Clinical trial NCT02648347
Conditions: Anemia Non-Dialysis-Dependent Chronic Kidney Disease
Keywords: Vadadustat AKB-6548 Chronic kidney disease anemia CKD chronic renal insufficiency renal impairment erythropoietin kidney renal oral anemia treatment hemoglobin hypoxia-inducible factor HIF hypoxia-inducible factor prolyl-hydroxylase inhibitor HIF-PHI efficacy safety Phase 3 cardiovascular NDD-CKD
Sponsor: Akebia Therapeutics
Start date: 2015-12-01; Completion date: 2020-07-31
Enrollment: 1751 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A multicenter, randomized, open-label, active-controlled Phase 3 study for the correction of anemia and maintenance of hemoglobin (Hb) in participants with Non-Dialysis-Dependent Chronic Kidney Disease (NDD-CKD)

Detailed description:
This is a multicenter, randomized, open-label, active-controlled Phase 3 study of the efficacy and safety of vadadustat versus Darbepoetin alfa for the correction of anemia and maintenance of Hb in participants with NDD-CKD

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Vadadustat intervention 2: Darbepoetin alfa
Intervention descriptions: intervention 1: Oral dose administered once daily for ≥36 weeks. Dose adjustment based on hemoglobin level as defined in the protocol. intervention 2: Subcutaneous or intravenous dose administered for ≥36 weeks. Initial dose based on the current package insert for investigational sites in the United States (US), and the Summary of Product Characteristics for all other investigational sites (non-US) for adult participants with chronic kidney disease not on dialysis.

Protocol documents:
Prot_000.pdf: 
AKB-6548-CI-0014 
This Supplement Contains: 
AKB-6548-CI-0014 (ClinicalTrials.gov Identifier: NCT02648347; EudraCT Number:
2015-004265-81)
1. Original Protocol
2. Final Protocol
3. Rationale for Change for Protocol Amendments
Date: 26 Feb 2019 


Protocol No.  AKB-6548-CI-0014 
 
Akebia — Company Confidential 
Page 1 of 76 
CLINICAL PROTOCOL 
PHASE 3, RANDOMIZED, OPEN-LABEL, ACTIVE-CONTROLLED STUDY 
EVALUATING THE EFFICACY AND SAFETY OF ORAL VADADUSTAT FOR THE 
CORRECTION OF ANEMIA IN SUBJECTS WITH NON-DIALYSIS-DEPENDENT 
CHRONIC KIDNEY DISEASE (NDD-CKD) (PRO2TECT – CORRECTION) 
Compound: 
Vadadustat (AKB-6548) 
Protocol Number: 
AKB-6548-CI-0014 
US IND Number: 
102,465 
EudraCT Number: 
2015-004265-81 
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-0014 
CLINICAL PROTOCOL APPROVAL FORM 
Protocol Title: 
Compound: 
Protocol Number: 
Status/Date: 
Sponsor Approval: 
Phase 3, Randomized, Open-Label, Active-Controlled Study 
Evaluating the Efficacy and Safety of Oral Vadadustat for 
the Correction of Anemia in Subjects with Non-Dialysis­
Dependent Chronic Kidney Disease (NDD-CKD) 
(PRO2TECT-Correction) 
Vadadustat (AKB-6548) 
AKB-6548-CI-00 14 
Version 1.0/
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. 
Date 
Akebia - Company Confidential 


Protocol No.  AKB-6548-CI-0014 
 
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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 


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TABLE OF CONTENTS 
1 
SIGNATURE PAGES .................................................................................................. 2 
Protocol Approval .................................................................................................... 2 
Investigator Agreement ............................................................................................ 3 
2 
PROTOCOL SYNOPSIS .............................................................................................. 8 
3 
LIST OF ABBREVIATIONS ..................................................................................... 17 
4 
BACKGROUND INFORMATION ........................................................................... 20 
Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors ..................................... 22 
Summary of Clinical Experience ........................................................................... 22 
Potential Benefits and Risks ................................................................................... 23 
5 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 24 
Primary Objective .................................................................................................. 24 
Primary Efficacy Endpoint ..................................................................................... 24 
Secondary Efficacy Endpoints ............................................................................... 24 
Safety Endpoints .................................................................................................... 24 
6 
STUDY DESIGN ........................................................................................................ 25 
Study Design .......................................................................................................... 25 
Rationale for Study Design .................................................................................... 26 
Dose Justification ................................................................................................... 28 
Independent Data Monitoring Committee .............................................................. 28 
Endpoint Adjudication Committee ......................................................................... 28 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 28 
General Criteria ...................................................................................................... 28 
Inclusion Criteria .................................................................................................... 29 
Exclusion Criteria ................................................................................................... 29 
Retesting and Rescreening ..................................................................................... 30 
7.4.1 
Retesting ............................................................................................................ 30 
7.4.2 
Rescreening ....................................................................................................... 30 
Subject Completion, Study Discontinuation, and Withdrawal of Subjects ............ 31 
7.5.1 
Subject Completion ........................................................................................... 31 
7.5.2 
Entire Study Termination .................................................................................. 31 
7.5.3 
Individual Study Site Termination .................................................................... 31 
7.5.4 
Individual Subject Discontinuation ................................................................... 31 
Temporary Interruption of Study Medication ............................................... 32 
Permanent Discontinuation of Study Medication ......................................... 32 
Complete Withdrawal from Further Study Visits/Assessments ................... 32 
Procedures to Encourage Continued Study Participation ............................. 33 
Procedures to Prevent “Lost to Follow-up” .................................................. 33 


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8 
STUDY PRODUCT AND TREATMENT OF SUBJECTS ....................................... 34 
Study Product, Supplies, and Storage .................................................................... 34 
8.1.1 
Vadadustat ......................................................................................................... 34 
8.1.2 
Darbepoetin Alfa ............................................................................................... 34 
Dispensing Procedures ........................................................................................... 35 
8.2.1 
Dispensing of Vadadustat .................................................................................. 35 
8.2.2 
Dispensing of Darbepoetin Alfa ........................................................................ 35 
Product Accountability and Destruction ................................................................ 35 
Treatment of Subjects ............................................................................................. 36 
8.4.1 
Treatment Group Assignments .......................................................................... 36 
8.4.2 
Randomization ................................................................................................... 36 
8.4.3 
Blinding ............................................................................................................. 36 
8.4.4 
Dosing and Dose Adjustment Guidelines .......................................................... 37 
Vadadustat Dosing and Dose Adjustment Guidelines .................................. 37 
Darbepoetin Alfa Dosing and Dose Adjustment Guidelines ........................ 38 
8.4.5 
Late or Missed Doses ........................................................................................ 39 
8.4.6 
Iron Supplementation ........................................................................................ 39 
8.4.7 
Rescue Therapy ................................................................................................. 39 
ESA Rescue (Optional) ................................................................................. 39 
Red Blood Cell Transfusion ......................................................................... 40 
8.4.8 
Phlebotomy ........................................................................................................ 40 
8.4.9 
Treatment Compliance ...................................................................................... 40 
8.4.10 
Continuation of Treatment ................................................................................ 41 
Prior and Concomitant Therapy ............................................................................. 41 
8.5.1 
General .............................................................................................................. 41 
8.5.2 
Investigational Medications ............................................................................... 41 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES ................................ 41 
Administrative Procedures ..................................................................................... 42 
9.1.1 
Informed Consent .............................................................................................. 42 
9.1.2 
Documentation of Screen Failures .................................................................... 42 
9.1.3 
Contraception and Pregnancy Avoidance Measures ......................................... 42 
9.1.4 
Laboratory Accreditation and Reference Ranges .............................................. 43 
Study Procedures and Evaluations ......................................................................... 43 
9.2.1 
Clinical Evaluations ........................................................................................... 43 
9.2.2 
Laboratory Evaluations ..................................................................................... 44 
Schedule of Activities ............................................................................................ 46 
9.3.1 
Pre-Screening Visit ............................................................................................ 46 
9.3.2 
Screening Visits ................................................................................................. 46 


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Screening Visit 1 (SV1) ................................................................................ 46 
Screening Visit 2 (SV2) ................................................................................ 47 
Subject Retesting .......................................................................................... 47 
9.3.3 
Subject Rescreening .......................................................................................... 47 
9.3.4 
Baseline Visit (Day 1) ....................................................................................... 48 
9.3.5 
Year 1 Treatment Period Visits (Day 2 through Week 52) ............................... 48 
9.3.6 
Year 2 Treatment Period Visits (Weeks 53 through 104) ................................. 49 
9.3.7 
Year 3/4 Treatment Period Visits (Weeks 116 through 208) ............................ 50 
9.3.8 
End-of-Treatment Visit ..................................................................................... 51 
9.3.9 
Follow-Up Visit ................................................................................................. 51 
10 
ADVERSE EVENTS .................................................................................................. 52 
Definitions .............................................................................................................. 52 
10.1.1 
Adverse Events .................................................................................................. 52 
10.1.2 
Serious Adverse Events ..................................................................................... 54 
Eliciting Adverse Event Information ..................................................................... 55 
Reporting ................................................................................................................ 55 
10.3.1 
Reporting Period ................................................................................................ 55 
10.3.2 
Reporting AEs ................................................................................................... 55 
10.3.3 
Reporting SAEs ................................................................................................. 55 
10.3.4 
Reporting Study Endpoints ................................................................................ 56 
10.3.5 
Relationship to Study Medication ..................................................................... 57 
10.3.6 
Severity .............................................................................................................. 57 
10.3.7 
Follow-Up of Unresolved Events ...................................................................... 58 
Exposure In Utero .................................................................................................. 58 
Special Situations ................................................................................................... 59 
11 
DATA ANALYSIS ..................................................................................................... 59 
Sample Size Determination .................................................................................... 59 
11.1.1 
Sample Size for the Primary Efficacy Endpoint ................................................ 59 
11.1.2 
Sample Size for the Primary Safety Endpoint ................................................... 60 
Study Analysis Populations .................................................................................... 60 
Analysis of Demographic and Pretreatment Variables .......................................... 61 
Disposition of Subjects ........................................................................................... 61 
Missing Data .......................................................................................................... 61 
Efficacy Analyses ................................................................................................... 62 
11.6.1 
Analysis of Primary Efficacy Endpoint ............................................................. 62 
Primary Analysis of Primary Efficacy Endpoint .......................................... 62 
Sensitivity Analyses of Primary Efficacy Endpoint ..................................... 62 
11.6.2 
Analysis of Key Secondary Efficacy Endpoints ............................................... 63 


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Analysis of mean change in HGB value between Baseline (mean 
pretreatment HGB) and the secondary evaluation period (Weeks 40-52) .... 63 
Analysis of proportion of subjects with mean HGB within the target range 
during the primary evaluation period (Weeks 24-36) ................................... 63 
Analysis of mean weekly dose of IV elemental iron administered from 
Baseline to Week 52 ..................................................................................... 63 
Analysis of proportion of subjects receiving RBC transfusion(s) from 
Baseline to Week 52 ..................................................................................... 63 
11.6.3 
Analysis of Additional Secondary Efficacy Endpoints ..................................... 64 
Safety Analyses ...................................................................................................... 64 
11.7.1 
Analysis of MACE ............................................................................................ 64 
11.7.2 
Analysis of Adverse Events ............................................................................... 64 
11.7.3 
Remaining Safety Endpoints ............................................................................. 64 
Additional Assessments ......................................................................................... 65 
11.8.1 
Concomitant Medications .................................................................................. 65 
11.8.2 
Biomarkers ........................................................................................................ 66 
11.8.3 
Pharmacokinetics ............................................................................................... 66 
12 
DATA HANDLING AND RECORD KEEPING ...................................................... 66 
Case Report Forms/Electronic Data Capture ......................................................... 66 
Record Retention .................................................................................................... 66 
13 
QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) ....................... 67 
Investigative Site Monitoring Visits ...................................................................... 67 
Protocol Deviations ................................................................................................ 67 
14 
STUDY DISCONTINUATION/INVESTIGATIVE STUDY SITE TERMINATION
 ..................................................................................................................................... 67 
Criteria for Premature Termination or Suspension of the Study ............................ 67 
Criteria for Premature Termination or Suspension of Investigational Study Sites 68 
Procedures for Premature Termination or Suspension of the Study or 
Investigational Sites ............................................................................................... 68 
15 
ETHICS ....................................................................................................................... 68 
Ethical Conduct of the Study ................................................................................. 68 
Institutional Review Board/Independent Ethics Committee .................................. 68 
Subject Information and Consent ........................................................................... 68 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .... 69 
Subject Confidentiality ........................................................................................... 69 
16 
PUBLICATION OF STUDY RESULTS ................................................................... 70 
17 
REFERENCES ............................................................................................................ 70 
APPENDIX A:  SCHEDULE OF ACTIVITIES ................................................................... 72 
APPENDIX B:  CKD-EPI CREATININE EQUATION ...................................................... 76 


Protocol No.  AKB-6548-CI-0014 
 
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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 Correction of Anemia in Subjects with 
Non-Dialysis-Dependent Chronic Kidney Disease (NDD-CKD) 
(PRO2TECT - CORRECTION) 
Protocol Number 
AKB-6548-CI-0014 
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) <10.0 g/dL, who are not being treated with an erythropoiesis-stimulating agent 
(ESA). 
Investigative Sites 
Approximately 272 investigative sites in North America, Latin America, Europe, and 
Asia Pacific. 
Number of Subjects 
Approximately 1000 subjects. 
Primary Objective 
Demonstrate the efficacy and safety of vadadustat compared with darbepoetin alfa for 
the correction and maintenance of HGB in subjects with anemia secondary to 
NDD-CKD. 
Study Design 
Overview 
Phase 3, randomized, open-label, active-controlled study of the efficacy and safety of 
vadadustat versus darbepoetin alfa for the correction of anemia and maintenance of 
HGB.  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 (United States [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 level (<9.5 versus ≥9.5 g/dL)
Following randomization, there will be 4 periods during the study: 

Correction Period (Weeks 0-23):  initial period on study medication for the
correction of HGB

Maintenance Period (Weeks 24-52):  period on study medication during
which efficacy will be assessed (primary evaluation period:  Weeks 24-36;
secondary evaluation period:  Weeks 40-52)

Long-Term Treatment Period (Weeks 53-End of Treatment [EOT]):
continued study medication to assess long-term safety

Follow-Up (EOT + 4 weeks):  post-treatment visit (either in person or via
telephone) for safety.
Study Duration 
Estimated time to full enrollment of approximately 1000 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 


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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.
Mean Screening HGB <10.0 g/dL as determined by the average of 2 HGB
values measured by the central laboratory during Screening
4.
Serum ferritin ≥100 ng/mL and transferrin saturation (TSAT) ≥20% at
Screening
5.
Folate and vitamin B12 measurements ≥lower limit of normal at Screening
6.
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.
Intravenous (IV) iron within 4 weeks prior to Screening
5.
Any ESA (eg, recombinant human erythropoietin [rhEPO] or darbepoetin
alfa) within 6 weeks prior to Screening
6.
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.
7.
Uncontrolled hypertension (confirmed diastolic blood pressure >110 mmHg
or systolic blood pressure >180 mmHg) at Screening
8.
Severe heart failure at Screening (New York Heart Association Class IV)
9.
Acute coronary syndrome (hospitalization for unstable angina or myocardial
infarction), urgent coronary revascularization, hospitalization for CHF, or
stroke within 12 weeks prior to Screening
10. 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
11. History of deep vein thrombosis (DVT) or pulmonary embolism (PE)
requiring active treatment within 8 weeks prior to Screening
12. History of hemosiderosis or hemochromatosis
13. 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)
14. 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
15. Previous participation in this study, receipt of vadadustat in another study, or
previous participation in a study with another hypoxia-inducible factor


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prolyl-hydroxylase inhibitor (HIF-PHI) 
16. Females who are pregnant or breast-feeding.  Women of childbearing
potential who are unable or unwilling to use an acceptable method of
contraception
17. Non-vasectomized male subjects who are unable or unwilling to use an
acceptable method of contraception
18. 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 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)

HGB increase of >1.0 g/dL from Baseline

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.
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


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
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) starting dose:  based on the approved local 
product label 
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.  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 increase and 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 
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). 
Correction Period (Weeks 0-23) 
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 the HGB has not increased by more than 0.5 g/dL above the Baseline value


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after 4 weeks of treatment, increase the vadadustat dose by 1 tablet.  Increase 
the dose by 1 tablet every 4 weeks until HGB is above 10.0 g/dL (maximum 
dose of vadadustat is 600 mg/day [4 tablets]). 

If the HGB rises rapidly (eg, more than 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.

If a dose adjustment is required to maintain HGB at the desired level, the
vadadustat dose is adjusted by 1 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 the HGB has not increased by more than 0.5 g/dL above the Baseline value
after 4 weeks of treatment, increase the vadadustat dose by 1 tablet.  Increase
the dose by 1 tablet every 4 weeks until HGB is above 10.0 g/dL (maximum
dose of vadadustat is 600 mg/day [4 tablets]).

If the HGB rises rapidly (eg, more than 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 12.0 g/dL, reduce the dose of vadadustat by 1 tablet.  If
the HGB exceeds 13.0 g/dL, interrupt vadadustat until the HGB decreases to
12.5 g/dL or below then resume dosing of vadadustat with 1 fewer tablet.

If a dose adjustment is required to maintain HGB at the desired level, the
vadadustat dose is adjusted by 1 tablet.
Darbepoetin alfa 
Subjects who are randomized to receive darbepoetin alfa will be dosed using 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. 
Maintenance Period (Weeks 24-52) and Long-Term Treatment Period 
(Weeks 53-EOT) 
Vadadustat 
Vadadustat should continue to be dosed according to the above Dose Adjustment 
Guidelines. 
Darbepoetin alfa 
Following the Correction Period, subsequent darbepoetin alfa doses may be adjusted in 
individual subjects based on the approved darbepoetin alfa local product label specific 
for maintenance of treatment.  Local standard of care and regional/national guidelines 
should be taken into consideration for treatment. 
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.  


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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. 
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


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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

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


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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 or 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 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 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. 
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 to 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. 


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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 500 subjects per treatment group, the noninferiority evaluation will 
have >90% 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 500 subjects per treatment group enrolled in this study, approximately 
20 months for accrual, and up to 36 months of follow-up, approximately 32% of the 
needed MACE events (203) 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). 
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 
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 
IDMC 
Independent Data Monitoring Committee 
IDMS 
isotope dilution mass spectrometry 


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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 
rhEPO 
recombinant human erythropoietin 
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 
TREAT 
Trial to Reduce Cardiovascular Events with Aranesp Therapy 


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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 2006; Singh et al. 2006; Pfefferet 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 
drugs, with a recommendation to keep HGB levels below 12 g/dL, while the Japanese practice 


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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. 
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. 
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 
vadadustat, including 125 healthy volunteers and 254 subjects with CKD (242 subjects with 


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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. 
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 
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. 


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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 
Primary Objective 
The primary objective of this study is to demonstrate the efficacy and safety of vadadustat 
compared with darbepoetin alfa for the correction and maintenance of HGB in subjects with 
anemia secondary to NDD-CKD. 
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). 
 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)

HGB increase of >1.0 g/dL from Baseline

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
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


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
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.
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 the correction of anemia and maintenance of HGB in 
subjects with NDD-CKD.  Target enrollment in this study is approximately 1000 subjects at 
approximately 272 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 at a starting dose of two 150 mg tablets once daily 
(300 mg/day) or darbepoetin alfa based on the approved local product label. 
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 (<9.5 g/dL versus ≥9.5 g/dL based on the most recent central 
laboratory HGB measurement prior to the Baseline/Randomization visit).  Following 
randomization, there will be 4 periods during the study: 

Correction period (Weeks 0-23):  the initial period on study medication for the correction
of HGB

Maintenance period (Weeks 24-52):  the period on study medication during which
efficacy will be assessed (primary evaluation period:  Weeks 24-36; secondary evaluation
period:  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 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 


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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 increase and 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.  Dosing and 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. 
During the Maintenance period, subjects randomized to receive vadadustat should continue to be 
dosed according to the Dose Adjustment Guidelines (Section 8.4.4.1, Vadadustat Dosing and 
Dose Adjustment Guidelines).  Subjects randomized to receive darbepoetin alfa may have their 
drug dose adjusted individually based on the local product label specific for the maintenance of 
treatment.  Local standard of care and regional/national guidelines should be taken into 
consideration for treatment maintenance. 
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 Correction period (Baseline [Week 0], 
Weeks 2, 4, 6, 8, 10, 12, 16, and 20), during the Maintenance period (Weeks 24, 28, 32, 36, 40, 
44, 48, and 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 
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 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 


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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 
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. 


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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. 
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 (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 
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 HGB level using a local 
point of care device to evaluate whether a patient 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. 


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 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. Mean Screening HGB <10.0 g/dL as determined by the average of 2 HGB values measured
by the central laboratory during Screening
4. Serum ferritin ≥100 ng/mL and TSAT ≥20% at Screening
5. Folate and vitamin B12 measurements ≥lower limit of normal (LLN) at Screening
6. 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 4 weeks prior to or during Screening
4. IV iron within 4 weeks prior to Screening
5. Any ESA (eg, recombinant human EPO [rhEPO] or darbepoetin alfa) within 6 weeks prior to
Screening
6. 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.
7. Uncontrolled hypertension (confirmed diastolic blood pressure >110 mmHg or systolic blood
pressure >180 mmHg) at Screening
8. Severe heart failure at Screening (New York Heart Association Class IV)
9. Acute coronary syndrome (hospitalization for unstable angina, myocardial infarction), urgent
coronary revascularization, hospitalization for CHF, or stroke within 12 weeks prior to
Screening
10. 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
11. History of DVT or PE requiring active treatment within 8 weeks prior to Screening
12. History of hemosiderosis or hemochromatosis
13. 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)
14. 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


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15. 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)
16. 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)
17. 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)
18. Any other reason that in the opinion of the Investigator would make the subject not suitable
for participation in the study.
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 Screening Visit 1 (SV1) is 10.0-10.5 g/dL, 1 retest CBC 
should be performed prior to SV2.  If retest HGB is >10.0 g/dL, the subject should not proceed 
with SV2.  If the HGB at SV1 is >10.5 g/dL, 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. 
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. 


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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 
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). 


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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. 
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. 
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. 
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”,
and these procedures must be followed by the Investigators, their staff, and all designated
study personnel).


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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.
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.


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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 
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). 
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). 
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. 


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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 dispensed according to the IWR system assignment.  
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). 
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. 


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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. 
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)
Target enrollment for each treatment group is approximately 500 subjects. 
8.4.2 Randomization 
This study will be open to approximately 1000 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 vs EU vs ROW); 
2) New York Heart Association CHF Class (0 or I vs II or III); and 3) study entry HGB level
(<9.5 vs ≥9.5 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, 


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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.  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 increase and 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 
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. 
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. 


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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 the HGB has not increased by more than 0.5 g/dL above the Baseline value after
4 weeks of treatment, increase the vadadustat dose by 1 tablet.  Increase dose by 1 tablet
every 4 weeks until HGB is above 10.0 g/dL (maximum dose of vadadustat is
600 mg/day [4 tablets]).

If the HGB rises rapidly (eg, more than 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.

If a dose adjustment is required to maintain HGB at the desired level, the vadadustat dose
is adjusted by 1 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 the HGB has not increased by more than 0.5 g/dL above the Baseline value after
4 weeks of treatment, increase the vadadustat dose by 1 tablet.  Increase the dose by
1 tablet every 4 weeks until the HGB is above 10.0 g/dL (maximum dose of vadadustat is
600 mg/day [4 tablets]).

If the HGB rises rapidly (eg, more than 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.

If a dose adjustment is required to maintain HGB at the desired level, the vadadustat dose
is adjusted by 1 tablet.
Darbepoetin Alfa Dosing and Dose Adjustment Guidelines 
Subjects who are randomized to receive darbepoetin alfa will be dosed with starting doses and 
dose adjustments based on the IWR assignment and the approved darbepoetin alfa 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 


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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. 
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


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
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). 
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. 
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. 


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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 within 30 days prior to the start of study medication and during the study 
should be recorded on the appropriate CRF.  In addition, for any subject with a history of ESA 
and IV iron use, the date of last dose and the ESA and iron treatment regimen 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

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. 


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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. 
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 drug administration or intrauterine contraception/device


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
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. 
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, patients 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:  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


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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, for
any subject with a history of ESA and IV iron use, the date of last dose and the ESA and
iron treatment regimen 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.

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 10.0-10.5 g/dL, 1 retest CBC should be
performed prior to SV2.  If retest HGB is >10.0 g/dL, the subject should not proceed with
SV2.  If the HGB at SV1 is >10.5 g/dL, 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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
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:  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 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.
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 Baseline, Week 12, Week 28, and EOT visits.


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
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).
Schedule of Activities 
The Schedule of Activities (see Appendix A) 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 <10.0 g/dL, 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 was 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. 
 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)


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
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 10.0-10.5 g/dL, 1 retest CBC should be performed prior to SV2.  If the 
retest HGB is >10.0 g/dL, the subject should not proceed with SV2.  If the HGB at SV1 is 
>10.5 g/dL, 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.
 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 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 <10.0 g/dL to qualify for 
inclusion into the trial.  If the subject’s HGB does not qualify after SV1 and/or SV2 +/- one 
retest HGB, the subject should be considered a Screen failure. 
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). 


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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
o
Coagulation Tests
o
C-reactive protein
o
CBC (including differential)
o
Reticulocyte count
o
Serum chemistry and eGFR
o
Liver function tests
o
Iron indices
o
Lipid profile
o
EPO
o
Biomarkers (hepcidin, VEGF)
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
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)


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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)

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 (Weeks 76 and 104)
o
Serum creatinine and eGFR (Week 64; also at Weeks 76 and 104 as part of the
serum chemistry)
o
Liver function tests (Weeks 76 and 104)
o
Iron indices (Weeks 64, 76, 88, and 104)

Safety assessments:


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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)
9.3.7 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)


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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. 
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)

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


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10 ADVERSE EVENTS 
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. 
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’. 


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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. 
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.


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o
Examples of AE terms include:  Lupus nephritis, diabetic kidney disease, and
glomerulonephritis

Progression of CKD Associated with Chronic Dialysis – Subjects that 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).

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.


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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 
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 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 


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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.
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 


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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: 
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. 


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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. 
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 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.


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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. 
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. 
Sample Size Determination 
The goal of this study is to demonstrate the efficacy and safety of vadadustat compared with 
darbepoetin alfa for the correction and maintenance of HGB in subjects with anemia secondary 
to NDD-CKD.  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). 


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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 500 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 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 500 subjects per treatment group enrolled in this study, approximately 20 months for 
accrual, and up to 36 months of follow-up, approximately 32% of the needed MACE would be 
captured assuming the dropout rate is negligible.  The remaining 68% of the needed MACE 
would be captured in Study AKB-6548-CI-0015. 
 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


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Efficacy analyses will utilize the randomized, full analysis, and PP populations while safety 
analyses will utilize the safety 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 
(correction, 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. 
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, a value 
of 0 will be used for the change from Baseline (ie, return to Baseline in the absence of 
assessments).  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. 


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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. 
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 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 to 36 (inclusive). 
 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 using a return-to-Baseline imputation 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. 
 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 set to zero for subjects receiving any form of rescue (transfusion or ESA)
prior to the primary evaluation period (ie, during the correction period Weeks 0-23).

Primary analysis will be repeated using all randomized subjects.


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
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.
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. 
 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 a return-to-Baseline 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. 
 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. 
 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. 
 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) 


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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 
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. 
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 standalone 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


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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). 
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. 
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. 


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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. 
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. 
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 


Protocol No.  AKB-6548-CI-0014 
 
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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 quality assurance 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 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. 
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.


Protocol No.  AKB-6548-CI-0014 
 
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
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 (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. 
 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. 
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. 


Protocol No.  AKB-6548-CI-0014 
 
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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. 
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). 


Protocol No.  AKB-6548-CI-0014 
 
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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). 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. 


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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. 
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, 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 
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 


Protocol No.  AKB-6548-CI-0014 
 
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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 
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 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 [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 
HGB 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 
Darbepoetin alfa 
Dosing per approved local product label [aa] 
Vadadustat Dose 
Adjustments [bb] 
Start at 300 mg once daily, then adjust dose as per Dose Adjustment Guidelines 
Oral Iron 
Supplementation [cc] 
As needed to maintain ferritin ≥100 ng/mL and TSAT ≥20% 
Abbreviations:  AE = adverse event; ALT/SGPT = alanine transaminase/serum glutamic-pyruvic transaminase; AST/SGOT = aspartate aminotransaminase/serum glutamic oxaloacetic transaminase; 


Protocol No.  AKB-6548-CI-0014 
 
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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
BUN = blood urea nitrogen; CBC = complete blood count; CPK = creatine phosphokinase; 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 events; 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 additional optional consent form for collection of blood samples for 
future genetic analysis will be provided at SV1.
[e] If the Pre-Screen HemoCue® HGB is <10.0 g/dL, 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.
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 10.0-10.5 g/dL, a single retest CBC should be performed prior to SV2.  If retest HGB is >10.0 g/dL, the subject should not proceed with SV2.  If the HGB at SV1 is >10.5 g/dL,
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).
[p] A full serum chemistry panel will be performed at 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 aminotransaminase (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.


Protocol No.  AKB-6548-CI-0014 
 
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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
[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] At each 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.  All AEs (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 up to and including 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, preferably between 7 AM and 2 PM.
[z] Hemoglobin will be monitored via local HemoCue® throughout the study to determine if the dose of study medication will be adjusted or suspended.
[aa] Refer to the approved local product label.  Vital signs and weight should be obtained prior to dosing per the local product label.
[bb] 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.
[cc] 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).


