Clinical trial NCT03799627
Conditions: Anemia Dialysis-dependent Chronic Kidney Disease
Keywords: Vadadustat AKB-6548 Anemia Chronic kidney disease (CKD) erythropoietin
Sponsor: Akebia Therapeutics
Start date: 2019-01-31; Completion date: 2020-07-15
Enrollment: 175 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2 open-label efficacy, safety, and pharmacokinetic/pharmacodynamic (PK/PD) study to evaluate oral Vadadustat for the treatment of anemia in hemodialysis participants converting from Epoetin Alfa therapy.

Detailed description:
This is a Phase 2, randomized, open-label study to evaluate efficacy and safety of oral Vadadustat for the treatment of anemia in hemodialysis participants converting from Epoetin Alfa therapy. The study will be conducted in two parts running in parallel: Part 1, Main Study in a hemodialysis population on maintenance treatment with Epoetin Alfa; Part 2 is in a hemodialysis population that are erythropoiesis-stimulating agent (ESA) hyporesponders on maintenance treatment with Epoetin Alfa. For all participants (Main and ESA hyporesponder parallel study), the study will include a Screening Period, a Treatment Period, and a Safety Follow-Up Period. PK and PD sampling will be done throughout the study. The aim is to achieve and maintain hemoglobin (Hb) levels within the target range of 10.0 to 11.0 grams per deciliter (g/dL), inclusive, while targeting the middle of the range and minimizing excursions outside the target range.

Arms: arm 1: The initial dose of Vadadustat (300, 450, or 600 milligrams \[mg\]) will be based upon the dose of Epoetin Alfa dose participants had received prior to Vadadustat treatment arm 2: Participants randomized to Vadadustat (Main and erythropoiesis-stimulating agent \[ESA\] hyporesponder parallel studies) who complete a once-daily dosing regimen treatment period and meet eligibility criteria for transition to three times weekly (TIW) dosing will switch to TIW dosing arm 3: Epoetin Alfa
Interventions: intervention 1: Vadadustat intervention 2: Epoetin Alfa intervention 3: Vadadustat TIW
Intervention descriptions: intervention 1: Vadadustat Tablets 150 mg intervention 2: Epoetin Alfa intervention 3: Oral Vadadustat

Protocol documents:
Prot_000.pdf: 
Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
Akebia — Company Confidential 
Page 1 of 88 
CLINICAL PROTOCOL 
PHASE 2, RANDOMIZED, OPEN-LABEL, ACTIVE-CONTROLLED, EFFICACY, 
SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS STUDY OF ORAL 
VADADUSTAT FOR THE TREATMENT OF ANEMIA IN HEMODIALYSIS 
SUBJECTS CONVERTING FROM EPOETIN ALFA 
Compound: 
Vadadustat (AKB-6548) 
Protocol Number: 
AKB-6548-CI-0025 
US IND Number: 
102,465 
Phase: 
Phase 2 
Original Protocol: 
27 JUNE 2018 
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 
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. 
NCT Number: NCT03799627


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Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 3 of 88 
1.2 
Investigator Agreement 
I confirm that I have read and that I understand this protocol, the Investigator Brochure, and other 
product information provided by the Sponsor. I agree to conduct this study in accordance with the 
requirements of this protocol and also protect the rights, safety, privacy, and well-being of study 
subjects in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 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 
 
 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 4 of 88 
TABLE OF CONTENTS 
1 
SIGNATURE PAGES .................................................................................................. 2 
1.1 
Protocol Approval .................................................................................................... 2 
1.2 
Investigator Agreement ............................................................................................ 3 
TABLE OF CONTENTS ......................................................................................................... 4 
2 
PROTOCOL SYNOPSIS .............................................................................................. 8 
3 
LIST OF ABBREVIATIONS ..................................................................................... 21 
4 
BACKGROUND INFORMATION............................................................................ 23 
4.1 
Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors ..................................... 24 
4.2 
Summary of Clinical Experience ........................................................................... 24 
4.3 
Potential Benefits and Risks ................................................................................... 26 
5 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 28 
5.1 
Primary Objective .................................................................................................. 28 
5.2 
Secondary Objectives ............................................................................................. 28 
5.3 
Efficacy Endpoints ................................................................................................. 28 
5.3.1 
Primary Endpoints ............................................................................................. 28 
5.3.2 
Key Secondary Endpoints ................................................................................. 28 
5.3.2.1 
Other Secondary Endpoints .......................................................................... 28 
5.3.2.2 
Exploratory Endpoints .................................................................................. 29 
5.4 
PK/PD Endpoints ................................................................................................... 29 
5.5 
Safety Endpoints .................................................................................................... 29 
6 
STUDY DESIGN ........................................................................................................ 30 
6.1 
Study Design .......................................................................................................... 30 
6.1.1 
Screening Period (up to 28 days; Day -28 to Baseline/Day 1) .......................... 31 
6.1.2 
Study Treatment Period (Baseline/Day 1 to Week 20) ..................................... 32 
6.1.2.1 
Vadadustat Treatment ................................................................................... 32 
6.1.2.2 
Epoetin Alfa Treatment ................................................................................ 32 
6.1.3 
Safety Follow-Up Period (Weeks 20 to 24) ...................................................... 32 
6.2 
Rationale for Study Design .................................................................................... 33 
6.3 
Dose Justification ................................................................................................... 34 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 35 
7.1 
General Criteria ...................................................................................................... 35 
7.2 
Inclusion Criteria .................................................................................................... 35 
7.3 
Exclusion Criteria ................................................................................................... 35 
7.4 
Retesting and Rescreening ..................................................................................... 37 
7.4.1 
Retesting ............................................................................................................ 37 
7.4.2 
Rescreening ....................................................................................................... 37 


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Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 5 of 88 
7.5 
Study Completion, Study Termination, and Individual Site Termination ............. 37 
7.5.1 
Study Completion .............................................................................................. 37 
7.5.2 
Study Termination ............................................................................................. 37 
7.5.3 
Individual Study Site Termination .................................................................... 38 
7.6 
Subject Completion and Subject Discontinuation .................................................. 38 
7.6.1 
Subject Completion ........................................................................................... 38 
7.6.2 
Temporary Interruption of Study Drug ............................................................. 38 
7.6.3 
Early Discontinuation from Study (Early Termination) .................................... 38 
8 
STUDY DRUG AND TREATMENT OF SUBJECTS .............................................. 40 
8.1 
Epoetin Alfa ........................................................................................................... 40 
8.2 
Vadadustat .............................................................................................................. 40 
8.2.1 
Supplies and Storage ......................................................................................... 40 
8.2.2 
Dispensing of Vadadustat .................................................................................. 40 
8.3 
Vadadustat Accountability and Destruction ........................................................... 41 
8.4 
Treatment of Subjects ............................................................................................. 41 
8.4.1 
Randomization ................................................................................................... 42 
8.4.2 
Blinding ............................................................................................................. 42 
8.4.3 
Measurement of Hb Levels for Dose Adjustment Consideration ..................... 42 
8.4.4 
Epoetin Alfa Dosing Regimen ........................................................................... 42 
8.4.5 
Vadadustat Dosing Regimen and Guidelines for Dose Adjustment.................. 43 
8.4.5.1 
Dosing Regimen for the Vadadustat Treatment Arm ................................... 43 
8.4.5.2 
Transition of Vadadustat Once Daily Dosing to TIW Dosing Regimen ...... 43 
8.4.6 
Guidelines for Dose Adjustments ...................................................................... 44 
8.4.7 
Late or Missed Doses ........................................................................................ 45 
8.4.8 
Iron Supplementation ........................................................................................ 45 
8.4.9 
Rescue Therapy ................................................................................................. 46 
8.4.9.1 
RBC Transfusion .......................................................................................... 46 
8.4.9.2 
ESA Use........................................................................................................ 46 
8.4.10 
Phlebotomy (Optional) ...................................................................................... 46 
8.4.11 
Treatment Compliance ...................................................................................... 46 
8.4.12 
Continuation of Treatment ................................................................................ 47 
8.5 
Prior and Concomitant Therapy ............................................................................. 47 
8.5.1 
General .............................................................................................................. 47 
8.5.2 
ESAs .................................................................................................................. 47 
8.5.3 
Dialysis Treatment and Renal Replacement Therapy ....................................... 47 
8.5.4 
Investigational Medications ............................................................................... 48 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES ................................ 49 
9.1 
Administrative Procedures ..................................................................................... 49 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 6 of 88 
9.1.1 
Informed Consent .............................................................................................. 49 
9.1.2 
eDiary ................................................................................................................ 50 
9.1.3 
Documentation of Screen Failures .................................................................... 50 
9.1.4 
Status Check ...................................................................................................... 50 
9.1.5 
Contraception and Pregnancy Avoidance Measures ......................................... 50 
9.1.6 
Laboratory Accreditation and Reference Ranges .............................................. 51 
9.2 
Study Procedures and Evaluations ......................................................................... 51 
9.2.1 
Clinical Evaluations ........................................................................................... 51 
9.2.2 
Laboratory Evaluations ..................................................................................... 52 
9.2.2.1 
PK/PD Sampling for Subjects Randomized to Vadadustat .......................... 54 
9.2.2.2 
PK Sampling for Subjects Randomized to Epoetin Alfa .............................. 55 
9.2.2.3 
PK/PD Sampling ........................................................................................... 55 
9.3 
Schedule of Activities ............................................................................................ 55 
9.3.1 
Screening Visits ................................................................................................. 55 
9.3.1.1 
SV1 ............................................................................................................... 56 
9.3.1.2 
SV2 ............................................................................................................... 56 
9.3.2 
Baseline/Day 1 (Visit 1) .................................................................................... 57 
9.3.3 
Visit 2 to Visit 13 (Weeks 1 to 20) .................................................................... 58 
9.3.4 
EOT Visit 14 (Week 20) .................................................................................... 59 
9.3.5 
Safety Follow-Up Visit 15 (Week 24) ............................................................... 60 
9.3.6 
Unscheduled Visits ............................................................................................ 60 
10 
ADVERSE EVENTS .................................................................................................. 61 
10.1 
Definitions .............................................................................................................. 61 
10.1.1 
AEs .................................................................................................................... 61 
10.1.2 
SAEs .................................................................................................................. 63 
10.2 
Eliciting AE Information ........................................................................................ 64 
10.3 
Reporting ................................................................................................................ 64 
10.3.1 
Reporting Period ................................................................................................ 64 
10.3.2 
Reporting AEs ................................................................................................... 64 
10.3.3 
Reporting SAEs ................................................................................................. 64 
10.3.4 
Relationship to Study Drug ............................................................................... 65 
10.3.5 
Severity .............................................................................................................. 66 
10.3.6 
Follow-up of Unresolved Events ....................................................................... 66 
10.4 
Exposure In-Utero .................................................................................................. 66 
10.5 
Special Situations ................................................................................................... 67 
10.6 
Safety Monitoring .................................................................................................. 68 
11 
DATA ANALYSIS ..................................................................................................... 69 
11.1 
Sample Size Estimation .......................................................................................... 69 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 7 of 88 
11.2 
Study Analysis Populations .................................................................................... 69 
11.3 
Analysis of Demographic and Pretreatment Variables .......................................... 70 
11.4 
Disposition of Subjects ........................................................................................... 70 
11.5 
Missing Data .......................................................................................................... 70 
11.6 
Efficacy Analyses ................................................................................................... 70 
11.7 
Safety Analyses ...................................................................................................... 70 
11.8 
Additional Assessments ......................................................................................... 71 
11.8.1 
PK Assessments ................................................................................................. 71 
11.8.2 
PD Assessments ................................................................................................. 71 
11.8.3 
Concomitant Medications .................................................................................. 71 
11.8.4 
Biomarkers ........................................................................................................ 71 
12 
DATA HANDLING AND RECORD KEEPING ...................................................... 72 
12.1 
CRFs/EDC .............................................................................................................. 72 
12.2 
Record Retention .................................................................................................... 72 
13 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 73 
13.1 
Study Site Monitoring Visits .................................................................................. 73 
13.2 
Protocol Deviations ................................................................................................ 73 
14 
STUDY DISCONTINUATION/STUDY SITE TERMINATION ............................. 75 
14.1 
Criteria for Premature Termination or Suspension of the Study ............................ 75 
14.2 
Criteria for Premature Termination or Suspension of Study Sites ......................... 75 
14.3 
Procedures for Premature Termination or Suspension of the Study or Study 
Sites ........................................................................................................................ 75 
15 
ETHICS ....................................................................................................................... 76 
15.1 
Ethical Conduct of the Study ................................................................................. 76 
15.2 
IRB ......................................................................................................................... 76 
15.3 
Subject Information and Consent ........................................................................... 76 
15.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .... 76 
15.5 
Subject Confidentiality ........................................................................................... 77 
16 
PUBLICATION OF STUDY RESULTS ................................................................... 78 
17 
REFERENCES ............................................................................................................ 79 
APPENDIX A: SCHEDULE OF ACTIVITIES .................................................................... 81 
APPENDIX B: PK/PD SAMPLING ..................................................................................... 86 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 8 of 88 
2 
PROTOCOL SYNOPSIS 
Study Title 
Phase 2, Randomized, Open-Label, Active-Controlled, Efficacy, Safety, 
Pharmacokinetics, and Pharmacodynamics Study of Oral Vadadustat for the Treatment 
of Anemia in Hemodialysis Subjects Converting from Epoetin Alfa 
Protocol Number 
AKB-6548-CI-0025 
Study Phase 
Phase 2 
Investigational 
Product 
Vadadustat; 150 mg tablets  
Reference Medicinal 
Product 
Epoetin alfa solution for intravenous (IV) injection in multi-dose vials or in single-dose 
vials  
Study Population 
The Main study population will consist of adult subjects receiving chronic, outpatient 
in-center hemodialysis three times weekly (TIW), with 2 screening hemoglobin (Hb) 
values between 8.5 and 11.0 g/dL (inclusive) and on maintenance treatment with 
epoetin alfa <300 U/kg/week. 
The erythropoiesis stimulating agent (ESA) hyporesponder parallel study will consist 
of adult subjects receiving chronic, outpatient in-center hemodialysis TIW, with 
2 screening Hb values between 8.0 and 10.0 g/dL (inclusive) and on maintenance 
treatment with epoetin alfa ≥300 U/kg/week.  
Study Sites 
Approximately 40 study sites in the United States 
Planned Number of 
Subjects 
Approximately 125 subjects 
• Main study: ~95 subjects 
• ESA hyporesponder parallel study: ~30 subjects 
Primary Objective 
To assess the efficacy and safety of daily dosing of vadadustat compared to epoetin 
alfa for 12 weeks in hemodialysis subjects 
Secondary Objectives 
• To assess the efficacy and safety of TIW dosing of vadadustat in selected 
hemodialysis subjects who have been successfully managed with daily dosing of 
vadadustat through Week 12 
• To evaluate the pharmacokinetics (PK)/pharmacodynamics (PD) of daily and TIW 
dosing of vadadustat in hemodialysis subjects compared to epoetin alfa  
• To assess the efficacy and safety of several dosing strategies of vadadustat compared 
to epoetin alfa during a 20-week Treatment Period in hemodialysis subjects 
Overview of Study 
Design 
This is a Phase 2, randomized, open-label study to evaluate vadadustat for the 
treatment of anemia in hemodialysis subjects converting from epoetin alfa therapy.  
For all subjects (Main and ESA hyporesponder parallel study), the study will include a 
Screening Period, a Treatment Period, and a Safety Follow-Up Period as described 
below.  PK and PD sampling will be done throughout the study (see PK and PD 
Sampling sections for details). 
The aim is to achieve and maintain Hb levels within the target range of 10.0 to 
11.0 g/dL, inclusive, while targeting the middle of the range and minimizing 
excursions outside the target range. 
Screening Period (up to 28 days; Day -28 to Baseline/Day 1) 
For all subjects (Main and ESA hyporesponder parallel study) the Screening Period 
starts at the time the informed consent is signed and will be a maximum of 28 days in 
duration.  Baseline/Day 1 will be performed within 28 days of the start of Screening.  
Subjects who meet all eligibility criteria will be randomized to a vadadustat treatment 
arm or an epoetin alfa treatment arm.  Subjects will be required to stop epoetin alfa 
treatment for a minimum duration of 5 days before Baseline/Day 1 in the Main study 
and for a minimum of 2 days before Baseline/Day 1 in the ESA hyporesponder parallel 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 9 of 88 
study.  In the Main study, randomization will be stratified by the mean weekly epoetin 
alfa dose calculated over a period of 8 weeks prior to Screening Visit 2 (SV2). 
• 
Low epoetin alfa dose group (≤90 units [U]/kg/week) or 
• 
High epoetin alfa dose group (>90 to <300 U/kg/week) 
Study Treatment Period (Baseline/Day 1 to Week 20) 
For all subjects (Main and ESA hyporesponder parallel study), the Treatment Period 
will run from Baseline/Day 1 to Week 20.  Dose will be adjusted to achieve and 
maintain Hb levels within the target range of 10.0 to 11.0 g/L, inclusive, while 
targeting the middle of the range and minimizing excursions outside of the target 
range. 
Subjects in the Main study randomized to vadadustat: 
• 
Subjects in the low epoetin alfa dose group will start vadadustat at an initial, 
randomly allocated dose of 300 mg or 450 mg daily.   
• 
Subjects in the high epoetin alfa dose group will start vadadustat at an initial, 
randomly allocated dose of 300 mg, 450 mg, or 600 mg daily.   
Subjects in the ESA hyporesponder parallel study randomized to vadadustat: 
• 
Subjects will receive a starting dose of vadadustat 600 mg daily.   
Transition to TIW for all subjects randomized to vadadustat: 
All subjects randomized to vadadustat (Main and ESA hyporesponder parallel study) 
who complete the 12-week once daily dosing regimen and who meet all the Week 12 
transition criteria for switching from daily to TIW dosing, will initiate TIW dosing at a 
starting dose one tablet greater (+150 mg) than the final dose in the daily dosing 
period.  Subjects who do not meet criteria for switching from daily to TIW dosing will 
remain on daily dosing.   
Subjects in both the Main and ESA hyporesponder parallel study randomized to 
epoetin alfa: 
All subjects randomized to epoetin alfa will receive TIW dosing for the entire 
Treatment Period based on the subject’s central laboratory Hb value and the approved 
epoetin alfa United States (US) Package Insert (PI) for adult patients with chronic 
kidney disease (CKD) on dialysis.  Dose will be adjusted to achieve and maintain Hb 
levels within the target range of 10.0 to 11.0 g/dL, inclusive, while targeting the middle 
of the range and minimizing excursions outside of the target range. 
Safety Follow-Up Period (Weeks 20 to 24) 
For all subjects (Main and ESA hyporesponder parallel study), the 4-week Safety 
Follow-Up Period starting at Week 20 will be followed by a post-treatment safety 
assessment conducted at the beginning of Week 24. 


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Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
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Study Schematic 
 
Study Duration 
Individual subjects will participate in the study for up to 28 weeks, including a 
Screening Period of up to 4 weeks, a 20-week Treatment Period and a 4-week Safety 
Follow-Up Period. 
Inclusion Criteria 
Subjects must meet the following inclusion criteria: 
1. ≥18 years of age 
2. Receiving chronic, outpatient in-center hemodialysis (TIW) for end-stage renal 
disease for at least 12 weeks prior to Screening 
3. Maintained on IV epoetin alfa therapy for 8 weeks prior to and including 
Screening through SV2 
4. Eligibility in the Main study and ESA hyporesponder parallel study is based on 
the following mean weekly epoetin alfa doses: 
• 
Main study: Mean weekly epoetin alfa dose <300 U/kg/week for 8 weeks 
prior to SV2 
• 
ESA hyporesponder parallel study: Mean weekly epoetin alfa dose 
≥300 U/kg/week for 8 weeks prior to SV2 
5. Two Hb values measured at least 4 days apart by the central laboratory during 
Screening as indicated below 
• 
Main study: 2 Hb values between 8.5 and 11.0 g/dL, inclusive 
• 
ESA hyporesponder parallel study: 2 Hb values between 8.0 and 10.0 g/dL, 
inclusive 
6. Serum ferritin ≥100 ng/mL and transferrin saturation (TSAT) ≥20% during 
Screening 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 11 of 88 
7. Folate and vitamin B12 measurements ≥ lower limit of normal during Screening 
8. Hemodialysis adequacy as indicated by single-pool Kt/Vurea ≥1.2 using the most 
recent historical measurement within 8 weeks prior to or during Screening 
9. Understands the procedures and requirements of the study and provides written 
informed consent and authorization for protected health information disclosure. 
Exclusion Criteria 
Subjects must not meet any of the following exclusion criteria: 
1. Anemia due to a cause other than CKD (e.g., sickle cell disease, myelodysplastic 
syndromes, bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic 
anemia, thalassemia, or pure red cell aplasia) 
2. Active bleeding or recent blood loss within 8 weeks prior to randomization 
3. Red blood cell (RBC) transfusion within 8 weeks prior to randomization 
4. Anticipated to discontinue hemodialysis during the study 
5. Judged by the Investigator that the subject is likely to need rescue therapy (ESA 
administration or RBC transfusion) immediately after enrollment in the study 
6. History of chronic liver disease (e.g., chronic infectious hepatitis, chronic 
autoimmune liver disease, cirrhosis or fibrosis of the liver)  
7. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase 
(SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase 
(SGPT), or total bilirubin >1.5 x upper limit of normal (ULN) during Screening.  
Subjects with a history of Gilbert’s syndrome are not excluded. 
8. Current uncontrolled hypertension as determined by the Investigator that would 
contraindicate the use of epoetin alfa 
9. 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 heart failure (HF) or New York Heart Association Class IV HF, or stroke 
within 12 weeks prior to or during Screening 
10. History of new or recurrent malignancy within 2 years prior to and during 
Screening or currently receiving treatment or suppressive therapy for cancer.  
Subjects with treated basal cell carcinoma of skin, curatively resected squamous 
cell carcinoma of skin, or cervical carcinoma in situ are not excluded. 
11. History of deep vein thrombosis or pulmonary embolism within 12 weeks prior 
to or during Screening 
12. History of hemosiderosis or hemochromatosis 
13. History of prior organ transplantation (subjects with a history of failed kidney 
transplant or corneal transplants are not excluded) 
14. Scheduled organ transplant from a living donor and subjects on the kidney 
transplant wait-list who are expected to receive a transplant within 6 months  
15. History of a prior hematopoietic stem cell or bone marrow transplant (stem cell 
therapy for knee arthritis is not excluded) 
16. Known hypersensitivity to vadadustat, epoetin alfa, or any of their excipients 
17. 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 Screening (subjects may participate in another concurrent study 
only if that study is a non-interventional, observational investigation) 
18. Previous participation in this study, or previous participation in a study with 
another hypoxia-inducible factor prolyl-hydroxylase inhibitor other than 
vadadustat 


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Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
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19. For female subjects: 
a. 
Of non-childbearing potential 
i. Inability to confirm surgical sterility (e.g., hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy) at least 
1 month prior to Screening, or  
ii. Not considered post-menopausal (no menses for >1 year with 
follicle stimulating hormone >40 U/L at Screening)  
b. Or, if of childbearing potential  
i. Lack of confirmation of the use of acceptable forms of 
contraception* for a minimum of one complete menstrual 
cycle prior to Screening  
ii. Positive serum pregnancy test at SV2 
iii. Unwilling to use two acceptable forms of contraception* (at 
least one of which must be a barrier method) starting 
Baseline/Day 1, throughout the Treatment Period and for 
30 days after the final study drug administration 
20. Breastfeeding during Screening or throughout the Treatment Period and for 
30 days after the final study drug administration. 
21. Donation of ova starting at Screening, throughout the Treatment Period, and for 
30 days after the final study drug administration. 
22. Male subjects who have not had a vasectomy and do not agree to the following: 
use of an acceptable form of contraception* during the study and for 30 days 
after the last dose of the study drug; to not donate semen during the study and for 
at least 30 days after the last dose of vadadustat. 
23. Any other reason, which in the opinion of the Investigator, would make the 
subject not suitable for participation in the study. 
 
 *  Acceptable forms of contraception include: 
• 
Established use of oral, injected or implanted hormonal methods of 
contraception. 
• 
Placement of an intrauterine device or intrauterine system. 
• 
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. 
Retesting/Rescreening 
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 
be retested once for each laboratory parameter within the 4-week Screening Period, per 
Investigator discretion. 
Rescreening 
Subjects who fail to qualify for the study based on laboratory tests may be considered 
for rescreening at the discretion of the Investigator if it is considered that the subject 
status has changed, and the subject may now qualify for the study.  Additionally, 
subjects who fail to qualify for the study based on inclusion criteria values for 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).  A new informed consent is required to be signed prior to every rescreening. 


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Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 14 of 88 
The PD parameters will include (but are not limited to) the following: 
• 
Erythropoietin (EPO) 
• 
Reticulocytes 
• 
Iron 
• 
Ferritin 
• 
Total iron binding capacity (TIBC) 
• 
Hepcidin 
Safety Endpoints 
• 
Adverse events (AEs)  
• 
Vital sign measurements and clinical laboratory values 
• 
Hb >12.0 g/dL, >13.0 g/dL, or >14.0 g/dL 
• 
Hb <8.0 g/dL and decline in Hb ≥0.5 g/dL from Baseline Hb (Main Study); 
Hb <7.5 g/dL and decline in Hb ≥0.5 g/dL from Baseline Hb (ESA 
hyporesponder parallel study) 
• 
Hb increase >1.0 g/dL within any 2-week interval 
Dosage and Regimens 
The aim is to achieve and maintain Hb levels within the target range of 10.0 to 
11.0 g/dL, inclusive, while targeting the middle of the range and minimizing 
excursions outside the target range. 
Dosing will be initiated at Baseline/Day 1 and the first dose of vadadustat will be 
administered at the study site after other Baseline/Day 1 procedures have been 
completed.   
Thereafter, vadadustat will be taken once daily on an outpatient basis.  Subjects may 
take vadadustat with or without food and will be instructed to swallow the tablet(s) 
whole.  Subjects will be instructed to take vadadustat at roughly the same time each 
day. 
Epoetin alfa dose will be administered intravenously at the hemodialysis clinic, based 
on the subject’s central laboratory Hb value and the approved epoetin alfa US PI for 
adult patients with CKD on dialysis. 
Note: For all subjects, no epoetin alfa will be administered after SV2 after the subject 
has met all eligibility criteria and before Baseline/Day 1, for a minimum duration of 
5 days in the Main study and 2 days in the ESA hyporesponder parallel study. 
 
Main Study: 
Subjects will be randomized to either a vadadustat treatment arm or epoetin alfa 
treatment arm.  Randomization will be stratified by mean weekly epoetin alfa dose 
calculated over a period of 8 weeks prior to SV2: 
• 
Low epoetin alfa dose group (≤90 U/kg/week) or 
• 
High epoetin alfa dose group (>90 to <300 U/kg/week) 
 
In the low epoetin alfa dose group, subjects will be randomized in a 3:3:2 ratio to 
receive either an initial vadadustat daily dose of 450 mg (3 tablets) or 300 mg 
(2 tablets), or epoetin alfa. 
In the high epoetin alfa dose group, subjects will be randomized in a 3:3:3:2 ratio to 
receive either an initial vadadustat daily dose of 600 mg (4 tablets), 450 mg (3 tablets) 
or 300 mg (2 tablets), or epoetin alfa. 
ESA Hyporesponder Parallel Study 
Subjects will be randomized in a 1:1 ratio to receive either an initial vadadustat daily 
dose of 600 mg (4 tablets) or epoetin alfa. 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 15 of 88 
Epoetin alfa arm in both the Main study and ESA hyporesponder parallel study: 
For subjects who are randomized to the epoetin alfa treatment arm, the initial dosing 
regimen in the study (starting from Baseline/Day 1) will be approximately the same 
weekly dose that they were receiving prior to randomization. 
Study Drug Guidelines for Dose Adjustment 
Dose adjustments will be guided by Hb concentrations and the Guidelines for Dose 
Adjustment (see below).  Hb will be monitored via central laboratory throughout the 
study to determine if the dose of study drug (vadadustat or epoetin alfa) will be 
adjusted, interrupted, or maintained as follows: 
• 
Dose adjustments are based on the Investigator’s clinical discretion, 
incorporating the protocol guidance below as well as the subject’s current Hb 
level, trajectory, and variability; symptoms; cardiovascular risk; and other 
features of his/her clinical condition(s). 
• 
If a dose increase or decrease is required to achieve and maintain Hb levels 
within the target range of 10.0 to 11.0 g/dL, inclusive, dose is adjusted by 1 dose 
level (for vadadustat 1 tablet [150 mg], for epoetin alfa approximately 25%). 
• 
In general, do not increase the dose more frequently than once every 4 weeks.  A 
one-time dose increase after 2 weeks is allowed on only two occasions.   
o 
A subject’s dose may be increased by 1 dose level if the subject has a 
decline in Hb ≥0.5 g/dL from Baseline/Day 1 in the first 2-week 
period (the initial period from Baseline/Day 1 to Week 2 following 
conversion from prior epoetin alfa therapy).   
o 
A subject’s dose may also be increased by 1 dose level in the first 2-
week period after initiation of TIW dosing (from Week 12 to 
Week 14) for subjects that meet criteria for transitioning from daily 
to TIW dosing. 
• 
Reduce or interrupt the dose in the setting of a rapid rise in Hb (defined as 
>1.0 g/dL in any 2-week period)  
• 
Reduce or interrupt the dose in the setting of Hb >11.0 g/dL 
• 
Interrupt the dose in the setting of a Hb >12.0 g/dL until Hb value falls below 
11.0 g/dL.  After Hb falls below 11.0 g/dL, restart study drug and consider 
restarting at a lower dose.  
The minimum dose of vadadustat will be 150 mg daily or TIW (1 tablet daily/TIW) 
and the maximum dose will be 900 mg daily or TIW (6 tablets daily/TIW). 
Transition of Vadadustat Once Daily Dosing to TIW Dosing Regimen 
All subjects randomized to vadadustat who complete 12 weeks of once daily dosing 
regimen and who meet all the Week 12 criteria below will be transitioned to a TIW 
vadadustat dosing regimen.  Subjects who meet all of the Week 12 criteria will 
transition to TIW dosing.  
Week 12 Transition criteria: 
• 
Vadadustat daily dose of 600 mg or lower at Week 12 
• 
Hb within target range of 10.0 to 11.0 g/dL, inclusive, at Week 12 confirmed by 
central laboratory Hb value from Week 11 (11 weeks of treatment completed)  
• 
No receipt of rescue therapy (ESA or RBC transfusion) for worsening of anemia 
due to CKD from Baseline to Week 12.   
o 
ESA or RBC transfusion prior to Week 12 for reasons unrelated to 
worsening of anemia due to CKD (e.g., surgery, gastrointestinal 
bleed, or inadvertent administration) is not considered rescue therapy 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 16 of 88 
• 
No other reason, based on the Investigator’s clinical discretion, that would make 
the subject not suitable for TIW dosing. 
Selected subjects who meet Week 12 transition criteria will transition to the TIW 
vadadustat dosing regimen at the Week 12 visit.  Subjects on 150 mg, 300 mg, 450 mg, 
or 600 mg of vadadustat daily at the Week 12 visit will transition to an initial 
vadadustat TIW dose one tablet greater (+150 mg), i.e., 300 mg, 450 mg, 600 mg, or 
750 mg vadadustat TIW, respectively.  Subjects will be instructed to take vadadustat 
on dialysis days. 
After 2 weeks of treatment in the TIW vadadustat dosing regimen (at Week 14), 
subjects in any vadadustat TIW dosing arms who have a decline in Hb ≥0.5 g/dL will 
be eligible for a dose increase by 1 tablet, based on the Investigator’s clinical 
discretion. 
Subjects who are not eligible to switch from daily vadadustat to TIW dosing at 
Week 12 will remain on daily dosing for the remainder of the study. 
Subjects on TIW dosing may be converted back to vadadustat once daily dosing at the 
discretion of the Investigator in the setting of inadequate Hb response.  The starting 
daily dose after the switch from TIW to daily dosing will be based on the Investigator’s 
discretion after review of the subject’s clinical status and dosing history, in particular, 
the daily dose previously administered to the subject prior to the transition to TIW 
dosing (Week 12).  Subjects who switch from vadadustat TIW to daily dosing will 
continue once daily vadadustat until the end of the Treatment Period. 
 
Subjects in the vadadustat arm will be guided for dosing compliance using an 
electronic diary (eDiary). 
PK/PD Sampling - 
vadadustat arm 
Blood for measurement of vadadustat, metabolites and EPO level in the vadadustat 
arm, in both the Main study and ESA hyporesponder parallel study, will be collected as 
outlined below (see Appendix B).  Preferably, PK/PD samples are to be taken on the 
day of hemodialysis after the first short interdialytic interval (e.g., at the second session 
of the week). 
At Baseline/Day 1, PK/PD samples will be collected prior to dialysis and 
administration of vadadustat. 
At Week 1 (after at least a full week of vadadustat treatment), vadadustat will be 
administered between 15 minutes to one hour prior to the start of dialysis.  Blood 
samples will be collected as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 
5 hours ± 30 minutes post-dose 
• 
From subjects enrolled at a subset of study sites only, additional samples will be 
collected at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
On the following non-dialysis day, blood samples will be collected as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 
5 hours ± 30 minutes post-dose 
• 
From subjects enrolled at a subset of study sites only, additional samples will be 
collected at 7 hours ± 30 minutes post-dose 
At Week 11, vadadustat will be administered between 15 minutes to one hour prior to 
the start of dialysis.  Blood samples will be collected as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 
5 hours ± 30 minutes post-dose 
• 
From subjects enrolled at a subset of study sites only, additional samples will be 
collected at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 17 of 88 
At Week 13 (after at least one week on TIW vadadustat dosing regimen), vadadustat 
will be administered between 15 minutes to one hour prior to the start of dialysis.  
Blood samples will be collected as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 
5 hours ± 30 minutes hours post-dose  
• 
From subjects enrolled at a subset of study sites only, additional samples will be 
collected at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
Note: Week 13 PK/PD sampling will only be done in subjects who transition to 
vadadustat TIW dosing regimen.  Subjects who do not qualify for vadadustat TIW 
dosing and remain on daily dosing regimen will not have Week 13 PK/PD sampling. 
PK Sampling - epoetin 
alfa arm 
Blood for measurement of EPO level in the epoetin alfa arm in both the Main study 
and ESA hyporesponder parallel study will be collected as outlined below (see 
Appendix B).  Preferably, PK samples are to be taken on the day of hemodialysis after 
the first short interdialytic interval (e.g., at the second session of the week). 
At Baseline/Day 1, a sample will be collected prior to dialysis and administration of 
epoetin alfa. 
At Week 1 (after at least a full week of study epoetin alfa treatment), epoetin alfa will 
be administered within 1 hour after start of dialysis.  Blood samples will be collected 
as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 
5 hours ± 30 minutes post-dose  
• 
From subjects enrolled at a subset of study sites only, additional samples will be 
collected at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
On the following dialysis day, one blood sample will be collected 15 minutes prior to 
administration of epoetin alfa. 
Iron Supplementation 
IV iron will be administered based on ferritin and TSAT levels measured by the central 
laboratory according to the standardized, low-intensity, iron supplementation protocol 
below: 
 
Ferritin 
<200 ng/mL 
Ferritin 
200-500 ng/mL 
Ferritin 
>500 ng/mL 
TSAT 
<20% 
IV Iron 100 mg 
every treatment 
(max 
400 mg/month) 
IV Iron 50 mg 
weekly 
Hold 
TSAT 
20-50% 
IV Iron 100 mg 
every week 
IV Iron 50 mg 
weekly 
Hold 
TSAT 
>50% 
Hold 
Hold 
Hold 
Intra-dialytic iron preparations (e.g., Triferic) and oral iron supplementation including 
iron-containing phosphate binders are prohibited during the study. 
Important: As the study will be assessing PK/PD parameters, and as there are no 
empirical data on concurrent administration of vadadustat and phosphate binders, 
vadadustat will not be administered concurrently with a phosphate binder.  Subjects 
will be instructed to take phosphate binders at least 3 hours before or at least 2 hours 
after the dose of vadadustat based on the guidance in the phosphate binder package 
inserts. 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 18 of 88 
Rescue Therapy 
Guidelines 
To ensure the safety of subjects and to standardize the use of rescue in the study, 
rescue therapy guidelines are provided. 
1. 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 will 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 medical 
necessity.  Study drug (vadadustat or epoetin alfa) may be continued during the 
transfusion period. 
Reasons for RBC transfusion will be captured in the appropriate CRF. 
2. ESA Use: ESA administration will be allowed when medically necessary at the 
discretion of the Investigator.  In general, ESA will not be administered in subjects 
with Hb ≥8.5 g/dL, and ESA rescue will be stopped when Hb ≥9.0 g/dL.  ESA 
therapy will be administered using an approved ESA and dosing as per the local 
institution’s guidelines and per the approved product label.   
While receiving ESA therapy, subjects randomized to vadadustat must temporarily 
interrupt vadadustat.  A minimum interval will be observed prior to restarting 
vadadustat after the last dose of ESA, and treatment will be resumed after the 
following intervals: 
• 2 days after last dose of epoetin alfa  
• 7 days after last dose of darbepoetin alfa  
• 14 days after last dose of methoxy polyethylene glycol-epoetin beta  
Following ESA administration, vadadustat will be resumed at the same dose as 
previously used or with one additional tablet (+150 mg) at the discretion of the 
Investigator.  
Reasons for ESA use will be captured in the appropriate CRF. 
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 clinical 
judgment.  The method of phlebotomy will be in accordance with the study site’s 
standard clinical practice. 
Concomitant 
Medications 
1. ESA 
Co-administration of any ESA with vadadustat is 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 ESA 
Rescue) if deemed medically necessary at the discretion of the Investigator.  
Guidelines for ESA administration as rescue therapy are provided above.  All efforts 
will be made to avoid inadvertent administration of ESAs resulting from adherence to 
ESA hemodialysis center protocols (e.g., DaVita ESA protocols for patients 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.  A minimum interval will be observed prior to 
restarting vadadustat after the last dose of ESA.  Vadadustat treatment may be resumed 
after the following intervals: 
• 
2 days after last dose of epoetin alfa  
• 
7 days after last dose of darbepoetin alfa  
• 
14 days after last dose of methoxy polyethylene glycol-epoetin beta 
2. Iron  
See guidance above (Iron Supplementation). 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 19 of 88 
Study Completion, 
Subject Completion, 
Temporary 
Interruption of Study 
Drug, Early 
Discontinuation from 
Study (Early 
Termination) 
Study Completion 
The study will be considered completed after all randomized subjects have completed 
their final study visit (Visit 15/Week 24, Safety Follow-Up or Early Termination).  
Subject Completion 
A subject will be considered as having completed the study after completion of their 
final study visit (Visit 15/Week 24, Safety Follow-Up or Early Termination).   
Temporary Interruption of Study Drug 
During the study, a subject may interrupt study drug (vadadustat or epoetin alfa) for 
any of the following reasons: 
• 
AE 
• 
Missed dialysis visit (epoetin alfa arm) 
• 
Investigator’s discretion 
• 
Rapid rise in Hb (defined as >1.0 g/dL in any 2-week period) 
• 
Hb above 11.0 g/dL 
• 
ESA use (vadadustat arm) 
Unless contraindicated, treatment will be resumed whenever possible and assessed at 
every visit following study drug interruption. 
Early Discontinuation from Study (Early Termination) 
Subjects who discontinue prematurely from the study will complete the 
End-of-Treatment visit (Visit 14) assessments and will complete the Safety Follow-Up 
(Visit 15) 4 weeks after Visit 14. 
Subjects may discontinue for any of the following reasons: 
• AE  
• Investigator’s discretion 
• Subject withdrawal of consent  
• Lack of efficacy 
• Lost to follow up despite reasonable efforts by the Investigator to locate the subject 
• Death  
• Other reasons (pregnancy, kidney transplantation, specific reasons to be 
documented by the Investigator) 
Study Termination/ 
Individual Study Site 
Termination 
The Sponsor may terminate this study prematurely, either in its entirety or at any study 
site, for reasonable cause provided that written notice is submitted in advance of the 
intended termination.  Advanced notice is not required if the study is stopped due to 
safety concerns.  If the Sponsor terminates the study for safety reasons, the Sponsor 
will immediately notify the Investigator and subsequently provide written instructions 
for study termination.  If the study has been suspended or terminated, prompt 
notification will be given to Investigators, IRBs, and regulatory authorities in 
accordance with regulatory requirements. 
Statistical 
Considerations 
Efficacy and safety endpoint analysis will be descriptive in nature.  Continuous 
variables will be summarized using number of subjects with mean, standard deviation 
(SD), median, minimum and maximum.  For categorical variables, the number and 
percentage of subjects in each category will be tabulated. 
PK and PD parameters will be summarized using descriptive statistics: number of 
subjects, mean, median, SD, minimum, maximum, and coefficient of variation, 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 20 of 88 
geometric mean and geometric mean SD.  Mean and individual plasma concentration-
time profiles will be presented graphically in both linear scale and log-linear scale. 
The ESA hyporesponder parallel study will be analyzed separately from the main 
study. 
PK Analysis 
A population PK analysis will be conducted to describe vadadustat PK and determine 
the covariates that impact the PK profile (i.e., demographics, laboratory values, 
concomitant iron, dosing relative to dialysis, etc).  PK analysis will be reported 
separately. 
PD Analysis 
An exposure-response analysis of vadadustat, EPO and other PD measures will be 
conducted as deemed appropriate.  PD analysis will be reported separately. 
Sample Size 
Estimation 
Approximately 95 subjects are planned for enrollment in the Main study with 40 and 
55 subjects randomized to the low epoetin alfa dose group and the high epoetin alfa 
dose group respectively.  Approximately 30 subjects are planned for enrollment in the 
ESA hyporesponder parallel study.  Sample size reflects the exploratory nature of this 
study.  
 
Enrollment may be increased by up to 20 additional subjects in the Main study, and by 
up to 30 additional subjects in the ESA hyporesponder parallel study to ensure 
adequate data is captured for the primary, PK/PD, and safety endpoints. 
Safety Monitoring 
This is an open label study allowing the study team full access to safety data which 
will be reviewed on a regular basis, throughout the course of the study.  Safety 
monitoring will be performed as described in the Medical Monitor Plan.   
 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 21 of 88 
3 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under concentration-time curve 
AUCinf 
area under concentration-time curve from dosing to infinity 
AUClast 
area under concentration-time curve from dosing to last 
measurable concentration  
BP 
blood pressure 
CBC 
complete blood count 
CKD 
chronic kidney disease 
CL/F 
apparent total body clearance 
Cmax 
maximum concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
DD-CKD 
dialysis dependent chronic kidney disease 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eDiary 
electronic diary 
EOT 
end-of-treatment 
EPO 
erythropoietin 
ESA 
erythropoiesis-stimulating agent 
ESRD 
end-stage renal disease 
FAS 
Full Analysis Population 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
Hb 
hemoglobin 
HF 
heart failure 
HIF 
hypoxia-inducible factor 
HIF-PH 
hypoxia-inducible factor prolyl-hydroxylase 
HIF-PHI 
hypoxia-inducible factor prolyl-hydroxylase inhibitor 
HR 
heart rate 
HRQOL 
health-related quality of life 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IRB 
Institutional Review Board 
IV 
intravenous 
IWRS 
Interactive Web Response System 
LFT 
liver function test 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger ribonucleic acid 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 22 of 88 
NDD-CKD 
non-dialysis dependent chronic kidney disease 
PGI-C 
patient global impression of change 
PGI-S 
patient global impression of severity 
PHD 
prolyl 4-hydroxylase domains 
PI 
Package Insert 
PK 
pharmacokinetic(s) 
PD 
pharmacodynamics(s) 
RBC 
red blood cell 
RR 
respiratory rate 
SAE 
serious adverse event 
SD 
standard deviation 
SF-36 
36-Item Short-Form General Health Survey 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SO2 
oxygen saturation 
TIW 
three times a week 
Tmax 
time to reach Cmax 
TSAT 
transferrin saturation 
U 
unit 
ULN 
upper limit of normal 
US 
United States 
Vd/F 
apparent volume of distribution 
VEGF 
vascular endothelial growth factor 
 


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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% to 16% of the population (Jha 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, infection, cancer, and mortality (Iseki 2007). 
The prevalence and severity of renal anemia in CKD increases as renal function deteriorates 
(Di Iorio 2007; Stauffer 2014).  As CKD progresses, the combined effect of decreased red blood 
cell (RBC) production from lower erythropoietin (EPO) signaling, increased rate of RBC 
destruction, and reduced iron availability to the bone marrow results in the increased prevalence 
and severity of anemia (Pergola 2016).  Anemia generally exists when hemoglobin (Hb) is less 
than 13.0 g/dL in men or less than 12.0 g/dL in women (KDIGO 2012).  Three principal factors 
contribute to the development of anemia as CKD progresses:  
• Peritubular fibroblasts, a type of cell in the kidney, are designed to sense the amount of 
oxygen carried by the blood.  These cells secrete EPO to adjust the production of RBCs by 
the bone marrow and maintain circulating oxygen levels at normal physiologic levels.  As 
kidney disease progresses, the number of peritubular fibroblasts is reduced and EPO 
secretion is significantly decreased, leading to a reduction in RBC production (Iseki 2007; 
Nurko 2006).  
• On average, the RBCs in CKD patients have a shorter lifespan (approximate lifespan of 
70 days) compared with the RBCs in healthy people (approximate lifespan of 90 to 120 days) 
(Ly 2004; Nurko 2006).  Such a condition leads to increased RBC production in CKD 
patients to maintain normal physiologic levels.  
• The availability of iron to the bone marrow is impaired.  Iron is a required component in the 
formation of Hb, and is essential for the transport of oxygen to the tissues of the body. 
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 2014).  In these patients, compensatory changes occur in cardiac structure and function 
including an increase in cardiac output and the development of left ventricular hypertrophy and 
eventually the development of heart failure (Metivier 2000).  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 patients (Iseki 2007; NICE 2011).  Overall, 
anemia contributes to a poorer prognosis in patients with CKD (Iseki 2007; Nurko 2006). 
The risks associated with erythropoiesis-stimulating agents (ESAs), including an increased risk 
of death and cardiovascular events (Besarab 1998; Drueke 2006; Pfeffer 2009a; Pfeffer 2009b; 
Singh 2006), 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 dialysis dependent CKD (DD-CKD) patients 
remains high.  To fulfill this unmet need, the vadadustat clinical program is focused on 
developing an orally active therapeutic agent for the treatment of anemia in patients with CKD. 


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4.1 
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 (HIF-PHs) for the treatment of anemia associated 
with CKD.  HIF-PH enzymes are also referred to as prolyl 4-hydroxylase domains (PHDs), of 
which the 2 most commonly expressed isoforms are PHD2 and PHD3.  Vadadustat is a slightly 
more potent inhibitor of PHD3 (50% inhibitory concentration [IC50] = 0.08 µM) than of PHD2 
(IC50 = 0.19 µM).  The inhibition of PHD3 and PHD2 stabilizes hypoxia-inducible factor 
(HIF)-2α and HIF-1α, which in turn stimulates the production of EPO.  In vivo animal efficacy 
and messenger ribonucleic acid (mRNA) data indicate that vadadustat induces the production of 
EPO from both renal and extra-renal sites (liver and brain), and this increase in EPO results in an 
increase in RBC production in the bone marrow.  In clinical trials, vadadustat has been shown to 
facilitate iron homeostasis by decreasing hepcidin and increasing transferrin levels in healthy 
adult male volunteers and male and female CKD patients.  This enables iron transport 
mechanisms that should enhance the terminal steps of erythropoiesis.  Vadadustat offers the 
potential of flexible oral dosing that provides a more gradual and reliable means of titration than 
injectable hormones.  Therefore, vadadustat is being developed as an alternative to the existing 
protein hormone ESAs. 
4.2 
Summary of Clinical Experience 
Please see the vadadustat Investigator Brochure for additional discussion and information for 
the following section. 
The efficacy, safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of 
vadadustat have been characterized in 10 completed Phase 1 studies in healthy volunteers 
including 1 ethno-bridging study in Caucasian and Japanese subjects, 1 completed Phase 1 study 
in subjects undergoing chronic hemodialysis, 3 completed Phase 2a studies in non-dialysis 
dependent CKD (NDD-CKD) subjects, 1 completed Phase 2b study in NDD-CKD subjects, and 
1 completed Phase 2 study in DD-CKD subjects.  The United States (US) 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, double-blind, placebo-
controlled study with 5 different dose groups dosed for 42 days.  The US Phase 2b, randomized, 
double-blind, placebo-controlled study evaluated Stages 3, 4, and 5 CKD (pre-dialysis) dosed for 
20 weeks.  The Japanese Phase 2, randomized, double-blind, placebo-controlled study evaluated 
Stages 3, 4, and 5 CKD (pre-dialysis) dosed for 16 weeks.  The US Phase 2 open-label study 
evaluated DD-CKD subjects on chronic hemodialysis dosed for 16 weeks.  The Japanese Phase 
2, randomized, double-blind, placebo-controlled study evaluated DD-CKD subjects on chronic 
hemodialysis dosed for 16 weeks.  In the studies completed to date, a total of 630 subjects have 
received vadadustat, including 200 healthy volunteers and 430 subjects with CKD. 
Vadadustat has shown 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 and Hb 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 consistent bioavailability with area under 
concentration-time curve (AUC) and Cmax in Phase 1 and Phase 2 studies covering the dose range 


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of 80 mg to 1200 mg after single administration and 500 to 900 mg after repeated daily 
administration for 10 days.  The plasma half-life of vadadustat was about 4 to 6 hours, 7 to 8 
hours, and 9 to 10 hours in healthy subjects, NDD-CKD patients, and DD-CKD patients, 
respectively. 
Vadadustat is extensively metabolized and its metabolites are eliminated from the body by dual 
routes of excretion (both 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.  
Multiple doses of 700 mg and 900 mg daily for up to 10 days (Study AKB-6548-CI-0002 
[CI-0002]) and single doses of 1200 mg (Study AKB-6548-CI-0001 [CI-0001], Study AKB-
6548-CI-0010 [CI-0010]) have been examined in healthy volunteers.  Vadadustat demonstrated 
dose-proportional PK and achieved serum EPO concentrations up to 34.4 mIU/mL, levels 
considered physiologic and below exposures achieved with injectable ESAs (Besarb 1992).  A 
higher incidence of adverse events (AEs) in the gastrointestinal System Organ Class (SOC) – 
nausea, diarrhea, abdominal pain, dyspepsia – was observed in groups treated with 700 mg, 
900 mg, or 1200 mg compared with lower vadadustat doses or placebo.  Most AEs were mild to 
moderate, short-lived (1 or 2 days), and assessed as unrelated by investigators.  No AEs led to 
study withdrawal, and no serious adverse events (SAEs) were reported.  No clinically 
meaningful changes or abnormalities in vital signs, safety laboratory studies, or ECG parameters 
were reported. 
A 16-week, open-label, multicenter, Phase 2 trial evaluated vadadustat in 94 subjects receiving 
chronic hemodialysis previously maintained on epoetin alfa and IV iron form the 3 months prior 
to Screening (Study AKB-6548-CI-0011 [CI-0011]).  Subjects were assigned to one of three 
vadadustat dose cohorts: 300 mg daily, 450 mg daily, or 450 mg three times a week (TIW).  
Dosing was fixed for the first 8 weeks; for the subsequent 8 weeks dose was adjusted according 
to Hb response based upon a dose adjustment algorithm.  Sixty-nine of the 94 subjects completed 
the study.  The primary endpoint was the mean Hb concentration change from pre-treatment 
average (Screening Visit 1, Screening Visit 2, and Baseline Visit) to mid-study (Weeks 7 to 8) 
and end-of-study (Weeks 15 to 16) and was analyzed using observed Hb values (no imputation 
for missing data).  No statistically significant mean change in Hb from pre-treatment average 
was observed for either of the two time points for any of the three treatment groups. 
Among subjects randomized to an initial dose of 300 mg daily, 450 mg daily, or 450 mg TIW, 
0% (0 of 30), 3% (1 of 33), and 19% (6 of 31) of subjects withdrew from the study due to 
worsening anemia, respectively.  In a sensitivity analysis using last observation carried forward 
(LOCF) for the primary efficacy endpoint, no significant mean change in Hb from pre-treatment 
levels was observed in the 300 mg daily dosing group.  At Weeks 15 to 16, modest, statistically 
significant mean decreases were observed in the 450 mg daily and 450 mg TIW dosing groups. 
In a post-hoc univariate analysis of baseline characteristics, higher pre-baseline epoetin alfa dose 
was associated with a decrease in mean Hb at Weeks 7 to 8 and Weeks 15 to 16 in the dosing 
cohorts.  Subjects who discontinued the study due to worsening anemia had a higher mean pre-
baseline epoetin alfa dose compared with subjects who discontinued due to other reasons or 
subjects who completed the study. 


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Based on 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.  
In the ongoing global Phase 3 and Japanese Phase 3 clinical studies, over 7000 subjects are 
planned to be treated with vadadustat or comparator.  
This study will evaluate efficacy, safety and PK/PD with different vadadustat dosing strategies in 
hemodialysis subjects converting from epoetin alfa to further characterize the optimal vadadustat 
regimen. 
4.3 
Potential Benefits and Risks 
Please see the vadadustat Investigator’s Brochure for additional information. 
Trials of injectable 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 2009a).  Post-hoc analyses performed by the Food and Drug 
Administration (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 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 2007).  Potential clinical benefits include enhanced 
erythropoiesis and decreased exogenous iron requirements.  
In nonclinical safety studies, the main findings originated from an exaggerated pharmacological 
response that results in increased erythropoiesis, polycythemia, blood hyperviscosity, and the 
formation of fibrin thrombi in multiple organs.  Early mortality noted in the mouse and rat and 
moribundity in the dog were due to the sequelae associated with polycythemia.  These findings 
were reproducible across species and studies, dose-dependent and showed reversibility.  Dose-
limiting toxicity in the exploratory toxicology studies was due to hemoglobinuric nephropathy 
(rat) and emesis associated with body weight loss (dog). 
In completed Phase 1 clinical studies of vadadustat in healthy volunteers, there were low 
numbers of treatment-emergent AEs.  The most frequently reported AEs were in the 
gastrointestinal disorders (i.e., nausea, diarrhea, abdominal pain, flatulence, dyspepsia) and 
nervous system disorders (i.e., headache, dizziness) SOC.  The majority of AEs were mild to 
moderate in severity.  
The most frequently reported AEs in completed Phase 2 studies of NDD- and DD-CKD subjects 
were in the following SOCs: gastrointestinal disorders (nausea, diarrhea, vomiting), 
cardiovascular disorders (hypertension, hypotension, coronary artery disease), renal (renal failure 
chronic, renal failure acute), infections and infestations (gastroenteritis, urinary tract infection, 


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Original Protocol 
 
Akebia — Company Confidential 
Page 27 of 88 
pneumonia), and metabolism and nutrition disorders (hyperkalemia, fluid overload).  Four deaths 
occurred in the completed Phase 2 clinical studies.  
Identified risks include nausea, diarrhea, vomiting, headache, abdominal pain, and uric acid 
elevations.  Hypersensitivity, hyperkalemia and hypertension have been identified as potential 
risks associated with vadadustat therapy. 
Review of safety data from completed Phase 1 and 2 clinical studies, as well as review of 
accumulating data from ongoing studies, continue to support further development of the 
vadadustat program. 
 


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Page 28 of 88 
5 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Primary Objective 
To assess the efficacy and safety of daily dosing of vadadustat compared to epoetin alfa for 
12 weeks in hemodialysis subjects. 
5.2 
Secondary Objectives 
• To assess the efficacy and safety of TIW dosing of vadadustat in selected hemodialysis 
subjects who have been successfully managed with daily dosing of vadadustat through 
Week 12 
• To evaluate the PK/PD of daily and TIW dosing of vadadustat in hemodialysis subjects 
compared to epoetin alfa 
• To assess the efficacy and safety of several dosing strategies of vadadustat compared to 
epoetin alfa during a 20-week Treatment Period in hemodialysis subjects 
5.3 
Efficacy Endpoints 
5.3.1 Primary Endpoints 
The primary endpoint will be the mean change in Hb between Baseline (average pretreatment 
Hb) and the primary evaluation period (average Hb from Weeks 10 to 12). 
5.3.2 Key Secondary Endpoints 
• Proportion of subjects with Hb values within the target range (10.0 to 11.0 g/dL, 
inclusive) at the primary evaluation period (Weeks 10 to 12) 
• For subjects who transitioned to TIW vadadustat dosing, mean change in Hb from 
primary evaluation period (average Hb from Weeks 10 to 12) to the secondary evaluation 
period (average Hb from Weeks 18 to 20) 
5.3.2.1 Other Secondary Endpoints 
• Mean change in Hb between Baseline (average pretreatment Hb) and the secondary 
evaluation period (average Hb from Weeks 18 to 20) 
• Proportion of subjects with Hb values within the target range (10.0 to 11.0 g/dL, 
inclusive) at the secondary evaluation period (Weeks 18 to 20) 
• For subjects who transitioned to TIW vadadustat dosing, proportion of subjects with Hb 
values within the target range (10.0 to 11.0 g/dL, inclusive) at the secondary evaluation 
period (Weeks 18 to 20) 
• Proportion of subjects with a mean increase in Hb from Baseline to the primary 
evaluation period ≥0.5 g/dL (average Hb from Weeks 10 to 12) or with Hb values within 
the target range (10.0 to 11.0 g/dL, inclusive) at the primary evaluation period 
(Weeks 10 to 12) 
• Proportion of subjects with a mean increase in Hb from Baseline to the secondary 
evaluation period ≥0.5 g/dL (average Hb from Weeks 18 to 20) or with Hb values within 
the target range (10.0 to 11.0 g/dL, inclusive) at the secondary evaluation period 
(Weeks 18 to 20) 


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Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
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6 
STUDY DESIGN 
6.1 
Study Design 
This is a Phase 2, randomized, open-label study to evaluate vadadustat for the treatment of 
anemia in hemodialysis subjects converting from epoetin alfa therapy. 
For all subjects (Main and ESA hyporesponder parallel study), the study (as shown in Figure 1) 
will include a Screening Period, a study Treatment Period, and a Safety Follow-Up Period as 
described below.  PK and PD sampling will be done throughout the study (see PK and PD 
Sampling Section 9.2.2.1, PK/PD Sampling for Subjects Randomized to Vadadustat and 
Section 9.2.2.2, PK Sampling for Subjects Randomized to Epoetin Alfa, respectively, for 
details). 
The aim is to achieve and maintain Hb levels within the target range of 10.0 to 11.0 g/dL, 
inclusive, while targeting the middle of the range and minimizing excursions outside the target 
range. 


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Figure 1: 
Overview of Study Design 
 
6.1.1 Screening Period (up to 28 days; Day -28 to Baseline/Day 1) 
For all subjects (Main and ESA hyporesponder parallel study), the Screening Period starts at the 
time the informed consent is signed and will be a maximum of 28 days in duration.  
Baseline/Day 1 will be performed within 28 days of the start of Screening.  Subjects who meet 
all eligibility criteria will be randomized to a vadadustat treatment arm or an epoetin alfa 
treatment arm.  Subjects will be required to stop epoetin alfa treatment for a minimum duration 
of 5 days before Baseline/Day 1 in the Main study and for a minimum of 2 days before 
Baseline/Day 1 in the ESA hyporesponder parallel study.  In the Main study, randomization will 
be stratified by the mean weekly epoetin dose calculated over a period of 8 weeks prior to 
Screening Visit 2 (SV2): 


Akebia Therapeutics, Inc. 
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Akebia — Company Confidential 
Page 32 of 88 
• Low epoetin alfa dose group (≤90 units [U]/kg/week) 
• High epoetin alfa dose group (>90 to <300 U/kg/week) or 
6.1.2 Study Treatment Period (Baseline/Day 1 to Week 20) 
For all subjects (Main and ESA hyporesponder parallel study), the Treatment Period will run 
from Baseline/Day 1 to Week 20.  Dose will be adjusted to achieve and maintain Hb levels 
within the target range of 10.0 to 11.0 g/dL, inclusive, while targeting the middle of the range 
and minimizing excursions outside of the target range. 
6.1.2.1 Vadadustat Treatment 
Subjects in the Main study randomized to vadadustat: 
• Subjects in the low epoetin alfa dose group will start vadadustat at an initial, randomly 
allocated dose of 300 mg or 450 mg daily.   
• Subjects in the high epoetin alfa dose group will start vadadustat at an initial, randomly 
allocated dose of 300 mg, 450 mg, or 600 mg daily.   
Subjects in the ESA hyporesponder parallel study randomized to vadadustat: 
• Subjects will receive a starting dose of vadadustat 600 mg daily.  
Transition to TIW for all subjects randomized to vadadustat: 
All subjects randomized to vadadustat (Main and ESA hyporesponder parallel study), who 
complete the 12-week once daily dosing regimen and who meet all the Week 12 transition 
criteria for switching from daily to TIW dosing, will initiate TIW dosing at a starting dose one 
tablet greater (+150 mg) than the final dose in the daily dosing period (see Section 8.4.5.2, 
Transition of Vadadustat Once Daily Dosing to TIW Dosing Regimen). 
Note: Subjects who are not eligible to switch from daily vadadustat to TIW dosing at Week 12 
will remain on daily dosing from the remainder of the study (see Section 8.4.5, Vadadustat 
Dosing Regimen and Guidelines for Dose Adjustment).  
6.1.2.2 Epoetin Alfa Treatment 
Subjects in both the Main and ESA hyporesponder parallel study randomized to epoetin alfa: 
All subjects randomized to epoetin alfa will receive TIW dosing for the entire Treatment Period 
based on the subject’s central laboratory Hb value and the approved epoetin alfa United States 
(US) Package Insert (PI) for adult patients with CKD on dialysis.  Dose will be adjusted to 
achieve and maintain Hb levels within the target range of 10.0 to 11.0 g/dL, inclusive, while 
targeting the middle of the range and minimizing excursions outside of the target range (see 
Section 8.4.4, Epoetin Alfa Dosing Regimen). 
6.1.3 Safety Follow-Up Period (Weeks 20 to 24) 
For all subjects (Main and ESA hyporesponder parallel study), the 4-week Safety Follow-Up 
Period starting at Week 20 will be followed by a post-treatment safety assessment conducted at 
the beginning of Week 24. 


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6.2 
Rationale for Study Design 
The Main Study and the ESA hyporesponder parallel study will evaluate different starting doses 
of vadadustat based on pre-baseline ESA doses.  Numerous studies have demonstrated that 
hemodialysis patients requiring higher ESA doses to treat their anemia have a higher burden of 
comorbidities, a more inflammatory state, and a greater risk of adverse outcomes (Besarb 1998; 
Parfrey 2005; Unger 2010).  As described above (Section 4.2, Summary of Clinical Experience) 
in a Phase 2 hemodialysis study (CI-0011), a post-hoc analysis suggested higher pre-baseline 
ESA doses were associated with lower observed mean Hb levels.  Subjects on higher pre-
baseline ESA doses may benefit from a higher starting dose of vadadustat after initial conversion 
from ESAs.  
Three levels of pre-baseline ESA dose will be evaluated.  In the Main Study subjects will be 
randomized to one of two cohorts based on pre-baseline ESA dose (≤90 U/kg/week and >90 to 
<300 U/kg/week).  The ESA threshold of 90 U/kg/week was based on the median ESA doses 
reported in the US Renal Data System and US Dialysis Outcomes and Practice Patterns Study, 
which ranged from approximately 90 to 110 U/kg/week. 
The ESA hyporesponder parallel study will evaluate subjects with Hb levels below the target 
range despite receiving ≥300 U/kg/week of epoetin alfa.  This ESA threshold was based on the 
definition of resistance to ESAs proposed in the ERA-EDTA 2004 guidelines (Locatelli 2004).  
The Main study and the ESA hyporesponder parallel study incorporate an approach to vadadustat 
dose adjustment designed to maximize the probability that Hb can be maintained within the 
target range of 10.0 to 11.0 g/dL, inclusive (see Section 8.4.5, Vadadustat Dosing Regimen and 
Guidelines for Dose Adjustment).  The approach to vadadustat dose adjustment in this Phase 2 
study includes several modifications as compared to the vadadustat dosing algorithms used in 
previously completed Phase 2 studies and the dosing algorithm used in the ongoing Phase 3 
studies.   
During this study, dose increases for vadadustat will be allowed at 4-week intervals, with the 
exception of the initial 2 weeks of treatment, in the daily and TIW dosing periods of the study.  
Dose increases will be permitted in the initial 2 weeks of treatment, in the daily and TIW dosing 
periods, in subjects with a Hb decline ≥0.5 g/dL from baseline and Week 12, respectively.  This 
approach is commonly used in clinical practice to treat patients with declining or low Hb values 
(Pfeffer 2009a; Singh 2006).  Risk of abrupt or excessive increases in Hb is minimized due to the 
underlying Hb trajectory and is further mitigated by close Hb monitoring. 
In the present study, the safety and efficacy of a vadadustat TIW dosing regimen is being 
evaluated as a potential alternative treatment regimen to a once daily dosing regimen in 
hemodialysis subjects.  Specifically, this study will evaluate conversion from once daily dosing 
to TIW dosing.  As described above (Section 4.2, Summary of Clinical Experience), the 16-week 
Phase 2 hemodialysis study evaluated hemodialysis subjects switching from ESA to vadadustat 
450 mg TIW for an 8-week fixed-dose period followed by 8 weeks of dose adjustment according 
to Hb response.  The primary efficacy analysis in CI-0011 using observed data showed stable 
mean Hb levels in this group.  Six of 31 (19%) subjects withdrew due to worsening anemia, and 
a sensitivity analysis imputing missing Hb values using LOCF demonstrated a decline in mean 
Hb levels.  To maximize the probability that subjects treated with vadadustat TIW will maintain 
Hb levels within the target range, this study will: examine subjects successfully treated with 


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Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
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daily dosing converting to TIW dosing; allow for earlier dose increase after 2 weeks of initial 
treatment; and permit dose increases up to 900 mg TIW. 
6.3 
Dose Justification 
In this study, vadadustat starting daily doses will be determined by pre-baseline ESA dose 
(Section 8.4.5, Vadadustat Dosing Regimen and Guidelines for Dose Adjustment).  In the Main 
study starting doses of vadadustat will be 300 mg and 450 mg daily in subjects converting from 
epoetin alfa doses ≤90 U/kg/week and 300 mg, 450 mg, and 600 mg daily in subjects converting 
from epoetin alfa doses >90 to <300 U/kg/week.  For the ESA hyporesponder parallel study, the 
starting doses will be 600 mg daily.  As described above (Section 4.2, Summary of Clinical 
Experience), the maximum vadadustat starting dose evaluated in completed Phase 2 NDD-CKD 
studies was 630 mg or 600 mg daily, in Study AKB-6548-CI-0005 (CI-0005) and Study 
AKB-6548-CI-0021 (CI-0021) respectively, and in completed Phase 2 DD-CKD studies was 
450 mg or 600 mg in Study AKB-6548-CI-0011 (CI-0011) and Study AKB-6548-CI-0022 
(CI-0022), respectively. 
Based on the dosing algorithm, vadadustat will be titrated to achieve and maintain Hb levels 
within the target range of 10.0 to 11.0 g/dL, inclusive.  The dose range for titration is 150 mg to 
900 mg daily or TIW.  Doses of 150 mg to 630 mg daily have been evaluated in studies 
evaluating subjects with NDD-CKD and DD-CKD.  The maximum vadadustat dose evaluated in 
healthy volunteers was 1200 mg in a single dose study (CI-0001 and CI-0010) and 900 mg daily 
in a 10-day multiple dose study (CI-0002), as described in Section 4.2, Summary of Clinical 
Experience. 
The rationale to evaluate higher maximum doses for titration is that to date, dose-ranging clinical 
studies have not identified a vadadustat dose at which a plateau in exposure or effect has been 
observed.  In Phase 1 studies in healthy volunteers, dose-proportional increases in AUC and Cmax 
and dose-related increases in serum EPO were observed up to the maximum doses studied, single 
doses of 1200 mg and multiple doses of 900 mg daily for 10 days (CI-0001, CI-0002).  In 
Phase 2 studies in anemic NDD-CKD and DD-CKD subjects, dose-dependent increases in Hb 
were observed up to the maximum dose studied of 600 mg or 630 mg daily (CI-0005, CI-0021, 
CI-0022).  It is anticipated that daily doses of vadadustat at 750 mg or 900 mg would yield an 
incremental erythropoietic effect greater than 600 mg for the treatment of renal anemia.  
This study design mitigates the risk of vadadustat doses of 750 mg or 900 mg.  Intensive Hb 
monitoring, a strict dose adjustment algorithm, and phlebotomy will be implemented to mitigate 
the potential risk of a rapid Hb rise, as follows:  
• Hb measurements are scheduled at least every 2 weeks to Week 20 
• The dose adjustment algorithm will target a narrow Hb range, 10.0 to 11.0 g/dL, inclusive 
• The protocol specifies that phlebotomy may be considered in the setting of high Hb levels 
(>14.0 g/dL) or a high Hb rate of rise, based on the Investigator’s judgment 
Importantly, the Phase 2 studies demonstrated that cessation of treatment resulted in prompt 
reduction in mean Hb to baseline values. 


