Clinical trial NCT03054350
Conditions: Anemia Dialysis Dependent Chronic Kidney Disease
Keywords: Anemia kidney dialysis dependent chronic kidney disease CKD DD renal vadadustat AKB-6548 hypoxia-inducible factor Akebia (AKB) hypoxia-inducible factor (HIF) HIF prolyl-hydroxylase inhibitor (PHI) PHI Japan Japanese
Sponsor: Akebia Therapeutics
Start date: 2016-12-01; Completion date: 2018-01-24
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, randomized, double-blind, placebo-controlled, dose-finding study to assess the efficacy, safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) of orally administered vadadustat in Japanese participants with anemia secondary to Dialysis-dependent Chronic Kidney Disease (DD-CKD).

Detailed description:

Arms: arm 1: Daily oral dose arm 2: Daily oral dose arm 3: Daily oral dose arm 4: Daily oral dose
Interventions: intervention 1: Vadadustat intervention 2: Placebo
Intervention descriptions: intervention 1: Daily oral dose intervention 2: Daily oral dose

Protocol documents:
Prot_000.pdf: 
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Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
Page 2 of 79 
1 
SIGNATURE PAGES 
1.1 
Protocol Approval 
Akebia Therapeutics, Inc. 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 3 of 79 
 
1.2 
Investigator Agreement 
I confirm that I have read and that I understand this protocol, any amendments to the protocol (if 
applicable, a history of protocol changes are appended at the end of this document), the 
Investigator’s Brochure, and other product information provided by the Sponsor.  I agree to 
conduct this study in accordance with the requirements of this protocol, and to protect the rights, 
safety, privacy, and well-being of study subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonization Guidance for Industry, Good Clinical 
Practice E6. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting serious adverse events defined in this protocol. 
• Terms outlined in the Clinical Study Site Agreement. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Phone Number 
 
Full Address 
 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 4 of 79 
 
TABLE OF CONTENTS 
1 
SIGNATURE PAGES ............................................................................................... 2 
1.1 
Protocol Approval ............................................................................................... 2 
1.2 
Investigator Agreement ....................................................................................... 3 
2 
PROTOCOL SYNOPSIS ........................................................................................ 10 
3 
LIST OF ABBREVIATIONS ................................................................................. 17 
4 
BACKGROUND ..................................................................................................... 19 
4.1 
Proposed Indication of Renal Anemia .............................................................. 19 
4.2 
Available Therapies for Anemia in Patients with CKD.................................... 20 
4.3 
Hypoxia-Inducible Factor ................................................................................. 20 
4.4 
Description and Mechanism of Action of Vadadustat ...................................... 21 
4.5 
Summary of Clinical Experience ...................................................................... 22 
4.6 
Ethno-Bridging Data from a Study of Healthy Japanese and Caucasian 
Volunteers ......................................................................................................... 23 
4.7 
Potential Benefits and Risks ............................................................................. 24 
5 
STUDY OBJECTIVES AND ENDPOINTS .......................................................... 25 
5.1 
Primary Objective and Endpoint ....................................................................... 25 
5.2 
Secondary Objectives and Endpoints................................................................ 25 
6 
STUDY DESIGN .................................................................................................... 26 
6.1 
Study Design ..................................................................................................... 26 
6.2 
Study Duration .................................................................................................. 28 
6.3 
Rationale for Study Design ............................................................................... 28 
6.4 
Dose Justification .............................................................................................. 29 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .......................................... 30 
7.1 
General Criteria ................................................................................................. 30 
7.2 
Inclusion Criteria .............................................................................................. 30 
7.3 
Exclusion Criteria ............................................................................................. 31 
7.4 
Retesting and Rescreening ................................................................................ 32 
7.4.1 
Retesting ............................................................................................................ 32 
7.4.2 
Rescreening ....................................................................................................... 33 
7.5 
Study Completion, Study Termination, and Individual Study Site Termination33 
7.5.1 
Study Completion .............................................................................................. 33 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
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7.5.2 
Study Termination ............................................................................................. 33 
7.5.3 
Individual Study Site Termination .................................................................... 33 
7.6 
Subject Completion and Individual Subject Discontinuation ........................... 33 
7.6.1 
Subject Completion ........................................................................................... 33 
7.6.2 
Conditions and Documentation of Individual Subject Study Drug 
Discontinuation .................................................................................................. 33 
7.6.3 
Individual Subject Discontinuation ................................................................... 34 
8 
STUDY DRUGS AND TREATMENT OF SUBJECTS ........................................ 34 
8.1 
Study Drugs ...................................................................................................... 34 
8.1.1 
Formulation ....................................................................................................... 34 
8.1.2 
Storage and Accountability ............................................................................... 35 
8.1.3 
Dispensing of Study Drugs ................................................................................ 35 
8.1.4 
Product Accountability and Destruction ........................................................... 35 
8.2 
Treatment of Subjects ....................................................................................... 36 
8.2.1 
Dosing Instructions ............................................................................................ 36 
8.2.2 
Randomization ................................................................................................... 36 
8.2.3 
Blinding During the Study and Breaking the Blind .......................................... 37 
8.2.4 
Study Drug Administration during the Primary Efficacy Period (Week 1 to 
Week 6) ............................................................................................................. 37 
8.2.5 
Study Drug Administration during the Dose Adjustment and Maintenance 
Period (Week 7 to Week16) .............................................................................. 38 
8.2.6 
Rescue Therapy Guidelines ............................................................................... 39 
8.2.7 
Iron Supplementation (Information on Allowed Use) ....................................... 39 
8.2.8 
Late or Missed Doses ........................................................................................ 40 
8.2.9 
Compliance with Study Drug Dosing ................................................................ 40 
8.2.10 
Continuation of Treatment ................................................................................ 40 
8.3 
Prior and Concomitant Therapy ........................................................................ 40 
8.4 
Prohibited Treatments ....................................................................................... 40 
8.4.1 
Investigational Medications ............................................................................... 40 
8.4.2 
ESAs and Blood Transfusion ............................................................................ 40 
8.4.3 
Iron Supplementation (Information on Prohibition) .......................................... 41 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES ............................ 41 
9.1 
Schedule of Visits ............................................................................................. 41 


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Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
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9.2 
Administrative Procedures ................................................................................ 43 
9.2.1 
Informed Consent .............................................................................................. 43 
9.2.2 
Documentation of Screen Failures .................................................................... 43 
9.2.3 
Review of Inclusion and Exclusion Criteria ...................................................... 43 
9.3 
Study Procedures and Evaluations .................................................................... 44 
9.3.1 
Clinical Evaluations ........................................................................................... 44 
9.3.2 
Laboratory Evaluations ..................................................................................... 45 
9.4 
Schedule of Activities (For Subjects Who Were Not Prescribed ESAs Prior to 
Study Entry) ...................................................................................................... 47 
9.4.1 
Screening Visit 1 ............................................................................................... 47 
9.4.2 
Screening Visit 2 ............................................................................................... 48 
9.4.3 
Baseline Visit (Day 1) ....................................................................................... 48 
9.4.4 
Week 2 Visit ...................................................................................................... 49 
9.4.5 
Week 4 Visit ...................................................................................................... 49 
9.4.6 
Week 6 Visit ...................................................................................................... 50 
9.4.7 
Week 8, 10, 12, 14 Visits .................................................................................. 50 
9.4.8 
Week 16 Visit (End-of-Treatment Visit for Subjects Who Complete the Dose 
Adjustment and Maintenance Period or for Subjects Who Withdraw Early from 
the Study Prior to Week 16) .............................................................................. 51 
9.4.9 
Week 18 Follow-Up Visit (or 2 Weeks after End-of-Treatment Follow-Up Visit)
 ........................................................................................................................... 51 
9.5 
Schedule of Activities (For Patients Who Were Prescribed ESAs Prior to Study 
Entry) ................................................................................................................ 52 
9.5.1 
Screening Visit 1 ............................................................................................... 52 
9.5.2 
Screening Visit 2 ............................................................................................... 53 
9.5.3 
Screening Visit 3 ............................................................................................... 53 
9.5.4 
Baseline Visit (Day 1) ....................................................................................... 53 
9.5.5 
Week 2 Visit ...................................................................................................... 54 
9.5.6 
Week 4 Visit ...................................................................................................... 54 
9.5.7 
Week 6 Visit ...................................................................................................... 55 
9.5.8 
Week 8, 10, 12, and 14 Visits ............................................................................ 56 
9.5.9 
Week 16 Visit (End-of-Treatment Visit for Subjects Who Complete the Dose 
Adjustment and Maintenance Period or for Subjects Who Withdraw Early from 
the Study Prior to Week 16) .............................................................................. 56 


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Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
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9.5.10 
Week 18 Follow-Up Visit (or 2 Weeks after End-of-Treatment Follow-Up Visit)
 ........................................................................................................................... 57 
10 
ADVERSE EVENTS .............................................................................................. 57 
10.1 
Definitions......................................................................................................... 57 
10.1.1 
Adverse Events (AEs) ....................................................................................... 57 
10.1.2 
Serious Adverse Events (SAEs) ........................................................................ 59 
10.2 
Eliciting Adverse Event Information ................................................................ 60 
10.3 
Reporting........................................................................................................... 60 
10.3.1 
Reporting Period ................................................................................................ 60 
10.3.2 
Reporting AEs ................................................................................................... 60 
10.3.3 
Reporting SAEs ................................................................................................. 60 
10.3.4 
Relationship to Study Medication ..................................................................... 61 
10.3.5 
Severity .............................................................................................................. 62 
10.3.6 
Follow-Up of Unresolved Events ...................................................................... 62 
10.3.7 
Special Situations .............................................................................................. 62 
10.4 
Exposure In Utero ............................................................................................. 62 
11 
DATA ANALYSIS ................................................................................................. 63 
11.1 
Primary Endpoint – Mean Change in Hb from Pre-treatment to the End of the 
Primary Efficacy Period (Week 6) .................................................................... 63 
11.2 
Primary Efficacy Analysis and Sample Size Determination ............................ 64 
11.3 
Preliminary (6-Week) Analysis ........................................................................ 65 
11.4 
Study Populations ............................................................................................. 65 
11.4.1 
Analysis Population for the Safety Analyses .................................................... 65 
11.4.2 
Analysis Populations for the Efficacy Analyses ............................................... 65 
11.5 
Analysis of Demographics and Pretreatment Variables ................................... 65 
11.6 
Disposition of Subjects ..................................................................................... 65 
11.7 
Safety Analyses ................................................................................................. 66 
12 
DATA HANDLING AND RECORD KEEPING ................................................... 66 
12.1 
Case Report Forms (CRFs) ............................................................................... 66 
12.2 
Record Retention .............................................................................................. 66 
13 
QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) ................... 67 
13.1 
Study Site Monitoring Visits ............................................................................ 67 
13.2 
Protocol Deviations ........................................................................................... 67 


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Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
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14 
STUDY DISCONTINUATION/INVESTIGATIVE STUDY SITE 
TERMINATION ..................................................................................................... 68 
14.1 
Criteria for Premature Termination or Suspension of the Study ...................... 68 
14.2 
Criteria for Premature Termination or Suspension of Investigational Sites ..... 68 
14.3 
Procedures for Premature Termination or Suspension of the Study or 
Investigational Site(s) ....................................................................................... 68 
15 
ETHICS ................................................................................................................... 68 
15.1 
Ethical Conduct of the Study ............................................................................ 68 
15.2 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) ...... 68 
15.3 
Subject Information and Consent...................................................................... 69 
15.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 69 
15.5 
Subject Confidentiality ..................................................................................... 69 
16 
PUBLICATION OF STUDY RESULTS ............................................................... 70 
17 
REFERENCES ........................................................................................................ 71 
18 
APPENDICES ......................................................................................................... 73 
 
 
 
 


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Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
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LIST OF TABLES 
Table 1: Identity of Study Drugs .................................................................................................. 34 
 
LIST OF FIGURES 
Figure 1 Mechanism of Action of Vadadustat ............................................................................. 21 
Figure 2 Mean (± Standard Error) Plasma Concentration versus Time Profiles Following 
Administration of a Repeated Once Daily Oral Dose of Vadadustat to Healthy Caucasian 
and Japanese Subjects on Day 10 (Study AKB-6548-CI-0020) ........................................... 24 
Figure 3: Overview of Study Design ............................................................................................. 27 
Figure 4: Absolute Change in Hemoglobin (± Standard Error of Mean, g/dL) at Week 6 
Compared to Baseline (Study AKB-6548-CI-0005) ............................................................. 29 
Figure 5: Randomization Scheme of Study Treatment ................................................................. 37 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
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2 
PROTOCOL SYNOPSIS 
Study Title 
Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study to Assess the 
Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Vadadustat in Japanese 
Subjects with Anemia Secondary to Dialysis-Dependent Chronic Kidney Disease (DD-CKD) 
Protocol 
Number 
AKB-6548-CI-0022 
Study Phase 
Phase 2 
Investigational 
Product 
Vadadustat; each tablet contains 150 mg of vadadustat for oral administration 
Study 
Population 
The study population will consist of male and female Japanese adults aged 20 years or older 
with anemia secondary to DD-CKD 
Investigative 
Sites 
Approximately 35 sites in Japan 
Planned Number 
of Subjects 
Approximately 48 subjects will be enrolled in the study, with 36 subjects receiving one of 
3 doses of vadadustat and 12 subjects receiving placebo during the primary efficacy period: 
• 150 mg vadadustat once daily (n=12) 
• 300 mg vadadustat once daily (n=12) 
• 600 mg vadadustat once daily (n=12) 
• Placebo (n=12) 
Study Objectives 
• Primary Objective:  To assess the dose-response relationship between oral vadadustat 
once daily dosing for 6 weeks and the change in hemoglobin (Hb) in Japanese subjects 
with anemia secondary to DD-CKD; this is to define the starting dose for use in Phase 3 
clinical studies in Japan 
• Secondary Objectives:  
- To assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics 
(PD) of oral vadadustat once daily dosing in Japanese subjects with anemia secondary 
to DD-CKD during the 6-week, primary efficacy period 
- To evaluate the effect of dose adjustments and demonstrate the maintenance effect on 
Hb during a 10-week dose adjustment and maintenance period 
- To assess the time to reach the target Hb level from baseline 
Overview of 
Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, dose-finding study to assess 
the efficacy, safety, tolerability, PK, and PD of orally administered vadadustat in Japanese 
subjects with anemia secondary to DD-CKD. 
The study will include the following periods: 
• Eligibility screening period (up to 11 weeks) 
• Primary efficacy period (6 weeks; Weeks 1 to 6) 
• Dose adjustment and maintenance period (10 weeks; Weeks 7 to 16) 
• Follow-up period (2 weeks; Weeks 17 and 18) 
During the screening period, subjects who have recently received ESA therapy and otherwise 
meet eligibility criteria will be required to washout from ESA therapy prior to evaluation of 
screening Hb (see “Inclusion Criteria” below). 
Following the screening period, eligible subjects will be randomized to receive blinded study 
drug, either vadadustat (150, 300, or 600 mg vadadustat) or placebo.  See “Dosage and 
Regimen” below for additional information regarding the randomization scheme. 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 11 of 79 
 
Fixed-dose treatment during the primary efficacy period will allow a dose-response 
relationship to be established.  No increase in study drug dose is permitted during this period.  
However, if Hb level increases rapidly or if the Hb level exceeds 13.0g/dL the study drug 
dose can be decreased or interrupted following the dose adjustment guidelines listed under 
“Dosage and Regimen” (see below). 
After completing the primary efficacy period, subjects will continue to a 10-week dose 
adjustment and maintenance period.  Subjects receiving placebo will be switched to 
vadadustat, and study drug dose will be adjusted to achieve a target Hb of 10.0-12.0 g/dL 
based on dose adjustment guidelines (see “Dosage and Regimen,” below). 
Study drug will be discontinued after the dose adjustment and maintenance period has been 
completed (Week 16) and subjects will continue to a 2-week follow-up period (Week 17-18). 
Study Duration 
Study duration will depend on ESA use as follows: 
• For subjects who were not prescribed ESAs prior to study entry:  Up to 22 weeks, 
including the eligibility screening period (up to 4 weeks, with 2 screening visits), 
primary efficacy period (6 weeks), dose adjustment and maintenance period (10 weeks), 
and follow-up period (2 weeks) 
• For subjects who were prescribed ESAs prior to study entry:  Up to 29 weeks, including 
the eligibility screening period (up to 11 weeks, with 3 screening visits), primary 
efficacy period (6 weeks), dose adjustment and maintenance period (10 weeks), and 
follow-up period (2 weeks) 
Note:  Subjects who discontinue prematurely from the study or permanently discontinue 
study medication will complete the end-of-treatment (Week 16) visit followed in two weeks 
by the Week 18 visit.   
Key Inclusion 
Criteria (the 
complete list is 
provided in the 
protocol) 
• Male and female Japanese subjects (20 years or older) 
• Receiving chronic maintenance hemodialysis for end-stage kidney disease for at least 
8 weeks prior to screening 
• ESA status and screening Hb that meet one of the following criteria:  
- 
For subjects who are not being treated with ESAs:  Mean Hb <10.0 g/dL; average of 
2 measurements obtained during screening. These subjects must be off ESAs for at 
least the following periods of time prior to screening visit 1:  
• 
2 weeks for epoetin alfa, epoetin beta, or epoetin kappa;  
• 
4 weeks for darbepoetin alfa;  
• 
8 weeks for epoetin beta pegol. 
- 
For subjects who are being treated with ESAs:  Mean Hb <10.0 g/dL; average of 
2 measurements obtained during screening after the protocol-defined ESA washout 
period. These subjects must washout ESA therapy for the following periods of time 
during the screening period, beginning at screening visit 1 and prior to screening 
visit 2: 
• 
2 weeks for epoetin alfa, epoetin beta, and epoetin kappa;  
• 
4 weeks for darbepoetin alfa;  
• 
8 weeks for epoetin beta pegol.  
• Serum ferritin ≥50 ng/mL during screening 
• Transferrin saturation (TSAT) ≥20% during screening 
• Folate and vitamin B12 ≥lower limit of normal during screening 
• For subjects who are receiving oral or intravenous iron supplementation, the dose of 
iron supplementation must be stable for at least 28 days prior to the screening period.  
For subjects who are not receiving oral or intravenous iron supplementation, no iron 
supplementation may have been administered for at least 28 days prior to the screening 