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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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CLINICAL PROTOCOL 
PHASE 3, RANDOMIZED, OPEN-LABEL, ACTIVE-CONTROLLED STUDY 
EVALUATING THE EFFICACY AND SAFETY OF ORAL VADADUSTAT FOR THE 
CORRECTION OF ANEMIA IN SUBJECTS WITH NON-DIALYSIS-DEPENDENT 
CHRONIC KIDNEY DISEASE (NDD-CKD) (PRO2TECT – CORRECTION) 
Compound: 
Vadadustat (AKB-6548) 
Protocol Number: 
AKB-6548-CI-0014 
US IND Number: 
102,465 
EudraCT Number: 
2015-004265-81 
Phase: 
Phase 3 
Status/Date: 
Amendment 7 (Version 8; 
) 
Amendment 6 (Version 7; 
) 
Amendment 5 (Version 6; 
) 
Amendment 4 (Version 5; 
) 
Amendment 3 (Version 4; 
) 
Amendment 2 (Version 3; 
) 
Amendment 1 (Version 2; 
) 
Original protocol (Version 1; 
) 
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 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 


Protocol No. AKB-6548-CI-0014 
Amendment 7 (Version 8) 
 
contents ofthis 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 
re uired b anv re ulations; however, ou will ,.ive rom t notice to the S onsor of an such disclosure. 
1 
SIGNATURE PAGES 
1.1 
Protocol Approval 
Signature 
, Clinical Developm
 
 
Signature 
, Drug Safety and Pharmacovigilance 
Clinical 
Date 
Date 
Date 
Date 
Akebia - Company Confidential 
Page 2 of 102 


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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 


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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 ..................................................................................... 20 
4 
BACKGROUND INFORMATION ........................................................................... 23 
Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors ..................................... 25 
Summary of Clinical Experience ........................................................................... 25 
Potential Benefits and Risks ................................................................................... 26 
5 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 27 
Primary Objective .................................................................................................. 27 
Primary Efficacy Endpoint ..................................................................................... 27 
Secondary Efficacy Endpoints ............................................................................... 27 
Safety Endpoints .................................................................................................... 28 
Exploratory Endpoints ............................................................................................ 28 
6 
STUDY DESIGN ........................................................................................................ 29 
Study Design .......................................................................................................... 29 
Rationale for Study Design .................................................................................... 30 
Dose Justification ................................................................................................... 31 
Executive Steering Committee and Independent Data Monitoring Committee ..... 32 
6.4.1 
Executive Steering Committee .......................................................................... 32 
6.4.2 
Independent Data Monitoring Committee ......................................................... 32 
Endpoint Adjudication Committee ......................................................................... 32 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 32 
General Criteria ...................................................................................................... 32 
Inclusion Criteria .................................................................................................... 33 
Exclusion Criteria ................................................................................................... 33 
Retesting and Rescreening ..................................................................................... 34 
7.4.1 
Retesting ............................................................................................................ 34 
7.4.2 
Rescreening ....................................................................................................... 34 
Study Completion, Subject Completion, Study Discontinuation, and 
Withdrawal of Subjects .......................................................................................... 35 
7.5.1 
Study Completion .............................................................................................. 35 
7.5.2 
Subject Completion ........................................................................................... 35 
7.5.3 
Entire Study Termination .................................................................................. 36 
7.5.4 
Individual Study Site Termination .................................................................... 36 


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7.5.5 
Individual Subject Discontinuation ................................................................... 36 
Temporary Interruption of Study Medication ............................................... 37 
Permanent Discontinuation of Study Medication ......................................... 37 
Complete Withdrawal from Further Study Visits/Assessments ................... 38 
Procedures to Support Continued Study Participation ................................. 38 
Procedures to Prevent “Lost to Follow-up” .................................................. 39 
8 
STUDY PRODUCT AND TREATMENT OF SUBJECTS ....................................... 39 
Study Product, Supplies, and Storage .................................................................... 39 
8.1.1 
Vadadustat ......................................................................................................... 40 
8.1.2 
Darbepoetin Alfa ............................................................................................... 40 
Dispensing Procedures ........................................................................................... 40 
8.2.1 
Dispensing of Vadadustat .................................................................................. 40 
8.2.2 
Dispensing of Darbepoetin Alfa ........................................................................ 40 
Product Accountability and Destruction ................................................................ 41 
Treatment of Subjects ............................................................................................. 42 
8.4.1 
Treatment Group Assignments .......................................................................... 42 
8.4.2 
Randomization ................................................................................................... 42 
8.4.3 
Blinding ............................................................................................................. 42 
8.4.4 
Dosing and Dose Adjustment Guidelines .......................................................... 42 
Vadadustat Dosing and Dose Adjustment Algorithms ................................. 43 
Darbepoetin Alfa Dosing and Dose Adjustment Algorithms ....................... 44 
8.4.5 
Late or Missed Doses ........................................................................................ 44 
8.4.6 
Iron Supplementation ........................................................................................ 44 
8.4.7 
Rescue Therapy ................................................................................................. 45 
ESA Rescue (Optional) ................................................................................. 45 
Red Blood Cell Transfusion (Optional) ........................................................ 46 
8.4.8 
Phlebotomy (Optional) ...................................................................................... 46 
8.4.9 
Treatment Compliance ...................................................................................... 46 
8.4.10 
Continuation of Treatment ................................................................................ 46 
Prior and Concomitant Therapy ............................................................................. 46 
8.5.1 
General .............................................................................................................. 46 
8.5.2 
Erythropoiesis-stimulation Agents .................................................................... 47 
8.5.3 
Transfusions ...................................................................................................... 47 
8.5.4 
Investigational Medications ............................................................................... 47 
8.5.5 
HMG-CoA Reductase Inhibitors (Statins) ........................................................ 47 
8.5.6 
Sulfasalazine and Other BCRP Substrates ........................................................ 48 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES ................................ 48 
Administrative Procedures ..................................................................................... 49 


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9.1.1 
Informed Consent .............................................................................................. 49 
9.1.2 
Documentation of Screen Failures .................................................................... 49 
9.1.3 
Contraception and Pregnancy Avoidance Measures ......................................... 49 
9.1.4 
Laboratory Accreditation and Reference Ranges .............................................. 50 
Study Procedures and Evaluations ......................................................................... 50 
9.2.1 
Clinical Evaluations ........................................................................................... 50 
9.2.2 
Laboratory Evaluations ..................................................................................... 51 
Schedule of Activities ............................................................................................ 53 
9.3.1 
Pre-Screening Visit ............................................................................................ 53 
9.3.2 
Screening Visits ................................................................................................. 53 
Screening Visit 1 (SV1) ................................................................................ 54 
Screening Visit 2 (SV2) ................................................................................ 54 
Subject Retesting .......................................................................................... 55 
9.3.3 
Subject Rescreening .......................................................................................... 55 
9.3.4 
Baseline Visit (Day 1) ....................................................................................... 55 
9.3.5 
Year 1 Treatment Period Visits (Day 2 through Week 52) ............................... 56 
9.3.6 
Year 2-4 Monthly Hb Monitoring ..................................................................... 57 
9.3.7 
Year 2 Treatment Period Visits (Weeks 53 through 104) ................................. 57 
9.3.8 
Year 3/4 Treatment Period Visits (Weeks 116 through 208) ............................ 58 
9.3.9 
End of Treatment (EOT) Visit ........................................................................... 58 
9.3.10 
Follow-Up Visit ................................................................................................. 59 
9.3.11 
Unscheduled Visits ............................................................................................ 59 
9.3.12 
End of Study Subject Status .............................................................................. 59 
Study Medication Stopping Rules .......................................................................... 60 
10 
ADVERSE EVENTS .................................................................................................. 61 
Definitions .............................................................................................................. 61 
10.1.1 
Adverse Events .................................................................................................. 61 
10.1.2 
Serious Adverse Events ..................................................................................... 64 
Eliciting Adverse Event Information ..................................................................... 65 
Reporting ................................................................................................................ 65 
10.3.1 
Reporting Period ................................................................................................ 65 
10.3.2 
Reporting AEs ................................................................................................... 65 
10.3.3 
Reporting SAEs ................................................................................................. 65 
10.3.4 
Reporting Study Endpoints ................................................................................ 66 
10.3.5 
Relationship to Study Medication ..................................................................... 67 
10.3.6 
Severity .............................................................................................................. 67 
10.3.7 
Follow-Up of Unresolved Events ...................................................................... 68 
Exposure In Utero .................................................................................................. 68 


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Special Situations ................................................................................................... 69 
11 
DATA ANALYSIS ..................................................................................................... 69 
Sample Size Determination .................................................................................... 70 
11.1.1 
Sample Size for the Primary Efficacy Endpoint ................................................ 70 
11.1.2 
Sample Size for the Primary Safety Endpoint ................................................... 70 
Study Analysis Populations .................................................................................... 70 
Analysis of Demographic and Pretreatment Variables .......................................... 71 
Disposition of Subjects ........................................................................................... 71 
Missing Data .......................................................................................................... 71 
Efficacy Analyses ................................................................................................... 72 
11.6.1 
Analysis of Primary Efficacy Endpoint ............................................................. 72 
Primary Analysis of Primary Efficacy Endpoint .......................................... 72 
Sensitivity Analyses of Primary Efficacy Endpoint ..................................... 72 
11.6.2 
Secondary Efficacy Analyses ............................................................................ 73 
Key Secondary Efficacy Analyses ................................................................ 73 
11.6.3 
Subgroups .......................................................................................................... 73 
Safety Analyses ...................................................................................................... 73 
11.7.1 
Analysis of MACE and Expanded MACE components .................................... 74 
11.7.2 
Analysis of Adverse Events ............................................................................... 74 
11.7.3 
Remaining Safety Endpoints ............................................................................. 75 
Additional Assessments ......................................................................................... 75 
11.8.1 
Concomitant Medications .................................................................................. 75 
11.8.2 
Biomarkers ........................................................................................................ 76 
11.8.3 
Pharmacokinetics ............................................................................................... 76 
12 
DATA HANDLING AND RECORD KEEPING....................................................... 76 
Case Report Forms/Electronic Data Capture ......................................................... 76 
Record Retention .................................................................................................... 76 
13 
QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) ....................... 77 
Investigative Site Monitoring Visits ...................................................................... 77 
Protocol Deviations ................................................................................................ 77 
14 
STUDY DISCONTINUATION/INVESTIGATIVE STUDY SITE 
TERMINATION ......................................................................................................... 77 
Criteria for Premature Termination or Suspension of the Study ............................ 77 
Criteria for Premature Termination or Suspension of Investigational Study Sites 78 
Procedures for Premature Termination or Suspension of the Study or 
Investigational Sites ............................................................................................... 78 
15 
ETHICS ....................................................................................................................... 78 
Ethical Conduct of the Study ................................................................................. 78 
Institutional Review Board/Independent Ethics Committee .................................. 78 


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Subject Information and Consent ........................................................................... 78 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .... 79 
Subject Confidentiality ........................................................................................... 79 
16 
PUBLICATION OF STUDY RESULTS ................................................................... 79 
17 
REFERENCES ............................................................................................................ 80 
APPENDIX A:  SCHEDULE OF ACTIVITIES ................................................................... 82 
APPENDIX B:  CKD-EPI CREATININE EQUATION....................................................... 86 
APPENDIX C:  VADADUSTAT DOSING AND DOSE ADJUSTMENT 
ALGORITHMS .......................................................................................................... 87 
APPENDIX D: DARBEPOETIN ALFA DOSING AND DOSE ADJUSTMENT 
ALGORITHMS .......................................................................................................... 91 
APPENDIX E:  END OF TREATMENT AND GLOBAL STUDY COMPLETION 
SUBJECT FLOW ....................................................................................................... 95 
APPENDIX F:  HISTORY OF AMENDMENTS TO THE PROTOCOL ........................... 96 


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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 Correction of Anemia in Subjects with 
Non-Dialysis-Dependent Chronic Kidney Disease (NDD-CKD) 
(PRO2TECT - CORRECTION) 
Protocol Number 
AKB-6548-CI-0014 
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) <10.0 g/dL, who are not being treated with an erythropoiesis-stimulating agent 
(ESA). 
Investigative Sites 
Approximately 390 investigative sites in North America, Latin America, Europe, and 
Asia Pacific. 
Number of Subjects 
Approximately 1850 subjects. 
Primary Objective 
Demonstrate the efficacy and safety of vadadustat compared with darbepoetin alfa for 
the correction and maintenance of Hb in subjects with anemia secondary to 
NDD-CKD. 
Study Design 
Overview 
Phase 3, randomized, open-label, active-controlled study of the efficacy and safety of 
vadadustat versus darbepoetin alfa for the correction of anemia and maintenance of 
Hb.  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 (United States [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 level (<9.5 versus ≥9.5 g/dL)
Following randomization, there will be 4 periods during the study: 
•
Correction Period (Weeks 0-23):  initial period on study medication for the
correction of Hb
•
Maintenance Period (Weeks 24-52):  period on study medication during
which efficacy will be assessed (primary evaluation period:  Weeks 24-36;
secondary evaluation period:  Weeks 40-52)
•
Long-Term Treatment Period (Weeks 53-End of Treatment [EOT]):
continued study medication to assess long-term safety
•
Follow-Up (EOT + 4 weeks):  post-treatment visit (either in person or via
telephone) for safety.
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 opportunity to have their Visit 13 (+/- 5 days).  All subjects will remain in the 


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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.
Mean Screening Hb <10.0 g/dL as determined by the average of 2 Hb values
measured by the central laboratory during Screening.
4.
Serum ferritin ≥100ng/mL and transferrin saturation (TSAT) ≥20% during
Screening
5.
Folate and vitamin B12 measurements ≥lower limit of normal during
Screening
6.
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.
Any ESA (eg, recombinant human erythropoietin [rhEPO], darbepoetin alfa,
or methoxy polyethylene glycol-epoetin beta) within 8 weeks prior to
randomization
5.
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.
6.
Uncontrolled hypertension (confirmed diastolic blood pressure >110 mmHg
or systolic blood pressure >180 mmHg) during Screening
7.
Severe heart failure during Screening (New York Heart Association Class IV)
8.
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
9.
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
10. History of deep vein thrombosis (DVT) or pulmonary embolism (PE) within
12 weeks prior to randomization
11. History of hemosiderosis or hemochromatosis
12. History of prior organ transplantation or scheduled organ transplant (subjects


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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) 
13. 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
14. Previous participation in this study, or previous participation in a study with a
hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) other than
vadadustat
15. Females who are pregnant or breast-feeding.  Women of childbearing
potential who are unable or unwilling to use an acceptable method of
contraception
16. Non-vasectomized male subjects who are unable or unwilling to use an
acceptable method of contraception
17. Any other reason that in the opinion of the Investigator would make
the subject not suitable for participation in the study
18. 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 therapy 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)
•
Proportion of subjects with Hb increase of >1.0 g/dL from Baseline
•
Time to achieve Hb increase of >1.0g/dL from Baseline


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•
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 to Week 52
•
Mean monthly dose of IV elemental iron administered from Baseline to Week
52 in subjects who have received IV iron
•
ESA rescue
•
Dose adjustments from Baseline to Week 52
•
Proportion of subjects receiving RBC transfusion(s) 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: 
•
Vadadustat starting dose:  2 tablets once daily (300 mg/day)
•
Darbepoetin alfa subcutaneous (SC) starting dose:  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
Dose Adjustment Guidelines – All Treatment Groups 


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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. 
 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 judgement 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, the Hb drawn as part of the local standard of care labs 
must be monitored monthly for dosing oversight.  Per the vadadustat or darbepoetin 
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 increase and 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. 
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 CKD (DD-CKD) and remain on study treatment, the dose 
adjustment should be based on the Dose Adjustment Algorithms (Appendices C and 
D). 
Vadadustat 
Vadadustat should be dosed according to the Dose Adjustment Algorithms in 
Appendix C. 


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Darbepoetin alfa 
Subjects who are randomized to receive darbepoetin alfa will be dosed according to the 
Dose Adjustment Algorithm (Appendix D). Darbepoetin alfa dosing is independent of 
the visit schedule, and the dosing schedule may shift per local standard of care, and 
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 
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.  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 BOTH of the following:
•
The subject has experienced worsening of the 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 


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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
transfusion will be captured in the appropriate CRF. Study medication (vadadustat or
darbepoetin alfa) may be continued during the transfusion period.
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 


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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
•
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 
subjects 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 


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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 in 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
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” (LTFU).  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 


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subjects during the study or in locating 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. 
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 to 36 (inclusive). 
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 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 date  to 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 assessment 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 


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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 over 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 1.25when 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.   
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
ESA
erythropoiesis-stimulating agent
ESC
Executive Steering Committee
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 Harmonisation 
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 
rhEPO 
recombinant human erythropoietin 
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 2006; Singh et al. 2006; Pfefferet 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 


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drugs, with a recommendation to keep Hb levels below 12 g/dL, while the Japanese practice 
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 & 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


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Phase 2b study evaluated Stages 3, 4, and 5 CKD (pre-dialysis) dosed for 20 weeks.  The phase 2 
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 correction and maintenance of Hb in subjects with 
anemia secondary to NDD-CKD. 
 
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
•
Time to achieve Hb increase of >1.0g/dL from Baseline


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•
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 to Week 52
•
Mean monthly dose of IV elemental iron administered from Baseline to Week 52 in subjects
who have received IV iron
•
ESA rescue
•
Dose adjustments from Baseline to Week 52
•
Proportion of subjects receiving RBC transfusion(s) 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:
-
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
•
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
•
AEs and SAEs
•
Vital signs and clinical laboratory values
Exploratory Endpoints 
•
Biomarkers (including but not limited to hepcidin and 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


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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 the correction of anemia and maintenance of Hb in 
subjects with NDD-CKD.  Target enrollment in this study is approximately 1850 subjects at 
approximately 390 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 at a starting dose of two 150 mg tablets once daily 
(300 mg/day) 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). 
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 (<9.5 g/dL versus ≥9.5 g/dL based on the most recent 
central laboratory Hb measurement prior to the Baseline/Randomization visit).  Following 
randomization, there will be 4 periods during the study: 
•
Correction period (Weeks 0-23):  the initial period on study medication for the correction of
Hb
•
Maintenance period (Weeks 24-52):  the period on study medication during which efficacy
will be assessed (primary evaluation period:  Weeks 24-36; secondary evaluation period:
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 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 increase and 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.  Dosing and dose 
adjustments will be based on the  Dose Adjustment Algorithm based on the current PI for 


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investigational sites in the US, and the SmPC for all other investigational sites (non-US)for adult 
patients with CKD not on dialysis (Section 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 Investigator discretion.   
During the Maintenance period, subjects randomized to receive vadadustat should continue to be 
dosed according to the Dose Adjustment Algorithms (Section 8.4.4.1, Vadadustat Dosing and 
Dose Adjustment Algorithms).  Subjects randomized to receive darbepoetin alfa may have their 
drug dose adjusted individually based on the PI for US sites or EU SmPC for non-US sites for 
the maintenance of treatment.  Local standard of care and regional/national guidelines should be 
taken into consideration for treatment maintenance. 
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 Correction period (Baseline [Week 0], 
Weeks 2, 4, 6, 8, 10, 12, 16, and 20), during the Maintenance period (Weeks 24, 28, 32, 36, 40, 
44, 48, and 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 


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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. 
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 


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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 
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 patient 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. 


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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
3. Mean Screening Hb <10.0 g/dL as determined by the average of 2 Hb values measured by
the central laboratory during Screening.
4. Serum ferritin ≥100 ng/mL and TSAT ≥20% during Screening
5. Folate and vitamin B12 measurements ≥lower limit of normal (LLN) during Screening
6. 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. Any ESA (eg, recombinant human EPO [rhEPO], darbepoetin alfa, or methoxy polyethylene
glycol-epoetin beta) within 8 prior to randomization
5. 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.
6. Uncontrolled hypertension (confirmed diastolic blood pressure >110 mmHg or systolic blood
pressure >180 mmHg) during Screening
7. Severe heart failure during Screening (New York Heart Association Class IV)
8. Acute coronary syndrome (hospitalization for unstable angina, 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
9. 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
10. History of DVT or PE within 12 weeks prior to randomization
11. History of hemosiderosis or hemochromatosis
12. 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)
13. 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


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14. Previous participation in this study or previous participation in a study with a hypoxia-
inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) other than vadadustat
15. 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)
16. 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)
17. Any other reason that in the opinion of the Investigator would make the subject not suitable
for participation in the study
18. 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 <10.0 g/dL.    
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 
therapy 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. 


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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 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).  
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 
key secondary efficacy analysis.  Thus, primary efficacy analyses will be based on the 
randomized population and every subject will have completed 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  


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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 
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


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•
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. 
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. 
 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.   
 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 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.  


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 Complete Withdrawal from Further Study Visits/Assessments 
A subject has the right to withdraw consent for participation in the study.  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 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 to ensure all options have been explored and that there is complete 
understanding by the subject for what constitutes withdrawal of consent. 
 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)


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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. 
 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.    


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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 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 PI for US sites or EU SmPC for non-US sites.  
 
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 redispensed 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.  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). 


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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 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. 


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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 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 vs EU vs ROW); 
2) New York Heart Association CHF Class (0 (no CHF) or I vs II or III); and 3) study entry Hb
level (<9.5 vs ≥9.5 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 study 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 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. 
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. 
Year 1-4 Treatment Period Visits 


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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 between study visits will be recorded in the appropriate CRF and the 
subject’s source when a HemoCue value 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.  lf the Investigator has an immediate clinical 
concern about a subject's HemoCue value, the Investigator may use clinical judgement 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, 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 increase and 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.  The Dose Adjustment Algorithm for darbepoetin alfa will follow 
the PI for investigational sites in the US, and the 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. 
 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 


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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. 
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 Algorithms 
(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). 
 Darbepoetin Alfa Dosing and Dose Adjustment Algorithms 
Subjects who are randomized to receive darbepoetin alfa will be dosed with starting doses based 
on the current PI for investigational sites in the US, and the SmPC for all other investigational 
sites (non-US).  Dose adjustments will be based on the Dose Adjustment Algorithm 
(APPENDIX D: Darbepoetin Alfa Dosing and Dose Adjustment Algorithms).  
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. 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 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 


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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 any other 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. 
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 the 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 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 Algorithm 
(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.   


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 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.   
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, for 
any subject with blood transfusion or IV iron use, the date of last, blood transfusion or iron 
treatment regimen 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. 


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8.5.2 Erythropoiesis-stimulation Agents 
Non-protocol ESAs are prohibited from Randomization until the end of the study, unless the 
subject is receiving ESA rescue therapy, interrupts study treatment 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 
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 


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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).
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)


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•
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. 
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). 


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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. 
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, patients 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


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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 the screening period is
less than 30 days, all medications taken within 30 days prior to the start of study medication
(vadadustat or darbepoetin alfa) will be recorded.  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, for any subject with blood transfusion or IV iron
use, the date of last blood transfusion or iron treatment regimen 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 


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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 
judgement 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 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 <10.0 g/dL.  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 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:  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 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.


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•
Biomarkers (including but not limited to, hepcidin, vascular endothelial growth factor
[VEGF]):  Samples for biomarker analysis will be drawn at 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.
•
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.
-
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 PK sampling will be documented.
-
Week 4, 12, 28, and 52 study visits: PK sampling will also be performed along with other
study laboratory samples being collected at the Week 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 <10.0 g/dL, 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. 


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The Investigator will maintain a log of subjects (both Pre-Screened and Screened) and indicate 
who of the Pre-Screened subjects was 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 subjects will undergo a number of Screening activities. 
 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:
-
CBC (without differential)
-
Iron indices
-
Folate and vitamin B12 levels
-
Serum Chemistry and eGFR
-
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. 
 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:
-
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 <10.0 g/dL 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. 


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 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 
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:
-
Random spot urine sample for uACR
-
Coagulation Tests
-
CRP
-
CBC (including differential)
-
Reticulocyte count
-
Serum chemistry and eGFR
-
Liver function tests
-
Iron indices
-
Lipid profile
-
EPO
-
Biomarkers
-
PK (see Section 9.2.2, Laboratory Evaluations; samples to be drawn only for subjects
randomly assigned to vadadustat)
-
Exploratory samples
•
Review of medical history for new conditions since Screening visit
•
Medication use since Screening visit
•
Study medication assessments and procedures:
-
Subject will take their first dose of study medication at the investigative site during the
Baseline visit
-
Hb by HemoCue for dose initiation
-
Vadadustat dispensing
-
Darbepoetin alfa dispensing


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-
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: 
•
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)
-
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)
-
Reticulocyte count (Weeks 4, 12, 28, and 52)
-
Serum chemistry (Weeks 28 and 52)
-
Serum creatinine and eGFR (Weeks 4, 8, 12, 20, 36, and 44; also at Weeks 28 and 52 as
part of the serum chemistry)
-
Liver function tests (Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44, and 52)
-
Iron indices (Weeks 4, 8, 12, 20, 28, 36, 44, and 52)
-
Lipid profile (Weeks 28 and 52)
-
EPO (Weeks 4, 12, 28, and 52)
-
CRP (Weeks 28 and 52)
-
Biomarkers (Weeks 12, 28, and 52)
-
PK (Weeks 4, 12, 28, and 52; see Section 9.2.2, Laboratory Evaluations; samples to be
drawn only for subjects randomized to vadadustat)
-
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:
-
AE assessment
-
RBC transfusions and ESA rescue
-
Therapeutic phlebotomy
-
MACE endpoint questionnaire
•
Medication assessments and procedures:
-
Review of concomitant medications
-
Hb by HemoCue for dose adjustment
-
Drug reconciliation:  Study medication (vadadustat or darbepoetin alfa) reconciliation
will be conducted per the pharmacy manual instructions.
-
Vadadustat dispensing as needed per Section 8.2.1, Dispensing of Vadadustat
-
Darbepoetin alfa dispensing
-
Iron supplementation as needed to maintain ferritin ≥100 ng/mL or TSAT ≥20% (per
local product label; see Section 8.4.6, Iron Supplementation)


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-
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.
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:
-
Random spot urine sample for uACR (Week 104)
-
CBC (Weeks 64, 76, 88, and 104; differential at Weeks 76 and 104)
-
Serum chemistry (Weeks 76 and 104)
-
Serum creatinine and eGFR (Weeks 76 and 104 as part of the serum chemistry)
-
Liver function tests (Weeks 64, 76, 88, and 104)
-
Iron indices (Weeks 64, 76, 88, and 104)
-
CRP (Week 104)
-
Biomarkers (Week 104)
-
Exploratory samples (Week 104)
•
Safety Assessments
-
AE assessment
-
RBC transfusions and ESA rescue
-
Therapeutic phlebotomy
-
MACE endpoint questionnaire
•
Medication assessments and procedures:
-
Review of concomitant medications
-
Hb by HemoCue for dose adjustment
-
Drug reconciliation:  Study medication (vadadustat or darbepoetin alfa) reconciliation
will be conducted per the pharmacy manual instructions.
-
Vadadustat dispensing as needed per Section 8.2.1, Dispensing of Vadadustat
-
Darbepoetin alfa dispensing
-
Iron supplementation to maintain ferritin ≥100 ng/mL or TSAT ≥20% (per local product
label; see Section 8.4.6, Iron Supplementation)
-
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


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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:
-
Random spot urine sample for uACR (Weeks 156 and 208)
-
CBC (Weeks 116, 128, 140, 156, 168, 180, 192, and 208; differential at Weeks 128, 156,
180, and 208)
-
Serum chemistry including serum creatinine and eGFR (Weeks 128, 156, 180, and 208)
-
Liver function tests (Weeks 116, 128, 140, 156, 168, 180, 192, and 208)
-
Iron indices (Weeks 116, 128, 140, 156, 168, 180, 192, and 208)
-
CRP (Week 156)
-
Biomarkers (Week 156)
-
Exploratory samples (Week 156)
•
Safety assessments:
-
AE assessment
-
RBC transfusions and ESA rescue
-
Therapeutic phlebotomy
-
MACE endpoint questionnaire
•
Medication assessments and procedures:
-
Review of concomitant medications
-
Hb by HemoCue for dose adjustmentDrug reconciliation:  Study medication (vadadustat
or darbepoetin alfa) reconciliation will be conducted per the pharmacy manual
instructions.
-
Vadadustat dispensing as needed per Section 8.2.1, Dispensing of Vadadustat
-
Darbepoetin alfa dispensing
-
Iron supplementation to maintain ferritin ≥100 ng/mL or TSAT ≥20% (per local product
label; see Section 8.4.6, Iron Supplementation)
-
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:


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-
Random spot urine sample for uACR
-
CBC (without differential)
-
Serum chemistry including serum creatinine and eGFR
-
Liver function tests
-
Iron indices
-
Biomarkers
-
CRP
-
Exploratory samples
•
Safety assessments:
-
AE assessment
-
RBC transfusions and ESA rescue
-
Therapeutic phlebotomy
-
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


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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
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 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 


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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  
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 or 
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.   
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 


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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):
-
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.
-
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.
-
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:
-
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
•
Examples of verbatim AE terms for intrarenal impairment include: acute tubular
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•
Examples of verbatim AE terms for postrenal impairment include: hydronephrosis,
pelvicaliectasis, and urinary tract obstruction
-
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.
-
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 of skin, 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.
•
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.


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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. 
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 


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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 
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. 


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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: 
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. 


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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 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. 
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.


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 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 
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. 


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 Sample Size Determination 
The goal of this study is to demonstrate the efficacy and safety of vadadustat compared with 
darbepoetin alfa for the correction and maintenance of Hb in subjects with anemia secondary to 
NDD-CKD.  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 over 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 
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.


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•
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, and 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 
(correction, 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. 
 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 


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(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 imputations will be used to impute the 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 to 36 (inclusive). 
 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 ≥ -0.75 g/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. 
 Sensitivity Analyses of Primary Efficacy Endpoint 
The following sensitivity analyses will be conducted:  
•
Primary analysis will be repeated using the full analysis population.


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•
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 or 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. 
 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. 
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 US vs. non-US, the endpoints will also be
analyzed for subsets based on the target Hb level:
-
the U.S. subset will be assessed due to the target Hb range being 10.0-11.0 g/dL in the
U.S.
-
the combined EU and ROW (non-US) will be assessed since the target Hb range is 10.0-
12 .0 g/dL in these two Regions
•
Geographic region (US, EU, ROW)
•
Age
•
Gender
•
Race
 Safety Analyses 
All analyses of safety data will use the randomized population. 


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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 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 standalone 
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
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: 


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•
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
An 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 
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. 


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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. 
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. 


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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 quality assurance 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. 
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. 


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 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. 
 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. 


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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. 
 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. 
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 


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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.; 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. 
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. 


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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. 
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, 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 
-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 
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 


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AbbreviationsAE = adverse event; ALT/SGPT = alanine transaminase/serum glutamic-pyruvic transaminase; AST/SGOT = aspartate aminotransaminase/serum glutamic oxaloacetic transaminase; BUN 
= blood urea nitrogen; CBC = complete blood count; CPK = creatine phosphokinase; 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 events; 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 retest.
[b] The Follow-Up visit can be performed either in person OR via the telephone. 
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 Algorithms [aa] 
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% 


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[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 procedures. The Screening
period starts at the time the informed consent is signed and will be a maximum of 8 weeks in duration. An additional optional consent form for collection of blood samples for future genetic analysis
will be provided at SV1.
[e] If the Pre-Screen HemoCue Hb is <10.0 g/dL, 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.
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]. For eligibility, the average of 2 Hb values measured by the central laboratory during Screening (SV1, SV2, or retest) must be <10.0 g/dL.    If the subject’s Hb does not qualify, the subject is 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, EOT.  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 aminotransaminase (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 and 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 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. 


