Clinical trial NCT04313153
Conditions: Anemia
Keywords: vadadustat hemodialysis erythropoiesis-stimulating agents darbepoetin alfa CKD Anemia
Sponsor: Akebia Therapeutics
Start date: 2020-05-27; Completion date: 2022-06-22
Enrollment: 319 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial will be conducted to demonstrate the efficacy and safety of vadadustat compared to darbepoetin alfa for the maintenance treatment of anemia in hemodialysis participants after conversion from current erythropoiesis-stimulating agent (ESA) therapy.

Detailed description:
This study consists of three periods:

1. Screening Period
2. Conversion and Maintenance Treatment Period
3. Safety Follow-up Period

Individual participants will participate in total trial duration of approximately 64 weeks.

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Vadadustat intervention 2: Darbepoetin alfa
Intervention descriptions: intervention 1: oral tablets intervention 2: intravenous or subcutaneous solution

Protocol documents:
Prot_000.pdf: 
Otsuka Pharmaceutical
Development & Commercialization, Inc.
Investigational Medicinal Product
Vadadustat
REVISED CLINICAL PROTOCOL
Phase 3b, Randomized, Open-label, Active-controlled Trial Evaluating the Efficacy and 
Safety of Oral Vadadustat Once Daily (QD) and Three Times Weekly (TIW) for the 
Maintenance Treatment of Anemia in Hemodialysis Subjects Converting from 
Erythropoiesis-Stimulating Agents (ESAs)
Protocol No. 404-201-00012
IND No. 102,465
EudraCT No. 2019-004851-36
CONFIDENTIAL  PROPRIETARY INFORMATION
Drug Development Phase:
3b
Sponsor:
Otsuka Pharmaceutical Development &
Commercialization, Inc. (OPDC)
2440 Research Boulevard
Rockville, Maryland 20850, United States
Sponsor Representatives:
 Global Clinical Development
 Global Clinical Development
Phone: 
Director, Clinical Management
 Clinical Management
Phone: 
Reporting Adverse Events: 
Reported via electronic data capture (EDC)
If EDC is unavailable, send paper Serious 
Adverse Event (SAE) Form, Pregnancy 
Form or Special Situations Form to: 
IQVIA™
Safety Mailbox: 
Amendment 1 Approval:
17 Mar 2021
Original Approval:
17 Jan 2020
NCT Number: NCT04313153
This NCT number has been applied to the document for purposes of posting on Clinicaltrials.gov
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Table of Contents
Table of Contents ..........................................................................................2
List of In-text Tables.....................................................................................8
List of In-text Figures ...................................................................................9
1
Protocol Summary .............................................................................10
1.1
Synopsis ............................................................................................................10
1.2
Schema ..............................................................................................................20
1.3
Schedule of Assessments ..................................................................................21
2
Introduction........................................................................................24
2.1
Background Information ...................................................................................24
2.2
Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors ................................25
2.3
Summary of Clinical Experience ......................................................................25
2.4
Known and Potential Risks and Benefits..........................................................28
2.5
Trial Rationale...................................................................................................29
3
Objectives and Endpoints..................................................................30
4
Trial Design.........................................................................................31
4.1
Type/Design of Trial.........................................................................................31
4.2
Scientific Rationale for Trial Design ................................................................33
4.3
Dosing Rationale...............................................................................................35
4.4
End of Trial Definition......................................................................................37
4.5
Definition of Completed Subjects.....................................................................37
5
Trial Population .................................................................................37
5.1
Subject Selection and Numbering.....................................................................38
5.2
Eligibility Criteria .............................................................................................38
5.2.1
Inclusion Criteria............................................................................................38
5.2.2
Exclusion Criteria...........................................................................................38
5.3
Lifestyle Considerations....................................................................................40
5.3.1
Meals and Dietary Restrictions ......................................................................40
5.3.2
Caffeine, Alcohol, and Tobacco.....................................................................40
5.3.3
Activity...........................................................................................................40
5.4
Screen Failures..................................................................................................41


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5.4.1
Retesting and Rescreening .............................................................................41
6
Trial Treatments ................................................................................42
6.1
Trial Treatments Administered .........................................................................42
6.1.1
Dosing and Dose Adjustment Guidelines.......................................................42
6.1.1.1
ESA Equivalent Dose Calculation..............................................................42
6.1.1.2
Dose Adjustment Algorithm.......................................................................42
6.1.1.3
Vadadustat Dosing......................................................................................43
6.1.1.4
Darbepoetin Alfa Dosing ............................................................................44
6.1.2
Dialysis Treatment and Renal Replacement Therapy ....................................44
6.1.3
Late or Missed Doses .....................................................................................44
6.2
Management of Investigational Medicinal Product ..........................................45
6.2.1
Packaging and Labeling .................................................................................45
6.2.2
Storage............................................................................................................46
6.2.3
Accountability ................................................................................................46
6.2.4
Returns and Destruction .................................................................................47
6.3
Measures to Minimize/Avoid Bias....................................................................47
6.3.1
Randomization................................................................................................47
6.3.2
Blinding ..........................................................................................................48
6.4
Subject Compliance ..........................................................................................49
6.5
Concomitant Medications or Therapies ............................................................49
6.5.1
Prohibited Medications...................................................................................49
6.5.1.1
Erythropoiesis-stimulating Agents..............................................................49
6.5.1.2
Sulfasalazine and Other BCRP Substrates and Probenecid........................50
6.5.2
Permitted Medications....................................................................................50
6.5.2.1
Iron Supplementation..................................................................................50
6.5.2.2
Phosphate Binders.......................................................................................50
6.5.2.3
HMG-CoA Reductase Inhibitors (Statins)..................................................50
6.5.3
Rescue Medications........................................................................................52
6.5.3.1
RBC Transfusion ........................................................................................52
6.5.3.2
ESA Use......................................................................................................52
6.5.3.3
Phlebotomy (Optional)................................................................................53
6.6
Intervention after the End of the Trial...............................................................53


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Stopping Rules, Withdrawal Criteria, and Procedures..................53
7.1
Entire Trial or Treatment ..................................................................................53
7.1.1
Criteria for Premature Termination or Suspension of the Trial .....................54
7.2
Individual Site ...................................................................................................55
7.3
Individual Subject Discontinuation...................................................................55
7.3.1
Treatment Interruption....................................................................................56
7.3.2
Treatment Discontinuation .............................................................................57
7.3.3
Documenting Reasons for Treatment Interruption or Discontinuation..........58
7.3.4
Withdrawal of Consent...................................................................................58
7.4
Definition of Subjects Lost to Follow-up..........................................................58
8
Trial Procedures.................................................................................59
8.1
Subject Reported Outcome Assessments..........................................................61
8.1.1
36-Item Short Form Health-related Quality of Life .......................................61
8.1.2
Patient Global Impression of Severity Life....................................................61
8.1.3
Patient Global Impression of Change.............................................................62
8.1.4
Functional Assessment of Cancer Therapy-Anemia ......................................62
8.2
Pharmacokinetic Assessments ..........................................................................62
8.3
Pharmacodynamic Assessments........................................................................63
8.7
Safety Assessments ...........................................................................................64
8.7.1
Clinical Laboratory Assessments ...................................................................64
8.7.2
Medical History, Demographics, and Physical Examination.........................65
8.7.3
Concomitant Medication Recording...............................................................65
8.7.4
Vital Signs ......................................................................................................65
8.7.5
Electrocardiogram ..........................................................................................66
8.7.6
Other Safety Variables ...................................................................................66
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8.7.6.1
Major Adverse Cardiovascular Events .......................................................66
8.8
Adverse Events..................................................................................................66
8.8.1
Definitions ......................................................................................................67
8.8.2
Eliciting and Reporting Adverse Events ........................................................70
8.8.2.1
Guidelines for Reporting Adverse Events ..................................................71
8.8.2.2
Reporting Serious Adverse Events .............................................................73
8.8.3
Procedure for Breaking the Blind...................................................................74
8.8.4
Follow-up of Adverse Events.........................................................................74
8.8.4.1
Follow-up of Nonserious Adverse Events..................................................75
8.9
Treatment of Overdose......................................................................................75
8.10
Subject Assessment Recording .........................................................................75
8.11
Other Assessments ............................................................................................76
8.11.1
Dialysis Adequacy and Treatment..................................................................76
9
Statistical Considerations..................................................................76
9.1
Sample Size.......................................................................................................76
9.2
Datasets for Analysis.........................................................................................77
9.3
Handling of Missing Data for Primary and Secondary Endpoint Analysis ......77
9.4
Statistical Analyses ...........................................................................................77
9.4.1
Efficacy Analyses...........................................................................................77
9.4.1.1
Primary Efficacy Endpoint Analysis ..........................................................78
9.4.1.1.1
Primary Estimand....................................................................................78
9.4.1.1.2
Primary Analysis of Primary Efficacy Endpoint.....................................78
9.4.1.1.3
Sensitivity Analyses of Primary Efficacy Endpoint Screening...............79
9.4.1.1.4
Analyses of Primary Efficacy Endpoint When All Randomized 
Subjects Complete Week 26 ...................................................................79
9.4.1.2
Key Secondary Efficacy Endpoint Analysis...............................................79
9.4.1.3
Other Efficacy Endpoint Analysis ..............................................................79
9.4.1.4
Subgroups ...................................................................................................79
9.4.2
Safety Analysis...............................................................................................80
9.4.2.1
Adverse Events ...........................................................................................80
9.4.2.2
Remaining Safety Endpoints.......................................................................81
9.4.3
Other Analyses ...............................................................................................81
9.4.3.1
Disposition of Subjects ...............................................................................81


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9.4.3.2
Analysis of Demographic and Baseline Characteristics .............................81
9.4.3.3
Concomitant Medications...........................................................................82
9.4.3.4
Pharmacokinetic Analysis...........................................................................82
9.4.3.5
Pharmacodynamic Analysis........................................................................82
9.4.3.6
Pharmacogenomic Analysis........................................................................82
9.4.3.7
Future Biospecimen Research Analysis......................................................82
9.4.3.8
Exploratory Endpoint Analysis...................................................................82
9.5
Data Monitoring, Safety Event Adjudication, and Independent Expert 
Panel Committees..............................................................................................82
10
Supporting Documentation and Operational Considerations .......84
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations ............84
10.1.1
Ethics and Responsibility ...............................................................................84
10.1.2
Institutional Review Board/Independent Ethics Committee ..........................84
10.1.3
Informed Consent ...........................................................................................85
10.1.4
Confidentiality................................................................................................85
10.1.5
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ................................................................................................................86
10.1.6
Quality Control and Quality Assurance .........................................................86
10.1.6.1
Monitoring ..................................................................................................86
10.1.6.2
Auditing ......................................................................................................86
10.1.7
Protocol Deviations ........................................................................................87
10.1.8
Records Management .....................................................................................87
10.1.8.1
Source Documents ......................................................................................87
10.1.8.2
Data Collection ...........................................................................................88
10.1.8.3
File Management at the Trial Site...............................................................88
10.1.8.4
Records Retention at the Trial Site .............................................................89
10.1.8.5
Publication of Trial Results ........................................................................89
10.1.8.5.1
Publication Authorship Requirements ....................................................90
10.2
Appendix 2: Clinical Laboratory Tests.............................................................91
10.3
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information........................................................................................................93
10.4
Appendix 4: Abbreviations ...............................................................................96
10.5
Appendix 5: Institutions Concerned with the Trial...........................................99


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10.6
Appendix 6: Protocol Amendments................................................................100
10.6.1
Protocol Amendment(s)/Administrative Change(s).....................................101
10.6.1.1
Protocol Amendment 1 .............................................................................101
11
References.........................................................................................107


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List of In-text Tables
Table 1.3-1
Schedule of Assessments...............................................................21
Table 3-1
Trial Objectives and Endpoints .....................................................30
Table 6.1.1.2-1
Guidelines for Dose Adjustment ...................................................43
Table 6.5.2.3-1
Results and Management of Concomitant Administration of 
Vadadustat with Statins .................................................................52
Table 7.3.2-1
Trial Medication Stopping Rules...................................................57
Table 8.2-1
Vadadustat Pharmacokinetic Sampling Schema ...........................62
Table 10.2-1
Clinical Laboratory Assessments ..................................................91
Table 10.6.1.1-1
General Revisions for Protocol Amendment 1............................102


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List of In-text Figures
Figure 1.2-1
Trial Design Schematic..................................................................20


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1
Protocol Summary
1.1
Synopsis
Name of Sponsor:
Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC)
Name of Investigational Medicinal Product:
Vadadustat
Protocol No.:
404-201-00012
IND No.:
102,465
EudraCT No.:
2019-004851-36
Protocol Title:
Phase 3b, Randomized, Open-label, Active-controlled Trial Evaluating the Efficacy and 
Safety of Oral Vadadustat Once Daily (QD) and Three Times Weekly (TIW) for the 
Maintenance Treatment of Anemia in Hemodialysis Subjects Converting from 
Erythropoiesis-stimulating Agents (ESAs)
Clinical Phase:
3b
Treatment/Indication:
Anemia of chronic kidney disease (CKD)
Objectives and Endpoints:
The primary objective of the trial is to demonstrate the efficacy and safety of vadadustat 
compared to darbepoetin alfa for the maintenance treatment of anemia in hemodialysis 
subjects after conversion from current ESA therapy.
Primary efficacy endpoints of the trial include efficacy parameters for change in 
hemoglobin (Hb) between Baseline (average pretreatment Hb) and the primary evaluation 
period (average Hb from Weeks 20 to 26, inclusive).


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Key secondary efficacy endpoints of the trial include efficacy parameters for change in 
Hb value between Baseline (average pretreatment Hb) and the secondary evaluation 
period (average Hb from Weeks 46 to 52).
Other efficacy endpoints of the trial include the following:

Proportion of subjects having average Hb values within the target range during the 
primary evaluation period (Weeks 20 to 26).

Proportion of subjects having average Hb values within the target range during the 
secondary evaluation period (Weeks 46 to 52).

Proportion of subjects receiving intravenous (IV) iron therapy from Baseline to 
Week 52.

Average monthly dose of IV elemental iron administered from Baseline to Week 52 
in subjects who have received IV elemental iron.

Receipt of ESA rescue.

Proportion of subjects receiving red blood cell (RBC) transfusions from Baseline to 
Week 26.

Proportion of subjects receiving RBC transfusions from Baseline to Week 52.

Change from Screening Visit 2 36-Item Short Form (SF-36v2) Health-related Quality 
of Life (HRQOL) scores.

Change from Screening Visit 2 to the average value in Anemia Subscale ("Additional 
Concerns") of Functional Assessment of Cancer Therapy-Anemia (FACT-An) Score.

Change from Screening Visit 2 to the average value in Total FACT-An Score.

Change from Screening Visit 2 in score of Patient Global Impression of Severity 
(PGI-S).

Score of Patient Global Impression of Change (PGI-C).
Safety endpoints of the trial include adverse events (AEs) and serious adverse events 
(SAEs), vital sign measurements, electrocardiograms (ECGs) and clinical laboratory 
values, episodes of Hb > 12.0 g/dL, > 13.0 g/dL, or > 14.0 g/dL, and the number of 
episodes of Hb increase > 1.0 g/dL within any 2-week interval or > 2.0 g/dL within any 
4-week interval.
Pharmacokinetic (PK): no PK analysis will be conducted. Vadadustat plasma 
concentrations may be included in a population PK analysis reported separately. 
Pharmacodynamic (PD) endpoints of the trial include parameters erythropoietin (EPO), 
reticulocytes, and markers of iron metabolism (iron, ferritin, total iron binding capacity 
[TIBC], etc.). 
 
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Trial Design:
Phase 3b, randomized, open-label, active-controlled trial of vadadustat versus 
darbepoetin alfa for the maintenance treatment of anemia in hemodialysis subjects, after 
conversion from ESA therapy.
Following a Screening period of up to 8 weeks (56 days), subjects who meet all eligibility 
criteria will be randomized 1:1:1 to vadadustat QD, vadadustat TIW, or darbepoetin alfa. 
Target enrollment in this trial is an estimated 300 subjects at up to 150 investigative sites 
in the United States (US) and Europe.
Subjects will be randomized at the Baseline Visit using an Interactive Web Response 
(IWR) system to receive either vadadustat QD, vadadustat TIW, or darbepoetin alfa.
Randomization will be stratified with respect to:

Geographic region (US versus Europe, approximately 90 subjects in Europe).

Mean weekly darbepoetin alfa dose (or ESA equivalent) calculated over a period of 
8 weeks prior to Screening Visit 2:

Low darbepoetin alfa dose group (≤ 0.45 µg/kg/week).

High darbepoetin alfa dose group (> 0.45 and ≤ 1.5 µg/kg/week).
In each stratum, there will be 3 arms: vadadustat QD, vadadustat TIW, and darbepoetin 
alfa.
Following screening and randomization, there will be 2 periods during the trial:

Conversion and Maintenance Treatment Period (Weeks 0 to 52): conversion to 
investigational medicinal product (IMP) for maintaining Hb (Weeks 0 to 20), primary 
efficacy evaluation (Weeks 20 to 26), and secondary efficacy evaluation (Weeks 46 
to 52).

Safety Follow-up Period (Early Termination [ET] and Follow-up): post-treatment 
Safety Follow-up Visit (ET/End of Treatment [EOT] + 4 weeks) (in person).
Individual subjects will participate in total trial duration of approximately 64 weeks.
A structured exit interview may be conducted at the EOT Visit at a subset of sites.
Trial Population:
An estimated 300 subjects with approximately:

100 subjects randomized to vadadustat QD arm.

100 subjects randomized to vadadustat TIW arm.

100 subjects randomized to darbepoetin alfa arm.


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The trial population will consist of subjects ≥ 18 years of age receiving chronic, 
outpatient in-center hemodialysis TIW, with 2 screening Hb values between 8.0 and 
11.0 g/dL (inclusive) in the US or between 9.0 and 12.0 g/dL (inclusive) in Europe, and 
on maintenance treatment with an ESA.
Inclusion Criteria:
Subjects are required to meet the following inclusion criteria:
1) ≥ 18 years of age.
2) Receiving chronic, outpatient TIW hemodialysis for end-stage renal disease for 
at least 12 weeks prior to Screening.
3) 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.
4) Use of any approved ESA for at least the 8 weeks prior to Screening Visit 2.
5) Two Hb values, at least 4 days apart, measured by the central laboratory during 
Screening within the following prespecified ranges:
a) Hb values between 8.0 and 11.0 g/dL (inclusive) in the US.
b) Hb values between 9.0 and 12.0 g/dL (inclusive) in Europe.
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.
Exclusion Criteria:
Subjects will be excluded if they meet any of the following exclusion criteria:
1) Women of childbearing potential (WOCBP) who do not agree to practice 
2 different methods of birth control or remain abstinent during the trial and for 
30 days after the last dose of IMP. If employing birth control, 2 of the following 
precautions must be used: vasectomy of partner, tubal ligation, vaginal 
diaphragm, or intrauterine device.
2) 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.
3) Women who are breast feeding and/or who have a positive pregnancy test result 
prior to receiving IMP.
4) Subjects with contraindication to required trial assessment.
5) Subjects who, is in opinion of the investigator or medical monitor, have a medical 
history or medical findings inconsistent with safety or trial compliance.


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6) Anemia due to a cause other than CKD (eg, sickle cell disease, myelodysplastic 
syndromes, bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic 
anemia, thalassemia, or pure red cell aplasia).
7) Subjects meeting cut-off of the following equivalent mean weekly doses 
calculated over 8 weeks prior to Screening Visit 2:
a) Methoxy polyethylene glycol-epoetin beta > 50 µg/week.
b) Darbepoetin alfa > 100 µg/week.
c) Epoetin analogues > 23000 IU/week.
8) Active bleeding or recent blood loss within 8 weeks prior to randomization.
9) Red blood cell transfusion within 8 weeks prior to randomization.
10) Anticipated to discontinue hemodialysis during the trial.
11) Judged by the investigator that the subject is likely to need rescue therapy (ESA 
administration or RBC transfusion) immediately after enrollment in the trial.
12) History of chronic liver disease (eg, chronic infectious hepatitis, chronic 
autoimmune liver disease, cirrhosis, or fibrosis of the liver).
13) 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.
14) Current uncontrolled hypertension as determined by the investigator that would 
contraindicate the use of an ESA.
15) 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.
16) 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.
17) History of a new or recurrent episode of deep vein thrombosis or pulmonary 
embolism within 12 weeks prior to or during Screening.
18) History of hemosiderosis or hemochromatosis.
19) History of prior organ transplantation (subjects with a history of failed kidney 
transplant or corneal transplants are not excluded).
20) 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. 
21) History of a prior hematopoietic stem cell or bone marrow transplant (stem cell 
therapy for knee arthritis is not excluded).
22) Known hypersensitivity to vadadustat, darbepoetin alfa, or any of their excipients.


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23) Use of an investigational medication within 30 days or 5 half-lives of the 
investigational medication (whichever is longer), prior to screening or during 
screening and any prior use of a hypoxia-inducible factor prolyl hydroxylase 
inhibitor. Subjects may participate in another concurrent trial only if that trial is a 
non-interventional, observational investigation.
24) Subjects with bilateral native nephrectomy.
25) Treated with probenecid within the 28-day Screening Period prior to 
randomization or during the study treatment duration.
26) Any other reason, which in the opinion of the investigator, would make the 
subject not suitable for participation in the trial.
Retesting/Rescreening
Subjects who initially fail to qualify for the trial based on laboratory test results may have 
any individual laboratory parameter retested 1 time within the 8-week Screening period at 
the discretion of the investigator. Retesting within the 8-week Screening period does not 
constitute rescreening; however, if retesting falls outside of the 8-week Screening period, 
it should be considered a rescreen. All screening laboratories, including any repeat 
measurements, must be performed within the 8-week Screening window with a minimum 
of 4 days between the last qualifying repeat measurement and the Baseline Visit.
Subjects who fail to qualify for the trial 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 trial. Each screening attempt 
includes the potential of a retest. Additionally, subjects who fail to qualify for the trial 
based on inclusion criteria values for TSAT, ferritin, folate, or B12 values may be 
considered for rescreening after receiving replacement therapy. A minimum of 3 weeks 
from IV iron replacement therapy (for low TSAT and ferritin values) must be observed 
prior to collecting next trial visit Hb value.
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. 
Trial Sites:
Targeting up to 150 investigative sites in the US and Europe.
Investigational Medicinal Product(s), Dose, Dosage Regimen, Treatment Duration, 
Formulation, Mode of Administration:
Vadadustat will be provided as 150 and 450 mg tablets, to be taken orally. Darbepoetin 
alfa will be dispensed as a solution in single-dose prefilled syringes, to be given by IV 
injection through dialysis vascular access.


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Subjects will be randomized 1:1:1 to vadadustat QD or vadadustat TIW or darbepoetin 
alfa.
Randomization will be stratified by mean weekly darbepoetin alfa dose (or equivalent) 
calculated over a period of 8 weeks prior to Screening Visit 2: 
Low darbepoetin alfa dose group (≤ 0.45 µg/kg/week) or
High darbepoetin alfa dose group (> 0.45 and ≤ 1.5 µg/kg/week)

In the low darbepoetin alfa dose group, subjects will be randomized in a 1:1:1 ratio to 
receive either an initial vadadustat daily dose of 300 mg daily or 600 mg TIW, or 
darbepoetin alfa.

In the high darbepoetin alfa dose group, subjects will be randomized in a 1:1:1 ratio 
to receive either an initial vadadustat daily dose of 450 mg daily, 750 mg TIW, or 
darbepoetin alfa.
Refer to the trial-specific Dosing Guideline for instructions on ESA medications 
conversion to an equivalent darbepoetin alfa dose for stratification and randomization.
Dosing will be initiated at the Baseline/Day 1 Visit and the first dose of vadadustat will 
be administered at the trial site after other Baseline/Day 1 procedures have been 
completed. Thereafter, vadadustat will be taken QD or TIW (on dialysis days) on an 
outpatient basis. Subjects may take vadadustat with or without food and should be 
instructed to swallow the tablet(s) whole, without chewing. Subjects will be instructed to 
take vadadustat at roughly the same time each day. Darbepoetin alfa will be initiated at 
Baseline/Day 1. For subjects who were receiving darbepoetin alfa during screening and 
randomized to the darbepoetin alfa arm, the initial dosing regimen in the trial (starting 
from Baseline/Day 1) will be approximately the same weekly dose that subjects were 
receiving prior to randomization. For subjects receiving darbepoetin alfa for the first 
time, the initial dosing regimen (starting from Baseline/Day 1) will be determined by the 
US Package Insert (USPI) or European Union (EU) Summary of Product Characteristics 
(SmPC), per the medical judgment of the investigator. Dose adjustments will be guided 
by the USPI or EU SmPC (Section 6.1.1.4).
For all subjects, it is recommended that no additional ESA doses be administered after 
Screening Visit 2 and prior to the Baseline Visit (Day 1).
For all subjects, it is required that a minimum period as outlined below be observed 
between the last dose of ESA administered during Screening and Randomization Visit: 

2 days after last dose of epoetin analogues.

7 days after last dose of darbepoetin alfa.


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
14 days after last dose of methoxy polyethylene glycol-epoetin beta.
After discussion with the Medical Monitor, screening may be extended for an additional 
2 to 4 weeks based on the subject’s Hb level or Hb trajectory or based on timing of the 
last ESA dose given during screening.
Dose Adjustment
Vadadustat dose adjustments will be guided by Hb concentrations and the Guidelines for 
Dose Adjustment.
Darbepoetin alfa dose adjustments are based on the USPI or EU SmPC per the medical 
judgment of the investigator, incorporating the Guidelines for Dose Adjustment as well 
as the subject’s current Hb level, trajectory, and variability; symptoms; cardiovascular 
risk; and other features of his/her clinical condition(s).
Hemoglobin will be monitored via central laboratory throughout the trial to determine if 
the dose of IMP (vadadustat or darbepoetin alfa) will be adjusted, interrupted, or 
maintained as per the Guidelines for Dose Adjustment as follows:
Guideline for Dose Adjustment
Status of Hb Levels
Dose Adjustmenta
Hb levels are to be maintained in the following target 
ranges:
US only: 10.0 to 11.0 g/dL, inclusive.
Europe only: 10.0 to 12.0 g/dL, inclusive.
A dose increase or decrease is required to 
achieve and maintain Hb levels within the 
target range. Dose is adjusted by 1 dose level 
(for vadadustat 1 tablet [150 mg], for 
darbepoetin alfa approximately 25%)
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 ESA) and if Hb is < 10.0 g/dL.
A subject’s dose may be increased by 1 dose 
level.
A rapid rise in Hb is observed (defined as follows):
> 1.0 g/dL in any 2-week period or 
> 2.0 g/dL in any 4-week period.
Reduce or interrupt the dose.b
Hb levels are in the following setting:
US only: Hb > 11.0 g/dL.
Europe only: > 12.0 g/dL.
Reduce or interrupt the dose. After Hb falls 
below 11.0 g/dL (US) or 12.0 g/dL (Europe), 
restart IMP and consider restarting at a lower 
dose.
aIn 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 one occasion. Dose adjustment should be based on the investigator’s 
clinical discretion.
bSee Section 7.3.1 (Treatment Interruption).
The minimum dose of vadadustat will be 150 mg daily and the maximum dose will be 
900 mg QD or 1200 mg TIW.


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Trial Assessments:
Assessments for subject reported outcomes: The SF-36v2 HRQOL, PGI-S, PGI-C, and 
FACT-An.
Assessments for PK: Plasma samples for PK evaluation will be collected only for 
subjects randomized to vadadustat to analyze for both the parent compound (vadadustat) 
and its metabolites. Collection time points for PK will include Week 12 Visit at predose 
and 0.5, 1, 2, and 3 hours postdose.
Assessments for PD: Blood samples for EPO, reticulocytes, and other iron indices 
(ferritin, iron, TIBC, and TSAT) will be obtained.
 
Assessments for Safety: AEs and SAEs, clinical laboratory tests, medical history, 
demographic information, physical examination findings including dry weight, 
concomitant medication recording, vital signs, ECG, major adverse cardiovascular events 
(MACE), RBC transfusions, ESA rescue, and therapeutic phlebotomy.
 
Statistical Methods:
For the primary efficacy analysis, it will be assumed that the difference in mean change 
from Baseline in Hb for vadadustat will be the same as the active control, darbepoetin 
alfa, and the common standard deviation for the mean change from Baseline will be 
assumed to be 1.2 g/dL. The noninferiority margin of -0.75 g/dL will be used (for 
vadadustat minus darbepoetin alfa). With these assumptions and approximately 
100 subjects per treatment group, the noninferiority test will have > 90% power with 
consideration of 30% drop out rate.
Primary Efficacy Endpoint Analysis
The primary efficacy endpoint is defined as the Hb change from Baseline (average 
pretreatment Hb) to the average Hb from Weeks 20 to 26 (inclusive).
The primary analysis of the primary endpoint will use the randomized population with an 
analysis of covariance, with randomization stratification factors and Baseline Hb as 
covariates.
A 2-sided, 95% confidence interval (CI) will be calculated for the difference in mean 
change in Hb from Baseline to the primary evaluation period between the vadadustat 
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group and darbepoetin alfa control group. Noninferiority of vadadustat will be established 
if the lower limit of this CI is ≥ -0.75 g/dL.
A hierarchical testing scheme will be used to correct for the multiplicity of the 2 primary 
endpoints: comparison between vadadustat QD vs. darbepoetin alfa and comparison 
between vadadustat TIW vs. darbepoetin alfa.

Step 1: comparison between vadadustat QD vs. darbepoetin alfa

If the noninferiority of vadadustat is established in step 1, then move to the step 2;

Step 2: comparison between vadadustat TIW vs. darbepoetin alfa
Blinded summary safety data will be provided for all subjects who had the opportunity to 
complete the Week 12 Visit by a cut-off date, with the cut-off date to be determined at a 
later date to support potential regulatory filing.
Trial Duration:
Each subject in this trial is expected to participate in the following periods of the trial 
(approximate durations listed):

Two Screening Visits (Screening Visit 1 and Screening Visit 2) (Weeks -8 to 0)

Baseline/Randomization Visit (Week 0/Day 1)

Treatment Period (Conversion and Maintenance) Trial Visits/Evaluations while 
receiving IMP: Weeks 2, 4, 6, 8, 10, 12, (± 3 days) 16, 20, 24, (± 5 days), 26 (± 3 
days), 30, 34, 38, 42, 46, 50, (± 5 days) 52/EOT (± 3 days).

ET Visit (+ 7 days)

Follow-up Visit/EOT (4 weeks after the ET [+ 7 days] visit).

Unscheduled visit(s)
Trial Completion: The trial will be considered completed after all randomized subjects 
have completed their final trial visit (ET, Week 52/EOT, or Safety Follow-up). 
Subject Completion: A subject will be considered as having completed the trial after 
completion of their final trial visit (ET or Week 52/EOT). Safety Follow-up Visit data 
summarization and analysis will be performed separately.
The trial duration for an individual subject from the time the informed consent form 
(ICF) is signed to the final subject assessment is expected to be approximately 64 weeks.


