management of 
subjects with ALT and AST abnormalities. 

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It is important to continue to follow subjects that permanently discontinue study medication. 
Please see Sections 7.5.5.1, Temporary Interruption of Study Medication and 7.5.5.2, Permanent 
Discontinuation of Study Medication, and Appendix A:  Schedule of Activities). 
Receipt of rescue therapy is not a reason for permanent study medication discontinuation.  While 
receiving ESA rescue, subjects must temporarily discontinue study medication (vadadustat or 
darbepoetin alfa), but should resume study medication once rescue therapy has ended, as detailed 
in Section 8.4.7, Rescue Therapy. 
As part of the informed consent process, only subjects who fully understand and agree to full 
participation and long-term follow-up should be consented to participate. 
7.5.5.1 Temporary Interruption of Study Medication 
Subjects who temporarily interrupt study medication (vadadustat or darbepoetin alfa) treatment 
after the first dose and prior to completion of the study will continue with study visits and 
assessments.  Unless contraindicated, treatment should be resumed wherever possible and 
routinely considered at every visit following study medication discontinuation.  If a subject does 
not return for a scheduled visit, every effort should be made to contact the subject. If a subject’s 
study medication has been temporarily interrupted for more than 60 days, the Investigator should 
contact the Medical Monitor before resuming study medication. 
7.5.5.2 Permanent Discontinuation of Study Medication 
Subjects who permanently discontinue study medication  prior to global study completion are 
expected to continue to be followed post discontinuation of study medication. These subjects are to 
have their EOT visit at the time of permanent discontinuation of study medication have the Follow-
up visit 4 weeks after the EOT visit and continue to be followed through global study completion. At 
global study completion, each subject will have an End of Study (EOS) assessment to complete 
participation in the study. Receipt of rescue therapy is not a reason for permanent study medication 
discontinuation. While receiving ESA rescue, subjects must temporarily discontinue study 
medication but should resume study medication following the end of rescue therapy. 
For subjects who permanently discontinue study medication, the Investigator will resume 
standard of care treatment, including ESAs and iron therapy, as deemed appropriate. 
It is important to continue to follow subjects that permanently discontinue study medication. 
7.5.5.3 Complete Withdrawal from Further Study Visits/Assessments 
A subject has the right to withdraw consent for participation in the studyWithdrawal of consent 
is a subject’s refusal of ALL methods of follow-up noted in the informed consent form:  
procedures, participation in reduced procedures/study visits, telephone contact only or alternative 
contact only, source document or designated alternative contact, or access to medical records 
from alternative sources. 
It is important to provide options for the subject to consider for long-term follow-up before the 
subject withdraws consent. It is important for the Investigator to review options with a subject that 
would allow follow-up through global study completion before the subject withdraws consent. For 
subjects considering withdrawal of consent, the Investigator should consult with the Medical Monitor 

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to ensure all options have been explored and that there is complete understanding by the subject for 
what constitutes withdrawal of consent. 
7.5.5.4 Procedures to Support Continued Study Participation 
As part of the informed consent process, only subjects who fully understand and agree to full 
participation and long-term follow-up should be consented to participate. It is important that 
subjects understand the long-term duration and purpose of a cardiovascular outcome trial 
and that the subject (or designee) continue to allow follow-up through global study 
completion which could be several years, even post subject’s permanent discontinuation of 
study medication.   
In all cases of impending study medication discontinuation or subject request for  stopping study 
visits, the Investigator will discuss with the subject their options of continuing in the study.   
It is important to continue to follow every randomized subject, even if discontinued study 
medication, through global study completion at a frequency and approach that is agreed to 
between the Investigator and subject.  Visit schedule and assessments are flexible and at the 
discretion of the Investigator and subject and will be clearly documented in the medical chart. 
Optimal data collection would include the following assessments through global study 
completion: 
•
EOS subject status (must collect at minimum)
•
MACE Endpoint Questionnaire
•
AE Assessment
The protocol allows flexibility of follow-up to maintain the subjects in active status post 
permanent discontinuation of study medication. For those subjects who decline full participation 
in the study post discontinuation of study medication, other options for continued follow-up on a 
subject include (but are not limited to):  
1. Reduced frequency of on-site visits
2. Telephone visits in lieu of on-site visits
3. Telephone or any contact method (e.g., email, site staff visit subject’s home, etc.) to
verify vital status
4. Telephone or any contact method with an alternative person (family member or medical
designee)
5. Study team access to medical records for reporting MACE data or vital status
In the most extreme case, the protocol will accommodate minimal contact with a subject or 
alternative method to obtain the subject’s vital status. The objective is to keep a subject’s study 
status active to ascertain at a minimum vital status (alive or deceased) at the global study 
completion.  
The Investigator will ensure understanding and documentation of the reason(s) for a subject’s 
desire to stop study procedures or stop study medication. 

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7.5.5.5 Procedures to Prevent “Lost to Follow-up” 
The Investigator must make every effort to contact subjects who fail to return for scheduled 
visits so that they will not be declared “lost to follow-up.”  These actions must include, but are 
not limited to, the following: 
1. Contact all numbers for the subject and their listed contacts (to be collected in source at the
subject’s entry into the study), as applicable.  This includes making calls after normal
business hours or on holidays and weekends.
2. Contact the subject’s primary care physician, referring specialist, pharmacist, and/or other
healthcare professional (using the contacts provided by the subject at entry into the study), as
applicable
3. Send email, text, and postal mail with registered (traceable or trackable) letters to all the
subject’s addresses and contact persons, as applicable. Registered (traceable or trackable)
letters will be returned with a copy of the signature from whomever signed, which can be
compared to the ICF for vital status data. If undeliverable, then send non-registered standard
letters, which may be forwarded to a new address if the subject has moved.
4. Review available medical records/notes for details of hospitalizations, clinic visits, or other
procedures that may indicate the status of the subject, as applicable
5. Utilize the internet to search for additional contact information  as applicable.
6. Check local, regional, and national public records to locate the subject or search for mortality
status as allowed by law, as applicable.
It is important to obtain at a minimum vital status (alive or deceased) at the global study 
completion for all randomized subjects, including those that have been LTFU during the course 
of the study. 
The Sponsor may utilize a third-party provider in accordance with all applicable guidelines and 
legislation to assist the site in locating contact information for all subjects during the study or in 
locating the vital status for all of their randomized subjects in anticipation of global study 
completion (end of trial). 
8 
STUDY PRODUCT AND TREATMENT OF SUBJECTS 
 
Study Product, Supplies, and Storage 
Oral vadadustat and darbepoetin alfa for injection will be provided and shipped by the Sponsor 
or its designated supplier/distributor.  Both vadadustat and darbepoetin alfa will be supplied as 
open-label supplies.  All study medication supplies must be kept in a temperature-controlled, 
locked facility, accessible only to authorized study personnel. 
The Investigator or designated study personnel will be responsible for preparing study 
medication for dispensing to the subject (Section 8.2, Dispensing Procedures) and for study 
medication supply accountability (Section 8.3, Product Accountability and Destruction). 

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8.1.1 Vadadustat 
Vadadustat will be provided as 150 mg white to off-white, round, bi-convex film-coated tablets 
for oral administration.  The tablets will be packaged in high-density polyethylene bottles with 
child-resistant closures, polypropylene liner, and induction seal.  Labeling will be in accordance 
with current Good Manufacturing Practices (GMP) and local regulatory requirements. 
Dose levels utilized in this study will include:  150 mg (1 tablet), 300 mg (2 tablets), 450 mg 
(3 tablets), and 600 mg (4 tablets) per day. 
Vadadustat should be stored per the product label.  Please consult the Pharmacy Manual for 
details on storage and managing temperature excursions. 
8.1.2 Darbepoetin Alfa 
Darbepoetin alfa will be provided in its commercially-approved primary packaging and stored 
per the Package Insert (PI) for investigational sites in the US, and the European Summary of 
Product Characteristics (SmPC) for all other investigational sites (non-US) for adult patients with 
CKD not on dialysis.. 
 
Dispensing Procedures 
The Investigator will maintain record of all vadadustat tablets and darbepoetin alfa injections 
dispensed to and returned from each subject during the study.  Subjects will receive either 
vadadustat tablets or darbepoetin alfa according to the randomization assignments provided via 
the IWR system (see Section 8.4.2, Randomization). 
8.2.1 Dispensing of Vadadustat 
Subjects will be provided with a supply of vadadustat at the Baseline visit according to the IWR 
system assignment.  Resupply of additional vadadustat at subsequent visits will be managed via 
the IWR system and will be dependent on the current dose level of vadadustat and the number of 
tablets remaining in the subject’s current vadadustat supply at a given study visit 
(Section 8.4.4.1, Vadadustat Dosing and Dose Adjustment Algorithms).  Subjects will be 
instructed to finish 1 bottle before opening a new bottle. 
At the Baseline visit, study subjects will be provided with 1 bottle of vadadustat.  Each bottle of 
vadadustat will contain 100 tablets of vadadustat (150 mg tablets). 
Subjects should be instructed to bring unused vadadustat and empty bottles to each study visit for 
product accountability.  Empty bottles will be collected at these study visits.  Previously 
dispensed bottles (whether opened or unopened) with remaining tablets may be re-dispensed to 
the subject during the dosing phase of the study. 
A Vadadustat Dosing Information Sheet will be provided to the subject at dispensing of study 
medication. 
8.2.2 Dispensing of Darbepoetin Alfa 
Darbepoetin alfa will be dispensed according to the IWR system assignment as follows: 
•
For subjects already on darbepoetin, the initial dosing regimen in the study should be
based on the prior dosing regimen.

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•
For subjects taking other ESAs, the initial dose of darbepoetin should be based on the
Package Insert (PI) for investigational sites in the US, and the European Summary of
Product Characteristics (SmPC) for all other investigational sites (non-US) for adult
patients with CKD not on dialysis. .
Dispensing of additional darbepoetin alfa at subsequent dosing visits will be managed by the 
IWR system (Section 8.4.4.2, Darbepoetin Alfa Dosing and Dose Adjustment Algorithms). 
Darbepoetin alfa doses may be self-administered or staff administered at the site facility or by 
the subject at home according to the investigator’s determination and local practice.  
Subjects should be instructed to bring the darbepoetin boxes to each study visit for drug 
accountability. There will be no physical accountability performed with used syringes. The 
investigative site will maintain site drug accountability records of the actual syringes dispensed 
and used by a subject. 
A Darbepoetin Alfa Dosing Information Sheet will be provided to the subject at dispensing of 
study medication.  
 
Product Accountability and Destruction 
Product accountability should be an ongoing process throughout the study.  All study medication 
(vadadustat and darbepoetin alfa) must be accounted for and any discrepancies explained.  The 
Investigator or designated study personnel are responsible for keeping accurate records of the 
clinical supplies received from the Sponsor, all supplies retained in inventory at the investigative 
site, and study medication dispensed to or returned from each subject.  Records will be 
maintained that accurately reflect the drug accountability of vadadustat and darbepoetin alfa at 
all times. 
Proper drug accountability includes, but is not limited to: 
•
Continuously monitoring expiration dates if expiry date or retest date is provided to the
Investigator
•
Frequently verifying that actual inventory matches documented inventory
•
Verifying that the log is completed for all drug received and that all required fields are
complete, accurate, and legible.
If any dispensing errors or discrepancies are discovered, the Sponsor must be notified 
immediately. 
During the study, the Investigator will be notified of any expiry dates or retest date extensions of 
clinical study material.  If an expiry date notification is received during the study, the 
investigative site must complete all instructions outlined in the notification, including 
segregation of expired clinical study material for return to the Sponsor or its designee for 
destruction. 
Prior to investigative site closure and at appropriate intervals during the study, a representative 
from the Sponsor will perform clinical study material accountability and reconciliation. 
At the end of the study, the Investigator will retain all original documentation regarding  study 
material accountability, return, and/or destruction, and copies will be sent to the Sponsor. 

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All unused and/or partially used vadadustat or darbepoetin alfa should be returned to the Sponsor 
or destroyed at the investigational site, as specified by the Sponsor.  Appropriate records of the 
disposal will be documented and maintained.  No unused vadadustat or darbepoetin alfa may be 
disposed of until fully accounted for by the Sponsor’s monitor (or designee).  Empty containers 
may be disposed of according to local procedures. 
Treatment of Subjects 
8.4.1 Treatment Group Assignments 
Subjects will be randomized in a 1:1 ratio via the IWR system to either: 
•
Vadadustat (starting dose of 2 tablets once daily [300 mg/day])
•
Darbepoetin alfa (starting dose based on the current PI for investigational sites in the US,
and the SmPC for all other investigational sites (non-US) for adult patients with CKD not
on dialysis)
For all subjects, it is recommended that no additional ESA doses be administered after SV2 and 
prior to the Randomization visit. 
Target enrollment for each treatment group is approximately 925 subjects. 
8.4.2 Randomization 
This study will be open to up to approximately 1850 subjects with NDD-CKD with an eGFR 
≤60 mL/min/1.73 m2 (pre-dialysis). 
Using an IWR system, eligible subjects will be assigned using permuted block randomization 
and a 1:1 ratio to either vadadustat or darbepoetin alfa during their Baseline visit. 
To maintain balance between vadadustat-treated and darbepoetin alfa-treated subjects, 
randomization will be stratified with respect to:  1) geographic region (US versus EU versus 
ROW); 2) New York Heart Association CHF Class (0  (no CHF) or I versus II or III); and 3) 
study entry Hb level (<10.0 versus ≥10.0 g/dL, based on the most recent central laboratory Hb 
measurement prior to the Baseline/Randomization visit). 
8.4.3 Blinding 
This will be an open-label study.  Treatment assignment will be done through the IWR system 
and the Investigator, Sponsor, and CRO teams will not be aware of which treatment will be 
assigned next.  Treatments will be administered in an open-label fashion.The Sponsor and CRO 
study teams will be blinded to’by treatment’ aggregated analyses except for the unblinded 
statistician.  In addition, the study will involve blinded adjudication of MACE, the use of an 
IDMC, and an identical schedule of visits, procedures, and assessments for both treatment groups 
in order to reduce the potential for bias.  However certain Sponsor personnel directly involved in 
medical oversight of the study, regulatory reporting of safety information, and on-site monitoring 
activities may become unblinded to the treatment assignments of individual subjects during the 
course of the study.  
The EAC will remain blinded throughout the full course of the study. 

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8.4.4 Dosing and Dose Adjustment Guidelines 
Dosing will be initiated at the Baseline visit, and the first dose of study medication (vadadustat 
or darbepoetin alfa) will be administered at the investigative site after other Baseline visit 
procedures have been completed.  The investigator may elect to postpone the initial dose of study 
medication until a subsequent visit based on the subject’s Hb level or Hb trajectory assessed at 
the Baseline visit, or based on timing of last ESA dose given during Screening. 
For all subjects, it is recommended that no additional ESA doses be administered after SV2 and 
prior to the Randomization visit. 
Year 1-4 Treatment Period Visits 
Hemoglobin will be monitored via HemoCue throughout the study to determine if the dose of 
study medication (vadadustat or darbepoetin alfa) will be adjusted, interrupted, or maintained.  
From Weeks 0 to 12, Hb will be obtained via HemoCue every 2 weeks for monitoring for dose 
adjustment.  From Week 12 to Week 52, Hb will be monitored every 4 weeks via HemoCue.   
From Week 53 through the study end, Hb will continue to be monitored via HemoCue to 
determine if the dose of study medication will be adjusted, interrupted, or maintained.  Any 
unscheduled measurement taken between study visits will be recorded in the appropriate CRF 
and the subject’s source when a Hemocue is taken.   Hemoglobin will also be assessed with a 
CBC through the central laboratory for efficacy and safety evaluations; however, dose 
adjustments should be based on the HemoCue Hb value. If the Investigator has an immediate 
clinical concern about a subject’s HemoCue value, the Investigator may use clinical judgment 
and repeat the HemoCue Hb, use local lab values, or wait for central lab results. The test method 
utilized to inform your treatment decision must be recorded in the appropriate CRF and subject’s 
source.  
Year 2-4 Monthly Hb Monitoring 
Additionally, after Week 52, the Hb drawn as part of the local standard of care labs must be 
monitored monthly for dosing oversight. Per the Dosing Algorithms, if the Hb value suggests a 
dose adjustment is needed, an unscheduled visit must be performed.  
If monthly standard of care labs are not available, a study unscheduled visit must be 
performed.  This visit will include, at minimum, the Hb measurement via HemoCue, dose 
adjustment assessment, and adverse events assessment.    
The monthly Hb monitoring method is flexible between study visits after Week 52 to minimize 
unnecessary travel or redundant blood sampling for the subject. 
The aim is to maintain a Hb level of 10.0-11.0 g/dL in the US and 10.0-12.0 g/dL outside of the 
US throughout the study. 
Dose adjustments for vadadustat and darbepoetin alfa will be guided by Hb concentration and the 
Dose Adjustment Algorithms.  TheDose Adjustment Algorithm for darbepoetin alfa will follow 
the Package Insert (PI) for investigational sites in the US, and the European Summary of Product 
Characteristics (SmPC) for all other investigational sites (non-US).  
This protocol provides guidance for the treatment of subjects with anemia associated with CKD 
in order to achieve and maintain Hb levels within the target Hb range. Dose adjustment should 