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Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
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period. 
Key Exclusion 
Criteria (the 
complete list is 
provided in the 
protocol) 
Anemia due to a cause other than CKD or presence of active bleeding or recent blood loss; 
sickle cell disease, myelodysplastic syndromes, bone marrow fibrosis, hematologic 
malignancy, myeloma, hemolytic anemia, thalassemia, or pure red cell aplasia; red blood cell 
(RBC) transfusion within 4 weeks prior to or during screening; anticipated to recover 
adequate kidney function to no longer require hemodialysis during study participation; on 
peritoneal dialysis or expected to change dialysis modality during study participation; and 
hypo-responsiveness to ESA defined as any of the following ESA treatments within 8 weeks 
prior to screening: (i) intravenous epoetin dose ≥3000 units/dose 3 times a week 
(9000 units/week), (ii) intravenous darbepoetin alfa dose ≥60 µg once a week, or (iii) epoetin 
beta pegol ≥200 µg once a month or ≥100 µg once every 2 weeks 
Retesting/ 
Rescreening 
Subjects who initially fail to qualify for the study based on laboratory test results may be 
retested once within the screening period, at the investigator’s discretion. 
Subjects who fail to meet the qualifying criteria for Hb during screening may be considered 
for rescreening at the discretion of the investigator, if it is felt that the subject’s status has 
changed and that the subject may now qualify for the study.  Additionally, subjects who fail 
to qualify for the study based on low ferritin, TSAT, folate, or vitamin B12 values may be 
considered for rescreening after receiving replacement therapy. 
Screening is limited to 3 attempts (initial screening and 2 additional rescreening attempts). 
Efficacy and 
Pharmacokinetic 
Endpoints 
Note that a pre-treatment average value for Hb is defined as the average of 3 values obtained 
prior to dosing, ie, the 2 qualifying screening values and the baseline value.  
Primary Endpoint: 
• Mean change in Hb levels from pre-treatment to the end of the primary efficacy period 
(Week 6) 
Secondary Endpoints: 
• Time to reach target Hb level of 10.0-12.0 g/dL from baseline 
• Mean Hb levels at the end of the primary efficacy period (Week 6) and the end of the 
dose adjustment and maintenance period (Week 16) 
• Proportion of subjects who achieve target Hb 10-12 g/dL at the end of the dose 
adjustment and maintenance period (Week 16) 
• Mean change in Hb between pre-treatment and the end of the dose adjustment and 
maintenance period (Week 16) 
• Mean change in hematocrit, RBC count, and reticulocyte count from baseline to the end 
of the primary efficacy period (Week 6) and the end of the dose adjustment and 
maintenance period (Week 16) 
• Mean change in iron indices (ie, iron, total iron-binding capacity [TIBC], TSAT, and 
ferritin) and hepcidin from baseline to the end of the primary efficacy period (Week 6) 
and the end of the dose adjustment and maintenance period (Week 16) 
• Proportion of subjects requiring rescue with RBC transfusion from baseline to the end 
of the primary efficacy period (Week 6) and the end of the dose adjustment and 
maintenance period (Week 16) 
• Proportion of subjects requiring rescue with ESAs from baseline to the end of the 
primary efficacy period (Week 6) and the end of the dose adjustment and maintenance 
period (Week 16) 
• Number of dose adjustments from baseline to the end of the dose adjustment and 
maintenance period (Week 16) 
• Plasma concentration profile of vadadustat and its metabolites using pre-dose sample 
from Week 4 


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Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 13 of 79 
 
Safety Endpoints 
Safety assessments, including adverse events, vital signs, electrocardiograms (ECGs), and 
other laboratory assay results (eg, chemistry, components of the complete blood count [CBC] 
other than the ones noted above, and vascular endothelial growth factor [VEGF]) 
Dosage and 
Regimen 
Study drug will be administered on an outpatient basis.  Subjects should take the study 
medication with water or another beverage and should be instructed to swallow the intact 
tablet(s).  Subjects may take the study medication with or without food. 
Primary efficacy period (Day 1 to Week 6) 
Using a central randomization system, subjects will be randomized at a 1:1:1 ratio to receive 
1 tablet (150 mg vadadustat or placebo), 2 tablets (300 mg vadadustat or placebo), or 
4 tablets (600 mg vadadustat or placebo) of study drug.  Within each tablet-count group, 
subjects will be randomized 3:1 to receive vadadustat or placebo as shown below. 
Figure.  Treatment Randomization Scheme 
 
The primary efficacy period involves fixed-dose treatment to establish a dose-response 
relationship.  No increase in study drug dose is permitted during this period.  However, the 
dose may be decreased or interrupted as described below. 
• 
If the Hb increases rapidly (eg, more than 1 g/dL in any 2-week period), reduce the 
dose by 1 tablet. 
• 
If the Hb exceeds 13.0 g/dL, interrupt study drug until the Hb decreases to 12.5 g/dL 
or below and then resume dosing with 1 fewer tablet.   
If dose reduction or interruption is recommended based on the central laboratory Hb result 
and protocol-specified guidelines, the investigative site will contact the subject within 1 
business day of receiving the Hb result from the central laboratory.  If possible, the subject 
will be scheduled for an additional visit within 3 business days.  If scheduling the subject 
within this time frame is not possible, dosing instructions will be provided to the subject over 
the telephone. 
Dose adjustment and maintenance period (Weeks 7 to 16): 
Subjects who complete the primary efficacy period will enter the dose adjustment and 
maintenance period.  Subjects receiving placebo will be switched to vadadustat.  Dose 
adjustments for study drug will follow the dose adjustment guidelines listed below to achieve 
a target Hb of 10.0-12.0 g/dL.  Dose adjustments will be based on central laboratory Hb 
results from study visits at Weeks 6, 8, 10, 12, and 14. 
• 
Do not increase the dose more frequently than once within any given 4-week 
interval.  For example, if a subject’s dose was increased based on Hb results from 
the Week 6 visit and the subject remains below the Hb target, the next opportunity 
to further increase the dose would be based on Hb results from the Week 10 visit.  
Decreases in dose can occur more frequently.  Avoid frequent dose adjustments. 
• 
If the Hb has not increased by more than 0.5 g/dL above the baseline value after the 
1 tablet
(n=16) 
Vadadustat 150 mg (n=12); 1 x 150 mg tablet once daily
Placebo (n=4); 1 tablet once daily
2 tablets
(n=16)
Vadadustat 300 mg (n=12); 2 x 150 mg tablets once daily
Placebo (n=4); 2 tablets once daily
4 tablets
(n=16)
Vadadustat 600 mg (n=12); 4 x 150 mg tablets once daily
Placebo (n=4); 4 tablets once daily


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 14 of 79 
 
first 6 weeks of treatment, increase the dose by 1 tablet. 
• 
Increase the dose by 1 tablet every 4 weeks until Hb is above 10.0 g/dL (maximum 
dose is 4 tablets). 
• 
If the Hb increases rapidly (eg, more than 1 g/dL in any 2-week period), reduce the 
dose by 1 tablet. 
• 
If the Hb falls below 10.0 g/dL, increase the dose by 1 tablet. 
• 
If the Hb exceeds 12.0 g/dL, reduce the dose by 1 tablet. 
• 
If the Hb exceeds 13.0 g/dL, interrupt study drug until the Hb decreases to 12.5 g/dL 
or below and then resume dosing with 1 fewer tablet. 
• 
If a dose adjustment is required to maintain Hb at the desired level, the dose 
adjustment is by 1 tablet. 
If dose adjustment is recommended based on the central laboratory Hb result and protocol-
specified guidelines, the investigative site will contact the subject within 1 business day of 
receiving the Hb result from the central laboratory.  If possible, the subject will be scheduled 
for an additional visit within 3 business days to discuss the dosing change and to dispense 
additional study drug if necessary (for subjects who receive a dose increase).  If scheduling 
the subject within this time frame is not possible, dosing instructions will be provided to the 
subject over the telephone. 
Note:  If subjects fail to achieve target Hb level despite administration of 4 tablets of study 
drug per day, this will not be considered a reason for subject discontinuation unless the 
subject initiates rescue therapy (see “Rescue Therapy Guidelines” below). 
Rescue Therapy 
Guidelines 
ESA Rescue Therapy 
In order to standardize the use of ESA rescue in the study, the following guidelines should be 
followed. ESA rescue therapy may be considered if: 
• 
ESA is considered warranted by the investigator’s judgment, AND 
• 
The subject experiences a clinically significant worsening of anemia or symptoms of 
anemia, AND 
• 
The subject has a confirmed Hb level <9.0 g/dL as defined by two consecutive Hb 
levels <9.0 g/dL. The investigator may schedule the subject to return for an 
unscheduled visit to confirm Hb level <9.0 g/dL prior to the subsequent scheduled 
study visit.  
If clinically indicated, the investigator at his/her discretion may initiate ESA rescue therapy 
without a confirmatory Hb level <9.0 g/dL if the first two criteria above are met. 
Red Blood Cell Transfusions 
Investigators should use their local institution’s transfusion guidelines when determining 
whether to transfuse a study subject.  
Subjects who initiate either rescue therapy, ESA Rescue Therapy or Red Blood Cell 
Transfusion, will be required to stop study drug treatment and will be discontinued from the 
study.  See “Study Duration” for follow-up of subjects who discontinue early from the study. 
Iron 
Supplementation 
Subjects who are receiving a stable dose of oral or intravenous iron supplementation for at 
least 28 days prior to the screening period should continue their iron supplementation at the 
same dose and route of administration through the primary efficacy period (through Week 6).  
Changes to iron supplementation dose during the primary efficacy period will be considered 
protocol deviations but will not be considered a reason for subject discontinuation.  After the 
Week 6 visit, investigators should prescribe iron supplementation as needed for subjects with 
ferritin <100 ng/mL and TSAT <20%, and the dose and route of iron administration will be 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 15 of 79 
 
selected at the investigator’s discretion. 
Subjects who are not receiving iron supplementation at the beginning of the screening period 
should not start iron supplementation through the primary efficacy period (through Week 6).  
Initiation of iron supplementation during the primary efficacy period will be considered a 
protocol deviation but will not be considered a reason for subject discontinuation.  After the 
Week 6 visit, investigators should prescribe iron supplementation as needed for subjects with 
ferritin <100 ng/mL and TSAT <20%, and the dose and route of iron administration will be 
selected at the investigator’s discretion. 
Important:  Because of the potential for oral iron to reduce the bioavailability of vadadustat, 
study drug (vadadustat or placebo) should not be administered concurrently with any oral 
iron supplement.  Any oral iron supplements (including multivitamins containing iron) 
should be taken at least 2 hours before or 2 hours after the dose of study drug. 
Statistical 
Considerations 
An analysis of covariance (ANCOVA) model will be used to compare change from pre-
treatment in Hb between the 3 vadadustat dosing groups and the placebo group.  The model 
will include treatment assignment (3 dosed groups and 1 placebo group) and pre-treatment 
Hb value as a covariate.  A step-down procedure will be used to control the overall type I 
error rate for the multiple comparisons.  Testing of the highest dose compared with placebo 
will be conducted first.  If and only if this comparison is significant, then testing will proceed 
to comparison of the next lower dose and placebo, and so on.  Thus, no multiplicity 
adjustment will be needed for this analysis. 
The sample size and power calculations are based on results from Study AKB-6548-CI-0005 
that was conducted in the United States and evaluated vadadustat in patients with anemia 
secondary to non-dialysis-dependent CKD.  It is reasonable to extrapolate these data to the 
current study based on the following findings: 
• PK parameters of vadadustat are similar between CKD patients who are receiving 
hemodialysis (Study AKB-6548-CI-0009) and CKD patients who are not receiving 
dialysis (Study AKB-6548-CI-0003) 
• Hemodialysis procedure has no significant impact on the PK of vadadustat 
(Study AKB-6548-CI-0009) 
• The dose range of 150-600 mg of vadadustat to be used in the current study has been 
shown to be generally well-tolerated and efficacious in raising and/or maintaining Hb at 
the desired target level in CKD patients who were either on hemodialysis 
(Study AKB-6548-CI-0011) or CKD patients who were not on dialysis 
(Studies AKB-6548-CI-0005 and AKB-6548-CI-0007) 
The target enrollment will be approximately 48 subjects for the study with 12 subjects 
enrolled in each of the 4 treatment groups.  
The study is powered based on a comparison of the highest dose vadadustat group (600 mg 
daily) and the placebo group. 
Based on the results from Study AKB-6548-CI-0005 that was conducted in the United States 
and evaluated vadadustat in patients with anemia secondary to NDD-CKD, it is assumed that 
the expected mean Hb changes from pre-treatment to Week 6 will be approximately 0 mg/dL 
for the placebo group and 1.35 g/dL for the highest dose vadadustat group (600 mg daily). 
Based on the results from Study AKB-6548-CI-0011 that was conducted in the United States 
and evaluated vadadustat in patients with anemia secondary to DD-CKD, it is assumed that 
the common Hb standard deviation will be 0.9 g/dL across treatment groups.  In addition, a 
dropout rate of 10% is assumed.  With these assumptions, the study with n=12 subjects per 
group will have >85% power to detect the difference between treatment group and control 
group, at 2-sided alpha of 0.05. 
In addition to the final analysis which will take place when all subjects have completed the 
study and will include all data collected, the 6-week efficacy and safety data will be 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 16 of 79 
 
summarized for administrative planning purposes after the last patient completes the primary 
efficacy period (Week 6).  The preliminary analysis will be performed and interpreted by 
sponsor and CRO study team personnel.  Subjects and sites will not be unblinded to 
treatment allocation.  Individuals from the sponsor and CRO study teams who are unblinded 
for the development and reporting of the preliminary analysis will not be involved in the 
conduct of the study after the preliminary analysis.  As the study conduct and final analysis 
will not be modified by this analysis, no alpha adjustment is proposed.  It is expected that this 
6week data will be identical for the preliminary administrative analysis and the final analysis 
of the complete dataset.  Any changes between the preliminary analysis and the final analysis 
will be documented. 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 17 of 79 
 
3 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
BUN 
blood urea nitrogen 
BV 
baseline visit 
C 
Celsius 
CBC 
complete blood count 
CKD 
chronic kidney disease 
CRF 
case report form 
CRO 
contract research organization 
CV 
cardiovascular 
DD-CKD 
dialysis-dependent chronic kidney disease 
dL 
deciliter 
DVT 
deep venous thrombosis 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EOT 
end-of-treatment 
EPO 
erythropoietin 
ESA 
erythropoiesis-stimulating agent 
EU 
European Union 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
g 
gram 
GCP 
Good Clinical Practice 
Hb 
hemoglobin 
HIF 
hypoxia-inducible factor 
HIF-PH 
hypoxia-inducible factor prolyl hydroxylase 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 18 of 79 
 
IV 
intravenous 
JSN 
Japanese Society of Nephrology 
KDIGO 
Kidney Disease Improving Global Outcomes 
kg 
kilogram 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
modified intent-to-treat (population) 
µM 
micromolar 
mg 
milligram 
mL 
milliliter 
NDD-CKD 
non-dialysis dependent chronic kidney disease 
ng 
nanogram 
PD 
pharmacodynamics(s) 
PE 
pulmonary embolism 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RBC 
red blood cell 
SAE 
serious adverse event 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
SV 
screening visit 
TIBC 
total iron binding capacity 
TSAT 
transferrin saturation 
ULN 
upper limit of normal 
US 
United States 
USA 
United States of America 
VEGF 
vascular endothelial growth factor 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 19 of 79 
 
4 
BACKGROUND 
4.1 
Proposed Indication of Renal Anemia 
Chronic kidney disease (CKD) is defined using the following criteria in accordance with the 
guidelines from the National Kidney Foundation Kidney Disease Outcomes Quality Initiative 
(NKF 2002) and Kidney Disease Improving Global Outcomes (KDIGO 2012): 
• Kidney damage for greater than 3 months, with or without decreased glomerular filtration 
rate (GFR) (ie, pathologic abnormalities or markers of damage, including abnormalities in 
composition of the blood or urine, or abnormalities in imaging tests) 
• Decreased GFR levels (ie, less than 60 mL/min/1.73 m2; GFR categories G3a-G5) for greater 
than 3 months, with or without kidney damage 
CKD is a major public health problem worldwide.  In Japan, the prevalence of GFR less than 
60 mL/min/1.73 m2 is estimated to be 20% of the adult population (Iseki 2008).  The number of 
CKD patients in Japan who require dialysis is >300,000 and has been increasing continually over 
the last 30 years (Imai 2011). 
The prevalence and severity of renal anemia in CKD increases as renal function deteriorates.  
Anemia generally exists when hemoglobin (Hb) is less than 13 g/dL in men or less than 12 g/dL 
in women.  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 erythropoietin (EPO) to adjust the 
production of red blood cells (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.  This decline in EPO 
leads to a reduction in RBC production. 
• 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).  
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. 
As CKD progresses, the combined effect of decreased RBC production from lower EPO 
signaling, increased rate of RBC destruction, and reduced iron availability to the bone marrow 
results in the increased prevalence and severity of anemia. 
The main impact of anemia on organ function is reduced oxygen delivery to tissues leading to a 
constellation of symptoms including fatigue, shortness of breath, and exercise intolerance 
(Stauffer 2014).  In these patients, compensatory changes occur in cardiac structure and function 
including an increase in cardiac output and the development of left ventricular hypertrophy and 
eventually the development of heart failure (Metivier 2000).  Other consequences from anemia in 
CKD patients include impaired cognitive function, sleep disorders, and depressed immune 
function which can impact the quality of life in patients (Iseki 2007, NICE 2011).  Overall, 
anemia contributes to a poorer prognosis in patients with CKD (Iseki 2007, Nurko 2006). 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 20 of 79 
 
4.2 
Available Therapies for Anemia in Patients with CKD 
Erythropoiesis-stimulating agent (ESAs), including epoetin alfa and darbepoetin alfa 
administered either intravenously or subcutaneously, along with iron therapy are currently the 
standard of care for treating anemia in patients with CKD.  Treatment with exogenous 
recombinant ESAs can raise Hb, relieve symptoms, and reduce the complications of anemia 
including avoiding RBC transfusions which carry the risks of infection, iron overload, and 
impact candidacy for kidney transplantation. 
Several large prospective randomized controlled trials in patients with CKD (GFR categories 
G3a to G5) have suggested an increased risk of death and cardiovascular (CV) events when 
targeting higher Hb levels (Besarab 1998, Drueke 2006, Pfeffer 2009a, Pfeffer 2009b, Singh 
2006).  Additional analyses suggest that the ESAs themselves may be causative of the increased 
events and not the Hb level, and is supported by studies in CKD patients on dialysis with 
naturally occurring higher Hb levels and no increase in CV events (Solomon 2010, Szczech 2008, 
Goodkin 2011).  The risks identified with ESAs from these trials have led to changes in 
prescribing information and clinical practice guidelines in the USA and Europe. 
In the USA, the mortality and CV risks associated with ESAs are outlined in a black-box 
warning in the prescribing information of ESAs with a recommendation to use the lowest dose 
possible to avoid transfusions. 
The European Union (EU) Summary of Product Characteristics (SmPC) for ESAs suggests 
caution with the use of ESAs with a recommendation to keep Hb levels between 10-12 g/dL.  
Furthermore, recent clinical practice guidelines (Locatelli 2013) recommended that risk factors 
for stroke (including a past history of stroke) and the presence of active malignancy or a past 
history of malignancy should be taken into account when making treatment decisions to use 
ESAs for the treatment of anemia. 
Although the CV risk is lower in Japanese subjects compared with Caucasian subjects, 
guidelines from the Japanese Society of Nephrology (JSN 2014) stated that ESA treatment 
targeting Hb levels 12–13 g/dL did not seem to be effective for preventing CKD progression or 
decreasing the incidence of CV disease compared to the Hb level of 9-11.5 g/dL, but rather had 
the potential to lead to an increase in the incidence of CV disease. 
The risks associated with currently available recombinant ESAs, including an increased risk for 
death and CV events, highlight the need for novel therapies that may potentially minimize or 
avoid such risks and slow CKD progression. 
4.3 
Hypoxia-Inducible Factor 
Hypoxia-inducible factor (HIF) is the primary regulator of the production of RBC and acts by 
simulating the body’s physiologic response to hypoxia (Haase 2013).  HIF proteins are 
consistently produced and their levels in cells are adjusted by the activity of the HIF-PH 
enzymes. 
During hypoxic conditions, a controlled and coordinated adaptive erythropoietic response occurs 
whereby, HIF-PH enzyme activity decreases in the kidney and liver, leading to stabilization and 
increase in intracellular levels of HIF-α proteins.  When HIF-α is stabilized, it travels to the 
nucleus of the cell, where it binds to the protein HIF-β (Figure 1).  Dimerized HIF-α and HIF-β 
proteins bind to a promotor on the EPO gene to induce an increase in the production of EPO 