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1.2
Schema
n = number of subjects; QD = once daily; TIW = three times weekly
Figure 1.2-1
Trial Design Schematic


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1.3
Schedule of Assessments
Table 1.3-1
Schedule of Assessments 
Trial Period
Screening
Treatment (Conversion and Maintenance)
Safety Follow-
up
Visit Type
SV1
SV2
BL
Primary Efficacy 
Evaluation
Secondary Efficacy 
Evaluation
Follow-
up
Week
-8 to 0
0
2
4
6
8
10
12
16
20
24
26
30
34
38
42
46
50
52/
EOT
ET
ET/EOT
+4 weeks
Visit Window (Days)
± 3
± 5
± 3
± 5
± 3
+ 7
Procedures/Assessments
Informed Consent
X
I/E Criteria
X
X
X
Vital signs [a]
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Actual Dry Weight After 
Dialysis
X
X
X
X
X
X
Demographics, Medical History
X
Physical Exam [b]
X
X
X
12-Lead ECG [c]
X
X
X
Randomization
X
SF-36v2 HRQOL
X
X
X
X
X
FACT-An 
X
X
X
X
X
PGI-S
X
X
X
X
X
PGI-C
X
X
X
X
Exit interviews [d]
X
Laboratory Procedures (note: the procedures grayed out and bolded can be retested)
Pregnancy Test [e]
X
Folate and Vitamin B12[f]
X 
C-Reactive Protein
X
X
X
X
CBC without diff
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CBC with diff [g]
X
X
X
Iron Indices [h,f]
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Chemistry [i,f]
X 
X
X
X
X
Liver Function Tests [j,f]
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipid Panel [k]
X
X
X
X
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Trial Period
Screening
Treatment (Conversion and Maintenance)
Safety Follow-
up
Visit Type
SV1
SV2
BL
Primary Efficacy 
Evaluation
Secondary Efficacy 
Evaluation
Follow-
up
Week
-8 to 0
0
2
4
6
8
10
12
16
20
24
26
30
34
38
42
46
50
52/
EOT
ET
ET/EOT
+4 weeks
Visit Window (Days)
± 3
± 5
± 3
± 5
± 3
+ 7
Reticulocyte Count
X
X
X
X
X
X
Erythropoietin
X
X
X
X
X
X
Dialysis adequacy
X
X
To be reported every 3 months
Safety Assessments
MACE Assessment 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
RBC Transfusions and ESA 
Rescue 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Therapeutic Phlebotomy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medication Assessments and Procedures
Concomitant Medicine Review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vadadustat/Darbepoetin alfa 
Medication Dispensing [n]
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vadadustat Medication Dosing
Daily or TIW dosing (see Section 6)
Darbepoetin alfa Dosing
Dosing according to USPI or EU SmPC
PK Sampling
PK Evaluation (Vadadustat 
dosing arms only)
X
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BL = baseline; CBC = complete blood count; ECG = electrocardiogram; EOT = end-of-treatment; 
ESA = erythropoiesis-stimulating agent; ET = early termination; FACT-An = Functional Assessment of Cancer Therapy-Anemia; 
 Hb = hemoglobin; HDL = high 
density lipoprotein; HRQOL = Health-related Quality of Life; I/E = inclusion/exclusion; LDH = lactate dehydrogenase; LDL = low density lipoprotein; MACE = major adverse cardiovascular event; 
PGI-C = Patient Global Impression of Change; PGI-S = Patient Global Impression of Severity; 
 PK = pharmacokinetic; RBC = red blood cell; SF-36v2 = 36-Item Short-
Form; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; SV1 = Screening Visit 1; SV2 = Screening Visit 2; TIBC = total iron binding capacity; 
TIW = three times per week; TSAT = transferrin saturation; US = United States; 
[a]
Vital signs to be assessed in the seated position after 5 minutes of rest before dialysis occurs.
[b]
During the Treatment period, an abbreviated physical examination should be performed at the discretion of the investigator, as clinically indicated.
[c]
An ECG should be performed prior to serum chemistry blood draw when possible and obtained after the subject has been resting for approximately 5 minutes. The clinical evaluations should be 
completed before dialysis occurs. ECGs may be measured up to 3 days before BL.
[d]
A structured exit interview may be conducted at the EOT Visit at a subset of sites.
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Trial Period
Screening
Treatment (Conversion and Maintenance)
Safety Follow-
up
Visit Type
SV1
SV2
BL
Primary Efficacy 
Evaluation
Secondary Efficacy 
Evaluation
Follow-
up
Week
-8 to 0
0
2
4
6
8
10
12
16
20
24
26
30
34
38
42
46
50
52/
EOT
ET
ET/EOT
+4 weeks
Visit Window (Days)
± 3
± 5
± 3
± 5
± 3
+ 7
[e] Serum pregnancy will be tested in women of childbearing potential at SV2. Additional serum or local urine pregnancy tests should be conducted throughout the trial in sufficient number, as 
determined by the investigator or required by local regulations, to establish the absence of pregnancy during the trial. If positive at SV2, the subject is not eligible to enter the trial. If a subject 
becomes pregnant during the trial, the subject must permanently discontinue investigational medicinal product (IMP) and should attend all subsequent trial visits and be continually monitored 
according to the Schedule of Activities for the duration of the trial.
[f]
Subjects may be retested.
[g]
For eligibility, 2 Hb values measured by the central laboratory during Screening (SV1, SV2 or retest) must be between 8.0 and 11.0 g/dL (inclusive) in the US and between 9.0 and 12.0 g/dL 
(inclusive) Europe.
[h]
Iron indices: ferritin, iron, TIBC, and TSAT.
[i]
If blood is collected on a hemodialysis day, the blood draw should be completed before dialysis occurs. 
[j]
Liver function tests: total bilirubin, alkaline phosphatase, ALT/SGPT, AST/SGOT, and LDH.
[k]
Lipids: total cholesterol, LDL, HDL, and triglycerides.
 
[n]
Subjects will be provided with a supply of vadadustat at the Baseline Visit and will be resupplied at subsequent visits as needed. Please refer to the drug dispensing instructions for further details. 
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2
Introduction
2.1
Background Information
Chronic kidney disease (CKD), defined as the presence of kidney damage or a decreased 
level of kidney function for > 3 months, is a major public health problem worldwide. 
Globally, CKD is estimated to affect between 8% to 16% of the population.1,2 At the 
most advanced stages of CKD, end-stage renal disease, patients require chronic dialysis, 
or kidney transplantation to sustain life. Chronic kidney disease is not only a cause of 
end-stage renal disease, but is also a significant risk factor for cardiovascular (CV) 
disease, infection, cancer, and mortality.3
The prevalence and severity of renal anemia in CKD increases as renal function 
deteriorates.4,5 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.6 Anemia generally exists when hemoglobin (Hb) is 
less than 13.0 g/dL in men or less than 12.0 g/dL in women.7 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.3,8

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).8,9 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.5 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 (HF).10 Other 
consequences from anemia in CKD patients include impaired cognitive function, sleep 


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disorders, and depressed immune function which can impact the quality of life in 
patients.3,11 Overall, anemia contributes to a poorer prognosis in patients with CKD.3,8
The risks associated with erythropoiesis-stimulating agents (ESAs), currently the 
standard of care, including an increased risk of death and CV events12,13,14,15,16 highlight 
the need for additional therapies that might minimize or avoid these risks. 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.
2.2
Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors
Please see the vadadustat Investigator’s Brochure (IB) for additional discussion and 
information for the following section.17
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] = 8 nM) than of PHD2 (IC50 = 12 nµM). 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 possibly other organs), and this increase in EPO results in an 
increase in RBC production in the bone marrow. In clinical studies, vadadustat has been 
shown to facilitate iron homeostasis by decreasing hepcidin and increasing transferrin 
levels in healthy adult male subjects 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.
 
 
 
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2.4
Known and Potential Risks and Benefits
Please see the vadadustat IB for additional information.
Trials of injectable ESAs in patients with anemia secondary to NDD-CKD or DD-CKD 
have demonstrated an increased risk of CV events associated with higher Hb 
targets.12,14,16 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.18,19 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 
studies 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).20 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 
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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 subjects, there were low 
numbers of treatment-emergent AEs. The most frequently reported AEs were in the 
gastrointestinal disorders (ie, nausea, diarrhea, abdominal pain, flatulence, dyspepsia) and 
nervous system disorders (ie, 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), CV 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. 
Important identified risks of hepatotoxicity and drug-drug interactions associated with 
vadadustat therapy have been confirmed. There have been reports of drug-induced liver 
injury possibly or probably related to vadadustat. All subjects recovered without 
sequelae. Other non-important identified risks include nausea, diarrhea, vomiting, 
abdominal pain, headache, and increased blood uric acid.
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.
2.5
Trial Rationale
This trial will evaluate efficacy and safety of different vadadustat dosing strategies in 
hemodialysis subjects converting from ESAs to further characterize the optimal 
vadadustat regimen. See Section 4.2 for additional rationale for the trial design elements.
Trial sites will receive updated versions of the IB17 when available, and trial sites should 
refer to the most current version as needed.


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3
Objectives and Endpoints
Table 3-1
Trial Objectives and Endpoints
Objectives
Endpoints
Primary: To demonstrate 
the efficacy and safety of 
vadadustat compared to 
darbepoetin alfa for the 
maintenance treatment of 
anemia in hemodialysis 
subjects after conversion 
from current ESA therapy.
Primary Efficacy: Change in Hb between Baseline 
(average pretreatment Hb) and the primary evaluation 
period (average Hb from Weeks 20 to 26, inclusive).
Key Secondary Efficacy: Change in Hb value between 
Baseline (average pretreatment Hb) and the secondary 
evaluation period (average Hb from Weeks 46 to 52).
Other Efficacy: 

Proportion of subjects having average Hb values 
within the target range during the primary evaluation 
period (Weeks 20 to 26).

Proportion of subjects having average Hb values 
within the target range during the secondary 
evaluation period (Weeks 46 to 52).

Proportion of subjects receiving IV iron therapy from 
Baseline to Week 52.

Average monthly dose of IV elemental iron 
administered from Baseline to Week 52 in subjects 
who have received IV elemental iron.

Receipt of ESA rescue.

Proportion of subjects receiving RBC transfusions 
from Baseline to Week 26.

Proportion of subjects receiving RBC transfusions 
from Baseline to Week 52.

Change from Screening Visit 2 36-Item Short Form 
(SF-36v2) Health-related Quality of Life (HRQOL) 
scores.

Change from Screening Visit 2 to the average value in 
Anemia Subscale ("Additional Concerns") of 
Functional Assessment of Cancer Therapy-Anemia 
(FACT-An) Score.

Change from Screening Visit 2 to the average value in 
Total FACT-An Score.

Change from Screening Visit 2 in score of Patient 
Global Impression of Severity (PGI-S).


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Table 3-1
Trial Objectives and Endpoints
Objectives
Endpoints

Score of Patient Global Impression of Change 
(PGI-C).
Safety endpoints: AEs and SAEs, vital sign 
measurements, ECGs and clinical laboratory values, 
episodes of Hb > 12.0 g/dL, > 13.0 g/dL, or > 14.0 g/dL, 
and number of episodes of Hb increase > 1.0 g/dL within 
any 2-week interval or > 2.0 g/dL within any 4-week 
interval.
Pharmacokinetic: No PK analysis will be conducted. 
Vadadustat plasma concentrations may be included in a 
population PK analysis reported separately (Table 8.2-1).
Pharmacodynamic: EPO, reticulocytes, and markers of 
iron metabolism (iron, ferritin, TIBC, etc.). 
 
Section 9.4 describes the statistical analysis of the endpoints.
4
Trial Design
4.1
Type/Design of Trial
This is a phase 3b, randomized, open-label, active-controlled trial of vadadustat versus 
darbepoetin alfa for the maintenance treatment of anemia in hemodialysis subjects, after 
conversion from ESA therapy.
Following a Screening period of up to 8 weeks (56 days), subjects who meet all eligibility 
criteria will be randomized 1:1:1 to vadadustat QD, vadadustat TIW, or darbepoetin alfa. 
Target enrollment in this trial is an estimated 300 subjects at up to 150 investigative sites 
in the US and Europe (Figure 1.2-1).
Subjects will be randomized at the Baseline Visit using an Interactive Web Response 
(IWR) system to receive either vadadustat QD, vadadustat TIW, or darbepoetin alfa. 
Randomization will be stratified with respect to: 

Geographic region (US versus Europe, approximately 90 subjects in Europe).

Mean weekly darbepoetin alfa dose (or ESA equivalent) calculated over a period of 
8 weeks prior to Screening Visit 2:

Low darbepoetin alfa dose group (≤ 0.45 µg/kg/week).

High darbepoetin alfa dose group (> 0.45 and ≤ 1.5 µg/kg/week).
PPD


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In each stratum, there will be 3 arms: vadadustat QD, vadadustat TIW, and darbepoetin 
alfa.
Following screening and randomization, there will be 2 periods during the trial:

Conversion and Maintenance Treatment Period (Weeks 0 to 52): conversion to 
investigational medicinal product (IMP) for maintaining Hb (Weeks 0 to 20), primary 
efficacy evaluation (Weeks 20 to 26), and secondary efficacy evaluation (Weeks 46 
to 52).

Safety Follow-up Period (Early Termination [ET] and Follow-up): post-treatment 
Safety Follow-up Visit (ET/End of Treatment [EOT] + 4 weeks) (in person).
Individual subjects will participate in total trial duration of approximately 64 weeks.
A structured exit interview may be conducted at the EOT Visit at a subset of 
sites.Hemoglobin will be assessed with a complete blood count (CBC) through the 
central laboratory for dose adjustments and efficacy and safety evaluations.
The aim of the dosing strategy is to maintain Hb levels of 10.0 g/dL to 11.0 g/dL in 
the US and 10.0 g/dL to 12.0 g/dL in Europe.
For subjects assigned to vadadustat, the initial dose of vadadustat will depend on mean 
weekly darbepoetin alfa dose (or equivalent) calculated over a period of 8 weeks prior to 
Screening Visit 2 as follows:

Low darbepoetin alfa dose group (≤ 0.45 µg/kg/week): vadadustat 300 mg QD, 
600 mg TIW.

High darbepoetin alfa dose group (> 0.45 and ≤ 1.5 µg/kg/week): vadadustat 450 mg 
QD, 750 mg TIW.
Refer to the trial-specific Dosing Guideline for instructions on ESA medications 
conversion to an equivalent darbepoetin alfa dose for stratification and randomization.
Adjustments to doses for vadadustat will be guided by Hb concentration and Dose 
Adjustment Algorithms (Section 6.1.1).
For subjects who were receiving darbepoetin alfa during screening and randomized to the 
darbepoetin alfa treatment arm, the initial dosing regimen in the trial (starting from 
Baseline/Day 1) will be approximately the same weekly dose that they were receiving 
prior to randomization. Darbepoetin alfa dose will be administered IV at the hemodialysis 
clinic. For subjects receiving darbepoetin alfa for the first time, the initial dosing regimen 
(starting from Baseline/Day 1) will be determined by the US Package Insert (USPI) or 
European Union (EU) Summary of Product Characteristics (SmPC), per the medical 


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judgement of the investigator. Dose adjustments will be guided by the USPI or EU SmPC 
(Section 6.1.1.4). ESA dosing is independent of the visit schedule, and the dosing 
schedule may shift per local standard of care and investigator discretion.
Investigators will prescribe iron supplementation (IV, oral, or intradialytic) as needed 
during the trial to maintain ferritin ≥100 ng/mL or transferrin saturation (TSAT) ≥20% 
(see Section 6.5.2.1 for details regarding iron supplementation during the trial). 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 IMP 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 vadadustat at least 1 hour before oral medications 
containing iron (Section 6.5.2.1).
Clinical and safety assessments will be performed as indicated at Screening, during the 
Conversion and Maintenance Period, and during the Follow-up Period (4 weeks after the 
EOT) as shown in the Schedule of Assessments (Table 1.3-1).
The trial will be considered completed (end of trial) after all randomized subjects have 
completed their final trial visit (ET, Week 52/EOT, or Safety Follow-up) or have 
prematurely withdrawn from the trial (lost to follow-up). A subject is considered as 
having completed the trial after completion of their final trial visit (ET or Week 52/EOT). 
Safety Follow-up Visit data summarization and analysis will be performed separately.
4.2
Scientific Rationale for Trial Design
This trial 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, inflammation, and 
a greater risk of adverse outcomes.12,19,21 As described above (Section 2.3) in a phase 2 
hemodialysis trial (AKB-6548-Cl-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.
Two levels of pre-baseline ESA dose will be evaluated. Subjects will be randomized to 
one of 2 cohorts based on pre-baseline darbepoetin alfa dose (≤ 0.45 µg/kg/week and 
between > 0.45 and ≤ 1.5 µg/kg/week) or equivalent. This dose threshold of 
0.45 µg/kg/week was determined by converting the ESA threshold of 90 U/kg/week. The 
ESA threshold of 90 U/kg/week was based on the median ESA doses reported in the US 


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Renal Data System and US Dialysis Outcomes and Practice Patterns Trial, which ranged 
from approximately 90 to 110 U/kg/week.
In this trial, darbepoetin alfa was chosen as an active comparator as it is marketed and 
available globally and has an extensive safety profile. This is particularly relevant in the 
current medical and regulatory climate given the accumulating trial findings that resulted 
in the FDA revising the prescribing information for the currently marketed ESAs. These 
trial results indicate an increased risk of death and adverse CV events, such as stroke and 
HF, particularly when using ESAs to achieve a higher Hb concentration. In addition, 
post-hoc analysis has also shown that higher ESA doses carry a higher risk for CV 
outcomes regardless of Hb. In the US, the mortality and CV risks associated with ESAs 
are outlined in a boxed warning in the prescribing information of ESAs, with a 
recommendation to use the lowest dose possible to avoid transfusions. While no similar 
major warnings exist in the EU SmPC, there is caution suggested with use of ESAs, and 
recommendation to keep Hb levels below 12.0 g/dL. Recent clinical practice guidelines22 
recommend that risk factors for stroke and malignancy should also be taken into account 
when making treatment decisions to use ESAs for the treatment of anemia.
This trial incorporates 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 in 
the US and 10.0 to 12.0 g/dL in Europe, inclusive (see Section 6.1.1.1). The approach to 
vadadustat dose adjustment in this phase 3b trial 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 trial, dose increases for vadadustat will be allowed at 4-week intervals, with 
the exception of the initial 2 weeks of treatment. An additional dose increase may occur 
after 2 weeks of treatment initiation based on the Hb trajectory, in the daily and TIW 
dosing arms, in subjects with a Hb decline ≥ 0.5 g/dL from Baseline/Day 1 to Week 2 
following conversion from prior ESA and if Hb is < 10 g/dL. This approach is commonly 
used in clinical practice to treat patients with declining or low Hb values.14,16 Risk of 
abrupt or excessive increases in Hb is minimized due to the underlying Hb trajectory and 
is further mitigated by close Hb monitoring.
This trial will evaluate efficacy and safety of different vadadustat dosing strategies in 
hemodialysis subjects converting from ESA to further characterize the optimal vadadustat 
regimen. This trial will be performed as an open-label trial. Because Hb values are 
objective and will be measured via a central laboratory for all efficacy endpoints, efficacy 
assessments are not considered to be subject to bias with an open-label design.


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4.3
Dosing Rationale
In this trial, vadadustat starting daily doses will be determined by pre-baseline ESA dose 
(Section 6.1.1.1). In this trial starting doses of vadadustat will be 300 mg QD or 600 mg 
TIW in subjects converting from darbepoetin alfa doses ≤ 0.45 µg/kg/week (or ESA 
equivalent) and 450 mg QD and 750 mg TIW in subjects converting from darbepoetin 
alfa doses > 0.45 and ≤ 1.5 µg/kg/week (or ESA equivalent).
The maximum vadadustat dose evaluated in completed phase 1 studies in healthy subjects 
was 1200 mg (single dose) and 900 mg (10 days). Vadadustat 750 mg and 900 mg QD as 
titration doses are being studied in an ongoing phase 2 trial in DD-CKD subjects and in 
an ongoing phase 1b trial, DD-CKD subjects have been dosed 900 mg QD. As described 
above (Section 2.3), the maximum vadadustat starting dose evaluated in completed 
phase 2 NDD-CKD studies was 630 or 600 mg QD, and in completed phase 2 DD-CKD 
studies was 450 or 600 mg.
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 in the US and 10.0 to 
12.0 g/dL inclusive in Europe. The dose range for titration is 150 to 900 mg QD and 
150 to 1200 mg TIW.
Doses of 150 to 630 mg QD have been evaluated in studies evaluating subjects with 
NDD-CKD and DD-CKD. Evaluation of higher doses is justified because 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 subjects, 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. 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. 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.
As described above (Section 2.3), the 16-week phase 2 hemodialysis trial 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 
TIW dosing regimen of 450 mg TIW maintained Hb levels through 16 weeks, similar to 
300 mg or 450 mg QD dosing regimens. However, six of the 31 patients in TIW arm 
were withdrawn from the trial because of worsening of anemia. Upon further analysis of 


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these patients, it was observed that these patients had higher baseline-ESA doses. It is 
postulated that these patients could have benefited with higher TIW starting and 
maximum dose of vadadustat to yield an increase in erythropoietic effect to overcome 
worsening of anemia. To maximize the probability that subjects treated with vadadustat 
TIW will maintain Hb levels within the target range, this trial will allow for earlier dose 
increase after 2 weeks of initial treatment and permit dose increases up to 1200 mg TIW.
The maximum dose of vadadustat in this trial is 900 mg daily and 1200 mg TIW. No 
accumulation was evident after repeat dosing with vadadustat exposure and therefore, the 
exposures with 1200 mg single dose was likely to be similar to 1200 mg TIW. Per total 
weekly dosing, 1200 mg TIW (3600 mg/week) is a lower dosing regimen compared 
900 mg QD (6300 mg/week) and no Cmax related AEs were evident throughout clinical 
development of vadadustat.
From a safety and tolerability standpoint, as described above (Section 2.3), multiple 
doses of 700 and 900 mg daily for up to 10 days and single doses of 1200 mg have been 
examined in healthy subjects. 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.23 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 (1 or 2 days), and assessed as 
unrelated by investigators. No AEs led to trial withdrawal, and no SAEs were reported. 
No clinically meaningful changes or abnormalities in vital signs, safety laboratory 
studies, or ECG parameters were reported.
The starting dose of vadadustat for the high darbepoetin alfa group TIW arm will be 
750 mg and for the low darbepoetin alfa TIW arm will be 600 mg. In the ongoing global 
phase 3 program, subjects are getting higher total weekly doses as subjects treated in the 
high darbepoetin alfa group may be administered 600 mg vadadustat daily for a total 
weekly dose of 4200 mg; no significant dose-related safety concerns have been identified 
by the Independent Data Monitoring Committee (IDMC) in these trials.
Assessment of animal-to-human safety margins is presented in the IB.
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 in the 
US and 10 to 12 g/dL in Europe.


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
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.
Phase 2 studies demonstrated that cessation of treatment resulted in prompt reduction in 
mean Hb within 2 to 4 weeks.
4.4
End of Trial Definition
The end of trial date is defined as the last date of contact or the date of final contact 
attempt from the safety follow-up electronic case report form (eCRF) page for the last 
subject completing or withdrawing from the trial.
The trial will be considered completed (end of trial) after all randomized subjects have 
completed their final trial visit (ET, Week 52/EOT, or Safety Follow-up).
4.5
Definition of Completed Subjects
A subject will be considered as having completed the trial after completion of their final 
trial visit (ET, or Week 52/EOT). Safety Follow-up Visit data summarization and 
analysis will be performed separately.
Subjects who discontinue prematurely from the trial will complete the ET Visit 
assessments and will complete the Safety Follow-up Visit, 4 weeks after their last dose of 
IMP.
The need for rescue therapy does not constitute trial completion unless it meets the 
criteria stated in Section 7.3.2. Also, the occurrence of a safety endpoint does not 
constitute trial completion and is not a criterion for subject withdrawal from the trial or 
IMP (vadadustat or darbepoetin alfa).
5
Trial Population
An estimated 300 subjects with approximately:

100 subjects randomized to vadadustat QD arm.

100 subjects randomized to vadadustat TIW arm.

100 subjects randomized to darbepoetin alfa arm.
The trial population will consist of subjects ≥ 18 years of age receiving chronic, 
outpatient in-center hemodialysis TIW, with 2 screening Hb values between 8.0 and 
11.0 g/dL (inclusive) in the US or between 9.0 and 12.0 g/dL (inclusive) in Europe, and 
on maintenance treatment with an ESA.


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5.1
Subject Selection and Numbering
All subjects will be assigned a unique subject number.
Demographic information (collection date, date of birth, sex, childbearing potential, race, 
and ethnicity) and medical history will be recorded in eCRF at Screening Visit.
Eligible subjects who are enrolled in the trial will be assigned a unique subject 
randomization number for treatment sequence assignment (see Section 6.3.1). Results of 
the eligibility assessment, date of randomization (or date of treatment assignment) and 
randomization number (or treatment group) will be recorded in the eCRF.
5.2
Eligibility Criteria
To be eligible for this trial, a subject must provide valid informed consent and must meet 
all of the following criteria. No trial procedures (including screening tests) may be 
performed until after the informed consent has been legally signed.
Exceptions for eligibility criteria will not be permitted during the trial, neither by the 
investigator nor by the medical monitor.
5.2.1
Inclusion Criteria
Subjects are required to meet the following inclusion criteria at the time points described 
in the schedule of assessments (Table 1.3-1).
1) ≥ 18 years of age.
2) Receiving chronic, outpatient TIW in-center hemodialysis for end-stage renal 
disease for at least 12 weeks prior to Screening.
3) 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.
4) Use of any approved ESA for at least the 8 weeks prior to Screening Visit 2. 
5) Two Hb values, at least 4 days apart, measured by the central laboratory during 
Screening within the following prespecified ranges:
a) Hb values between 8.0 and 11.0 g/dL (inclusive) in the US.
b) Hb values between 9.0 and 12.0 g/dL (inclusive) in Europe.
6) Serum ferritin ≥ 100 ng/mL and TSAT ≥ 20% during Screening.
7) Folate and vitamin B12 measurements ≥ lower limit of normal during Screening.
5.2.2
Exclusion Criteria
Subjects will be excluded if they meet any of the following exclusion criteria at the time 
points described in the schedule of assessments (Table 1.3-1).


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1) Women of childbearing potential (WOCBP) who do not agree to practice 
2 different methods of birth control or remain abstinent during the trial and for 
30 days after the last dose of investigational medicinal product (IMP). If 
employing birth control, 2 of the following precautions must be used: vasectomy 
of partner, tubal ligation, vaginal diaphragm, or intrauterine device (see Section 
10.3).
2) 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 (see Section 10.3) 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.
3) Women who are breast feeding and/or who have a positive pregnancy test result 
prior to receiving IMP.
4) Subjects with contraindication to required trial assessment.
5) Subjects who, is in opinion of the investigator or medical monitor, have a medical 
history or medical findings inconsistent with safety or trial compliance.
6) Anemia due to a cause other than CKD (eg, sickle cell disease, myelodysplastic 
syndromes, bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic 
anemia, thalassemia, or pure red cell aplasia).
7) Subjects meeting cut-off of the following equivalent mean weekly doses 
calculated over 8 weeks prior to Screening Visit 2:
a) Methoxy polyethylene glycol-epoetin beta > 50 µg/week.
b) Darbepoetin alfa > 100 µg/week.
c) Epoetin analogues > 23000 IU/week. 
8) Active bleeding or recent blood loss within 8 weeks prior to randomization.
9) Red blood cell transfusion within 8 weeks prior to randomization.
10) Anticipated to discontinue hemodialysis during the trial.
11) Judged by the investigator that the subject is likely to need rescue therapy (ESA 
administration or RBC transfusion) immediately after enrollment in the trial.
12) History of chronic liver disease (eg, chronic infectious hepatitis, chronic 
autoimmune liver disease, cirrhosis, or fibrosis of the liver).
13) 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.
14) Current uncontrolled hypertension as determined by the investigator that would 
contraindicate the use of an ESA.
15) Acute coronary syndrome (hospitalization for unstable angina or myocardial 
infarction), surgical or percutaneous intervention for coronary, cerebrovascular or 
peripheral artery disease (aortic or lower extremity), surgical or percutaneous 
valvular replacement or repair, sustained ventricular tachycardia, hospitalization 
for HF or New York Heart Association Class IV HF, or stroke within 12 weeks 
prior to or during Screening.


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16) 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.
17) History of a new or recurrent episode of deep vein thrombosis or pulmonary 
embolism within 12 weeks prior to or during Screening.
18) History of hemosiderosis or hemochromatosis.
19) History of prior organ transplantation (subjects with a history of failed kidney 
transplant or corneal transplants are not excluded).
20) 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.
21) History of a prior hematopoietic stem cell or bone marrow transplant (stem cell 
therapy for knee arthritis is not excluded).
22) Known hypersensitivity to vadadustat, darbepoetin alfa, or any of their excipients.
23) Use of an investigational medication within 30 days or 5 half-lives of the 
investigational medication (whichever is longer), prior to screening or during 
screening and any prior use of a hypoxia-inducible factor prolyl hydroxylase 
inhibitor. Subjects may participate in another concurrent trial only if that trial is a 
non-interventional, observational investigation.
24) Subjects with bilateral native nephrectomy.
25) Treated with probenecid within the 28-day Screening Period prior to 
randomization or during the study treatment duration.
26) Any other reason, which in the opinion of the investigator, would make the 
subject not suitable for participation in the trial.
A definition of childbearing potential can be found in Section 10.3.
Subjects must agree to restrictions to medications described in Section 6.5.1.
5.3
Lifestyle Considerations
Not applicable.
5.3.1
Meals and Dietary Restrictions
Not applicable.
5.3.2
Caffeine, Alcohol, and Tobacco
Not applicable.
5.3.3
Activity
Not applicable.


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5.4
Screen Failures
A screen failure is a subject from whom informed consent is obtained and is documented 
in writing (ie, subject signs an informed consent form [ICF]), but who is not randomized 
or assigned trial treatment.
If the subject meets the definition of a screen failure in this trial, the following 
information (at a minimum) will be recorded in the eCRF:

Date of informed consent.

Visit date (Screening Visit).

Demographics (collection date, birth date, sex, race, ethnicity, country).

Result of eligibility assessment.

Screen failure date.

Reason for screen failure.
Investigators must account for all subjects who sign informed consent and will maintain a 
log of subjects screened and indicate who was randomized or excluded. If the subject is 
found not to be eligible for randomization, the reason(s) for ineligibility must be 
documented by the investigator.
Screening numbers assigned to subjects who fail Screening will not be reused.
Subjects who fail to qualify for the trial at the initial Screening Visit will receive a new 
subject number for each rescreening attempt (see Section 5.4.1). If rescreened, the subject 
will also sign a new ICF and will repeat all Screening procedures.
5.4.1
Retesting and Rescreening
Subjects who initially fail to qualify for the trial based on laboratory test results may have 
any individual laboratory parameter retested 1 time within the 8-week Screening period at 
the discretion of the investigator. Retesting within the 8-week Screening period does not 
constitute rescreening; however, if retesting falls outside of the 8-week Screening period, 
it should be considered a rescreen. All screening laboratories, including any repeat 
measurements, must be performed within the 8-week Screening window with a minimum 
of 4 days between the last qualifying repeat measurement and the Baseline Visit.
Subjects who fail to qualify for the trial 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 trial. Each screening attempt 


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includes the potential of a retest. Additionally, subjects who fail to qualify for the trial 
based on inclusion criteria values for TSAT, ferritin, folate, or B12 values may be 
considered for rescreening after receiving replacement therapy. A minimum of 3 weeks 
from IV iron replacement therapy (for low TSAT and ferritin values) must be observed 
prior to collecting next trial visit Hb value.
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.
6
Trial Treatments
6.1
Trial Treatments Administered
The investigator or designated trial personnel will be responsible for preparing IMP for 
dispensing to the subject (Section 6.2) and for IMP supply accountability (Section 6.2.3).
For information regarding the dose regimen and treatment period(s), including any 
follow-up period(s) for each treatment group/arm of the trial, see Section 4.1.
6.1.1
Dosing and Dose Adjustment Guidelines
Dosing and dose adjustments are described below for vadadustat (Section 6.1.1.3) and 
darbepoetin alfa (Section 6.1.1.4).
6.1.1.1
ESA Equivalent Dose Calculation
Following a Screening Period of up to 8 weeks, subjects who meet all eligibility criteria 
will be randomized 1:1:1 to vadadustat QD, vadadustat TIW, or darbepoetin alfa. Mean 
weekly darbepoetin alfa dose (or ESA equivalent) will be calculated over a period of 
8 weeks prior to Screening Visit 2 and stratified into 2 groups:

Low darbepoetin alfa dose group (≤ 0.45 µg/kg/week).

High darbepoetin alfa dose group (> 0.45 and ≤ 1.5 µg/kg/week).
Refer to the trial-specific Dosing Guideline for instructions on ESA medications 
conversion to an equivalent darbepoetin alfa dose for stratification and randomization.
6.1.1.2
Dose Adjustment Algorithm
This protocol provides guidance for the treatment of subjects with anemia associated with 
CKD in order to achieve and maintain Hb levels within the target Hb range. Dose 
adjustment should be based on the investigator’s clinical discretion, incorporating the 
protocol guidance, and considering the subject’s clinical condition, Hb rate of rise, Hb 
rate of decline, Hb variability, and IMP responsiveness. In cases where the investigator 


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does not follow the dosing algorithm, the clinical circumstances must be documented in 
the subject’s source or dosing approach may be considered a protocol deviation.
Hemoglobin will be monitored via central laboratory throughout the trial to determine if 
the dose of IMP (vadadustat or darbepoetin alfa) will be adjusted, interrupted, or 
maintained and is used for the Guidelines for Dose Adjustment (see Table 6.1.1.2-1).
Table 6.1.1.2-1
Guidelines for Dose Adjustment
Status of Hb Levels
Dose Adjustmenta
Hb levels are to be maintained in the following target 
ranges:
US only: 10.0 to 11.0 g/dL, inclusive.
Europe only: 10.0 to 12.0 g/dL, inclusive.
A dose increase or decrease is required to 
achieve and maintain Hb levels within the 
target range. Dose is adjusted by 1 dose level 
(for vadadustat 1 tablet [150 mg], for 
darbepoetin alfa approximately 25%)
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 ESA) and if Hb is < 10.0 g/dL.
A subject’s dose may be increased by 1 dose 
level.
A rapid rise in Hb is observed (defined as follows):
> 1.0 g/dL in any 2-week period or 
> 2.0 g/dL in any 4-week period.
Reduce or interrupt the dose.b
Hb levels are in the following setting:
US only: Hb > 11.0 g/dL.
Europe only: > 12.0 g/dL.
Reduce or interrupt the dose. After Hb falls 
below 11.0 g/dL (US) or 12.0 g/dL (Europe), 
restart IMP and consider restarting at a lower 
dose.
aIn 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 one occasion. Dose adjustment should be based on the investigator’s 
clinical discretion.
bSee Section 7.3.1 (Treatment Interruption).
6.1.1.3
Vadadustat Dosing
For subjects assigned to vadadustat, the initial dose of vadadustat will depend on mean 
weekly darbepoetin alfa dose (or ESA equivalent) calculated over a period of 8 weeks 
prior to Screening Visit 2 (see Section 6.1.1.1) as follows:

Low darbepoetin alfa dose group (≤ 0.45 µg/kg/week) will receive either an initial 
vadadustat dose of 300 mg QD or 600 mg TIW or

High darbepoetin alfa dose group (> 0.45 and ≤ 1.5 µg/kg/week) will receive either 
an initial vadadustat dose of 450 mg QD or 750 mg TIW.
Dosing will be initiated at the Baseline/Day 1 Visit and the first dose of vadadustat will 
be administered at the trial site after other Baseline/Day 1 Visit procedures have been 
completed. Thereafter, vadadustat will be taken QD or TIW (on dialysis days) on an 
outpatient basis. Subjects may take vadadustat with or without food and should be 


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instructed to swallow the tablet(s) whole, without chewing. Subjects should be instructed 
to take vadadustat at roughly the same time each day.
During the trial, vadadustat should be dosed according to the Dose Adjustment Algorithm 
(Section 6.1.1.2), and dose adjustments will be guided by Hb concentrations and the 
Guidelines for Dose Adjustment (see Table 6.1.1.2-1).
The minimum dose of vadadustat will be 150 mg and the maximum dose will be 900 mg 
QD or 1200 mg TIW.
6.1.1.4
Darbepoetin Alfa Dosing
For subjects who were receiving darbepoetin alfa during screening and randomized to the 
darbepoetin alfa treatment arm, the initial dosing regimen in the trial (starting from 
Baseline/Day 1) will be approximately the same weekly dose that they were receiving 
prior to randomization. For subjects receiving darbepoetin alfa for the first time, the 
initial dosing regimen (starting from Baseline/Day 1) will be determined by the USPI or 
EU SmPC, per the medical judgment of the investigator. Darbepoetin alfa will be 
dispensed as a solution in single-dose prefilled syringes, to be given by IV injection 
through dialysis vascular access.
6.1.2
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.
6.1.3
Late or Missed Doses
Subjects on vadadustat should be instructed to take the IMP at roughly the same time 
each day. For QD dosing, if a dose is forgotten, subjects should be instructed to take the 
dose as soon as they remember during the same day. If a forgotten dose is not 
remembered on the same day, the subject should skip the dose and resume the normal 
dosing schedule the following day. Subjects should not double-up on missed doses.
Subjects on TIW dosing regimen should be instructed to take the dose on dialysis days. If 
a dose is forgotten, subjects should be instructed to take the dose as soon as they 
remember during the same day or the next non-dialysis day. Subjects should not 
double-up on missed doses.
Site personnel who are administering darbepoetin alfa should be instructed to administer 
the IMP, including handling of late or missed dosed, as described in the USPI or EU 
SmPC.