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7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
General Criteria 
To be eligible for this study, a subject or their legally acceptable representative must provide 
valid informed consent and the subject must meet all eligibility criteria.  No study procedures 
(including Screening tests) may be performed until after the informed consent has been legally 
signed. 
7.2 
Inclusion Criteria 
Subjects must meet the following inclusion criteria: 
1. ≥18 years of age 
2. Receiving chronic, outpatient in-center hemodialysis (TIW) for ESRD for at least 12 weeks 
prior to Screening 
3. Maintained on IV epoetin alfa therapy for 8 weeks prior to and including Screening through 
SV2 
4. Eligibility in the Main study and ESA hyporesponder parallel study is based on the following 
mean weekly epoetin alfa doses: 
• Main study: Mean weekly epoetin alfa dose <300 U/kg/week for 8 weeks prior to 
SV2 
• ESA hyporesponder parallel study: Mean weekly epoetin alfa dose ≥300 U/kg/week 
for 8 weeks prior to SV2 
5. Two Hb values measured at least 4 days apart by the central laboratory during Screening as 
indicated below 
• Main study: 2 Hb values between 8.5 and 11.0 g/dL, inclusive 
• ESA hyporesponder parallel study: 2 Hb values between 8.0 and 10.0 g/dL, inclusive 
6. Serum ferritin ≥100 ng/mL and transferrin saturation (TSAT) ≥20% during Screening 
7. Folate and vitamin B12 measurements ≥ lower limit of normal during Screening 
8. Hemodialysis adequacy as indicated by single-pool Kt/Vurea ≥1.2 using the most recent 
historical measurement within 8 weeks prior to or during Screening 
9. Understands the procedures and requirements of the study and provides written informed 
consent and authorization for protected health information disclosure. 
7.3 
Exclusion Criteria 
Subjects must not meet any of the following exclusion criteria: 
1. Anemia due to a cause other than CKD (e.g., sickle cell disease, myelodysplastic syndromes, 
bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic anemia, thalassemia, or 
pure red cell aplasia) 
2. Active bleeding or recent blood loss within 8 weeks prior to randomization 
3. RBC transfusion within 8 weeks prior to randomization 
4. Anticipated to discontinue hemodialysis during the study 
5. Judged by the Investigator that the subject is likely to need rescue therapy (ESA 
administration or RBC transfusion) immediately after enrollment in the study 
6. History of chronic liver disease (e.g., chronic infectious hepatitis, chronic autoimmune liver 
disease, cirrhosis or fibrosis of the liver)  


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7. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine 
aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total bilirubin 
>1.5 x upper limit of normal (ULN) during Screening.  Subjects with a history of Gilbert’s 
syndrome are not excluded. 
8. Current uncontrolled hypertension as determined by the Investigator that would 
contraindicate the use of epoetin alfa 
9. 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 heart failure (HF) or New York Heart 
Association Class IV HF, or stroke within 12 weeks prior to or during Screening 
10. History of new or recurrent malignancy within 2 years prior to and during Screening or 
currently receiving treatment or suppressive therapy for cancer.  Subjects with treated basal 
cell carcinoma of skin, curatively resected squamous cell carcinoma of skin, or cervical 
carcinoma in situ are not excluded. 
11. History of deep vein thrombosis or pulmonary embolism within 12 weeks prior to or during 
Screening 
12. History of hemosiderosis or hemochromatosis 
13. History of prior organ transplantation (subjects with a history of failed kidney transplant or 
corneal transplants are not excluded) 
14. Scheduled organ transplant from a living donor and subjects on the kidney transplant wait-
list who are expected to receive a transplant within 6 months  
15. History of a prior hematopoietic stem cell or bone marrow transplant (stem cell therapy for 
knee arthritis is not excluded) 
16. Known hypersensitivity to vadadustat, epoetin alfa, or any of their excipients 
17. 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 
Screening (subjects may participate in another concurrent study only if that study is a non-
interventional, observational investigation) 
18. Previous participation in this study, or previous participation in a study with another hypoxia-
inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) other than vadadustat 
19. For female subjects: 
• Of non-childbearing potential 
o Inability to confirm surgical sterility (e.g., hysterectomy, bilateral tubal ligation, 
bilateral oophorectomy) at least 1 month prior to Screening, or  
o Not considered post-menopausal (no menses for >1 year with follicle stimulating 
hormone [FSH] >40 U/L at Screening)  
• Or, if of childbearing potential,  
o Lack of confirmation of the use of acceptable forms of contraception* for a 
minimum of one complete menstrual cycle prior to Screening 
o Positive serum pregnancy test at SV2 
o Unwilling to use two acceptable forms of contraception* (at least one of which 
must be a barrier method) starting Baseline/Day 1, throughout the Treatment 
Period and for 30 days after the final study drug administration 
(refer to Section 9.1.5, Contraception and Pregnancy Avoidance Measures) 


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20. Breastfeeding during Screening or throughout the Treatment Period and for 30 days after the 
final study drug administration. 
21. Donation of ova starting at Screening, throughout the Treatment Period, and for 30 days after 
the final study drug administration. 
22. Male subjects who have not had a vasectomy and do not agree to the following: use of an 
acceptable form of contraception* (refer to Section 9.1.5, Contraception and Pregnancy 
Avoidance Measures) during the study and for 30 days after the last dose of the study drug; 
to not donate semen during the study and for at least 30 days after the last dose of vadadustat. 
23. Any other reason, which in the opinion of the Investigator, would make the subject not 
suitable for participation in the study. 
7.4 
Retesting and Rescreening 
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 be retested 
once for each laboratory parameter within the 4-week Screening Period, per Investigator 
discretion. 
7.4.2 Rescreening 
Subjects who fail to qualify for the study based on laboratory tests may be considered for 
rescreening at the discretion of the Investigator if it is considered that the subject status has 
changed, and the subject may now qualify for the study.  Additionally, subjects who fail to 
qualify for the study based on inclusion criteria values for 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).  A 
new informed consent is required to be signed prior to every rescreening. 
7.5 
Study Completion, Study Termination, and Individual Site Termination 
7.5.1 Study Completion 
The study will be considered completed after all randomized subjects have completed their final 
study visit (Visit 15/Week 24), Safety Follow-Up or Early Termination). 
7.5.2 Study Termination 
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  Advanced notice is not required if the study is stopped due to safety concerns.  If a 
study site has been suspended or terminated, prompt notification will be given to Investigators, 
IRBs, and regulatory authorities in accordance with regulatory requirements.  Criteria and 
procedures for premature study termination or suspension are detailed in Section 14.1, Criteria 
for Premature Termination or Suspension of the Study. 


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7.5.3 Individual Study Site Termination 
Study participation may be suspended or terminated at an individual study site for various 
reasons.  Criteria and procedures for premature termination or suspension of an study site are 
detailed in Section 14.2, Criteria for Premature Termination or Suspension of Study Sites and 
Section 14.3, Procedures for Premature Termination or Suspension of the Study or Study Sites.  
If a study site has been suspended or terminated, prompt notification will be given to 
Investigators, IRBs, and regulatory authorities in accordance with regulatory requirements.  
7.6 
Subject Completion and Subject Discontinuation 
7.6.1 Subject Completion 
A subject will be considered as having completed the study after completion of their final study 
visit (Visit 15/Week 24, Safety Follow-Up or Early Termination). 
7.6.2 Temporary Interruption of Study Drug 
Subjects who temporarily interrupt their study drug (vadadustat or epoetin alfa) after receiving 
the first dose and prior to completion of the study, will continue with the study visits, safety 
assessments, and other activities as deemed applicable through Week 20, and will complete the 
4-week Safety Follow-Up Period and the Visit 15/Week 24 assessments (see Appendix A: 
Schedule of Activities. 
During the study, a subject may interrupt study drug (vadadustat or epoetin alfa) for any of the 
following reasons: 
• AE 
• Missed dialysis visit (epoetin alfa arm) 
• Investigator’s discretion 
• Rapid rise in Hb (defined as >1.0 g/dL in any 2-week period) 
• Hb above 11.0 g/dL 
• ESA use (vadadustat arm) 
Unless contraindicated, treatment will be resumed whenever possible and assessed at every visit 
following study drug interruption.  
7.6.3 Early Discontinuation from Study (Early Termination) 
Subjects who discontinue prematurely from the study will complete the End-of-Treatment (EOT) 
visit (Visit 14) assessments and will complete the Safety Follow-Up (Visit 15) 4 weeks after 
Visit 14. 
Subjects may discontinue for any of the following reasons: 
• AE 
• Investigator’s discretion 
• Subject withdrawal of consent  


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• Lack of efficacy, defined as inadequate response to vadadustat or epoetin alfa in the 
Investigator’s opinion 
• Lost to follow-up despite reasonable efforts by the Investigator to locate the subject.  
Every reasonable effort is to be made to contact any subject lost to follow-up during the 
course of the study to complete study-related assessments, record outstanding data, and 
retrieve study drug. 
• Death  
• Others reasons (pregnancy, kidney transplantation, specific reasons to be documented by 
the Investigator) 
 


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8 
STUDY DRUG AND TREATMENT OF SUBJECTS 
Subjects will receive either vadadustat or epoetin alfa according to the randomization 
assignments provided via the Interactive Web Response System (IWRS) (see Section 8.4.1, 
Randomization). 
Both vadadustat and epoetin alfa will be used as open-label supplies.  All study drug supplies 
will 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 drug for 
dispensing to the subject (Section 8.1, Epoetin Alfa and Section 8.2.2, Dispensing of Vadadustat) 
and for study drug supply accountability (Section 8.3, Vadadustat Accountability and 
Destruction). 
8.1 
Epoetin Alfa 
Epoetin alfa solution for IV injection in multi-dose vials (e.g., 20,000 Units/2 mL and 
20,000 Units/1 mL) or in single-dose vials (e.g., 2,000 Units/mL, 3,000 Units/mL, 
4,000 Units/mL, and 10,000 Units/mL) will be provided by the sites in commercially-approved 
primary packaging and stored per the approved label. 
8.2 
Vadadustat 
8.2.1 Supplies and Storage 
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 and local regulatory requirements. 
Dose levels utilized in this study will include: 150 mg (1 tablet), 300 mg (2 tablets), 450 mg 
(3 tablets), 600 mg (4 tablets), 750 mg (5 tablets), and 900 mg (6 tablets) per day or TIW. 
Vadadustat will be stored per the product label. 
8.2.2 Dispensing of Vadadustat 
At Baseline/Day 1, subjects who are randomized to vadadustat treatment will be administered the 
first dose of vadadustat at the study site.   
Thereafter, vadadustat will be taken once daily from Baseline/Day 1 to Week 12 and TIW from 
Weeks 12 to 20 if Week 12 criteria are met (Section 8.4.5.2, Transition of Vadadustat Once 
Daily Dosing to TIW Dosing Regimen).  If the Investigator determined criteria for Week 12 is 
not met, daily dosing will continue on an outpatient basis.  Subjects who are randomized to the 
vadadustat treatment arm will be provided with up to 2 bottles of vadadustat.  Each bottle of 
vadadustat will contain 100 tablets of vadadustat (150 mg/tablet).  Subjects may take vadadustat 
with or without food and will be instructed to swallow the tablet(s) whole.  Subjects will be 
instructed to take vadadustat at approximately the same time each day. 
Subjects will be instructed to bring unused vadadustat and empty bottles to each study visit for 
product accountability.  Subjects will be instructed to finish 1 bottle before opening a new bottle. 


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Empty bottles will be collected at the study visits.  Previously dispensed bottles (whether opened 
or unopened) with remaining tablets may be re-dispensed to the subject during the dosing phase 
of the study. 
Resupply of additional vadadustat at subsequent visits will be managed via the IWRS 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. 
8.3 
Vadadustat Accountability and Destruction 
Drug accountability will be an ongoing process throughout the study.  All vadadustat will 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 study site, and study drug dispensed to or returned from 
each subject.  Records will be maintained that accurately reflect the drug accountability of 
vadadustat at all times.  An electronic Diary (eDiary) will be utilized throughout the study to 
guide dosing for subjects in the vadadustat arm (see Section 9.1.2, eDiary). 
Proper drug accountability includes, but is not limited to: 
• Continuously monitoring expiration dates  
• Frequently verifying that actual inventory matches documented inventory. 
• Verifying that the log is completed for all vadadustat received and that all required fields 
are complete, accurate, and legible. 
If any dispensing errors or discrepancies are discovered, the Sponsor will 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 study site 
will complete all instructions outlined in the notification, including segregation of expired 
clinical study material for return to the Sponsor or its designee for destruction as specified by the 
Sponsor. 
Prior to study 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 other study materials will be returned to the 
Sponsor or destroyed at the study site, as specified by the Sponsor.  Appropriate records of the 
disposal will be documented and maintained.  No unused vadadustat may be disposed of until 
fully accounted for by the Sponsor’s monitor (or designee).  Empty containers may be disposed 
of according to local procedures. 
8.4 
Treatment of Subjects 
The aim of the study is to achieve and maintain Hb levels within the target range of 
10.0 to 11.0 g/dL, inclusive, while targeting the middle of the range and minimizing excursions 
outside the target range. 


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8.4.1 
Randomization 
Main Study: 
Subjects will be randomized to either a vadadustat treatment arm or epoetin alfa treatment arm.  
Randomization will be stratified by mean weekly epoetin alfa dose calculated over a period of 
8 weeks prior to SV2: 
• Low epoetin alfa dose group (≤90 U/kg/week) or 
• High epoetin alfa dose group (>90 to <300 U/kg/week) 
In the low epoetin alfa dose group, subjects will be randomized in a 3:3:2 ratio to receive either 
an initial vadadustat daily dose of 450 mg (3 tablets) or 300 mg (2 tablets), or epoetin alfa.  
In the high epoetin alfa dose group, subjects will be randomized in a 3:3:3:2 ratio to receive 
either an initial vadadustat daily dose of 600 mg (4 tablets), 450 mg (3 tablets) or 300 mg 
(2 tablets), or epoetin alfa.  
ESA Hyporesponder Parallel Study: 
Subjects will be randomized in a 1:1 ratio to receive either an initial vadadustat daily dose of 
600 mg (4 tablets) or epoetin alfa. 
Note: No epoetin alfa will be administered after SV2 after the subject has met all eligibility 
criteria and before Baseline/Day 1, for a minimum duration of 5 days in the Main study and 
2 days in the ESA hyporesponder parallel study. 
8.4.2 
Blinding 
This is an open-label study and will not involve any blinding procedures. 
8.4.3 
Measurement of Hb Levels for Dose Adjustment Consideration 
Hb values will be measured by a central laboratory.  Study drug treatment will aim to achieve 
and maintain Hb levels within the target range of 10.0 to 11.0 g/dL, inclusive, while targeting the 
middle of the range and minimizing excursions outside the target range.  Hb will be monitored 
throughout the study to determine the dose of study drug (vadadustat or epoetin alfa) that 
subjects will receive (see Section 8.4.6, Guidelines for Dose Adjustments).  Hb levels can be 
measured more frequently based on Investigator’s clinical judgment. 
In both the vadadustat and epoetin alfa arm, if dose adjustment is recommended based on Hb 
value and protocol-specified guidelines, dosing instructions can be provided to the subject over 
the telephone or at the next dialysis session at the study site (or dialysis center) or during an 
unscheduled site visit within 3 business days after receiving the Hb result from the central 
laboratory. 
8.4.4 
Epoetin Alfa Dosing Regimen 
Epoetin alfa arm in both the Main study and ESA hyporesponder parallel study: 
For subjects who are randomized to the epoetin alfa treatment arm, the initial dosing regimen in 
the study (starting from Baseline/Day 1) will be approximately the same weekly dose that they 
were receiving prior to randomization.  


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Epoetin alfa dose will be administered based on the subject’s central laboratory Hb value and the 
approved epoetin alfa US PI for adult patients with CKD on dialysis. 
From Baseline/Day 1 to Week 20, dose will be adjusted to achieve and maintain Hb levels within 
the target range of 10.0 and 11.0 g/dL, inclusive. 
8.4.5 
Vadadustat Dosing Regimen and Guidelines for Dose Adjustment 
8.4.5.1 Dosing Regimen for the Vadadustat Treatment Arm 
Subjects in the low epoetin alfa dose group randomized to vadadustat treatment will start at an 
initial dose of vadadustat 300 mg or 450 mg daily.  Subjects in the high epoetin alfa dose group 
randomized to vadadustat treatment will receive an initial dose of 300 mg, 450 mg, or 600 mg 
daily.  Subjects in the ESA hyporesponder parallel study randomized to vadadustat treatment will 
receive a starting dose of vadadustat 600 mg daily.  
After completing the 12-week once daily dosing regimen, subjects randomized to vadadustat 
who meet criteria for switching from daily to TIW dosing will initiate TIW dosing at a starting 
dose 1 tablet greater (+150 mg) than the final dose in the daily dosing period (see 
Section 8.4.5.2, Transition of Vadadustat Once Daily Dosing to TIW Dosing Regimen).  
Subjects who do not meet criteria for switching from daily to TIW dosing will remain on daily 
dosing.  From Baseline/Day 1 to Week 20, dose will be adjusted to achieve and maintain Hb 
levels within the target range of 10.0 to 11.0 g/dL, inclusive.  
8.4.5.2 Transition of Vadadustat Once Daily Dosing to TIW Dosing Regimen 
All subjects randomized to vadadustat who complete 12 weeks of once daily dosing regimen and 
who meet all the Week 12 criteria below will be transitioned to a TIW vadadustat dosing 
regimen.  
Week 12 Transition criteria: 
• Vadadustat daily dose of 600 mg or lower at Week 12 
• Hb within target range of 10.0 to 11.0 g/dL, inclusive, at Week 12 confirmed by central 
laboratory Hb value from Week 11 (11 weeks of treatment completed) 
• No receipt of rescue therapy (ESA or RBC transfusion) for worsening of anemia due to 
CKD from Baseline/Day 1 to Week 12.   
o ESA or RBC transfusion prior to Week 12 for reasons unrelated to worsening of 
anemia due to CKD (e.g., surgery, gastrointestinal bleed, or inadvertent 
administration) is not considered rescue therapy 
• No other reason, based on the Investigator’s clinical discretion, that would make the 
subject not suitable for TIW dosing. 
Selected subjects who meet Week 12 transition criteria will transition to the TIW vadadustat 
dosing regimen at the Week 12 visit.  Subjects on 150 mg, 300 mg, 450 mg, or 600 mg of 
vadadustat daily at the Week 12 visit will transition to an initial vadadustat TIW dose one  tablet 
greater (+150 mg), i.e., 300 mg, 450 mg, 600 mg, or 750 mg vadadustat TIW, respectively.  
Subjects will be instructed to take vadadustat on dialysis days. 


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After 2 weeks of treatment in the TIW vadadustat dosing regimen (at Week 14), subjects in any 
vadadustat TIW dosing arms who have a decline in Hb ≥0.5 g/dL will be eligible for a dose 
increase by 1 tablet, based on the Investigator’s clinical discretion. 
Subjects who are not eligible to switch from daily vadadustat to TIW dosing at Week 12 will 
remain on daily dosing for the remainder of the study.  
Subjects on TIW dosing may be converted back to vadadustat once daily dosing at the discretion 
of the Investigator in the setting of inadequate Hb response.  The starting daily dose after the 
switch from TIW to daily dosing will be based on the Investigator’s discretion after review of the 
subject’s clinical status and dosing history, in particular, the daily dose previously administered 
to the subject prior to the transition to TIW dosing (Week 12).  Subjects who switch from 
vadadustat TIW to daily dosing will continue once daily vadadustat until the end of the 
Treatment Period. 
Subjects in the vadadustat arm will be guided for dosing compliance using an eDiary (see 
Section 9.1.2, eDiary). 
8.4.6 Guidelines for Dose Adjustments 
Dose adjustments will be guided by Hb concentrations and the Guidelines for Dose Adjustment 
(see below).  Hb will be monitored via central laboratory throughout the study to determine if the 
dose of study drug (vadadustat or epoetin alfa) will be adjusted, interrupted, or maintained as 
follows: 
• Dose adjustments are based on the Investigator’s clinical discretion, incorporating the 
protocol guidance below as well as the subject’s current Hb level, trajectory, and 
variability; symptoms; cardiovascular risk; and other features of his/her clinical 
condition(s). 
• If a dose increase or decrease is required to achieve and maintain Hb levels within the 
target range of 10.0 to 11.0 g/dL, inclusive, dose is adjusted by 1 dose level (for 
vadadustat 1 tablet [150 mg], for epoetin alfa approximately 25%). 
• In general, do not increase the dose more frequently than once every 4 weeks.  A one-
time dose increase after 2 weeks is allowed on only two occasions.   
o A subject’s dose may be increased by 1 dose level if the subject has a decline in 
Hb ≥0.5 g/dL from Baseline/Day 1 in the first 2-week period (the initial period 
from Baseline/Day 1 to Week 2 following conversion from prior epoetin alfa 
therapy).   
o A subject’s dose may also be increased by 1 dose level in the first 2-week period 
after initiation of TIW dosing (from Week 12 to Week 14) for subjects that meet 
criteria for transitioning from daily to TIW dosing. 
• Reduce or interrupt the dose in the setting of a rapid rise in Hb (defined as >1.0 g/dL in 
any 2-week period) 
• Reduce or interrupt the dose in the setting of Hb >11.0 g/dL 
• Interrupt the dose in the setting of a Hb >12.0 g/dL until Hb value falls below 11.0 g/dL.  
After Hb falls below 11.0 g/dL, restart study drug and consider restarting at a lower dose. 


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Note: The minimum dose of vadadustat will be 150 mg daily or TIW (1 tablet daily/TIW) and 
the maximum dose will be 900 mg daily or TIW (6 tablets daily/TIW). 
8.4.7 Late or Missed Doses 
Subjects on vadadustat will be instructed to take the study drug at approximately the same time 
each day.  If a dose is forgotten, subjects will be instructed to take the dose as soon as they 
remember during the same day.   
• Daily dosing regimen: If a forgotten dose is not remembered on the same day, the subject 
will skip the dose and resume the normal dosing schedule the following day. 
• TIW dosing regimen: If a forgotten dose is not remembered on the same day, the subject will 
take the dose on the following day (a non-dialysis day).  If a forgotten dose is not 
remembered on the same day or the following day of a long interdialytic gap, the subject will 
take the dose on the subsequent day (the second non-dialysis day).  Thereafter, the subject 
should resume the normal dosing schedule. 
• Subjects will not double-up on missed doses. 
Epoetin alfa dose (including handling of late or missed dose) will be administered at the site and 
titrated based on the subject’s central laboratory Hb value and the approved epoetin alfa US PI 
for adult patients with CKD on dialysis. 
8.4.8 Iron Supplementation 
IV iron will be administered based on ferritin and TSAT levels measured by the central 
laboratory according to the standardized, low-intensity, iron supplementation protocol in Table 1. 
Table 1: 
Iron Supplementation Protocol 
 
Ferritin 
<200 ng/mL 
Ferritin 
200-500 ng/mL 
Ferritin 
>500 ng/mL 
TSAT 
<20% 
IV Iron 100 mg every 
treatment 
(max 400 mg/month) 
IV Iron 50 mg weekly 
Hold 
TSAT 
20-50% 
IV Iron 100 mg every week 
IV Iron 50 mg weekly 
Hold 
TSAT 
>50% 
Hold 
Hold 
Hold 
Intra-dialytic iron preparations (e.g., Triferic) and oral iron supplementation including iron-
containing phosphate binders are prohibited during the study. 
Important: As the study will be assessing PK/PD parameters, and as there are no empirical data 
on concurrent administration of vadadustat and phosphate binders, vadadustat will not be 
administered concurrently with a phosphate binder.  Subjects will be instructed to take phosphate 
binders at least 3 hours before or at least 2 hours after the dose of vadadustat based on the 
guidance in the phosphate binder package inserts. 


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8.4.9 Rescue Therapy 
To ensure the safety of subjects and to standardize the use of rescue in the study, rescue therapy 
guidelines are provided. 
8.4.9.1 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 will 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 medical necessity.  Study drug (vadadustat or 
epoetin alfa) may be continued during the transfusion period. 
Reasons for RBC transfusion will be captured in the appropriate CRF. 
8.4.9.2 ESA Use 
ESA administration will be allowed when medically necessary at the discretion of the 
Investigator.  In general, ESA will not be administered in subjects with Hb ≥8.5 g/dL, and ESA 
will be stopped when Hb ≥9.0 g/dL.  ESA therapy will be administered using an approved ESA 
and dosing as per the local institution’s guidelines and per the approved product label. 
While receiving ESA therapy, subjects randomized to vadadustat must temporarily interrupt 
vadadustat.  A minimum interval will be observed prior to restarting vadadustat after the last 
dose of ESA, and treatment will be resumed after the following intervals: 
• 2 days after last dose of epoetin alfa  
• 7 days after last dose of darbepoetin alfa  
• 14 days after last dose of methoxy polyethylene glycol-epoetin beta  
Following ESA administration, vadadustat will be resumed at the same dose as previously used 
or with one additional tablet (+150 mg) at the discretion of the Investigator. 
Reasons for ESA use will be captured in the appropriate CRF. 
8.4.10 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 clinical judgment.  The method of 
phlebotomy will be in accordance with the study site’s standard clinical practice. 
8.4.11 Treatment Compliance 
Throughout the study, subjects in the vadadustat arm will be guided regarding dosing compliance 
using an eDiary.  The focus of the vadadustat eDiary is to guide subjects to remind them of the 
dose, instruct them to hold their dose for the PK/PD sample dates and guide them if they have 
transitioned from daily dosing to TIW dosing.  Subjects will also be questioned at study visits on 
whether they have questions or have experienced any problems related to the dosing of 
vadadustat.  Subject compliance with eDiary data entry will be routinely monitored to identify 
potential issues that may impact or prevent data entry.  The Investigator will also maintain drug 
accountability logs itemizing all study drugs dispensed to and returned from each subject during 


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the study.  Treatment compliance will be determined from these logs, subject questioning, and 
the study drug Case Report Form (CRF)  
For epoetin alfa, the dose that is administered is required to be entered in the electronic data 
capture (EDC) system, and the EDC system will be used to determine dosing compliance. 
Subjects who miss doses will be counseled on the importance of compliance. 
8.4.12 Continuation of Treatment 
Subjects in the vadadustat dosing groups will not receive vadadustat beyond the Treatment 
Period of approximately 20 weeks.  However, enrollment may be increased by up to 
20 additional subjects on the Main study and up to 30 additional subjects on the ESA 
hyporesponder parallel study to ensure adequate data is captured for the primary, PK/PD, and 
safety endpoints.  Subjects in the vadadustat dosing groups who complete Visit 14 (Week 20), or 
discontinue early, will resume dosing with epoetin alfa (or another ESA) as per standard of care 
after all EOT procedures are completed. 
8.5 
Prior and Concomitant Therapy 
8.5.1 General 
Any medicinal product, prescribed or non-prescribed (including vitamins, minerals, natural 
and herbal remedies, topicals, inhaled, intranasal and dietary supplements) taken before 
entering the study is considered prior medication.  All medicinal products other than the study 
drug, including prescribed or non-prescribed treatments used during the Treatment Period will 
be considered concomitant medication. 
8.5.2 ESAs 
Co-administration of any ESA with vadadustat is 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 8.4.9.2, ESA Use) if deemed 
medically necessary at the discretion of the Investigator.  Guidelines for ESA administration as 
rescue therapy are provided in Section 8.4.9.2, ESA Use.  All efforts will be made to avoid 
inadvertent administration of ESAs resulting from adherence to ESA hemodialysis center 
protocols (e.g., DaVita ESA protocols for patients 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.  A minimum interval will be 
observed prior to restarting vadadustat after the last dose of ESA.  Vadadustat treatment may be 
resumed after the following intervals: 
• 2 days after last dose of epoetin alfa  
• 7 days after last dose of darbepoetin alfa  
• 14 days after last dose of methoxy polyethylene glycol-epoetin beta  
8.5.3 Dialysis Treatment and Renal Replacement Therapy 
Information on dialysis treatment including dialysis vascular access type, dialysis adequacy, and 
history of and changes in renal replacement therapies will be collected as described in Section 9, 
Study Procedures and Schedule of Activities and Appendix A: Schedule of Activities. 


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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 had previous 
participation in a study with another HIF-PHI other than vadadustat. 
Additionally, subjects should not take another investigational medication while participating in 
this study.  Subjects may participate in another concurrent study only if that study is a non-
interventional, observational investigation. 


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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: 
• Eligibility Screening Period (from Day -28 to Baseline/Day 1) 
The Screening Period starts at the time the informed consent is signed and will be a 
maximum of 28-days in duration.  Two Screening visits (SV1 and SV2) must be 
performed within the Screening Period and prior to dosing (Baseline/Day 1).   
o Screening Visit 1 (SV1) 
o Screening Visit 2 (SV2) 
• Study Treatment Period will consist of study visits from Baseline/Day 1 through 
Week 20 visit.  In weeks where there is no schedule study visit a subject will have a 
status check performed during one of their dialysis treatment appointments. 
o Baseline/Day 1, Visit 1 
o Visit 2, Week 1 +5 days 
o Visit 3, Week 2 ± 3 days 
o Visit 4, Week 4 ± 3 days 
o Visit 5, Week 6 ± 3 days 
o Visit 6, Week 8 ± 3 days 
o Visit 7, Week 10 ± 3 days 
o Visit 8, Week 11 ± 3 days 
o Visit 9, Week 12 ± 3 days (Transition to TIW dosing if all Week 12 criteria are 
met) 
o Visit 10, Week 13 +5 days 
o Visit 11, Week 14 ± 3 days 
o Visit 12, Week 16 ± 3 days 
o Visit 13, Week 18 ± 3 days 
o Visit 14, Week 20 ± 3 days (EOT visit) 
• Safety Follow-Up Period (from Week 20 to 24) 
o Visit 15, Week 24 visit ± 5 days 
The following sections describe the procedures to be completed during the study.  Subjects are to 
be assessed by the same Investigator or study site personnel whenever possible. 
9.1 
Administrative Procedures 
9.1.1 Informed Consent 
Informed consent will be obtained and legally signed prior to the subject entering into the study 
and before any protocol-directed procedures (including Screening activities) are performed (see 
Section 15.3, Subject Information and Consent).  After providing informed consent and receiving 
a unique subject identification number, subjects will undergo various Screening activities.  


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9.1.2 eDiary 
An eDiary will be utilized throughout the study for completion of SF-36 and PGI assessments.  
In addition, the eDiary will guide dosing for subjects in the vadadustat arm.  The focus of the 
vadadustat eDiary is to guide subjects to remind them of the dose, instruct them to hold their 
dose for the PK/PD sample dates and guide them if they have transitioned from daily dosing to 
TIW dosing.  At SV2, subjects will be instructed on data entry procedures for the eDiary.  
Subject compliance with eDiary data entry will be routinely monitored to identify potential 
issues that may impact or prevent data entry. 
9.1.3 Documentation of Screen Failures 
Investigators will account for all subjects who sign informed consent and will maintain a log of 
subjects screened and indicate who was randomized or excluded and reasons for screen failure.  
If the subject is found to be ineligible for randomization, the reason(s) for ineligibility and not 
proceeding to Screening or study enrollment, will be documented by the Investigator. 
Screening numbers assigned to subjects who fail Screening will not be re-used. 
9.1.4 Status Check 
In weeks where there is no scheduled study visit, a subject will have a status check performed 
during one of their dialysis treatment appointments in the week.  It will include a review of the 
subject’s vital signs and a review of current health status for identification of any issues that may 
require follow-up by the Investigator or delegated staff personnel.  Documentation of the review 
must be done in the subject’s source documentation.  No data will be captured on the status 
checks in the EDC system.  If an AE is identified at the status check or other actions result from 
the status check, these will be captured per the protocol. 
9.1.5 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 of vadadustat in the rat are ongoing, 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 drug. 
Adequate contraception for subjects is defined as follows: 
• For females of non-childbearing potential 
o Confirmation of surgical sterility (e.g., hysterectomy, bilateral tubal ligation, 
bilateral oophorectomy) at least 1 month prior to Screening, or  
o Post-menopausal (no menses for >1 year with FSH >40 U/L at Screening)  
• For females of childbearing potential  
o Subjects must confirm the use of acceptable forms of contraception*, for a 
minimum of one complete menstrual cycle prior to Screening.  


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o Must have a negative serum pregnancy test at SV2. 
o Starting Baseline/Day 1, subjects must use two acceptable forms of contraception* 
(at least one of which must be a barrier method) throughout the Treatment Period 
and for 30 days after the final study drug administration 
• For males subjects who have not had a vasectomy must agree to the following: use of an 
acceptable form of contraception* during the study and for 30 days after the last dose of 
the study drug; to not donate sperm during the study and for at least 30 days after the last 
dose of vadadustat. 
*  Acceptable forms of contraception include: 
• Established use of oral, injected or implanted hormonal methods of contraception. 
• Placement of an intrauterine device or intrauterine system. 
• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository. 
9.1.6 Laboratory Accreditation and Reference Ranges 
The Investigator and the Sponsor will maintain a copy of the laboratory accreditation and the 
reference ranges for the central laboratory used for clinical laboratory evaluations.  Additionally, 
other accreditation(s) will be collected as required. 
9.2 
Study Procedures and Evaluations 
9.2.1 Clinical Evaluations 
The following clinical evaluations will be conducted during the course of the study.  If the 
evaluations occur on a hemodialysis day, the evaluations will be completed before dialysis, if 
applicable. 
• 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 will be documented.  After SV2, an abbreviated, symptom-directed physical 
examination will be performed at the discretion of the Investigator, as clinically 
indicated. 
• Dialysis Adequacy: Dialysis adequacy, as available from local collection, will be 
recorded in the CRF at SV1 and Visits 9 and 14 (EOT). 
• SF-36 HRQOL and PGI-S: The SF-36, a patient-reported survey of patient health, and 
PGI-S will be completed at SV2, Visits 9, 14 (EOT) and 15.  Assessments will be 
completed by subjects using the eDiary. The PGI assessment will be completed after the 
other assessments. 
• PGI-C: The PGI-C will be completed at the Safety Follow-Up (Visit 15).  The assessment 
will be completed by subjects using the eDiary.  The PGI assessment will be completed 
after the other assessments.  
• Vital Sign Measurements: Vital signs will include temperature, heart rate (HR), BP, 
respiratory rate (RR), oxygen saturation (SO2), and dry weight.  Temperature, HR, BP, 


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RR, and SO2 will be assessed in the seated position after 5 minutes of rest.  For BP, a 
total of two measurements at intervals of at least 2 minutes should be performed.  
Temperature, HR, BP, RR, and SO2 will be collected at SV1, SV2, Baseline/Day 1, 
during all study visits, and Visit 14 (EOT).  Measurements will be taken prior to blood 
draws when possible.   
Dry weight will be collected for all subjects at SV2, Baseline/Day 1, Visit 9 and 14 
(EOT).  For subjects on epoetin alfa, subjects will be weighed for dosing as per the local 
standard of care. 
• 12-Lead Electrocardiogram (ECG): A standard 12-lead ECG will be performed at 
Baseline/Day 1, which may be obtained up to 3 days prior to Baseline/Day 1.  The ECG 
will be obtained after the subject has been resting comfortably in a supine position for 
approximately 5 minutes and will be taken prior to vital sign assessments and blood 
draws when possible.  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. 
• AE Assessments: Beginning with the first dose of study drug (vadadustat or epoetin alfa) 
at Baseline/Day 1 and through study end (Follow-Up Visit), the Investigator and study 
personnel will review each subject’s laboratory and clinical evaluation findings and query 
the subject directly regarding AEs (see Section 10, Adverse Events).  Subjects must be 
followed for AEs until the final required protocol visit (study end date) or until all drug-
related toxicities and SAEs have resolved (or are considered chronic/stable), whichever is 
later. 
• Prior and Concomitant Medication Recording: All prior and concomitant medications 
(except those routinely administered as part of the hemodialysis procedures, such as 
heparin or saline flushes used for routine catheter maintenance, unless relevant for an AE 
or SAE) taken within 30 days prior to Baseline/Day 1 and through the final study visit 
will be recorded on the appropriate CRF.   
Iron treatment regimen 30 days prior to Baseline/Day 1 and through the final study visit 
will be recorded on the appropriate CRF.  In addition, to ensure adequate collection of 
prior ESA dosing history, a minimum of 8 weeks of ESA therapy prior to start of study 
drug will be recorded on the appropriate CRF page. 
At each study visit, subjects will be asked whether they have started, changed or 
discontinued any medication since their previous study visit.  This includes single use or 
as needed medication use.  All medications and changes in dosage and frequency will be 
recorded on the appropriate CRF Page.  Documentation for all medicinal products will 
include the medication name, indication, dose, dosing frequency and dates of 
administration.   
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.  If blood is collected on a dialysis day, blood draws 


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will be done prior to dialysis, if applicable.  The Investigator is responsible for reviewing 
laboratory results for clinical significance. 
For eligibility purposes, one retest for each parameter may be performed during the Screening 
window.  Refer to Section 7.4.1, Retesting and Section 7.4.2, Rescreening for further details 
regarding repeating laboratory measurements during the Screening Period. 
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 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 drug.  A 
FSH test will be performed at SV2 for post-menopausal females. 
• Complete Blood Count (CBC): A CBC with differential will be performed at 
Baseline/Day 1 and at Visit 14 (EOT).  At all other noted visits in Appendix A: Schedule 
of Activities, including SV1 and SV2, a CBC without differential will be performed.  The 
CBC without differential will include: Hb, hematocrit, RBCs, mean corpuscular Hb, 
mean corpuscular Hb concentration, red cell width distribution, white blood cell count 
and platelets.  The CBC with differential will include the same parameters as CBC 
without differential with the addition of white blood cell count with differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils). 
Hb will be monitored throughout the study via central laboratory to determine the dose of 
study drug (vadadustat or epoetin alfa) that subjects will receive.  Refer to Section 8.4.3, 
Measurement of Hb Levels for Dose Adjustment Consideration.  Hb levels can be 
measured more frequently based on Investigator’s clinical judgment. 
• Reticulocyte Count: An automated reticulocyte count (both absolute and percent) will be 
performed at Baseline/Day 1 and at Visits 2, 4, 6, 8, 9, 10, 12, and 14 (EOT). 
• Folate and Vitamin B12: A blood sample will be drawn at SV1 to assess the folate and 
Vitamin B12 levels. 
• CRP: A blood sample for CRP will be collected at the Baseline/Day 1, 
Visit 9 and 14 (EOT).  
• Serum Chemistry: Blood samples to assess serum chemistry will be collected at SV1, 
Baseline/Day 1, Visit 9 and 14 (EOT).  The serum chemistry will include the following 
assays: sodium, potassium, bicarbonate, chloride, calcium, magnesium, phosphorus, 
glucose, creatinine, blood urea nitrogen, creatine phosphokinase, uric acid, albumin, and 
total protein. 
• Liver Function Tests (LFTs): Blood samples to assess liver function will be collected at 
SV1, Baseline/Day 1, Visit 4, 6, 9, 12 and 14 (EOT).  LFTs will include: total bilirubin, 
alkaline phosphatase (ALP), ALT/SGPT, AST/SGOT, and lactate dehydrogenase. 
• Iron Indices: Blood samples to assess the iron indices will be collected at SV1, 
Baseline/Day 1, Visit 4, 6, 9, 12 and 14 (EOT).  Assessments will include the following 
indices: ferritin, iron, transferrin, TIBC, and TSAT. 


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• Lipid Profile: Blood samples will be collected at the Baseline/Day 1 and Visit 14 (EOT) 
to assess the cholesterol levels and will be tested for the following types of lipids: total 
cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides. 
• Biomarkers (including, but not limited to, vascular endothelial growth factor [VEGF], 
and hepcidin): Samples for VEGF and hepcidin biomarker analyses will be drawn at the 
Baseline/Day 1, Visit 9 and 14 (EOT).   
9.2.2.1 PK/PD Sampling for Subjects Randomized to Vadadustat 
Refer to Appendix B for a schematic overview of the PK/PD samples for the vadadustat arm. 
Blood for measurement of vadadustat, metabolites and EPO level in the vadadustat arm, in both 
the Main study and ESA hyporesponder parallel study, will be collected as outlined below.  
Preferably, PK/PD samples are to be taken on the day of hemodialysis after the first short 
interdialytic interval (e.g., at the second session of the week).   
At Baseline/Day 1, PK/PD samples will be collected prior to dialysis and administration of 
vadadustat. 
At Week 1 (after at least a full week of vadadustat treatment), vadadustat will be administered 
between 15 minutes to one hour prior to the start of dialysis.  Blood samples will be collected as 
follows: 
• 15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes and 5 hours ± 
30 minutes post-dose 
• From subjects enrolled at a subset of study sites only, additional samples will be collected 
at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
On the following non-dialysis day, blood samples will be collected as follows: 
• 15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 5 hours ± 
30 minutes post-dose 
• From subjects enrolled at a subset of study sites only, additional samples will be collected 
at 7 hours ± 30 minutes post-dose 
At Week 11, vadadustat will be administered between 15 minutes to one hour prior to the start of 
dialysis.  Blood samples will be collected as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 5 hours ± 
30 minutes post-dose 
• 
From subjects enrolled at a subset of study sites only, additional samples will be collected 
at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
At Week 13 (after at least one week on TIW vadadustat dosing regimen), vadadustat will be 
administered between 15 minutes to one hour prior to the start of dialysis.  Blood samples will be 
collected as follows: 
• 15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 5 hours ± 
30 minutes post-dose 
• From subjects enrolled at a subset of study sites only, additional samples will be collected 
at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 


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Note: Week 13 PK/PD sampling will only be done in subjects who transition to vadadustat TIW 
dosing regimen.  Subjects who do not qualify for vadadustat TIW dosing and remain on daily 
dosing regimen will not have Week 13 PK/PD sampling. 
9.2.2.2 PK Sampling for Subjects Randomized to Epoetin Alfa 
Refer to Appendix B for a schematic overview of the PK samples for the epoetin alfa arm. 
Blood for measurement of EPO level in the epoetin alfa arm, in both the Main study and ESA 
hyporesponder parallel study, will be collected as outlined below.  Preferably, PK samples are to 
be taken on the day of hemodialysis after the first short interdialytic interval (e.g., at the second 
session of the week).   
At Baseline/Day 1, a sample will be collected prior to dialysis and administration of epoetin alfa. 
At Week 1 (after at least a full week of study epoetin alfa treatment), epoetin alfa will be 
administered within 1 hour after start of dialysis.  Blood samples will be collected as follows: 
• 15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 5 hours ± 
30 minutes post-dose 
• From subjects enrolled at a subset of study sites only, additional samples will be collected 
at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
On the following dialysis day, one blood sample will be collected 15 minutes prior to 
administration of epoetin alfa. 
9.2.2.3 PK/PD Sampling   
For all PK and PD sampling the time of the previous dose of study drug (vadadustat or epoetin 
alfa) is to be collected for the pre-dose sample and the timing of administration of study drug 
(epoetin alfa and vadadustat) and the start and stop time of the dialysis session will be recorded. 
9.3 
Schedule of Activities 
The Schedule of Activities (see Appendix A: Schedule of Activities) shows the timing of 
planned study procedures.  Every effort will be made to adhere to this procedure schedule and all 
assessments will be completed at each study visit.  Where possible, study visits will be 
performed and scheduled as part of a patients regularly scheduled dialysis session. 
9.3.1 Screening Visits 
Subjects will need to sign a full consent form prior to SV1 procedures.  The consent form 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 28-days in duration.  Two Screening visits (SV1 and 
SV2) must be performed within the Screening Period and prior to dosing (Baseline/Day 1).   
The Investigator will arrange for sufficient time (a minimum 4 days) between SV1 and SV2 and 
between SV2 or last retest (if applicable) and Baseline/Day 1 to allow for all laboratory results to 
be available that are required to assess eligibility for the next study visit.   
In addition, subjects will be required to stop epoetin alfa treatment for a minimum duration of 
5 days before Baseline/Day 1 in the Main study and for a minimum of 2 days before 
Baseline/Day 1 in the ESA hyporesponder parallel study. 


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After obtaining informed consent, subjects will undergo a number of Screening activities.  
9.3.1.1 SV1 
At SV1, the following activities/procedures will be performed: 
• Informed consent  
• Review of eligibility criteria 
• Review of acceptable methods of contraception 
• Vital signs including temperature, HR, BP, RR and SO2 (assessed in seated position after 
5 minutes of rest and prior to blood draws) 
• Dialysis adequacy 
• Laboratory procedures: 
o CBC (without differential) 
o Folate and vitamin B12 levels 
o Serum Chemistry  
o LFTs  
o Iron indices 
Refer to Section 7.4.1, Retesting and Section 7.4.2, Rescreening for further details 
regarding repeating laboratory measurements during the Screening Period. 
• Visit registration in IWRS 
• Review of prior medication 
• Epoetin alfa dosing will continue 
9.3.1.2 SV2 
At SV2, the following activities/procedures will be performed: 
• Review of eligibility criteria 
• Review of acceptable methods of contraception 
• SF-36 and PGI-S assessments 
• Physical examination (including height) 
• Demographics and medical history 
• Vital signs including temperature, HR, BP, RR and SO2 (assessed in seated position after 
5 minutes of rest and prior to blood draws), and dry weight 
• Laboratory procedures: 
o Serum pregnancy test for females of childbearing potential (eligible subjects will be 
advised to use an adequate contraceptive method see Section 9.2.2, Laboratory 
Evaluations for additional information).  A FSH test will be performed at SV2 for 
post-menopausal females. 
o CBC (without differential) 
Subjects must have 2 Hb values measured by the central laboratory during Screening as 
indicated below: 
o Main study: 2 Hb values between 8.5 and 11.0 g/dL, inclusive 
o ESA hyporesponder parallel study: 2 Hb values between 8.0 and 10.0 g/dL, inclusive 
If the subject’s Hb does not qualify after SV1, SV2, or retest Hb, the subject will be 
considered a screen failure 


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• Visit registration in IWRS 
• Introduction to and instruction on the use of the eDiary 
• Prior and current medication use 
• Epoetin alfa dosing will stop for a minimum of 5 days in the Main study or 2 days in the 
ESA hyporesponder parallel study until Baseline/Day 1 
9.3.2 Baseline/Day 1 (Visit 1) 
Epoetin alfa dosing will have been stopped for a minimum of 5 days in the Main study or 2 days 
in the ESA hyporesponder parallel study until Baseline/Day 1. 
On Baseline/Day 1, blood sample collection and other Baseline/Day 1 procedures will be 
completed prior to dosing with study drug (vadadustat or epoetin alfa).  On Baseline/Day 1, 
study drug will be administered at the study site, and will be administered after the PK sample is 
collected and prior to the dialysis session.  
At Baseline/Day 1, the following activities/procedures will be performed: 
• Review of study eligibility criteria 
• Review acceptable methods of contraception 
• Abbreviated, symptom-directed physical examination, at the discretion of the 
Investigator, as clinically indicated 
• 12-lead ECG.  ECGs will be completed prior to blood draws when possible and will be 
obtained after the subject has been resting supine comfortably for approximately 
5 minutes; ECG may be completed and reviewed by the Investigator on Baseline/Day 1 
or if needed for scheduling reasons (e.g., dialysis treatment is scheduled for early 
morning of Baseline/Day 1), the ECG can be completed and reviewed up to 1-3 days 
prior to Baseline/Day 1. 
• Randomization 
• Vital signs including temperature, HR, BP, RR and SO2 (assessed in seated position after 
5 minutes of rest and prior to blood draws), and dry weight 
• Laboratory Procedures: 
o CBC (including differential) 
o Reticulocyte count 
o CRP 
o Serum chemistry  
o LFTs 
o Iron indices 
o Lipid profile 
o Biomarkers (VEGF, and Hepcidin) 
o PK prior to vadadustat or epoetin alfa dosing (see Section 9.2.2.1, PK/PD Sampling 
for Subjects Randomized to Vadadustat and Section 9.2.2.2, PK Sampling for 
Subjects Randomized to Epoetin Alfa) and prior to the dialysis session 
• Review of medical history for new conditions since SV2 
• Review of medication use since SV2 
• Study drug assessments and procedures: 
o Subject will take/receive their first dose of study drug at the study site during 
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o For subjects in the vadadustat treatment arm only: 
▪ Initiate vadadustat dosing 
▪ Vadadustat drug dispensation 
▪ Review vadadustat dosing instructions 
o Epoetin alfa dosing will continue for the subjects in the epoetin alfa arm 
o Iron supplementation as needed to maintain ferritin ≥100 ng/mL or TSAT ≥20% (per 
local product label; see Section 8.4.8, Iron Supplementation 
o Visit registration in IWRS 
• Safety assessments: 
o AE review as needed (after receiving the first dose of study drug) 
o Review use of rescue therapy 
9.3.3 Visit 2 to Visit 13 (Weeks 1 to 20) 
At the Baseline/Day 1, Visit 7 and Visit 9, subjects in the vadadustat treatment arm will be 
reminded and instructed to hold their vadadustat dose on the day of Visit 2, Visit 8, and if 
applicable Visit 10, respectively, as blood sample for PK analysis will be collected on the day of 
Visit 2, Visit 8, and Visit 10 prior to vadadustat administration at the study site. 
The following activities/procedures will be performed at Visit 2 to Visit 13, unless noted 
otherwise: 
• Abbreviated, symptom-directed physical examination, at the discretion of the 
Investigator, as clinically indicated 
• Vital signs including temperature, HR, BP, RR and SO2 (assessed in seated position after 
5 minutes of rest and prior to blood draws).  Dry weight will be collected at Visit 9 only.  
o A status check (BP, vital signs, and review of current health status) will be 
performed during weeks with no scheduled study visit. 
• Dialysis adequacy, as available from local information (Visit 9 only) 
• SF-36 and PGI-S assessments (Visit 9 only) 
• Safety assessments: 
o AE review 
o RBC transfusions and ESA rescue  
o Therapeutic phlebotomy 
• Laboratory procedures (if blood samples are collected on a day of dialysis, blood draws 
will be done prior to dialysis, if applicable): 
o CBC  
o Reticulocyte count (Visit 2, 4, 6, 8, 9, 10 and 12 only) 
o CRP (Visit 9 only) 
o Serum chemistry (Visit 9 only) 
o LFTs (Visit 4, 6, 9 and 12 only) 
o Iron indices (Visit 4, 6, 9 and 12 only) 
o Biomarkers (VEGF and Hepcidin, Visit 9 only) 
o Vadadustat PK/PD sampling (Visit 2, 8 and 10 only) for details, see 
Section 9.2.2.1, PK/PD Sampling for Subjects Randomized to Vadadustat and 
Section 9.2.2.3, PK/PD Sampling) 


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o Epoetin alfa PK sampling (Visit 2 only) for details, see Section 9.2.2.2, PK 
Sampling for Subjects Randomized to Epoetin Alfa and Section 9.2.2.3, PK/PD 
Sampling) 
• Medication assessments and procedures: 
o Review of concomitant medications 
o Subjects in epoetin alfa treatment arm will continue to receive epoetin alfa  
o For subjects in the vadadustat treatment arm only: 
▪ Visit registration in IWRS (for bottle dispensing only) 
▪ Vadadustat drug dispensation (scheduled Visits 4, 6, 9 and 12) 
▪ Review vadadustat dosing instructions 
▪ Review of vadadustat dosing compliance 
▪ Vadadustat reconciliation 
o Review of iron supplementation as needed to maintain ferritin ≥100 ng/mL or TSAT 
≥20% (per local product label; see Section 8.4.8, Iron Supplementation) 
9.3.4 EOT Visit 14 (Week 20) 
EOT evaluations will be performed when the Treatment Period (Baseline/Day 1 to Visit 13) is 
completed.  Subjects who prematurely discontinue study drug for any reason will also attend this 
visit.  
At Visit 14 (EOT), the following activities/procedures will be performed: 
• Vital signs including, HR, BP, RR and SO2 (assessed in seated position after 5 minutes of 
rest and prior to blood draws), as well as temperature and dry weight 
• Dialysis adequacy, as available from local information 
• SF-36 and PGI-S assessments 
• Safety assessments: 
o AE review 
o RBC transfusions and ESA rescue  
o Therapeutic phlebotomy 
• Laboratory Procedures: 
o CBC (with differential) 
o Reticulocyte count 
o CRP 
o Serum chemistry 
o LFTs 
o Iron indices 
o Lipid panel 
o Biomarkers (VEGF and Hepcidin) 
• Medication assessments and procedures: 
o Review of concomitant medications 
o Subjects in epoetin alfa treatment arm will continue to receive epoetin alfa.  
o For subjects in the vadadustat treatment arm only: 
▪ Review of vadadustat dosing compliance 
▪ Vadadustat reconciliation 
▪ Resume dosing with epoetin alfa (or another ESA): After the end of 
vadadustat treatment at Visit 14 (or following early discontinuation of 


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vadadustat), subjects may resume dosing with epoetin alfa (or another ESA), 
based on standard of care. 
o Visit registration in IWRS 
o Review of iron supplementation as needed to maintain ferritin ≥100 ng/mL or TSAT 
≥20% (per local product label; see Section 8.4.8, Iron Supplementation) 
9.3.5 Safety Follow-Up Visit 15 (Week 24) 
At the Visit 15, the following activities/procedures will be performed:  
• SF-36 HRQOL, PGI-S, and PGI-C assessments 
• AE review 
• Review use of rescue therapy (RBC transfusions and ESA rescue therapy) 
• Review use of therapeutic phlebotomy 
• Concomitant medication review 
9.3.6 Unscheduled Visits 
Unscheduled assessments may be conducted at any time as medically warranted.  The following 
activities/procedures will be performed at minimum: 
• Safety assessments: 
o AE review 
o RBC transfusions and ESA rescue  
o Therapeutic phlebotomy 
• Medication assessments and procedures: 
o Review of concomitant medications 
• Any other procedures that are medically warranted at the discretion of the Investigator. 


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10 ADVERSE EVENTS 
10.1 Definitions 
10.1.1 AEs 
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. 
AEs therefore include the following:  
• All AEs, whether suspected to be causally related to study drug or otherwise. 
• All AEs secondary to any medication overdose, medication error, 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 (e.g., a fall secondary to dizziness), the medical condition (dizziness) and the 
accident (fall) will 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 (e.g., elevated liver enzymes in a subject with jaundice) will 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 will 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 will be the reported AE term, instead of fever and dyspnea, 
when the diagnosis has been established.  Signs and symptoms will 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, 
will not be reported as AEs.  However, the medical condition for which the procedure was 
performed will be reported if it meets the definition of an AE.  For example, an acute 


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appendicitis that begins during the AE reporting period will 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 will not be reported as AEs. 
Pre-existing Conditions – In this study, a pre-existing condition (i.e., a disorder present before 
the AE reporting period started and noted on the pretreatment medical history/physical 
examination form) will 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 will 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 will also be reported as AEs.  Any abnormal laboratory value which requires 
treatment or further diagnostic testing and/or results in discontinuation from study will 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 will be reported to the Sponsor’s Medical Monitor or Contract Research Organization 
(CRO) designee within 24 hours of awareness as an SAE with ‘other medically important event’ 
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 (e.g., 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 study drug; 
• 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; 
• Study drug will not be resumed until monitoring indicates abnormalities have resolved or are 
stable. 
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 will not be 
considered an AE unless the worsening of anemia is associated with a cause other than the 
subject’s CKD. 
Transplantation – During this study, it is anticipated that subjects may receive a kidney 
transplant.  These events will not be recorded as AEs.  Subjects who discontinue study drug for 


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receipt of a kidney transplant will complete the EOT visit (Visit 14) assessments and will 
complete the Safety Follow-Up (Visit 15) 4 weeks after Visit 14 as described in Section 7.6.3, 
Early Discontinuation from Study. 
10.1.2 SAEs 
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 situation will also 
be classified as serious for purposes of this study:  
• Malignancies – Newly diagnosed malignancies or a recurrence of a malignancy will 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.   
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 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 (e.g., 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. 


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10.2 Eliciting AE 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 study drug. 
10.3 Reporting 
Each AE is to be classified by the Investigator as SERIOUS or NONSERIOUS. 
All AEs that occur in study subjects during the AE reporting period specified in this protocol will 
be reported, whether or not the event is considered related to study drug (vadadustat or epoetin 
alfa). 
10.3.1 Reporting Period 
The AE reporting period for this study begins upon receiving the first dose of study drug 
(vadadustat or epoetin alfa) and ends at the final protocol-required visit. 
In addition, any SAE that occurs subsequent to the AE reporting period that the Investigator 
assesses as related to the study drug will also be reported as an SAE. 
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, will be reported to the Sponsor’s Medical Monitor or 
CRO designee within 24 hours after the Investigator becomes aware of the SAE.  Compliance 
with this time requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
The initial SAE report should be completed as fully as possible but will contain, at a minimum 
items number 1 to 6: 
1. Subject number/ID, sex, and age/date of birth 
2. The date of report 
3. Name of the reporter 
4. Name of the suspected medicinal product 
5. A description of the event, including event term(s), seriousness criteria, and a clinical 
summary of the event 
6. Causality assessment 
If the causality assessment is not provided in the initial report an updated report with the 
causality must be provided within 24 hours, once assessed. 
Information about all SAEs (either initial or follow-up information) will be collected and 
recorded in English on the electronic SAE Report Form within the EDC system.  The 
Investigator will assess the relationship to each specific component of the study treatment.  If the 
event meets serious criteria and it is not possible to access the EDC system, a paper SAE Report 
Form will be sent to the CRO via email or fax, or the Investigator will call the CRO SAE hotline 


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within 24 hours of being made aware of the SAE (reference the site manual for contact 
information).  When the EDC system becomes available again, the SAE information will be 
entered within 24 hours of the system becoming available. 
The Investigator will report follow-up information relating to an SAE to the Sponsor’s Medical 
Monitor or CRO designee within 24 hours of awareness 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 will be entered within 
24 hours.  The subject will 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 IRB 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 study site. 
10.3.4 Relationship to Study Drug 
The causal relationship of the AE to study drug (vadadustat or epoetin alfa) will be assessed by 
both the Investigator and the Sponsor.   
The assessment of causal relationship to study drug will be evidence-based, and not based on the 
premise that all AEs are possibly causally related to study drug until proven otherwise.   
Examples of evidence that would suggest a causal relationship between the study drug and the 
AE include the occurrence of an AE that is uncommon and known to be strongly associated with 
drug exposure (e.g., 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 drug are generally uninformative and do 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 treatment, 


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other treatment (concomitant, or previous), withdrawal of study treatment, administration error, 
protocol-related procedure, others (specify). 
10.3.5 Severity 
The Investigator will assess each AE as either MILD, MODERATE, or SEVERE using the 
following guidelines to describe the maximum severity of the AE: 
MILD: Does not interfere with subject's usual function 
MODERATE: Interferes to some extent with subject's usual function 
SEVERE: Interferes significantly with subject's usual function 
Note that a severe AE is not necessarily a serious AE.  For example, a headache may be severe 
in intensity, but would not be classified as serious unless it met 1 of the criteria for serious events 
listed above. 
10.3.6 Follow-up of Unresolved Events 
All AEs will be followed until they are resolved or the Investigator assesses them as chronic or 
stable or the subject’s participation in the trial ends (i.e., until a final report is completed for that 
subject). 
In addition, all SAEs and those nonserious events assessed by the Investigator as related to the 
study drug will continue to be followed even after the subject's participation in the trial is over.  
Such events will be followed until they resolve or until the Investigator assesses them as 
“chronic” or “stable”.  Resolution of such events is to be documented on the appropriate CRF. 
10.4 Exposure In-Utero 
A pregnancy in a female subject will be confirmed by a positive serum β human chorionic 
gonadotropin test. 
The study drug will 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 drug 
(vadadustat or epoetin alfa) or within 30 days of discontinuing the study drug, the pregnancy will 
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 will also be reported. 
The Pregnancy Reporting Form/Exposure in Utero Form will be completed with all known 
information regarding the pregnancy at the time of reporting.  Study 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 an SAE 
(i.e., spontaneous abortion, stillbirth, neonatal death within 1 month of birth, or congenital 


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anomaly [including that in an aborted fetus]), the Investigator will also follow the procedures for 
reporting an 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 will be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 1 month that the Investigator 
assesses as related or unrelated to the in utero exposure to the study drug will also be 
reported. 
• In the case of a live birth, the “normality” of the newborn can be assessed at time of birth. 
• The “normality” of an aborted fetus can be assessed by gross visual inspection unless 
there are pre-abortion laboratory findings suggestive of a congenital anomaly. 
10.5 Special Situations 
Certain safety events, called ‘Special Situations’, that occur in association with study drug may 
require reporting.  These Special Situations include, but are not limited to, the following: 
• Overdose of the medicinal product 
o Epoetin alfa overdose – The PI or SmPC will be referenced for information on 
epoetin alfa overdosing.   
o Vadadustat overdose – There is no known antidote for vadadustat.  In cases of 
suspected overdose, subjects will 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 will be 
discontinued and standard treatment for polycythemic hyperviscosity syndrome 
will be initiated (i.e., phlebotomy). 
Dose-limiting toxicity in exploratory toxicology studies was due to 
hemoglobinuric nephropathy in the rat and emesis associated with body weight 
loss in the dog.  In the rat, doses ≥500 mg/kg were not tolerated in two 7-day 
exploratory toxicology studies.  The probable cause of the findings is considered 
to be intravascular hemolysis leading to hemoglobinuric nephropathy. 
The clinical data from human volunteer subjects and renal study subjects 
demonstrate that currently there is no evidence of any drug-related hemolysis 
associated with vadadustat at the doses studied.  The highest dose in the majority 
of subjects exposed to vadadustat was up to 600 mg daily with minimal exposures 
at doses higher than this (up to 1200 mg single dose and up to 900 mg daily for 
10 days).  No conclusion concerning the safety profile of vadadustat at doses 
higher than 600 mg daily can be drawn. 


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• 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 exposure to the 
Sponsor’s medicinal product [e.g., name confusion]) 
• Drug-drug interaction. 
Special situations will be reported on the Special Situations CRF whether they result in an 
AE/SAE or not.  Special situations with associated AE/SAE will also be reported on the 
corresponding AE/SAE forms, following applicable AE or SAE process. 
10.6 Safety Monitoring 
This is an open label study allowing the study team full access to safety data which will be 
reviewed on a regular basis, throughout the course of the study.  Safety monitoring will be 
performed as described in the Medical Monitor Plan. 
 


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11 DATA ANALYSIS 
Data collected throughout the study will be summarized using descriptive statistics and listed in 
the by-subject listings.  Continuous variables will be summarized using number of subjects with 
mean, standard deviation (SD), 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. 
11.1 Sample Size Estimation 
Approximately 95 subjects are planned for enrollment in the Main study with 40 and 55 subjects 
randomized to the low epoetin alfa dose group and the high epoetin alfa dose group, respectively.  
Approximately 30 subjects are planned for enrollment in the ESA hyporesponder parallel study.  
Sample size reflects the exploratory nature of this study. 
Enrollment may be increased by up to 20 additional subjects in the Main study and by up to 
30 additional subjects in the ESA hyporesponder parallel study to ensure adequate data is 
captured for the primary, PK/PD, and safety endpoints. 
11.2 Study Analysis Populations 
The following analysis populations will be used in this study: 
• Randomized population: defined as all randomized subjects.  Analyses of this population 
will be based on the randomized treatment. 
• Full Analysis Population (FAS): all subjects in the randomized population who received 
at least one dose of study drug and had at least one Hb assessment during the primary 
efficacy evaluation period.  Analyses of this population will be based on the randomized 
treatment. 
• Safety Population: all subjects in the randomized population who received at least one 
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 epoetin alfa will be 
classified by the more frequently received drug. 
• Per protocol (PP) population: all randomized subjects who received study drug during the 
primary evaluation period, had at least one Hb assessment during the primary efficacy 
evaluation period, received no rescue therapy (with ESA or transfusion) prior to the 
evaluation period, and had no major protocol deviation affecting the primary endpoint 
analyses.  Major protocol deviations leading to exclusion from the PP population will be 
specified prior to database lock and recorded in a separate document.  Analyses of this 
population will be based on actual treatment received. 
Efficacy analyses will utilize the Randomized, Full Analysis, and PP Populations while safety 
analyses will utilize the Safety Population. 


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11.3 Analysis of Demographic and Pretreatment Variables 
Descriptive statistics will be generated for demographic and pretreatment variables for 
Randomized Population and other analysis populations which will be defined in detail in the 
Statistical Analysis Plan. 
Medical history terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by System Organ Class (SOC) and Preferred Term (PT) for each 
treatment group based on the safety population. 
11.4 Disposition of Subjects 
The number and percentage of subjects randomized and included in each analysis population will 
be summarized by treatment and overall.  Reasons for excluding subjects from the analysis 
populations will be presented in a by-subject listing. 
The number of randomized subjects who completed the study, discontinued early from study 
drug, completed or discontinued from the study, and reasons for discontinuation will be 
summarized by treatment group and overall. 
11.5 Missing Data 
It is expected that few subjects will discontinue Follow-Up.  The reasons for any missing data 
will be summarized by treatment arm.  Missing Hb values will be imputed using last observation 
carried forward (LOCF). 
11.6 Efficacy Analyses 
The primary efficacy endpoint as well as all other secondary endpoints will be summarized using 
descriptive statistics (means or proportions) by treatment groups and in total, 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. 
11.7 Safety Analyses 
Safety analyses will be descriptive in nature.  
All AEs will be coded using MedDRA.  Treatment-emergent and post-treatment AEs will be 
summarized by SOC and PT for each treatment group.  AEs will also be summarized by their 
maximum severity. 
Summaries will also be provided for the following types of AEs: 
• SAEs 
• Related AEs, as determined by the Investigator 
• AEs leading to early discontinuation of study drug 
All Hb related safety endpoints will be tabulated for each treatment groups. 
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. 


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Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
Akebia — Company Confidential 
Page 71 of 88 
11.8 Additional Assessments 
PK and PD parameters will be summarized using descriptive statistics: number of subjects, 
mean, median, SD, minimum, maximum, and coefficient of variation, geometric mean and 
geometric mean SD.  Mean and individual plasma concentration-time profiles will be presented 
graphically in both linear scale and log-linear scale. 
11.8.1 PK Assessments 
A population PK analysis will be conducted to describe vadadustat PK and determine the 
covariates that impact the PK profile (i.e., demographics, laboratory values, concomitant iron, 
dosing relative to dialysis, etc.).  PK analysis will be reported separately. 
11.8.2 PD Assessments 
An exposure-response analysis of vadadustat, EPO and other PD measures will be conducted as 
deemed appropriate.  PD analysis will be reported separately. 
11.8.3 Concomitant Medications 
Prior and concomitant medications will be coded using World Health Organization Drug 
dictionary.  Refer to Section 8.5, Prior and Concomitant Therapy. 
11.8.4 Biomarkers 
Biomarkers (including, but not limited to, hepcidin and VEGF) will be summarized descriptively 
at Baseline/Day 1 and by visit post-Baseline/Day 1.  


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Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
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Page 72 of 88 
12 DATA HANDLING AND RECORD KEEPING 
12.1 CRFs/EDC 
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.  CRFs available through this system are required and will be completed for 
each randomized subject. 
Any form of data from the electronic system are the sole property of the Sponsor and will 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 will 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 will match the data in those charts. 
12.2 Record Retention 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, e.g., 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 (e.g., letters, meeting minutes, and 
telephone calls reports).  The records will be retained by the Investigator according to the 
International Council for Harmonisation of Technical Requires for Pharmaceuticals for Human 
Use (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 (e.g., retirement and relocation), the Sponsor will be prospectively notified.  The 
study records will be transferred to a designee acceptable to the Sponsor, such as another 
Investigator, another institution, or to the Sponsor.  The Investigator will obtain Sponsor’s 
written permission before disposing of any records, even if retention requirements have been 
met. 


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Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
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Page 73 of 88 
13 QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 Study 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 study 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, and/or to 
inspection by appropriate regulatory authorities. 
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
13.2 Protocol Deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change.  The Investigator is responsible for ensuring the 
study is conducted in accordance with the procedures and evaluations described in this protocol 
and must protect the rights, safety, and welfare of subjects.  The Investigator should not 
implement any deviation from, or changes of, the protocol, unless it is necessary to eliminate an 
immediate hazard to trial subjects.   
A protocol waiver is a documented prospective approval of a request from an Investigator to 
deviate from the protocol.  Protocol waivers are strictly prohibited. 
For the purposes of this protocol, deviations requiring notification to Sponsor are defined as any 
subject who: 
• Entered into the study even though they did not satisfy entry criteria.  
• Developed withdrawal criteria during the study and not withdrawn. 
• Received wrong treatment or incorrect dose.  
• Received excluded concomitant treatment. 
When a deviation from the protocol is identified for an individual subject, the Investigator or 
designee must ensure the Sponsor is notified.  The Sponsor will follow-up with the Investigator, 
as applicable, to assess the deviation and the possible impact to the safety and/or efficacy of the 
subject to determine subject continuation in the study.  
If a deviation impacts the safety of a subject, the investigator must contact the Sponsor 
immediately. 
The Investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately.  All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
Sponsor and maintained within the Trial Master File. 


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Original Protocol 
 
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Note: Other deviations outside of the categories defined above that are required to be reported by 
the IRB/IEC in accordance with local requirements will be reported, as applicable. 


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Original Protocol 
 
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Page 75 of 88 
14 STUDY DISCONTINUATION/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 will contact all participating subjects within a time period 
specified by the Sponsor to inform them of the decision to discontinue the study. 
14.1 Criteria for Premature Termination or Suspension of the Study 
The following criteria may result in either temporary suspension or early termination of the 
study: 
• New information regarding the safety or efficacy of the study drug 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 
• Request from regulatory agencies 
The Sponsor reserves the right to discontinue the study for other valid administrative reasons. 
If the study has been suspended or terminated, prompt notification will be given to Investigators, 
IRBs, and regulatory authorities in accordance with regulatory requirements. 
14.2 Criteria for Premature Termination or Suspension of 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. 
The Investigator will notify the Sponsor if the trial is terminated by the Investigator or the IRB at 
the site.  If the Investigator, IRB, or Sponsor decides to terminate or suspend the trial conduct at 
a particular study site for safety, non-enrollment, non-compliance with the protocol, or other 
unanticipated reasons, the above parties will be promptly notified. 
14.3 Procedures for Premature Termination or Suspension of the Study or Study 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 study sites during the 
course of termination or study suspension. 
 