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a. Normoxia
(normal HIF-PH activity)
b. Hypoxia
(deceased HIF-PH activity)
HIF-PH
HIF-PH
EPO
HIF-PH
c. Inhibition of HIF-PH by 
vadadustat mimics hypoxic 
conditions
Vadadustat
EPO
EPO


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 22 of 79 
 
vadadustat had a single excursion ≥ 13.0 g/dL.  In addition, a third Phase 2 trial 
(AKB-6548-CI-0011) demonstrated the desired outcome of maintaining stable Hb levels in 
hemodialysis patients who were converted from existing ESA therapy to vadadustat. 
• Vadadustat restores the normal diurnal variation of EPO:  Instead of binding directly to and 
saturating the EPO receptor for prolonged periods, as is the case with current injectable ESA 
therapies, vadadustat acts by simulating the body’s natural response to hypoxia by stabilizing 
HIF-α.  Vadadustat allows for an enhancement in the normal diurnal variation in EPO 
concentration without continuous elevation of EPO levels. 
• Oral, once-daily dosing:  As demonstrated in NDD-CKD patients (Phase 2b 
Study AKB-6548-CI-0007), vadadustat offers flexible once-daily oral dosing that provides a 
more gradual and reliable means of Hb response and maintenance.  This was also 
demonstrated in the Phase 2 study AKB-6548-CI-0011 in DD-CKD patients, where 
vadadustat maintained stable Hb levels in patients converting from ESA therapy.  Vadadustat 
also offers improved convenience for patients as compared to injectable ESAs.  This 
convenience may increase access to anemia therapy and improve patient compliance. 
• Improved mobilization of iron supply to the bone marrow for RBC production:  In clinical 
trials, vadadustat has demonstrated improved iron mobilization as reflected by a decrease in 
hepcidin and ferritin levels and an increase in total iron binding capacity.  Thus, unlike 
injectable recombinant ESAs which do not increase iron mobilization, vadadustat offers the 
added potential benefit of reducing the amount of supplemental iron required by anemic 
CKD patients.  The potential for an intravenous iron sparing effect of vadadustat will be 
assessed in the global Phase 3 program in DD-CKD patients. 
• Differentiated safety profile:  Vadadustat’s novel mechanism of action offers the potential 
opportunity to reduce the risk for CV and thrombotic events relative to injectable ESAs since 
CV risks have been associated with supraphysiological increases in EPO levels and excessive 
Hb fluctuations and/or excursions (McCullough 2013).  The incidence of CV adverse events 
on vadadustat as compared with ESAs will be assessed in the global Phase 3 program.  
Furthermore, the risk of pure red cell aplasia (PRCA) observed with recombinant ESAs is not 
expected with vadadustat. 
4.5 
Summary of Clinical Experience 
Please see the vadadustat Investigator’s Brochure for additional information. 
Overall, vadadustat has demonstrated consistent, dose-proportional pharmacodynamics (PD), 
producing the desired and anticipated effects of raising EPO concentrations in a dose-dependent 
manner in both Phase 1 and Phase 2 studies.  The changes in EPO have been accompanied by 
dose-responsive increases in iron mobilization (increased total iron binding capacity [TIBC] and 
transferrin, and decreased hepcidin and ferritin).  Together, these effects stimulated an increase 
in reticulocytes and Hb.  Thus, current data support both an efficacious dose range and a 
controlled means of dose adjustment for vadadustat that optimizes individualized patient dosing.  
Additionally, vadadustat has been generally well tolerated. 
Vadadustat is eliminated from the body by dual routes of elimination, both renal and fecal, which 
makes the compound appropriate for use in patients with CKD.  Given the dual routes of 
elimination, it is unlikely that vadadustat will accumulate in patients with CKD.  In a clinical 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 23 of 79 
 
study in hemodialysis patients, it was determined that dialysis treatment did not have a notable 
effect on the PK parameters of vadadustat, indicating that vadadustat can be administered 
irrespective of the dialysis treatment. 
A Phase 2a randomized, placebo-controlled, 6-week, dose range-finding study was performed in 
subjects with anemia (HGB ≤10.5 g/dL) secondary to NDD-CKD.  The results demonstrated a 
significant dose-related increase in Hb and TIBC and decreases in hepcidin and ferritin.  The 
plasma concentrations of vadadustat and the glucuronide metabolites exhibited a dose-related 
increase.  Vadadustat was generally well tolerated. 
A completed Phase 2b, randomized, double-blind, placebo-controlled study to assess the 
hematologic PD response, safety, and tolerability of oral vadadustat for 20 weeks was performed 
in 210 subjects with anemia associated with NDD-CKD (AKB-6548-CI-0007).  Subjects were 
assigned to a study group based on their ESA status at screening (naïve, previously treated, or 
actively treated) and were randomized 2:1 to receive either vadadustat at a starting dose of 
450 mg/day or placebo.  The dose of vadadustat was adjusted based on Hb levels and changes in 
Hb.  A significantly higher proportion of subjects with a successful Hb response at the end of 
treatment was observed with vadadustat treatment when compared with placebo (p<0.0001).  
The dosing algorithm was effective in minimizing excessive Hb levels (>13.0 g/dL) and a 
consistent and sustained improvement in iron mobilization was observed with vadadustat 
treatment.  The safety profile of vadadustat in this study was generally consistent with that 
observed in prior clinical studies. 
Based on the Phase 1 and Phase 2 study results, vadadustat is a suitable candidate for continued 
development as a treatment for anemia in patients with CKD. 
4.6 
Ethno-Bridging Data from a Study of Healthy Japanese and Caucasian Volunteers 
Study AKB-6548-CI-0020 was a randomized, double-blind, placebo-controlled, dose escalation 
study conducted at a single clinical site in the United States.  The study was conducted to 
compare the pharmacokinetics (PK) and PD of vadadustat in healthy adult male and female 
volunteers of Japanese and Caucasian descent. 
Brief Overview of Study Design 
The primary study entry criteria included male or female subjects between 20 and 55 years of 
age, with a body mass index of 18-30 kg/m2, and a body weight of 45-90 kg for Japanese 
subjects and a body weight of 50-100 kg for Caucasian subjects.  For study eligibility, the 
Caucasian subjects had to be Caucasian of European or Latin American descent.  The Japanese 
subjects had to fulfill the following eligibility criteria:  Must have been born in Japan; must have 
had 2 biological Japanese parents and 4 Japanese grandparents as confirmed by interview; must 
have been living outside of Japan for up to 10 years at the time of the screening visit; and the 
subject’s lifestyle, including diet, must not have changed significantly since leaving Japan. 
Eligible subjects were enrolled into one of 3 dose cohorts:  150, 300, or 600 mg daily oral doses 
of vadadustat (or placebo).  Subjects received daily doses of study drug (either vadadustat or 
placebo) for 10 days.  Each of the 3 dose cohorts enrolled 8 Japanese and 8 Caucasian subjects.  
Within each dose cohort assignment, subjects were randomized at a 3:1 ratio to receive either 
vadadustat (n=6) or placebo (n=2). 


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Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 25 of 79 
 
rise in Hb concentration.  This less aggressive approach to modifying the Hb concentration may 
be of benefit based on suggestion from the US Food and Drug Administration (FDA) that 
fluctuations in Hb concentrations, rapidly increasing Hb levels, and excursions above the target 
level are associated with an increased risk of CV events (Unger 2010). 
In addition, HIF activation is associated with increased expression of ferroportin and transferrin 
and  decreased expression of hepcidin (Liu 2012, Peyssonnaux 2007, Tacchini 1999).  These 
changes in iron biomarkers are consistent with enhanced iron mobilization and utilization to 
promote hemoglobin synthesis and erythropoiesis.  In the Phase 1b multiple ascending dose 
study, a prominent effect on iron metabolism was noted with the dosing of vadadustat, including 
a rapid increase in iron uptake, a dose responsive increase in TIBC, decreases in hepcidin and 
ferritin, and an increase in transferrin.  A similar pattern was observed in the Phase 2a and 2b 
studies, with dose responsive increases in TIBC and decreases in ferritin and hepcidin. 
To date, the acute findings observed at doses less than the maximum tolerated dose (MTD) in 
animals have been shown to be reversible and dose-related.  In addition, most of the findings 
have followed a pattern that would have been predicted based on the known HIF and HIF-PH 
biochemistry, pharmacology, and human genetic variations (eg, Chuvash polycythemia).  In the 
completed clinical studies, vadadustat has been generally well-tolerated. 
5 
STUDY OBJECTIVES AND ENDPOINTS 
Note that a pre-treatment average value for Hb is defined as the average of 3 values obtained 
prior to dosing, ie, the 2 qualifying screening values and the baseline value. 
5.1 
Primary Objective and Endpoint 
The primary objective of this study is to assess the dose-response relationship between oral 
vadadustat once daily dosing for 6 weeks and the change in hemoglobin (Hb) in Japanese 
subjects with anemia secondary to DD-CKD; this is to define the starting dose for use in Phase 3 
clinical studies in Japan. 
The primary endpoint that will be used to assess this objective is the mean change in Hb levels 
from pre-treatment to the end of the primary efficacy period (Week 6). 
5.2 
Secondary Objectives and Endpoints 
The secondary objectives of this study are:  
• To assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of 
oral vadadustat once daily dosing in Japanese subjects with anemia secondary to DD-CKD 
during the 6-week, primary efficacy period 
• To evaluate the effect of dose adjustments and demonstrate the maintenance effect on Hb 
during a 10-week dose adjustment and maintenance period 
The efficacy endpoints that will be used to assess these objectives include the following: 
• Time to reach target Hb level of 10.0-12.0 g/dL from baseline 
• Mean Hb levels at the end of the primary efficacy period (Week 6) and at the end of the dose 
adjustment and maintenance period (Week 16) 


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Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
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• Proportion of subjects who achieve target Hb 10-12 g/dL at the end of the dose adjustment 
and maintenance period (Week 16) 
• Mean change in Hb between pre-treatment and the end of the dose adjustment and 
maintenance period (Week 16) 
• Mean change in hematocrit, RBC count, and reticulocyte count from baseline to the end of 
the primary efficacy period (Week 6) and the end of the dose adjustment and maintenance 
period (Week 16) 
• Mean change in iron indices (ie, iron, total iron-binding capacity [TIBC], TSAT, and ferritin) 
and hepcidin from baseline to the end of the primary efficacy period (Week 6) and the end of 
the dose adjustment and maintenance period (Week 16) 
• Proportion of subjects requiring rescue with RBC transfusion from baseline to the end of the 
primary efficacy period (Week 6) and the end of the dose adjustment and maintenance period 
(Week 16) 
• Proportion of subjects requiring rescue with ESAs from baseline to the end of the primary 
efficacy period (Week 6) and the end of the dose adjustment and maintenance period 
(Week 16) 
• Number of dose adjustments from baseline to the end of the dose adjustment and 
maintenance period (Week 16) 
• Plasma concentration profile of vadadustat and its metabolites using pre-dose sample from 
Week 4 
The safety endpoints that will be used to assess these objectives include the following: 
• Safety assessments, including adverse events, vital signs, electrocardiograms (ECGs), and 
other laboratory assay results (eg, chemistry, components of the complete blood count [CBC] 
other than the ones noted above, and vascular endothelial growth factor [VEGF]) 
6 
STUDY DESIGN 
6.1 
Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, dose-finding study to assess the 
efficacy, safety, tolerability, PK, and PD of orally administered vadadustat in Japanese male and 
female subjects with anemia secondary to DD-CKD.  The study does not include a pre-specified 
male-to-female ratio. 
The study has a planned enrollment of 48 subjects to be enrolled at approximately 35 sites in 
Japan.  There will be 16 subjects in each of the 3 tablet-count groups. 
An overview of the study design is presented in Figure 3. 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 27 of 79 
 
Figure 3: 
Overview of Study Design 
 
 
The study will include the following periods: 
• Eligibility screening period (see Section 9.1 for additional information regarding screening 
visits and ESA washout period for subjects who were prescribed ESAs at study entry) 
- Up to 4 weeks for subjects who were not prescribed ESAs prior to study entry (Day -28 to 
Day 0) 
- Up to 6 weeks for subjects who were prescribed epoetin alfa, epoetin beta, and epoetin 
kappa prior to study entry (Day -42 to Day 0) 
- Up to 8 weeks for subjects who were prescribed darbepoetin alfa prior to study entry 
(Day -56 to Day 0) 
- Up to 11 weeks for subjects who were prescribed epoetin beta pegol prior to study entry 
(Day -77 to Day 0) 
• Primary efficacy period (6 weeks; Weeks 1 to 6) 
• Dose adjustment and maintenance period (10 weeks; Weeks 7 to 16) 
• Follow-up period (2 weeks; Weeks 17 and 18) 
Subjects will participate in a screening period to determine study eligibility. Subjects who have 
not recently received ESA therapy will participate in 2 screening visits. Subjects who have 
recently received ESA therapy and otherwise meet eligibility criteria will be required to washout 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
Page 28 of 79 
 
from ESA therapy prior to evaluation of screening Hb, and will participate in 3 screening visits 
(see Section 7.2).  
Eligible subjects will be randomized following the screening period using a central 
randomization system.  Subjects will be randomized 1:1:1 to receive 1, 2, or 4 tablets at their 
baseline visit (Day 1).  Within each tablet-count group, subjects will be randomized 3:1 to 
receive vadadustat (150, 300, or 600 mg vadadustat) or placebo.  See Section 8.2.2 for 
information regarding the randomization scheme. 
Study drug treatment will be administered during a 6-week primary efficacy period.  See 
Section 8.2.4 for information on study drug administration.  The primary efficacy period includes 
fixed-dose treatment to establish a dose-response relationship.  However, if Hb level increases 
rapidly or if the Hb levels exceeds 13 g/dL, the study drug dose can be decreased or interrupted 
(see Section 8.2.4). 
After completing the primary efficacy period, subjects will continue to a 10-week dose 
adjustment and maintenance period (see Section 8.2.5).  Subjects receiving placebo will be 
switched to vadadustat, and study drug dose will be adjusted to achieve a target Hb of 
10.0-12.0 g/dL based on dose adjustment guidelines (see Section 8.2.5). 
Vadadustat treatment will stop after the dose adjustment and maintenance period has been 
completed (Week 16) and subjects will continue in a 2-week follow-up period (Week 17-18). 
For subjects who were not being treated with ESAs, the clinical and safety assessments will be 
performed as described in Section 9.4 and as listed in Appendices 
Appendix A.  For subjects who were being treated with ESAs prior to study entry, the clinical 
and safety assessments will be performed as described in Section 9.5 and as listed in Appendix B. 
6.2 
Study Duration 
Study duration will depend on ESA use as follows: 
• For subjects who were not prescribed ESAs at study entry:  Up to 22 weeks, including the 
eligibility screening period (up to 4 weeks, with 2 screening visits), primary efficacy period 
(6 weeks), dose adjustment and maintenance period (10 weeks), and follow-up period 
(2 weeks) 
• For subjects who were prescribed ESAs prior to study entry:  Up to 29 weeks, including the 
eligibility screening period (up to 11 weeks, with 3 screening visits), primary efficacy period 
(6 weeks), adjustment and maintenance period (10 weeks), and follow-up period (2 weeks) 
Note:  See Section 7.6.3 for subjects who discontinue study drug or withdraw early from the 
study. 
6.3 
Rationale for Study Design 
The study design of this randomized, double-blind, placebo-controlled, dose-finding study in 
Japanese subjects with anemia secondary to DD-CKD is modeled on a previously completed 
dose-finding study in subjects with anemia secondary to NDD-CKD that included a majority of 
Caucasian and Black/African American subjects (Study AKB-6548-CI-0005). 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
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A treatment duration of 6 weeks will be adequate to demonstrate the dose-response relationship 
of vadadustat with change in Hb, as 6 weeks of treatment with vadadustat in 
Study AKB-6548-CI-0005 was adequate to establish a statistically significant dose-response 
relationship (as shown in Figure 4).  An additional 10-week dose adjustment and maintenance 
period will be conducted to evaluate the effect of dose adjustments and demonstrate the 
maintenance effect on Hb. 
Figure 4: 
Absolute Change in Hemoglobin (± Standard Error of Mean, g/dL) at Week 6 
Compared to Baseline (Study AKB-6548-CI-0005) 
 
Note:  25% of the subjects in the 630 mg vadadustat treatment group and 10% of subjects in the 500 mg vadadustat 
treatment group had their doses reduced by Week 4. 
Note:  Two tailed paired t-test of hemoglobin:  Baseline versus Week 6, p <0.01 
6.4 
Dose Justification 
The doses to be used in the present study (150, 300, and 600 mg once daily) were previously 
evaluated in the ethno-bridging study (Study AKB-6548-CI-0020).  The results from 
Study AKB-6548-CI-0020 showed that the doses are generally well tolerated, and similar PK 
and PD responses to vadadustat were demonstrated between the Caucasian and Japanese healthy 
subjects. 
Furthermore, the same dose range of 150 mg to 600 mg was previously tested in US-based 
studies enrolling more than 200 subjects with either NDD-CKD (Phase 2 studies 
AKB-6548-CI-0005 and AKB-6548-CI-0007) or DD-CKD (Phase 2 study AKB-6548-CI-0011).  
In these completed studies, the dose range of 150-600 mg was shown to be generally 
well-tolerated, and efficacious in raising and/or maintaining Hb at the desired target level in 
patients with anemia secondary to NDD-CKD or DD-CKD.  Importantly, the dose range 
provides great flexibility in enabling adjustment of vadadustat dose per an individual patient’s 
Hb response.  The product labeling for NESP® and ESPO® in Japan also allow for adjustable 
dosing based on Hb response in individual patients. 
-0.5
0
0.5
1
1.5
2
0.5
0
-0.5
1.0
1.5
2.0
Placebo
370 mg
240 mg
630 mg
500 mg
*Primary ANOVA p <0.0001
*
*
*
*