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Subjects should be questioned regarding dosing compliance at every visit and whether 
they have questions or have experienced any problems related to the dosing of IMP 
(vadadustat only).
6.2
Management of Investigational Medicinal Product
The investigator will maintain record of all vadadustat tablets and darbepoetin alfa 
injections dispensed to and returned from each subject during the trial. Subjects will 
receive either vadadustat or darbepoetin alfa according to the randomization assignments 
provided via the IWR system (see Section 6.3.1).
Subjects will be provided with a supply of vadadustat at the Baseline Visit according to 
the IWR system assignment. Resupply of additional vadadustat at subsequent visits will 
be managed via the IWR system and will be dependent on the current dose level of 
vadadustat and the number of tablets remaining in the subject’s current vadadustat supply 
at a given trial visit (Section 6.1.1.1).
Subjects should be instructed to bring unused vadadustat and empty bottles to each trial 
visit for product accountability. Empty bottles will be collected at these trial visits. If the 
subject moves from 300 mg to 450 mg, the subject should return the 150 mg bottles to the 
site for accountability.
A Vadadustat Dosing Information Sheet will be provided to the subject at dispensing of 
IMP.
Darbepoetin alfa will be dispensed according to the IWR system assignment.

For subjects already on darbepoetin alfa, the initial dosing regimen in the trial should 
be based on the prior dosing regimen.

For subjects on epoetin analogues or methoxy polyethylene glycol-epoetin beta, who 
are randomized to darbepoetin alfa arm, the starting dose of darbepoetin alfa will be 
determined by USPI or EU SmPC.
Dispensing of additional darbepoetin alfa at subsequent dosing visits will be managed by 
the IWR system (Section 6.1.1.4).
For full details on IMP management, please refer to the vadadustat IB.17
6.2.1
Packaging and Labeling
Vadadustat for oral administration and darbepoetin alfa for injection will be provided and 
shipped by the sponsor or its designated supplier/distributor. Both vadadustat and 
darbepoetin alfa will be supplied as open label supplies.


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Vadadustat will be provided as 150 mg white, round, film-coated, or 450 mg pink, oval, 
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.
Darbepoetin alfa will be provided in its commercially-approved primary packaging.
Investigational medicinal product will be provided to the investigators and the persons 
designated by the investigator(s) or institution(s) by the sponsor or designated agent. 
Labeling will be in accordance with current Good Manufacturing Practices (GMP) and 
local regulatory requirements and each IMP used in the dosing period will be labeled to 
clearly disclose the subject identifier (ID), compound ID, trial number, sponsor’s name 
and address, instructions for use, route of administration, and appropriate precautionary 
statements.
6.2.2
Storage
All IMP supplies must be kept in a temperature controlled, locked facility, accessible 
only to authorized trial personnel. Access will be limited to investigators and their 
designees.
Vadadustat should be stored at controlled room temperature of 15°C to 30°C (59°F to 
86°F). Please consult the Pharmacy Manual for details on storage and managing 
temperature excursions.
Darbepoetin alfa will be stored per the USPI for US sites or EU SmPC for EU sites.
The clinical site staff will maintain a temperature log in the IMP storage area to record 
the temperature.
6.2.3
Accountability
The investigator or designee must maintain an inventory record of IMP received, 
dispensed, administered, and returned. Neither the investigator nor any designees may 
provide IMP to any subject not participating in this protocol.
Product accountability should be an ongoing process throughout the trial. All IMP 
(vadadustat and darbepoetin alfa) must be accounted for and any discrepancies explained. 
The investigator or designated trial personnel are responsible for keeping accurate 
records of the clinical supplies received from the sponsor, all supplies retained in 
inventory at the investigative site, and IMP dispensed to or returned from each subject. 
Records will be maintained that accurately reflect the drug accountability of vadadustat 
and darbepoetin alfa at all times.


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Proper drug accountability includes, but is not limited to:

Continuously monitoring expiration dates if expiry date or retest date is provided to 
the investigator.

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for all drug received and that all required fields 
are complete, accurate, and legible.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately.
During the trial, the investigator will be notified of any expiry dates or retest date 
extensions of clinical trial material. If an expiry date notification is received during the 
trial, the investigative site must complete all instructions outlined in the notification, 
including segregation of expired clinical trial material for return to the sponsor or its 
designee for destruction.
Prior to investigative site closure and at appropriate intervals during the trial, a 
representative from the sponsor will perform clinical trial material accountability and 
reconciliation.
At the end of the trial, the investigator will retain all original documentation regarding 
clinical trial material accountability, return, and/or destruction, and copies will be sent to 
the sponsor.
6.2.4
Returns and Destruction
All unused and/or partially used vadadustat or darbepoetin alfa should be returned to the 
sponsor or destroyed at the investigational site, as specified by the sponsor. Appropriate 
records of the disposal will be documented and maintained. No unused vadadustat or 
darbepoetin alfa may be disposed of until fully accounted for by the sponsor’s monitor 
(or designee). Empty containers may be disposed of according to local procedures.
6.3
Measures to Minimize/Avoid Bias
6.3.1
Randomization
This trial will be open to an estimated 300 subjects ≥ 18 years of age receiving chronic, 
outpatient in-center hemodialysis TIW with 2 screening Hb values (at least 4 days apart) 
between 8.0 and 11.0 g/dL (inclusive) in the US and between 9.0 and 12.0 g/dL 
(inclusive) in Europe, and on maintenance treatment with an ESA.


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Using an IWR system, eligible subjects will be assigned using permuted block 
randomization and a 1:1:1 ratio to either vadadustat QD, vadadustat TIW, or darbepoetin 
alfa during their Baseline Visit.
To maintain balance between vadadustat QD-treated, vadadustat TIW-treated and 
darbepoetin alfa-treated subjects, randomization will be stratified with respect to: 

Geographic region (US versus Europe, approximately 90 subjects in Europe).

Mean weekly darbepoetin alfa dose (or ESA equivalent) calculated over a period of 
8 weeks prior to Screening Visit 2:

Low darbepoetin alfa dose group ( ≤ 0.45 µg/kg/week)

High darbepoetin alfa dose group ( > 0.45 and ≤ 1.5 µg/kg/week)

In the low darbepoetin alfa dose group, subjects will be randomized in a 1:1:1 ratio to 
receive either an initial vadadustat daily dose of 300 mg daily or 600 mg TIW, or 
darbepoetin alfa.

In the high darbepoetin alfa dose group, subjects will be randomized in a 1:1:1 ratio 
to receive either an initial vadadustat daily dose of 450 mg daily, 750 mg TIW, or 
darbepoetin alfa.
Refer to the trial-specific Dosing Guide for instructions on ESA medications conversion 
to darbepoetin alfa equivalent dose for stratification.
6.3.2
Blinding
This will be an open-label trial. Treatment assignment will be done through the IWR 
system and the investigator, sponsor, and contract research organization (CRO) trial 
teams will not be aware of which treatment will be assigned next. Treatments will be 
administered in an open-label fashion. The sponsor and CRO trial teams will be blinded 
to “by treatment” aggregated analyses except for the unblinded personnel. Because Hb 
values are objective and will be measured via a central laboratory for all efficacy 
endpoints, efficacy assessments are not considered to be subject to bias with an 
open-label design. In addition, the trial will involve the use of an IDMC, and an identical 
schedule of visits, procedures, and assessments for all treatment groups in order to reduce 
the potential for bias. Adjustments to doses for vadadustat will be based on Hb 
concentration and Dose Adjustment Algorithms and darbepoetin alfa will be based on 
USPI or EU SmPC.
As described in Section 9.5, the Safety Event Adjudication Committee (SEAC) will 
remain blinded throughout the full course of the trial.


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6.4
Subject Compliance
Subjects will be questioned regarding dosing compliance at every visit and whether they 
have questions or have experienced any problems related to the dosing of the IMP 
(vadadustat or darbepoetin alfa). Treatment compliance will be determined from drug 
accountability logs along with the subject questioning and the IMP eCRFs. Dosing 
compliance for vadadustat or darbepoetin alfa is defined as 80% to 120% over the course 
of the Treatment Period.
Subjects who miss doses will be counseled on the importance of compliance.
6.5
Concomitant Medications or Therapies
The investigator will record all medications and therapies taken by the subject from 
8 weeks prior to signing of informed consent through the Safety Follow-up Visit on the 
eCRF. The investigator will also record all medications and therapies taken by the subject 
for treatment of an AE or which caused an AE until the end of the trial (defined as the 
last date of contact or date of final contact attempt) on the eCRF.
Erythropoiesis-stimulating agents (ESAs), blood transfusions, and iron treatment regimen 
prior to randomization and the date of last dose will be recorded on a separate disease-
related concomitant therapy eCRF pages.
6.5.1
Prohibited Medications
6.5.1.1
Erythropoiesis-stimulating Agents
Co-administration of any ESA with vadadustat is prohibited. If ESA rescue therapy is 
deemed medically necessary, vadadustat treatment must be stopped during ESA 
administration (see Section 6.5.3.2 for guidelines). All efforts will be made to avoid 
inadvertent administration of ESA resulting from adherence to ESA hemodialysis center 
protocols (eg, ESA protocols for subjects on hemodialysis). If ESA is inadvertently 
administered to subjects actively receiving vadadustat treatment, vadadustat treatment 
will be stopped and the event will be reported as a protocol deviation.17
For all subjects, it is required that a minimum period as outlined below be observed 
between the last dose of ESA administered during Screening and Randomization Visit: 

2 days after last dose of epoetin analogues.

7 days after last dose of darbepoetin alfa.

14 days after last dose of methoxy polyethylene glycol-epoetin beta.


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Non-protocol ESAs are prohibited from randomization until the end of the trial, unless 
the subject is receiving ESA rescue therapy, interrupts IMP for other reasons, or 
permanently discontinues the IMP. Reasons for ESA use will be captured in the 
appropriate eCRF (eg, AE, inadvertent administration, etc.).
6.5.1.2
Sulfasalazine and Other BCRP Substrates and Probenecid
Exposure to sulfasalazine was moderately increased with co-administration of vadadustat 
based on a trial 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. If there are questions regarding a specific 
concomitant medication, please consult with the Trial Team Medical Monitor.
Probenecid, an inhibitor of uridine 5'-diphospho-glucuronosyltransferase and the organic 
anion transporter 1/3 transporters, increased vadadustat area under the curve and is 
prohibited during the trial.
6.5.2
Permitted Medications
6.5.2.1
Iron Supplementation
Investigators will prescribe iron supplementation (IV, oral, or intradialytic) during the 
trial to maintain ferritin ≥ 100 ng/mL or TSAT ≥ 20%. The use of iron-based phosphate 
binders (eg, ferric citrate) is permitted.
Important: 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 IMP is not to be administered concurrently 
with an oral iron supplement (including multivitamins containing iron), iron-containing 
and non-iron-containing phosphate binders, or any oral medications containing iron.
Subjects will be instructed to take vadadustat at least 1 hour before oral medications 
containing iron. Iron supplementation details will be captured in the appropriate eCRF.
6.5.2.2
Phosphate Binders
Subjects will be instructed to take vadadustat at least 1 hour before or 2 hours after 
non-iron-containing phosphate binders.
6.5.2.3
HMG-CoA Reductase Inhibitors (Statins)
Numerous drug-drug interactions have been reported following concomitant 
administration of vadadustat with various statins and the following guidelines regarding 
the concomitant use of statins during the trial should be considered.


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Exposures to atorvastatin and an active metabolite (para-hydroxy atorvastatin) were 
mildly increased in the setting of vadadustat co-administration in healthy adults. No dose 
adjustment of atorvastatin is recommended. 
Exposures to simvastatin and an active metabolite (beta-hydroxy acid) were both mildly 
to moderately increased with co-administration of vadadustat in healthy adults. For 
subjects taking vadadustat who are concomitantly taking simvastatin, the recommended 
maximum daily dose of simvastatin is 20 mg. Investigators should review simvastatin 
dosing and consider clinical guidelines and local prescribing information including 
specific guidance in product labels with reference to renal impairment as well as hepatic 
impairment, concomitant medications and other medical factors relevant to the 
management of the subject.
Exposure to rosuvastatin was moderately increased with co-administration of vadadustat 
based on a trial in healthy adults. For subjects taking vadadustat who are concomitantly 
taking rosuvastatin, the recommended maximum daily dose of rosuvastatin is 10 mg. 
Investigators should review rosuvastatin dosing and consider clinical guidelines and local 
prescribing information including specific guidance in product labels with reference to 
renal impairment as well as hepatic impairment, concomitant medications, and other 
medical factors relevant to the management of the subject.
Exposure to pravastatin was studied in the setting of vadadustat co-administration in 
healthy adults. There was no interaction. No dose adjustment of pravastatin is 
recommended.
Exposures to the other statins may be increased with co-administration of vadadustat. 
When used with vadadustat, upward titration of other statins to higher doses should be 
carried out with caution.
A summary of results and management of concomitant administration of vadadustat with 
the various statins is provided in Table 6.5.2.3-1.


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Table 6.5.2.3-1
Results and Management of Concomitant Administration of 
Vadadustat with Statins
Statin
Change in Statin Exposure 
When Dosed with Vadadustata
Recommended Statin Dosing in Subjects 
Receiving Concomitant Vadadustat
Atorvastatin
Mild increase
No dose adjustment
Pravastatin
No increase
No dose adjustment
Rosuvastatin
Moderate increase
Maximum daily dose of 10 mg
Simvastatin
Mild-to-moderate increase
Maximum daily dose of 20 mg
Other statins
Not studied
Upward titration to higher doses should be 
done with caution
aBased on FDA guidance, inhibitor potency is based on an increase in exposure of ≥ 1.25- to < 2-fold, 
≥ 2- to < 5-fold, or ≥ 5-fold for weak, moderate, or strong interactions, respectively.24
6.5.3
Rescue Medications
To ensure the safety of subjects and to standardize the use of rescue therapy in the trial, 
rescue therapy guidelines are provided.
6.5.3.1
RBC Transfusion
Investigators will use their local institution’s transfusion guidelines when determining 
whether to transfuse a trial subject. In general, in the event of an acute or severe loss of 
blood, an 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. Trial medication (vadadustat or darbepoetin alfa) may be continued 
during the transfusion period.
Reasons for RBC transfusion will be captured in the appropriate eCRF.
6.5.3.2
ESA Use
ESA administration will be allowed when medically necessary at the discretion of the 
investigator. 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 if deemed medically necessary at the discretion of the investigator. In 
general, ESA rescue will be allowed in subjects with Hb < 9.5 g/dL, and ESA will be 
stopped when Hb ≥ 10.0 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 rescue therapy, subjects randomized to vadadustat must temporarily 
interrupt vadadustat. A minimum interval must be observed prior to restarting vadadustat 
after the last dose of ESA rescue medication, and treatment may be resumed after the 
following intervals:


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
2 days after last dose of epoetin analogue.

7 days after last dose of darbepoetin alfa.

14 days after last dose of methoxy polyethylene glycol-epoetin beta.
Please refer to local prescribing information.
Following ESA rescue 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 eCRF.
6.5.3.3
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 trial site’s standard 
clinical practice.
6.6
Intervention after the End of the Trial
Subjects will be treated based on the investigator’s clinical judgment.
7
Stopping Rules, Withdrawal Criteria, and Procedures
7.1
Entire Trial or Treatment
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to investigators, Institutional Review Board (IRBs)/Independent Ethics Committee 
(IECs), and regulatory authorities in accordance with regulatory requirements.
The entire trial may be suspended or terminated by the sponsor, or the IRB for safety or 
other unanticipated reasons or upon request of regulatory agencies. If this occurs, prompt 
notification will be given to investigators, IRBs/IECs, and regulatory authorities in 
accordance with regulatory requirements.
The investigator must notify the sponsor if the trial is terminated by the investigator or 
the IRB/IEC at the site. If the investigator, IRB/IEC, or sponsor decides to terminate or 
suspend the trial conduct at a particular investigative site for safety, non-enrollment, 
non-compliance with the protocol, or other unanticipated reasons, the above parties will 
be promptly notified.


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7.1.1
Criteria for Premature Termination or Suspension of the Trial
The following criteria may result in either temporary suspension or early termination of 
the trial:
New information regarding the safety or efficacy of the IMP 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 trial.
Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary trial objectives or compromises subject safety.
Regulatory requirements for the archival of records for this trial necessitate that 
participating investigators maintain detailed clinical data for the longest of the following 
3 periods:

A period of at least 2 years following the date on which approval to market the drug 
is obtained (or if IMP development is discontinued, the date regulatory authorities 
were notified of discontinuation); OR

A period of at least 3 years after the sponsor notifies the investigator that the final 
report has been filed with regulatory authorities.

Up to 25 years or longer according to region-specific storage requirements, if 
applicable.
The investigator must not dispose of any records relevant to this trial without either
1) Written permission from the sponsor or 
2) Provision of an opportunity for sponsor to collect such records.
The investigator will be responsible to maintain adequate and accurate electronic or hard 
copy source documents of all observations and data generated during this trial. Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities. 
If the investigator withdraws from the trial (eg, due to relocation or retirement), all 
trial-related records should be transferred to a mutually agreed-upon designee within a 
sponsor-specified timeframe. Notice of such transfer will be given to the sponsor in 
writing.
The sponsor reserves the right to discontinue the trial for other valid administrative 
reasons.


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7.2
Individual Site
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the IRB/IEC if judged to be necessary for medical, safety, regulatory, ethical, or other 
reasons consistent with applicable laws, regulations, and GCP. The investigator will 
notify the sponsor promptly if the trial is terminated by the investigator or the IRB/IEC at 
the site.
A trial site may be terminated prematurely or suspended if the trial 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 trial.
In the event that the sponsor elects to terminate or suspend the trial or the participation of 
an investigational trial site, a trial-specific procedure for early termination or suspension 
will be provided by the sponsor; the procedure will be followed by applicable 
investigational trial sites during the course of termination or trial suspension.
7.3
Individual Subject Discontinuation
During this trial, it is anticipated that some subjects may permanently discontinue IMP 
(vadadustat or darbepoetin alfa).
Subjects who discontinue IMP prematurely and the investigator determines that the 
subject will be permanently discontinued from the trial (see Section 7.3.1), will complete 
the ET Visit assessments and the Safety Follow-up Visit, 4 weeks after ET Visit.
Subjects may discontinue prematurely from the trial for any of the following reasons:

Adverse Event.

Subject withdrawal of consent.

Investigator’s discretion.

Lack of efficacy, defined as inadequate response to darbepoetin alfa or vadadustat in 
the investigator’s opinion.

Lost to follow-up despite reasonable efforts by the investigator to locate the subject.

Receipt of a solid organ (including kidney), hematopoietic stem cell, or bone marrow 
transplantation.

Meeting criteria for Trial Medication Stopping Rules (see Section 7.3.2).

Change in dialysis modality (ie, from hemodialysis to peritoneal dialysis or change 
from in center hemodialysis to home/nocturnal hemodialysis).

Permanent change in frequency of in-center hemodialysis from three-times per week.

Death.

Other reasons (pregnancy [see Section 10.3], specific reasons to be documented by 
the investigator).


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A subject has the right to withdraw consent for participation in the trial at any time 
(Section 7.3.4).
See Table 7.3.2-1 for additional details on the management of subjects with ALT and 
AST abnormalities.
7.3.1
Treatment Interruption
Subjects who temporarily interrupt IMP (vadadustat or darbepoetin alfa) treatment after 
the first dose and prior to completion of the trial will continue with trial visits and 
assessments. Unless contraindicated, treatment with IMP should be resumed within a 
30-day time period from the start date of interruption and routinely considered at every 
visit following IMP interruption. If a subject does not return for a scheduled visit, every 
effort should be made to contact the subject.
During the trial, a subject may interrupt the IMP (vadadustat or darbepoetin alfa) for any 
of the following reasons:

Adverse event.

Missed dialysis visit (darbepoetin alfa arm).

Investigator’s discretion.

Rapid rise in Hb (defined as > 1.0 g/dL in any 2-week period or > 2.0 g/dL in any 
4-week period).

Hb above 11.0 g/dL (US) or above 12 g/dL (Europe).

New elevations in ALT or AST > 3x ULN, without elevation in total bilirubin.

Vadadustat arm: ESA use.

Darbepoetin alfa arm: ESA use other than darbepoetin alfa IMP.
While receiving ESA rescue, subjects must temporarily discontinue IMP. Unless 
contraindicated, treatment with IMP should be resumed within a 30-day time period from 
the start date of the interruption. Re-start of IMP should be assessed at every visit 
following IMP interruption.
If a subject is receiving a tolerated dose of IMP prior to interruption, the subject may 
interrupt IMP for a maximum duration of 30 days. Re-start of IMP should be assessed at 
every visit following IMP interruption. Prior to the end of the 30-day time period from 
the start date of interruption, the investigator, in consultation with the sponsor's Medical 
Monitor or CRO designee, should assess either if the subject can or cannot be re-started 
on the IMP. If by Day 30 the subject will not be re-starting IMP, they will be 


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permanently discontinued from the trial and will complete the ET Visit and the Safety 
Follow-up Visit assessments.
7.3.2
Treatment Discontinuation
After treatment assignment, a subject may stop treatment permanently for a variety of 
reasons. Treatment discontinuations may be initiated by a subject who is not satisfied 
with treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator. 
However, each investigator must comprehensively review the circumstances and offer the 
subject options for continued treatment to the degree possible. If, after discussion with 
the investigator about possible mitigations for AEs, etc., the subject still chooses to 
discontinue IMP, the subject will permanently discontinue IMP and will complete the ET 
Visit assessments and will complete the Safety Follow-Up Visit, 4 weeks after last dose 
of IMP and the subject will not be allowed to re-start the IMP.
Trial medication is to be permanently discontinued if ESA rescue (other than darbepoetin 
alfa in comparator arm, any ESA in vadadustat arm) is not in the setting of acute bleeding 
(ie, gastrointestinal bleed, surgery, excess bleeding) and one of the following:

The first cycle of ESA rescue lasts >30 days or

Subject requires a second cycle of ESA for rescue (that must be related to anemia) at 
any time.
Trial medication must be permanently discontinued if a subject meets one of the criteria 
in Table 7.3.2-1.
Table 7.3.2-1
Trial 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 weeksa
Permanently Discontinue Treatment
ALT or AST > 3x ULN with symptoms including eg, 
fatigue, nausea, vomiting, right upper quadrant pain, 
fever, rash or eosinophilia
Permanently Discontinue Treatment
INR: international normalized ratio; ULN: upper limit of normal
aRe-challenge generally should be avoided with ALT or AST > 5x ULN unless there are no other good 
therapeutic options.
See Section 8.8 for reporting requirements related to a subject being permanently 
discontinued based on meeting the laboratory abnormalities list above in Table 7.3.2-1.


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For subjects who permanently discontinue IMP, the investigator will resume standard of 
care treatment, including ESAs and iron therapy, as deemed appropriate.
7.3.3
Documenting Reasons for Treatment Interruption or 
Discontinuation
A subject may temporarily interrupt or discontinue IMP for the reasons listed in 
Section 7.3.1 and Section 7.3.2.
If the subject temporarily interrupts or discontinues IMP due to an AE, the investigator, 
or other trial personnel, will make every effort to follow the event until it has resolved or 
stabilized. Follow-up procedures in Section 7.3.1 and Section 7.3.2 must be followed.
7.3.4
Withdrawal of Consent
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The investigator can also 
discontinue a subject’s participation in the trial at any time if medically necessary. 
Withdrawal of consent is a critical trial event and, therefore, should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial.
 
 
7.4
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before the Safety Follow-up Visit after the 
treatment period, who do not have a known reason for discontinuation (eg, withdrew 
consent or AE), and for whom a survival status at the end of the trial cannot be 
determined will be classified as “lost to follow-up”. Survival status can be determined 
from a variety of sources, either by obtaining acceptable documentation for death 
(ie, death certificate, medical records, public records, statement by a family member or 
primary care physician) or acceptable documentation for life (ie, direct contact with the 
subject, medical records, successful telephone contact with the subject, statement by a 
family member or primary care physician, or public records).
The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
PPD


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the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status.
If the subject was classified as “lost to follow-up”, “Were you able to contact the 
subject?”, “Date of contact/Date of final contact attempt” and “Contact method” will be 
recorded in the source documents.
8
Trial Procedures
The Schedule of Assessments (Table 1.3-1) shows the timing of planned trial procedures. 
Every effort should be made to adhere to this procedure schedule and all assessments 
should be completed at each trial visit. Where possible, trial visits should be performed 
and scheduled as part of a subjects regularly scheduled dialysis session. 
Subjects are to be assessed by the same investigator or investigative site personnel 
whenever possible.
Screening Visits
The ICF will be signed at Screening Visit 1. Subjects will need to sign the ICF prior to 
any Screening Visit 1 procedures. The Screening period starts at the time the ICF is 
signed and will be up to 8 weeks in duration. Two Screening visits must be performed 
within 8 weeks prior to dosing (Baseline Visit/Day 1). There must be a minimum of 
4 days between the 2 Screening Visits and a minimum of 4 days (based on last ESA use) 
between Screening Visit 2 or last retest and the Baseline Visit.
The investigator will maintain a log of subjects and indicate who of the Screened subjects 
were enrolled or excluded and the reason for exclusion.
After obtaining informed consent, subjects will undergo a number of screening activities.
Two Hb values, at least 4 days apart, measured by the central laboratory during Screening 
must be between 8.0 and 11.0 g/dL (inclusive) in the US or between 9.0 and 12.0 g/dL 
(inclusive) in Europe to qualify for inclusion into the trial. If the subject’s Hb does not 
qualify after Screening Visit 1, Screening Visit 2, or retest Hb, the subject should be 
considered a Screen failure. Refer to Section 5.4.1 for further details regarding repeating 
laboratory measurements during the Screening period.
For all subjects, it is recommended that no additional ESA doses be administered after 
Screening Visit 2 and prior to the Baseline Visit (Day 1).
For all subjects, it is required that a minimum period as outlined below be observed 
between the last dose of ESA administered during Screening and Randomization Visit: 

2 days after last dose of epoetin analogues.


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
7 days after last dose of darbepoetin alfa.

14 days after last dose of methoxy polyethylene glycol-epoetin beta.
After discussion with the Medical Monitor, screening may be extended for an additional 
2 to 4 weeks based on the subject’s Hb level or Hb trajectory or based on timing of the 
last ESA dose given during screening.
Baseline Visit (Day 1)
The Baseline Visit must be performed after a minimum period as outlined above. Subject 
will take their first dose of IMP at the investigative site during the Baseline Visit.
Iron supplementation as needed to maintain ferritin ≥ 100 ng/mL or TSAT ≥ 20% (per 
local product label; see Section 6.5.2.1). Subjects will be instructed to take vadadustat at 
least 1 hour before oral medications containing iron. AEs should be assessed after 
receiving the first dose of IMP.
Treatment Period Visits (Week 2 through Week 52)
Treatment Period Visits will occur from Weeks 2 to 52. The primary efficacy evaluation 
period will occur from Weeks 20 to 26, and the secondary efficacy evaluation period will 
occur from Week 46 to 52. 
End of Treatment Visit/Early Termination Visit
The EOT Visit will be conducted on Week 52 for subjects that complete the 52-week 
treatment period (± 3 days). For subjects that end treatment prior to Week 52, the ET 
assessments should be performed within 7 days after stopping IMP.
Exit Interview
Using a semi-structured interview guide, a contributing CRO will conduct a single 
individual telephone interview with subjects at a subset of sites. The purpose of the exit 
interview is to document the subject’s evaluation of the treatment received as well as 
their overall experience of the clinical trial. The information obtained during the exit 
interview will help to gain a better understanding of the both the disease and treatment 
from the subject’s perspective. It is anticipated that each interview will be approximately 
60 minutes. All exit interviews will be conducted by the CRO, audio recorded, and 
transcribed for analysis during the 4-week follow-up period.
A sample size of 60 subjects in the US and up to 30 subjects from Europe is targeted and 
sufficient to address trial objectives. The sample size was selected based on the subject 
diversity in the trial population; the minimum sample size required for exit interviews is 


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20 subjects. Interviews will be conducted using English or translated versions of the 
interview guide as appropriate.
The interview guide will begin with a very brief overview of the interview process and 
very general questions intended to get the subjects talking about their experiences 
associated with anemia due to CKD (the symptoms and impact of anemia) prior to 
entering the trial, most important or most bothersome aspects of the disease, and 
expectations of treatment prior to the trial. As the discussion continues, the 
semi-structured interview will focus on identifying and understanding the breadth and 
magnitude of subjects' perceived treatment benefits, including general experiences with 
trial treatment; anticipated or unanticipated benefits, impact of those benefits; impact of 
treatment on daily life/functioning; how well treatment addresses most 
important/bothersome symptoms; treatment satisfaction and reasons for satisfaction.
Follow-up Visit
The Follow-up Visit will be conducted 4 weeks after the EOT Visit, or 4 weeks after the 
last dose of IMP for ET.
Unscheduled Visits
Unscheduled assessments may be conducted at any time as medically warranted. At 
minimum, the following activities/procedures will be performed. 

Adverse Event assessments.

Major adverse cardiovascular events (MACE) assessment.

Any other procedures that are medically warranted at the discretion of the 
investigator.
8.1
Subject Reported Outcome Assessments
8.1.1
36-Item Short Form Health-related Quality of Life
The SF-36v2 HRQOL is a subject-reported survey of subject health status which will be 
completed within the ePRO application during the dialysis visits, according to the 
Schedule of Assessments (Table 1.3-1).
8.1.2
Patient Global Impression of Severity Life
The PGI-S is a global index that is used to rate the severity of disease. It will be 
completed within the ePRO application during the dialysis visits, according to the 
Schedule of Assessments (Table 1.3-1).


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8.1.3
Patient Global Impression of Change
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. It will be completed within the 
ePRO application during the dialysis visits, according to the Schedule of Assessments 
(Table 1.3-1).
8.1.4
Functional Assessment of Cancer Therapy-Anemia
The FACT-An is a subject-reported outcome measure which evaluates quality of life 
concerns related to anemia and fatigue. It will be completed within the ePRO application 
during the dialysis visits, according to the Schedule of Assessments (Table 1.3-1).
8.2
Pharmacokinetic Assessments
Plasma samples for PK evaluation will be collected only for subjects randomized to 
vadadustat to analyze for both the parent compound (vadadustat) and its metabolites.
Collection time points are as shown in Table 8.2-1 and Table 1.3-1 (Schedule of 
Assessments). Vadadustat may be dosed before or after the start of dialysis. The predose 
sample should be collected as close to the same time as the serum chemistry sample.
Blood samples will be collected and processed according to the Operations/Laboratory 
Manual. The actual date and time of the PK sample collection will be recorded in the 
eCRF. Additionally, the time of the dose of IMP will be recorded in the eCRF and the 
start and stop time of the dialysis session will be recorded in the eCRF.
Table 8.2-1
Vadadustat Pharmacokinetic Sampling Schema
Week 12
Dialysis Day
Predose, within 60 minutes
X
0.5 hours ± 5 minutes (post-dose)
X
1 hour ± 10 minutes (post-dose)
X
2 hours ± 10 minutes (post-dose)
X
3 hours ± 15 minutes (post-dose)
X
After processing into plasma, aliquots will be placed into appropriately labeled tubes and 
will be placed in a freezer set at −70°C or −20°C, unless otherwise instructed in the 
Operations/Laboratory Manual.
All plasma samples will be shipped to the bioanalytical laboratory for analysis. 
Information will be provided in the Operations/Laboratory Manual.


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8.3
Pharmacodynamic Assessments
Blood samples for EPO, reticulocytes, and other iron indices (ferritin, iron, TIBC, and 
TSAT) analysis will be collected at the times noted in the Schedule of Assessments 
(Table 1.3-1). Blood samples will be collected and processed according to the 
Operations/Laboratory Manual. For all PD sampling, the time of the previous dose of 
IMP is to be recorded in the eCRF and the timing of administration of IMP and the start 
and stop time of the dialysis session will be recorded in the eCRF.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PP
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8.7
Safety Assessments
Details pertaining to the definitions, collection, reporting, and follow-up of AEs are 
described in Section 8.8. If the evaluations will occur on a hemodialysis day, the clinical 
evaluations should be completed before dialysis, if applicable.
8.7.1
Clinical Laboratory Assessments
Clinical laboratory samples will be collected at the time points described in the Schedule 
of Assessments (Table 1.3-1) to perform the clinical laboratory assessments described in 
Section 10.2.
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 central laboratory. If blood is collected on a hemodialysis day, blood 
draws should be done prior to dialysis, if applicable. The investigator is responsible for 
reviewing laboratory results for clinical significance.
Blood samples will be collected for the laboratory evaluations listed in Section 10.2 and 
will be conducted during the course of the trial. For details regarding the timing of these 
assessments refer to the Schedule of Assessments (Table 1.3-1).