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Original Protocol 
 
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Page 76 of 88 
15 ETHICS 
15.1 Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical Principles 
for Medical Research Involving Human Subjects, adopted by the General Assembly of the World 
Medical Association (2013). 
In addition, the study will be conducted in accordance with the protocol, the ICH E6 guideline on 
GCP, and applicable local regulatory requirements and laws. 
15.2 IRB 
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, (e.g., recruitment 
advertisements, if applicable) from the IRB.  All correspondence with the IRB will be retained in 
the Investigator File.  Copies of IRB approvals will 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 approval is where 
the change is necessary to eliminate apparent immediate hazards to the subjects.  In that event, 
the Investigator will notify the IRB and the Sponsor in writing immediately after the 
implementation. 
15.3 Subject Information and Consent 
The Investigator or designee will explain the nature of the study to the subject or their legally 
acceptable representative, and answer all questions regarding this study.  Prior to any study-
related screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject or their legally acceptable representative, the 
person who administered the informed consent and any other signatories according to local 
requirements.  A copy of the signed ICF will be given to the subject and the original will be 
placed in the subject’s medical record.  An entry must also be made in the subject’s dated source 
documents to confirm that informed consent was obtained prior to any study-related procedures 
and that the subject received a signed copy. 
The signed consent forms will be retained by the Investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request. 
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, will be prospectively approved by both the IRB and the Sponsor 
before use. 
15.4 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (i.e., 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 will 
be informed immediately. 


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Original Protocol 
 
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Page 77 of 88 
In addition, the Investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the Investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP, defined as a breach that will likely affect the 
safety or physical or mental integrity of subjects or the scientific value of the trial, that comes to 
the attention of the Investigator. 
15.5 Subject Confidentiality 
All parties will ensure protection of subject personal data and will not include subject names on 
any Sponsor forms, reports, publications, or in any other disclosures, except where required by 
law.  In case of data transfer, the Sponsor will maintain high standards of confidentiality and 
protection of subject personal data. 
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy.  Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number.  As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH guidelines for GCP and to verify compliance with this protocol, the 
Sponsor requires the Investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (e.g., FDA), the Sponsor’s designated auditors, and the appropriate 
IRBs 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 will have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s CRF). 


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Protocol No. AKB-6548-CI-0025 
Original Protocol 
 
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Page 78 of 88 
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 will 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 will 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. 
 
 


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17 REFERENCES 
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):584-90. 
Besarb A, Flaharty KK, Ersley AJ, McCrea JB, Vlasses PH, Medina F, et al. Clinical 
pharmacology and economics of recombinant human erythropoietin in end-stage renal disease: 
the case for subcutaneous administration. J Am Soc Nephrol. 1992;2(9):1405-16. 
Di Iorio B, Cirillo M, Bellizzi V, Stellato D, De Santo NG. Prevalence and correlates of anemia 
and uncontrolled anemia in chronic hemodialysis patients – The Campania Dialysis Registry. Int 
J Antif Organs. 2007;30(4):325-33. 
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):2071-84. 
Iseki K, Kohagura K. Anemia as a risk factor for chronic kidney disease. Kidney Int Suppl. 
2007;(107):S4-9. 
Jha V, Garcia-Garcia G, Iseki K, Li K, Naicker S, Plattner B, et al. Chronic kidney disease: 
global dimension and perspectives. Lancet. 2013;382(9888):260-72. 
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 
Locatelli F, Aljama P, Barany P, Canaud B, Carrera F, Eckhardt KU, et al. Revised European 
best practice guidelines for the management of anaemia in patients with chronic renal failure. 
Nephrol Dial Transplant. 2004;19(Suppl2):1-47. 
Ly J, Marticrena R, Donnelly S. Red blood cell survival in chronic renal failure. Am J Kidney 
Dis. 2004;44(4):715-9. 
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. 
NICE. Anaemia management in people with chronic kidney disease. National Institute for Health 
and Care Excellence. 2011:1-39. 
Nurko S. Anemia in chronic kidney disease: causes, diagnosis, treatment. Cleve Clin J Med. 
2006;73(3):289-97. 
Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D. Double-blind comparison 
of full and partial anemia correction in incident hemodialysis patients without symptomatic heart 
disease. J Am Soc Nephrol. 2005;16(7):2180-9. 
Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH. Vadadustat, a novel oral HIF 
stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease. 
Kidney Int. 2016;90(5):1115-22. 


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Original Protocol 
 
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Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, et al. 
Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin 
Invest. 2007;117(7):1926-32. 
Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al. A trial of 
darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 
2009a;361(21):2019-32. 
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):2085-98. 
Stauffer ME, Fan T. Prevalence of anemia in chronic kidney disease in the United States. PLoS 
One. 2014;9(1):e84943. 
Unger EF, Thompson AM, Blank MJ, Temple R. Erythropoiesis-stimulating agents - time for a 
reevaluation. N Engl J Med. 2010;362(3):189-92. 
 


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 Original Protocol 
 
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Page 81 of 88 
APPENDIX A: SCHEDULE OF ACTIVITIES 
Study Period 
Screening [a] 
Study Treatment Period 
Safety Follow-
Up 
Visit 
SV1 
SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 [c] 
15 
Weeks of study completed 
Study Day 
Day -28 to 0 
Baseline/ 
Day 1 [b] 
Week 1 
Day 8 
Week 2 
Day 15 
Week 4 
Day 29 
Week 6 
Day 43 
Week 8 
Day 57 
Week 10 
Day 71 
Week 11 
Day 78 
Week 12 
Day 85 
Week 13 
Day 92 
Week 14 
Day 99  
Week 16 
Day 113 
Week 18 
Day 127 
EOT 
Week 20 
Day 141 
Week 24
Day 169 
Visit Window (Days) 
― 
― 
+5 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+5 
±3 
±3 
±3 
±3 
±5 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria [d] 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Contraception 
methods [e] 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs [f] 
X 
X [g] 
X [g] 
X 
X 
X 
X 
X 
X 
X 
X [g] 
X 
X 
X 
X 
X [g] 
 
Demographics, Medical 
History [h] 
 
X 
X [i] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam [j] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG [k] 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dialysis Adequacy (Kt/V) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
SF-36  
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
PGI-S 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
PGI-C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment for meeting 
criteria to switch from daily 
to TIW dosing 
(vadadustat arm) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Status check [l] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE review [m] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Protocol No. AKB-6548-CI-0025 
 
 Original Protocol 
 
Akebia — Company Confidential 
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Study Period 
Screening [a] 
Study Treatment Period 
Safety Follow-
Up 
Visit 
SV1 
SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 [c] 
15 
Weeks of study completed 
Study Day 
Day -28 to 0 
Baseline/ 
Day 1 [b] 
Week 1 
Day 8 
Week 2 
Day 15 
Week 4 
Day 29 
Week 6 
Day 43 
Week 8 
Day 57 
Week 10 
Day 71 
Week 11 
Day 78 
Week 12 
Day 85 
Week 13 
Day 92 
Week 14 
Day 99  
Week 16 
Day 113 
Week 18 
Day 127 
EOT 
Week 20 
Day 141 
Week 24
Day 169 
Review use of rescue 
therapy (RBC transfusions 
and ESA therapy) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of therapeutic 
phlebotomy 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy test [n] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC [o] [p] 
X 
X 
X [q] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X [q] 
 
Reticulocyte count 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
Folate and vitamin B12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Serum chemistry [r] 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
LFTs [s] 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
Iron indices [t] 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
Lipid panel [u] 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Biomarkers (VEGF and 
Hepcidin) [v] 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
PK/PD for vadadustat arm 
[w] 
 
 
X 
X 
 
 
 
 
 
X 
 
X [x] 
 
 
 
 
 
PK for epoetin alfa arm [y] 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication Assessments and Procedures 
Concomitant medication 
review [z] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Epoetin alfa dosing during 
Screening and resume 
standard of care after EOT 
X [aa] 
 
 
 
 
 
 
 
 
 
 
 
 
 
X [bb] 


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Protocol No. AKB-6548-CI-0025 
 
 Original Protocol 
 
Akebia — Company Confidential 
Page 83 of 88 
Study Period 
Screening [a] 
Study Treatment Period 
Safety Follow-
Up 
Visit 
SV1 
SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 [c] 
15 
Weeks of study completed 
Study Day 
Day -28 to 0 
Baseline/ 
Day 1 [b] 
Week 1 
Day 8 
Week 2 
Day 15 
Week 4 
Day 29 
Week 6 
Day 43 
Week 8 
Day 57 
Week 10 
Day 71 
Week 11 
Day 78 
Week 12 
Day 85 
Week 13 
Day 92 
Week 14 
Day 99  
Week 16 
Day 113 
Week 18 
Day 127 
EOT 
Week 20 
Day 141 
Week 24
Day 169 
Study Drug (vadadustat or 
epoetin alfa) dosing [cc] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X [dd] 
X 
X 
X 
X 
 
 
Vadadustat dispensation 
[ee] 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
Review vadadustat dosing 
instructions and vadadustat 
dosing compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vadadustat reconciliation 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review use of iron 
supplementation [ff] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Visit Registration in IWRS 
X 
X 
X 
 
 
X 
[gg] 
 
X [gg] 
 
 
X [gg] 
 
 
X [gg] 
 
X 
 
eDiary instruction 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = 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; CRP = C-reactive protein; ECG = electrocardiogram; EOT = end of treatment; EPO = erythropoietin; 
ESA = erythropoiesis-stimulating agent; HDL = high density lipoprotein; IWRS = Interactive Web Response System; LDL = low density lipoprotein; LFT = liver function test; MCH = mean 
corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; PD = pharmacodynamics; PGI-C = Patient Global Impression of Change; PGI-
S = Patient Global Impression of Severity; PK = pharmacokinetic; RBC = red blood cell; RDW = red cell distribution width; SF-36 = 36-Item Short-Form General Health Survey; SV1 = Screening 
visit 1; SV2 = Screening visit 2; TIBC = total iron binding capacity; TSAT = transferrin saturation; VEGF = vascular endothelial growth factor; WBC = white blood cell; wks = weeks. 
[a] The Screening Period is a maximum of 28 days in duration and starts at the time the informed consent is signed. 
[b] The Investigator will arrange for sufficient time (a minimum of 4 days) between SV2 or last retest (if applicable) and Baseline/Day 1 to allow for all laboratory results to be available that are 
required to assess eligibility for the next study visit.  
[c] The EOT evaluations will be performed when the Treatment Period (Baseline/Day 1 to Week 20 [Visits 1 to 13]) is completed.  Subjects who permanently discontinue study drug for any reason or 
discontinue prematurely from the study will complete the EOT visit (Visit 14) assessments and will complete the Safety Follow-Up (Visit 15) 4 weeks after Visit 14 
[d] Eligibility criteria will be reviewed at the SV1, SV2, and Baseline/Day 1. 
[e] Contraception methods will be reviewed at Screening and Baseline/Day 1, as well as throughout the study as needed. 
[f] Vital signs will include temperature, HR, BP, RR, SO2, and dry weight.  Temperature, HR, BP, RR and SO2 will be assessed in the seated position after 5 minutes of rest.  For BP, a total of two 
measurements at intervals of at least 2 minutes should be performed.  Temperature, HR, BP, RR and SO2 will be collected at SV1, SV2, Baseline/Day 1, during all study visits, and Visit 14 (EOT).  
Measurements will be and will be taken prior to blood draws when possible.   
[g] Dry weight will be collected as part of the vital signs for all subjects at SV2, Baseline/Day 1, Visit 9 and 14 (EOT).  For subjects on epoetin alfa, subjects will be weighed for dosing as per the local 
standard of care. 
[h] Relevant medical history (with particular emphasis on previous medical conditions that may lead to exclusion) and significant ongoing medical conditions or diseases will be documented. 


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Protocol No. AKB-6548-CI-0025 
 
 Original Protocol 
 
Akebia — Company Confidential 
Page 84 of 88 
[i] Review of medical history for new conditions since SV2. 
[j] A physical examination (including height) is required at SV2.  Thereafter, an abbreviated symptom-directed physical examination will be performed at the discretion of the Investigator, as clinically 
indicated. 
[k] A standard 12-lead ECG will be performed at Baseline/Day 1, which may be obtained up to 3 days prior to Baseline/Day 1.  The ECG will be obtained after the subject has been resting comfortably 
in a supine position for approximately 5 minutes and will be taken prior to vital sign assessments and blood draws when possible.  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. 
[l] In weeks where there is no scheduled study visit (Weeks 3, 5, 7, 9, 15, and 17), a subject will have a status check performed during one of their dialysis treatment appointments in the week.  It will 
include a review of the subject’s vital signs and a review of current health status for identification of any issues that may require follow-up by the Investigator or delegated staff personnel.  
Documentation of the review must be done in the subject’s source documentation.  No data will be captured on the status checks in the EDC system.  If an AE is identified at the status check or other 
actions result from the status check, these will be captured per the protocol.  
[m] Beginning with the first dose of study drug (vadadustat or epoetin alfa) at Baseline/Day 1 and through 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.  Subjects must be followed for AEs until the final required protocol visit (study end date) or until all drug-
related toxicities and SAEs have resolved (or are considered chronic/stable), whichever is later. 
[n] A serum pregnancy test will be performed at SV2 for females of childbearing potential.  Additional serum 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 drug.  A FSH test will be performed at SV2 for post-menopausal females.   
[o] A CBC without differential will be performed at all noted visits, except Baseline/Day 1 and Visit 14 (EOT).  The CBC without differential will include: Hb, hematocrit, RBCs, MCV, MCH, 
MCHC, RDW, WBC count, and platelets. 
[p] Hb will be monitored throughout the study via central laboratory to determine the dose of study drug (vadadustat or epoetin alfa) that subjects will receive.  Hb levels can be measured more 
frequently based on Investigator’s clinical judgment.  For eligibility purposes, one retest for Hb may be performed during the Screening Period.  Two Hb values measured at least 4 days apart by the 
central laboratory during Screening (SV1, SV2 or retest) must be between 8.5 and 11.0 g/dL, inclusive, for the Main study and 8.0 and 10.0 g/dL, inclusive, for the ESA hyporesponder parallel study. 
[q] A CBC with differential will be performed at Baseline/Day 1 and Visit 14 (EOT).  The CBC with differential will include the same parameters as CBC without differential with the addition of 
WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils).   
[r] The serum chemistry will include the following assays: sodium, potassium, bicarbonate, chloride, calcium, magnesium, phosphorus, glucose, creatinine, BUN, CPK, uric acid, albumin, and total 
protein. 
[s] LFTs: total bilirubin, ALP, ALT/SGPT, AST/SGOT, and lactate dehydrogenase. 
[t] Iron Indices: ferritin, iron, transferrin, TIBC, and TSAT. 
[u] Lipid Profile: total cholesterol, LDL, HDL, and triglycerides. 
[v] The biomarkers will include, but are not limited to, VEGF and hepcidin.  Samples for VEGF and hepcidin biomarker analyses will be drawn at Baseline/Day 1, Visit 9 and 14 (EOT).   
[w] Blood for measurement of vadadustat, metabolites and EPO level in the vadadustat arm, in both the Main study and ESA hyporesponder parallel study will be collected at Baseline/Day 1, Week 1, 
and Week 11 as outlined in Section 9.2.2.1.  For all PK and PD sampling, the time of the previous dose of vadadustat will be collected for the pre-dose sample and the timing of administration of 
vadadustat, and the start and stop time of the dialysis session will be recorded.   
[x] Visit 10/Week 13 PK/PD sampling will only be done in subjects who transition to vadadustat TIW dosing regimen.  Subjects who do not qualify for vadadustat TIW dosing and remain on daily 
dosing regimen will not have Visit 10/Week 13 PK/PD sampling. 
[y] Blood for measurement of EPO level in the epoetin alfa arm, in both the Main study and ESA hyporesponder parallel study, will be collected at Baseline/Day 1 and Week 1 as outlined in 
Section 9.2.2.2.  For all PK sampling the time of the previous dose of epoetin alfa is to be collected for the pre-dose sample and the timing of administration of epoetin alfa and the start and stop time of 
the dialysis session will be recorded.   
[z] Concomitant medications should be collected and recorded at each visit as noted.  All medications taken within 30 days prior to Baseline/Day 1 will be recorded. 
[aa] Epoetin alfa dosing will stop for a minimum of 5 days before Baseline/Day 1 in the Main study or 2 days before Baseline/Day 1 in the ESA hyporesponder parallel study. 
[bb] After the end of vadadustat treatment at Visit 14/Week 20 (or following early discontinuation of vadadustat), subjects will resume dosing with epoetin alfa (or another ESA), based on standard of 
care. 
[cc] Subjects in the low epoetin alfa dose group randomized to vadadustat treatment will start at an initial dose of vadadustat 300 mg or 450 mg daily.  Subjects in the high epoetin alfa dose group 
randomized to vadadustat treatment will receive an initial dose of 300 mg, 450 mg, or 600 mg daily.  Subjects in the ESA hyporesponder parallel study randomized to vadadustat treatment will receive a 
starting dose of vadadustat 600 mg daily.  For subjects who are randomized to the epoetin alfa treatment arm, the initial dosing regimen in the study (starting from Baseline/Day 1) will be approximately 
the same weekly dose that they were receiving prior to randomization. 
[dd] After completing the 12-week once daily dosing regimen, subjects randomized to vadadustat who meet criteria for switching from daily to TIW dosing will initiate TIW dosing at a starting dose 
1 tablet greater (+150 mg) than the final dose in the daily dosing period.  Central laboratory Hb values from Visit 8/Week 11 (11 weeks of treatment completed) will be used to determine if subjects 
meet Week 12 Transition criteria. 
[ee] Subjects will be provided with a supply of vadadustat at Baseline/Day 1 and will be resupplied at Visit 4, 6, 9 and 12 or an unscheduled dispensing visit as needed.  Subjects will be instructed to 
complete 1 bottle before opening a new bottle.  The dose should be taken at approximately the same time each day. 


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Protocol No. AKB-6548-CI-0025 
 
 Original Protocol 
 
Akebia — Company Confidential 
Page 85 of 88 
[ff] IV iron will be administered based on ferritin and TSAT levels measured by the central laboratory according to the standardized, low-intensity, iron supplementation protocol in Section 8.4.8.  Oral 
iron supplementation including iron-containing phosphate binders are prohibited during the study. 
[gg] IWRS visit registration for vadadustat arm only for bottle dispensing 
 
 


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Protocol No. AKB-6548-CI-0025 
 
 Original Protocol 
 
Akebia — Company Confidential 
Page 86 of 88 
APPENDIX B: PK/PD SAMPLING  
PK/PD Sampling in Vadadustat Arm Subjects Who Transition to TIW Dosing at Week 12 
 
Baseline/Day 1 
QD 
Week 1  
QD 
Week 1  
+ 1 day  
Week 11  
QD 
  
Week 13  
TIW 
 
Dialysis  
Day 
Dialysis 
Day 
Non-Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Baseline/Day 1 
(Prior to first dose) 
● 
  
  
  
  
  
 
15 minutes (pre-dose) 
  
● 
● 
● 
 
● 
 
2 hours ± 15 minutes 
(post-dose) 
  
● 
● 
● 
 
● 
 
3.5 hours ± 15 minutes 
(post-dose) 
  
● 
● 
● 
 
● 
 
5 hours ± 30 minutes 
(post-dose) 
  
● 
● 
● 
 
● 
 
7 hours ± 30 minutes 
(post-dose) 
  
● 
● 
● 
 
● 
 
10.5 hours ± 1.5 hours 
(post-dose) 
 
● 
 
● 
 
● 
 
Note: Gray shading indicates sample collection at a subset of study sites only. 
 
 


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Protocol No. AKB-6548-CI-0025 
 
 Original Protocol 
 
Akebia — Company Confidential 
Page 87 of 88 
PK/PD Sampling in Vadadustat Arm Subjects Who Do Not Transition to TIW Dosing at Week 12 
 
Baseline/Day 1 
QD 
Week 1  
QD 
Week 1  
+ 1 day  
Week 11  
QD 
  
Week 13  
TIW 
 
Dialysis  
Day 
Dialysis 
Day 
Non-Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Baseline/Day 1 
(Prior to first dose) 
● 
  
  
  
  
  
 
15 minutes (pre-dose) 
  
● 
● 
● 
 
 
 
2 hours ± 15 minutes 
(post-dose) 
  
● 
● 
● 
 
 
 
3.5 hours ± 15 minutes 
(post-dose) 
  
● 
● 
● 
 
 
 
5 hours ± 30 minutes 
(post-dose) 
  
● 
● 
● 
 
 
 
7 hours ± 30 minutes 
(post-dose) 
  
● 
● 
● 
 
 
 
10.5 hours ± 1.5 hours 
(post-dose) 
 
● 
 
● 
 
 
 
Note: Gray shading indicates sample collection at a subset of study sites only. 
 
 
 


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Protocol No. AKB-6548-CI-0025 
 
 Original Protocol 
 
Akebia — Company Confidential 
Page 88 of 88 
PK Sampling in Epoetin Alfa Arm 
 
Baseline/Day 1 
TIW 
Week 1  
TIW 
Week 1  
+ 2 days 
Week 11  
TIW 
  
Week 13  
TIW 
 
Dialysis  
Day 
Dialysis 
Day 
Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Baseline/Day 1 
(Prior to first dose) 
● 
  
  
  
  
  
 
15 minutes (pre-dose) 
  
● 
● 
 
 
 
 
2 hours ± 15 minutes 
(post-dose) 
  
● 
 
 
 
 
 
3.5 hours ± 15 minutes 
(post-dose) 
  
● 
 
 
 
 
 
5 hours ± 30 minutes 
(post-dose) 
  
● 
 
 
 
 
 
7 hours ± 30 minutes 
(post-dose) 
  
● 
 
 
 
 
 
10.5 hours ± 1.5 hours 
(post-dose) 
 
● 
 
 
 
 
 
Note: Gray shading indicates sample collection at a subset of study sites only. 
 


Akebia Therapeutics, Inc. 
Amendment 1 (Version 2.0) 
Protocol No. AKB-6548-CI-0025 
11 September 2018 
 
Akebia — Company Confidential 
Page 1 of 89 
 
 
 
CLINICAL PROTOCOL 
 
PHASE 2, RANDOMIZED, OPEN-LABEL, ACTIVE-CONTROLLED, EFFICACY, 
SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS STUDY OF ORAL 
VADADUSTAT FOR THE TREATMENT OF ANEMIA IN HEMODIALYSIS 
SUBJECTS CONVERTING FROM EPOETIN ALFA 
 
Compound: 
Vadadustat (AKB-6548) 
Protocol Number: 
AKB-6548-CI-0025 
US IND Number: 
102,465 
Phase: 
Phase 2 
Protocol Version / Date: 
Amendment 1 (Version 2.0 / 11 SEPTEMBER 2018) 
Original Version 1.0 / 27 JUNE 2018  
 
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 
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. 


Akcbia Therapeutics, Inc. 
Protocol No. AKB-6548-Cl-0025 
l 
SIGNATUREPAGES 
l.l 
Protocol Approval 
Signature 
Date 
Date 
Amendment l (Version 2.0) 
11 September 2018 
Akebia -
Company Confidential 
Page 2 of89 


Akebia Therapeutics, Inc. 
Amendment 1 (Version 2.0) 
Protocol No. AKB-6548-CI-0025 
11 September 2018 
 
Akebia — Company Confidential 
Page 3 of 89 
1.2 
Investigator Agreement 
I confirm that I have read and that I understand this protocol, the Investigator Brochure, and other 
product information provided by the Sponsor. I agree to conduct this study in accordance with the 
requirements of this protocol and also protect the rights, safety, privacy, and well-being of study 
subjects in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 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 


Akebia Therapeutics, Inc. 
Amendment 1 (Version 2.0) 
Protocol No. AKB-6548-CI-0025 
11 September 2018 
 
Akebia — Company Confidential 
Page 4 of 89 
TABLE OF CONTENTS 
1 
SIGNATURE PAGES .................................................................................................. 2 
1.1 
Protocol Approval .................................................................................................... 2 
1.2 
Investigator Agreement ............................................................................................ 3 
TABLE OF CONTENTS ......................................................................................................... 4 
2 
PROTOCOL SYNOPSIS .............................................................................................. 8 
3 
LIST OF ABBREVIATIONS ..................................................................................... 21 
4 
BACKGROUND INFORMATION ........................................................................... 23 
4.1 
Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors ..................................... 24 
4.2 
Summary of Clinical Experience ........................................................................... 24 
4.3 
Potential Benefits and Risks ................................................................................... 26 
5 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 28 
5.1 
Primary Objective .................................................................................................. 28 
5.2 
Secondary Objectives ............................................................................................. 28 
5.3 
Efficacy Endpoints ................................................................................................. 28 
5.3.1 
Primary Endpoints ............................................................................................. 28 
5.3.2 
Key Secondary Endpoints ................................................................................. 28 
5.3.2.1 
Other Secondary Endpoints .......................................................................... 28 
5.3.2.2 
Exploratory Endpoints .................................................................................. 29 
5.4 
PK/PD Endpoints ................................................................................................... 29 
5.5 
Safety Endpoints .................................................................................................... 29 
6 
STUDY DESIGN ........................................................................................................ 30 
6.1 
Study Design .......................................................................................................... 30 
6.1.1 
Screening Period (up to 28 days; Day -28 to Baseline/Day 1) .......................... 31 
6.1.2 
Study Treatment Period (Baseline/Day 1 to Week 20) ..................................... 32 
6.1.2.1 
Vadadustat Treatment ................................................................................... 32 
6.1.2.2 
Epoetin Alfa Treatment ................................................................................ 32 
6.1.3 
Safety Follow-Up Period (Weeks 20 to 24) ...................................................... 32 
6.2 
Rationale for Study Design .................................................................................... 33 
6.3 
Dose Justification ................................................................................................... 34 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 35 
7.1 
General Criteria ...................................................................................................... 35 
7.2 
Inclusion Criteria .................................................................................................... 35 
7.3 
Exclusion Criteria ................................................................................................... 35 
7.4 
Retesting and Rescreening ..................................................................................... 37 
7.4.1 
Retesting ............................................................................................................ 37 
7.4.2 
Rescreening ....................................................................................................... 37 


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7.5 
Study Completion, Study Termination, and Individual Site Termination ............. 37 
7.5.1 
Study Completion .............................................................................................. 37 
7.5.2 
Study Termination ............................................................................................. 37 
7.5.3 
Individual Study Site Termination .................................................................... 38 
7.6 
Subject Completion and Subject Discontinuation .................................................. 38 
7.6.1 
Subject Completion ........................................................................................... 38 
7.6.2 
Temporary Interruption of Study Drug ............................................................. 38 
7.6.3 
Early Discontinuation from Study (Early Termination) .................................... 38 
8 
STUDY DRUG AND TREATMENT OF SUBJECTS .............................................. 40 
8.1 
Epoetin Alfa ........................................................................................................... 40 
8.2 
Vadadustat .............................................................................................................. 40 
8.2.1 
Supplies and Storage ......................................................................................... 40 
8.2.2 
Dispensing of Vadadustat .................................................................................. 40 
8.3 
Vadadustat Accountability and Destruction ........................................................... 41 
8.4 
Treatment of Subjects ............................................................................................. 41 
8.4.1 
Randomization ................................................................................................... 42 
8.4.2 
Blinding ............................................................................................................. 42 
8.4.3 
Measurement of Hb Levels for Dose Adjustment Consideration ..................... 42 
8.4.4 
Epoetin Alfa Dosing Regimen ........................................................................... 42 
8.4.5 
Vadadustat Dosing Regimen and Guidelines for Dose Adjustment ................. 43 
8.4.5.1 
Dosing Regimen for the Vadadustat Treatment Arm ................................... 43 
8.4.5.2 
Transition of Vadadustat Once Daily Dosing to TIW Dosing Regimen ...... 43 
8.4.6 
Guidelines for Dose Adjustments ...................................................................... 44 
8.4.7 
Late or Missed Doses ........................................................................................ 45 
8.4.8 
Iron Supplementation ........................................................................................ 45 
8.4.9 
Rescue Therapy ................................................................................................. 46 
8.4.9.1 
RBC Transfusion .......................................................................................... 46 
8.4.9.2 
ESA Use ........................................................................................................ 46 
8.4.10 
Phlebotomy (Optional) ...................................................................................... 46 
8.4.11 
Treatment Compliance ...................................................................................... 46 
8.4.12 
Continuation of Treatment ................................................................................ 47 
8.5 
Prior and Concomitant Therapy ............................................................................. 47 
8.5.1 
General .............................................................................................................. 47 
8.5.2 
ESAs .................................................................................................................. 47 
8.5.3 
Rosuvastatin, Pravastatin, and Other HMG-CoA Reductase Inhibitors 
(Statins) .............................................................................................................. 47 
8.5.4 
Dialysis Treatment and Renal Replacement Therapy ....................................... 48 
8.5.5 
Investigational Medications ............................................................................... 48 


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Amendment 1 (Version 2.0) 
Protocol No. AKB-6548-CI-0025 
11 September 2018 
 
Akebia — Company Confidential 
Page 6 of 89 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES ................................ 49 
9.1 
Administrative Procedures ..................................................................................... 49 
9.1.1 
Informed Consent .............................................................................................. 49 
9.1.2 
eDiary ................................................................................................................ 50 
9.1.3 
Documentation of Screen Failures .................................................................... 50 
9.1.4 
Status Check ...................................................................................................... 50 
9.1.5 
Contraception and Pregnancy Avoidance Measures ......................................... 50 
9.1.6 
Laboratory Accreditation and Reference Ranges .............................................. 51 
9.2 
Study Procedures and Evaluations ......................................................................... 51 
9.2.1 
Clinical Evaluations ........................................................................................... 51 
9.2.2 
Laboratory Evaluations ..................................................................................... 52 
9.2.2.1 
PK/PD Sampling for Subjects Randomized to Vadadustat .......................... 54 
9.2.2.2 
PK Sampling for Subjects Randomized to Epoetin Alfa .............................. 55 
9.2.2.3 
PK/PD Sampling ........................................................................................... 55 
9.3 
Schedule of Activities ............................................................................................ 55 
9.3.1 
Screening Visits ................................................................................................. 55 
9.3.1.1 
SV1 ............................................................................................................... 56 
9.3.1.2 
SV2 ............................................................................................................... 56 
9.3.2 
Baseline/Day 1 (Visit 1) .................................................................................... 57 
9.3.3 
Visit 2 to Visit 13 (Weeks 1 to 20) .................................................................... 58 
9.3.4 
EOT Visit 14 (Week 20) .................................................................................... 59 
9.3.5 
Safety Follow-Up Visit 15 (Week 24) ............................................................... 60 
9.3.6 
Unscheduled Visits ............................................................................................ 60 
10 
ADVERSE EVENTS .................................................................................................. 61 
10.1 
Definitions .............................................................................................................. 61 
10.1.1 
AEs .................................................................................................................... 61 
10.1.2 
SAEs .................................................................................................................. 63 
10.2 
Eliciting AE Information ........................................................................................ 64 
10.3 
Reporting ................................................................................................................ 64 
10.3.1 
Reporting Period ................................................................................................ 64 
10.3.2 
Reporting AEs ................................................................................................... 64 
10.3.3 
Reporting SAEs ................................................................................................. 64 
10.3.4 
Relationship to Study Drug ............................................................................... 65 
10.3.5 
Severity .............................................................................................................. 66 
10.3.6 
Follow-up of Unresolved Events ....................................................................... 66 
10.4 
Exposure In-Utero .................................................................................................. 66 
10.5 
Special Situations ................................................................................................... 67 
10.6 
Safety Monitoring .................................................................................................. 68 


Akebia Therapeutics, Inc. 
Amendment 1 (Version 2.0) 
Protocol No. AKB-6548-CI-0025 
11 September 2018 
 
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Page 7 of 89 
11 
DATA ANALYSIS ..................................................................................................... 69 
11.1 
Sample Size Estimation .......................................................................................... 69 
11.2 
Study Analysis Populations .................................................................................... 69 
11.3 
Analysis of Demographic and Pretreatment Variables .......................................... 70 
11.4 
Disposition of Subjects ........................................................................................... 70 
11.5 
Missing Data .......................................................................................................... 70 
11.6 
Efficacy Analyses ................................................................................................... 70 
11.7 
Safety Analyses ...................................................................................................... 70 
11.8 
Additional Assessments ......................................................................................... 71 
11.8.1 
PK Assessments ................................................................................................. 71 
11.8.2 
PD Assessments ................................................................................................. 71 
11.8.3 
Concomitant Medications .................................................................................. 71 
11.8.4 
Biomarkers ........................................................................................................ 71 
12 
DATA HANDLING AND RECORD KEEPING ...................................................... 72 
12.1 
CRFs/EDC .............................................................................................................. 72 
12.2 
Record Retention .................................................................................................... 72 
13 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 73 
13.1 
Study Site Monitoring Visits .................................................................................. 73 
13.2 
Protocol Deviations ................................................................................................ 73 
14 
STUDY DISCONTINUATION/STUDY SITE TERMINATION ............................. 75 
14.1 
Criteria for Premature Termination or Suspension of the Study ............................ 75 
14.2 
Criteria for Premature Termination or Suspension of Study Sites ......................... 75 
14.3 
Procedures for Premature Termination or Suspension of the Study or Study 
Sites ........................................................................................................................ 75 
15 
ETHICS ....................................................................................................................... 76 
15.1 
Ethical Conduct of the Study ................................................................................. 76 
15.2 
IRB ......................................................................................................................... 76 
15.3 
Subject Information and Consent ........................................................................... 76 
15.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .... 76 
15.5 
Subject Confidentiality ........................................................................................... 77 
16 
PUBLICATION OF STUDY RESULTS ................................................................... 78 
17 
REFERENCES ............................................................................................................ 79 
APPENDIX A: SCHEDULE OF ACTIVITIES .................................................................... 81 
APPENDIX B: PK/PD SAMPLING ..................................................................................... 86 
APPENDIX C: HISTORY OF AMENDMENTS TO THE PROTOCOL ............................ 89 


Akebia Therapeutics, Inc. 
Amendment 1 (Version 2.0) 
Protocol No. AKB-6548-CI-0025 
11 September 2018 
 
Akebia — Company Confidential 
Page 8 of 89 
2 
PROTOCOL SYNOPSIS 
Study Title 
Phase 2, Randomized, Open-Label, Active-Controlled, Efficacy, Safety, 
Pharmacokinetics, and Pharmacodynamics Study of Oral Vadadustat for the Treatment 
of Anemia in Hemodialysis Subjects Converting from Epoetin Alfa 
Protocol Number 
AKB-6548-CI-0025 
Study Phase 
Phase 2 
Investigational 
Product 
Vadadustat; 150 mg tablets  
Reference Medicinal 
Product 
Epoetin alfa solution for intravenous (IV) injection in multi-dose vials or in single-dose 
vials  
Study Population 
The Main study population will consist of adult subjects receiving chronic, outpatient 
in-center hemodialysis three times weekly (TIW), with 2 screening hemoglobin (Hb) 
values between 8.5 and 11.0 g/dL (inclusive) and on maintenance treatment with 
epoetin alfa <300 U/kg/week. 
The erythropoiesis stimulating agent (ESA) hyporesponder parallel study will consist 
of adult subjects receiving chronic, outpatient in-center hemodialysis TIW, with 
2 screening Hb values between 8.0 and 10.0 g/dL (inclusive) and on maintenance 
treatment with epoetin alfa ≥300 U/kg/week.  
Study Sites 
Approximately 40 study sites in the United States 
Planned Number of 
Subjects 
Approximately 125 subjects 
• Main study: ~95 subjects 
• ESA hyporesponder parallel study: ~30 subjects 
Primary Objective 
To assess the efficacy and safety of daily dosing of vadadustat compared to epoetin 
alfa for 12 weeks in hemodialysis subjects 
Secondary Objectives 
• To assess the efficacy and safety of TIW dosing of vadadustat in selected 
hemodialysis subjects who have been successfully managed with daily dosing of 
vadadustat through Week 12 
• To evaluate the pharmacokinetics (PK)/pharmacodynamics (PD) of daily and TIW 
dosing of vadadustat in hemodialysis subjects compared to epoetin alfa  
• To assess the efficacy and safety of several dosing strategies of vadadustat compared 
to epoetin alfa during a 20-week Treatment Period in hemodialysis subjects 
Overview of Study 
Design 
This is a Phase 2, randomized, open-label study to evaluate vadadustat for the 
treatment of anemia in hemodialysis subjects converting from epoetin alfa therapy.  
For all subjects (Main and ESA hyporesponder parallel study), the study will include a 
Screening Period, a Treatment Period, and a Safety Follow-Up Period as described 
below.  PK and PD sampling will be done throughout the study (see PK and PD 
Sampling sections for details). 
The aim is to achieve and maintain Hb levels within the target range of 10.0 to 
11.0 g/dL, inclusive, while targeting the middle of the range and minimizing 
excursions outside the target range. 
Screening Period (up to 28 days; Day -28 to Baseline/Day 1) 
For all subjects (Main and ESA hyporesponder parallel study) the Screening Period 
starts at the time the informed consent is signed and will be a maximum of 28 days in 
duration.  Baseline/Day 1 will be performed within 28 days of the start of Screening.  
Subjects who meet all eligibility criteria will be randomized to a vadadustat treatment 
arm or an epoetin alfa treatment arm.  Subjects will be required to stop epoetin alfa 
treatment for a minimum duration of 5 days before Baseline/Day 1 in the Main study 
and for a minimum of 2 days before Baseline/Day 1 in the ESA hyporesponder parallel 


Akebia Therapeutics, Inc. 
Amendment 1 (Version 2.0) 
Protocol No. AKB-6548-CI-0025 
11 September 2018 
 
Akebia — Company Confidential 
Page 9 of 89 
study.  In the Main study, randomization will be stratified by the mean weekly epoetin 
alfa dose calculated over a period of 8 weeks prior to Screening Visit 2 (SV2). 
• 
Low epoetin alfa dose group (≤90 units [U]/kg/week) or 
• 
High epoetin alfa dose group (>90 to <300 U/kg/week) 
Study Treatment Period (Baseline/Day 1 to Week 20) 
For all subjects (Main and ESA hyporesponder parallel study), the Treatment Period 
will run from Baseline/Day 1 to Week 20.  Dose will be adjusted to achieve and 
maintain Hb levels within the target range of 10.0 to 11.0 g/L, inclusive, while 
targeting the middle of the range and minimizing excursions outside of the target 
range. 
Subjects in the Main study randomized to vadadustat: 
• 
Subjects in the low epoetin alfa dose group will start vadadustat at an initial, 
randomly allocated dose of 300 mg or 450 mg daily.   
• 
Subjects in the high epoetin alfa dose group will start vadadustat at an initial, 
randomly allocated dose of 300 mg, 450 mg, or 600 mg daily.   
Subjects in the ESA hyporesponder parallel study randomized to vadadustat: 
• 
Subjects will receive a starting dose of vadadustat 600 mg daily.   
Transition to TIW for all subjects randomized to vadadustat: 
All subjects randomized to vadadustat (Main and ESA hyporesponder parallel study) 
who complete the 12-week once daily dosing regimen and who meet all the Week 12 
transition criteria for switching from daily to TIW dosing, will initiate TIW dosing at a 
starting dose one tablet greater (+150 mg) than the final dose in the daily dosing 
period.  Subjects who do not meet criteria for switching from daily to TIW dosing will 
remain on daily dosing.   
Subjects in both the Main and ESA hyporesponder parallel study randomized to 
epoetin alfa: 
All subjects randomized to epoetin alfa will receive TIW dosing for the entire 
Treatment Period based on the subject’s central laboratory Hb value and the approved 
epoetin alfa United States (US) Package Insert (PI) for adult patients with chronic 
kidney disease (CKD) on dialysis.  Dose will be adjusted to achieve and maintain Hb 
levels within the target range of 10.0 to 11.0 g/dL, inclusive, while targeting the middle 
of the range and minimizing excursions outside of the target range. 
Safety Follow-Up Period (Weeks 20 to 24) 
For all subjects (Main and ESA hyporesponder parallel study), the 4-week Safety 
Follow-Up Period starting at Week 20 will be followed by a post-treatment safety 
assessment conducted at the beginning of Week 24. 


Akebia Therapeutics, Inc. 
Amendment 1 (Version 2.0) 
Protocol No. AKB-6548-CI-0025 
11 September 2018 
 
Akebia — Company Confidential 
Page 10 of 89 
Study Schematic 
 
Study Duration 
Individual subjects will participate in the study for up to 28 weeks, including a 
Screening Period of up to 4 weeks, a 20-week Treatment Period and a 4-week Safety 
Follow-Up Period. 
Inclusion Criteria 
Subjects must meet the following inclusion criteria: 
1. ≥18 years of age 
2. Receiving chronic, outpatient in-center hemodialysis (TIW) for end-stage renal 
disease for at least 12 weeks prior to Screening 
3. Maintained on IV epoetin alfa therapy for 8 weeks prior to and including 
Screening through SV2 
4. Eligibility in the Main study and ESA hyporesponder parallel study is based on 
the following mean weekly epoetin alfa doses: 
• 
Main study: Mean weekly epoetin alfa dose <300 U/kg/week for 8 weeks 
prior to SV2 
• 
ESA hyporesponder parallel study: Mean weekly epoetin alfa dose 
≥300 U/kg/week for 8 weeks prior to SV2 
5. Two Hb values measured at least 4 days apart by the central laboratory during 
Screening as indicated below 
• 
Main study: 2 Hb values between 8.5 and 11.0 g/dL, inclusive 
• 
ESA hyporesponder parallel study: 2 Hb values between 8.0 and 10.0 g/dL, 
inclusive 
6. Serum ferritin ≥100 ng/mL and transferrin saturation (TSAT) ≥20% during 
Screening 


Akebia Therapeutics, Inc. 
Amendment 1 (Version 2.0) 
Protocol No. AKB-6548-CI-0025 
11 September 2018 
 
Akebia — Company Confidential 
Page 11 of 89 
7. Folate and vitamin B12 measurements ≥ lower limit of normal during Screening 
8. Hemodialysis adequacy as indicated by single-pool Kt/Vurea ≥1.2 using the most 
recent historical measurement within 8 weeks prior to or during Screening 
9. Understands the procedures and requirements of the study and provides written 
informed consent and authorization for protected health information disclosure. 
Exclusion Criteria 
Subjects must not meet any of the following exclusion criteria: 
1. Anemia due to a cause other than CKD (e.g., sickle cell disease, myelodysplastic 
syndromes, bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic 
anemia, thalassemia, or pure red cell aplasia) 
2. Active bleeding or recent blood loss within 8 weeks prior to randomization 
3. Red blood cell (RBC) transfusion within 8 weeks prior to randomization 
4. Anticipated to discontinue hemodialysis during the study 
5. Judged by the Investigator that the subject is likely to need rescue therapy (ESA 
administration or RBC transfusion) immediately after enrollment in the study 
6. History of chronic liver disease (e.g., chronic infectious hepatitis, chronic 
autoimmune liver disease, cirrhosis or fibrosis of the liver)  
7. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase 
(SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase 
(SGPT), or total bilirubin >1.5 x upper limit of normal (ULN) during Screening.  
Subjects with a history of Gilbert’s syndrome are not excluded. 
8. Current uncontrolled hypertension as determined by the Investigator that would 
contraindicate the use of epoetin alfa 
9. 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 heart failure (HF) or New York Heart Association Class IV HF, or stroke 
within 12 weeks prior to or during Screening 
10. History of new or recurrent malignancy within 2 years prior to and during 
Screening or currently receiving treatment or suppressive therapy for cancer.  
Subjects with treated basal cell carcinoma of skin, curatively resected squamous 
cell carcinoma of skin, or cervical carcinoma in situ are not excluded. 
11. History of deep vein thrombosis or pulmonary embolism within 12 weeks prior 
to or during Screening 
12. History of hemosiderosis or hemochromatosis 
13. History of prior organ transplantation (subjects with a history of failed kidney 
transplant or corneal transplants are not excluded) 
14. Scheduled organ transplant from a living donor and subjects on the kidney 
transplant wait-list who are expected to receive a transplant within 6 months  
15. History of a prior hematopoietic stem cell or bone marrow transplant (stem cell 
therapy for knee arthritis is not excluded) 
16. Known hypersensitivity to vadadustat, epoetin alfa, or any of their excipients 
17. 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 Screening (subjects may participate in another concurrent study 
only if that study is a non-interventional, observational investigation) 
18. Previous participation in this study, or previous participation in a study with 
another hypoxia-inducible factor prolyl-hydroxylase inhibitor other than 
vadadustat 


Akebia Therapeutics, Inc. 
Amendment 1 (Version 2.0) 
Protocol No. AKB-6548-CI-0025 
11 September 2018 
 
Akebia — Company Confidential 
Page 12 of 89 
19. For female subjects: 
a. 
Of non-childbearing potential 
i. Inability to confirm surgical sterility (e.g., hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy) at least 
1 month prior to Screening, or  
ii. Not considered post-menopausal (no menses for >1 year with 
follicle stimulating hormone >40 U/L at Screening)  
b. Or, if of childbearing potential  
i. Lack of confirmation of the use of acceptable forms of 
contraception* for a minimum of one complete menstrual 
cycle prior to Screening  
ii. Positive serum pregnancy test at SV2 
iii. Unwilling to use two acceptable forms of contraception* (at 
least one of which must be a barrier method) starting 
Baseline/Day 1, throughout the Treatment Period and for 
30 days after the final study drug administration 
20. Breastfeeding during Screening or throughout the Treatment Period and for 
30 days after the final study drug administration. 
21. Donation of ova starting at Screening, throughout the Treatment Period, and for 
30 days after the final study drug administration. 
22. Male subjects who have not had a vasectomy and do not agree to the following: 
use of an acceptable form of contraception* during the study and for 30 days 
after the last dose of the study drug; to not donate semen during the study and for 
at least 30 days after the last dose of vadadustat. 
23. Subjects with bilateral native nephrectomy. 
24. Any other reason, which in the opinion of the Investigator, would make the 
subject not suitable for participation in the study. 
 
 *  Acceptable forms of contraception include: 
• 
Established use of oral, injected or implanted hormonal methods of 
contraception. 
• 
Placement of an intrauterine device or intrauterine system. 
• 
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. 
Retesting/Rescreening 
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 
be retested once for each laboratory parameter within the 4-week Screening Period, per 
Investigator discretion. 
Rescreening 
Subjects who fail to qualify for the study based on laboratory tests may be considered 
for rescreening at the discretion of the Investigator if it is considered that the subject 
status has changed, and the subject may now qualify for the study.  Additionally, 
subjects who fail to qualify for the study based on inclusion criteria values for 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).  A new informed consent is required to be signed prior to every rescreening. 


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Akebia Therapeutics, Inc. 
Amendment 1 (Version 2.0) 
Protocol No. AKB-6548-CI-0025 
11 September 2018 
 
Akebia — Company Confidential 
Page 14 of 89 
The PD parameters will include (but are not limited to) the following: 
• 
Erythropoietin (EPO) 
• 
Reticulocytes 
• 
Iron 
• 
Ferritin 
• 
Total iron binding capacity (TIBC) 
• 
Hepcidin 
Safety Endpoints 
• 
Adverse events (AEs)  
• 
Vital sign measurements and clinical laboratory values 
• 
Hb >12.0 g/dL, >13.0 g/dL, or >14.0 g/dL 
• 
Hb <8.0 g/dL and decline in Hb ≥0.5 g/dL from Baseline Hb (Main Study); 
Hb <7.5 g/dL and decline in Hb ≥0.5 g/dL from Baseline Hb (ESA 
hyporesponder parallel study) 
• 
Hb increase >1.0 g/dL within any 2-week interval 
Dosage and Regimens 
The aim is to achieve and maintain Hb levels within the target range of 10.0 to 
11.0 g/dL, inclusive, while targeting the middle of the range and minimizing 
excursions outside the target range. 
Dosing will be initiated at Baseline/Day 1 and the first dose of vadadustat will be 
administered at the study site after other Baseline/Day 1 procedures have been 
completed.   
Thereafter, vadadustat will be taken once daily on an outpatient basis.  Subjects may 
take vadadustat with or without food and will be instructed to swallow the tablet(s) 
whole.  Subjects will be instructed to take vadadustat at roughly the same time each 
day. 
Epoetin alfa dose will be administered intravenously at the hemodialysis clinic, based 
on the subject’s central laboratory Hb value and the approved epoetin alfa US PI for 
adult patients with CKD on dialysis. 
Note: For all subjects, no epoetin alfa will be administered after SV2 after the subject 
has met all eligibility criteria and before Baseline/Day 1, for a minimum duration of 
5 days in the Main study and 2 days in the ESA hyporesponder parallel study. 
 
Main Study: 
Subjects will be randomized to either a vadadustat treatment arm or epoetin alfa 
treatment arm.  Randomization will be stratified by mean weekly epoetin alfa dose 
calculated over a period of 8 weeks prior to SV2: 
• 
Low epoetin alfa dose group (≤90 U/kg/week) or 
• 
High epoetin alfa dose group (>90 to <300 U/kg/week) 
 
In the low epoetin alfa dose group, subjects will be randomized in a 3:3:2 ratio to 
receive either an initial vadadustat daily dose of 450 mg (3 tablets) or 300 mg 
(2 tablets), or epoetin alfa. 
In the high epoetin alfa dose group, subjects will be randomized in a 3:3:3:2 ratio to 
receive either an initial vadadustat daily dose of 600 mg (4 tablets), 450 mg (3 tablets) 
or 300 mg (2 tablets), or epoetin alfa. 
ESA Hyporesponder Parallel Study 
Subjects will be randomized in a 1:1 ratio to receive either an initial vadadustat daily 
dose of 600 mg (4 tablets) or epoetin alfa. 


Akebia Therapeutics, Inc. 
Amendment 1 (Version 2.0) 
Protocol No. AKB-6548-CI-0025 
11 September 2018 
 
Akebia — Company Confidential 
Page 15 of 89 
Epoetin alfa arm in both the Main study and ESA hyporesponder parallel study: 
For subjects who are randomized to the epoetin alfa treatment arm, the initial dosing 
regimen in the study (starting from Baseline/Day 1) will be approximately the same 
weekly dose that they were receiving prior to randomization. 
Study Drug Guidelines for Dose Adjustment 
Dose adjustments will be guided by Hb concentrations and the Guidelines for Dose 
Adjustment (see below).  Hb will be monitored via central laboratory throughout the 
study to determine if the dose of study drug (vadadustat or epoetin alfa) will be 
adjusted, interrupted, or maintained as follows: 
• 
Dose adjustments are based on the Investigator’s clinical discretion, 
incorporating the protocol guidance below as well as the subject’s current Hb 
level, trajectory, and variability; symptoms; cardiovascular risk; and other 
features of his/her clinical condition(s). 
• 
If a dose increase or decrease is required to achieve and maintain Hb levels 
within the target range of 10.0 to 11.0 g/dL, inclusive, dose is adjusted by 1 dose 
level (for vadadustat 1 tablet [150 mg], for epoetin alfa approximately 25%). 
• 
In general, do not increase the dose more frequently than once every 4 weeks.  A 
one-time dose increase after 2 weeks is allowed on only two occasions.   
o 
A subject’s dose may be increased by 1 dose level if the subject has a 
decline in Hb ≥0.5 g/dL from Baseline/Day 1 in the first 2-week 
period (the initial period from Baseline/Day 1 to Week 2 following 
conversion from prior epoetin alfa therapy).   
o 
A subject’s dose may also be increased by 1 dose level in the first 2-
week period after initiation of TIW dosing (from Week 12 to 
Week 14) for subjects that meet criteria for transitioning from daily 
to TIW dosing. 
• 
Reduce or interrupt the dose in the setting of a rapid rise in Hb (defined as 
>1.0 g/dL in any 2-week period)  
• 
Reduce or interrupt the dose in the setting of Hb >11.0 g/dL 
• 
Interrupt the dose in the setting of a Hb >12.0 g/dL until Hb value falls below 
11.0 g/dL.  After Hb falls below 11.0 g/dL, restart study drug and consider 
restarting at a lower dose.  
The minimum dose of vadadustat will be 150 mg daily or TIW (1 tablet daily/TIW) 
and the maximum dose will be 900 mg daily or TIW (6 tablets daily/TIW). 
Transition of Vadadustat Once Daily Dosing to TIW Dosing Regimen 
All subjects randomized to vadadustat who complete 12 weeks of once daily dosing 
regimen and who meet all the Week 12 criteria below will be transitioned to a TIW 
vadadustat dosing regimen.  Subjects who meet all of the Week 12 criteria will 
transition to TIW dosing.  
Week 12 Transition criteria: 
• 
Vadadustat daily dose of 600 mg or lower at Week 12 
• 
Hb within target range of 10.0 to 11.0 g/dL, inclusive, at Week 12 confirmed by 
central laboratory Hb value from Week 11 (11 weeks of treatment completed)  
• 
No receipt of rescue therapy (ESA or RBC transfusion) for worsening of anemia 
due to CKD from Baseline to Week 12.   
o 
ESA or RBC transfusion prior to Week 12 for reasons unrelated to 
worsening of anemia due to CKD (e.g., surgery, gastrointestinal 
bleed, or inadvertent administration) is not considered rescue therapy 


Akebia Therapeutics, Inc. 
Amendment 1 (Version 2.0) 
Protocol No. AKB-6548-CI-0025 
11 September 2018 
 
Akebia — Company Confidential 
Page 16 of 89 
• 
No other reason, based on the Investigator’s clinical discretion, that would make 
the subject not suitable for TIW dosing. 
Selected subjects who meet Week 12 transition criteria will transition to the TIW 
vadadustat dosing regimen at the Week 12 visit.  Subjects on 150 mg, 300 mg, 450 mg, 
or 600 mg of vadadustat daily at the Week 12 visit will transition to an initial 
vadadustat TIW dose one tablet greater (+150 mg), i.e., 300 mg, 450 mg, 600 mg, or 
750 mg vadadustat TIW, respectively.  Subjects will be instructed to take vadadustat 
on dialysis days. 
After 2 weeks of treatment in the TIW vadadustat dosing regimen (at Week 14), 
subjects in any vadadustat TIW dosing arms who have a decline in Hb ≥0.5 g/dL will 
be eligible for a dose increase by 1 tablet, based on the Investigator’s clinical 
discretion. 
Subjects who are not eligible to switch from daily vadadustat to TIW dosing at 
Week 12 will remain on daily dosing for the remainder of the study. 
Subjects on TIW dosing may be converted back to vadadustat once daily dosing at the 
discretion of the Investigator in the setting of inadequate Hb response.  The starting 
daily dose after the switch from TIW to daily dosing will be based on the Investigator’s 
discretion after review of the subject’s clinical status and dosing history, in particular, 
the daily dose previously administered to the subject prior to the transition to TIW 
dosing (Week 12).  Subjects who switch from vadadustat TIW to daily dosing will 
continue once daily vadadustat until the end of the Treatment Period. 
 
Subjects in the vadadustat arm will be guided for dosing compliance using an 
electronic diary (eDiary). 
PK/PD Sampling - 
vadadustat arm 
Blood for measurement of vadadustat, metabolites and EPO level in the vadadustat 
arm, in both the Main study and ESA hyporesponder parallel study, will be collected as 
outlined below (see Appendix B).  Preferably, PK/PD samples are to be taken on the 
day of hemodialysis after the first short interdialytic interval (e.g., at the second session 
of the week). 
At Baseline/Day 1, PK/PD samples will be collected prior to dialysis and 
administration of vadadustat. 
At Week 1 (after at least a full week of vadadustat treatment), vadadustat will be 
administered between 15 minutes to one hour prior to the start of dialysis.  Blood 
samples will be collected as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 
5 hours ± 30 minutes post-dose 
• 
From subjects enrolled at a subset of study sites only, additional samples will be 
collected at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
On the following non-dialysis day, blood samples will be collected as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 
5 hours ± 30 minutes post-dose 
• 
From subjects enrolled at a subset of study sites only, additional samples will be 
collected at 7 hours ± 30 minutes post-dose 
At Week 11, vadadustat will be administered between 15 minutes to one hour prior to 
the start of dialysis.  Blood samples will be collected as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 
5 hours ± 30 minutes post-dose 
• 
From subjects enrolled at a subset of study sites only, additional samples will be 
collected at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 


Akebia Therapeutics, Inc. 
Amendment 1 (Version 2.0) 
Protocol No. AKB-6548-CI-0025 
11 September 2018 
 
Akebia — Company Confidential 
Page 17 of 89 
At Week 13 (after at least one week on TIW vadadustat dosing regimen), vadadustat 
will be administered between 15 minutes to one hour prior to the start of dialysis.  
Blood samples will be collected as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 
5 hours ± 30 minutes hours post-dose  
• 
From subjects enrolled at a subset of study sites only, additional samples will be 
collected at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
Note: Week 13 PK/PD sampling will only be done in subjects who transition to 
vadadustat TIW dosing regimen.  Subjects who do not qualify for vadadustat TIW 
dosing and remain on daily dosing regimen will not have Week 13 PK/PD sampling. 
PK Sampling - epoetin 
alfa arm 
Blood for measurement of EPO level in the epoetin alfa arm in both the Main study 
and ESA hyporesponder parallel study will be collected as outlined below (see 
Appendix B).  Preferably, PK samples are to be taken on the day of hemodialysis after 
the first short interdialytic interval (e.g., at the second session of the week). 
At Baseline/Day 1, a sample will be collected prior to dialysis and administration of 
epoetin alfa. 
At Week 1 (after at least a full week of study epoetin alfa treatment), epoetin alfa will 
be administered within 1 hour after start of dialysis.  Blood samples will be collected 
as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 
5 hours ± 30 minutes post-dose  
• 
From subjects enrolled at a subset of study sites only, additional samples will be 
collected at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
On the following dialysis day, one blood sample will be collected 15 minutes prior to 
administration of epoetin alfa. 
Iron Supplementation 
IV iron will be administered based on ferritin and TSAT levels measured by the central 
laboratory according to the standardized, low-intensity, iron supplementation protocol 
below: 
Ferritin 
<200 ng/mL 
Ferritin 
200-500 ng/mL 
Ferritin 
>500 ng/mL 
TSAT 
<20% 
IV Iron 100 mg 
every treatment 
(max 
400 mg/month) 
IV Iron 50 mg 
weekly 
Hold 
TSAT 
20-50% 
IV Iron 100 mg 
every week 
IV Iron 50 mg 
weekly 
Hold 
TSAT 
>50% 
Hold 
Hold 
Hold 
Intra-dialytic iron preparations (e.g., Triferic) and oral iron supplementation including 
iron-containing phosphate binders are prohibited during the study. 
Important: As the study will be assessing PK/PD parameters, and as there are no 
empirical data on concurrent administration of vadadustat and phosphate binders, 
vadadustat will not be administered concurrently with a phosphate binder.  Subjects 
will be instructed to take phosphate binders at least 3 hours before or at least 2 hours 
after the dose of vadadustat based on the guidance in the phosphate binder package 
inserts. 


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Rescue Therapy 
Guidelines 
To ensure the safety of subjects and to standardize the use of rescue in the study, 
rescue therapy guidelines are provided. 
1. 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 will 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 medical 
necessity.  Study drug (vadadustat or epoetin alfa) may be continued during the 
transfusion period. 
Reasons for RBC transfusion will be captured in the appropriate CRF. 
2. ESA Use: ESA administration will be allowed when medically necessary at the 
discretion of the Investigator.  In general, ESA will not be administered in subjects 
with Hb ≥8.5 g/dL, and ESA rescue will be stopped when Hb ≥9.0 g/dL.  ESA 
therapy will be administered using an approved ESA and dosing as per the local 
institution’s guidelines and per the approved product label.   
While receiving ESA therapy, subjects randomized to vadadustat must temporarily 
interrupt vadadustat.  A minimum interval will be observed prior to restarting 
vadadustat after the last dose of ESA, and treatment will be resumed after the 
following intervals: 
• 2 days after last dose of epoetin alfa  
• 7 days after last dose of darbepoetin alfa  
• 14 days after last dose of methoxy polyethylene glycol-epoetin beta  
Following ESA administration, vadadustat will be resumed at the same dose as 
previously used or with one additional tablet (+150 mg) at the discretion of the 
Investigator.  
Reasons for ESA use will be captured in the appropriate CRF. 
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 clinical 
judgment.  The method of phlebotomy will be in accordance with the study site’s 
standard clinical practice. 
Concomitant 
Medications 
1. ESA 
Co-administration of any ESA with vadadustat is 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 ESA 
Rescue) if deemed medically necessary at the discretion of the Investigator.  
Guidelines for ESA administration as rescue therapy are provided above.  All efforts 
will be made to avoid inadvertent administration of ESAs resulting from adherence to 
ESA hemodialysis center protocols (e.g., DaVita ESA protocols for patients 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.  A minimum interval will be observed prior to 
restarting vadadustat after the last dose of ESA.  Vadadustat treatment may be resumed 
after the following intervals: 
• 
2 days after last dose of epoetin alfa  
• 
7 days after last dose of darbepoetin alfa  
• 
14 days after last dose of methoxy polyethylene glycol-epoetin beta 
2. Iron  
See guidance above (Iron Supplementation). 


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Study Completion, 
Subject Completion, 
Temporary 
Interruption of Study 
Drug, Early 
Discontinuation from 
Study (Early 
Termination) 
Study Completion 
The study will be considered completed after all randomized subjects have completed 
their final study visit (Visit 15/Week 24, Safety Follow-Up or Early Termination).  
Subject Completion 
A subject will be considered as having completed the study after completion of their 
final study visit (Visit 15/Week 24, Safety Follow-Up or Early Termination).   
Temporary Interruption of Study Drug 
During the study, a subject may interrupt study drug (vadadustat or epoetin alfa) for 
any of the following reasons: 
• 
AE 
• 
Missed dialysis visit (epoetin alfa arm) 
• 
Investigator’s discretion 
• 
Rapid rise in Hb (defined as >1.0 g/dL in any 2-week period) 
• 
Hb above 11.0 g/dL 
• 
ESA use (vadadustat arm) 
Unless contraindicated, treatment will be resumed whenever possible and assessed at 
every visit following study drug interruption. 
Early Discontinuation from Study (Early Termination) 
Subjects who discontinue prematurely from the study will complete the 
End-of-Treatment visit (Visit 14) assessments and will complete the Safety Follow-Up 
(Visit 15) 4 weeks after Visit 14. 
Subjects may discontinue for any of the following reasons: 
• AE  
• Investigator’s discretion 
• Subject withdrawal of consent  
• Lack of efficacy 
• Lost to follow up despite reasonable efforts by the Investigator to locate the subject 
• Death  
• Other reasons (pregnancy, kidney transplantation, specific reasons to be 
documented by the Investigator) 
Subjects who undergo a solid organ (including kidney), hematopoietic stem cell, or 
bone marrow transplantation will have their study medication (vadadustat or epoetin 
alfa) permanently discontinued and will complete the End-of-Treatment (Visit 14) and 
Safety Follow-Up (Visit 15) visit assessments. 
Study Termination/ 
Individual Study Site 
Termination 
The Sponsor may terminate this study prematurely, either in its entirety or at any study 
site, for reasonable cause provided that written notice is submitted in advance of the 
intended termination.  Advanced notice is not required if the study is stopped due to 
safety concerns.  If the Sponsor terminates the study for safety reasons, the Sponsor 
will immediately notify the Investigator and subsequently provide written instructions 
for study termination.  If the study has been suspended or terminated, prompt 
notification will be given to Investigators, IRBs, and regulatory authorities in 
accordance with regulatory requirements. 
Statistical 
Considerations 
Efficacy and safety endpoint analysis will be descriptive in nature.  Continuous 
variables will be summarized using number of subjects with mean, standard deviation 
(SD), median, minimum and maximum.  For categorical variables, the number and 
percentage of subjects in each category will be tabulated. 


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PK and PD parameters will be summarized using descriptive statistics: number of 
subjects, mean, median, SD, minimum, maximum, and coefficient of variation, 
geometric mean and geometric mean SD.  Mean and individual plasma concentration-
time profiles will be presented graphically in both linear scale and log-linear scale. 
The ESA hyporesponder parallel study will be analyzed separately from the main 
study. 
PK Analysis 
A population PK analysis will be conducted to describe vadadustat PK and determine 
the covariates that impact the PK profile (i.e., demographics, laboratory values, 
concomitant iron, dosing relative to dialysis, etc).  PK analysis will be reported 
separately. 
PD Analysis 
An exposure-response analysis of vadadustat, EPO and other PD measures will be 
conducted as deemed appropriate.  PD analysis will be reported separately. 
Sample Size 
Estimation 
Approximately 95 subjects are planned for enrollment in the Main study with 40 and 
55 subjects randomized to the low epoetin alfa dose group and the high epoetin alfa 
dose group respectively.  Approximately 30 subjects are planned for enrollment in the 
ESA hyporesponder parallel study.  Sample size reflects the exploratory nature of this 
study.  
 
Enrollment may be increased by up to 20 additional subjects in the Main study, and by 
up to 30 additional subjects in the ESA hyporesponder parallel study to ensure 
adequate data is captured for the primary, PK/PD, and safety endpoints. 
Safety Monitoring 
This is an open label study allowing the study team full access to safety data which 
will be reviewed on a regular basis, throughout the course of the study.  Safety 
monitoring will be performed as described in the Medical Monitor Plan.   
 
 


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3 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under concentration-time curve 
AUCinf 
area under concentration-time curve from dosing to infinity 
AUClast 
area under concentration-time curve from dosing to last 
measurable concentration  
BP 
blood pressure 
CBC 
complete blood count 
CKD 
chronic kidney disease 
CL/F 
apparent total body clearance 
Cmax 
maximum concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
DD-CKD 
dialysis dependent chronic kidney disease 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eDiary 
electronic diary 
EOT 
end-of-treatment 
EPO 
erythropoietin 
ESA 
erythropoiesis-stimulating agent 
ESRD 
end-stage renal disease 
FAS 
Full Analysis Population 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
Hb 
hemoglobin 
HF 
heart failure 
HIF 
hypoxia-inducible factor 
HIF-PH 
hypoxia-inducible factor prolyl-hydroxylase 
HIF-PHI 
hypoxia-inducible factor prolyl-hydroxylase inhibitor 
HR 
heart rate 
HRQOL 
health-related quality of life 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IRB 
Institutional Review Board 
IV 
intravenous 
IWRS 
Interactive Web Response System 
LFT 
liver function test 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger ribonucleic acid 


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NDD-CKD 
non-dialysis dependent chronic kidney disease 
PGI-C 
patient global impression of change 
PGI-S 
patient global impression of severity 
PHD 
prolyl 4-hydroxylase domains 
PI 
Package Insert 
PK 
pharmacokinetic(s) 
PD 
pharmacodynamics(s) 
RBC 
red blood cell 
RR 
respiratory rate 
SAE 
serious adverse event 
SD 
standard deviation 
SF-36 
36-Item Short-Form General Health Survey 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
TIW 
three times a week 
Tmax 
time to reach Cmax 
TSAT 
transferrin saturation 
U 
unit 
ULN 
upper limit of normal 
US 
United States 
Vd/F 
apparent volume of distribution 
VEGF 
vascular endothelial growth factor 
 


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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% to 16% of the population (Jha 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, infection, cancer, and mortality (Iseki 2007). 
The prevalence and severity of renal anemia in CKD increases as renal function deteriorates 
(Di Iorio 2007; Stauffer 2014).  As CKD progresses, the combined effect of decreased red blood 
cell (RBC) production from lower erythropoietin (EPO) signaling, increased rate of RBC 
destruction, and reduced iron availability to the bone marrow results in the increased prevalence 
and severity of anemia (Pergola 2016).  Anemia generally exists when hemoglobin (Hb) is less 
than 13.0 g/dL in men or less than 12.0 g/dL in women (KDIGO 2012).  Three principal factors 
contribute to the development of anemia as CKD progresses:  
• Peritubular fibroblasts, a type of cell in the kidney, are designed to sense the amount of 
oxygen carried by the blood.  These cells secrete EPO to adjust the production of RBCs by 
the bone marrow and maintain circulating oxygen levels at normal physiologic levels.  As 
kidney disease progresses, the number of peritubular fibroblasts is reduced and EPO 
secretion is significantly decreased, leading to a reduction in RBC production (Iseki 2007; 
Nurko 2006).  
• On average, the RBCs in CKD patients have a shorter lifespan (approximate lifespan of 
70 days) compared with the RBCs in healthy people (approximate lifespan of 90 to 120 days) 
(Ly 2004; Nurko 2006).  Such a condition leads to increased RBC production in CKD 
patients to maintain normal physiologic levels.  
• The availability of iron to the bone marrow is impaired.  Iron is a required component in the 
formation of Hb, and is essential for the transport of oxygen to the tissues of the body. 
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 2014).  In these patients, compensatory changes occur in cardiac structure and function 
including an increase in cardiac output and the development of left ventricular hypertrophy and 
eventually the development of heart failure (Metivier 2000).  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 patients (Iseki 2007; NICE 2011).  Overall, 
anemia contributes to a poorer prognosis in patients with CKD (Iseki 2007; Nurko 2006). 
The risks associated with erythropoiesis-stimulating agents (ESAs), including an increased risk 
of death and cardiovascular events (Besarab 1998; Drueke 2006; Pfeffer 2009a; Pfeffer 2009b; 
Singh 2006), 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 dialysis dependent CKD (DD-CKD) patients 
remains high.  To fulfill this unmet need, the vadadustat clinical program is focused on 
developing an orally active therapeutic agent for the treatment of anemia in patients with CKD. 