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Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
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7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
General Criteria 
To be eligible for this study, a subject or their legally acceptable representative must have 
provided valid informed consent and must meet the following criteria.  No study procedures 
(including screening tests) may be performed until after the informed consent has been legally 
signed. 
7.2 
Inclusion Criteria 
Subjects must meet the following inclusion criteria to be eligible for study participation: 
1. Male and female Japanese subjects (20 years or older) 
2. Receiving chronic maintenance hemodialysis for end-stage kidney disease for at least 
8 weeks prior to screening 
3. ESA status and screening Hb that meet one of the following criteria:  
a. For subjects who are not being treated with ESAs:  Hb <10.0 g/dL, average of 
2 measurements obtained during screening. These subjects must be off ESAs for at 
least the following periods of time prior to screening visit 1 (refer to Appendix C for 
examples):  
i. 2 weeks for epoetin alfa, epoetin beta, or epoetin kappa;  
ii. 4 weeks for darbepoetin alfa;  
iii. 8 weeks for epoetin beta pegol. 
b. For subjects who are being treated with ESAs:  Hb <10.0 g/dL, average of 
2 measurements obtained during screening after the protocol-defined ESA washout 
period. These subjects must washout ESA therapy for the following periods of time 
during the screening period, beginning at screening visit 1 and prior to screening visit 
2 (refer to Appendix C for examples): 
i. 2 weeks for epoetin alfa, epoetin beta, and epoetin kappa;  
ii. 4 weeks for darbepoetin alfa;  
iii. 8 weeks for epoetin beta pegol. 
4.  Serum ferritin ≥50 ng/mL during screening 
5. Transferrin saturation (TSAT) ≥20% during screening 
6. Folate and vitamin B12 ≥lower limit of normal during screening 
7. For subjects who are receiving oral or intravenous iron supplementation, the dose of iron 
supplementation must be stable for at least 28 days prior to the screening period.  For 
subjects who are not receiving oral or intravenous iron supplementation, no iron 


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Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
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supplementation may have been administered for at least 28 days prior to the screening 
period. 
8. Understands the procedures and requirements of the study and provides written informed 
consent and authorization for protected health information disclosure 
7.3 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not qualify for study participation: 
1. Anemia due to a cause other than CKD or presence of active bleeding or recent blood loss. 
2. Sickle cell disease, myelodysplastic syndromes, bone marrow fibrosis, hematologic 
malignancy, myeloma, hemolytic anemia, thalassemia, or pure red cell aplasia. 
3. Red blood cell (RBC) transfusion within 4 weeks prior to or during screening. 
4. Anticipated to recover adequate kidney function to no longer require hemodialysis during 
study participation. 
5. On peritoneal dialysis or expected to change dialysis modality during study participation. 
6. Hypo-responsiveness to ESA defined as any of the following ESA treatments within 8 weeks 
prior to screening: (i) intravenous epoetin dose ≥3,000 units/dose 3 times a week 
(9,000 units/week), (ii) intravenous darbepoetin alfa dose ≥60 µg once a week, or 
(iii) epoetin beta pegol ≥200 µg once a month or ≥100 µg once every 2 weeks. 
7. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine 
aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total bilirubin 
>2.0 x upper limit of normal during screening.  A history of Gilbert’s syndrome is not an 
exclusion criterion. 
8. Uncontrolled hypertension (defined as confirmed pre-dialysis systolic blood pressure [BP] 
>190 mmHg or diastolic BP >110 mmHg at rest) during screening. 
9. Body mass index (BMI) >42.0 kg/m2. 
10. Severe heart failure during screening (New York Heart Association Class III or IV). 
11. History of untreated proliferative diabetic retinopathy, diabetic macular edema, age-related 
macular degeneration, central retinal vein occlusion, active retinal hemorrhage, or ongoing 
ocular treatment with laser photocoagulation or anti-VEGF therapies. 
12. 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, or stroke within 12 weeks 
prior to or during screening. 


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Protocol Version 2 
 
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13. History of active malignancy within 2 years prior to or during screening, except for treated 
basal cell carcinoma of skin, curatively resected squamous cell carcinoma of skin, cervical 
carcinoma in situ, or resected benign colonic polyps. 
14. History of deep vein thrombosis (DVT) or pulmonary embolism (PE) requiring active 
treatment within 8 weeks prior to or during screening.  Note:  Active treatment indicates 
treatment with an anticoagulant (blood thinner), such as heparin, enoxaparin, warfarin, 
rivaroxaban, apixaban, edoxaban, argatroban, and fondaparinux.  Aspirin is not considered 
active treatment for DVT or PE. 
15. History of hemosiderosis or hemochromatosis. 
16. History of prior organ transplantation or scheduled organ transplant, or prior hematopoietic 
stem cell or bone marrow transplant.  Note:  Subjects on kidney transplant wait-list, or with a 
history of failed kidney transplant, corneal transplants, or stem cell therapy for knee arthritis 
are not exclusion criteria. 
17. Use of an investigational medication or participation in an investigational study within 
30 days or 5 half-lives of the investigational medication (whichever is longer), prior to 
screening. 
18. Previous participation in a study with a hypoxia-inducible factor prolyl-hydroxylase inhibitor 
(HIF-PHI), other than vadadustat, within 90 days prior to screening.  
19. Hypersensitivity to vadadustat, or to any of its excipients. 
20. Females who are pregnant or breast-feeding. 
21. Females of childbearing potential who are unable or unwilling to use an acceptable method 
of contraception. 
22. Non-vasectomized males who are unable or unwilling to use an acceptable method of 
contraception. 
23. Any other reason that in the opinion of the investigator would make the subject not suitable 
for participation in the study. 
7.4 
Retesting and Rescreening 
7.4.1 Retesting  
All screening laboratory tests, including any repeat measurements, must be performed within the 
screening window (see Section 9.1).  Subjects who initially fail to qualify for the study based on 
laboratory test results may have their laboratory value retested once within the screening period, 
at the investigator’s discretion. 
Retesting within the screening period does not constitute rescreening; however, if retesting falls 
outside of the screening period, it should be considered a rescreen.   


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Protocol Version 2 
 
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7.4.2 Rescreening  
Subjects who fail to meet the qualifying criteria for Hb during screening may be considered for 
rescreening at the discretion of the investigator, if it is felt that the subject’s status has changed 
and that the subject may now qualify for the study.  Additionally, subjects who fail to qualify for 
the study based on low ferritin, TSAT, folate, or vitamin B12 values may be considered for 
rescreening after receiving replacement therapy. 
Screening is limited to 3 attempts (during the initial screening and 2 additional rescreening 
attempts).  Subjects who fail to qualify for the study at the initial screening visit will receive a 
new subject number for each rescreening attempt.  If rescreened, the subject will also sign a new 
informed consent form and will repeat all screening procedures for each rescreening attempt. 
7.5 
Study Completion, Study Termination, and Individual Study Site Termination 
7.5.1 Study Completion 
The study will be considered completed after all enrolled subjects have completed study 
participation, and the adverse event (AE) reporting period has been completed for each enrolled 
subject (see Section 10.3.1 for information regarding the AE reporting period). 
7.5.2 Study Termination 
The entire study may be suspended or terminated by the sponsor for safety or other unanticipated 
reasons or upon request of regulatory agencies.  Criteria for premature study termination or 
suspension are detailed in Section 14.1. 
7.5.3 Individual Study Site Termination 
Study participation may be suspended or terminated at an individual investigational site for 
various reasons.  Criteria and procedures for premature termination or suspension of an 
investigational site are detailed in Section 14.2 and Section 14.3. 
7.6 
Subject Completion and Individual Subject Discontinuation 
7.6.1 Subject Completion 
A subject will be considered as having completed the study after completing participation in the 
Week 18 visit (end of the 2-week follow-up period). 
Note:  See Section 7.6.3 for subjects who discontinue study drug or withdraw early from the 
study. 
See Section 10.3.6 for information regarding follow-up of unresolved events. 
7.6.2 Conditions and Documentation of Individual Subject Study Drug Discontinuation 
Subjects may discontinue study medication for any of the following conditions: 
• Completion of the protocol-defined dosing period (see Appendices 
• Appendix A and Appendix B) 
• Worsening of anemia requiring ESA rescue or blood transfusion 


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Vadadustat 
Protocol Version 2 
 
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• Unacceptable toxicity or drug intolerability 
• Investigator discretion 
• Subject withdrawal of consent 
• Subject becomes pregnant 
• Subject receives kidney transplant 
• Other reasons 
The investigator must document the primary reason for discontinuation in the appropriate case 
report form (CRF). 
7.6.3 Individual Subject Discontinuation 
Subjects permanently discontinuing study drug or withdrawing early from the study prior to the 
Week 16 visit should complete the Week 16 (EOT) clinical and laboratory assessments within 
1 day of stopping study medication, if possible.  Such subjects should also complete the 2-week 
follow-up period and complete the Week 18 visit assessments (see Appendices 
Appendix A and Appendix B). 
For subjects who discontinue study medication, the investigator should resume standard of care 
treatment, as deemed appropriate. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. 
8 
STUDY DRUGS AND TREATMENT OF SUBJECTS 
8.1 
Study Drugs 
The study drugs will be vadadustat and placebo (Table 1). 
Table 1: 
Identity of Study Drugs 
Study Drug 
Formulation 
Strength 
Route of Administration 
Vadadustat 
Tablet 
150 mg per tablet 
Oral 
Placebo 
Tablet 
Not applicable 
Oral 
 
8.1.1 Formulation 
Vadadustat tablets and matching placebo will be provided to sites by the sponsor or its designee. 
Vadadustat is formulated for oral dosing.  The tablets are white to off-white, round, bi-convex 
film-coated tablets (8.0 mm diameter) containing 150 mg vadadustat and the following inactive 
ingredients:  microcrystalline cellulose (MCC), sodium starch glycolate, hydroxypropyl 
methylcellulose (HPMC), colloidal silicon dioxide, and magnesium stearate, and a film coating. 
Packaging and labeling will be in accordance with current Good Manufacturing Practice and 
local regulatory requirements. 


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Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
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8.1.2 Storage and Accountability 
Vadadustat and placebo should be stored at 1–30 ºC.  All study medication supplies must be kept 
in a locked facility and accessible only to authorized study personnel.  A temperature log should 
be maintained with drug storage temperatures recorded per the Pharmacy Manual.  A min-max 
thermometer is preferred for this study. 
The site pharmacist or designated study personnel will be responsible for supply accountability, 
preparing study drugs for dispensation, and will maintain an investigational medication 
distribution form itemizing all trial medications dispensed to and returned from each subject 
during the study. 
8.1.3 Dispensing of Study Drugs  
Based on the randomized treatment assignment, individual subjects will be provided with 
1 bottle of study drug (placebo or vadadustat) at the baseline visit (Day 1).  Each bottle will 
contain 100 tablets of study drug.  Subjects will be instructed to finish 1 bottle before opening a 
new bottle. 
At the Week 6 visit, sites will collect all unused study drug tablets dispensed during the primary 
efficacy period.  Each subject will then be provided with 1 bottle of vadadustat.  Each bottle will 
contain 100 tablets of vadadustat.   
Resupply of additional study drug as needed will be dependent on the dose level and the number 
of tablets remaining in the subject’s current supply at a given study visit.  Subjects will be 
instructed to finish 1 bottle before opening a new bottle. 
To allow for some flexibility in study visit scheduling, sites should ensure that subjects have an 
adequate supply of study medication. 
Subjects should be instructed to bring unused and empty bottles to each study visit for product 
accountability.  Empty bottles will be collected at these study visits.  Previously dispensed 
bottles (whether opened or unopened) with remaining tablets may be re-dispensed to the subject 
depending on the dosing period of the study. 
8.1.4 Product Accountability and Destruction 
Product accountability should be an ongoing process throughout the study.  All study drug must 
be accounted for and any discrepancies explained.  The designated study personnel are 
responsible for keeping accurate records of the clinical supplies, all supplies retained in 
inventory at the investigative site, and study drug dispensed to or returned from each subject.  
Records will be maintained that accurately reflect the drug accountability. 
Proper drug accountability includes, but is not limited to: 
• 
Continuously monitoring expiration dates, if expiry date or retest date is provided to the site 
• 
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 or designee must be notified 
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During the study, the investigator will be notified of any expiry dates or retest date extensions of 
clinical study material.  If an expiry date notification is received during the study, the 
investigative site must complete all instructions outlined in the notification, including 
segregation of expired clinical study material for return to the sponsor or its designee for 
destruction. 
Prior to investigative site closure and at appropriate intervals during the study, a representative 
from the sponsor will perform clinical study material accountability and reconciliation. 
At the end of the study, the investigator will retain all original documentation regarding clinical 
study material accountability, return, and/or destruction, and copies will be sent to the sponsor or 
designee. 
All unused and/or partially used study drug 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 study drug may be disposed of until fully accounted for 
by the sponsor’s monitor or designee.  Empty containers may be disposed of per local procedures. 
8.2 
Treatment of Subjects 
8.2.1 Dosing Instructions 
Study drug will be administered on an outpatient basis.  Subjects should take the study drug with 
water or another beverage and should be instructed to swallow the intact tablet(s).  Subjects may 
take the study medication with or without food. 
Subjects should be instructed to take the study medication at approximately the same time each 
day, preferably between 7 am and 2 pm, with the following exception: On the day of the Week 4 
visit, the dose of study medication should be held until after the pre-dose PK sample has been 
obtained. 
8.2.2 Randomization 
Prior to start of dosing on Day 1, a central randomization system will be used to randomize 
subjects at a 1:1:1 ratio to receive 1, 2, or 4 tablets. 
Within each tablet-count group, subjects will be randomized 3:1 to receive vadadustat or placebo 
as shown in Figure 5. 


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Figure 5: 
Randomization Scheme of Study Treatment 
 
8.2.3 Blinding During the Study and Breaking the Blind 
Throughout the study, all subjects, investigators, site personnel, and site pharmacists will be 
blinded to subject randomization status.  All sponsor and CRO personnel will be blinded to 
randomization until the last subject completes the primary efficacy period (Week 6).  At that 
time, the preliminary analysis will be performed and interpreted by sponsor and CRO study team 
personnel.  Individuals from the sponsor and CRO study teams who are unblinded for the 
development and reporting of the preliminary analysis will not be involved in the conduct or 
interpretation of the study after the preliminary analysis.  These activities will be transitioned to 
sponsor and CRO personnel who will remain blinded to randomization status throughout the 
remainder of the study. 
The blind may be broken for individual subjects in the case of a medical emergency (where 
knowledge of the study drug administered would affect the treatment of the emergency).  The 
decision to break the blind will be made on a case-by-case basis, at the discretion of the site 
investigator in collaboration with the sponsor’s medical monitor/medical director (or designee). 
The sponsor’s and/or the CRO’s safety medical monitor/medical director (or designee) and 
related safety personnel will be unblinded for safety data that would require assessment for 
expedited reporting.   
8.2.4 Study Drug Administration during the Primary Efficacy Period (Week 1 to Week 6) 
The primary efficacy period involves fixed-dose treatment to establish a dose-response 
relationship.  No increase in study drug dose is permitted during this period.  However, the dose 
may be decreased or interrupted as described below: 
• If the Hb increases rapidly (eg, more than 1 g/dL in any 2-week period), reduce the dose 
by 1 tablet. 
• If the Hb exceeds 13.0 g/dL, interrupt study drug until the Hb decreases to 12.5 g/dL or 
below and then resume dosing with 1 fewer tablet.   
If dose reduction or interruption is recommended based on the central laboratory Hb result and 
protocol-specified guidelines, the investigative site will contact the subject within 1 business day 
of receiving the Hb result from the central laboratory.  If possible, the subject will be scheduled 
1 tablet
(n=16) 
Vadadustat 150 mg (n=12); 1 x 150 mg tablet once daily
Placebo (n=4); 1 tablet once daily
2 tablets
(n=16)
Vadadustat 300 mg (n=12); 2 x 150 mg tablets once daily
Placebo (n=4); 2 tablets once daily
4 tablets
(n=16)
Vadadustat 600 mg (n=12); 4 x 150 mg tablets once daily
Placebo (n=4); 4 tablets once daily


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for an additional visit within 3 business days.  If scheduling the subject within this time frame is 
not possible, dosing instructions will be provided to the subject over the telephone. 
8.2.5 Study Drug Administration during the Dose Adjustment and Maintenance Period 
(Week 7 to Week16) 
Subjects who complete the primary efficacy period will enter the dose adjustment and 
maintenance period.  Subjects receiving placebo will be switched to vadadustat at the Week 6 
visit.  Specifically, at the Week 6 visit, sites will collect all unused study drug tablets dispensed 
during the primary efficacy period.  Each subject will then be provided with 1 bottle of 
vadadustat.  Each subject will initially take the same number of tablets of study drug after the 
Week 6 visit as before the Week 6 visit.  For example, subjects taking 2 tablets of study drug 
(vadadustat or placebo) prior to the Week 6 visit will initially take 2 tablets of vadadustat after 
the Week 6 visit.  
Subsequently, study drug dose will be adjusted to achieve a target Hb of 10.0-12.0 g/dL based on 
central laboratory Hb results and dose adjustment guidelines described below.  Dose adjustments 
will be based on central laboratory Hb results from study visits at Weeks 6, 8, 10, 12, and 14.  
• Do not increase the dose more frequently than once within any given 4-week interval.  
For example, if a subject’s dose was increased based on Hb results from the Week 6 visit 
and the subject remains below the Hb target, the next opportunity to further increase the 
dose would be based on Hb results from the Week 10 visit.  Decreases in dose can occur 
more frequently.  Avoid frequent dose adjustments. 
• If the Hb has not increased by more than 0.5 g/dL above the baseline value after the first 
6 weeks of treatment, increase the dose by 1 tablet. 
• Increase the dose by 1 tablet every 4 weeks until Hb is above 10.0 g/dL (maximum dose 
is 4 tablets). 
• If the Hb increases rapidly (eg, more than 1 g/dL in any 2-week period), reduce the dose 
by 1 tablet. 
• If the Hb falls below 10.0 g/dL, increase the dose by 1 tablet. 
• If the Hb exceeds 12.0 g/dL, reduce the dose by 1 tablet. 
• If the Hb exceeds 13.0 g/dL, interrupt study drug until the Hb decreases to 12.5 g/dL or 
below and then resume dosing with 1 fewer tablet. 
• If a dose adjustment is required to maintain Hb at the desired level, the dose adjustment is 
by 1 tablet.   
When adjusting therapy, investigators should consider Hb rate of rise, rate of decline, and 
variability as well as the subject’s clinical condition (including recent illness, volume depletion, 
and volume overload).  As clinically indicated, investigators may elect to dose outside the dosing 
guidelines to maintain the Hb within the target range. In such cases, the clinical circumstances 
must be documented in the subject’s record. 
If dose adjustment is recommended based on the central laboratory Hb result and protocol-
specified guidelines, the investigative site will contact the subject within 1 business day of 
receiving the Hb result from the central laboratory.  If possible, the subject will be scheduled for 


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an additional visit within 3 business days.  If scheduling the subject within this time frame is not 
possible, dosing instructions will be provided to the subject over the telephone. 
Note:  If subjects fail to achieve target Hb level despite administration of 4 tablets of study drug 
per day, this will not be considered a reason for subject discontinuation unless the subject 
initiates rescue therapy (see Section 8.2.6). 
8.2.6 Rescue Therapy Guidelines 
ESA Rescue Therapy 
In order to standardize the use of ESA rescue in the study, the following guidelines should be 
followed. ESA rescue therapy may be considered if: 
• ESA is considered warranted by the investigator’s judgment, AND 
• The subject experiences a clinically significant worsening of anemia or symptoms of 
anemia, AND 
• The subject has a confirmed Hb level <9.0 g/dL as defined by two consecutive Hb levels 
<9.0 g/dL. The investigator may schedule the subject to return for an unscheduled visit to 
confirm Hb level <9.0 g/dL prior to the subsequent scheduled study visit.  
If clinically indicated, the investigator at his/her discretion may initiate ESA rescue therapy 
without a confirmatory Hb level <9.0 g/dL if the first two criteria above are met. 
Red Blood Cell Transfusions 
Investigators should use their local institution’s transfusion guidelines when determining whether 
to transfuse a study subject. 
Subjects who initiate either rescue therapy, ESA Rescue Therapy or Red Blood Cell Transfusion, 
will be required to stop study drug treatment and will be discontinued from the study.  See 
Section 7.6.3 for subjects who discontinue study drug or withdraw early from the study. 
8.2.7 Iron Supplementation (Information on Allowed Use) 
Subjects who are receiving a stable dose of oral or intravenous iron supplementation for at least 
28 days prior to the screening period should continue their iron supplementation at the same dose 
and route of administration through the primary efficacy period (through Week 6).  Changes to 
iron supplementation dose during the primary efficacy period will be considered protocol 
deviations but will not be considered a reason for subject discontinuation.  After the Week 6 visit, 
investigators should prescribe iron supplementation as needed for subjects with ferritin 
<100 ng/mL and TSAT <20%, and the dose and route of iron administration will be selected at 
the investigator’s discretion. 
Subjects who are not receiving iron supplementation at the beginning of the screening period 
should not start iron supplementation through the primary efficacy period (through Week 6).  
Initiation of iron supplementation during the primary efficacy period will be considered a 
protocol deviation but will not be considered a reason for subject discontinuation.  After the 
Week 6 visit, investigators should prescribe iron supplementation as needed for subjects with 
ferritin <100 ng/mL and TSAT <20%, and the dose and route of iron administration will be 
selected at the investigator’s discretion. 