Pregnancy Test: A serum pregnancy test will be performed according to the Schedule 
of Assessments (Table 1.3-1) for females of childbearing potential. Additional serum 
or local urine (if possible) pregnancy tests may be conducted throughout the trial in 
sufficient number, as determined by the investigator or required by local regulations, 
P
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to establish the absence of pregnancy during the trial. These results must be available 
and must be negative before the subject takes the first dose of IMP.
8.7.2
Medical History, Demographics, and Physical Examination
Medical history, demographic information, and physical examination (including height) 
will be collected according to the Schedule of Assessments (Table 1.3-1). Relevant 
medical history (with particular emphasis on previous medical conditions that may lead 
to exclusion) and significant ongoing medical conditions or diseases should be 
documented. Dialysis events/issues (ie, the common issues that occur in a given dialysis 
patient such as pruritus, nausea, hypotension) should be recorded as medical history on 
the appropriate eCRF.
During the Treatment period, an abbreviated physical examination should be performed 
at the discretion of the investigator, as clinically indicated.
Dry weight will be collected for all subjects according to the Schedule of Assessments 
(Table 1.3-1). For subjects on ESA, subjects will be weighed for dosing as per the local 
standard of care.
8.7.3
Concomitant Medication Recording
All medications (both prescription and non-prescription, and including vitamins, herbals, 
topicals, inhaled, and intranasal), taken during the screening period and throughout the 
trial, ending at the final protocol required visit, should be recorded on the appropriate 
eCRF. At each trial visit, subjects will be asked whether they have started or discontinued 
any medication since their previous trial visit. This includes single-use or as-needed 
medication use. Any medications taken within 30 days of a reportable event must be 
reported on the Concomitant Medication eCRF.
All medications and treatments, including vitamin supplements, over the-counter 
medications and oral herbal preparations must be recorded in the eCRFs. Routine 
medications and treatments used during each hemodialysis session, such as heparin 
injections or saline flushes, are not required to be recorded unless relevant for an AE or 
SAE. In addition, the ESA, blood transfusion, and iron treatment regimen prior to 
randomization and date of last dose will be recorded.
8.7.4
Vital Signs
Vital signs will be collected at the time points described in the schedule of assessments 
(Table 1.3-1).


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Vital sign measurements including temperature, heart rate, blood pressure, and 
respiratory rate will be assessed in the seated position after 5 minutes of rest prior to 
blood draws. For blood pressure, a total of 2 measurements at intervals of at least 
2 minutes will be performed. Measurements will be taken prior to scheduled blood draws 
when possible. 
8.7.5
Electrocardiogram
Electrocardiograms will be performed at the time points described in the schedule of 
assessments (Table 1.3-1).
A standard 12-lead ECG will be performed at Baseline, which may be obtained up to 
3 days prior to the Baseline Visit. The ECG should be obtained after the subject has been 
resting comfortably in a supine position for approximately 5 minutes and should be taken 
prior to vital sign assessments and blood draws when possible. With the subject in a 
supine position, obtain the 12-lead tracing. All ECGs will be reviewed by the investigator 
for the presence of rhythms of potential clinical concern. A record of the tracing(s) will 
be made and retained with other source documents.
8.7.6
Other Safety Variables
8.7.6.1
Major Adverse Cardiovascular Events
At each post-randomization trial visit, the subject must specifically be questioned 
regarding the occurrence of any potential MACE (all-cause mortality, nonfatal 
myocardial infarction, or nonfatal stroke) plus hospitalization for HF or thromboembolic 
event excluding vascular access thrombosis since the last trial visit. The eCRF must be 
completed in full at each visit even if no potential MACE (all-cause mortality, nonfatal 
myocardial infarction, or nonfatal stroke) plus hospitalization for HF or thromboembolic 
event excluding vascular access thrombosis events have occurred.
8.8
Adverse Events
AE collection will begin from time of signing the ICF through the Safety Follow-up 
Visit. The investigator and trial personnel will review each subject’s laboratory and 
clinical evaluation findings and query the site directly regarding AEs (see Section 8.8.1). 
Subjects must be followed for AEs until the final required protocol visit or until all 
drug-related toxicities and SAEs have resolved (or are considered chronic/stable), 
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8.8.1
Definitions
An AE is defined as any untoward medical occurrence (including an abnormal laboratory 
finding) in a clinical trial subject administered an IMP that occurs in the protocol-
specified AE reporting period and which does not necessarily have a causal relationship 
with this treatment or usage. Adverse events would not include information recorded as 
medical history at Screening for pre-planned procedures for which the underlying 
condition was known and no worsening occurred. An adverse reaction is any untoward 
and unintended response to an IMP related to any dose administered.
An AE includes medical conditions, signs, and symptoms not previously observed in the 
subject that emerge during the protocol-specified AE reporting period, including signs or 
symptoms associated with pre-existing underlying conditions that were not present prior 
to the AE reporting period.
Adverse events therefore include the following: 

All AEs, whether suspected to be causally related to the IMP or otherwise.

All AEs secondary to any medication overdose, medication error, abuse, withdrawal, 
sensitivity, or toxicity.

Illnesses apparently unrelated to the IMP, including the worsening of a pre-existing 
illness (see paragraph below on Pre-existing Conditions).

Injury or accidents. Note that if a medical condition is known to have caused the 
injury or accident (eg, a fall secondary to dizziness), the medical condition (dizziness) 
and the accident (fall) should be reported as 2 separate AEs.

Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test).

Laboratory abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they are associated with an 
already reported clinical event. Laboratory abnormalities associated with a clinical 
event reported as an AE (eg, elevated liver enzymes in a subject with jaundice) 
should be described under ‘Comments’ on the report of the clinical event rather than 
reported as separate AEs.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE. For the purpose of Investigational New Drug (IND) safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between 
the IMP and the AE. Suspected adverse reaction implies a lesser degree of certainty about 
causality.


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Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the 
start of open-label treatment. In more detail, TEAEs are all adverse events which started 
after start of open-label IMP treatment; or if the event was continuous from baseline and 
was worsening, serious, IMP related, or resulted in death, discontinuation, interruption or 
reduction of IMP.
The sponsor maintains and updates a listing of any adverse event of special interest 
(AESI), serious or non-serious, which is of scientific and medical concern specific to the 
sponsor’s product or program, for which ongoing monitoring and rapid communication 
by the investigator to the sponsor could be appropriate.
A SAE includes any event that results in any of the following outcomes:

Death.

Life-threatening; 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.

Persistent or significant incapacity/disability or substantial disruption of the 
ability to conduct normal life functions.

Disability is defined as a substantial disruption in a person’s ability to conduct 
normal life functions.

Requires inpatient hospitalization or prolongs hospitalization.

Hospitalization is defined as an overnight admission with observation of a 
minimum of 24 hours. A hospitalization planned before the start of the trial 
for a pre-existing condition that has not worsened during the AE reporting 
period does not constitute an SAE unless an untoward event occurs related to 
the procedure (eg, elective hospitalization for a total knee replacement due to 
a pre-existing condition of osteoarthritis of the knee that has not worsened 
during the course of the trial).

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.


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In addition to the above criteria for classifying AEs as serious, the following situations 
will also be classified as serious for purposes of this trial: 

Malignancies – If a subject develops basal cell carcinoma of skin, squamous cell 
carcinoma of skin, or cervical carcinoma in situ during the trial, or has worsening of 
these events from baseline, the event will be reported as an SAE by the investigator. 
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. 

Abnormalities in ALT or AST – New elevations in ALT or AST > 3 times ULN, 
with or without an elevation of total serum bilirubin > 2 times ULN are to be reported 
to the sponsor’s Medical Monitor or CRO designee within 24 hours of awareness as 
an SAE with “medically important” criteria selected. The following steps are to be 
taken for subjects who experience new elevations in ALT or AST > 3 times ULN, 
without an elevation of total serum bilirubin > 2 times ULN:

Temporary interruption of IMP.

Repeat testing of ALT, AST, alkaline phosphatase (ALP), and total bilirubin, to 
be completed within 48 to 72 hours to confirm the abnormalities and to determine 
trend.

Trial medication should not be resumed until monitoring indicates abnormalities 
have resolved or are stable.
Nonserious AEs are all AEs that do not meet the criteria for a "serious" AE.
Clinical Laboratory Test Value Changes: It is the investigator’s responsibility to review 
the results of laboratory tests for each individual subject as they become available. This 
review will be documented by the investigator’s dated signature on the laboratory report. 
The investigator may repeat the laboratory test or request additional tests to verify the 
results of the original laboratory tests. If this laboratory value is considered medically 
relevant (ie, clinically significant) by the investigator (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, and/or fulfills a seriousness criterion, this is considered an AE. 
Severity: Adverse events will be graded on a 3-point scale and reported as indicated on 
the eCRF. The severity of an adverse experience is defined as follows:
1 = Mild:
Does not interfere with subject's usual function.
2 = Moderate:
Interferes to some extent with subject's usual function.
3 = Severe:
Interferes significantly with subject's usual function.
Note that a severe AE is not necessarily a serious AE. For example, a headache may be 
severe in intensity, but would not be classified as serious unless it met 1 of the criteria for 
serious events listed above.


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IMP Causality: The causal relationship of the AE to the IMP (vadadustat or darbepoetin 
alfa) will be assessed by both the investigator and the sponsor.
The assessment of causal relationship to the IMP should be evidence-based, and not 
based on the premise that all AEs are possibly causally related to the IMP until proven 
otherwise.
Examples of evidence that would suggest a causal relationship between the IMP and the 
AE include the occurrence of an AE that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, hepatic injury, and Stevens-Johnson 
syndrome) or an AE that is uncommon in the population exposed to the drug.
The causal relationship of the AE is assessed using a binary system, and AEs are 
classified as either “related” or “unrelated” as follows:
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 the IMP is 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, IMP, 
other treatment (concomitant, or previous), withdrawal of IMP, administration error, 
protocol-related procedure, others (specify).
8.8.2
Eliciting and Reporting Adverse Events
The investigator will regularly assess subjects for the occurrence of AEs. To avoid bias in 
eliciting AEs, subjects should be asked the nonleading question: “How have you felt 
since your last visit?” All AEs (serious and nonserious) reported by the subject must be 
recorded on the source documents and eCRF provided by the sponsor. Adverse event 
collection will begin from the time a subject signs the ICF.


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Medical terminology should be used for AE reporting. Adverse events should be reported 
as a single unifying diagnosis whenever possible or, in the absence of a unifying 
diagnosis, as individual signs or symptoms.
Exacerbation or disease progression should be reported as an AE.
In addition, the sponsor must be notified immediately by telephone, fax, or e-mail. 
Special attention should be paid to recording hospitalization and concomitant 
medications.
Adverse event start date and time, end date and time, seriousness, severity, relationship to 
trial treatment (IMP Causality), action taken with trial treatment and outcome will be 
recorded on the source documents and in the eCRF.
8.8.2.1
Guidelines for Reporting Adverse Events
Each AE is to be classified by the investigator as SERIOUS or NONSERIOUS and all 
AEs (serious and non-serious) are to be reported on the AE eCRFs.
All AEs that occur in trial subjects during the AE reporting period specified in this 
protocol must be reported, whether or not the event is considered related to IMP 
(vadadustat or darbepoetin alfa). In addition, each trial subject will be questioned about 
AEs at each visit following the initiation of treatment as described in Section 8.8.2.
The AE collection for this trial begins from time of ICF signing through the Safety 
Follow-up Visit.
In addition, any AE that occurs subsequent to the AE reporting period that the 
investigator assesses as related to the IMP should also be reported as an AE.
The following guidelines are to be used when reporting AEs for this trial:
Medical Diagnoses – Whenever possible, a medical diagnosis term should be used to 
report AEs instead of signs and symptoms due to a common etiology, as determined by 
qualified medical trial staff. For example, pneumonia should be the reported AE term, 
instead of fever and dyspnea, when the diagnosis has been established. Signs and 
symptoms should be reported as event terms only when the medical diagnosis remains 
unknown and revised to a medical diagnosis term once it has been established.
Procedures – Diagnostic and therapeutic non-invasive and invasive procedures, such as 
surgery, should not be reported as AEs. However, the medical condition for which the 
procedure was performed should be reported if it meets the definition of an AE. For 
example, an acute appendicitis that begins during the AE reporting period should be 
reported as the AE and the resulting appendectomy noted under “Comments”.


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Pre-planned therapeutic procedures not associated with a new medical condition or 
worsening pre-existing condition should not be reported as AEs.
Pre-existing Conditions – In this trial, a pre-existing condition (ie, a disorder present 
before the AE reporting period started and noted on the pretreatment medical 
history/physical examination form) should not be reported as an AE unless the condition 
worsens or episodes increase in frequency during the AE reporting period.
Abnormal Test Findings – All laboratory test results will be reviewed by the 
investigator. The investigator will utilize his/her judgment in determining if out-of-range 
laboratory values are clinically significant (CS) and will denote this using the 
abbreviation “CS” on the laboratory report for source documentation. If there are 
significant changes in a laboratory report from a previous visit that are determined to be 
CS, these should also be reported as AEs. An expected laboratory abnormality from a 
condition that is part of the medical history is not considered CS for the purposes of the 
trial unless it represents a worsening of the condition.
Abnormalities in ALT, AST, and Total Bilirubin – Abnormalities in ALT, AST, and 
total bilirubin should be reported to the sponsor’s Medical Monitor or CRO designee 
within 24 hours of awareness as 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
If new elevations in ALT or AST > 3 times ULN, without an elevation of total serum 
bilirubin > 2 times ULN are identified, the following steps are to be taken:

Temporary interruption of IMP;

Repeat testing of ALT, AST, ALP, and total bilirubin, should be completed within 48 
to 72 hours to confirm the abnormalities and to determine trend;

Trial medication should not be resumed until monitoring indicates abnormalities have 
resolved or are stable.

Details on the management of subjects with other ALT and AST abnormalities are further 
described in Table 7.3.2-1.
Worsening of Anemia – In this trial, it is possible that some subjects may experience a 
worsening of anemia. As the primary endpoint of this trial assesses Hb response, 
worsening of anemia is captured as part of this efficacy parameter. Worsening of anemia 
should not be considered an AE unless the worsening of anemia is associated with a 
cause other than the subject’s CKD. However, if an event of worsening of anemia is due 


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to CKD and meets any serious criteria (see Section 8.8.1), it should be reported as an 
SAE.
Transplantation – During this long-term trial, it is anticipated that some subjects may 
receive a kidney transplant. These events will not be recorded as AEs. Subjects will 
discontinue IMP for receipt of a kidney, other solid organ, hematopoietic stem cell or 
bone marrow transplant and should continue with the Schedule of Assessments and safety 
assessments as described in Section 7.3.2.
Malignancy – During this long-term trial, some subjects may develop a newly diagnosed 
malignancy or a recurrence of a malignancy. At the discretion of the investigator, these 
subjects may continue IMP (vadadustat or darbepoetin alfa). For reporting of AEs of 
malignancy, see Section 8.8.1.
Reporting MACE – Investigators will be counseled to report any MACE (all-cause 
mortality, nonfatal myocardial infarction, or nonfatal stroke) plus hospitalization for HF 
or thromboembolic event excluding vascular access thrombosis events that they assess as 
requiring adjudication. All events will be submitted in a blinded fashion to the SEAC for 
adjudication. To protect the integrity of the trial, already adjudicated events will not be 
unblinded or reported to either Health Authorities or investigators as safety reports unless 
otherwise requested or required by Health Authorities or Ethics Committees. After trial 
completion, these events will be included in the final analysis which will be unblinded 
and submitted to Health Authorities with the trial report.
8.8.2.2
Reporting Serious Adverse Events
Any SAE, regardless of causal relationship, must be reported to the sponsor’s Medical 
Monitor or CRO designee within 24 hours after the investigator becomes aware of the 
SAE. Compliance with this time requirement is essential so that the sponsor may comply 
with its regulatory obligations.
The initial SAE report should be completed as fully as possible but should contain, at a 
minimum:

Subject number/identification, sex, and age/date of birth.

The date of report.

Name of the reporter.

Name of the suspected medicinal product.

A description of the event, including event term(s), seriousness criteria, and a clinical 
summary of the event.

Causality assessment.


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Information about all SAEs (either initial or follow-up information) should be collected 
and recorded in English on the electronic SAE Report Form within the electronic data 
capture (EDC) system. The investigator must assess the relationship to each specific 
component of the IMP. If the event meets serious criteria and it is not possible to access 
the EDC system, a paper SAE Report Form should be sent to the CRO via email or fax, 
or the investigator will call the CRO SAE hotline within 24 hours of being made aware of 
the SAE (reference the site manual for contact information). When the EDC system 
becomes available, the SAE information must be entered within 24 hours of the system 
becoming available.
The investigator must report follow-up information relating to an SAE to the sponsor’s 
Medical Monitor or CRO designee within 24 hours of awareness updating the electronic 
eCRF with the new information or by submitting a paper SAE Report Form in the event 
that the EDC is not available. When the EDC system becomes available, the SAE 
information must be entered within 24 hours. The subject should be observed and 
monitored carefully until the condition resolves or stabilizes.
All deaths are to be thoroughly investigated and reported. Autopsy reports and death 
certificates are to be obtained, if possible.
The sponsor and/or its designee are responsible for reporting SAEs to all applicable 
regulatory agencies and the central ethics committees within the required timeline.
The investigators are responsible for submitting required safety information to their local 
IRB or IEC as per local regulations. This information includes, but is not limited to, any 
safety alert letter received from the sponsor and any SAEs occurring at their investigative 
site.
8.8.3
Procedure for Breaking the Blind
Blinding procedures are described in Section 6.3.2.
8.8.4
Follow-up of Adverse Events
All AEs should be followed until they are resolved or return to baseline, or the 
investigator assesses them as chronic or stable, or the subject’s participation in the trial 
ends (ie, until a final report is completed for that subject).
In addition, all SAEs and those nonserious events assessed by the investigator as related 
to the IMP should continue to be followed even after the subject's participation in the trial 
is over. Such events should be followed until they resolve or until the investigator 
assesses them as “chronic” or “stable”. Resolution of such events is to be documented on 
the appropriate eCRF.


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8.8.4.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF with the current status (ongoing or resolved/recovered) noted. For any AE 
having been identified throughout the trial, during analysis, additional relevant medical 
history information may be requested by the sponsor to further ascertain causality 
(including, but not limited to, information such as risk-related behavior, family history 
and occupation).
8.9
Treatment of Overdose
Certain safety events, called “Special Situations”, that occur in association with the IMP 
may require reporting. These Special Situations include, but are not limited to, the 
following:

Overdose of the medicinal product

Darbepoetin alfa overdose – The USPI or SmPC should be referenced for 
information on darbepoetin alfa overdosing. 

Vadadustat overdose - There is no known antidote for vadadustat. In cases of 
suspected overdose, subjects should be treated per standard medical practice 
based on the investigator’s judgment and dose delays, reductions, or interruptions 
may be implemented as necessary. See Section 8.8 for guidance on AEs and 
SAEs.

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 [eg, name confusion]).

Drug-drug interaction.
Note: Chronic overdosage with vadadustat may result in excessive production of RBCs 
and polycythemia. Polycythemia can be potentially life threatening and may result in 
severe thrombosis and death (known as hyperviscosity syndrome). If hyperviscosity 
syndrome is observed, vadadustat should be discontinued and standard treatment for 
polycythemic hyperviscosity syndrome should be initiated (ie, phlebotomy).
Special situations should be reported on the Special Situations eCRF whether they result 
in an AE/SAE or not. Special situations with associated AE/SAE should also be reported 
on the corresponding AE/SAE forms, following applicable AE or SAE process.
8.10
Subject Assessment Recording
Not applicable.


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8.11
Other Assessments
8.11.1
Dialysis Adequacy and Treatment
Dialysis adequacy, as documented in the dialysis records, will be recorded in the eCRF. 
During screening, the most recent dialysis adequacy measurement within 8 weeks prior to 
or during screening should be recorded in the eCRF. Thereafter, dialysis adequacy should 
be assessed every 3 months.
Dialysis Treatment includes hemodialysis vascular access type use and any changes at 
baseline and monthly; and changes in renal replacement therapy (from in-center 
hemodialysis).
9
Statistical Considerations
Data collected throughout the trial will be summarized using descriptive statistics and 
listed in by-subject listings. Continuous variables will be summarized using number of 
subjects with data, mean, standard deviation, median, minimum, and maximum. For 
categorical variables, the number and percentage of subjects in each category will be 
tabulated. Summaries will be provided by treatment group within appropriate analysis 
populations (as defined in Section 9.2) and by time point/time period, as appropriate.
For Hb, Baseline will be calculated as the average of the last 2 central laboratory Hb 
measurements of samples taken at or prior to the date of randomization. For other 
parameters, unless otherwise specified, Baseline will be defined as the last available 
value prior to the first dose of IMP.
Hemoglobin values will be assessed through the central laboratory for dose adjustments, 
efficacy, and safety evaluations.
9.1
Sample Size
The primary efficacy endpoint is defined as the Hb change from Baseline (average 
pretreatment Hb) to the average Hb from Weeks 20 to 26 (inclusive).
The primary efficacy objective of this trial is to first show that vadadustat QD is 
noninferior to darbepoetin alfa within the noninferiority margin. Noninferiority will be 
established based on a margin of -0.75 g/dL (for vadadustat minus darbepoetin alfa). If 
vadadustat QD meets the noninferiority margin, then the next objective is to show that 
vadadustat TIW is noninferior to darbepoetin alfa within the noninferiority margin.
For the primary efficacy analysis in this trial, it is assumed that the mean change from 
Baseline in Hb for vadadustat will be the same as for the active control darbepoetin alfa, 
and the common standard deviation for the mean change from Baseline is assumed to be 


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1.2 g/dL. Noninferiority will be established based on a 2-sided 95% confidence interval 
(CI) for the difference between the vadadustat group and darbepoetin alfa group and 
using a noninferiority margin of -0.75 g/dL.
With these assumptions and approximately 100 subjects per treatment group, the 
noninferiority test will have > 90% power with consideration of a 30% drop out rate.
9.2
Datasets for Analysis
The following analysis populations will be used in this trial:

Randomized population: defined as all subjects randomized. Analyses of this 
population will be based on the randomized treatment.

Full Analysis Set (FAS) population: defined as all subjects in the randomized 
population who received at least 1 dose of IMP and had at least 1 post dose Hb. 
Analyses of this population will be based on the randomized treatment.

Per protocol (PP) population: defined as all randomized subjects who received IMP 
during the primary evaluation period, had at least 1 Hb assessments during the 
primary evaluation period, and had no critical or major protocol deviation affecting 
the primary endpoint analyses (ie, prior to Week 26). Analyses of this population will 
be based on actual treatment received, as described for the Safety population.

Safety population: defined as all subjects in the randomized population who received 
at least 1 dose of IMP. Analysis of this population will be based on the actual 
treatment received. Subjects who received in error some vadadustat and some 
darbepoetin alfa (excluding rescue therapy) will be classified by the more frequently 
received drug.
Efficacy analyses will utilize the randomized, FAS, and PP populations while safety 
analyses will utilize the safety population.
9.3
Handling of Missing Data for Primary and Secondary Endpoint 
Analysis
It is expected that up to 30% of subjects will discontinue the trial. The reasons for 
discontinuation will be summarized by treatment arm. Missing Hb values will be imputed 
using multiple imputation.
9.4
Statistical Analyses
9.4.1
Efficacy Analyses
The primary efficacy endpoint as well as all key secondary and other efficacy endpoints 
will be summarized using descriptive statistics by treatment group, as well as by trial visit 
and/or analysis period as appropriate. Mean values of Hb as well as selected other 
efficacy parameters will be plotted across trial visits/periods by treatment group.


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9.4.1.1
Primary Efficacy Endpoint Analysis
The primary efficacy endpoint is defined as the change in Hb between Baseline (average 
pretreatment Hb) and the primary evaluation period (average Hb from Weeks 20 to 26, 
inclusive).
9.4.1.1.1
Primary Estimand
The primary estimand defining the treatment effect of interest in this trial uses the 
treatment policy strategy specified in the ICH E9 (R1) Addendum.25 In this trial, the 
research question is to compare the assignment of darbepoetin alfa to vadadustat, 
regardless of intercurrent events. The primary analysis will be performed in the 
randomized population in accordance with intent-to-treat. This means the analysis will 
include individuals who never received treatment, discontinued treatment, were rescued 
with any therapy, and withdrew consent. The estimate of the treatment effect of interest 
will be the one regardless of whether the intercurrent event occurred.
The primary estimand for this trial is defined by the following components:

Population: randomized population.

Variable: change in Hb from Baseline (average pretreatment Hb) to the primary 
evaluation period (average Hb from Weeks 20 to 26, inclusive).

Intercurrent event: never received treatment, discontinued treatment, rescued with any 
therapy, or withdrew consent.

Population-level summary: difference in mean change in Hb from baseline to the 
primary evaluation period between the vadadustat groups and darbepoetin alfa control 
group.
9.4.1.1.2
Primary Analysis of Primary Efficacy Endpoint
The primary analysis will use the randomized population with an analysis of covariance, 
with randomization stratification factors and Baseline Hb as covariates.
A 2-sided, 95% CI will be calculated for the difference in mean change in Hb from 
Baseline to the primary evaluation period between the vadadustat group and darbepoetin 
alfa control group. Noninferiority of vadadustat will be established if the lower limit of 
this CI is ≥ -0.75 g/dL.
A hierarchical testing scheme will be used to correct for the multiplicity of the 2 primary 
endpoints: comparison between vadadustat QD vs. darbepoetin alfa and comparison 
between vadadustat TIW vs. darbepoetin alfa.

Step 1: comparison between vadadustat QD vs. darbepoetin alfa.

If the noninferiority of vadadustat is established in step 1, then move to the step 2;


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
Step 2: comparison between vadadustat TIW vs. darbepoetin alfa.
9.4.1.1.3
Sensitivity Analyses of Primary Efficacy Endpoint Screening
The following sensitivity analyses will be conducted: 

Primary analysis will be repeated using the FAS population.

Primary analysis will be repeated using the PP population with the actual treatment 
received.

Primary analysis will be repeated with imputation of data which may have been 
affected by a subject’s having received any form of rescue (transfusion or ESA). 
Details are provided in the Statistical Analysis Plan (SAP).

A mixed model for repeated measures will be fit to the observed data only.
9.4.1.1.4
Analyses of Primary Efficacy Endpoint When All Randomized 
Subjects Complete Week 26
Analyses of the primary efficacy endpoint may be conducted when all randomized 
subjects either complete their Week 26 evaluations or early discontinue the trial before 
Week 26.
9.4.1.2
Key Secondary Efficacy Endpoint Analysis
The key secondary endpoint will be formally analyzed once the non-inferiorities have 
been established in the primary endpoint for vadadustat QD and TIW regimens.
Mean change in Hb value between Baseline (average pretreatment Hb) and the secondary 
evaluation period (average Hb from Weeks 46 to 52) will be analyzed using the same 
methodology as specified for the primary efficacy endpoint. Sensitivity analyses similar 
to those of the primary efficacy endpoint will be performed and details will be provided 
in the SAP.
9.4.1.3
Other Efficacy Endpoint Analysis
Other efficacy endpoints analyses will be performed using the randomized and FAS 
population, using the assigned treatment as described in Section 9.2. Analysis for the key 
secondary efficacy endpoints will be repeated using the PP population with the actual 
treatment received.
9.4.1.4
Subgroups
Analyses of the primary efficacy endpoint and key secondary efficacy endpoints will also 
be performed using the randomized and FAS populations, using the assigned treatment, 
for subgroups based on the following:


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
Low darbepoetin alfa dose group (≤ 0.45 µg/kg/week) or high darbepoetin alfa dose 
group (> 0.45 and ≤ 1.5 µg/kg/week).

Due to use of different target Hb levels in the US versus non-US, the endpoints will 
also be analyzed for subsets based on the target Hb level: 

The US subset will be assessed due to the target Hb range of 10.0 to 11.0 g/dL in 
the US.

The European subset will be assessed due to the target Hb range of 10.0 to 
12.0 g/dL in the EU.

Geographic region (US, Europe).

Age.

Gender.

Race.
Blinded summary safety data will be provided for all subjects who had the opportunity to 
complete the Week 12 Visit by a cut-off date, with the cut-off date to be determined at a 
later date to support potential regulatory filing.
9.4.2
Safety Analysis
All analyses of safety data will use the safety population.
9.4.2.1
Adverse Events
Adverse events will be summarized using the number and percentage of subjects with 
AEs for all subjects in the safety population. Summaries will also be provided for 
subgroups including Region, Age, Gender, and Race.
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent and post-treatment AEs will be summarized by SOC and preferred 
term for each treatment group. Adverse events will also be summarized by their 
maximum severity.
Summaries will also be provided for the following types of AEs:

SAEs.

Related AEs (including all categories for relationship to IMP other than “Unrelated”, 
as determined by the investigator).

AEs leading to early discontinuation of IMP.

Summaries on adjudicated events (see Section 9.5) will be provided by treatment 
group.


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9.4.2.2
Remaining Safety Endpoints
The analysis of the safety endpoints will be detailed in the SAP.
Any Hb value postdose above a set threshold will be considered as a “yes” in the Hb 
related safety analysis. Subjects with no available data post Baseline will be excluded 
from this analysis. All other subjects will be classified to the “no” category.
The analysis of proportion of subjects with any Hb increase > 1.0 g/dL within any 2-week 
interval or > 2.0 g/dL within any 4-week interval post Baseline will classify a subject as a 
“yes” if at least 1 of the following criteria at any point after Day 1 is met:

Hb increase > 1.0 g/dL within any 2-week interval.

Hb increase > 2.0 g/dL within any 4-week interval.
Subjects with no available data post Baseline will be excluded from this analysis. All 
other subjects will be classified to the “no” category.
Observed values of continuous and categorical parameters and changes from Baseline for 
continuous parameters to each trial visit will be summarized descriptively for vital signs 
and clinical laboratory results. Graphical displays of selected laboratory parameters will 
also be provided.
9.4.3
Other Analyses
9.4.3.1
Disposition of Subjects
The number and percentage of subjects randomized and included in each analysis 
population will be summarized by treatment and overall. Reasons for excluding subjects 
from the analysis populations will be presented in a by-subject listing.
The number of randomized subjects who completed each period of IMP treatment 
(Conversion and Maintenance, and Long-term Treatment), discontinued from IMP early, 
and completed or discontinued from the trial and reasons for discontinuation will be 
summarized by treatment group and overall.
9.4.3.2
Analysis of Demographic and Baseline Characteristics
Descriptive statistics will be generated for demographic and pretreatment variables for 
each analysis population defined in Section 9.2.
Medical history terms will be coded using the MedDRA and summarized by SOC and 
preferred term for each treatment group based on the safety population.


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9.4.3.3
Concomitant Medications
Prior and concomitant medications will be coded using the World Health Organization 
Drug dictionary.
Prior medications will be defined as any medications that were taken before the date of 
the first dose of the IMP. Concomitant medications will be defined as any medications 
taken at any time from the date of the first dose of the IMP through the date of the last 
dose of the IMP.
9.4.3.4
Pharmacokinetic Analysis
Vadadustat plasma concentrations may be included in a population PK analysis that 
would be reported separately. Vadadustat and metabolite concentrations will be listed. 
9.4.3.5
Pharmacodynamic Analysis
A by-subject listing of all PD variables (EPO, reticulocytes, and iron indices) 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. For PD variables analyzed after database lock, values will be reported 
separately.
9.4.3.6
Pharmacogenomic Analysis
No PGx analysis is planned.
9.4.3.7
Future Biospecimen Research Analysis
No FBR analysis is planned.
 
9.5
Data Monitoring, Safety Event Adjudication, and Independent 
Expert Panel Committees
An IDMC will be established to review and discuss trial safety data as subjects are 
enrolled and followed. The team will have no affiliation with any trial site, and will meet 
as per IDMC charter guidelines. The IDMC will be unblinded and will include, at a 
minimum, a nephrologist, a cardiologist, and a biostatistician. The discussions of the 
IDMC will include a review of key safety endpoint data (ie, AEs, SAEs, vital signs, 
ECGs, and laboratory assessments). Written records of the IDMC meetings, the materials 
reviewed, and the decisions made will be maintained. Details on the roles and 
PPD


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responsibilities of the IDMC and guidelines for monitoring trial safety data will be 
described further in the IDMC charter.
An independent SEAC that is composed of independent experts will be formed prior to 
trial commencement to adjudicate MACE (all-cause mortality, nonfatal myocardial 
infarction, or nonfatal stroke) plus hospitalization for HF or thromboembolic event 
excluding vascular access thrombosis events. The committee will have no affiliation with 
any trial site and will be blinded throughout the course of the trial. Details on the 
responsibilities of the SEAC will be described further in the SEAC charter.
An Independent Expert Panel Committee for Hepatic Events of Interest will also be 
formed prior to trial commencement to adjudicate hepatic events.