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be based on the Investigator’s clinical discretion, incorporating the protocol guidance and 
considering the subject’s clinical condition, Hb rate of rise, Hb rate of decline, Hb variability, 
and ESA responsiveness.  
In cases where the Investigator does not follow the dosing algorithm, the clinical circumstances 
must be documented in the subject’s source.  
8.4.4.1 Vadadustat Dosing and Dose Adjustment Algorithms 
Subjects assigned to vadadustat will initiate dosing at 2 tablets once daily (300 mg/day).  Dose 
levels of vadadustat utilized in this study include 150, 300, 450, and 600 mg (available tablet 
strength is 150 mg). 
Dosing will be initiated at the Baseline visit and the first dose of vadadustat will be administered 
at the investigative site (study physician’s clinic) after other Baseline visit procedures have been 
completed.  The Investigator may elect to postpone the initial dose of study medication until a 
subsequent visit based on the subject’s Hb level or Hb trajectory assessed at the Baseline visit,  
or based on timing of the last ESA dose given during screening. 
Thereafter, vadadustat will be taken once daily on an outpatient basis.  Subjects may take 
vadadustat with or without food and should be instructed to swallow the tablet(s) whole.  
Subjects should be instructed to take vadadustat at roughly the same time each day. 
During the study, vadadustat should be dosed according to the  Dose Adjustment Algorithm in 
Appendix C:  Vadadustat Dosing and Dose Adjustment Algorithms. 
For subjects progressed to DD-CKD, and continuing on vadadustat, the dose adjustment should 
be based on the Dose Adjustment Algorithms (Appendix C:  Vadadustat Dosing and Dose 
Adjustment Algorithms). 
8.4.4.2 Darbepoetin Alfa Dosing and Dose Adjustment Algorithms 
For subjects randomized to receive darbepoetin alfa, the initial dose will be determined as 
follows: 
•
For subjects already on darbepoetin, the initial dosing regimen in the study should be
based on the prior dosing regimen.
•
For subjects taking other ESAs, the initial dose of darbepoetin should be based on the PI
for investigational sites in the US, and the SmPC for all other investigational sites (non-
US) for adult patients with CKD not on dialysis.
For subjects progressed to DD-CKD and continuing on darbepoetin alfa, the dose adjustment 
should be based on the Dose Adjustment Algorithms (Appendix D:  Darbepoetin Alfa Dosing 
and Dose Adjustment Algorithms).  
Each subject will receive their first dose of darbepoetin alfa at the Baseline visit. The 
Investigator may elect to postpone the initial dose of study medication until a subsequent visit 
based on the subject’s Hb level or Hb trajectory assessed at the Baseline visit,  or based on 
timing of the last ESA dose given during screening. 
Subsequent administration of darbepoetin alfa may occur at the clinic or may be 
self-administered at home per regional standard of care.  Darbepoetin alfa dosing is independent 

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of the visit schedule, and the dosing schedule may shift per local standard of care and 
Investigator discretion.  
8.4.5 Late or Missed Doses 
Subjects on vadadustat should be instructed to take the study medication at roughly the same 
time each day.   If a dose is forgotten, subjects should be instructed to take the dose as soon as 
they remember during the same day.  If a forgotten dose is not remembered on the same day, the 
subject should skip the dose and resume the normal dosing schedule the following day.  Subjects 
should not double-up on missed doses. 
Subjects on darbepoetin alfa should be instructed to take the study medication, including 
handling of late or missed dosed, as described in the PI or SmPC.. 
Subjects should be questioned regarding dosing compliance and whether they have questions or 
have experienced any problems related to the dosing of study medication (vadadustat or 
darbepoetin alfa). 
8.4.6 Iron Supplementation 
Investigators will prescribe iron supplementation during the study to maintain ferritin 
≥100 ng/mL or TSAT ≥20%.  In general, oral iron should be considered before initiating IV iron.   
The use of iron-based phosphate binders (eg, ferric citrate) is permitted. For subjects who initiate 
dialysis, iron maintenance therapy via dialysate (eg, ferric pyrophosphate citrate) is also 
permitted. However, the duration, dosage, and frequency of intradialytic iron should be 
documented in CRF. 
Important:  Because of the potential for oral iron to reduce the bioavailability of vadadustat, the 
study medication is not to be administered concurrently with an oral iron supplement (including 
multivitamins containing iron), iron containing phosphate binders, or medications containing 
iron.  The subject should be instructed to take these medications at least 2 hours before or 2 
hours after the dose of vadadustat. 
8.4.7 Rescue Therapy 
To ensure the safety of study subjects and to standardize the use of rescue in the study, rescue 
therapy guidelines are provided. 
8.4.7.1 ESA Rescue (Optional) 
Starting at Week 6, subjects in both treatment arms will be allowed (although will not be 
required) to have their Hb rescued with ESA therapy per the local standard of care.  Drug 
product and supplies for ESA rescue will not be provided by the Sponsor. 
If possible, a subject on vadadustat should be on a maximum dose of vadadustat for 2 weeks 
prior to ESA rescue.  A subject on darbepoetin alfa may rescue with another ESA per the 
standard of care.  To qualify for ESA rescue, a subject must fulfill BOTH of the following: 
•
The subject has experienced worsening of  symptoms of anemia (eg, fatigue, weakness,
shortness of breath, chest pain, confusion, or dizziness) compared with Baseline
•
The subject’s Hb is <9.0 g/dL

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However, in the event the subject does not meet the above criteria for ESA rescue, ESA rescue is 
permitted when medically necessary at the discretion of the Investigator. Reasons for ESA use 
will be captured in the appropriate CRF. 
The ESA rescue therapy should be administered as per the local institution’s guidelines and per 
the approved local product label.  While receiving ESA rescue therapy, subjects must 
temporarily discontinue taking study medication (vadadustat or darbepoetin alfa).  Hemoglobin 
will be monitored throughout the study at scheduled visits as defined in the Schedule of 
Activities using HemoCue, and ESA rescue treatment should be stopped when Hb is ≥9.5 g/dL.  
A minimum interval must be observed prior to restarting vadadustat after the last dose of rescue 
medication, and treatment may be resumed after the following intervals: 
•
2 days after last dose of epoetin rescue
•
7 days after last dose of darbepoetin alfa rescue
•
14 days after last dose of methoxy polyethylene glycol-epoetin beta rescue.
Following ESA rescue, the study medication should be resumed at the same dose as previously 
used or one dose higher and adjusted according to the Dose Adjustment Algorithms 
(Section 8.4.4, Dosing and Dose Adjustment Guidelines). If a subject’s study medication has been 
temporarily interrupted for more than 60 days, the Investigator should contact the Medical Monitor 
before resuming study medication. 
8.4.7.2 Red Blood Cell Transfusion (Optional) 
Investigators will use their local institution’s transfusion guidelines when determining whether to 
transfuse a study subject.  In general, in the event of an acute or severe loss of blood, a RBC 
transfusion should be administered as clinically indicated.  In less severe instances but where 
there may be worsening of anemia or moderate to severe symptoms of anemia, RBC transfusions 
are permitted at the discretion of the Investigator given the medical necessity. Reasons for RBC 
transfusion will be captured in the appropriate CRF (e.g., worsening anemia due to CKD, blood loss, 
surgery, etc.).  Study medication (vadadustat or darbepoetin alfa) may be continued during the 
RBC transfusion period.  
8.4.8 Phlebotomy (Optional) 
If a subject’s Hb exceeds 14.0 g/dL or the rate of rise of Hb raises concern to the Investigator, 
the subject may be phlebotomized based on the Investigator’s judgment.  The method of 
phlebotomy will be in accordance with the local institution’s guidelines and standard clinical 
practice. 
8.4.9 Treatment Compliance 
Subjects will be questioned regarding dosing compliance and whether they have questions or 
have experienced any problems related to the dosing of study medication (vadadustat or 
darbepoetin alfa).  The Investigator will also maintain drug accountability logs itemizing all 
study medications dispensed to and returned from each subject during the study.  Treatment 
compliance will be determined from these forms along with the subject questioning and the study 
medication CRFs. Dosing compliance for vadadustat or darbepoetin alfa is defined as 80 to 
120% over the course of the Treatment Period.   

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Subjects who miss doses will be counseled on the importance of compliance. 
Subjects will also be questioned regarding the timing of their last dose of vadadustat prior to the 
PK samples at the Week 4, 12, 28, and 52 study visits.  The date and time of these doses will be 
recorded on the CRF. 
8.4.10 Continuation of Treatment 
Subjects may receive study medication (vadadustat or darbepoetin alfa) up until the EOT visit. 
Prior and Concomitant Therapy 
8.5.1 General 
All medications taken during the screening period  and during the study should be recorded on 
the appropriate CRF. If the duration of the screening period is less than 30 days, all medications 
taken within 30 days prior to first dose of study medication will be recorded.  In addition, the 
ESA, blood transfusion, and iron treatment regimen prior to randomization and the date of last 
dose will be recorded.  
To ensure adequate collection of prior ESA dosing history, a minimum of 8 weeks of ESA 
therapy prior to start of study medication will be recorded. 
8.5.2 Erythropoiesis-stimulation Agents  
For all subjects, it is recommended that no additional ESA doses be administered after Screening 
visit 2 (SV2) and prior to the Randomization visit.  
Non-protocol ESAs are prohibited from Randomization until the end of the study, unless the subject 
is receiving ESA rescue therapy, interrupts study medication for other reasons, or permanently 
discontinues study medication. Reasons for ESA use will be captured in the appropriate CRF (e.g., 
adverse event, inadvertent administration, etc.).  
Concomitant use of an ESA with study medication is strictly prohibited. 
In the setting of ESA rescue therapy, the initial dose of ESA rescue therapy may be administered on 
the same day as the last vadadustat dose prior to vadadustat dose interruption (see Section 7.5.5.1, 
Temporary Interruption of Study Medication) if deemed medically necessary at the discretion of the 
Investigator. Guidelines for ESA administration as rescue therapy are provided in Section 8.4.7.1, 
ESA Rescue.  
All efforts will be made to avoid inadvertent administration of ESAs resulting from following routine 
ESA hemodialysis protocols (e.g., dialysis center ESA protocols for subjects on hemodialysis). If 
ESA is inadvertently administered to subjects actively receiving vadadustat treatment, vadadustat 
treatment will be stopped and the event will be reported as a protocol deviation 
8.5.3 Transfusions  
Documentation of transfusions will be collected. The receipt of any transfusions for 4 weeks prior to 
Screening will be recorded. 
8.5.4 Investigational Medications 
Study subjects should not have received any investigational medications or participated in an 
investigational study within 30 days or 5 half-lives of the investigational medication, whichever 

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is longer, prior to the Screening visit.  In addition, subjects should not have participated in a 
study with another HIF-PHI. 
Additionally, subjects should not take another investigational medication while participating in 
this study. 
8.5.5 HMG-CoA Reductase Inhibitors (Statins) 
Exposures to atorvastatin and an active metabolite (para-hydroxy atorvastatin) were mildly 
increased in the setting of vadadustat co-administration in healthy adults.  No dose adjustment of 
atorvastatin is recommended.  
Exposures to simvastatin and an active metabolite (beta-hydroxy acid) were both mildly to 
moderately increased with co-administration of vadadustat in healthy adults.  For subjects taking 
vadadustat who are concomitantly taking simvastatin, the recommended maximum daily dose of 
simvastatin is 20 mg.  Investigators should review simvastatin dosing and consider clinical 
guidelines and local prescribing information including specific guidance in product labels with 
reference to renal impairment as well as hepatic impairment, concomitant medications and other 
medical factors relevant to the management of the subject. 
Exposure to rosuvastatin was moderately increased with co-administration of vadadustat based 
on a study in healthy adults.  For subjects taking vadadustat who are concomitantly taking 
rosuvastatin, the recommended maximum daily dose of rosuvastatin is 10 mg.  Investigators 
should review rosuvastatin dosing and consider clinical guidelines and local prescribing 
information including specific guidance in product labels with reference to renal impairment as 
well as hepatic impairment, concomitant medications, and other medical factors relevant to the 
management of the subject. 
Exposure to pravastatin was studied in the setting of vadadustat co-administration in healthy 
adults.  There was no interaction.  No dose adjustment of pravastatin is recommended.  
Exposures to the other statins may be increased with co-administration of vadadustat.  When 
used with vadadustat, upward titration of other statins to higher doses should be carried out with 
caution. 
A summary of results and management of concomitant administration of vadadustat with the 
various statins is provided below:    
Statin 
Change in Statin Exposure 
When Dosed with Vadadustat* 
Recommended Statin Dosing in Subjects 
Receiving Concomitant Vadadustat 
Atorvastatin 
Mild increase 
No dose adjustment 
Pravastatin 
No increase 
No dose adjustment 
Rosuvastatin 
Moderate increase 
Maximum daily dose of 10 mg 
Simvastatin 
Mild-to-moderate increase 
Maximum daily dose of 20 mg 
Other statins 
Not studied 
Upward titration to higher doses should be 
done with caution 
* Based on FDA guidance, an increase in exposure of ≥ 1.25- to < 2-fold, ≥ 2- to < 5-fold, or ≥ 5-fold is classified as a mild,
moderate, or strong interaction, respectively (FDA 2017).

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8.5.6 Sulfasalazine and Other BCRP Substrates 
Exposure to sulfasalazine was moderately increased with co-administration of vadadustat based 
on a study in healthy adults; mesalamine exposure was mildly increased, and no increase was 
observed in exposure to the metabolite sulfapyridine.  Sulfasalazine and other breast cancer 
resistant protein (BCRP) substrates should be used with caution when taken concomitantly with 
vadadustat. 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES 
Please see Appendix A:  Schedule of Activities for a detailed table of the Schedule of Activities. 
This study includes the following visits: 
•
Optional Pre-Screening
•
Two Screening visits (SV1 and SV2)
•
Baseline/Randomization visit (Week 0/Day 1)
•
Year 1 Treatment Period Study Visits/Evaluations while receiving study medication:
Weeks 2, 4, 6, 8, 10, 12 (± 3 days), and every 4 weeks thereafter until Week 52 (± 5 days)
•
Year 2 Treatment Period Study Visits/Evaluations while receiving study medication:
Weeks 64, 76, 88, and 104 (± 10 days)
•
Year 3 Treatment Period Study Visits/Evaluations while receiving study medication:
Weeks 116, 128, 140, and 156 (± 10 days)
•
Year 4 Treatment Period Study Visits/Evaluations while receiving study medication:
Weeks 168, 180, 192, and 208 (± 10 days)
•
EOT visit (± 7 days)
•
Follow-up visit:  4 weeks after the EOT (± 7 days).
•
Unscheduled Visit(s)
The following sections describe the procedures to be completed during the study.  Subjects 
are to be assessed by the same Investigator or investigative site personnel whenever possible. 
Administrative Procedures 
9.1.1 Informed Consent 
Informed consent must be obtained prior to the subject entering into the study and before any 
protocol-directed procedures are performed (including Screening activities).  Subjects 
participating in the optional Pre-Screening visit must sign an abbreviated consent form or full 
consent form prior to Pre-Screening and, if eligible, may proceed with the Screening visit after 
full consent has been obtained (see Section 9.3.1, Pre-Screening Visit and Section 15.3, Subject 
Information and Consent for additional details).  Additionally, subjects may be asked to provide 
a separate, optional consent to obtain and store a blood sample(s) for future genetic analyses. 

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9.1.2 Documentation of Screen Failures 
Investigators will maintain documentation of Pre-Screening activities, to include information on 
potential study candidates evaluated and reasons that subjects considered for the study did not 
qualify. 
Investigators must account for all subjects who sign informed consent and will maintain a log of 
subjects screened and indicate who was randomized or excluded.  If the subject is found not to be 
eligible for randomization, the reason(s) for ineligibility must be documented by the Investigator. 
Screening numbers assigned to subjects who fail Screening will not be re-used. 
9.1.3 Contraception and Pregnancy Avoidance Measures 
In nonclinical animal embryo-fetal development and fertility studies, there was no evidence of 
teratogenicity, no skeletal or visceral malformations, and no changes in male or female 
reproductive and fertility indices, or in sperm parameters.  In rats, decreased fetal body weight 
and reduced skeletal ossification were noted at the highest dose tested of 160 mg/kg/day.  
Peri-postnatal development studies have not yet been conducted with vadadustat, and there are 
no data on the transmission of vadadustat in breast milk or the effect of vadadustat on infants. 
Although the potential risk of vadadustat on the developing fetus is limited based on studies to 
date, the study requires that all subjects must agree to use adequate contraception throughout the 
study and for 30 days after the last dose of study medication. 
Adequate contraception is defined as follows: 
Female subjects must be surgically sterile, postmenopausal (no menses for at least one year), or 
have negative pregnancy test results at Screening (serum). 
Female subjects not surgically sterile or postmenopausal (no menses for at least one year) and 
non-vasectomized male subjects must practice at least 1 of the following methods of birth 
control: 
•
Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior
to Screening visit, throughout the study, and for 30 days after the last dose of study
medication)
•
A vasectomized partner
•
Hormonal contraceptives (oral, parenteral, or transdermal) for at least 3 months prior to
study medication administration or intrauterine contraception/device throughout the
study, and for 30 days after the last dose of study medication
•
Double-barrier method (such as male condom, female condom, diaphragm, sponge, or
cervical cap together with spermicidal foam/gel/film/suppository) (starting at SV1,
throughout the study, and for 30 days after the last dose of study medication).
9.1.4 Laboratory Accreditation and Reference Ranges 
The Investigator and the Sponsor will maintain a copy of the laboratory accreditation and the 
reference ranges for the central laboratory used for clinical laboratory evaluations.  Additionally, 
other accreditation(s) will be collected as required. 