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Important:  Because of the potential for oral iron to reduce the bioavailability of vadadustat, 
study drug (vadadustat or placebo) should not be administered concurrently with any oral iron 
supplement.  Any oral iron supplements (including multivitamins containing iron) should be 
taken at least 2 hours before or 2 hours after the dose of study drug. 
8.2.8 Late or Missed Doses 
Subjects should be instructed to take the study medication at roughly the same time each day, 
preferably between 7 am and 2 pm.   
If a dose is forgotten, subjects should be instructed to take the dose as soon as they remember 
until 11 pm the same day.  If a forgotten dose is not remembered until after 11 pm, the subject 
should skip the dose and resume the normal dosing schedule on the following day. 
8.2.9 Compliance with Study Drug Dosing 
Subjects will be questioned regarding dosing compliance and whether they have questions or 
have experienced any problems related to the dosing of study drug.  The investigator will also 
maintain drug accountability logs itemizing vadadustat dispensed to and returned from each 
subject during the study.  Treatment compliance will be determined from these forms along with 
the subject questioning. 
Subjects who miss doses will be counseled on the importance of treatment compliance. 
Subjects will also be questioned regarding the timing of their last dose of vadadustat during PK 
sample collection.  The date and time of these doses will be recorded on the CRF. 
8.2.10  Continuation of Treatment 
Subjects participating in this study will not be considered for continuation of treatment with the 
study medication past the maximum duration of treatment of approximately 16 weeks. 
8.3 
Prior and Concomitant Therapy 
All medications taken within 30 days prior to the start of study drug and during study 
participation should be recorded on the appropriate case report form. 
8.4 
Prohibited Treatments 
8.4.1 Investigational Medications 
Study subjects should not have received any investigational medications or participated in an 
investigational study within 30 days or 5 half-lives of the investigational medication, whichever 
is longer, prior to Day 1. 
Additionally, subjects should not take another investigational medication while participating in 
this study. 
8.4.2 ESAs and Blood Transfusion 
Note:  ESAs and RBC transfusions are allowed as rescue therapies, please refer to Section 8.2.6 
for the rescue therapy guidelines.  Subjects who initiate rescue therapy will be required to stop 


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study drug treatment and will be discontinued from the study.  See Section 7.6.3 for subjects who 
discontinue study drug or withdraw early from the study. 
• 
Prohibitions related to ESA use:  See Section 9.1 for washout period for ESAs.   
• For subjects who are not currently being treated with ESAs:  
o Subjects may not receive any ESA during the screening, treatment, and follow-up 
study periods except in the context of ESA rescue (see ESA rescue guidelines, 
section 8.2.6). 
• For subjects who are currently being treated with ESAs: 
o After screening visit 1 and prior to screening visit 2, subjects must not receive 
ESAs for at least the following time periods: 
 
ESA 
ESA washout period (Minimum duration of time without ESA 
treatment after screening visit 1 and prior to screening visit 2) 
Epoetin alfa 
Epoetin beta 
Epoetin kappa 
2 weeks 
Darbepoetin alfa 
4 weeks  
Epoetin beta pegol 
8 weeks 
 
o After screening visit 2 and through the remaining screening period, subjects must 
not use any ESA. Any ESA use during this period would result in exclusion from 
the study. 
During the treatment and follow-up study periods, subjects may not receive any ESA except in 
the context of ESA rescue (see ESA rescue guidelines, section 8.2.6).  
• 
Prohibitions related to blood transfusions:  Subjects may not receive blood transfusion within 
4 weeks prior to the screening period and through the follow-up period. 
8.4.3 Iron Supplementation (Information on Prohibition) 
Subjects who are not receiving iron supplementation at the beginning of the screening period 
should not start iron supplementation through the primary efficacy period (through Week 6).  
Initiation of iron supplementation during the primary efficacy period will be considered a 
protocol deviation but will not be considered a reason for subject discontinuation. 
See Section 8.2.7 for information on circumstances allowing use of oral iron supplementation. 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES 
9.1 
Schedule of Visits 
As presented in Appendices 
Appendix A and Appendix B, this study includes the following visits: 
• 
Eligibility screening period 


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o For subjects who were not prescribed ESAs at study entry, the screening visits must 
be performed within 4 weeks (Day -28 to Day 0) prior to dosing on Day 1, in addition,  
screening visit 2 should be ≥4 days from screening visit 1, and baseline visit (Day 1) 
should be ≥4 days from screening visit 2. 
o For subjects who were prescribed epoetin alfa, epoetin beta, and epoetin kappa prior 
to study entry, the screening visits must be performed within 6 weeks (Day 42 to 
Day 0) prior to dosing on Day 1.  There will be a 2-week ESA washout period 
between screening visit 1 and screening visit 2, in addition,  screening visit 2 after the 
≥2-wk ESA washout; screening visit 3 should be ≥4 days from screening visit 2; and 
baseline visit (Day 1) should be ≥4 days from screening visit 3. 
o For subjects who were prescribed darbepoetin alfa prior to study entry, the screening 
visits must be performed within 8 weeks (Day -56 to Day 0) prior to dosing on Day 1.  
There will be a 4-week ESA washout period between screening visit 1 and screening 
visit 2, in addition, screening visit 2 after the ≥4-wk ESA washout; screening visit 3 
should be ≥4 days from screening visit 2; and baseline visit should be ≥4 days from 
screening visit 3. 
o For subjects who were prescribed epoetin beta pegol prior to study entry, the 
screening visits must be performed within 11 weeks (Day -77 to Day 0) prior to 
dosing on Day 1.  There will be an 8-week washout period between screening visit1 
and screening visit 2, in addition,  screening visit 2 after the ≥8-wk ESA washout; 
screening visit 3 should be ≥4 days from screening visit 2; and baseline visit should 
be ≥4 days from screening visit 3. 
• 
Primary efficacy period (from Day 1 to Week 6 visit) 
o Baseline visit (Day 1) 
o Week 2 visit ± 1 day 
o Week 4 visit ± 3 days 
o Week 6 visit ± 3 days 
• 
Dose adjustment and maintenance period (after the Week 6 visit to Week 16 visit) 
o Week 8 visit ± 3 days 
o Week 10 visit ± 3 days 
o Week 12 visit ± 3 days 
o Week 14 visit ± 3 days 
o Week 16 visit ± 3 days 
• 
Follow-up period (after the Week 16 visit to the Week 18 visit) 
o Week 18 visit ± 3 days 
Note:  The following visits will be scheduled on the first hemodialysis session of the week. 
• 
For subjects who were not prescribed ESAs at study entry:  Screening visit 1, screening visit 
2, baseline visit (Day 1), Week 6, and Week 16 visit 


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• 
For subjects who were prescribed ESAs prior to study entry:  Screening visit 2, screening 
visit 3, baseline visit (Day 1), Week 6, and Week 16 visit 
As visit scheduling permits, effort should be made to try to schedule other visits for the first 
hemodialysis of the week, acknowledging that this may not be feasible due to subject or site 
scheduling constraints. 
9.2 
Administrative Procedures 
9.2.1 Informed Consent 
Informed consent must be obtained and legally signed prior to a subject entering the study and 
before any protocol-directed procedures (including screening tests) are performed (see 
Section 15.3). 
9.2.2 Documentation of Screen Failures 
To account for screen failures throughout the screening process, investigators must maintain a 
log of subjects and their disposition beginning at the screening stage. 
For each screened subject, investigators must indicate whether the subject enrolled in the study.  
Reasons for ineligibility and not proceeding to screening or study enrollment must be provided. 
9.2.3 Review of Inclusion and Exclusion Criteria 
A subject must meet all inclusion criteria listed in Section 7.2 to be eligible for study 
participation. 
A subject who meets any of the exclusion criteria listed in Section 7.3 will not qualify for study 
participation.  Information on acceptable methods of contraception is provided in Section 9.2.3.1. 
9.2.3.1 Acceptable Methods of Contraception 
In nonclinical animal embryo-fetal development and fertility studies, there was no evidence of 
teratogenicity, no skeletal or visceral malformations, and no changes in male or female 
reproductive and fertility indices, or in sperm parameters.  In rats, decreased fetal body weight 
and reduced skeletal ossification were noted at the highest dose tested of 160 mg/kg/day.  
Peri-postnatal development studies of vadadustat in the rat are ongoing, and there are no data on 
the transmission of vadadustat in breast milk or the effect of vadadustat on infants. 
The potential risk of vadadustat on the developing fetus is limited based on available study 
results.  However, this protocol requires that all subjects must agree to use acceptable methods of 
contraception throughout the study and for 30 days after the last dose of study medication.  In 
addition, men must not donate sperm during the study and for at least 90 days after the last dose 
of study medication. 
Acceptable methods of contraception are defined as follows: 
• 
Female subjects must be surgically sterile, postmenopausal (no menses for at least 1 year), or 
have negative pregnancy test results at screening (assessed using serum pregnancy test). 


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• 
Female subjects who are not surgically sterile or postmenopausal (no menses for at least 
1 year) and male subjects who are not vasectomized must practice at least one of the 
following acceptable methods of contraception: 
o Total abstinence from sexual intercourse, with a minimum of one complete menstrual 
cycle prior to screening visit, throughout the study, and for 30 days after the last dose 
of study medication 
o A vasectomized partner 
o Hormonal contraceptives (oral, parenteral, or transdermal) for at least 3 months prior 
to study drug administration, throughout the study, and for 30 days after the last dose 
of study medication 
o Intrauterine contraception/device starting at the screening visit, throughout the study, 
and for 30 days after the last dose of study medication 
o Double-barrier method (such as male condom, female condom, diaphragm, sponge, or 
cervical cap together with spermicidal foam/gel/film/suppository) starting at the 
screening visit, throughout the study, and for 30 days after the last dose of study 
medication 
9.3 
Study Procedures and Evaluations 
9.3.1 Clinical Evaluations 
The following clinical evaluations will be conducted during the study.   
For subjects who were not prescribed ESAs at study entry, detailed information regarding the 
timing of the assessments is presented in Section 9.4 and summarized in Appendices 
Appendix A.  For subjects who were prescribed ESAs prior to study entry, detailed information 
regarding the timing of the assessments is presented in Section 9.5 and summarized in Appendix 
B. 
• Demographics and medical history:  Relevant medical history (with emphasis on previous 
medical conditions that may lead to exclusion) and significant ongoing medical conditions or 
diseases should be documented. 
• Physical examination:  Physical examination, including height assessments 
• Dry weight assessment 
• Dialysis adequacy:  Dialysis adequacy (measured as Kt/V), as available from local collection, 
will be recorded. 
• Dialysis treatment review:  Review of dialysis treatment should include frequency of dialysis 
and vascular access type (eg, AV fistula, AV graft, and venous catheter). 
• Vital signs:  Vital signs will include blood pressure, heart rate, respiratory rate, and body 
temperature.  Blood pressure and heart rate will be collected in the seated position after 
5 minutes of rest.  Vital signs should be collected prior to blood draws, when possible. 
• 12-lead ECG:  A standard 12-lead ECG should be obtained after the subject has been resting 
comfortably in a supine position for approximately 10 minutes.  ECGs should be taken prior 
to blood draws when possible.  The subject should consume no more than a light meal or 


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snack during the 1-hour period prior to the ECG.  With the subject in a supine position obtain 
the 12-lead tracing.  Each 12-lead ECG must be recorded with a paper speed of 25 mm/sec 
and printed as a paper copy.  The investigator (or a qualified observer at the investigational 
site) will interpret the ECG and record the results including the following parameters:  Heart 
rate, PR interval, QT interval, QRS interval, and QTc (corrected). 
All abnormal rhythms will be reviewed by the study physician for the presence of rhythms of 
potential clinical concern.  A printed record of the tracing(s) of the clinically significant 
rhythm(s) will be made and retained with other source documents. 
• Adverse event review:  Beginning with the first dose of study medication and through the 
follow-up visit, the investigator and study personnel will review each subject’s laboratory 
and clinical evaluation findings and query the subject directly regarding AEs.  Additional 
information is provided in Section 10 and follow-up of unresolved AEs, serious adverse 
events (SAEs), and non-serious events is described in Section 10.3.6. 
• Rescue therapy (ESA rescue and RBC transfusion) review:  Beginning with the first 
post-baseline visit (after Day 1) and through the follow-up visit, the investigator and study 
personnel will review whether a subject received rescue therapy (ESA rescue or RBC 
transfusion). 
• Concomitant medication review:  All medications taken within 30 days prior to the start of 
study medication and through the final study visit should be recorded on the appropriate CRF.  
In addition, the ESA and iron treatment regimen prior to randomization and date of last dose 
will be recorded. 
At each study visit, subjects will be asked whether they have started or discontinued any 
medication since their previous study visit.  This includes single use or as needed medication 
use.  All medications and treatments, including vitamin supplements, over-the-counter 
medications, and oral herbal preparations must be recorded in the CRFs. 
9.3.2 Laboratory Evaluations 
Samples for laboratory assays will be sent to a central laboratory for analysis.  Detailed 
instructions for the collection, processing, and shipment of laboratory samples will be provided 
by the sponsor and the central laboratory.  The investigator is responsible for reviewing 
laboratory results for clinical significance. 
The following laboratory evaluations will be conducted during the study: 
• Serum pregnancy tests:  Female subjects who are of childbearing potential (ie, are not 
surgically sterile or postmenopausal) will participate in serum pregnancy tests (to be 
analyzed by the central lab).  The screening pregnancy test results must be available and must 
be negative for a subject to initiate study drug.  
• Note: Additional serum or local urine (if possible) pregnancy tests may be conducted, as 
determined by the investigator or required by local regulations, to establish the absence of 
pregnancy during the study. Coagulation tests:  Blood sample will be collected to assess the 
prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio 
(INR). 


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• Folate and vitamin B12:  Blood sample will be collected to assess folate and Vitamin B12 
levels. 
• CBC:  Blood sample will be collected to assess CBC, including Hb, hematocrit, RBC count, 
mean corpuscular volume, mean corpuscular Hb, mean corpuscular Hb concentration, red 
cell distribution width, white blood cell count with differential (neutrophils, bands, 
lymphocytes, monocytes, eosinophils, and basophils), platelets, and automated reticulocyte 
count (both absolute and percent).  
Blood samples for CBC/Hb assessment will be collected with the patient in the supine 
position and prior to hemodialysis (per the Japanese Society for Dialysis Therapy [JSDT] 
guidelines).  As noted in Appendices 
Appendix A and Appendix B, the following visits will be scheduled for the first hemodialysis 
of the week:  
o For patients not prescribed ESAs:  Screening visit 1, screening visit 2, baseline 
visit/Day 1, Week 6, Week 16 
o For patients prescribed ESAs:  Screening visit 2, screening visit 3, baseline 
visit/Day 1, Week 6, Week 16 
As visit scheduling permits, effort should be made to try to schedule other visits for the first 
hemodialysis of the week, acknowledging that this may not be feasible due to subject or site 
scheduling constraints.  The CRF will describe how blood samples for central Hb analysis 
are drawn (ie, supine, prior to hemodialysis, on the day of the first hemodialysis session of 
the week).  
• Chemistry:  Including sodium, potassium, bicarbonate, chloride, calcium, phosphorus, 
glucose, creatinine, blood urea nitrogen, creatine phosphokinase, uric acid, albumin, total 
protein, total bilirubin, alkaline phosphatase, ALT (SGPT), AST (SGOT), lactate 
dehydrogenase (LDH), and total cholesterol.  Glucose will be measured using plasma 
samples and the other chemistry parameters will be measured using serum samples. 
• Iron indices:  Blood samples will be collected to assess serum iron, TIBC, TSAT, and ferritin. 
• Hepcidin:  Blood samples will be collected to assess hepcidin. 
• C-reactive protein:  Blood sample will be collected to assess C-reactive protein. 
• VEGF:  Blood sample will be collected to assess VEGF levels. 
• PK analysis:  Week 4 pre-dose sample will be analyzed for vadadustat and its metabolites.  
Study drug dose on this day should be held until after the pre-dose PK sample has been 
obtained.  After the labs are drawn, the subject should take their scheduled dose of study drug. 
Blood samples will be collected in tubes with K2EDTA anticoagulant, plasma prepared, and 
frozen within 1 hour of blood collection.  Analysis of samples for vadadustat and metabolite 
concentration determinations will be performed by a sponsor-designated contract research 
organization (CRO) using a validated Liquid Chromatography-Mass Spectrometry and 
Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) method.  Detailed 
instructions for collection, processing, storage, and shipment of the samples for PK and 
metabolite analyses will be provided by the sponsor or a designated laboratory. 