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[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 therapy 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), or iron containing phosphate binders, or any iron-containing medications.  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 (EOS) status will be done to capture subject status at the global completion of the study or at the 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, their EOS status will be collected at the Follow-up visit.  For subjects that have permanently discontinued study medication and continue to be 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 


Protocol No. AKB-6548-CI-0014 
 
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Page 87 of 102 
APPENDIX C:  VADADUSTAT DOSING AND DOSE ADJUSTMENT ALGORITHMS 


Protocol No. AKB-6548-CI-0014 
 
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Akebia — Company Confidential 
Page 88 of 102 
PR02TECT-CORRECTION (Cl-0014) 
Vadadustat Dose Adjustment - Outside United States 
Tarnet Hb: 10.0 ~/d L - 12.0 ~/dL 
• Do not increasethe dose more frequently than once every 4 w eeks. 
• Decreases in dose can occur more frequently. 
• If a dose adj ustment is requ ired to ach ieve or maintain Hb at the desired level, the vadadustat dose i s adj usted by 1 tablet (150 mg). 
• The protocol provi des guidance for the treatment of subjects w ith anemia assoc iated with CKD in order to ach ieve and maintain Hb levels w ith in the target Hb 
range. Dose adj ustment shoul d be based on the investigator's cl inica l discreti on, incorporatingthe protocol guidance and consi dering the subj ect's cl inical 
cond it i on, Hb rate of rise, Hb rate of decl ine, and Hb vari ability. 
• Dose opti ons are 150, 300, 450, or 600 mg. 
Current 
HemoCue Hb 
Rapid Ri,e in Hb 
(>l.Og/ dl incre= in 
a 2 w eek period or 
>2.0 g/ dl increase in 
a 4w eek period) 
Dose increase 
within 4weeks 
No 
Dose 
Increase 
Recommendation 
dose by 1 
tabl et 
<10.0g/dl 
No 
Yes 
Yes 
Maintain 
Reduced ose by 1 
dose 
t ablet or maintain 
dose 
HemoCue Hb (g/dL) 
10.0 g/d L-12.0 g/d L 
No 
Maintain 
dose 
Yes 
Decrease 
doseby l 
tabl et or 
maimain 
dose 
> 12.0g/dl 
Reduce dose 
by 1 tabl et 
> 13.0g/dl 
Interrupt 
If t he Hb has not 
increased by 
> 0.5 g/ dl above t he 
baseline value after 
4 weeks of treat ment, 
and Hb < 10.0 g/ dl, 
increase t he vadadustat 
dose by 1 t ablet. 
dose until HbS 12.0 
g/ dl, then resumewith 
1 few er t ablet. If subject 
w as on 1 t ab et prior to 
interruption, then 
resume dosing with 1 
tabl et 


Protocol No. AKB-6548-CI-0014 
 
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Page 89 of 102 
PR02TECT-CORRECTION (Cl-0014) 
Vadadustat Arm Initiating Dialysis to Follow Vadadustat Dose Adjustment Algorithm for 
DD-CKD - United States 
Target Hgb: 10.0 g/ dl -11.0 g/ dl 
• Do not increase the dose more frequently than once every 4weeks 
• Decreases in dose can occur more frequently 
• If a dose adj ustment is requ ired to achieve or maintain Hgb at the desired level, the vadadustat dose is adj usted by 1 tablet (150 mg) 
• The protocol provi des guidance for the treatment of subjects w ith anemia assoc iated with CKD in order to ach ieve and maintain Hb levels w ith in the target Hb 
range. Dose adj ustment shoul d be based on the investigator's cli nica l discreti on, incorporatingthe protocol guidance and consi dering the subj ect's clinical 
cond it ion, Hgb r ate of rise, Hgb rate of decl ine, and Hgb variability 
• Dose options are 150, 300, 450, or 600 mg 
Current 
HemoCue Hgb 
Rapid Ri,e in Hgb 
(>1.0g/ dl incre= in a 2 
w eek period or >2.0 g/ dl 
increase in a 4w eek 
period) 
Dose increase 
within 4weeks 
No 
Dose 
Increase 
Recommendation 
dose by 1 
tabl et 
<10.0g/dl 
No 
Yes 
Yes 
Maintain 
Reduced ose by 1 
dose 
t ablet or maintain 
dose 
HemoCue Hgb (g/dL) 
10.0 g/dl-11.0 g/dl 
No 
Maintain 
dose 
Yes 
Reduce 
dose by 1 t ablet 
or maintain 
dose 
> 11.og/dl 
If t he Hgb has not 
increased by 
> 0 .5 g/ dl above t he 
baseline value after 
4 w eeks of treat ment, 
and Hgb < 10.0 g/ dL, 
increase t he vadadustat 
dose by 1 t ablet 
Interrupt dose until Hgb 
decreases; 11.0g/ dl, then 
resumewith 1 few er tablet. If 
subject w as on 1 tablet prior to 
interruption, then resume 
dosing with 1 tablet 


Protocol No. AKB-6548-CI-0014 
 
Amendment 7 (Version 8) 
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Page 90 of 102 


Protocol No. AKB-6548-CI-0014 
 
Amendment 7 (Version 8) 
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APPENDIX D: DARBEPOETIN ALFA DOSING AND DOSE ADJUSTMENT ALGORITHMS 


Protocol No. AKB-6548-CI-0014 
 
Amendment 7 (Version 8) 
Akebia — Company Confidential 
Page 92 of 102 
PR02 TECT-CORRECTION (Cl-0014) 
Darbepoetin Alfa Dose Adjustment-Outside United States 
Ta rget Hb: 10.0 g/dL - 12.0 g/dL 
• Do not increasethe dose more freq uently than once every 4 w eeks. 
• Decreases in dose can occur more frequently. 
• If a dose adj ustment is requ ired to achieve or maintain Hb at the desired level, the darbepoetin dose is adj usted by-2 5%. 
• The protocol provi des guidance for the treatment of subjects with anemia assoc iated with CKD in order to ach ieve and maintain Hb levels w ith in the target Hb 
range. Dose adj ustment shoul d be based on the investigator's cl inica l discreti on, incorporatingthe protocol guidance and consi dering the subj ect's cl inical 
cond it ion, Hb rate of rise, Hb rate of decl ine, and Hb vari ability. 
Current 
HemoCue Hb 
Rapid Ri,e in Hb 
(>1.0 g/ dl increase 
in a 2 w eek period 
or >2.0 g/ dl 
increase in a 4 week 
peri od) 
Do,e increa,e 
w ithin 4week, 
No 
Dose 
Increase 
Recommendation 
dose by 
-25% 
No 
< 10.0 g/ dl 
Yes 
Maintain 
dose 
_L 
Yes 
Reducedaseor 
maintain 
dose 
HemoCue Hb (g/dl) 
10.0 g/ dl-12.0 g/ dl 
No 
Maintain 
dose 
Yes 
Reduce 
dose by 
-25% or 
maintain 
dose 
> ll.Og/ dl 
If t he Hb has not 
increased by more t han 
1.0 g/ dl above t he 
baseline value after 4 
weeks of treat ment AND 
Hb is < 10.0 g/ dl, 
increase t he 
darbepoet in alfa dose by 
-2s%. 
If the Hb > 12.0g/ dl, a dose reduction should 
be considered. 
If the Hb continues to increase, the dose should 
be reduced by-25%. 
If after a d ase reduction, H b continues to 
increase, the d ase should be temporarily 
w ithheld until th e Hb begins to decrease, at 
w hich point t herapy should be reinitiated at 
-25% l owerthanthe previous dose. 


Protocol No. AKB-6548-CI-0014 
 
Amendment 7 (Version 8) 
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Page 93 of 102 
PR02TECT-CORRECTION (Cl-0014) 
Darbepoetin A fa Arm Initiating Dialysis to Follow Darbepoetin Alfa Dose Adjustment 
Algorithm for DD-CKD- United States 
Target Hgb: 10.0 g/d L - 11.0 g/d L 
• Do not increasethe dose more frequently than once every 4 w eeks 
• Decreases in dose can occur more frequently 
• If a dose adj ustment is required to ach ieve or maintain Hgb at the desired level, the darbepoetin dose is adj usted by-25% 
• The protocol provi des guidance for the treatment of subjects w ith anemia assoc iated with CKD in order to ach ieve and maintain Hgb levels w ith in the target 
Hgb range. Dose adj ustment shou ld be based on the investigator's cl inical discreti on, incorporating the protocol gui dance and consi deringthe subject's cl inical 
cond it i on, Hgb rate of rise, Hgb rat e of decl ine, and Hgb variability. 
Current 
HemoCue Hgb 
Rapid Rise in Hgb 
(>l.Og/ dlincrease in 
a 2 w eek period or 
>2.0 g/ dl increase in 
a 4w eek period) 
Dose increase 
within 4weeks 
No 
Dose 
Increase 
Recommendation 
dose by 
-25% 
No 
< 10.0 g/dl 
Yes 
Maintain 
dose 
_L 
Yes 
Reduce dose by 
-25% or 
maintain 
dose 
HemoCue Hgb (g/dL) 
10.0 g/dl -11.0g/dl 
No 
Maintain 
dose 
Yes 
Reduce 
dose by 
- 25% or 
maintain 
dose 
> 11.0g/dl 
Interrupt dose or 
reduce doseby-25% 
If t he Hgb has not 
increased by more t han 
1.0 g/ dL above t he 
baseline value after 4 
weeks of treat ment AND 
Hgb is < 10.0 g/ dL, 
increase t he 
darbepoet in alfa dose by 
- 2s%. 


Protocol No. AKB-6548-CI-0014 
 
Amendment 7 (Version 8) 
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Protocol No. AKB-6548-CI-0014 
 
Amendment 7 (Version 8) 
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APPENDIX E:  END OF TREATMENT AND GLOBAL STUDY COMPLETION 
SUBJECT FLOW 


Protocol No. AKB-6548-CI-0014 
 
Amendment 7 (Version 8) 
Akebia — Company Confidential 
Page 96 of 102 
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.”
•
Added that 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, a Clinical Expert 
Advisory Board, and 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:
-
Exclusion Criterion No. 9: Additional clarification of exclusionary cardiovascular events
within 12 weeks prior to screening
-
Exclusion Criterion No. 10: To not exclude subjects with basal cell carcinoma who have
been successfully treated with cryotherapy instead of surgical resection
-
Exclusion Criterion No. 13: To specifically exclude subjects with a history of
hematopoietic stem cell transplant
-
Exclusion Criterion No. 15: 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 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


Protocol No. AKB-6548-CI-0014 
 
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Page 97 of 102 
•
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 3 (Version 4;
) 
Amendment 3 was issue 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.
-
Screening period changed from up to 4 weeks to up to 8 weeks
-
One retest will be allowed for each laboratory parameter, within the screening period.
-
Subjects who receive iron replacement therapy may retest screening Hb a minimum of 3
weeks after completion of iron replacement therapy.
•
To update the following exclusion criterion:
-
Exclusion Criterion No. 3: Adjusted due to increase of screening period from up to 4
weeks to up to 8 weeks
-
Deletion of Exclusion Criterion No.  4: Intravenous (IV) iron within 4 weeks prior to or
during screening
-
Exclusion Criterion No. 5 (now 4): Adjusted due to increase of screening period from up
to 4 weeks to up to 8 weeks
-
Exclusion Criterion No 10 (now 9): To clarify that benign colonic polyps is not a
malignancy, therefore removed to correct the error
-
Exclusion Criterion No. 11 (now 10): 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


Protocol No. AKB-6548-CI-0014 
 
Amendment 7 (Version 8) 
Akebia — Company Confidential 
Page 98 of 102 
•
The number of total sites has been increased in efforts to increase enrollment.  Enrollment
may be extended up to 1600 patients, to achieve the primary safety endpoint if the actual
MACE accrual is lower than initially estimated.
•
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.
•
To clarify that IV iron may be given to subjects who are intolerant or not responding well to
oral iron.
•
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 Darbepoetin alfa administration and accountability
-
Darbepoetin alfa should be administered per the label.
-
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.
-
Added additional information on return of darbepoetin for drug accountability and
compliance assessment.
•
9.2.2 Laboratory Evaluations was revised to reflect the following:
-
Modification to the frequency of protocol specified Biomarker sample collection
-
Additional exploratory sample collection
•
A clarification of the study analysis populations has been provided.
Amendment 4 (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 5.3 Secondary Efficacy Endpoints was updated to reflect addition of several key
secondary, other secondary efficacy endpoints and safety endpoints in alignment with the
Statistical Analysis Plan (SAP).
•
Section 7.4.1 Retesting was updated for simplification.
•
Section 7.5.5 Individual Subject Discontinuation was updated to add Lack of Efficacy as a
reason for permanent discontinuation of study medication or study participation for accurate
data capture.
•
Section 7.5.1 Study Completion was revised to clarify that all enrolled subjects in this study
will have completed (at least) the week 36 visit.
•
Section 8.4.4 Dosing and Dose Adjustment Guidelines was revised to guide Investigators to
follow printed dose adjustment algorithms in the protocol Appendices in lieu of IWRS-
programmed dosing recommendations due to some aspects of IWRS-programmed dosing
instructions did not operate as planned. Updated guidance to Investigators to use clinical
judgement and other Hb data to appropriately dose subjects in cases of clinical concern


Protocol No. AKB-6548-CI-0014 
 
Amendment 7 (Version 8) 
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Page 99 of 102 
regarding HemoCue value. 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 study medications.
•
Section 8.5 Prior and Concomitant Therapy was updated to clarify 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 Hb drawn as part of local standard of care labs or via an unscheduled visit.
•
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 define overdose of study medications.
•
Section 11.1.1 Sample Size for Primary Efficacy Endpoint was updated to a change in the
non-inferiority margin from -0.5 to -1.0 g/dL.
•
Section 11.1.2 Sample Size for the Primary Safety Endpoint was updated with enrollment
projections and median study drug exposure times.
•
Section 11.5 Missing Data was updated to align with Statistical Analysis Plan (SAP).
•
Section 11.6.3 Subgroups was updated to pre-specify key subgroups for subsequent analysis.
•
Section 11.7.2 Analysis of Adverse Events was updated to provide AE summaries for
specific sub groups.
Amendment 5 (Version 6.0; 
) 
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.


Protocol No. AKB-6548-CI-0014 
 
Amendment 7 (Version 8) 
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Page 100 of 102 
•
Section 7.5.5 Individual Subject Discontinuation was updated to emphasize the
importance of continuing to follow subjects through global study completion.
•
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 updated 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 to 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 9.3.8 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 9.3.11 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.


Protocol No. AKB-6548-CI-0014 
 
Amendment 7 (Version 8) 
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Page 101 of 102 
•
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.
•
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 (Version 7.0; 
) 
Amendment 6 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 (Version 8; 
) 
Amendment 7 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.


Protocol No. AKB-6548-CI-0014 
 
Amendment 7 (Version 8) 
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Page 102 of 102 
•
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.


Protocol No. AKB-6548-CI-0014 
 
Amendment 6 (Version 7) 
Akebia — Company Confidential 
Page 1 of 5 
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 
Correction of Anemia in subjects with Non-Dialysis-
dependent Chronic Kidney Disease (NDD-CKD) 
(PRO2TECT – CORRECTION) 
Protocol Number: 
AKB-6548-CI-0014 
Compound:  
Vadadustat (AKB-6548)  
Status / Date: 
Amendment 7 (Version 8; 
) 
Amendment 6 (Version 7; 
) 
Amendment 5 (Version 6; 
) 
Amendment 4 (Version 5; 
) 
Amendment 3 (Version 4; 
) 
Amendment 2 (Version 3; 
) 
Amendment 1 (Version 2; 
) 
Original Protocol (Version 1; 
) 


Protocol No. AKB-6548-CI-0014 
 
Amendment 6 (Version 7) 
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 red and deleted text is identified by strikethrough, red font. 
Protocol Section 
Text in Version 7.0 (Amendment 6) 
Changes through Version 8.0 (Amendment 7) 
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. 


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Akebia — Company Confidential 
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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
bilirubin (eg, viral hepatitis, acute
liver disease).
(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).
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);
To include language for 
elevations in ALT or AST 
>3 times ULN.


Protocol No. AKB-6548-CI-0014 
 
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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.
•
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 
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
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 of skin, 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.
•
Designated Medical Events - The sponsor maintains
a list of designated medical events  (DME) that they
will always classify as serious adverse events.   If an
To define a list of designated 
medical events that shall 
always be classified as serious 
adverse events (SAEs).   


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met. If a subject develops basal 
cell carcinoma of skin, squamous 
cell carcinoma of skin, 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.   
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. 

SAP_001.pdf: 
AKB-6548-CI-0014 and AKB-6548-CI-0015
This Supplement Contains: 
•
Combined Statistical Analysis Plan (SAP) for study AKB-6548-CI-0014 (NCT02648347) 
and AKBˇ6548-0015(NCT02680574)  (only 1 version)
•
Combined SAP to monitor Major Adverse Cardiovascular Events (MACE) for study 
AKB-6548-CI-0014 (NCT02648347) and AKBˇ6548-0015(NCT02680574) (only 1 
version)
Date: 29 Jan 2020


Akebia Therapeutics, Inc.  
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Confidential 
Page 1 
Statistical Analysis Plan 
PHASE 3, RANDOMIZED, OPEN-LABEL, ACTIVE-CONTROLLED 
STUDY EVALUATING THE EFFICACY AND SAFETY OF ORAL 
VADADUSTAT FOR THE CORRECTION OF ANEMIA IN SUBJECTS 
WITH NON-DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE 
(NDD-CKD)  
(PRO2TECT – CORRECTION, AKB-6548-CI-0014) 
and 
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, AKB-6548-CI-0015) 
AKB-6548-CI-0014 and AKB-6548-CI-0015 
Sponsored by: 
Akebia Therapeutics, Inc. 
Version: 1.0 
Confidentiality Statement 
Part or all of the information in this statistical analysis plan may be unpublished material. 
Accordingly, this document is to be treated as confidential and restricted to its intended use. This 
material is the property of Akebia Therapeutics, Inc. and must not be disclosed or used except as 
authorized in writing by Akebia Therapeutics, Inc. 


Akebia Therapeutics, Inc.  
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1 
TABLE OF CONTENTS 
Statistical Analysis Plan .................................................................................................................. 1 
1 
Table of Contents ................................................................................................................... 2 
1 
Introduction ............................................................................................................................ 9 
2 
Description of the Studies ...................................................................................................... 9 
2.1 
Randomization and Stratification .............................................................................. 9 
2.2 
Study Periods ........................................................................................................... 10 
2.3 
Target Hb Ranges .................................................................................................... 10 
2.4 
Primary Objectives of the Trials .............................................................................. 11 
2.5 
Blinding.................................................................................................................... 11 
2.6 
Sample Size .............................................................................................................. 11 
2.7 
Efficacy .................................................................................................................... 11 
2.8 
Safety ....................................................................................................................... 12 
3 
Analysis Populations ............................................................................................................ 12 
3.1 
The Analysis Populations ........................................................................................ 12 
3.2 
Characterization of the Analysis Population ............................................................ 13 
4 
Quality of the trials .............................................................................................................. 13 
4.1 
Study Drug Dosing and Compliance ....................................................................... 13 
4.2 
Protocol Deviations .................................................................................................. 13 
4.3 
Baseline Characteristics, Exposure, and Retention by Treatment Group ................ 13 
5 
General Conventions ............................................................................................................ 14 
5.1 
Visit and Analysis Time Period Classification ........................................................ 14 
5.2 
Definition of Baseline .............................................................................................. 16 
5.3 
Prior and Concomitant Medication .......................................................................... 16 
5.4 
Handling of Missing Data ........................................................................................ 17 
6 
Efficacy Endpoints ............................................................................................................... 18 
6.1 
Primary Efficacy Endpoint ...................................................................................... 18 
6.2 
Key Secondary Efficacy Endpoints ......................................................................... 18 
6.3 
Other Efficacy Endpoints ......................................................................................... 18 
6.3.1 Definition of Rescue Episode ...................................................................... 18 
6.3.2 Endpoints Related to Hb .............................................................................. 18 


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6.3.3 Endpoints Related to Iron ............................................................................ 19 
6.3.4 Other Laboratory Parameters ....................................................................... 19 
6.3.5 Dose Adjustments and Interruptions ............................................................ 20 
6.3.6 Progression of CKD ..................................................................................... 20 
6.3.7 Endpoints Related to RBC Transfusion ....................................................... 20 
6.3.8 Endpoints Related to ESA Usage ................................................................ 20 
6.3.9 Rescue Therapy: Series of Definitions ........................................................ 21 
7 
Non-Mace Safety Endpoints ................................................................................................ 22 
8 
PHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) ANALYSIS ........................ 22 
9 
Efficacy Endpoints and Analyses ........................................................................................ 23 
9.1 
Definition of Primary Efficacy Endpoint: Change from Baseline in Hb ................. 23 
9.1.1 Baseline Hb .................................................................................................. 23 
9.1.2 Hb in the Primary Efficacy Period ............................................................... 23 
9.1.3 Change in Hb From Baseline to the Primary Efficacy Period ..................... 24 
9.1.4 Analysis of Change From Baseline in Hb to the Primary Efficacy Period .. 24 
9.1.5 Sensitivity Analyses to the Primary Efficacy Results.................................. 24 
9.2 
Secondary Efficacy Endpoints: Definitions and Analyses ...................................... 25 
9.3 
Other Efficacy Endpoints: Strategies for Analysis .................................................. 25 
9.3.1 Having Average Hb Value in the Geography-Specific Target Range in 
Weeks 24 to 36......................................................................................................... 25 
9.3.2 Having Average Hb Value in the Geography-specific Target Range in 
Weeks 40 to 52......................................................................................................... 26 
10 
Safety Analyses .................................................................................................................... 27 
10.1 
Mortality .................................................................................................................. 27 
10.2 
Hb-related Safety Endpoints .................................................................................... 28 
10.3 
Adverse Events and Serious Adverse Events .......................................................... 28 
10.4 
Other Safety Endpoints ............................................................................................ 29 
11 
Subgroups ............................................................................................................................ 29 
12 
Other Exploratory Analyses ................................................................................................. 31 
13 
Database Lock and Unblinding ............................................................................................ 31 
13.1 
Blind Review of Selected Data Prior to Final Database Lock ................................. 31 
13.2 
Final Database Lock ................................................................................................ 32 
13.3 
Authorization for Unblinding .................................................................................. 32 


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Appendix A. 
Justification of the Noninferiority Margin ........................................................ 33 
A.1. 
Historical Trials for Indication................................................................................. 33 
A.2. 
Characteristics of Study Arms ................................................................................. 33 
A.2.1. Placebo Control ........................................................................................................ 35 
A.2.2. Baseline and Target Hb Levels ................................................................................ 35 
A.3. 
Statistical Methods ................................................................................................... 36 
Derivation of Input Statistics ................................................................................... 36 
Placebo Adjustment ................................................................................................. 36 
Justification of the Model ........................................................................................ 37 
A.4. 
Results of Meta-analysis .......................................................................................... 38 
A.5. 
Rationale for Margin ................................................................................................ 39 
Appendix B. 
Missing data (including multiple imputation) .................................................. 41 
B.1. 
Overall Approach ..................................................................................................... 41 
B.2. 
Multiple Imputation of all Missing Values .............................................................. 43 
B.3. 
Primary Efficacy Analysis ....................................................................................... 43 
B.3.1. SAS Code for Standard Multiple Imputation using FCS ......................................... 43 
B.3.2. Tipping Point Sensitivity Analysis for Missing Data .............................................. 45 
B.4. 
Secondary Efficacy Analyses .................................................................................. 46 
B.5. 
Other Efficacy Analyses .......................................................................................... 46 
B.6. 
Random Seed Specification ..................................................................................... 47 
Appendix C. 
Analysis of continuous endpoints ..................................................................... 49 
Analyses using ANCOVA ....................................................................................... 49 
C.1.1. Primary Analysis ...................................................................................................... 49 
C.1.2. Select Sensitivity Analyses for the Primary Efficacy Endpoint .............................. 50 
C.1.3. Analysis of Continuous Secondary Endpoint .......................................................... 50 
C.1.4. Analysis of Additional Continuous Endpoints ........................................................ 51 
Analyses Using MMRM .......................................................................................... 51 
Appendix D. 
Analysis of non-normal endpoints .................................................................... 53 
D.1. 
Analysis of Binary Endpoints .................................................................................. 53 
D.2. 
Analysis of Count Data ............................................................................................ 54 
D.3. 
Analysis of Time to Event Data ............................................................................... 54 
Appendix E. 
Clinical laboratory and vital sign Safety endpoints .......................................... 56 
E.1. 
Clinical Laboratory Evaluation ................................................................................ 56 


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E.1.1 Liver Function Abnormality .................................................................................... 56 
E.1.2 Serum and Urine Pregnancy Tests ........................................................................... 56 
E.1.3 Urine Albumin-to-creatinine Ratio (uACR) ............................................................ 56 
E.1.4 Complete Blood Count ............................................................................................ 57 
E.1.5 Chemistry and Estimated Glomerular Filtration Rate (eGFR) ................................ 57 
E.1.6 C-reactive protein and Vascular Endothelial Growth Factor ................................... 58
E.1.7 Erythropoietin .......................................................................................................... 58 
E.2. 
Vital Signs, ECGs, and Physical Findings ............................................................... 59 
E.2.1 Vital Signs and Weight ............................................................................................ 59 
E.2.2 12-lead ECG ............................................................................................................. 59
Appendix F. 
Adverse events of special interest .................................................................... 60 
F.1. 
Potential Risks ......................................................................................................... 60 
F.2. 
Events of Special Interest......................................................................................... 60 
F.3. 
Events Under Monitoring ........................................................................................ 60 
14 
References ............................................................................................................................ 61 
15 
Attachments ......................................................................................................................... 63 
Approval Sheet.............................................................................................................................. 63 
2 
LIST OF TABLES 
Table 1. 
Classification of Assessments at Every Visit for Years 1 through 4 ....................... 15 
Table 2. 
Classification of assessments at select visits for Years 1 through 4 ........................ 16 
Table 3. 
Other Efficacy Endpoints ......................................................................................... 26 
Table 4. 
Hb-related Safety Endpoints from First Dose Date to Last Visit ............................ 28 
3 
LIST OF APPENDIX TABLES 
Table A 1. Study Characteristics ............................................................................................... 34 
Table A 2. Input Dataset for Meta-analysis ............................................................................... 37 
Table A 3. Percent of Treatment Effect Preserved by Study Type and Margin ........................ 40 
Table B 1. 
Outcome Variables and Covariates in the Multiple Imputation Models ................. 42 
4 
LIST OF APPENDIX FIGURES 
Figure A 1. 
Treatment Effect by Baseline and Target Hemoglobin Levels ............................. 35 
Figure A 2. 
Forest Plot of Placebo-adjusted Treatment Effect of ESAs on Hemoglobin ........ 39 


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5 
LIST OF APPENDIX LISTINGS 
Listing B 1. 
Random Seed Assignment for all Planned Analyses ............................................ 48 
6 
LIST OF APPENDIX EXHIBITS 
Exhibit B 1. 
SAS Code for Standard Imputation of Missing Values for the Primary Efficacy 
Analysis 
44 
Exhibit B 2. 
SAS Code to Compute the M Estimates of Treatment Effect ............................... 44 
Exhibit B 3. 
SAS Code to Obtain the Overall Estimate and Standard Error ............................. 45 
Exhibit B 4. 
SAS Code for Tipping Point Analysis .................................................................. 46 
Exhibit B 5. 
SAS Code to Obtain the Mantel-Haenszel Estimate of Risk Difference .............. 47 
Exhibit B 6. 
SAS Code for Random Seed Generation .............................................................. 47 
Exhibit C 1. 
SAS Code for Primary Analysis ............................................................................ 50 
Exhibit C 2. 
SAS Code for Sensitivity Analysis for the Primary Efficacy Endpoint ................ 52 
Exhibit D 1. SAS Code for Analyzing Binary Endpoints .......................................................... 53 
Exhibit D 2. SAS Code for Analyzing Count Endpoints ........................................................... 54 
Exhibit D 3. SAS Code for Time to Event Data Analysis ......................................................... 55 


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Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
CBC 
complete blood count 
CHF 
congestive heart failure 
CKD 
chronic kidney disease 
CRF 
case report form 
CRP 
c-reactive protein
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DA 
darbepoetin alfa 
DBP 
diastolic blood pressure 
DD 
dialysis dependent 
ECG 
electrocardiography 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
Epo 
erythropoietin 
EpoA 
erythropoietin alfa 
EOS 
end of study 
EOT 
end of treatment 
ESA 
erythropoietin-stimulating agent 
EU 
European Union 
FAS 
Full Analysis Set 
FCS 
fully conditional specification 
Hb 
hemoglobin 
HDL 
high-density lipoprotein 
HLGT 
gigh-level group term 
HLT 
high-level term 
HR 
hazard ratio 
IDMC 
Independent Data Monitoring Committee 
IV 
intravenous 


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Abbreviation 
Definition 
IWR 
interactive web response 
LDL 
low-density lipoprotein 
LLD 
lower limits of detection 
MACE 
major adverse cardiovascular event(s) 
MAR 
missing at random 
MNAR 
missing not at random 
MMRM 
mixed models for repeated measurements 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDD-CKD 
non-dialysis-dependent chronic kidney disease 
NEC 
not elsewhere classfied 
NYHA 
New York Heart Association 
PEP 
primary efficacy period 
PK 
pharmacokinetic 
PP 
per protocol 
PT 
preferred term 
RBC 
red blood cell 
ROW 
Rest of World 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SC 
subcutaneous 
SD 
standard deviation 
SEP 
secondary efficacy period 
SMQ 
Standardized MedDRA Query 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TIBC 
total iron-binding capacity 
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 cells 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) covers the two PRO2TECT studies, Protocols 
AKB-6548-CI-0014 and AKB-6548-CI-0015, hereafter referred to as CI-0014 and CI-0015, 
respectively. 
The SAP supports the Statistical Methods Section of the clinical study reports (CSRs). It 
elaborates upon the protocol-specified endpoint definitions and the formal statistical methods 
that will be used in analyzing both studies. Unless otherwise specified, all analyses will be 
conducted for each study separately.  
Throughout this SAP, planned analyses of both studies are identical to each other except in those 
places that specifically identify where the plans diverge. Akebia does not intend to pool data 
together for formal efficacy and general safety analyses; however, analyses of major adverse 
cardiovascular events (MACE) will be pooled from both studies. A separate SAP will describe 
the planned methodology for the MACE analyses. 
If the analyses described in the protocols differ from those in this SAP, the methods of the SAP 
prevail.  
This SAP contains language and programming code that specifies the exact intent of each 
analysis. The sponsor will finalize and sign this document prior to locking the database and 
unblinding (see Section 2.5). Many of the analyses described in this SAP are quite complex. A 
blinded team of clinicians and statisticians will review the data carefully to develop conventions 
and analytic methods not anticipated in writing this SAP. 
2 
DESCRIPTION OF THE STUDIES 
Both PRO2TECT studies are Phase 3, randomized, open-label, active-controlled trials of the 
efficacy and safety of vadadustat compared to darbepoetin alfa (DA). CI-0014 addresses the 
correction of anemia and maintenance of hemoglobin (Hb) in subjects with anemia secondary to 
non-dialysis-dependent chronic kidney disease (NDD-CKD). CI-0015 addresses the maintenance 
treatment of anemia after conversion from current erythropoietin-stimulating agent (ESA) 
therapy in subjects with anemia secondary to NDD-CKD. 
2.1 
Randomization and Stratification 
In each study, subjects who meet all inclusion and no exclusion criteria are randomized 1:1 to 
vadadustat or darbepoetin alfa. Randomization is stratified by the following three variables: 
•
Geographic region: United States (US); European Union (EU); Rest of World (ROW)
•
New York Heart Association (NYHA) congestive heart failure (CHF) class: 0 or I; II or III
In addition, each study has the following strata defined by Hb levels at entry: 
Study entry Hb level 
CI-0014
CI-0015
<9.5 g/dL; ≥9.5 g/dL 
<10 g/dL; ≥ 10 g/dL 


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2.2 
Study Periods 
Following randomization, the studies have the following initial study periods: 
Study CI-0014 
•
Correction Period (Weeks 0 to 23): initial period on study medication for correction of Hb
•
Maintenance Period (Weeks 24 to 52):
o
Weeks 24 to 36: primary efficacy period (PEP)
o
Weeks 40 to 52: secondary efficacy period (SEP)
Study CI-0015 
•
Conversion and Maintenance Period (Weeks 0-52):
o
Weeks 0 to 23: conversion to study treatment for maintaining Hb
o
Weeks 24 to 36: PEP
o
Weeks 40 to 52: SEP
After Week 52, subjects in both studies will proceed to the following 2 periods: 
•
Long-Term Treatment Period (Weeks 53-End of Treatment [EOT]): continued treatment
with study medication to assess long-term safety
•
Follow-up Period (EOT + 4 weeks): post-treatment visit (either in person or by telephone)
to assess safety
The duration of the trial will depend on how long it takes for a total of 631 adjudicated MACE to 
occur in the 2 studies combined. A separate SAP will describe the planned MACE analyses, 
including the method planned for pooling data from the 2 PRO2TECT studies. 
The safety reporting period for a subject enrolled in this study begins upon randomization and 
ends at the final protocol-required study contact (visit or telephone), also known as a subject’s 
end of study (EOS). In addition, the Investigator should report any adverse event (AE) that 
occurs after this period if he or she assesses it as possibly or probably related to the study 
medication. 
According to the schedule of visits in the protocol, no laboratory assessments, physical exams, or 
other procedures are planned after the subject’s permanent discontinuation of study medication, 
also known as EOT; however, AE and rescue therapy assessments, including monitoring for 
MACE endpoints, will continue until a subject’s EOS. 
The analysis time periods for efficacy divide the Correction/Conversion and Maintenance 
periods, Year 1 collectively, into four windows (see Table 1).  
2.3 
Target Hb Ranges 
In several places, this SAP refers to the following target Hb ranges as specified in the 
2 protocols: 
•
US target:
10-11 g/dL
•
EU, ROW target:
10-12 g/dL


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2.4 
Primary Objectives of the Trials 
The primary objectives of CI-0014 trial are to compare the efficacy and safety of vadadustat to 
darbepoetin alfa for the correction and maintenance of Hb in subjects with anemia secondary to 
NDD-CKD. For CI-0015, the primary objectives relate to the conversion and maintenance of Hb. 
2.5 
Blinding 
Both trials are randomized open-label studies. Because of their open-label design, the protocols 
include careful steps to avoid bias. 
An interactive web response (IWR) system governs treatment assignment. The investigators are 
not aware of which treatment will be assigned next. Because Hb values are objective and will be 
measured at a central laboratory for all efficacy endpoints, efficacy assessments are not subject 
to bias.  
The studies include blinded adjudication of MACE, the use of an unblinded Independent Data 
Monitoring Committee (IDMC), and an identical schedule of visits, procedures, and assessments 
for both treatment groups as strategies to reduce the potential for bias. 
To reduce subjectivity of dose adjustment, adjustments to doses for vadadustat and darbepoetin 
alfa are based on Hb concentration and Dose Adjustment Algorithms. The protocols contain 
details of the algorithms for vadadustat and darbepoetin alfa. 
In order to reduce potential execution bias further, special steps will be taken to restrict access to 
the study data; the Blinding Procedures and Oversight Plan contains details. 
2.6 
Sample Size 
The planned sample sizes are approximately 925 subjects per arm for both Study CI-0014 and 
Study CI-0015. The sample sizes have been selected to contribute adequate MACE for a pooled 
analysis that will take place using the results from both studies. See Sections 2.7 and 2.8 for the 
operating characteristics of the studies, given these samples sizes, with respect to the stand-alone 
efficacy analysis to be performed on change in Hb and the pooled MACE analysis.  
2.7 
Efficacy 
For clarity, this SAP uses the word “mean” to refer to averages over the study groups and 
“average” to refer to the within-person average during specified evaluation periods. 
The primary efficacy endpoint in each study is the change in Hb from Baseline to the average Hb 
over the PEP (Weeks 24 to 36). Vadadustat and darbepoetin alpha will be compared with respect 
to the mean change in Hb in each study arm. The primary efficacy objective is to show that 
vadadustat is noninferior to darbepoetin alfa where establishment of noninferiority is based on a 
margin of -0.75 g/dL applied to the difference in mean change: vadadustat minus darbepoetin 
alfa. Appendix A provides a rationale for this margin.  
For the primary efficacy analysis power, the mean change from Baseline in Hb for vadadustat 
and darbepoetin alfa is assumed to be identical with a common standard deviation (SD) of 
1.5 g/dL. For each trial, noninferiority will be established if the lower limit of the 2-sided 95% 
confidence interval for the difference between the mean in the vadadustat group and the mean in 
the darbepoetin alfa group is -0.75 g/dL or higher. Under these assumptions, a sample size of 
925 subjects per treatment group in the CI-0014 trial will yield greater than 90% power to show 


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noninferiority. The power for the CI-0015 trial is also greater than 90% because the sample size 
is also planned to be about 925 subjects per group. 
If the lower limit of the 2-sided 95% confidence interval for the difference between the mean in 
the vadadustat group and the mean in the darbepoetin alfa group is above zero, superiority will 
have been established and the finding will be interpreted as providing evidence of a greater 
change from baseline in Hb for vadadustat relative to the control arm. 
2.8 
Safety 
The primary safety endpoint is the time from the first dose date to the first adjudicated MACE 
(defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke). 
The primary safety analysis will include all first events that accrue over the pair of PRO2TECT 
studies. The sample size for the MACE endpoint is based on a 2-sided 95% confidence interval 
for the hazard ratio (HR) (vadadustat/darbepoetin alfa) and a noninferiority margin of 1.25 
(upper bound of the 95% confidence interval) for FDA decision making. Under the assumption 
that the MACE rate is the same in the 2 groups (i.e., the HR =1), 631 subjects with MACEs will 
be required in the 2 trials combined to have 80% power to establish noninferiority. If the HR is 
0.95 favoring vadadustat, the power will be above 90%. Based on a noninferiority margin of 
1.30 for EMA decision making, the power will be above 90% under the assumption that the HR 
is 1. 
Additional safety presentations are described below (Section 7 and Section 10). 
3 
ANALYSIS POPULATIONS 
3.1 
The Analysis Populations 
Each study has the following four analysis populations: 
•
Randomized population: all subjects randomized. Analyses of this population will be based
on the randomized treatment.
•
Full Analysis Set (FAS) population: all subjects in the randomized population who received
at least 1 dose of study medication and had at least 1 post dose Hb . Analyses of this
population will be based on the randomized treatment.
•
Safety population: all subjects in the randomized population who received at least 1 dose of
study treatment. Analysis of this population will be based on the actual treatment received.
Subjects who received in error some vadadustat and some darbepoetin alfa (excluding rescue
therapy) will be classified by the more frequently received drug.
•
Per Protocol (PP) population: all randomized subjects who received study medication during
the PEP, had at least 1 Hb assessments during the PEP, and had no critical or major protocol
deviation affecting the primary endpoint analyses, i.e., prior to Week 36. Analyses of this
population will be based on actual treatment received, as described for the Safety population.
Major protocol deviations or causes for site closure leading to exclusion from the PP populations 
will be specified prior to database lock on a blinded basis. 
Efficacy analyses will utilize the randomized, FAS, and PP populations while safety analyses 
(including analyses of MACE) will utilize the safety population.  