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Study Procedures and Evaluations 
9.2.1 Clinical Evaluations 
The following clinical evaluations will be conducted during the course of the study: 
•
Medical history, demographics, and physical examination:  Medical history, demographic
information, and physical examination (including height) will be collected at SV2.
Relevant medical history (with particular emphasis on previous medical conditions that
may lead to exclusion) and significant ongoing medical conditions or diseases should be
documented.  After SV2, an abbreviated, symptom-directed physical examination should
be performed at the discretion of the Investigator as clinically indicated.
•
Vital signs:  Vital signs will include heart rate and blood pressure.  Heart rate and blood
pressure should be assessed in the seated position after 5 minutes of rest.  Vital signs will
be collected at SV1, SV2, Baseline, during study visits, and EOT and should be taken
prior to blood draws when possible.
•
Weight:  Weight will be collected for all subjects at SV2, at Weeks 12, 24, 36, and 52,
yearly thereafter, and at the EOT visit.  For subjects on darbepoetin alfa, subjects will be
weighed for dosing as per the local standard of care.
•
12-Lead electrocardiogram (ECG):  A standard 12-lead ECG will be performed at
Baseline.  The ECG should be obtained after the subject has been resting comfortably in a
supine position for approximately 5 minutes and should be taken prior to vital sign
assessments and blood draws when possible.  With the subject in a supine position, obtain
the 12-lead tracing.  All ECGs will be reviewed by the Investigator for the presence of
rhythms of potential clinical concern.  A record of the tracing(s) will be made and
retained with other source documents.
•
Completion of MACE Endpoint Questionnaire:  At each post-randomization study visit,
the subject must specifically be questioned regarding the occurrence of any potential
MACE endpoint event since the last study visit.  IMPORTANT:  The endpoint
questionnaire electronic CRF must be completed in full at each visit even if no
potential MACE endpoints have occurred.  If a potential endpoint event is reported,
the date of the event should be recorded and the appropriate source documents should be
collected according to the endpoint packet checklist.
•
AE Assessments:  AE collection will begin from time of randomization through global
study completion. The Investigator and study personnel will review each subject’s
laboratory and clinical evaluation findings and query the subject directly regarding AEs
(see Section 10, Adverse Events).  Subjects must be followed for AEs until the final
required protocol visit or until all drug-related toxicities and SAEs have resolved (or are
considered chronic/stable), whichever is later.
•
Concomitant Medication Recording:  All medications (both prescription and
non-prescription, and including vitamins, herbals, topicals, inhaled, and intranasal) taken
during the screening period and throughout the study, ending at the final protocol
required visit, should be recorded on the appropriate CRF.  If the duration of screening
period is less than 30 days, all medications taken within 30 days prior to the start of study
medication (vadadustat or darbepoetin alfa). At each study visit, subjects will be asked

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whether they have started or discontinued any medication since their previous study visit.  
This includes single-use or as-needed medication use.  All medications and treatments, 
including vitamin supplements, over-the-counter medications, and oral herbal 
preparations must be recorded in the CRFs.  In addition, for any subject with ESA, blood 
transfusion or IV iron use, the date of last treatment of ESA, blood transfusion, or iron 
treatment regimen prior to randomization and date of last dose will be recorded. 
9.2.2 Laboratory Evaluations 
Samples for laboratory assays will be sent to a central laboratory for analysis.  Detailed 
instructions for the collection, processing, and shipment of laboratory samples will be provided 
by the Sponsor and the central laboratory.  The Investigator is responsible for reviewing 
laboratory results for clinical significance. 
The following laboratory evaluations will be conducted during the course of the study: 
•
Pregnancy test:  A serum pregnancy test will be performed at SV2 for females of
childbearing potential.  Additional serum or local urine pregnancy tests may be
conducted throughout the study in sufficient number, as determined by the Investigator or
required by local regulations, to establish the absence of pregnancy during the study.  The
SV2 results must be available and must be negative before the subject takes the first dose
of study medication.
•
Complete Blood Count (CBC):  A CBC with differential will be performed at Baseline
and twice annually at Weeks 28, 52, 76, 104, 128, 156, 180, 208.  At all other noted visits
in Appendix A:  Schedule of Activities, including SV1 and SV2, a CBC without
differential will be performed.  The CBC with differential will include:  Hb, hematocrit,
RBCs, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean
corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW),
white blood cell (WBC) count with differential (neutrophils, lymphocytes, monocytes,
eosinophils, basophils), and platelets.
Hemoglobin assessed by central laboratory CBC will be used for evaluations of efficacy
and safety.Hemoglobin levels assessed by HemoCue should be used for dose adjustments
as described in Section 8.4.4 Dosing and Dose Adjustment Guidelines). lf the
Investigator has an immediate clinical concern about a subject's HemoCue value, the
Investigator may use clinical judgment and repeat the HemoCue Hb, use local lab values,
or wait for central lab results. The test method utilized to inform the treatment decision
must be recorded in the appropriate CRF and subject’s source.
For eligibility purposes, one retest for Hb may be performed during the screening
window,  The average of 2 Hb values measured by the central laboratory during
Screening (SV1, SV2, or retest) must be < 11.0 g/dl in the US and <12.0 g/dl outside the
US.
Refer to Sections 7.4.1, Retesting and 7.4.2, Rescreening for further details regarding
repeating laboratory measurements during the Screening period.
•
Point of care Hb:  Using HemoCue, Hb will be monitored throughout the study to
determine if the dose of study medication (vadadustat or darbepoetin alfa) will be

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adjusted, interrupted, or maintained as described in Section 8.4.4 Dosing and Dose 
Adjustment Guidelines. 
•
Reticulocyte count:  An automated reticulocyte count (both absolute and percent) will be
performed at Baseline and at Weeks 4, 12, 28, and 52.
•
Coagulation tests:  Blood samples will be drawn at Baseline to assess the prothrombin
time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR).
•
Folate and Vitamin B12:  A blood sample will be drawn at SV1 to assess the folate and
Vitamin B12 levels. 
•
Urine albumin-to-creatinine ratio (uACR):  A random urine spot sample should be
collected at the investigative site during the Baseline, Weeks 28, 52, 104, 156, 208, and
EOT to assess the uACR.  Subjects should refrain from heavy exercise 24 hours before
the test.
•
C-reactive protein (CRP):  A blood sample for CRP will be collected at the Baseline,
Weeks 28, 52, 104, 156, and EOT.
•
Serum Chemistry:  Blood samples to assess serum chemistry will be collected at SV1,
Baseline, and twice annually at Weeks 28, 52, 76, 104, 128, 156, 180, 208, EOT.  At all
other noted visits in Appendix A:  Schedule of Activities, serum creatinine and eGFR
will be performed only at Weeks 4, 8, 12, 20, 36, 44.  The serum chemistry will include
the following assays:  sodium, potassium, bicarbonate, chloride, calcium, magnesium,
phosphorus, glucose, creatinine, blood urea nitrogen (BUN), creatine phosphokinase
(CPK), uric acid, albumin, total protein, and eGFR calculation.
Note:  When a ≥50% decline in eGFR from the Baseline value is observed, a repeat
central laboratory measure should be performed within 30 to 60 days.
•
Liver Function Tests: Blood samples to assess liver function will be collected at SV1,
Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44, 52, 64, 76, 88, 104, 116, 128, 140, 156,
168, 180, 192, 208, and EOT.  Liver function tests will include: total bilirubin, alkaline
phosphatase, ALT/SGPT, AST/SGOT, and lactate dehydrogenase (LDH).
•
Iron indices:  Blood samples to assess the iron indices will be collected at SV1, Baseline,
Weeks 4, 8, 12, 20, 28, 36, 44, 52, 64, 76, 88, 104, 116, 128, 140, 156, 168, 180, 192,
208, and EOT.  Assessments will include the following indices:  ferritin, iron, TIBC, and
TSAT.
•
Lipid Profile:  Blood samples will be collected at the Baseline, Week 28, and Week 52
visits to assess the cholesterol levels and will be tested for the following types of lipids:
total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and
triglycerides.
•
Biomarkers (including, but not limited to, hepcidin, vascular endothelial growth factor
[VEGF]):  Samples for biomarker analysis will be drawn at the Baseline, Weeks 12, 28,
52, 104, 156, and EOT.
•
EPO:  Blood samples for EPO analysis will be obtained at Baseline and at Weeks 4, 12,
28, and 52.

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•
PK Evaluations (samples to be drawn only for subjects randomized to vadadustat):
Plasma samples for PK evaluation will be collected to analyze for both the parent
compound (vadadustat) and its metabolites.  Collection time points for PK will include
Study Day 1 (Baseline), and Weeks 4, 12, 28, and 52.
o
Study Day 1 (Baseline Visit): Vadadustat will be administered on Study Day 1
(Baseline Visit) in the clinic after the Baseline procedures, and the PK sample will be
collected between 15 minutes to 1 hour after vadadustat administration. The times of
vadadustat dose and the PK sampling will be documented.
o
Weeks 4, 12, 28, and 52 study visits: PK sampling will also be performed along with
other study laboratory samples being collected at the Weeks 4, 12, 28, and 52 study
visits. The date and times of vadadustat administration and PK sampling will be
documented.
Samples should be collected along with the other laboratory samples being collected
at the study visit.  Subjects will be questioned regarding the timing of their last dose
of vadadustat prior to the collection of PK samples.  The date and time of these doses
will be recorded by the sites.
•
Exploratory Samples:  Additional blood and urine samples will be collected at Baseline,
Weeks 28, 52, 104, 156, and EOT which may be used for exploratory measurement of
biomarkers (eg, factors relating to the activation of the HIF pathway).  Subjects will also
be asked to provide optional consent to obtain a blood sample at Baseline and EOT, to be
stored for future genetic analyses (eg, DNA, mRNA).
 
Schedule of Activities 
The Schedule of Activities (see Appendix A:  Schedule of Activities) shows the timing of 
planned study procedures.  Every effort should be made to adhere to this procedure schedule and 
all assessments should be completed at each study visit. 
9.3.1 Pre-Screening Visit 
To minimize Screen failures, there will be an optional Pre-Screening visit which will enable the 
subject to have a HemoCue Hb prior to proceeding with full Screening.  Subjects will need to 
sign an abbreviated Pre-Screening informed consent form or full consent form prior to 
Pre-Screening.  If the Pre-Screen HemoCue Hb is between 8.0 and 11.0 g/dL (inclusive) in the 
US or between 9.0 and 12.0 g/dL (inclusive) outside the US, the investigative site may proceed 
with SV1, which preferably will occur on the same day as Pre-Screening. 
9.3.2 Screening Visits 
Subjects will need to sign a full consent form prior to SV1 procedures. The consent form may be 
signed in advance of SV1 procedures. The Screening period starts at the time the informed 
consent is signed and will be a maximum of 8 weeks in duration.  Two Screening visits (SV1 and 
SV2) must be performed within 8 weeks prior to dosing (Baseline visit or Day 1).  There must be 
a minimum of 4 days between the 2 Screening visits and a minimum of 4 days between SV2 or 
last retest and the Baseline visit. 
The Investigator will maintain a log of subjects (both Pre-Screened and Screened) and indicate 
who of the Pre-Screened subjects were brought in for informed consent and Screening and who 
of the Screened subjects were enrolled or excluded and the reason for exclusion. 

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After obtaining informed consent, subjects will undergo a number of Screening activities. 
9.3.2.1 Screening Visit 1 (SV1) 
At SV1, the following activities/procedures will be performed: 
•
Informed consent (including an additional optional consent for blood samples for future
genetic analyses.
•
Review of eligibility criteria
•
Vital signs including heart rate and blood pressure (assessed in seated position after
5 minutes of rest and prior to blood draws)
•
Laboratory procedures:
o
CBC (without differential)
o
Iron indices
o
Folate and vitamin B12 levels
o
Serum chemistry including serum creatinine and eGFR
o
Liver Function Tests
•
Visit registration in IWR
Refer to Sections 7.4.1, Retesting and 7.4.2, Rescreening for further details regarding repeating 
laboratory measurements during the Screening period. 
9.3.2.2 Screening Visit 2 (SV2) 
At SV2, the following activities/procedures will be performed: 
•
Review of eligibility criteria
•
Physical examination
•
Demographics and medical history
•
Vital signs including heart rate and blood pressure (assessed in seated position after
5 minutes of rest and prior to blood draws), as well as height and weight
•
Laboratory procedures:
o
CBC (without differential)
•
Serum pregnancy test for females of childbearing potential (eligible subjects will be
advised to use an adequate contraceptive method)
•
Prior and current medication use.
The mean of 2 Hb values from the central laboratory must be between 8.0 and 11.0 g/dL 
(inclusive) in the US or between 9.0 and 12.0 g/dL (inclusive) outside the US to qualify for 
inclusion into the trial.  If the subject’s Hb does not qualify after SV1,SV2, or retest - Hb, the 
subject should be considered a Screen failure. 
9.3.2.3 Subject Retesting 
Subjects who initially fail to qualify for the study based on laboratory test results may be retested 
once within the 8-week Screening period, per Investigator discretion (Section 7.4.1, Retesting). 
9.3.3 Subject Rescreening 
Subjects who fail to meet the qualifying criteria for Hb or eGFR during the Screening period 
may be considered for rescreening at the discretion of the Investigator if it is felt that the 

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subject’s status has progressed and that the subject may now qualify for the study.  Additionally, 
subjects who fail to qualify for the study based on low TSAT, ferritin, folate, or B12 values may 
be considered for rescreening after receiving replacement therapy.  Screening is limited to 
3 attempts (Screening and 2 additional rescreening attempts) (Section 7.4.2, Rescreening). 
9.3.4 Baseline Visit (Day 1) 
The Baseline visit must be performed at a minimum of 4 days from the last Screening visit (SV2) 
procedure including retest(s). 
At the Baseline visit, the following activities/procedures will be performed: 
•
Randomization
•
12-lead ECG (prior to vital sign assessments and blood draws).
•
Vital signs including heart rate and blood pressure (assessed in seated position after
5 minutes of rest and prior to blood draws)
•
Laboratory Procedures:
o
Random spot urine sample for uACR
o
Coagulation Tests
o
CRP
o
CBC (including differential)
o
Reticulocyte count
o
Serum chemistry including serum creatinine and eGFR
o
Liver function tests
o
Iron indices
o
Lipid profile
o
EPO
o
Biomarkers
o
PK (see Section 9.2.2, Laboratory Evaluations; samples to be drawn only for subjects
randomly assigned to vadadustat)
o
Exploratory samples
•
Review of medical history for new conditions since Screening visit
•
Medication use since Screening visit
•
Study medication assessments and procedures:
o
Subject will take their first dose of study medication at the investigative site during
the Baseline visit
o
Hb by HemoCue for dose initiation
o
Vadadustat dispensing
o
Darbepoetin alfa dispensing )
o
Oral iron supplementation as needed to maintain ferritin ≥100 ng/mL or TSAT ≥20%
(per local product label; see Section 8.4.6, Iron Supplementation)
•
AE assessment as needed (after receiving the first dose of study medication).
•
Visit Registration in IWR
9.3.5 Year 1 Treatment Period Visits (Day 2 through Week 52) 
During the Year 1 Treatment Period visits at Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 
44, 48, and 52, the following activities/procedures will be performed: 

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•
Vital signs including heart rate and blood pressure (assessed in seated position after
5 minutes of rest and prior to blood draws)
•
Weight (Weeks 12, 24, 36, and 52)
•
Laboratory procedures:
•
Random spot urine sample for uACR (Weeks 28 and 52)
o
CBC (Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52; differential
at Weeks 28 and 52)
o
Reticulocyte count (Weeks 4, 12, 28, and 52)
o
Serum chemistry (Weeks 28 and 52)
o
Serum creatinine and eGFR (Weeks 4, 8, 12, 20, 36, and 44; also at Weeks 28 and 52
as part of the serum chemistry)
o
Liver function tests (Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44, and 52)
o
Iron indices (Weeks 4, 8, 12, 20, 28, 36, 44, and 52)
o
Lipid profile (Weeks 28 and 52)
o
EPO (Weeks 4, 12, 28, and 52)
o
CRP (Weeks 28 and 52)
o
Biomarkers (Weeks 12, 28, and 52)
o
PK (Weeks 4, 12, 28, and 52; see Section 9.2.2, Laboratory Evaluations; samples to
be drawn only for subjects randomized to vadadustat)
o
Exploratory samples (Weeks 28 and 52)
•
Record date and time of subject’s last dose of vadadustat prior to the PK sample
(Weeks 4, 12, 28, and 52)
•
Safety assessments:
o
AE assessment
o
RBC transfusions and ESA rescue
o
Therapeutic phlebotomy
o
MACE endpoint questionnaire
•
Medication assessments and procedures:
o
Review of concomitant medications
o
Hb by HemoCue for dose adjustment
o
Drug reconciliation:  Study medication (vadadustat or darbepoetin alfa) reconciliation
will be conducted per the pharmacy manual instructions.
o
Vadadustat dispensing as needed per Section 8.2.1, Dispensing of Vadadustat
o
Darbepoetin alfa dispensing
o
Iron supplementation as needed to maintain ferritin ≥100 ng/mL or TSAT ≥20% (per
local product label; see Section 8.4.6, Iron Supplementation)
o
Question subject regarding dosing compliance and whether they have questions or
have experienced any problems related to the dosing of study medication (vadadustat
or darbepoetin alfa).
•
Visit Registration in IWR
9.3.6 Year 2-4 Monthly Hb Monitoring 
•
Monthly monitoring of Hb as part of local standard of care labs or at unscheduled visits
for dose adjustment.

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9.3.7 Year 2 Treatment Period Visits (Weeks 53 through 104) 
During the Year 2 Treatment Period visits at Weeks 64, 76, 88, and 104, the following 
activities/procedures will be performed: 
•
Vital signs including heart rate and blood pressure (assessed in seated position after
5 minutes of rest and prior to blood draws)
•
Weight (Week 104)
•
Laboratory Procedures:
o
Random spot urine sample for uACR (Week 104)
o
CBC (Weeks 64, 76, 88, and 104; differential at Weeks 76 and 104)
o
Serum chemistry including serum creatinine and eGFR (Weeks 76 and 104)
o
Liver function tests (Weeks 64, 76, 88, and 104)
o
Iron indices (Weeks 64, 76, 88, and 104)
o
CRP (Week 104)
o
Biomarkers (Week 104)
o
Exploratory samples (Week 104)
•
Safety assessments:
o
AE assessment
o
RBC transfusions and ESA rescue
o
Therapeutic phlebotomy
o
MACE endpoint questionnaire
•
Medication assessments and procedures:
o
Review of concomitant medications
o
Hb by HemoCue for dose adjustment
o
Drug reconciliation:  Study medication (vadadustat or darbepoetin alfa) reconciliation
will be conducted per the pharmacy manual instructions.
o
Vadadustat dispensing as needed per Section 8.2.1, Dispensing of Vadadustat
o
Darbepoetin alfa dispensing
o
Iron supplementation to maintain ferritin ≥100 ng/mL or TSAT ≥20% (per local
product label; see Section 8.4.6, Iron Supplementation)
o
Question subject regarding dosing compliance and whether they have questions or
have experienced any problems related to the dosing of study medication (vadadustat
or darbepoetin alfa).
•
Visit Registration in IWR
9.3.8 Year 3/4 Treatment Period Visits (Weeks 116 through 208) 
During the Year 3/4 Treatment Period visits at Weeks 116, 128, 140, 156, 168, 180, 192, 
and 208, the following activities/procedures will be performed: 
•
Vital signs including heart rate and blood pressure (assessed in seated position after
5 minutes of rest and prior to blood draws)
•
Weight (Weeks 156 and 208)
•
Laboratory Procedures:
o
Random spot urine sample for uACR (Weeks 156 and 208)
o
CBC (Weeks 116, 128, 140, 156, 168, 180, 192, and 208; differential at Weeks 128,
156, 180, and 208)