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10
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight 
Considerations
10.1.1
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, FDA regulations 
International Council for Harmonisation (ICH) GCP: Consolidated Guideline (E6), 
international ethical principles derived from the Declaration of Helsinki on Ethical 
Principles for Medical Research Involving Human Subjects, adopted by the General 
Assembly of the World Medical Association (2013) and Council for International 
Organizations of Medical Science (CIOMS) guidelines, and applicable local laws and 
regulations. Each trial site will seek approval/favorable opinion by an IRB or IEC 
according to regional requirements, and the investigator will provide that documentation 
to the sponsor. The IRB/IEC will evaluate the ethical, scientific, and medical 
appropriateness of the trial. Further, in preparing and handling the eCRF, the investigator, 
subinvestigator and their staff will take measures to ensure adequate care in protecting 
subject privacy. To this end, a subject ID will be used to identify each subject.
Financial aspects, subject insurance and the publication policy for the trial will be 
documented in the agreement between the sponsor and the investigator.
10.1.2
Institutional Review Board/Independent Ethics Committee
It is the responsibility of the investigator to have prospective approval of the trial 
protocol, protocol amendments, ICFs, and other relevant documents, (eg, recruitment 
advertisements, if applicable) from the IRB/IEC. All correspondence with the IRB/IEC 
should be retained in the investigator file. Copies of IRB/IEC approvals should be 
forwarded to the sponsor or its designee.
In case of substantial protocol amendment, the sponsor will obtain approval from 
responsible Regulatory Authorities before implementation.
The only circumstance in which an amendment may be initiated prior to IRB/IEC 
approval is where the change is necessary to eliminate apparent immediate hazards to the 
subjects. In that event, the investigator must notify the IRB/IEC and the sponsor in 
writing immediately after the implementation.


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10.1.3
Informed Consent
Informed consent will be freely obtained from all subjects (or their guardian as applicable 
for local laws) prior to inclusion in the trial. The ICF will be approved by the same 
IRB/IEC that approves this protocol. 
Each ICF will comply with the ICH GCP: Consolidated Guideline E626 and local 
regulatory requirements. The investigator will ensure that the sponsor reviews and 
authorizes any written site-specific ICF used in the trial before submission to the 
IRB/IEC.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent. However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s).
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject by the investigator (or a qualified designee), and it has 
been documented that the subject has had the opportunity to ask questions and have those 
questions answered, the IRB/IEC-approved written ICF will be signed and dated by both 
the subject and the person obtaining consent (investigator or designee), as well as by any 
other parties required by the IRB/IEC. The subject will receive a copy of the signed ICF; 
the original shall be kept on file by the investigator. Subjects may be asked to sign 
additional ICFs if the protocol is amended and the changes to the protocol results in 
additional information that needs to be provided to the subjects, so that they can make a 
knowledgeable and voluntary decision on continued trial participation. Female partners 
of male subjects who become pregnant during the course of the trial may be asked to sign 
additional ICFs in order to collect additional information regarding the nonsubject partner 
and fetus.
 
10.1.4
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region(s) where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
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(or their representatives or development partners) may be allowed full access to inspect 
and copy the records, consistent with local requirements. All IMPs, subject bodily fluids, 
and/or other materials collected shall be used solely in accordance with this protocol, 
unless otherwise agreed to in writing by the sponsor.
Subjects will be identified only by unique subject ID in eCRF. If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations.
10.1.5
Reporting of Safety Issues and Serious Breaches of the Protocol 
or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority, or if the investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of the investigational product, the 
sponsor should be informed immediately.
In addition, the investigator will inform the sponsor immediately of any urgent safety 
measures taken by the investigator to protect the trial 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.
10.1.6
Quality Control and Quality Assurance
10.1.6.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH GCP: Consolidated Guideline (E6), and 
applicable regulatory requirements and local laws. As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor's monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all investigators and trial 
site personnel will undergo initial and ongoing training for this particular trial, and this 
training will be clearly documented.
10.1.6.2
Auditing
The sponsor's Quality Assurance Unit (or representative) may conduct trial site audits. 
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, and a review of the eCRF with source documents, as 
applicable. The investigator agrees to participate with audits. It is important that the 


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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.
Regulatory authorities may inspect the investigator site during or after the trial. The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
10.1.7
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, treatment assignment error, subject enrolled in violation of eligibility criteria or 
concomitant medication criteria, fraud or misconduct, increased health risk to the subject, 
or confounded interpretation of primary trial assessments), or except where necessary to 
eliminate an immediate hazard to trial subjects, the investigator or designee will contact 
the sponsor or designee (and IRB/IEC, as required) at the earliest possible time by 
telephone or via e-mail. If needed, the investigator and sponsor (or designee) will come 
as quickly as possible to a joint decision regarding the subject’s continuation in the trial. 
This decision will be documented by the investigator and the sponsor (or designee) and 
reviewed by the site monitor.
Any major protocol deviation will be recorded in the eCRF along with the start date and 
details of the deviation.
10.1.8
Records Management
10.1.8.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to medical 
records, electronic data, screening logs, dialysis records or flow sheets, and recorded data 
from automated instruments. All source documents pertaining to this trial will be 
maintained by the investigators and made available for direct inspection by authorized 
persons.
Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF. In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements.


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10.1.8.2
Data Collection
During each subject’s visit to the site, an investigator or their designee participating in the 
trial will record information to document all significant observations. At a minimum, 
these notes will contain:

Documentation of the informed consent process, including any revised consents;

Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial;

The date of the visit and the corresponding Visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator's assessment of relationship to IMP must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed; 

The signature (or initials) and date of the investigator (or designee) who made an 
entry in the medical record.
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above.
Information from medical records and other source documents will be entered by 
investigative site personnel onto eCRFs in the sponsor’s EDC system that is 21 Code of 
Federal Regulations (CFR) Part 11 compliant. Changes to the data will be captured by an 
automatic audit trail in the EDC system.
Electronic data not entered on eCRF, such as data received from central laboratories will 
be reconciled using key data fields by the sponsor or the CRO with the eCRF data to 
ensure consistency.
10.1.8.3
File Management at the Trial Site
The investigator will ensure that the trial site file is maintained in accordance with 
Section 8 of the ICH GCP: Consolidated Guideline (E6) and as required by applicable 
local regulations. The investigator/institution will take measures to prevent accidental or 
premature destruction of these documents.


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10.1.8.4
Records Retention at the Trial Site
Regulatory requirements for the archival of records for this trial necessitate that 
participating investigators maintain detailed clinical data for the longest of the following 
3 periods:

A period of at least 2 years after the date on which approval to market the drug is 
obtained (or if IMP development is discontinued, the date regulatory authorities were 
notified of discontinuation); OR

A period of at least 3 years after the sponsor notifies the investigator that the final 
report has been filed with regulatory authorities.

Longer, region-specific storage requirements, if applicable.
The investigator must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) provision of an opportunity for sponsor to 
collect such records. The investigator will be responsible to maintain adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial including any data clarification forms received from the sponsor. Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities. 
If the investigator withdraws from the trial (eg, due to relocation or retirement), all 
trial-related records should be transferred to a mutually agreed-upon designee within a 
sponsor-specified timeframe. Notice of such transfer will be given to the sponsor in 
writing.
10.1.8.5
Publication of Trial Results
No publication or disclosure of trial results will be permitted, except under the terms and 
conditions of a separate, written agreement between the sponsor (Otsuka Pharmaceutical 
Development & Commercialization, Inc. [OPDC] in collaboration with Akebia) and the 
investigator and/or the investigator’s institution. The sponsor and Akebia must have the 
opportunity to review and approve all proposed abstracts, manuscripts, or presentations 
regarding this trial prior to submission for publication/presentation. Any information 
identified by the sponsor or Akebia as confidential must be deleted prior to submission.
For all publications relating to the trial, 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 (ICMJE).


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10.1.8.5.1
Publication Authorship Requirements
Authorship for any Otsuka- or Akebia-sponsored publications resulting from the conduct 
of this trial will be based on ICMJE authorship criteria 
(http://www.icmje.org/recommendations). According to ICMJE guidelines, one may be 
considered an author only if the following criteria are met:
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial subjects who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial subjects consent to such acknowledgement in any 
publications resulting from its conduct.


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10.2
Appendix 2: Clinical Laboratory Tests
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.
The tests detailed in Table 10.2-1 will be performed.
Table 10.2-1
Clinical Laboratory Assessments
Complete Blood Count
Iron Indices
Serum Chemistry
Hb
Ferritin
Sodium
Hematocrit
Iron
Potassium
RBC
TIBC
Bicarbonate
MCV
TSAT
Chloride
MCH
Calcium
MCHC
Magnesium
Platelets
Lipid Profile
Phosphorus
RDW
Total Cholesterol
Glucose
WBC
LDL
Creatinine
Differential WBC
HDL
BUN
  Neutrophils
Triglycerides
CPK
  Lymphocytes
Uric Acid
  Monocytes
Liver Function Tests
Albumin
  Eosinophils
Total bilirubin
Total Protein
  Basophils
ALP
Hematology panel without 
differential
ALT/SGPT
Hb
AST/SGOT
Hematocrit
LDH
RBC
MCH
MCHC
RDW
RBC morphology and MCV
Platelets
WBC
Additional Laboratory Tests
β-HCG
Reticulocyte Counta
Folate
Vitamin B12
CRP
Erythropoietin
INRb
PTb
β-HCG = beta human chorionic gonadotropin; ALP = alkaline phosphatase; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CPK = creatine 
phosphokinase; CRP = C-reactive protein; Hb = hemoglobin; HDL = high density lipoprotein; 
INR = international normalized ratio; LDH = lactate dehydrogenase; LDL = low density lipoprotein; 
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV 


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= mean corpuscular volume; PT = prothrombin time; RBC = red blood cell; RDW = red blood cell 
distribution; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic 
transaminase; TIBC = total iron-binding capacity; TSAT = transferrin saturation; WBC = white blood 
cell.
aAn automated reticulocyte count should include both absolute and percent.
b INR and PT to be collected at the discretion of the investigator and sent to the central laboratory for 
analysis only if ALT or AST > 3x ULN to evaluate stopping criteria.


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10.3
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information
In nonclinical animal embryo-fetal development and fertility studies, there was no 
evidence of teratogenicity, no skeletal or visceral malformations, and no changes in male 
or female reproductive and fertility indices, or in sperm parameters. In rats, decreased 
fetal body weight and reduced skeletal ossification were noted at the highest dose tested 
of 160 mg/kg/day. Peri-postnatal development studies have not yet been conducted with 
vadadustat, and there are no data on the transmission of vadadustat in breast milk or the 
effect of vadadustat on infants.
Although the potential risk of vadadustat on the developing fetus is limited based on 
studies to date, the trial requires that all subjects must agree to use adequate contraception 
throughout the trial and for 30 days after the last dose of IMP.
All WOCBP are females whose menstruation has started and who are not documented as 
sterile (eg, have had a bilateral oophorectomy, or hysterectomy, or who have been 
postmenopausal for at least 12 months).
For males and WOCBP, who are sexually active, there must be a documented agreement 
that the subject and their partner will take effective measures (ie, 2 different approved 
methods of birth control or remains abstinent) to prevent pregnancy during the course of 
the trial and for 30 days after the last dose of IMP. Unless the subject is surgically sterile 
(ie, females who have had a bilateral oophorectomy, have had a hysterectomy, or have 
been postmenopausal for at least 12 consecutive months; or males who have had a 
vasectomy), has negative pregnancy test results at Screening (serum), or remains 
abstinent during the trial and for 30 days after the last dose of IMP, 2 of the following 
approved methods of birth control must be used: 

Total abstinence from sexual intercourse (minimum one complete menstrual cycle 
prior to Screening Visit, throughout the trial, and for 30 days after the last dose of 
IMP).

A partner who has had a vasectomy.

Hormonal contraceptives (oral, parenteral, or transdermal) for at least 3 months prior 
to IMP administration or intrauterine contraception/device, throughout the trial, and 
for 30 days after the last dose of IMP.

Double-barrier method (such as male condom, female condom, diaphragm, sponge, or 
cervical cap together with spermicidal foam/gel/film/suppository) starting at 
Screening Visit 1, throughout the trial, and for 30 days after the last dose of IMP.


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The contraceptive method will be documented in the eCRF. Male subjects must also 
agree not to donate sperm from trial screening through 30 days after the last dose of IMP.
Before enrolling males and females in this clinical trial, investigators must review the 
below information about trial participation as part of the ICF process. The topics should 
generally include:

General information.

Informed consent form.

Pregnancy prevention information.

Drug interactions with hormonal contraceptives.

Contraceptives in current use.

Follow-up of a reported pregnancy.
Before trial enrollment, males and WOCBP must be advised of the importance of 
avoiding pregnancy during trial participation and the potential risk factors for an 
unintentional pregnancy. Subjects must sign the ICF confirming that the above-
mentioned risk factors and the consequences were discussed.
A urine or serum pregnancy test for human chorionic gonadotropin (hCG) will be 
performed at screening on all WOCBP. If a urine test is performed and is positive, the 
investigator will follow-up with a confirmatory serum test.
During the trial, all WOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle). Male subjects 
must be instructed to contact the investigator immediately, during the trial, if their partner 
suspects that they might be pregnant (eg, missed or late menstrual cycle).
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy tests are available. If the pregnancy 
is confirmed, the subject must not receive the IMP and must not be enrolled in the trial. If 
pregnancy is suspected while the subject is taking IMP (vadadustat or ESA) or within 
30 days of discontinuing the IMP, the IMP must be withheld immediately (if reasonable, 
taking into consideration any potential withdrawal risks) until the result of the pregnancy 
test is known. If pregnancy is confirmed, the IMP will be permanently discontinued in an 
appropriate manner and the subject will be withdrawn from the trial. Exceptions to trial 
discontinuation may be considered for life-threatening conditions only after consultations 
with the Medical Monitor. If EDC is unavailable, send paper Pregnancy Form as 
indicated on the title page of this protocol.


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Any pregnancy must be recorded on the Pregnancy Reporting Form/Exposure in Utero 
Form in EDC within 24 hours of awareness of the pregnancy or the investigator will call 
the CRO SAE hotline within 24 hours of being made aware of the pregnancy.
Pregnancy during this time frame of the female partner of a male subject should also be 
reported. This will require agreement and separate written informed consent on the part 
of the pregnant female partner.
The paper Pregnancy Reporting Form/Exposure in Utero Form must be completed with 
all known information regarding the pregnancy at the time of reporting. Investigative site 
personnel will update the form with additional information regarding the pregnancy and 
the outcome of the pregnancy as it becomes available until the outcome of the pregnancy 
is reported.
The investigator will follow the subject (or female partner of a male subject) until 
completion of the pregnancy. If the outcome of the pregnancy meets the criteria for 
classification as an SAE (ie, spontaneous abortion, stillbirth, neonatal death within 1 
month of birth, or congenital anomaly [including 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 should 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 IMP should 
also be reported.

In the case of a live birth, the “normality” of the newborn can be assessed at time of 
birth.

The “normality” of an aborted fetus can be assessed by gross visual inspection unless 
there are pre-abortion laboratory findings suggestive of a congenital anomaly.
Protocol required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
investigator must report to the sponsor, on the Pregnancy Report Form/Exposure in Utero 
Form, follow-up information regarding the course of the pregnancy, including perinatal 
and neonatal outcome. Infants will be followed for a minimum of 6 months from the date 
of birth.


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10.4
Appendix 4: Abbreviations
Abbreviation
Definition
β-HCG
beta human chorionic gonadotropin 
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase (SGPT)
ALP
Alkaline phosphatase 
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
BCRP
Breast cancer resistance protein
BL
Baseline
BUN
Blood urea nitrogen
CBC
Complete blood count
CFR
Code of Federal Regulations
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Science
CKD
Chronic kidney disease
Cmax
Maximum observed plasma concentration
CPK
Creatine phosphokinase
CRO
Contract research organization
CRP
C-reactive protein
CS
Clinically significant
CV
Cardiovascular
DD-CKD
Dialysis-dependent chronic kidney disease
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EOT
End of treatment
EPO
Erythropoietin
ESA
Erythropoiesis-stimulating agent
ET
Early termination
EU
European Union
EudraCT
European Clinical Trial Data Base
FACT-An
Functional Assessment of Cancer Therapy-Anemia
FAS
Full Analysis Set
FBR
Future biospecimen research
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
hCG
Human chorionic gonadotropin
HF
Heart failure
Hb
Hemoglobin
HDL
High density lipoprotein
HIF
Hypoxia-inducible factor


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Abbreviation
Definition
HIF-PH
Hypoxia-inducible factor prolyl-hydroxylase
HRQOL
Health-related Quality of Life
IB
Investigator’s Brochure
IC50
50% inhibitory concentration
ICF
Informed consent form
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors
ID
Identifier
IDMC
Independent Data Monitoring Committee
I/E
Inclusion/exclusion
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IND
Investigational new drug
INR
International normalized ratio
IRB
Institutional Review Board
IV
Intravenous
IWR
Interactive Web Response
LDH
Lactate dehydrogenase
LDL
Low density lipoprotein
MACE
Major adverse cardiovascular events
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities 
mRNA
Messenger ribonucleic acid
MTPC
Mitsubishi Tanabe Pharma Corporation
n
Number of subjects
NDD-CKD
Non-dialysis-dependent chronic kidney disease
OPDC
Otsuka Pharmaceutical Development & Commercialization, Inc.
PD
Pharmacodynamics(s)
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PGx
Pharmacogenomic(s)
PHD
Prolyl 4-hydroxylase domain
PK
Pharmacokinetic(s)
PP
Per protocol
PT
Prothrombin time
QD
Once daily
RBC
Red blood cell
RDW
Red blood cell distribution
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SEAC
Safety Event Adjudication Committee
SF-36v2
36-Item Short Form


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Abbreviation
Definition
SGOT
Serum glutamic oxaloacetic transaminase (AST)
SGPT
Serum glutamic pyruvic transaminase (ALT)
SmPC
Summary of product characteristics
SOC
System organ class
SV1
Screening Visit 1
SV2
Screening Visit 2
TEAE
Treatment-emergent adverse event
TIBC
Total iron binding capacity
TIW
Three times weekly
TSAT
Transferrin saturation
ULN
Upper limit of normal
US
United States
USPI
US Package Insert
WBC
White blood cell
WOCBP
Women of childbearing potential
PPD


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10.5
Appendix 5: Institutions Concerned with the Trial
Akebia Therapeutics, Inc.
245 First Street
Cambridge, MA 02142
United States of America
Within Akebia, this protocol is referred to as Protocol #AKB-6548-CI-0036


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10.6
Appendix 6: Protocol Amendments
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval/favorable opinion by the IRB/IEC. Any 
permanent change to the protocol, whether an overall change or a change for specific trial 
site(s), must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB/IEC, as required by local 
regulations. Except for “administrative” or “nonsubstantial” amendments, investigators 
will wait for IRB/IEC approval/favorable opinion of the amended protocol before 
implementing the change(s). Administrative amendments are defined as having no effect 
on the safety of subjects, conduct or management of the trial, trial design, or the quality 
or safety of IMP(s) used in the trial. A protocol change intended to eliminate an apparent 
immediate hazard to subjects should be implemented immediately after agreement by the 
sponsor and investigator, followed by IRB/IEC notification within local applicable 
timelines. The sponsor will submit protocol amendments to the applicable regulatory 
agencies within local applicable timelines.
When the IRB/IEC, investigators, and/or the sponsor conclude that the protocol 
amendment substantially alters the trial design and/or increases the potential risk to the 
subject, the currently approved written ICF will require similar modification. In such 
cases, after approval/favorable opinion of the new ICF by the IRB/IEC, repeat written 
informed consent will be obtained from subjects enrolled in the trial before expecting 
continued participation and before the amendment-specified changes in the trial are 
implemented.


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10.6.1
Protocol Amendment(s)/Administrative Change(s)
10.6.1.1
Protocol Amendment 1
Amendment 1 Approval Date:
17 Mar 2021
PURPOSE:
The purpose of this protocol amendment is to:

Add that analyses of the primary efficacy endpoint may be conducted when all 
randomized subjects complete their Week 26 evaluations or early discontinue the trial 
before Week 26;

Remove the PK endpoints of Cmax and trough concentration;

Adjust terminology applicable for the reporting of AEs by removing “immediately 
reportable event (IRE)” and “designated medical event (DME)” throughout the 
protocol;

Change the definition of “subject completion” to after completion of their final visit 
(ET or Week 52/EOT). Safety Follow-up Visit data summarization and analysis will 
be performed separately.
Additional administrative and clarifying changes were made and are documented below. 
Finally, minor editorial revisions were made for consistency with Otsuka style and for 
internal consistency.
BACKGROUND:
These changes to clinical trial protocol 404-201-00012, originally issued on 17 Jan 2020, 
were made to add the possibility to conduct analyses on the primary efficacy endpoint at 
Week 26.
The PK endpoints of Cmax and trough concentration were removed as analyses of 
concentration data from previous protocols indicated that these endpoints did not produce 
robust exposure estimates. Instead, concentrations may be included in a population PK 
analysis.
For the reporting of AEs, the terms immediately reportable event “IRE” and designated 
medical event “DME” (Otsuka’s terminology) were removed throughout the protocol. 
This is an operational change that is specific to Otsuka processes only (not Akebia). From 
the onset of this trial, Akebia’s pharmacovigilance processes have been followed. 
Removal of this terminology does not interfere with the current drug safety 
pharmacovigilance process. Removal of these terms ensures the protocol text for AE and 
SAE processes are consistent with Akebia’s terminology and processes.


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The definition of “subject completion” has been revised to after completion of their final 
visit (ET or Week 52/EOT) and will not include the Safety Follow-up. Safety Follow-up 
Visit data summarization and analysis will be performed separately.
MODIFICATIONS TO PROTOCOL:
General Revisions:
Table 10.6.1.1-1
General Revisions for Protocol Amendment 1
Location
Description of Text
Title Page
Updated “Director, Global Clinical Development” and 
contact information.
Updated “Associate Director, Clinical Management” to 
“Director, Clinical Management.”
Title Page,
Section 8.8.1 (Definitions), 
Section 8.8.2 (Eliciting and Reporting Adverse 
Events),
Section 8.8.2.1 (Guidelines for Reporting 
Adverse Events),
Section 8.8.4.1 (Follow-up of Nonserious 
Adverse Events),
Section 8.8.4.2 (Follow-up of Immediately 
Reportable Events),
Section 8.8.4.3 (Follow-up and Reporting of 
Immediately Reportable Events Occurring 
After Last Scheduled Contact), and 
Section 10.3 (Appendix 3: Contraceptive 
Guidance and Collection of Pregnancy 
Information)
Adjusted terminology applicable for the reporting of AEs 
by deleting “immediately reportable event (IRE)” and 
“designated medical event (DME)” throughout the 
protocol.
Synopsis (Objectives and Endpoints), 
Table 3-1 (Trial Objectives and Endpoints), 
and Section 9.4.1.2 (Key Secondary Efficacy 
Endpoint Analysis)
Updated key secondary efficacy endpoints to clarify that 
Baseline refers to the “average pretreatment Hb.” 
Synopsis (Objectives and Endpoints) and 
Table 3-1 (Trial Objectives and Endpoints)
Clarified the safety “endpoints” (instead of “variables”). 
Synopsis (Objectives and Endpoints) and 
Table 3-1 (Trial Objectives and Endpoints) 
Removed details on specific clinical laboratory values as 
these details are found in Appendix 10.2 and Table 1.3-1 
(Schedule of Assessments).
Synopsis (Objectives and Endpoints) and 
Table 3-1 (Trial Objectives and Endpoints)
Updated PK endpoints to state that no PK analysis will 
be conducted and vadadustat plasma concentrations may 
be included in a population PK analysis reported 
separately. 
Synopsis (Objectives and Endpoints and Trial 
Assessments), Table 1.3-1 (Schedule of 
Assessments), Table 3-1 (Trial Objectives and 
Endpoints), and Section 8 (Trial Procedures)
 
Synopsis (Objectives and Endpoints), 
Table 3-1 (Trial Objectives and Endpoints), 
and Section 9.4.3.5 (Pharmacodynamic 
Analysis)
Deleted exposure response analysis in PD endpoints.
Synopsis (Trial Design) and Section 4.1 
(Type/Design of Trial)
Removed “sponsor-blind.”
PPD


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Table 10.6.1.1-1
General Revisions for Protocol Amendment 1
Location
Description of Text
Synopsis (Trial Design), Section 4.1 
(Type/Design of Trial), and Section 6.3.1 
(Randomization)
Replaced “at least” with “approximately” for the number 
of subjects in Europe.
Synopsis (Trial Design), Table 1.3-1 (Schedule 
of Assessments), Section 4.1 (Type/Design of 
Trial), and Section 8 (Trial Procedures)
Removed “/other” from the definition of secondary 
efficacy evaluation.
Synopsis (Trial Design), Table 1.3-1 (Schedule 
of Assessments), and Section 4.1 (Type/Design 
of Trial)
Clarified that a “structured” exit interview “may” be 
conducted.
Synopsis (Trial Population) and Section 5 
(Trial Population)
Specified 100 subjects randomized to “vadadustat” QD 
arm, 100 subjects randomized to “vadadustat” TIW arm, 
and 100 subjects randomized to darbepoetin alfa arm.
Synopsis (Exclusion Criteria) and Section 5.2.2 
(Exclusion Criteria)
Removed “birth control” as one of the precautions to be 
used in Exclusion Criteria No. 1.
Synopsis (Investigational Medicinal Product(s), 
Dose, Dosage Regimen, Treatment Duration, 
Formulation, Mode of Administration), 
Table 1.3-1 (Schedule of Assessments), 
Section 4.1 (Type/Design of Trial), 
Section 6.1.1.4 (Darbepoetin Alfa Dosing), 
Section 6.1.3 (Late or Missed Doses), 
Section 6.2 (Management of Investigational 
Medicinal Product), and Section 6.3.2 
(Blinding)
Clarification on how darbepoetin alfa will be dispensed, 
initial dosing regimen, and/or information on dose 
adjustment was added/revised.
Synopsis (Investigational Medicinal Product(s), 
Dose, Dosage Regimen, Treatment Duration, 
Formulation, Mode of Administration), 
Section 4.1 (Type/Design of Trial), and 
Section 6.1.1.4 (Darbepoetin Alfa Dosing)
Removed “SC” as a route of administration for 
darbepoetin alfa.
Synopsis (Investigational Medicinal Product(s), 
Dose, Dosage Regimen, Treatment Duration, 
Formulation, Mode of Administration), 
Section 4.1 (Type/Design of Trial), 
Section 6.1.1.1 (ESA Equivalent Dose 
Calculation), and Section 6.3.1 
(Randomization)
Removed details on “ESA medications conversions” as 
they are provided in the Dosing Guideline.
Synopsis (Investigational Medicinal Product(s), 
Dose, Dosage Regimen, Treatment Duration, 
Formulation, Mode of Administration) and 
Table 6.1.1.2-1 
Added a table note to “See to Section 7.3.1 (Treatment 
Interruption)” in the Guideline for Dose Adjustment 
Table.
Synopsis (Trial Assessments), Table 1.3-1 
(Schedule of Assessments), Section 8 (Trial 
Procedures), and Section 8.7.6.1 (Major 
Adverse Cardiovascular Events)
Removed “Endpoint Questionnaire” from MACE 
assessment.
Synopsis (Trial Assessments) 
Added “RBC transfusions, ESA rescue, and therapeutic 
phlebotomy” to Assessments for Safety in-line with 
Table 1.3-1 (Schedule of Assessments).
Synopsis (Trial Duration), Section 4.1 
(Type/Design of Trial), and Section 4.5 
(Definition of Completed Subjects)
Changed the definition of “subject completion” to after 
completion of their final visit (ET or Week 52/EOT). 
Safety Follow-up Visit data summarization and analysis 
will be performed separately.


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Table 10.6.1.1-1
General Revisions for Protocol Amendment 1
Location
Description of Text
Figure 1.2-1
Updated Trial Design Schematic for clarity of vadadustat 
dosing.
Section 2 (Introduction)
Updated text in-line with current vadadustat IB.
Section 4.1 (Type/Design of Trial), 
Section 6.5.2.1 (Iron Supplementation), and 
Section 8 (Trial Procedures).
Clarified that subjects will be instructed to take 
vadadustat at least 1 hour before oral medications 
containing iron.
Section 4.2 (Scientific Rationale for Trial 
Design)
Added clarification that higher ESA doses carry a higher 
risk for CV outcomes regardless of Hb and changed 
“black box” warning to “boxed” warning.
Section 6.1.3 (Late or Missed Doses)
Added that for subjects on TIW dosing, “subjects should 
not double-up on missed doses.” Also, clarified that 
subjects should be questioned regarding dosing 
compliance at every visit.
Section 6.2.2 (Storage)
For darbepoetin alfa, removed “per local prescribing 
label for adult subjects with CKD on dialysis” as 
darbepoetin alfa will be stored per the USPI for US sites 
or EU SmPC for EU sites.
Section 6.3.2 (Blinding)
Updated to “unblinded personnel” instead of “unblinded 
statistician” as there will be unblinded programmers as 
well.
Section 6.4 (Subject Compliance)
Clarified that subjects will be questioned regarding 
dosing compliance at every visit.
Section 6.5.1.1 (Erythropoiesis-stimulating 
Agents)
Clarified that “co-administration of any ESA with 
vadadustat is prohibited. If ESA rescue therapy is 
deemed medically necessary, vadadustat treatment must 
be stopped during ESA administration.”
Section 6.5.1.2 (Sulfasalazine and Other BCRP 
Substrates and Probenecid)
Heading title was revised.
Removed “prohibited” and updated section to state that 
sulfasalazine and other BCRP substrates should be used 
with caution when taken concomitantly with vadadustat 
and added a sentence to clarify to consult the Medical 
Monitor if there are questions about a specific 
concomitant medication.
A sentence was added to state that probenecid is 
prohibited during the trial.
Section 6.5.2 (Permitted Medications)
Changed section heading to “Permitted Medications” for 
clarity.
Section 6.5.2.1 (Iron Supplementation)
Changed “iron-containing phosphate binders” to “iron-
containing and non-iron-containing phosphate binders.”
Section 6.5.2.2 (Phosphate Binders)
Clarified that subjects will be instructed to take 
vadadustat at least 1 hour before or 2 hours after non-
iron-containing phosphate binders.
Table 6.5.2.3-1 (Results and Management of 
Concomitant Administration of Vadadustat 
with Statins)
Clarified guidance on inhibitor potency.
Section 7.3 (Individual Subject 
Discontinuation)
Clarified that subjects who discontinue IMP prematurely 
and the investigator determines that the subject will be 
permanently discontinued from the trial will complete 
the ET Visit assessments and the Safety Follow-up Visit, 
4 weeks after ET Visit.


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Table 10.6.1.1-1
General Revisions for Protocol Amendment 1
Location
Description of Text
Section 7.3.1 (Treatment Interruption)
Clarified that, unless contraindicated, treatment with 
IMP should be resumed within a 30-day time period 
from the start date of interruption and routinely 
considered at every visit following IMP interruption.
Updated text for clarification on re-start of IMP 
following treatment interruption.
Section 8 (Trial Procedures)
Clarified that the ICF will be signed at Screening Visit 1 
prior to any Screening Visit 1 procedures.
Under “Exit Interview,” added the purpose of the exit 
interviews, removed “the United Kingdom, France, 
Germany, Italy, and Spain” (as countries may be deleted 
or other countries may be added), and added a sentence 
on how the sample size was selected.
Section 8.1 (Subject Reported Outcome 
Assessments)
Updated the timing of assessments to “during the 
dialysis visits” for all 4 assessments.
Section 8.2 (Pharmacokinetic Assessments)
Clarified that vadadustat may be dosed before or after 
the start of dialysis.
Section 8.7.1 (Clinical Laboratory 
Assessments)
Removed “the sponsor” from providing instructions for 
collection, processing, and shipment of laboratory 
samples as these will be provided by the central 
laboratory.
Section 8.7.3 (Concomitant Medication 
Recording)
Added a sentence to clarify reporting of concomitant 
medications.
Section 8.7.6.1 (Major Adverse Cardiovascular 
Events)
Added clarification of MACE (all-cause mortality, 
nonfatal myocardial infarction, or nonfatal stroke) plus 
hospitalization for HF or thromboembolic event 
excluding vascular access thrombosis.
The sentence referring to ‘the endpoint packet checklist’ 
was deleted.
Section 8.8.1 (Definitions)
Added a sentence on “AESIs” and clarified that 
malignancies will be reported as an SAE by the 
investigator.
Section 8.8.1 (Definitions) and
Section 8.8.2.1 (Guidelines for Reporting 
Adverse Events)
Replaced “temporary discontinuation of trial 
medication” with “temporary interruption of IMP” for 
clarification.
Section 8.8.2 (Eliciting and Reporting Adverse 
Events) and Section 8.8.2.1 (Guidelines for 
Reporting Adverse Events)
Clarified that AE collection will be from the time of ICF 
signing through the Safety Follow-up Visit.
Section 8.8.2.1 (Guidelines for Reporting 
Adverse Events)
Changed “Reporting Trial Endpoints” to “Reporting 
MACE” and clarified that Investigators will be 
counseled to report any MACE (all-cause mortality, 
nonfatal myocardial infarction, or nonfatal stroke) plus 
hospitalization for HF or thromboembolic event 
excluding vascular access thrombosis events that they 
assess as requiring adjudication. All events will be 
submitted in a blinded fashion to the SEAC for 
adjudication.