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4.1 
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 (HIF-PHs) for the treatment of anemia associated 
with CKD.  HIF-PH enzymes are also referred to as prolyl 4-hydroxylase domains (PHDs), of 
which the 2 most commonly expressed isoforms are PHD2 and PHD3.  Vadadustat is a slightly 
more potent inhibitor of PHD3 (50% inhibitory concentration [IC50] = 0.08 µM) than of PHD2 
(IC50 = 0.19 µM).  The inhibition of PHD3 and PHD2 stabilizes hypoxia-inducible factor 
(HIF)-2α and HIF-1α, which in turn stimulates the production of EPO.  In vivo animal efficacy 
and messenger ribonucleic acid (mRNA) data indicate that vadadustat induces the production of 
EPO from both renal and extra-renal sites (liver and brain), and this increase in EPO results in an 
increase in RBC production in the bone marrow.  In clinical trials, vadadustat has been shown to 
facilitate iron homeostasis by decreasing hepcidin and increasing transferrin levels in healthy 
adult male volunteers and male and female CKD patients.  This enables iron transport 
mechanisms that should enhance the terminal steps of erythropoiesis.  Vadadustat offers the 
potential of flexible oral dosing that provides a more gradual and reliable means of titration than 
injectable hormones.  Therefore, vadadustat is being developed as an alternative to the existing 
protein hormone ESAs. 
4.2 
Summary of Clinical Experience 
Please see the vadadustat Investigator Brochure for additional discussion and information for 
the following section. 
The efficacy, safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of 
vadadustat have been characterized in 10 completed Phase 1 studies in healthy volunteers 
including 1 ethno-bridging study in Caucasian and Japanese subjects, 1 completed Phase 1 study 
in subjects undergoing chronic hemodialysis, 3 completed Phase 2a studies in non-dialysis 
dependent CKD (NDD-CKD) subjects, 1 completed Phase 2b study in NDD-CKD subjects, and 
1 completed Phase 2 study in DD-CKD subjects.  The United States (US) 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, double-blind, placebo-
controlled study with 5 different dose groups dosed for 42 days.  The US Phase 2b, randomized, 
double-blind, placebo-controlled study evaluated Stages 3, 4, and 5 CKD (pre-dialysis) dosed for 
20 weeks.  The Japanese Phase 2, randomized, double-blind, placebo-controlled study evaluated 
Stages 3, 4, and 5 CKD (pre-dialysis) dosed for 16 weeks.  The US Phase 2 open-label study 
evaluated DD-CKD subjects on chronic hemodialysis dosed for 16 weeks.  The Japanese Phase 
2, randomized, double-blind, placebo-controlled study evaluated DD-CKD subjects on chronic 
hemodialysis dosed for 16 weeks.  In the studies completed to date, a total of 630 subjects have 
received vadadustat, including 200 healthy volunteers and 430 subjects with CKD. 
Vadadustat has shown 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 and Hb 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 consistent bioavailability with area under 
concentration-time curve (AUC) and Cmax in Phase 1 and Phase 2 studies covering the dose range 


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of 80 mg to 1200 mg after single administration and 500 to 900 mg after repeated daily 
administration for 10 days.  The plasma half-life of vadadustat was about 4 to 6 hours, 7 to 8 
hours, and 9 to 10 hours in healthy subjects, NDD-CKD patients, and DD-CKD patients, 
respectively. 
Vadadustat is extensively metabolized and its metabolites are eliminated from the body by dual 
routes of excretion (both 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.  
Multiple doses of 700 mg and 900 mg daily for up to 10 days (Study AKB-6548-CI-0002 
[CI-0002]) and single doses of 1200 mg (Study AKB-6548-CI-0001 [CI-0001], Study AKB-
6548-CI-0010 [CI-0010]) have been examined in healthy volunteers.  Vadadustat demonstrated 
dose-proportional PK and achieved serum EPO concentrations up to 34.4 mIU/mL, levels 
considered physiologic and below exposures achieved with injectable ESAs (Besarb 1992).  A 
higher incidence of adverse events (AEs) in the gastrointestinal System Organ Class (SOC) – 
nausea, diarrhea, abdominal pain, dyspepsia – was observed in groups treated with 700 mg, 
900 mg, or 1200 mg compared with lower vadadustat doses or placebo.  Most AEs were mild to 
moderate, short-lived (1 or 2 days), and assessed as unrelated by investigators.  No AEs led to 
study withdrawal, and no serious adverse events (SAEs) were reported.  No clinically 
meaningful changes or abnormalities in vital signs, safety laboratory studies, or ECG parameters 
were reported. 
A 16-week, open-label, multicenter, Phase 2 trial evaluated vadadustat in 94 subjects receiving 
chronic hemodialysis previously maintained on epoetin alfa and IV iron form the 3 months prior 
to Screening (Study AKB-6548-CI-0011 [CI-0011]).  Subjects were assigned to one of three 
vadadustat dose cohorts: 300 mg daily, 450 mg daily, or 450 mg three times a week (TIW).  
Dosing was fixed for the first 8 weeks; for the subsequent 8 weeks dose was adjusted according 
to Hb response based upon a dose adjustment algorithm.  Sixty-nine of the 94 subjects completed 
the study.  The primary endpoint was the mean Hb concentration change from pre-treatment 
average (Screening Visit 1, Screening Visit 2, and Baseline Visit) to mid-study (Weeks 7 to 8) 
and end-of-study (Weeks 15 to 16) and was analyzed using observed Hb values (no imputation 
for missing data).  No statistically significant mean change in Hb from pre-treatment average 
was observed for either of the two time points for any of the three treatment groups. 
Among subjects randomized to an initial dose of 300 mg daily, 450 mg daily, or 450 mg TIW, 
0% (0 of 30), 3% (1 of 33), and 19% (6 of 31) of subjects withdrew from the study due to 
worsening anemia, respectively.  In a sensitivity analysis using last observation carried forward 
(LOCF) for the primary efficacy endpoint, no significant mean change in Hb from pre-treatment 
levels was observed in the 300 mg daily dosing group.  At Weeks 15 to 16, modest, statistically 
significant mean decreases were observed in the 450 mg daily and 450 mg TIW dosing groups. 
In a post-hoc univariate analysis of baseline characteristics, higher pre-baseline epoetin alfa dose 
was associated with a decrease in mean Hb at Weeks 7 to 8 and Weeks 15 to 16 in the dosing 
cohorts.  Subjects who discontinued the study due to worsening anemia had a higher mean pre-
baseline epoetin alfa dose compared with subjects who discontinued due to other reasons or 
subjects who completed the study. 


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Based on 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.  
In the ongoing global Phase 3 and Japanese Phase 3 clinical studies, over 7000 subjects are 
planned to be treated with vadadustat or comparator.  
This study will evaluate efficacy, safety and PK/PD with different vadadustat dosing strategies in 
hemodialysis subjects converting from epoetin alfa to further characterize the optimal vadadustat 
regimen. 
4.3 
Potential Benefits and Risks 
Please see the vadadustat Investigator’s Brochure for additional information. 
Trials of injectable 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 2009a).  Post-hoc analyses performed by the Food and Drug 
Administration (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 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 2007).  Potential clinical benefits include enhanced 
erythropoiesis and decreased exogenous iron requirements.  
In nonclinical safety studies, the main findings originated from an exaggerated pharmacological 
response that results in increased erythropoiesis, polycythemia, blood hyperviscosity, and the 
formation of fibrin thrombi in multiple organs.  Early mortality noted in the mouse and rat and 
moribundity in the dog were due to the sequelae associated with polycythemia.  These findings 
were reproducible across species and studies, dose-dependent and showed reversibility.  Dose-
limiting toxicity in the exploratory toxicology studies was due to hemoglobinuric nephropathy 
(rat) and emesis associated with body weight loss (dog). 
In completed Phase 1 clinical studies of vadadustat in healthy volunteers, there were low 
numbers of treatment-emergent AEs.  The most frequently reported AEs were in the 
gastrointestinal disorders (i.e., nausea, diarrhea, abdominal pain, flatulence, dyspepsia) and 
nervous system disorders (i.e., headache, dizziness) SOC.  The majority of AEs were mild to 
moderate in severity.  
The most frequently reported AEs in completed Phase 2 studies of NDD- and DD-CKD subjects 
were in the following SOCs: gastrointestinal disorders (nausea, diarrhea, vomiting), 
cardiovascular disorders (hypertension, hypotension, coronary artery disease), renal (renal failure 
chronic, renal failure acute), infections and infestations (gastroenteritis, urinary tract infection, 


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pneumonia), and metabolism and nutrition disorders (hyperkalemia, fluid overload).  Four deaths 
occurred in the completed Phase 2 clinical studies.  
Identified risks include nausea, diarrhea, vomiting, headache, abdominal pain, and uric acid 
elevations.  Hypersensitivity, hyperkalemia and hypertension have been identified as potential 
risks associated with vadadustat therapy. 
Review of safety data from completed Phase 1 and 2 clinical studies, as well as review of 
accumulating data from ongoing studies, continue to support further development of the 
vadadustat program. 
 


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5 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Primary Objective 
To assess the efficacy and safety of daily dosing of vadadustat compared to epoetin alfa for 
12 weeks in hemodialysis subjects. 
5.2 
Secondary Objectives 
• To assess the efficacy and safety of TIW dosing of vadadustat in selected hemodialysis 
subjects who have been successfully managed with daily dosing of vadadustat through 
Week 12 
• To evaluate the PK/PD of daily and TIW dosing of vadadustat in hemodialysis subjects 
compared to epoetin alfa 
• To assess the efficacy and safety of several dosing strategies of vadadustat compared to 
epoetin alfa during a 20-week Treatment Period in hemodialysis subjects 
5.3 
Efficacy Endpoints 
5.3.1 Primary Endpoints 
The primary endpoint will be the mean change in Hb between Baseline (average pretreatment 
Hb) and the primary evaluation period (average Hb from Weeks 10 to 12). 
5.3.2 Key Secondary Endpoints 
• Proportion of subjects with Hb values within the target range (10.0 to 11.0 g/dL, 
inclusive) at the primary evaluation period (Weeks 10 to 12) 
• For subjects who transitioned to TIW vadadustat dosing, mean change in Hb from 
primary evaluation period (average Hb from Weeks 10 to 12) to the secondary evaluation 
period (average Hb from Weeks 18 to 20) 
5.3.2.1 Other Secondary Endpoints 
• Mean change in Hb between Baseline (average pretreatment Hb) and the secondary 
evaluation period (average Hb from Weeks 18 to 20) 
• Proportion of subjects with Hb values within the target range (10.0 to 11.0 g/dL, 
inclusive) at the secondary evaluation period (Weeks 18 to 20) 
• For subjects who transitioned to TIW vadadustat dosing, proportion of subjects with Hb 
values within the target range (10.0 to 11.0 g/dL, inclusive) at the secondary evaluation 
period (Weeks 18 to 20) 
• Proportion of subjects with a mean increase in Hb from Baseline to the primary 
evaluation period ≥0.5 g/dL (average Hb from Weeks 10 to 12) or with Hb values within 
the target range (10.0 to 11.0 g/dL, inclusive) at the primary evaluation period 
(Weeks 10 to 12) 
• Proportion of subjects with a mean increase in Hb from Baseline to the secondary 
evaluation period ≥0.5 g/dL (average Hb from Weeks 18 to 20) or with Hb values within 
the target range (10.0 to 11.0 g/dL, inclusive) at the secondary evaluation period 
(Weeks 18 to 20) 


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6 
STUDY DESIGN 
6.1 
Study Design 
This is a Phase 2, randomized, open-label study to evaluate vadadustat for the treatment of 
anemia in hemodialysis subjects converting from epoetin alfa therapy. 
For all subjects (Main and ESA hyporesponder parallel study), the study (as shown in Figure 1) 
will include a Screening Period, a study Treatment Period, and a Safety Follow-Up Period as 
described below.  PK and PD sampling will be done throughout the study (see PK and PD 
Sampling Section 9.2.2.1, PK/PD Sampling for Subjects Randomized to Vadadustat and 
Section 9.2.2.2, PK Sampling for Subjects Randomized to Epoetin Alfa, respectively, for 
details). 
The aim is to achieve and maintain Hb levels within the target range of 10.0 to 11.0 g/dL, 
inclusive, while targeting the middle of the range and minimizing excursions outside the target 
range. 


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Figure 1: 
Overview of Study Design 
 
6.1.1 Screening Period (up to 28 days; Day -28 to Baseline/Day 1) 
For all subjects (Main and ESA hyporesponder parallel study), the Screening Period starts at the 
time the informed consent is signed and will be a maximum of 28 days in duration.  
Baseline/Day 1 will be performed within 28 days of the start of Screening.  Subjects who meet 
all eligibility criteria will be randomized to a vadadustat treatment arm or an epoetin alfa 
treatment arm.  Subjects will be required to stop epoetin alfa treatment for a minimum duration 
of 5 days before Baseline/Day 1 in the Main study and for a minimum of 2 days before 
Baseline/Day 1 in the ESA hyporesponder parallel study.  In the Main study, randomization will 
be stratified by the mean weekly epoetin dose calculated over a period of 8 weeks prior to 
Screening Visit 2 (SV2): 


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• Low epoetin alfa dose group (≤90 units [U]/kg/week) 
• High epoetin alfa dose group (>90 to <300 U/kg/week) or 
6.1.2 Study Treatment Period (Baseline/Day 1 to Week 20) 
For all subjects (Main and ESA hyporesponder parallel study), the Treatment Period will run 
from Baseline/Day 1 to Week 20.  Dose will be adjusted to achieve and maintain Hb levels 
within the target range of 10.0 to 11.0 g/dL, inclusive, while targeting the middle of the range 
and minimizing excursions outside of the target range. 
6.1.2.1 Vadadustat Treatment 
Subjects in the Main study randomized to vadadustat: 
• Subjects in the low epoetin alfa dose group will start vadadustat at an initial, randomly 
allocated dose of 300 mg or 450 mg daily.   
• Subjects in the high epoetin alfa dose group will start vadadustat at an initial, randomly 
allocated dose of 300 mg, 450 mg, or 600 mg daily.   
Subjects in the ESA hyporesponder parallel study randomized to vadadustat: 
• Subjects will receive a starting dose of vadadustat 600 mg daily.  
Transition to TIW for all subjects randomized to vadadustat: 
All subjects randomized to vadadustat (Main and ESA hyporesponder parallel study), who 
complete the 12-week once daily dosing regimen and who meet all the Week 12 transition 
criteria for switching from daily to TIW dosing, will initiate TIW dosing at a starting dose one 
tablet greater (+150 mg) than the final dose in the daily dosing period (see Section 8.4.5.2, 
Transition of Vadadustat Once Daily Dosing to TIW Dosing Regimen). 
Note: Subjects who are not eligible to switch from daily vadadustat to TIW dosing at Week 12 
will remain on daily dosing from the remainder of the study (see Section 8.4.5, Vadadustat 
Dosing Regimen and Guidelines for Dose Adjustment).  
6.1.2.2 Epoetin Alfa Treatment 
Subjects in both the Main and ESA hyporesponder parallel study randomized to epoetin alfa: 
All subjects randomized to epoetin alfa will receive TIW dosing for the entire Treatment Period 
based on the subject’s central laboratory Hb value and the approved epoetin alfa United States 
(US) Package Insert (PI) for adult patients with CKD on dialysis.  Dose will be adjusted to 
achieve and maintain Hb levels within the target range of 10.0 to 11.0 g/dL, inclusive, while 
targeting the middle of the range and minimizing excursions outside of the target range (see 
Section 8.4.4, Epoetin Alfa Dosing Regimen). 
6.1.3 Safety Follow-Up Period (Weeks 20 to 24) 
For all subjects (Main and ESA hyporesponder parallel study), the 4-week Safety Follow-Up 
Period starting at Week 20 will be followed by a post-treatment safety assessment conducted at 
the beginning of Week 24. 


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6.2 
Rationale for Study Design 
The Main Study and the ESA hyporesponder parallel study will evaluate different starting doses 
of vadadustat based on pre-baseline ESA doses.  Numerous studies have demonstrated that 
hemodialysis patients requiring higher ESA doses to treat their anemia have a higher burden of 
comorbidities, a more inflammatory state, and a greater risk of adverse outcomes (Besarb 1998; 
Parfrey 2005; Unger 2010).  As described above (Section 4.2, Summary of Clinical Experience) 
in a Phase 2 hemodialysis study (CI-0011), a post-hoc analysis suggested higher pre-baseline 
ESA doses were associated with lower observed mean Hb levels.  Subjects on higher pre-
baseline ESA doses may benefit from a higher starting dose of vadadustat after initial conversion 
from ESAs.  
Three levels of pre-baseline ESA dose will be evaluated.  In the Main Study subjects will be 
randomized to one of two cohorts based on pre-baseline ESA dose (≤90 U/kg/week and >90 to 
<300 U/kg/week).  The ESA threshold of 90 U/kg/week was based on the median ESA doses 
reported in the US Renal Data System and US Dialysis Outcomes and Practice Patterns Study, 
which ranged from approximately 90 to 110 U/kg/week. 
The ESA hyporesponder parallel study will evaluate subjects with Hb levels below the target 
range despite receiving ≥300 U/kg/week of epoetin alfa.  This ESA threshold was based on the 
definition of resistance to ESAs proposed in the ERA-EDTA 2004 guidelines (Locatelli 2004).  
The Main study and the ESA hyporesponder parallel study incorporate an approach to vadadustat 
dose adjustment designed to maximize the probability that Hb can be maintained within the 
target range of 10.0 to 11.0 g/dL, inclusive (see Section 8.4.5, Vadadustat Dosing Regimen and 
Guidelines for Dose Adjustment).  The approach to vadadustat dose adjustment in this Phase 2 
study includes several modifications as compared to the vadadustat dosing algorithms used in 
previously completed Phase 2 studies and the dosing algorithm used in the ongoing Phase 3 
studies.   
During this study, dose increases for vadadustat will be allowed at 4-week intervals, with the 
exception of the initial 2 weeks of treatment, in the daily and TIW dosing periods of the study.  
Dose increases will be permitted in the initial 2 weeks of treatment, in the daily and TIW dosing 
periods, in subjects with a Hb decline ≥0.5 g/dL from baseline and Week 12, respectively.  This 
approach is commonly used in clinical practice to treat patients with declining or low Hb values 
(Pfeffer 2009a; Singh 2006).  Risk of abrupt or excessive increases in Hb is minimized due to the 
underlying Hb trajectory and is further mitigated by close Hb monitoring. 
In the present study, the safety and efficacy of a vadadustat TIW dosing regimen is being 
evaluated as a potential alternative treatment regimen to a once daily dosing regimen in 
hemodialysis subjects.  Specifically, this study will evaluate conversion from once daily dosing 
to TIW dosing.  As described above (Section 4.2, Summary of Clinical Experience), the 16-week 
Phase 2 hemodialysis study evaluated hemodialysis subjects switching from ESA to vadadustat 
450 mg TIW for an 8-week fixed-dose period followed by 8 weeks of dose adjustment according 
to Hb response.  The primary efficacy analysis in CI-0011 using observed data showed stable 
mean Hb levels in this group.  Six of 31 (19%) subjects withdrew due to worsening anemia, and 
a sensitivity analysis imputing missing Hb values using LOCF demonstrated a decline in mean 
Hb levels.  To maximize the probability that subjects treated with vadadustat TIW will maintain 
Hb levels within the target range, this study will: examine subjects successfully treated with 


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daily dosing converting to TIW dosing; allow for earlier dose increase after 2 weeks of initial 
treatment; and permit dose increases up to 900 mg TIW. 
6.3 
Dose Justification 
In this study, vadadustat starting daily doses will be determined by pre-baseline ESA dose 
(Section 8.4.5, Vadadustat Dosing Regimen and Guidelines for Dose Adjustment).  In the Main 
study starting doses of vadadustat will be 300 mg and 450 mg daily in subjects converting from 
epoetin alfa doses ≤90 U/kg/week and 300 mg, 450 mg, and 600 mg daily in subjects converting 
from epoetin alfa doses >90 to <300 U/kg/week.  For the ESA hyporesponder parallel study, the 
starting doses will be 600 mg daily.  As described above (Section 4.2, Summary of Clinical 
Experience), the maximum vadadustat starting dose evaluated in completed Phase 2 NDD-CKD 
studies was 630 mg or 600 mg daily, in Study AKB-6548-CI-0005 (CI-0005) and Study 
AKB-6548-CI-0021 (CI-0021) respectively, and in completed Phase 2 DD-CKD studies was 
450 mg or 600 mg in Study AKB-6548-CI-0011 (CI-0011) and Study AKB-6548-CI-0022 
(CI-0022), respectively. 
Based on the dosing algorithm, vadadustat will be titrated to achieve and maintain Hb levels 
within the target range of 10.0 to 11.0 g/dL, inclusive.  The dose range for titration is 150 mg to 
900 mg daily or TIW.  Doses of 150 mg to 630 mg daily have been evaluated in studies 
evaluating subjects with NDD-CKD and DD-CKD.  The maximum vadadustat dose evaluated in 
healthy volunteers was 1200 mg in a single dose study (CI-0001 and CI-0010) and 900 mg daily 
in a 10-day multiple dose study (CI-0002), as described in Section 4.2, Summary of Clinical 
Experience. 
The rationale to evaluate higher maximum doses for titration is that to date, dose-ranging clinical 
studies have not identified a vadadustat dose at which a plateau in exposure or effect has been 
observed.  In Phase 1 studies in healthy volunteers, dose-proportional increases in AUC and Cmax 
and dose-related increases in serum EPO were observed up to the maximum doses studied, single 
doses of 1200 mg and multiple doses of 900 mg daily for 10 days (CI-0001, CI-0002).  In 
Phase 2 studies in anemic NDD-CKD and DD-CKD subjects, dose-dependent increases in Hb 
were observed up to the maximum dose studied of 600 mg or 630 mg daily (CI-0005, CI-0021, 
CI-0022).  It is anticipated that daily doses of vadadustat at 750 mg or 900 mg would yield an 
incremental erythropoietic effect greater than 600 mg for the treatment of renal anemia.  
This study design mitigates the risk of vadadustat doses of 750 mg or 900 mg.  Intensive Hb 
monitoring, a strict dose adjustment algorithm, and phlebotomy will be implemented to mitigate 
the potential risk of a rapid Hb rise, as follows:  
• Hb measurements are scheduled at least every 2 weeks to Week 20 
• The dose adjustment algorithm will target a narrow Hb range, 10.0 to 11.0 g/dL, inclusive 
• The protocol specifies that phlebotomy may be considered in the setting of high Hb levels 
(>14.0 g/dL) or a high Hb rate of rise, based on the Investigator’s judgment 
Importantly, the Phase 2 studies demonstrated that cessation of treatment resulted in prompt 
reduction in mean Hb to baseline values. 


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7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
General Criteria 
To be eligible for this study, a subject or their legally acceptable representative must provide 
valid informed consent and the subject must meet all eligibility criteria.  No study procedures 
(including Screening tests) may be performed until after the informed consent has been legally 
signed. 
7.2 
Inclusion Criteria 
Subjects must meet the following inclusion criteria: 
1. ≥18 years of age 
2. Receiving chronic, outpatient in-center hemodialysis (TIW) for ESRD for at least 12 weeks 
prior to Screening 
3. Maintained on IV epoetin alfa therapy for 8 weeks prior to and including Screening through 
SV2 
4. Eligibility in the Main study and ESA hyporesponder parallel study is based on the following 
mean weekly epoetin alfa doses: 
• Main study: Mean weekly epoetin alfa dose <300 U/kg/week for 8 weeks prior to 
SV2 
• ESA hyporesponder parallel study: Mean weekly epoetin alfa dose ≥300 U/kg/week 
for 8 weeks prior to SV2 
5. Two Hb values measured at least 4 days apart by the central laboratory during Screening as 
indicated below 
• Main study: 2 Hb values between 8.5 and 11.0 g/dL, inclusive 
• ESA hyporesponder parallel study: 2 Hb values between 8.0 and 10.0 g/dL, inclusive 
6. Serum ferritin ≥100 ng/mL and transferrin saturation (TSAT) ≥20% during Screening 
7. Folate and vitamin B12 measurements ≥ lower limit of normal during Screening 
8. Hemodialysis adequacy as indicated by single-pool Kt/Vurea ≥1.2 using the most recent 
historical measurement within 8 weeks prior to or during Screening 
9. Understands the procedures and requirements of the study and provides written informed 
consent and authorization for protected health information disclosure. 
7.3 
Exclusion Criteria 
Subjects must not meet any of the following exclusion criteria: 
1. Anemia due to a cause other than CKD (e.g., sickle cell disease, myelodysplastic syndromes, 
bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic anemia, thalassemia, or 
pure red cell aplasia) 
2. Active bleeding or recent blood loss within 8 weeks prior to randomization 
3. RBC transfusion within 8 weeks prior to randomization 
4. Anticipated to discontinue hemodialysis during the study 
5. Judged by the Investigator that the subject is likely to need rescue therapy (ESA 
administration or RBC transfusion) immediately after enrollment in the study 
6. History of chronic liver disease (e.g., chronic infectious hepatitis, chronic autoimmune liver 
disease, cirrhosis or fibrosis of the liver)  


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7. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine 
aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total bilirubin 
>1.5 x upper limit of normal (ULN) during Screening.  Subjects with a history of Gilbert’s 
syndrome are not excluded. 
8. Current uncontrolled hypertension as determined by the Investigator that would 
contraindicate the use of epoetin alfa 
9. 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 heart failure (HF) or New York Heart 
Association Class IV HF, or stroke within 12 weeks prior to or during Screening 
10. History of new or recurrent malignancy within 2 years prior to and during Screening or 
currently receiving treatment or suppressive therapy for cancer.  Subjects with treated basal 
cell carcinoma of skin, curatively resected squamous cell carcinoma of skin, or cervical 
carcinoma in situ are not excluded. 
11. History of deep vein thrombosis or pulmonary embolism within 12 weeks prior to or during 
Screening 
12. History of hemosiderosis or hemochromatosis 
13. History of prior organ transplantation (subjects with a history of failed kidney transplant or 
corneal transplants are not excluded) 
14. Scheduled organ transplant from a living donor and subjects on the kidney transplant wait-
list who are expected to receive a transplant within 6 months  
15. History of a prior hematopoietic stem cell or bone marrow transplant (stem cell therapy for 
knee arthritis is not excluded) 
16. Known hypersensitivity to vadadustat, epoetin alfa, or any of their excipients 
17. 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 
Screening (subjects may participate in another concurrent study only if that study is a non-
interventional, observational investigation) 
18. Previous participation in this study, or previous participation in a study with another hypoxia-
inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) other than vadadustat 
19. For female subjects: 
• Of non-childbearing potential 
o Inability to confirm surgical sterility (e.g., hysterectomy, bilateral tubal ligation, 
bilateral oophorectomy) at least 1 month prior to Screening, or  
o Not considered post-menopausal (no menses for >1 year with follicle stimulating 
hormone [FSH] >40 U/L at Screening)  
• Or, if of childbearing potential,  
o Lack of confirmation of the use of acceptable forms of contraception* for a 
minimum of one complete menstrual cycle prior to Screening 
o Positive serum pregnancy test at SV2 
o Unwilling to use two acceptable forms of contraception* (at least one of which 
must be a barrier method) starting Baseline/Day 1, throughout the Treatment 
Period and for 30 days after the final study drug administration 
(refer to Section 9.1.5, Contraception and Pregnancy Avoidance Measures) 


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20. Breastfeeding during Screening or throughout the Treatment Period and for 30 days after the 
final study drug administration. 
21. Donation of ova starting at Screening, throughout the Treatment Period, and for 30 days after 
the final study drug administration. 
22. Male subjects who have not had a vasectomy and do not agree to the following: use of an 
acceptable form of contraception* (refer to Section 9.1.5, Contraception and Pregnancy 
Avoidance Measures) during the study and for 30 days after the last dose of the study drug; 
to not donate semen during the study and for at least 30 days after the last dose of vadadustat. 
23. Subjects with bilateral native nephrectomy. 
24. Any other reason, which in the opinion of the Investigator, would make the subject not 
suitable for participation in the study. 
7.4 
Retesting and Rescreening 
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 be retested 
once for each laboratory parameter within the 4-week Screening Period, per Investigator 
discretion. 
7.4.2 Rescreening 
Subjects who fail to qualify for the study based on laboratory tests may be considered for 
rescreening at the discretion of the Investigator if it is considered that the subject status has 
changed, and the subject may now qualify for the study.  Additionally, subjects who fail to 
qualify for the study based on inclusion criteria values for 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).  A 
new informed consent is required to be signed prior to every rescreening. 
7.5 
Study Completion, Study Termination, and Individual Site Termination 
7.5.1 Study Completion 
The study will be considered completed after all randomized subjects have completed their final 
study visit (Visit 15/Week 24), Safety Follow-Up or Early Termination). 
7.5.2 Study Termination 
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  Advanced notice is not required if the study is stopped due to safety concerns.  If a 
study site has been suspended or terminated, prompt notification will be given to Investigators, 
IRBs, and regulatory authorities in accordance with regulatory requirements.  Criteria and 
procedures for premature study termination or suspension are detailed in Section 14.1, Criteria 
for Premature Termination or Suspension of the Study. 


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7.5.3 Individual Study Site Termination 
Study participation may be suspended or terminated at an individual study site for various 
reasons.  Criteria and procedures for premature termination or suspension of an study site are 
detailed in Section 14.2, Criteria for Premature Termination or Suspension of Study Sites and 
Section 14.3, Procedures for Premature Termination or Suspension of the Study or Study Sites.  
If a study site has been suspended or terminated, prompt notification will be given to 
Investigators, IRBs, and regulatory authorities in accordance with regulatory requirements.  
7.6 
Subject Completion and Subject Discontinuation 
7.6.1 Subject Completion 
A subject will be considered as having completed the study after completion of their final study 
visit (Visit 15/Week 24, Safety Follow-Up or Early Termination). 
7.6.2 Temporary Interruption of Study Drug 
Subjects who temporarily interrupt their study drug (vadadustat or epoetin alfa) after receiving 
the first dose and prior to completion of the study, will continue with the study visits, safety 
assessments, and other activities as deemed applicable through Week 20, and will complete the 
4-week Safety Follow-Up Period and the Visit 15/Week 24 assessments (see Appendix A: 
Schedule of Activities. 
During the study, a subject may interrupt study drug (vadadustat or epoetin alfa) for any of the 
following reasons: 
• AE 
• Missed dialysis visit (epoetin alfa arm) 
• Investigator’s discretion 
• Rapid rise in Hb (defined as >1.0 g/dL in any 2-week period) 
• Hb above 11.0 g/dL 
• ESA use (vadadustat arm) 
Unless contraindicated, treatment will be resumed whenever possible and assessed at every visit 
following study drug interruption.  
7.6.3 Early Discontinuation from Study (Early Termination) 
Subjects who discontinue prematurely from the study will complete the End-of-Treatment (EOT) 
visit (Visit 14) assessments and will complete the Safety Follow-Up (Visit 15) 4 weeks after 
Visit 14. 
Subjects may discontinue for any of the following reasons: 
• AE 
• Investigator’s discretion 
• Subject withdrawal of consent  


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• Lack of efficacy, defined as inadequate response to vadadustat or epoetin alfa in the 
Investigator’s opinion 
• Lost to follow-up despite reasonable efforts by the Investigator to locate the subject.  
Every reasonable effort is to be made to contact any subject lost to follow-up during the 
course of the study to complete study-related assessments, record outstanding data, and 
retrieve study drug. 
• Death  
• Other reasons (pregnancy, kidney transplantation, specific reasons to be documented by 
the Investigator) 
Subjects who undergo a solid organ (including kidney), hematopoietic stem cell, or bone marrow 
transplantation will have their study medication (vadadustat or epoetin alfa) permanently 
discontinued and will complete the End-of-Treatment (Visit 14) and Safety Follow-Up (Visit 15) 
visit assessments. 
 


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8 
STUDY DRUG AND TREATMENT OF SUBJECTS 
Subjects will receive either vadadustat or epoetin alfa according to the randomization 
assignments provided via the Interactive Web Response System (IWRS) (see Section 8.4.1, 
Randomization). 
Both vadadustat and epoetin alfa will be used as open-label supplies.  All study drug supplies 
will 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 drug for 
dispensing to the subject (Section 8.1, Epoetin Alfa and Section 8.2.2, Dispensing of Vadadustat) 
and for study drug supply accountability (Section 8.3, Vadadustat Accountability and 
Destruction). 
8.1 
Epoetin Alfa 
Epoetin alfa solution for IV injection in multi-dose vials (e.g., 20,000 Units/2 mL and 
20,000 Units/1 mL) or in single-dose vials (e.g., 2,000 Units/mL, 3,000 Units/mL, 
4,000 Units/mL, and 10,000 Units/mL) will be provided by the sites in commercially-approved 
primary packaging and stored per the approved label. 
8.2 
Vadadustat 
8.2.1 Supplies and Storage 
Vadadustat will be provided as 150 mg, white to off-white, round, bi-convex film-coated, 
debossed or non-debossed 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 and local 
regulatory requirements. 
Dose levels utilized in this study will include: 150 mg (1 tablet), 300 mg (2 tablets), 450 mg 
(3 tablets), 600 mg (4 tablets), 750 mg (5 tablets), and 900 mg (6 tablets) per day or TIW. 
Vadadustat will be stored per the product label. 
8.2.2 Dispensing of Vadadustat 
At Baseline/Day 1, subjects who are randomized to vadadustat treatment will be administered the 
first dose of vadadustat at the study site.   
Thereafter, vadadustat will be taken once daily from Baseline/Day 1 to Week 12 and TIW from 
Weeks 12 to 20 if Week 12 criteria are met (Section 8.4.5.2, Transition of Vadadustat Once 
Daily Dosing to TIW Dosing Regimen).  If the Investigator determined criteria for Week 12 is 
not met, daily dosing will continue on an outpatient basis.  Subjects who are randomized to the 
vadadustat treatment arm will be provided with up to 2 bottles of vadadustat.  Each bottle of 
vadadustat will contain 100 tablets of vadadustat (150 mg/tablet).  Subjects may take vadadustat 
with or without food and will be instructed to swallow the tablet(s) whole.  Subjects will be 
instructed to take vadadustat at approximately the same time each day. 
Subjects will be instructed to bring unused vadadustat and empty bottles to each study visit for 
product accountability.  Subjects will be instructed to finish 1 bottle before opening a new bottle. 


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Empty bottles will be collected at the study visits.  Previously dispensed bottles (whether opened 
or unopened) with remaining tablets may be re-dispensed to the subject during the dosing phase 
of the study. 
Resupply of additional vadadustat at subsequent visits will be managed via the IWRS 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. 
8.3 
Vadadustat Accountability and Destruction 
Drug accountability will be an ongoing process throughout the study.  All vadadustat will 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 study site, and study drug dispensed to or returned from 
each subject.  Records will be maintained that accurately reflect the drug accountability of 
vadadustat at all times.  An electronic Diary (eDiary) will be utilized throughout the study to 
guide dosing for subjects in the vadadustat arm (see Section 9.1.2, eDiary). 
Proper drug accountability includes, but is not limited to: 
• Continuously monitoring expiration dates  
• Frequently verifying that actual inventory matches documented inventory. 
• Verifying that the log is completed for all vadadustat received and that all required fields 
are complete, accurate, and legible. 
If any dispensing errors or discrepancies are discovered, the Sponsor will 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 study site 
will complete all instructions outlined in the notification, including segregation of expired 
clinical study material for return to the Sponsor or its designee for destruction as specified by the 
Sponsor. 
Prior to study 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 other study materials will be returned to the 
Sponsor or destroyed at the study site, as specified by the Sponsor.  Appropriate records of the 
disposal will be documented and maintained.  No unused vadadustat may be disposed of until 
fully accounted for by the Sponsor’s monitor (or designee).  Empty containers may be disposed 
of according to local procedures. 
8.4 
Treatment of Subjects 
The aim of the study is to achieve and maintain Hb levels within the target range of 
10.0 to 11.0 g/dL, inclusive, while targeting the middle of the range and minimizing excursions 
outside the target range. 


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8.4.1 
Randomization 
Main Study: 
Subjects will be randomized to either a vadadustat treatment arm or epoetin alfa treatment arm.  
Randomization will be stratified by mean weekly epoetin alfa dose calculated over a period of 
8 weeks prior to SV2: 
• Low epoetin alfa dose group (≤90 U/kg/week) or 
• High epoetin alfa dose group (>90 to <300 U/kg/week) 
In the low epoetin alfa dose group, subjects will be randomized in a 3:3:2 ratio to receive either 
an initial vadadustat daily dose of 450 mg (3 tablets) or 300 mg (2 tablets), or epoetin alfa.  
In the high epoetin alfa dose group, subjects will be randomized in a 3:3:3:2 ratio to receive 
either an initial vadadustat daily dose of 600 mg (4 tablets), 450 mg (3 tablets) or 300 mg 
(2 tablets), or epoetin alfa.  
ESA Hyporesponder Parallel Study: 
Subjects will be randomized in a 1:1 ratio to receive either an initial vadadustat daily dose of 
600 mg (4 tablets) or epoetin alfa. 
Note: No epoetin alfa will be administered after SV2 after the subject has met all eligibility 
criteria and before Baseline/Day 1, for a minimum duration of 5 days in the Main study and 
2 days in the ESA hyporesponder parallel study. 
8.4.2 
Blinding 
This is an open-label study and will not involve any blinding procedures. 
8.4.3 
Measurement of Hb Levels for Dose Adjustment Consideration 
Hb values will be measured by a central laboratory.  Study drug treatment will aim to achieve 
and maintain Hb levels within the target range of 10.0 to 11.0 g/dL, inclusive, while targeting the 
middle of the range and minimizing excursions outside the target range.  Hb will be monitored 
throughout the study to determine the dose of study drug (vadadustat or epoetin alfa) that 
subjects will receive (see Section 8.4.6, Guidelines for Dose Adjustments).  Hb levels can be 
measured more frequently based on Investigator’s clinical judgment. 
In both the vadadustat and epoetin alfa arm, if dose adjustment is recommended based on Hb 
value and protocol-specified guidelines, dosing instructions can be provided to the subject over 
the telephone or at the next dialysis session at the study site (or dialysis center) or during an 
unscheduled site visit within 3 business days after receiving the Hb result from the central 
laboratory. 
8.4.4 
Epoetin Alfa Dosing Regimen 
Epoetin alfa arm in both the Main study and ESA hyporesponder parallel study: 
For subjects who are randomized to the epoetin alfa treatment arm, the initial dosing regimen in 
the study (starting from Baseline/Day 1) will be approximately the same weekly dose that they 
were receiving prior to randomization.  


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Epoetin alfa dose will be administered based on the subject’s central laboratory Hb value and the 
approved epoetin alfa US PI for adult patients with CKD on dialysis. 
From Baseline/Day 1 to Week 20, dose will be adjusted to achieve and maintain Hb levels within 
the target range of 10.0 and 11.0 g/dL, inclusive. 
8.4.5 
Vadadustat Dosing Regimen and Guidelines for Dose Adjustment 
8.4.5.1 Dosing Regimen for the Vadadustat Treatment Arm 
Subjects in the low epoetin alfa dose group randomized to vadadustat treatment will start at an 
initial dose of vadadustat 300 mg or 450 mg daily.  Subjects in the high epoetin alfa dose group 
randomized to vadadustat treatment will receive an initial dose of 300 mg, 450 mg, or 600 mg 
daily.  Subjects in the ESA hyporesponder parallel study randomized to vadadustat treatment will 
receive a starting dose of vadadustat 600 mg daily.  
After completing the 12-week once daily dosing regimen, subjects randomized to vadadustat 
who meet criteria for switching from daily to TIW dosing will initiate TIW dosing at a starting 
dose 1 tablet greater (+150 mg) than the final dose in the daily dosing period (see 
Section 8.4.5.2, Transition of Vadadustat Once Daily Dosing to TIW Dosing Regimen).  
Subjects who do not meet criteria for switching from daily to TIW dosing will remain on daily 
dosing.  From Baseline/Day 1 to Week 20, dose will be adjusted to achieve and maintain Hb 
levels within the target range of 10.0 to 11.0 g/dL, inclusive.  
8.4.5.2 Transition of Vadadustat Once Daily Dosing to TIW Dosing Regimen 
All subjects randomized to vadadustat who complete 12 weeks of once daily dosing regimen and 
who meet all the Week 12 criteria below will be transitioned to a TIW vadadustat dosing 
regimen.  
Week 12 Transition criteria: 
• Vadadustat daily dose of 600 mg or lower at Week 12 
• Hb within target range of 10.0 to 11.0 g/dL, inclusive, at Week 12 confirmed by central 
laboratory Hb value from Week 11 (11 weeks of treatment completed) 
• No receipt of rescue therapy (ESA or RBC transfusion) for worsening of anemia due to 
CKD from Baseline/Day 1 to Week 12.   
o ESA or RBC transfusion prior to Week 12 for reasons unrelated to worsening of 
anemia due to CKD (e.g., surgery, gastrointestinal bleed, or inadvertent 
administration) is not considered rescue therapy 
• No other reason, based on the Investigator’s clinical discretion, that would make the 
subject not suitable for TIW dosing. 
Selected subjects who meet Week 12 transition criteria will transition to the TIW vadadustat 
dosing regimen at the Week 12 visit.  Subjects on 150 mg, 300 mg, 450 mg, or 600 mg of 
vadadustat daily at the Week 12 visit will transition to an initial vadadustat TIW dose one  tablet 
greater (+150 mg), i.e., 300 mg, 450 mg, 600 mg, or 750 mg vadadustat TIW, respectively.  
Subjects will be instructed to take vadadustat on dialysis days. 


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After 2 weeks of treatment in the TIW vadadustat dosing regimen (at Week 14), subjects in any 
vadadustat TIW dosing arms who have a decline in Hb ≥0.5 g/dL will be eligible for a dose 
increase by 1 tablet, based on the Investigator’s clinical discretion. 
Subjects who are not eligible to switch from daily vadadustat to TIW dosing at Week 12 will 
remain on daily dosing for the remainder of the study.  
Subjects on TIW dosing may be converted back to vadadustat once daily dosing at the discretion 
of the Investigator in the setting of inadequate Hb response.  The starting daily dose after the 
switch from TIW to daily dosing will be based on the Investigator’s discretion after review of the 
subject’s clinical status and dosing history, in particular, the daily dose previously administered 
to the subject prior to the transition to TIW dosing (Week 12).  Subjects who switch from 
vadadustat TIW to daily dosing will continue once daily vadadustat until the end of the 
Treatment Period. 
Subjects in the vadadustat arm will be guided for dosing compliance using an eDiary (see 
Section 9.1.2, eDiary). 
8.4.6 Guidelines for Dose Adjustments 
Dose adjustments will be guided by Hb concentrations and the Guidelines for Dose Adjustment 
(see below).  Hb will be monitored via central laboratory throughout the study to determine if the 
dose of study drug (vadadustat or epoetin alfa) will be adjusted, interrupted, or maintained as 
follows: 
• Dose adjustments are based on the Investigator’s clinical discretion, incorporating the 
protocol guidance below as well as the subject’s current Hb level, trajectory, and 
variability; symptoms; cardiovascular risk; and other features of his/her clinical 
condition(s). 
• If a dose increase or decrease is required to achieve and maintain Hb levels within the 
target range of 10.0 to 11.0 g/dL, inclusive, dose is adjusted by 1 dose level (for 
vadadustat 1 tablet [150 mg], for epoetin alfa approximately 25%). 
• In general, do not increase the dose more frequently than once every 4 weeks.  A one-
time dose increase after 2 weeks is allowed on only two occasions.   
o A subject’s dose may be increased by 1 dose level if the subject has a decline in 
Hb ≥0.5 g/dL from Baseline/Day 1 in the first 2-week period (the initial period 
from Baseline/Day 1 to Week 2 following conversion from prior epoetin alfa 
therapy).   
o A subject’s dose may also be increased by 1 dose level in the first 2-week period 
after initiation of TIW dosing (from Week 12 to Week 14) for subjects that meet 
criteria for transitioning from daily to TIW dosing. 
• Reduce or interrupt the dose in the setting of a rapid rise in Hb (defined as >1.0 g/dL in 
any 2-week period) 
• Reduce or interrupt the dose in the setting of Hb >11.0 g/dL 
• Interrupt the dose in the setting of a Hb >12.0 g/dL until Hb value falls below 11.0 g/dL.  
After Hb falls below 11.0 g/dL, restart study drug and consider restarting at a lower dose. 


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Note: The minimum dose of vadadustat will be 150 mg daily or TIW (1 tablet daily/TIW) and 
the maximum dose will be 900 mg daily or TIW (6 tablets daily/TIW). 
8.4.7 Late or Missed Doses 
Subjects on vadadustat will be instructed to take the study drug at approximately the same time 
each day.  If a dose is forgotten, subjects will be instructed to take the dose as soon as they 
remember during the same day.   
• Daily dosing regimen: If a forgotten dose is not remembered on the same day, the subject 
will skip the dose and resume the normal dosing schedule the following day. 
• TIW dosing regimen: If a forgotten dose is not remembered on the same day, the subject will 
take the dose on the following day (a non-dialysis day).  If a forgotten dose is not 
remembered on the same day or the following day of a long interdialytic gap, the subject will 
take the dose on the subsequent day (the second non-dialysis day).  Thereafter, the subject 
should resume the normal dosing schedule. 
• Subjects will not double-up on missed doses. 
Epoetin alfa dose (including handling of late or missed dose) will be administered at the site and 
titrated based on the subject’s central laboratory Hb value and the approved epoetin alfa US PI 
for adult patients with CKD on dialysis. 
8.4.8 Iron Supplementation 
IV iron will be administered based on ferritin and TSAT levels measured by the central 
laboratory according to the standardized, low-intensity, iron supplementation protocol in Table 1. 
Table 1: 
Iron Supplementation Protocol 
 
Ferritin 
<200 ng/mL 
Ferritin 
200-500 ng/mL 
Ferritin 
>500 ng/mL 
TSAT 
<20% 
IV Iron 100 mg every 
treatment 
(max 400 mg/month) 
IV Iron 50 mg weekly 
Hold 
TSAT 
20-50% 
IV Iron 100 mg every week 
IV Iron 50 mg weekly 
Hold 
TSAT 
>50% 
Hold 
Hold 
Hold 
Intra-dialytic iron preparations (e.g., Triferic) and oral iron supplementation including iron-
containing phosphate binders are prohibited during the study. 
Important: As the study will be assessing PK/PD parameters, and as there are no empirical data 
on concurrent administration of vadadustat and phosphate binders, vadadustat will not be 
administered concurrently with a phosphate binder.  Subjects will be instructed to take phosphate 
binders at least 3 hours before or at least 2 hours after the dose of vadadustat based on the 
guidance in the phosphate binder package inserts. 


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8.4.9 Rescue Therapy 
To ensure the safety of subjects and to standardize the use of rescue in the study, rescue therapy 
guidelines are provided. 
8.4.9.1 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 will 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 medical necessity.  Study drug (vadadustat or 
epoetin alfa) may be continued during the transfusion period. 
Reasons for RBC transfusion will be captured in the appropriate CRF. 
8.4.9.2 ESA Use 
ESA administration will be allowed when medically necessary at the discretion of the 
Investigator.  In general, ESA will not be administered in subjects with Hb ≥8.5 g/dL, and ESA 
will be stopped when Hb ≥9.0 g/dL.  ESA therapy will be administered using an approved ESA 
and dosing as per the local institution’s guidelines and per the approved product label. 
While receiving ESA therapy, subjects randomized to vadadustat must temporarily interrupt 
vadadustat.  A minimum interval will be observed prior to restarting vadadustat after the last 
dose of ESA, and treatment will be resumed after the following intervals: 
• 2 days after last dose of epoetin alfa  
• 7 days after last dose of darbepoetin alfa  
• 14 days after last dose of methoxy polyethylene glycol-epoetin beta  
Following ESA administration, vadadustat will be resumed at the same dose as previously used 
or with one additional tablet (+150 mg) at the discretion of the Investigator. 
Reasons for ESA use will be captured in the appropriate CRF. 
8.4.10 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 clinical judgment.  The method of 
phlebotomy will be in accordance with the study site’s standard clinical practice. 
8.4.11 Treatment Compliance 
Throughout the study, subjects in the vadadustat arm will be guided regarding dosing compliance 
using an eDiary.  The focus of the vadadustat eDiary is to guide subjects to remind them of the 
dose, instruct them to hold their dose for the PK/PD sample dates and guide them if they have 
transitioned from daily dosing to TIW dosing.  Subjects will also be questioned at study visits on 
whether they have questions or have experienced any problems related to the dosing of 
vadadustat.  Subject compliance with eDiary data entry will be routinely monitored to identify 
potential issues that may impact or prevent data entry.  The Investigator will also maintain drug 
accountability logs itemizing all study drugs dispensed to and returned from each subject during 


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the study.  Treatment compliance will be determined from these logs, subject questioning, and 
the study drug Case Report Form (CRF)  
For epoetin alfa, the dose that is administered is required to be entered in the electronic data 
capture (EDC) system, and the EDC system will be used to determine dosing compliance. 
Subjects who miss doses will be counseled on the importance of compliance. 
8.4.12 Continuation of Treatment 
Subjects in the vadadustat dosing groups will not receive vadadustat beyond the Treatment 
Period of approximately 20 weeks.  However, enrollment may be increased by up to 
20 additional subjects on the Main study and up to 30 additional subjects on the ESA 
hyporesponder parallel study to ensure adequate data is captured for the primary, PK/PD, and 
safety endpoints.  Subjects in the vadadustat dosing groups who complete Visit 14 (Week 20), or 
discontinue early, will resume dosing with epoetin alfa (or another ESA) as per standard of care 
after all EOT procedures are completed. 
8.5 
Prior and Concomitant Therapy 
8.5.1 General 
Any medicinal product, prescribed or non-prescribed (including vitamins, minerals, natural 
and herbal remedies, topicals, inhaled, intranasal and dietary supplements) taken before 
entering the study is considered prior medication.  All medicinal products other than the study 
drug, including prescribed or non-prescribed treatments used during the Treatment Period will 
be considered concomitant medication. 
8.5.2 ESAs 
Co-administration of any ESA with vadadustat is 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 8.4.9.2, ESA Use) if deemed 
medically necessary at the discretion of the Investigator.  Guidelines for ESA administration as 
rescue therapy are provided in Section 8.4.9.2, ESA Use.  All efforts will be made to avoid 
inadvertent administration of ESAs resulting from adherence to ESA hemodialysis center 
protocols (e.g., DaVita ESA protocols for patients 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.  A minimum interval will be 
observed prior to restarting vadadustat after the last dose of ESA.  Vadadustat treatment may be 
resumed after the following intervals: 
• 2 days after last dose of epoetin alfa  
• 7 days after last dose of darbepoetin alfa  
• 14 days after last dose of methoxy polyethylene glycol-epoetin beta  
8.5.3 Rosuvastatin, Pravastatin, and Other HMG-CoA Reductase Inhibitors (Statins) 
Rosuvastatin exposure (AUC, Cmax) was increased 2- to 3-fold with co-administration of 
vadadustat based on preliminary data of a drug-drug interaction study in healthy volunteers. For 
subjects randomized to vadadustat who are concomitantly taking rosuvastatin, the recommended 


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maximum daily dose of rosuvastatin is 10 mg. Investigators should review rosuvastatin dosing to 
consider clinical guidelines and local prescribing information including specific guidance and 
product labels with reference to renal impairment as well as hepatic function, concomitant 
medications and other medical factors relevant to the management of the subject.  
Pravastatin exposure was studied in the setting of vadadustat co-administration in healthy 
volunteers. Preliminary results indicate no clinically significant interaction. No dose adjustment 
of pravastatin is necessary. 
Exposure to atorvastatin, fluvastatin, lovastatin, pitavastatin, and simvastatin may be increased 
with co-administration of vadadustat. When used with vadadustat, these statins should be used 
with caution.  
Co-administration of vadadustat may increase exposures to other drugs that are substrates of 
BCRP, OATP1B1, and/or OATP1B3.  
8.5.4 Dialysis Treatment and Renal Replacement Therapy 
Information on dialysis treatment including dialysis vascular access type, dialysis adequacy, and 
history of and changes in renal replacement therapies will be collected as described in Section 9, 
Study Procedures and Schedule of Activities and Appendix A: Schedule of Activities. 
8.5.5 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 had previous 
participation in a study with another HIF-PHI other than vadadustat. 
Additionally, subjects should not take another investigational medication while participating in 
this study.  Subjects may participate in another concurrent study only if that study is a non-
interventional, observational investigation. 


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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: 
• Eligibility Screening Period (from Day -28 to Baseline/Day 1) 
The Screening Period starts at the time the informed consent is signed and will be a 
maximum of 28-days in duration.  Two Screening visits (SV1 and SV2) must be 
performed within the Screening Period and prior to dosing (Baseline/Day 1).   
o Screening Visit 1 (SV1) 
o Screening Visit 2 (SV2) 
• Study Treatment Period will consist of study visits from Baseline/Day 1 through 
Week 20 visit.  In weeks where there is no schedule study visit a subject will have a 
status check performed during one of their dialysis treatment appointments. 
o Baseline/Day 1, Visit 1 
o Visit 2, Week 1 +5 days 
o Visit 3, Week 2 ± 3 days 
o Visit 4, Week 4 ± 3 days 
o Visit 5, Week 6 ± 3 days 
o Visit 6, Week 8 ± 3 days 
o Visit 7, Week 10 ± 3 days 
o Visit 8, Week 11 ± 3 days 
o Visit 9, Week 12 ± 3 days (Transition to TIW dosing if all Week 12 criteria are 
met) 
o Visit 10, Week 13 +5 days 
o Visit 11, Week 14 ± 3 days 
o Visit 12, Week 16 ± 3 days 
o Visit 13, Week 18 ± 3 days 
o Visit 14, Week 20 ± 3 days (EOT visit) 
• Safety Follow-Up Period (from Week 20 to 24) 
o Visit 15, Week 24 visit ± 5 days 
The following sections describe the procedures to be completed during the study.  Subjects are to 
be assessed by the same Investigator or study site personnel whenever possible. 
9.1 
Administrative Procedures 
9.1.1 Informed Consent 
Informed consent will be obtained and legally signed prior to the subject entering into the study 
and before any protocol-directed procedures (including Screening activities) are performed (see 
Section 15.3, Subject Information and Consent).  After providing informed consent and receiving 
a unique subject identification number, subjects will undergo various Screening activities.  


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9.1.2 eDiary 
An eDiary will be utilized throughout the study for completion of SF-36 and PGI assessments.  
In addition, the eDiary will guide dosing for subjects in the vadadustat arm.  The focus of the 
vadadustat eDiary is to guide subjects to remind them of the dose, instruct them to hold their 
dose for the PK/PD sample dates and guide them if they have transitioned from daily dosing to 
TIW dosing.  At SV2, subjects will be instructed on data entry procedures for the eDiary.  
Subject compliance with eDiary data entry will be routinely monitored to identify potential 
issues that may impact or prevent data entry. 
9.1.3 Documentation of Screen Failures 
Investigators will account for all subjects who sign informed consent and will maintain a log of 
subjects screened and indicate who was randomized or excluded and reasons for screen failure.  
If the subject is found to be ineligible for randomization, the reason(s) for ineligibility and not 
proceeding to Screening or study enrollment, will be documented by the Investigator. 
Screening numbers assigned to subjects who fail Screening will not be re-used. 
9.1.4 Status Check 
In weeks where there is no scheduled study visit, a subject will have a status check performed 
during one of their dialysis treatment appointments in the week.  It will include a review of the 
subject’s vital signs and a review of current health status for identification of any issues that may 
require follow-up by the Investigator or delegated staff personnel.  Documentation of the review 
must be done in the subject’s source documentation.  No data will be captured on the status 
checks in the EDC system.  If an AE is identified at the status check or other actions result from 
the status check, these will be captured per the protocol. 
9.1.5 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 of vadadustat in the rat are ongoing, 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 drug. 
Adequate contraception for subjects is defined as follows: 
• For females of non-childbearing potential 
o Confirmation of surgical sterility (e.g., hysterectomy, bilateral tubal ligation, 
bilateral oophorectomy) at least 1 month prior to Screening, or  
o Post-menopausal (no menses for >1 year with FSH >40 U/L at Screening)  
• For females of childbearing potential  
o Subjects must confirm the use of acceptable forms of contraception*, for a 
minimum of one complete menstrual cycle prior to Screening.  


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o Must have a negative serum pregnancy test at SV2. 
o Starting Baseline/Day 1, subjects must use two acceptable forms of contraception* 
(at least one of which must be a barrier method) throughout the Treatment Period 
and for 30 days after the final study drug administration 
• For males subjects who have not had a vasectomy must agree to the following: use of an 
acceptable form of contraception* during the study and for 30 days after the last dose of 
the study drug; to not donate sperm during the study and for at least 30 days after the last 
dose of vadadustat. 
*  Acceptable forms of contraception include: 
• Established use of oral, injected or implanted hormonal methods of contraception. 
• Placement of an intrauterine device or intrauterine system. 
• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository. 
9.1.6 Laboratory Accreditation and Reference Ranges 
The Investigator and the Sponsor will maintain a copy of the laboratory accreditation and the 
reference ranges for the central laboratory used for clinical laboratory evaluations.  Additionally, 
other accreditation(s) will be collected as required. 
9.2 
Study Procedures and Evaluations 
9.2.1 Clinical Evaluations 
The following clinical evaluations will be conducted during the course of the study.  If the 
evaluations occur on a hemodialysis day, the evaluations will be completed before dialysis, if 
applicable. 
• 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 will be documented.  After SV2, an abbreviated, symptom-directed physical 
examination will be performed at the discretion of the Investigator, as clinically 
indicated. 
• Dialysis Adequacy: Dialysis adequacy, as available from local collection, will be 
recorded in the CRF at SV1 and Visits 9 and 14 (EOT). 
• SF-36 HRQOL and PGI-S: The SF-36, a patient-reported survey of patient health, and 
PGI-S will be completed at SV2, Visits 9, 14 (EOT) and 15.  Assessments will be 
completed by subjects using the eDiary. The PGI assessment will be completed after the 
other assessments. 
• PGI-C: The PGI-C will be completed at the Safety Follow-Up (Visit 15).  The assessment 
will be completed by subjects using the eDiary.  The PGI assessment will be completed 
after the other assessments.  
• Vital Sign Measurements: Vital signs will include temperature, heart rate (HR), BP, 
respiratory rate (RR), and dry weight.  Temperature, HR, BP, and RR will be assessed in 


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the seated position after 5 minutes of rest.  For BP, a total of two measurements at 
intervals of at least 2 minutes should be performed.  Temperature, HR, BP, and RR will 
be collected at SV1, SV2, Baseline/Day 1, during all study visits, and Visit 14 (EOT).  
Measurements will be taken prior to blood draws when possible.   
Dry weight will be collected for all subjects at SV2, Baseline/Day 1, Visit 9 and 14 
(EOT).  For subjects on epoetin alfa, subjects will be weighed for dosing as per the local 
standard of care. 
• 12-Lead Electrocardiogram (ECG): A standard 12-lead ECG will be performed at 
Baseline/Day 1, which may be obtained up to 3 days prior to Baseline/Day 1.  The ECG 
will be obtained after the subject has been resting comfortably in a supine position for 
approximately 5 minutes and will be taken prior to vital sign assessments and blood 
draws when possible.  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. 
• AE Assessments: AE collection will begin from time of randomization through study end 
(Follow-Up Visit).  The Investigator and study personnel will review each subject’s 
laboratory and clinical evaluation findings and query the subject directly regarding AEs 
(see Section 10, Adverse Events).  Subjects must be followed for AEs until the final 
required protocol visit (study end date) or until all drug-related toxicities and SAEs have 
resolved (or are considered chronic/stable), whichever is later. 
• Prior and Concomitant Medication Recording: All prior and concomitant medications 
(except those routinely administered as part of the hemodialysis procedures, such as 
heparin or saline flushes used for routine catheter maintenance, unless relevant for an AE 
or SAE) taken within 30 days prior to Baseline/Day 1 and through the final study visit 
will be recorded on the appropriate CRF.   
Iron treatment regimen 30 days prior to Baseline/Day 1 and through the final study visit 
will be recorded on the appropriate CRF.  In addition, to ensure adequate collection of 
prior ESA dosing history, a minimum of 8 weeks of ESA therapy prior to start of study 
drug will be recorded on the appropriate CRF page. 
At each study visit, subjects will be asked whether they have started, changed or 
discontinued any medication since their previous study visit.  This includes single use or 
as needed medication use.  All medications and changes in dosage and frequency will be 
recorded on the appropriate CRF Page.  Documentation for all medicinal products will 
include the medication name, indication, dose, dosing frequency and dates of 
administration.   
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.  If blood is collected on a dialysis day, blood draws 
will be done prior to dialysis, if applicable.  The Investigator is responsible for reviewing 
laboratory results for clinical significance. 


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For eligibility purposes, one retest for each parameter may be performed during the Screening 
window.  Refer to Section 7.4.1, Retesting and Section 7.4.2, Rescreening for further details 
regarding repeating laboratory measurements during the Screening Period. 
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 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 drug.  A 
FSH test will be performed at SV2 for post-menopausal females. 
• Complete Blood Count (CBC): A CBC with differential will be performed at 
Baseline/Day 1 and at Visit 14 (EOT).  At all other noted visits in Appendix A: Schedule 
of Activities, including SV1 and SV2, a CBC without differential will be performed.  The 
CBC without differential will include: Hb, hematocrit, RBCs, mean corpuscular Hb, 
mean corpuscular Hb concentration, red cell width distribution, white blood cell count 
and platelets.  The CBC with differential will include the same parameters as CBC 
without differential with the addition of white blood cell count with differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils). 
Hb will be monitored throughout the study via central laboratory to determine the dose of 
study drug (vadadustat or epoetin alfa) that subjects will receive.  Refer to Section 8.4.3, 
Measurement of Hb Levels for Dose Adjustment Consideration.  Hb levels can be 
measured more frequently based on Investigator’s clinical judgment. 
• Reticulocyte Count: An automated reticulocyte count (both absolute and percent) will be 
performed at Baseline/Day 1 and at Visits 2, 4, 6, 8, 9, 10, 12, and 14 (EOT). 
• Folate and Vitamin B12: A blood sample will be drawn at SV1 to assess the folate and 
Vitamin B12 levels. 
• CRP: A blood sample for CRP will be collected at the Baseline/Day 1, 
Visit 9 and 14 (EOT).  
• Serum Chemistry: Blood samples to assess serum chemistry will be collected at SV1, 
Baseline/Day 1, Visit 9 and 14 (EOT).  The serum chemistry will include the following 
assays: sodium, potassium, bicarbonate, chloride, calcium, magnesium, phosphorus, 
glucose, creatinine, blood urea nitrogen, creatine phosphokinase, uric acid, albumin, and 
total protein. 
• Liver Function Tests (LFTs): Blood samples to assess liver function will be collected at 
SV1, Baseline/Day 1, Visit 4, 6, 9, 12 and 14 (EOT).  LFTs will include: total bilirubin, 
alkaline phosphatase (ALP), ALT/SGPT, AST/SGOT, and lactate dehydrogenase. 
• Iron Indices: Blood samples to assess the iron indices will be collected at SV1, 
Baseline/Day 1, Visit 4, 6, 9, 12 and 14 (EOT).  Assessments will include the following 
indices: ferritin, iron, transferrin, TIBC, and TSAT. 


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• Lipid Profile: Blood samples will be collected at the Baseline/Day 1 and Visit 14 (EOT) 
to assess the cholesterol levels and will be tested for the following types of lipids: total 
cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides. 
• Biomarkers (including, but not limited to, vascular endothelial growth factor [VEGF], 
and hepcidin): Samples for VEGF and hepcidin biomarker analyses will be drawn at the 
Baseline/Day 1, Visit 9 and 14 (EOT).   
9.2.2.1 PK/PD Sampling for Subjects Randomized to Vadadustat 
Refer to Appendix B for a schematic overview of the PK/PD samples for the vadadustat arm. 
Blood for measurement of vadadustat, metabolites and EPO level in the vadadustat arm, in both 
the Main study and ESA hyporesponder parallel study, will be collected as outlined below.  
Preferably, PK/PD samples are to be taken on the day of hemodialysis after the first short 
interdialytic interval (e.g., at the second session of the week).   
At Baseline/Day 1, PK/PD samples will be collected prior to dialysis and administration of 
vadadustat. 
At Week 1 (after at least a full week of vadadustat treatment), vadadustat will be administered 
between 15 minutes to one hour prior to the start of dialysis.  Blood samples will be collected as 
follows: 
• 15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes and 5 hours ± 
30 minutes post-dose 
• From subjects enrolled at a subset of study sites only, additional samples will be collected 
at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
On the following non-dialysis day, blood samples will be collected as follows: 
• 15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 5 hours ± 
30 minutes post-dose 
• From subjects enrolled at a subset of study sites only, additional samples will be collected 
at 7 hours ± 30 minutes post-dose 
At Week 11, vadadustat will be administered between 15 minutes to one hour prior to the start of 
dialysis.  Blood samples will be collected as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 5 hours ± 
30 minutes post-dose 
• 
From subjects enrolled at a subset of study sites only, additional samples will be collected 
at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
At Week 13 (after at least one week on TIW vadadustat dosing regimen), vadadustat will be 
administered between 15 minutes to one hour prior to the start of dialysis.  Blood samples will be 
collected as follows: 
• 15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 5 hours ± 
30 minutes post-dose 
• From subjects enrolled at a subset of study sites only, additional samples will be collected 
at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 


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Note: Week 13 PK/PD sampling will only be done in subjects who transition to vadadustat TIW 
dosing regimen.  Subjects who do not qualify for vadadustat TIW dosing and remain on daily 
dosing regimen will not have Week 13 PK/PD sampling. 
9.2.2.2 PK Sampling for Subjects Randomized to Epoetin Alfa 
Refer to Appendix B for a schematic overview of the PK samples for the epoetin alfa arm. 
Blood for measurement of EPO level in the epoetin alfa arm, in both the Main study and ESA 
hyporesponder parallel study, will be collected as outlined below.  Preferably, PK samples are to 
be taken on the day of hemodialysis after the first short interdialytic interval (e.g., at the second 
session of the week).   
At Baseline/Day 1, a sample will be collected prior to dialysis and administration of epoetin alfa. 
At Week 1 (after at least a full week of study epoetin alfa treatment), epoetin alfa will be 
administered within 1 hour after start of dialysis.  Blood samples will be collected as follows: 
• 15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 5 hours ± 
30 minutes post-dose 
• From subjects enrolled at a subset of study sites only, additional samples will be collected 
at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
On the following dialysis day, one blood sample will be collected 15 minutes prior to 
administration of epoetin alfa. 
9.2.2.3 PK/PD Sampling   
For all PK and PD sampling the time of the previous dose of study drug (vadadustat or epoetin 
alfa) is to be collected for the pre-dose sample and the timing of administration of study drug 
(epoetin alfa and vadadustat) and the start and stop time of the dialysis session will be recorded. 
9.3 
Schedule of Activities 
The Schedule of Activities (see Appendix A: Schedule of Activities) shows the timing of 
planned study procedures.  Every effort will be made to adhere to this procedure schedule and all 
assessments will be completed at each study visit.  Where possible, study visits will be 
performed and scheduled as part of a patients regularly scheduled dialysis session. 
9.3.1 Screening Visits 
Subjects will need to sign a full consent form prior to SV1 procedures.  The consent form 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 28-days in duration.  Two Screening visits (SV1 and 
SV2) must be performed within the Screening Period and prior to dosing (Baseline/Day 1).   
The Investigator will arrange for sufficient time (a minimum 4 days) between SV1 and SV2 and 
between SV2 or last retest (if applicable) and Baseline/Day 1 to allow for all laboratory results to 
be available that are required to assess eligibility for the next study visit.   
In addition, subjects will be required to stop epoetin alfa treatment for a minimum duration of 
5 days before Baseline/Day 1 in the Main study and for a minimum of 2 days before 
Baseline/Day 1 in the ESA hyporesponder parallel study. 