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o
Serum chemistry including serum creatinine and eGFR (Weeks 128, 156, 180, and
208)
o
Liver function tests (Weeks 116, 128, 140, 156, 168, 180, 192, and 208)
o
Iron indices (Weeks 116, 128, 140, 156, 168, 180, 192, and 208)
o
CRP (Week 156)
o
Biomarkers (Week 156)
o
Exploratory samples (Week 156)
•
Safety assessments:
o
AE assessment
o
RBC transfusions and ESA rescue
o
Therapeutic phlebotomy
o
MACE endpoint questionnaire
•
Medication assessments and procedures:
o
Review of concomitant medications
o
Hb by HemoCue for dose adjustment
o
Drug reconciliation:  Study medication (vadadustat or darbepoetin alfa) reconciliation
will be conducted per the pharmacy manual instructions.
o
Vadadustat dispensing as needed per Section 8.2.1, Dispensing of Vadadustat
o
Darbepoetin alfa dispensing (per PI for investigational sites in the US, and the SmPC
for all other investigational sites (non-US)
o
Iron supplementation to maintain ferritin ≥100 ng/mL or TSAT ≥20% (per local
product label; see Section 8.4.6, Iron Supplementation)
o
Question subject regarding dosing compliance and whether they have questions or
have experienced any problems related to the dosing of study medication (vadadustat
or darbepoetin alfa).
•
Visit Registration in IWR
9.3.9 End of Treatment (EOT) Visit 
The EOT visit will be performed at the time a subject permanently discontinues study medication 
or for subjects on study medication at the time of notification of  global study completion (See 
Appendix A: Schedule of Activities). 
At the EOT visit, the following activities/procedures will be performed: 
•
Vital signs including heart rate and blood pressure (assessed in seated position after
5 minutes of rest and prior to blood draws), as well as weight
•
Laboratory Procedures:
o
Random spot urine sample for uACR
o
CBC (without differential)
o
Serum chemistry including serum creatinine and eGFR
o
Liver function tests
o
Iron indices
o
Biomarkers
o
CRP
o
Exploratory samples
•
Safety assessments:
o
AE assessment

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o
RBC transfusions and ESA rescue
o
Therapeutic phlebotomy
o
MACE endpoint questionnaire
•
Recording of concomitant medications
•
Drug reconciliation:  Study medication (vadadustat or darbepoetin alfa) reconciliation
will be conducted per the pharmacy manual instructions.
•
Question subject regarding dosing compliance and whether they have experienced any
problems related to the dosing of study medication (vadadustat or darbepoetin alfa).
•
Visit Registration in IWR
9.3.10 Follow-Up Visit 
The Follow-up visit will be conducted in person or via the telephone 4 weeks after the EOT visit. 
The following activities/procedures will be performed: 
•
AE assessment
•
RBC transfusions and ESA rescue
•
Therapeutic phlebotomy
•
MACE endpoint questionnaire.
•
Recording of concomitant medications
9.3.11 Unscheduled Visits 
Unscheduled assessments may be conducted at any time as medically warranted.  The following 
activities/procedures will be performed. At a minimum,  
•
MACE Endpoint Questionnaire
•
AE assessments
•
Any other procedures that are medically warranted at the discretion of the Investigator
9.3.12 End of Study Subject Status  
The End of Study (EOS) assessment documents the subject status at the global study completion or at 
the time of subject withdrawal of consent or when subject is deemed LTFU or upon death. The table 
below outlines how to handle each subject based on their status.  
The following activities/procedures will be performed. At minimum, 
•
EOS subject status
Subject Status 
Global Study Completion 
Subject on Study Medication (includes those 
on temporary interruption) at time of global 
study completion 
•
Perform EOT visit
•
Perform the Follow-up visit 4 weeks after
EOT and include EOS subject status

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Subject permanently discontinued study 
medication and continues to be followed in 
the study 
Optimal data collection would include the 
following assessments: 
•
EOS subject status (must collect at
minimum)
•
MACE Endpoint Questionnaire
•
AE Assessment
NOTE:  EOT and the Follow-up visit 4 
weeks after EOT visit to be performed at time 
study medication is permanently 
discontinued. 
Subject Lost to Follow-up 
Work with third party vendor to ascertain 
vital status and complete EOS subject status. 
If subject-site contact is reestablished and 
possible, collect available information for 
EOS subject status.  
Subject Withdrawn Consent 
Complete the EOS subject status form at the 
time of withdrawal of consent, absolute 
refusal of ALL methods of MACE and health 
status follow-up. 
Subject Death 
Complete the EOS subject status form at the 
time of death (see Section 10 Adverse Events 
for more details on other actions related to 
reporting a death).   
 
Study Medication Stopping Rules 
Study medication must be permanently discontinued if a subject meets one of the criteria in 
Table 2 below 
Table 2. 
Study Medication Stopping Rules 
ALT or AST >3x ULN and total bilirubin >2x ULN 
Permanently Discontinue Treatment 
ALT or AST >3x ULN and INR >1.5 
Permanently Discontinue Treatment 
ALT or AST >8x ULN 
Permanently Discontinue Treatment 
ALT or AST remains >5x ULN over 2 weeks* 
Permanently Discontinue Treatment 
ALT or AST >3x ULN with symptoms including e.g., 
fatigue, nausea, vomiting, right upper quadrant pain, 
fever, rash or eosinophilia 
Permanently Discontinue Treatment 
* Re-challenge generally should be avoided with ALT or AST >5 times ULN unless there are no other good
therapeutic options. 

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ALT: alanine transferase; AST: asparagine transferase; INR: international normalized ratio; ULN: upper limit of 
normal  
See Section 10.1.1, Adverse Events for reporting requirements related to a subject being 
permanently discontinued based on meeting the laboratory abnormalities list above in Table 2. 
10 ADVERSE EVENTS 
Definitions 
10.1.1 Adverse Events 
For the purposes of this study, an AE is any untoward medical occurrence (including an 
abnormal laboratory finding) that occurs in the protocol-specified AE reporting period; the event 
does not necessarily have a causal relationship with that treatment or usage.  
An AE includes medical conditions, signs, and symptoms not previously observed in the subject 
that emerge during the protocol-specified AE reporting period, including signs or symptoms 
associated with pre-existing underlying conditions that were not present prior to the AE reporting 
period. 
Adverse events therefore include the following: 
•
All AEs, whether suspected to be causally related to study medication or otherwise
•
All AEs secondary to any medication overdose, medication error, abuse, withdrawal,
sensitivity, or toxicity
•
Illnesses apparently unrelated to study medication, including the worsening of a pre-
existing illness (see paragraph below on Pre-existing Conditions)
•
Injury or accidents.  Note that if a medical condition is known to have caused the injury
or accident (eg, a fall secondary to dizziness), the medical condition (dizziness) and the
accident (fall) should be reported as 2 separate AEs.
•
Abnormalities in physiological testing or physical examination findings that require
clinical intervention or further investigation (beyond ordering a repeat [confirmatory]
test)
•
Laboratory abnormalities that require clinical intervention or further investigation
(beyond ordering a repeat [confirmatory] test) unless they are associated with an already
reported clinical event.  Laboratory abnormalities associated with a clinical event
reported as an AE (eg, elevated liver enzymes in a subject with jaundice) should be
described under ‘Comments’ on the report of the clinical event rather than reported as
separate AEs.
The following guidelines are to be used when reporting AEs for this study: 
Medical Diagnoses – Whenever possible, a medical diagnosis term should be used to report AEs 
instead of signs and symptoms due to a common etiology, as determined by qualified medical 
study staff.  For example, pneumonia should be the reported AE term, instead of fever and 
dyspnea, when the diagnosis has been established.  Signs and symptoms should be reported as 

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event terms only when the medical diagnosis remains unknown, and revised to a medical 
diagnosis term once it has been established. 
Procedures – Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as AEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE.  For example, an acute 
appendicitis that begins during the AE reporting period should be reported as the AE and the 
resulting appendectomy noted under ‘Comments’. 
Pre-planned therapeutic procedures not associated with a new medical condition or worsening 
pre-existing condition should not be reported as AEs (with the exception of kidney transplant, 
see below). 
Pre-existing Conditions – In this study, a pre-existing condition (ie, a disorder present before 
the AE reporting period started and noted on the pretreatment medical history/physical 
examination form) should not be reported as an AE unless the condition worsens or episodes 
increase in frequency during the AE reporting period. 
Abnormal Test Findings – All laboratory test results will be reviewed by the Investigator.  The 
Investigator will utilize his/her judgment in determining if out of range laboratory values are 
clinically significant and will denote this using the abbreviation “CS” on the laboratory report for 
source documentation.  Laboratory tests that are labeled as clinically significant should be 
reported as AEs, either separately or as part of a description of a symptomatic AE.  If there are 
significant changes in a laboratory report from a previous visit that are determined to be 
clinically significant, these should also be reported as AEs.  Any abnormal laboratory value 
which requires treatment or further diagnostic testing and/or results in discontinuation from study 
should be reported as an AE.  An expected laboratory abnormality from a condition that is part of 
the medical history is not considered clinically significant for the purposes of the study unless it 
represents a worsening of the condition. 
Abnormalities in ALT, AST and Total Bilirubin - Abnormalities in ALT, AST and Total 
Bilirubin should be reported to the Sponsor’s Medical Monitor or CRO designee within 24 hours 
of awareness as SAE with “medical significance” criteria selected, if the following conditions are 
met: 
•
New elevation in ALT or AST > 3 times ULN, with or without an elevation of total
serum bilirubin > 2 times ULN; AND
If new elevations in ALT or AST > 3 times ULN, without an elevation of total serum bilirubin 
>2 times ULN are identified, the following steps are to be taken:
•
Temporary discontinuation of Investigational Medicinal Product (IMP);
•
Repeat testing of ALT, AST, ALP, and total bilirubin, should be completed within 48 to
72 hours to confirm the abnormalities and to determine trend;
•
IMP should not be resumed until monitoring indicates abnormalities have resolved or
have stabilized.
Details on the management of subjects with other ALT and AST abnormalities are further 
described in Section 9.4, Study Medication Stopping Rules. 

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Worsening of Anemia – In this study, it is possible that some subjects may experience a 
worsening of anemia.  As the primary endpoint of this study assesses Hb response, worsening of 
anemia is captured as part of this efficacy parameter.  Worsening of anemia should not be 
considered an AE unless the worsening of anemia is associated with a cause other than the 
subject’s CKD. 
Transplantation – During this long-term study, it is anticipated that some subjects may receive a 
kidney transplant. These events will not be recorded as AEs. Subjects will discontinue study 
medication for receipt of a kidney, other solid organ, hematopoietic stem cell or bone marrow 
transplant and should continue with the Schedule of Activities and safety assessments as described in 
Section 7.5.5.2, Permanent Discontinuation of Study Medication. 
Malignancy – During this long-term study, some subjects may develop a newly diagnosed 
malignancy or a recurrence of a malignancy. At the discretion of the Investigator, these subjects may 
continue study medication (vadadustat or darbepoetin alfa). For reporting of adverse events of 
malignancy, see Section 10.1.2 Serious Adverse Events. 
Renal-Related Events - Some subjects will experience a progression of their CKD over the 
course of this study as part of the natural course of the disease.  In addition, the study population 
is prone to experience acute, transient loss of kidney function of different etiologies, sometimes 
concomitantly complicated by progression of CKD. 
To ensure consistent reporting of renal events, the following guidelines are to be used when 
reporting a renal-related AE: 
•
The following situations should always be reported as SAEs with seriousness criterion
“medically important,” if no other seriousness criteria are met (see Section 10.1.2,
Serious Adverse Events):
o
Progression of CKD leading to chronic dialysis: When a subject undergoes transition
to chronic maintenance dialysis an SAE should be reported using the verbatim term
of “end-stage renal disease”, with the outcome denoted as recovered with sequelae of
chronic dialysis.
o
Any medical event requiring transient acute dialysis: When a subject  undergoes
transient acute dialysis, an SAE should be reported using the verbatim term reflecting
the indication for the dialysis. Examples of verbatim AE terms include: hyperkalemia,
volume overload, acute kidney injury, and uremia.
o
Kidney transplantation: When a subject  receives a kidney transplant, an SAE should
be reported using the verbatim term “Progression of CKD”, with the outcome denoted
as recovered with sequelae of “kidney transplant.”
•
The following situations will be reported as SAEs if they meet seriousness criteria
(see Section 10.1.2, Serious Adverse Events); otherwise, they should be reported as AEs:
o
Acute kidney injury not requiring dialysis – The reported AE term should reflect the
etiology for the impairment of the renal function.  Non-specific AE terms such as
“Decreased eGFR” or “Increased creatinine” should be avoided whenever the
underlying etiology is known.

Examples of verbatim AE terms for prerenal impairment include:  hypovolemia,
hepatorenal syndrome, and heart failure

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
Examples of verbatim AE terms for intrarenal impairment include:  acute tubular
necrosis, acute interstitial nephritis, and glomerulonephritis

Examples of verbatim AE terms for postrenal impairment include:
hydronephrosis, pelvicaliectasis, and urinary tract obstruction.
o
Progression of CKD not requiring dialysis – If permanent loss of renal function due to
underlying CKD has occurred, the reported AE term should reflect the underlying
etiology.  Non-specific terms such as “Decreased eGFR,” “Increased creatinine,” or
“Worsening CKD” should be avoided whenever the underlying etiology is known.
Examples of verbatim AE terms include:  worsening lupus nephritis, worsening
diabetic kidney disease, and worsening glomerulonephritis
o
Medical conditions related to CKD that occur without acute kidney injury or
progression of CKD – If there is no decline in kidney function, the medical
complication of CKD itself should be reported. AE terms such as “Progression of
CKD” or “Acute Kidney Injury,” should be avoided when there is no decline in
kidney function, Examples of AE terms include:  edema and hyperkalemia.
10.1.2 Serious Adverse Events 
Each AE is to be classified by the Investigator as SERIOUS or NONSERIOUS.  An AE that 
meets 1 or more of the following criteria/outcomes is classified as serious: 
•
Death
•
Life-threatening (see paragraph below on life-threatening)
•
In-patient hospitalization or prolongation of existing hospitalization (see paragraph below
on hospitalization)
•
Persistent or significant disability/incapacity (see paragraph below on disability)
•
Congenital anomaly/birth defect
•
Is considered a medically important event not meeting the above criteria, but which may
jeopardize a subject, or may require medical or surgical intervention to prevent one of the
criteria listed in this definition.
In addition to the above criteria for classifying AEs as serious, the following situations will also 
be classified as serious for purposes of this study: 
•
Dialysis or Transplantation - Events requiring transition to chronic, ongoing dialysis, or
requiring an acute transient course of dialysis, or requiring an immediate kidney
transplantation (ie, not pre-planned) will be classified as serious.  Guidance for the
reporting of these events is provided in Section 10.1.1, Adverse Events.
•
Malignancies – Newly diagnosed malignancies or a recurrence of a malignancy should
be reported as an SAE with the seriousness criterion “medically important” if no other
seriousness criteria are met. If a subject develops basal cell carcinoma of skin, squamous
cell carcinoma, or cervical carcinoma in situ during the study, or has worsening of these
events from Baseline, the Investigator will determine if the event is reported as an AE or
SAE.

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•
Designated Medical Events - The sponsor maintains a list of designated medical
events  (DME) that they will always classify as serious adverse events.   If an event on
the DME list is reported as an AE additional information on the event (e.g. investigator
confirmation of seriousness, causality) will be requested from the Investigator.
Serious also includes any other event that the Investigator or Sponsor judges to be serious.  If 
there is any doubt whether the information constitutes an AE or SAE, the information is to be 
treated as an SAE. 
The Sponsor has a list of events that they classify as “always serious” events. If an AE is reported 
that is considered to be an event per this classification as “always serious”, additional information on 
the event may be requested. 
Life-threatening – Any event in which the subject was at risk of death at the time of the event; 
“life-threatening” does not refer to an event which hypothetically might have caused death if it 
were more severe. For example, drug-induced hepatitis that resolved without evidence of hepatic 
failure would not be considered life threatening, even though drug-induced hepatitis of a more 
severe nature can be fatal. 
Hospitalization – Hospitalization is defined as an overnight admission with observation of a 
minimum of 24 hours.  A hospitalization planned before the start of the study for a pre-existing 
condition that has not worsened during the AE reporting period does not constitute an SAE 
unless an untoward event occurs related to the procedure (eg, elective hospitalization for a total 
knee replacement due to a preexisting condition of osteoarthritis of the knee that has not 
worsened during the course of the study). 
Disability – Defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
 Eliciting Adverse Event Information 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study subject.  In addition, each study subject will be questioned about AEs at each visit 
following the initiation of treatment. 
 Reporting 
Each AE is to be classified by the Investigator as SERIOUS or NONSERIOUS. 
All AEs that occur in study subjects during the AE reporting period specified in the protocol 
must be reported, whether or not the event is considered related to study medication (vadadustat 
or darbepoetin alfa). 
10.3.1 Reporting Period 
The AE reporting period for this study begins  from time of randomization through global study 
completion. 
In addition, any AE that occurs subsequent to the AE reporting period that the Investigator 
assesses as related to the study medication should also be reported as an AE. 
10.3.2 Reporting AEs 
NONSERIOUS AEs are to be reported on the AE CRFs. 