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3.2 
Characterization of the Analysis Population 
Number and percent of subjects included in the analysis sets will be summarized. 
4 
QUALITY OF THE TRIALS 
4.1 
Study Drug Dosing and Compliance 
Subjects track their own drug use at home. At each visit, the site records each subject's 
self-reported compliance. 
The proportion of subjects who report at least 80% compliance at each visit will be tabulated and 
summarized for both safety population and FAS.  
In addition to self-reported compliance, the calculated compliance rate for a given time period 
will be derived from exposure data as the number of days on dosing period collected on 
electronic case report forms (eCRFs) divided by the number of days in that time period.  
4.2 
Protocol Deviations 
Definitions of critical, major, and minor protocol deviations will be described in master Protocol 
Deviation log file, including those protocol deviations leading to exclusion from the PP 
populations. These will be specified prior to database lock on a blinded basis. 
Protocol deviations will be summarized in the randomized population as the number and 
percentage of subjects with a protocol deviation by treatment group and study period. A 
by-subject listing of protocol deviations, indicating those exclusionary from the PP population, 
will be provided. 
4.3 
Baseline Characteristics, Exposure, and Retention by Treatment Group 
Baseline characteristics collected in the case report form (CRF) will be summarized in analysis 
populations (Section 3). Summaries of demographics, medical history, prior and concomitant 
medications, and treatment exposure will be displayed by treatment groups.  
The total number of randomized subjects by treatment group and the number randomized but not 
treated will be tabulated. This summary will be performed in the randomized population. 
The average weekly dosages by treatment groups will be categorized for the safety and FAS 
populations(see Section 5.1). 
The number of subjects who discontinued treatment and the reason for treatment discontinuation 
will be tabulatedfor the Randomized populations. 


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5 
GENERAL CONVENTIONS 
Study days are defined as follows: 
Study Day = [Event date – First dosing date + 1] if after first dosing date 
[Event date – First dosing date] if before first dosing date. 
Note that with the definition above, days of "0" will not be used. As such, the study day can be 
interpreted as the number of days before or after first day of dosing. Event date refers to the date 
associated with the result being summarized. In some cases, this is the date of an assessment or 
measurement; in other cases, this is the onset date of an adverse or outcome event. 
For subjects whose reference date is missing, the study day will also be categorized as missing. 
5.1 
Visit and Analysis Time Period Classification 
The time windows in this section reflect the administrative range around each visit for analysis. 
They are wider than those stated in the protocol to reduce missing values by capturing as many 
observation dates as possible. Table 1 provides the convention to classify assessment dates into 
protocol-defined visits and analysis time periods for assessments at every visit, such as Hb and 
vital signs. Table 1 will also be used for liver function assessments. 
Table 2 presents visit windows for values according to a slightly less frequent assessment 
schedule, i.e., the iron indices. And, Table 2 will also be used for all other assessments, such as 
periodic complete blood count (CBC) with differential, chemistry laboratory tests, C-reactive 
protein (CRP), urine albumin-to-creatinine ratio (uACR) and lipids etc.  
Unless otherwise specified, all assessments will be mapped to visit windows on the basis of the 
date of the assessment relative to the first dose date (i.e., Study Day), regardless of subject 
disposition or the CRF page completed, e.g., “Unscheduled”, “End of Treatment”, “End of 
Study”, scheduled visit number. Similarly, all values collected within a reporting period will be 
considered for identification of safety events of interest. 
If more than 1 laboratory-based efficacy outcome value (e.g., Hb, ferritin, hepcidin, TSAT, 
serum iron, TIBC, and lipids) is available in an analysis time period post-baseline, the average of 
all observed values (at most 1 per day) will be assigned to that period. For example, the window 
for the primary efficacy outcome, analysis time period 3, includes any Hb value (at most 1 per 
day) assessed between Study Days 155 to 266, corresponding to Weeks 24, 28, 32, and 36 
(Visits 10 through 13). 
Efficacy evaluations will use Hb values as assessed by the central laboratory. (Local HemoCue 
Hb values are used only for dose adjustments.) 
When more than 1 assessment is made for other measures (not part of laboratory-based efficacy) 
within a given visit window post-baseline, the value of the assessment closest to the end of the 
window is the value associated with that visit for summaries over time. Most summaries of 
results by visit (e.g., laboratory or vital sign results for general safety) will use the single value 


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for each visit determined by this convention. Notable exceptions to this convention are the 
primary efficacy outcome and clinically significant changes. 
If no assessment is available within a time window, then the associated visit and week 
classifications will be missing. 
Table 1. 
Classification of Assessments at Every Visit for Years 1 through 4 
Time Period 
Visit Classification 
Target Week 
Target Day 
Actual Study Day of Visit 
Baseline 
Screening Visit 1a 
- 
- 
- 
Screening Visit 2a 
- 
- 
- 
Visit 1 
Week 0 
Day 1 
Day 1 (first dose date) b 
1) Weeks 2-8
Visit 2 
Week 2 
Day 14 
Day 2-21 
Visit 3 
Week 4 
Day 28 
Day 22-35 
Visit 4 
Week 6 
Day 42 
Day 36-49 
Visit 5 
Week 8 
Day 56 
Day 50-63 
2) Weeks 10-20
Visit 6 
Week 10 
Day 70 
Day 64-77 
Visit 7 
Week 12 
Day 84 
Day 78-98 
Visit 8 
Week 16 
Day 112 
Day 99-126 
Visit 9 
Week 20 
Day 140 
Day 127-154 
3) Primary Efficacy
Period (PEP)
(Weeks 24-36) 
Visit 10 
Week 24 
Day 168 
Day 155-182 
Visit 11 
Week 28 
Day 196 
Day 183-210 
Visit 12 
Week 32 
Day 224 
Day 211-238 
Visit 13 
Week 36 
Day 252 
Day 239-266 
4) Secondary
Efficacy Period (SEP)
(Weeks 40-52) 
Visit 14 
Week 40 
Day 280 
Day 267-294 
Visit 15 
Week 44 
Day 308 
Day 295-322 
Visit 16 
Week 48 
Day 336 
Day 323-350 
Visit 17 
Week 52 
Day 364 
Day 351-406 
- 
Visit 18 
Week 64 
Day 448 
Day 407-490 
- 
Visit 19 
Week 76 
Day 532 
Day 491-574 
- 
Visit 20 
Week 88 
Day 616 
Day 575-672 
- 
Visit 21 
Week 104 
Day 728 
Day 673-770 
- 
Visit 22 
Week 116 
Day 812 
Day 771-854 
- 
Visit 23 
Week 128 
Day 896 
Day 855-938 
- 
Visit 24 
Week 140 
Day 980 
Day 939-1036 
- 
Visit 25 
Week 156 
Day 1092 
Day 1037-1134 
- 
Visit 26 
Week 168 
Day 1176 
Day 1135-1218 
- 
Visit 27 
Week 180 
Day 1260 
Day 1219-1302 
- 
Visit 28 
Week 192 
Day 1344 
Day 1303-1400 
- 
Visit 29 
Week 208 
Day 1456 
Day 1401-1498 
a. The Screening period, which starts when the informed consent form is signed, will last a maximum of
8 weeks. Two Screening visits (Screening Visit 1 and Screening Visit 2) must be performed within 8 weeks
prior to dosing (Baseline visit or Day 1). There must be a minimum of 4 days between the two Screening
visits and a minimum of 4 days between Screening Visit 2 or last retest and the Baseline visit.
b. If patient has no first dose date, day 1 will be the randomization date.


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Table 2. 
Classification of assessments at select visits for Years 1 through 4 
Time Period 
Visit Classification 
Target Week 
Target Day 
Actual Study Day of Visit 
Baseline 
Screening Visit 1a 
- 
- 
- 
Screening Visit 2a 
- 
- 
- 
Visit 1 
Week 0 
Day 1 
Day 1 (first dose date)b 
1) Weeks 2-8
Visit 3 
Week 4 
Day 28 
Day 2-42 
Visit 5 
Week 8 
Day 56 
Day 43-63 
2) Weeks 10-20
Visit 7 
Week 12 
Day 84 
Day 64-112 
Visit 9 
Week 20 
Day 140 
Day 113-154 
3) Primary efficacy
period (PEP)
(Weeks 24-36) 
Visit 11 
Week 28 
Day 196 
Day 155-224 
Visit 13 
Week 36 
Day 252 
Day 225-266 
4) Secondary efficacy
period (SEP)
(Weeks 40-52) 
Visit 15 
Week 44 
Day 308 
Day 267-336 
Visit 17 
Week 52 
Day 364 
Day 337-406 
- 
Visit 18 
Week 64 
Day 448 
Day 407-490 
- 
Visit 19 
Week 76 
Day 532 
Day 491-574 
- 
Visit 20 
Week 88 
Day 616 
Day 575-672 
- 
Visit 21 
Week 104 
Day 728 
Day 673-770 
- 
Visit 22 
Week 116 
Day 812 
Day 771-854 
- 
Visit 23 
Week 128 
Day 896 
Day 855-938 
- 
Visit 24 
Week 140 
Day 980 
Day 939-1036 
- 
Visit 25 
Week 156 
Day 1092 
Day 1037-1134 
- 
Visit 26 
Week 168 
Day 1176 
Day 1135-1218 
- 
Visit 27 
Week 180 
Day 1260 
Day 1219-1302 
- 
Visit 28 
Week 192 
Day 1344 
Day 1303-1400 
- 
Visit 29 
Week 208 
Day 1456 
Day 1401-1498 
a. The Screening period, which starts when the informed consent form is signed, will last a maximum of
8 weeks. Two Screening visits (Screening Visit 1 and Screening Visit 2) must be performed within 8 weeks
prior to dosing (Baseline visit or Day 1). There must be a minimum of 4 days between the two Screening
visits and a minimum of 4 days between Screening Visit 2 or last retest and the Baseline visit.
b. If patient has no first dose date, day 1 will be the randomization date.
5.2 
Definition of Baseline 
In general, the baseline value will also be the value of assessment closest to the end of the 
window, i.e., Day 1 (first dose date). The baseline value must be assessed prior to initiation of 
study treatment. In contrast, the baseline value for laboratory-based efficacy outcomes (e.g., Hb, 
ferritin, hepcidin, TSAT, serum iron, TIBC, and lipids) will be an average of the last 1 or 2 
values prior to or on the first dose date, as specified in Section 9.1.1. 
5.3 
Prior and Concomitant Medication 
Prior and concomitant medications will be coded using World Health Organization Drug 
Dictionary (WHO DD; Mar 2017 or latest version) and summarized for each treatment group 
based on the safety population. Prior medication is defined as any medication taken prior to the 


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first dose of the study medication in the initial treatment period. Any medication taken on or 
after the day of first dose of the study treatment will be considered as concomitant medication for 
the treatment analysis. 
5.4 
Handling of Missing Data 
Missing data will be handled using a procedure specific to each variable and particular analysis 
as described in the sections relevant to each endpoint. If no method for missing data is discussed, 
descriptive analyses will be based upon observed data without imputation. Appendix B describes 
the general approaches to be used for missing data. 
For the analysis of safety variables, only partial dates will be imputed unless otherwise specified. 
The algorithms for imputation of partial dates depend upon the parameter, as follows. 
Adverse event onset: 
•
If onset date is completely missing, date is set to date of first dose.
•
If year is present and month and day are missing or year and day are present and month is
missing:
o
If year = year of first dose, then set month and day to month and day of first dose.
o
If year < year of first dose, then set month and day to December 31.
o
If year > year of first dose, then set month and day to January 1.
•
If month and year are present and day is missing:
o
If year = year of first dose and
•
month = month of first dose, then set day to day of first dose date.
•
month < month of first dose, then set day to last day of month.
•
month > month of first dose, then set day to first day of month.
o
If year < year of first dose, then set day to last day of month.
o
If year > year of first dose, then set day to first day of month.
•
For all other cases, set date to date of first dose.
Adverse event end date: 
•
If year is present and month and day are missing or year and day are present and month is
missing, set end month and day to December 31.
•
If month and year are present and day is missing, set the day to last day of the month.
•
If fatal event, date is set to minimum of imputed end date and death date.
•
For all other cases, set date to missing.
Concomitant medication: 
•
If start date is completely missing, start date will not be imputed.
•
If start year is present and month and day are missing or year and day are present and month
is missing, set start month and day to January 1.
•
If start year and month are present and day is missing, set start day to 1st day of month.


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•
If end date is completely missing, end date will not be imputed.
•
If end year is present and month and day are missing or year and day are present and month
is missing, set end month and day to December 31.
•
If end year and month are present and day is missing, set end day to last day of the month.
•
The imputed dates must be logical, ensuring that no end date is after database lock or death
or before the start date.
If site queries fail to resolve partial dates for laboratory values and vital signs, including for 
efficacy, the date is missing and will not be imputed. 
6 
EFFICACY ENDPOINTS 
This section lists the efficacy endpoints; Section 9 describes their definitions and the plans for 
the analysis of each endpoint. 
6.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is change in average Hb between Baseline and the PEP 
(Weeks 24 to 36). 
6.2 
Key Secondary Efficacy Endpoints 
Change in average Hb value between Baseline and the SEP (Weeks 40 to 52). 
6.3 
Other Efficacy Endpoints 
This section describes the other efficacy endpoints of the studies. 
6.3.1 
Definition of Rescue Episode 
For summaries of potential rescue therapies (i.e., red blood cell [RBC] transfusion, and ESA), 
exposure to the therapy will be grouped temporally into episodes, which could contain multiple 
administrations based on the gap in time between the end of 1 and the start of the next. For ESA 
medication , the longest such gap within a single episode is 30 days, while the maximum gap is 
7 days for RBC transfusion. 
6.3.2 
Endpoints Related to Hb 
The following efficacy endpoints are related to Hb: 
•
Change in average Hb value between Baseline and the combined PEP and SEP
(Weeks 24 to 52)
•
Having average Hb value in the geography-specific target range in Weeks 24 to 36 (yes/no
variable)
•
Having average Hb value in the geography-specific target range in Weeks 40 to 52 (yes/no
variable)
•
Having at least 1 Hb value in the geography-specific target range in Weeks 24 to 36 (yes/no
variable)


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•
Having at least 1 Hb value in the geography-specific target range in Weeks 40 to 52 (yes/no
variable)
•
Having Hb values in the geography-specific target range for at least 1/2 of the observations
in Weeks 24 to 36 (yes/no variable)
•
Having Hb values in the geography-specific target range for at least 1/2 of the observations
in Weeks 40 to 52 (yes/no variable)
These endpoints apply only to study CI-0014: 
•
Hb increase of >1.0 g/dL from Baseline to Week 52 (yes/no variable)
•
Time to achieve Hb increase of >1.0 g/dL from Baseline Hb (censored at Week 52)
6.3.3 
Endpoints Related to Iron 
These sections address iron-related endpoints from randomization through the end of the trials. 
The study population will be divided into the following baseline iron groups:  
•
0 – those not receiving any iron at baseline,
•
I – those receiving only oral iron at baseline,
•
II – those receiving only intravenous (IV) iron at baseline, and
•
III – those receiving IV and oral iron at baseline.
6.3.3.1 Hepcidin, Ferritin, Total Iron-Binding Capacity, Serum Iron, and Transferrin 
Saturation 
For hepcidin, ferritin, total iron-binding capacity (TIBC), serum iron, and transferrin saturation 
(TSAT), the 2 treatment groups will be compared with respect to mean change from baseline and 
percentage change from baseline in the PEP and SEP. Subgroup analyses and variation with 
rescue and Hb may be considered. 
6.3.3.2 Elemental Iron 
For each baseline iron group and the whole population, a table will present by treatment group 
the proportion of subjects who received each of the relevant routes and the mean weekly dose of 
elemental iron. The calculation of mean weekly dose will include subjects with iron 
administration and will count only weeks in which a subject was still being followed in the 
denominator.  
6.3.4 
Other Laboratory Parameters 
The following efficacy endpoints are related to laboratory chemistry: 
•
Change in serum glucose between Baseline and the PEP (Weeks 24 to 36).
•
Change in lipid parameters between Baseline and the PEP (Weeks 24 to 36) – including total
cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL)
cholesterol, and triglycerides.


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6.3.5 
Dose Adjustments and Interruptions 
An important aspect of evaluating the efficacy of vadadustat arm is to understand how often dose 
adjustments are needed to maintain target Hb levels. To that end, the pattern of dose changes in 
the 2 treatment arms will be described, including percent with dose adjustment or treatment 
interruption for the whole study and by the four analysis time periods in Year 1 (see Section 5.1). 
6.3.6 
Progression of CKD 
Progression of chronic kidney disease (CKD) in both studies is defined as experiencing any of 
the following: 
•
Transition to chronic dialysis, or
•
Receipt of a kidney transplant, or
•
Estimated glomerular filtration rate (eGFR) <15 mL/min per 1.73 m² and confirmed by
another measurement with a reduction of eGFR <15 mL/min per 1.73 m², which should be at
least 28 days apart from the first reduction, or
•
Reduction in eGFR of 40% or more from baseline (confirmed by second measurement at
least 28 days later).
•
The endpoint for analysis is time to progression of CKD. See Coresh, 2019; Heerspink, 2019;
Levey, 2014 for a description of the endpoint.
6.3.7 
Endpoints Related to RBC Transfusion 
These endpoints address RBC transfusion for the entire length of study, by the four analysis time 
periods in Year 1 (see Section 5.1), and in the long-term treatment/follow-up period (Week 52 to 
EOS) unless otherwise specified. 
•
Receipt of any RBC transfusion
•
Time to first RBC transfusion (for entire study)
•
Total number of RBC transfusion episodes received
•
Rate of RBC transfusions, calculated as the number of episodes divided by the duration of at-
risk follow-up in person-years
RBC transfusion may be considered rescue when “Worsening Anaemia due to CKD” is the 
reason indicated on the CRF. 
6.3.8 
Endpoints Related to ESA Usage 
The study will consider the following efficacy endpoints specific to ESA usage for the entire 
length of study, by the four analysis time periods in Year 1 (see Section 5.1), and in the 
long-term treatment/follow-up period (Week 52 to EOS) unless otherwise specified.  
•
Receipt of any ESA medication (in the darbepoetin alfa arm, use only includes ESA other
than darbepoetin alfa as well as increases in darbepoetin alfa the investigator specifically
designates as rescue)
•
Time to first ESA medication (for entire study)
•
Total number and maximum duration of ESA episodes.


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ESA medication may be considered rescue when any of the following reasons are indicated on 
the relevant version of the CRF: 
•
[Original CRF] “the subject experienced a clinically significant worsening of their anaemia
or symptoms of anaemia (e.g., fatigue, weakness, shortness of breath, chest pain, confusion,
or dizziness) compared with Baseline”
•
[Original CRF] “the subject's HGB is <9.0 g/dL”
•
[CRF updated mid-2018] “Worsening of symptoms of anemia and Hb <9.0 g/dL”
•
[CRF updated mid-2018] “Investigator discretion not meeting protocol-defined rescue
criteria”
•
[CRF updated mid-2018] “Other Specify” which include either one of the 2 reasons from the
original CRF
Analyzing the impact of pre-baseline or post-baseline ESA on vadadustat efficacy requires 
conversion of ESA dose into common units. The epoetin alfa analogues, darbepoetin alfa and 
methoxy polyethylene glycol epoetin beta (Mircera), will be converted to IV epoetin equivalent 
units per kilogram per week (U/kg/week).  
The following conversions have been derived from published literature and input from clinical 
experts [Paganini, 1995; Kaufman, 1998; Cremieux, 2006; Gosselin, 2006; Levin, 2008; 
FDA 2011; Jordan, 2012; Choi, 2013; Vega, 2014; Wright, 2015]. 
•
Subcutaneous (SC) epoetin to IV epoetin: 1:1.25
SC Epoetin 
IV Epoetin 
Darbepoetin alfa to epoetin 
1:160 
1:200 
Methoxy polyethylene glycol-epoetin beta to epoetin 
1:176 
1:220 
6.3.9 
Rescue Therapy: Series of Definitions 
Rescue will be defined from narrow to broad, based on the type, timing, intensity, and reason for 
treatment. These treatments may be considered rescue therapy for anemia secondary to chronic 
kidney disease: ESA medication, and RBC transfusion. 
The possible reasons for such treatments include: 
•
Investigator-ordered rescue (per protocol for worsening of anemia),
•
Adverse events (unrelated to anemia),
•
Maintenance during prolonged interruption of study treatment, and
•
Inadvertent use (at hospital or dialysis center).
If a given therapy starts the same day as permanent discontinuation of study drug, then that 
therapy will be considered on treatment for rescue definitions. 
For the vadadustat arm, any use of ESA may be considered rescue. For the control arm, the study 
drug itself is an ESA and so is not necessarily rescue, yet change to another ESA may be 
considered rescue. Because darbepoetin alfa is titratable, increase in dose is not considered 
rescue unless the investigator specifically designates it as such; however, increases in dose 
relative to last dose will be characterized in three categories by percentage increase: <50%, 


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≥50% and <100%, and ≥100%. Subjects will be presented by their maximum category of 
increase within each of the four analysis time periods in Year 1 (see Section 5.1). All ESA use 
will be converted to IV epoetin alfa equivalents. 
The CRFs collect reasons for ESA medication and RBC transfusion. The series of rescue 
definitions are defined as follows: 
•
Narrow: Rescue for worsening anemia with ESA medication or RBC transfusion defined in
Section 6.3.7 and Section 6.3.8, not starting after permanent study treatment discontinuation.
•
Broad-on-treatment: Any exposure to ESA medication (aside from darbepoetin alfa not
designated as rescue in the control arm) or RBC transfusion for any reason not starting after
permanent study treatment discontinuation.
In addition to the sensitivity analyses (Section 9.1.4), the report will include a summary of the 
incidence, timing, duration, intensity, and frequency for each definition of rescue, including a 
Kaplan-Meier plot of time to first rescue. 
7 
NON-MACE SAFETY ENDPOINTS 
While the primary safety endpoints relate to MACE, defined as all-cause mortality, nonfatal 
myocardial infarction, or nonfatal stroke, this SAP addresses only the non-MACE endpoints. As 
stated above, a separate SAP will describe the analyses of MACE and the individual components 
of the MACE endpoint as well as expanded MACE definitions where expanded MACE will 
include hospitalization for heart failure and thromboembolic events. 
The safety reporting period for this study begins upon randomization and ends at the final 
protocol-required study contact. A treatment-emergent adverse event (TEAE) is one that begins 
or worsens after treatment initiation. The AE CRF has been designed to capture all events after 
randomization. AEs that occur during the screening period are not reported on the CRF. The 
treatment groups will be compared with respect to the following non-MACE safety endpoints: 
•
Adverse events (AEs) and serious adverse events (SAEs)
•
Treatment-emergent adverse events (TEAEs) and treatment-emergent SAEs
•
Vital signs and clinical laboratory values (see Appendix E)
•
Adverse events of special interest (AESI) (see Appendix F)
•
Any value of Hb >12.0 g/dL; >13.0 g/dL, >14.0 g/dL, <9.0 g/dl or <8.0 g/dl
•
An Hb increase >1.0 g/dL within any 2-week interval or >2.0 g/dL within any 4-week
interval.
8 
PHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) ANALYSIS 
Serum samples will be taken and stored for use in biomarker studies. PK sample will be 
collected between 15 minutes to 1 hour after vadadustat administration at baseline visit, and will 
also be performed along with other study laboratory samples being collected at the Weeks 4, 12, 
28, and 52. For each visit, one serum sample is collected for each subject. Discriptive anlaysis of 
PK concentration will be provided by treatment groups. Analysis for EPO is listed in 
Section E.1.7 


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9 
EFFICACY ENDPOINTS AND ANALYSES 
This section briefly describes the methods to be used for each of the efficacy endpoints. Rather 
than providing details for each endpoint, the accompanying Appendices describe the approaches 
to be used for specific types of data. For all the models and methods described below, see 
Appendix B for handling of any missing data. 
The general approach to analysis of continuous outcomes will be analysis of covariance 
(ANCOVA) with multiple imputation for missing data or mixed models for repeated 
measurements (MMRM) on observed data. For a description of the models to be used, see 
Appendix C. 
For binary variables, the general approach will be Mantel-Haenszel estimation of risk difference 
stratified (Mantel, 1954) by the baseline strata with (or without) multiple imputation to deal with 
missing data. See Appendix D. 
Some endpoints come from count data (e.g., the number of RBC transfusions) that are likely to 
have a spike at zero and a long tail. Such data are often complicated to analyze because of their 
highly skewed distributions. While the samples sizes are so large that the Central Limit Theorem 
ensures that the means of these distributions are essentially normal, some interpretation of the 
nature of the distributions may be useful clinically. To the extent reasonable, we have described 
the planned methods for such data, but ad hoc methods may be necessary if the skewness is 
extreme. See Appendix D for the general approach. 
For time-to-event variables, the general approach will be to use Cox models stratified by the 
baseline randomization strata. See Appendix D. 
9.1 
Definition of Primary Efficacy Endpoint: Change from Baseline in Hb 
The primary efficacy endpoint is the change in average Hb between baseline and the PEP 
(Weeks 24 to 36). 
The primary analysis will use the randomized population. As described in Section 2.7, 
establishment of noninferiority will be based on a margin of -0.75 g/dL applied to the difference 
in mean change: vadadustat minus darbepoetin alfa. 
9.1.1 
Baseline Hb 
Baseline Hb will be calculated as the average of the last 2 central laboratory Hb measurements of 
samples taken at the visits prior to or on the date of first dose date.  
Subjects may be rescreened up to three times. A minimum of 1 Hb value is required for the 
calculation of baseline. 
9.1.2 
Hb in the Primary Efficacy Period 
Hb for the PEP will be calculated as the average of all Hb measurements from the central 
laboratory within the four visit windows during Weeks 24 through 36, regardless of intercurrent 
events. At least 1 Hb measurement is required for the calculation; otherwise, the value will be 
missing and therefore imputed. The PEP corresponds to Visits 10 through 13, also called analysis 
time period 3 (Table 1). 


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9.1.3 
Change in Hb From Baseline to the Primary Efficacy Period 
The change from baseline will be calculated for each subject as the PEP value minus the baseline 
value.  
9.1.4 
Analysis of Change From Baseline in Hb to the Primary Efficacy Period 
The primary analysis will be performed in the randomized population, as defined in Section 3.1, 
to address an estimand of treatment policy in accordance with the Intention to Treat philosophy. 
In this open-label study, the research question is to compare the assignment of a standard of care, 
darbepoetin, to the investigational new drug, vadadustat, regardless of intercurrent events. This 
analysis includes individuals who never receive treatment, discontinue treatment, are rescued 
with any therapy, or withdraw consent. 
The primary analysis will use multiple imputation with ANCOVA as the substantive model. 
Missing primary endpoint data will be imputed with the group to which the subject was 
randomized as described in Appendix B. An ANCOVA model, as described in detail in 
Appendix C, will be used to compare the mean change from baseline in Hb between the 
2 groups.  
The primary analysis model will contain treatment group, baseline Hb level, and the 
2 stratification factors (region and NYHA CHF class) as predictor variables. The stratification 
factor of entry Hb level will not be included in the model because of the inclusion of baseline 
Hb. The stratification factor assignments at randomization will be respected in the analysis. 
The random seeds for all the multiple imputation runs for each trial will be generated from a 
single master seed. The master seeds will be 10014 for CI-0014, and 10015 for CI-0015. The 
generation code, resulting random seeds, and corresponding analysis assignments are listed in 
Appendix B. 
The data will have shown noninferiority of vadadustat if the lower bound of the 95% confidence 
interval for the difference in estimated change from baseline in the 2 groups (vadadustat minus 
darbepoetin) exceeds the noninferiority margin of -0.75. This ensures a 1-sided alpha of 0.025 
for the primary analysis. If the lower limit of the 2-sided 95% confidence interval for the 
difference between the mean in the vadadustat group and the mean in the darbepoetin alfa group 
is above zero, superiority will have been established and the finding will be interpreted as 
providing evidence of a greater change from baseline in Hb for vadadustat relative to the control 
arm. 
9.1.5 
Sensitivity Analyses to the Primary Efficacy Results 
To assess the robustness of the findings from the primary analysis, the following set of 
sensitivity analyses will be performed using a method analogous to that of the primary analysis 
(including multiple imputation) unless otherwise specified: 
•
The primary analysis will be repeated after setting to missing all per-visit Hb values within
four weeks of administration rescue therapy or after EOT visits. The definition of rescue
therapy will vary across the series described in Section 6.3.9.
•
Tipping point analyses (see Appendix Section B.3.2) will be performed to assess the effect of
the missing data.