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After obtaining informed consent, subjects will undergo a number of Screening activities.  
9.3.1.1 SV1 
At SV1, the following activities/procedures will be performed: 
• Informed consent  
• Review of eligibility criteria 
• Review of acceptable methods of contraception 
• Vital signs including temperature, HR, BP, and RR (assessed in seated position after 
5 minutes of rest and prior to blood draws) 
• Dialysis adequacy 
• Laboratory procedures: 
o CBC (without differential) 
o Folate and vitamin B12 levels 
o Serum Chemistry  
o LFTs  
o Iron indices 
Refer to Section 7.4.1, Retesting and Section 7.4.2, Rescreening for further details 
regarding repeating laboratory measurements during the Screening Period. 
• Visit registration in IWRS 
• Review of prior medication 
• Epoetin alfa dosing will continue 
9.3.1.2 SV2 
At SV2, the following activities/procedures will be performed: 
• Review of eligibility criteria 
• Review of acceptable methods of contraception 
• SF-36 and PGI-S assessments 
• Physical examination (including height) 
• Demographics and medical history 
• Vital signs including temperature, HR, BP, and RR (assessed in seated position after 
5 minutes of rest and prior to blood draws), and dry weight 
• Laboratory procedures: 
o Serum pregnancy test for females of childbearing potential (eligible subjects will be 
advised to use an adequate contraceptive method see Section 9.2.2, Laboratory 
Evaluations for additional information).  A FSH test will be performed at SV2 for 
post-menopausal females. 
o CBC (without differential) 
Subjects must have 2 Hb values measured by the central laboratory during Screening as 
indicated below: 
o Main study: 2 Hb values between 8.5 and 11.0 g/dL, inclusive 
o ESA hyporesponder parallel study: 2 Hb values between 8.0 and 10.0 g/dL, inclusive 
If the subject’s Hb does not qualify after SV1, SV2, or retest Hb, the subject will be 
considered a screen failure 


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• Visit registration in IWRS 
• Introduction to and instruction on the use of the eDiary 
• Prior and current medication use 
• Epoetin alfa dosing will stop for a minimum of 5 days in the Main study or 2 days in the 
ESA hyporesponder parallel study until Baseline/Day 1 
9.3.2 Baseline/Day 1 (Visit 1) 
Epoetin alfa dosing will have been stopped for a minimum of 5 days in the Main study or 2 days 
in the ESA hyporesponder parallel study until Baseline/Day 1. 
On Baseline/Day 1, blood sample collection and other Baseline/Day 1 procedures will be 
completed prior to dosing with study drug (vadadustat or epoetin alfa).  On Baseline/Day 1, 
study drug will be administered at the study site, and will be administered after the PK sample is 
collected and prior to the dialysis session.  
At Baseline/Day 1, the following activities/procedures will be performed: 
• Review of study eligibility criteria 
• Review acceptable methods of contraception 
• Abbreviated, symptom-directed physical examination, at the discretion of the 
Investigator, as clinically indicated 
• 12-lead ECG.  ECGs will be completed prior to blood draws when possible and will be 
obtained after the subject has been resting supine comfortably for approximately 
5 minutes; ECG may be completed and reviewed by the Investigator on Baseline/Day 1 
or if needed for scheduling reasons (e.g., dialysis treatment is scheduled for early 
morning of Baseline/Day 1), the ECG can be completed and reviewed up to 1-3 days 
prior to Baseline/Day 1. 
• Randomization 
• Vital signs including temperature, HR, BP, and RR (assessed in seated position after 
5 minutes of rest and prior to blood draws), and dry weight 
• Laboratory Procedures: 
o CBC (including differential) 
o Reticulocyte count 
o CRP 
o Serum chemistry  
o LFTs 
o Iron indices 
o Lipid profile 
o Biomarkers (VEGF, and Hepcidin) 
o PK prior to vadadustat or epoetin alfa dosing (see Section 9.2.2.1, PK/PD Sampling 
for Subjects Randomized to Vadadustat and Section 9.2.2.2, PK Sampling for 
Subjects Randomized to Epoetin Alfa) and prior to the dialysis session 
• Review of medical history for new conditions since SV2 
• Review of medication use since SV2 
• Study drug assessments and procedures: 
o Subject will take/receive their first dose of study drug at the study site during 
Baseline/Day 1 


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o For subjects in the vadadustat treatment arm only: 
▪ Initiate vadadustat dosing 
▪ Vadadustat drug dispensation 
▪ Review vadadustat dosing instructions 
o Epoetin alfa dosing will continue for the subjects in the epoetin alfa arm 
o Iron supplementation as needed to maintain ferritin ≥100 ng/mL or TSAT ≥20% (per 
local product label; see Section 8.4.8, Iron Supplementation 
o Visit registration in IWRS 
• Safety assessments: 
o AE review as needed  
o Review use of rescue therapy 
9.3.3 Visit 2 to Visit 13 (Weeks 1 to 20) 
At the Baseline/Day 1, Visit 7 and Visit 9, subjects in the vadadustat treatment arm will be 
reminded and instructed to hold their vadadustat dose on the day of Visit 2, Visit 8, and if 
applicable Visit 10, respectively, as blood sample for PK analysis will be collected on the day of 
Visit 2, Visit 8, and Visit 10 prior to vadadustat administration at the study site. 
The following activities/procedures will be performed at Visit 2 to Visit 13, unless noted 
otherwise: 
• Abbreviated, symptom-directed physical examination, at the discretion of the 
Investigator, as clinically indicated 
• Vital signs including temperature, HR, BP, and RR (assessed in seated position after 
5 minutes of rest and prior to blood draws).  Dry weight will be collected at Visit 9 only.  
o A status check (BP, vital signs, and review of current health status) will be 
performed during weeks with no scheduled study visit. 
• Dialysis adequacy, as available from local information (Visit 9 only) 
• SF-36 and PGI-S assessments (Visit 9 only) 
• Safety assessments: 
o AE review 
o RBC transfusions and ESA rescue  
o Therapeutic phlebotomy 
• Laboratory procedures (if blood samples are collected on a day of dialysis, blood draws 
will be done prior to dialysis, if applicable): 
o CBC  
o Reticulocyte count (Visit 2, 4, 6, 8, 9, 10 and 12 only) 
o CRP (Visit 9 only) 
o Serum chemistry (Visit 9 only) 
o LFTs (Visit 4, 6, 9 and 12 only) 
o Iron indices (Visit 4, 6, 9 and 12 only) 
o Biomarkers (VEGF and Hepcidin, Visit 9 only) 
o Vadadustat PK/PD sampling (Visit 2, 8 and 10 only) for details, see 
Section 9.2.2.1, PK/PD Sampling for Subjects Randomized to Vadadustat and 
Section 9.2.2.3, PK/PD Sampling) 


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o Epoetin alfa PK sampling (Visit 2 only) for details, see Section 9.2.2.2, PK 
Sampling for Subjects Randomized to Epoetin Alfa and Section 9.2.2.3, PK/PD 
Sampling) 
• Medication assessments and procedures: 
o Review of concomitant medications 
o Subjects in epoetin alfa treatment arm will continue to receive epoetin alfa  
o For subjects in the vadadustat treatment arm only: 
▪ Visit registration in IWRS (for bottle dispensing only) 
▪ Vadadustat drug dispensation (scheduled Visits 4, 6, 9 and 12) 
▪ Review vadadustat dosing instructions 
▪ Review of vadadustat dosing compliance 
▪ Vadadustat reconciliation 
o Review of iron supplementation as needed to maintain ferritin ≥100 ng/mL or TSAT 
≥20% (per local product label; see Section 8.4.8, Iron Supplementation) 
9.3.4 EOT Visit 14 (Week 20) 
EOT evaluations will be performed when the Treatment Period (Baseline/Day 1 to Visit 13) is 
completed.  Subjects who prematurely discontinue study drug for any reason will also attend this 
visit.  
At Visit 14 (EOT), the following activities/procedures will be performed: 
• Vital signs including, HR, BP, and RR (assessed in seated position after 5 minutes of rest 
and prior to blood draws), as well as temperature and dry weight 
• Dialysis adequacy, as available from local information 
• SF-36 and PGI-S assessments 
• Safety assessments: 
o AE review 
o RBC transfusions and ESA rescue  
o Therapeutic phlebotomy 
• Laboratory Procedures: 
o CBC (with differential) 
o Reticulocyte count 
o CRP 
o Serum chemistry 
o LFTs 
o Iron indices 
o Lipid panel 
o Biomarkers (VEGF and Hepcidin) 
• Medication assessments and procedures: 
o Review of concomitant medications 
o Subjects in epoetin alfa treatment arm will continue to receive epoetin alfa.  
o For subjects in the vadadustat treatment arm only: 
▪ Review of vadadustat dosing compliance 
▪ Vadadustat reconciliation 
▪ Resume dosing with epoetin alfa (or another ESA): After the end of 
vadadustat treatment at Visit 14 (or following early discontinuation of 


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vadadustat), subjects may resume dosing with epoetin alfa (or another ESA), 
based on standard of care. 
o Visit registration in IWRS 
o Review of iron supplementation as needed to maintain ferritin ≥100 ng/mL or TSAT 
≥20% (per local product label; see Section 8.4.8, Iron Supplementation) 
9.3.5 Safety Follow-Up Visit 15 (Week 24) 
At the Visit 15, the following activities/procedures will be performed:  
• SF-36 HRQOL, PGI-S, and PGI-C assessments 
• AE review 
• Review use of rescue therapy (RBC transfusions and ESA rescue therapy) 
• Review use of therapeutic phlebotomy 
• Concomitant medication review 
9.3.6 Unscheduled Visits 
Unscheduled assessments may be conducted at any time as medically warranted.  The following 
activities/procedures will be performed at minimum: 
• Safety assessments: 
o AE review 
o RBC transfusions and ESA rescue  
o Therapeutic phlebotomy 
• Medication assessments and procedures: 
o Review of concomitant medications 
• Any other procedures that are medically warranted at the discretion of the Investigator. 


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10 ADVERSE EVENTS 
10.1 Definitions 
10.1.1 AEs 
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. 
AEs therefore include the following:  
• All AEs, whether suspected to be causally related to study drug or otherwise. 
• All AEs secondary to any medication overdose, medication error, 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 (e.g., a fall secondary to dizziness), the medical condition (dizziness) and the 
accident (fall) will 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 (e.g., elevated liver enzymes in a subject with jaundice) will 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 will 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 will be the reported AE term, instead of fever and dyspnea, 
when the diagnosis has been established.  Signs and symptoms will 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, 
will not be reported as AEs.  However, the medical condition for which the procedure was 
performed will be reported if it meets the definition of an AE.  For example, an acute 


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appendicitis that begins during the AE reporting period will 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 will not be reported as AEs. 
Pre-existing Conditions – In this study, a pre-existing condition (i.e., a disorder present before 
the AE reporting period started and noted on the pretreatment medical history/physical 
examination form) will 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 will 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 will also be reported as AEs.  Any abnormal laboratory value which requires 
treatment or further diagnostic testing and/or results in discontinuation from study will 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 will be reported to the Sponsor’s Medical Monitor or Contract Research Organization 
(CRO) designee within 24 hours of awareness as an SAE with ‘other medically important event’ 
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 (e.g., 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 study drug; 
• 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; 
• Study drug will not be resumed until monitoring indicates abnormalities have resolved or are 
stable. 
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 will not be 
considered an AE unless the worsening of anemia is associated with a cause other than the 
subject’s CKD. 
Transplantation – During this study, it is anticipated that subjects may receive a kidney 
transplant.  These events will not be recorded as AEs.  Subjects will discontinue study drug for 


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receipt of a kidney, other solid organ, hematopoietic stem cell or bone marrow transplant, will 
complete the EOT visit (Visit 14) assessments and will complete the Safety Follow-Up (Visit 15) 
4 weeks after Visit 14 as described in Section 7.6.3, Early Discontinuation from Study. 
10.1.2 SAEs 
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 situation will also 
be classified as serious for purposes of this study:  
• Malignancies – Newly diagnosed malignancies or a recurrence of a malignancy will 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.   
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 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 (e.g., 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. 


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10.2 Eliciting AE 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 randomization. 
10.3 Reporting 
Each AE is to be classified by the Investigator as SERIOUS or NONSERIOUS. 
All AEs that occur in study subjects during the AE reporting period specified in this protocol will 
be reported, whether or not the event is considered related to study drug (vadadustat or epoetin 
alfa). 
10.3.1 Reporting Period 
The AE reporting period for this study begins from time of randomization and ends at the final 
protocol-required Safety Follow-Up (Visit 15). 
In addition, any SAE that occurs subsequent to the AE reporting period that the Investigator 
assesses as related to the study drug will also be reported as an SAE. 
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, will be reported to the Sponsor’s Medical Monitor or 
CRO designee within 24 hours after the Investigator becomes aware of the SAE.  Compliance 
with this time requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
The initial SAE report should be completed as fully as possible but will contain, at a minimum 
items number 1 to 6: 
1. Subject number/ID, sex, and age/date of birth 
2. The date of report 
3. Name of the reporter 
4. Name of the suspected medicinal product 
5. A description of the event, including event term(s), seriousness criteria, and a clinical 
summary of the event 
6. Causality assessment 
If the causality assessment is not provided in the initial report an updated report with the 
causality must be provided within 24 hours, once assessed. 
Information about all SAEs (either initial or follow-up information) will be collected and 
recorded in English on the electronic SAE Report Form within the EDC system.  The 
Investigator will assess the relationship to each specific component of the study treatment.  If the 
event meets serious criteria and it is not possible to access the EDC system, a paper SAE Report 
Form will be sent to the CRO via email or fax, or the Investigator will call the CRO SAE hotline 


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within 24 hours of being made aware of the SAE (reference the site manual for contact 
information).  When the EDC system becomes available again, the SAE information will be 
entered within 24 hours of the system becoming available. 
The Investigator will report follow-up information relating to an SAE to the Sponsor’s Medical 
Monitor or CRO designee within 24 hours of awareness 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 will be entered within 
24 hours.  The subject will 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 IRB 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 study site. 
10.3.4 Relationship to Study Drug 
The causal relationship of the AE to study drug (vadadustat or epoetin alfa) will be assessed by 
both the Investigator and the Sponsor.   
The assessment of causal relationship to study drug will be evidence-based, and not based on the 
premise that all AEs are possibly causally related to study drug until proven otherwise.   
Examples of evidence that would suggest a causal relationship between the study drug and the 
AE include the occurrence of an AE that is uncommon and known to be strongly associated with 
drug exposure (e.g., 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 drug are generally uninformative and do 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 treatment, 


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other treatment (concomitant, or previous), withdrawal of study treatment, administration error, 
protocol-related procedure, others (specify). 
10.3.5 Severity 
The Investigator will assess each AE as either MILD, MODERATE, or SEVERE using the 
following guidelines to describe the maximum severity of the AE: 
MILD: Does not interfere with subject's usual function 
MODERATE: Interferes to some extent with subject's usual function 
SEVERE: Interferes significantly with subject's usual function 
Note that a severe AE is not necessarily a serious AE.  For example, a headache may be severe 
in intensity, but would not be classified as serious unless it met 1 of the criteria for serious events 
listed above. 
10.3.6 Follow-up of Unresolved Events 
All AEs will be followed until they are resolved or the Investigator assesses them as chronic or 
stable or the subject’s participation in the trial ends (i.e., until a final report is completed for that 
subject). 
In addition, all SAEs and those nonserious events assessed by the Investigator as related to the 
study drug will continue to be followed even after the subject's participation in the trial is over.  
Such events will be followed until they resolve or until the Investigator assesses them as 
“chronic” or “stable”.  Resolution of such events is to be documented on the appropriate CRF. 
10.4 Exposure In-Utero 
A pregnancy in a female subject will be confirmed by a positive serum β human chorionic 
gonadotropin test. 
The study drug will 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 drug 
(vadadustat or epoetin alfa) or within 30 days of discontinuing the study drug, the pregnancy will 
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 will also be reported. 
The Pregnancy Reporting Form/Exposure in Utero Form will be completed with all known 
information regarding the pregnancy at the time of reporting.  Study 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 an SAE 
(i.e., spontaneous abortion, stillbirth, neonatal death within 1 month of birth, or congenital 


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anomaly [including that in an aborted fetus]), the Investigator will also follow the procedures for 
reporting an 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 will be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 1 month that the Investigator 
assesses as related or unrelated to the in utero exposure to the study drug will also be 
reported. 
• In the case of a live birth, the “normality” of the newborn can be assessed at time of birth. 
• The “normality” of an aborted fetus can be assessed by gross visual inspection unless 
there are pre-abortion laboratory findings suggestive of a congenital anomaly. 
10.5 Special Situations 
Certain safety events, called ‘Special Situations’, that occur in association with study drug may 
require reporting.  These Special Situations include, but are not limited to, the following: 
• Overdose of the medicinal product 
o Epoetin alfa overdose – The PI or SmPC will be referenced for information on 
epoetin alfa overdosing.   
o Vadadustat overdose – There is no known antidote for vadadustat.  In cases of 
suspected overdose, subjects will 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 will be 
discontinued and standard treatment for polycythemic hyperviscosity syndrome 
will be initiated (i.e., phlebotomy). 
Dose-limiting toxicity in exploratory toxicology studies was due to 
hemoglobinuric nephropathy in the rat and emesis associated with body weight 
loss in the dog.  In the rat, doses ≥500 mg/kg were not tolerated in two 7-day 
exploratory toxicology studies.  The probable cause of the findings is considered 
to be intravascular hemolysis leading to hemoglobinuric nephropathy. 
The clinical data from human volunteer subjects and renal study subjects 
demonstrate that currently there is no evidence of any drug-related hemolysis 
associated with vadadustat at the doses studied.  The highest dose in the majority 
of subjects exposed to vadadustat was up to 600 mg daily with minimal exposures 
at doses higher than this (up to 1200 mg single dose and up to 900 mg daily for 
10 days).  No conclusion concerning the safety profile of vadadustat at doses 
higher than 600 mg daily can be drawn. 


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• 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 exposure to the 
Sponsor’s medicinal product [e.g., name confusion]) 
• Drug-drug interaction. 
Special situations will be reported on the Special Situations CRF whether they result in an 
AE/SAE or not.  Special situations with associated AE/SAE will also be reported on the 
corresponding AE/SAE forms, following applicable AE or SAE process. 
10.6 Safety Monitoring 
This is an open label study allowing the study team full access to safety data which will be 
reviewed on a regular basis, throughout the course of the study.  Safety monitoring will be 
performed as described in the Medical Monitor Plan. 
 


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11 DATA ANALYSIS 
Data collected throughout the study will be summarized using descriptive statistics and listed in 
the by-subject listings.  Continuous variables will be summarized using number of subjects with 
mean, standard deviation (SD), 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. 
11.1 Sample Size Estimation 
Approximately 95 subjects are planned for enrollment in the Main study with 40 and 55 subjects 
randomized to the low epoetin alfa dose group and the high epoetin alfa dose group, respectively.  
Approximately 30 subjects are planned for enrollment in the ESA hyporesponder parallel study.  
Sample size reflects the exploratory nature of this study. 
Enrollment may be increased by up to 20 additional subjects in the Main study and by up to 
30 additional subjects in the ESA hyporesponder parallel study to ensure adequate data is 
captured for the primary, PK/PD, and safety endpoints. 
11.2 Study Analysis Populations 
The following analysis populations will be used in this study: 
• Randomized population: defined as all randomized subjects.  Analyses of this population 
will be based on the randomized treatment. 
• Full Analysis Population (FAS): all subjects in the randomized population who received 
at least one dose of study drug and had at least one Hb assessment during the primary 
efficacy evaluation period.  Analyses of this population will be based on the randomized 
treatment. 
• Safety Population: all subjects in the randomized population who received at least one 
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 epoetin alfa will be 
classified by the more frequently received drug. 
• Per protocol (PP) population: all randomized subjects who received study drug during the 
primary evaluation period, had at least one Hb assessment during the primary efficacy 
evaluation period, received no rescue therapy (with ESA or transfusion) prior to the 
evaluation period, and had no major protocol deviation affecting the primary endpoint 
analyses.  Major protocol deviations leading to exclusion from the PP population will be 
specified prior to database lock and recorded in a separate document.  Analyses of this 
population will be based on actual treatment received. 
Efficacy analyses will utilize the Randomized, Full Analysis, and PP Populations while safety 
analyses will utilize the Safety Population. 


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11.3 Analysis of Demographic and Pretreatment Variables 
Descriptive statistics will be generated for demographic and pretreatment variables for 
Randomized Population and other analysis populations which will be defined in detail in the 
Statistical Analysis Plan. 
Medical history terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by System Organ Class (SOC) and Preferred Term (PT) for each 
treatment group based on the safety population. 
11.4 Disposition of Subjects 
The number and percentage of subjects randomized and included in each analysis population will 
be summarized by treatment and overall.  Reasons for excluding subjects from the analysis 
populations will be presented in a by-subject listing. 
The number of randomized subjects who completed the study, discontinued early from study 
drug, completed or discontinued from the study, and reasons for discontinuation will be 
summarized by treatment group and overall. 
11.5 Missing Data 
It is expected that few subjects will discontinue Follow-Up.  The reasons for any missing data 
will be summarized by treatment arm.  Missing Hb values will be imputed using last observation 
carried forward (LOCF). 
11.6 Efficacy Analyses 
The primary efficacy endpoint as well as all other secondary endpoints will be summarized using 
descriptive statistics (means or proportions) by treatment groups and in total, 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. 
11.7 Safety Analyses 
Safety analyses will be descriptive in nature.  
All AEs will be coded using MedDRA.  Treatment-emergent and post-treatment AEs will be 
summarized by SOC and PT for each treatment group.  AEs will also be summarized by their 
maximum severity. 
Summaries will also be provided for the following types of AEs: 
• SAEs 
• Related AEs, as determined by the Investigator 
• AEs leading to early discontinuation of study drug 
All Hb related safety endpoints will be tabulated for each treatment groups. 
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. 


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11.8 Additional Assessments 
PK and PD parameters will be summarized using descriptive statistics: number of subjects, 
mean, median, SD, minimum, maximum, and coefficient of variation, geometric mean and 
geometric mean SD.  Mean and individual plasma concentration-time profiles will be presented 
graphically in both linear scale and log-linear scale. 
11.8.1 PK Assessments 
A population PK analysis will be conducted to describe vadadustat PK and determine the 
covariates that impact the PK profile (i.e., demographics, laboratory values, concomitant iron, 
dosing relative to dialysis, etc.).  PK analysis will be reported separately. 
11.8.2 PD Assessments 
An exposure-response analysis of vadadustat, EPO and other PD measures will be conducted as 
deemed appropriate.  PD analysis will be reported separately. 
11.8.3 Concomitant Medications 
Prior and concomitant medications will be coded using World Health Organization Drug 
dictionary.  Refer to Section 8.5, Prior and Concomitant Therapy. 
11.8.4 Biomarkers 
Biomarkers (including, but not limited to, hepcidin and VEGF) will be summarized descriptively 
at Baseline/Day 1 and by visit post-Baseline/Day 1.  


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12 DATA HANDLING AND RECORD KEEPING 
12.1 CRFs/EDC 
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.  CRFs available through this system are required and will be completed for 
each randomized subject. 
Any form of data from the electronic system are the sole property of the Sponsor and will 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 will 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 will match the data in those charts. 
12.2 Record Retention 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, e.g., 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 (e.g., letters, meeting minutes, and 
telephone calls reports).  The records will be retained by the Investigator according to the 
International Council for Harmonisation of Technical Requires for Pharmaceuticals for Human 
Use (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 (e.g., retirement and relocation), the Sponsor will be prospectively notified.  The 
study records will be transferred to a designee acceptable to the Sponsor, such as another 
Investigator, another institution, or to the Sponsor.  The Investigator will obtain Sponsor’s 
written permission before disposing of any records, even if retention requirements have been 
met. 


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13 QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 Study 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 study 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, and/or to 
inspection by appropriate regulatory authorities. 
It is important that the Investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
13.2 Protocol Deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change.  The Investigator is responsible for ensuring the 
study is conducted in accordance with the procedures and evaluations described in this protocol 
and must protect the rights, safety, and welfare of subjects.  The Investigator should not 
implement any deviation from, or changes of, the protocol, unless it is necessary to eliminate an 
immediate hazard to trial subjects.   
A protocol waiver is a documented prospective approval of a request from an Investigator to 
deviate from the protocol.  Protocol waivers are strictly prohibited. 
For the purposes of this protocol, deviations requiring notification to Sponsor are defined as any 
subject who: 
• Entered into the study even though they did not satisfy entry criteria.  
• Developed withdrawal criteria during the study and not withdrawn. 
• Received wrong treatment or incorrect dose.  
• Received excluded concomitant treatment. 
When a deviation from the protocol is identified for an individual subject, the Investigator or 
designee must ensure the Sponsor is notified.  The Sponsor will follow-up with the Investigator, 
as applicable, to assess the deviation and the possible impact to the safety and/or efficacy of the 
subject to determine subject continuation in the study.  
If a deviation impacts the safety of a subject, the investigator must contact the Sponsor 
immediately. 
The Investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately.  All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
Sponsor and maintained within the Trial Master File. 


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Note: Other deviations outside of the categories defined above that are required to be reported by 
the IRB/IEC in accordance with local requirements will be reported, as applicable. 


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14 STUDY DISCONTINUATION/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 will contact all participating subjects within a time period 
specified by the Sponsor to inform them of the decision to discontinue the study. 
14.1 Criteria for Premature Termination or Suspension of the Study 
The following criteria may result in either temporary suspension or early termination of the 
study: 
• New information regarding the safety or efficacy of the study drug 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 
• Request from regulatory agencies 
The Sponsor reserves the right to discontinue the study for other valid administrative reasons. 
If the study has been suspended or terminated, prompt notification will be given to Investigators, 
IRBs, and regulatory authorities in accordance with regulatory requirements. 
14.2 Criteria for Premature Termination or Suspension of 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. 
The Investigator will notify the Sponsor if the trial is terminated by the Investigator or the IRB at 
the site.  If the Investigator, IRB, or Sponsor decides to terminate or suspend the trial conduct at 
a particular study site for safety, non-enrollment, non-compliance with the protocol, or other 
unanticipated reasons, the above parties will be promptly notified. 
14.3 Procedures for Premature Termination or Suspension of the Study or Study 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 study sites during the 
course of termination or study suspension. 
 


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15 ETHICS 
15.1 Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical Principles 
for Medical Research Involving Human Subjects, adopted by the General Assembly of the World 
Medical Association (2013). 
In addition, the study will be conducted in accordance with the protocol, the ICH E6 guideline on 
GCP, and applicable local regulatory requirements and laws. 
15.2 IRB 
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, (e.g., recruitment 
advertisements, if applicable) from the IRB.  All correspondence with the IRB will be retained in 
the Investigator File.  Copies of IRB approvals will 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 approval is where 
the change is necessary to eliminate apparent immediate hazards to the subjects.  In that event, 
the Investigator will notify the IRB and the Sponsor in writing immediately after the 
implementation. 
15.3 Subject Information and Consent 
The Investigator or designee will explain the nature of the study to the subject or their legally 
acceptable representative, and answer all questions regarding this study.  Prior to any study-
related screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject or their legally acceptable representative, the 
person who administered the informed consent and any other signatories according to local 
requirements.  A copy of the signed ICF will be given to the subject and the original will be 
placed in the subject’s medical record.  An entry must also be made in the subject’s dated source 
documents to confirm that informed consent was obtained prior to any study-related procedures 
and that the subject received a signed copy. 
The signed consent forms will be retained by the Investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request. 
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, will be prospectively approved by both the IRB and the Sponsor 
before use. 
15.4 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (i.e., 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 will 
be informed immediately. 


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In addition, the Investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the Investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP, defined as a breach that will likely affect the 
safety or physical or mental integrity of subjects or the scientific value of the trial, that comes to 
the attention of the Investigator. 
15.5 Subject Confidentiality 
All parties will ensure protection of subject personal data and will not include subject names on 
any Sponsor forms, reports, publications, or in any other disclosures, except where required by 
law.  In case of data transfer, the Sponsor will maintain high standards of confidentiality and 
protection of subject personal data. 
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy.  Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number.  As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH guidelines for GCP and to verify compliance with this protocol, the 
Sponsor requires the Investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (e.g., FDA), the Sponsor’s designated auditors, and the appropriate 
IRBs 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 will have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s CRF). 


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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 will 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 will 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. 
 
 


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17 REFERENCES 
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):584-90. 
Besarb A, Flaharty KK, Ersley AJ, McCrea JB, Vlasses PH, Medina F, et al. Clinical 
pharmacology and economics of recombinant human erythropoietin in end-stage renal disease: 
the case for subcutaneous administration. J Am Soc Nephrol. 1992;2(9):1405-16. 
Di Iorio B, Cirillo M, Bellizzi V, Stellato D, De Santo NG. Prevalence and correlates of anemia 
and uncontrolled anemia in chronic hemodialysis patients – The Campania Dialysis Registry. Int 
J Antif Organs. 2007;30(4):325-33. 
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):2071-84. 
Iseki K, Kohagura K. Anemia as a risk factor for chronic kidney disease. Kidney Int Suppl. 
2007;(107):S4-9. 
Jha V, Garcia-Garcia G, Iseki K, Li K, Naicker S, Plattner B, et al. Chronic kidney disease: 
global dimension and perspectives. Lancet. 2013;382(9888):260-72. 
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 
Locatelli F, Aljama P, Barany P, Canaud B, Carrera F, Eckhardt KU, et al. Revised European 
best practice guidelines for the management of anaemia in patients with chronic renal failure. 
Nephrol Dial Transplant. 2004;19(Suppl2):1-47. 
Ly J, Marticrena R, Donnelly S. Red blood cell survival in chronic renal failure. Am J Kidney 
Dis. 2004;44(4):715-9. 
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. 
NICE. Anaemia management in people with chronic kidney disease. National Institute for Health 
and Care Excellence. 2011:1-39. 
Nurko S. Anemia in chronic kidney disease: causes, diagnosis, treatment. Cleve Clin J Med. 
2006;73(3):289-97. 
Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D. Double-blind comparison 
of full and partial anemia correction in incident hemodialysis patients without symptomatic heart 
disease. J Am Soc Nephrol. 2005;16(7):2180-9. 
Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH. Vadadustat, a novel oral HIF 
stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease. 
Kidney Int. 2016;90(5):1115-22. 


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Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, et al. 
Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin 
Invest. 2007;117(7):1926-32. 
Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al. A trial of 
darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 
2009a;361(21):2019-32. 
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):2085-98. 
Stauffer ME, Fan T. Prevalence of anemia in chronic kidney disease in the United States. PLoS 
One. 2014;9(1):e84943. 
Unger EF, Thompson AM, Blank MJ, 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 
Screening [a] 
Study Treatment Period 
Safety Follow-
Up 
Visit 
SV1 
SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 [c] 
15 
Weeks of study completed 
Study Day 
Day -28 to 0 
Baseline/ 
Day 1 [b] 
Week 1 
Day 8 
Week 2 
Day 15 
Week 4
Day 29 
Week 6 
Day 43 
Week 8 
Day 57 
Week 10 
Day 71 
Week 11 
Day 78 
Week 12 
Day 85 
Week 13 
Day 92 
Week 14 
Day 99  
Week 16 
Day 113 
Week 18 
Day 127 
EOT 
Week 20 
Day 141 
Week 24 
Day 169 
Visit Window (Days) 
― 
― 
+5 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+5 
±3 
±3 
±3 
±3 
±5 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria [d] 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Contraception 
methods [e] 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs [f] 
X 
X [g] 
X [g] 
X 
X 
X 
X 
X 
X 
X 
X [g] 
X 
X 
X 
X 
X [g] 
 
Demographics, Medical 
History [h] 
 
X 
X [i] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam [j] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG [k] 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dialysis Adequacy (Kt/V) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
SF-36  
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
PGI-S 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
PGI-C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment for meeting 
criteria to switch from daily 
to TIW dosing 
(vadadustat arm) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Status check [l] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE review [m] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Study Period 
Screening [a] 
Study Treatment Period 
Safety Follow-
Up 
Visit 
SV1 
SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 [c] 
15 
Weeks of study completed 
Study Day 
Day -28 to 0 
Baseline/ 
Day 1 [b] 
Week 1 
Day 8 
Week 2 
Day 15 
Week 4
Day 29 
Week 6 
Day 43 
Week 8 
Day 57 
Week 10 
Day 71 
Week 11 
Day 78 
Week 12 
Day 85 
Week 13 
Day 92 
Week 14 
Day 99  
Week 16 
Day 113 
Week 18 
Day 127 
EOT 
Week 20 
Day 141 
Week 24 
Day 169 
Review use of rescue 
therapy (RBC transfusions 
and ESA therapy) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of therapeutic 
phlebotomy 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy test [n] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC [o] [p] 
X 
X 
X [q] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X [q] 
 
Reticulocyte count 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
Folate and vitamin B12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Serum chemistry [r] 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
LFTs [s] 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
Iron indices [t] 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
Lipid panel [u] 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Biomarkers (VEGF and 
Hepcidin) [v] 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
PK/PD for vadadustat arm 
[w] 
 
 
X 
X 
 
 
 
 
 
X 
 
X [x] 
 
 
 
 
 
PK for epoetin alfa arm [y] 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication Assessments and Procedures 
Concomitant medication 
review [z] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Epoetin alfa dosing during 
Screening and resume 
standard of care after EOT 
X [aa] 
 
 
 
 
 
 
 
 
 
 
 
 
 
X [bb] 


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Study Period 
Screening [a] 
Study Treatment Period 
Safety Follow-
Up 
Visit 
SV1 
SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 [c] 
15 
Weeks of study completed 
Study Day 
Day -28 to 0 
Baseline/ 
Day 1 [b] 
Week 1 
Day 8 
Week 2 
Day 15 
Week 4
Day 29 
Week 6 
Day 43 
Week 8 
Day 57 
Week 10 
Day 71 
Week 11 
Day 78 
Week 12 
Day 85 
Week 13 
Day 92 
Week 14 
Day 99  
Week 16 
Day 113 
Week 18 
Day 127 
EOT 
Week 20 
Day 141 
Week 24 
Day 169 
Study Drug (vadadustat or 
epoetin alfa) dosing [cc] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X [dd] 
X 
X 
X 
X 
 
 
Vadadustat dispensation 
[ee] 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
Review vadadustat dosing 
instructions and vadadustat 
dosing compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vadadustat reconciliation 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review use of iron 
supplementation [ff] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Visit Registration in IWRS 
X 
X 
X 
 
 
X 
[gg] 
 
X [gg] 
 
 
X [gg] 
 
 
X [gg] 
 
X 
 
eDiary instruction 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = 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; CRP = C-reactive protein; ECG = electrocardiogram; EOT = end of treatment; EPO = erythropoietin; 
ESA = erythropoiesis-stimulating agent; HDL = high density lipoprotein; IWRS = Interactive Web Response System; LDL = low density lipoprotein; LFT = liver function test; MCH = mean 
corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; PD = pharmacodynamics; PGI-C = Patient Global Impression of Change; PGI-
S = Patient Global Impression of Severity; PK = pharmacokinetic; RBC = red blood cell; RDW = red cell distribution width; SF-36 = 36-Item Short-Form General Health Survey; SV1 = Screening 
visit 1; SV2 = Screening visit 2; TIBC = total iron binding capacity; TSAT = transferrin saturation; VEGF = vascular endothelial growth factor; WBC = white blood cell; wks = weeks. 
[a] The Screening Period is a maximum of 28 days in duration and starts at the time the informed consent is signed. 
[b] The Investigator will arrange for sufficient time (a minimum of 4 days) between SV2 or last retest (if applicable) and Baseline/Day 1 to allow for all laboratory results to be available that are 
required to assess eligibility for the next study visit.  
[c] The EOT evaluations will be performed when the Treatment Period (Baseline/Day 1 to Week 20 [Visits 1 to 13]) is completed.  Subjects who permanently discontinue study drug for any reason or 
discontinue prematurely from the study will complete the EOT visit (Visit 14) assessments and will complete the Safety Follow-Up (Visit 15) 4 weeks after Visit 14 
[d] Eligibility criteria will be reviewed at the SV1, SV2, and Baseline/Day 1. 
[e] Contraception methods will be reviewed at Screening and Baseline/Day 1, as well as throughout the study as needed. 
[f] Vital signs will include temperature, HR, BP, RR, and dry weight.  Temperature, HR, BP, and RR will be assessed in the seated position after 5 minutes of rest.  For BP, a total of two 
measurements at intervals of at least 2 minutes should be performed.  Temperature, HR, BP, and RR will be collected at SV1, SV2, Baseline/Day 1, during all study visits, and Visit 14 (EOT).  
Measurements will be and will be taken prior to blood draws when possible.   
[g] Dry weight will be collected as part of the vital signs for all subjects at SV2, Baseline/Day 1, Visit 9 and 14 (EOT).  For subjects on epoetin alfa, subjects will be weighed for dosing as per the local 
standard of care. 
[h] Relevant medical history (with particular emphasis on previous medical conditions that may lead to exclusion) and significant ongoing medical conditions or diseases will be documented. 


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[i] Review of medical history for new conditions since SV2. 
[j] A physical examination (including height) is required at SV2.  Thereafter, an abbreviated symptom-directed physical examination will be performed at the discretion of the Investigator, as clinically 
indicated. 
[k] A standard 12-lead ECG will be performed at Baseline/Day 1, which may be obtained up to 3 days prior to Baseline/Day 1.  The ECG will be obtained after the subject has been resting comfortably 
in a supine position for approximately 5 minutes and will be taken prior to vital sign assessments and blood draws when possible.  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. 
[l] In weeks where there is no scheduled study visit (Weeks 3, 5, 7, 9, 15, and 17, and 19), a subject will have a status check performed during one of their dialysis treatment appointments in the week.  
It will include a review of the subject’s vital signs and a review of current health status for identification of any issues that may require follow-up by the Investigator or delegated staff personnel.  
Documentation of the review must be done in the subject’s source documentation.  No data will be captured on the status checks in the EDC system.  If an AE is identified at the status check or other 
actions result from the status check, these will be captured per the protocol.  
[m]  AE collection will begin from time of randomization through 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.  Subjects must be followed for AEs until the final required protocol visit (study end date) or until all drug-related toxicities and SAEs have 
resolved (or are considered chronic/stable), whichever is later. 
[n] A serum pregnancy test will be performed at SV2 for females of childbearing potential.  Additional serum 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 drug.  A FSH test will be performed at SV2 for post-menopausal females.   
[o] A CBC without differential will be performed at all noted visits, except Baseline/Day 1 and Visit 14 (EOT).  The CBC without differential will include: Hb, hematocrit, RBCs, MCV, MCH, 
MCHC, RDW, WBC count, and platelets. 
[p] Hb will be monitored throughout the study via central laboratory to determine the dose of study drug (vadadustat or epoetin alfa) that subjects will receive.  Hb levels can be measured more 
frequently based on Investigator’s clinical judgment.  For eligibility purposes, one retest for Hb may be performed during the Screening Period.  Two Hb values measured at least 4 days apart by the 
central laboratory during Screening (SV1, SV2 or retest) must be between 8.5 and 11.0 g/dL, inclusive, for the Main study and 8.0 and 10.0 g/dL, inclusive, for the ESA hyporesponder parallel study. 
[q] A CBC with differential will be performed at Baseline/Day 1 and Visit 14 (EOT).  The CBC with differential will include the same parameters as CBC without differential with the addition of 
WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils).   
[r] The serum chemistry will include the following assays: sodium, potassium, bicarbonate, chloride, calcium, magnesium, phosphorus, glucose, creatinine, BUN, CPK, uric acid, albumin, and total 
protein. 
[s] LFTs: total bilirubin, ALP, ALT/SGPT, AST/SGOT, and lactate dehydrogenase. 
[t] Iron Indices: ferritin, iron, transferrin, TIBC, and TSAT. 
[u] Lipid Profile: total cholesterol, LDL, HDL, and triglycerides. 
[v] The biomarkers will include, but are not limited to, VEGF and hepcidin.  Samples for VEGF and hepcidin biomarker analyses will be drawn at Baseline/Day 1, Visit 9 and 14 (EOT).   
[w] Blood for measurement of vadadustat, metabolites and EPO level in the vadadustat arm, in both the Main study and ESA hyporesponder parallel study will be collected at Baseline/Day 1, Week 1, 
and Week 11 as outlined in Section 9.2.2.1.  For all PK and PD sampling, the time of the previous dose of vadadustat will be collected for the pre-dose sample and the timing of administration of 
vadadustat, and the start and stop time of the dialysis session will be recorded.   
[x] Visit 10/Week 13 PK/PD sampling will only be done in subjects who transition to vadadustat TIW dosing regimen.  Subjects who do not qualify for vadadustat TIW dosing and remain on daily 
dosing regimen will not have Visit 10/Week 13 PK/PD sampling. 
[y] Blood for measurement of EPO level in the epoetin alfa arm, in both the Main study and ESA hyporesponder parallel study, will be collected at Baseline/Day 1 and Week 1 as outlined in 
Section 9.2.2.2.  For all PK sampling the time of the previous dose of epoetin alfa is to be collected for the pre-dose sample and the timing of administration of epoetin alfa and the start and stop time of 
the dialysis session will be recorded.   
[z] Concomitant medications should be collected and recorded at each visit as noted.  All medications taken within 30 days prior to Baseline/Day 1 will be recorded. 
[aa] Epoetin alfa dosing will stop for a minimum of 5 days before Baseline/Day 1 in the Main study or 2 days before Baseline/Day 1 in the ESA hyporesponder parallel study. 
[bb] After the end of vadadustat treatment at Visit 14/Week 20 (or following early discontinuation of vadadustat), subjects will resume dosing with epoetin alfa (or another ESA), based on standard of 
care. 
[cc] Subjects in the low epoetin alfa dose group randomized to vadadustat treatment will start at an initial dose of vadadustat 300 mg or 450 mg daily.  Subjects in the high epoetin alfa dose group 
randomized to vadadustat treatment will receive an initial dose of 300 mg, 450 mg, or 600 mg daily.  Subjects in the ESA hyporesponder parallel study randomized to vadadustat treatment will receive a 
starting dose of vadadustat 600 mg daily.  For subjects who are randomized to the epoetin alfa treatment arm, the initial dosing regimen in the study (starting from Baseline/Day 1) will be approximately 
the same weekly dose that they were receiving prior to randomization. 
[dd] After completing the 12-week once daily dosing regimen, subjects randomized to vadadustat who meet criteria for switching from daily to TIW dosing will initiate TIW dosing at a starting dose 
1 tablet greater (+150 mg) than the final dose in the daily dosing period.  Central laboratory Hb values from Visit 8/Week 11 (11 weeks of treatment completed) will be used to determine if subjects 
meet Week 12 Transition criteria. 
[ee] Subjects will be provided with a supply of vadadustat at Baseline/Day 1 and will be resupplied at Visit 4, 6, 9 and 12 or an unscheduled dispensing visit as needed.  Subjects will be instructed to 
complete 1 bottle before opening a new bottle.  The dose should be taken at approximately the same time each day. 


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[ff] IV iron will be administered based on ferritin and TSAT levels measured by the central laboratory according to the standardized, low-intensity, iron supplementation protocol in Section 8.4.8.  Oral 
iron supplementation including iron-containing phosphate binders are prohibited during the study. 
[gg] IWRS visit registration for vadadustat arm only for bottle dispensing 
 
 


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APPENDIX B: PK/PD SAMPLING  
PK/PD Sampling in Vadadustat Arm Subjects Who Transition to TIW Dosing at Week 12 
 
Baseline/Day 1 
QD 
Week 1  
QD 
Week 1  
+ 1 day  
Week 11  
QD 
  
Week 13  
TIW 
 
Dialysis  
Day 
Dialysis 
Day 
Non-Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Baseline/Day 1 
(Prior to first dose) 
● 
  
  
  
  
  
 
15 minutes (pre-dose) 
  
● 
● 
● 
 
● 
 
2 hours ± 15 minutes 
(post-dose) 
  
● 
● 
● 
 
● 
 
3.5 hours ± 15 minutes 
(post-dose) 
  
● 
● 
● 
 
● 
 
5 hours ± 30 minutes 
(post-dose) 
  
● 
● 
● 
 
● 
 
7 hours ± 30 minutes 
(post-dose) 
  
● 
● 
● 
 
● 
 
10.5 hours ± 1.5 hours 
(post-dose) 
 
● 
 
● 
 
● 
 
Note: Gray shading indicates sample collection at a subset of study sites only. 
 
 


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PK/PD Sampling in Vadadustat Arm Subjects Who Do Not Transition to TIW Dosing at Week 12 
 
Baseline/Day 1 
QD 
Week 1  
QD 
Week 1  
+ 1 day  
Week 11  
QD 
  
Week 13  
TIW 
 
Dialysis  
Day 
Dialysis 
Day 
Non-Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Baseline/Day 1 
(Prior to first dose) 
● 
  
  
  
  
  
 
15 minutes (pre-dose) 
  
● 
● 
● 
 
 
 
2 hours ± 15 minutes 
(post-dose) 
  
● 
● 
● 
 
 
 
3.5 hours ± 15 minutes 
(post-dose) 
  
● 
● 
● 
 
 
 
5 hours ± 30 minutes 
(post-dose) 
  
● 
● 
● 
 
 
 
7 hours ± 30 minutes 
(post-dose) 
  
● 
● 
● 
 
 
 
10.5 hours ± 1.5 hours 
(post-dose) 
 
● 
 
● 
 
 
 
Note: Gray shading indicates sample collection at a subset of study sites only. 
 
 
 


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PK Sampling in Epoetin Alfa Arm 
 
Baseline/Day 1 
TIW 
Week 1  
TIW 
Week 1  
+ 2 days 
Week 11  
TIW 
  
Week 13  
TIW 
 
Dialysis  
Day 
Dialysis 
Day 
Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Baseline/Day 1 
(Prior to first dose) 
● 
  
  
  
  
  
 
15 minutes (pre-dose) 
  
● 
● 
 
 
 
 
2 hours ± 15 minutes 
(post-dose) 
  
● 
 
 
 
 
 
3.5 hours ± 15 minutes 
(post-dose) 
  
● 
 
 
 
 
 
5 hours ± 30 minutes 
(post-dose) 
  
● 
 
 
 
 
 
7 hours ± 30 minutes 
(post-dose) 
  
● 
 
 
 
 
 
10.5 hours ± 1.5 hours 
(post-dose) 
 
● 
 
 
 
 
 
Note: Gray shading indicates sample collection at a subset of study sites only.


Akebia Therapeutics, Inc. 
 
Amendment 1 (Version 2.0) 
Protocol No. AKB-6548-CI-0025 
 
11 September 2018 
 
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Page 89 of 89 
APPENDIX C: HISTORY OF AMENDMENTS TO THE PROTOCOL  
Amendment 1 (Version 1.3 10 September 2018) 
 
Amendment 1 was issued based on sponsor assessment and external input.   
  
The major changes introduced in the amendment are summarized below: 
• Addition of an Exclusion Criterion of Subjects with bilateral native nephrectomy, to 
minimize potential variability in hemoglobin response observed in this Phase 2 PK/PD 
study that may arise from a decreased capacity to augment endogenous erythropoietin 
(EPO) production in the setting of bilateral nephrectomy. 
• Addition of language to provide explicit guidance on early termination from the study for 
subjects who undergo a solid organ, hematopoietic stem cell, or bone marrow 
transplantation while participating in the study. 
• Update to the description of the vadadustat tablet since new lots of vadadustat may 
include imprinting on the tablet.  This is also referred to as a debossed tablet. 
• Preliminary results of clinical drug-drug interaction studies showed a moderate 
interaction between vadadustat and rosuvastatin and no clinically significant interaction 
between vadadustat and pravastatin.  Based on the data from these studies, guidance has 
been added to the protocol on how to manage the use of statins in combination with 
vadadustat. 
• Removal of the requirement to assess and document oxygen saturation (SO2) levels in 
study subjects for consistency with past and current Akebia DD-CKD protocols, and 
given that measurement of SO2 levels is not required in the setting of vadadustat or 
epoetin alfa use or in the routine management of subjects with DD-CKD.    
• AE reporting period clarified as starting at randomization in case there is a delay between 
date of randomization and date of first study drug dose. 
 


Akebia Therapeutics, Inc. 
Amendment 2 (Version 3.0) 
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05 April 2019 
 
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Page 1 of 105 
                                                       
 
 
 
CLINICAL PROTOCOL   
 
PHASE 2, RANDOMIZED, OPEN-LABEL, ACTIVE-CONTROLLED, EFFICACY, 
SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS STUDY OF ORAL 
VADADUSTAT FOR THE TREATMENT OF ANEMIA IN HEMODIALYSIS 
SUBJECTS CONVERTING FROM EPOETIN ALFA (FO2RWARD-2) 
 
Compound: 
Vadadustat (AKB-6548) 
Protocol Number: 
AKB-6548-CI-0025 
US IND Number: 
102,465 
Phase: 
Phase 2 
Protocol Version / Date: 
Amendment 2 (Version 3.0 / 05 APRIL 2019) 
Amendment 1 (Version 2.0 / 11 SEPTEMBER 2018) 
Original Version 1.0 / 27 JUNE 2018  
 
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 
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. 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0025 
1 
SIGNATURE PAGES 
1.1 
Protocol Approval 
Signature 
Amendment 2 (Version 3.0) 
05 April 2019 
Signature 
Signature 
Date 
Date 
Date 
Date 
Akebia -
Company Confidential 
Page 2of105 


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05 April 2019 
 
Akebia — Company Confidential 
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1.2 
Investigator Agreement 
I confirm that I have read and that I understand this protocol, the Investigator Brochure, and other 
product information provided by the sponsor. I agree to conduct this study in accordance with the 
requirements of this protocol and also protect the rights, safety, privacy, and well-being of study 
subjects in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 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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05 April 2019 
 
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TABLE OF CONTENTS 
1 
SIGNATURE PAGES .................................................................................................. 2 
1.1 
Protocol Approval .................................................................................................... 2 
1.2 
Investigator Agreement ............................................................................................ 3 
TABLE OF CONTENTS ......................................................................................................... 4 
2 
PROTOCOL SYNOPSIS .............................................................................................. 9 
3 
LIST OF ABBREVIATIONS ..................................................................................... 22 
4 
BACKGROUND INFORMATION ........................................................................... 24 
4.1 
Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors ..................................... 25 
4.2 
Summary of Clinical Experience ........................................................................... 25 
4.3 
Potential Benefits and Risks ................................................................................... 27 
5 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 29 
5.1 
Primary Objective .................................................................................................. 29 
5.2 
Secondary Objectives ............................................................................................. 29 
5.3 
Efficacy Endpoints ................................................................................................. 29 
5.3.1 
Primary Endpoints ............................................................................................. 29 
5.3.2 
Key Secondary Endpoints ................................................................................. 29 
5.3.2.1 
Other Secondary Endpoints .......................................................................... 29 
5.3.2.2 
Exploratory Endpoints .................................................................................. 30 
5.4 
PK/PD Endpoints ................................................................................................... 30 
5.5 
Safety Endpoints .................................................................................................... 30 
6 
STUDY DESIGN ........................................................................................................ 31 
6.1 
Study Design .......................................................................................................... 31 
6.1.1 
Screening Period (up to 28 days; Day -28 to Baseline/Day 1) .......................... 32 
6.1.2 
Study Treatment Period (Baseline/Day 1 to Week 20) ..................................... 33 
6.1.2.1 
Vadadustat Treatment ................................................................................... 33 
6.1.2.2 
Epoetin Alfa Treatment ................................................................................ 33 
6.1.3 
Safety Follow-Up Period (Weeks 20 to 24) ...................................................... 34 
6.2 
Rationale for Study Design .................................................................................... 34 
6.3 
Dose Justification ................................................................................................... 35 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 37 
7.1 
General Criteria ...................................................................................................... 37 
7.2 
Inclusion Criteria .................................................................................................... 37 
7.3 
Exclusion Criteria ................................................................................................... 37 
7.4 
Retesting and Rescreening ..................................................................................... 39 
7.4.1 
Retesting ............................................................................................................ 39 
7.4.2 
Rescreening ....................................................................................................... 39 


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7.5 
Study Completion, Study Termination, and Individual Site Termination ............. 39 
7.5.1 
Study Completion .............................................................................................. 39 
7.5.2 
Study Termination ............................................................................................. 39 
7.5.3 
Individual Study Site Termination .................................................................... 40 
7.6 
Subject Completion and Subject Discontinuation .................................................. 40 
7.6.1 
Subject Completion ........................................................................................... 40 
7.6.2 
Temporary Interruption of Study Drug ............................................................. 40 
7.6.3 
Early Discontinuation from Study (Early Termination) .................................... 40 
8 
STUDY DRUG AND TREATMENT OF SUBJECTS .............................................. 42 
8.1 
Epoetin Alfa ........................................................................................................... 42 
8.2 
Vadadustat .............................................................................................................. 42 
8.2.1 
Supplies and Storage ......................................................................................... 42 
8.2.2 
Dispensing of Vadadustat .................................................................................. 42 
8.3 
Vadadustat Accountability and Destruction ........................................................... 43 
8.4 
Treatment of Subjects ............................................................................................. 44 
8.4.1 
Randomization ................................................................................................... 44 
8.4.2 
Blinding ............................................................................................................. 44 
8.4.3 
Measurement of Hb Levels for Dose Adjustment Consideration ..................... 44 
8.4.4 
Epoetin Alfa Dosing Regimen ........................................................................... 45 
8.4.5 
Vadadustat Dosing Regimen and Guidelines for Dose Adjustment ................. 45 
8.4.5.1 
Dosing Regimen for the Vadadustat Treatment Arm ................................... 45 
8.4.5.2 
Transition of Vadadustat Once Daily Dosing to TIW Dosing Regimen ...... 45 
8.4.6 
Guidelines for Dose Adjustments ...................................................................... 46 
8.4.7 
Late or Missed Doses ........................................................................................ 47 
8.4.8 
Iron Supplementation ........................................................................................ 47 
8.4.9 
Rescue Therapy ................................................................................................. 48 
8.4.9.1 
RBC Transfusion .......................................................................................... 48 
8.4.9.2 
ESA Use ........................................................................................................ 48 
8.4.10 
Phlebotomy (Optional) ...................................................................................... 48 
8.4.11 
Treatment Compliance ...................................................................................... 49 
8.4.12 
Continuation of Treatment ................................................................................ 49 
8.5 
Prior and Concomitant Therapy ............................................................................. 49 
8.5.1 
General .............................................................................................................. 49 
8.5.2 
ESAs .................................................................................................................. 49 
8.5.3 
HMG-CoA Reductase Inhibitors (Statins) ........................................................ 50 
8.5.4 
Sulfasalazine and Other BCRP Substrates ........................................................ 50 
8.5.5 
Phosphate Binders ............................................................................................. 50 
8.5.6 
Dialysis Treatment and Renal Replacement Therapy ....................................... 50 


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8.5.7 
Investigational Medications ............................................................................... 51 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES ................................ 52 
9.1 
Administrative Procedures ..................................................................................... 52 
9.1.1 
Informed Consent .............................................................................................. 52 
9.1.2 
eDiary ................................................................................................................ 53 
9.1.3 
Documentation of Screen Failures .................................................................... 53 
9.1.4 
Status Check ...................................................................................................... 53 
9.1.5 
Contraception and Pregnancy Avoidance Measures ......................................... 53 
9.1.6 
Laboratory Accreditation and Reference Ranges .............................................. 54 
9.2 
Study Procedures and Evaluations ......................................................................... 54 
9.2.1 
Clinical Evaluations ........................................................................................... 54 
9.2.2 
Laboratory Evaluations ..................................................................................... 56 
9.2.2.1 
PK/PD Sampling for Subjects Randomized to Vadadustat .......................... 57 
9.2.2.2 
PK Sampling for Subjects Randomized to Epoetin Alfa .............................. 58 
9.2.2.3 
PK/PD Sampling ........................................................................................... 58 
9.3 
Schedule of Activities ............................................................................................ 58 
9.3.1 
Screening Visits ................................................................................................. 59 
9.3.1.1 
SV1 ............................................................................................................... 59 
9.3.1.2 
SV2 ............................................................................................................... 59 
9.3.2 
Baseline/Day 1 (Visit 1) .................................................................................... 60 
9.3.3 
Visit 2 to Visit 13 (Weeks 1 to 20) .................................................................... 61 
9.3.4 
EOT Visit 14 (Week 20) .................................................................................... 62 
9.3.5 
Safety Follow-Up Visit 15 (Week 24) ............................................................... 63 
9.3.6 
Unscheduled Visits ............................................................................................ 64 
9.4 
Study Medication Stopping Rules .......................................................................... 64 
10 
ADVERSE EVENTS .................................................................................................. 65 
10.1 
Definitions .............................................................................................................. 65 
10.1.1 
AEs .................................................................................................................... 65 
10.1.2 
SAEs .................................................................................................................. 67 
10.1.3 
Adverse Events of Special Interest .................................................................... 68 
10.2 
Eliciting AE Information ........................................................................................ 68 
10.3 
Reporting ................................................................................................................ 68 
10.3.1 
Reporting Period ................................................................................................ 68 
10.3.2 
Reporting AEs ................................................................................................... 68 
10.3.3 
Reporting SAEs ................................................................................................. 68 
10.3.4 
Relationship to Study Drug ............................................................................... 69 
10.3.5 
Severity .............................................................................................................. 70 
10.3.6 
Follow-up of Unresolved Events ....................................................................... 70 


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10.4 
Exposure In-Utero .................................................................................................. 70 
10.5 
Special Situations ................................................................................................... 71 
10.6 
Safety Monitoring .................................................................................................. 72 
11 
DATA ANALYSIS ..................................................................................................... 73 
11.1 
Sample Size Estimation .......................................................................................... 73 
11.2 
Study Analysis Populations .................................................................................... 73 
11.3 
Analysis of Demographic and Pretreatment Variables .......................................... 73 
11.4 
Disposition of Subjects ........................................................................................... 74 
11.5 
Missing Data .......................................................................................................... 74 
11.6 
Efficacy Analyses ................................................................................................... 74 
11.7 
Safety Analyses ...................................................................................................... 74 
11.8 
Additional Assessments ......................................................................................... 75 
11.8.1 
PK Assessments ................................................................................................. 75 
11.8.2 
PD Assessments ................................................................................................. 75 
11.8.3 
Concomitant Medications .................................................................................. 75 
11.8.4 
Biomarkers ........................................................................................................ 75 
12 
DATA HANDLING AND RECORD KEEPING....................................................... 76 
12.1 
CRFs/EDC .............................................................................................................. 76 
12.2 
Record Retention .................................................................................................... 76 
13 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 77 
13.1 
Study Site Monitoring Visits .................................................................................. 77 
13.2 
Protocol Deviations ................................................................................................ 77 
14 
STUDY DISCONTINUATION/STUDY SITE TERMINATION ............................. 78 
14.1 
Criteria for Premature Termination or Suspension of the Study ............................ 78 
14.2 
Criteria for Premature Termination or Suspension of Study Sites ......................... 78 
14.3 
Procedures for Premature Termination or Suspension of the Study or Study 
Sites ........................................................................................................................ 78 
15 
ETHICS ....................................................................................................................... 79 
15.1 
Ethical Conduct of the Study ................................................................................. 79 
15.2 
IRB ......................................................................................................................... 79 
15.3 
Subject Information and Consent ........................................................................... 79 
15.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .... 79 
15.5 
Subject Confidentiality ........................................................................................... 80 
16 
PUBLICATION OF STUDY RESULTS ................................................................... 81 
17 
REFERENCES ............................................................................................................ 82 
APPENDIX A: SCHEDULE OF ACTIVITIES .................................................................... 84 
APPENDIX B: PK/PD SAMPLING ..................................................................................... 89 
APPENDIX C: SF-36v2 Standard ......................................................................................... 92 


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APPENDIX D: PATIENT GLOBAL IMPRESSION OF SEVERITY (PGI-S) ................... 98 
APPENDIX E: PATIENT GLOBAL IMPRESSION OF CHANGE (PGI-C) ...................... 99 
APPENDIX F: EUROQOL 5 DIMENSIONS 5 LEVELS (EQ-5D-5L) ............................. 100 
APPENDIX G: HISTORY OF AMENDMENTS TO THE PROTOCOL .......................... 103 


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05 April 2019 
 
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2 
PROTOCOL SYNOPSIS 
Study Title 
Phase 2, Randomized, Open-Label, Active-Controlled, Efficacy, Safety, 
Pharmacokinetics, and Pharmacodynamics Study of Oral Vadadustat for the Treatment 
of Anemia in Hemodialysis Subjects Converting from Epoetin Alfa (FO2RWARD-2) 
Protocol Number 
AKB-6548-CI-0025 
Study Phase 
Phase 2 
Investigational 
Product 
Vadadustat; 150 mg tablets  
Reference Medicinal 
Product 
Epoetin alfa solution for intravenous (IV) injection in multi-dose vials or in single-dose 
vials  
Study Population 
The Main study population will consist of adult subjects receiving chronic, outpatient 
in-center hemodialysis three times weekly (TIW), with 2 screening hemoglobin (Hb) 
values between 8.5 and 11.0 g/dL (inclusive) and on maintenance treatment with 
epoetin alfa <300 U/kg/week. 
The erythropoiesis-stimulating agent (ESA) hyporesponder parallel study will consist 
of adult subjects receiving chronic, outpatient in-center hemodialysis TIW, with 
2 screening Hb values between 8.0 and 10.0 g/dL (inclusive) and on maintenance 
treatment with epoetin alfa ≥300 U/kg/week.  
Study Sites 
Approximately 40 study sites in the United States (US) 
Planned Number of 
Subjects 
Approximately 125 subjects 
• Main study: ~95 subjects 
• ESA hyporesponder parallel study: ~30 subjects 
Primary Objective 
To assess the efficacy and safety of daily dosing of vadadustat compared to epoetin 
alfa for 12 weeks in hemodialysis subjects 
Secondary Objectives 
• To assess the efficacy and safety of TIW dosing of vadadustat in selected 
hemodialysis subjects who have been successfully managed with daily dosing of 
vadadustat through Week 12 
• To evaluate the pharmacokinetics (PK)/pharmacodynamics (PD) of daily and TIW 
dosing of vadadustat in hemodialysis subjects compared to epoetin alfa  
• To assess the efficacy and safety of several dosing strategies of vadadustat compared 
to epoetin alfa during a 20-week Treatment Period in hemodialysis subjects 
Overview of Study 
Design 
This is a Phase 2, randomized, open-label study to evaluate vadadustat for the 
treatment of anemia in hemodialysis subjects converting from epoetin alfa therapy.  
For all subjects (Main study and ESA hyporesponder parallel study), the study will 
include a Screening Period, a Treatment Period, and a Safety Follow-Up Period as 
described below.  PK and PD sampling will be done throughout the study (see PK and 
PD Sampling sections for details). 
The aim is to achieve and maintain Hb levels within the target range of 10.0 to 
11.0 g/dL, inclusive, while targeting the middle of the range and minimizing 
excursions outside the target range. 
Screening Period (up to 28 days; Day -28 to Baseline/Day 1) 
For all subjects (Main study and ESA hyporesponder parallel study) the Screening 
Period starts at the time the informed consent is signed and will be a maximum of 
28 days in duration.  Baseline/Day 1 will be performed within 28 days of the start of 
Screening.  Subjects who meet all eligibility criteria will be randomized to a vadadustat 
treatment arm or an epoetin alfa treatment arm.  Subjects will be required to stop 
epoetin alfa treatment for a minimum duration of 5 days before Baseline/Day 1 in the 
Main study and for a minimum of 2 days before Baseline/Day 1 in the ESA 


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hyporesponder parallel study.  In the Main study, randomization will be stratified by 
the mean weekly epoetin alfa dose calculated over a period of 8 weeks prior to 
Screening Visit 2 (SV2). 
• 
Low epoetin alfa dose group (≤90 U/kg/week) or 
• 
High epoetin alfa dose group (>90 to <300 U/kg/week) 
Study Treatment Period (Baseline/Day 1 to Week 20) 
For all subjects (Main study and ESA hyporesponder parallel study), the Treatment 
Period will run from Baseline/Day 1 to Week 20.  Dose will be adjusted to achieve and 
maintain Hb levels within the target range of 10.0 to 11.0 g/L, inclusive, while 
targeting the middle of the range and minimizing excursions outside of the target 
range. 
Subjects in the Main study randomized to vadadustat: 
• 
Subjects in the low epoetin alfa dose group will start vadadustat at an initial, 
randomly allocated dose of 300 or 450 mg daily.   
• 
Subjects in the high epoetin alfa dose group will start vadadustat at an initial, 
randomly allocated dose of 300, 450, or 600 mg daily.   
Subjects in the ESA hyporesponder parallel study randomized to vadadustat: 
• 
Subjects will receive a starting dose of vadadustat 600 mg daily.   
Transition to TIW for all subjects randomized to vadadustat: 
All subjects randomized to vadadustat (Main study and ESA hyporesponder parallel 
study) who complete the 12-week once daily dosing regimen and who meet all the 
Week 12 transition criteria for switching from daily to TIW dosing, will initiate TIW 
dosing at a starting dose one tablet greater (+150 mg) than the final dose in the daily 
dosing period.  Subjects who do not meet criteria for switching from daily to TIW 
dosing will remain on daily dosing.   
Subjects in both the Main study and ESA hyporesponder parallel study randomized to 
epoetin alfa: 
All subjects randomized to epoetin alfa will receive TIW dosing for the entire 
Treatment Period based on the subject’s central laboratory Hb value and the approved 
epoetin alfa US Package Insert (PI) for adult patients with chronic kidney disease 
(CKD) on dialysis.  Dose will be adjusted to achieve and maintain Hb levels within the 
target range of 10.0 to 11.0 g/dL, inclusive, while targeting the middle of the range and 
minimizing excursions outside of the target range. 
Safety Follow-Up Period (Weeks 20 to 24) 
For all subjects (Main study and ESA hyporesponder parallel study), the 4-week Safety 
Follow-Up Period starting at Week 20 will be followed by a post-treatment safety 
assessment conducted at the beginning of Week 24. 


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Study Schematic 
 
Study Duration 
Individual subjects will participate in the study for up to 28 weeks, including a 
Screening Period of up to 4 weeks, a 20-week Treatment Period and a 4-week Safety 
Follow-Up Period. 
Inclusion Criteria 
Subjects must meet the following inclusion criteria: 
1. ≥18 years of age 
2. Receiving chronic, outpatient in-center hemodialysis (TIW) for end-stage renal 
disease for at least 12 weeks prior to Screening 
3. Maintained on IV epoetin alfa therapy for 8 weeks prior to and including 
Screening through SV2 
4. Eligibility in the Main study and ESA hyporesponder parallel study is based on 
the following mean weekly epoetin alfa doses: 
• 
Main study: Mean weekly epoetin alfa dose <300 U/kg/week for 8 weeks 
prior to SV2 
• 
ESA hyporesponder parallel study: Mean weekly epoetin alfa dose 
≥300 U/kg/week for 8 weeks prior to SV2 
5. Two Hb values measured by the central laboratory at least 4 days apart between 
SV1 and SV2 as indicated below: 
• 
Main study: 2 Hb values between 8.5 and 11.0 g/dL, inclusive 
• 
ESA hyporesponder parallel study: 2 Hb values between 8.0 and 10.0 g/dL, 
inclusive 
6. Serum ferritin ≥100 ng/mL and transferrin saturation (TSAT) ≥20% during 
Screening 


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7. Folate and vitamin B12 measurements ≥ lower limit of normal during Screening 
8. Hemodialysis adequacy as indicated by single-pool Kt/Vurea ≥1.2 using the most 
recent historical measurement within 8 weeks prior to or during Screening 
9. Understands the procedures and requirements of the study and provides written 
informed consent and authorization for protected health information disclosure. 
Exclusion Criteria 
Subjects must not meet any of the following exclusion criteria: 
1. Anemia due to a cause other than CKD (e.g., sickle cell disease, myelodysplastic 
syndromes, bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic 
anemia, thalassemia, or pure red cell aplasia) 
2. Active bleeding or recent blood loss within 8 weeks prior to randomization 
3. Red blood cell (RBC) transfusion within 8 weeks prior to randomization 
4. Anticipated to discontinue hemodialysis during the study 
5. Judged by the investigator that the subject is likely to need rescue therapy (ESA 
administration or RBC transfusion) immediately after enrollment in the study 
6. History of chronic liver disease (e.g., chronic infectious hepatitis, chronic 
autoimmune liver disease, cirrhosis or fibrosis of the liver)  
7. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase 
(SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase 
(SGPT), or total bilirubin >1.5 x upper limit of normal (ULN) during Screening.  
Subjects with a history of Gilbert’s syndrome are not excluded. 
8. Current uncontrolled hypertension as determined by the investigator that would 
contraindicate the use of epoetin alfa 
9. 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 heart failure (HF) or New York Heart Association Class IV HF, or stroke 
within 12 weeks prior to or during Screening 
10. History of new or recurrent malignancy within 2 years prior to and during 
Screening or currently receiving treatment or suppressive therapy for cancer.  
Subjects with treated basal cell carcinoma of skin, curatively resected squamous 
cell carcinoma of skin, or cervical carcinoma in situ are not excluded. 
11. History of deep vein thrombosis or pulmonary embolism within 12 weeks prior 
to or during Screening 
12. History of hemosiderosis or hemochromatosis 
13. History of prior organ transplantation (subjects with a history of failed kidney 
transplant or corneal transplants are not excluded) 
14. Scheduled organ transplant from a living donor and subjects on the kidney 
transplant wait-list who are expected to receive a transplant within 6 months  
15. History of a prior hematopoietic stem cell or bone marrow transplant (stem cell 
therapy for knee arthritis is not excluded) 
16. Known hypersensitivity to vadadustat, epoetin alfa, or any of their excipients 
17. Any prior use of a HIF-PH inhibitor or any use of an investigational medication 
within 30 days or 5 half-lives of the investigational medication (whichever is 
longer), prior to randomization.  
18. For female subjects: 
a. 
Of non-childbearing potential 
i. Inability to confirm surgical sterility (e.g., hysterectomy, bilateral tubal 
ligation, bilateral oophorectomy) at least 1 month prior to Screening, or  


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ii. Not considered post-menopausal (no menses for >1 year with follicle 
stimulating hormone >40 U/L at Screening)  
b. Or, if of childbearing potential  
i. Lack of confirmation of the use of acceptable forms of contraception* 
for a minimum of one complete menstrual cycle prior to Screening  
ii. Positive serum pregnancy test at SV2 
iii. Unwilling to use two acceptable forms of contraception* (at least one of 
which must be a barrier method) starting Baseline/Day 1, throughout the 
Treatment Period and for 30 days after the final study drug 
administration 
19. Breastfeeding during Screening or throughout the Treatment Period and for 
30 days after the final study drug administration. 
20. Donation of ova starting at Screening, throughout the Treatment Period, and for 
30 days after the final study drug administration. 
21. Male subjects who have not had a vasectomy and do not agree to the following: 
use of an acceptable form of contraception* during the study and for 30 days 
after the last dose of the study drug; to not donate semen during the study and for 
at least 30 days after the last dose of vadadustat. 
22. Subjects with bilateral native nephrectomy. 
23. Any other reason, which in the opinion of the investigator, would make the 
subject not suitable for participation in the study. 
 *  Acceptable forms of contraception include: 
• 
Established use of oral, injected or implanted hormonal methods of 
contraception. 
• 
Placement of an intrauterine device or intrauterine system. 
• 
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. 
Retesting/Rescreening 
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 
be retested once for each laboratory parameter within the 4-week Screening Period, per 
investigator discretion. 
Rescreening 
Subjects who fail to qualify for the study based on laboratory tests may be considered 
for rescreening at the discretion of the investigator if it is considered that the subject 
status has changed, and the subject may now qualify for the study.  Additionally, 
subjects who fail to qualify for the study based on inclusion criteria values for 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).  A new informed consent is required to be signed prior to every rescreening. 