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10.3.3 Reporting SAEs 
Any SAE, regardless of causal relationship, must be reported to the Sponsor’s Medical Monitor 
or CRO designee within 24 hours after the Investigator becomes aware of the SAE.  Compliance 
with this time requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
The initial SAE report should be completed as fully as possible but should contain, at a minimum: 
•
Subject number/ID, sex, and age/date of birth
•
The date of report
•
Name of the reporter
•
Name of the suspected medicinal product
•
A description of the event, including event term(s), seriousness criteria, and a clinical
summary of the event
•
Causality assessment.
Information about all SAEs (either initial or follow-up information) should be collected and 
recorded in English on the electronic SAE Report Form within the electronic data capture (EDC) 
system.  The Investigator must assess the relationship to each specific component of the study 
medication.  If the event meets serious criteria and it is not possible to access the EDC system, a 
paper SAE Report Form should be sent to the CRO via email or fax or the Investigator will call 
the CRO SAE hotline within 24 hours of being made aware of the SAE (reference the site 
manual for contact information).  When the EDC system becomes available, the SAE 
information must be entered within 24 hours of the system becoming available. 
The Investigator must report follow-up information relating to an SAE to the Sponsor’s Medical 
Monitor or CRO designee within 24 hours of awareness by the Investigator by updating the 
electronic CRF with the new information or by submitting a paper SAE Report Form in the event 
that the EDC is not available.  When the EDC system becomes available, the SAE information 
must be entered within 24 hours.  The subject should be observed and monitored carefully until 
the condition resolves or stabilizes. 
All deaths are to be thoroughly investigated and reported.  Autopsy reports and death certificates 
are to be obtained, if possible. 
The Sponsor and/or its designee are responsible for reporting SAEs to all applicable regulatory 
agencies and the central ethics committees within the required timeline. 
The Investigators are responsible for submitting required safety information to their local 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) as per local 
regulations.  This information includes, but is not limited to, any safety alert letter received from 
the Sponsor and any SAEs occurring at their investigative site. 
10.3.4 Reporting Study Endpoints 
Investigators will be counseled to report any event that they assess as potentially being a study 
endpoint requiring adjudication (death, myocardial infarction, stroke, thromboembolic events, 
and hospitalization for HF).  All study endpoint events will be submitted blinded to the EAC for 

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adjudication.  To protect the integrity of the trial, already adjudicated events will not be 
unblinded or reported to either Health Authorities (HAs) or Investigators as safety reports unless 
otherwise requested by HAs or Ethics Committees.  After study completion, these events will be 
included in the final analysis which will be unblinded and submitted to HAs with the study 
report. 
10.3.5 Relationship to Study Medication 
The causal relationship of the AE to study medication (vadadustat or darbepoetin alfa) will be 
assessed by both the Investigator and the Sponsor. 
The assessment of causal relationship to study medication should be evidence-based, and not based 
on the premise that all AEs are possibly causally related to study medication until proven otherwise. 
Examples of evidence that would suggest a causal relationship between the study medication and the 
AE include the occurrence of an AE that is uncommon and known to be strongly associated with 
drug exposure (eg, angioedema, hepatic injury, and Stevens-Johnson syndrome) or an AE that is 
uncommon in the population exposed to the drug. 
The causal relationship of the AE is assessed using a binary system, and AEs are classified as 
either ‘related’ or ‘unrelated’: 
Related: There is ‘reasonable possibility’ that the drug caused the AE. The AE follows a 
reasonable temporal sequence from the time of drug administration. There is supportive evidence 
(facts) to suggest a possible causal relationship, irrespective of the degree of certainty between 
the observed AE and the drug. 
Unrelated: An AE does not follow a reasonable temporal sequence from administration of the 
product and/or there is no reasonable possibility that the drug caused the AE. This assessment 
includes situations where the AE is related to other factors such as the subject’s clinical state, 
other therapeutic interventions, or concomitant drugs administered to the subject. 
Default assessments using the “related” category without supportive evidence for a causal 
relationship to study medication is generally uninformative and does not contribute meaningfully 
to the development of the safety profile of the drug or to subject protection. 
Investigators are encouraged to choose the most plausible cause for the event(s) from the 
following list: medical history, lack of efficacy/worsening of treated condition, study medication, 
other treatment (concomitant or previous), withdrawal of study medication, administration error, 
protocol-related procedure, and others (specify). 
10.3.6 Severity 
The Investigator will assess each AE as either MILD, MODERATE, or SEVERE using the 
following guidelines to describe the maximum severity of the AE: 

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MILD:  Does not interfere with subject's usual function 
MODERATE:  Interferes to some extent with subject's usual function 
SEVERE:  Interferes significantly with subject's usual function 
Note that a severe AE is not necessarily a serious AE.  For example, a headache may be severe 
in intensity, but would not be classified as serious unless it met 1 of the criteria for serious events 
listed above. 
10.3.7 Follow-Up of Unresolved Events 
All AEs should be followed until they are resolved or the Investigator assesses them as chronic 
or stable or the subject’s participation in the trial ends (ie, until a final report is completed for 
that subject). 
In addition, all SAEs and those nonserious events assessed by the Investigator as possibly or 
probably related to the study medication should continue to be followed even after the subject's 
participation in the trial is over.  Such events should be followed until they resolve or until the 
Investigator assesses them as “chronic” or “stable”.  Resolution of such events is to be 
documented on the appropriate CRF. 
 Exposure In Utero 
A pregnancy in a female subject must be confirmed by a positive serum β human chorionic 
gonadotropin (β-HCG) test. 
The study medication should be immediately discontinued once the pregnancy of a female study 
participant has been confirmed. 
If any study participant becomes or is found to be pregnant while receiving a study medication 
(vadadustat or darbepoetin alfa) or within 30 days of discontinuing the study medication, the 
pregnancy must be recorded on the Pregnancy Reporting Form/Exposure in Utero Form in the 
EDC within 24 hours of awareness of the pregnancy or the Investigator will call the CRO SAE 
hotline within 24 hours of being made aware of the pregnancy. 
Pregnancy during this time frame of the female partner of a male subject should also be reported. 
The Pregnancy Reporting Form/Exposure in Utero Form must be completed with all known 
information regarding the pregnancy at the time of reporting.  Investigative site personnel will 
update the form with additional information regarding the pregnancy and the outcome of the 
pregnancy as it becomes available until the outcome of the pregnancy is reported. 
The Investigator will follow the subject (or female partner of a male subject) until completion of 
the pregnancy.  If the outcome of the pregnancy meets the criteria for classification as a SAE (ie, 
spontaneous abortion, stillbirth, neonatal death within 1 month of birth, or congenital anomaly 
[including that in an aborted fetus]), the Investigator will also follow the procedures for reporting 
a SAE within 24 hours of awareness.  A pregnancy in and of itself is not considered an AE; 
however, unexpected complications are considered AEs. 

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Additional information about pregnancy outcomes follows: 
•
Note that “spontaneous abortion” includes miscarriage and missed abortion.
•
All neonatal deaths that occur within 1 month of birth should be reported, without regard
to causality, as SAEs.  In addition, any infant death after 1 month that the Investigator
assesses as related to the in utero exposure to the study medication should also be
reported.
•
In the case of a live birth, the “normality” of the newborn can be assessed at time of birth.
•
The “normality” of an aborted fetus can be assessed by gross visual inspection unless
there are pre-abortion laboratory findings suggestive of a congenital anomaly.
 Special Situations 
Certain safety events, called ‘Special Situations’, that occur in association with study 
medication(s) may require reporting.  These Special Situations include, but are not limited to, the 
following: 
•
Overdose of the medicinal product
•
Darbepoetin alfa Overdose: The  PI or SmPC should be referenced for information on
darbepoetin alfa overdosing.
•
Vadadustat Overdose: There is no known antidote for vadadustat.  In cases of
suspected overdose, Subjects should be treated per standard medical practice based on
the Investigator’s judgment and dose delays and reductions may be implemented as
necessary.
Chronic overdosage with vadadustat may result in excessive production of red blood
cells and polycythemia.  Polycythemia can be potentially life threatening and may
result in severe thrombosis and death (known as hyperviscosity syndrome).  If
hyperviscosity syndrome is observed, vadadustat should be discontinued and standard
treatment for polycythemic hyperviscosity syndrome should be initiated (i.e.,
phlebotomy).
•
Suspected abuse/misuse of the medicinal product
•
Inadvertent or accidental exposure to the medicinal product
•
Medication error involving the medicinal product (with or without subject/patient
exposure to the Sponsor medicinal product, eg, name confusion)
•
Drug-drug interaction.
Special situations should be reported on the Special Situations CRF whether they result in an 
AE/SAE or not.  Special situations with associated AE/SAE should also be reported on the 
corresponding AE/SAE forms, following applicable AE or SAE process. 
11 DATA ANALYSIS 
Data collected throughout the study will be summarized using descriptive statistics and listed in 
by-subject listings.  Continuous variables will be summarized using number of subjects with 

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data, mean, standard deviation, median, minimum, and maximum.  For categorical variables, the 
number and percentage of subjects in each category will be tabulated.  Summaries will be 
provided by treatment group within appropriate analysis populations (as defined in Section 11.2, 
Study Analysis Populations) and by time point/time period as appropriate. 
For Hb, Baseline will be calculated as the average of the central laboratory Hb measurements of 
samples taken at the screening visit closest to the date of randomization and the measurement taken 
at randomization.  For other parameters, unless otherwise specified, Baseline will be defined as 
the last available value prior to the first dose of study medication. 
Hemoglobin values as assessed through the central laboratory will be used for efficacy and safety 
evaluations; local HemoCue Hb values will be used only for dose adjustments. 
 Sample Size Determination 
The goal of this study is to demonstrate the efficacy and safety of vadadustat compared with 
darbepoetin alfa for the maintenance treatment of anemia in subjects with anemia secondary to 
NDD-CKD after conversion from current ESA therapy.  The sample size is calculated to ensure 
sufficient power for testing both efficacy in this trial and the primary safety endpoints as part of a 
pooled analysis. 
11.1.1 Sample Size for the Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the mean change in Hb from Baseline (mean 
pretreatment Hb) to the average Hb over the primary evaluation period (mean Hb from Weeks 
24-36).
The primary efficacy objective of this study is to show that vadadustat is noninferior to 
darbepoetin alfa within the noninferiority margin.  Noninferiority will be established based on a 
margin of -0.75 g/dL (for vadadustat minus darbepoetin alfa). 
For the primary efficacy analysis in this study, it is assumed that the mean change from Baseline 
in Hb for vadadustat will be the same as for darbepoetin alfa, and the common standard deviation 
for the mean change from Baseline is assumed to be 1.5 g/dL.  Noninferiority will be established 
based on a 2-sided 95% confidence interval for the difference between the vadadustat group and 
darbepoetin alfa and using a noninferiority margin of -0.75 g/dL.  With these assumptions and 
approximately 925 subjects per treatment group for the primary efficacy analysis, the 
noninferiority assessment will have > 90% power. 
11.1.2 Sample Size for the Primary Safety Endpoint 
The primary safety endpoint is the time from randomization date to the first (adjudicated) MACE 
+1.
The primary safety analysis will be based upon all events that accrue across the 2 NDD-CKD 
studies (Studies AKB-6548-CI-0014 and AKB-6548-CI-0015).  The sample size with respect to 
the MACE endpoint has been determined based on the number of events needed to demonstrate 
noninferiority of the 2-sided 95% confidence interval for the hazard ratio 
(vadadustat/darbepoetin alfa).  It has been calculated that 631 events will be required overall to 
have 80% power to establish noninferiority with a margin of 1.25, and >90% power to establish 
noninferiority with a margin of 1.3, assuming no difference between treatment groups.  The 

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power is >90% to establish a noninferiority margin of 1.25 if the hazard ratio is 0.95 favoring 
vadadustat.  A MACE rate of 10% annually is anticipated in both treatment arms based on a 
comprehensive review of available epidemiology and prospective clinical studies in the field.   
The number of MACE in each study will be a function of the actual pattern and size of enrollment as 
well as the duration of follow-up. 
 Study Analysis Populations 
The following analysis populations will be used in this study: 
•
Randomized population:  defined as all randomized subjects
•
Full analysis population:  defined as randomized subjects receiving 1 or more doses of
study medication and had at least one Hb assessment during the primary efficacy
evaluation period. This population will be analyzed based upon the randomized
treatment.
•
Per protocol (PP) population:  defined as all randomized subjects who received study
medication (vadadustat or darbepoetin alfa) during the primary evaluation period, had at
least 2 Hb assessments during the primary evaluation period, received no rescue therapy
(with ESA or RBC transfusion) in the 8 weeks prior to the evaluation period, and have no
protocol deviations affecting the primary endpoint analyses. Protocol deviations leading
to exclusion from the per protocol population will be specified prior to database lock on a
blinded basis and recorded in a separate document.
•
Safety population:  defined as all subjects who received at least 1 dose of study
medication.  This population will be analyzed based upon the actual treatment received.
Efficacy analyses will utilize the randomized, full analysis, and PP populations while safety 
analyses (including MACE) will utilize the randomized population. 
 Analysis of Demographic and Pretreatment Variables 
Descriptive statistics will be generated for demographic and pretreatment variables for each 
analysis population defined in Section 11.2, Study Analysis Populations. 
Medical history terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by System Organ Class and Preferred Term for each treatment 
group based on the safety population. 
 Disposition of Subjects 
The number and percentage of subjects randomized and included in each analysis population will 
be summarized by treatment and overall.  Reasons for excluding subjects from the analysis 
populations will be presented in a by-subject listing. 
The number of randomized subjects who completed each period of study medication treatment 
(maintenance and long-term treatment), discontinued from study medication early, and 
completed or discontinued from the study and reasons for discontinuation will be summarized by 
treatment group and overall. 

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 Missing Data 
Subjects who stop study medication treatment after randomization and prior to completion of the 
study should continue with planned study visits and assessments unless they withdraw consent 
for participation in the study.  Similarly, subjects will continue with study medication and study 
procedures following the initiation of rescue therapy, with the exception that the subjects must 
discontinue taking study medication while receiving an ESA rescue therapy.  Treatment with 
study medication should be resumed after an appropriate interval following the ESA rescue 
therapy as described in Section 8.4.7, Rescue Therapy.  Data will continue to be collected 
following initiation of the rescue therapy as per the study Schedule of Activities. 
All data collected during the study, including at any point after the initiation of rescue therapy as 
well as after early discontinuation of study medication treatment, will be used for the primary 
analysis as well as main analyses of all efficacy endpoints.  Sensitivity analyses will be 
performed to assess an impact of rescue therapy on study conclusions. 
In the primary analysis of the primary efficacy endpoint, all available qualifying Hb 
measurements during the pretreatment period and during the primary evaluation period 
(Weeks 24-36) will be used to calculate an average Hb during each period respectively, for each 
subject.  For any subject with no available Hb measurements during the primary evaluation 
period, multiple imputation  will be used to impute a  change from Baseline value (details are 
provided in the SAP). In an analogous manner, an average Hb will be calculated for the 
secondary evaluation period (Weeks 40-52) for each subject. Given the design of this study 
where the subjects will continue to be assessed after early study medication discontinuation, it is 
expected that there will be only a minimal amount of missing data and the primary analysis 
should not be substantially affected by the imputation. 
All data pertaining to the MACE endpoint collected at any point during the study, both during 
study medication treatment and post study medication treatment discontinuation, and regardless 
of the rescue therapy, will be used for the primary analysis of the MACE endpoint and its 
individual components. 
Unless stated otherwise in the SAP, missing data for all other secondary efficacy and safety 
endpoints will not be imputed and the analysis will be based on observed data.  For certain 
responder-type binary endpoints, subjects with no available data will be classified into one of the 
categories as described in the relevant sections of the SAP 
 Efficacy Analyses 
The primary efficacy endpoint as well as all key and other secondary endpoints will be 
summarized using descriptive statistics by treatment group, as well as by study visit and/or 
analysis period as appropriate.  Mean values of Hb as well as selected other efficacy parameters 
will be plotted across study visits/periods by treatment group. 
11.6.1 Analysis of Primary Efficacy Endpoint  
The primary efficacy endpoint is defined as the mean Hb change from Baseline (mean 
pretreatment Hb) to the mean Hb from Weeks 24-36 (inclusive). 

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11.6.1.1 Primary Analysis of Primary Efficacy Endpoint 
The primary analysis will use an analysis of covariance (ANCOVA) with multiple imputation, 
stratified by the randomization strata and using Baseline Hb as the covariate.   
A 2-sided 95% confidence interval (CI) will be calculated for the difference between treatment 
groups (vadadustat minus darbepoetin alfa). 
Noninferiority of vadadustat will be established if the lower limit of this CI is ≥-0.75g/dL. 
The primary analysis will be performed using the randomized population and the assigned 
treatment as described in Section 11.2, Study Analysis Populations.  All data collected during the 
study for subjects included in the randomized population at the time of analysis, including data 
collected at any point after the initiation of rescue therapy as well as after early discontinuation 
of study medication treatment, will be used for the primary analysis.  Missing data will be 
handled using multiple imputation methodology as described in the SAP.  
11.6.1.2 Sensitivity Analyses of Primary Efficacy Endpoint 
•
The following sensitivity analyses will be conducted: Primary analysis will be repeated
using the full analysis population.
•
Primary analysis will be repeated using only subjects with available Hb data during the
primary evaluation period, ie, excluding subjects with no available data during the
primary evaluation period.
•
Primary analysis will be repeated using the PP population with the actual treatment
received.
•
Primary analysis will be repeated with alternate approaches to imputation of missing data
as described in the SAP.
•
Primary analysis will be repeated with imputation of data which may have been affected
by a subject’s having received any form of rescue (transfusion of ESA). Details are
provided in the SAP.
11.6.2  Secondary Efficacy Analyses   
Secondary efficacy endpoints analyses will be performed using the randomized and full analysis 
populations and the assigned treatment as described in Section 11.2, Study Analysis Populations.  
Analysis for the key secondary efficacy endpoints will be repeated using the PP population with 
the actual treatment received. 
11.6.2.1 Key Secondary Efficacy Analyses  
Mean change in Hb value between Baseline and the secondary evaluation period (Weeks 40-52) 
will be analyzed using the same methodology as specified for the primary efficacy endpoint. 
Sensitivity analyses similar to those of the primary efficacy endpoint will be performed and 
details will be provided in the SAP. 