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•
The FAS population will be used instead of the randomized population without a new
multiple imputation. This analysis will be performed only if the size of the FAS is less than
95% of the randomized population.
•
The PP population with the actual treatment received without imputation
•
A mixed model for repeated measures (MMRM) will be fit to the observed data only without
imputing missing values. The repeated measures will be the observed averages for analysis
time periods 1, 2, and 3 (See definitions in Section 5.1 and analysis details in Appendix C).
9.2 
Secondary Efficacy Endpoints: Definitions and Analyses 
The study has one secondary efficacy endpoint which will be analyzed formally only if the 
primary analysis meets the noninferiority margin.  
•
Change in average Hb value between Baseline and the SEP (Weeks 40 to 52)
Evaluation of the average change in Hb will employ the approach described for the primary 
endpoint (see Section 2.7 and Section 9.1) assessing Weeks 40 to 52 instead of Weeks 24 to 36. 
The power for this endpoint for a noninferiority margin of -0.75 g/dL is expected to be close to 
the power of the primary endpoint.  
Sensitivity analyses analogous to those performed for the primary efficacy endpoint will be 
repeated to assess mean change in Hb from Baseline to Weeks 40 to 52. For ANCOVA models, 
analysis time period 4 will replace 3, and for MMRM, the models will be extended to include 
four post-baseline timepoints. 
9.3 
Other Efficacy Endpoints: Strategies for Analysis 
The study has many other efficacy endpoints. Because of their exploratory nature, they will not 
be corrected for multiplicity.  
9.3.1 
Having Average Hb Value in the Geography-Specific Target Range in Weeks 
24 to 36 
All subjects will be defined as either being in their geography-specific target range (see 
Section 2.3) in Weeks 24 through 36 (“yes”) or not (“no”), based on the average Hb value during 
the four visit windows in Weeks 24 through 36. Subjects with no Hb value in the PEP value will 
be treated as missing and handled according to Appendix B. 
The proportion of subjects within target range will be calculated and tested with a 
Mantel-Haenszel test stratified by the baseline strata. See Appendix B and Appendix D. 
Noninferiority will be evaluated using a 2-sided confidence interval for the difference in 
proportions. Noninferiority will have been established if the lower limit of the confidence 
interval is above -15%. The power for this endpoint is expected to be roughly 90%. 
If the lower limit of the 2-sided confidence interval for the difference in proportions is above 
zero, superiority will have been established and the finding will be interpreted as providing 
evidence of a higher proportion of subjects being within the target range for vadadustat relative 
to the control arm. 


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9.3.2 
Having Average Hb Value in the Geography-specific Target Range in 
Weeks 40 to 52 
All subjects will be defined as either being in their geography-specific target range (see 
Section 2.3) in Weeks 40 to 52 (“yes”) or not (“no”), based on the average Hb value during the 
Weeks 40 to 52 visit windows. Subjects with no Hb value in the SEP value will be treated as 
missing and handled according to Appendix B. 
The proportion of subjects within target range will be calculated and tested with a 
Mantel-Haenszel test stratified by the baseline strata. See Appendix D. 
Noninferiority will be evaluated using a 2-sided confidence interval for the difference in 
proportions. Noninferiority will have been established if the lower limit of the confidence 
interval is above -15%. The power for this endpoint is expected to be roughly 90%. 
If the lower limit of the 2-sided confidence interval for the difference in proportions is above 
zero, superiority will have been established and the finding will be interpreted as providing 
evidence of a higher proportion of subjects being within the target range for vadadustat relative 
to the control arm. 
Table 3 lists the other efficacy endpoints. All analyses will stratify by the randomization 
(baseline) strata.  
Table 3. 
Other Efficacy Endpoints 
Endpoint 
Approach to Analysis 
Comments 
Hb endpoints – Section 6.3.2 
Change in average Hb value between 
Baseline and the combined primary efficacy 
period (PEP) and secondary efficacy periods 
(SEP) (Weeks 24-52)  
Analysis of covariance 
(ANCOVA) stratified by 
baseline strata.  
Average may include imputed 
values for PEP and/or SEP. 
Having Hb values in the geography-specific 
target range during PEP or SEP (2 alternate 
definitions) 
Mantel-Haenszel test stratified 
by the baseline strata 
This analysis includes the 
observed hemoglobin values. 
CI-0014 only: Hb increase of >1.0 g/dL from
Baseline to any time before Week 52
Mantel-Haenszel test stratified 
by baseline strata 
This analysis includes the 
observed hemoglobin values. 
CI-0014 only: Time to achieve Hb increase of
>1.0 g/dL from Baseline Hb (censored at
Week 52)
Time – to –event 
This analysis will use only 
observed data. 
Progression of CKD (Section 6.3.6) 
Progression of CKD (entire length of study) 
Time – to – event 
Iron endpoints (Section 6.3.3) 
Receipt of at least 1 administration of 
elemental iron ( IV, or oral) 
Mantel-Haenszel test stratified 
by baseline strata 
Average weekly dose of elemental iron, IV, 
or oral 
ANCOVA stratified by baseline 
strata. 
If the distribution is highly 
skewed either because of a large 
spike at zero or a long tail to the 
right (or both), other methods 
may be considered. 


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Endpoint 
Approach to Analysis 
Comments 
Hepcidin, Ferritin, TIBC 
Four outcomes – change from 
baseline to PEP, change from 
baseline to SEP, percentage 
change from baseline to PEP, and 
percentage change from baseline 
to SEP.  
Analysis of covariance stratified 
by baseline strata for change 
from baseline to PEP or SEP. 
This analysis will use only 
observed data 
Serum Iron 
TSAT 
Other laboratory endpoints (Section 6.3.4) 
Change from baseline in serum glucose and 
lipid parameters at PEP and SEP 
ANCOVA stratified by baseline 
strata. 
No imputation. 
RBC transfusion endpoints (Section 6.3.7) 
Receipt of any RBC transfusion 
Mantel-Haenszel test stratified 
by the baseline strata 
Total number of RBC transfusions received 
(entire length of study) 
See Appendix D . 
If the distribution is highly 
skewed either because of a large 
spike at zero or a long tail to the 
right (or both), other methods 
may be considered.  
Dose adjustment (Section 6.3.5) 
Dose adjustments (entire length of study) 
Descriptive statistics 
Other methods may be 
considered. 
ESA and Rescue endpoints (Section 6.3.8 and Section 6.3.9) 
Receipt of any ESA rescue medication 
Mantel-Haenszel test stratified 
by the baseline strata 
Receipt of any rescue therapy (series of 
definitions from narrow to broad) 
Mantel-Haenszel test stratified 
by the baseline strata 
10 SAFETY ANALYSES 
Unless otherwise specified, safety analyses will be performed using the safety population. 
Most of the analysis of safety data will be descriptive without formal statistical testing. In some 
cases, 95% confidence intervals for the change from baseline as well as for the difference 
between the study groups may be reported. 
Formal statistical methodology will be used for the MACE data; the methods are described in a 
separate SAP. 
10.1 Mortality 
The number and cause of death will be reported and summarized by treatment arm. 


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10.2 Hb-related Safety Endpoints 
Hb-related safety endpoints will be defined using data from the central laboratory. The analyses 
will use all central laboratory values in the database starting from randomization. No imputation 
will be performed for missing data. For each endpoint in Table 4, the proportion of the study 
group who satisfy the definition will be calculated stratified by the baseline strata. The 95% 
confidence intervals for these proportions will be reported along with the difference in 
proportions as well as the odds ratio; a Mantel-Haenszel weighting method will be used to 
calculate the 95% confidence intervals for these statistics (see Appendix D). 
Table 4. 
Hb-related Safety Endpoints from First Dose Date to Last Visit 
Variable 
Criterion for "yes" 
Hb >12.0 g/dL 
Any Hb >12.0 g/dL after Day 1 
Hb >13.0 g/dL 
Any Hb >13.0 g/dL after Day 1 
Hb >14.0 g/dL 
Any Hb >14.0 g/dL after Day 1 
Hb increase >1.0 g/dL within any 2-week interval 
Difference between 2 Hb values within any 2 weeks 
>1.0 g/dL after Day 1
Hb increase >2.0 g/dL within any 4-week interval 
Difference between 2 Hb values within any 4 weeks
>2.0 g/dL after Day 1
Hb<9.0 g/dL 
Any Hb <9.0 g/dL after Day 1
Hb<8.0 g/dL 
Any Hb <8.0 g/dL after Day 1
Hb: hemoglobin 
10.3 Adverse Events and Serious Adverse Events 
The AE CRF has been designed to capture all events after randomization. A TEAE is one that 
begins or worsens after treatment initiation. The AE reporting period for this study begins upon 
randomization and ends at the final protocol-required study contact. In addition, any AE that 
occurs after the AE reporting period is to be reported as an AE if the Investigator assesses it as 
possibly or probably related to the study medication. 
Serious adverse events (SAEs) will be handled in a fashion analogous to the methods described 
for AEs. 
Each AE will be summarized by Medical Dictionary for Regulatory Activities (MedDRA) 
system organ class (SOC) and preferred term (PT). All AE summaries will provide the number 
of subjects reporting at least 1 AE. Tables will present the number and percentage of subjects by 
treatment group reporting at least 1 of the following: 
•
Treatment-emergent AE (TEAE), SOC, and PT
o
TEAE leading to withdrawal of study medication, SOC, and PT
o
TEAE, severity, SOC and PT
o
Drug-related TEAE, SOC, and PT
o
Drug-related TEAE leading to withdrawal of study medication, SOC, and PT


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•
Treatment-emergent SAE, SOC, and PT
o
Drug-related treatment-emergent SAE, SOC, and PT
o
Fatal TEAE, SOC and PT
A summary table will show number of subjects with at least 1 of each of the following: 
•
TEAE
•
Severe TEAE
•
TEAE leading to withdrawal of study medication
•
Drug-related TEAE leading to withdrawal of study medication
•
Drug-related TEAE
•
Treatment-emergent SAE
•
Drug-related treatment-emergent SAE
•
Fatal TEAE
A summary by treatment group and PT will be presented of TEAEs reported by at least 5% of 
subjects in either treatment group. 
AE summaries will be ordered by decreasing pooled percentage for SOC, and PT within SOC. 
TEAEs will be summarized by 1) worst severity, and 2) worst causality by SOC and PT. For 
each subject and each PT, the worst severity recorded will be used in the by-severity summaries. 
Similarly, the worst causality (most related to treatment) will be attributed and used in the by-
causality summaries. If severity or causality is missing, data will be imputed to the worst 
category. 
A by-subject listing of all TEAEs will be provided. This listing will be presented by treatment 
group and will include: center, subject identifier, age, sex, race, AE (SOC, PT, and verbatim 
term), study day of onset, study day of resolution, duration, severity, seriousness, relationship to 
the study medication, action taken, outcome and causality.  
AESI, listed in Appendix F, will be summarized by treatment group. The number and percentage 
of subjects reporting these AESI will be provided.  
10.4 Other Safety Endpoints 
Vital signs and clinical laboratory values will be presented as outlined in Appendix E. 
The following additional safety endpoints will be presented: 
•
The number of usage of hypertensive medications added after first dose by study period/visit.
The separate MACE SAP will describe the methodology for the adjudicated analyses. 
11 SUBGROUPS 
Descriptive summary statistics for the primary and secondary efficacy endpoints will be 
presented separately in the following subgroups of the Randomized Population. The methods for 
analysis will be those described for the respective primary and secondary endpoints. When 


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analyzing a subgroup that is itself a stratification variable, it will be removed from the analysis 
model. These studies will enroll subjects from many centers; however, most centers will have 
small sample sizes. Therefore, no center-specific analyses are planned. In addition, stratification 
variables may be removed from the models in case of small sample size for a subgroup. A table 
will summarize the distribution of subjects by each subgroup and treatment group. 
Randomization stratification factors 
•
Hb stratification level at baseline
o
CI-0014

<9.5 g/dL

≥9.5 g/dL
o
CI-0015

<10.0 g/dL

≥10.0 g/dL
•
Region (actual according to CRF)
o
US
o
EU
o
ROW
•
NYHA CHF stratification level
o
0 and 1
o
2 and 3
•
Target Hb level: These targets are completely confounded with region. The 10 to 11 g/dL
target consists of subjects from the US while the 10 to 12 g/dL target applies to the EU and
the ROW.
o
10 to 11 g/dL
o
10 to 12 g/dL
Demographics and medical history 
•
Age
o
<65 years
o
≥65 years
•
Sex
o
Male
o
Female
•
Race
o
White
o
All others
•
Diabetes mellitus
o
No diabetes mellitus
o
Diabetes mellitus


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•
Hypertension
o
No Hypertension
o
Hypertension
o
Medications (CI-0015 only)
•
Baseline ESA dose (See Locatelli, 2004 for justification of the choice of cut-off values)
o
≤90 U/kg/week
o
>90 and <300 U/kg/week
o
≥300 U/kg/week
Baseline laboratory measurements 
•
Urine albumin-to-creatinine ratio (uACR) – reference for cutoff: Gansevoort, 2011.
o
<300 g/kg
o
≥300 g/kg
•
Estimated GFR – The threshold of 15 represents a value between CKD eGFR stages 4 and 5
o
<15 mL/min/1.73m2
o
≥ 15 mL/min/1.73m2
•
C-reactive protein. In Q2 laboratories, which are the labs used in these studies, the normal
range is 0 to 0.6 mg/dL.
o
≤0.6 mg/dL
o
>0.6 mg/dL
•
Baseline TSAT
o
< median of Baseline TSAT (%)
o
≥ median of Baseline TSAT (%)
•
Baseline ferritin
o
< median of baseline ferritin (ng/mL)
o
≥ median of baseline ferritin (ng/mL)
12 OTHER EXPLORATORY ANALYSES 
In addition to the planned analyses described above, the study team will likely perform many 
other descriptive analyses of efficacy and safety. For example, the team is likely to provide 
descriptions of the trajectory of subjects who transition to chronic dialysis, which will include 
the figures for Hb and other labs after the date of initiation of dialysis. 
13 DATABASE LOCK AND UNBLINDING 
13.1 Blind Review of Selected Data Prior to Final Database Lock 
Upon database release, protocol deviation and analysis population outputs will be produced and 
will be sent to Sponsor for review. An analysis population classification meeting will be 
arranged to discuss the outputs and to decide which subjects and/or subject data will be excluded 
from certain analyses. Decisions made regarding the exclusion of subjects and/or subject data 


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from analyses will be made prior to unblinding and will be documented and approved by 
Sponsor.   
The following summary of analysis population will be provided: 
•
A summary of the number and percentage of subjects allocated to each analysis population
by blinded treatment group and overall (Analysis population: All Subjects Randomized)
A by-subject listing of analysis population details will be provided. This listing will be presented 
by blinded treatment group and include: site, subject identifier, inclusion/exclusion flag for each 
population and reason for exclusion from each population. All subjects randomized will appear 
on this listing. Other data may also be selected for blind review if deemed necessary. 
13.2 Final Database Lock 
After completion of all Blind Data Review, validation of the project databases, and Akebia’s 
approval of the review, the clinical database will be locked. After the database lock and the 
authorization for unblinding (Section 13.3), the treatment codes will be merged to the analysis 
datasets. Any change to the clinical database after this time will require written authorization, 
with explanation, by Akebia. In addition, beginning at the time of database lock, an audit trail 
will be maintained of all versions of the analysis datasets that may result from refinements of the 
algorithms for derived variables in the course of the analysis. 
13.3 Authorization for Unblinding 
After database lock and upon receipt of written authorization from Akebia, a blinded study team 
will receive the actual treatment codes directly from the group maintaining them for data 
analysis.  


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APPENDIX A. JUSTIFICATION OF THE NONINFERIORITY MARGIN 
A.1. 
Historical Trials for Indication
Several drugs in the erythropoiesis stimulating agent (ESA) class have been studied and 
approved for increasing hemoglobin (Hb) levels in subjects with anemia related to chronic 
kidney disease (CKD). They are, in order of FDA approval: 
•
erythropoietin alfa (EpoA from Amgen, 1986)
•
darbepoetin alfa (DA from Amgen, 1998)
•
Mircera (Roche, 2004)
•
Omontys (Affymax, 2007).
We have combined the results of the pivotal trials leading to the approval of these agents with 
the results from several other studies and performed a meta-analysis of 16 study arms to estimate 
the placebo-adjusted change from baseline in Hb after 24 to 36 weeks of correction treatment. 
The growing precedence for this endpoint plus the summary treatment effect estimated here 
support the noninferiority margin of -0.75 g/dL used for the primary analyses in the PRO2TECT 
(CI-0014, CI-0015) and INNO2VATE (CI-0016, CI-0017) trials. 
A.2. 
Characteristics of Study Arms
The 16 study arms included (see Table A 1) vary in several key characteristics, namely: dialysis 
dependence (DD) or non-dialysis-dependent (NDD); the maximum allowable Hb level for 
inclusion of participants; the average baseline Hb level; the therapeutic drug; the timing of the 
primary efficacy outcome; and the target range of Hb. The timing for the PRO2TECT and 
INNO2VATE studies is planned for 24 to 36 weeks for the primary endpoint, and the target 
range of Hb is 10 to 11 g/dL in the United States (US) and 10 to 12 g/dL ex-US.  
The Mircera and Omontys trials used noninferiority margins of -0.75 and -1.0 ng/dL, 
respectively. 


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Table A 1. 
Study Characteristics 
Study Label 
Drug 
Labela 
Number 
Treated 
Target Hb 
Levelb 
Average Baseline 
Hb (g/dL) 
Dialaysis 
Dependence 
Reference to 
Literaturec 
TREAT 
DA 
2012 
High 
10.4 
No 
4 
Affymax 
OM1 
328 
High 
10.0 
No 
5 
Affymax 
OM2 
328 
High 
10.0 
No 
5 
Affymax 
DA 
327 
High 
10.0 
No 
5 
Roche 
DA 
162 
High 
10.2 
No 
3 
Roche 
MI 
162 
High 
10.2 
No 
3 
Akizawa 
DA 
161 
High 
9.2 
No 
6 
Akizawa 
Epo 
160 
Low 
9.2 
No 
6 
Amgen202 
DA 
129 
High 
9.3 
No 
1,2 
Amgen202 
Epo 
37 
High 
9.8 
No 
1,2 
AmgenDial 
Epo1 
201 
High 
7.4 
Yes 
7 
Amgen211 
DA 
91 
High 
8.8 
Yes 
1,2 
AmgenCAN 
Epo1 
44 
Low 
6.9 
Yes 
8 
AmgenCAN 
Epo2 
38 
High 
7.1 
Yes 
8 
AmgenDial 
Epo2 
35 
High 
8.2 
Yes 
7 
Amgen211 
Epo 
31 
High 
8.5 
Yes 
1,2 
CAN: Canada; DA: darbepoetin alfa; Dial: dialysis; Epo: epoetin alfa; MI: Mircera; OM: Omontys. 
a.
Suffixes indicate various dosing regimens.
b.
The high target Hb levels range from 11 to 13.5 g/dL, and the low levels range from 9 to 11 g/dL.
c.
Reference key follows.
1.
Macdougall IC. Darbepoetin alfa: a new therapeutic agent for renal anemia. Kidney Int Suppl. 2002;61(80):55-
61. doi:10.1046/j.1523-1755.61.s80.11.x.
2.
Locatelli F, Olivares J, Walker R, et al. Novel erythropoiesis stimulating protein for treatment of anemia in
chronic renal insufficiency. Kidney Int. 2001;60(2):741-747. doi:10.1046/j.1523-1755.2001.060002741.x.
3.
Macdougall, I. C., Walker, R., Provenzano, R., de Alvaro, F., Locay, H. R., Nader, P. C., … Investigators, A.
S. (2008). C.E.R.A. corrects anemia in patients with chronic kidney disease not on dialysis: results of a
randomized clinical trial. Clin J Am Soc Nephrol, 3(2), 337–347. https://doi.org/10.2215/CJN.00480107
4.
18 October 2010 CRDAC Meeting Briefing Document Epoetin alfa (EPOGEN®/PROCRIT®) and
darbepoetin alfa (Aranesp®) https://wayback.archive-it.org/7993/20170403223814/https://www.fda.gov/
AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee
/ucm192863.htm
5.
CDER, FDA. Omontys (peginesatide) BLA.
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202799orig1s000statr.pdf. Published 2012.
6.
Akizawa T, Gejyo F, Nishi S, et al. Positive outcomes of high hemoglobin target in patients with chronic
kidney disease not on dialysis: a randomized controlled study. Ther Apher Dial. 2011;15(5):431-440.
doi:10.1111/j.1744-9987.2011.00931.x.
7.
Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant human erythropoietin in anemic patients with
end-stage renal disease. Results of a phase III multicenter clinical trial. Ann Intern Med. 1989;111(12):992-
1000. http://www.ncbi.nlm.nih.gov/pubmed/2688507.
8.
Canadian Erythropoietin Study Group, Group CES, Group CES. Association between recombinant human
erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. Canadian
Erythropoietin Study Group. BMJ. 1990;300(6724):573-578. doi:10.1136/bmj.300.6724.573.
Table created manually. 


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A.2.1. Placebo Control
Only 2 of these studies included a placebo arm: TREAT (for DA) and Amgen Canadian (for 
EpoA). In both cases, the mean estimated change from baseline in Hb was 0.3 g/dL after 
approximately 20 weeks. Most of the other studies were noninferiority trials that used either 
EpoA or DA as the reference group; they did not include a placebo group. See the methods 
below for handling this gap in available data. 
A.2.2. Baseline and Target Hb Levels
Since the primary outcome variable is constrained by screening limits as well by therapeutic 
target ranges, the treatment effect for an effective drug (i.e., one increasing Hb into the target 
range) would naturally vary according to the average baseline Hb in the sample, guided 
somewhat by inclusion criteria, as well as the target Hb level. The treatment effect would be 
lower for the low-target studies than for the high-target ones. As Figure A 1 shows, the DD 
group of studies has lower average baseline Hb and higher treatment effect than the NDD 
studies. This suggests a moderator effect of baseline Hb in the 16 study arms included here: the 
higher the average baseline Hb level, the smaller the treatment effect. We interpret this result 
cautiously, however, because baseline Hb and DD/NDD status are almost completely 
confounded. 
Figure A 1. 
Treatment Effect by Baseline and Target Hemoglobin Levels 


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A.3. 
Statistical Methods
The most important decisions in conducting a meta-analysis concern both the input data and the 
statistical method. The choice of input data (presented in Table A 2) depends on what studies to 
include and how to handle unavailable data. We faced a problem because so few previous studies 
had placebo arms and some of the studies had missing information about the pre and post 
treatment outcome variances and correlations. Our choice of statistical method, fixed effects 
model, was based on several packages in R (metafor, MAd) and accompanying literature. 
Derivation of Input Statistics 
We used the data collected from publications and applied the following rules to fill in the desired 
baseline and post-baseline means and standard deviations. Post-baseline refers to assessment 
after at least 20 weeks of treatment: 
1. Compute the standard deviations from standard errors or half-widths of the reported
confidence intervals.
2. Compute post-baseline means based on baseline and reported changes from baseline.
3. Use available data to impute missing means and SDs, making the post-baseline SD the same
or slightly larger than SD for the baseline.
4. Compute correlation between baseline and post-baseline means (based on three arms with a
standard error for the difference).
5. Set remaining pre-post correlations to 0.30, splitting the difference between the observed
values from 0.14 to 0.58, to compute SD for the change scores. The largest study, TREAT,
was “penalized” with a lower correlation of 0.10.
Placebo Adjustment 
Three study arms had a placebo control arm. For the remaining 13 study arms, we introduced a 
hypothetical placebo arm with a mean of 0.3 and sample size and SD equivalent to the active 
treatment comparison arm. In this counterfactual scenario, we imagine each study had a placebo 
arm of size, baseline, and variance equal to the active treatment arm. Since there is general 
agreement that the placebo effect is essentially negligible, adding an imaginary placebo arm with 
small change from baseline will not distort the results away from the null hypothesis of no 
treatment effect. 


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Table A 2. 
Input Dataset for Meta-analysis 
ID Study Arm 
DD 
Hb 
Target 
Active treatment 
Placebo control 
N 
Mean BL 
(g/dL) 
Mean Change 
(SD) (g/dL) 
N 
Mean 
BL 
(g/dL) 
Mean Change 
(SD) (g/dL) 
Pre-post 
corrla 
1 
TREAT-DA 
No 
high 
2012 10.4 
2.00 (1.56) 
2026 10.3 
0.30 (1.56) 
0.1 
2 
Affymax-OM1 
No 
high 
328 
10.0 
1.50 (0.85) 
328 
10.0 
0.30 (0.85) 
0.3 
3 
Affymax-OM2 
No 
high 
328 
10.0 
1.70 (0.85) 
328 
10.0 
0.30 (0.85) 
0.3 
4 
Affymax-DA 
No 
high 
327 
10.0 
1.39 (0.85) 
327 
10.0 
0.30 (0.85) 
0.3 
5 
Roche-DA 
No 
high 
162 
10.2 
1.81 (1.03) 
162 
10.2 
0.30 (1.03) 
0.3 
6 
Roche-MI 
No 
high 
162 
10.2 
2.10 (1.03) 
162 
10.2 
0.30 (1.03) 
0.3 
7 
Akizawa-DA 
No 
high 
161 
9.2 
2.80 (1.11) 
161 
9.2 
0.30 (1.11) 
0.3 
8 
Akizawa-Epo 
No 
low 
160 
9.2 
0.90 (1.07) 
160 
9.2 
0.30 (1.07) 
0.3 
9 
Amgen202-DA 
No 
high 
129 
9.3 
2.70 (0.99) 
129 
9.3 
0.30 (0.99) 
0.5 
10 Amgen202-Epo 
No 
high 
37 
9.8 
2.20 (1.01) 
37 
9.8 
0.30 (1.01) 
0.6 
11 AmgenDial-
Epo1 
Yes 
high 
201 
7.4 
3.80 (2.15) 
201 
7.4 
0.30 (2.15) 
0.3 
12 Amgen211-DA 
Yes 
high 
91 
8.8 
2.70 (1.38) 
91 
8.8 
0.30 (1.38) 
0.1 
13 AmgenCAN-
Epo1 
Yes 
low 
44 
6.9 
3.30 (1.18) 
48 
7.1 
0.30 (1.40) 
0.3 
14 AmgenCAN-
Epo2 
Yes 
high 
38 
7.1 
4.60 (1.55) 
48 
7.1 
0.30 (1.40) 
0.3 
15 AmgenDial-
Epo2 
Yes 
high 
35 
8.2 
3.50 (2.15) 
35 
8.2 
0.30 (2.15) 
0.3 
16 Amgen211-Epo 
Yes 
high 
31 
8.5 
3.70 (1.43) 
31 
8.5 
0.30 (1.43) 
0.3 
BL: baseline ; CAN: Canada; corr: correlation; DA: darbepoetin alfa; DD: dialysis dependence; 
Epo: epopoetin alfa; Hb: hemoglobin; MI: Mircera; OM: Omontys SD: standard deviation 
The placebo statistics for records in red are reported for a true placebo control arm. 
a.The correlation between baseline and post-treatment sample means was derivable for study arms with IDs of 9, 1
0, and 12. In all other cases, it was assumed to be 0.1 or 0.3.
Data cut: 01Dec2017 
E:\proj\akebia\programs\l_meta1.sas v.002 (last run: 01/17/2018, 13:33) l_meta1.rtf (page 1 of 1) 
Justification of the Model 
Meta-analytic techniques are often used to obtain overall estimates of treatment effects. When at 
least 25 studies are available for analysis, there is sufficient information to provide confidence in 
the combined estimates, confidence intervals, and statistical tests. When a sufficient number of 
studies is available, both the between and within-study variability can be estimated and used in 
calculating an overall treatment effect. Some statisticians favor random effects meta-analytic 
methods in this situation; however, most meta-analyses are not based on a large number of 
studies and the fixed effects approach becomes necessary. Moreover, the weights assigned to 


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studies in random effects analyses are similar across studies allowing small studies to have the 
same effect on the overall estimates as large studies. Therefore, many statisticians favor fixed 
effects models even when a lot of studies are available. 
Fixed effects meta-analysis approaches are based on the following set of assumptions: there is 
one true effect size; inferences are based on the studies included in the meta-analysis and cannot 
be formally extended beyond the collection of studies; the properties of the estimates, tests and 
confidence intervals are based on the total number of subjects across the studies rather than the 
number of studies; and the weights are approximately proportional to the sample size or 
follow-up time, in time-to-event studies. In this analysis, the 16 study arms range in size from 
35 subjects to 2026 subjects per group favoring the use of the fixed effects approach. 
A.4. 
Results of Meta-analysis
See Figure A 2 for the results of the specified meta-analysis model fit to the 16 study arms, 
augmented with placebo adjustment, with an overall mean as the sole fixed effect. The estimated 
placebo-adjusted change from baseline in Hb is 1.58 g/dL with a lower 95% confidence interval 
bound of 1.53 g/dL. We have also used this method to perform separate meta-analyses on the DD 
and NDD studies. The overall treatment effect estimates and 95% confidence intervals in g/dL 
were 1.50 (1.44, 1.55) and 3.17 (2.95, 3.38) for the NDD and DD subgroups, respectively. 


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Figure A 2. 
Forest Plot of Placebo-adjusted Treatment Effect of ESAs on Hemoglobin 
A.5. 
Rationale for Margin
Based on the 95% lower confidence bounds for the pooled and subgroup overview analyses, the 
percent of treatment effect that would be preserved varies according to the choice of 
noninferiority margin (see Table A 3). A noninferiority margin of -1.0 g/dL would preserve a 
third of the treatment effect for CI-0014 (not dialysis dependent [DD], ESA-naive) study and 
two-thirds of the treatment effect for the CI-0016 (dialysis dependent, -ESA-naive) study. 
A noninferiority margin of -0.75 g/dL would preserve a half of the treatment effect for CI-0014 
(not dialysis dependent, ESA-naive) study and three-quarters of the treatment effect for the 
CI-0016 (dialysis dependent, ESA-naive) study.


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Table A 3. 
Percent of Treatment Effect Preserved by Study Type and Margin 
Analysis Population  
(Number of Study Arms) 
95% Lower 
Bound (g/dL) 
Noninferiority Margin (g/dL) 
-1
-0.75
-0.5
All studies pooled (16)  
1.53 
35% 
51% 
67% 
Not dialysis dependent (10) 
1.44 
31% 
48% 
65% 
Dialysis dependent (6) 
2.95 
66% 
75% 
83% 
Table created manually. 


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APPENDIX B. MISSING DATA (INCLUDING MULTIPLE IMPUTATION) 
This appendix describes the methods planned to handle missing data for the primary and 
secondary efficacy outcomes. Standard multiple imputation, where imputation of missing values 
is based on the group to which the subject was randomized, will be used for all analyses except 
the tipping point analysis. The tipping point analysis is described below to explore deviations 
from the assumptions that missing data would follow observed treatment arm trends. 
The literature for handling missing data in noninferiority studies is limited and the considerations 
differ from those for a superiority study. For example, in a superiority study one can impute all 
missing data using the data obtained from the placebo group under a reference based imputation. 
Such an approach is generally considered a conservative analysis in the setting of a superiority 
study as imputation of missing data in the treated group is based on the assumption that no 
treatment was received. In this noninferiority setting, reference-based imputation is not a 
conservative approach as efforts to make the vadadustat group behave more like the darbepoetin 
alfa group are anti-conservative. We are not aware of any published statistical proposal for 
“conservative” imputation in a noninferiority study, but Wiens and Rosenkranz, (2013) 
demonstrated that standard imputation performs best for the handling of missing data in 
noninferiority studies.  
B.1. 
Overall Approach
Missing data will be imputed through multiple imputation under fully conditional specification 
(FCS) with M = 100 imputed datasets. The general framework for the process is as follows: 
•
In the first step of the analysis, all missing values will be imputed for hemoglobin outcomes,
all other efficacy outcomes, and any covariates to be used in the models. The primary
outcome and secondary outcomes will be derived from the imputed values of Hb in the
primary efficacy period (PEP) and secondary efficacy periods (SEP). The variables in the
imputation model are delineated in Table B 1.
•
A set of pre-assigned seeds are shown in Listing B 1. These seeds will be used for all
imputations required in both efficacy and MACE safety analyses.
•
All multiple imputation will be implemented using FCS.
•
The type of model used for FCS will be tailored to the variable with missing outcome data.
Specifically, the following types of regression will be used:
o
Continuous variables: regression
o
Binary variables: logistic regression
o
Ordinal classification variables: response logistic regression
o
Nominal classification variables: response logistic regression
•
Rubin’s rule will be used to obtain the final result which can be computed using PROC
MIANALYZE.
•
A total of 40 iterations will be used for the burn-in.
•
Before inclusion in the model, variables will be assessed for collinearity using the condition
index and regression coefficient variance-decomposition matrix computed using PROC REG in
SAS.