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Akebia Therapeutics, Inc. 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
05 April 2019 
 
Akebia — Company Confidential 
Page 15 of 105 
• 
Terminal half-life (t1/2) 
The PD parameters will include (but are not limited to) the following: 
• 
Erythropoietin (EPO) 
• 
Reticulocytes 
• 
Iron 
• 
Ferritin 
• 
Total iron binding capacity (TIBC) 
• 
Hepcidin 
Safety Endpoints 
• 
Adverse events (AEs)  
• 
Vital sign measurements and clinical laboratory values 
• 
Hb >12.0 g/dL, >13.0 g/dL, or >14.0 g/dL 
• 
Hb <8.0 g/dL and decline in Hb ≥0.5 g/dL from Baseline Hb (Main Study); 
Hb <7.5 g/dL and decline in Hb ≥0.5 g/dL from Baseline Hb (ESA hyporesponder 
parallel study) 
• 
Hb increase >1.0 g/dL within any 2-week interval 
Dosage and Regimens 
The aim is to achieve and maintain Hb levels within the target range of 10.0 to 
11.0 g/dL, inclusive, while targeting the middle of the range and minimizing 
excursions outside the target range. 
Dosing will be initiated at Baseline/Day 1 and the first dose of vadadustat will be 
administered at the study site after other Baseline/Day 1 procedures have been 
completed.   
Thereafter, vadadustat will be taken once daily on an outpatient basis.  Subjects may 
take vadadustat with or without food and will be instructed to swallow the tablet(s) 
whole.  Subjects will be instructed to take vadadustat at roughly the same time each 
day. 
Epoetin alfa dose will be administered intravenously at the hemodialysis clinic, based 
on the subject’s central laboratory Hb value and the approved epoetin alfa US PI for 
adult patients with CKD on dialysis. 
Note: A subject may enter the washout period only after all eligibility criteria have 
been met.  During the washout period, no epoetin alfa will be administered for 5 days 
in the Main study, and 2 days in the ESA hyporesponder parallel study.  
Main Study: 
Subjects will be randomized to either a vadadustat treatment arm or epoetin alfa 
treatment arm.  Randomization will be stratified by mean weekly epoetin alfa dose 
calculated over a period of 8 weeks prior to SV2: 
• 
Low epoetin alfa dose group (≤90 U/kg/week) or 
• 
High epoetin alfa dose group (>90 to <300 U/kg/week) 
In the low epoetin alfa dose group, subjects will be randomized in a 3:3:2 ratio to 
receive either an initial vadadustat daily dose of 450 mg (3 tablets) or 300 mg 
(2 tablets), or epoetin alfa. 
In the high epoetin alfa dose group, subjects will be randomized in a 3:3:3:2 ratio to 
receive either an initial vadadustat daily dose of 600 mg (4 tablets), 450 mg (3 tablets) 
or 300 mg (2 tablets), or epoetin alfa. 
ESA Hyporesponder Parallel Study 
Subjects will be randomized in a 1:1 ratio to receive either an initial vadadustat daily 
dose of 600 mg (4 tablets) or epoetin alfa. 


Akebia Therapeutics, Inc. 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
05 April 2019 
 
Akebia — Company Confidential 
Page 16 of 105 
Epoetin alfa arm in both the Main study and ESA hyporesponder parallel study: 
For subjects who are randomized to the epoetin alfa treatment arm, the initial dosing 
regimen in the study (starting from Baseline/Day 1) will be approximately the same 
weekly dose that they were receiving prior to randomization. 
Study Drug Guidelines for Dose Adjustment 
Dose adjustments will be guided by Hb concentrations and the Guidelines for Dose 
Adjustment (see below).  Hb will be monitored via central laboratory throughout the 
study to determine if the dose of study drug (vadadustat or epoetin alfa) will be 
adjusted, interrupted, or maintained as follows: 
• 
Dose adjustments are based on the investigator’s clinical discretion, incorporating 
the protocol guidance below as well as the subject’s current Hb level, trajectory, 
and variability; symptoms; cardiovascular risk; and other features of his/her 
clinical condition(s). 
• 
If a dose increase or decrease is required to achieve and maintain Hb levels within 
the target range of 10.0 to 11.0 g/dL, inclusive, dose is adjusted by 1 dose level 
(for vadadustat 1 tablet [150 mg], for epoetin alfa approximately 25%). 
• 
In general, do not increase the dose more frequently than once every 4 weeks.  A 
one-time dose increase after 2 weeks is allowed on only two occasions.   
o 
A subject’s dose may be increased by 1 dose level if the subject has a decline 
in Hb ≥0.5 g/dL from Baseline/Day 1 in the first 2-week period (the initial 
period from Baseline/Day 1 to Week 2 following conversion from prior 
epoetin alfa therapy).   
o 
A subject’s dose may also be increased by 1 dose level in the first 2-week 
period after initiation of TIW dosing (from Week 12 to Week 14) for subjects 
that meet criteria for transitioning from daily to TIW dosing. 
• 
Reduce or interrupt the dose in the setting of a rapid rise in Hb (defined as 
>1.0 g/dL in any 2-week period)  
• 
Reduce or interrupt the dose in the setting of Hb >11.0 g/dL 
• 
Interrupt the dose in the setting of a Hb >12.0 g/dL until Hb value falls below 
11.0 g/dL.  After Hb falls below 11.0 g/dL, restart study drug and consider 
restarting at a lower dose.  
The minimum dose of vadadustat will be 150 mg daily or TIW (1 tablet daily/TIW) 
and the maximum dose will be 900 mg daily or TIW (6 tablets daily/TIW). 
Transition of Vadadustat Once Daily Dosing to TIW Dosing Regimen 
All subjects randomized to vadadustat who complete 12 weeks of once daily dosing 
regimen and who meet all the Week 12 criteria below will be transitioned to a TIW 
vadadustat dosing regimen.  Subjects who meet all of the Week 12 criteria will 
transition to TIW dosing.  
Week 12 Transition criteria: 
• 
Vadadustat daily dose of 600 mg or lower at Week 12 
• 
Hb within target range of 10.0 to 11.0 g/dL, inclusive, at Week 12 confirmed by 
central laboratory Hb value from Week 11 (11 weeks of treatment completed)  
• 
No receipt of rescue therapy (ESA or RBC transfusion) for worsening of anemia 
due to CKD from Baseline/Day 1 to Week 12.   
o 
ESA or RBC transfusion prior to Week 12 for reasons unrelated to worsening 
of anemia due to CKD (e.g., surgery, gastrointestinal bleed, or inadvertent 
administration) is not considered rescue therapy 


Akebia Therapeutics, Inc. 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
05 April 2019 
 
Akebia — Company Confidential 
Page 17 of 105 
• 
No other reason, based on the investigator’s clinical discretion, that would make 
the subject not suitable for TIW dosing. 
Selected subjects who meet Week 12 transition criteria will transition to the TIW 
vadadustat dosing regimen at the Week 12 visit.  Subjects on 150, 300, 450, or 600 mg 
of vadadustat daily at the Week 12 visit will transition to an initial vadadustat TIW 
dose one tablet greater (+150 mg), i.e., 300, 450, 600, or 750 mg vadadustat TIW, 
respectively.  Subjects will be instructed to take vadadustat on dialysis days. 
After 2 weeks of treatment in the TIW vadadustat dosing regimen (at Week 14), 
subjects in any vadadustat TIW dosing arms who have a decline in Hb ≥0.5 g/dL will 
be eligible for a dose increase by 1 tablet, based on the investigator’s clinical 
discretion. 
Subjects who are not eligible to switch from daily vadadustat to TIW dosing at 
Week 12 will remain on daily dosing for the remainder of the study. 
Subjects on TIW dosing may be converted back to vadadustat once daily dosing at the 
discretion of the investigator in the setting of inadequate Hb response.  The starting 
daily dose after the switch from TIW to daily dosing will be based on the investigator’s 
discretion after review of the subject’s clinical status and dosing history, in particular, 
the daily dose previously administered to the subject prior to the transition to TIW 
dosing (Week 12).  Subjects who switch from vadadustat TIW to daily dosing will 
continue once daily vadadustat until the end of the Treatment Period. 
Subjects in the vadadustat arm will be guided for dosing compliance using an 
electronic diary (eDiary) or through paper dosing reminders. 
PK/PD Sampling - 
vadadustat arm 
Blood for measurement of vadadustat, metabolites and EPO level in the vadadustat 
arm, in both the Main study and ESA hyporesponder parallel study, will be collected as 
outlined below.  Preferably, PK/PD samples are to be taken on the day of hemodialysis 
after the first short interdialytic interval (e.g., at the second session of the week). 
At Baseline/Day 1, PK/PD samples will be collected prior to dialysis and 
administration of vadadustat. 
At Week 1 (after at least a full week of vadadustat treatment), vadadustat will be 
administered between 15 minutes to one hour prior to the start of dialysis.  Blood 
samples will be collected as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 
5 hours ± 30 minutes post-dose 
• 
From subjects enrolled at a subset of study sites only, additional samples will be 
collected at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
On the following non-dialysis day, blood samples will be collected as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 
5 hours ± 30 minutes post-dose 
• 
From subjects enrolled at a subset of study sites only, additional samples will be 
collected at 7 hours ± 30 minutes post-dose 
At Week 11, vadadustat will be administered between 15 minutes to one hour prior to 
the start of dialysis.  Blood samples will be collected as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 
5 hours ± 30 minutes post-dose 
• 
From subjects enrolled at a subset of study sites only, additional samples will be 
collected at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
At Week 13 (after at least one week on TIW vadadustat dosing regimen), vadadustat 
will be administered between 15 minutes to one hour prior to the start of dialysis.  
Blood samples will be collected as follows: 


Akebia Therapeutics, Inc. 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
05 April 2019 
 
Akebia — Company Confidential 
Page 18 of 105 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 
5 hours ± 30 minutes hours post-dose  
• 
From subjects enrolled at a subset of study sites only, additional samples will be 
collected at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
Note: Week 13 PK/PD sampling will only be done in subjects who transition to 
vadadustat TIW dosing regimen.  Subjects who do not qualify for vadadustat TIW 
dosing and remain on daily dosing regimen will not have Week 13 PK/PD sampling. 
PK Sampling - epoetin 
alfa arm 
Blood for measurement of EPO level in the epoetin alfa arm in both the Main study 
and ESA hyporesponder parallel study will be collected as outlined below.  Preferably, 
PK samples are to be taken on the day of hemodialysis after the first short interdialytic 
interval (e.g., at the second session of the week). 
At Baseline/Day 1, a sample will be collected prior to dialysis and administration of 
epoetin alfa. 
At Week 1 (after at least a full week of study epoetin alfa treatment), epoetin alfa will 
be administered within 1 hour after start of dialysis.  Blood samples will be collected 
as follows: 
• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 
5 hours ± 30 minutes post-dose  
• 
From subjects enrolled at a subset of study sites only, additional samples will be 
collected at 7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
On the following dialysis day, one blood sample will be collected 15 minutes prior to 
administration of epoetin alfa. 
Iron Supplementation 
IV iron will be administered based on ferritin and TSAT levels measured by the central 
laboratory according to the standardized, low-intensity, iron supplementation protocol 
below: 
 
Ferritin 
<200 ng/mL 
Ferritin 
200-500 ng/mL 
Ferritin 
>500 ng/mL 
TSAT 
<20% 
IV Iron 100 mg every 
treatment 
(max 400 mg/month) 
IV Iron 50 mg 
weekly 
Hold 
TSAT 
20-50% 
IV Iron 100 mg every 
week 
IV Iron 50 mg 
weekly 
Hold 
TSAT 
>50% 
Hold 
Hold 
Hold 
IV: intravenous; TSAT: transferrin saturation 
Subjects already receiving oral iron supplementation as part of their treatment plan 
may continue their current treatment regimen.  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 oral medications containing iron.   
Subjects will be instructed to take any oral medications containing iron at least 2 hours 
after the dose of vadadustat.  


Akebia Therapeutics, Inc. 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
05 April 2019 
 
Akebia — Company Confidential 
Page 19 of 105 
Rescue Therapy 
Guidelines 
To ensure the safety of subjects and to standardize the use of rescue in the study, 
rescue therapy guidelines are provided. 
1. 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 will 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 medical 
necessity.  Study drug (vadadustat or epoetin alfa) may be continued during the 
transfusion period. 
Reasons for RBC transfusion will be captured in the appropriate CRF. 
2. ESA Use: ESA administration will be allowed when medically necessary at the 
discretion of the investigator.  In general, ESA will not be administered in subjects 
with Hb ≥8.5 g/dL, and ESA rescue will be stopped when Hb ≥9.0 g/dL.  ESA 
therapy will be administered using an approved ESA and dosing as per the local 
institution’s guidelines and per the approved product label.   
While receiving ESA therapy, subjects randomized to vadadustat must temporarily 
interrupt vadadustat.  A minimum interval will be observed prior to restarting 
vadadustat after the last dose of ESA, and treatment will be resumed after the 
following intervals: 
• 2 days after last dose of epoetin alfa  
• 7 days after last dose of darbepoetin alfa  
• 14 days after last dose of methoxy polyethylene glycol-epoetin beta  
Following ESA administration, vadadustat will be resumed at the same dose as 
previously used or with one additional tablet (+150 mg) at the discretion of the 
investigator.  
Reasons for ESA use will be captured in the appropriate CRF. 
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 clinical 
judgment.  The method of phlebotomy will be in accordance with the study site’s 
standard clinical practice. 
Study Medication 
Stopping Rules 
Study medication must be permanently discontinued if a subject meets one of the 
following criteria:  
• 
ALT or AST >3x Upper Limit of Normal (ULN) and total bilirubin >2x ULN 
• 
ALT or AST >3x ULN and international normalized ratio (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 
Concomitant 
Medications 
1. ESA 
Co-administration of any ESA with vadadustat is 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 ESA 
Rescue) if deemed medically necessary at the discretion of the investigator.  Guidelines 
for ESA administration as rescue therapy are provided above.  All efforts will be made 
to avoid inadvertent administration of ESAs resulting from adherence to ESA 
hemodialysis center protocols (e.g., DaVita ESA protocols for patients on 
hemodialysis).  If ESA is inadvertently administered to subjects actively receiving 
vadadustat treatment, vadadustat treatment will be stopped and the event will be 


Akebia Therapeutics, Inc. 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
05 April 2019 
 
Akebia — Company Confidential 
Page 20 of 105 
reported as a protocol deviation.  A minimum interval will be observed prior to 
restarting vadadustat after the last dose of ESA.  Vadadustat treatment may be resumed 
after the following intervals: 
• 
2 days after last dose of epoetin alfa  
• 
7 days after last dose of darbepoetin alfa  
• 
14 days after last dose of methoxy polyethylene glycol-epoetin beta 
2. Iron  
See guidance above (Iron Supplementation). 
3. Phosphate binders 
Subjects will be instructed to take phosphate binders (iron-containing and 
non-iron-containing phosphate binders) at least 2 hours after the dose of vadadustat.  
Study Completion, 
Subject Completion, 
Temporary 
Interruption of Study 
Drug, Early 
Discontinuation from 
Study (Early 
Termination) 
Study Completion 
The study will be considered completed after all randomized subjects have completed 
their final study visit (Visit 15/Week 24, Safety Follow-Up or Early Termination).  
Subject Completion 
A subject will be considered as having completed the study after completion of their 
final study visit (Visit 15/Week 24, Safety Follow-Up or Early Termination).   
Temporary Interruption of Study Drug 
During the study, a subject may interrupt study drug (vadadustat or epoetin alfa) for 
any of the following reasons: 
• 
AE 
• 
Missed dialysis visit (epoetin alfa arm) 
• 
Investigator’s discretion 
• 
Rapid rise in Hb (defined as >1.0 g/dL in any 2-week period) 
• 
Hb above 11.0 g/dL 
• 
ESA use (vadadustat arm) 
Unless contraindicated, treatment will be resumed whenever possible and assessed at 
every visit following study drug interruption. 
Early Discontinuation from Study (Early Termination) 
Subjects who discontinue prematurely from the study will complete the 
End-of-Treatment visit (Visit 14) assessments and will complete the Safety Follow-Up 
(Visit 15) 4 weeks after Visit 14. 
Subjects may discontinue for any of the following reasons: 
• AE  
• Investigator’s discretion 
• Subject withdrawal of consent  
• Lack of efficacy 
• Lost to follow up despite reasonable efforts by the investigator to locate the subject 
• Death  
• Other reasons (pregnancy, kidney transplantation, specific reasons to be documented 
by the investigator) 
Subjects who undergo a solid organ (including kidney), hematopoietic stem cell, or 
bone marrow transplantation will have their study medication (vadadustat or epoetin 
alfa) permanently discontinued and will complete the End-of-Treatment (Visit 14) and 


Akebia Therapeutics, Inc. 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
05 April 2019 
 
Akebia — Company Confidential 
Page 21 of 105 
Safety Follow-Up (Visit 15) visit assessments. 
Study Termination/ 
Individual Study Site 
Termination 
The sponsor may terminate this study prematurely, either in its entirety or at any study 
site, for reasonable cause provided that written notice is submitted in advance of the 
intended termination.  Advanced notice is not required if the study is stopped due to 
safety concerns.  If the sponsor terminates the study for safety reasons, the sponsor will 
immediately notify the investigator and subsequently provide written instructions for 
study termination.  If the study has been suspended or terminated, prompt notification 
will be given to investigators, IRBs, and regulatory authorities in accordance with 
regulatory requirements. 
Statistical 
Considerations 
Efficacy and safety endpoint analysis will be descriptive in nature.  Continuous 
variables will be summarized using number of subjects with mean, standard deviation 
(SD), median, minimum and maximum.  For categorical variables, the number and 
percentage of subjects in each category will be tabulated. 
PK and PD parameters will be summarized using descriptive statistics: number of 
subjects, mean, median, SD, minimum, maximum, and coefficient of variation, 
geometric mean and geometric mean SD.   
The ESA hyporesponder parallel study will be analyzed separately from the main 
study. 
PK Analysis 
A PK analysis will be conducted using non-compartmental analyses to describe 
vadadustat PK parameters.  PK analysis will be reported separately. 
PD Analysis 
Samples for the PD endpoints (EPO, reticulocytes, iron, Ferritin, hepcidin, and TIBC) 
will be collected at multiple intervals during the study.  An exposure-response analysis 
of vadadustat, EPO and other PD measures will be conducted as deemed appropriate.  
PD analysis may be reported separately. 
Sample Size 
Estimation 
Approximately 95 subjects are planned for enrollment in the Main study with 40 and 
55 subjects randomized to the low epoetin alfa dose group and the high epoetin alfa 
dose group respectively.  Approximately 30 subjects are planned for enrollment in the 
ESA hyporesponder parallel study.  Sample size reflects the exploratory nature of this 
study.  
Enrollment may be increased by up to approximately 20 additional subjects in the 
Main study, and by up to approximately 30 additional subjects in the ESA 
hyporesponder parallel study to ensure adequate data are captured for the primary, 
PK/PD, and safety endpoints. 
Safety Monitoring 
This is an open label study allowing the study team full access to safety data which 
will be reviewed on a regular basis, throughout the course of the study.  Safety 
monitoring will be performed as described in the Medical Monitor Plan.   
 


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3 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under concentration-time curve 
AUCinf 
area under concentration-time curve from dosing to infinity 
AUClast 
area under concentration-time curve from dosing to last 
measurable concentration  
BCRP 
breast cancer resistance protein 
BP 
blood pressure 
CBC 
complete blood count 
CKD 
chronic kidney disease 
CL/F 
apparent total body clearance 
Cmax 
maximum concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
DD-CKD 
dialysis dependent chronic kidney disease 
DME 
Designated Medical Event(s) 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eDiary 
electronic diary 
EOT 
end-of-treatment 
EPO 
erythropoietin 
EQ-5D-5L 
EuroQol 5 Dimensions 5 Levels 
ESA 
erythropoiesis-stimulating agent 
ESRD 
end-stage renal disease 
FAS 
Full Analysis Population 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
Hb 
hemoglobin 
HF 
heart failure 
HIF 
hypoxia-inducible factor 
HIF-PH 
hypoxia-inducible factor prolyl-hydroxylase 
HR 
heart rate 
HRQOL 
health-related quality of life 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
IWRS 
Interactive Web Response System 


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LFT 
liver function test 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger ribonucleic acid 
NDD-CKD 
non-dialysis dependent chronic kidney disease 
PGI-C 
patient global impression of change 
PGI-S 
patient global impression of severity 
PHD 
prolyl 4-hydroxylase domains 
PI 
Package Insert 
PK 
pharmacokinetic(s) 
PD 
pharmacodynamics(s) 
PT 
Prothrombin Time 
RBC 
red blood cell 
RR 
respiratory rate 
SAE 
serious adverse event 
SD 
standard deviation 
SF-36v2 
36-Item Short-Form General Health Survey 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
System Organ Class 
t1/2 
terminal half life 
TIBC 
total iron binding capacity  
TIW 
three times a week 
Tmax 
time to reach Cmax 
TSAT 
transferrin saturation 
ULN 
upper limit of normal 
US 
United States 
Vd/F 
apparent volume of distribution 
VEGF 
vascular endothelial growth factor 
 


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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% to 16% of the population (Jha 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, infection, cancer, and mortality (Iseki 2007). 
The prevalence and severity of renal anemia in CKD increases as renal function deteriorates 
(Di Iorio 2007; Stauffer 2014).  As CKD progresses, the combined effect of decreased red blood 
cell (RBC) production from lower erythropoietin (EPO) signaling, increased rate of RBC 
destruction, and reduced iron availability to the bone marrow results in the increased prevalence 
and severity of anemia (Pergola 2016).  Anemia generally exists when hemoglobin (Hb) is less 
than 13.0 g/dL in men or less than 12.0 g/dL in women (KDIGO 2012).  Three principal factors 
contribute to the development of anemia as CKD progresses:  
• Peritubular fibroblasts, a type of cell in the kidney, are designed to sense the amount of 
oxygen carried by the blood.  These cells secrete EPO to adjust the production of RBCs by 
the bone marrow and maintain circulating oxygen levels at normal physiologic levels.  As 
kidney disease progresses, the number of peritubular fibroblasts is reduced and EPO 
secretion is significantly decreased, leading to a reduction in RBC production (Iseki 2007; 
Nurko 2006).  
• On average, the RBCs in CKD patients have a shorter lifespan (approximate lifespan of 
70 days) compared with the RBCs in healthy people (approximate lifespan of 90 to 120 days) 
(Ly 2004; Nurko 2006).  Such a condition leads to increased RBC production in CKD 
patients to maintain normal physiologic levels.  
• The availability of iron to the bone marrow is impaired.  Iron is a required component in the 
formation of Hb, and is essential for the transport of oxygen to the tissues of the body. 
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 2014).  In these patients, compensatory changes occur in cardiac structure and function 
including an increase in cardiac output and the development of left ventricular hypertrophy and 
eventually the development of heart failure (Metivier 2000).  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 patients (Iseki 2007; NICE 2011).  Overall, 
anemia contributes to a poorer prognosis in patients with CKD (Iseki 2007; Nurko 2006). 
The risks associated with erythropoiesis-stimulating agents (ESAs), including an increased risk 
of death and cardiovascular events (Besarab 1998; Drüeke 2006; Pfeffer 2009a; Pfeffer 2009b; 
Singh 2006), 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 dialysis dependent CKD (DD-CKD) patients 
remains high.  To fulfill this unmet need, the vadadustat clinical program is focused on 
developing an orally active therapeutic agent for the treatment of anemia in patients with CKD. 


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4.1 
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 (HIF-PHs) for the treatment of anemia associated 
with CKD.  HIF-PH enzymes are also referred to as prolyl 4-hydroxylase domains (PHDs), of 
which the 2 most commonly expressed isoforms are PHD2 and PHD3.  Vadadustat is a slightly 
more potent inhibitor of PHD3 (50% inhibitory concentration [IC50] = 0.08 µM) than of PHD2 
(IC50 = 0.19 µM).  The inhibition of PHD3 and PHD2 stabilizes hypoxia-inducible factor 
(HIF)-2α and HIF-1α, which in turn stimulates the production of EPO.  In vivo animal efficacy 
and messenger ribonucleic acid (mRNA) data indicate that vadadustat induces the production of 
EPO from both renal and extra-renal sites (liver and brain), and this increase in EPO results in an 
increase in RBC production in the bone marrow.  In clinical trials, vadadustat has been shown to 
facilitate iron homeostasis by decreasing hepcidin and increasing transferrin levels in healthy 
adult male volunteers and male and female CKD patients.  This enables iron transport 
mechanisms that should enhance the terminal steps of erythropoiesis.  Vadadustat offers the 
potential of flexible oral dosing that provides a more gradual and reliable means of titration than 
injectable hormones.  Therefore, vadadustat is being developed as an alternative to the existing 
protein hormone ESAs. 
4.2 
Summary of Clinical Experience 
Please see the vadadustat Investigator Brochure for additional discussion and information for 
the following section. 
The efficacy, safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of 
vadadustat have been characterized in 10 completed Phase 1 studies in healthy volunteers 
including 1 ethno-bridging study in Caucasian and Japanese subjects, 1 completed Phase 1 study 
in subjects undergoing chronic hemodialysis, 3 completed Phase 2a studies in non-dialysis 
dependent CKD (NDD-CKD) subjects, 1 completed Phase 2b study in NDD-CKD subjects, and 
1 completed Phase 2 study in DD-CKD subjects.  The United States (US) 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, double-blind, 
placebo-controlled study with 5 different dose groups dosed for 42 days.  The US Phase 2b, 
randomized, double-blind, placebo-controlled study evaluated Stages 3, 4, and 5 CKD 
(pre-dialysis) dosed for 20 weeks.  The Japanese Phase 2, randomized, double-blind, 
placebo-controlled study evaluated Stages 3, 4, and 5 CKD (pre-dialysis) dosed for 16 weeks.  
The US Phase 2 open-label study evaluated DD-CKD subjects on chronic hemodialysis dosed 
for 16 weeks.  The Japanese Phase 2, randomized, double-blind, placebo-controlled study 
evaluated DD-CKD subjects on chronic hemodialysis dosed for 16 weeks.  In the studies 
completed to date, a total of 630 subjects have received vadadustat, including 200 healthy 
volunteers and 430 subjects with CKD. 
Vadadustat has shown 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 and Hb 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 consistent bioavailability with area under 


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concentration-time curve (AUC) and maximum concentration (Cmax) in Phase 1 and Phase 2 
studies covering the dose range of 80 to 1200 mg after single administration and 500 to 900 mg 
after repeated daily administration for 10 days.  The plasma half-life of vadadustat was about 
4 to 6 hours, 7 to 8 hours, and 9 to 10 hours in healthy subjects, NDD-CKD patients, and 
DD-CKD patients, respectively. 
Vadadustat is extensively metabolized and its metabolites are eliminated from the body by dual 
routes of excretion (both 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.  
Multiple doses of 700 and 900 mg daily for up to 10 days (Study AKB-6548-CI-0002 [CI-0002]) 
and single doses of 1200 mg (Study AKB-6548-CI-0001 [CI-0001], Study AKB-6548-CI-0010 
[CI-0010]) have been examined in healthy volunteers.  Vadadustat demonstrated dose-
proportional PK and achieved serum EPO concentrations up to 34.4 mIU/mL, levels considered 
physiologic and below exposures achieved with injectable ESAs (Besarb 1992).  A higher 
incidence of adverse events (AEs) in the gastrointestinal System Organ Class (SOC) – nausea, 
diarrhea, abdominal pain, dyspepsia – was observed in groups treated with 700, 900, or 1200 mg 
compared with lower vadadustat doses or placebo.  Most AEs were mild to moderate, short-lived 
(1 or 2 days), and assessed as unrelated by investigators.  No AEs led to study withdrawal, and 
no serious adverse events (SAEs) were reported.  No clinically meaningful changes or 
abnormalities in vital signs, safety laboratory studies, or electrocardiogram (ECG) parameters 
were reported. 
A 16-week, open-label, multicenter, Phase 2 trial evaluated vadadustat in 94 subjects receiving 
chronic hemodialysis previously maintained on epoetin alfa and IV iron form the 3 months prior 
to Screening (Study AKB-6548-CI-0011 [CI-0011]).  Subjects were assigned to one of three 
vadadustat dose cohorts: 300 mg daily, 450 mg daily, or 450 mg three times a week (TIW).  
Dosing was fixed for the first 8 weeks; for the subsequent 8 weeks dose was adjusted from 
150 to 600 mg according to Hb response based upon a dose adjustment algorithm.  Sixty-nine of 
the 94 subjects completed the study.  The primary endpoint was the mean Hb concentration 
change from pre-treatment average (Screening Visit 1, Screening Visit 2, and Baseline Visit) to 
mid-study (Weeks 7 to 8) and end-of-study (Weeks 15 to 16) and was analyzed using observed 
Hb values (no imputation for missing data).  No statistically significant mean change in Hb from 
pre-treatment average was observed for either of the two time points for any of the three 
treatment groups. 
Among subjects randomized to an initial dose of 300 mg daily, 450 mg daily, or 450 mg TIW, 
0% (0 of 30), 3% (1 of 33), and 19% (6 of 31) of subjects withdrew from the study due to 
worsening anemia, respectively.  In a sensitivity analysis using last observation carried forward 
(LOCF) for the primary efficacy endpoint, no significant mean change in Hb from pre-treatment 
levels was observed in the 300 mg daily dosing group.  At Weeks 15 to 16, modest, statistically 
significant mean decreases were observed in the 450 mg daily and 450 mg TIW dosing groups. 
In a post-hoc univariate analysis of baseline characteristics, higher pre-baseline epoetin alfa dose 
was associated with a decrease in mean Hb at Weeks 7 to 8 and Weeks 15 to 16 in the dosing 
cohorts.  Subjects who discontinued the study due to worsening anemia had a higher mean pre-


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baseline epoetin alfa dose compared with subjects who discontinued due to other reasons or 
subjects who completed the study. 
Based on 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.  
In the ongoing global Phase 3 and Japanese Phase 3 clinical studies, over 7000 subjects are 
planned to be treated with vadadustat or comparator.  
This study will evaluate efficacy, safety and PK/PD with different vadadustat dosing strategies in 
hemodialysis subjects converting from epoetin alfa to further characterize the optimal vadadustat 
regimen.  This study is the first study to examine vadadustat doses of 750 and 900 mg in 
DD-CKD subjects. 
4.3 
Potential Benefits and Risks 
Please see the vadadustat Investigator’s Brochure for additional information. 
Trials of injectable 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 2009a).  Post-hoc analyses performed by the Food and Drug 
Administration (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 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 2007).  Potential clinical benefits include enhanced 
erythropoiesis and decreased exogenous iron requirements.  
In nonclinical safety studies, the main findings originated from an exaggerated pharmacological 
response that results in increased erythropoiesis, polycythemia, blood hyperviscosity, and the 
formation of fibrin thrombi in multiple organs.  Early mortality noted in the mouse and rat and 
moribundity in the dog were due to the sequelae associated with polycythemia.  These findings 
were reproducible across species and studies, dose-dependent and showed reversibility.  
Dose-limiting toxicity in the exploratory toxicology studies was due to hemoglobinuric 
nephropathy (rat) and emesis associated with body weight loss (dog). 
In completed Phase 1 clinical studies of vadadustat in healthy volunteers, there were low 
numbers of treatment-emergent AEs.  The most frequently reported AEs were in the 
gastrointestinal disorders (i.e., nausea, diarrhea, abdominal pain, flatulence, dyspepsia) and 
nervous system disorders (i.e., headache, dizziness) SOC.  The majority of AEs were mild to 
moderate in severity.  
The most frequently reported AEs in completed Phase 2 studies of NDD- and DD-CKD subjects 
were in the following SOCs: gastrointestinal disorders (nausea, diarrhea, vomiting), 


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cardiovascular disorders (hypertension, hypotension, coronary artery disease), renal (renal failure 
chronic, renal failure acute), infections and infestations (gastroenteritis, urinary tract infection, 
pneumonia), and metabolism and nutrition disorders (hyperkalemia, fluid overload).  Four deaths 
occurred in the completed Phase 2 clinical studies.  
Identified risks include nausea, diarrhea, vomiting, headache, abdominal pain, and uric acid 
elevations.  Hypersensitivity, hyperkalemia and hypertension have been identified as potential 
risks and hepatotoxicity has been identified as an important potential risk associated with 
vadadustat therapy.  
Review of safety data from completed Phase 1 and 2 clinical studies, as well as review of 
accumulating data from ongoing studies, continue to support further development of the 
vadadustat program. 
 


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5 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Primary Objective 
To assess the efficacy and safety of daily dosing of vadadustat compared to epoetin alfa for 
12 weeks in hemodialysis subjects. 
5.2 
Secondary Objectives 
• To assess the efficacy and safety of TIW dosing of vadadustat in selected hemodialysis 
subjects who have been successfully managed with daily dosing of vadadustat through 
Week 12 
• To evaluate the PK/PD of daily and TIW dosing of vadadustat in hemodialysis subjects 
compared to epoetin alfa 
• To assess the efficacy and safety of several dosing strategies of vadadustat compared to 
epoetin alfa during a 20-week Treatment Period in hemodialysis subjects 
5.3 
Efficacy Endpoints 
5.3.1 Primary Endpoints 
The primary endpoint will be the mean change in Hb between Baseline (average pretreatment 
Hb) and the primary evaluation period (average Hb from Weeks 10 to 12). 
5.3.2 Key Secondary Endpoints 
• Proportion of subjects with Hb values within the target range (10.0 to 11.0 g/dL, inclusive) at 
the primary evaluation period (Weeks 10 to 12) 
• For subjects who transitioned to TIW vadadustat dosing, mean change in Hb from primary 
evaluation period (average Hb from Weeks 10 to 12) to the secondary evaluation period 
(average Hb from Weeks 18 to 20) 
5.3.2.1 Other Secondary Endpoints 
• Mean change in Hb between Baseline (average pretreatment Hb) and the secondary 
evaluation period (average Hb from Weeks 18 to 20) 
• Proportion of subjects with Hb values within the target range (10.0 to 11.0 g/dL, inclusive) at 
the secondary evaluation period (Weeks 18 to 20) 
• For subjects who transitioned to TIW vadadustat dosing, proportion of subjects with Hb 
values within the target range (10.0 to 11.0 g/dL, inclusive) at the secondary evaluation 
period (Weeks 18 to 20) 
• Proportion of subjects with a mean increase in Hb from Baseline to the primary evaluation 
period ≥0.5 g/dL (average Hb from Weeks 10 to 12) or with Hb values within the target 
range (10.0 to 11.0 g/dL, inclusive) at the primary evaluation period (Weeks 10 to 12) 
• Proportion of subjects with a mean increase in Hb from Baseline to the secondary evaluation 
period ≥0.5 g/dL (average Hb from Weeks 18 to 20) or with Hb values within the target 
range (10.0 to 11.0 g/dL, inclusive) at the secondary evaluation period (Weeks 18 to 20) 
• Intravenous (IV) iron supplementation 


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6 
STUDY DESIGN 
6.1 
Study Design 
This is a Phase 2, randomized, open-label study to evaluate vadadustat for the treatment of 
anemia in hemodialysis subjects converting from epoetin alfa therapy. 
For all subjects (Main study and ESA hyporesponder parallel study), the study (as shown in 
Figure 1) will include a Screening Period, a study Treatment Period, and a Safety Follow-Up 
Period as described below.  PK and PD sampling will be done throughout the study (see PK and 
PD Sampling Section 9.2.2.1, PK/PD Sampling for Subjects Randomized to Vadadustat and 
Section 9.2.2.2, PK Sampling for Subjects Randomized to Epoetin Alfa, respectively, for 
details). 
The aim is to achieve and maintain Hb levels within the target range of 10.0 to 11.0 g/dL, 
inclusive, while targeting the middle of the range and minimizing excursions outside the target 
range. 


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FIGURE 1: OVERVIEW OF STUDY DESIGN 
 
ESA: erythropoiesis-stimulating agent; Hb: hemoglobin; n: number of subjects; SV: screening visit; TIW: three 
times per week; W: week 
6.1.1 Screening Period (up to 28 days; Day -28 to Baseline/Day 1) 
For all subjects (Main study and ESA hyporesponder parallel study), the Screening Period starts 
at the time the informed consent is signed and will be a maximum of 28 days in duration.  
Baseline/Day 1 will be performed within 28 days of the start of Screening.  Subjects who meet 
all eligibility criteria will be randomized to a vadadustat treatment arm or an epoetin alfa 
treatment arm.  Subjects will be required to stop epoetin alfa treatment for a minimum duration 
of 5 days before Baseline/Day 1 in the Main study and for a minimum of 2 days before 
Baseline/Day 1 in the ESA hyporesponder parallel study.  In the Main study, randomization will 


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be stratified by the mean weekly epoetin dose calculated over a period of 8 weeks prior to 
Screening Visit 2 (SV2): 
• Low epoetin alfa dose group (≤90 U/kg/week) or 
• High epoetin alfa dose group (>90 to <300 U/kg/week) 
6.1.2 Study Treatment Period (Baseline/Day 1 to Week 20) 
For all subjects (Main study and ESA hyporesponder parallel study), the Treatment Period will 
run from Baseline/Day 1 to Week 20.  Dose will be adjusted to achieve and maintain Hb levels 
within the target range of 10.0 to 11.0 g/dL, inclusive, while targeting the middle of the range 
and minimizing excursions outside of the target range. 
6.1.2.1 Vadadustat Treatment 
Subjects in the Main study randomized to vadadustat: 
• Subjects in the low epoetin alfa dose group will start vadadustat at an initial, randomly 
allocated dose of 300 or 450 mg daily.   
• Subjects in the high epoetin alfa dose group will start vadadustat at an initial, randomly 
allocated dose of 300, 450, or 600 mg daily.   
Subjects in the ESA hyporesponder parallel study randomized to vadadustat: 
• Subjects will receive a starting dose of vadadustat 600 mg daily.  
Transition to TIW for all subjects randomized to vadadustat: 
All subjects randomized to vadadustat (Main study and ESA hyporesponder parallel study), who 
complete the 12-week once daily dosing regimen and who meet all the Week 12 transition 
criteria for switching from daily to TIW dosing, will initiate TIW dosing at a starting dose one 
tablet greater (+150 mg) than the final dose in the daily dosing period (see Section 8.4.5.2, 
Transition of Vadadustat Once Daily Dosing to TIW Dosing Regimen). 
Note: Subjects who are not eligible to switch from daily vadadustat to TIW dosing at Week 12 
will remain on daily dosing from the remainder of the study (see Section 8.4.5, Vadadustat 
Dosing Regimen and Guidelines for Dose Adjustment).  
6.1.2.2 Epoetin Alfa Treatment 
Subjects in both the Main study and ESA hyporesponder parallel study randomized to epoetin 
alfa: 
All subjects randomized to epoetin alfa will receive TIW dosing for the entire Treatment Period 
based on the subject’s central laboratory Hb value and the approved epoetin alfa US Package 
Insert (PI) for adult patients with CKD on dialysis.  Dose will be adjusted to achieve and 
maintain Hb levels within the target range of 10.0 to 11.0 g/dL, inclusive, while targeting the 
middle of the range and minimizing excursions outside of the target range (see Section 8.4.4, 
Epoetin Alfa Dosing Regimen). 


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6.1.3 Safety Follow-Up Period (Weeks 20 to 24) 
For all subjects (Main study and ESA hyporesponder parallel study), the 4-week Safety 
Follow-up Period starting at Week 20 will be followed by a post-treatment safety assessment 
conducted at the beginning of Week 24. 
6.2 
Rationale for Study Design 
The Main Study and the ESA hyporesponder parallel study will evaluate different starting doses 
of vadadustat based on pre-baseline ESA doses.  Numerous studies have demonstrated that 
hemodialysis patients requiring higher ESA doses to treat their anemia have a higher burden of 
comorbidities, a more inflammatory state, and a greater risk of adverse outcomes (Besarb 1998; 
Parfrey 2005; Unger 2010).  As described above (Section 4.2, Summary of Clinical Experience) 
in a Phase 2 hemodialysis study (CI-0011), a post-hoc analysis suggested higher pre-baseline 
ESA doses were associated with lower observed mean Hb levels.  Subjects on higher pre-
baseline ESA doses may benefit from a higher starting dose of vadadustat after initial conversion 
from ESAs.  
Three levels of pre-baseline ESA dose will be evaluated.  In the Main Study subjects will be 
randomized to one of two cohorts based on pre-baseline ESA dose (≤90 U/kg/week and 
>90 to <300 U/kg/week).  The ESA threshold of 90 U/kg/week was based on the median ESA 
doses reported in the US Renal Data System and US Dialysis Outcomes and Practice Patterns 
Study, which ranged from approximately 90 to 110 U/kg/week. 
The ESA hyporesponder parallel study will evaluate subjects with Hb levels below the target 
range despite receiving ≥300 U/kg/week of epoetin alfa.  This ESA threshold was based on the 
definition of resistance to ESAs proposed in the ERA-EDTA 2004 guidelines (Locatelli 2004).  
The Main study and the ESA hyporesponder parallel study incorporate an approach to vadadustat 
dose adjustment designed to maximize the probability that Hb can be maintained within the 
target range of 10.0 to 11.0 g/dL, inclusive (see Section 8.4.5, Vadadustat Dosing Regimen and 
Guidelines for Dose Adjustment).  The approach to vadadustat dose adjustment in this Phase 2 
study includes several modifications as compared to the vadadustat dosing algorithms used in 
previously completed Phase 2 studies and the dosing algorithm used in the ongoing Phase 3 
studies.   
During this study, dose increases for vadadustat will be allowed at 4-week intervals, with the 
exception of the initial 2 weeks of treatment, in the daily and TIW dosing periods of the study.  
Dose increases will be permitted in the initial 2 weeks of treatment, in the daily and TIW dosing 
periods, in subjects with a Hb decline ≥0.5 g/dL from baseline and Week 12, respectively.  This 
approach is commonly used in clinical practice to treat patients with declining or low Hb values 
(Pfeffer 2009a; Singh 2006).  Risk of abrupt or excessive increases in Hb is minimized due to the 
underlying Hb trajectory and is further mitigated by close Hb monitoring. 
In the present study, the safety and efficacy of a vadadustat TIW dosing regimen is being 
evaluated as a potential alternative treatment regimen to a once daily dosing regimen in 
hemodialysis subjects.  Specifically, this study will evaluate conversion from once daily dosing 
to TIW dosing.  As described above (Section 4.2, Summary of Clinical Experience), the 16-week 
Phase 2 hemodialysis study evaluated hemodialysis subjects switching from ESA to vadadustat 
450 mg TIW for an 8-week fixed-dose period followed by 8 weeks of dose adjustment according 
to Hb response.  The primary efficacy analysis in CI-0011 using observed data showed stable 


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mean Hb levels in this group.  Six of 31 (19%) subjects withdrew due to worsening anemia, and 
a sensitivity analysis imputing missing Hb values using LOCF demonstrated a decline in mean 
Hb levels.  To maximize the probability that subjects treated with vadadustat TIW will maintain 
Hb levels within the target range, this study will: examine subjects successfully treated with 
daily dosing converting to TIW dosing; allow for earlier dose increase after 2 weeks of initial 
treatment; and permit dose increases up to 900 mg TIW. 
6.3 
Dose Justification 
In this study, vadadustat starting daily doses will be determined by pre-baseline ESA dose 
(Section 8.4.5, Vadadustat Dosing Regimen and Guidelines for Dose Adjustment).  In the Main 
study starting doses of vadadustat will be 300 and 450 mg daily in subjects converting from 
epoetin alfa doses ≤90 U/kg/week and 300, 450, and 600 mg daily in subjects converting from 
epoetin alfa doses >90 to <300 U/kg/week.  For the ESA hyporesponder parallel study, the 
starting doses will be 600 mg daily.  As described above (Section 4.2, Summary of Clinical 
Experience), the maximum vadadustat starting dose evaluated in completed Phase 2 NDD-CKD 
studies was 630 or 600 mg daily, in Study AKB-6548-CI-0005 (CI-0005) and 
Study AKB-6548-CI-0021 (CI-0021) respectively, and in completed Phase 2 DD-CKD studies 
was 450 or 600 mg in Study CI-0011 and Study AKB-6548-CI-0022 (CI-0022), respectively. 
Based on the dosing algorithm, vadadustat will be titrated to achieve and maintain Hb levels 
within the target range of 10.0 to 11.0 g/dL, inclusive.  The dose range for titration is 
150 to 900 mg daily or TIW.  Doses of 150 to 630 mg daily have been evaluated in studies 
evaluating subjects with NDD-CKD and DD-CKD.  The maximum vadadustat dose evaluated in 
healthy volunteers was 1200 mg in a single dose study (CI-0001 and CI-0010) and 900 mg daily 
in a 10-day multiple dose study (CI-0002), as described in Section 4.2, Summary of Clinical 
Experience.  This study is the first study to examine vadadustat doses of 750 and 900 mg in 
DD-CKD subjects. 
The justification to evaluate higher doses is that to date, dose-ranging clinical studies have not 
identified a vadadustat dose at which a plateau in exposure or effect has been observed.  In 
Phase 1 studies in healthy volunteers, dose-proportional increases in AUC and Cmax and 
dose-related increases in serum EPO were observed up to the maximum doses studied, single 
doses of 1200 mg and multiple doses of 900 mg daily for 10 days (CI-0001, CI-0002).  In Phase 
2 studies in anemic NDD-CKD and DD-CKD subjects, dose-dependent increases in Hb were 
observed up to the maximum dose studied of 600 or 630 mg daily (CI-0005, CI-0021, CI-0022).  
It is anticipated that daily doses of vadadustat at 750 or 900 mg, which yield an increase in 
systemic exposure above 600 mg of approximately 25% and 50%, respectively, would yield an 
incremental erythropoietic effect greater than 600 mg for the treatment of anemia associated with 
CKD.  
From a safety and tolerability standpoint, as described above (Section 4.2, Summary of Clinical 
Experience), multiple doses of 700 and 900 mg daily for up to 10 days (CI-0002) and single 
doses of 1200 mg (CI-0001, CI-0010) have been examined in healthy volunteers.  Vadadustat 
demonstrated dose-proportional PK and achieved serum EPO concentrations up to 34.4 mIU/mL, 
levels considered physiologic and below exposures achieved with injectable ESAs 
(Besarb 1992).  A higher incidence of AEs in the gastrointestinal SOC – nausea, diarrhea, 
abdominal pain, dyspepsia – was observed in groups treated with 700, 900, or 1200 mg 
compared with lower vadadustat doses or placebo.  Most AEs were mild to moderate, short-lived 


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(1 or 2 days), and assessed as unrelated by investigators.  No AEs led to study withdrawal, and 
no SAEs were reported.  No clinically meaningful changes or abnormalities in vital signs, safety 
laboratory studies, or ECG parameters were reported. 
Assessment of animal-to-human safety margins is presented in the Investigator Brochure.  
This study design mitigates the risk of vadadustat doses of 750 or 900 mg.  Intensive Hb 
monitoring, a strict dose adjustment algorithm, and phlebotomy will be implemented to mitigate 
the potential risk of a rapid Hb rise, as follows:  
• Hb measurements are scheduled at least every 2 weeks to Week 20 
• The dose adjustment algorithm will target a narrow Hb range, 10.0 to 11.0 g/dL, inclusive 
• The protocol specifies that phlebotomy may be considered in the setting of high Hb levels 
(>14.0 g/dL) or a high Hb rate of rise, based on the investigator’s judgment 
Importantly, the Phase 2 studies demonstrated that cessation of treatment resulted in prompt 
reduction in mean Hb within 2 to 4 weeks. 


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7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
General Criteria 
To be eligible for this study, a subject or their legally acceptable representative must provide 
valid informed consent and the subject must meet all eligibility criteria.  No study procedures 
(including Screening tests) may be performed until after the informed consent has been legally 
signed. 
7.2 
Inclusion Criteria 
Subjects must meet the following inclusion criteria: 
1. ≥18 years of age 
2. Receiving chronic, outpatient in-center hemodialysis (TIW) for ESRD for at least 12 weeks 
prior to Screening 
3. Maintained on IV epoetin alfa therapy for 8 weeks prior to and including Screening through 
SV2 
4. Eligibility in the Main study and ESA hyporesponder parallel study is based on the following 
mean weekly epoetin alfa doses: 
• Main study: Mean weekly epoetin alfa dose <300 U/kg/week for 8 weeks prior to SV2 
• ESA hyporesponder parallel study: Mean weekly epoetin alfa dose ≥300 U/kg/week for 8 
weeks prior to SV2 
5. Two Hb values measured by the central laboratory at least 4 days apart between SV1 and 
SV2 as indicated below: 
• Main study: 2 Hb values between 8.5 and 11.0 g/dL, inclusive 
• ESA hyporesponder parallel study: 2 Hb values between 8.0 and 10.0 g/dL, inclusive 
6. Serum ferritin ≥100 ng/mL and transferrin saturation (TSAT) ≥20% during Screening 
7. Folate and vitamin B12 measurements ≥ lower limit of normal during Screening 
8. Hemodialysis adequacy as indicated by single-pool Kt/Vurea ≥1.2 using the most recent 
historical measurement within 8 weeks prior to or during Screening 
9. Understands the procedures and requirements of the study and provides written informed 
consent and authorization for protected health information disclosure. 
7.3 
Exclusion Criteria 
Subjects must not meet any of the following exclusion criteria: 
1. Anemia due to a cause other than CKD (e.g., sickle cell disease, myelodysplastic syndromes, 
bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic anemia, thalassemia, or 
pure red cell aplasia) 
2. Active bleeding or recent blood loss within 8 weeks prior to randomization 
3. RBC transfusion within 8 weeks prior to randomization 
4. Anticipated to discontinue hemodialysis during the study 
5. Judged by the investigator that the subject is likely to need rescue therapy (ESA 
administration or RBC transfusion) immediately after enrollment in the study 


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6. History of chronic liver disease (e.g., chronic infectious hepatitis, chronic autoimmune liver 
disease, cirrhosis or fibrosis of the liver)  
7. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine 
aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total bilirubin 
>1.5 x upper limit of normal (ULN) during Screening.  Subjects with a history of Gilbert’s 
syndrome are not excluded. 
8. Current uncontrolled hypertension as determined by the investigator that would 
contraindicate the use of epoetin alfa 
9. 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 heart failure (HF) or New York Heart 
Association Class IV HF, or stroke within 12 weeks prior to or during Screening 
10. History of new or recurrent malignancy within 2 years prior to and during Screening or 
currently receiving treatment or suppressive therapy for cancer.  Subjects with treated basal 
cell carcinoma of skin, curatively resected squamous cell carcinoma of skin, or cervical 
carcinoma in situ are not excluded. 
11. History of deep vein thrombosis or pulmonary embolism within 12 weeks prior to or during 
Screening 
12. History of hemosiderosis or hemochromatosis 
13. History of prior organ transplantation (subjects with a history of failed kidney transplant or 
corneal transplants are not excluded) 
14. Scheduled organ transplant from a living donor and subjects on the kidney transplant wait-
list who are expected to receive a transplant within 6 months  
15. History of a prior hematopoietic stem cell or bone marrow transplant (stem cell therapy for 
knee arthritis is not excluded) 
16. Known hypersensitivity to vadadustat, epoetin alfa, or any of their excipients 
17. Any prior use of a HIF-PH inhibitor or any use of an investigational medication within 
30 days or 5 half-lives of the investigational medication (whichever is longer), prior to 
randomization 
18. For female subjects: 
• Of non-childbearing potential 
o Inability to confirm surgical sterility (e.g., hysterectomy, bilateral tubal ligation, 
bilateral oophorectomy) at least 1 month prior to Screening, or  
o Not considered post-menopausal (no menses for >1 year with follicle stimulating 
hormone [FSH] >40 U/L at Screening)  
• Or, if of childbearing potential,  
o Lack of confirmation of the use of acceptable forms of contraception* for a minimum 
of one complete menstrual cycle prior to Screening 
o Positive serum pregnancy test at SV2 


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o Unwilling to use two acceptable forms of contraception* (at least one of which must 
be a barrier method) starting Baseline/Day 1, throughout the Treatment Period and for 
30 days after the final study drug administration 
(refer to Section 9.1.5, Contraception and Pregnancy Avoidance Measures) 
19. Breastfeeding during Screening or throughout the Treatment Period and for 30 days after the 
final study drug administration. 
20. Donation of ova starting at Screening, throughout the Treatment Period, and for 30 days after 
the final study drug administration. 
21. Male subjects who have not had a vasectomy and do not agree to the following: use of an 
acceptable form of contraception* (refer to Section 9.1.5, Contraception and Pregnancy 
Avoidance Measures) during the study and for 30 days after the last dose of the study drug; 
to not donate semen during the study and for at least 30 days after the last dose of vadadustat. 
22. Subjects with bilateral native nephrectomy. 
23. Any other reason, which in the opinion of the investigator, would make the subject not 
suitable for participation in the study. 
7.4 
Retesting and Rescreening 
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 be retested 
once for each laboratory parameter within the 4-week Screening Period, per investigator 
discretion. 
7.4.2 Rescreening 
Subjects who fail to qualify for the study based on laboratory tests may be considered for 
rescreening at the discretion of the investigator if it is considered that the subject status has 
changed, and the subject may now qualify for the study.  Additionally, subjects who fail to 
qualify for the study based on inclusion criteria values for 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).  A 
new informed consent is required to be signed prior to every rescreening. 
7.5 
Study Completion, Study Termination, and Individual Site Termination 
7.5.1 Study Completion 
The study will be considered completed after all randomized subjects have completed their final 
study visit (Visit 15/Week 24), Safety Follow-Up or Early Termination). 
7.5.2 Study Termination 
The sponsor may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  Advanced notice is not required if the study is stopped due to safety concerns.  If a 
study site has been suspended or terminated, prompt notification will be given to investigators, 
IRBs, and regulatory authorities in accordance with regulatory requirements.  Criteria and 


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procedures 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 study site for various 
reasons.  Criteria and procedures for premature termination or suspension of a study site are 
detailed in Section 14.2, Criteria for Premature Termination or Suspension of Study Sites and 
Section 14.3, Procedures for Premature Termination or Suspension of the Study or Study Sites.  
If a study site has been suspended or terminated, prompt notification will be given to 
investigators, IRBs, and regulatory authorities in accordance with regulatory requirements.  
7.6 
Subject Completion and Subject Discontinuation 
7.6.1 Subject Completion 
A subject will be considered as having completed the study after completion of their final study 
visit (Visit 15/Week 24, Safety Follow-Up or Early Termination). 
7.6.2 Temporary Interruption of Study Drug 
Subjects who temporarily interrupt their study drug (vadadustat or epoetin alfa) after receiving 
the first dose and prior to completion of the study, will continue with the study visits, safety 
assessments, and other activities as deemed applicable through Week 20, and will complete the 
4-week Safety Follow-Up Period and the Visit 15/Week 24 assessments (see Appendix A: 
Schedule of Activities. 
During the study, a subject may interrupt study drug (vadadustat or epoetin alfa) for any of the 
following reasons: 
• AE 
• Missed dialysis visit (epoetin alfa arm) 
• Investigator’s discretion 
• Rapid rise in Hb (defined as >1.0 g/dL in any 2-week period) 
• Hb above 11.0 g/dL 
• ESA use (vadadustat arm) 
Unless contraindicated, treatment will be resumed whenever possible and assessed at every visit 
following study drug interruption.  
7.6.3 Early Discontinuation from Study (Early Termination) 
Subjects who discontinue prematurely from the study will complete the End-of-Treatment (EOT) 
visit (Visit 14) assessments and will complete the Safety Follow-Up (Visit 15) 4 weeks after 
Visit 14. 
Subjects may discontinue for any of the following reasons: 
• AE 
• Investigator’s discretion 
• Subject withdrawal of consent  


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• Lack of efficacy, defined as inadequate response to vadadustat or epoetin alfa in the 
investigator’s opinion 
• Lost to follow-up despite reasonable efforts by the investigator to locate the subject.  Every 
reasonable effort is to be made to contact any subject lost to follow-up during the course of 
the study to complete study-related assessments, record outstanding data, and retrieve study 
drug. 
• Death  
• Other reasons (pregnancy, kidney transplantation, specific reasons to be documented by the 
investigator) 
Subjects who undergo a solid organ (including kidney), hematopoietic stem cell, or bone marrow 
transplantation will have their study medication (vadadustat or epoetin alfa) permanently 
discontinued and will complete the End-of-Treatment (Visit 14) and Safety Follow-up (Visit 15) 
visit assessments. 
See Section 9.4, Study Medication Stopping Rules for additional details on the management of 
subjects with ALT and AST abnormalities. 


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8 
STUDY DRUG AND TREATMENT OF SUBJECTS 
Subjects will receive either vadadustat or epoetin alfa according to the randomization 
assignments provided via the Interactive Web Response System (IWRS) (see Section 8.4.1, 
Randomization). 
Both vadadustat and epoetin alfa will be used as open -label supplies.  All study drug supplies 
will 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 drug for 
dispensing to the subject (Section 8.1, Epoetin Alfa and Section 8.2.2, Dispensing of Vadadustat) 
and for study drug supply accountability (Section 8.3, Vadadustat Accountability and 
Destruction). 
8.1 
Epoetin Alfa 
Epoetin alfa solution for IV injection in multi-dose vials (e.g., 20000 U/2 mL and 
20000 U/1 mL) or in single-dose vials (e.g., 2000, 3000, 4000, and 10000 U/mL) will be 
provided by the sites in commercially-approved primary packaging and stored per the approved 
label. 
8.2 
Vadadustat 
8.2.1 Supplies and Storage 
Vadadustat will be provided as 150 mg, white to off-white, round, bi-convex film-coated, 
debossed or non-debossed 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 and local 
regulatory requirements. 
Dose levels utilized in this study will include: 150 mg (1 tablet), 300 mg (2 tablets), 450 mg 
(3 tablets), 600 mg (4 tablets), 750 mg (5 tablets), and 900 mg (6 tablets) per day or TIW. 
Vadadustat will be stored per the product label.  Please consult the Pharmacy Manual for details 
on storage and managing temperature excursions. 
8.2.2 Dispensing of Vadadustat 
At Baseline/Day 1, subjects who are randomized to vadadustat treatment will be administered the 
first dose of vadadustat at the study site.   
Thereafter, vadadustat will be taken once daily from Baseline/Day 1 to Week 12 and TIW from 
Weeks 12 to 20 if Week 12 criteria are met (Section 8.4.5.2, Transition of Vadadustat Once 
Daily Dosing to TIW Dosing Regimen).  If the investigator determined criteria for Week 12 is 
not met, daily dosing will continue on an outpatient basis.  Subjects who are randomized to the 
vadadustat treatment arm will be provided with up to 2 bottles of vadadustat.  Each bottle of 
vadadustat will contain 100 tablets of vadadustat (150 mg/tablet).  Subjects may take vadadustat 
with or without food and will be instructed to swallow the tablet(s) whole.  Subjects will be 
instructed to take vadadustat at approximately the same time each day. 


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Subjects will be instructed to bring unused vadadustat and empty bottles to each study visit for 
product accountability.  Subjects will be instructed to finish 1 bottle before opening a new bottle. 
Empty bottles will be collected at the study visits.  Previously dispensed bottles (whether opened 
or unopened) with remaining tablets may be re-dispensed to the subject during the dosing phase 
of the study. 
Resupply of additional vadadustat at subsequent visits will be managed via the IWRS 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. 
8.3 
Vadadustat Accountability and Destruction 
Drug accountability will be an ongoing process throughout the study.  All vadadustat will 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 study site, and study drug dispensed to or returned from 
each subject.  Records will be maintained that accurately reflect the drug accountability of 
vadadustat at all times.  An electronic Diary (eDiary) or paper dosing reminders will be utilized 
throughout the study to guide dosing for subjects in the vadadustat arm (see Section 9.1.2, 
eDiary). 
Proper drug accountability includes, but is not limited to: 
• Continuously monitoring expiration dates  
• Frequently verifying that actual inventory matches documented inventory. 
• Verifying that the log is completed for all vadadustat received and that all required fields are 
complete, accurate, and legible. 
If any dispensing errors or discrepancies are discovered, the sponsor will 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 study site 
will complete all instructions outlined in the notification, including segregation of expired 
clinical study material for return to the sponsor or its designee for destruction as specified by the 
sponsor. 
Prior to study 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 other study materials will be returned to the 
sponsor or destroyed at the study site, as specified by the sponsor.  Appropriate records of the 
disposal will be documented and maintained.  No unused vadadustat 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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8.4 
Treatment of Subjects 
The aim of the study is to achieve and maintain Hb levels within the target range of 
10.0 to 11.0 g/dL, inclusive, while targeting the middle of the range and minimizing excursions 
outside the target range. 
8.4.1 
Randomization 
Main Study: 
Subjects will be randomized to either a vadadustat treatment arm or epoetin alfa treatment arm.  
Randomization will be stratified by mean weekly epoetin alfa dose calculated over a period of 
8 weeks prior to SV2: 
• Low epoetin alfa dose group (≤90 U/kg/week) or 
• High epoetin alfa dose group (>90 to <300 U/kg/week) 
In the low epoetin alfa dose group, subjects will be randomized in a 3:3:2 ratio to receive either 
an initial vadadustat daily dose of 450 mg (3 tablets) or 300 mg (2 tablets), or epoetin alfa.  
In the high epoetin alfa dose group, subjects will be randomized in a 3:3:3:2 ratio to receive 
either an initial vadadustat daily dose of 600 mg (4 tablets), 450 mg (3 tablets) or 300 mg 
(2 tablets), or epoetin alfa.  
ESA Hyporesponder Parallel Study: 
Subjects will be randomized in a 1:1 ratio to receive either an initial vadadustat daily dose of 
600 mg (4 tablets) or epoetin alfa. 
Note: A subject may enter the washout period only after all eligibility criteria have been met.  
During the washout period, no epoetin alfa will be administered for 5 days in the Main study and 
2 days in the ESA hyporesponder parallel study.   
8.4.2 
Blinding 
This is an open-label study and will not involve any blinding procedures. 
8.4.3 
Measurement of Hb Levels for Dose Adjustment Consideration 
Hb values will be measured by a central laboratory.  Study drug treatment will aim to achieve 
and maintain Hb levels within the target range of 10.0 to 11.0 g/dL, inclusive, while targeting the 
middle of the range and minimizing excursions outside the target range.  Hb will be monitored 
throughout the study to determine the dose of study drug (vadadustat or epoetin alfa) that 
subjects will receive (see Section 8.4.6, Guidelines for Dose Adjustments).  Hb levels can be 
measured more frequently based on investigator’s clinical judgment. 
In both the vadadustat and epoetin alfa arm, if dose adjustment is recommended based on Hb 
value and protocol-specified guidelines, dosing instructions can be provided to the subject over 
the telephone or at the next dialysis session at the study site (or dialysis center) or during an 
unscheduled site visit within 3 business days after receiving the Hb result from the central 
laboratory. 


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8.4.4 
Epoetin Alfa Dosing Regimen 
Epoetin alfa arm in both the Main study and ESA hyporesponder parallel study: 
For subjects who are randomized to the epoetin alfa treatment arm, the initial dosing regimen in 
the study (starting from Baseline/Day 1) will be approximately the same weekly dose that they 
were receiving prior to randomization.  
Epoetin alfa dose will be administered based on the subject’s central laboratory Hb value and the 
approved epoetin alfa US PI for adult patients with CKD on dialysis. 
From Baseline/Day 1 to Week 20, dose will be adjusted to achieve and maintain Hb levels within 
the target range of 10.0 and 11.0 g/dL, inclusive. 
8.4.5 
Vadadustat Dosing Regimen and Guidelines for Dose Adjustment 
8.4.5.1 Dosing Regimen for the Vadadustat Treatment Arm 
Subjects in the low epoetin alfa dose group randomized to vadadustat treatment will start at an 
initial dose of vadadustat 300 mg or 450 mg daily.  Subjects in the high epoetin alfa dose group 
randomized to vadadustat treatment will receive an initial dose of 300, 450, or 600 mg daily.  
Subjects in the ESA hyporesponder parallel study randomized to vadadustat treatment will 
receive a starting dose of vadadustat 600 mg daily.  
After completing the 12-week once daily dosing regimen, subjects randomized to vadadustat 
who meet criteria for switching from daily to TIW dosing will initiate TIW dosing at a starting 
dose 1 tablet greater (+150 mg) than the final dose in the daily dosing period (see 
Section 8.4.5.2, Transition of Vadadustat Once Daily Dosing to TIW Dosing Regimen).  
Subjects who do not meet criteria for switching from daily to TIW dosing will remain on daily 
dosing.  From Baseline/Day 1 to Week 20, dose will be adjusted to achieve and maintain Hb 
levels within the target range of 10.0 to 11.0 g/dL, inclusive.  
8.4.5.2 Transition of Vadadustat Once Daily Dosing to TIW Dosing Regimen 
All subjects randomized to vadadustat who complete 12 weeks of once daily dosing regimen and 
who meet all the Week 12 criteria below will be transitioned to a TIW vadadustat dosing 
regimen.  
Week 12 Transition criteria: 
• Vadadustat daily dose of 600 mg or lower at Week 12 
• Hb within target range of 10.0 to 11.0 g/dL, inclusive, at Week 12 confirmed by central 
laboratory Hb value from Week 11 (11 weeks of treatment completed) 
• No receipt of rescue therapy (ESA or RBC transfusion) for worsening of anemia due to CKD 
from Baseline/Day 1 to Week 12.   
o ESA or RBC transfusion prior to Week 12 for reasons unrelated to worsening of anemia 
due to CKD (e.g., surgery, gastrointestinal bleed, or inadvertent administration) is not 
considered rescue therapy 


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• No other reason, based on the investigator’s clinical discretion that would make the subject 
not suitable for TIW dosing. 
Selected subjects who meet Week 12 transition criteria will transition to the TIW vadadustat 
dosing regimen at the Week 12 visit.  Subjects on 150, 300, 450, or 600 mg of vadadustat daily 
at the Week 12 visit will transition to an initial vadadustat TIW dose one  tablet greater 
(+150 mg), i.e., 300, 450, 600, or 750 mg vadadustat TIW, respectively.  Subjects will be 
instructed to take vadadustat on dialysis days. 
After 2 weeks of treatment in the TIW vadadustat dosing regimen (at Week 14), subjects in any 
vadadustat TIW dosing arms who have a decline in Hb ≥0.5 g/dL will be eligible for a dose 
increase by 1 tablet, based on the investigator’s clinical discretion. 
Subjects who are not eligible to switch from daily vadadustat to TIW dosing at Week 12 will 
remain on daily dosing for the remainder of the study.  
Subjects on TIW dosing may be converted back to vadadustat once daily dosing at the discretion 
of the investigator in the setting of inadequate Hb response.  The starting daily dose after the 
switch from TIW to daily dosing will be based on the investigator’s discretion after review of the 
subject’s clinical status and dosing history, in particular, the daily dose previously administered 
to the subject prior to the transition to TIW dosing (Week 12).  Subjects who switch from 
vadadustat TIW to daily dosing will continue once daily vadadustat until the end of the 
Treatment Period. 
Subjects in the vadadustat arm will be guided for dosing compliance using an eDiary or through 
paper dosing reminders (see Section 9.1.2, eDiary). 
8.4.6 Guidelines for Dose Adjustments 
Dose adjustments will be guided by Hb concentrations and the Guidelines for Dose Adjustment 
(see below).  Hb will be monitored via central laboratory throughout the study to determine if the 
dose of study drug (vadadustat or epoetin alfa) will be adjusted, interrupted, or maintained as 
follows: 
• Dose adjustments are based on the investigator’s clinical discretion, incorporating the 
protocol guidance below as well as the subject’s current Hb level, trajectory, and variability; 
symptoms; cardiovascular risk; and other features of his/her clinical condition(s). 
• If a dose increase or decrease is required to achieve and maintain Hb levels within the target 
range of 10.0 to 11.0 g/dL, inclusive, dose is adjusted by 1 dose level (for vadadustat 1 tablet 
[150 mg], for epoetin alfa approximately 25%). 
• In general, do not increase the dose more frequently than once every 4 weeks.  A one-time 
dose increase after 2 weeks is allowed on only two occasions.   
o A subject’s dose may be increased by 1 dose level if the subject has a decline in Hb 
≥0.5 g/dL from Baseline/Day 1 in the first 2-week period (the initial period from 
Baseline/Day 1 to Week 2 following conversion from prior epoetin alfa therapy).   
o A subject’s dose may also be increased by 1 dose level in the first 2-week period after 
initiation of TIW dosing (from Week 12 to Week 14) for subjects that meet criteria for 
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• Reduce or interrupt the dose in the setting of a rapid rise in Hb (defined as >1.0 g/dL in any 
2-week period) 
• Reduce or interrupt the dose in the setting of Hb >11.0 g/dL 
• Interrupt the dose in the setting of a Hb >12.0 g/dL until Hb value falls below 11.0 g/dL.  
After Hb falls below 11.0 g/dL, restart study drug and consider restarting at a lower dose. 
Note: The minimum dose of vadadustat will be 150 mg daily or TIW (1 tablet daily/TIW) and 
the maximum dose will be 900 mg daily or TIW (6 tablets daily/TIW). 
8.4.7 Late or Missed Doses 
Subjects on vadadustat will be instructed to take the study drug at approximately the same time 
each day.  If a dose is forgotten, subjects will be instructed to take the dose as soon as they 
remember during the same day.   
• Daily dosing regimen: If a forgotten dose is not remembered on the same day, the subject 
will skip the dose and resume the normal dosing schedule the following day. 
• TIW dosing regimen: If a forgotten dose is not remembered on the same day, the subject will 
take the dose on the following day (a non-dialysis day).  If a forgotten dose is not 
remembered on the same day or the following day of a long interdialytic gap, the subject will 
take the dose on the subsequent day (the second non-dialysis day).  Thereafter, the subject 
should resume the normal dosing schedule. 
• Subjects will not double-up on missed doses. 
Epoetin alfa dose (including handling of late or missed dose) will be administered at the site and 
titrated based on the subject’s central laboratory Hb value and the approved epoetin alfa US PI 
for adult patients with CKD on dialysis. 
8.4.8 Iron Supplementation 
IV iron will be administered based on ferritin and TSAT levels measured by the central 
laboratory according to the standardized, low-intensity, iron supplementation protocol in Table 1. 
TABLE 1 IRON SUPPLEMENTATION PROTOCOL 
 
Ferritin 
<200 ng/mL 
Ferritin 
200-500 ng/mL 
Ferritin 
>500 ng/mL 
TSAT 
<20% 
IV Iron 100 mg every 
treatment 
(max 400 mg/month) 
IV Iron 50 mg weekly 
Hold 
TSAT 
20-50% 
IV Iron 100 mg every week
IV Iron 50 mg weekly 
Hold 
TSAT 
>50% 
Hold 
Hold 
Hold 
IV: intravenous; TSAT: transferrin saturation


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Subjects already receiving oral iron supplementation as part of their treatment plan may continue 
their current treatment regimen.  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 oral medications containing iron.   
Subjects will be instructed to take any oral medications containing iron at least 2 hours after the 
dose of vadadustat.  
8.4.9 Rescue Therapy 
To ensure the safety of subjects and to standardize the use of rescue in the study, rescue therapy 
guidelines are provided. 
8.4.9.1 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 will 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 medical necessity.  Study drug (vadadustat or 
epoetin alfa) may be continued during the transfusion period. 
Reasons for RBC transfusion will be captured in the appropriate CRF. 
8.4.9.2 ESA Use 
ESA administration will be allowed when medically necessary at the discretion of the 
investigator.  In general, ESA will not be administered in subjects with Hb ≥8.5 g/dL, and ESA 
will be stopped when Hb ≥9.0 g/dL.  ESA therapy will be administered using an approved ESA 
and dosing as per the local institution’s guidelines and per the approved product label. 
While receiving ESA therapy, subjects randomized to vadadustat must temporarily interrupt 
vadadustat.  A minimum interval will be observed prior to restarting vadadustat after the last 
dose of ESA, and treatment will be resumed after the following intervals: 
• 2 days after last dose of epoetin alfa  
• 7 days after last dose of darbepoetin alfa  
• 14 days after last dose of methoxy polyethylene glycol-epoetin beta  
Following ESA administration, vadadustat will be resumed at the same dose as previously used 
or with one additional tablet (+150 mg) at the discretion of the investigator. 
Reasons for ESA use will be captured in the appropriate CRF. 
8.4.10 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 clinical judgment.  The method of 
phlebotomy will be in accordance with the study site’s standard clinical practice. 