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11.6.3 Subgroups 
Analyses of the primary efficacy endpoint and key secondary efficacy endpoints will also be 
performed using the randomized and full analysis populations, using the assigned treatment, for 
subgroups based on the following: 
•
Hb stratification level
•
NYHA CHF stratification level
•
Due to use of different target Hb levels in the U.S. vs. non-US, the endpoints will also be
analyzed for subsets based on the target Hb level:
o
the U.S. subset will be assessed due to the target Hb range being 10.0-11.0 g/dL in the
U.S.
o
the combined EU and ROW  (non-US) subset will be assessed since the target Hb
range is 10.0-12.0 g/dL in these two Regions
•
Geographic region (U.S., EU, ROW)
•
Age
•
Gender
•
Race
Safety Analyses
All analyses of safety data will use the randomized population. 
11.7.1 Analysis of MACE and Expanded MACE Components 
The primary safety endpoint, time to the first adjudicated MACE, will be analyzed as [date of the 
first MACE minus the date of randomization +1].  A MACE is defined as all-cause mortality, 
non-fatal myocardial infarction, or non-fatal stroke.  Subjects who have not experienced a 
MACE by study closure will be censored on the date of their last study assessment.  The hazard 
ratio (vadadustat/darbepoetin alfa) and its 95% confidence interval will be obtained from a 
stratified Cox proportional hazards model.  As this study has not been designed to provide a 
stand-alone assessment of MACE, this analysis will be considered a descriptive analysis.  A 
similar analysis as described for the primary analysis of the MACE endpoint will be performed 
with censoring of subjects 4 weeks following discontinuation of study medication if they did not 
have a MACE prior to that time. 
An additional analysis as described for the primary analysis of the MACE endpoint will be 
performed with censoring at time of chronic dialysis initiation for subjects who have progressed 
to chronic dialysis and who did not have a MACE prior to that time. 
The following safety endpoints will also be summarized using time to event methods as for 
MACE: 
1) Individual components (all-cause mortality, non-fatal myocardial infarction, non-fatal
stroke) of MACE
2) Thromboembolic events (defined as arterial thrombosis, DVT, PE, or vascular access
thrombosis)
3) Hospitalization for heart failure

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4) Expanded MACE, defined as all-cause mortality, non-fatal myocardial infarction, non-
fatal stroke, hospitalization for HF, or thromboembolic event
For these endpoints the incidence ("yes"/"no") of the endpoint will be presented for each 
treatment arm.  Kaplan-Meier curves will be presented for each endpoint as the time of endpoint 
free survival (ie, time until endpoint or death). 
The primary MACE analysis will be based upon all events that accrue over the 2 NDD-CKD 
studies (Studies AKB-6548-CI-0014 and AKB-6548-CI-0015) (see Section 11.1.2,Sample Size 
for the Primary Safety Endpoint). 
The SAP for this pooled MACE assessment in NDD-CKD subjects provides details of the 
primary analyses for MACE, for individual components of MACE, and for an expanded version 
of MACE.   Details of sensitivity analyses and subgroup analyses are also provided in the MACE 
SAP. 
11.7.2 Analysis of Adverse Events 
Adverse events will be summarized using the number and percentage of subjects with AEs for 
all subjects in the safety population. Summaries will also be provided for subgroups including 
Region, Age, Gender and Race. 
All AEs will be coded using MedDRA.  Treatment-emergent and post-treatment AEs will be 
summarized by System Organ Class and Preferred Term for each treatment group.  Adverse 
events will also be summarized by their maximum severity. 
Summaries will also be provided for the following types of AEs: 
•
SAEs
•
Related AEs (including all categories for relationship to study medication other than
“Unrelated”, as determined by the Investigator)
•
AEs leading to early discontinuation of study medication.
11.7.3 Remaining Safety Endpoints 
The analysis of the following safety endpoints will be detailed in the SAP: 
The analysis of proportion of subjects with Hb >12.0 g/dL, >13.0 g/dL, or >14.0 g/dL 
post-Baseline will classify a subject as a “yes” if: 
•
Any value Hb >12.0 g/dL at any time after Day 1
•
Any confirmed value Hb >12.0 g/dL at any time after Day 1
•
Any value Hb >13.0 g/dL at any time after Day 1
•
Any confirmed value Hb >13.0 g/dL at any time after Day 1
•
Any value Hb >14.0 g/dL at any time after Day 1
•
Any confirmed value Hb >14.0 g/dL at any time after Day 1.
A Hb value above a set threshold will be considered as confirmed if there are 2 consecutive 
values above that threshold.  The second of the 2 consecutive assessments should be done at 

Protocol No. AKB-6548-CI-0015 
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most 12 weeks after the first assessment.  Subjects with no available data post-Baseline will be 
excluded from this analysis.  All other subjects will be classified to the “no” category. 
The analysis of proportion of subjects with any Hb increase >1.0 g/dL within any 2-week 
interval or >2.0 g/dL within any 4-week interval post-Baseline will classify a subject as a “yes” 
if at least 1 of the following criteria at any point after Day 1 is met: 
•
Hb increase >1.0 g/dL within any 2-week interval
•
Hb increase >2.0 g/dL within any 4-week interval.
Subjects with no available data post-Baseline will be excluded from this analysis.  All 
other subjects will be classified to the “no” category. 
Observed values of continuous and categorical parameters and changes from Baseline for 
continuous parameters to each study visit will be summarized descriptively for vital signs and 
clinical laboratory results.  Graphical displays of selected laboratory parameters will also be 
provided. 
Additional Assessments 
11.8.1 Concomitant Medications 
Prior and concomitant medications will be coded using World Health Organization (WHO) Drug 
dictionary. 
Prior medications will be defined as any medications that were taken before the date of the first 
dose of study medication.  Concomitant medications will be defined as any medications taken at 
any time from the date of the first dose of study medication through the date of the last dose of 
the study medication. 
11.8.2 Biomarkers 
Biomarkers (including but not limited to, hepcidin and VEGF) will be summarized descriptively 
at Baseline and by visit post-Baseline.  
11.8.3 Pharmacokinetics 
Descriptive and graphical summaries will be generated for PK measurements. 
12 DATA HANDLING AND RECORD KEEPING 
 Case Report Forms/Electronic Data Capture 
This study will utilize an EDC system to manage data collection during this trial.  The system is 
fully Code of Federal Regulations 21 part 11 compliant.  An EDC system contains certain 
functionality including, but not limited to, a graphical user interface to help facilitate data entry, 
a data validation element to check user data, and a reporting function to assist with the review 
and analysis of data.  Case report forms available through this system are required and should be 
completed for each randomized subject. 
Any form of data from the electronic system are the sole property of the Sponsor and should not 
be made available in any form to third parties, except for authorized representatives of the 
Sponsor or appropriate regulatory authorities, without written permission from the Sponsor. 

Protocol No. AKB-6548-CI-0015 
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The Investigator has ultimate responsibility for the accuracy, authenticity, and timely collection 
and reporting of all clinical, safety, and laboratory data entered in the EDC or any other data 
collection forms.  The CRFs must be signed electronically by the Investigator to attest that the 
data contained on the CRFs is true. 
In most cases, the source documents are contained in the subject’s chart at the hospital or the 
physician's office.  In these cases, data collected on the CRFs must match the data in those 
charts. 
 Record Retention 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, eg, CRFs and hospital records), all original signed informed consent forms, 
copies of all CRFs, SAE forms, source documents, detailed records of drug disposition, and 
adequate documentation of relevant correspondence (eg, letters, meeting minutes, telephone calls 
reports).  The records should be retained by the Investigator according to the International 
Conference on Harmonization (ICH), local regulations, or as specified in the Clinical Study 
Agreement, whichever is longer. 
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), the Sponsor should be prospectively notified.  The 
study records must be transferred to a designee acceptable to the Sponsor, such as another 
Investigator, another institution, or to the Sponsor.  The Investigator must obtain Sponsor’s 
written permission before disposing of any records, even if retention requirements have been 
met. 
13 QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) 
 Investigative Site Monitoring Visits 
During study conduct, the Sponsor or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practice (GCP) are being followed.  The monitors will 
review source documents to confirm that the data recorded on the CRFs is accurate.  The 
Investigator/institution will allow the Sponsor’s monitors or designees and appropriate regulatory 
authorities direct access to source documents to perform this verification. 
The investigative site may also be subject to QA audits performed by the Sponsor or companies 
working with or on behalf of the Sponsor, and/or review by the IRB/IEC, and/or to inspection by 
appropriate regulatory authorities. 
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
 Protocol Deviations 
The Investigator will not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects.  Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the Investigator will consult with the 
Sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 

Protocol No. AKB-6548-CI-0015 
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The investigative site should document all protocol deviations in the subject’s source documents.  
In the event of a significant deviation, the investigative site should notify the Sponsor or its 
designee (and IRB or IEC, as required).  Significant deviations include, but are not limited to, 
those that involve fraud or misconduct, increase the health risk to the subject, or confound 
interpretation of primary study assessments. 
14 STUDY DISCONTINUATION/INVESTIGATIVE STUDY SITE TERMINATION 
The Sponsor reserves the right to discontinue the study prior to inclusion of the intended number 
of subjects, but intends only to exercise this right for valid scientific or administrative reasons.  
After such a decision, the Investigator must contact all participating subjects within a time period 
specified by the Sponsor to inform them of the decision to discontinue the study. 
 Criteria for Premature Termination or Suspension of the Study 
The following criteria may result in either temporary suspension or early termination of the 
study: 
•
New information regarding the safety or efficacy of the study medication that indicates a
change in the known risk/benefit profile for the compound, such that the risk/benefit is no
longer acceptable for subjects participating in the study
•
Significant violation of GCP that compromises the ability to achieve the primary study
objectives or compromises subject safety.
The Sponsor reserves the right to discontinue the study for other valid administrative reasons. 
 Criteria for Premature Termination or Suspension of Investigational Study Sites 
A study site may be terminated prematurely or suspended if the study site (including the 
Investigator) is found to be in significant violation of GCP, protocol, contractual agreement, or is 
unable to ensure adequate performance of the study. 
Procedures for Premature Termination or Suspension of the Study or Investigational 
Sites 
In the event that the Sponsor elects to terminate or suspend the study or the participation of an 
investigational study site, a study-specific procedure for early termination or suspension will be 
provided by the Sponsor; the procedure will be followed by applicable investigational study sites 
during the course of termination or study suspension. 
15 ETHICS 
Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical Principles 
for Medical Research Involving Human Subjects, adopted by the General Assembly of the World 
Medical Association (2013). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws. 

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 Institutional Review Board/Independent Ethics Committee 
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, (eg, recruitment 
advertisements, if applicable) from the IRB/IEC.  All correspondence with the IRB/IEC should 
be retained in the Investigator File.  Copies of IRB/IEC approvals should be forwarded to the 
Sponsor or its designee. 
In case of substantial protocol amendment, the sponsor will obtain approval from responsible 
Regulatory Authorities before implementation. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In that 
event, the Investigator must notify the IRB/IEC and the Sponsor in writing immediately after the 
implementation. 
 Subject Information and Consent 
It is the responsibility of the Investigator to give each subject (or the subject’s acceptable 
representative), prior to inclusion in the study, full and adequate verbal and written information 
regarding the objective and procedures of the study and the possible risks involved.  The subjects 
must be informed about their right to withdraw from the study at any time. 
Furthermore, it is the responsibility of the Investigator, or a person designated by the 
Investigator, to obtain signed informed consent from each subject or the subject’s legally 
acceptable representative prior to inclusion in the study.  The Investigator will retain the original 
of each subject's signed consent form. 
The informed consent forms will be in compliance with ICH GCP, local regulatory requirements, 
and legal requirements.  The informed consent forms used in this study, and any changes made 
during the course of the study, must be prospectively approved by both the IRB/IEC and the 
Sponsor before use. 
 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority, or if the Investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of the investigational product, the Sponsor 
should be informed immediately. 
In addition, the Investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the Investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP, defined as a breach that will likely affect the 
safety or physical or mental integrity of subjects or the scientific value of the trial, that comes to 
the attention of the Investigator. 
 Subject Confidentiality 
All parties will ensure protection of subject personal data and will not include subject names on 
any Sponsor forms, reports, publications, or in any other disclosures, except where required by 
law.  In case of data transfer, the Sponsor will maintain high standards of confidentiality and 
protection of subject personal data. 

Protocol No. AKB-6548-CI-0015 
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The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy.  Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number.  As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH guidelines for GCP and to verify compliance with this protocol, the 
Sponsor requires the Investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, FDA), the Sponsor’s designated auditors, and the appropriate 
IRBs and IECs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports.  Access to a subject’s original medical records requires the specific authorization of 
the subject as part of the informed consent process. 
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s CRF). 
16 PUBLICATION OF STUDY RESULTS 
No publication or disclosure of study results will be permitted, except under the terms and 
conditions of a separate, written agreement between Sponsor and the Investigator and/or the 
Investigator’s institution.  The Sponsor must have the opportunity to review and approve all 
proposed abstracts, manuscripts, or presentations regarding this study prior to submission for 
publication/presentation.  Any information identified by the Sponsor as confidential must be 
deleted prior to submission. 
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including:  Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors. 
17 REFERENCES 
Abramson JL, Jurkovitz CT, Vaccarino V et al. Chronic kidney disease, anemia, and incident 
stroke in a middle-aged, community-based population: the ARIC study.  Kidney Int (2003) 
64(2): 610-615. 
Aranesp (package insert). Tousand Oaks, CA: Amgen, Inc.; 2017. 
Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, et al.  The effects 
of normal as compared with low hematocrit values in patients with cardiac disease who are 
receiving hemodialysis and epoetin.  N Engl J Med (1998) 339(9):584-590. 
Darbepoetin alfa: Information on darbepoetin alfa in the US is available in the package insert for 
Aranesp (Amgen, Thousand Oaks, CA; 2017); and detailed information on darbepoetin alfa in 
the EU is available on the European Medicines Agency web site. 

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Amendment 7-COL 
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Page 83 of 105 
Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al.  Normalization 
of hemoglobin level in patients with chronic kidney disease and anemia.  N Engl J Med (2006) 
355(20):2071-2084. 
FDA Guidance: Clinical Drug Interaction Studies 2017.  Available at: 
https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf. 
Goodkin DA, Fuller DS, Robinson BM, Combe C, Fluck R, Mendelssohn D, et al.  Naturally 
occurring higher hemoglobin concentration does not increase mortality among hemodialysis 
patients.  J Am Soc Nephrol (2011) 22(2):358-365. 
Iseki K and Kohagura K.  Anemia as a risk factor for chronic kidney disease.  Kidney Int (2007) 
Suppl 72:S4-9. 
Japanese Society of Nephrology.  Evidence-based clinical practice guideline for CKD 2013. Clin 
Exp Nephrol (2014) 18(3):346-423. 
Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and 
perspectives. Lancet (2013) 382(9888): 260-272.  
KDIGO CKD Working Group. KDIGO clinical practice guideline for the evaluation and 
management of chronic kidney disease. Kidney Int Suppl (2013) 3(1): 1-150. 
KDIGO.  KDIGO clinical practice guideline for anemia in chronic kidney disease.  Kidney Int 
(2012) 2(4):1-64.  Available at: 
http://www2.kidney.org/professionals/kdoqi/guidelines_ckd/p4_class_g1.htm 
Levey AS, Stevens LA, Schmid CH, et al.  A new equation to estimate glomerular filtration rate. 
Ann Intern Med (2009) 150(9):604-612. 
Locatelli F, Bárány P, Covic A, De Francisco A, Del Vecchio L, Goldsmith D, et al.  Kidney 
Disease: Improving Global Outcomes guidelines on anaemia management in chronic kidney 
disease: a European Renal Best Practice position statement.  Nephrol Dial Transplant (2013) 
28(6):1346-1359. 
McCullough PA, Barnhart HX, Inrig JK, Reddan D, Sapp S, Patel UD, Singh AK, Szczech LA, 
Califf RM. Cardiovascular toxicity of epoetin-alfa in patients with chronic kidney disease.  2013; 
37 (6): 549-58. Doi:10.1159/000351175. Epub 2013 May 25. 
Metivier F, Marchais SJ, Guerin AP, Pannier B, London GM.  Pathophysiology of anaemia: 
focus on the heart and blood vessels.  Nephrol Dial Transplant (2000) 15 Suppl 3: 14-18. 
National Institute for Health and Care Excellence (NICE).  Chronic kidney disease: managing 
anaemia. NICE clinical guideline. Published: 3 June 2015. http://nice.org.uk/guidance/ng8Nurko 
S. Anemia in chronic kidney disease: causes, diagnosis, treatment.  Cleve Clin J Med (2006)
73(3):289-297.
Nurko S. Anemia in chronic kidney disease: causes, diagnosis, treatment. Cleve Clin J Med 
(2006) 73(3):289-297. 
Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, Nizet V, and 
Johnson RS.  Regulation of iron homeostasis by the hypoxia-inducible transcription factors 
(HIFs).  J Clin Invest (2007) 117(7):1926-1932. 

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Amendment 7-COL 
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Pfeffer MA, Burdmann EA, Chen CY, et al.  A trial of darbepoetin alfa in type 2 diabetes and 
chronic kidney disease.  N Engl J Med (2009a) 361(21):2019-2032. 
Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al.  Baseline 
characteristics in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). 
Am J Kidney Dis (2009b) 54(1):59-69. 
Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al.  Correction of anemia 
with epoetin alfa in chronic kidney disease.  N Engl J Med (2006) 355(20):2085-2098. 
Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA, et al.  Erythropoietic 
response and outcomes in kidney disease and type 2 diabetes.  N Engl J Med (2010) 363(12): 
1146-1155. 
Stauffer ME and Fan T.  Prevalence of anemia in chronic kidney disease in the United States. 
PLoS One (2014) 9(1): e84943. 
Szczech LA, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, et al.  Secondary analysis 
of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes.  Kidney Int (2008) 
74(6):791-798. 
Tsubakihara Y, Nishi S, Akiba T, et al.  2008 Japanese Society for Dialysis Therapy:  Guidelines 
for renal anemia in chronic kidney disease.  Ther Apher and Dial (2010) 14(3):240-275. 
Unger EF.  FDA perspectives on erythropoiesis-stimulating agents (ESAs) for anemia of chronic 
renal failure: Hemoglobin target and dose optimization (Slide presentation from the Sep 11, 2007 
Joint Meeting of the Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety 
and Risk Management Advisory Committee).  Retrieved from 
http://www.fda.gov/ohrms/dockets/ac/07/slides/2007-4315s1-10-FDA-Unger.ppt. 
Unger EF, Thompson AM, Blank MJ, and Temple R.  Erythropoiesis-stimulating agents - Time 
for a reevaluation.  N Engl J Med (2010) 362(3):189-92. 