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Table 10.6.1.1-1
General Revisions for Protocol Amendment 1
Location
Description of Text
Section 8.9 (Treatment of Overdose)
Replaced “discontinuation” with “interruptions” for 
clarity and added a link to Section 8.8 for guidance on 
AEs and SAEs.
Section 9.2 (Datasets for Analysis)
Correction to “Week 26” from “Week 36” for the PP 
population definition. 
Section 9.3 (Handling of Missing Data for 
Primary and Secondary Endpoint Analysis)
Clarified that the reasons for “discontinuation” will be 
summarized by treatment arm.
Section 9.4.1.1.1 (Primary Estimand)
Section 11 (References)
New section added to outline the treatment policy 
strategy specified in ICH E9 (R1) Addendum and added 
associated literature reference.
Section 9.4.1.1.2 (Primary Analysis of Primary 
Efficacy Endpoint)
Deleted primary efficacy endpoint definition as it is 
previously stated in Section 9.4.1.1.
Section 9.4.1.1.4 (Analyses of Primary 
Efficacy Endpoint When All Randomized 
Subjects Complete Week 26)
New section added to add the possibility to conduct 
analyses on the primary efficacy endpoint at Week 26.
Section 9.4.3.4 (Pharmacokinetic Analysis)
Clarified that a population PK analysis may be reported 
separately.
Section 9.4.3.5 (Pharmacodynamic Analysis)
Updated how PD variables will be reported.
Section 9.4.3.7 (Future Biospecimen Research 
Analysis)
Add new section to state “No FBR analysis is planned.”
Section 9.4.3.8 (Exploratory Endpoint 
Analysis)
 
Section 9.5 (Data Monitoring, Safety Event 
Adjudication, and Independent Expert Panel 
Committees)
The heading title was revised.
The IDMC meeting frequency was removed.
Added “SAEs” and “ECGs” to key safety endpoint data 
for clarification. 
Clarified that an independent SEAC will adjudicate 
MACE (all-cause mortality, nonfatal myocardial 
infarction, or nonfatal stroke) plus hospitalization for HF 
or thromboembolic event excluding vascular access 
thrombosis events.
Clarified that an “Independent” Expert Panel Committee 
for Hepatic Events of Interest will also be formed prior 
to trial commencement to adjudicate hepatic events.
Section 10.1.7 (Protocol Deviations)
Clarified that “if needed,” the investigator and sponsor 
will come as quickly as possible to a joint decision 
regarding subject’s continuation in the trial.
Section 10.1.8.2 (Data Collection)
Removed “central ECG readers” as they will not be 
used.
Table 10.2-1 (Clinical Laboratory 
Assessments)
Updated “Complete Blood Count,” “Iron Indices” and 
instructions for “INR and PT collection.” Also added 
“Hematology panel without differential.”
Section 11 (References)
The list of references was updated.
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.
PPD


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11
References
1
Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Chronic kidney 
disease: global dimension and perspectives. Lancet. 2013;382(9888):260-272.
2
KDIGO. KDIGO clinical practice guideline for the evaluation and management of 
chronic kidney disease. Kidney Int Suppl. 2013;3(1):1-136.
3
Iseki K, Kohagura K. Anemia as a risk factor for chronic kidney disease. Kidney Int 
Suppl. 2007;(107):S4-9.
4
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):325-333.
5
Stauffer ME and Fan T. Prevalence of anemia in chronic kidney disease in the United 
States. PLoS One. 2014;9(1):e84943.
6
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):1115-1122.
7
KDIGO.  KDIGO clinical practice guideline for anemia in chronic kidney disease. 
Kidney Int Suppl. 2012,2(4):279-331 
8
Nurko S. Anemia in chronic kidney disease: causes, diagnosis, treatment. Cleve Clin 
J Med. 2006;73(3):289-297.
9
Ly J, Marticrena R, Donnelly S. Red blood cell survival in chronic renal failure. Am J 
Kidney Dis. 2004;44(4):715-719.
10 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.
11 NICE Clinical Guideline 114. Anaemia management in people with chronic kidney 
disease. National Institute for Health and Care Excellence. 2011:1-39.
12 Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, et al. 
The effects of normal as compared with low hematocrit values in patients with 
cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 
1998;339(9):584-590.
13 Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al. 
Normalization of hemoglobin level in patients with chronic kidney disease and 
anemia. N Engl J Med. 2006;355(20):2071-2084.
14 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. 
2009;361(21):2019-2032.
15 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. 2009;54(1):59-69.
16 Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al. Correction of 
anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 
2006;355(20):2085-2098.


Protocol 404-201-00012
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17 Akebia Therapeutics, Inc. Vadadustat (AKB-6548) Investigator’s Brochure, Edition 
13. Issued 17 Dec 2020.
18 McCullough PA, Barnhart HX, Inrig JK, Reddan D, Sapp S, Patel UD, et al. 
Cardiovascular toxicity of epoetin-alfa in patients with chronic kidney disease. Am J 
Nephrol. 2013;37(6):549-558.
19 Unger EF, Thompson AM, Blank MJ, Temple R. Erythropoiesis-stimulating agents - 
Time for a reevaluation. N Engl J Med. 2010;362(3):189-192.
20 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):1926-1932.
21 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.
22 Locatelli F, Bárány P, Covic A, De Francisco A, Del Vecchio L, Goldsmith D, et al.  
Kidney disease: improving global outcomes guidelines on anaemia management in 
chronic kidney disease: a european renal best practice position statement. Nephrol 
Dial Transplant. 2013; 28(6):1346-1359.
23 Besarab 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):1405-1416.
24 FDA Guidance for Industry: Clinical Drug Interaction Studies —Cytochrome P450 
Enzyme- and Transporter-Mediated Drug Interactions. 2020.  Available at: 
https://www.fda.gov/media/134581/download.
25 International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use. ICH Harmonized Guideline. E9(R1) Statistical 
Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in 
Clinical Trials. [Draft 16 June 2017]. 
26 International Council for Harmonisation (ICH) [homepage on the Internet]. E6(R2): 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) [finalized 2016 
November; cited 2018 Dec 3]. Available from: 
https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf


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Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator's Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor's (or designee's) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, vadadustat, the concurrent medications, 
the efficacy and safety parameters and the conduct of the trial in general. I am aware that this protocol 
must be approved by the Institutional Review Board (IRB) or receive a favorable opinion by the 
Independent Ethics Committee (IEC) responsible for such matters in the clinical trial facility where 
vadadustat will be tested prior to commencement of this trial. I agree to adhere strictly to the attached 
protocol (unless amended in the manner set forth in the sponsor's Clinical Trial Agreement, at which 
time I agree to adhere strictly to the protocol as amended).
I understand that this IRB/IEC-approved protocol will be submitted to the appropriate regulatory 
authority/ies by the sponsor. I agree that clinical data entered on eCRF by me and my staff will be 
utilized by the sponsor in various ways, such as for submission to governmental regulatory authorities 
and/or in combination with clinical data gathered from other research sites, whenever applicable. I 
agree to allow sponsor and designee monitors and auditors full access to all medical records at the 
research facility for subjects screened or enrolled in the trial.
I agree to await IRB/IEC approval before implementation of any substantial amendments to this 
protocol. If, however, there is an immediate hazard to subjects, I will implement the amendment 
immediately, and provide the information to the IRB/IEC within the required local applicable 
timelines. Administrative changes to the protocol will be transmitted to the IRB/IEC for informational 
purposes only, if required by local regulations.
I agree to provide all subjects with informed consent forms, as required by the applicable regulations 
and by ICH guidelines. I agree to report to the sponsor any adverse experiences in accordance with the 
terms of the sponsor's Clinical Trial Agreement and the relevant regional regulation(s) and 
guideline(s). I further agree to provide all required information regarding financial certification or 
disclosure to the sponsor for all investigators and subinvestigators in accordance with the terms of the 
relevant regional regulation(s). I understand that participation in the protocol involves a commitment 
to publish the data from this trial in a cooperative publication before publication of efficacy and safety 
results on an individual basis may occur, and I consent to be acknowledged in any such cooperative 
publications that result.
____________________________
_____________________________
___________
Principal Investigator Print Name
Signature
Date


This page is a manifestation of an electronically captured signature
SIGNATURE PAGE
Document Name: 404-201-00012 Protocol Amendment 1
Document Number: 1000061634
Document Version: 3.0
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:min) -
UTC timezone
Safety Approval
21-Mar-2021
20:23:33
Clinical Approval
21-Mar-2021
22:10:32
Clinical Pharmacology
Approval
22-Mar-2021
16:37:51
Biostatistics Approval
22-Mar-2021
05:21:03

SAP_001.pdf: 
SAP 404-201-00012 
Confidential - Proprietary Information  
1
26 November 2018
6 June 2022
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigational Medicinal Product
Vadadustat
Phase 3b, Randomized, Open-label, Active-controlled Trial Evaluating the Efficacy and 
Safety of Oral Vadadustat Once Daily (QD) and Three Times Weekly (TIW) for the 
Maintenance Treatment of Anemia in Hemodialysis Subjects Converting from 
Erythropoiesis-stimulating Agents (ESAs)
Protocol No. 404-201-00012
IND No. 102,465
EudraCT No. 2019-004851-36
Statistical Analysis Plan
Version: 2.0
Date: June 6, 2022
CONFIDENTIAL – PROPRIETARY INFORMATION
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Otsuka Pharmaceutical Development & Commercialization, Inc.
NCT Number: NCT04313153
This NCT number has been applied to the document for purposes of posting on Clinicaltrials.gov


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Table of Contents
Table of Contents ..........................................................................................2
1
Introduction..........................................................................................8
2
Description of the Studies....................................................................8
2.1
Randomization and Stratification........................................................................8
2.2
Study Periods.......................................................................................................8
2.3
Target Hb Ranges................................................................................................9
2.4
Primary Objectives of the Trial...........................................................................9
2.5
Blinding...............................................................................................................9
2.6
Sample Size.......................................................................................................10
2.7
Efficacy .............................................................................................................10
2.8
Safety.................................................................................................................11
3
Analysis Populations ..........................................................................11
3.1
The Analysis Populations..................................................................................11
3.2
Characterization of the Analysis Population.....................................................12
4
Quality of the Trials...........................................................................12
4.1
Study Drug Dosing and Compliance.................................................................12
4.2
Protocol Deviations...........................................................................................12
4.3
Baseline Characteristics, Exposure, and Retention by Treatment Group .........12
5
General Conventions..........................................................................13
5.1
Visit and Analysis Time Period Classification .................................................13
5.2
Definition of Baseline .......................................................................................15
5.3
Prior and Concomitant Medication ...................................................................15
5.4
Handling of Missing Data .................................................................................15
6
Efficacy Endpoints .............................................................................16
6.1
Primary Efficacy Endpoint................................................................................17
6.2
Key Secondary Efficacy Endpoints...................................................................17
6.3
Other Efficacy Endpoints..................................................................................17
6.4
Rescue Therapy.................................................................................................17
7
Safety Endpoints.................................................................................19


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8
Pharmacokinetic (PK)/ Pharmacodynamic (PD)/ 
Pharmacogenomic (PGx) Analysis ...................................................19
8.1
Pharmacokinetic Analysis.................................................................................19
8.2
Pharmacodynamic Analysis ..............................................................................19
8.3
Pharmacogenomic Analysis ..............................................................................19
9
Efficacy Endpoints and Analyses......................................................20
9.1
Primary Estimand..............................................................................................20
9.2
Definition of Primary Efficacy Endpoint: Change from Baseline in Hb ..........20
9.2.1
Baseline Hb.....................................................................................................21
9.2.2
Hb in the Primary Efficacy Period..................................................................21
9.2.3
Change in Hb from Baseline to the Primary Efficacy Period.........................21
9.2.4
Analysis of Change from Baseline in Hb to the Primary Efficacy Period .....21
9.2.5
Sensitivity Analyses to the Primary Efficacy Results ....................................23
9.3
Secondary Efficacy Endpoints: Definitions and Analyses................................24
9.4
Other Efficacy Endpoints: Strategies for Analysis............................................24
9.4.1
Proportion of Subjects Having Average Hb Values within the Target Range 
during the PEP (Weeks 20 to 26) ...................................................................24
9.4.2
Proportion of Subjects Having Average Hb Values within the Target Range 
during the SEP (Weeks 46 to 52) ...................................................................25
9.4.3
Proportion of Subjects Receiving IV Iron Therapy from Baseline to Week 
52 ....................................................................................................................26
9.4.4
Average Weekly Dose of IV Elemental Iron Administered from Baseline to 
Week 52..........................................................................................................26
9.4.5
Receipt of ESA Rescue...................................................................................26
9.4.6
Proportion of Subjects Receiving Red Blood Cell (RBC) Transfusions........26
9.4.7
Change from Baseline in 36-Item Short Form Version 2 (SF-36v2) Health-
Related Quality of Life (HRQOL) Scores......................................................27
9.4.8
Change from Baseline to the Average Value in Functional Assessment of 
Cancer Therapy-Anemia (FACT-An) Anemia Subscale ("Additional 
Concerns") Score and Total Score..................................................................27
9.4.9
Change from Baseline in Score of Patient Global Impression of Severity 
(PGI-S)............................................................................................................28
9.4.10
Score of Patient Global Impression of Change (PGI-C) ................................28
9.5
Study Level Type I Error Control .....................................................................29


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10
Safety Analyses...................................................................................30
10.1
Mortality............................................................................................................30
10.2
Hb-related Safety Endpoints .............................................................................30
10.3
Adverse Events and Serious Adverse Events....................................................31
10.4
Major Adverse Cardiovascular Event (MACE)................................................32
10.5
Other Safety Endpoints .....................................................................................33
10.5.1
Clinical Laboratory Evaluation.......................................................................33
10.5.2
Vital Signs, ECGs, and Physical Findings......................................................34
11
Subgroups ...........................................................................................34
13
Interim Analysis .................................................................................35
17
Appendix D Adverse Event of Special Interest ...............................39
18
References ...........................................................................................44
19
Proposed List of Summary Tables....................................................46
20
Revision Changes................................................................................60
 
PP
D
PP
D


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Abbreviations
Abbreviation
Definition
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine aminotransferase
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
AST
Aspartate aminotransferase
BP
Bodily Pain
CBC
Complete Blood Count
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus Disease 2019
CRO
Contract Research Organization
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events 
ECG
Electrocardiography
eCRF
electronic Case Report Form
EOS
End of Study
EOT
End of Treatment
EPO
Erythropoietin
ESA
Erythropoiesis-Stimulating Agent
ET
Early Termination
EU
European Union
FAS
Full Analysis Set
FACT-An
Functional Assessment of Cancer Therapy-Anemia
FBR
Future Biospecimen Research
FDA
Food and Drug Administration


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Abbreviation
Definition
FSC
Fully Conditional Specification
GH
General Health
Hb
Hemoglobin
HLGT
High-Level Group Term
HLT
High-Level Term
HRQOL
Health-Related Quality of Life
IDMC
Independent Data Monitoring Committee
IMP
Investigational Medicinal Product
ISS
Integrated Safety Summary
IV
Intravenous
IWR
Interactive Web Response
LLD
Lower Limits of Detection
MCS
Mental Summary Component
MedDRA
Medical Dictionary for Regulatory Activities
MH
Mental Health
MMRM
Mixed Models for Repeated Measurements
NDA
New Drug Application 
NEC
Not Elsewhere Classified
NYHA
New York Heart Association
PCS
Physical Summary Component
PD
Pharmacodynamic
PEP
Primary Efficacy Period
PF
Physical Functioning
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PGx
Pharmacogenomic
PI
Package Insert


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Abbreviation
Definition
PK
Pharmacokinetic
PP
Per Protocol
PT
Preferred Term
QD
Once Daily
RBC
Red Blood Cell
RE
Role-Emotional
RP
Role-Physical
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SEAC
Safety Event Adjudication Committee
SEP
Secondary Efficacy Period
SF
Social Functioning
SF-36v2
36-Item Short Form Version 2
SmPC
Summary of Product Characteristics
SMQ
Standardised MedDRA Query
SOC
System Organ Class
TEAE
Treatment-Emergent Adverse Event
TIBC
Total Iron Binding Capacity
TIW
Three Times Weekly
TSAT
Transferrin saturation
ULN
Upper Limit of Normal
US
United States
VT
Vitality
WBC
White Blood Cells
WNL
Within Normal Limits
PPD


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1
Introduction
This statistical analysis plan (SAP) covers the 404-201-00012 MO₂DIFY Study.
The SAP supports the Statistical Methods Section and documents the pre-planned statistical 
analyses plan of the clinical study report (CSR). It elaborates upon the protocol-specified 
endpoint definitions and the formal statistical methods that will be used in analyzing the 
study. Unless otherwise specified, all analyses will be conducted. If the analyses described in 
the protocols differ from those in this SAP, the methods of the SAP prevail. 
2
Description of the Studies
This study is a phase 3b, randomized, open-label, active-controlled trial evaluating the 
efficacy and safety of oral vadadustat once daily (QD) and three times weekly (TIW) for the 
maintenance treatment of anemia in hemodialysis subjects converting from erythropoiesis-
stimulating agents (ESAs).
2.1
Randomization and Stratification
Subjects who meet all eligibility criteria are randomized 1:1:1 to vadadustat QD, vadadustat 
TIW, or darbepoetin alfa.  Randomization is stratified with respect to:
•
Geographic region: United States (US) versus Europe, approximately 90 subjects in 
Europe. 
•
Mean weekly darbepoetin alfa dose (or ESA equivalent) calculated over a period of 8 
weeks prior to Screening Visit 2:
o
Low darbepoetin alfa dose group (≤ 0.45 μg/kg/week).
o
High darbepoetin alfa dose group (> 0.45 and ≤ 1.5 μg/kg/week).
In each stratum, there are 3 arms: vadadustat QD, vadadustat TIW, and darbepoetin alfa.
2.2
Study Periods
Following randomization, the study has 2 study periods during the trial:
•
Conversion and Maintenance Treatment Period (Weeks 0 to 52):
o
Weeks 0 to 20: conversion to investigational medicinal product (IMP) for 
maintaining hemoglobin (Hb).
o
Weeks 20 to 26: primary efficacy period (PEP).
o
Weeks 26 to 46: ongoing maintenance period.
o
Weeks 46 to 52: secondary efficacy period (SEP).


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•
Safety Follow-up Period (Early Termination [ET] and Follow-up): post-treatment 
Safety Follow-up Visit (ET/End of Treatment [EOT] + 4 weeks).
Individual subjects will participate in total trial duration of approximately 64 weeks. An exit 
interview will also be conducted at the EOT visit at a subset of sites.  Subjects’ end of study 
(EOS) will be their safety follow-up visit (ET/EOT+4 weeks) or if afterwards, the date of the 
determined survival status per documented attempt(s) as defined in the protocol. 
The analysis time periods for efficacy divide the Conversion and Maintenance Treatment 
period into five windows (see Table 1). 
2.3
Target Hb Ranges
Hb levels are to be maintained in the following target ranges:
•
US: 10.0 to 11.0 g/dL, inclusive.
•
Europe: 10.0 to 12.0 g/dL, inclusive.
2.4
Primary Objectives of the Trial
The primary objective of the trial is to demonstrate the efficacy and safety of vadadustat 
compared to darbepoetin alfa for the maintenance treatment of anemia in hemodialysis 
subjects after conversion from current ESA therapy.
2.5
Blinding
This is an open-label study. 
Treatment assignment is done through the interactive web response (IWR) system and the 
investigator, sponsor, and contract research organization (CRO) study teams are not aware of 
which treatment will be assigned next.  Treatments is administered in an open-label fashion.  
The sponsor and CRO study teams are blinded to “by treatment” aggregated analyses except 
for the unblinded personnel.  Because Hb values are objective and will be measured via a 
central laboratory for all efficacy endpoints, efficacy assessments are not considered to be 
subject to bias with an open label design.  In order to reduce potential execution bias further, 
special steps will be taken to restrict access to the study data. Please refer to a separate 
document, Blinding Procedures and Oversight Plan, for additional details. 
Adjustments to doses for vadadustat are based on Hb concentration and Dose Adjustment 
Guideline, which was addressed in Protocol.  Darbepoetin alfa dose adjustments are based on 
US package insert (PI), European Union (EU) Summary of Product Characteristics (SmPC), 
local prescribing information, or investigator’s clinical discretion, incorporating the Dose 


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Adjustment Guideline as well as the subject’s current Hb level, trajectory, variability, 
symptoms, cardiovascular risk, and other features of his/her clinical condition(s).
In addition, the study involves the use of an Independent Data Monitoring Committee 
(IDMC), and an identical schedule of visits, procedures, and assessments for all treatment 
groups in order to reduce the potential bias.  An external independent group of unblinded 
biostatisticians and programmers will provide the support to IDMC.  
The Safety Event Adjudication Committee (SEAC) remains blinded throughout the full 
course of the study.
An Independent Expert Panel Committee for Hepatic Events of Interest will also be formed 
prior to trial commencement to adjudicate hepatic events.  An internal independent group of 
unblinded biostatisticians and programmers will provide the support to the Independent 
Hepatic Expert Panel.   
2.6
Sample Size
For the primary efficacy analysis in this trial, it is assumed that the mean change from 
Baseline in Hb for vadadustat will be the same as for the active control darbepoetin alfa, and 
the common standard deviation for the mean change from Baseline is assumed to be 1.2 g/dL.  
Noninferiority will be established based on a 2-sided 95% confidence interval (CI) for the 
difference between vadadustat QD group and darbepoetin alfa group and using a 
noninferiority margin of -0.75 g/dL.  With these assumptions and approximately 100 subjects 
per treatment group, the noninferiority test will have > 90% power with consideration of a 
30% drop out rate. Same assumptions and sample size calculations will be applied to the 
difference between vadadustat TIW group and darbepoetin alfa group. After the noninferiority 
of vadadustat QD is demonstrated, the noninferiority of vadadustat TIW group to darbepoetin 
alfa group will be tested hierarchically with 2-sided significant level of 0.05. 
2.7
Efficacy
Treatment comparisons in efficacy analyses are between vadadustat QD and darbepoetin alfa, 
and between vadadustat TIW and darbepoetin alfa.  
For clarity, this SAP uses the word “mean” to refer to averages over the study groups and 
“average” to refer to the within-person average during specified evaluation periods.
The primary efficacy endpoint is defined as the Hb change from Baseline (average 
pretreatment Hb) to the average Hb from Weeks 20 to 26 (inclusive). 


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The primary efficacy objective is to first show that vadadustat QD is noninferior to 
darbepoetin alfa within the noninferiority margin.  Noninferiority will be established based on 
a margin of -0.75g/dL (for vadadustat minus darbepoetin alfa).  If vadadustat QD meets the 
noninferiority criterion, then the next objective is to show that vadadustat TIW is noninferior 
to darbepoetin alfa within the noninferiority margin.  
If the lower limit of the 2-sided 95% confidence interval for the difference between the mean 
Hb change from baseline to Weeks 20 to 26 in the vadadustat group and the mean Hb change 
from baseline in the darbepoetin alfa group is above zero, superiority will have been 
established and the finding will be interpreted as providing evidence of a greater change from 
baseline in Hb for vadadustat relative to the control arm. Because the same 95% confidence 
interval is used to the superiority test, no adjust of multiplicity is needed.
2.8
Safety
Safety analyses include adverse events (AEs), serious adverse events (SAEs) and Hb-related 
safety endpoints. Additional safety presentations are described below (Section 7 and Section 
10).
3
Analysis Populations
3.1
The Analysis Populations
The following analysis populations are used in this trial:
•
Randomized population: defined as all subjects randomized. Analyses of this 
population will be based on the randomized treatment.
•
Full Analysis Set (FAS) population: defined as all subjects in the randomized 
population who received at least 1 dose of study medication and had at least 1 post 
dose Hb. Analyses of this population will be based on the randomized treatment.
•
Per protocol (PP) population: defined as all randomized subjects who received study 
medication during the primary evaluation period, had at least 1 Hb assessments during 
the primary evaluation period, and had no critical or major protocol deviation affecting 
the primary endpoint analyses (ie, prior to Week 26). Analyses of this population will 
be based on actual treatment received, as described for the Safety population. 
•
Safety population: defined as all subjects in the randomized population who received 
at least 1 dose of study treatment. Analysis of this population will be based on the 
actual treatment received. Subjects who received in error some vadadustat and some 


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darbepoetin alfa (excluding rescue therapy) will be classified by the more frequently 
received drug.
•
Pharmacokinetic (PK) population: defined as all subjects in the safety population who 
have at least 1 measurable vadadustat plasma concentration.
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.
3.2
Characterization of the Analysis Population
Number and percent of subjects included in the analysis sets will be summarized.
4
  Quality of the Trials
4.1
Study Drug Dosing and Compliance
The IMP (vadadustat or darbepoetin alfa) dosing electronic case report forms (eCRFs) will 
collect study drug dosing information and whether they have experienced any problems 
related to the dosing of IMP. 
The study drug compliance rate for a given time period will be derived from exposure data as 
the number of days on dosing period collected on eCRFs divided by the number of days in 
that time period.
The average weekly dosages and the proportion of subjects who have at least 80% compliance 
will be tabulated and summarized by treatment group and analysis period for safety and FAS 
populations. The number and percentage of subjects with any study medication interruptions 
and their reasons for interruption, collected in eCRF, will be summarized as well.
4.2
Protocol Deviations
Protocol deviations will be summarized in the randomized population as the number and 
percentage of subjects with a protocol deviation by treatment group.  A by-subject listing of 
protocol deviations will be provided.  Protocol deviations due to coronavirus disease 2019 
(COVID-19) will be summarized as well.
4.3
Baseline Characteristics, Exposure, and Retention by Treatment 
Group
Descriptive statistics will be generated by treatment group for demographic and pretreatment 
variables for each analysis population.


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The total number of randomized subjects, treated subjects, and randomized but not treated 
subjects will be tabulated by treatment group in the randomized population.
The number of subjects who discontinued the study and the reason for discontinuation will be 
summarized for randomized population.
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.
5
General Conventions
Study days are defined as follows:
Study Day =
[Event date – First dosing date + 1] if on or after first dosing date
[Event date – First dosing date] if before first dosing date.
Note that with the definition above, days of “0” will not be used. As such, the study day can 
be interpreted as the number of days before or after first day of dosing. Event date refers to 
the date associated with the result being summarized. In some cases, this is the date of an 
assessment or measurement; in other cases, this is the onset date of an adverse or outcome 
event.
For subjects whose reference date is missing, the study day will also be categorized as 
missing.
5.1
Visit and Analysis Time Period Classification
The time windows in this section reflect the administrative range around each visit for 
analysis. They are wider than those stated in the protocol to reduce missing values by 
capturing as many observation dates as possible. Table 1. provides the convention to classify 
assessment dates into protocol-defined visits and analysis time periods for assessments 
conducted at every visit, such as Hb value. 
Unless otherwise specified, all assessments will be mapped to visit windows based on the date 
of the assessment relative to the first dose date, regardless of subject disposition or the CRF 
page completed, e.g., “Unscheduled”, “End of Treatment”, etc.  Similarly, all values collected 
within a reporting period will be considered for identification of safety events of interest.
If more than 1 Hb value is available in an analysis time period post-baseline, the average of 
all observed values (at most 1 per day) will be assigned to that period. For example, the 


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window for the primary efficacy outcome, analysis time period 3, includes any Hb value (at 
most 1 per day) assessed between Study Days 127 to 196, corresponding to Weeks 20, 24 and 
26.
Efficacy evaluations will use Hb values as assessed by the central laboratory.
When more than 1 assessment is made for other measures (not Hb) within a given visit 
window post-baseline, the value of the assessment closest to the end of the window is the 
value associated with that visit for summaries over time. Most summaries of results by visit 
(e.g., laboratory or vital sign results) will use the single value for each visit determined by this 
convention. Notable exceptions to this convention are the primary efficacy outcome and 
clinically significant changes.
If no assessment is available within a time window, then the associated visit and week 
classifications will be missing.
Table 1.  Classification of Assessments at Every Visit
Time Period
Visit/Week
Target Day
Actual Study Day of Visit
Screening Visit 1
-
-
Screening Visit 2
-
-
Baseline
Baseline Visit
Day 1
Day 1 (first dose date)a
Week 2
Day 14
Day 2-21
Week 4
Day 28
Day 22-35
Week 6
Day 42
Day 36-49
1) Weeks 2-8
Week 8
Day 56
Day 50-63
Week 10
Day 70
Day 64-77
Week 12
Day 84
Day 78-98
2) Weeks 10-16
Week 16
Day 112
Day 99-126
Week 20
Day 140
Day 127-154
Week 24
Day 168
Day 155-175
3) Primary Efficacy 
Period (PEP)
(Weeks 20-26)
Week 26
Day 182
Day 176-196
Week 30
Day 210
Day 197-224
Week 34
Day 238
Day 225-252
Week 38
Day 266
Day 253-280
4) Weeks 30-42
Week 42
Day 294
Day 281-308
Week 46
Day 322
Day 309-336
Week 50
Day 350
Day 337-357
5) Secondary Efficacy 
Period (SEP)
(Weeks 46-52)
Week 52
Day 364
Day 358-378
Safety Follow-up
Follow-up
ET/EOT + 4 
Weeks
ET/EOT+15 Days – 
ET/EOT+42 Days
ET=Early Termination; EOT=End of Treatment.
a If patient has no first dose date, day 1 will be the randomization date.  


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5.2
Definition of Baseline
The baseline value must be assessed prior to initiation of study treatment. For Hb, baseline 
will be calculated as an average of the last 2 values prior to or on the first dose date, as 
specified in Section 9.2.1. For other parameters, unless otherwise specified, baseline will be 
defined as the last available value prior to the first dose of IMP.
5.3
Prior and Concomitant Medication
Prior medication is defined as any medications taken before the date of the first dose of IMP.  
Concomitant medication is defined as any medications taken at any time from the date of the 
first dose of IMP through the date of the last dose of the IMP.
Prior and concomitant medications will be coded using World Health Organization Drug 
dictionary and summarized for each treatment group based on the safety population.  Prior 
and concomitant ESA medications and their reasons of usage will be summarized by 
treatment group.  Number of subjects taking concomitant anti-hypertensive medications, and 
number of concomitant anti-hypertensive medications taken will be summarized by study 
period for each treatment group as well.
5.4
Handling of Missing Data
Missing data will be handled using a procedure specific to each variable and analysis as 
described in the sections relevant to each endpoint.  If no method for missing data is 
discussed, descriptive analyses will be based upon observed data without imputation. 
For the analysis of safety variables, only partial dates will be imputed unless otherwise 
specified. The algorithms for imputation of partial dates depend upon the parameter, as 
follows.
Adverse event onset
•
If onset date is completely missing, date is set to date of first dose.
•
If year is present and month and day are missing, or year and day are present, but 
month is missing:
o
If year = year of first dose, then set month and day to month and day of first 
dose.
o
If year < year of first dose, then set month and day to December 31.
o
If year > year of first dose, then set month and day to January 1.
•
If month and year are present and day is missing: 


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o
If year = year of first dose and 
▪
month = month of first dose, then set day to day of first dose date.
▪
month < month of first dose, then set day to last day of month.
▪
month > month of first dose, then set day to first day of month.
o
If year < year of first dose, then set day to last day of month.
o
If year > year of first dose, then set day to first day of month.
•
For all other cases, set date to date of first dose.
Adverse event end date
•
If year is present and month and day are missing, or year and day are present and 
month is missing, set end month and day to December 31.
•
If month and year are present and day is missing, set the day to last day of the month.
•
If fatal event, date is set to minimum of imputed end date and death date.
•
For all other cases, set date to missing.
Concomitant medication
•
If start date is completely missing, start date will not be imputed.
•
If start year is present and month and day are missing, or year and day are present and 
month is missing, set start month and day to January 1.
•
If start year and month are present and day is missing, set start day to 1st day of 
month.
•
If end date is completely missing, end date will not be imputed.
•
If end year is present and month and day are missing, or year and day are present and 
month is missing, set end month and day to December 31.
•
If end year and month are present and day is missing, set end day to last day of the 
month.
•
The imputed dates must be logical, ensuring that no end date is after database lock or 
death or before the start date.
If site queries fail to resolve partial dates for laboratory values and vital signs, including for 
efficacy, the date is missing and will not be imputed.
6
Efficacy Endpoints
This section lists the efficacy endpoints; Section 9 describes their definitions and the plans for 
the analysis of each endpoint.