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This appendix provides SAS code for the imputations for all variables of interest. This code, and 
the associated seeds, will be used to generate the analysis datasets. 
To ensure uniformity across all analyses, the change from baseline and binary outcomes derived 
from Hb measures will be imputed by calculating the imputed value of the continuous measure 
and then deriving the change score or binary outcome (Ratitch, 2016). This procedure will be 
adjusted if the imputation model proves inconsistent with the substantive model. 
Table B 1. 
Outcome Variables and Covariates in the Multiple Imputation Models 
Type 
Variablea 
Description 
Baseline, Post, Outcome Levels 
Continuous 
HBBL 
Baseline Hb 
Baseline 
n/a 
Continuous 
HBS1 
Hb in Weeks 2-8 
Post 
n/a 
Continuous 
HBS2 
Hb in Weeks 10-20 
Post 
n/a 
Continuous 
HBS3 
Hb in PEP (Weeks 24-36) 
HBCHGS3, HBRNGS3 n/a 
Continuous 
HBS4 
Hb in SEP (Weeks 40-52) 
HBCHGS4, HBRNGS4 n/a 
Continuous 
TIBCBL 
Baseline TIBC 
Baseline 
n/a 
Continuous 
HEPCNBL 
Baseline hepcidin 
Baseline 
n/a 
Continuous 
FERRBL 
Baseline ferritin 
Baseline 
n/a 
Continuous 
UACRBL 
Baseline uACR (PRO2 only) 
Baseline 
n/a 
Continuous 
CRPBL 
Baseline CRP 
Baseline 
n/a 
Continuous 
TSATBL 
Baseline TSAT 
Baseline 
n/a 
Continuous 
EGFRBL 
Baseline eGFR (PRO2 only) 
Baseline 
n/a 
Continuous 
TIBCS3 
TIBC in PEP (Weeks 24-36) 
Post 
n/a 
Continuous 
HEPCNS3 
Hepcidin in PEP (Weeks 24-36) 
Post 
n/a 
Continuous 
FERRS3 
Ferritin in PEP (Weeks 24-36) 
Post 
n/a 
Continuous 
UACRS3 
uACR in PEP (Weeks 24-36) (PRO2 only) 
Post 
n/a 
Continuous 
CRPS3 
CRP in PEP (Weeks 24-36) 
Post 
n/a 
Continuous 
TSATS3 
TSAT in PEP (Weeks 24-36) 
Post 
n/a 
Continuous 
EGFRS3 
eGFR in PEP (Weeks 24-36) (PRO2 only) 
Post 
n/a 
Continuous 
ESABL 
Baseline ESA dose 
Baseline 
n/a 
Continuous 
TDIALBL 
Time on dialysis prior to Screening Visit 1 
(INNO2 only) 
Baseline 
n/a 
Continuous 
AGE 
Age 
Baseline 
n/a 
Binary 
SEX 
Sex male 
Baseline 
2 
Nominal 
RACEGR2 
Race: white, black, other 
Baseline 
3 
Binary 
TRT01P 
Randomized treatment 
Baseline 
2 
Binary 
DIALTYP 
Dialysis type (INNO2 only) 
Baseline 
2 
Binary 
DMHX 
History of diabetes mellitus 
Baseline 
2 
Binary 
CVHX 
History of CV disease (coronary artery disease, 
MI, stroke, HF) 
Baseline 
2 
Binary 
CVOTHHX History of other CV disease (DVT, Arterial 
Thrombosis, PE, Vascular Access Thrombosis) 
Baseline 
2 
Ordinal 
SMOKEHX Smoking history 
Baseline 
3 
Binary 
STRAT3P 
NYHA CHF class 0/1 vs. 2/3 
Baseline 
2 
Nominal 
STRAT2A 
Geographical region 
Baseline 
3 


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Table created manually. 
a.
Variables names are preliminary and will be adjusted to comply with CDISC.
B.2. 
Multiple Imputation of all Missing Values
Multiple imputation will be used to create M datasets for the primary and secondary efficacy 
analyses. The imputation relies on the use of FCS and model code provided in Exhibit B 1 
below. The examples of code come from version 9.4 of SAS. Code will be modified slightly as 
needed according to software updates and compatibility with actual data. 
The variables in Table B 1 will be used to populate macro variables &BINVARS for all binary 
variables, &NOMVARS for all nominal variables, and &ORDVARS for all ordinal variables. The 
variables are imputed sequentially in the order specified in the VAR statement. 
Except where specified, imputation procedure will rely on the default behavior of FCS for the 
method and predictor covariates. The variable being imputed is sampled from a posterior 
distribution conditional on all the values, observed and imputed, of variables to the left of it in 
the VAR statement and all the observed-only values of variables to its right. If no FCS statement is 
included for a variable with missing data, the default method depends on the variable type. The 
regression method is default for continuous variables, and the discriminant function method is 
default for categorical variables (list in CLASS statement). 
B.3. 
Primary Efficacy Analysis
The primary efficacy analysis is based on the difference between the changes from baseline 
(average pretreatment Hb) to the PEP (average of up to 4 per-visit observations in 
Weeks 24 to 36). The noninferiority analysis is based on a margin of -0.75 g/dL applied to the 
difference in mean change between vadadustat and darbepoetin alfa. To establish noninferiority, 
the lower limit of the confidence interval of the mean change in vadadustat minus the mean 
change in darbepoetin alfa must be -0.75 g/dL or higher. ANCOVA with multiple imputation for 
missing data will be used to calculate the 95% confidence interval of the difference.  
Multiple imputation will rely on the method of fully conditional specification (FSC). Under this 
assumption, data for each variable with missing values will be imputed with a separate 
regression model allowing for all available data to be used in the imputation process. For 
continuous variables, the regression method will be used for imputations. For categorical 
variables, logistic regression models will be used for binary outcomes, ordinal logistic regression 
for ordinal responses, and nominal response logistic regression for nominal responses. The 
models for imputation under each of these conditions will be described in this appendix.  
The output from the multiple imputation procedure is M complete datasets. For the primary 
analysis, these datasets are analyzed using ANCOVA and the code in Exhibit B 2 below. The M 
estimates of the difference in the change from baseline in the PEP are then “combined” using 
PROC MIANALYZE to obtain a final estimate and its associated significance level.  
B.3.1. 
SAS Code for Standard Multiple Imputation using FCS
This section describes the procedures to impute missing values for the primary efficacy analysis. 
Missing values are imputed separately for each treatment group using a BY statement in PROC MI. 


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Exhibit B 1. SAS Code for Standard Imputation of Missing Values for the 
Primary Efficacy Analysis 
proc mi data=&INDAT. nimpute=&M. seed=&SEED1. out=&OUTDAT.; 
by TRT; 
class &BINVARS. &NOMVARS. &ORDVARS.; 
var 
STRAT2_HF STRAT3_REG  
SEX RACE AGE HX_CV4 HX_CV_OTH HX_DM ESA_BL SMOKE_BL 
HEP_BL FERR_BL TIBC_BL CRP_BL TSAT_BL HB_BL 
HB_1 HB_2 HEP_3 FERR_3 TIBC_3 CRP_3 TSAT_3  
    HB_3 HB_4; 
/* continuous - primary */ 
fcs plots=trace reg ( HB_3) nbiter=40; 
/* continuous example - other */ 
fcs reg ( HB_1) nbiter=40; 
/* binary or ordinal example */ 
fcs logistic( SEX / link=logit likelihood=augment) nbiter=40; 
/* nomial example */ 
fcs logistic (RACE/link=glogit likelihood=augment) nbiter=40 
run; 
Exhibit B 2. SAS Code to Compute the M Estimates of Treatment Effect 
*** derive primary and other endpoints; 
data &OUTDAT2.; 
set &OUTDAT.; 
DELT_HB3 = HB_3 – HBBL; 
DELT_HB4 = HB_4 – HBBL; 
if (STRAT3 eq “US” and 10 le DELT_HB3 le 11) or 
   (STRAT3 ne “US” and 10 le DELT_HB3 le 12) then 
HBRNGS3=”Yes”; 
else HBRNGS3=”No”; 
if (STRAT3 eq “US” and 10 le DELT_HB4 le 11) or 
   (STRAT3 ne “US” and 10 le DELT_HB4 le 12) then 


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HBRNGS4=”Yes”; 
else HBRNGS4=”No”; 
run; 
proc genmod data=&OUTDAT2.; 
      by _IMPUTATION_ 
class TRT (ref="DARB") STRAT1 STRAT2 ; 
model DELT_HB3=HB_BL STRAT1 STRAT2 TRT 
/ alpha=0.05 cl diagnostics residuals ; 
estimate “Primary Efficacy” TRT 1 -1; 
lsmeans TRT / cl pdiff cov; 
ods output diffs = MI_ESTIMATES lsmeans=MI_ESTIMATES2; 
run; 
The execution of the above set of SAS code will provide the datasets MI_ESTIMATES and 
MI_ESTIMATES2 which will contain M lines of data that include the estimates and standard 
errors for each imputed dataset. The final result is then obtained with application of PROC 
MIANALYZE provided in Exhibit B 3. 
Exhibit B 3. SAS Code to Obtain the Overall Estimate and Standard Error 
proc mianalyze data= MI_ESTIMATES2 (or MI_ESTIMATES);
modeleffects estimate; 
stderr; 
ods output ParameterEstimates=MI_PRIMARY; 
run; 
The final results will be contained in the output dataset MI_primary. This dataset will contain the 
95% confidence limits of the difference. The primary hypothesis is tested by comparing the 
lower limit of this confidence interval to -0.75 g/dL. 
B.3.2. 
Tipping Point Sensitivity Analysis for Missing Data
This multiple imputation model for the primary efficacy model described above assumes that 
data in both treatment arms are missing at random (MAR) and would therefore follow the trend 
of observed data. The tipping point analysis assesses the effect of potential deviations from this 
assumption and explores the consequences of assuming that data in the vadadustat arm are 
missing not at random (MNAR) (i.e., subjects in the vadadustat arm with missing outcome are   
assumed to have a lower Hb values than subjects in the darbepoetin alfa arm). The specific steps 
are as follows: 


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A. The missing information on Hb in the vadadustat arm will be multiply imputed using a shift
parameter S applied to lower the mean Hb values in that arm. The sample SAS code for
performing multiple imputation with a shift S in the vadadustat arm is presented in
Exhibit B 4. Missing data in the darbepoetin alfa arm will continue to be imputed assuming
MAR, using the same code as for the primary efficacy analysis subset to the darbepoetin arm.
B. The multiply-imputed data will be analysed using standard multiple imputation combining
rules to obtain an estimated treatment effect and its associated 95% confidence interval.
These analyses provide a realistic estimate of variance for the treatment effect that takes into
account the uncertainty caused by the missing data.
C. Steps A and B will then be repeated. The shift parameter S starts from 0, which corresponds
to the primary efficacy analysis with no shift effect, and increased in the negative direction
by a certain amount in each step until the analysis reaches the “tipping point”, the point at
which the effect of vadadustat is no longer noninferior to that of darbepoetin alfa. The more
the tipping point diverges from the observed data, the more robust the conclusion based on
primary efficacy analysis.
The tipping point analysis will use a single seed from Listing B 1 to generate however many 
seeds are needed, i.e., 1 per treatment group per shift. 
Exhibit B 4. SAS Code for Tipping Point Analysis 
proc mi data=&INDAT. (where=(TRT=”VADA”)) nimpute=&M. 
seed=&SEED2. out=&OUTDAT.; 
   class &BINVARS. &NOMVARS. &ORDVARS.; 
   var    
  STRAT2_HF STRAT3_REG  
  SEX RACE AGE HX_CV4 HX_CV_OTH HX_DM ESA_BL SMOKE_BL 
  HEP_BL FERR_BL TIBC_BL CRP_BL TSAT_BL HB_BL  
  HB_1 HB_2 HEP_3 FERR_3 TIBC_3 CRP_3 TSAT_3 HB_3  
  HB_4; 
   fcs reg ( HB_3) nbiter=40; 
   mnar adjust ( HB_3 / shift=&S. ); 
  run; 
B.4. 
Secondary Efficacy Analyses
The secondary endpoint, change in Hb at Time 4, is continuous and will be analyzed in a manner 
similar to the method to be used for the primary efficacy analysis. 
B.5. 
Other Efficacy Analyses
For the below 2 efficacy endpoints of having average Hb value in the geography-specific target 
range in weeks 24-36 and having average Hb value in the geography-specific target range in 
weeks 40-52, their endpoints are binary; they will be analyzed according to the Mantel-Haenszel 
estimate of stratified risk differences. These binary outcome measures will be computed from the 
continuous imputed data which will serve as the input data set for the computation of the 
estimate of risk difference. The code for this analysis is provided in Exhibit B 5. Rubin’s rule 
requires that the input statistic is normally distributed, which we assume for this estimate. 


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Exhibit B 5. SAS Code to Obtain the Mantel-Haenszel Estimate of Risk Difference 
*** compute the MH estimate; 
proc freq data=&OUTDAT2.; 
  by _IMPUTATION_; 
  tables STRAT1*STRAT2*STRAT3*TRT*&OUTCOME/riskdiff(common) cmh; 
  ods output CommonPdiff=CommonPdiff; 
run; 
*** combine the results; 
proc mianalyze data= CommonPdiff; 
modeleffects Value; 
stderr; 
ods output parameterestimates=MI_SEC; 
run; 
Multiple imputation is not currently planned for the other efficacy analyses, except in the case 
that outcomes for these analyses are part of the multiple imputation for the primary efficacy 
analysis. If analysis of a covariate included in the overall imputation model (Table B 1) is 
desired, follow the procedure for the primary or secondary analyses, depending on the variable 
type. 
B.6. 
Random Seed Specification
This section presents the generation code, resulting random seeds, and corresponding analysis 
assignments for all analyses with multiple imputation. The random seeds for all the multiple 
imputation runs for each trial will be generated from a single master seed. The master seeds will 
be 10014 for CI-0014, and 10015 for CI-0015. 
Exhibit B 6. SAS Code for Random Seed Generation 
 data SEED; 
   call streaminit(&MASTER.); 
   do I = 1 to &NUMSEED. ; 
 SEED = put(ceil( ((2**31) - 1) * rand("UNIFORM") ), best.); 
 output; 
   end; 
 run; 
The seeds and their analysis assignments are shown in Listing B 1. These will be used for all 
imputations required in both efficacy and MACE safety analyses for this set of trials. 


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Listing B 1. 
Random Seed Assignment for all Planned Analyses 
PRO2TECT 
INNO2VATE 
Analysis Category 
Analysis ID Analysis Detail 
CI-0014a
CI-0015b
CI-0016c
CI-0017d
Primary Efficacy, Secondary, & 
All Subgroups 
PE 
Impute missing Hb & covariates 
635320903 
1987393372 
32552474 
1864814524 
Primary Efficacy - Sensitivity 
PES1 
Rescue definition 1 (narrow) 
429585122 
1373196336 
1027066416 
928246872 
PES2 
Rescue definition 2 (broad-on-treatment) 
549618248 
1156395436 
477818637 
2071955541 
PES3 
Tipping point 
340408944 
1747908400 
1450082522 
216479710 
Analyses that use a shared seed between CI-0014 and CI-0015 or CI-0016 and CI-0017 are highlighted in yellow. 
a. Seeds for CI-0014 are generated based on a master seed of 10014.
b. Seeds for CI-0015 are generated based on a master seed of 10015.
c. Seeds for CI-0016 are generated based on a master seed of 10016.
d. Seeds for CI-0017 are generated based on a master seed of 10017.


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APPENDIX C. ANALYSIS OF CONTINUOUS ENDPOINTS 
This appendix provides details related to the analysis of the continuous endpoints in the studies. 
It includes a description of the statistical approaches and provides examples of the SAS code for 
the analysis of specific continuous endpoints. The primary efficacy analysis will be an analysis 
of covariance (ANCOVA) with multiple imputation for missing data based on standard 
imputation. The details of this approach are provided in Appendix B.  
Additional analyses will use the ANCOVA method including some sensitivity analyses for the 
primary efficacy endpoint, secondary efficacy endpoint analyses, and other continuous 
exploratory endpoint analyses. Other sensitivity analyses for the primary efficacy endpoint will 
use a mixed model repeated measures (MMRM) without imputing missing data. 
Analyses using ANCOVA 
C.1.1. Primary Analysis
The primary analysis is based on the change in average Hb between the baseline and the primary 
efficacy period (PEP), Weeks 24 to 36. The noninferiority analysis will be based on a margin 
of -0.75 g/dL applied to the mean change in vadadustat minus darbepoetin alfa. To establish 
noninferiority, the lower limit of the confidence interval of the mean change in vadadustat minus 
darbepoetin alfa must be -0.75 g/dL or higher. If the lower limit of the 2-sided 95% confidence 
interval for the difference between the mean in the vadadustat group and the mean in the 
darbepoetin alfa group is above zero, superiority will have been established and the finding will 
be interpreted as providing evidence of a greater change from baseline in Hb for vadadustat 
relative to the control arm. 
The primary efficacy analysis is based on the estimated confidence interval estimated from an 
ANCOVA model. The computation of this confidence interval is described in this section. 
Modifications for additional continuous endpoints are outlined in a separate section.  
The ANCOVA model will be fit using PROC GENMOD in SAS with the following variables: 
•
HB_BL – this is the average of the last 2 Hb measure on or prior to the first dose date
•
DELT_HB3 – this is computed as the average Hb measure computed from the PEP
(Week 24 to 36) visits minus HB_BL
•
TRT – denotes treatment group; vadadustat or darbepoetin alfa
•
STRAT1 – stratification factor of geographic region (US, EU, versus Rest of World)
•
STRAT2 – NYHA CHF class 0 or I versus II or III
The basic SAS code to fit the model is in Exhibit C 1, but the full process includes multiple 
imputed datasets as seen in Exhibit B 2. 


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Exhibit C 1. SAS Code for Primary Analysis 
proc genmod data=&OUTDAT2.; 
class TRT (ref="DARB") STRAT1 STRAT2 ; 
model DELT_HB3=HB_BL STRAT1 STRAT2 TRT 
/ alpha=0.05 cl diagnostics residuals ; 
estimate “Primary Efficacy” TRT 1 -1; 
lsmeans TRT / cl pdiff cov; 
ods output diffs = MI_ESTIMATES lsmeans=MI_ESTIMATES2; 
run; 
The confidence limits for the coefficient associated with TRT in the above model are used to 
compute the confidence intervals based on M imputed datasets. 
C.1.2. Select Sensitivity Analyses for the Primary Efficacy Endpoint
To assess the robustness of the primary efficacy analysis, the sensitivity analyses outlined below 
will be conducted using the same method in the primary efficacy analysis, but starting from 
different missing data patterns, imputation models, or analysis populations. As with the primary 
analysis, the following sensitivity analyses will use multiple imputation and ANCOVA. 
•
The primary analysis will be repeated after setting to missing all per-visit hemoglobin values
within four weeks of administration rescue therapy. The definition of rescue therapy will
vary across the series described in Section 6.3.9.
•
Tipping point analyses (see Appendix Section B.3.2) will be performed to assess the effect of
the missing data.
•
The Full Analysis Set (FAS) population will be used instead of the randomized population.
This analysis will be performed only if the size of the FAS is less than 95% of the
randomized population.
C.1.3. Analysis of Continuous Secondary Endpoint
The secondary efficacy endpoint is the change in average Hb value between Baseline and the 
secondary efficacy period (SEP), Weeks 40 to 52. Analyses of the other efficacy endpoints are 
described in Appendix D. 
The analysis of this secondary continuous endpoint will be similar to the analysis approach for 
the primary efficacy shown in Exhibit B 2 and Exhibit C 1, except the outcome of interest in the 
model statement DELT_HB3 will be replaced with DELT_HB4, the change in Hb from baseline 
to the SEP. This is computed as the average Hb measure computed from the Week 40 to 52 visits 
minus HB_BL. 
The assessment of noninferiority will be tested using the same approach with the lower limit of 
the confidence interval compared to -0.75 g/dL. 


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Note that of all the continuous efficacy endpoints, only the primary efficacy endpoint and the 
secondary efficacy endpoint of the change in Hb between baseline and the SEP will be formally 
tested. All other continuous endpoint analyses will be descriptive. 
C.1.4. Analysis of Additional Continuous Endpoints
The analysis of additional continuous endpoints will be similar to the analysis approach for the 
primary efficacy analysis (see either Exhibit C 1 or Exhibit B 2 ) depending on whether using 
multiple imputation), and adjustments to these analyses approaches are outlined for each 
example. The team may consider alternative methods or links to analyze the certain endpoints as 
noted below. Several additional continuous endpoints are to be evaluated: 
•
Change in average Hb value between Baseline and the combined PEP and SEP
(Weeks 24 to 52).
•
Average weekly dose of elemental iron administered. This model will include the average
weekly dose of elemental iron by route groups (oral, IV) for each analysis time period in
Year 1 and Weeks 52 to EOS. Note that some variants will not be multiply imputed, in which
case the analysis will be a single ANCOVA of the observed values.
•
Change in hepcidin, ferritin, TSAT, serum iron, and TIBC over time. The code for this
analysis is identical to that for the primary analysis with the new outcome measure of
interest. Four outcomes will be tested for each lab value – the change from baseline to PEP,
the change from baseline to SEP, the percentage change from baseline to PEP, and the
percentage change from baseline to SEP.
Analyses Using MMRM 
Additional sensitivity analyses will be performed under an alternate framework to assess the 
robustness of the primary efficacy analysis with respect to missing data. 
A mixed model repeated measures (MMRM) will be fit to the observed data only without 
imputing missing values. The repeated measures will be the observed averages for analysis time 
periods 1, 2, and 3 (See definitions, Section 5.1). Note that analysis time period 4 will be 
included in the sensitivity analysis for the continuous secondary efficacy endpoint (Section 9.2). 
The following variables will be used in the model: 
•
DELT_HB – this is computed as the Hb measure minus HB_BL
•
ASPER – refers to the subperiod number post-baseline (1, 2, 3)
•
SUBJID – denotes subject identifier


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The SAS code to fit the model is as follows: 
Exhibit C 2. SAS Code for Sensitivity Analysis for the Primary Efficacy Endpoint 
proc mixed data = &LONGDAT. method=reml alpha=0.05 covtest; 
where ASPER le 3; 
 class SUBJID TRT (ref="DARB") ASPER (ref=last) 
STRAT1 STRAT2 ; 
model DELT_HB3 = HB_BL STRAT1 STRAT2 TRT ASPER 
       HB_BL*ASPER TRT * ASPER / s ddfm=kr 
repeated ASPER / subject = SUBJID type = UN r; 
estimate "MMRM Sensitivity" TRT 1 -1 TRT*ASPER 0 0 1 0 0 -1/ cl; 
 ods output estimates=MMRM_EST; 
run;
The test of efficacy is obtained from the ESTIMATE statement. The model will have the 
following characteristics: 
•
The response variable will be the vector of observed change (average of per-window
changes) in the primary efficacy endpoint from baseline to the average value in each analysis
time period. The endpoint will consist of the three repeated measures defined as Analysis
Time Period X Hb – baseline Hb.
•
Repeated post-baseline measurements from each subject will be identified by the subject
identifier denoted as SUBJID in the PROC MIXED code.
•
Within-subject correlations will be modeled using an unstructured covariance structure.
•
In the unlikely situation that this model does not converge, the model will use the
heterogeneous Toeplitz structure, which assumes the correlation between 2 repeated
measurements depends solely on their lag in visit number and that the variance of the
endpoint may differ over time.
•
If the model still does not converge with the heterogeneous Toeplitz structure, the model will
use a homogeneous Toeplitz structure.
•
Finally, if the model using the homogeneous Toeplitz structure does not converge, the model
will use a compound symmetry structure which assumes equal correlation for a subject’s
measurements, regardless of how far apart in time they were taken.
•
The Kenward-Roger degrees of freedom approximation will be used in calculating the
ESTIMATE contrasts for the sensitivity analysis.


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APPENDIX D. ANALYSIS OF NON-NORMAL ENDPOINTS 
D.1. 
Analysis of Binary Endpoints
This section describes the methods for analyzing other binary endpoints.
For each binary endpoint, a 95% confidence interval will be calculated for each proportion by 
treatment group using the Clopper-Pearson method [Clopper, 1934].  
For analyses conducted in the randomized population, the weighted difference in proportions 
between treatment groups, adjusting for the stratification factors, and the corresponding 2-sided 
95% confidence interval will be calculated by weighting according to the Mantel-Haenszel 
method The associated odds ratio and corresponding 2-sided 95% confidence interval will also 
be calculated. Subgroup analysis will be conducted similarly. 
The below efficacy endpoints have binary outcome measures and will use the code structure 
presented in Exhibit D 1. For the first 4 endpoint, noninferiority will have been established if the 
lower limit of the confidence interval for the risk difference is above -15%.  
•
At least 1 Hb value in the geography-specific target range in Weeks 24 to 36
•
At least 1 Hb value in the geography-specific target range in Weeks 40 to 52
•
Hb values in the geography-specific target range for at least 1/2 of the observations in
Weeks 24 to 36
•
Hb values in the geography-specific target range for at least 1/2 of the observations in
Weeks 40 to 52
•
Hb increase of >1.0 g/dL in Year 1 (CI-0014)
•
Receipt of at least 1 administration of elemental iron, repeated using each route, intravenous
(IV), or oral
•
Receipt of any red blood cell (RBC) transfusion
•
Receipt of any erythropoietin-stimulating agent (ESA) rescue medication
•
Receipt of any rescue therapy (series of definitions from narrow to broad)
•
Hb values >12, 13, or 14 g/dL
•
Hb values <8 or 9 g/dL
•
Hb increase of >1.0 g/dL within any 2-week period (CI-0015)
•
Hb increase of >2.0 g/dL within any four-week period (CI-0015)
Exhibit D 1. SAS Code for Analyzing Binary Endpoints 
proc freq data=&OUTDAT2.; 
  tables STRAT1*STRAT2*STRAT3*TRT*&OUTCOME/riskdiff(common) cmh; 
  ods output CommonPdiff=CommonPdiff; 
run; 


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D.2. 
Analysis of Count Data
This section describes the methods for analyzing endpoints measured as counts. These endpoints 
include: 
•
Number of ESA episodes
•
Number of RBC transfusion episodes
The initial analysis approach will be descriptive, reporting the proportion of subjects with counts 
greater than 0 and the mean number for this population. Statistical modeling based on a zero-
inflated Poisson regression model, as outlined in Exhibit D 2, will be used to account for 
stratification factors. 
Exhibit D 2. SAS Code for Analyzing Count Endpoints 
proc genmod data=&INDAT.; 
class TRT (ref="DARB") STRAT1 STRAT2; 
model COUNT = TRT HB_BL STRAT1 STRAT2 / dist=zip 
offset=LN_FUT; 
zeromodel; 
output out=ZIP predicted=PRED pzero=PZERO; 
estimate "Treatment Effect” TRT 1 -1 @ZERO TRT 1 -1; 
ods output modelfit=FIT estimates=ZIPEST; 
run; 
D.3. 
Analysis of Time to Event Data
This section describes the methods for analyzing time-to-event endpoints, for example, time to:
•
achieve 1g/dL increase in Hb in Year 1 (CI-0014)
•
first rescue therapy (by series of definitions)
•
first RBC transfusion
•
first ESA use (aside from control arm medication not specified as rescue)
•
progression of chronic kidney disease (CKD).
•
study discontinuation
Time-to-event distributions will be estimated using the Kaplan-Meier product-limit method and 
log rank test.  
The hazard ratio and corresponding 95% confidence interval for the comparison of vadadustat to 
darbepoetin alfa will be estimated using a Cox proportional hazards model, with treatment group 
and other predictors as covariates. Analyses in the randomized population will be stratified by 
the stratification factors; analyses in subgroups will be conducted similarly. The predictor 
variables (&PREDVAR. in Exhibit D 3) for hemoglobin-related events are baseline ESA dose (three 


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levels specified in Section 11) and continuous baseline Hb. For CKD progression, the predictor 
variable is continuous baseline eGFR. 
Exhibit D 3. SAS Code for Time to Event Data Analysis 
*** compute median times with KM product limit method; 
proc lifetest data=&TTEDAT. alphaqt=0.05 conftype=LOGLOG confband=ALL 
timelim=OBSERVED outsurv=RATES timelist= 0 24 36 40 52 reduceout; 
     by TRT; 
     time AVAL * CNSRN(1); 
run; 
*** compute hazard ratios with Cox proportional hazards model; 
proc phreg data=TTE; 
class TRT; 
model AVAL * Status(0) = TRT HB_BL STRAT1 STRAT2 &PREDVAR. / ties=Efron; 
hazardratio 'Cox proportional hazard' TRT; 
ods output HazardRatios=hazard; 
run; 
For laboratory-based time-to-event endpoints, subjects who do not experience an event will be 
censored on the date of the last evaluable assessment of the laboratory parameter. For time to 
progression of CKD, subjects who do not experience CKD progression will be censored on date 
of last visit with no kidney transplant or dialysis. 


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APPENDIX E. CLINICAL LABORATORY AND VITAL SIGN SAFETY ENDPOINTS 
This appendix lists endpoints and cut-off points for vital signs, physical findings, and other 
observations related to safety. Summary tables by visit, and by-subject listings in select cases, 
will be provided for all outcomes, observed and change from baseline, in this section. All listings 
will be sorted by treatment group, subject, parameter, and time period as appropriate. 
If the central laboratory uses assays that have lower limits of detection (LLD), all laboratory 
results below the LLD will be imputed with the LLD. Results reported as greater than a value 
(i.e., “> value”) will be imputed as 1.5 × that value. 
E.1. 
Clinical Laboratory Evaluation
E.1.1 Liver Function Abnormality
A summary of liver function abnormalities by analysis period will be provided by treatment 
group. 
Any subject with at least 1 of the following liver function abnormalities will be summarized: 
•
Alanine aminotransferase (ALT) >2 × and ≤3 × upper limit of normal (ULN); ALT >3 × and
≤5 × ULN; ALT >5 × and ≤10× ULN; ALT >10 × ULN
•
Aspartate aminotransferase (AST) >2 × and ≤3 × ULN; AST > 3× and ≤ 5 × ULN;
AST >5 × and ≤10 × ULN; AST >10 × ULN
•
Bilirubin >2× and ≤3× ULN; Bilirubin >3× ULN
In addition, a table will summarize the occurrence of events that satisfy the following versions of 
Hy’s Law:  
•
(ALT or AST >3× ULN and <= 5xULN) and total bilirubin >2× ULN;
•
(ALT or AST >5× ULN and <= 10xULN) and total bilirubin >2× ULN;
•
ALT or AST >10× ULN and total bilirubin >2× ULN
E.1.2 Serum and Urine Pregnancy Tests
Serum pregnancy test for females of childbearing potential will be performed at screening visit 2 
and will be used for the subject’s inclusion or exclusion. A urine pregnancy test will be 
performed during the screening visit and the results must be negative before subject’s initiation 
of study drug. Additional pregnancy tests may be conducted during the study to establish the 
absence of pregnancy based on the investigator’s clinical judgment or as required by local 
regulations. 
A by-subject listing of serum and urine pregnancy tests will be provided. 
E.1.3 Urine Albumin-to-creatinine Ratio (uACR)
A random urine spot sample is collected at the investigative site during the Baseline, Weeks 28, 
52, 104, 156, 208 and end of treatment (EOT) to assess the urine albumin-to-creatinine ratio 
(uACR). A by-subject listing of change and percentage change from baseline in uACR will be 
provided, as well as geometric means (logarithmic scale) over time. The number and percent of 
subjects with a percent change in uACR exceeding 30% (in either direction) will be presented. 