Protocol No. AKB-6548-CI-0015 
 
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APPENDIX A:  SCHEDULE OF ACTIVITIES 
Study Period 
Optional 
Pre-
Screen 
Screening 
Treatment Period 
Post 
Treatment 
BL/ 
rand. [a]
Year 1 
Year 2 
Year 3/Year 4 
Visit 
PS 
SV1 SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22/ 
26 
23/ 
27 
24/ 
28 
25/ 
29 
End of 
Trtmt 
Follow-
up [b] 
Week 
-8 to 0
0 
2 
4 
6 
8 
10 12 16 20 24 28 32 36 40 44 48 52 64 76 88 104 116/ 
168 
128/ 
180 
140/ 
192 
156/ 
208 
EOT [c] 
EOT 
+4
wks
[dd]
Visit Window (Days) 
±3 ±3 ±3 ±3 ±3 ±3 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±10 ±10 ±10 ±10 ±10 ±10 ±10 
±10 
±7 
±7 
Procedures/Assessments 
Informed Consent 
X [d] 
X [d] 
Pre-Screening Local Hb 
[e] 
X 
I/E Criteria [f] 
X 
X 
X 
Vital Signs [g] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics, Med 
History 
X 
Physical Exam [h] 
X 
12-Lead ECG [i]
X 
Randomization 
X 
Laboratory Procedures 
Pregnancy Test [j] 
X 
Folate and Vitamin B12 
X[k] 
Coagulation Tests [l] 
X 
C-Reactive Protein
X 
X 
X 
X 
X 
X 
Urine 
Albumin/Creatinine 
(uACR) 
X 
X 
X 
X 
X 
X 
CBC [m] with periodic 
diff  
X [k,] X 
[k,n] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Iron Indices [o] 
X[k] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chem and 
eGFR [p] 
X[k] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

Protocol No. AKB-6548-CI-0015 
 
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Study Period 
Optional 
Pre-
Screen 
Screening 
Treatment Period 
Post 
Treatment 
BL/ 
rand. [a]
Year 1 
Year 2 
Year 3/Year 4 
Visit 
PS 
SV1 SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22/ 
26 
23/ 
27 
24/ 
28 
25/ 
29 
End of 
Trtmt 
Follow-
up [b] 
Week 
-8 to 0
0 
2 
4 
6 
8 
10 12 16 20 24 28 32 36 40 44 48 52 64 76 88 104 116/ 
168 
128/ 
180 
140/ 
192 
156/ 
208 
EOT [c] 
EOT 
+4
wks 
[dd] 
Visit Window (Days) 
±3 ±3 ±3 ±3 ±3 ±3 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±10 ±10 ±10 ±10 ±10 ±10 ±10 
±10 
±7 
±7 
Liver Function Tests [q] 
X[k] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipid Panel [r] 
X 
X 
X 
Biomarkers [s] 
X 
X 
X 
X 
X 
X 
X 
Reticulocyte Count 
X 
X 
X 
X 
X 
Erythropoietin 
X 
X 
X 
X 
X 
PK [t] 
X 
X 
X 
X 
X 
Exploratory Samples [u] 
X 
X 
X 
X 
X 
X 
Safety Assessments 
MACE Endpoint 
Questionnaire [v] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessment [w] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transfusions and ESA 
Rescue 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Therapeutic Phlebotomy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Assessments and Procedures 
Concomitant Med 
Review [x] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vadadustat Medication 
Dispensing [y] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug Reconciliation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visit Registration in IWR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hb via HemoCue for 
Dose Adjustment [z] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Monthly Hb Monitoring 
[z] 
X 
X 
X 
X 
X 
X 
X 
X 
Darbepoetin Alfa 
Dosing according to Dose Adjustment Algorithms  [aa] 

Protocol No. AKB-6548-CI-0015 
 
Amendment 7-COL 
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Page 87 of 105 
Study Period 
Optional 
Pre-
Screen 
Screening 
Treatment Period 
Post 
Treatment 
BL/ 
rand. [a]
Year 1 
Year 2 
Year 3/Year 4 
Visit 
PS 
SV1 SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 22/ 
26 
23/ 
27 
24/ 
28 
25/ 
29 
End of 
Trtmt 
Follow-
up [b] 
Week 
-8 to 0
0 
2 
4 
6 
8 
10 12 16 20 24 28 32 36 40 44 48 52 64 76 88 104 116/ 
168 
128/ 
180 
140/ 
192 
156/ 
208 
EOT [c] 
EOT 
+4
wks
[dd]
Visit Window (Days) 
±3 ±3 ±3 ±3 ±3 ±3 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±10 ±10 ±10 ±10 ±10 ±10 ±10 
±10 
±7 
±7 
Vadadustat Dose 
Adjustments [bb] 
Start at 300 mg once daily, then adjust dose as per Dose Adjustment Algorithms 
Oral or IV Iron 
Supplementation [cc] 
As needed to maintain ferritin ≥100 ng/mL or TSAT ≥20% 
Abbreviations:  AE = adverse event; ALT/SGPT = alanine aminotransferase/serum glutamic-pyruvic transaminase; AST/SGOT = aspartate aminotransferase/serum glutamic oxaloacetic transaminase; 
BUN = blood urea nitrogen; CBC = complete blood count; CPK = creatine phosphokinase; CRF = case report form; diff = differential; ECG = electrocardiogram; eGFR = estimated glomerular filtration 
rate; EOT = end of treatment; ESA = erythropoiesis-stimulating agent; HDL = high density lipoprotein; Hb = hemoglobin; HIF = hypoxia inducible factor; ICF = informed consent form; 
I/E = inclusion/exclusion; INR = international normalized ratio; IWR = interactive web response; LDH = lactate dehydrogenase; LDL = low density lipoprotein; MACE = major adverse cardiovascular 
event; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; med = medication; PK = pharmacokinetic; PS = Pre-Screening; 
PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cell; RDW = red cell distribution width; SV1 = Screening visit 1; SV2 = Screening visit 2; TIBC = total iron binding 
capacity; Trtmt = treatment; TSAT = transferrin saturation; uACR = urine albumin to creatinine ratio; VEGF = vascular endothelial growth factor; WBC = white blood cell; wks = weeks. 
[a] The Screening period is a maximum of 8 weeks in duration.  The Baseline visit must be performed at a minimum of 4 days from the last Screening visit  (SV2), or date of last re-test. 
[b] The Follow-up visit can be performed either in person OR via the telephone.
[c] The EOT visit will be performed at the time a subject permanently discontinues study medication (vadadustat or darbepoetin alfa) or for subjects on study medication at the time of notification of 
global study completion. It is important to continue to follow subjects that discontinue study medication through global study completion at a frequency and approach that is agreed to between the 
Investigator and subject. Visit schedule and assessments are flexible and at the discretion of the investigator and subject and will be clearly documented in the medical chart. 
[d] An abbreviated ICF will be used for Pre-Screening.  If the subject is eligible for Screening, a separate full ICF will be used, which may be signed in advance of the SV1 pocedures. The Screening 
period starts at the time the informed consent is signed and will be a maximum of 8 weeks in duration.  An optional consent form for collection of blood samples for future genetic analysis will be 
provided at SV1.  An additional optional consent form for participation in an adrenal function substudy in 200 subjects in the EU will also be provided at SV1. 
[e] If the Pre-Screen HemoCue Hb is between 8.0 and 11.0 g/dL (inclusive) within the US or between 9.0 and 12.0 g/dL (inclusive) outside of the US, the investigative site may proceed with Screening 
Visit 1 (SV1), preferably on the same day as Pre-Screening. 
[f] Inclusion/Exclusion criteria will be reviewed at the Pre-Screening and Screening visits (SV1 and SV2).  Final eligibility determination will occur following the Screening visits when all data are 
available.
[g] Vitals: Heart rate and blood pressure to be assessed in the seated position after 5 minutes of rest.  Height (SV2 only) and weight (SV2, Weeks 12, 24, 36, and 52, yearly thereafter, and at the EOT 
visit) will also be measured.
[h] Physical exam:  a physical exam is required at SV2 as outlined in the protocol.  Thereafter, an abbreviated symptom-directed physical exam should be performed at the discretion of the Investigator
as clinically indicated.
[i] ECG should be performed prior to blood draws when possible and obtained after the subject has been resting comfortably in a supine position for approximately 5 minutes. 
[j]
Serum pregnancy will be tested in women of childbearing potential at SV2.  (Eligible subjects will be advised to use an adequate contraceptive method.)  Additional serum or local urine pregnancy 
tests should be conducted throughout the study in sufficient number, as determined by the Investigator or required by local regulations, to establish the absence of pregnancy during the study.  If
positive at SV2, the subject is not eligible to enter the study.  If a subject becomes pregnant during the study, the subject must permanently discontinue study medication and should attend all 
subsequent study visits and be continually monitored according to the Schedule of Activities for the duration of the study. 
[k] Subjects may be retested and/or rescreened as detailed in Section 7.4 Retesting and Rescreening 
[l]
Coagulation tests:  prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR). 
[m] A CBC with differential will be performed at Baseline and twice annually at Weeks 28, 52, 76, 104, 128, 156, 180, 208.  At all other noted visits, a CBC without differential will be performed.

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CBC:  hemoglobin, hematocrit, red blood cells (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell 
distribution width (RDW), white blood cell (WBC) count with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils), and platelets. 
[n] Mean Screening Hb between 8.0 and 11.0 g/dL (inclusive) in the US and between 9.0 and 12.0 g/dL (inclusive) outside of the US, as determined by the average of 2 Hb values measured by the 
central laboratory during Screening. If the subject’s Hb does not qualify after SV1, SV2, or retest, the subject should be considered a Screen Failure.
[o] Iron indices:  ferritin, iron, total iron binding capacity (TIBC), and transferrin saturation (TSAT). 
[p] A full serum chemistry panel will be performed at SV1, Baseline, and twice annually at Weeks 28, 52, 76, 104, 128, 156, 180, 208.  At all other noted visits, serum creatinine and eGFR will be 
performed.  Serum chemistry:  sodium, potassium, bicarbonate, chloride, calcium, magnesium, phosphorus, glucose, creatinine, blood urea nitrogen (BUN)/urea, creatine phosphokinase (CPK), uric
acid, albumin, total protein, and eGFR. 
[q] Liver function tests:  total bilirubin, alkaline phosphatase, alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), and lactate dehydrogenase (LDH).
[r] Lipids:  total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides.
[s] The biomarkers include, but are not limited to, hepcidin and VEGF.
[t]
PK samples are to be drawn only for subjects randomized to vadadustat.  Subjects will be questioned regarding the timing of their last dose of vadadustat. 
[u] Additional blood and urine samples will be collected at Baseline, Weeks 28, 52, 104, 156, and EOT which may be used for exploratory measurement of biomarkers (eg, factors relating to the 
activation of the HIF pathway).  Subjects will also be asked to provide optional consent to obtain a blood sample at Baseline and EOT to be stored for future genetic analyses (eg, DNA, mRNA).
[v] At each post-randomization study visit, the subject must specifically be questioned regarding the occurrence of any potential MACE endpoint events since the last study visit.  If a potential endpoint
event is reported, the date of the event should be recorded and the appropriate source documents should be collected according to the endpoint packet checklist. 
[w] Adverse events should be documented and recorded at each visit. The AE reporting period for this study begins upon randomization through global study completion. All adverse events (serious and
non-serious, and related and non-related) will be documented and recorded through the follow-up visit.  Subjects must be followed for adverse events until the final required protocol visit or until all 
drug-related toxicities and serious adverse events have resolved (or are considered chronic/stable). 
[x] Concomitant medications should be collected and recorded at each visit as noted.  All concomitant medications received during the screening window  (minimum of  30 days prior to the start of
study medication) through the EOT visit will be recorded.
[y] Subjects will be provided with a supply of vadadustat at the Baseline visit and will be resupplied at subsequent visits as needed.  Subjects will be instructed to complete 1 bottle prior to opening the 
next bottle.  The dose should be taken at approximately the same time each day.
[z]Hemoglobin will be monitored via local HemoCue throughout the study to determine if the dose of study medication will be adjusted, interrupted, or maintained.  From Week 53, Hb will be 
monitored monthly as part of local standard of care labs or at unscheduled visits for dose adjustment. 
[aa] Refer to the Dosing Algorithm  adult patients with CKD not on dialysis. If the subject progresses to DD-CKD during the study and is able to continue study medication, use the Appendix Dosing 
Algorithms for adult patients with DD-CKD. Vital signs and weight should be obtained prior to dosing .    Darbepoetin alfa dosing is independent of the visit schedule, thus, the dosing schedule may 
shift per local standard of care and Investigator discretion. . 
[bb] The dose will be adjusted in accordance with the Dose Adjustment Algorithms.  Changes to dose will be accomplished by changing the number of tablets to be taken per day. 
[cc] Iron supplementation will be prescribed during the study to maintain ferritin ≥100 ng/mL or TSAT ≥20%.  In general, only oral iron should be considered before initiating IV iron for therapy. 
Subjects who fail to qualify for the study based on low TSAT, ferritin, folate, or B12 values may receive replacement therapy based on the investigative sites’ standard of care during the screening
period and retest the laboratory parameter(s). Subjects who receive iron replacement may retest screening Hb a minimum of 3 weeks after completion of iron replacement therapy.  Vadadustat is not 
to be administered concurrently with the oral iron supplement (including multivitamins containing iron), iron containing phosphate binders or any medications containing iron.  Oral iron supplement
should be taken at least 2 hours before or 2 hours after the dose of study medication.  (See study protocol for further details regarding iron administration and potential intravenous therapy).
[dd] End of Study status will be done to capture subject status at the global completion of the study or time of withdrawal of consent or when subject deemed LTFU or death. Subjects active on the study 
(including those permanently discontinued from study medication and are being followed) will complete the Follow-up visit. For subjects active on the study medication at global study completion,
the EOS status will be collected at the at the Follow-up visit. For subjects that have permanently discontinued study medication and are being followed until global study completion, the EOS status 
will be as collected, which includes activities outlined at the Follow-up visit.

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APPENDIX B:  CKD-EPI CREATININE EQUATION 
The estimated glomerular filtration rate (eGFR) will be calculated from serum creatinine (isotope 
dilution mass spectrometry [IDMS] calibrated in mg/dL) using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) creatinine equation (Levey et al. 2009). 
The CKD-EPI creatinine equation is: 
eGFR = 141 x min(SCr/k,1)α x max(SCr/k,1)-1.209 x 0.993Age x [1.018 if female] x [1.159 if 
black] 
where: 
SCr is serum creatinine (in mg/dL) 
k = 0.7 for females 
k = 0.9 for males 
α = -0.329 for females 
α = -0.411 for males 
min = the minimum of SCr/k or 1 
max = the maximum of SCr/k or 1 

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APPENDIX C:  VADADUSTAT DOSING AND DOSE ADJUSTMENT ALGORITHMS 

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APPENDIX D:  DARBEPOETIN ALFA DOSING AND DOSE ADJUSTMENT ALGORITHMS 

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APPENDIX E:  END OF TREATMENT AND GLOBAL STUDY COMPLETION SUBJECT FLOW 

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APPENDIX F:  HISTORY OF AMENDMENTS TO THE PROTOCOL 
Amendment 1 (Version 2; 
  
Amendment 1 was issued based on requests from health authorities during review of the protocol 
under the European Voluntary Harmonisation Procedures (VHP). 
Amendment 1 was issued to a limited number of sites. 
The major changes introduced in the amendment are summarized below: 
•
Added Exclusion Criterion No. 19: “Hypersensitivity to darbepoetin or vadadustat, or to
any of their excipients.”
•
Clarified that the adrenal function assessment (adrenocorticotropic hormone [ACTH]
stimulation test) will be conducted in a subset of 200 subjects in the European Union
(100 subjects from the vadadustat treatment arm and 100 subjects from the darbepoetin
alfa treatment arm) across the 2 non-dialysis dependent chronic kidney disease (NDD-
CKD) studies AKB-6548-CI-0014 and AKB-6548-CI-0015.
•
Defined that the study completion date (end of trial) will take place when 631 major
adverse cardiovascular events (MACE) events have accrued over the 2 NDD-CKD
studies (Studies AKB-6548-CI-0014 and AKB-6548-CI-0015).
•
Clarified that the double-barrier method should be practiced starting at Screening Visit 1,
throughout the study, and for 30 days after the last dose of study medication.
•
Added that “In case of substantial protocol amendment, the sponsor will obtain approval
from responsible Regulatory Authorities before implementation.”
Amendment 2 (Version 3; 
 
Amendment 2 was issued based on feedback from regulatory authorities and a Clinical Expert 
Advisory Board, as well as requests from study sites for additional clarification. 
All protocol changes present in Amendment 1 have also been included in Amendment 2. 
The major changes introduced in the amendment are summarized below: 
•
To update the following exclusion criteria:
o
Exclusion Criterion No. 7: Additional clarification of exclusionary cardiovascular
events within 12 weeks prior to screening
o
Exclusion Criterion No. 8: To not exclude subjects with basal cell carcinoma who
have been successfully treated with cryotherapy instead of surgical resection
o
Exclusion Criterion No. 11: To specifically exclude subjects with a history of
hematopoietic stem cell transplant
o
Exclusion Criterion No. 13: Considering the short half-life of vadadustat and
clinical experience in previous Phase 1 and Phase 2 studies in NDD-CKD and
DD-CKD subjects, it could be beneficial for subjects who participated in previous

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vadadustat studies to be considered for this global Phase 3 study, provided the 
subject meets all eligibility criteria 
•
To add hospitalization for heart failure (HF) as an adjudicated safety endpoint in addition
to MACE and thromboembolic events
•
To clarify that the darbepoetin alfa dosing adjustment guidelines is based on the approved
local product label for adult patients with CKD not on dialysis
•
To allow subjects who transition to hemodialysis or peritoneal dialysis during the study
to continue to receive study medication (vadadustat or darbepoetin alfa). This is
supported by acceptable safety data from a recently-completed Phase 2 trial of vadadustat
in subjects with dialysis-dependent chronic kidney disease (DD-CKD).
•
To introduce a binary causality system (ie, “related” or “unrelated”) for clinical trial
investigators to assign causality of adverse events to study drugs in accordance with
recommendations from the Council for International Organizations of Medical Sciences
(CIOMS) VI Working Group
•
Following discussions with the United States Food and Drug Administration (US FDA),
it was requested that the sparse pharmacokinetic (PK) sampling scheme be described and
justified. The results of PK simulations indicated that collection of a sample between 0.25
to 1 hour after administration of the first dose along with sparse samples collected during
Weeks 4, 12, 28 and 52 will provide additional information to help characterize the
population PK and PK/PD relationships
•
Adverse event reporting related to critically increased liver function test results were
aligned with the US FDA Drug-Induced Liver Injury (DILI) guidelines to provide
instructions to study sites regarding reporting for improved consistency and case quality
•
To add visit windows to provide flexibility to the subjects and the study sites during
scheduling of study visits
•
To clarify definitions for renal events to improve understanding and site compliance
Amendment 2-COL (
 Colombia-specific protocol amendment) 
Amendment 2-COL was issued based on requests from the Instituto Nacional de Vigilancia de 
Medicamentos y Alimentos (Invima) during review of the protocol.  This amendment is 
country-specific and will only be issued to investigative sites in Colombia. 
Following is a list of the changes in Amendment 2-COL compared with the original protocol: 
•
All changes to the original protocol that were included in Amendment 1 and
Amendment 2 have also been included in Amendment 2-COL.
•
The protocol language specifying that site investigators should encourage patients (who
wish to discontinue study medication or withdraw from the study) to continue study
participation has been removed.
•
The protocol language describing procedures to encourage patients to continue study
participation has been removed.

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Amendment 3-COL (Version 4; 
 
Amendment 3 was issued based on a Clinical Expert Advisory Board, and requests from study 
sites for additional clarification. 
The major changes introduced in the amendment are summarized below: 
•
To update the study design from the current screening period of up to 4 weeks to up to 8
weeks and allow iron, vitamin B12, and folate supplementation as needed during the
screening period.
o
Screening period changed from up to 4 weeks to up to 8 weeks
o
One retest will be allowed for each laboratory parameter, within the screening
period.
o
Subjects who receive iron replacement may retest screening Hb a minimum of 3
weeks after completion of iron replacement therapy.
•
Inclusion Criterion No. 3 adjusted due to increase of screening period from up to 4 weeks
to up to 8 weeks.
•
To update the following exclusion criterion:
o
Exclusion Criterion No. 3: Adjusted due to increase of screening period from up
to 4 weeks to up to 8 weeks.
o
Exclusion Criterion No. 8: To clarify that benign colonic polyps is not a
malignancy, therefore removed to correct the error
o
Exclusion Criterion No. 9: Adjusted due to increase of screening period from up
to 4 weeks to up to 8 weeks, and to clarify that chronic treatment with
anticoagulants for a history of DVT or PE over 12 weeks prior to randomization is
not exclusionary.
•
The number of total sites has been increased in efforts to increase enrollment.
•
Vadadustat dosing and dose adjustment guidelines were updated to clarify that patients
receiving 1 tablet of dosing prior to interruption will resume treatment with 1 tablet after
interruption.
•
Section 4.2 Summary of Clinical Experiences was updated to reflect information from
recently completed trials.
•
Section 6.4.1 Executive Steering Committee has been added.
•
To clarify Darbeopoetin alfa administration and accountability
o
Darbepoetin alfa should be administered per the label.
o
Darbepoetin alfa doses may be self-administered or administered by health care
professionals at the clinics, site facility, or at home according to the investigator’s
determination and local practice.
o
Added additional information on return of darbepoetin for drug accountability and
compliance assessment.