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6.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change in Hb between Baseline (average pretreatment 
Hb) and the primary evaluation period (average Hb from Weeks 20 to 26, inclusive).
6.2
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoint is the change in Hb between Baseline and the secondary 
evaluation period (average Hb from Weeks 46 to 52).
6.3
Other Efficacy Endpoints
Other efficacy endpoints include the following:
•
Proportion of subjects having average Hb values within the target range during the 
primary evaluation period (Weeks 20 to 26).
•
Proportion of subjects having average Hb values within the target range during the 
secondary evaluation period (Weeks 46 to 52).
•
Proportion of subjects receiving intravenous (IV) iron therapy from Baseline to Week 
52.
•
Average weekly dose of IV elemental iron administered from Baseline to Week 52 in 
subjects who have received IV elemental iron.
•
Receipt of ESA rescue.
•
Proportion of subjects receiving red blood cell (RBC) transfusions from Baseline to 
Week 26.
•
Proportion of subjects receiving RBC transfusions from Baseline to Week 52. 
•
Change from baseline in 36-Item Short Form Version 2 (SF-36v2) Health-Related 
Quality of Life (HRQOL) scores.
•
Change from baseline to the average value in Anemia Subscale ("Additional 
Concerns") of Functional Assessment of Cancer Therapy-Anemia (FACT-An) Score.
•
Change from baseline to the average value in Total FACT-An Score.
•
Change from baseline in score of Patient Global Impression of Severity (PGI-S).
•
Score of Patient Global Impression of Change (PGI-C).
6.4
Rescue Therapy
The narrow and broad-on-treatment rescue therapies are defined as follows:
•
Narrow: For all treatment arms, narrow rescue therapy is defined as rescue for 
worsening anemia with ESA medication or RBC transfusion, not starting after 
permanent study treatment discontinuation.  Reason includes “Hb <9.5 g/dL”. For 


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darbepoetin alfa arm, darbepoetin alfa with increases in dose ≥50% or ≥100% will be 
considered as ESA rescue medication.
•
Broad-on-treatment: For all treatment arms, broad-on-treatment rescue therapy is 
defined as any exposure to ESA medication (aside from darbepoetin alfa not 
designated as rescue in the control arm) or RBC transfusion for any reason not starting 
after permanent study treatment discontinuation. For darbepoetin alfa arm, darbepoetin 
alfa with increases in dose ≥50% or ≥100% will be considered as ESA rescue 
medication.
Reasons for ESA medication and RBC transfusion will be collected in eCRF.  If a given 
therapy starts the same day as permanent discontinuation of study drug, then that therapy will 
be considered on treatment for rescue definitions.
In vadadustat arms, any use of ESA may be considered rescue.  In darbepoetin alfa arm, since 
the study drug itself is an ESA, the use of another ESA may be considered rescue, and the 
increase dose in darbepoetin alfa may be planned titration or a rescue.  Subjects treated 
darbepoetin alfa with increases in dose relative to last dose by percentage of <50%, ≥50% and 
<100%, and ≥100%.  Darbepoetin alfa treatment with ≥50% or ≥100% dose increases from 
last dose will be considered as rescue therapies.  Subjects will be presented by their maximum 
category of increase within each of the five analysis time periods (see Section 5.1). 
The time to the first ESA medication or RBC transfusion (narrow or broad-on-treatment 
therapy with ≥50% or ≥100% dose increase in darbepoetin alfa) will be analyzed by Cox 
regression model for treatment comparison in the randomized population. The estimated 
hazard ratio and its 95% CI will be performed. Kaplan-Meier curve will be displayed as well.  
Analyzing the impact of pre-baseline or post-baseline ESA on vadadustat efficacy requires 
conversion of ESA dose into common units.  The epoetin alfa analogues, darbepoetin alfa and 
methoxy polyethylene glycol epoetin beta (Mircera), will be converted to IV epoetin 
equivalent units per kilogram per week (U/kg/week).  The following conversions have been 
derived from published literature and input from clinical experts [Paganini, 1995; Kaufman, 
1998; Cremieux, 2006; Gosselin, 2006; Levin, 2008; FDA, 2011; Jordan, 2012; Choi, 2013; 
Vega, 2014; Wright, 2015]:


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Table 2.  ESA Unit Conversion
SC Epoetin
IV Epoetin
Darbepoetin alfa to epoetin
1:160
1:200
Methoxy polyethylene glycol-epoetin beta to epoetin
1:176
1:220
Subcutaneous (SC) epoetin to intravenous (IV) epoetin is 1:1.25.
7
Safety Endpoints
The following safety endpoints will be summarized by treatment groups:
•
Adverse events (AEs) and serious adverse events (SAEs).
•
Treatment-emergent adverse events (TEAEs) and treatment-emergent SAEs.
•
Adverse events of special interest (AESI).
•
Vital signs, ECGs and clinical laboratory values.
•
Episodes of Hb >11.0 g/dL for US, > 12.0 g/dL, > 13.0 g/dL, > 14.0 g/dL, < 8.0 g/dL, 
or < 9.0 g/dL.
•
Number of episodes of Hb increase > 1.0 g/dL within any 2-week interval or > 2.0 
g/dL within any 4-week interval.
8
Pharmacokinetic (PK)/ Pharmacodynamic (PD)/ 
Pharmacogenomic (PGx) Analysis
8.1
Pharmacokinetic Analysis
Plasma concentrations, time of sample collection and time post-dose calculations will be 
listed.  Concentrations may be part of a population PK analysis that will be reported 
separately.
8.2
Pharmacodynamic Analysis
A by-subject listing of all PD variables, including erythropoietin (EPO), reticulocytes, and 
iron indices (iron, ferritin, TIBC, and TSAT), 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.  For PD variables analyzed after database 
lock, values will be reported separately.
8.3
Pharmacogenomic Analysis
No PGx analysis is planned.


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9
Efficacy Endpoints and Analyses
The general approach for analysis of continuous outcomes will be analysis of covariance 
(ANCOVA) with multiple imputation for missing data or mixed models for repeated 
measurements (MMRM) on observed data. 
For binary variables, the general approach will be Mantel-Haenszel estimation of risk 
difference stratified by the baseline strata with (or without) multiple imputation for handling 
missing data [Mantel, 1959].
9.1
Primary Estimand
The primary estimand defining the treatment effect of interest in this trial uses the treatment 
policy strategy specified in the ICH E9 (R1) Addendum [FDA 2021b]. In this trial, the 
research question is to compare the assignment of darbepoetin alfa to vadadustat, regardless 
of intercurrent events. The primary analysis will be performed in the randomized population 
in accordance with intent-to-treat. This means the analysis will include individuals who never 
received treatment, discontinued treatment, were rescued with any therapy, and withdrew 
consent. The estimate of the treatment effect of interest will be the one regardless of whether 
the intercurrent event occurred.
The primary estimand for this trial is defined by the following components:
•
Treatment: vadadustat with rescue therapy as needed versus darbepoetin alfa with 
rescue therapy as needed.   
•
Population: randomized population.
•
Variable: change in Hb from Baseline to the primary evaluation period (average Hb 
from Weeks 20 to 26, inclusive).
•
Intercurrent event: never received treatment, discontinued treatment, rescued with any 
therapy or withdrew consent.
•
Population-level summary: difference in mean change in Hb from baseline to the 
primary evaluation period between the vadadustat groups and darbepoetin alfa control 
group.
9.2
Definition of Primary Efficacy Endpoint: Change from Baseline in Hb
The primary efficacy endpoint is the change in average Hb between baseline and the PEP 
(Weeks 20 to 26, inclusive).


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The primary analysis will use the randomized population with an ANCOVA, with 
randomization stratification factors and baseline Hb as covariates.
A 2-sided, 95% CI will be calculated for the difference in mean change in Hb from baseline to 
the PEP between the vadadustat group and darbepoetin alfa control group.  Noninferiority of 
vadadustat will be established if the lower limit of this CI is ≥ -0.75 g/dL.
A hierarchical testing scheme will be used to correct for the multiplicity of the 2 primary 
endpoints: comparison between vadadustat QD vs. darbepoetin alfa and comparison between 
vadadustat TIW vs. darbepoetin alfa.
•
Step 1: comparison between vadadustat QD vs. darbepoetin alfa.
•
If the noninferiority of vadadustat is established in step 1, then move to the step 2;
•
Step 2: comparison between vadadustat TIW vs. darbepoetin alfa.
9.2.1
Baseline Hb
Baseline Hb will be calculated as the average of the last 2 central laboratory Hb 
measurements of samples taken at the visits prior to or on the date of first dose date. If there is 
only one available Hb value prior to or on the date of first dose date, then it will be used for 
the calculation of baseline. If there is more than one available Hb values, the last 2 Hb values 
prior to or on the date of first dose date will be used. 
9.2.2
Hb in the Primary Efficacy Period
Hb for the PEP will be calculated as the average of all Hb measurements from the central 
laboratory within the three visit windows during Weeks 20 through 26, regardless of 
intercurrent events. At least 1 Hb measurement is required for the calculation; otherwise, the 
value will be missing and therefore imputed. The PEP is also called analysis time period 3 
(see Table 1).
9.2.3
Change in Hb from Baseline to the Primary Efficacy Period
The change from baseline will be calculated for each subject as the PEP value minus the 
baseline value.
9.2.4
Analysis of Change from Baseline in Hb to the Primary Efficacy 
Period
The primary analysis will use multiple imputation with ANCOVA as the substantive model 
and will be performed in the randomized population.  


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All intercurrent events will be handled by treatment policy strategy (see Section 9.1).  
Unobserved data after intercurrent events, including hemoglobin outcomes and any covariates 
to be used in the models, will be imputed with randomized subjects using multiple imputation 
under fully conditional specification (FSC) method.  Under the assumption of FSC, data for 
each variable with missing values will be imputed with a separate regression model allowing 
for all available data to be used in the imputation process.  For continuous variables, the 
regression method will be used for imputations.  For categorical variables, logistic regression 
models will be used for binary outcomes, and nominal response logistic regression for 
nominal responses.
An ANCOVA model will be used to compare the mean change from baseline in Hb between 
2 treatment groups with the complete dataset from multiple imputation.  The ANCOVA 
model will contain treatment group, baseline Hb level, and the 2 stratification factors 
(geographic region and mean weekly darbepoetin alfa dose prior to Screening Visit 2) as 
predictor variables.  The stratification factor assignments at randomization will be used in the 
analysis.
The data will have shown noninferiority of vadadustat if the lower bound of the 95% 
confidence interval for the difference in estimated change from baseline in the 2 groups 
(vadadustat minus darbepoetin) exceeds the noninferiority margin of -0.75g/dL.  This ensures 
a 1-sided alpha of 0.025 for the primary analysis.  If the lower limit of the 2-sided 95% 
confidence interval for the difference between the mean in the vadadustat group and the mean 
in the darbepoetin alfa group is above zero, superiority will have been established and the 
finding will be interpreted as providing evidence of a greater change from baseline in Hb for 
vadadustat relative to the control arm.
The procedure of primary analysis follows these steps:
1) Missing data will be imputed separately for each treatment group using FSC method 
with 100 imputed datasets and 40 iterations from PROC MI. The SAS codes of PROC MI 
with outcome variables and covariates will be as follows.  
 
 
 
     
     
               
     
     
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2) The output from the multiple imputation procedure 1) will be 100 imputed complete 
datasets. These 100 imputed complete datasets will be used not only for primary 
efficacy analysis, but also secondary efficacy analysis and other efficacy analysis for 
proportion of subjects having average Hb values within target range.
3) An ANCOVA model will be used to compare the mean change from baseline in Hb 
between treatment groups with the complete dataset.  
 
 
 
 
 
 
 
 
     
     
     
     
4) The output from the ANCOVA model 3) will include the estimate (ESTIMATE) and 
standard error (STDERR) of change from baseline for each imputed complete dataset.
5) The overall results will be obtained using PROC MIANALYZE.  
 
 
     
     
9.2.5
Sensitivity Analyses to the Primary Efficacy Results
To assess the robustness of the findings from the primary analysis, the following set of 
sensitivity analyses will be performed:
•
Primary analysis will be repeated using the FAS population.
•
Primary analysis will be repeated using the PP population with the actual treatment 
received.
•
Primary analysis will be repeated with imputation of data which may have been 
affected by a subject’s having received any form of rescue (transfusion or ESA).  All 
per-visit Hb values within four weeks of administration rescue therapy (narrow or 
broad-on-treatment defined in Section 6.4) will be set as missing prior to imputation. 
 
 
 
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•
A mixed model for repeated measures (MMRM) will be fit to the observed data only 
and will be performed in the randomized population.
 
 
     
     
     
In the MMRM model, the within-subject correlations will use an unstructured covariance 
structure (TYPE=UN).  In the unlikely situation that this model does not converge, the following 
variance covariance matrix structures will be used in the order of 1) heterogeneous Toeplitz 
(TYPE=TOEPH), 2) homogeneous Toeplitz (TYPE=TOEP), and 3) compound symmetry (TYPE=CS).  
9.3
Secondary Efficacy Endpoints: Definitions and Analyses
The key secondary efficacy endpoint will be formally analyzed once the non-inferiorities have 
been established in the primary endpoint for vadadustat QD and TIW regimens.
Mean change in Hb value between Baseline and the secondary evaluation period (average Hb 
from Weeks 46 to 52) will be analyzed using the same methodology as specified for the 
primary efficacy endpoint.  Sensitivity analyses like those of the primary efficacy endpoint 
will be performed.
9.4
Other Efficacy Endpoints: Strategies for Analysis
Except for specifying the analysis population, other efficacy endpoints analyses will be 
performed using the randomized and full analysis population, with the assigned treatment as 
described in Section 3.1.  There will be no correction for multiplicity for these endpoints.
9.4.1
Proportion of Subjects Having Average Hb Values within the Target 
Range during the PEP (Weeks 20 to 26)
All subjects will be defined as either being in their geography-specific target range (see 
Section 2.3) in Weeks 20 through 26 (“yes”) or not (“no”), based on the average Hb value 
during the three visit windows in Weeks 20 through 26.  Subjects with no Hb value in the 
PEP value will be treated as missing.  To ensure uniformity across all analyses, the missing 
binary outcomes will be computed from the imputed complete dataset in primary analysis (see 
Section 9.1.4) [Ratitch, 2013].
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The proportion of subjects within target range will be calculated, and a 95% confidence 
interval of the proportion will be performed by treatment group.
A Mantel-Haenszel estimation of risk difference stratified by the baseline strata will be 
conducted, and the corresponding 2-sided 95% confidence interval for the risk difference will 
be calculated.  Noninferiority will have been established if the lower limit of the confidence 
interval is above -15% when tested per the testing procedure (Section 9.5).  
If the lower limit of the 2-sided confidence interval for the risk difference is above zero, 
superiority will have been established and the finding will be interpreted as providing 
evidence of a higher proportion of subjects being within the target range for vadadustat 
relative to the control arm when tested per the testing procedure (Section 9.5).
The associated odds ratio and corresponding 2-sided 95% confidence interval will also be 
calculated.
The analysis of proportion of subjects within target range follows these steps:
1) 100 imputed complete datasets will be obtained from the multiple imputation 
procedure 1) of Section 9.2.4.
2) The proportion of subjects within target range will be calculated based on the 100 
imputed complete datasets.  A Mantel-Haenszel estimation of risk difference stratified 
by the baseline strata will be conducted.  
 
     
     
3) The overall results from 2) will be obtained using PROC MIANALYZE.  
 
 
 
     
     
9.4.2
Proportion of Subjects Having Average Hb Values within the Target 
Range during the SEP (Weeks 46 to 52)
Proportion of subjects having average Hb values within the target range during the SEP 
(Weeks 46 to 52) will be analyzed using the same methodology as specified for the PEP (see 
Section 9.4.1).
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9.4.3
Proportion of Subjects Receiving IV Iron Therapy from Baseline to 
Week 52
The proportion of subjects receiving at least one intravenous (IV) iron therapy from Baseline 
to Week 52 will be calculated, and a Mantel-Haenszel estimation of risk difference stratified 
by the baseline strata will be performed.
In addition, the following subgroups of baseline iron will be performed:
•
Subjects not receiving any iron at baseline, and 
•
Subjects receiving IV or oral iron at baseline.
9.4.4
Average Weekly Dose of IV Elemental Iron Administered from 
Baseline to Week 52
Average weekly dose of IV elemental iron administered from Baseline to Week 52 in subjects 
who have received IV elemental iron will be calculated, and an analysis of variance 
(ANOVA) model with 2 stratification factors at randomization will be performed.   If the 
distribution is highly skewed because of a long tail to the right, other methods may be 
considered.
9.4.5
Receipt of ESA Rescue
The proportion of subjects with any ESA rescue medications including narrow or broad-on-
treatment therapies with ≥50% or ≥100% dose increase in darbepoetin alfa defined in Section 
6.4 will be calculated.  A Mantel-Haenszel estimation of risk difference stratified by the 
baseline strata for each study period will be performed.
The time to the first ESA rescue (narrow or broad-on-treatment therapies with ≥50% or 
≥100% dose increase in darbepoetin alfa) will be analyzed by Cox regression model for 
treatment comparison in the randomized population. The estimated hazard ratio and its 95% 
CI will be performed. Kaplan-Meier curve will be displayed as well.
9.4.6
Proportion of Subjects Receiving Red Blood Cell (RBC) Transfusions
The proportion of subjects receiving RBC transfusions (narrow or broad-on-treatment 
therapy) will be calculated from Baseline to Week 26 and from Baseline to Week 52.  A 
Mantel-Haenszel estimation of risk difference stratified by the baseline strata will be 
performed.
The time to the first RBC transfusion (narrow or broad-on-treatment therapy) will be analyzed 
by Cox regression model for treatment comparison in the randomized population. The 


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estimated hazard ratio and its 95% CI will be performed. Kaplan-Meier curve will be 
displayed as well.  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
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9.4.10
Score of Patient Global Impression of Change (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.  Subjects will answer the following 
question:  
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•
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 before your last visit)?
The question will be rated as “very much worsened”, “much worsened”, “minimally 
worsened”, “not changed”, “minimally improved”, “much improved”, or “very much 
improved”.  PGI-C scale score will be summarized by visit and by treatment group.  
9.5
Study Level Type I Error Control
The study-wise type I error control for multiple testing of efficacy endpoints is controlled at 
0.05 level, two-sided by using hierarchical testing procedure. The order of hierarchy is listed 
below. Upon the demonstration of the non-inferiority of the primary endpoint of vadadustat 
QD vs. darbepoetin alfa for the change in average Hb between baseline and the PEP, the non-
inferiority of the other primary endpoint of vadadustat TIW vs. darbepoetin alfa for the 
change in average Hb between baseline and the PEP will be examined with pre-specified 
margin. If it meets the noninferiority margin, the secondary efficacy endpoints in the list will 
be examined against the pre-specified statistical criteria and so on.  In other words, an 
endpoint will only be tested against pre-specified statistical criteria when the previous 
endpoint meets statistical criteria. Once an endpoint did not meet the statistical criteria, any 
endpoints after it will not be formally tested. The hierarchical testing order will be as follows: 
1. Noninferiority of vadadustat QD vs. darbepoetin alfa for the change in average Hb 
between baseline and the PEP (primary efficacy endpoint).
2. Noninferiority of vadadustat TIW vs. darbepoetin alfa for the change in average Hb 
between baseline and the PEP (primary efficacy endpoint).
3. Noninferiority of vadadustat QD vs. darbepoetin alfa for the change in average Hb 
between baseline and the SEP (secondary efficacy endpoint).
4. Noninferiority of vadadustat TIW vs. darbepoetin alfa for the change in average Hb 
between baseline and the SEP (secondary efficacy endpoint).
5. Noninferiority of vadadustat QD vs. darbepoetin alfa for the proportion of subjects 
having average Hb values within the target range during the PEP (other efficacy 
endpoint).
6. Noninferiority of vadadustat TIW vs. darbepoetin alfa for the proportion of subjects 
having average Hb values within the target range during the PEP (other efficacy 
endpoint).
7. Noninferiority of vadadustat QD vs. darbepoetin alfa for the proportion of subjects 
having average Hb values within the target range during the SEP (other efficacy 
endpoint).


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8. Noninferiority of vadadustat TIW vs. darbepoetin alfa for the proportion of subjects 
having average Hb values within the target range during the SEP (other efficacy 
endpoint).
10
Safety Analyses
All analyses of safety data will use the safety population.
Most of the analysis of safety data will be descriptive without formal statistical testing. In 
some cases, 95% confidence intervals for the change from baseline as well as for the 
difference between the study groups will be reported.
10.1
Mortality
The number and cause of death will be reported and summarized by treatment arm.
10.2
Hb-related Safety Endpoints
Hb-related safety endpoints will be defined using data from the central laboratory.  The 
analyses will use all central laboratory values in the database starting from randomization.  No 
imputation will be performed for missing data.
Any post-baseline Hb value above a set threshold will be considered as a “yes” in the Hb 
related safety analysis.  Subjects with no available post-baseline data will be excluded from 
this analysis.  All other subjects will be classified to the “no” category.
The number and proportion of subjects with at least 1 of the following criteria at any post-
baseline time point will be summarized by analysis time period. The denominator for 
calculating proportion is the total number of subjects with available post-baseline Hb values 
in each analysis time period. A 95% confidence interval of the proportion will be performed 
by treatment group using the Clopper-Pearson exact method [Clopper, 1934].
•
Hb > 11.0 g/dL for US.
•
Hb > 12.0 g/dL.
•
Hb > 13.0 g/dL.
•
Hb > 14.0 g/dL.
•
Hb increase > 1.0 g/dL within any 2-week interval.
•
Hb increase > 2.0 g/dL within any 4-week interval.
•
Hb < 8.0 g/dL.
•
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A Mantel-Haenszel estimation of risk difference stratified by the baseline strata will be 
conducted, and the corresponding 2-sided 95% confidence interval of the risk difference will 
be calculated.  The associated odds ratio and corresponding 2-sided 95% confidence interval 
will also be calculated.
10.3
Adverse Events and Serious Adverse Events
The AE eCRF has been designed to capture all events from time of signing the informed 
consent through the Safety Follow-up visit.  Subjects must be followed for AEs until the final 
required protocol visit or until all drug-related toxicities and serious adverse events (SAEs) 
have resolved (or are considered chronic/stable), whichever is later.  All AEs will be coded by 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and 
preferred term (PT). The MedDRA version used for reporting this study will be described in a 
footnote on AE related outputs. 
Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the start 
of IMP treatment. In more detail, TEAEs are all adverse events which started after start of 
IMP treatment; or if the event was continuous from baseline and was worsening, serious, IMP 
related, or resulted in death, discontinuation, interruption or reduction of IMP.
All TEAE summaries will provide the number of subjects reporting at least 1 TEAE.  Tables 
will present the number and percentage of subjects by treatment group reporting at least 1 of 
the following:
•
TEAE, SOC, and PT
o
TEAE leading to withdrawal of study medication, SOC, and PT
o
TEAE, severity, SOC and PT
o
Drug-related TEAE, SOC, and PT
o
Drug-related TEAE leading to withdrawal of study medication, SOC, and PT
•
Treatment-emergent SAE, SOC, and PT
o
Drug-related treatment-emergent SAE, SOC, and PT
o
Fatal TEAE, SOC and PT.
A summary table will show number of subjects with at least 1 of each of the following:
•
AE,
•
SAE,
•
TEAE, 
•
Severe TEAE 
•
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•
Drug-related TEAE leading to withdrawal of study treatment, 
•
Drug-related TEAE, 
•
Treatment-emergent SAE,
•
Drug-related treatment-emergent SAE,
•
Fatal TEAE,
•
All death.
TEAEs reported at least 5% of subjects in any treatment groups, and non-serious TEAEs 
reported at least 5% of subjects in any treatment groups will be summarized by SOC and PT 
for each treatment group.  
TEAEs will be summarized by 1) worst severity, and 2) worst causality by SOC and PT.  For 
each subject and each PT, the worst severity recorded will be used in the by-severity 
summaries.  Similarly, the most conservative causality assessment (most related to treatment) 
will be attributed and used in the by-causality summaries.  If severity or causality is missing, 
data will be imputed to the worst category.
A by-subject listing of all AEs will be provided.  This listing will be presented by treatment 
group and will include center, subject identifier, age, sex, race, AE (SOC, PT, and verbatim 
term), flag of TEAE, study day of onset, study day of resolution, duration, severity, 
seriousness, relationship to the study medication, action taken, outcome and causality. 
AEs of special interest (AESI) listed in Appendix D  will be summarized by treatment group.  
The number and percentage of subjects reporting these AESI will be provided.
10.4
Major Adverse Cardiovascular Event (MACE) 
Potential safety events will be collected in Safety Event Data Collection eCRF page.  The 
occurrence of any potential safety events will be summarized by SOC and PT for each 
treatment group, and a by-subject listing will be provided.
An independent Safety Event Adjudication Committee (SEAC) that is composed of 
independent experts will be formed prior to trial commencement to adjudicate the MACE (all-
cause mortality, non-fatal myocardial infarction (MI), and non-fatal stroke) plus 
hospitalization for heart failure (HF) or thromboembolic event excluding vascular access 
thrombosis.  Adjudicated safety events will be summarized for each treatment group, and a 
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10.5
Other Safety Endpoints
Observed values of continuous and categorical parameters and changes from baseline for 
continuous parameters to each trial visit will be summarized descriptively for vital signs and 
clinical laboratory results.  Graphical displays of selected laboratory parameters will also be 
provided.
10.5.1
Clinical Laboratory Evaluation
Observed values and changes (absolute and percent) from baseline in continuous clinical 
laboratory results will be summarized by visit and by treatment group.  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.  
A summary of liver function abnormalities will be provided by treatment group.  Any subject 
with at least 1 of the following liver function abnormalities will be summarized:
•
Alanine aminotransferase (ALT):
o
>2 × and ≤3 × upper limit of normal (ULN). 
o
>3 × and ≤5 × ULN.
o
>5 × and ≤10× ULN.
o
>10 × ULN.
•
Aspartate aminotransferase (AST):
o
>2 × and ≤3 × ULN.
o
> 3× and ≤ 5 × ULN.
o
>5 × and ≤10 × ULN.
o
>10 × ULN.
•
Total bilirubin:
o
>2× and ≤3× ULN.
o
>3× ULN.
The occurrence of events that satisfy the following laboratory values fulfilling potential liver 
injury criteria will be summarized. For each subject, the worse laboratory results will be 
considered.
•
(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.


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The number and percentage of subjects experiencing clinically significant values for 
Potassium >6.0 mmol/L will be presented by analysis time period. 
10.5.2
Vital Signs, ECGs, and Physical Findings
Observed values and changes from baseline in vital signs and body weight will be 
summarized by visit and by treatment group. A summary of each electrocardiography (ECG) 
parameter will be provided by treatment group.
The number and percentage of subjects experiencing the following findings will be 
summarized by treatment group and by analysis time periods. The denominator for calculating 
percentage is the total number of subjects with available values in each analysis time period. 
•
Systolic blood pressure (SBP):
o
≥ 180 mmHg.
o
≥ 160 mmHg.
o
≤ 90 mmHg.
o
Increase from Baseline ≥ 20 mmHg.
o
Decrease from Baseline ≥ 20 mmHg.
•
Diastolic blood pressure (DBP):
o
≥ 110 mmHg.
o
≤ 50 mmHg.
o
Increase from Baseline ≥ 20 mmHg.
o
Decrease from Baseline ≥ 20 mmHg.
•
QTc interval: > 450 msec (males); >470 msec (females).
11
Subgroups
Analyses of the primary efficacy endpoint and key secondary efficacy endpoint will also be 
performed using the randomized and FAS populations, using the assigned treatment, for 
subgroups based on the following:
•
Low darbepoetin alfa dose group (≤ 0.45 μg/kg/week) or High darbepoetin alfa dose 
group (> 0.45 and ≤ 1.5 μg/kg/week).
Due to use of different target Hb levels in the US versus non-US, the endpoints will also be 
analyzed for subsets based on the target Hb level:
•
The US subset will be assessed due to the target Hb range being 10.0 to 11.0 g/dL in 
the US. 


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•
The European subset will be assessed since the target Hb range is 10.0 to 12.0 g/dL in 
the Europe.
•
Geographic region (US, Europe).
•
Age (<65 years, ≥65 years).
•
Sex (Male, Female).
•
Race (White, Black or Other).
•
Baseline Hb (<10.0 g/dL, ≥10.0 g/dL).
Subgroup analyses will be performed only if the total number of outcomes in a subgroup, 
combined over the two compared treatment groups, is at least 30.
 
 
 
 
13
Interim Analysis
No interim analyses will be performed. No analyses of the primary efficacy endpoint will be 
conducted when all randomized subjects complete their Week 26 evaluations. .
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17
Appendix D Adverse Event of Special Interest
The list of adverse events of special interest (AESI) in the following is from Vadadustat 
Adverse Events of Special Interest Version 2 Final.  
•
Worsening of Hypertension: Hypertension MedDRA SMQ Narrow.
•
Hepatotoxicity: Drug related hepatic disorders Comprehensive SMQ.
•
Pulmonary Hypertension: Pulmonary Hypertension SMQ Narrow.
•
Adrenal disorder: MedDRA HLGT Adrenal gland disorders and the MedDRA HLT 
Adrenal cortex tests.
•
Malignancies including renal cell carcinoma: Malignant or unspecified tumors (SMQ) 
Broad.
•
Congestive heart failure: Cardiac failure MedDRA SMQ Narrow.
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Adverse event preferred terms used in key queries from Food and Drug Administration (FDA) 
[FDA, 2021a] are listed below.
•
Thrombosis (FDA):
Cerebral infarction
Embolic cerebral infarction
Ischaemic stroke
Cerebellar infarction
Lacunar stroke
Embolic stroke
Brain stem stroke
Lacunar infarction
Thrombosis in device
Arteriovenous fistula thrombosis 
Arteriovenous graft thrombosis 
Vascular access site thrombosis 
Vascular graft thrombosis
Graft thrombosis
Shunt thrombosis
Acute myocardial infarction 
Myocardial infarction
Deep vein thrombosis 
Thrombosis
Atrial thrombosis
Peripheral artery thrombosis 
Subclavian vein thrombosis 
Brachiocephalic vein thrombosis 
Subclavian artery thrombosis 
Vena cava thrombosis 
Thrombophlebitis superficial 


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Arterial thrombosis 
Thrombophlebitis
Jugular vein thrombosis
Venous thrombosis
Pelvic venous thrombosis 
Venous thrombosis limb
Cardiac ventricular thrombosis
Intracardiac thrombus
•
Device/shunt thrombosis/occlusion/malfunction/Stenosis (FDA): 
Thrombosis in device 
Arteriovenous fistula thrombosis 
Arteriovenous graft thrombosis 
Vascular access site thrombosis 
Vascular graft thrombosis 
Medical device site thrombosis 
Device occlusion
Arteriovenous fistula occlusion 
Vascular access site occlusion 
Vascular access complication 
Vascular access malfunction 
Arteriovenous graft site stenosis 
Shunt occlusion
Shunt malfunction
Vascular graft stenosis 
Anastomotic stenosis
Vascular access site complication 
Vascular graft occlusion
•
Device/shunt thrombosis (FDA):


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Thrombosis in device 
Arteriovenous fistula thrombosis 
Arteriovenous graft thrombosis 
Vascular access site thrombosis 
Vascular graft thrombosis
Graft thrombosis
Shunt thrombosis
Medical device site thrombosis 
Device related thrombosis 
Injection site thrombosis
•
Seizure (FDA):
Epilepsy
Epileptic encephalopathy 
Seizure
Generalised tonic-clonic seizure 
Idiopathic partial epilepsy
Partial seizures
Tonic convulsion
•
Stroke (FDA):
Cerebral infarction
Embolic cerebral infarction 
Ischaemic stroke 
Cerebellar infarction
Lacunar stroke
Embolic stroke
Brain stem stroke
Lacunar infarction 


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Cerebrovascular accident 
Haemorrhagic stroke
Brain stem haemorrhage
•
Sepsis/septic shock (FDA):
Device related sepsis 
Enterococcal sepsis 
Sepsis
Urosepsis 
Streptococcal sepsis 
Pseudomonal sepsis 
Staphylococcal sepsis 
Septic shock
Sepsis syndrome 
Biliary sepsis
Bacterial sepsis
Fungal sepsis 
Citrobacter sepsis 
Listeria sepsis 
Abdominal sepsis 
Septic encephalopathy 
Escherichia sepsis


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18
References
Abe S, Yoshizawa M, Nakanishi N, Yazawa T, Yokota K, et al. Electrocardiographic 
abnormalities in patients receiving hemodialysis.  Am Heart J. 1996; 131: 1137-44.
Choi P, Farouk M, Manamley N, Addison J. Dose conversion ratio in hemodialysis patients 
switched from darbepoetin alfa to peg-epoetin beta: AFFIRM study. Adv Ther 2013; 30:1007-
17.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 1934; 26:404-23.
Cremieux PY, Van Audenrode M, Lefebvre P. The relative dosing of epoetin alfa and 
darbepoetin alfa in chronic kidney disease. Curr Med Res Opin 2006; 22:2329-36. Food and 
Drug Administration. Aranesp (Darbepoetin alfa) label. 2011. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103951Orig1s5173_103951Orig
1s5258lbl.pdf. 
Food and Drug Administration. Briefing Document. Cardiovascular and Renal Drugs 
Advisory Committee Meeting 2021a. Roxadustat. Table 34. Available at: 
https://www.fda.gov/media/150728/download.
Food and Drug Administration. E9(R1) Statistical Principles for Clinical Trials: Addendum: 
Estimands and Sensitivity Analysis in Clinical Trials Guidance for Industry. 2021b. Available 
at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e9r1-
statistical-principles-clinical-trials-addendum-estimands-and-sensitivity-analysis-clinical.
Gosselin A, McKenzie R, Lefebvre P, et al. Dose-conversion ratio for epoetin alfa and 
darbepoetin alfa in chemotherapy patients with anemia and cancer. P&T 2006; 31:594-6, 601-
3.
Jordan J, Breckles J, Leung V, et al. Conversion from epoetin alfa to darbepoetin alfa: effects 
on patients’ hemoglobin and costs to Canadian dialysis centres. Can J Hosp Pharm 2012; 
65:443-9.
Kaufman JS, Reda DJ, Fye CL, et al. Subcutaneous compared with intravenous epoetin in 
patients receiving hemodialysis. Department of Veterans Affairs cooperative study group on 
erythropoietin in hemodialysis patients. N Engl J Med 1998; 339:578-83. 
Levin NW, Fishbane S, Cañedo FV, et al. Intravenous methoxy polyethylene glycol-epoetin 
beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a 


SAP 404-201-00012 
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randomised non-inferiority trial (MAXIMA). Lancet 2007; 370:1415-21. Erratum in: Lancet 
2008; 371:386.
Mantel N, Haenszel W. Statistical aspects of analysis of data from retrospective studies of 
disease. J Natl Cancer Inst 1959; 22:719–48.
Paganini EP, Eschbach JW, Lazarus JM, et al. Intravenous versus subcutaneous dosing of 
epoetin alfa in hemodialysis patients. Am J Kidney Dis 1995; 6:331-40.
QualityMetric Incorporated. User’s Manual for the SF-36v2 Health Survey, Third Edition. 
2011. Chapter 5, 55-61.
Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharm Stat 2013;12(6):337-347.
Sofia Skampardoni S, Poulikakos D, Malik M, Green D, Kalra PA. The potential of 
electrocardiography for cardiac risk prediction in chronic and end-stage kidney disease. 
Nephrol Dial Transplant. 2019; 34: 1089–1098.
Vega A, Abad S, Verdalles U, et al. Dose equivalence between continuous erythropoietin 
receptor activator (CERA), darbepoetin, and epoetin in patients with advanced chronic kidney 
disease. Hippokratia 2014; 18:315-18.
Waks JW, Tereshchenko LG, Parekh RS. Electrocardiographic Predictors of Mortality and 
Sudden Cardiac Death in Patients with End Stage Renal Disease on Hemodialysis. J 
Electrocardiol. 2016; 49(6): 848–854. 
Wright DG, Wright EC, Narva AS, et al. Association of erythropoietin dose and route of 
administration with clinical outcomes for patients on hemodialysis in the United States. Clin J 
Am Soc Nephrol 2015; 10:1822-30.