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E.1.4 Complete Blood Count
The following components of the complete blood count (CBC) will be analyzed:
•
mean corpuscular volume
•
mean corpuscular Hb
•
mean corpuscular Hb Concentration
•
red cell distribution width
•
white blood cell count with differential (neutrophils, lymphocytes, monocytes, eosinophils,
and basophils)
•
platelets
•
hematocrit
•
RBC counts
Summary statistics will be provided for the following: 
•
Each component of the CBC by treatment group.
•
Change from baseline in each component of the CBC by treatment group.
•
Changes from baseline category to the worst reported Common Terminology Criteria for
Adverse Events (CTCAE) grade in each analysis time period in Year 1 and Weeks 52 to
EOS.
A by-subject listing of all components of the CBC will be provided by treatment group. 
In addition for white blood cells (WBC), lymphocytes, neutrophils, and platelets, a summary of 
the number and percentage of subjects experiencing abnormal values will be presented by 
treatment group and analysis time period. This summary will indicate the worst reported 
Common Terminology Criteria for Adverse Events (CTCAE) grade for the analysis time period 
for all subjects experiencing CTCAE grade 3 values or higher. 
E.1.5 Chemistry and Estimated Glomerular Filtration Rate (eGFR)
The following laboratory parameters (with preferred units in parentheses) will be analyzed:
•
Sodium (mmol/L)
•
Potassium (mmol/L)
•
Bicarbonate (mEq/L)
•
Chloride (mmol/L)
•
Calcium (mmol/L)
•
Magnesium (mEq/L)
•
Phosphorus (mmol/L)
•
Phosphate (mmol/L)
•
Glucose (mg/dL)
•
Creatinine (umol/L)
•
Blood urea nitrogen (mg/dL)
•
Creatine phosphokinase (U/L)
•
Uric acid (umol/L)
•
Albumin (g/dL)
•
Total protein (g/L)
•
Total bilirubin (umol/L)
•
Alkaline phosphatase (U/L)
•
Alanine aminotransferase (ALT) (U/L)
•
Aspartate aminotransferase (AST) (U/L)
•
Lactate dehydrogenase (U/L)


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•
Total cholesterol (mg/dL)
•
Low-density lipoprotein (LDL) cholesterol
(mg/dL)
•
High-density lipoprotein (HDL)
cholesterol (mg/dL)
•
Triglycerides (mg/dL)
•
Derived parameter: non-HDL-cholesterol
(= total cholesterol minus HDL
cholesterol) (mg/dL)
•
Estimated glomerular filtration rate
(eGFR) (calculated from serum
creatinine) (mL/min/1.73 m2).
Summary statistics will be provided for the following: 
•
All chemistry parameters and eGFR by treatment group.
•
Change (absolute and percent) from baseline in chemistry and eGFR by treatment group.
•
Changes from baseline category to the worst reported Common Terminology Criteria for
Adverse Events (CTCAE) grade in each analysis time period in Year 1 and Weeks 52 to
EOS.
The eGFR will be calculated from serum creatinine by the formula of the 2009 Chronic Kidney 
Disease Epidemiological Collaboration (CKD-EPI). See Appendix B of the protocols. 
A by-subject listing of chemistry and eGFR will be provided by treatment group. The categories 
for the shift tables will be based on CTCAE grades if available.  
In addition, a summary of the number and percentage of subjects experiencing clinically 
significant values for each of the following parameter definitions will be presented by analysis 
time period: 
•
Decrease in eGFR ≥40% from baseline.
•
Potassium >6.0 mmol/L.
E.1.6 C-reactive protein and Vascular Endothelial Growth Factor
Summary statistics will be provided for the following:
•
C-reactive protein (CRP) and vascular endothelial growth factor (VEGF) by treatment group.
•
Change (absolute and percent) from baseline in CRP and VEGF by treatment group.
A by-subject listing of CRP and VEGF will be provided by treatment group. 
E.1.7 Erythropoietin
Blood samples for erythropoietin (Epo) analysis are obtained at Baseline and at Weeks 4, 12, 28, 
and 52.  
A by-subject listing and a summary table of Epo (absolute level and change from baseline) by 
treatment group and time of collection will be provided.  


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E.2. 
Vital Signs, ECGs, and Physical Findings
E.2.1 Vital Signs and Weight
Body weight and the following vital signs will be summarized:
•
Systolic BP
•
Diastolic BP
•
Heart rate
•
Respiratory rate
•
Body temperature.
Summary statistics will be provided for the following: 
•
Vital Signs and Weight by treatment group.
•
Change from baseline in Vital Signs and Weight by treatment group.
•
The number and percentage of subjects experiencing the following findings by treatment
group and by analysis time periods:
o
Systolic blood pressure (SBP) ≥ 160 mmHg or diastolic blood pressure (DBP)
≥ 110 mmHg
o
SBP ≤ 90 mmHg or DBP ≤ 50 mmHg
o
change in SBP or DBP in either direction ≥ 20 mmHg
o
Systolic blood pressure (SBP) ≥ 180 mmHg
E.2.2 12-lead ECG
The following variables will be summarized at the Baseline Visit:
•
Heart rate
•
PR interval
•
QT interval
•
QRS interval
•
QTc (corrected)
•
Overall result
A summary of each electrocardiography (ECG) parameter will be provided by treatment group. 
In addition, a by-subject listing of 12-lead ECG results will be provided. 


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APPENDIX F. ADVERSE EVENTS OF SPECIAL INTEREST 
F.1. 
Potential Risks
The following potential risk factors will be presented as adverse events of special interest 
(AESI): 
•
Hypersensitivity: Hypersensitivity Standardised MedDRA Query (SMQ) Narrow
•
Hyperkalemia: Hyperkaliemia MedDRA PT, Blood potassium abnormal MedDRA PT,
Blood potassium increased MedDRA PT
•
Hypertension: Hypertension MedDRA SMQ Narrow
F.2. 
Events of Special Interest
The following will be presented as AESI:
•
Hepatotoxicity: Drug related hepatic disorders Comprehensive SMQ broad
•
Pulmonary Hypertension: Pulmonary Hypertension SMQ narrow
•
Cardiac Valve disorders: Cardiac Valve disorders high-level group term (HLGT)
•
Adrenal disorder: high-level term (HLT) Adrenal gland disorders not elsewhere classfied
(NEC), HLT Adrenal cortex tests
F.3. 
Events Under Monitoring
The following will be presented as AESI:
•
Malignancies: Malignancies MedDRA SMQ Narrow
•
Congestive heart failure: Cardiac failure MedDRA SMQ Narrow
•
Retinal effects due to Vascular Endothelial Growth Factor (VEGF) expression: Retinal
disorders SMQ Narrow


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Cremieux PY, Van Audenrode M, Lefebvre P. The relative dosing of epoetin alfa and 
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Gansevoort RT, Matsushita K, van der Velde M, et al. Lower estimated GFR and higher 
albuminuria are associated with adverse kidney outcomes. Kidney Int 2011; 80:93-104. 
Gosselin A, McKenzie R, Lefebvre P, et al. Dose-conversion ratio for epoetin alfa and 
darbepoetin alfa in chemotherapy patients with anemia and cancer. P&T 2006; 31:594-6, 601-3. 
Heerspink HJL, Greene T, Tighiouart H, et al. Change in albuminuria as a surrogate endpoint for 
progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials. 
Lancet Diabetes Endocinol 2019; 7:128-39. 
Jordan J, Breckles J, Leung V, et al. Conversion from epoetin alfa to darbepoetin alfa: effects on 
patients' hemoglobin and costs to Canadian dialysis centres. Can J Hosp Pharm 2012; 65:443-9. 
Kaufman JS, Reda DJ, Fye CL, et al. Subcutaneous compared with intravenous epoetin in 
patients receiving hemodialysis. Department of Veterans Affairs cooperative study group on 
erythropoietin in hemodialysis patients. N Engl J Med 1998; 339:578-83.  
Levey AS, Inker LA, Matsushita K, et al. GFR decline as an end point for clinical trials in CKD: 
a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug 
Administration. Am J Kidney Dis 2014; 64(6):821-35. 
Levin NW, Fishbane S, Cañedo FV, et al. Intravenous methoxy polyethylene glycol-epoetin beta 
for haemoglobin control in patients with chronic kidney disease who are on dialysis: a 
randomised non-inferiority trial (MAXIMA). Lancet 2007;370:1415-21. Erratum in: Lancet 
2008; 371:386. 
Mantel N, Haenszel W. Statistical aspects of analysis of data from retrospective studies of 
disease. J Natl Cancer Inst 1959;22:719–48. 
Paganini EP, Eschbach JW, Lazarus JM, et al. Intravenous versus subcutaneous dosing of 
epoetin alfa in hemodialysis patients. Am J Kidney Dis 1995;6:331-40. 
Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharm Stat 2013;12(6):337-347. 


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Vega A, Abad S, Verdalles U, et al. Dose equivalence between continuous erythropoietin 
receptor activator (CERA), darbepoetin, and epoetin in patients with advanced chronic kidney 
disease. Hippokratia 2014;18:315-18. 
Wiens BL, Rosenkranz GK. Missing data in noninferiority studies. Stat Biopharm Res 
2013;5:383-93. 
Wright DG, Wright EC, Narva AS, et al. Association of erythropoietin dose and route of 
administration with clinical outcomes for patients on hemodialysis in the United States. Clin J 
Am Soc Nephrol 2015;10:1822-30. 


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15 ATTACHMENTS 
Product: 
Protocol Number: 
SAP Version: 
Approval Sheet 
Statistical Analysis Plan 
AKB-6548-CI-0014 and -0015 
1.0 
The individuals signing below have reviewed and approve this statistical analysis plan. 
Senior Director, Biostatistics 
Senior Medical Director 
Confidential 
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Date 
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Statistical Analysis Plan
MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) IN SUBJECTS  
WITH NON-DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE (NDD-CKD) 
(PROTOCOLS AKB-6548-CI-0014 AND AKB-6548-CI-0015: PRO2TECT) 
AND 
MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) IN SUBJECTS 
WITH DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE (DD-CKD) 
(PROTOCOLS AKB-6548-CI-0016 AND AKB-6548-CI-0017: INNO2VATE) 
Sponsored by: Akebia Therapeutics, Inc. 
Version: 1.0 
Date Approved: FINAL 
Confidentiality Statement 


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Part or all of the information in this statistical analysis plan may be unpublished material. 
Accordingly, this document is to be treated as confidential and restricted to its intended use. 
This material is the property of Akebia Therapeutics, Inc. and must not be disclosed or used 
except as authorized in writing by Akebia Therapeutics, Inc. 


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TABLE OF CONTENTS 
1 
Introduction ............................................................................................................................ 5 
2 
Study description .................................................................................................................... 6 
2.1 
Study Periods .............................................................................................................. 6 
2.1.1 The Correction (CI-0014) and Correction/Conversion Study (CI-0016) ....... 6 
2.1.2 The Conversion Studies (CI-0015 and CI-0017) ............................................ 7 
2.2 
Method of Assigning Subjects to Treatment Groups ................................................. 7 
2.3 
Primary Safety Outcome: Major Adverse Cardiovascular Event (MACE) ............... 7 
2.4 
Blinding ...................................................................................................................... 8 
2.5 
Sample Size ................................................................................................................ 8 
2.5.1 The PRO2TECT studies (CI-0014 and CI-0015) ........................................... 8 
2.5.2 The INNO2VATE studies (CI-0016 and CI-0017) ........................................ 8 
3 
Safety Outcomes ..................................................................................................................... 9 
3.1 
Adjudicated Outcomes ............................................................................................... 9 
3.2 
Time to Adjudicated MACE: Primary Safety Outcome ........................................... 10 
3.2.1 Potential MACE: Descriptive Safety Outcome ............................................ 10 
3.2.2 Time to MACE Within 4 Weeks of End of Treatment................................. 10 
3.2.3 Individual CEC-Adjudicated Components of MACE: Descriptive Safety 
Outcome ................................................................................................................... 10 
3.2.4 Time to Components of Adjudicated MACE ............................................... 11 
3.3 
Time to Expanded MACE ........................................................................................ 11 
3.4 
Time to cardiovascular death, nonfatal MI, or nonfatal stroke ................................ 11 
4 
Statistical Analysis ............................................................................................................... 11 
4.1 
Analysis Population .................................................................................................. 12 
4.2 
Global Study Completion Date ................................................................................ 12 
4.3 
Reference dates ......................................................................................................... 13 
4.4 
Primary MACE Analysis .......................................................................................... 13 
4.5 
Secondary MACE endpoints: Definition and Analysis ............................................ 14 
4.6 
Analyses of Secondary and Other Cardiovascular Safety Outcomes ....................... 15 
5 
Subgroups ............................................................................................................................. 17 
5.1 
Prespecified Subgroups ............................................................................................ 17 


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5.2 
Subgroup Analyses of Other Outcomes ................................................................... 20 
6 
Supportive analysis - restricted mean survival time ............................................................. 20 
7 
Data Safety Monitoring ........................................................................................................ 21 
8 
Handling of missing dates .................................................................................................... 21 
9 
Subject disposition, treatment adherence, and treatment exposure ...................................... 21 
10 
References ............................................................................................................................ 23 
Appendix A. 
SAS Code .......................................................................................................... 25 
Appendix B.  
Justification of the noninferiority margin .......................................................... 26 
Background ............................................................................................................... 26 
FDA Decision Making ............................................................................................. 26 
C.2.1. Feasibility of and MACE Event Rates in Trials of Subjects with Anemia Secondary to
CKD .......................................................................................................................... 26 
C.2.2. Safety Plan for Development of a New Anemia Therapy in CKD .......................... 27 
C.2.3. Conclusion ................................................................................................................ 28 
EMA Decision Making ............................................................................................. 29 
C.3.1. Rationale ................................................................................................................... 29 
C.3.2. Conclusion ................................................................................................................ 31 
Approval Sheet .............................................................................................................................. 32 


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ABBREVIATIONS 
Abbreviation 
Definition 
CEC 
Clinical Endpoint Committee 
CHF 
congestive heart failure 
CKD 
chronic kidney disease 
CRP 
C-reactive protein
CV 
cardiovascular 
DD 
dialysis-dependent 
DVT 
deep vein thrombosis 
EAS 
Endpoint Adjudication System 
EOT 
end of treatment 
ESA 
erythropoietin-stimulating agent 
EU 
European Union 
GSCD 
global study completion date 
HF 
heart failure 
HR 
hazard ratio 
IDMC 
Independent Data Monitoring Committee 
MACE 
major adverse cardiovascular events 
MAR 
missing at random 
MI 
myocardial infarction 
MNAR 
missing not at random 
NDD 
non-dialysis dependent 
NI 
noninferiority 
PE 
pulmonary embolism 
RMST 
restricted mean survival time 
ROW 
rest of world 
SAP 
statistical analysis plan 
SMQ 
Standard MedDRA Queries 
uACR 
urine albumin creatinine ratio 
US 
United States 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the methods to be used to analyze the major 
adverse cardiovascular events (MACE) in Akebia’s PRO2TECT Protocols (AKB-6548-CI-0014 
and AKB-6548-CI-0015) and INNO2VATE Protocols (AKB-6548-CI-0016 and AKB-6548-CI-
0017). CI-0014 and CI-0015 are studying vadadustat in subjects with non-dialysis dependent 
(NDD) chronic kidney disease (CKD) while CI-0016 and CI-0017 are studying vadadustat in 
dialysis-dependent (DD) CKD. These four trials, referred to hereafter as CI-0014, CI-0015, CI-
0016, and CI-0017, constitute Akebia’s Phase 3 program for vadadustat. 
Note that while this SAP covers all four trials, the analyses will be performed by study pair, 
PRO2TECT (CI-0014 and CI-0015) or INNO2VATE  (CI-0016 and CI-0017), in particular at 
such time as the specified target is met in each respective pair, independent of the progress in the 
other pair of studies. Thus, the analyses in this SAP will not necessarily be conducted on the 
same calendar date. 
In addition to the plans for analysis of MACE, this SAP also describes plans for analysis of other 
cardiovascular and thrombotic events.  
(For simplicity, sometimes MACE refers to the singular and sometimes the plural. The context is 
always clear.) 
Protocol CI-0014 is a “correction study”. CI-0014 enrolls subjects not on an erythropoietin-
stimulating agent (ESA).  
Protocols CI-0015 and CI-0017, the “conversion studies”, which are designated here as CI-
0015/17, enroll subjects on any dose of ESA. 
Protocol CI-0016 is a “correction/conversion study”, enrolling incident dialysis subjects who 
may be on an ESA or not. 
For each safety parameter described in this SAP, the outcomes of most interest are estimates that 
combine data from each pair CI-0014/15 and CI-0016/17 calculated by considering as a stratum 
each component study of the pair. In addition, estimates will be presented for each study 
separately. 
The protocols for the four studies, as well as the general SAPs for the PRO2TECT and 
INNO2VATE Protocols, provide information about the plans for the studies and their analyses 
exclusive of the MACE analyses. 
This SAP contains language and programming code that specifies the intent of each analysis. 
The sponsor will finalize and sign this document prior to locking the database and unblinding. 
Many of the analyses described in this SAP are quite complex. A blinded team of clinicians and 
statisticians will review the data carefully to develop conventions and analytic methods not 
anticipated in writing this SAP.  


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2 
STUDY DESCRIPTION 
CI-0014 and CI-0015 are studying vadadustat in subjects with NDD-CKD while CI-0016 and
CI-0017 are studying vadadustat in DD-CKD. Darbepoetin alfa is the control drug in all four
studies.
The Phase 3 program is designed so that meta-analyses of the PRO2TECT and INNO2VATE 
pairs of studies will have a sufficient number of independently adjudicated endpoints to allow a 
meaningful comparison of vadadustat and darbepoetin alfa with respect to MACE in each pair of 
trials. The PRO2TECT pair of trials will continue until at least 631 subjects experience an 
adjudicated MACE in the pair of trials. Similarly, the INNO2VATE pair of trials will continue 
until at least 631 subjects experience an adjudicated MACE in that pair. The individual trials in 
each pair will continue after the planned number of MACE have occurred in order to ensure that 
each subject is followed the minimum amount of time specified in the individual protocols.  
2.1 
Study Periods 
2.1.1 The Correction (CI-0014) and Correction/Conversion Study (CI-0016) 
Following randomization, CI-0014 and CI-0016 will have five periods: 
•
Correction
o
CI-0014: Correction Period (Weeks 0-23): initial period on study medication for
correction of Hb
o
CI-0016: Correction and Conversion Period (Weeks 0-23): initial period on study
medication for correction of Hb or conversion to study treatment
•
Maintenance Period (Weeks 24-52): this period will be divided into weeks 24-36
(primary efficacy evaluation period) and Weeks 40-52 (secondary efficacy evaluation
period)
•
Long-Term Treatment Period (Weeks 53-End of Treatment [EOT]): continued study
medication to assess long-term safety
•
Follow-Up (EOT + 4 weeks): post-treatment visit (either in person or by telephone) for
safety
•
Continued MACE Follow-up: each subject, except those who are lost to follow-up or
who withdraw consent, will be followed for MACE until the end of the study.


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2.1.2 The Conversion Studies (CI-0015 and CI-0017) 
Following randomization, each conversion study will have four periods: 
•
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 (either in person or by
telephone) for safety
•
Continued MACE Follow-up: each subject, except those who are lost to follow-up or
who withdraw consent, will be followed for MACE until the end of the study.
Each pair of trials (CI-0014/15 and CI-0016/17) will continue until at least 631 events occur in 
the respective pair.  
2.2 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized 1:1 using permuted block randomization. Randomization will be 
stratified in each of the four studies by the following: 
•
Geographic region
o
United States (US)
o
European Union (EU)
o
Rest of World (ROW)
•
New York Heart Association congestive heart failure (CHF) class
o
Class 0 or I
o
Class II or III
•
Baseline Hb (g/dL)
o
<9.5 versus ≥9.5 for CI-0014 and 0016
o
<10 versus ≥10 for CI-0015 and 0017
2.3 
Primary Safety Outcome: Major Adverse Cardiovascular Event (MACE) 
The primary safety outcome in each study is MACE, defined as all-cause mortality, nonfatal 
myocardial infarction (MI), or nonfatal stroke, occurring at any time on or following first dose 
date and prior to each subject’s end of study (EOS) date. 


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2.4 
Blinding 
All four studies are randomized open-label trials. An interactive web response system governs 
treatment assignment. Investigators are not aware of which treatment will be assigned next.  
The studies involve blinded adjudication of MACE, the use of an unblinded 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. 
The protocols discuss the method of guiding dose adjustment for vadadustat and darbepoetin 
alfa. 
As further mechanisms to reduce potential execution bias in the trials, special steps have been 
taken to restrict access to the study data (see the Blinding Procedures and Oversight Plan). 
2.5 
Sample Size 
The primary safety endpoint is the time from first dose date to the first adjudicated MACE. This 
section describes the justification for the sample sizes of the four studies. 
2.5.1 The PRO2TECT studies (CI-0014 and CI-0015) 
The primary safety analysis will be based upon all first events that accrue over the two 
PRO2TECT trials. If the noninferiority (NI) margin is 1.25 and the event rate is the same in the 
two treatment groups (i.e., the hazard ratio (HR) is 1.0), then 631 events are needed to establish 
NI with 80% power; 631 events yields more than 90% power to exclude an NI margin of 1.30. If 
the HR is 0.95 favoring vadadustat, the power is above 90% when the NI margin is 1.25.   
Justification for the NI margin of 1.25 for FDA decision making and 1.30 for EMA decision 
making is provided in Appendix C. 
An annual MACE rate of 10% is anticipated. This rate is based on a comprehensive review of 
available epidemiology and prospective clinical studies in NDD-CKD. Therefore, a projected 
total of 3700 subjects will be enrolled in studies CI-0014 and CI-0015. With 1850 subjects 
planned per treatment group in studies CI-0014 and CI-0015 and a planned accrual period of 
approximately 20 months, and up to 36 months of follow-up (with expected mean follow-up 
about 2 years), 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.   
2.5.2 The INNO2VATE studies (CI-0016 and CI-0017) 
The primary safety analysis will be based upon all first events that accrue over two 
INNO2VATE studies (CI-0016 and CI-0017). As described in the previous section, to have 80% 
power to establish NI if the NI margin is 1.25 and the event rate is the same in the two treatment 
groups  (i.e., the HR=1.0), 631 events are needed; this number of events yields more than 90% 


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power to exclude an NI margin of 1.30. If the HR is 0.95 favoring vadadustat, the power is above 
90% when the NI margin is 1.25.  
An annual MACE rate of 12% is anticipated. This rate is based on a comprehensive review of 
available epidemiology and prospective clinical studies in DD-CKD. Therefore, an estimated 
total of 3700 subjects will be enrolled in studies CI-0016 and CI-0017. With 1850 subjects 
planned per treatment group enrolled in study CI-0016 and CI-0017, a planned accrual period of 
approximately 20 months, and up to 36 months of follow-up (with expected mean follow-up 
about 2 years), 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. 
3 
SAFETY OUTCOMES 
This section defines the outcomes to be used for the analyses of MACE and related events. 
3.1 
Adjudicated Outcomes 
Study investigators will solicit potential cardiovascular events at each study visit. Each of these 
potential events will be recorded on the eCRF. Potential cardiovascular events will also be 
identified through periodic review of Standard MedDRA Queries (SMQs) of adverse events and 
serious adverse events irrespective of the source of identification. An Endpoint Management 
Plan will provide details describing the SMQs terms and processes related to identifying these 
potential events. Events not reported by study investigators identified through SMQ search or 
CEC will be manually entered into EAS (Endpoint Adjudication System) database. 
The Clinical Endpoint Committee (CEC) adjudicates all potential cardiovascular events. The 
formal cardiovascular safety analyses will only include CEC-adjudicated events (i.e., events 
confirmed by the CEC).  
The CEC adjudicates the following events CEC Manual of Operations (MOP) outlines the 
program endpoint definitions and requirements for committee adjudication.  
•
All-cause mortality (The CEC will attribute cause of death to responsible underlying
disease cause).
•
Non-cardiovascular death
•
Unknown death
•
Cardiovascular death

Sudden death

Non-sudden cardiovascular death


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
Fatal or nonfatal MI

Fatal or nonfatal stroke
•
Thromboembolic event

Arterial thrombosis

Deep vein thrombosis (DVT)

Pulmonary embolism (PE)

Vascular access thrombosis
•
Hospitalization for heart failure (HF)
3.2 
Time to Adjudicated MACE: Primary Safety Outcome 
An adjudicated MACE, the primary safety outcome, is defined as any death, CEC-confirmed 
nonfatal MI, or CEC-confirmed nonfatal stroke occurring between first dose date and each 
subject’s EOS date. The following subsections describe variations on, and components of, the 
primary safety outcome. 
3.2.1 Potential MACE: Descriptive Safety Outcome 
All potential MACE are all cases adjudicated as MACE by the CEC (i.e., primary safety 
outcome events confirmed by the CEC) plus those potential MACE cases reported by the 
investigator, submitted for adjudication, but then adjudicated as non-MACE (i.e., events refuted 
by the CEC). All deaths are included in this descriptive safety outcome. 
3.2.2 Time to MACE Within 4 Weeks of End of Treatment 
Only a MACE that occurs up to and within 28 days inclusive after permanent discontinuation of 
study treatment (End of Treatment, EOT) will be included as a MACE Within 4 weeks of End of 
Treatment.  
3.2.3 Individual CEC-Adjudicated Components of MACE: Descriptive Safety Outcome 
The components of CEC-Adjudicated MACE are as follows: 
•
All-cause mortality
•
CEC-confirmed nonfatal MI
•
CEC-confirmed nonfatal stroke
The total number of these outcomes equals the total number of CEC-adjudicated MACE. They 
will be reported simply to help interpret the primary MACE outcome. No formal analysis of 
these outcomes is planned. 


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3.2.4 Time to Components of Adjudicated MACE 
The following CEC-confirmed MACE will be reported and analyzed as time-to-first event. As 
with the primary safety outcome, the CEC adjudication of cause does not exclude any death from 
all-cause mortality.: 
•
All-cause mortality: death from cardiovascular (CV), non-CV, and unknown causes.
o
Cardiovascular death

Fatal MI

Fatal stroke

Sudden death
o
Non-cardiovascular death
•
Non-fatal  MI
•
Non-fatal stroke
3.3 
Time to Expanded MACE 
The studies have several outcomes that expand the definition of MACE. Each of these outcomes 
includes MACE (all-cause mortality, nonfatal MI and nonfatal stroke) plus one or more other 
type of event. The events are as follows: 
•
MACE plus thromboembolic event
•
MACE plus thromboembolic event excluding vascular access thrombosis
•
MACE plus hospitalization for heart failure (HF)
•
MACE plus hospitalization for HF or thromboembolic event
•
MACE plus hospitalization for HF or thromboembolic event excluding vascular access
thrombosis
3.4 
Time to cardiovascular death, nonfatal MI, or nonfatal stroke 
This alternate MACE definition is the same as the primary safety outcome, except includes only 
deaths positively adjudicated by the CEC as cardiovascular (i.e., only CEC-confirmed CV 
deaths). This excludes non-cardiovascular deaths as well as unknown deaths. 
4 
STATISTICAL ANALYSIS 
For each subject in the four studies, duration of follow-up will be calculated as the number of 
days between date of first dose date and last contact date during the study plus one. For each 
outcome, the number of events that occur during that period may be included in the analysis. The 
event rate will be calculated as the number events divided by the duration of at-risk follow-up in 


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person-years. Survival analyses will include only the first event for each subject in that period. 
For each type of event, the event rate will be summarized by treatment group for each study and 
for each pair of studies (CI-0014/15 and CI-0016/17).  
For each type of event that includes all-cause death (including the primary endpoint), the method 
of analysis for each pair of studies will be a Cox regression with the randomized treatment 
assignment as a predictor. The models will be stratified by study. Subjects without an event will 
be censored at their last study contact (visit or telephone contact) at which all components of the 
outcome were assessed. Deaths that occur between withdrawal of consent or loss to follow up 
and the global study completion date (GSCD) and that are identified, prior to database lock, 
through public records will be included in the analyses as an event. The models will use other 
covariates as well, as described below.  
For all other events, analyses will use competing risk methods. These methods produce valid 
estimates of the marginal probability of the event in case other events preclude observation of the 
event of interest. For each pair of studies, the models include the randomized treatment 
assignment as a predictor and, should a competing event not occur, subjects will be censored on 
their last study contact (visit or telephone contact) at which all components of the outcome were 
assessed. The models will use other covariates as well, as described below. Models for the 
overall analysis of PRO2TECT and of INNO2VATE will also stratify by study. Appendix A 
provides SAS code for the competing risk analysis. 
The studies will enroll subjects from many centers; however, most centers will have small 
sample sizes. Therefore, as described in the general SAPs for PRO2TECT and INNO2VATE, no 
center-specific analyses are planned. 
4.1 
Analysis Population 
The analyses will be based on a Safety Population, which includes randomized subjects who 
receive at least one dose of study treatment and which classifies subjects by the more frequently 
received drug. 
4.2 
Global Study Completion Date 
The sponsor will notify the sites approximately three months prior to the global study completion 
date (GSCD) for each study so that they can schedule visits with all subjects who are alive and 
have not withdrawn consent. At that visit the investigators should try to assess whether the 
subjects have had any MACE, Hospitalized for HF or Thromboembolic event. At a minimum the 
investigators will attempt to contact each subject to determine whether that subject is still alive. 
Additionally, investigators will request that subjects who continued study treatment until this 
visit come in for another follow-up visit four weeks later. 
Operationally this plan is designed to capture all MACE, hospitalized for HF and 
Thromboembolic events that occurred in subjects still being followed and with onset within three 


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months of GSCD in the clinical database. Should subjects who remained on study treatment until 
that visit subsequently experience MACE, Thromboembolic events or hospitalized for HF 
between that visit and four weeks later, these events may also be captured. 
Analytically, any outcome event with onset on or before the last contact date will be included in 
the primary safety outcome analysis, and all subjects without events will be censored at the last 
contact date.  
The earliest GSCD of a pair of studies will be a date that ensures each pair of studies will have 
the planned number of safety outcome events (i.e., 631) and each study in each pair has the 
protocol-required amount of safety follow-up.  
4.3 
Reference dates 
This SAP uses the following terms to refer to dates used to calculate time. 
Date of last visit for MACE and other adjudicated events is the date of the last visit when all 
events could be assessed. This visit may be conducted in person at the site or by telephone. 
Date of last contact is the last date when the site had any contact at all with the subject. 
4.4 
Primary MACE Analysis 
The endpoint for the primary analysis is defined as the first occurrence of all-cause mortality, 
adjudicated nonfatal MI, or adjudicated nonfatal stroke after taking the first dose of 
investigational drug. Treatment comparisons will be based on the estimated hazard ratio and its 
95% CI from the Cox model described below. As specified earlier, there will be a primary 
MACE analysis for each pair of trials, one for the CI-0014 and CI-0015 NDD-CKD trials and 
one for the CI-0016 and CI-0017 DD-CKD trials. 
Counts and proportions of patients who experience a primary endpoint event will be calculated 
for each treatment arm, as well as the proportion difference (95% CI) in proportions between the 
groups. Mantel-Haenszel confidence interval will be reported for the proportion difference. In 
addition to event rate, person-years of follow-up for the primary endpoint and the incidence rate, 
calculated by dividing the number of patients who developed the event during the study period 
by the event-specific person-years of at-risk follow-up, will be provided.   
For each subject who has experienced a MACE, the time to the first adjudicated MACE is 
defined as the date of the first MACE – date of first dose +1. 
Subjects who have not experienced a MACE will be censored at the date of the last study contact 
(visit or telephone contact) at which all components of MACE were assessed. 
For each of the four studies and for each pair of studies, Kaplan-Meier curves for the time to 
first adjudicated MACE will be generated. 