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•
9.2.2 Laboratory Evaluations was revised to reflect the following:
o
Modification to the frequency of protocol specified Biomarker sample collection
o
Additional exploratory sample collection
•
A clarification of the study analysis populations has been provided.
Amendment 4-COL (Version 5; 
 
Amendment 4 was issued based on sponsor internal assessment, external input from nephrology  
experts, and investigative sites. 
The major changes introduced in the amendment are summarized below: 
•
Section 4.2 Summary of Clinical Experiences was updated to reflect information from
recently completed trials and for alignment with  vadadustat Investigator’s Brochure.
•
Section 4.3 Secondary Efficacy Endpoints was updated to reflect addition of several key
secondary, other secondary efficacy endpoints and Safety Endpoints  to align with the
Statistical Analysis Plan (SAP)
•
Section 7.4.1 Retesting was updated for simplification
•
Section 7.5.1 Study Completion was revised to clarify that all enrolled subjects in this
study will have the opportunity to complete (at least) the week 36 visit.
•
Section 7.5.5 Individual Subject Discontinuation was updated to add Lack of Efficacy as
a reason for discontinuation for accurate data capture.
•
Section 8.4.4 Dosing and Dose Adjustment Guidelines was revised to guide Investigators
to follow printed dose adjustment algorithms in lieu of IWRS-programmed dosing
recommendations due to some aspects of IWRS-programmed dosing instructions not
operating as planned. Also, updated guidance to Investigators to use clinical judgement
and other Hb data to appropriately dose subjects in cases of clinical concern regarding
HemoCue value. Another clarification was added that after a subject completes ESA
rescue, the Investigator has the option to resume study drug at the same dose as
previously used or with one dose higher. Monthly Hb monitoring for dosing oversight  in
Year 2-4 was also added to this section.
•
Section 8.4.6 Iron Supplementation was updated to align with published guidelines to
prescribe iron supplementation during the study when serum ferritin is less than 100
mcg/L or when serum transferrin saturation is less than 20%
•
Section 8.4.7.1 ESA Rescue (Optional) was updated to align with published guidelines
and to permit Investigator initiation of rescue when medically necessary even if protocol
defined criteria are not met.
•
Section 8.4.9 Dosing Compliance was updated to specify a range of 80% to 120% which
is commonly used in clinical trials with oral products.

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•
Section 8.5 Prior and Concomitant Therapy was updated to include text clarifying that if
the duration of the screening period is less than 30 days, all medications taken within 30
days prior to first dose of study medication will be recorded.
•
Section 9.3.6 Year 2- 4 Monthly Hb monitoring was added, with the requirement for
monthly monitoring of Hgb drawn as part of local standard of care labs or via an
unscheduled visit.
•
Section 10.1.1 was updated to add text defining overdose of study drugs.
•
Section 10.1.2 Serious Adverse Events was updated to require all new and recurrent
malignancies (with a few exceptions) to be reported as a Serious Adverse Events (SAEs)
to standardize reporting. If a subject develops basal cell carcinoma of skin, squamous cell
carcinoma, or cervical carcinoma in situ during the study, or has worsening of these
events from Baseline, the Investigator will determine if the event is reported as an AE or
SAE.
•
Section 10.5 Special Situations  was updated to add text defining overdose of study
drugs.
•
Section 11.1.1 Sample Size for Primary Efficacy Endpoint was updated to reflect a
change in the non-inferiority margin from -0.5 g/dl to -1.0 g/dl
•
Section 11.1.2 Sample Size for the Primary Safety Endpoint was updated with enrollment
projections as well as median study drug exposure times.
•
Section 11.5 Missing Data was updated to align with Statistical Analysis Plan (SAP)
•
Section 11.6.3 Subgroups is updated to pre-specify key subgroups for subsequent
analysis
•
Section 11.7.2 Analysis of Adverse Events was updated and AE summaries will be
provided for specific sub groups.
Amendment 5 (Version 6; XX 
)  
Amendment 5 was issued based on sponsor assessment, external input, regulatory authority 
engagement and investigative sites feedback.  
The major changes introduced in the amendment are summarized below: 
•
Section 6.1 Study Design was updated with revised subject number
•
Section 7.5.1 Study Completion was updated to clarify that all enrolled subjects will be
allowed to complete the primary evaluation period (Weeks 24-36) prior to global study
completion.
•
Section 7.5.2 Subject Completion was updated to clarify procedures at time of global study
completion.
•
Section 7.5.5 Individual Subject Discontinuation was updated to emphasize the importance of
continuing to follow subjects through global study completion.

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•
Section 7.5.5.1 Temporary Interruption of Study Medication was updated to state that if study
medication is temporarily interrupted for more than 60 days, Medical Monitor should be
contacted before resuming study medication.
•
Section 7.5.5.2 Permanent Discontinuation of Study Medication was updated to have the
EOT visit and Follow up visit performed at the time of permanent discontinuation of study
medication. Emphasized importance of continuing to follow subjects through global study
completion.
•
Section 7.5.5.3 Complete Withdrawal from Further Study Visits/Assessments is updated to
reflect all options that must be considered by the Investigator before a subject withdraws
consent.
•
Section 7.5.5.4 Procedures to Support Continued Study Participation is added to include all
options available to the Investigator to follow subjects that permanently discontinue study
medication.
•
Section 7.5.5.5 Procedures to Prevent “Lost to Follow-up” details steps to support sites in
efforts to identify subjects lost to follow-up.
•
Section 8.4.3 Blinding was updated to reflect information for which the Sponsor and CRO
study teams will remain blinded.
•
Section 8.4.7 Rescue Therapy was clarified reflect restarting of study medication after ESA
Rescue and RBC Transfusion.
•
Section 8.5.2 Erythropoiesis-stimulating Agents was updated to provide clarity on study
medication dosing following ESA administration.
•
Section 8.5.5 Rosuvastatin, Pravastatin, and Other HMG-CoA Reductase Inhibitors (Statins)
was added to provide guidance on how to manage concomitant use of statins with vadadustat.
•
Section 9.2.1 Clinical Evaluations was updated to include collection of AEs from the time of
randomization through global study completion.
•
Section 9.3.9 EOT Visit was updated to include detail on managing subjects that permanently
stop study medication during the study and managing subjects on study medication at global
study completion.
•
Section 9.3.12 End of Study Subject Status is added to define the end of study assessments
that document subject status at the global study completion or at the time of subject
withdrawal or when subject is deemed LTFU or upon death.
•
Section 10.1.1 Adverse Events is updated by adding guidance on managing subjects who
develop malignancy while on study medication.
•
Section 10.1.2 Serious Adverse Events is updated to indicate that Sponsor has defined events
that will be classified as serious regardless of their assessment.
•
Section 10.3.1 Reporting Period is updated to clarify that the AE reporting period begins at
the time of randomization and continues through global study completion.
•
Section 11 Data Analysis was updated to reflect how Baseline will be calculated for Hb.
•
Section 11.1.1 Sample Size for Primary Efficacy Endpoint was updated to reflect a change in
the non-inferiority margin from -1.0 g/dL to -0.75g/dL.
•
Section 11.1.2 Sample Size for the Primary Safety Endpoint was modified to include updated
definition for primary safety endpoint and how noninferiority is established between
treatment groups.

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•
Section 11.2 Study Analysis Populations is updated with definition of full analysis
population.
•
Section 11.6.1.1 Primary Analysis of Primary Efficacy Endpoint is updated with use of
ANCOVA with multiple imputation, stratified by the randomization strata and using Baseline
Hb as the covariate.
Amendment 6-COL (Version 7.0; 
 
Amendment 6-COL was issued based on preliminary results of a drug-drug interaction study. 
The major changes are summarized below: 
•
Section 8.1.1 Vadadustat was updated to include reference to the Pharmacy Manual
which provides further details on storage and managing temperature excursions.
•
Section 8.5.5 HMG-CoA Reductase Inhibitors (Statins) was updated to provide further
guidance regarding concomitant use of simvastatin drug interactions with vadadustat.
•
Section 8.5.6 Sulfasalazine and Other BCRP Substrates was added to provide guidance
regarding concomitant use of BCRP substrates with vadadustat.
•
Section 10.5 Special Situations was updated to reflect recent results of investigative
toxicology studies.
•
Liver function tests were increased in Year 2, 3, and 4 to include Week 64, 88, 116, 140,
168, and 192 for gathering data to better understand the hepatic profile of vadadustat.
This change is reflected in Section 9.2.2 Laboratory Evaluations, Section 9.3.7 Year 2
Treatment Period Visits (Weeks 53 through 104), Section 9.3.8 Year 3/4 Treatment
Period Visits (Weeks 116 through 208), and Appendix A: Schedule of Activities.
Amendment 7-COL (Version 8.0; 
 
Amendment 7-COL was issued based on FDA guidance regarding potential drug-induced liver 
injury. 
•
Section 7.5.5 Individual Subject Discontinuation was updated to include a reference to
Study Medication Stopping Rules for management of subjects with ALT and AST
abnormalities.
•
Section 9.4 Study Medication Stopping Rules was added to include a table of liver
function test results that would require permanent discontinuation of vadadustat.
•
Section 10.1.1 Adverse events was updated to exclude elevations in ALT or AST
>3 times ULN with an elevation of total serum bilirubin >2 times ULN from conditions
of temporary discontinuation, as this is now a condition for permanent discontinuation.
•
Section 10.1.2 Serious adverse events was updated to include information defining
designated medical events.

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1. IDENTIYFING INFORMATION FOR AMENDMENT
Protocol Title: 
Phase 3, Randomized, Open-Label, Active-Controlled Study Evaluating the Efficacy 
And Safety Of Oral Vadadustat For The Maintenance Treatment Of Anemia In 
Subjects With Non-Dialysis-Dependent Chronic Kidney Disease (NDD-CKD) 
(PRO2TECT – CONVERSION) 
Protocol Number: 
AKB-6548-CI-0015 
Compound:  
Vadadustat (AKB-6548) 
Status / Date:  
Original Protocol; 
 
Amendment 1; 
 
Amendment 2; 
 
Amendment 2-COL; 
 (Colombia-specific 
protocol amendment) 
Amendment 3-COL; 
 (Colombia-specific 
protocol amendment) 
Amendment 4-COL; 
 (Colombia-specific 
protocol amendment) 
Amendment 5-COL; 
 (Colombia-specific protocol amendment) 
Amendment 6-COL; 
 (Colombia-specific protocol amendment) 
Amendment 7-COL; 
 (Colombia-specific protocol amendment) 

Protocol No. AKB-6548-CI-0015 
 
Amendment 7-COL 
Akebia — Company Confidential 
Page 2 of 5 
2. PROTOCOL CHANGES DETAILS
Amendments to the protocol are detailed below, except for editorial changes and minor clarification changes. If it is necessary to clarify 
the edits, newly added text is identified using in blue and deleted text is identified by strikethrough, red font. 
Protocol Section 
Text in Version 7.0 (Amendment 6-COL) 
Changes through Version 8.0 (Amendment 7-COL) 
Rationale for Change 
Section 7.5.5 
(Paragraph 3) 
Subjects who undergo a solid organ 
(including kidney), hematopoietic stem cell, 
or bone marrow transplantation will have 
their study medication (vadadustat or 
darbepoetin alfa) permanently discontinued. 
(Paragraph 3) 
Subjects who undergo a solid organ (including kidney), 
hematopoietic stem cell, or bone marrow transplantation 
will have their study medication (vadadustat or darbepoetin 
alfa) permanently discontinued. 
See Section 9.4, Study Medication Stopping Rules for 
additional details on the management of subjects with ALT 
and AST abnormalities. 
To include a reference to 
Study Medication 
Stopping Rules for 
management of subjects 
with ALT and AST 
abnormalities. 
Section 9.4 
(added) 
Study Medication Stopping Rules 
Study medication must be permanently discontinued if a 
subject meets one of the criteria in Table 2 below 
Table 1.  Study Medication Stopping Rules 
See Section 10.1.1, Adverse Events for reporting 
requirements related to a subject being permanently 
discontinued based on meeting the laboratory abnormalities 
list above in Table 2. 
To include a table of 
liver function test results 
that would require 
permanent 
discontinuation of 
vadadustat. 

Protocol No. AKB-6548-CI-0015 
 
Amendment 7-COL 
Akebia — Company Confidential 
Page 3 of 5 
ALT or AST >3x ULN and 
total bilirubin >2x ULN 
Permanently 
Discontinue Treatment 
ALT or AST >3x ULN and 
INR >1.5 
Permanently 
Discontinue Treatment 
ALT or AST >8x ULN 
Permanently 
Discontinue Treatment 
ALT or AST remains >5x 
ULN over 2 weeks* 
Permanently 
Discontinue Treatment 
ALT or AST >3x ULN with 
symptoms including e.g., 
fatigue, nausea, vomiting, 
right upper quadrant pain, 
fever, rash or eosinophilia 
Permanently 
Discontinue Treatment 
*Re-challenge generally should be avoided with ALT or
AST >5 times ULN unless there are no other good
therapeutic options.
ALT: alanine transferase; AST: asparagine transferase;
INR: international normalized ratio; ULN: upper limit of
normal
Section 10.1.1 
(paragraph 8) 
Abnormalities in ALT, AST and Total 
Bilirubin - Abnormalities in ALT, AST and 
Total Bilirubin should be reported to the 
Sponsor’s Medical Monitor or CRO designee 
within 24 hours of awareness as SAE with 
“medical significance” criteria selected, if the 
following conditions are met: 
•
New elevation in ALT or AST > 3
times ULN, with or without an
elevation of total serum bilirubin >
2 times ULN; AND
•
No other reason was identified that
explains the increased ALT/AST
with or without an increased
(paragraph 8) 
Abnormalities in ALT, AST and Total Bilirubin - 
Abnormalities in ALT, AST and Total Bilirubin should be 
reported to the Sponsor’s Medical Monitor or CRO 
designee within 24 hours of awareness as SAE with 
“medical significance” criteria selected, if the following 
conditions are met: 
•
New elevation in ALT or AST > 3 times ULN,
with or without an elevation of total serum
bilirubin > 2 times ULN; AND
•
No other reason was identified that explains the
increased ALT/AST with or without an increased
bilirubin (eg, viral hepatitis, acute liver disease).
To include language for 
elevations in ALT or 
AST >3 times ULN. 

Protocol No. AKB-6548-CI-0015 
 
Amendment 7-COL 
Akebia — Company Confidential 
Page 4 of 5 
bilirubin (eg, viral hepatitis, acute 
liver disease). 
If new elevations in ALT or AST > 3 times 
ULN, with or without an elevation of total 
serum bilirubin > 2 times ULN are identified, 
the following steps are to be taken: 
•
Temporary discontinuation of
Investigational Medicinal Product
(IMP);
•
Repeat testing of ALT, AST, ALP
and total bilirubin, to be completed
within 48 to 72 hours to confirm the
abnormalities and to determine
trend;
•
IMP should not be resumed until
monitoring indicates abnormalities
have resolved or have stabilized.
If new elevations in ALT or AST > 3 times ULN, with or 
without an elevation of total serum bilirubin > 2 times 
ULN are identified, the following steps are to be taken: 
•
Temporary discontinuation of Investigational
Medicinal Product (IMP);
•
Repeat testing of ALT, AST, ALP, and total
bilirubin, to should be completed within 48 to
72 hours to confirm the abnormalities and to
determine trend;
•
IMP should not be resumed until monitoring
indicates abnormalities have resolved or have
stabilized.
Details on the management of subjects with other ALT and 
AST abnormalities are further described in Section 9.4, 
Study Medication Stopping Rules. 
Section 10.1.2 
(paragraph 2) 
In addition to the above criteria for 
classifying AEs as serious, the following 
situations will also be classified as serious 
for purposes of this study: 
•
Dialysis or
Transplantation- - Events
requiring transition to chronic,
ongoing dialysis, or requiring an
acute transient course of dialysis, or
requiring an immediate kidney
transplantation (ie, not pre-planned)
will be classified as serious.
Guidance for the reporting of these
events is provided in Section 10.1.1,
Adverse Events.
•
Malignancies – Newly diagnosed
malignancies or a recurrence of a
(paragraph 2) 
In addition to the above criteria for classifying AEs as 
serious, the following situations will also be classified as 
serious for purposes of this study: 
•
Dialysis or Transplantation- - Events requiring
transition to chronic, ongoing dialysis, or requiring
an acute transient course of dialysis, or requiring
an immediate kidney transplantation (ie, not pre-
planned) will be classified as serious.  Guidance
for the reporting of these events is provided in
Section 10.1.1, Adverse Events.
•
Malignancies – Newly diagnosed malignancies or
a recurrence of a malignancy should be reported as
an SAE with the seriousness criterion “medically
important” if no other seriousness criteria are met.
If a subject develops basal cell carcinoma of skin,
squamous cell carcinoma, or cervical carcinoma in
situ during the study, or has worsening of these
To define a list of 
designated medical 
events that shall always 
be classified as serious 
adverse events (SAEs).  

Protocol No. AKB-6548-CI-0015 
 
Amendment 7-COL 
Akebia — Company Confidential 
Page 5 of 5 
malignancy should be reported as an 
SAE with the seriousness criterion 
“medically important” if no other 
seriousness criteria are met. If a 
subject develops basal cell 
carcinoma of skin, squamous cell 
carcinoma, or cervical carcinoma in 
situ during the study, or has 
worsening of these events from 
Baseline, the Investigator will 
determine if the event is reported as 
an AE or SAE. 
events from Baseline, the Investigator will 
determine if the event is reported as an AE or 
SAE. 
•
Designated Medical Events - The sponsor
maintains a list of designated medical
events  (DME) that they will always classify as
serious adverse events.   If an event on the DME
list is reported as an AE additional information on
the event (e.g. investigator confirmation of
seriousness, causality) will be requested from the
Investigator.