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8.4.11 Treatment Compliance 
Throughout the study, subjects in the vadadustat arm will be guided regarding dosing compliance 
using an eDiary or paper dosing reminders.  The focus of the vadadustat eDiary is to guide 
subjects to remind them of the dose, instruct them to hold their dose for the PK/PD sample dates 
and guide them if they have transitioned from daily dosing to TIW dosing.  Subjects will also be 
questioned at study visits on whether they have questions or have experienced any problems 
related to the dosing of vadadustat.  The investigator will also maintain drug accountability logs 
itemizing all study drugs dispensed to and returned from each subject during the study.  
Treatment compliance will be determined from these logs, subject questioning, and the study 
drug Case Report Form (CRF).  
For epoetin alfa, the dose that is administered is required to be entered in the electronic data 
capture (EDC) system, and the EDC system will be used to determine dosing compliance. 
Subjects who miss doses will be counseled on the importance of compliance. 
8.4.12 Continuation of Treatment 
Subjects in the vadadustat dosing groups will not receive vadadustat beyond the Treatment 
Period of approximately 20 weeks.  However, enrollment may be increased by up to 
approximately 20 additional subjects in the Main study and up to approximately 30 additional 
subjects in the ESA hyporesponder parallel study to ensure adequate data are captured for the 
primary, PK/PD, and safety endpoints.  Subjects in the vadadustat dosing groups who complete 
Visit 14 (Week 20), or discontinue early, will resume dosing with epoetin alfa (or another ESA) 
as per standard of care after all EOT procedures are completed. 
8.5 
Prior and Concomitant Therapy 
8.5.1 General 
Any medicinal product, prescribed or non-prescribed (including vitamins, minerals, natural 
and herbal remedies, topicals, inhaled, intranasal and dietary supplements) taken before 
entering the study is considered prior medication.  All medicinal products other than the study 
drug, including prescribed or non-prescribed treatments used during the Treatment Period will 
be considered concomitant medication. 
8.5.2 ESAs 
Co-administration of any ESA with vadadustat is 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 8.4.9.2, ESA Use) if deemed 
medically necessary at the discretion of the investigator.  Guidelines for ESA administration as 
rescue therapy are provided in Section 8.4.9.2, ESA Use.  All efforts will be made to avoid 
inadvertent administration of ESAs resulting from adherence to ESA hemodialysis center 
protocols (e.g., DaVita ESA protocols for patients 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.  A minimum interval will be 
observed prior to restarting vadadustat after the last dose of ESA.  Vadadustat treatment may be 
resumed after the following intervals: 


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• 2 days after last dose of epoetin alfa  
• 7 days after last dose of darbepoetin alfa  
• 14 days after last dose of methoxy polyethylene glycol-epoetin beta  
8.5.3 HMG-CoA Reductase Inhibitors (Statins) 
Exposures to atorvastatin and an active metabolite (para-hydroxy) were mildly increased in the 
setting of vadadustat co-administration in healthy adults.  No dose adjustment of atorvastatin is 
recommended.  
Exposures to simvastatin and an active metabolite (beta-hydroxy acid) were both mildly to 
moderately increased with co-administration of vadadustat in healthy adults.  For subjects taking 
vadadustat who are concomitantly taking simvastatin, the recommended maximum daily dose of 
simvastatin is 20 mg.  Investigators should review simvastatin dosing and consider clinical 
guidelines and local prescribing information including specific guidance in product labels with 
reference to renal impairment as well as hepatic impairment, concomitant medications and other 
medical factors relevant to the management of the subject.  
Exposure to rosuvastatin was moderately increased with co-administration of vadadustat based 
on a study in healthy adults.  For subjects taking vadadustat who are concomitantly taking 
rosuvastatin, the recommended maximum daily dose of rosuvastatin is 10 mg.  Investigators 
should review rosuvastatin dosing and consider clinical guidelines and local prescribing 
information including specific guidance in product labels with reference to renal impairment as 
well as hepatic impairment, concomitant medications and other medical factors relevant to the 
management of the subject. 
Exposure to pravastatin was studied in the setting of vadadustat co-administration in healthy 
adults.  There was no interaction.  No dose adjustment of pravastatin is recommended. 
Exposures to the other statins may be increased with co-administration of vadadustat.  When 
used with vadadustat, upward titration of other statins to higher doses should be done with 
caution.   
8.5.4 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 
resistance protein (BCRP) substrates should be used with caution when taken concomitantly with 
vadadustat. 
8.5.5 Phosphate Binders 
Subjects will be instructed to take phosphate binders (iron-containing and non-iron-containing 
phosphate binders) at least 2 hours after the dose of vadadustat. 
8.5.6 Dialysis Treatment and Renal Replacement Therapy 
Information on dialysis treatment including dialysis vascular access type, dialysis adequacy, and 
history of and changes in renal replacement therapies will be collected as described in Section 9, 
Study Procedures and Schedule of Activities and Appendix A: Schedule of Activities. 


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8.5.7 Investigational Medications 
Study subjects are not to have received any investigational medications within 30 days or 
5 half-lives of the investigational medication (whichever is longer), prior to randomization.  In 
addition, subjects cannot have had any prior use of a HIF-PH inhibitor.  
Additionally, subjects are not to take another investigational medication while participating in 
this study. 


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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: 
• Eligibility Screening Period (from Day -28 to Baseline/Day 1) 
The Screening Period starts at the time the informed consent is signed and will be a 
maximum of 28-days in duration.  Two Screening visits (SV1 and SV2, with a minimum of 
4 days in between) must be performed within the Screening Period and prior to dosing 
(Baseline/Day 1).   
o Screening Visit 1 (SV1) 
o Screening Visit 2 (SV2) 
• Study Treatment Period will consist of study visits from Baseline/Day 1 through Week 20 
visit.  In weeks where there is no schedule study visit a subject will have a status check 
performed during one of their dialysis treatment appointments. 
o Baseline/Day 1, Visit 1 
o Visit 2, Week 1 +5 days 
o Visit 3, Week 2 ± 3 days 
o Visit 4, Week 4 ± 3 days 
o Visit 5, Week 6 ± 3 days 
o Visit 6, Week 8 ± 3 days 
o Visit 7, Week 10 ± 3 days 
o Visit 8, Week 11 ± 3 days 
o Visit 9, Week 12 ± 3 days (Transition to TIW dosing if all Week 12 criteria are met) 
o Visit 10, Week 13 +5 days 
o Visit 11, Week 14 ± 3 days 
o Visit 12, Week 16 ± 3 days 
o Visit 13, Week 18 ± 3 days 
o Visit 14, Week 20 ± 3 days (EOT visit) 
• Safety Follow-Up Period (from Week 20 to 24) 
o Visit 15, Week 24 visit ± 5 days 
The following sections describe the procedures to be completed during the study.  Subjects are to 
be assessed by the same investigator or study site personnel whenever possible. 
9.1 
Administrative Procedures 
9.1.1 Informed Consent 
Informed consent will be obtained and legally signed prior to the subject entering into the study 
and before any protocol-directed procedures (including Screening activities) are performed (see 
Section 15.3, Subject Information and Consent).  After providing informed consent and receiving 
a unique subject identification number, subjects will undergo various Screening activities.  


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9.1.2 eDiary 
An eDiary will be utilized throughout the study for completion of SF-36v2 and PGI assessments.  
Paper dosing reminders will also be provided to subjects randomized to the vadadustat treatment 
arm.  In addition, the eDiary will guide dosing for subjects in the vadadustat arm.  The focus of 
the eDiary is to guide subjects to remind them of when to take the dose, or instruct them to hold 
their dose for the PK/PD sample dates and provide reminders if they have transitioned from daily 
dosing to TIW dosing.  Once eligibility has been confirmed at Baseline/Day 1, subjects will be 
instructed on data entry procedures for the eDiary and will complete the SF-36v2, PGI-S in the 
eDiary and the EQ-5D-5L paper form prior to dialysis and any other study procedures being 
performed. 
Thereafter, the SF-36v2, PGI-C, and PGI-S will be completed in the eDiary and the EQ-5D-5L 
will be completed on paper at appropriate visits prior to dialysis and any study procedures being 
performed.   
9.1.3 Documentation of Screen Failures 
Investigators will account for all subjects who sign informed consent and will maintain a log of 
subjects screened and indicate who was randomized or excluded and reasons for screen failure.  
If the subject is found to be ineligible for randomization, the reason(s) for ineligibility and not 
proceeding to Screening or study enrollment, will be documented by the investigator. 
Screening numbers assigned to subjects who fail Screening will not be re-used. 
9.1.4 Status Check 
In weeks where there is no scheduled study visit, a subject will have a status check performed 
during one of their dialysis treatment appointments in the week.  It will include a review of the 
subject’s vital signs and a review of current health status for identification of any issues that may 
require follow-up by the investigator or delegated staff personnel.  Documentation of the review 
must be done in the subject’s source documentation.  If an AE is identified at the status check or 
other actions result from the status check, these will be captured per the protocol. 
9.1.5 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 of vadadustat in the rat are ongoing, 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 drug. 
Adequate contraception for subjects is defined as follows: 
• For females of non-childbearing potential 
o Confirmation of surgical sterility (e.g., hysterectomy, bilateral tubal ligation, bilateral 
oophorectomy) at least 1 month prior to Screening, or  


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o Post-menopausal (no menses for >1 year with FSH >40 U/L at Screening)  
• For females of childbearing potential  
o Subjects must confirm the use of acceptable forms of contraception*, for a minimum of one 
complete menstrual cycle prior to Screening.  
o Must have a negative serum pregnancy test at SV2. 
o Starting Baseline/Day 1, subjects must use two acceptable forms of contraception* (at least 
one of which must be a barrier method) throughout the Treatment Period and for 30 days 
after the final study drug administration 
• For males subjects who have not had a vasectomy must agree to the following: use of an 
acceptable form of contraception* during the study and for 30 days after the last dose of the 
study drug; to not donate sperm during the study and for at least 30 days after the last dose of 
vadadustat. 
*  Acceptable forms of contraception include: 
• Established use of oral, injected or implanted hormonal methods of contraception. 
• Placement of an intrauterine device or intrauterine system. 
• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository. 
9.1.6 Laboratory Accreditation and Reference Ranges 
The investigator and the sponsor will maintain a copy of the laboratory accreditation and the 
reference ranges for the central laboratory used for clinical laboratory evaluations.  Additionally, 
other accreditation(s) will be collected as required. 
9.2 
Study Procedures and Evaluations 
9.2.1 Clinical Evaluations 
The following clinical evaluations will be conducted during the course of the study.  If the 
evaluations occur on a hemodialysis day, the evaluations will be completed before dialysis, if 
applicable. 
• 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 will be documented.  After 
SV2, an abbreviated, symptom-directed physical examination will be performed at the 
discretion of the investigator, as clinically indicated. 
• Dialysis Adequacy: Dialysis adequacy, as available from local collection, will be recorded at 
SV1 and Visits 9 and 14 (EOT). 
• SF-36v2 HRQOL: The SF-36v2, a patient-reported survey of patient health status (See 
Appendix C: SF-36v2 Standard).  It will be completed within the eDiary at the beginning of 
the study visit, prior to dialysis and any study procedures being performed.  It will be 
administered at Baseline/Day 1, and Visits 9, 14 (EOT), and 15.    


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• PGI-S: The PGI-S is a global index that is used to rate the severity of disease (See 
Appendix D: Patient Global Impression of Severity [PGI-S]).  It will be completed within the 
eDiary at the beginning of the study visit, prior to dialysis and any study procedures being 
performed.  It will be administered at Baseline/Day 1, and Visits 9, 14 (EOT), and 15.   
• PGI-C: The PGI-C is a scale that evaluates all aspects of a subject’s health and assesses if 
there has been an improvement or decline in clinical status (see Appendix E: Patient Global 
Impression of Change [PGI-C]).  It will be completed within the eDiary at the beginning of 
the Safety Follow-Up (Visit 15), prior to dialysis and any study procedures and assessments 
being performed.  
• EQ-5D-5L HRQOL: The EQ-5D-5L is a patient reported outcomes measurement of health 
status on the five dimensions of mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression (See Appendix F: EuroQol 5 Dimensions 5 Levels [EQ-5D-5L]).  It is a 
paper assessment that will be completed at the beginning of the study visit, prior to dialysis 
and any procedures being performed.  It will be administered at Baseline/Day 1, and Visits 9, 
14 (EOT), and 15. 
• Vital Sign Measurements: Vital signs will include temperature, heart rate (HR), BP, 
respiratory rate (RR), and dry weight.  Temperature, HR, BP, and RR will be assessed in the 
seated position after 5 minutes of rest.  For BP, a total of two measurements at intervals of at 
least 2 minutes should be performed.  Temperature, HR, BP, and RR will be collected at 
SV1, SV2, Baseline/Day 1, during all study visits, and Visit 14 (EOT).  Measurements will 
be taken prior to blood draws when possible.   
Dry weight will be collected for all subjects at SV2, Baseline/Day 1, Visit 9 and 14 (EOT).  
For subjects on epoetin alfa, subjects will be weighed for dosing as per the local standard of 
care. 
• 12-Lead ECG: A standard 12-lead ECG will be performed at Baseline/Day 1, which may be 
obtained up to 3 days prior to Baseline/Day 1.  The ECG will be obtained after the subject 
has been resting comfortably in a supine position for approximately 5 minutes and will be 
taken prior to vital sign assessments and blood draws when possible.  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. 
• AE Assessments: AE collection will begin from time of randomization through study end 
(Follow-Up Visit).  The investigator and study personnel will review each subject’s 
laboratory and clinical evaluation findings and query the subject directly regarding AEs (see 
Section 10, Adverse Events).  Subjects must be followed for AEs until the final required 
protocol visit (study end date) or until all drug-related toxicities and SAEs have resolved (or 
are considered chronic/stable), whichever is later. 
• Prior and Concomitant Medication Recording: All prior and concomitant medications (except 
those routinely administered as part of the hemodialysis procedures, such as heparin or saline 
flushes used for routine catheter maintenance, unless relevant for an AE or SAE) taken 
within 30 days prior to Baseline/Day 1 and through the final study visit will be recorded on 
the appropriate CRF.   


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Iron treatment regimen 30 days prior to Baseline/Day 1 and through the final study visit will 
be recorded on the appropriate CRF.  In addition, to ensure adequate collection of prior ESA 
dosing history, a minimum of 8 weeks of ESA therapy prior to start of study drug will be 
recorded on the appropriate CRF page. 
At each study visit, subjects will be asked whether they have started, changed or discontinued 
any medication since their previous study visit.  This includes single use or as needed 
medication use.  All medications and changes in dosage and frequency will be recorded on 
the appropriate CRF Page.  Documentation for all medicinal products will include the 
medication name, indication, dose, dosing frequency and dates of administration.   
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.  If blood is collected on a dialysis day, blood draws 
will be done prior to dialysis, if applicable.  The investigator is responsible for reviewing 
laboratory results for clinical significance. 
For eligibility purposes, one retest for each parameter may be performed during the Screening 
window.  Refer to Section 7.4.1, Retesting and Section 7.4.2, Rescreening for further details 
regarding repeating laboratory measurements during the Screening Period. 
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 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 drug.  A FSH test will be 
performed at SV2 for post-menopausal females. 
• Complete Blood Count (CBC): A CBC with differential will be performed at Baseline/Day 1 
and at Visit 14 (EOT).  At all other noted visits in Appendix A: Schedule of Activities, 
including SV1 and SV2 (with a minimum of 4 days in between), a CBC without differential 
will be performed.  The CBC without differential will include: Hb, hematocrit, RBCs, mean 
corpuscular Hb, mean corpuscular Hb concentration, red cell width distribution, white blood 
cell count and platelets.  The CBC with differential will include the same parameters as CBC 
without differential with the addition of white blood cell count with differential (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils). 
Hb will be monitored throughout the study via central laboratory to determine the dose of 
study drug (vadadustat or epoetin alfa) that subjects will receive.  Refer to Section 8.4.3, 
Measurement of Hb Levels for Dose Adjustment Consideration.  Hb levels can be measured 
more frequently based on investigator’s clinical judgment. 
• Reticulocyte Count: An automated reticulocyte count (both absolute and percent) will be 
performed at Baseline/Day 1 and at Visits 2, 4, 6, 8, 9, 10, 12, and 14 (EOT). 
• Folate and Vitamin B12: A blood sample will be drawn at SV1 to assess the folate and 
Vitamin B12 levels. 


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• CRP: A blood sample for CRP will be collected at the Baseline/Day 1, Visit 9 and 14 (EOT).  
• Serum Chemistry: Blood samples to assess serum chemistry will be collected at SV1, 
Baseline/Day 1, Visit 9 and 14 (EOT).  The serum chemistry will include the following 
assays: sodium, potassium, bicarbonate, chloride, calcium, magnesium, phosphorus, glucose, 
creatinine, blood urea nitrogen, creatine phosphokinase, uric acid, albumin, and total protein. 
• Liver Function Tests (LFTs): Blood samples to assess liver function will be collected at SV1, 
Baseline/Day 1, and every 2 weeks at Visits 3, 4, 5, 6, 7, 9, 11, 12, 13, and 14 (EOT).  LFTs 
will include: total bilirubin, alkaline phosphatase (ALP), ALT/SGPT, AST/SGOT, and 
lactate dehydrogenase. 
• Iron Indices: Blood samples to assess the iron indices will be collected at SV1, 
Baseline/Day 1, Visit 4, 6, 9, 12 and 14 (EOT).  Assessments will include the following 
indices: ferritin, iron, transferrin, TIBC, and TSAT. 
• Lipid Profile: Blood samples will be collected at the Baseline/Day 1 and Visit 14 (EOT) to 
assess the cholesterol levels and will be tested for the following types of lipids: total 
cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides. 
• Biomarkers (including, but not limited to, vascular endothelial growth factor [VEGF], and 
hepcidin): Samples for VEGF and hepcidin biomarker analyses will be drawn at the 
Baseline/Day 1, Visit 9 and 14 (EOT).   
9.2.2.1 PK/PD Sampling for Subjects Randomized to Vadadustat 
Refer to Appendix B for a schematic overview of the PK/PD samples for the vadadustat arm. 
Blood for measurement of vadadustat, metabolites and EPO level in the vadadustat arm, in both 
the Main study and ESA hyporesponder parallel study, will be collected as outlined below.  
Preferably, PK/PD samples are to be taken on the day of hemodialysis after the first short 
interdialytic interval (e.g., at the second session of the week).   
At Baseline/Day 1, PK/PD samples will be collected prior to dialysis and administration of 
vadadustat. 
At Week 1 (after at least a full week of vadadustat treatment), vadadustat will be administered 
between 15 minutes to one hour prior to the start of dialysis.  Blood samples will be collected as 
follows: 
• 15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes and 5 hours ± 
30 minutes post-dose 
• From subjects enrolled at a subset of study sites only, additional samples will be collected at 
7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
On the following non-dialysis day, blood samples will be collected as follows: 
• 15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 5 hours ± 
30 minutes post-dose 
• From subjects enrolled at a subset of study sites only, additional samples will be collected at 
7 hours ± 30 minutes post-dose 
At Week 11, vadadustat will be administered between 15 minutes to one hour prior to the start of 
dialysis.  Blood samples will be collected as follows: 


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• 
15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 5 hours ± 
30 minutes post-dose 
• 
From subjects enrolled at a subset of study sites only, additional samples will be collected at 
7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
At Week 13 (after at least one week on TIW vadadustat dosing regimen), vadadustat will be 
administered between 15 minutes to one hour prior to the start of dialysis.  Blood samples will be 
collected as follows: 
• 15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 5 hours ± 
30 minutes post-dose 
• From subjects enrolled at a subset of study sites only, additional samples will be collected at 
7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
Note: Week 13 PK/PD sampling will only be done in subjects who transition to vadadustat TIW 
dosing regimen.  Subjects who do not qualify for vadadustat TIW dosing and remain on daily 
dosing regimen will not have Week 13 PK/PD sampling. 
9.2.2.2 PK Sampling for Subjects Randomized to Epoetin Alfa 
Refer to Appendix B for a schematic overview of the PK samples for the epoetin alfa arm. 
Blood for measurement of EPO level in the epoetin alfa arm, in both the Main study and ESA 
hyporesponder parallel study, will be collected as outlined below.  Preferably, PK samples are to 
be taken on the day of hemodialysis after the first short interdialytic interval (e.g., at the second 
session of the week).   
At Baseline/Day 1, a sample will be collected prior to dialysis and administration of epoetin alfa. 
At Week 1 (after at least a full week of study epoetin alfa treatment), epoetin alfa will be 
administered within 1 hour after start of dialysis.  Blood samples will be collected as follows: 
• 15 minutes pre-dose, and 2 hours ± 15 minutes, 3.5 hours ± 15 minutes, and 5 hours ± 
30 minutes post-dose 
• From subjects enrolled at a subset of study sites only, additional samples will be collected at 
7 hours ± 30 minutes and 10.5 hours ± 1.5 hours post-dose 
On the following dialysis day, one blood sample will be collected 15 minutes prior to 
administration of epoetin alfa. 
9.2.2.3 PK/PD Sampling   
For all PK and PD sampling the time of the previous dose of study drug (vadadustat or epoetin 
alfa) is to be collected for the pre-dose sample and the timing of administration of study drug 
(epoetin alfa and vadadustat) and the start and stop time of the dialysis session will be recorded. 
9.3 
Schedule of Activities 
The Schedule of Activities (see Appendix A: Schedule of Activities) shows the timing of 
planned study procedures.  Every effort will be made to adhere to this procedure schedule and all 
assessments will be completed at each study visit.  Where possible, study visits will be 
performed and scheduled as part of a patients regularly scheduled dialysis session. 


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9.3.1 Screening Visits 
Subjects will need to sign a full consent form prior to SV1 procedures.  The consent form 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 28-days in duration.  Two Screening visits (SV1 and 
SV2, with a minimum of 4 days in between) must be performed within the Screening Period and 
prior to dosing (Baseline/Day 1).   
A subject may enter the washout period only after all eligibility criteria have been met following 
SV2.  During the washout period, no epoetin alfa will be administered before Baseline/Day 1 for 
5 days in the Main study and 2 days in the ESA hyporesponder parallel study.   
After obtaining informed consent, subjects will undergo a number of Screening activities.  
9.3.1.1 SV1 
At SV1, the following activities/procedures will be performed: 
• Informed consent  
• Review of study eligibility criteria 
• Review of acceptable methods of contraception 
• Vital signs including temperature, HR, BP, and RR (assessed in seated position after 
5 minutes of rest and prior to blood draws) 
• Dialysis adequacy 
• Laboratory procedures: 
o CBC (without differential) 
o Folate and vitamin B12 levels 
o Serum Chemistry  
o LFTs  
o Iron indices 
Refer to Section 7.4.1, Retesting and Section 7.4.2, Rescreening for further details 
regarding repeating laboratory measurements during the Screening Period. 
• Visit registration in IWRS 
• Review of prior medication 
• Epoetin alfa dosing will continue 
9.3.1.2 SV2 
At SV2, the following activities/procedures will be performed: 
• Review of eligibility criteria 
• Review of acceptable methods of contraception 
• Physical examination (including height) 
• Demographics and medical history 
• Vital signs including temperature, HR, BP, and RR (assessed in seated position after 
5 minutes of rest and prior to blood draws), and dry weight 


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• Laboratory procedures: 
o Serum pregnancy test for females of childbearing potential (eligible subjects will be 
advised to use an adequate contraceptive method see Section 9.2.2, Laboratory 
Evaluations for additional information).  A FSH test will be performed at SV2 for 
post-menopausal females. 
o CBC (without differential) 
Subjects must have 2 Hb values measured by the central laboratory during Screening (at 
least 4 days apart between SV1 and SV2) as indicated below: 
o Main study: 2 Hb values between 8.5 and 11.0 g/dL, inclusive 
o ESA hyporesponder parallel study: 2 Hb values between 8.0 and 10.0 g/dL, inclusive 
If the subject’s Hb does not qualify after SV1, SV2, or retest Hb, the subject will be 
considered a screen failure 
• Visit registration in IWRS 
• Prior and current medication use 
• Epoetin alfa dosing will stop for a minimum of 5 days in the Main study or 2 days in the ESA 
hyporesponder parallel study until Baseline/Day 1 
9.3.2 Baseline/Day 1 (Visit 1) 
Epoetin alfa dosing will have been stopped for a minimum of 5 days in the Main study or 2 days 
in the ESA hyporesponder parallel study until Baseline/Day 1. 
On Baseline/Day 1, blood sample collection and other Baseline/Day 1 procedures will be 
completed prior to dosing with study drug (vadadustat or epoetin alfa).  On Baseline/Day 1, 
study drug will be administered at the study site, and will be administered after the PK sample is 
collected and prior to the dialysis session.  
At Baseline/Day 1, the following activities/procedures will be performed: 
• Review of study eligibility criteria 
• Review of acceptable methods of contraception 
• Review of medical history for new conditions since SV2 
• Review of medication use since SV2 
• Randomization 
• Introduction to and instruction on the use of the eDiary and paper dosing reminders 
• SF-36v2, PGI-S, and EQ-5D-5L assessments 
• Abbreviated, symptom-directed physical examination, at the discretion of the investigator, as 
clinically indicated 
• 12-lead ECG:  ECGs will be completed prior to blood draws when possible and will be 
obtained after the subject has been resting supine comfortably for approximately 5 minutes; 
ECG may be completed and reviewed by the investigator on Baseline/Day 1 or if needed for 
scheduling reasons (e.g., dialysis treatment is scheduled for early morning of Baseline/Day 
1), the ECG can be completed and reviewed up to 1-3 days prior to Baseline/Day 1. 
• Vital signs including temperature, HR, BP, and RR (assessed in seated position after 
5 minutes of rest and prior to blood draws), and dry weight 


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• Laboratory Procedures: 
o CBC (including differential) 
o Reticulocyte count 
o CRP 
o Serum chemistry  
o LFTs 
o Iron indices 
o Lipid profile 
o Biomarkers (VEGF, and Hepcidin) 
o PK prior to vadadustat or epoetin alfa dosing (see Section 9.2.2.1, PK/PD Sampling for 
Subjects Randomized to Vadadustat and Section 9.2.2.2, PK Sampling for Subjects 
Randomized to Epoetin Alfa) and prior to the dialysis session 
• Study drug assessments and procedures: 
o Subject will take/receive their first dose of study drug at the study site during 
Baseline/Day 1 
o For subjects in the vadadustat treatment arm only: 
 Initiate vadadustat dosing 
 Vadadustat drug dispensation 
 Review vadadustat dosing instructions 
o Epoetin alfa dosing will continue for the subjects in the epoetin alfa arm 
o Iron supplementation as needed to maintain ferritin ≥100 ng/mL or TSAT ≥20% (per 
local product label; see Section 8.4.8, Iron Supplementation 
o Visit registration in IWRS 
• Safety assessments: 
o AE review as needed  
o Review use of rescue therapy (RBC transfusions and ESA therapy) 
9.3.3 Visit 2 to Visit 13 (Weeks 1 to 20) 
At the Baseline/Day 1, Visit 7, and Visit 9, subjects in the vadadustat treatment arm will be 
reminded and instructed to hold their vadadustat dose on the day of Visit 2, Visit 8, and if 
applicable Visit 10, respectively, as blood sample for PK analysis will be collected on the day of 
Visit 2, Visit 8, and Visit 10 prior to vadadustat administration at the study site. 
The following activities/procedures will be performed at Visit 2 to Visit 13, unless noted 
otherwise: 
• SF-36v2, PGI-S, and EQ-5D-5L assessments (Visit 9 only) 
• Abbreviated, symptom-directed physical examination, at the discretion of the investigator, as 
clinically indicated 
• Vital signs including temperature, HR, BP, and RR (assessed in seated position after 
5 minutes of rest and prior to blood draws).  Dry weight will be collected at Visit 9 only.  


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o A status check (BP, vital signs, and review of current health status) will be performed 
during weeks with no scheduled study visit. 
• Dialysis adequacy, as available from local information (Visit 9 only) 
• Safety assessments: 
o AE review 
o Review use of rescue therapy (RBC transfusions and ESA therapy) 
o Review of therapeutic phlebotomy 
• Laboratory procedures (if blood samples are collected on a day of dialysis, blood draws will 
be done prior to dialysis, if applicable): 
o CBC  
o Reticulocyte count (Visits 2, 4, 6, 8, 9, 10 and 12 only) 
o CRP (Visit 9 only) 
o Serum chemistry (Visit 9 only) 
o LFTs (Visits 3, 4, 5, 6, 7, 9, 11, 12, and 13) 
o Iron indices (Visits 4, 6, 9 and 12 only) 
o Biomarkers (VEGF and Hepcidin, Visit 9 only) 
o Vadadustat PK/PD sampling (Visits 2, 8 and 10 only) for details, see Section 9.2.2.1, 
PK/PD Sampling for Subjects Randomized to Vadadustat and Section 9.2.2.3, PK/PD 
Sampling) 
o Epoetin alfa PK sampling (Visit 2 only) for details, see Section 9.2.2.2, PK Sampling for 
Subjects Randomized to Epoetin Alfa and Section 9.2.2.3, PK/PD Sampling) 
• Medication assessments and procedures: 
o Assessment for meeting criteria to switch from daily to TIW dosing (vadadustat arm) 
o Review of concomitant medications 
o Subjects in epoetin alfa treatment arm will continue to receive epoetin alfa  
o For subjects in the vadadustat treatment arm only: 
 Visit registration in IWRS (for bottle dispensing only) 
 Vadadustat drug dispensation (scheduled Visits 4, 6, 9, and 12) 
 Review vadadustat dosing instructions 
 Review of vadadustat dosing compliance 
 Vadadustat reconciliation 
o Review of iron supplementation as needed to maintain ferritin ≥100 ng/mL or TSAT 
≥20% (per local product label; see Section 8.4.8, Iron Supplementation) 
9.3.4 EOT Visit 14 (Week 20) 
EOT evaluations will be performed when the Treatment Period (Baseline/Day 1 to Visit 13) is 
completed.  Subjects who prematurely discontinue study drug for any reason will also attend this 
visit.  
At Visit 14 (EOT), the following activities/procedures will be performed: 


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• SF-36v2, PGI-S, and EQ-5D-5L assessments 
• Vital signs including, HR, BP, and RR (assessed in seated position after 5 minutes of rest and 
prior to blood draws), as well as temperature and dry weight 
• Dialysis adequacy, as available from local information 
• Safety assessments: 
o AE review 
o Review use of rescue therapy (RBC transfusions and ESA therapy)  
o Review of therapeutic phlebotomy 
• Laboratory Procedures: 
o CBC (with differential) 
o Reticulocyte count 
o CRP 
o Serum chemistry 
o LFTs 
o Iron indices 
o Lipid panel 
o Biomarkers (VEGF and Hepcidin) 
• Medication assessments and procedures: 
o Review of concomitant medications 
o Subjects in epoetin alfa treatment arm will continue to receive epoetin alfa.  
o For subjects in the vadadustat treatment arm only: 
 Review of vadadustat dosing compliance 
 Vadadustat reconciliation 
 Resume dosing with epoetin alfa (or another ESA): After the end of vadadustat 
treatment at Visit 14 (or following early discontinuation of vadadustat), subjects may 
resume dosing with epoetin alfa (or another ESA), based on standard of care. 
o Visit registration in IWRS 
o Review of iron supplementation as needed to maintain ferritin ≥100 ng/mL or TSAT 
≥20% (per local product label; see Section 8.4.8, Iron Supplementation) 
9.3.5 Safety Follow-Up Visit 15 (Week 24) 
At the Visit 15, the following activities/procedures will be performed:  
• SF-36v2, EQ-5D-5L, PGI-S, and PGI-C assessments 
• AE review 
• Review use of rescue therapy (RBC transfusions and ESA therapy) 
• Review use of therapeutic phlebotomy 
• Concomitant medication review 


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9.3.6 Unscheduled Visits 
Unscheduled assessments may be conducted at any time as medically warranted.  All laboratory 
assessments required in the study are included in the central laboratory Unscheduled Visit kits to 
allow for re-testing of any study laboratory parameters.  Additionally, the Unscheduled Visit kits 
include a coagulation panel (international normalized ratio [INR], prothrombin time (PT), and 
activated partial thromboplastin time [aPTT]) for testing INR (see Section 9.4, Study Medication 
Stopping Rules).   
Starting from Baseline/Day 1, the following activities/procedures will be performed at an 
Unscheduled Visit at minimum: 
• Safety assessments: 
o AE review 
o Review use of rescue therapy (RBC transfusions and ESA therapy) 
o Review of Therapeutic phlebotomy 
• Medication assessments and procedures: 
o Review of concomitant medications 
• Any other procedures that are medically warranted at the discretion of the investigator. 
9.4 
Study Medication Stopping Rules  
Study medication must be permanently discontinued if a subject meets one of the following 
criteria in Table 2 below: 
TABLE 2 STUDY MEDICATION STOPPING RULES 
ALT or AST >3x ULN and total bilirubin >2x ULN 
Permanently Discontinue Treatment 
ALT or AST >3x ULN and INR >1.5 
Permanently Discontinue Treatment 
ALT or AST >8x ULN 
Permanently Discontinue Treatment 
ALT or AST remains >5x ULN over 2 weeks 
Permanently Discontinue Treatment 
ALT or AST >3x ULN with symptoms (e.g., fatigue, 
nausea, vomiting, right upper quadrant pain, fever, 
rash) or eosinophilia 
Permanently Discontinue Treatment 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; INR: international normalized ratio; 
ULN: upper limit of normal 
See Section 10.1.1, AEs for reporting requirements related to a subject being permanently 
discontinued based on meeting the laboratory abnormalities list above in Table 2. 


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10 ADVERSE EVENTS 
10.1 Definitions 
10.1.1 AEs 
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. 
AEs therefore include the following:  
• All AEs, whether suspected to be causally related to study drug or otherwise. 
• All AEs secondary to any medication overdose, medication error, 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 (e.g., a fall secondary to dizziness), the medical condition (dizziness) and the 
accident (fall) will 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 
(e.g., elevated liver enzymes in a subject with jaundice) will 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 will 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 will be the reported AE term, instead of fever and dyspnea, 
when the diagnosis has been established.  Signs and symptoms will 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, 
will not be reported as AEs.  However, the medical condition for which the procedure was 
performed will be reported if it meets the definition of an AE.  For example, an acute 
appendicitis that begins during the AE reporting period will 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 will not be reported as AEs. 


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Pre-existing Conditions – In this study, a pre-existing condition (i.e., a disorder present before 
the AE reporting period started and noted on the pretreatment medical history/physical 
examination form) will 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 will 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 will also be reported as AEs.  Any abnormal laboratory value which requires 
treatment or further diagnostic testing and/or results in discontinuation from study will 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 Contract Research Organization 
(CRO) designee within 24 hours of awareness as an 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 and without meeting any criteria listed in Table 2 are identified, the following 
steps are to be taken:  
• Temporary discontinuation of study medication; 
• 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; 
• Study medication 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 will not be 
considered an AE unless the worsening of anemia is associated with a cause other than the 
subject’s CKD. 
Transplantation – During this study, it is anticipated that subjects may receive a kidney 
transplant.  These events will not be recorded as AEs.  Subjects will discontinue study drug for 
receipt of a kidney, other solid organ, hematopoietic stem cell or bone marrow transplant, will 
complete the EOT visit (Visit 14) assessments and will complete the Safety Follow-Up (Visit 15) 
4 weeks after Visit 14 as described in Section 7.6.3, Early Discontinuation from Study. 


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10.1.2 SAEs 
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  
o Life-threatening is defined as 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.  
• In-patient hospitalization or prolongation of existing hospitalization   
o 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 (e.g., 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). 
• Persistent or significant disability/incapacity 
o Disability is defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
• 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. 
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. 
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:  
• Malignancies – Newly diagnosed malignancies or a recurrence of a malignancy will 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 Akebia specific designated 
medical events (DME) that they will always classify as SAEs.  If an event on the DME list is 
reported as an AE, the investigator will be notified and additional information on the event 
(e.g., investigator confirmation of seriousness, causality) will be requested from the 
investigator.  The DME list will be available upon request. 


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10.1.3 Adverse Events of Special Interest 
The following are considered to be AEs of special interest for this study: 
• Malignancy (see Section 10.1.2, SAEs) 
• Elevation in ALT or AST >3 times ULN (see Section 10.1.1, AEs) 
• Pulmonary hypertension 
• Pregnancy (see Section 10.4, Exposure In-Utero) 
Reporting and classification of these events as AEs (see Section 10.1.1, AEs) or SAEs (see 
Section 10.1.2, SAEs) will be as per investigator decision.  
10.2 Eliciting AE 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 randomization. 
10.3 Reporting 
Each AE is to be classified by the investigator as SERIOUS or NONSERIOUS based on the 
criteria in Section 10.1.2, SAEs. 
All AEs that occur in study subjects during the AE reporting period specified in this protocol will 
be reported, whether or not the event is considered related to study drug (vadadustat or epoetin 
alfa). 
10.3.1 Reporting Period 
The AE reporting period for this study begins from time of randomization and ends at the final 
protocol-required Safety Follow-Up (Visit 15). 
In addition, any SAE that occurs subsequent to the AE reporting period that the investigator 
assesses as related to the study drug will also be reported as an SAE. 
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, will be reported to the sponsor’s Medical Monitor or 
CRO designee within 24 hours after the investigator becomes aware of the SAE.  Compliance 
with this time requirement is essential so that the sponsor may comply with its regulatory 
obligations. 
The initial SAE report should be completed as fully as possible but will contain, at a minimum 
items number 1 to 6: 
1. Subject number/ID, sex, and age/date of birth 
2. The date of report 
3. Name of the reporter 
4. Name of the suspected medicinal product 


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5. A description of the event, including event term(s), seriousness criteria, and a clinical 
summary of the event 
6. Causality assessment 
If the causality assessment is not provided in the initial report an updated report with the 
causality must be provided within 24 hours, once assessed. 
Information about all SAEs (either initial or follow-up information) will be collected and 
recorded in English on the electronic SAE Report Form within the EDC system.  The 
investigator will assess the relationship to each specific component of the study treatment.  If the 
event meets serious criteria and it is not possible to access the EDC system, a paper SAE Report 
Form will 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 again, the SAE information will be 
entered within 24 hours of the system becoming available. 
The investigator will report follow-up information relating to an SAE to the sponsor’s Medical 
Monitor or CRO designee within 24 hours of awareness 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 will be entered within 
24 hours.  The subject will 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 IRB 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 study site. 
10.3.4 Relationship to Study Drug 
The causal relationship of the AE to study drug (vadadustat or epoetin alfa) will be assessed by 
both the investigator and the sponsor.   
The assessment of causal relationship to study drug will be evidence-based, and not based on the 
premise that all AEs are possibly causally related to study drug until proven otherwise.   
Examples of evidence that would suggest a causal relationship between the study drug and the 
AE include the occurrence of an AE that is uncommon and known to be strongly associated with 
drug exposure (e.g., 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. 


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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 drug are generally uninformative and do 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 treatment, 
other treatment (concomitant, or previous), withdrawal of study treatment, administration error, 
protocol-related procedure, others (specify). 
10.3.5 Severity 
The investigator will assess each AE as either MILD, MODERATE, or SEVERE using the 
following guidelines to describe the maximum severity of the AE: 
MILD: Does not interfere with subject's usual function 
MODERATE: Interferes to some extent with subject's usual function 
SEVERE: Interferes significantly with subject's usual function 
Note that a severe AE is not necessarily a serious AE.  For example, a headache may be severe 
in intensity, but would not be classified as serious unless it met 1 of the criteria for serious events 
listed above. 
10.3.6 Follow-up of Unresolved Events 
All AEs will be followed until they are resolved or the investigator assesses them as chronic or 
stable or the subject’s participation in the trial ends (i.e., until a final report is completed for that 
subject). 
In addition, all SAEs and those nonserious events assessed by the investigator as related to the 
study drug will continue to be followed even after the subject's participation in the trial is over.  
Such events will be followed until they resolve or until the investigator assesses them as 
“chronic” or “stable”.  Resolution of such events is to be documented on the appropriate CRF. 
10.4 Exposure In-Utero 
A pregnancy in a female subject will be confirmed by a positive serum β human chorionic 
gonadotropin test. 
The study drug will 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 drug 
(vadadustat or epoetin alfa) or within 30 days of discontinuing the study drug, the pregnancy will 
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. 
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The Pregnancy Reporting Form/Exposure in Utero Form will be completed with all known 
information regarding the pregnancy at the time of reporting.  Study 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 an SAE 
(i.e., 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 an 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 will be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 1 month that the investigator assesses 
as related or unrelated to the in utero exposure to the study drug will also be reported. 
• In the case of a live birth, the “normality” of the newborn can be assessed at time of birth. 
• The “normality” of an aborted fetus can be assessed by gross visual inspection unless there 
are pre-abortion laboratory findings suggestive of a congenital anomaly. 
10.5 Special Situations 
Certain safety events, called ‘Special Situations’, that occur in association with study drug may 
require reporting.  These Special Situations include, but are not limited to, the following: 
• Overdose of the medicinal product 
o Epoetin alfa overdose – The US PI will be referenced for information on epoetin alfa 
overdosing.   
o Vadadustat overdose – There is no known antidote for vadadustat.  In cases of suspected 
overdose, subjects will 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 will be discontinued and standard treatment for 
polycythemic hyperviscosity syndrome will 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 exposure to the 
sponsor’s medicinal product [e.g., name confusion]) 
• Drug-drug interaction. 


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Special situations will be reported on the Special Situations CRF whether they result in an 
AE/SAE or not.  Special situations with associated AE/SAE will also be reported on the 
corresponding AE/SAE forms, following applicable AE or SAE process. 
10.6 Safety Monitoring 
This is an open label study allowing the study team full access to safety data which will be 
reviewed on a regular basis, throughout the course of the study.  Safety monitoring will be 
performed as described in the Medical Monitor Plan. 
 


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11 DATA ANALYSIS 
Data collected throughout the study will be summarized using descriptive statistics and listed in 
the by-subject listings.  Continuous variables will be summarized using number of subjects with 
mean, standard deviation (SD), 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. 
11.1 Sample Size Estimation 
Approximately 95 subjects are planned for enrollment in the Main study with 40 and 55 subjects 
randomized to the low epoetin alfa dose group and the high epoetin alfa dose group, respectively.  
Approximately 30 subjects are planned for enrollment in the ESA hyporesponder parallel study.  
Sample size reflects the exploratory nature of this study. 
Enrollment may be increased by up to approximately 20 additional subjects in the Main study 
and by up to approximately 30 additional subjects in the ESA hyporesponder parallel study to 
ensure adequate data are captured for the primary, PK/PD, and safety endpoints. 
11.2 Study Analysis Populations 
The following analysis populations will be used in this study: 
• Randomized population: defined as all randomized subjects.  Analyses of this population will 
be based on the randomized treatment. 
• Full Analysis Population (FAS): all subjects in the randomized population who received at 
least one dose of study drug and had at least one Hb assessment during the primary efficacy 
evaluation period.  Analyses of this population will be based on the randomized treatment. 
• Safety Population: all subjects in the randomized population who received at least one 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 epoetin alfa will be 
classified by the more frequently received drug. 
• Per protocol (PP) population: all randomized subjects who received study drug during the 
primary evaluation period, had at least one Hb assessment during the primary efficacy 
evaluation period, received no rescue therapy (with ESA or transfusion) prior to the 
evaluation period, and had no major protocol deviation affecting the primary endpoint 
analyses.  Major protocol deviations leading to exclusion from the PP population will be 
specified prior to database lock and recorded in a separate document.  Analyses of this 
population will be based on actual treatment received. 
Efficacy analyses will utilize the Randomized, Full Analysis, and PP Populations while safety 
analyses will utilize the Safety Population. 
11.3 Analysis of Demographic and Pretreatment Variables 
Descriptive statistics will be generated for demographic and pretreatment variables for 
Randomized Population and other analysis populations which will be defined in detail in the 
Statistical Analysis Plan. 


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Medical history terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by SOC and Preferred Term for each treatment group based on the 
safety population. 
11.4 Disposition of Subjects 
The number and percentage of subjects randomized and included in each analysis population will 
be summarized by treatment and overall.  Reasons for excluding subjects from the analysis 
populations will be presented in a by-subject listing. 
The number of randomized subjects who completed the study, discontinued early from study 
drug, completed or discontinued from the study, and reasons for discontinuation will be 
summarized by treatment group and overall. 
11.5 Missing Data 
It is expected that few subjects will discontinue Follow-Up.  The reasons for any missing data 
will be summarized by treatment arm.  Missing Hb values will be imputed using last observation 
carried forward (LOCF). 
11.6 Efficacy Analyses 
The primary efficacy endpoint as well as all other secondary endpoints will be summarized using 
descriptive statistics (means or proportions) by treatment groups and in total, 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. 
11.7 Safety Analyses 
Safety analyses will be descriptive in nature.  
All AEs will be coded using MedDRA.  Treatment-emergent and post-treatment AEs will be 
summarized by SOC and preferred term for each treatment group.  AEs will also be summarized 
by their maximum severity. 
Summaries will also be provided for the following types of AEs: 
• SAEs 
• AEs of Special Interest (See Section 10.1.3, Adverse Events of Special Interest) 
• Related AEs, as determined by the investigator 
• AEs leading to early discontinuation of study drug 
All Hb related safety endpoints will be tabulated for each treatment groups. 
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. 


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11.8 Additional Assessments 
PK and PD parameters will be summarized using descriptive statistics: number of subjects, 
mean, median, SD, minimum, maximum, and coefficient of variation, geometric mean and 
geometric mean SD. 
11.8.1 PK Assessments 
Plasma concentrations will be summarized using descriptive statistics.  Mean and individual 
subject vadadustat concentrations and O-glucuronide (primary metabolite of vadadustat) 
concentrations will be plotted versus time on linear and semi-logarithmic axes.  The following 
PK parameters for vadadustat and O-glucuronide will be estimated as deemed appropriate from 
the plasma concentrations using standard methods of non-compartmental analyses: Cmax, Tmax, 
AUClast, AUCinf, elimination rate constant (λz), and t1/2.  CL/F and Vd/F will be estimated for 
vadadustat.  PK analysis will be reported separately. 
11.8.2 PD Assessments 
A by-subject listing of all PD variables will be provided including the changes from Baseline/Day 1.  
The observed and change from Baseline/Day 1 values of all PD assessments will be summarized 
using descriptive statistics.  An exposure-response analysis of vadadustat, EPO and other PD 
measures will be conducted as deemed appropriate.  PD analysis may be reported separately. 
11.8.3 Concomitant Medications 
Prior and concomitant medications will be coded using World Health Organization Drug 
dictionary.  Refer to Section 8.5, Prior and Concomitant Therapy. 
11.8.4 Biomarkers 
Biomarkers (including, but not limited to, hepcidin and VEGF) will be summarized descriptively 
at Baseline/Day 1 and by visit post-Baseline/Day 1.  


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12 DATA HANDLING AND RECORD KEEPING 
12.1 CRFs/EDC 
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.  CRFs available through 
this system are required and will be completed for each randomized subject. 
Any form of data from the electronic system are the sole property of the sponsor and will 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 will 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 will match the data in those charts. 
12.2 Record Retention 
To enable evaluations and/or audits from regulatory authorities or the sponsor, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, e.g., 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 (e.g., letters, meeting minutes, and 
telephone calls reports).  The records will be retained by the investigator according to the 
International Council for Harmonisation of Technical Requires for Pharmaceuticals for Human 
Use (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 (e.g., retirement and relocation), the sponsor will be prospectively notified.  The 
study records will be transferred to a designee acceptable to the sponsor, such as another 
investigator, another institution, or to the sponsor.  The investigator will obtain sponsor’s written 
permission before disposing of any records, even if retention requirements have been met. 


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13 QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 Study 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 study 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, and/or to 
inspection by appropriate regulatory authorities. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
13.2 Protocol Deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change.  The investigator is responsible for ensuring the 
study is conducted in accordance with the procedures and evaluations described in this protocol 
and must protect the rights, safety, and welfare of subjects.  The investigator should not 
implement any deviation from, or changes of, the protocol, unless it is necessary to eliminate an 
immediate hazard to trial subjects.   
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol.  Protocol waivers are strictly prohibited. 
For the purposes of this protocol, deviations requiring notification to sponsor are defined as any 
subject who: 
• Entered into the study even though they did not satisfy entry criteria.  
• Developed withdrawal criteria during the study and not withdrawn. 
• Received wrong treatment or incorrect dose.  
• Received excluded concomitant treatment. 
When a deviation from the protocol is identified for an individual subject, the investigator or 
designee must ensure the sponsor is notified.  The sponsor will follow-up with the investigator, 
as applicable, to assess the deviation and the possible impact to the safety and/or efficacy of the 
subject to determine subject continuation in the study.  
If a deviation impacts the safety of a subject, the investigator must contact the sponsor 
immediately. 
The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately.  All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
sponsor and maintained within the Trial Master File. 
Note: Other deviations outside of the categories defined above that are required to be reported by 
the IRB/IEC in accordance with local requirements will be reported, as applicable. 


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14 STUDY DISCONTINUATION/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 will contact all participating subjects within a time period 
specified by the sponsor to inform them of the decision to discontinue the study. 
14.1 Criteria for Premature Termination or Suspension of the Study 
The following criteria may result in either temporary suspension or early termination of the 
study: 
• New information regarding the safety or efficacy of the study drug 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 
• Request from regulatory agencies 
The sponsor reserves the right to discontinue the study for other valid administrative reasons. 
If the study has been suspended or terminated, prompt notification will be given to investigators, 
IRBs, and regulatory authorities in accordance with regulatory requirements. 
14.2 Criteria for Premature Termination or Suspension of 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. 
The investigator will notify the sponsor if the trial is terminated by the investigator or the IRB at 
the site.  If the investigator, IRB, or sponsor decides to terminate or suspend the trial conduct at a 
particular study site for safety, non-enrollment, non-compliance with the protocol, or other 
unanticipated reasons, the above parties will be promptly notified. 
14.3 Procedures for Premature Termination or Suspension of the Study or Study 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 study sites during the 
course of termination or study suspension. 
 


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15 ETHICS 
15.1 Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical Principles 
for Medical Research Involving Human Subjects, adopted by the General Assembly of the World 
Medical Association (2013). 
In addition, the study will be conducted in accordance with the protocol, the ICH E6 guideline on 
GCP, and applicable local regulatory requirements and laws. 
15.2 IRB 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, (e.g., recruitment 
advertisements, if applicable) from the IRB.  All correspondence with the IRB will be retained in 
the investigator File.  Copies of IRB approvals will 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 approval is where 
the change is necessary to eliminate apparent immediate hazards to the subjects.  In that event, 
the investigator will notify the IRB and the sponsor in writing immediately after the 
implementation. 
15.3 Subject Information and Consent 
The investigator or designee will explain the nature of the study to the subject or their legally 
acceptable representative, and answer all questions regarding this study.  Prior to any study-
related screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject or their legally acceptable representative, the 
person who administered the informed consent and any other signatories according to local 
requirements.  A copy of the signed ICF will be given to the subject and the original will be 
placed in the subject’s medical record.  An entry must also be made in the subject’s dated source 
documents to confirm that informed consent was obtained prior to any study-related procedures 
and that the subject received a signed copy. 
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request. 
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, will be prospectively approved by both the IRB and the sponsor 
before use. 
15.4 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (i.e., 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 will 
be informed immediately. 


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In addition, the investigator will inform the sponsor immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP, defined as a breach that will likely affect the 
safety or physical or mental integrity of subjects or the scientific value of the trial, that comes to 
the attention of the investigator. 
15.5 Subject Confidentiality 
All parties will ensure protection of subject personal data and will not include subject names on 
any sponsor forms, reports, publications, or in any other disclosures, except where required by 
law.  In case of data transfer, the sponsor will maintain high standards of confidentiality and 
protection of subject personal data. 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy.  Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number.  As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (e.g., FDA), the sponsor’s designated auditors, and the appropriate IRBs 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 will have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s CRF). 


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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 will 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 will 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. 
 
 


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17 REFERENCES 
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):584-90. 
Besarb A, Flaharty KK, Ersley AJ, McCrea JB, Vlasses PH, Medina F, et al. Clinical 
pharmacology and economics of recombinant human erythropoietin in end-stage renal disease: 
the case for subcutaneous administration. J Am Soc Nephrol. 1992;2(9):1405-16. 
Di Iorio B, Cirillo M, Bellizzi V, Stellato D, De Santo NG. Prevalence and correlates of anemia 
and uncontrolled anemia in chronic hemodialysis patients – The Campania Dialysis Registry. Int 
J Antif Organs. 2007;30(4):325-33. 
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):2071-84. 
Iseki K, Kohagura K. Anemia as a risk factor for chronic kidney disease. Kidney Int Suppl. 
2007;(107):S4-9. 
Jha V, Garcia-Garcia G, Iseki K, Li K, Naicker S, Plattner B, et al. Chronic kidney disease: 
global dimension and perspectives. Lancet. 2013;382(9888):260-72. 
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 
Locatelli F, Aljama P, Barany P, Canaud B, Carrera F, Eckhardt KU, et al. Revised European 
best practice guidelines for the management of anaemia in patients with chronic renal failure. 
Nephrol Dial Transplant. 2004;19(Suppl2):1-47. 
Ly J, Marticrena R, Donnelly S. Red blood cell survival in chronic renal failure. Am J Kidney 
Dis. 2004;44(4):715-9. 
McCullough PA, Barnhart HX, Inrig JK, et al.  Cardiovascular toxicity of epoetin-alfa in patients 
with chronic kidney disease.  Am J Nephrol 2013;37(6):549-558. 
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. 
NICE. Anaemia management in people with chronic kidney disease. National Institute for Health 
and Care Excellence. 2011:1-39. 
Nurko S. Anemia in chronic kidney disease: causes, diagnosis, treatment. Cleve Clin J Med. 
2006;73(3):289-97. 
Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D. Double-blind comparison 
of full and partial anemia correction in incident hemodialysis patients without symptomatic heart 
disease. J Am Soc Nephrol. 2005;16(7):2180-9. 


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Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH. Vadadustat, a novel oral HIF 
stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease. 
Kidney Int. 2016;90(5):1115-22. 
Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, et al. 
Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin 
Invest. 2007;117(7):1926-32. 
Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al. A trial of 
darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 
2009a;361(21):2019-32. 
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):2085-98. 
Stauffer ME, Fan T. Prevalence of anemia in chronic kidney disease in the United States. PLoS 
One. 2014;9(1):e84943. 
Unger EF, Thompson AM, Blank MJ, 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 
Screening 
[a] 
Study Treatment Period 
Safety Follow-
Up 
Visit 
SV1 SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 [c]
15 
Weeks of study completed 
Study Day 
Day -28 to 0 
Baseline/ 
Day 1 [b]
Week 1
Day 8 
Week 2
Day 15
Week 4
Day 29
Week 6
Day 43
Week 8
Day 57
Week 10
Day 71
Week 11 
Day 78 
Week 12
Day 85 
Week 13 
Day 92 
Week 14
Day 99 
Week 16
Day 113
Week 18
Day 127 
EOT
Week 20
Day 141
Week 
24 
Day 169
Visit Window (Days) 
― 
― 
+5 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+5 
±3 
±3 
±3 
±3 
±5 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria [d] 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Contraception 
methods [e] 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs [f] 
X 
X [g] X [g] 
X 
X 
X 
X 
X 
X 
X 
X [g] 
X 
X 
X 
X 
X [g] 
 
Demographics, Medical 
History [h] 
 
X 
X [i] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam [j] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG [k] 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dialysis Adequacy (Kt/V) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
EQ-5D-5L 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
SF-36v2  
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
PGI-S 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
PGI-C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment for meeting 
criteria to switch from daily to 
TIW dosing 
(vadadustat arm) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Status check [l] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Period 
Screening 
[a] 
Study Treatment Period 
Safety Follow-
Up 
Visit 
SV1 SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 [c]
15 
Weeks of study completed 
Study Day 
Day -28 to 0 
Baseline/ 
Day 1 [b]
Week 1
Day 8 
Week 2
Day 15
Week 4
Day 29
Week 6
Day 43
Week 8
Day 57
Week 10
Day 71
Week 11 
Day 78 
Week 12
Day 85 
Week 13 
Day 92 
Week 14
Day 99 
Week 16
Day 113
Week 18
Day 127 
EOT
Week 20
Day 141
Week 
24 
Day 169
AE review [m] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review use of rescue therapy 
(RBC transfusions and ESA 
therapy) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of therapeutic 
phlebotomy 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy test [n] 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC [o] [p] 
X 
X 
X [q] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X [q] 
 
Reticulocyte count 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
Folate and vitamin B12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Serum chemistry [r] 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
LFTs [s] 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Iron indices [t] 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
Lipid panel [u] 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Biomarkers (VEGF and 
Hepcidin) [v] 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
PK/PD for vadadustat arm [w] 
 
 
X 
X 
 
 
 
 
 
X 
 
X [x] 
 
 
 
 
 
PK for epoetin alfa arm [y] 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication Assessments and Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
review [z] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Epoetin alfa dosing during 
Screening and resume standard 
of care after EOT 
X [aa] 
 
 
 
 
 
 
 
 
 
 
 
 
 
X [bb] 


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Study Period 
Screening 
[a] 
Study Treatment Period 
Safety Follow-
Up 
Visit 
SV1 SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 [c]
15 
Weeks of study completed 
Study Day 
Day -28 to 0 
Baseline/ 
Day 1 [b]
Week 1
Day 8 
Week 2
Day 15
Week 4
Day 29
Week 6
Day 43
Week 8
Day 57
Week 10
Day 71
Week 11 
Day 78 
Week 12
Day 85 
Week 13 
Day 92 
Week 14
Day 99 
Week 16
Day 113
Week 18
Day 127 
EOT
Week 20
Day 141
Week 
24 
Day 169
Study Drug (vadadustat or 
epoetin alfa) dosing [cc] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X [dd]
X 
X 
X 
X 
 
 
Vadadustat dispensation [ee] 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
Review vadadustat dosing 
instructions and vadadustat 
dosing compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vadadustat reconciliation 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review use of iron 
supplementation [ff] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Visit Registration in IWRS 
X 
X 
X 
 
 
X [gg]
 
X [gg]
 
 
X [gg]
 
 
X [gg]
 
X 
 
eDiary instruction 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE: adverse event; ALT/SGPT: alanine aminotransferase/serum glutamic pyruvic transaminase; aPTT: activated partial thromboplastin time; AST/SGOT: aspartate aminotransferase/serum glutamic 
oxaloacetic transaminase; BUN: blood urea nitrogen; CBC: complete blood count; CPK: creatine phosphokinase; CRP: C-reactive protein; ECG: electrocardiogram; EOT: end-of-treatment; 
EPO: erythropoietin; EQ-5D-5L: EuroQol 5 Dimensions 5 Levels; ESA: erythropoiesis-stimulating agent; HDL: high density lipoprotein; INR: international normalized ratio; IWRS: Interactive Web 
Response System; LDL: low density lipoprotein; LFT: liver function test; MCH: mean corpuscular hemoglobin; MCHC: mean corpuscular hemoglobin concentration; MCV: mean corpuscular volume; 
PD: pharmacodynamics; PGI-C: Patient Global Impression of Change; PGI-S: Patient Global Impression of Severity; PK: pharmacokinetic; PTT: partial thromboplastin time; RBC: red blood cell; 
RDW: red cell distribution width; SF-36v2: 36-Item Short-Form General Health Survey; SV1: Screening visit 1; SV2: Screening visit 2; TIBC: total iron binding capacity; TIW: three times per week; 
TSAT: transferrin saturation; VEGF: vascular endothelial growth factor; WBC: white blood cell; wks: weeks.  
 
[a] The Screening Period is a maximum of 28 days in duration and starts at the time the informed consent is signed. 
[b] The Screening Period starts at the time the informed consent is signed and will be a maximum of 28-days in duration.  Two Screening visits (SV1 and SV2, with a minimum of 4 days in between) 
must be performed within the Screening Period and prior to dosing (Baseline/Day 1). A subject may enter the washout period only after all eligibility criteria have been met following SV2.  During the 
washout period, no epoetin alfa will be administered before Baseline/Day 1 for 5 days in the Main study, and 2 days in the ESA hyporesponder parallel study. 
[c] The EOT evaluations will be performed when the Treatment Period (Baseline/Day 1 to Week 20 [Visits 1 to 13]) is completed.  Subjects who permanently discontinue study drug for any reason or 
discontinue prematurely from the study will complete the EOT visit (Visit 14) assessments and will complete the Safety Follow-Up (Visit 15) 4 weeks after Visit 14. 
[d] Eligibility criteria will be reviewed at the SV1, SV2, and Baseline/Day 1. 
[e] Contraception methods will be reviewed at Screening and Baseline/Day 1, as well as throughout the study as needed. 
[f] Vital signs will include temperature, HR, BP, RR, and dry weight.  Temperature, HR, BP, and RR will be assessed in the seated position after 5 minutes of rest.  For BP, a total of two 
measurements at intervals of at least 2 minutes should be performed.  Temperature, HR, BP, and RR will be collected at SV1, SV2, Baseline/Day 1, during all study visits, and Visit 14 (EOT).  
Measurements will be and will be taken prior to blood draws when possible.   
[g] Dry weight will be collected as part of the vital signs for all subjects at SV2, Baseline/Day 1, Visit 9 and 14 (EOT).  For subjects on epoetin alfa, subjects will be weighed for dosing as per the local 
standard of care. 
[h] Relevant medical history (with particular emphasis on previous medical conditions that may lead to exclusion) and significant ongoing medical conditions or diseases will be documented. 
[i] Review of medical history for new conditions since SV2. 


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[j] A physical examination (including height) is required at SV2.  Thereafter, an abbreviated symptom-directed physical examination will be performed at the discretion of the investigator, as clinically 
indicated. 
[k] A standard 12-lead ECG will be performed at Baseline/Day 1, which may be obtained up to 3 days prior to Baseline/Day 1.  The ECG will be obtained after the subject has been resting comfortably 
in a supine position for approximately 5 minutes and will be taken prior to vital sign assessments and blood draws when possible.  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. 
[l] In weeks where there is no scheduled study visit (Weeks 3, 5, 7, 9, 15, and 17, and 19), a subject will have a status check performed during one of their dialysis treatment appointments in the week.  
It will include a review of the subject’s vital signs and a review of current health status for identification of any issues that may require follow-up by the investigator or delegated staff personnel.  
Documentation of the review must be done in the subject’s source documentation.  If an AE is identified at the status check or other actions result from the status check, these will be captured per the 
protocol.  
[m]  AE collection will begin from time of randomization through 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.  Subjects must be followed for AEs until the final required protocol visit (study end date) or until all drug-related toxicities and SAEs have 
resolved (or are considered chronic/stable), whichever is later. 
[n] A serum pregnancy test will be performed at SV2 for females of childbearing potential.  Additional serum 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 drug.  A FSH test will be performed at SV2 for post-menopausal females.   
[o] A CBC without differential will be performed at all noted visits, except Baseline/Day 1 and Visit 14 (EOT).  The CBC without differential will include: Hb, hematocrit, RBCs, MCV, MCH, 
MCHC, RDW, WBC count, and platelets. 
[p] Hb will be monitored throughout the study via central laboratory to determine the dose of study drug (vadadustat or epoetin alfa) that subjects will receive.  Hb levels can be measured more 
frequently based on investigator’s clinical judgment.  For eligibility purposes, one retest for Hb may be performed during the Screening Period.  Two Hb values measured by the central laboratory at 
least 4 days apart between SV1 and SV2 must be between 8.5 and 11.0 g/dL, inclusive, for the Main study and 8.0 to 10.0 g/dL, inclusive, for the ESA hyporesponder parallel study. 
[q] A CBC with differential will be performed at Baseline/Day 1 and Visit 14 (EOT).  The CBC with differential will include the same parameters as CBC without differential with the addition of 
WBC count with differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils).   
[r] The serum chemistry will include the following assays: sodium, potassium, bicarbonate, chloride, calcium, magnesium, phosphorus, glucose, creatinine, BUN, CPK, uric acid, albumin, and total 
protein. 
[s] LFTs: total bilirubin, ALP, ALT/SGPT, AST/SGOT, and lactate dehydrogenase.  Elevation in ALT or AST >3x ULN will require collection of Unscheduled Visit central laboratory coagulation 
panel (INR, PT, aPTT) to confirm INR value >1.5 and permanent discontinuation of study medication  per Section 9.4. 
[t] Iron Indices: ferritin, iron, transferrin, TIBC, and TSAT. 
[u] Lipid Profile: total cholesterol, LDL, HDL, and triglycerides. 
[v] The biomarkers will include, but are not limited to, VEGF and hepcidin.  Samples for VEGF and hepcidin biomarker analyses will be drawn at Baseline/Day 1, Visit 9 and 14 (EOT).   
[w] Blood for measurement of vadadustat, metabolites and EPO level in the vadadustat arm, in both the Main study and ESA hyporesponder parallel study will be collected at Baseline/Day 1, Week 1, 
and Week 11 as outlined in Section 9.2.2.1.  For all PK and PD sampling, the time of the previous dose of vadadustat will be collected for the pre-dose sample and the timing of administration of 
vadadustat, and the start and stop time of the dialysis session will be recorded.   
[x] Visit 10/Week 13 PK/PD sampling will only be done in subjects who transition to vadadustat TIW dosing regimen.  Subjects who do not qualify for vadadustat TIW dosing and remain on daily 
dosing regimen will not have Visit 10/Week 13 PK/PD sampling. 
[y] Blood for measurement of EPO level in the epoetin alfa arm, in both the Main study and ESA hyporesponder parallel study, will be collected at Baseline/Day 1 and Week 1 as outlined in 
Section 9.2.2.2.  For all PK sampling the time of the previous dose of epoetin alfa is to be collected for the pre-dose sample and the timing of administration of epoetin alfa and the start and stop time of 
the dialysis session will be recorded.   
[z] Concomitant medications should be collected and recorded at each visit as noted.  All medications taken within 30 days prior to Baseline/Day 1 will be recorded. 
[aa] Epoetin alfa dosing will stop for a minimum of 5 days before Baseline/Day 1 in the Main study or 2 days before Baseline/Day 1 in the ESA hyporesponder parallel study. 
[bb] After the end of vadadustat treatment at Visit 14/Week 20 (or following early discontinuation of vadadustat), subjects will resume dosing with epoetin alfa (or another ESA), based on standard of 
care. 
[cc] Subjects in the low epoetin alfa dose group randomized to vadadustat treatment will start at an initial dose of vadadustat 300 mg or 450 mg daily.  Subjects in the high epoetin alfa dose group 
randomized to vadadustat treatment will receive an initial dose of 300 mg, 450 mg, or 600 mg daily.  Subjects in the ESA hyporesponder parallel study randomized to vadadustat treatment will receive a 
starting dose of vadadustat 600 mg daily.  For subjects who are randomized to the epoetin alfa treatment arm, the initial dosing regimen in the study (starting from Baseline/Day 1) will be approximately 
the same weekly dose that they were receiving prior to randomization. 
[dd] After completing the 12-week once daily dosing regimen, subjects randomized to vadadustat who meet criteria for switching from daily to TIW dosing will initiate TIW dosing at a starting dose 
1 tablet greater (+150 mg) than the final dose in the daily dosing period.  Central laboratory Hb values from Visit 8/Week 11 (11 weeks of treatment completed) will be used to determine if subjects 
meet Week 12 Transition criteria. 
[ee] Subjects will be provided with a supply of vadadustat at Baseline/Day 1 and will be resupplied at Visit 4, 6, 9 and 12 or an unscheduled dispensing visit as needed.  Subjects will be instructed to 
complete 1 bottle before opening a new bottle.  The dose should be taken at approximately the same time each day. 


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[ff] IV iron will be administered based on ferritin and TSAT levels measured by the central laboratory according to the standardized, low-intensity, iron supplementation protocol in Section 8.4.8. 
[gg] IWRS visit registration for vadadustat arm only for bottle dispensing.