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For each pair of studies, analysis of time to first MACE will be based on a stratified Cox 
regression model with study as a stratification factor. The model will also include covariates of 
baseline Hb, randomization strata of region (US; EU; ROW) and NYHA (0 or I; II or III), sex 
(male; female), age (> 65; ≤65), race (white or non-white), preexisting cardiovascular disease as 
defined in Section 5.1 (yes/no), and diabetes mellitus (yes/no). The following kernel of SAS 
code (details in Appendix A) will be used for PRO2TECT (for INNO2VATE, the study strata 
will be replaced with CI-0016/17): 
proc phreg; 
strata /*study pair*/ CI-0014/15; 
model time to first MACE * censor = trtgrp 
/*covariates*/ age sex race pre-existing 
cardiovascular disease DM region NYHA 
Hb_base;  
run; 
The hazard ratio (vadadustat/darbepoetin alfa) and its 95% confidence interval will be presented 
for each study and each pair of studies. For a given pair of studies (PRO2TECT and 
INNO2VATE), Vadadustat will be considered to have non-inferior risk of MACE relative to 
darbepoetin alfa if the upper limit of this 95% CI of the pair is less than 1.25 (for FDA 
assessment) or 1.30 (for EMA assessment).  
Vadadustat will be considered be superior to darbepoetin alfa with respect to the MACE outcome 
in a particular disease population if the upper limit of this 95% CI of the pair of studies is less 
than 1. 
The stratified Cox regression model (primary safety analysis) allows the underlying hazard to 
vary by stratum (i.e. by study) but it makes the assumption that the effects of covariates are 
proportional over time within each stratum. The proportionality assumption will be assessed 
graphically and visually. If the assumption is violated, alternative method may be explored.  
4.5 
Secondary MACE endpoints: Definition and Analysis 
The study has the below key secondary MACE endpoints which will be analyzed formally only 
if the primary analysis meets the noninferiority margin. A hierarchical testing scheme will be 
used to correct for the multiplicity of these endpoints. These endpoints are prioritized according 
to the following ordering: 
•
MACE plus hospitalization for HF or thromboembolic event excluding vascular access
thrombosis
•
Cardiovascular death, non-fatal MI or non-fatal stroke
•
Cardiovascular death
•
All cause death


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For each of these secondary MACE endpoints, the hazard ratio (vadadustat/darbepoetin 
alfa) and its 95% confidence interval will be presented for each study and each pair of 
studies by the similar approach described for the primary MACE analysis. Kaplan-Meier or 
cumulative incidence curves will be generated too. 
4.6 
Analyses of Secondary and Other Cardiovascular Safety Outcomes 
The following table summarize the cardiovascular safety outcomes related to MACE, the 
associated definitions, and the model that will be applied to each outcome.  
Adjudicated Outcome 
Definition of Outcome 
First bullet: time to event for subjects with a 
MACE 
Second bullet: time to censoring for subject who 
do not experience a MACE 
Model 
Time to MACE within 4 
weeks of End of 
Treatment 
• Date of the first MACE occurring within 4 weeks
of EOT – date of first dose +1
• Date of last study visit (including telephone
contact) within 4 weeks of EOT where all the
components of MACE were assessed – date first
dose +1
Cox regression model with 
same stratification factors 
and covariates as primary 
MACE analysis 
Individual CEC-
adjudicated components 
of MACE 
The frequency of each MACE component (all-cause 
mortality, nonfatal myocardial infarction, and 
nonfatal stroke) will be shown. For each subject, the 
total number of these outcomes (i.e., total number of 
MACE) will be calculated, and descriptive statistics 
for total number of MACE will be shown. 
Not applicable 
Time to components of 
adjudicated MACE  
• Date of the first MACE components – date of first
dose +1
• Date of last study visit (included telephone contact)
when where all the components of MACE were
assessed – date of first dose +1
Cox regression model or 
competing risk analysis with 
same stratification factors 
and covariates as primary 
MACE analysis 
Time to expanded 
MACE 
• Date of the first MACE (expanded definition) –
date of first dose +1
• Date of last study visit (included telephone contact)
when where all the components of MACE
(expanded  definition) were assessed – date of first
dose +1
Cox regression model with 
same stratification factors 
and covariates as primary 
MACE analysis 
Time to Cardiovascular 
death, non-fatal MI or 
non-fatal stroke 
• Date of first MACE – date of first dose +1
• Subject’s date of last contact – date of first dose +1
Competing risk analysis 
with same stratification 
factors and covariates as 
primary MACE analysis. 
Non-cardiovascular and 
unknown deaths are 
competing events. 
All-cause death 
• Date of death – date of first dose +1
• Subject’s date of last contact – date of first dose +1
Cox regression model with 
same stratification factors 
and covariates as primary 
MACE analysis 


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Adjudicated Outcome 
Definition of Outcome 
First bullet: time to event for subjects with a 
MACE 
Second bullet: time to censoring for subject who 
do not experience a MACE 
Model 
Cardiovascular death 
• Date of cardiovascular death – date of first dose +1
• Subject’s date of last contact – date of first dose +1
Competing risk analysis 
with same stratification 
factors and covariates as 
primary MACE analysis. 
Non-cardiovascular and 
unknown deaths are 
competing events. 
Non-cardiovascular 
death 
• Date of non-cardiovascular death – date of first
dose +1
• Subject’s date of last contact – date of first dose +1
Competing risk analysis 
with same stratification 
factors and covariates as 
primary MACE analysis. 
Cardiovascular and 
unknown deaths are 
competing events. 
Time to any 
thromboembolic event 
• Date of first occurrence of adjudicated arterial
thrombosis, DVT, PE, or vascular access
thrombosis – date of first dose +1
• Date of last study visit (including telephone
contact) where such events were assessed – date of
first dose +1
Competing risk analysis 
with same stratification 
factors and covariates as 
primary MACE analysis. 
All –cause death is a 
competing event. 
Time to arterial 
thrombosis, DVT, or PE 
• Date of first occurrence of adjudicated arterial
thrombosis, DVT, or PE thrombosis – date of first
dose +1
• Date of last study visit (including telephone
contact) where such events were assessed – date of
first dose +1
Time to venous 
thromboembolic event 
(DVT or PE) 
• Date of first occurrence of adjudicated DVT or PE
– date of first dose +1
• Date of last study visit (including telephone
contact) where such events were assessed – date of
first dose + 1
Hospitalization for heart 
failure 
• Date of first occurrence of adjudicated
hospitalization for heart failure – date of first dose
+1
• Date of last study visit (including telephone
contact) where such events were assessed – date of
first dose + 1
The following outcomes will be summarized as proportions and are purely descriptive as they do 
preserve the randomized groups. That is, only subjects with CEC-confirmed MI or strokes are 
included in these calculations, respectively. 


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30-day MI fatality
The proportion is calculated as the number of 
deaths occurring within 30 days of an CEC-
confirmed MI divided by the number of subjects 
who had an CEC-confirmed MI. 
30-day stroke fatality
The proportion is calculated as the number of 
deaths occurring within 30 days of an CEC-
confirmed MI divided by the number of subjects 
who had an CEC-confirmed MI. 
5 
SUBGROUPS 
The effects of vadadustat compared to darbepoetin alfa on the incidence of the primary safety 
outcome will be examined across the following subgroups. All subgroup analyses are regarded as 
exploratory. 
5.1 
Prespecified Subgroups 
The main MACE analysis will be presented separately within the following subgroups. In each 
case, if the subgroup is a stratification factor or a covariate (indicated in italics), the model will 
be the same as the overall model with the deletion of the respective stratification factor or 
covariate. Subgroup analyses will be performed only if the total number of outcomes in a 
stratum, combined over the two treatment groups, is at least 100. 
Randomization stratification factors 
•
Hb stratification level at baseline
o
PRO2TECT

Low level group (<9.5 g/dL for CI-0014; <10.0 g/dL for CI-0015)

High level group (≥9.5 g/dL for CI-0014; ≥10.0 g/dL for CI-0015)
o
INNO2VATE

Low level group (<9.5 g/dL for CI-0016; <10.0 g/dL for CI-0017)

High level group (≥9.5 g/dL for CI-0016; ≥10.0 g/dL for CI-0017)
•
Region
o
US
o
EU
o
ROW
•
NYHA CHF stratification level
o
0 and 1


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o
2 and 3
•
Target Hb level: These targets are completely confounded with region. The 10-11 g/dL
target consists of subjects from the US while the 10-12 g/dL target applies to the EU
and the ROW.
o
10-11 g/dL
o
10-12 g/dL
Demographics and medical history 
•
Age
o
<65 years
o
≥65 years
•
Sex
o
Male
o
Female
•
Ethnicity
o
Hispanic
o
Non-Hispanic
•
Race
o
White
o
All others
•
Diabetes mellitus
o
No diabetes mellitus
o
Diabetes mellitus
•
History of cardiovascular disease (defined as medical history of coronary artery disease,
myocardial infarction, stroke, or heart failure as captured by four separate questions on
the Case Report Form)
o
Yes
o
No
•
For CI-0016 and CI-0017 only, type of dialysis


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o
Hemodialysis
o
Peritoneal dialysis
Medications (CI-0015 and CI-0017 only) 
•
Baseline ESA dose (See Locatelli, 2004 for justification of the choice of cut-off values)
o
<90 U/kg/week
o
≥90 U kg/week
o
>300 U/kg/week
Baseline laboratory measurements 
•
For CI-0014 and CI-0015 only, urine albumin creatinine ratio (uACR) (See Gansevoort,
2011 for a justification of the choice of cut-off values)
o
<300 mg/g
o
≥300 mg/g
•
For CI-0014 and CI-0015 only, estimated GFR (The threshold of 15 represents a value
between CKD eGFR Categories 4 and 5)
o
<15 ml/min/1.73m2  (CKD Stage 5)
o
≥ 15 ml/min/1.73m2 (CKD stage 4 or lower)
•
C-reactive protein. In Q2 laboratories, which are the laboratories used in these studies,
the normal range is 0-0.6mg/dL.
o
≤0.6 mg/dL
o
>0.6 mg/dL
•
Baseline transferrin saturation (TSAT)
o
CI-0014 and CI-0015

< median of CI-0014 and CI-0015 combined

≥ median of CI-0014 and CI-0015 combined
o
CI-0016 and CI-0017

< median of CI-0016 and CI-0017 combined

≥ median of CI-0016 and CI-0016 combined
•
Baseline ferritin


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o
CI-0014 and CI-0015

< median of CI-0014 and CI-0015 combined

≥ median of CI-0014 and CI-0015 combined
o
CI-0016 and CI-0017

< median of CI-0016 and CI-0017 combined

≥ median of CI-0016 and CI-0017 combined
•
Incident Dialysis Patients
o
CI-0016 and CI-0017

All patients in CI-0016 plus patients who have ≤16 weeks of dialysis history
from the date of informed consent in CI-0017
•
Pooled analysis of patients with CKD G5 and incident dialysis patients (those who
initiated dialysis within 16 weeks) after all studies indicted below are completed
o
<15 ml/min/1.73m2  (CKD Stage 5) at baseline from CI-0014 and CI-0015
o
All patients in CI-0016 plus patients who have ≤16 weeks of dialysis history
from the date of informed consent in CI-0017
In these summary statistics, only the primary analysis method will be presented. Hazard ratios 
and their 95% confidence intervals for subgroups will be displayed using forest plots. 
5.2 
Subgroup Analyses of Other Outcomes 
Exploratory post-hoc analyses of other outcomes may be performed to gain insight into the effect 
of the drugs in other subgroups. 
6 
SUPPORTIVE ANALYSIS - RESTRICTED MEAN SURVIVAL TIME 
Recent papers on time to event, especially regarding trials assessing cardiovascular safety of 
non-cardiovascular drugs [e.g., Uno, 2015, Zhao, 2016] have recommended use of the restricted 
mean survival time (RMST), rather than hazard ratio, to assess the effect of drugs. As a 
supportive analysis, we will compare the RMST in the two treatment arms for the PRO2TECT 
and INNO2VATE pairs of studies for the primary MACE event. 
To specify RMST, one needs to select a time T. An event that occurs prior to time T “counts” in 
the analysis; events that occur after T do not enter the analysis. T will be selected as the 75th 
percentile of follow-up time. 


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7 
DATA SAFETY MONITORING 
An independent statistical analysis center performs analyses in support of the IDMC which 
meets approximately every 4 to 6 months throughout the course of the study.   
The IDMC and the independent statistician will be the only people who will be unblinded to 
these MACE data. 
The IDMC will also consider early termination if the quality of trial conduct is such that the trial 
will not be able to provide a timely and reliable answer to the questions it was designed to 
address. 
8 
HANDLING OF MISSING DATES 
For all adjudicated events, the CEC-determined date of the event will be used in all analyses. In 
the unlikely event that this date is missing then the investigator-reported date will be used. 
For an incomplete date of an endpoint event, imputation will be performed as outlined below: 
•
If the event date is completely missing, date is set to date of first dose.
•
If year is present and month and day are missing or year and day are present and month is
missing:
o
If year = year of first dose, then set month and day to month and day of first dose.
o
If year < year of first dose, then set month and day to December 31.
o
If year > year of first dose, then set month and day to January 1.
•
If month and year are present and day is missing:
If year = year of first dose and
•
month = month of first dose, then set day to day of first dose date.
•
month < month of first dose, then set day to last day of month.
•
month > month of first dose, then set day to first day of month.
If year < year of first dose, then set day to last day of month.
If year > year of first dose, then set day to first day of month.
•
For all other cases, set date to date of first dose.
If the above imputations produce an illogical date, a logical date will be selected by a statistical 
team blinded to everything but the dates. 
For an incomplete death date, imputation will be performed using the same rule as described 
above. 
9 
SUBJECT DISPOSITION, TREATMENT ADHERENCE, AND TREATMENT 
EXPOSURE 
The main SAPs for PRO2TECT and INNO2VATE summarize methods for describing subject 
disposition, adherence to treatment, and exposure to treatment. 


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Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low 
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Centers for Disease Control. Anemia or Iron Deficiency. National Center for Health Statistics 
[web]. March 17, 2017.Available at: http://www.cdc.gov/nchs/fastats/anemia.htm. Accessed 
August 13, 2015. 
De Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 
chronic kidney disease. N Engl J Med 2013; 369:2492-503. 
EVOLVE trial investigators, Chertow GM, Block GA, et al. Effect of cinacalcet on 
cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012; 367:2482-2494. 
Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in 
patients undergoing hemodialysis. N Engl J Med 2009; 360:1395-1407. 
Fishbane S, Shiller B, Locatelli F, et al. Peginesatide in patients with anemia undergoing 
hemodialysis. N Engl J Med 2013; 368:307-319. 
Fleiss JL, Bigger Jr. M, McDermott M, et al. Nonfatal myocardial infarction is, by itself, an 
inappropriate end point in clinical trials in cardiology. Circulation 1990; 81:684-5. 
Food and Drug Administration. FDA drug safety communication: Modified dosing 
recommendations to improve the safe use of erythropoiesis-stimulating agents (ESAs) in chronic 
kidney disease. Drug Safety and Availability [web]. June 24, 2011. Available at: http://www. 
fda.gov/Drugs/DrugSafety/ucm259639.htm. Accessed September 1, 2011.  
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fda.gov/downloads/Drugs/GuidanceComplianceRegulatory%20Information%20/Guidances/UC
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Little, RJ, Wang J, Sun X, et al. The treatment of missing data in a large cardiovascular clinical 
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Locatelli F, Covic A, Chazot C, et al.  Hypertension and cardiovascular risk assessment in 
dialysis patients. Nephro Dial Transplant 2004; 19:1058-1068. 
Macdougall IC, Provenzano R, Sharma A, et al. Peginesatide for anemia in patients with chronic 
kidney disease not receiving dialysis.  N Engl J Med 2013; 368:320-332. 
O’Kelly M, Ratitch B. Clinical trials with missing data: a guide for practitioners. West Sussex, 
United Kingdom: John Wiley & Sons, 2014. 


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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 2009; 361:2019-32. 
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1987. 
Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney 
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heart failure. N Engl J Med 2013; 368:1210-1219. 
Thamer M, Zhang Y, Kshirsager O, et al. Erythropoiesis-stimulating agent use among 
nondialysis--dependent CKD patients before and after the trial to reduce cardiovascular events 
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64:706-713. 
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Uno H, Wittes J, Fu H, et al. Alternatives to hazard ratios for comparing efficacy or safety of 
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Yuan Y. Sensitivity analysis in multiple imputation for missing data. Paper presented at: SAS 
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analysis. Biometrics 2016; 72:215-221. 


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APPENDIX A. SAS CODE  
This below SAS codes are for competing risk analysis and restricted mean survival time analysis. 
Competing Risk 
proc phreg data=&INDAT.; 
  class study TRT(ref="DARB") STRAT2_HF STRAT3_REG AGE SEX  
RACE HX_CV_ALL HX_DM; 
  strata study; 
  model T*Status(0)= HB_base STRAT2_HF STRAT3_REG TRT AGE SEX RACE 
HX_CV_ALL HX_DM / eventcode=1 ties=Efron rl; 
  Ods ouput ParameterEstimates = HR_EST; 
Run; 
Restricted Mean Survival Time (RMST) 
proc lifetest data=&INDAT. plots=(rmst) rmst(tau=&fut); 
   time SurvTime*Censor(1); 
   strata study /group=TRT; 
run; 
where &fut is the 75th percentile of follow-up time. 


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APPENDIX B.   JUSTIFICATION OF THE NONINFERIORITY MARGIN 
This appendix provides the rationale for the noninferiority margin of 1.25 in MACE analysis for 
FDA decision making and for the noninferiority margin of 1.30 for EMA decision making. 
Background 
Many scientific questions are unanswered to date and there remains an unmet medical need for a 
new therapy for anemia in CKD. Among the unanswered questions are: 
•
Can Hgb be safely raised with a novel agent other than an ESA without increasing CV
risk?
•
Are hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHIs) as safe as or
safer than ESAs?
The primary safety outcome in each study is MACE, defined as all-cause mortality, nonfatal 
myocardial infarction (MI) or nonfatal stroke, occurring at any time following randomization and 
prior to each subject’s end-of-study date. The endpoint for the primary analysis will be the first 
occurrence after randomization of all-cause mortality, adjudicated nonfatal MI, or adjudicated 
nonfatal stroke. Treatment comparisons will be based on the estimated hazard ratio 
(vadadustat/darbepoetin alfa) and its 95% CI from a Cox proportional hazards model for the pair 
of NDD studies and for the pair of DD studies. 
Vadadustat will be considered to have non-inferior risk of MACE relative to darbepoetin alfa if 
the upper limit of this 95% CI of each pair of studies is less than or equal to the prespecified 
noninferiority margin. 
FDA Decision Making 
C.2.1. Feasibility of and MACE Event Rates in Trials of Subjects with Anemia
Secondary to CKD
While the number of adults diagnosed with CKD in the US is 3.9 million (CDC 2015), the 
number of individuals with anemia and NDD-CKD is significantly lower.  According to recent 
claims data, 10% of NDD-CKD stage 3 patients and 20% of NDD-CKD stage 4 patients have 
Hgb<10 g/dL (Thamer 2014).  Moreover, the number of patients being treated for anemia 
continues to decline.  This is consistent with recent claims data demonstrating that 11% of NDD-
CKD stage 3 patients and 27% of NDD-CKD stage 4 patients are being treated with an ESA 
(Thamer 2014).  This low utilization of ESA reflects changes in practice patterns as a result of 
TREAT (Pfeffer 2009) as well as the change in the ESA labels in the US.  As a result, the impact 
on the feasibility of successfully executing a clinical trial of anemia in CKD must be considered 
with these changing practices. In fact, recent trials have taken longer to execute than did trials in 
the past.  For example, the CHOIR (Singh 2006) and PEARL (Macdougall 2013) trials had broad 
inclusion/exclusion (I/E) criteria (e.g., Hgb<11.0 g/dL) and were able to recruit patients at a rate 
of 0.30-0.40 patients per site per month (p/s/m).  In contrast, more recent trials requiring Hgb 
inclusion of <10.0 g/dL have had recruitment rates of 0.10-0.15 p/s/m (ClinicalTrials.gov 
NCT00922587 and NCT01887600).  Put into practical terms, a trial needing 2000 CKD patients 
with Hgb<10.0 g/dL and recruiting at a rate of 0.10 p/s/m would require nearly 850 sites to 
recruit over 24 months.  This is impractical given the limited number of nephrology 


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investigators; utilizing so many sites risks making a trial unfeasible.  As a consequence, future 
trials require an extended timeline for recruitment, leading to a delay in the availability of new 
therapies for patients with CKD.  In addition, these delays limit the potential clinical 
applicability as patient populations and practice patterns evolve. 
Of the nearly 500,000 patients with dialysis-dependent CKD (DD-CKD) in the US, more than 
80% require therapy for anemia and would potentially qualify for inclusion into a trial.  
However, addition of specific I/E criteria, competition with other trials, and the limited number 
of nephrology research centers available to perform research again negatively impact execution 
of DD-CKD trials.  For example, for an incident dialysis trial where only 0 or 1 new patient 
starts dialysis per month in a given research center, anticipated recruitment rate is <0.20 p/s/m.  
Thus, a trial requiring enrollment of 400 patients would need at least 80 sites enrolling for over 
24 months, not including time for start-up. 
In addition to the aforementioned considerations, the event rate must also be factored into the 
feasibility of a trial.  In development of our trials, while we have assumed a 10% annualized 
MACE event rate in NDD-CKD and 12% in DD-CKD, we understand that this event rate may 
decrease over time with improved medical care.  Our event rates are based on review of 
contemporary population level data (USRDS), recent CKD trials (BEACON [de Zeeuw 2013]), 
and anemia in CKD trials.  For NDD-CKD, given the narrower inclusion criteria of Hgb<10 
g/dL, we assumed most patients would have later stage CKD with MACE event rates similar to 
that in TREAT at 10% overall.  For MACE in DD-CKD, we reviewed the event rates from 
contemporary population-level data (USRDS), recent ESRD trials, EVOLVE (Chertow 2012), 
AURORA (Fellstrom 2009), and anemia in ESRD trials EMERALD (Fishbane 2013) and NHT 
(Besarab 1998).  Only EMERALD and EVOLVE had applicable information on MACE event 
rate.  While EMERALD had a MACE event rate of ~14.5%, EVOLVE had an 11.5% rate and 
thus 12% was conservatively selected.  While Akebia considered enrichment to reduce the 
overall sample size knowing the difficulty we may have enrolling these trials, the feasibility 
trade-offs ruled out this option.  For example, RED-HF (Swedberg 2013), an anemia trial in 
patients with heart failure, recruited at <0.10 p/s/m and had to extend enrollment to nearly 6 
years.  Rather than enrich the Akebia trials, we have assumed moderate event rates with the 
knowledge that the trials may need to be extended if the event rates decrease over time.  For 
example, if an annual event rate of 8% is observed rather than our estimated 10%, the NDD-
CKD studies will need to be extended by approximately 6 months given our baseline 
assumptions. 
Taken together, we have considered the prevalence of anemia in CKD, narrower I/E criteria, and 
lower event rates over time when determining a reasonable trial design and sample size for our 
development program. 
C.2.2. Safety Plan for Development of a New Anemia Therapy in CKD
The question around how to develop a new therapy for anemia in CKD is challenging, as we 
need to ensure the product is both efficacious and safe in the setting of the clinical trial logistical 
limitations cited above. For a new therapy to be approved, it must not increase risk, and ideally 
would decrease CV risk, compared to the currently approved ESAs.  However, the long timelines 
and increased cost of developing such products need to be weighed against the practicality of 
executing the development programs.  Furthermore, the design of these anemia CV outcome 
trials must assess event rates in the setting of current ESA use, recognizing the difference in ESA 


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practice patterns since publication of CHOIR and TREAT and subsequent modification to the 
ESA labels (Thamer 2014).  While we are familiar with the increased risk of stroke seen with 
targeting higher Hgb levels with ESAs in TREAT, the population- level risk associated with 
targeting lower Hgb levels and the use of lower doses of ESAs as currently prescribed remains 
unknown.  Therefore, while a CV safety superiority study with vadadustat is desirable, the 
uncertainty about the CV event rate of ESAs prescribed under their current labeling requirements 
(e.g., dosing to avoid transfusions) make planning a well-powered superiority study challenging.  
Data from the TREAT trial provide some information on acceptable risk for a new therapy.  The 
overall HR for MACE within TREAT when targeting a higher Hgb level compared to placebo 
was 1.10 (95% CI 0.97-1.24).  However, it was the individual component of stroke that raised 
concerns with targeting higher Hgb with ESAs (HR=1.923, CI 1.379-2.681). 
We anticipate that a new treatment for anemia in CKD should not meaningfully increase the risk 
of MACE relative to ESAs.  The currently available trial data suggest that the HR for a new 
treatment compared to an ESA could be near or slightly below 1.0 with the upper limit of the 
two-sided 95% CI being no more than 1.25 (this upper limit in TREAT was 1.24).  See Table C1 
for examples of sample size calculations based on a variety of non-inferiority (NI) margins with 
similar assumptions.  If the true HR is 0.95, the study will have roughly 90% power. The table 
includes a line for an NI margin of 1.3, the margin approved by the EMA and the margin 
typically used in trials of Type II diabetes. 
Table C 1. 
Summary of statistical assessment of MACE safety endpoint 
NI 
Margin 
Hazard 
Ratio 
Power 
MACE 
Events (Per 
Indication) 
NDD-CKD 
Sample Size 
(Event Rate 
10%) 
DD-CKD
Sample Size 
(Event Rate 
12%) 
Total Sample Size 
1.3 
1.00 
85% 
522 
2564 
2162 
4726 
1.25 
0.95 
85% 
477 
2398 
2020 
4418 
90% 
559 
2810 
2367 
5177 
1.25 
1.00 
80% 
631 
3100 
2612 
5712 
85% 
721 
3546 
2988 
6534 
1.20 
0.95 
80% 
576 
2950 
2500 
5450 
85% 
659 
3314 
2792 
6106 
1.20 
1.00 
85% 
1080 
5310 
4476 
9786 
C.2.3. Conclusion
We have developed an evidence-based clinical development program designed to exclude a 
clinically meaningful increased risk associated with vadadustat compared to ESA. We believe 
the proposed event driven studies which utilize an NI margin of 1.25 for the upper limit of the 
two-sided 95% CI will allow for a rigorous analysis of the safety of vadadustat compared to the 
current standard of care (ESAs), while being logistically feasible.   


Akebia Therapeutics, Inc. 
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An earlier version of this rationale for a non-inferiority margin of 1.25 for the MACE analysis 
was provided to the FDA in Akebia’s Type C Meeting Information Package dated 31 Aug 2015. 
FDA agreed with the use of 1.25 as the non-inferiority margin in Meeting Minutes dated 1 Oct 
2015 and 12 Jan 2016. 
EMA Decision Making 
In materials submitted to EMA/CHMP for Scientific Advice on Vadadustat (AKB-6548) in 
November 2015, Akebia proposed to assess MACE, time to first event, using Cox regression via 
a non-inferiority analysis; e.g., a margin of 1.3 for the 95% upper confidence interval for the 
hazard ratio (vadadustat/epoetin alfa) for the MACE safety endpoint in the pooled analysis of 
each pair of studies (CI-0016/17 for DD-CKD and CI-0014/15 for NDD-CKD).  
It was calculated that 631 events will be required overall in a pair of studies to have >90% power 
to establish non-inferiority with a margin of 1.3 when evaluated with a 2- sided 95% confidence 
interval assuming no difference between the treatments.  The planned sample size (totalling an 
estimated enrolment of 2600 in the Phase 3 DD-CKD program and 3100 in the Phase 3 NDD-
CKD program, one-half of which will receive vadadustat) and planned duration (about 20 
months recruitment and up to 36 months of treatment - average follow-up duration 1.8 years) of 
the Phase 3 studies will far exceed what is required to adequately assess efficacy and safety of a 
novel agent for the treatment of anaemia of CKD.
C.3.1. Rationale
The margin chosen for assessing MACE was proposed based upon a review of historical trials 
assessing cardiovascular outcomes associated with the use of ESAs in CKD (patients receiving 
haemodialysis and not receiving haemodialysis). In particular, randomized controlled trials were 
identified where an increased risk has been associated with ESA use. As the choice of a margin 
for a safety endpoint is inherently based upon a subjective assessment of risk benefit, these trials 
were selected due to their size, length, and degree of follow-up to provide insight into what 
levels of increased risk have been found to be perceived as unacceptable. With the exception of 
the peginesatide trials (see Table D2), these trials all compared targeting higher versus lower 
target haemoglobin levels. In the peginesatide trial, a similar target was used for the treatment 
arms being compared.  


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Table C 2. 
Overview of Cardiovascular Safety Outcomes for Erythropoiesis-Stimulating 
Agents in Chronic Kidney Disease 
Trial 
ESA 
Design 
CV Safety Assessment 
Result 
Normal 
Hematocrit 
Study 
Epoetin 
alfa 
1265 subjects with CKD 
receiving hemodialysis with a 
history of either chronic heart 
failure or ischemic heart 
disease; randomization to 
maintain a target HCT of 42 
± 3% (“normal” HCT) or to 
maintain a target HCT of 30 
±3% (low HCT) 
Time to death or first nonfatal 
myocardial infarction 
Hazard ratio for 
the composite 
endpoint of 1.3 
(95% CI 0.9, 
1.9) favoring low 
HCT treatment 
Correction of 
Hemoglobin 
and 
Outcomes in 
Renal 
Insufficiency 
CHOIR 
Epoetin 
alfa 
1432 subjects with CKD not 
receiving dialysis; 
randomization to maintain a 
target HGB of either 13.5 
g/dL (high HGB group) or 
11.3 g/dL (low HGB group) 
Time to the composite of death, non- 
fatal myocardial infarction, 
hospitalization for congestive heart 
failure, and stroke 
Hazard ratio for 
the composite 
endpoint of 1.34 
(95% CI 
1.03, 1.74) 
favoring lower 
HGB target 
CREATE 
Erythro- 
poietin 
beta 
603 subjects with CKD not 
receiving dialysis; 
randomization to randomized 
to a high hemoglobin target 
(13 to 15 g/dL) or a low 
hemoglobin target (10.5 to 
11.5 g/dL); with rescue ESA 
therapy 
Composite of eight cardiovascular 
events: sudden death, myocardial 
infarction, acute heart failure, stroke, 
transient ischemic attack, angina 
pectoris resulting in hospitalization 
for 24 hours or more or prolongation 
of hospitalization, complication of 
peripheral vascular disease 
(amputation or necrosis), or cardiac 
arrhythmia resulting in 
hospitalization for 24 hours or more. 
Hazard ratio of 
1.28 (95% CI, 0.88 
to 
1.89) favoring 
lower HGB target 
TREAT 
Darbe- 
poetin 
alfa 
4038 subjects with CKD not 
receiving dialysis; 
randomized to a high 
hemoglobin target (13.5 
g/dL) or a placebo; with 
rescue ESA therapy if 
hemoglobin level falls below 
9 g/dl 
CV composite endpoint and renal 
composite endpoint 
Hazard ratio of 
1.06 (95% CI-
0.95, 
1.19) for 
composite 
favoring placebo. 
Hazard ratio for 
stroke of 1.92 
(95% 
CI 1.38, 2.68) 
favoring placebo. 
AFX01-11/13 
Pegines- 
atide 
983 subjects with CKD not 
receiving dialysis; 
randomization to 
peginesatide or darbepoetin 
Sponsor-defined CSE events: death, 
stroke, MI, congestive heart failure, 
unstable angina, and arrhythmia. 
MACE endpoint: death, stroke and 
MI. 
Hazard ratios CSE 
1.32 (90% 
CI 1.02, 1.72) 
MACE 1.28 (95% 
CI 0.84, 1.94) 
Source: FDA Briefing Document for Peginesatide Injection Oncology Drugs Advisory Committee Meeting 
(December 7, 2011) 


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C.3.2. Conclusion
Thus, Akebia proposed the MACE hazard ratio (HR) for a new treatment compared to ESA to be 
equal to or less than 1.0 with the upper limit of the two-sided 95% confidence interval less than 
or equal to the noninferiority margin of 1.3 for the DD-CKD program (Studies AKB-6548-CI-
0016 and AKB-6548-CI-0017), as well as for the NDD-CKD program (Studies AKB-6548-CI-
0014 and AKB-6548-CI-0015). 
The CHMP endorsed (response dated 28JAN2016) the plan to rule out an excess risk for MACE 
with a non-inferiority margin of 1.3. However, it was noted in the response that the final 
assessment of the MAA will not be merely based on just the efficacy from the primary outcome 
and the exclusion of harm based on this safety analysis, but on the overall benefit-risk 
assessment. CHMP agreed with Akebia’s rationale that the point estimate of the HR for this 
product should be below 1 considering the ESA cardiovascular safety profile. 


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