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9.4 
Schedule of Activities (For Subjects Who Were Not Prescribed ESAs Prior to Study 
Entry) 
The Schedule of Events in Appendices 
Appendix A shows the timing of planned study procedures.  Every effort should be made to 
adhere to this procedure schedule and all assessments should be completed at each study visit. 
Note:  The following visits will be scheduled on the day of the first hemodialysis session of the 
week, in keeping with JSDT Guidelines from Hb measurement:  Screening visit 1, screening 
visit 2, baseline visit (Day 1), Week 6, and Week 16.  As visit scheduling permits, effort should 
be made to try to schedule other visits on the day of the first hemodialysis session of the week, 
acknowledging that this may not be feasible due to subject or site scheduling constraints. 
Note:  Blood samples for CBC/Hb assessment should be collected with the patient in the supine 
position and prior to hemodialysis. 
See Section 7.4 for information regarding retesting and rescreening. 
9.4.1 Screening Visit 1 
This visit will be scheduled on the day of the first hemodialysis session of the week.  
Informed consent must be obtained and legally signed before performing any protocol-directed 
procedures (including screening tests). 
After obtaining informed consent and receiving a unique subject identification number, subjects 
will undergo screening procedures.  The investigator will maintain a log of subjects and indicate 
who was enrolled or excluded and the reason for exclusion (see Section 9.2.2). 
At screening visit 1, the following activities/procedures will be performed: 
• Signing of informed consent 
• Review study inclusion and exclusion criteria 
• Demographics, medical history, and physical examination 
• Vital signs 
• Dry weight 
• AE review 
• Laboratory procedures: 
o Serum pregnancy test for females of childbearing potential (eligible subjects will 
be advised to use an adequate contraceptive method).  The serum pregnancy test 
will be analyzed by the central lab.  The screening results must be available and 
must be negative before the subject takes the first dose of study drug.  
o Iron indices 
o Folate and vitamin B12 levels 
o CBC  
o Chemistry 


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9.4.2 Screening Visit 2 
This visit will be scheduled on the day of the first hemodialysis session of the week. 
At screening visit 2, the following activities/procedures will be performed: 
• Review study inclusion and exclusion criteria 
• Vital signs 
• Dry weight 
• AE review 
• Laboratory procedures: 
o Serum pregnancy test for females of childbearing potential (eligible subjects will 
be advised to use an adequate contraceptive method).  The serum pregnancy test 
must be performed within 4-8 days prior to visit 1/Day 1 to allow sufficient time 
to obtain the pregnancy test result prior to randomization, and the screening 
results must be available and must be negative before the subject takes the first 
dose of study drug.   In the event screening visit 2 is >8 days prior to Day 1, the 
subject will be asked to return to the study site for an unscheduled serum 
pregnancy test to verify eligibility prior to Day 1. The serum pregnancy test will 
be analyzed by the central lab.  
o CBC  
9.4.3 Baseline Visit (Day 1) 
This visit will be scheduled on the day of the first hemodialysis session of the week. 
At the baseline visit, the following activities/procedures will be performed: 
• Review study inclusion and exclusion criteria 
• Vital signs 
• Dry weight 
• Randomization 
• 12-lead ECG (prior to blood draws when possible and obtained after the subject has been 
resting supine comfortably for approximately 10 minutes) 
• Dialysis treatment review 
• Dialysis adequacy (Kt/V) 
• AE review 
• Laboratory procedures: 
o CBC 
o Iron indices 
o Chemistry 
o Coagulation tests 
o Hepcidin 
o C-reactive protein 
o VEGF 
• Concomitant medication review 
• Dispense one bottle of study drug 
• Review dosing instructions 


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9.4.4 Week 2 Visit 
At the Week 2 visit, the following activities/procedures will be performed: 
• Vital signs 
• Dry weight 
• Dialysis treatment review 
• AE review 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Laboratory procedures: 
o CBC 
o Iron indices 
o Chemistry 
• Concomitant medication review 
• Dispense study drug (as necessary) 
• Subjects should be questioned regarding dosing compliance 
• Review dosing instructions and remind subjects that they may be contacted by telephone 
to discuss dose reduction if central lab Hb result demonstrates excess Hb response  
• Remind/instruct subjects to hold their dose of study medication on the day of the Week 4 
visit until after the pre-dose PK blood sample has been collected 
• If central lab Hb result demonstrates excess Hb response, contact subject for dose 
reduction (Section 8.2.4)  
9.4.5 Week 4 Visit 
When possible, this visit should be scheduled in the morning due to the pre-dose PK evaluation.  
The morning dose of study medication should be held until after the pre-dose PK sample is 
drawn. 
At the Week 4 visit, the following activities/procedures will be performed: 
• Vital signs 
• Dry weight 
• Dialysis treatment review 
• AE review 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Laboratory procedures: 
o CBC 
o Chemistry 
o Iron indices 
o Pre-dose PK sample 
• Record date and time of the last dose of the study drug that was taken prior to the 
pre-dose PK sample 
• Concomitant medication review 
• Dispense study drug (as necessary) 
• Subjects should be questioned regarding dosing compliance 
• Review dosing instructions and remind subjects that they may be contacted by telephone 
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• If central lab Hb result demonstrates excess Hb response, contact subject for dose 
reduction (Section 8.2.4)  
9.4.6 Week 6 Visit 
This visit will be scheduled on the day of the first hemodialysis session of the week. 
At the Week 6 visit, the following activities/procedures will be performed: 
• Vital signs 
• Dry weight 
• Dialysis treatment review 
• AE review 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Laboratory procedures: 
o CBC 
o Chemistry 
o Iron indices 
o Hepcidin 
o C-reactive protein 
o VEGF 
• Concomitant medication review 
• Collect study bottle and all remaining study drug tablets remaining from the primary 
efficacy period (last dose to be taken on day of Week 6 visit) 
• Dispense one bottle of vadadustat (first dose to be taken day after Week 6 visit) 
• Subjects should be questioned regarding dosing compliance 
• Review dosing instructions and remind subjects that they may be contacted by telephone 
to discuss dose adjustment depending on central lab Hb result 
• If central lab Hb result obtained from this visit supports dose adjustment based on dose 
adjustment guidelines, contact subject for dose adjustment (Section 8.2.5) 
9.4.7 Week 8, 10, 12, 14 Visits 
At these visits, the following activities/procedures will be performed: 
• Vital signs (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
• Dry weight 
• Dialysis treatment review 
• AE review 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Concomitant medication review 
• Laboratory procedures: 
o CBC 
o Chemistry  
o Iron indices (Week 8 and Week 12 visits only) 
• Dispense vadadustat (as necessary) 
• Subjects should be questioned regarding dosing compliance 


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• Review dosing instructions and remind subjects that they may be contacted by telephone 
to discuss dose adjustment depending on central lab Hb result 
• If central lab Hb result obtained from this visit supports dose adjustment based on dose 
adjustment guidelines, contact subject for dose adjustment (Section 8.2.5) 
9.4.8 Week 16 Visit (End-of-Treatment Visit for Subjects Who Complete the Dose 
Adjustment and Maintenance Period or for Subjects Who Withdraw Early from the 
Study Prior to Week 16) 
This visit will be scheduled on the day of the first hemodialysis session of the week. 
All subjects should complete the Week 16 (end of treatment) assessments. 
Subjects who withdraw prematurely from the study prior to the Week 16 visit should undergo the 
clinical and laboratory assessments specified below within 1 day of stopping study medication, if 
possible.  Such subjects should also complete the requisite 2-week follow-up period (see 
Section 9.4.9). 
At the Week 16 visit, the following activities/procedures will be performed: 
• Vital signs 
• Dry weight 
• Dialysis treatment review 
• AE review (see Section 10.3.6 for follow-up of unresolved events) 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Laboratory procedures: 
o Serum pregnancy test 
o Iron indices 
o CBC 
o Chemistry 
o Hepcidin 
o C-reactive protein 
o VEGF 
• Concomitant medication review 
• Subjects should be questioned regarding dosing compliance 
9.4.9 Week 18 Follow-Up Visit (or 2 Weeks after End-of-Treatment Follow-Up Visit) 
For subjects who complete the dose adjustment and maintenance period, the follow-up visit will 
be conducted 2 weeks after their end-of-treatment visit (Week 16). 
For subjects who discontinue the study prematurely (ie, prior to Week 16), the follow-up visit 
will be conducted 2 weeks after their end-of-treatment visit. 
At the follow-up visit, the following activities/procedures will be performed: 
• Vital signs 
• Dry weight 
• AE review (see Section 10.3.6 for follow-up of unresolved events) 
• Rescue therapy (ESA rescue and RBC transfusion) review 


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• Laboratory procedures: 
o CBC 
o Chemistry 
9.5 
Schedule of Activities (For Patients Who Were Prescribed ESAs Prior to Study 
Entry) 
The Schedule of Events in Appendix B shows the timing of planned study procedures.  Every 
effort should be made to adhere to this procedure schedule and all assessments should be 
completed at each study visit. 
Note:  The following visits will be scheduled on the day of the first hemodialysis session of the 
week, in keeping with JSDT Guidelines from Hb measurement:  Screening visit 2, screening visit 
3, baseline visit, Week 6, and Week 16.  As visit scheduling permits, effort should be made to try 
to schedule other visits on the day of the first hemodialysis of the week, acknowledging that this 
may not be feasible due to subject or site scheduling constraints. 
Note:  Blood samples for Hb assessment should be collected with the patient in the supine 
position and prior to hemodialysis. 
See Section 7.4 for information regarding retesting and rescreening. 
9.5.1 Screening Visit 1 
Informed consent must be obtained and legally signed before performing any protocol-directed 
procedures (including screening tests). 
After obtaining informed consent and receiving a unique subject identification number, subjects 
will undergo several screening activities.  The investigator will maintain a log of subjects and 
indicate who was enrolled or excluded and the reason for exclusion (see Section 9.2.2). 
At this screening visit, the following activities/procedures will be performed: 
• Signing of informed consent 
• Review study inclusion and exclusion criteria 
• Demographics, medical history, and physical examination 
• Vital signs 
• Dry weight 
• AE review 
• Laboratory procedures: 
o Serum pregnancy test for females of childbearing potential (eligible subjects will be 
advised to use an adequate contraceptive method).  The serum pregnancy test will be 
analyzed by the central lab.  The screening results must be available and must be negative 
before the subject takes the first dose of study drug. 
o CBC 
o Chemistry 
o Iron indices 
o Folate and vitamin B12 
Subjects who remain eligible for the study after screening visit 1 will undergo ESA washout.  
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washout for 2 weeks prior to screening visit 2.  Subjects who were prescribed darbepoetin alfa 
will undergo ESA washout for 4 weeks prior to screening visit 2.  Subjects who were prescribed 
epoetin beta pegol will undergo ESA washout for 8 weeks prior to screening visit 2. 
9.5.2 Screening Visit 2 
This visit will be scheduled on the day of the first hemodialysis session of the week after the 
ESA washout periods described above. 
At this screening visit, the following activities/procedures will be performed: 
• Review study inclusion and exclusion criteria 
• Vital signs 
• Dry weight 
• AE review 
• Laboratory procedures: 
o CBC 
9.5.3 Screening Visit 3 
This visit will be scheduled on the day of the first hemodialysis session of the week. 
At screening visit 3, the following activities/procedures will be performed: 
• Review study inclusion and exclusion criteria 
• Vital signs 
• Dry weight 
• AE review 
• Laboratory procedures: 
o Serum pregnancy test for females of childbearing potential (eligible subjects will 
be advised to use an adequate contraceptive method).  The serum pregnancy test 
must be performed within 4-8 days prior visit 1/Day 1 to allow sufficient time to 
obtain the pregnancy test result prior to randomization, and the screening results 
must be available and must be negative before the subject takes the first dose of 
study drug. In the event screening visit 3 is >8 days prior to Day 1, the subject 
will be asked to return to the study site for an unscheduled serum pregnancy test 
to verify eligibility prior to Day 1. The serum pregnancy test will be analyzed by 
the central lab.   
o CBC  
9.5.4 Baseline Visit (Day 1) 
At the baseline visit, the following activities/procedures will be performed: 
• Review study inclusion and exclusion criteria 
• Vital signs 
• Dry weight 
• Randomization 
• 12-lead ECG (prior to blood draws when possible and obtained after the subject has been 
resting supine comfortably for approximately 10 minutes) 


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• Dialysis treatment review 
• Dialysis adequacy (Kt/V) 
• AE review 
• Laboratory procedures: 
o Iron indices 
o CBC 
o Chemistry 
o Coagulation tests 
o Hepcidin 
o C-reactive protein 
o VEGF 
• Concomitant medication review 
• Dispense one bottle of study drug 
• Review dosing instructions 
9.5.5 Week 2 Visit 
At the Week 2 visit, the following activities/procedures will be performed: 
• Vital signs 
• Dry weight 
• Dialysis treatment review 
• AE review 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Laboratory procedures: 
o CBC 
o Chemistry 
o Iron indices 
• Concomitant medication review 
• Dispense study drug (as necessary) 
• Subjects should be questioned regarding dosing compliance 
• Review dosing instructions and remind subjects that they may be contacted by telephone to 
discuss dose reduction if central lab Hb result demonstrates excess Hb response  
• Remind/instruct subjects to hold their dose of study medication on the day of the Week 4 
visit until after the pre-dose PK blood sample has been collected 
• If central lab Hb result demonstrates excess Hb response, contact subject for dose reduction 
(Section 8.2.4)  
9.5.6 Week 4 Visit 
When possible, this visit should be scheduled in the morning due to the pre-dose PK evaluation.  
The morning dose of study medication should be held until after the pre-dose PK sample is 
drawn. 
At the Week 4 visit, the following activities/procedures will be performed: 
• Vital signs 
• Dry weight 


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• Dialysis treatment review 
• AE review 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Laboratory procedures: 
o CBC 
o Chemistry 
o Iron indices 
o Pre-dose PK sample 
• Record date and time of the last dose of the study drug that was taken prior to the pre-dose 
PK sample 
• Concomitant medication review 
• Dispense blinded study drug (as necessary) 
• Subjects should be questioned regarding dosing compliance 
• Review dosing instructions and remind subjects that they may be contacted by telephone to 
discuss dose reduction if central lab Hb result demonstrates excess Hb response 
• If central lab Hb result demonstrates excess Hb response, contact subject for dose reduction 
(Section 8.2.4)  
9.5.7 Week 6 Visit 
This visit will be scheduled on the day of the first hemodialysis session of the week. 
At the Week 6 visit, the following activities/procedures will be performed: 
• Vital signs 
• Dry weight 
• Dialysis treatment review 
• AE review 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Laboratory procedures: 
o CBC 
o Chemistry 
o Iron indices 
o Hepcidin 
o C-reactive protein 
o VEGF 
• Concomitant medication review 
• Collect study bottle and all remaining study drug tablets remaining from the primary efficacy 
period (last dose to be taken on day of Week 6 visit) 
• Dispense one bottle of vadadustat (first dose to be taken day after Week 6 visit) 
• Subjects should be questioned regarding dosing compliance 
• Review dosing instructions and remind subjects that they may be contacted by telephone to 
discuss dose adjustment depending on central lab Hb result 
• If central lab Hb result obtained from this visit supports dose adjustment based on dose 
adjustment guidelines, contact subject for dose adjustment (Section 8.2.5) 


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9.5.8 Week 8, 10, 12, and 14 Visits 
At these visits, the following activities/procedures will be performed: 
• Vital signs  
• Dry weight 
• Dialysis treatment review 
• AE review 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Concomitant medication review 
• Laboratory procedures: 
o CBC 
o Chemistry 
o Iron indices (Week 8 and Week 12 visits only) 
• Dispense vadadustat (as necessary) 
• Subjects should be questioned regarding dosing compliance 
• Review dosing instructions and remind subjects that they may be contacted by telephone to 
discuss dose adjustment depending on central lab Hb result 
• If central lab Hb result obtained from this visit supports dose adjustment based on dose 
adjustment guidelines, contact subject for dose adjustment (Section 8.2.5) 
9.5.9 Week 16 Visit (End-of-Treatment Visit for Subjects Who Complete the Dose 
Adjustment and Maintenance Period or for Subjects Who Withdraw Early from the 
Study Prior to Week 16) 
This visit will be scheduled on the day of the first hemodialysis session of the week. 
All subjects should complete the Week 16 (end of treatment) assessments. 
Subjects who withdraw prematurely from the study prior to the Week 16 visit or permanently 
discontinue study medication prior to the Week 16 visit, should undergo the clinical and 
laboratory assessments specified below within 1 day of stopping study medication, if possible.  
Such subjects should also complete the requisite 2-week safety follow-up period (see 
Section 9.4.9). 
At the Week 16 visit, the following activities/procedures will be performed: 
• Vital signs 
• Dry weight 
• Dialysis treatment review 
• AE review (see Section 10.3.6 for follow-up of unresolved events) 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Laboratory procedures: 
o Serum pregnancy test 
o Iron indices 
o CBC 
o Chemistry 
o Hepcidin 
o C-reactive protein 


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o VEGF 
• Concomitant medication review 
• Subjects should be questioned regarding dosing compliance 
9.5.10  Week 18 Follow-Up Visit (or 2 Weeks after End-of-Treatment Follow-Up Visit) 
For subjects who complete the dose adjustment and maintenance period, the follow-up visit will 
be conducted 2 weeks after their end-of-treatment visit (Week 16). 
For subjects who discontinue the study prematurely (ie, prior to Week 16), the follow-up visit 
will be conducted 2 weeks after their end-of-treatment visit. 
At the follow-up visit, the following activities/procedures will be performed: 
• Vital signs 
• Dry weight 
• AE review (see Section 10.3.6 for follow-up of unresolved events) 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Laboratory procedures: 
o CBC 
o Chemistry 
10 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse Events (AEs) 
For the purposes of this study, an AE is any untoward medical occurrence (including a clinically 
significant abnormal laboratory finding) that occurs in the protocol-specified AE reporting 
period; the event does not necessarily have a causal relationship with that treatment or usage. 
An AE includes medical conditions, signs, and symptoms not previously observed in the subject 
that emerge during the protocol-specified AE reporting period, including signs or symptoms 
associated with pre-existing underlying conditions that were not present prior to the AE reporting 
period. 
Adverse events therefore include the following:  
• All AEs, whether suspected to be causally related to study drug or otherwise. 
• All AEs secondary to any medication overdose, medication error, abuse, withdrawal, 
sensitivity, or toxicity. 
• Illnesses apparently unrelated to study drug, including the worsening of a pre-existing illness 
(see paragraph below on Pre-existing Conditions). 
• Injury or accidents.  Note that if a medical condition is known to have caused the injury or 
accident (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). 