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Proposed List of Summary Tables
Table Number
Table Title
Population
14.1.1
Subject Disposition
All Subjects
14.1.2.1
Analysis Population
Randomized Population
14.1.2.2
Clinical Study Report (CSR) Reportable 
Protocol Deviation
Randomized Population
14.1.3.1
Demographics
Randomized Population
14.1.3.2
Demographics
Safety Population 
14.1.3.3
Demographics
Full Analysis Set Population
14.1.3.4
Demographics
Per Protocol Population
14.1.4.1
Baseline Characteristics
Randomized Population
14.1.4.2
Baseline Characteristics
Safety Population 
14.1.4.3
Baseline Characteristics
Full Analysis Set Population
14.1.4.4
Baseline Characteristics
Per Protocol Population
14.1.5.1
Baseline Laboratory Measurements
Randomized Population
14.1.5.2
Baseline Laboratory Measurements
Safety Population 
14.1.5.3
Baseline Laboratory Measurements
Full Analysis Set Population
14.1.5.4
Baseline Laboratory Measurements
Per Protocol Population
14.1.6.1
Etiology of CKD
Randomized Population
14.1.6.2.1
Medical History
Randomized Population
14.1.6.2.2
Other Medical History
Randomized Population
14.1.7.1
Prior Medications
Safety Population
14.1.7.2
Concomitant Medications
Safety Population
14.1.7.3
Prior ESA Medications
Safety Population
14.1.7.4
Concomitant ESA Medications
Safety Population
14.1.7.5.1
Concomitant Procedures
Safety Population
14.1.7.5.2
Concomitant Procedures - Transfusion
Safety Population
14.1.7.5.3
Concomitant Procedures - Phlebotomy
Safety Population


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Table Number
Table Title
Population
14.1.7.6.1
Summary of COVID 19 Vaccines
Safety Population
14.1.7.6.2
Listing of COVID 19 Vaccines
Safety Population
14.1.8.1
Number of Subjects Taking Concomitant 
Anti-Hypertensive Medications
Safety Population
14.1.8.2
Number of Concomitant Anti-Hypertensive 
Medications Taken Per Subject
Safety Population
14.1.9.1.1
Study Treatment Compliance Rate by Study 
Period 
Safety Population
14.1.9.1.2
Study Treatment Compliance Rate by Study 
Period 
Full Analysis Set Population
14.1.9.2.1
Study Treatment Compliance Rate by Visit 
Safety Population
14.1.9.2.2
Study Treatment Compliance Rate by Visit 
Full Analysis Set Population
14.1.9.3.1
Average Weekly Dose of Study Treatment
Safety Population
14.1.9.3.2
Average Weekly Dose of Study Treatment
Full Analysis Set Population
14.1.9.3.3.1
Average Weekly Dose of Study Treatment by 
Baseline Hb Category
Safety Population
14.1.9.3.3.2
Average Weekly Dose of Study Treatment by 
Baseline ESA Type
Safety Population
14.1.9.3.3.3
Average Weekly Dose of Study Treatment by 
Baseline ESA Dose Group
Safety Population
14.1.9.4.1
Number of Subjects by Vadadustat Dose 
Level
Safety Population
14.1.9.4.2
Number of Subjects by Vadadustat Dose 
Level
Full Analysis Set Population
14.1.9.5.1
Summary of Maximum Increase in Dose 
Amount of Darbepoetin Alfa
Safety Population
14.1.9.5.2
Summary of Maximum Increase in Dose 
Amount of Darbepoetin Alfa
Full Analysis Set Population
14.1.9.6.1
Total Duration of Exposure (Week) to Study 
Treatment During the Study
Safety Population


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Table Number
Table Title
Population
14.1.9.6.2
Total Duration of Exposure (Week) to Study 
Treatment During the Study
Full Analysis Set Population
14.1.9.7.1
Reason for Study Drug Change and 
Interruption
Safety Population
14.1.9.7.2
Reason for Study Drug Change and 
Interruption
Full Analysis Set Population
14.2.1.1
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 20-26 
(ANCOVA with Multiple Imputations)
Randomized Population
14.2.1.2.1
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 20-26 
(ANCOVA with Multiple Imputations)
Full Analysis Set Population
14.2.1.2.2
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 20-26 
(ANCOVA with Multiple Imputations)
Per Protocol Population
14.2.1.2.3.1
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 20-26 
(ANCOVA with Multiple Imputations of Data 
Affected by any Rescue - Narrow Therapy 
with ≥50% Increases in Darbepoetin Alfa 
Treatment)
Randomized Population
14.2.1.2.3.2
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 20-26 
(ANCOVA with Multiple Imputations of Data 
Affected by any Rescue - Narrow Therapy 
with ≥100% Increases in Darbepoetin Alfa 
Treatment)
Randomized Population
14.2.1.2.4.1
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 20-26 
(ANCOVA with Multiple Imputations of Data 
Affected by any Rescue - Broad-on-treatment 
Therapy with ≥50% Increases in Darbepoetin 
Alfa Treatment)
Randomized Population


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Table Number
Table Title
Population
14.2.1.2.4.2
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 20-26 
(ANCOVA with Multiple Imputations of Data 
Affected by any Rescue - Broad-on-treatment 
Therapy with ≥100% Increases in Darbepoetin 
Alfa Treatment)
Randomized Population
14.2.1.3
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 20-26 
(MMRM)
Randomized Population
14.2.2.1
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 46-52 
(ANCOVA with Multiple Imputations)
Randomized Population
14.2.2.2.1
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 46-52 
(ANCOVA with Multiple Imputations)
Full Analysis Set Population
14.2.2.2.2
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 46-52 
(ANCOVA with Multiple Imputations)
Per Protocol Population
14.2.2.2.3.1
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 46-52 
(ANCOVA with Multiple Imputations of Data 
Affected by any Rescue - Narrow Therapy 
with ≥50% Increases in Darbepoetin Alfa 
Treatment)
Randomized Population
14.2.2.2.3.2
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 46-52 
(ANCOVA with Multiple Imputations of Data 
Affected by any Rescue - Narrow Therapy 
with ≥100% Increases in Darbepoetin Alfa 
Treatment)
Randomized Population
14.2.2.2.4.1
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 46-52 
(ANCOVA with Multiple Imputations of Data 
Affected by any Rescue - Broad-on-treatment 
Randomized Population


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Table Number
Table Title
Population
Therapy with ≥50% Increases in Darbepoetin 
Alfa Treatment)
14.2.2.2.4.2
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 46-52 
(ANCOVA with Multiple Imputations of Data 
Affected by any Rescue - Broad-on-treatment 
Therapy with ≥100% Increases in Darbepoetin 
Alfa Treatment)
Randomized Population
14.2.2.3
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average over Weeks 46-52 
(MMRM)
Randomized Population
14.2.3.1.1
Proportion of Subjects Having Average Hb 
Values within the Target Range during 
Primary Efficacy Period (Weeks 20 to 26)
Randomized Population
14.2.3.1.2
Proportion of Subjects Having Average Hb 
Values within the Target Range during 
Primary Efficacy Period (Weeks 20 to 26)
Full Analysis Set Population
14.2.3.2.1
Proportion of Subjects Having Average Hb 
Values within the Target Range during 
Secondary Efficacy Period (Weeks 46 to 52)
Randomized Population
14.2.3.2.2
Proportion of Subjects Having Average Hb 
Values within the Target Range during 
Secondary Efficacy Period (Weeks 46 to 52)
Full Analysis Set Population
14.2.4.1.1
Proportion of Subjects Receiving IV Iron 
Therapy by Baseline Iron Group
Randomized Population
14.2.4.1.2
Proportion of Subjects Receiving IV Iron 
Therapy by Baseline Iron Group
Full Analysis Set Population
14.2.4.2.1
Average Weekly Dose (mg) of IV Elemental 
Iron Administered in Subjects Who Have 
Received IV Elemental Iron 
Randomized Population
14.2.4.2.2
Average Weekly Dose (mg) of IV Elemental 
Iron Administered in Subjects Who Have 
Received IV Elemental Iron 
Full Analysis Set Population


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Table Number
Table Title
Population
14.2.4.3.1.1
Proportion of Subjects with any ESA Rescue 
Medications - Narrow Therapy with ≥50% 
Increases in Darbepoetin Alfa Treatment
Randomized Population
14.2.4.3.1.2
Proportion of Subjects with any ESA Rescue 
Medications - Narrow Therapy with ≥50% 
Increases in Darbepoetin Alfa Treatment
Full Analysis Set Population
14.2.4.3.2.1
Proportion of Subjects with any ESA Rescue 
Medications - Narrow Therapy with ≥100% 
Increases in Darbepoetin Alfa Treatment
Randomized Population
14.2.4.3.2.2
Proportion of Subjects with any ESA Rescue 
Medications - Narrow Therapy with ≥100% 
Increases in Darbepoetin Alfa Treatment
Full Analysis Set Population
14.2.4.3.3.1
Proportion of Subjects with any ESA Rescue 
Medications - Broad-on-treatment Therapy 
with ≥50% Increases in Darbepoetin Alfa 
Treatment
Randomized Population
14.2.4.3.3.2
Proportion of Subjects with any ESA Rescue 
Medications - Broad-on-treatment Therapy 
≥50% Increases in Darbepoetin Alfa 
Treatment
Full Analysis Set Population
14.2.4.3.4.1
Proportion of Subjects with any ESA Rescue 
Medications - Broad-on-treatment Therapy 
with ≥100% Increases in Darbepoetin Alfa 
Treatment
Randomized Population
14.2.4.3.4.2
Proportion of Subjects with any ESA Rescue 
Medications - Broad-on-treatment Therapy 
with ≥100% Increases in Darbepoetin Alfa 
Treatment
Full Analysis Set Population
14.2.4.4.1
Time to First ESA Rescue Medication - 
Narrow Therapy with ≥50% Increases in 
Darbepoetin Alfa Treatment
Randomized Population


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Table Number
Table Title
Population
14.2.4.4.2
Time to First ESA Rescue Medication - 
Narrow Therapy with ≥100% Increases in 
Darbepoetin Alfa Treatment
Randomized Population
14.2.4.4.3
Time to First ESA Rescue Medication - 
Broad-on-treatment Therapy with ≥50% 
Increases in Darbepoetin Alfa Treatment
Randomized Population
14.2.4.4.4
Time to First ESA Rescue Medication - 
Broad-on-treatment Therapy with ≥100% 
Increases in Darbepoetin Alfa Treatment
Randomized Population
14.2.4.5.1.1
Proportion of Subjects Receiving any Red 
Blood Cell (RBC) Transfusions - Narrow 
Therapy
Randomized Population
14.2.4.5.1.2
Proportion of Subjects Receiving any Red 
Blood Cell (RBC) Transfusions - Narrow 
Therapy
Full Analysis Set Population
14.2.4.5.2.1
Proportion of Subjects Receiving any Red 
Blood Cell (RBC) Transfusions - Broad-on-
treatment Therapy
Randomized Population
14.2.4.5.2.2
Proportion of Subjects Receiving any Red 
Blood Cell (RBC) Transfusions - Broad-on-
treatment Therapy
Full Analysis Set Population
14.2.4.6.1
Time to First Red Blood Cell (RBC) 
Transfusion - Narrow Therapy
Randomized Population
14.2.4.6.2
Time to First Red Blood Cell (RBC) 
Transfusion - Broad-on-treatment Therapy
Randomized Population
14.2.4.7.1
Time to First ESA Rescue Medication or RBC 
Transfusion - Narrow Therapy with ≥50% 
Increases in Darbepoetin Alfa Treatment
Randomized Population
14.2.4.7.2
Time to First ESA Rescue Medication or RBC 
Transfusion - Narrow Therapy with ≥100% 
Increases in Darbepoetin Alfa Treatment
Randomized Population
14.2.4.7.3
Time to First ESA Rescue Medication or RBC 
Transfusion - Broad-on-treatment Therapy 
Randomized Population


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Table Number
Table Title
Population
with ≥50% Increases in Darbepoetin Alfa 
Treatment
14.2.4.7.4
Time to First ESA Rescue Medication or RBC 
Transfusion - Broad-on-treatment Therapy 
with ≥100% Increases in Darbepoetin Alfa 
Treatment
Randomized Population
14.2.5.1.1
Change from Baseline in SF-36v2 Health-
related Quality of Life (HRQOL) Score
Randomized Population
14.2.5.1.2
Change from Baseline in SF-36v2 Health-
related Quality of Life (HRQOL) Score
Full Analysis Set Population
14.2.5.2.1
Change from Baseline to the Average Value in 
FACT-An Anemia Subscale Score and Total 
Score
Randomized Population
14.2.5.2.2
Change from Baseline to the Average Value in 
FACT-An Anemia Subscale Score and Total 
Score
Full Analysis Set Population
14.2.5.3.1
Change from Baseline in Patient Global 
Impression of Severity (PGI-S)
Randomized Population
14.2.5.3.2
Change from Baseline in Patient Global 
Impression of Severity (PGI-S)
Full Analysis Set Population
14.2.5.4.1
Summary of Patient Global Impression of 
Change (PGI-C)
Randomized Population
14.2.5.4.2
Summary of Patient Global Impression of 
Change (PGI-C)
Full Analysis Set Population
14.2.6.1.1
Subgroup Analysis of Change from Baseline 
in Hemoglobin (Hb, g/dL) to the Average over 
Weeks 20-26 (ANCOVA with Multiple 
Imputations)
Randomized Population
14.2.6.1.2
Subgroup Analysis of Change from Baseline 
in Hemoglobin (Hb, g/dL) to the Average over 
Weeks 20-26 (ANCOVA with Multiple 
Imputations)
Full Analysis Set Population


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Table Number
Table Title
Population
14.2.6.2.1
Subgroup Analysis of Change from Baseline 
in Hemoglobin (Hb, g/dL) to the Average over 
Weeks 46-52 (ANCOVA with Multiple 
Imputations)
Randomized Population
14.2.6.2.2
Subgroup Analysis of Change from Baseline 
in Hemoglobin (Hb, g/dL) to the Average over 
Weeks 46-52 (ANCOVA with Multiple 
Imputations)
Full Analysis Set Population
14.3.1.1
Overall Summary of Adverse Events
Safety Population
14.3.1.2.1
Treatment-Emergent Adverse Events
Safety Population
14.3.1.2.2
Treatment-Emergent Adverse Events by 
Severity
Safety Population
14.3.1.2.3
Drug-Related Treatment-Emergent Adverse 
Events
Safety Population
14.3.1.3.1
Serious Treatment-Emergent Adverse Events
Safety Population
14.3.1.3.2
Drug-Related Serious Treatment-Emergent 
Adverse Events
Safety Population
14.3.1.4.1
Treatment-Emergent Adverse Events Leading 
to Study Drug Discontinuation
Safety Population
14.3.1.4.2
Drug-Related Treatment-Emergent Adverse 
Events Leading to Study Drug 
Discontinuation
Safety Population
14.3.1.5
Treatment-Emergent Adverse Events 
Resulting in Death
Safety Population
14.3.1.6.1
Treatment-Emergent Adverse Events Reported 
at least 5% of Subjects in Any Treatment 
Groups
Safety Population
14.3.1.6.2
Non-Serious Treatment-Emergent Adverse 
Events Reported at least 5% of Subjects in 
Any Treatment Groups
Safety Population
14.3.1.7
Treatment-Emergent Adverse Events of 
Special Interest
Safety Population


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Table Number
Table Title
Population
14.3.1.8
Adjudicated Safety Events
Safety Population
14.3.2.1
Listing of Serious Adverse Events
Safety Population
14.3.2.2
Listing of Treatment-Emergent Adverse 
Events Leading to Study Drug 
Discontinuation
Safety Population
14.3.2.3
Listing of Treatment-Emergent Adverse 
Events Resulting in Death
Safety Population
14.3.2.4
Listing of All Deaths
Safety Population
14.3.2.5
Listing of Treatment-Emergent Adverse 
Events for Subjects Who Discontinued from 
Study Due to Withdrawal of Consent
Safety Population
14.3.2.6.1
Listing of Reported Safety Events 
Safety Population
14.3.2.6.2
Listing of Adjudicated Safety Events
Safety Population
14.3.2.7.1
COVID 19 Related Adverse Events
Safety Population
14.3.2.7.2
Listing of COVID 19 Related Adverse Events
Safety Population
14.3.5.1.1.1
Change from Baseline in Laboratory Test 
Results by Visit -- Complete Blood Count 
(Conventional Unit)
Safety Population
14.3.5.1.1.2
Change from Baseline in Laboratory Test 
Results by Visit -- Complete Blood Count (SI 
Unit)
Safety Population
14.3.5.1.2.1
Percent Change from Baseline in Laboratory 
Test Results by Visit -- Complete Blood 
Count (Conventional Unit)
Safety Population
14.3.5.1.2.2
Percent Change from Baseline in Laboratory 
Test Results by Visit -- Complete Blood 
Count (SI Unit)
Safety Population
14.3.5.2.1.1
Change from Baseline in Laboratory Test 
Results by Visit -- Chemistry (Conventional 
Unit)
Safety Population


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Table Number
Table Title
Population
14.3.5.2.1.2
Change from Baseline in Laboratory Test 
Results by Visit -- Chemistry (SI Unit)
Safety Population
14.3.5.2.2.1
Percent Change from Baseline in Laboratory 
Test Results by Visit -- Chemistry 
(Conventional Unit)
Safety Population
14.3.5.2.2.2
Percent Change from Baseline in Laboratory 
Test Results by Visit -- Chemistry (SI Unit)
Safety Population
14.3.5.3.1.1
Change from Baseline in Laboratory Test 
Results by Visit -- Liver Function Tests 
(Conventional Unit)
Safety Population
14.3.5.3.1.2
Change from Baseline in Laboratory Test 
Results by Visit -- Liver Function Tests (SI 
Unit)
Safety Population
14.3.5.3.2.1
Percent Change from Baseline in Laboratory 
Test Results by Visit -- Liver Function Tests 
(Conventional Unit)
Safety Population
14.3.5.3.2.2
Percent Change from Baseline in Laboratory 
Test Results by Visit -- Liver Function Tests 
(SI Unit)
Safety Population
14.3.5.4.1.1
Change from Baseline in Laboratory Test 
Results by Visit -- Iron indices (Conventional 
Unit)
Safety Population
14.3.5.4.1.2
Change from Baseline in Laboratory Test 
Results by Visit -- Iron indices (SI Unit)
Safety Population
14.3.5.4.2.1
Percent Change from Baseline in Laboratory 
Test Results by Visit -- Iron indices 
(Conventional Unit)
Safety Population
14.3.5.4.2.2
Percent Change from Baseline in Laboratory 
Test Results by Visit -- Iron indices (SI Unit)
Safety Population
14.3.5.5.1.1
Change from Baseline in Laboratory Test 
Results by Visit -- Lipids (Conventional Unit)
Safety Population


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Table Number
Table Title
Population
14.3.5.5.1.2
Change from Baseline in Laboratory Test 
Results by Visit -- Lipids (SI Unit)
Safety Population
14.3.5.5.2.1
Percent Change from Baseline in Laboratory 
Test Results by Visit -- Lipids (Conventional 
Unit)
Safety Population
14.3.5.5.2.2
Percent Change from Baseline in Laboratory 
Test Results by Visit -- Lipids (SI Unit)
Safety Population
14.3.5.6.1.1
Change from Baseline in Laboratory Test 
Results by Visit -- C-reactive protein, 
Vascular Endothelial Growth Factor and 
Hepcidin (Conventional Unit)
Safety Population
14.3.5.6.1.2
Change from Baseline in Laboratory Test 
Results by Visit -- C-reactive protein, 
Vascular Endothelial Growth Factor and 
Hepcidin (SI Unit)
Safety Population
14.3.5.6.2.1
Percent Change from Baseline in Laboratory 
Test Results by Visit -- C-reactive protein, 
Vascular Endothelial Growth Factor and 
Hepcidin (Conventional Unit)
Safety Population
14.3.5.6.2.2
Percent Change from Baseline in Laboratory 
Test Results by Visit -- C-reactive protein, 
Vascular Endothelial Growth Factor and 
Hepcidin (SI Unit)
Safety Population
14.3.5.7.1
Change from Baseline in Laboratory Test 
Results by Visit -- Erythropoietin and 
Reticulocytes (Conventional Unit)
Safety Population
14.3.5.7.2
Change from Baseline in Laboratory Test 
Results by Visit -- Erythropoietin and 
Reticulocytes (SI Unit)
Safety Population
14.3.5.8.1
Cumulative Number (%) of Subjects with 
Abnormal Laboratory Test Results -- Potential 
Liver Injury
Safety Population


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Table Number
Table Title
Population
14.3.5.8.2
Number (%) of Subjects with Abnormal 
Laboratory Test Results -- Liver Function and 
Potassium
Safety Population
14.3.5.9
Hemoglobin (Hb)-Related Safety Endpoints
Safety Population
14.3.6.1
Change from Baseline in Vital Signs and 
Body Weight by Visit
Safety Population
14.3.6.2
Number (%) of Subjects with Abnormal 
Findings in Vital Signs 
Safety Population
14.3.7.1
Change from Baseline in ECG by Visit
Safety Population
14.3.7.2
Number (%) of Subjects with Abnormal 
Findings in ECG
Safety Population
14.3.8.1
Summary of Dialysis History and Details
Safety Population
14.3.8.2
Summary of Dialysis Adequacy
Safety Population
14.3.9
Summary of Special Situations
Safety Population
Listing Number
Listing Title
Population
16.2.1.1
Informed Consent
Randomized Population
16.2.1.2
Subject Disposition
Randomized Population
16.2.2
Protocol Deviations
Randomized Population
16.2.3.1
Subject Randomization
Randomized Population
16.2.3.2
Analysis Sets
Randomized Population
16.2.3.3
Subjects not Meet Inclusion/Exclusion 
Criteria
Randomized Population
16.2.4.1
Demography
Randomized Population
16.2.4.2
Etiology of CKD
Randomized Population
16.2.4.3.1
Medical History
Randomized Population
16.2.4.3.2
Other Medical History
Randomized Population
16.2.4.4
Iron Therapy and RBC Transfusion History
Randomized Population


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Listing Number
Listing Title
Population
16.2.4.5
Prior and Concomitant Medications
Randomized Population
16.2.4.6.1
Prior ESA Administration
Randomized Population
16.2.4.6.2
ESA Administration
Randomized Population
16.2.4.7
Iron Supplementation
Randomized Population
16.2.4.8
Red Blood Cell (RBC) Transfusion
Randomized Population
16.2.4.9
Concomitant Procedures
Randomized Population
16.2.5.1
Study Drug Administration
Randomized Population
16.2.5.2
Subject Compliance
Randomized Population
16.2.5.3
Pharmacokinetic Plasma Concentrations
Pharmacokinetic Population
16.2.6.1
Change from Baseline in Hemoglobin (Hb, 
g/dL) to the Average Value in an Analysis 
Period
Randomized Population
16.2.6.2
Average Weekly Dose of IV Elemental Iron 
by Baseline Iron Group
Randomized Population
16.2.6.3
36-Item Short Form Version 2 (SF-36v2) 
Health-Related Quality of Life (HRQOL) 
Score
Randomized Population
16.2.6.4
Functional Assessment of Cancer Therapy-
Anemia (FACT-An) Score
Randomized Population
16.2.6.5
Patient Global Impression of Severity (PGI-S)
Randomized Population
16.2.6.6
Patient Global Impression of Change (PGI-C)
Randomized Population
16.2.7
Adverse Events
Randomized Population
16.2.8.1.1
Laboratory Test Results -- Complete Blood 
Count
Randomized Population
16.2.8.1.2
Laboratory Test Results -- Chemistry
Randomized Population
16.2.8.1.3
Laboratory Test Results -- Liver Function 
Tests
Randomized Population
16.2.8.1.4
Laboratory Test Results -- Iron Indices
Randomized Population
16.2.8.1.5
Laboratory Test Results -- Lipids
Randomized Population


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Listing Number
Listing Title
Population
16.2.8.1.6
Laboratory Test Results – Erythropoietin and 
Reticulocytes
Randomized Population
16.2.8.1.7
Laboratory Test Results -- Other Labs
Randomized Population
16.2.8.2 
Physical Examination
Randomized Population
16.2.8.3
Vital Signs
Randomized Population
16.2.8.4
12-Lead Electrocardiogram
Randomized Population
16.2.8.5.1
Pregnancy Test
Randomized Population
16.2.8.5.2
Pregnancy Report
Randomized Population
16.2.8.6.1
Dialysis History
Randomized Population
16.2.8.6.2
Dialysis Details
Randomized Population
16.2.8.6.3
Dialysis Adequacy
Randomized Population
16.2.8.7
Special Situations
Randomized Population
16.2.8.8
Lost to Follow-up Status
Randomized Population
16.2.8.9
Screening Failures
Screening Failure Subjects
20
Revision Changes
The purpose of this SAP revision is to align with the Protocol Amendment 1 and to make 
clarifying changes. The description of changes is documented below. 
Location
Description of Changes
Header
Corrected the protocol number.
Abbreviation
Added abbreviations.
Section 1 (Introduction)
Clarified that SAP documents the pre-planned statistical 
analyses plan of CSR.
Section 2.1 (Randomization and 
Stratification)
Added “approximately 90 subjects in Europe”.
Section 2.2 (Study Periods)
Changed “trial medication” to “investigational medicinal 
product (IMP)”.


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Section 2.5 (Blinding)
Clarified that the group of unblinded biostatisticians and 
programmers are external/internal independent.
Section 2.6 (Sample Size)
Clarified that the sample size calculation between vadadustat 
QD and darbepoetin alfa is the same as the one between 
vadadustat TIW and darbepoetin alfa.
Section 2.7 (Efficacy)
Clarified the treatment groups in treatment comparison.
Section 4.1 (Study Drug Dosing 
and Compliance)
Clarified the dosing compliance.
Moved sentences related to dosing from Section 4.3 to 4.1. 
Section 4.2 (Protocol Deviations)
Clarified the protocol deviation listing and summary. 
Section 4.3 (Baseline 
Characteristics, Exposure, and 
Retention by Treatment Group)
Moved sentences related to dosing from Section 4.3 to 4.1. 
Section 5.1 (Visit and Analysis 
Time Period Classification)
Changed the relative date of visit windows from 
“Randomization date” to “first dose date”.
Added a footnote of “a If patient has no first dose date, day 1 
will be the randomization date” for “Day 1 (first dose date)” at 
Table 1.  
Section 5.2 (Definition of 
Baseline)
Section 5.3 (Prior and 
Concomitant Medication)
Changed “trial medication” to “IMP”.
Section 6.3 (Other Efficacy 
Endpoints)
Changed “average monthly dose of IV elemental iron” to 
“average weekly dose of IV elemental iron”.
Section 6.4 (Rescue Therapy)
Changed the reason of narrow rescue therapy for all treatment 
arms to “Hb <9.5 g/dL” only.
Added “For darbepoetin alfa arm, darbepoetin alfa with 
increases in dose ≥50% or ≥100%.” in narrow and broad-on-
treatment rescue therapies.
Remove “phlebotomy” from broad-on-treatment rescue.
Changed the category of darbepoetin alfa with increases in 
dose to <50%, ≥50% and <100%, and ≥100%, and removed 
“recorded in eCRF”.


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Added time to first ESA medication and RBC transfusion 
analyses.
Section 7 (Safety Endpoints)
Clarified that safety endpoints will be summarized by treatment 
groups.
Removed “Major Adverse Cardiovascular Event (MACE)”.
Section 9.1 (Primary Estimand)
Added a section of primary estimand.
Section 9.2.1 (Baseline Hb)
Clarified the calculation of baseline Hb value.
Section 9.2.4 (Analysis of Change 
from Baseline in Hb to the 
Primary Efficacy Period)
Clarified intercurrent event data handling.
 
Clarified the 100 imputed complete datasets will be used not 
only for primary efficacy analysis, but also secondary efficacy 
analysis and other efficacy analysis.
Added “ESTIMATE” and “STDERR” for estimate and 
standard error, respectively. 
Section 9.2.5 (Sensitivity 
Analyses to the Primary Efficacy 
Results)
Changed the FAS population to randomized population for 
mixed model for repeated measures (MMRM).
Section 9.4 (Other Efficacy 
Endpoints: Strategies for 
Analysis)
Clarified the analysis population used for other efficacy 
endpoints.
Section 9.4.1 (Proportion of 
Subjects Having Average Hb 
Values within the Target Range 
during the PEP (Weeks 20 to 26))
Added “when tested per the testing procedure (Section 9.5)”.
Clarified that Mantel-Haenszel method will be used for 
estimation of risk difference.
Section 9.4.3 (Proportion of 
Subjects Receiving IV Iron 
Therapy from Baseline to Week 
52)
Clarified that Mantel-Haenszel method will be used for 
estimation of risk difference.
Reduced the performed subgroups. 
Section 9.4.4 (Average Weekly 
Dose of IV Elemental Iron 
Administered from Baseline to 
Week 52)
Removed the subgroup analyses.
Removed the large spike at zero for the distribution of average 
weekly dose of IV elemental iron administered in subjects who 
have received IV elemental iron.
PPD
PPD


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Section 9.4.5 (Receipt of ESA 
Rescue)
Clarified that ESA rescue medications include narrow or 
broad-on-treatment therapies with ≥50% or ≥100% dose 
increase in darbepoetin alfa. 
Clarified that Mantel-Haenszel method will be used for 
estimation of risk difference.
Added time to first ESA rescue analyses.
Section 9.4.6 (Proportion of 
Subjects Receiving Red Blood 
Cell (RBC) Transfusions)
Clarified that RBC transfusions include narrow or broad-on-
treatment. 
Clarified that Mantel-Haenszel method will be used for 
estimation of risk difference.
Added time to first RBC transfusion analyses.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 9.5 (Study Level Type I 
Error Control)
Added a section of study level type I error control.
PPD


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Section 10.2 (Hb-related Safety 
Endpoints)
Clarified that calculation of number and proportion of subjects 
in Hb-related safety endpoints.
Section 10.3 (Adverse Events and 
Serious Adverse Events)
Clarified that AE will be coded by SOC and PT, and MedDRA 
version will be shown in AE outputs.
Clarified the definition of TEAE.
Added AE, SAE and all death in the summary table.
Removed the AE summary order statement.
Clarified the most conservative causality AE assessment will 
be used in the by-causality summaries.
Changed TEAE listing to AE listing and added a flag of TEAE 
in AE listing.
Section 10.4 (Major Adverse 
Cardiovascular Event)
Added “excluding vascular access thrombosis” to the 
“thromboembolic event”.
Removed “by SOC and PT” from the summary of adjudicated 
safety events.
Remove time to the first occurrence of MACE analyses.
Section 10.5.1 (Clinical 
Laboratory Evaluation)
Removed “by analysis period” from the summary of liver 
function abnormalities.
Changed “versions of Hy’s Law” to “laboratory values 
fulfilling potential liver injury criteria”.
Removed summary and shift from baseline of abnormal 
laboratory values in CTCAE grade.
Removed summary of additional laboratory parameters listed 
in Appendix, and removed the corresponding Appendix.  
Section 10.5.2 (Vital Signs, 
ECGs, and Physical Findings)
Clarified the calculation of percentage of subjects experiencing 
findings.
Added “QTc interval” criteria.
Removed “at baseline” from the ECG summary.
Removed summary of potential clinical relevance listed in 
Appendix, and removed the corresponding Appendix.
Section 11 (Subgroups)
Combined the “Black” and “Other” in race to “Black or 
Other”.


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Added subgroup analyses of baseline Hb.
Removed subgroup analyses of medical history of diabetes 
mellitus, hypertension and NYHA class, and baseline value of 
ESA dose, C-reactive protein, TSAT and ferritin. 
Clarified that subgroup analyses will be performed only if the 
total number of outcomes is at least 30.
Remove subgroup analyses of AE and time to the first 
occurrence of MACE analyses.
Section 12 (Other Exploratory 
Analyses)
Clarified that exit interview data will be reported separately.
Section 13 (Interim Analysis)
Clarified that no interim analysis will be conducted, and no 
analyses of the primary efficacy endpoint will be conducted 
when all randomized subjects complete their Week 26 
evaluations.
Section 14 (Description of 
Variables Used in SAS Codes)
Updated the description.
Section 15 (Random Seed 
Assignment)
Added a section to describe the assigned random seeds.
Section 17 (Adverse Event of 
Special Interest)
Removed thrombotic events SMQ.
Added FDA key query adverse event preferred terms. 
Original Appendix (Criteria for 
Identifying Measurements of 
Potential Clinical Relevance)
Removed.
Section 18 (References)
Updated the references.
Section 19 (Proposed List of 
Summary Tables)
Updated the list of summary tables and listings.
Section 20 (Revision Changes)
Added a section of revision changes.


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Document Name: Statistical_Analysis_Plan_404-201-00012_v2.0
Document Number: 1000193297
Document Version: 2.0
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Server Date
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Clinical Pharmacology
Approval
12-Jun-2022
16:50:03
Biostatistics Approval
09-Jun-2022
13:34:19
Clinical Approval
14-Jun-2022
17:37:41
PPD
PPD
PPD