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APPENDIX B: PK/PD SAMPLING  
PK/PD Sampling in Vadadustat Arm Subjects Who Transition to TIW Dosing at Week 12 
 
 
Baseline/Day 1 
QD 
Week 1  
QD 
Week 1  
+ 1 day  
Week 11  
QD 
  
Week 13  
TIW 
 
 
Dialysis  
Day 
Dialysis 
Day 
Non-Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Baseline/Day 1 
(Prior to first dose) 
● 
  
  
  
  
  
 
15 minutes (pre-dose) 
  
● 
● 
● 
 
● 
 
2 hours ± 15 minutes 
(post-dose) 
  
● 
● 
● 
 
● 
 
3.5 hours ± 15 minutes 
(post-dose) 
  
● 
● 
● 
 
● 
 
5 hours ± 30 minutes 
(post-dose) 
  
● 
● 
● 
 
● 
 
7 hours ± 30 minutes 
(post-dose) 
  
● 
● 
● 
 
● 
 
10.5 hours ± 1.5 hours 
(post-dose) 
 
● 
 
● 
 
● 
 
Note: Gray shading indicates sample collection at a subset of study sites only. 
 
 


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PK/PD Sampling in Vadadustat Arm Subjects Who Do Not Transition to TIW Dosing at Week 12 
 
 
Baseline/Day 1 
QD 
Week 1  
QD 
Week 1  
+ 1 day  
Week 11  
QD 
  
Week 13  
TIW 
 
 
Dialysis  
Day 
Dialysis 
Day 
Non-Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Baseline/Day 1 
(Prior to first dose) 
● 
  
  
  
  
  
 
15 minutes (pre-dose) 
  
● 
● 
● 
 
 
 
2 hours ± 15 minutes 
(post-dose) 
  
● 
● 
● 
 
 
 
3.5 hours ± 15 minutes 
(post-dose) 
  
● 
● 
● 
 
 
 
5 hours ± 30 minutes 
(post-dose) 
  
● 
● 
● 
 
 
 
7 hours ± 30 minutes 
(post-dose) 
  
● 
● 
● 
 
 
 
10.5 hours ± 1.5 hours 
(post-dose) 
 
● 
 
● 
 
 
 
Note: Gray shading indicates sample collection at a subset of study sites only. 
 
 
 


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PK Sampling in Epoetin Alfa Arm 
 
 
Baseline/Day 1 
TIW 
Week 1  
TIW 
Week 1  
+ 2 days 
Week 11  
TIW 
  
Week 13  
TIW 
 
 
Dialysis  
Day 
Dialysis 
Day 
Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Dialysis  
Day 
Non-Dialysis 
Day 
Baseline/Day 1 
(Prior to first dose) 
● 
  
  
  
  
  
 
15 minutes (pre-dose) 
  
● 
● 
 
 
 
 
2 hours ± 15 minutes 
(post-dose) 
  
● 
 
 
 
 
 
3.5 hours ± 15 minutes 
(post-dose) 
  
● 
 
 
 
 
 
5 hours ± 30 minutes 
(post-dose) 
  
● 
 
 
 
 
 
7 hours ± 30 minutes 
(post-dose) 
  
● 
 
 
 
 
 
10.5 hours ± 1.5 hours 
(post-dose) 
 
● 
 
 
 
 
 
Note: Gray shading indicates sample collection at a subset of study sites only.


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APPENDIX C: SF-36v2 Standard  
 


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Akebia Therapeutics, Inc. 
 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
 
05 April 2019 
 
Akebia — Company Confidential 
Page 97 of 105 
 


Akebia Therapeutics, Inc. 
 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
 
05 April 2019 
 
Akebia — Company Confidential 
Page 98 of 105 
APPENDIX D: PATIENT GLOBAL IMPRESSION OF SEVERITY (PGI-S) 
 


Akebia Therapeutics, Inc. 
 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
 
05 April 2019 
 
Akebia — Company Confidential 
Page 99 of 105 
APPENDIX E: PATIENT GLOBAL IMPRESSION OF CHANGE (PGI-C) 
 


Akebia Therapeutics, Inc. 
 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
 
05 April 2019 
 
Akebia — Company Confidential 
Page 100 of 105 
APPENDIX F: EUROQOL 5 DIMENSIONS 5 LEVELS (EQ-5D-5L) 


Akebia Therapeutics, Inc. 
 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
 
05 April 2019 
 
Akebia — Company Confidential 
Page 101 of 105 
 


Akebia Therapeutics, Inc. 
 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
 
05 April 2019 
 
Akebia — Company Confidential 
Page 102 of 105 
 


Akebia Therapeutics, Inc. 
 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
 
05 April 2019 
 
Akebia — Company Confidential 
Page 103 of 105 
APPENDIX G: HISTORY OF AMENDMENTS TO THE PROTOCOL  
Amendment 1 (Version 2.0; 11 September 2018) 
 
Amendment 1 was issued based on sponsor assessment and external input.   
  
The major changes introduced in the amendment are summarized below: 
• Addition of an Exclusion Criterion of Subjects with bilateral native nephrectomy, to 
minimize potential variability in hemoglobin response observed in this Phase 2 PK/PD study 
that may arise from a decreased capacity to augment endogenous erythropoietin (EPO) 
production in the setting of bilateral nephrectomy. 
• Addition of language to provide explicit guidance on early termination from the study for 
subjects who undergo a solid organ, hematopoietic stem cell, or bone marrow transplantation 
while participating in the study. 
• Update to the description of the vadadustat tablet since new lots of vadadustat may include 
imprinting on the tablet.  This is also referred to as a debossed tablet. 
• Preliminary results of clinical drug-drug interaction studies showed a moderate interaction 
between vadadustat and rosuvastatin and no clinically significant interaction between 
vadadustat and pravastatin.  Based on the data from these studies, guidance has been added to 
the protocol on how to manage the use of statins in combination with vadadustat. 
• Removal of the requirement to assess and document oxygen saturation (SO2) levels in study 
subjects for consistency with past and current Akebia DD-CKD protocols, and given that 
measurement of SO2 levels is not required in the setting of vadadustat or epoetin alfa use or 
in the routine management of subjects with DD-CKD.    
• AE reporting period clarified as starting at randomization in case there is a delay between 
date of randomization and date of first study drug dose. 
Amendment 2 (Version 3.0; 05 April 2019) 
Amendment 2 was issued based on sponsor assessment, external input, regulatory authority 
engagement, investigative site feedback, and results of a drug-drug interaction study. 
The major changes are summarized below: 
• Signature page:  Dennis Vargo, Senior Director has replaced Geoffrey Ross as Vice 
President; Ajit Chavan, Senior Director has replaced Susan Paulson as Clinical 
Pharmacology.  
• Section 4.2 Summary of Clinical Experience was updated to include the language of specific 
dose adjustment from 150 to 600 mg, and to highlight that this study is the first study to 
examine doses of 750 and 900 mg in DD-CKD subjects.  
• Section 4.3: Potential Benefits and Risks: Addition of text to indicate hepatotoxicity as an 
identified important potential risk. 
• Section 6.3 Dose Justification was updated to include additional details for the doses being 
used in the study.  


Akebia Therapeutics, Inc. 
 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
 
05 April 2019 
 
Akebia — Company Confidential 
Page 104 of 105 
• Section 7.3 Exclusion Criteria was updated to exclude persons who are concurrently 
participating in another study, or any prior use of a HIF-PH inhibitor. 
• Section 7.6.3 Early Discontinuation From Study (Early Termination) was updated to include 
a reference to Study Medication Stopping Rules for management of subjects with ALT and 
AST abnormalities. 
• Section 8.4.8 Iron Supplementation was updated to prohibit concurrent administration of oral 
iron supplementation of vadadustat and instruct them to take their iron supplementation at 
least 2 hours after dosing with vadadustat.  
• Section 8.5.3 HMG-CoA Reductase Inhibitors (Statins) was updated to provide further 
guidance regarding concomitant use of HMG-CoA Reductase Inhibitor drug interactions with 
vadadustat. 
• Section 8.5.4 Sulfasalazine and Other BCRP Substrates was added to provide guidance 
regarding concomitant use of Sulfasalazine and other BCRP substrates with vadadustat. 
• Section 8.5.5 Phosphate Binders was added to provide guidance regarding concomitant use 
of Phosphate Binders with vadadustat. 
• Section 9.1.2 eDiary was updated to also allow use of paper dosing reminders, and timing of 
completing questionnaires was clarified. 
• Section 9.2.1 EQ-5D-5L was added as a patient reported outcomes measurement.  Additional 
instructions have been provided to ensure consistency across all subjects in the timing of 
when the SF-36v2, HRQOL, PGI-S, and PGI-C. 
• Section 9.2.2 Laboratory Evaluations were updated with additional Liver Function Test 
(LFT) timepoints, such that LFTs are performed every 2 weeks instead of every 4 weeks after 
Baseline/Day 1.  Given expansion of potential risks to include hepatotoxicity associated with 
use of vadadustat. 
• Section 9.3.1 Screening Visits was updated to remove the 4-day minimum requirement 
between SV2 and Baseline/Day 1 visits and to clarify that a subject may enter the washout 
period only after all eligibility criteria have been met following SV2.  During the washout 
period, no epoetin alfa will be administered before Baseline/Day 1 for a minimum duration 
of 5 days in the Main study, and 2 days in the ESA hyporesponder parallel study. 
• Section 9.3.2 Baseline/Day 1 (Visit 1) was updated to introduce the eDiary and HRQOL 
questionnaires at the Baseline/Day 1 visit instead of at SV2. 
• Section 9.3.6 Unscheduled Visits was updated to clarify that a coagulation panel (INR, PT, 
aPTT) was added to the Unscheduled Visit central laboratory kit for testing INR (see Section 
9.4 Study Medication Stopping Rules). 
• 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 AEs 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.  


Akebia Therapeutics, Inc. 
 
Amendment 2 (Version 3.0) 
Protocol No. AKB-6548-CI-0025 
 
05 April 2019 
 
Akebia — Company Confidential 
Page 105 of 105 
• Section 10.1.2 SAEs was updated to include information defining Designated Medical 
Events. 
• Section 10.1.3 Adverse Events of Special Interest was added to include a classification for 
Malignancies, elevations of ALTs, ASTs, pregnancy, and pulmonary hypertension. 

SAP_001.pdf: 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0025                                                                                      Akebia Therapeutics, Inc. 
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STATISTICAL ANALYSIS PLAN 
Protocol: 
Compound: 
Protocol Number: 
US IND Number: 
Phase: 
Sponsor: 
Author: 
Version: 
Release Date 
NCT Number: 
Phase 2, randomized, open-label, active-controlled, 
pharmacokinetics / pharmacodynamics and dose 
optimization study of oral vadadustat for the 
treatment of anemia in hemodialysis subjects 
converting from epoetin alfa 
Vadadustat (AKB-6548) 
AKB-6548-CI-0025 
102,465 
Phase 2 
Akebia Therapeutics, Inc. 
245 First Street 
Cambridge, MA 02142 
United States of America 
H2O Clinical, LLC 
224 Schilling Circle, STE 1888 
Hunt Valley, MD 21031 
Final 2.0 
July 02, 2020 
NCT03799627


Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0025                                                                                      Akebia Therapeutics, Inc. 
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Revision History 
Version 
Version Date 
Author 
Summary of Changes Made 
Draft 0.1 
09 July 2018 
New Document 
Draft 0.2 
20 July 2018 
Per sponsor’s comments 
Draft 0.3 
11 August 2018 
Per sponsor’s comments 
Draft 0.4 
13 January 2019 
Per sponsor’s comments 
Draft 0.5 
27 February 2019 
Per sponsor’s comments 
Draft 0.6 
16 April 2019 
Added new QoL assessment 
Draft 0.7 
19 July 2019 
Per sponsor’s comments 
Final 1.0 
24 July 2019 
Added section 9.5 for any potential 
sensitivity analyses. 
Modified the definition of PK 
population per Rishi. 
Final 2.0 
02 July 2020 
Updated based on Protocol 
amendment 2, no IA analyses for 
the study. Added sensitivity 
analyses by excluding some HB data 
due to the Eurofins Ransomware 
Attack  


 
 
 
 
 
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Approval Signatures: 
 
 
 
 
 
 
 
Akebia Therapeutics, Inc 
 
 
 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
Akebia Therapeutics, Inc 
 
 
 
 
Signature 
 
Date 
 
Prepared by: 
 
 
 
 
 
 
 
 
 
 
 
Firma Clinical Research, LLC 
 
 
 
Signature 
 
 
Date 
 
 
 
 
Firma Clinical Research, LLC  
 
Signature 
 
Date 
 
 


 
 
 
 
 
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Contents 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................................................ 7 
1 
INTRODUCTION ..................................................................................................................................... 9 
2 
STUDY OBJECTIVE AND DESIGN .......................................................................................................... 10 
2.1 
Study Objectives ......................................................................................................................... 10 
2.1.1 
Primary Objective ................................................................................................................ 10 
2.1.2 
Secondary Objectives .......................................................................................................... 10 
3 
Study Design........................................................................................................................................ 11 
3.1 
Screening Period (up to 28 days; Day -28 to Baseline/Day 1) .................................................... 13 
3.2 
Study Treatment Period (Baseline/Day 1 to Week 20) ............................................................... 13 
3.3 
Vadadustat Treatment ................................................................................................................ 13 
3.4 
Epoetin Alfa Treatment ............................................................................................................... 14 
3.5 
Safety Follow-Up Period (Weeks 20 to 24) ................................................................................. 14 
3.6 
Study Medication Stopping Rules ............................................................................................... 14 
4 
changes from the protocol.................................................................................................................. 15 
5 
Primary and secondary endpoints ...................................................................................................... 16 
5.1 
Primary Efficacy Endpoint ........................................................................................................... 16 
5.2 
Key Secondary Efficacy Endpoints .............................................................................................. 16 
5.3 
Other Secondary Efficacy Endpoints ........................................................................................... 16 
5.4 
Exploratory Endpoints ................................................................................................................. 16 
5.5 
PK/PD Endpoints ......................................................................................................................... 17 
5.6 
Safety Endpoints ......................................................................................................................... 17 
6 
GENERAL ANALYSIS DEFINITION ......................................................................................................... 18 
7 
SAMPLE SIZE JUSTIFICATION ............................................................................................................... 21 
8 
STUDY ANALYSES ................................................................................................................................ 22 
8.1 
General Consideration ................................................................................................................ 22 
8.2 
Analysis Population ..................................................................................................................... 23 
8.3 
Disposition of Subjects ................................................................................................................ 23 
8.4 
Protocol Deviations ..................................................................................................................... 24 
8.5 
Demographics and Baseline Characteristics ............................................................................... 24 


 
 
 
 
 
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8.6 
Baseline Laboratory Data ............................................................................................................ 24 
8.7 
Medical History ........................................................................................................................... 24 
8.8 
Prior and Concomitant Medication ............................................................................................. 25 
8.9 
Study Medication Exposure and Compliance ............................................................................. 25 
9 
EFFICACY ANALYSIS ............................................................................................................................. 27 
9.1 
Primary Endpoint ........................................................................................................................ 27 
9.2 
Secondary Endpoints .................................................................................................................. 27 
9.3 
Other Secondary Endpoints ........................................................................................................ 28 
9.4 
Exploratory Endpoints ................................................................................................................. 29 
9.4.1 
Health--related quality of life (HRQOL) measure 36-Item Short-Form General Health 
Survey (SF-36v2) ................................................................................................................................. 30 
9.4.2 
Patient Global Impression of Severity (PGI-S) ..................................................................... 32 
9.4.3 
Patient Global Impression of Change (PGI-C) ..................................................................... 32 
9.4.4 
HRQOL measure EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) ............................................. 33 
9.5 
Additional Sensitivity Analyses ................................................................................................... 34 
10 
SAFETY ANALYSIS ............................................................................................................................ 35 
10.1 
Adverse Events ............................................................................................................................ 35 
10.2 
Laboratory ................................................................................................................................... 35 
10.3 
Vital Signs .................................................................................................................................... 37 
10.4 
Electrocardiogram (ECG) ............................................................................................................. 37 
10.5 
Physical Examinations ................................................................................................................. 37 
11 
PHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) ANALYSIS ...................................................... 38 
12 
SOFTWARE AND PROGRAMMING SPECIFICATIONS ....................................................................... 41 
13 
REFERENCES .................................................................................................................................... 42 
Appendix 1 .................................................................................................................................................. 43 
Appendix 2: SF-36 v2 ................................................................................................................................... 44 
Appendix 3. 
SF-36 v2 Scoring Assigment ................................................................................................ 50 
Appendix 4. 
Adverse events of special interest ...................................................................................... 54 
F.1. 
Potential risks .............................................................................................................................. 54 
F.2. 
Events of special interest ............................................................................................................ 54 
F.3. 
Events under monitoring ............................................................................................................ 54 


 
 
 
 
 
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Appendix 5:  Elemental Iron Content in IV Iron .......................................................................................... 55 
 
 


 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUCinf 
area under concentration-time curve from dosing to infinity 
AUClast 
area under concentration-time curve from dosing to last 
measurable concentration  
BLQ 
below the limit of quantification 
BP 
blood pressure 
CBC 
complete blood count 
CKD 
chronic kidney disease 
CL/F 
apparent total body clearance 
Cmax 
maximum concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CTCAE 
common terminology criteria for adverse events 
CVD 
cardiovascular disease 
DD-CKD 
dialysis dependent chronic kidney disease 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EOT 
end-of-treatment 
EPO 
erythropoietin 
ESA 
erythropoiesis-stimulating agent 
ESRD 
end-stage renal disease 
FAS 
Full Analysis Population 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
Hb 
hemoglobin 
HF 
heart failure 
HIF 
hypoxia-inducible factor 
HIF-PH 
hypoxia-inducible factor prolyl-hydroxylase 
HIF-PHI 
hypoxia-inducible factor prolyl-hydroxylase inhibitor 
HR 
heart rate 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IRB 
Institutional Review Board 
IV 
intravenous 
IWRS 
Interactive Web Response System 
LFT 
liver function test 
LPO 
last patient out 


 
 
 
 
 
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MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger ribonucleic acid 
MCS 
mental component score 
NDD-CKD 
non-dialysis dependent chronic kidney disease 
PCS 
physical component score 
PD 
pharmacodynamics(s) 
PGI-C 
patient global impression of change 
PGI-S 
patient global impression of severity 
PHD 
prolyl 4-hydroxylase domains 
PI 
Package Insert 
PK 
pharmacokinetic(s) 
RBC 
red blood cell 
RR 
respiratory rate 
SAE 
serious adverse event 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SO2 
oxygen saturation 
TIW 
three times a week 
Tmax 
time to reach Cmax 
TSAT 
transferrin saturation 
U 
unit 
ULN 
upper limit of normal 
US 
United States 
Vd/F 
apparent volume of distribution 
VEGF 
vascular endothelial growth factor 
λz  
 
 
 
elimination rate constant  
 
 


 
 
 
 
 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
analysis methods that will be used to analyze, and report results for Akebia Protocol 
AKB-6548-CI-0025.   
 
This document is prepared based on the final study protocol Amendment 2, version 3 (dated 
April 05, 2019).  Reader can refer to the study protocol, the case report form (CRF), and general 
CRF completion guidelines for details of study design, conduct and data collection. 
Specifications of tables, figures, and data listings are contained in a separate document.  


 
 
 
 
 
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2 
STUDY OBJECTIVE AND DESIGN 
2.1 
 Study Objectives 
2.1.1 Primary Objective 
To assess the efficacy and safety of daily dosing of vadadustat compared to epoetin alfa for 
12 weeks in hemodialysis subjects. 
2.1.2 Secondary Objectives 
• To assess the efficacy and safety of TIW dosing of vadadustat in selected hemodialysis 
subjects who have been successfully managed with daily dosing of vadadustat through 
Week 12. 
• To evaluate the PK/PD of daily and TIW dosing of vadadustat in hemodialysis subjects 
compared to epoetin alfa. 
• To assess the efficacy and safety of several dosing strategies of vadadustat compared to 
epoetin alfa during a 20-week Treatment Period in hemodialysis subjects. 


 
 
 
 
 
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3 
 STUDY DESIGN 
This is a Phase 2, randomized, open-label study to evaluate vadadustat for the treatment of 
anemia in hemodialysis subjects converting from epoetin alfa therapy. 
 
For all subjects (Main study and ESA hyporesponder parallel study), the study (as shown in 
Figure 1) will include a Screening Period, a study Treatment Period, and a Safety Follow-Up 
Period as described below.  
 
The aim is to achieve and maintain Hb levels within the target range of 10.0 to 11.0 g/dL, 
inclusive, while targeting the middle of the range and minimizing excursions outside the target 
range. 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
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Figure 1: Overview of Study Design 
 
 
 
 
 
 


 
 
 
 
 
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3.1 
Screening Period (up to 28 days; Day -28 to Baseline/Day 1) 
 
For all subjects (Main study and ESA hyporesponder parallel study), the Screening Period starts 
at the time the informed consent is signed and will be a maximum of 28 days in duration. 
Baseline/Day 1 will be performed within 28 days of the start of Screening. Subjects who meet 
all eligibility criteria will be randomized to a vadadustat treatment arm or an epoetin alfa 
treatment arm. Subjects will be required to stop epoetin alfa treatment for a minimum duration 
of 5 days before Baseline/Day 1 in the Main study and for a minimum of 2 days before 
Baseline/Day 1 in the ESA hyporesponder parallel study. In the Main study, randomization will 
be stratified by the mean weekly epoetin dose calculated over a period of 8 weeks prior to 
Screening Visit 2 (SV2): 
 
• Low epoetin alfa dose group (≤90 U/kg/week) 
• High epoetin alfa dose group (>90 to <300 U/kg/week)  
 
3.2 
Study Treatment Period (Baseline/Day 1 to Week 20) 
 
For all subjects (Main study and ESA hyporesponder parallel study), the Treatment Period will 
run from Baseline/Day 1 to Week 20. Dose will be adjusted to achieve and maintain Hb levels 
within the target range of 10.0 to 11.0 g/dL, inclusive, while targeting the middle of the range 
and minimizing excursions outside of the target range. 
 
3.3 
Vadadustat Treatment  
 
Subjects in the Main study randomized to vadadustat: 
• Subjects in the low epoetin alfa dose group will start vadadustat at an initial, randomly 
allocated dose of 300 or 450 mg daily. 
• Subjects in the high epoetin alfa dose group will start vadadustat at an initial, randomly 
allocated dose of 300, 450, or 600 mg daily. 
 
Subjects in the ESA hyporesponder parallel study randomized to vadadustat: 
 
• Subjects will receive a starting dose of vadadustat 600 mg daily. 
 
Transition to TIW for all subjects randomized to vadadustat: 
 
All subjects randomized to vadadustat (Main study and ESA hyporesponder parallel study), who 
complete the 12-week once daily dosing regimen and who meet all the Week 12 transition 
criteria for switching from daily to TIW dosing, will initiate TIW dosing at a starting dose one 
tablet greater (+150 mg) than the final dose in the daily dosing. 
 


 
 
 
 
 
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Note: Subjects who are not eligible to switch from daily vadadustat to TIW dosing at Week 12 
will remain on daily dosing for the remainder of the study. 
 
3.4 
Epoetin Alfa Treatment 
 
Subjects in both the Main study and ESA hyporesponder parallel study randomized to epoetin 
alfa: 
 
All subjects randomized to epoetin alfa will receive TIW dosing for the entire Treatment Period 
based on the subject’s central laboratory Hb value and the approved epoetin alfa US Package 
Insert (PI) for adult patients with CKD on dialysis. Dose will be adjusted to achieve and maintain 
Hb levels within the target range of 10.0 to 11.0 g/dL, inclusive, while targeting the middle of 
the range and minimizing excursions outside of the target range. 
 
3.5 
Safety Follow-Up Period (Weeks 20 to 24) 
 
For all subjects (Main study and ESA hyporesponder parallel study), the 4-week Safety Follow-
Up Period starting at Week 20 will be followed by a post-treatment safety assessment conducted 
at the beginning of Week 24. 
 
 
3.6 
Study Medication Stopping Rules 
 
Study medication must be permanently discontinued if a subject meets one of the following 
criteria:  
• ALT or AST >3x Upper Limit of Normal (ULN) and total bilirubin >2x ULN 
• ALT or AST >3x ULN and international normalized ratio (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. 
 


 
 
 
 
 
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4 
CHANGES FROM THE PROTOCOL 
No changes in planned analyses were done compared to the protocol in this SAP. But due to the 
Eurofins Ransomware Attack, the change from baseline in Hemoglobin (Hb, g/dL) with 
excluding subjects who were randomized before July 23, 2019 for vadadustat group will be 
provided as sensitivity analyses.  
 


 
 
 
 
 
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5 
PRIMARY AND SECONDARY ENDPOINTS 
 
5.1 
Primary Efficacy Endpoint 
 
The primary endpoint will be the mean change in Hb between Baseline (average pretreatment 
Hb) and the primary evaluation period (average Hb from Weeks 10 to 12). 
 
5.2 
Key Secondary Efficacy Endpoints 
 
• Proportion of subjects with Hb values within the target range (10.0 to 11.0 g/dL, 
inclusive) at the primary evaluation period (Weeks 10 to 12). 
• For subjects who transitioned to TIW vadadustat dosing, mean change in Hb from 
primary evaluation period (average Hb from Weeks 10 to 12) to the secondary evaluation 
period (average Hb from Weeks 18 to 20). 
 
5.3 
Other Secondary Efficacy Endpoints 
 
• Mean change in Hb between Baseline (average pretreatment Hb) and the secondary 
evaluation period (average Hb from Weeks 18 to 20) 
• Proportion of subjects with Hb values within the target range (10.0 to 11.0 g/dL, 
inclusive) at the secondary evaluation period (Weeks 18 to 20) 
• For subjects who transitioned to TIW vadadustat dosing, proportion of subjects with Hb 
values within the target range (10.0 to 11.0 g/dL, inclusive) at the secondary evaluation 
period (Weeks 18 to 20) 
• Proportion of subjects with a mean increase in Hb from Baseline to the primary 
evaluation period ≥0.5 g/dL (average Hb from Weeks 10 to 12) or with Hb values within 
the target range (10.0 to 11.0 g/dL, inclusive) at the primary evaluation period 
(Weeks 10 to 12) 
• Proportion of subjects with a mean increase in Hb from Baseline to the secondary 
evaluation period ≥0.5 g/dL (average Hb from Weeks 18 to 20) or with Hb values within 
the target range (10.0 to 11.0 g/dL, inclusive) at the secondary evaluation period 
(Weeks 18 to 20) 
• Intravenous (IV) iron supplementation 
• ESA rescue 
• 
RBC transfusion 
 
5.4 
Exploratory Endpoints 
 
PPD


 
 
 
 
 
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5.5 
PK/PD Endpoints 
 
 
The PK parameters will include (but not limited to) the following: 
• 
 Area under concentration-time curve from dosing to last measurable concentration 
(AUClast) 
•  Area under concentration-time curve from dosing to infinity (AUCinf) 
• Maximum concentration Cmax 
• Time to reach Cmax (Tmax) 
• Apparent total body clearance (CL/F) 
• Apparent volume of distribution (Vd/F) 
• Terminal half-life (t1/2) 
 
The PD parameters will include (but are not limited to) the following: 
• EPO 
• Reticulocytes 
• Iron 
• Ferritin 
• TIBC 
• 
Hepcidin 
 
5.6 
Safety Endpoints 
Safety endpoints in this study include the following: 
• AEs 
• Vital sign measurements and clinical laboratory values 
• Hb >12.0 g/dL, >13.0 g/dL, or >14.0 g/dL 
• Hb <8.0 g/dL and decline in Hb ≥0.5 g/dL from Baseline Hb (Main Study); 
• Hb <7.5 g/dL and decline in Hb ≥0.5 g/dL from Baseline Hb (ESA hyporesponder 
parallel study) 
• 
Hb increase >1.0 g/dL within any 2-week interval 
 
PPD


 
 
 
 
 
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Protocol No. AKB-6548-CI-0025                                                                                      Akebia Therapeutics, Inc. 
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6 
GENERAL ANALYSIS DEFINITION 
Data collected throughout the study will be summarized using descriptive statistics and listed in 
the by-subject listings. The continuous variables will be summarized by descriptive statistics (n, 
mean, SD, median, minimum, and maximum). Categorical variables will be summarized with 
frequency and percentage. Summaries will be provided by treatment group within appropriate 
analysis populations, and by time point/time period, as appropriate. Baseline is defined as the last 
observation before the first dose of study drug administration except for the parameters specified 
below. 
 
Primary evaluation period is defined as Weeks 10 to 12 and the secondary evaluation period is 
defined as Weeks 18 to 20. 
 
Study day is 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. 
Assessments will be assigned to analysis visits based on the date the assessment took place 
regardless of the CRF page completed (i.e., scheduled visit number). Assessments will be 
mapped to visits based on Study Day.  
If more than 1 Hb result is available in an analysis time period post-baseline, the average of all 
observed values will be assigned to that period. When more than 1 assessment is made for other 
measures within a given visit window post-baseline, the value of the assessment closest to the 
scheduled visit should be used. If the assessments are equally close, the value from the last 
assessment should be used. 
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. 
For subjects whose reference date is missing, the study day will also be categorized as missing. 
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: 


 
 
 
 
 
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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. 
 
The following table provides the convention to classify assessment dates into protocol-defined 
visits. The time windows reflect the administrative range around each visit. These windows are 
wider than those stated in the protocol. 
 
 
 
 


 
 
 
 
 
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Table 1.  Classification of assessments at every visit during the study 
 
Target week / day 
Actual visit day 
Visit / Week classification 
Week 0 / Day 1 
Day 1  
Visit 1 / Week 0 
 
Week 1 / Day 8  
Day 2-11 
Visit 2 / Week 1 
        Week 2 / Day 15 
Day 12-21 
Visit 3 / Week 2 
Week 4 / Day 29 
Day 22-35 
Visit 4 / Week 4 
Week 6 / Day 43 
Day 36-49 
Visit 5 / Week 6 
Week 8 / Day 57 
Day 50-63 
Visit 6 / Week 8 
Week 10 / Day 71 
Day 64-74 
Visit 7 / Week 10 
Week 11 / Day 78 
Day 75-81 
Visit 8 / Week 11 
Week 12 / Day 85 
Day 82-88 
Visit 9 / Week 12 
Week 13 / Day 92 
Day 89-95 
Visit 10 / Week 13 
Week 14 / Day 99 
Day 96-105 
Visit 11 / Week 14 
Week 16 / Day 113 
Day 106-119 
Visit 12 / Week 16 
Week 18 / Day 127 
Day 120-133 
Visit 13 / Week 18 
Week 20 / Day 141 
Day 134 - (last dose day + 7) 
Visit 14 / Week 20 
Follow up / Day last dose 
day + 28 
≥ last dose day + 8 
                   Visit 15 / Week 24 (Follow up) 
Note: Week 20 is the end of treatment. 
 
It is expected that some subjects will discontinue Follow-Up.  The reasons for any missing data 
will be summarized by treatment arm.  The primary analysis will be based upon observed data 
without imputation.  As a sensitivity analysis for primary efficacy endpoint, missing Hb in weeks 
10 to 12 will be imputed using last observation carried forward (LOCF). Similarly, for certain 
secondary efficacy endpoints, missing Hb in weeks 18-20 will be imputed using LOCF.  
 
 


 
 
 
 
 
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7 
SAMPLE SIZE JUSTIFICATION  
Sample size is not based on a power analysis. Sample size reflects the exploratory nature of this 
study. 
 
Approximately 95 subjects are planned for enrollment in the Main study with 40 and 55 subjects 
randomized to the low epoetin alfa dose group and the high epoetin alfa dose group, respectively. 
Approximately 30 subjects are planned for enrollment in the ESA hyporesponder parallel study.  
 
Enrollment may be increased by up to approximately 20 additional subjects in the Main study 
and by up to approximately 30 additional subjects in the ESA hyporesponder parallel study to 
ensure adequate data are captured for the primary, PK/PD, and safety endpoints. 
 


 
 
 
 
 
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8 
STUDY ANALYSES 
 
8.1 
 General Consideration 
The following rules will be adopted when summarizing the data: 
1. The Main Study and the ESA Hyporesponder Parallel Study will be summarized 
separately, but in an analogous manner, for all endpoints. 
a. For the Main study, the low epoetin dose group (≤90 U/kg/week), 450 mg of 
vadadustat, 300 mg of vadadustat and epoetin will be displayed side by side. In 
addition, the total vadadustat will be presented as well. 
 
b. For the Main study, the high epoetin dose group (>90 and < 300 U/kg/week), 600 
mg, 450 mg, 300 mg of vadadustat and epoetin will be displayed side by side. In 
addition, the total vadadustat will be presented as well. 
 
c. For the Main study, a summary of total vadadustat vs. epoetin will be presented as 
well. For the background information, a total column for all randomized patients 
will be presented except certain PK/PD parameters. 
 
d. For the ESA Hyporesponder Parallel Study (≥300 U/kg/week), 600 mg and 
epoetin will be displayed side by side. 
 
 
2. For efficacy data analysis, 3 tables will be presented for some selected efficacy 
endpoints:  
a. Overall summary by week including the first weeks and post Week 12 by 
treatment group which is based on the randomized dose group.   
b. For subjects who switched Vadadustat dosing from QD to TIW dosing. 
c. For subjects who did not switch from QD to TIW dosing after Week 12. 
 
3. For safety data analysis, 5 sets of tables will be presented for some selected safety 
parameters:  
a. Overall summary for all weeks including the first 12 weeks and post Week 12 by 
treatment group 
b. Overall summary for the first 12 weeks of treatment. 
c. Overall summary for Weeks 12 to the end of study for both switched and not 
switched patients at Week 12 
d. Overall summary for Weeks 12 to the end of study for switched patients 
e. Overall summary for Weeks 12 to the end of study for not switched patients  
 
4. For patients who switched Vadadustat dosing from QD to TIW dosing at week 12, and 
then switched back to QD, if there are less than or equal to 20 subjects, only patient 


 
 
 
 
 
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listings/profiles will be created. If there are more than 20 patients, summary tables will be 
created by treatment groups for efficacy and safety. 
8.2 
 Analysis Population 
The following analysis populations will be used in this study: 
 
• Randomized population: defined as all randomized subjects.  Analyses of this population 
will be based on the randomized treatment. 
 
• Full Analysis Population (FAS): all subjects in the randomized population who received 
at least one dose of study drug and had at least one Hb assessment during the primary 
efficacy evaluation period.  Analyses of this population will be based on the randomized 
treatment. 
 
• Safety Population: all subjects in the randomized population who received at least one 
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 epoetin alfa will be 
classified by the more frequently received drug. 
 
• Per protocol (PP) population: all randomized subjects who received study drug during the 
primary evaluation period, had at least one Hb assessment during the primary efficacy 
evaluation period, received no rescue therapy (with ESA or transfusion) prior to the 
evaluation period, and had no major protocol deviation affecting the primary endpoint 
analyses.  Major protocol deviations leading to exclusion from the PP population will be 
specified prior to database lock on a blinded basis and recorded in a separate document.  
Analyses of this population will be based on actual treatment received. 
 
• Pharmacokinetic (PK) population: will include all randomized subjects who received 
study medication (vadadustat or EPO) and had enough drug concentrations to estimate 
AUC and Cmax. Analysis of this population will be based on the dose amount taken at 
the date of PK sampling for vadadustat group.  
 
Efficacy analyses will utilize the Randomized, FAS, and PP Populations while safety analyses 
will utilize the Safety Population. PK analyses will utilize the PK Population. However, if the 
population size of FAS and PP is ≥ 95% of the size of randomized population, no additional 
summary table will be presented for FAS and PP populations. 
.    
8.3 
 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. 
 


 
 
 
 
 
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The number of randomized subjects who completed the study period for QD period, switched to 
TIW period, completed TIW period, switched dosing from TIW back to QD, completed study, 
discontinued early from study drug, completed or discontinued from the study, and reasons for 
discontinuation will be summarized by treatment group and overall. For dose changes including 
dose increase, decrease for different reasons and “dose not changed” will be described in section 
8.9. 
8.4 
Protocol Deviations 
Deviations from the protocol including violations of inclusion/exclusion criteria will be assessed 
as “minor” or “major” in cooperation with Akebia. Major deviation will be categorized and 
summarized in table. A data listing of protocol deviations will be provided. 
8.5 
 Demographics and Baseline Characteristics 
Continuous demographic variables, such as age, weight, BMI, and height, will be summarized 
for the Randomized population, FAS, PP, and Safety using descriptive statistics (n, mean, 
median, SD, minimum, and maximum value). Categorical demographic variables, such as age 
category, race, ethnicity, and gender, will be summarized as a proportion of the Randomized 
population, FAS, PP, and Safety populations.  
 
Ethnic group, race, gender, and age will be included in the demographics and baseline 
characteristics table. Age will be calculated as using function floor of (informed consent date – 
birth date + 1)/365.25. 
8.6 
Baseline Laboratory Data  
Baseline laboratory including hematology, chemistry, folate, vitamin B12, iron indices (serum 
iron, ferritin, transferrin, TIBC, TSAT) and biomarkers (VEGF and hepcidin) will be 
summarized for each treatment group based on the safety population. 
8.7 
Medical History 
Medical history terms including renal and cardiovascular History will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) version 23. and the number and percent 
of subjects with medical history will be summarized by (SOC) and Preferred Term (PT) for each 
treatment group based on the safety population. 
 
Etiology of CKD, smoking status, and New York Heart Association Class (NYHA) of 
cardiovascular history will be summarized for each treatment group for safety population.  
 
In addition, the history of dialysis, CKD diagnosis duration in years will be summarized for each 
treatment group based on the safety population.  
 


 
 
 
 
 
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8.8 
 Prior and Concomitant Medication 
Prior and concomitant medications will be coded using World Health Organization Drug 
Dictionary (WHO DD; Sep 2018) and summarized for each treatment group based on the safety 
population. Prior medication is defined as any medication taken prior to the first dose of the 
study medication in the initial treatment period.  Any medication taken from the day of first dose 
of the study treatment up to the day of last date of the same study drug date + 4 weeks will be 
considered as concomitant medication for the treatment analysis. 
8.9 
 Study Medication Exposure and Compliance 
Study medication exposure and compliance will be summarized using descriptive statistics for the 
FAS and Safety Population. Study medication and subject dosing diary data will also be presented in 
data listings. 
 
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. 
 
Compliance will be summarized as follows: 
• 
Descriptive statistics will be summarized by treatment group for entire treatment period. 
• 
Percent compliance will be categorized according to the following categories for entire 
treatment period for safety population by treatment group: 
o less than 50% (significant drug noncompliance) 
o at least 50%, less than 80% (moderate drug noncompliance) 
o greater or equal 80% (drug compliance) 
o unknown 
 
Study medication exposure and compliance will be summarized for the first 12 weeks, Weeks 12 – 
20, and entire treatment period for each treatment group. In addition, for Weeks 12 – 20, patients 
who switched from daily vadadustat dose to TIW and patients who did not switch at Week 12 
will be summarized separately.  
 
For epoetin alfa group, increases in dose relative to last dose will be characterized in the 
following categories by percentage increase: <50%, ≥50% and <100%, and ≥100%. Subjects will 
be presented by their maximum category of increase for the first 12 weeks, Weeks 12 – 20, and 
entire treatment period. 
 
Dose change information including the following categories will be summarized for the first 12 
weeks and Weeks 12 – 20 treatment period for each treatment group:  
• Dose not changed 
• Protocol guided dose reduction 
• Dose increased based on Hb assessment 
• Dose decreased based on Hb assessment 


 
 
 
 
 
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• Dose interrupted based on Hb assessment 
• Dose decreased due to adverse event 
• Dose interrupted due to adverse event 
• Dose restarted 
• Transitioned from QD to TIW dosing 
• Converted back from TIW to QD dosing 


 
 
 
 
 
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9 
EFFICACY ANALYSIS 
 
The primary efficacy endpoint as well as all other secondary endpoints will be summarized using 
descriptive statistics by treatment group, as well as by study visit and/or analysis period (the first 
12 weeks and Weeks 12 – 20) as appropriate.  The ESA hyporesponder parallel study will be 
analyzed separately from the main study. Mean values of Hb as well as selected other efficacy 
parameters will be plotted across study visits/periods by treatment group. No adjustment for 
multiplicity is being used in this exploratory study. 
 
Primary efficacy endpoint will be analyzed and presented for Randomized population, FAS and 
PP Population. Key secondary efficacy endpoints will be analyzed for Randomized population 
and PP PopulationThe rest of efficacy endpoints will be analyzed for Randomized population. 
No inferential statistical modeling will be used for the efficacy analysis. All efficacy endpoints 
related to Hb, the observed data will be used for the analysis tables. In addition, a sensitivity 
analysis of LOCF to impute the missing Hb data will be performed for summary of change from 
baseline in Hb based on Randomized population.  
9.1 
Primary Endpoint 
Mean change in Hb between Baseline (average pretreatment Hb) and the primary evaluation 
period (average Hb from Weeks 10 to 12). Baseline value is defined as the average of the final 
two Hb values prior to start of dosing on day 1.  
 
Observed baseline, post-baseline values, and change from baseline values will be presented in 
descriptive statistics summary 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. 
 
 
9.2 
 Secondary Endpoints 
 
Similarly, all secondary endpoints will be summarized using descriptive statistics. For 
continuous variables, observed values at specified time points and changes between specified 
time points will be presented in descriptive statistics summary by treatment group, as well as by 
study visit and/or analysis period as appropriate. Counts of subjects satisfying stated criteria will 
be summarized analogously, using descriptive statistics for categorical variables.  
 
• Proportion of subjects with Hb values within the target range (10.0 to 11.0 g/dL, 
inclusive) at the primary evaluation period (Weeks 10 to 12) for each treatment group 
• For subjects who transitioned to TIW vadadustat dosing, mean change in Hb from 
primary evaluation period (average Hb from Weeks 10 to 12) to the secondary evaluation 
period (average Hb from Weeks 18 to 20) for each vadadustat dosing group 


 
 
 
 
 
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• Mean change in Hb between Baseline (average pretreatment Hb) and the secondary 
evaluation period (average Hb from Weeks 18 to 20) for each treatment group 
• Proportion of subjects with Hb values within the target range (10.0 to 11.0 g/dL, 
inclusive) at the secondary evaluation period (Weeks 18 to 20) for each treatment group   
• For subjects who transitioned to TIW vadadustat dosing, proportion of subjects with Hb 
values within the target range (10.0 to 11.0 g/dL, inclusive) at the secondary evaluation 
period (Weeks 18 to 20) for each vadadustat dosing group 
• Proportion of subjects with a mean increase in Hb from Baseline to the primary 
evaluation period ≥0.5 g/dL (average Hb from Weeks 10 to 12) or with Hb values within 
the target range (10.0 to 11.0 g/dL, inclusive) at the primary evaluation period (Weeks 10 
to 12) for each treatment group 
• 
Proportion of subjects with a mean increase in Hb from Baseline to the secondary 
evaluation period ≥0.5 g/dL (average Hb from Weeks 18 to 20) or with Hb values within 
the target range (10.0 to 11.0 g/dL, inclusive) at the secondary evaluation period (Weeks 
18 to 20) for each treatment group 
9.3 
Other Secondary Endpoints 
• Intravenous (IV) iron supplementation and oral iron 
The average weekly elemental iron use during the treatment period which is defined as 
first dose date to last dose date + 7 days will be calculated for weekly intervals from both 
oral and IV iron medications (Oral iron dose will be converted to elemental iron dose; the 
list will come from the medical team.). The treatment period will be divided in periods of 
7 days and for each of these periods the weekly mean of IV iron will be used using the 
following formula:  
 
Weekly iron use for each subject = Total iron in mg / [(last dose date + 7 – first 
dose date +1)/ 7] 
 
The average weekly iron use will be summarized by treatment group using descriptive 
statistics. The content of elemental iron for different kinds of IV iron is presented in 
Appendix 5. 
 
In addition, numbers and percentages of subjects with at least one administration of 
elemental iron will be summarized by treatment group. 
 
• ESA administration and RBC transfusion 
ESA medication will be considered as rescue if the ESA medication was taken between 
the first dose date to the last dose date + 7 days and the reasons for the ESA medication 
use is checked as confirmed Hb <8.5 g/dL on the CRF and the ESA medication wasn’t 
taken during the period of Eurofins ransomware attack (after Jun 20, 2019 and before  
July 9, 2019).  
 


 
 
 
 
 
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Epoetin alfa dose will be administered based on the subject’s central laboratory Hb value 
and the approved epoetin alfa US PI for adult patients with CKD on dialysis. From 
Baseline/Day 1 to Week 20, dose will be adjusted to achieve and maintain Hb levels 
within the target range of 10.0 and 11.0 g/dL, inclusive. Because epoetin 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%, ≥50% and <100%, and ≥100%. In addition to 
the investigator’s judgement of rescue, the increase in dose ≥50% or ≥100% will be 
considered as additional conditions for ESA rescue in EPO group.  
 
RBC transfusion will be considered as rescue if the RBC transfusion was taken between 
the first dose date to the last dose date + 7 days and the reasons for the RBC transfusion 
is checked as Worsening Anemia due to CKD on the CRF.  
 
The study will consider the following efficacy endpoints related to ESA administration 
and RBC transfusion.  
o Receipt of any ESA administration 
o Receipt of any ESA administration or dose with at least 50% increase for the 
EPO group  
o Receipt of any ESA administration or dose with at least 100% increase for the 
EPO group 
o Receipt of ESA administration as rescue  
o Receipt of ESA administration as rescue or dose with at least 50% increase for 
the EPO group  
o Receipt of ESA administration as rescue or dose with at least 100% increase 
for the EPO group 
o Receipt of any RBC transfusion  
o Receipt of RBC transfusion as recue  
 
Number of subjects received ESA administration (any or rescue) and RBC transfusion 
(any or rescue) will be summarized by treatment group and time period.  The following 
time periods will be summarizing: 
o Baseline visit (inclusive) to week 12 (inclusive) 
o Week 12 (exclusive) to week 20 (inclusive) 
o Baseline visit (inclusive) to week 20 (inclusive) 
 
9.4 
Exploratory Endpoints 
PPD


 
 
 
 
 
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9.4.1 Health--related quality of life (HRQOL) measure 36-Item Short-Form General 
Health Survey (SF-36v2) 
 
The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36v2) is a multi-purpose, 
short-form health survey with 36 questions (see appendix 1). It yields an 8-scale profile of 
functional health and well-being scores as well as psychometrically-based physical and mental 
health summary measures. It is a generic measure, as opposed to one that targets a specific age, 
disease, or treatment group. Accordingly, the SF-36 has proven useful in surveys of general and 
specific populations, comparing the relative burden of diseases, and in differentiating the health 
benefits produced by a wide range of different treatments. 
 
The SF-36 contains 36 items that measure eight dimensions: (1) physical functioning (PF); (2) 
role limitations due to physical health problems (RP); (3) bodily pain (BP); (4) social functioning 
(SF); (5) general health perceptions (GH); (6) role limitations due to emotional problems (RE); 
(7) vitality, energy or fatigue (VT); and (8) mental health (MH). 
 
The SF-36v2 will be scored for the 8 domains according to the standard SF-36v2 scoring 
algorithms (0 to 100 scales) explained in the SF-36v2 Manual and Interpretation Guide (Ware et 
al., 1993).  The PCS and MCS will be scored according to the standard SF-36v2 scoring 
algorithm (0 to 100 scales) explained in the SF-36v2 Physical and Mental Health Summary 
Scales Manual (Ware et al., 1994).   
 
Each of these 8 domains is consisted of several questions. Table 1 and Appendix 1 describe the 
individual item for each domain. 
 
Table 1: SF-36 8 Dimensions and Component Items 
 
Domain 
Individual Item 
Physical Functioning (PF) 
3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j 
Role-Physical (RP) 
4a, 4b, 4c, 4d 
Body Pain (BP) 
7, 8 
General Health (GH) 
1, 11a, 11b, 11c, 11d 
Vitality (VT) 
9a, 9c, 9g, 9i 
Social Function (SF) 
6, 10 
Role-Emotional (RE) 
5a, 5b, 5c 
Mental Health (MH) 
9b, 9c, 9d, 9f, 9g 
  
PPD


 
 
 
 
 
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Table 2 
Transformation of SF-36 items to a scale from 0 to 100 
Question # (Appendix 2) 
Self-perceived health 
0 (Poor) 
100 (Better) 
1, 2, 6, 8, 9a, 9d, 9e, 9h, 11b, 11d 
5 
1 
3a to 3j 
1 
3 
4a to 4d, 5a to 5c, 9b, 9c, 9f, 9g, 9i, 10, 11a, 11c 
1 
5 
7 
6 
1 
Programming note: Once transformed – the items should each span the range 0 to 100. 
 
Item scores for each dimension are coded, summed, and transformed to a scale from 0 to 100, 
with higher scores indicating better self-perceived health (See detail in Appendix 1 and 
Appendix 2). The calculation of the normalized domain scores relative to the original item 
response is presented in Appendix 3.  The score for each domain ranges from 0 to 100. 
In addition to the domain scores described above, standardized and norm-based scores are 
calculated for each domain.  The formulae are given below. 
 
Domain 
Standardization (Z-score) 
Norm-Based Score 
 
 
 
Physical functioning 
PF_Z = (PF-83.29094)/23.75883 
50+10*PF_Z 
Role-physical 
RP_Z = (RP-82.50964)/25.52028 
50+10*RP_Z 
Bodily pain 
BP_Z = (BP-71.32527)/23.66224 
50+10*BP_Z 
General health 
GH_Z = (GH-70.84570/20.97821 
50+10*GH_Z 
Vitality 
VT_Z = (VT-58.31411)/20.01923 
50+10*VT_Z 
Social functioning 
SF_Z = (SF-84.30250)/22.91921 
50+10*SF_Z 
Role-emotional 
RE_Z = (RE-87.39733)/21.43778 
50+10*RE_Z 
Mental heath 
MH_Z = (MH-74.98685)/17.75604 
50+10*MH_Z 
Note:  Standardization is based on the 1998 general United States population. 
 
SF-36 physical and mental component transformed scores are calculated using the conventions 
described below. 
 
Score 
Calculation 
Aggregate Standardized Score 
 
 
Physical component 
AGG_PHYS = (PF_Z * 0.42402) + (RP_Z * 0.35119) 
 +  (BP_Z * 0.31754) + (GH_Z * 0.24954)  
 + (VT_Z * 0.02877) + (SF_Z * -0.00753)  
 + (RE_Z * -0.19206) + (MH_Z * -0.22069) 


 
 
 
 
 
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Score 
Calculation 
Aggregate Standardized Score 
 
 
Mental component 
AGG_MENT = (PF_Z * -0.22999)  
  + (RP_Z * -0.12329) + (BP_Z * -0.09731)  
  + (GH_Z * -0.01571) + (VT_Z * 0.23534)  
  + (SF_Z * 0.26876) + (RE_Z * 0.43407)  
  + (MH_Z * 0.48581) 
Transformed Summary 
 
 
Transformed physical 
PCS = 50 + (AGG_PHYS * 10) 
 
Transformed mental 
MCS = 50 + (AGG_MENT * 10) 
 
For each of the 8 dimensions, if less than 50% of the items which constitute that dimension are 
missing, the dimension score will be calculated by the mean of the available non-missing items.  
The physical health composite summary (PCS) and mental health composite summary (MCS) 
will only be calculated if a score has been calculated for all 4 dimensions that constitute the 
composite summary.  
 
The physical component score (PCS) includes 4 domains of the SF-36: (1) physical functioning 
(PF); (2) role limitations due to physical health problems (RP); (3) bodily pain (BP) and (4) 
general health perceptions (GH); while the mental component score (MCS) includes the other 4 
domains.  The mean change in these endpoints at weeks 12, 20, and 24 will be summarized by 
treatment group with descriptive statistics. 
 
9.4.2 Patient Global Impression of Severity (PGI-S) 
The patient global impression of severity (PGI-S) includes 2 questions with the patient response 
score of 0 (no impact at all) to 10 (as bad as it can be): 
 
1. How would you rate the impact of your anemia and its treatment on how you feel? 
2. How much does the treatment you currently take for anemia help you daily activities? 
 
The change from baseline in PGI-S will be summarized by treatment group with descriptive 
statistics including the number of subjects, mean, median, standard deviation and range.  
 
9.4.3 Patient Global Impression of Change (PGI-C) 
The patient global impression of change (PGI-C) includes 1 question of “How would you 
compare the impact of your anemia and its treatment on how you feel now to when you were on 
the previous treatment (or the period your last visit)?” There are 7 patient responses for selection: 
very much worsened, much worsened, minimally worsened, no changed, minimally improved, 
much improved, and very much improved.   
 


 
 
 
 
 
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The PGI-C will be summarized with the number and percentage of subjects with response by 
treatment.  
 
9.4.4 HRQOL measure EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) 
EQ-5D-5L includes 5 questions with “Under each heading, please check the ONE that best 
describes your health TODAY”: 
1. Mobility with 5 responses:  
a. I have no problems walking 
b. I have slight problems walking 
c. I have moderate problems walking 
d. I have severe problems walking 
e. I am unable to walk 
 
2. Self-care with 5 responses:  
a. I have no problems washing or dressing myself 
b. I have slight problems washing or dressing myself 
c. I have moderate problems washing or dressing myself 
d. I have severe problems washing or dressing myself 
e. I am unable to wash or dress myself 
 
3. Usual activities with 5 responses: 
 
a. I have no problems doing my usual activities 
b. I have slight problems doing my usual activities 
c. I have moderate problems doing my usual activities 
d. I have severe problems doing my usual activities 
e. I am unable to do my usual activities 
 
4. Pain/Discomfort with 5 responses: 
 
a. I have no pain or discomfort  
b. I have slight pain or discomfort 
c. I have moderate pain or discomfort 
d. I have severe pain or discomfort 
e. I have extreme pain or discomfort 
 
5. Anxiety / Depression with 5 responses: 
 
a. I am not anxious or depressed  
b. I am slightly anxious or depressed 
c. I am moderately anxious or depressed 
d. I am severely anxious or depressed 


 
 
 
 
 
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e. I am extremely anxious or depressed 
 
EQ-5D-5L data will be summarized with the number and percentage of subjects with response 
by treatment.  
 
In addition, the last question of EQ-5D-5L include “We would like to know how good or bad 
your health is TODAY.” A 0-100 scale will be marked by each patient using “X” and as a score 
of 0-100 will be recorded by the patient 0 indicates the worst health you can imagine and 100 
indicates the best heath you can imagine. This health score of today will be summarized by 
treatment group with descriptive statistics including the number of subjects, mean, median, 
standard deviation and range.  
 
9.5 
Additional Sensitivity Analyses 
 
Due to the Eurofins Ransomware Attack, the analysis of primary endpoint with excluding 
subjects who were randomized before July 23, 2019 for vadadustat group will be provided as 
sensitivity analyses.  
For the above-mentioned efficacy endpoints, additional sensitivity analyses may be performed.  


 
 
 
 
 
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10 SAFETY ANALYSIS 
The safety analysis will be performed using the Safety Population. Safety parameters include 
adverse events, laboratory parameters, vital signs, ECG parameters, and physical examinations. 
For selected safety data, in additional, to the regular safety summary, for Weeks 12 – 20, patients 
who switched from daily vadadustat dose to TIW and patients who did not switch at Week 12 
will be summarized separately.  
10.1 Adverse Events 
Safety analyses will be descriptive in nature.  
All AEs will be coded using MedDRA version 23.0.   
 
An AE (classified by preferred term) started during the treatment period will be considered a 
treatment-emergent adverse event (TEAE) if it was not present prior to the first dose of study 
medication, or it was present prior to the first dose of study medication but increased in severity 
during the treatment period An AE that occurs more than 28 days after the last dose of study 
medication will not be counted as a TEAE. 
The number and percentage of subjects reporting TEAEs in each treatment group and each 
treatment period will be tabulated by system organ class and preferred term; by system organ 
class, preferred term, and severity; and by system organ class, preferred term, and relationship to 
study medication. If more than one event occurs with the same preferred term for the same 
patient, the patient will be counted only once for that preferred term using the most severe and 
most related occurrence for the summarization by severity and by relationship to the study 
medication.  
The distribution of TEAEs by severity and relationship to study medication will be summarized 
by SOC and PT and treatment group. AEs will also be summarized by their maximum severity. 
Summaries will also be provided for the following types of TEAEs: 
• SAEs 
• Related TEAEs, as determined by the Investigator 
• TEAEs leading to early discontinuation of study drug 
• Adverse events of special interest (AESI); AESI is defined in Appendix 4.  
 
 
10.2  Laboratory 
 
Numbers and percentage of subjects with the following category will be summarized by 
treatment: 
• Hb >12.0 g/dL,  
• Hb>13.0 g/dL,  
• Hb>14.0 g/dL 


 
 
 
 
 
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• Hb <8.0 g/dL and decline in Hb ≥0.5 g/dL from Baseline Hb (Main Study); 
• Hb <7.5 g/dL and decline in Hb ≥0.5 g/dL from Baseline Hb (ESA hyporesponder 
parallel study) 
• Hb increase >1.0 g/dL within any 2-week interval 
 
All Hb related safety endpoints will be tabulated for each treatment group. 
 
Descriptive statistics for laboratory values (in US conventional and SI units) and changes from 
baseline at each assessment time point will be presented by treatment group for the following 
laboratory parameters collected in the study including but are not limited to the following: 
 
• Hematology: Hemoglobin, hematocrit, RBC count, RDW, MCV, MCH, MCHC, WBC 
count, WBC differential, platelet counts and Reticulocyte count; 
• Chemistry: Alkaline phosphatase, ALT, AST, total bilirubin, LDH, total protein, 
albumin, glucose, phosphate, uric acid, BUN, creatinine, sodium, and potassium; 
HbA1C; 
 
Shift tables will be presented using common terminology criteria for adverse events (CTCAE) 
grade.   
 
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 
 
The following 3 data listings will be presented by subject: 
 
• A listing of lab values for all lab tests at all collected time points. 
• A listing of subjects with post-baseline (CTCAE) grade 3 or higher will be provided 
including the baseline and post-baseline values. 


 
 
 
 
 
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• A listing of all AEs for subjects with (CTCAE) grade 3 or higher including lipid profile, 
glucose, potassium, etc. will also be provided. 
 
10.3  Vital Signs 
 
Descriptive statistics for vital signs (e.g., systolic and diastolic blood pressure, heart rate, 
respiratory rate and SO2 (assessed in seated position after 5 minutes of rest and prior to blood 
draws), and dry weight and their changes from baseline at each visit and at the end of study will 
be presented by treatment group. 
 
Vital sign values are potentially clinically significant (PCS) if they meet both the observed value 
criteria and the change from baseline criteria listed in Table 2 below. The number and percentage 
of subjects with post-baseline PCS values will be tabulated by treatment group. The percentages 
are to be calculated relative to the number of subjects with baseline and at least one post-baseline 
assessment. The numerator is the total number of subjects with at least one post-baseline PCS 
vital sign value. A supportive listing of subjects with post-baseline PCS values will be provided 
including the patient ID, study center, baseline, and post-baseline values. A listing of all AEs for 
subjects with PCS vital signs will also be provided. 
 
Table 2. 
Criteria for Potentially Clinically Significant Vital Signs 
Vital Sign 
Parameter 
Flag 
Criteria* 
Observed Value 
Change from Baseline 
Systolic Blood 
Pressure (mmHg) 
High 
≥ 160 
Increase of  ≥ 20, 10 
Low 
≤   90 
Decrease of ≥ 20, 10 
Diastolic Blood 
Pressure (mmHg) 
High 
≥ 110 
Increase of ≥  20, 10  
Low 
≤   50 
Decrease of ≥ 20, 10 
Pulse Rate 
(bpm) 
High 
≥ 120 
Increase of ≥ 20 
Low 
≤   50 
Decrease of ≥ 20 
 
 
10.4 Electrocardiogram (ECG)  
 
Baseline ECG data will be presented by subject listing. 
 
10.5 Physical Examinations  
 
Baseline physical examination data will be presented by subject listing. 
 
 


 
 
 
 
 
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11 PHARMACOKINETIC/PHARMACODYNAMIC (PK/PD) ANALYSIS 
 
Pharmacokinetic (PK) parameters of Vadadustat, its O-glucuronide metabolite in Vadadustat 
treatment group and of EPO level in EPO treatment group and pharmacodynamics analyses of 
EPO level in Vadadustat treatment group will be evaluated. PK parameters will be calculated 
using SAS® program which will follow the same algorithm as that implemented in WinNonlin® 
Professional (Version 7.0, Pharsight Corporation, A Certara Company, St. Louis, MO). In 
addition, the SAS results will be validated using the parameters generated from WinNonlin 7.0. 
The baseline-adjusted and baseline-unadjusted PK parameters will be calculated for each subject 
for EPO. The baseline adjustment will use the concentration result at day 1 pre-dose timepoint. If 
any concentration is missing, the reason of the missing (e.g., lost sample; sample not collected) 
will be identified. 
 
For pharmacokinetic analysis, all values below the limit of quantification (BLQ) will be 
presented as “BLQ” in the individual concentration data listing and treated as “0” in the 
descriptive summary statistics of concentration data. Leading BLQ values prior to the first 
measurable concentration will be treated as 0 when calculating the PK parameters; embedded 
and trailing BLQ values (post Cmax) will be treated as "missing" when calculating PK parameters 
(e.g., AUClast λz). All values above the upper limit of quantification (ULOQ) will be presented as 
“ULOQ” in the individual concentration data listing and treated as “missing” in the descriptive 
summary statistics of concentration data as well as calculating the PK parameters.  
 
An exposure-response analysis of vadadustat and PD measures will be conducted as deemed 
appropriate. 
 
The vadadustat and epoetin PK parameters will include (but not limited to) the following: 
• AUClast 
• AUCinf 
• Cmax 
• Time to reach Cmax (Tmax) 
• Apparent total body clearance (CL/F) 
• Apparent volume of distribution (Vd/F) 
• Terminal half-life (t1/2) 
• Elimination rate constant (λz) 
 
The PD parameters will include (but are not limited to) the following: 
• Hb 
• EPO 
• Reticulocytes 
• Ferritin 
• TIBC 


 
 
 
 
 
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• Hepcidin 
 
PK and PD parameters will be summarized using descriptive statistics: number of 
subjects (N), mean, median, SD, minimum, maximum, and coefficient of variation, geometric 
mean and geometric mean SD. Mean plasma concentration over time 
profiles will be presented graphically. 
 
For PK parameters, the following rules will be followed when presenting the summary statistics 
and data: 
• Cmax (µg/mL) and AUC (µg*hr/mL) values will be presented for both summary tables 
and individual listings of parameters. 
• For summary tables, summary statistics including mean, median, min, max will be 
presented in 3 significant figures; while SD will have an additional figure. 
• For individual PK parameters, 6 digits of the PK concentration will be used to calculate 
the summary statistics. 
• Summary statistics for Tmax (median, min and max) will be presented using two decimal 
places. 
• When dose interrupted at the time of PK sampling, the vadadustat concentration should 
be 0 and will be excluded from analysis.  
• If PK concentration <BLQ at all the timepoints for a visit, those records will be excluded 
from analysis. 
• If Cmax and AUC values are 0, those records will be excluded from analysis. 
• PK parameter tables will be summarized with or without dose normalization.  
 
The ESA hyporesponder parallel study will be analyzed separately from the main study. 
 
Specific PD analyses for Hb and EPO will include the following: 
• Hb response as defined by Hb increments of 1 g/dL and 2 g/dL by vadadustat dose 
• EPO parameters (e.g. Cmax, AUC) by vadadustat dose, with any ESA usage, the PD 
records will be removed which happened within 5 days (IV)  usage of Epo Alfa, 5 days 
(IV) or 9 days (SC) usage of Darbe  , 30 days (IV) usage of Micera. 
 
In addition, the following parameters may be summarized: 
• Iron indices: serum Iron, ferritin, TSAT, Hepcidin 
• Serum EPO levels:  
o 24-hour profile 
o Cmax and AUC (correct/uncorrected) 
• Glucose change from baseline 
• Lipid profile;  
o Total chol 
o LDL chol 


 
 
 
 
 
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o HDL Chol 
o HDL/Total ratio 
• Inflammatory biomarkers  
o CRP 
• Other biomarker: VEGF 
 
 


 
 
 
 
 
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12 SOFTWARE AND PROGRAMMING SPECIFICATIONS 
Statistical analyses will be performed using SAS version 9.4 (or later versions).   


 
 
 
 
 
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13 REFERENCES 
Ware, J.E., Snow, K.K., Kosinski, M., & Gandek, B.  (1993).  SF-36® Health Survey Manual 
and Interpretation Guide.  Boston, MA: New England Medical Center, The Health Institute 
Ware, J.E., Kosinski, M., & Keller, S.K.  (1994).  SF-36® Physical and Mental Health Summary 
Scales: A User's Manual.  Boston, MA: The Health Institute 
 
 


 
 
 
 
 
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APPENDIX 1 
Figure 1.  SF-36 Model V2 
 


 
 
 
 
 
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APPENDIX 2: SF-36 V2 
 
 
 


 
 
 
 
 
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SF-36 v2 
 
 
 


 
 
 
 
 
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SF-36 v2 
 
 
 


 
 
 
 
 
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SF-36 v2 
 


 
 
 
 
 
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SF-36 v2 
 


 
 
 
 
 
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SF-36 v2
 


 
 
 
 
 
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APPENDIX 3. SF-36 V2 SCORING ASSIGMENT  
Scale 
Item 
Coding 
Range of Raw 
Score 
Normalized 
Score* 
Physical 
functioning 
Items 3a to 3j 
Yes, limited a lot = 1 
Yes, limited a little = 2 
No, not limited = 3 
10-30 
(S-10)/20 × 
100 
 
Role-physical  
Items 4a to 4d 
All of the time = 1 
Most of the time = 2 
Some of the time = 3 
A little of the time = 4 
None of the time = 5 
4-20 
(S-4)/16 × 100 
Bodily pain 
Item 7 
None = 6 
Very mild = 5.4 
Mild = 4.2 
Moderate = 3.1 
Severe = 2.2 
Very severe=1 
2-12 
(S-2)/10 × 100 
Item 8 if both items 
7 and 8 are 
answered 
Not at all and item7 equals 
'None' = 6 
Not at all and item7 not 
equal 'None' = 5 
A little bit = 4 
Moderately = 3 
Quite a bit = 2 
Extremely = 1 


 
 
 
 
 
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Scale 
Item 
Coding 
Range of Raw 
Score 
Normalized 
Score* 
Item 8 if item 7 is 
not answered 
Not at all = 6 
A little bit = 4.75 
Moderately =3.5 
Quite a bit = 2.25 
Extremely = 1 
General health  
Item 1 
Excellent = 5 
Very good = 4.4 
Good = 3.4 
Fair = 2 
Poor = 1 
5-25 
(S-5)/20 × 100 
Items 11a and 11c 
Definitely true = 1 
Mostly true = 2 
Don't know = 3 
Mostly false = 4 
Definitely false = 5 
Items 11b and 11d 
Definitely true = 5 
Mostly true = 4 
Don't know = 3 
Mostly false = 2 
Definitely false = 1 


 
 
 
 
 
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Scale 
Item 
Coding 
Range of Raw 
Score 
Normalized 
Score* 
Vitality 
Items 9a and 9e 
All of the time = 5 
Most of the time = 4 
Some of the time = 3 
A little of the time = 2 
None of the time = 1 
4-20 
(S-4)/16×100 
Items 9g and 9i 
All of the time = 1 
Most of the time = 2 
Some of the time = 3 
A little of the time = 4 
None of the time = 5 
Social functioning 
Item 6 
Not at all = 5 
Slightly = 4 
Moderately = 3 
Quite a bit = 2 
Extremely = 1 
2-10 
(S-2)/8 × 100 
Item 10 
All of the time = 1 
Most of the time = 2 
Some of the time = 3 
A little of the time = 4 
None of the time = 5 


 
 
 
 
 
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Scale 
Item 
Coding 
Range of Raw 
Score 
Normalized 
Score* 
Role-emotional  
Items 5a to 5c 
All of the time = 1 
Most of the time = 2 
Some of the time = 3 
A little of the time = 4 
None of the time = 5 
3-15 
(S-3)/12 × 100 
Mental health 
Items 9b, 9c and 9f 
All of the time = 1 
Most of the time = 2 
Some of the time = 3 
A little of the time = 4 
None of the time = 5 
5-25 
(S-5)/20 × 100 
Items 9d and 9h 
All of the time = 5 
Most of the time = 4 
Some of the time = 3 
A little of the time = 2 
None of the time = 1 
*S = raw score = sum of item scores after coding 
 
 


 
 
 
 
 
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APPENDIX 4. ADVERSE EVENTS OF SPECIAL INTEREST 
F.1. 
Potential risks 
The following potential risks associated with vadadustat will be presented as adverse events of 
special interest (AESI). 
• Hypersensitivity: Hypersensitivity MedDRA 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 HGLT 
• Adrenal disorder: HLT Adrenal gland disorders 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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APPENDIX 5:  ELEMENTAL IRON CONTENT IN IV IRON  
 
 
 
 
 
Commercial Name
Active ingredient
Amount of elemental iron
COSMOFER
Iron dextran
50 mg Iron (ferric) /ml
DIAFER
Iron isomaltoside
50 mg Iron (ferric) /ml
FER MYLAN
iron sucrose
100 mg iron/5 ml
FERAHEME
ferumoxytol
30 mg iron / ml
FERINGEKT
Ferric carboxymaltose
50 mg iron / ml
FERRIC HYDROXIDE SACCARATE
FERRIC HYDROXIDE SACCHARATE
20 mg iron/ml
FERRIC PYROPHOSPHATE (triferic)
FERRIC PYROPHOSPHATE
(5.44 mg of iron (III) per mL
FERRIECIT
Sodium ferric gluconate
62.5mg iron /5ml
FERROVIN
Ferric hydroxide sucrose complex
20mg/mL
INFED / IRON DEXTRAN
iron dextran complex
50 mg iron/ml
IRON POLYMALTOSE
Iron(III)hydroxide-polymaltose
100 mg iron/2ml
MONOVER
Iron(III) isomaltoside 1000
100 mg iron/ml
Venofer
iron sucrose
20 mg/mL