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• Laboratory abnormalities that require clinical intervention or further investigation (beyond 
ordering a repeat [confirmatory] test) unless they are associated with an already reported 
clinical event.  Laboratory abnormalities associated with a clinical event reported as an AE 
(eg, elevated liver enzymes in a subject with jaundice) should be described under 
‘Comments’ on the report of the clinical event rather than reported as separate AEs. 
The following guidelines are to be used when reporting AEs for this study: 
Medical Diagnoses – Whenever possible, a medical diagnosis term should be used to report AEs 
instead of signs and symptoms due to a common etiology, as determined by qualified medical 
study staff.  For example, pneumonia should be the reported AE term, instead of fever, dyspnea, 
etc., when the diagnosis has been established.  Signs and symptoms should be reported as event 
terms only when the medical diagnosis remains unknown, and revised to a medical diagnosis 
term once it has been established. 
Procedures – Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as AEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE.  For example, an acute 
appendicitis that begins during the AE reporting period should be reported as the AE and the 
resulting appendectomy noted under “Comments.” 
Pre-planned therapeutic procedures not associated with a new medical condition or worsening 
pre-existing condition should not be reported as AEs. 
Preexisting Conditions – In this study, a pre-existing condition (ie, a disorder present before the 
AE reporting period started and noted on the pre-treatment medical history/physical examination 
form) should not be reported as an AE unless the condition worsens or episodes increase in 
frequency during the AE reporting period. 
Abnormal Test Findings – All laboratory test results will be reviewed by the investigator.  The 
investigator will utilize his/her judgment in determining if out of range laboratory values are 
clinically significant and should denote this using the abbreviation “CS” on the laboratory report 
for source documentation.  Laboratory tests that are labeled as clinically significant should be 
reported as AEs, either separately or as part of a description of a symptomatic AE.  If there are 
significant changes in a laboratory report from a previous visit that are determined to be 
clinically significant, these should also be reported as AEs.  Any abnormal laboratory value 
which requires treatment or further diagnostic testing and/or results in discontinuation from study 
should be reported as AEs.  An expected laboratory abnormality from a condition that is part of 
the medical history is not considered clinically significant for the purposes of the study unless it 
represents a worsening of the condition. 
Abnormalities in ALT, AST and Total Bilirubin – Abnormalities in ALT, AST and total 
bilirubin should be reported to the sponsor’s medical monitor/medical director or CRO designee 
within 24 hours of awareness as an SAE with ‘other medically important event’ criterion selected, 
if the following conditions are met: 
• New elevation in ALT or AST >3 times the upper limit of normal (ULN), with or without an 
elevation of total serum bilirubin >2 times ULN, AND 
• No other reason was identified that explains the increased ALT/AST with or without an 
increased bilirubin (eg, viral hepatitis, acute liver disease). 


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If new elevations in ALT or AST > 3 times ULN, with or without an elevation of total serum 
bilirubin > 2 times ULN are identified, the following steps are to be taken: 
• Temporary discontinuation of study medication. 
• Repeat testing of ALT, AST, ALP and total bilirubin, to be completed within 48 to 72 hours 
to confirm the abnormalities and to determine trend. 
• Study medication should not be resumed until monitoring indicates abnormalities have 
resolved, are stable, or are not rapidly increasing. 
Worsening of Anemia – In this study, it is possible that some subjects may experience a 
worsening of anemia.  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. 
Kidney Transplantation – During this study, some subjects may receive a kidney transplant.  
Kidney transplantation will not be recorded as an AE. 
10.1.2 Serious Adverse Events (SAEs) 
Each AE must be classified by the investigator as SERIOUS or NONSERIOUS.  An AE that 
meets 1 or more of the following criteria/outcomes is classified as serious: 
• Death 
• Life-threatening (see paragraph below on Life-threatening) 
• In-patient hospitalization or prolongation of existing hospitalization (see paragraph below on 
Hospitalization) 
• Persistent or significant disability/incapacity (see paragraph below on Disability)  
• Congenital anomaly/birth defect 
• Is considered a medically important event not meeting the above criteria, but which may 
jeopardize a subject, or may require medical or surgical intervention to prevent one of the 
criteria listed in this definition. 
Serious also includes any other event that the investigator or sponsor judges to be serious.  If 
there is any doubt whether the information constitutes an AE or SAE, the information is to be 
treated as an SAE. 
Life-threatening – Any event in which the subject was at risk of death at the time of the event; 
‘life-threatening’ does not refer to an event which hypothetically might have caused death if it 
were more severe. 
Hospitalization – Hospitalization is defined as an overnight admission with observation of a 
minimum of 24 hours.  A hospitalization planned before the start of the study for a pre-existing 
condition that has not worsened during the AE reporting period does not constitute an SAE. 
Disability – Defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 


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10.2 
Eliciting Adverse Event Information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study subject.  In addition, each study subject will be questioned about AEs at each visit 
following the initiation of treatment. 
10.3 
Reporting 
Each AE is to be classified by the investigator as SERIOUS or NONSERIOUS. 
All AEs that occur in study subjects during the AE reporting period specified in the protocol 
must be reported, whether or not the event is considered related to study medication. 
10.3.1 Reporting Period 
The reporting period for all non-serious AEs and all SAEs not related to protocol procedures 
begins upon receiving the first dose of study medication and ends at the final protocol-required 
visit. 
SAEs that are assessed by the investigator to be related to protocol procedures (eg, ESA 
washout) must be reported after signing of the informed consent form. 
In addition, SAEs that occur after the protocol-defined AE reporting period that are considered to 
be related to the study medication should be recorded and reported to the sponsor’s medical 
monitor or CRO designee. 
10.3.2 Reporting AEs 
NONSERIOUS AEs are to be reported on the AE CRFs. 
10.3.3 Reporting SAEs 
Any SAE, regardless of causal relationship, must be reported to the sponsor’s medical 
monitor/medical director or CRO designee within 24 hours after the investigator becomes aware 
of the SAE.  Compliance with this time requirement is essential so that the sponsor may comply 
with its regulatory obligations. 
The initial SAE report should be completed as fully as possible but should contain, at a 
minimum: 
• Subject number/ID, sex, and age/date of birth 
• The date of report 
• Name of the reporter 
• Description of the event, including event term(s), seriousness criteria, and a clinical summary 
of the event 
• Causality assessment 
Information about all SAEs (either initial or follow-up information) should be collected and 
recorded in English on the SAE Report Form.  The investigator must assess the relationship to 
each specific component of the study treatment.  If the event meets serious criteria, SAE Report 
Form should be sent to the CRO via email or fax, or the investigator should call the CRO SAE 


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hotline within 24 hours of being made aware of the SAE (reference the site manual for contact 
information). 
The investigator must report follow-up information relating to an SAE to the sponsor’s medical 
monitor/medical director or CRO designee within 24 hours of awareness by submitting a new 
SAE Report Form.  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 are to be obtained, if 
possible, and sent to the CRO via email or fax. 
The sponsor and/or its designee are responsible for reporting SAEs to all applicable regulatory 
agencies and the central ethics committees within the required timeline. 
The investigators are responsible for submitting required safety information to their local 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) per local regulations.  
This information includes but is not limited to, any safety alert letter received from the sponsor 
and any SAEs occurring at their investigative site. 
10.3.4 Relationship to Study Medication 
The causal relationship of the AE to study medication will be assessed by both the investigator 
and the sponsor.   
The assessment of causal relationship to study drug should be evidence-based, and not based on 
the premise that all AEs are possibly causally related to study drug until proven otherwise.   
Examples of evidence that would suggest a causal relationship between the drug and the AE 
include the occurrence of an AE that is uncommon and known to be strongly associated with 
drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome), or an AE that is 
uncommon in the population exposed to the drug. 
The causal relationship of the AE is assessed using a binary system, and AEs are classified as 
either ‘related’ or ‘unrelated’: 
Related:  There is ‘reasonable possibility’ that the drug caused the AE.  The AE follows a 
reasonable temporal sequence from the time of drug administration.  There is supportive 
evidence (facts) to suggest a possible causal relationship, irrespective of the degree of certainty 
between the observed AE and the drug. 
Unrelated:  An AE does not follow a reasonable temporal sequence from administration of the 
product and/or there is no reasonable possibility that the drug caused the AE.  This assessment 
includes situations where the AE is related to other factors such as the subject’s clinical state, 
other therapeutic interventions, or concomitant drugs administered to the subject. 
Default assessments using the ‘related’ category without supportive evidence for a causal 
relationship to study drug is generally uninformative and does not contribute meaningfully to the 
development of the safety profile of the drug or to subject protection. 
Investigators are encouraged to choose the most plausible cause for the event(s) from the 
following list:  Medical history, lack of efficacy/worsening of treated condition, study treatment, 
other treatment (concomitant, or previous), withdrawal of study treatment, administration error, 
protocol-related procedure, others (specify). 


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10.3.5 Severity 
The investigator will assess each AE as either MILD, MODERATE, or SEVERE using the 
following guidelines to describe the maximum severity of the AE: 
• MILD:  Does not interfere with subject's usual function. 
• MODERATE:  Interferes to some extent with subject's usual function 
• SEVERE:  Interferes significantly with subject's usual function. 
Note that a severe AE is not necessarily a serious AE.  For example, a headache may be severe 
in intensity, but would not be classified as serious unless it met 1 of the criteria for serious events 
listed above. 
10.3.6 Follow-Up of Unresolved Events 
All AEs should be followed until they are resolved or the investigator assesses them as chronic 
or stable or the subject’s participation in the trial ends. 
In addition, all SAEs and those non-serious events assessed by the investigator as related to the 
study medication should continue to be followed even after the subject's participation in the trial 
is over.  Such events should be followed until they resolve or until the investigator assesses them 
as “chronic” or “stable.” Resolution of such events is to be documented on the appropriate CRF. 
10.3.7 Special Situations  
Certain safety events, called ‘Special Situations’, that occur in association with study 
medication(s) may require reporting.  These Special Situations include, but are not limited to, the 
following:  
• Overdose of the medicinal product  
• Suspected abuse/misuse of the medicinal product  
• Inadvertent or accidental exposure to the medicinal product  
• Medication error involving the medicinal product (with or without subject/patient exposure 
to the sponsor’s medicinal product, eg, name confusion)  
• Drug-drug interaction  
Special situations should be reported on the Special Situations CRF whether they result in an 
AE/SAE or not.  Special situations with associated AE/SAE should also be reported on the 
corresponding AE/SAE forms, following applicable AE or SAE process. 
10.4 
Exposure In Utero 
A pregnancy in a female subject must be confirmed by a positive serum β human chorionic 
gonadotropin (β-HCG) test. 
The study medication should be immediately discontinued once the pregnancy of a female study 
participant has been confirmed. 
If any study participant becomes or is found to be pregnant while receiving a study medication or 
within 30 days of discontinuing the study medication, the pregnancy must be recorded on the 


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Pregnancy Reporting Form/Exposure In Utero Form within 24 hours of awareness of the 
pregnancy and sent to the CRO via email or fax (reference the site manual for contact 
information). 
The Pregnancy Reporting Form/Exposure In Utero Form must be completed with all known 
information regarding the pregnancy at the time of reporting.  Investigative site personnel will 
update the form with additional information regarding the pregnancy and the outcome of the 
pregnancy as it becomes available until the outcome of the pregnancy is reported. 
Pregnancy during this time frame of the female partner of a male subject should also be 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 immediate classification as 
an SAE (ie, spontaneous abortion, stillbirth, neonatal death within 1 month of birth, or congenital 
anomaly [including that in an aborted fetus]), the investigator should 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. 
• Neonates should be followed through gestational age of 46 weeks. 
• Follow-up information includes the course, duration and the outcome of the pregnancy and 
the neonate’s health. 
• 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 study medication should also be 
reported. 
• In the case of a live birth, the “normality” of the newborn can be assessed at time of birth. 
• The “normality” of an aborted fetus can be assessed by gross visual inspection unless there 
are pre-abortion laboratory findings suggestive of a congenital anomaly. 
11 
DATA ANALYSIS 
An overview of the statistical approach to the primary endpoint and safety analyses are provided 
below.  The details of the planned analysis of the primary endpoint as well as the planned 
analyses of secondary endpoints, PK, PD, and safety will be documented in the statistical 
analysis plan (SAP). 
11.1 
Primary Endpoint – Mean Change in Hb from Pre-treatment to the End of the 
Primary Efficacy Period (Week 6)  
The primary objective of this study is to evaluate the dose-response relationship between oral 
vadadustat once daily dosing for 6 weeks and the change in Hb in Japanese subjects with anemia 
secondary to DD-CKD; this is to define the starting dose for use in Phase 3 clinical studies in 
Japan.   


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The primary endpoint is the mean change in Hb from pre-treatment to the end of the primary 
efficacy period (Week 6).  Pre-treatment Hb is defined as the average of 3 Hb values obtained 
prior to treatment based on 2 qualifying screening Hb values and the Hb value at the baseline 
visit (Day 1). 
11.2 
Primary Efficacy Analysis and Sample Size Determination 
An analysis of covariance (ANCOVA) model will be used to compare change from pre-
treatment in Hb between the three vadadustat dosing groups and the placebo group.  The model 
will include treatment assignment (3 dosed groups and one placebo group) and pre-treatment Hb 
value as a covariate.  A step-down procedure will be used to control the overall type I error rate 
for the multiple comparisons.  Testing of the highest dose compared with placebo will be 
conducted first.  If and only if this comparison is significant, then testing will proceed to 
comparison of the next lower dose and placebo, and so on.  Thus, no multiplicity adjustment will 
be needed for this analysis. 
The sample size and power calculations are based on results from Study AKB-6548-CI-0005 that 
was conducted in the United States and evaluated vadadustat in patients with anemia secondary 
to non-dialysis-dependent CKD.  It is reasonable to extrapolate these data to the current study 
based on the following findings: 
• PK parameters of vadadustat are similar between CKD patients who are receiving 
hemodialysis (Study AKB-6548-CI-0009) and CKD patients who are not receiving dialysis 
(Study AKB-6548-CI-0003) 
• Hemodialysis procedure has no significant impact on the PK of vadadustat 
(Study AKB-6548-CI-0009) 
• The dose range of 150-600 mg of vadadustat to be used in the current study has been shown 
to be generally well-tolerated, and efficacious in raising and/or maintaining Hb at the desired 
target level in CKD patients who were either on hemodialysis (Study AKB-6548-CI-0011) or 
CKD patients who were not on dialysis (Studies AKB-6548-CI-0005 and 
AKB-6548-CI-0007) 
The target enrollment will be approximately 48 subjects for the study with 12 subjects enrolled 
in each of the 4 treatment groups. 
The study is powered based on a comparison of the highest dose vadadustat group (600 mg 
daily) and the placebo group. 
Based on the results from Study AKB-6548-CI-0005 that was conducted in the United States and 
evaluated vadadustat in patients with anemia secondary to NDD-CKD, it is assumed that the 
expected mean Hb changes from pre-treatment to Week 6 will be approximately 0 mg/dL for the 
placebo group and 1.35 g/dL for the highest dose vadadustat group (600 mg daily).  
Based on the results from Study AKB-6548-CI-0011 that was conducted in the United States and 
evaluated vadadustat in patients with anemia secondary to DD-CKD, it is assumed that the 
common Hb standard deviation will be 0.9 g/dL across treatment groups.  In addition, a dropout 
rate of 10% is assumed.  With these assumptions, the study with n=12 subjects per group will 
have >85% power to detect the difference between treatment group and control group, at 2-sided 
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11.3 
Preliminary (6-Week) Analysis 
In addition to the final analysis which will take place when all subjects have completed the study 
and will include all data collected, the 6-week efficacy and safety data will be summarized for 
administrative planning purposes after the last patient completes the primary efficacy period 
(Week 6).  The preliminary analysis will be performed and interpreted by the sponsor and CRO 
study team personnel.  Subjects and sites will not be unblinded to treatment allocation.  
Individuals from the sponsor and CRO study teams who are unblinded for the development and 
reporting of the preliminary analysis will not be involved in the conduct of the study after the 
preliminary analysis.  As the study conduct and final analysis will not be modified by this 
analysis, no alpha adjustment is proposed.  It is expected that this 6-week data will be identical 
for the preliminary administrative analysis and the final analysis of the complete dataset.  Any 
changes between the preliminary analysis and the final analysis will be documented. 
11.4 
Study Populations 
11.4.1 Analysis Population for the Safety Analyses 
The safety population is defined as all enrolled subjects who receive at least 1 dose of study 
medication.  The safety population will be based on the actual treatment that patients received.  
All safety analyses will be performed using the safety population. 
11.4.2 Analysis Populations for the Efficacy Analyses 
The modified intent-to-treat (MITT) population is defined as all randomized subjects who 
receive at least 1 dose of study medication, have a pre-treatment Hb average, and at least one 
post-baseline Hb measurement.  A pre-treatment average value for Hb is defined as the average 
of 3 values obtained prior to dosing, ie, the 2 qualifying screening values and the baseline value.  
The MITT population will be based on the treatment to which patients are randomized. 
The per-protocol (PP) population will consist of the subjects in the MITT population who have 
completed the study and have efficacy data through Week 6, have a study medication 
compliance of ≥80%, and do not have any major protocol deviations expected to significantly 
affect the primary efficacy endpoint.  Subjects with major protocol deviations expected to 
significantly affect the primary efficacy endpoint will be identified and documented prior to data 
unblinding. 
As sensitivity analyses, efficacy endpoints will also be analyzed using the PP population. 
11.5 
Analysis of Demographics and Pretreatment Variables 
Descriptive statistics (eg, number of subjects, mean, standard deviation (SD), median, minimum, 
and maximum) will be generated for selected continuous variables (including age, selected 
laboratory assays, and vital signs).  The number and percentage of subjects in each class of 
categorical demographic and baseline variables (eg, gender, ethnicity, race, and CKD stage) will 
be tabulated.  Individual subject demographic and baseline characteristic data will be listed. 
11.6 
Disposition of Subjects 
The number of subjects who are randomized, discontinued, or complete the study and reasons for 
discontinuation will be summarized in tabular format. 


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11.7 
Safety Analyses 
The reporting of safety data is descriptive, and will include all subjects who receive at least one 
dose of study medication.  The following variables are the safety endpoints:  Adverse events, 
vital signs, ECGs, and laboratory parameters. 
AEs will be summarized based on the frequency of AEs and their severity for all treated subjects.  
Overall safety and tolerability will be assessed with treatment-emergent AEs, laboratory results, 
and other safety variables including summaries of vital signs and ECGs.  As appropriate, 
summaries may also include change from baseline and shift tables.  All AEs will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by dose level.  
Data will be summarized using preferred term and primary system organ class. 
12 
DATA HANDLING AND RECORD KEEPING 
12.1 
Case Report Forms (CRFs) 
This study will utilize an EDC system to manage data collection during this trial.  The system is 
fully Code of Federal Regulations 21 part 11 compliant.  An EDC system contains certain 
functionality including, but not limited to, a graphical user interface to help facilitate data entry, 
a data validation element to check user data, and a reporting function to assist with the review 
and analysis of data.  CRFs available through this system are required and should be completed 
for each randomized subject. 
Any form of data from the electronic system are the sole property of the sponsor and should not 
be made available in any form to third parties, except for authorized representatives of the 
sponsor or appropriate regulatory authorities, without written permission from the sponsor. 
The investigator has ultimate responsibility for the accuracy, authenticity, and timely collection 
and reporting of all clinical, safety, and laboratory data entered in the EDC or any other data 
collection forms.  The CRFs must be signed electronically by the Investigator to attest that the 
data contained on the CRFs is true. 
In most cases, the source documents are contained in the subject’s chart at the hospital or the 
physician's office.  In these cases, data collected on the CRFs must match the data in those charts. 
12.2 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or the sponsor, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, eg, CRFs and hospital records), all original signed Informed Consent Forms, 
copies of all CRFs, SAE forms, source documents, detailed records of drug disposition, and 
adequate documentation of relevant correspondence (eg, letters, meeting minutes, telephone calls 
reports).  The records should be retained by the investigator according to the International 
Conference on Harmonisation (ICH), local regulations, or as specified in the Clinical Study 
Agreement, whichever is longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), the sponsor should be prospectively notified.  The 
study records must be transferred to a designee acceptable to the sponsor, such as another 


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investigator, another institution, or to the sponsor.  The investigator must obtain sponsor’s 
written permission before disposing of any records, even if retention requirements have been met. 
13 
QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) 
13.1 
Study Site Monitoring Visits 
During study conduct, the sponsor or its designee will conduct periodic monitoring visits to 
ensure that the protocol and Good Clinical Practice (GCP) are being followed.  The monitors will 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
investigator/institution will allow the sponsor’s monitors or designees and appropriate regulatory 
authorities direct access to source documents to perform this verification. 
The study site may also be subject to quality assurance audits performed by the sponsor or its 
designees, and/or review by the IRB/IEC, and/or to inspection by appropriate regulatory 
authorities. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
13.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects.  Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
The site should document all protocol deviations in the subject’s source documents.  In the event 
of a major protocol deviation, the site should notify the sponsor or its designee (and IRB or IEC, 
as required).  Major protocol deviations include, but are not limited to, those that involve fraud 
or misconduct, increase the health risk to the subject, or confound interpretation of primary study 
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14 STUDY DISCONTINUATION/INVESTIGATIVE STUDY SITE TERMINATION 
The sponsor reserves the right to discontinue the trial prior to inclusion of the intended number 
of subjects, but intends only to exercise this right for valid scientific or administrative reasons.  
After such a decision, the investigator must contact all participating subjects within a time period 
specified by the sponsor to inform them of the decision to discontinue the trial. 
14.1 
Criteria for Premature Termination or Suspension of the Study 
The following criteria may result in either temporary suspension or early termination of the 
study: 
• New information regarding the safety or efficacy of the study medication that indicates a 
change in the known risk/benefit profile for the compound, such that the risk/benefit is no 
longer acceptable for subjects participating in the study. 
• Major violation of GCP that compromises the ability to achieve the primary study objectives 
or compromises subject safety. 
The sponsor reserves the right to discontinue the trial for other valid administrative reasons. 
14.2 
Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found to be in major violation of GCP, protocol, contractual agreement, or is unable to ensure 
adequate performance of the study. 
14.3 
Procedures for Premature Termination or Suspension of the Study or 
Investigational Site(s) 
In the event that the sponsor elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites 
during the course of termination or study suspension. 
15 
ETHICS 
15.1 
Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical Principles 
for Medical Research Involving Human Subjects, adopted by the General Assembly of the World 
Medical Association (2013). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws. 
15.2 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, (eg, recruitment 
advertisements, if applicable) from the IRB/IEC.  All correspondence with the IRB/IEC should 


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be retained in the Investigator File.  Copies of IRB/IEC approvals should be forwarded to the 
sponsor. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In that 
event, the investigator must notify the IRB/IEC and the sponsor in writing immediately after the 
implementation. 
15.3 
Subject Information and Consent 
Prior to inclusion in the study, it is the responsibility of the investigator to give each subject (or 
the subject’s acceptable representative) full and adequate verbal and written information 
regarding the objective and procedures of the trial and the possible risks involved.  The subjects 
must be informed about their right to withdraw from the trial at any time.   
Furthermore, it is the responsibility of the investigator, or a person designated by the investigator, 
to obtain signed informed consent from each subject or the subject’s legally acceptable 
representative prior to inclusion in the trial.  The investigator will retain the original of each 
subject's signed consent form. 
The informed consent form must be in compliance with ICH GCP, local regulatory requirements, 
and legal requirements.  The informed consent form used in this study, and any changes made 
during the study, must be prospectively approved by both the IRB/IEC and sponsor before use. 
15.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
Competent Authority, or if the investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of the investigational product, the sponsor 
should be informed immediately.   
In addition, the investigator will inform the sponsor immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP that comes to the attention of the investigator. 
15.5 
Subject Confidentiality 
All parties will ensure protection of subject personal data and will not include subject names on 
any sponsor forms, reports, publications, or in any other disclosures, except where required by 
law.  In case of data transfer, the sponsor will maintain high standards of confidentiality and 
protection of subject personal data. 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy.  Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number.  As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, US FDA), the sponsor’s designated auditors, and the 


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appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports.  Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process. 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s CRF). 
16 
PUBLICATION OF STUDY RESULTS 
No publication or disclosure of study results will be permitted, except under the terms and 
conditions of a separate, written agreement between sponsor and the investigator and/or the 
investigator’s institution.  The sponsor must have the opportunity to review and approve all 
proposed abstracts, manuscripts, or presentations regarding this study prior to submission for 
publication/presentation.  Any information identified by the sponsor as confidential must be 
deleted prior to submission. 
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including:  Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors. 
 
 


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17 
REFERENCES 
Besarab A, Bolton WK, Browne JK, 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;339:584-90. 
Bigham AW, Lee FS. Human high-altitude adaptation: forward genetics meets the HIF pathway. 
Genes Dev 2014;28:2189-204. 
Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with 
chronic kidney disease and anemia. N Engl J Med 2006;355:2071-84. 
Goodkin DA, Fuller DS, Robinson BM, et al. Naturally occurring higher hemoglobin 
concentration does not increase mortality among hemodialysis patients. J Am Soc Nephrol 
2011;22:358-65. 
Haase VH. Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev 2013;27:41-53. 
Imai E, Yasuda Y, Makino H. Japan Association of Chronic Kidney Diease Initiatives (J-CKDI). 
JMAJ 2011;54:403-5. 
Iseki K. Chronic Kidney Disease in Japan. Internal Medicine 2008;47:681-9. 
Iseki K, Kohagura K. Anemia as a risk factor for chronic kidney disease. Kidney Int Suppl 
2007;107:S4-9. 
JSN. Japanese Society of Nephrology, Evidence-Based Clinical Practice Guideline for CKD 
2013. Clin Exp Nephrol 2014;18:346-423. 
KDIGO. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int 
2012;2:1-64. 
Liu Q, Davidoff O, Niss K, et al. Hypoxia-inducible factor regulates hepcidin via erythropoietin-
induced erythropoiesis. J Clin Invest 2012;122:4635-44. 
Locatelli F, Barany P, Covic A, 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;28:1346-59. 
McCullough PA, Barnhart HX, Inrig JK, et al. Cardiovascular toxicity of epoetin-alfa in patients 
with chronic kidney disease. Am J Nephrol 2013;37:549-58. 
Metivier F, Marchais SJ, Guerin AP, et al. Pathophysiology of anaemia: focus on the heart and 
blood vessels. Nephrol Dial Transplant 2000;15 Suppl 3:14-8. 
NICE. Anaemia management in people with chronic kidney disease. National Institute for 
Health and Care Excellence 20111-39. 
NKF. National Kidney Foundation, K/DOQI Clinical Practice Guidelines for Chronic Kidney 
Disease: Evaluation, Classification and Stratification. Am J Kidney Dis 2002;39:S1-S266. 
Nurko S. Anemia in chronic kidney disease: causes, diagnosis, treatment. Cleve Clin J Med 
2006;73:289-97. 


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Peyssonnaux C, Zinkernagel AS, Schuepbach RA, et al. Regulation of iron homeostasis by the 
hypoxia-inducible transcription factors (HIFs). J Clin Invest 2007;117:1926-32. 
Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and 
chronic kidney disease. N Engl J Med 2009a;361:2019-32. 
Pfeffer MA, Burdmann EA, Chen CY, et al. Baseline characteristics in the Trial to Reduce 
Cardiovascular Events With Aranesp Therapy (TREAT). Am J Kidney Dis 2009b;54:59-69. 
Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney 
disease. N Engl J Med 2006;355:2085-98. 
Solomon SD, Uno H, Lewis EF, et al. Erythropoietic response and outcomes in kidney disease 
and type 2 diabetes. N Engl J Med 2010;363:1146-55. 
Stauffer ME, Fan T. Prevalence of anemia in chronic kidney disease in the United States. PLoS 
One 2014;9:e84943. 
Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetin-alpha 
dose and achieved hemoglobin outcomes. Kidney Int 2008;74:791-8. 
Tacchini L, Bianchi L, Bernelli-Zazzera A, et al. Transferrin receptor induction by hypoxia. HIF-
1-mediated transcriptional activation and cell-specific post-transcriptional regulation. J Biol 
Chem 1999;274:24142-6. 
Unger EF, Thompson AM, Blank MJ, et al. Erythropoiesis-stimulating agents--time for a 
reevaluation. N Engl J Med 2010;362:189-92. 
 
 


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18 APPENDICES 
APPENDIX A:  SCHEDULE OF ACTIVITIES FOR SUBJECTS WHO WERE NOT PRESCRIBED ESAS PRIOR 
TO STUDY ENTRY 
Please refer to Section 9.1 for information regarding the visit schedule (including duration of the screening period), Section 9.3 for 
detailed information regarding the study procedures and evaluations, and Section 9.4 for detailed information regarding the activities 
to be performed at each study visit. 
Screening Visits and 
Study Week 
Screening period 
(Week -4 to 0) 
Primary efficacy period  
(Day 1-Week 6) 
Dose adjustment and maintenance period  
(Week 7-16) 
Follow-up 
(Week 17-
18) 
SV1 [a] 
SV2 [a] 
BV [a] 
2 
4 
6 [a] 
8 
10 
12 
14 
16 (EOT) 
18 
Study Day 
SV2 ≥4 days from SV1 
BV ≥4 days from SV2 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
Visit Window (Days) 
― 
― 
― 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion/ 
exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics, 
medical history, 
physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, dry 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
12-lead ECG 
 
 
X 
 
 
 
 
 
 
 
 
 
Dialysis treatment 
review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dialysis adequacy 
(Kt/V) 
 
 
X 
 
 
 
 
 
 
 
 
 
Adverse event review 
[b] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Rescue therapy (ESA 
rescue and RBC 
transfusion) review 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Screening Visits and 
Study Week 
Screening period 
(Week -4 to 0) 
Primary efficacy period  
(Day 1-Week 6) 
Dose adjustment and maintenance period  
(Week 7-16) 
Follow-up 
(Week 17-
18) 
SV1 [a] 
SV2 [a] 
BV [a] 
2 
4 
6 [a] 
8 
10 
12 
14 
16 (EOT) 
18 
Study Day 
SV2 ≥4 days from SV1 
BV ≥4 days from SV2 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
Serum pregnancy test 
[c] 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Iron indices 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Folate and vitamin 
B12 
X 
 
 
 
 
 
 
 
 
 
 
 
CBC including Hb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation tests 
 
 
X 
 
 
 
 
 
 
 
 
 
Hepcidin 
 
 
X 
 
 
X 
 
 
 
 
X 
 
C-reactive protein 
 
 
X 
 
 
X 
 
 
 
 
X 
 
VEGF 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Pre-dose PK sample 
 
 
 
 
X 
 
 
 
 
 
 
 
Concomitant 
medication review 
 
 
X  
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug 
dispensation 
 
 
X 
 
 
 
 
 
 
 
 
 
Study drug 
dispensation, as 
necessary 
 
 
 
X 
X 
 
 
 
 
 
 
 
Vadadustat 
dispensation 
 
 
 
 
 
X 
 
 
 
 
 
 
Vadadustat 
dispensation, as 
necessary 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
Review dosing 
instructions 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study drug 
compliance check 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
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Page 75 of 79 
Screening Visits and 
Study Week 
Screening period 
(Week -4 to 0) 
Primary efficacy period  
(Day 1-Week 6) 
Dose adjustment and maintenance period  
(Week 7-16) 
Follow-up 
(Week 17-
18) 
SV1 [a] 
SV2 [a] 
BV [a] 
2 
4 
6 [a] 
8 
10 
12 
14 
16 (EOT) 
18 
Study Day 
SV2 ≥4 days from SV1 
BV ≥4 days from SV2 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
Based on Hb results 
from the visits noted, 
dose reduction for 
excess Hb response as 
needed (Section 8.2.4) 
 
 
 
X 
X 
 
 
 
 
 
 
 
Based on Hb results 
from the visits noted, 
dose adjustment to 
achieve target Hb 
10-12 g/dL 
(Section 8.2.5) 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
Abbreviations: BV, baseline visit; CBC, complete blood count; ECG, electrocardiogram; EOT, end of treatment; ESA, erythropoietin-stimulating agent; 
Hb, hemoglobin; PK, pharmacokinetics; RBC, red blood cells; SV1, screening visit 1; SV2, screening visit 2; VEGF, vascular endothelial growth factor 
[a] The following visits will be scheduled on the day of the first hemodialysis session of the week, in keeping with JSDT Guidelines from Hb measurement:  
Screening visit 1, screening visit 2, baseline visit, Week 6, and Week 16.  As visit scheduling permits, effort should be made to try to schedule other visits on 
the day of the first hemodialysis session of the week, acknowledging that this may not be feasible due to subject or site scheduling constraints. 
[b] SAEs that are deemed by the investigator to be related to protocol procedures must be reported after signing of the informed consent form.  The reporting 
period for all non-serious AEs and all SAEs not related to protocol procedures begins upon receiving the first dose of study medication and ends at the final 
protocol-required visit. 
[c]   In the event screening visit 2 is >8 days prior to Day 1, the subject will be asked to return to the study site for an unscheduled serum pregnancy test to verify 
eligibility prior to Day 1. 
 
 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
76 
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Page 76 of 79 
APPENDIX B: SCHEDULE OF ACTIVITIES FOR SUBJECTS WHO WERE PRESCRIBED ESAS PRIOR TO 
STUDY ENTRY (ESA WASHOUT IS REQUIRED) 
Please refer to Section 9.1 for information regarding the visit schedule (including duration of the screening period and the washout 
period), Section 9.3 for detailed information regarding the study procedures and evaluations, and Section 9.5 for detailed information 
regarding the activities to be performed at each study visit. 
• For subjects who were prescribed epoetin alfa, epoetin beta, and epoetin kappa prior to study entry:  Screening visits must be 
performed within 6 weeks (Day -42 to Day 0) prior to dosing on baseline visit (BV); screening visit 2 (SV2) after ≥2-weeks 
ESA washout; SV3 should be ≥4 days from SV2; and BV should be ≥4 days from SV3. 
• For subjects who were prescribed darbepoetin alfa prior to study entry:  Screening visits must be performed within 8 weeks 
(Day -56 to Day 0) prior to dosing on Day 1; SV2 after ≥4-wk ESA washout; SV3 should be ≥4 days from SV2; and BV 
should be ≥4 days from SV3. 
• For subjects who were prescribed epoetin beta pegol prior to study entry:  Screening visits must be performed within 11 weeks 
(Day -77 to Day 0) prior to dosing on Day 1; SV2 after ≥8-wk ESA washout; SV3 should be ≥4 days from SV2; and BV 
should be ≥4 days from SV3. 
Screening Visits 
and Study Week  
Screening period 
Primary efficacy period  
(Day 1-Week 6) 
Drug adjustment and maintenance period 
(Week 7-16) 
Follow-up  
(Week 17-18) 
SV1 
SV2 
[a] 
SV3 
[a] 
BV [a] 
2 
4 
6 [a] 
8 
10 
12 
14 
16 (EOT) 
18 
Study Day 
See bullet points above 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
Visit Window 
(Days) 
― 
― 
― 
― 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion/ 
exclusion criteria 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics, 
medical history, 
physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, dry 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
 
12-lead ECG 
 
 
 
X 
 
 
 
 
 
 
 
 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
77 
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Page 77 of 79 
Screening Visits 
and Study Week  
Screening period 
Primary efficacy period  
(Day 1-Week 6) 
Drug adjustment and maintenance period 
(Week 7-16) 
Follow-up  
(Week 17-18) 
SV1 
SV2 
[a] 
SV3 
[a] 
BV [a] 
2 
4 
6 [a] 
8 
10 
12 
14 
16 (EOT) 
18 
Dialysis treatment 
review 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dialysis adequacy 
(Kt/V) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Adverse event 
review [b] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Rescue therapy 
(ESA rescue and 
RBC transfusion) 
review 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy 
test  
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
Iron indices 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Folate and 
vitamin B12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC including 
Hb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation tests 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Hepcidin 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
C-reactive protein 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
VEGF 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
Pre-dose PK 
sample 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Concomitant 
medication 
review 
 
 
 
X  
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug 
dispensation 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Study drug 
dispensation, as 
necessary 
 
 
 
 
X 
X 
 
 
 
 
 
 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
Protocol Version 2 
 
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Screening Visits 
and Study Week  
Screening period 
Primary efficacy period  
(Day 1-Week 6) 
Drug adjustment and maintenance period 
(Week 7-16) 
Follow-up  
(Week 17-18) 
SV1 
SV2 
[a] 
SV3 
[a] 
BV [a] 
2 
4 
6 [a] 
8 
10 
12 
14 
16 (EOT) 
18 
Vadadustat 
dispensation 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Vadadustat 
dispensation, as 
necessary 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
Review dosing 
instructions 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study drug 
compliance check 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Based on Hb 
results from the 
visits noted, dose 
reduction for 
excess Hb 
response as 
needed 
(Section 8.2.4) 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
Based on Hb 
results from the 
visits noted, dose 
adjustment to 
achieve target Hb 
10-12 g/dL 
(Section 8.2.5) 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
Abbreviations: BV, baseline visit; CBC, complete blood count; ECG, electrocardiogram; EOT, end of treatment; ESA, erythropoietin-stimulating agent; 
Hb, hemoglobin; PK, pharmacokinetics; SV1, screening visit 1; SV2, screening visit 2; SV3, screening visit 3; VEGF, vascular endothelial growth factor 
[a] The following visits will be scheduled on the day of the first hemodialysis session of the week, in keeping with JSDT Guidelines from Hb measurement:  
Screening visit 2, screening visit 3, baseline visit, Week 6, and Week 16.  As visit scheduling permits, effort should be made to try to schedule other visits on 
the day of the first hemodialysis of the week, acknowledging that this may not be feasible due to subject or site scheduling constraints. 
[b] SAEs that are deemed by the investigator to be related to protocol procedures (eg, ESA washout) must be reported after signing of the informed consent 
form.  The reporting period for all non-serious AEs and all SAEs not related to protocol procedures begins upon receiving the first dose of study medication 
and ends at the final protocol-required visit. 
[c]   In the event screening visit 3 is >8 days prior to Day 1, the subject will be asked to return to the study site for an unscheduled serum pregnancy test to verify 
eligibility prior to Day 1.  


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Protocol No. AKB-6548-CI-0022 
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Protocol Version 2 
 
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APPENDIX C: DEFINITIONS OF ESA STATUS INCLUSION CRITERIA AND ESA WASHOUT PERIOD 
 
  
ESA use
ESA washout*
SV1
SV2
SV3
Baseline Visit
ESA use
ESA washout
ESA use
ESA washout
SV1
SV2
No prior ESA use
Baseline Visit
No ESA washout required
SV1
SV2
Baseline Visit
No ESA washout required
ESA use
ESA washout*
SV1
SV2
SV3
Baseline Visit
Subjects who are not being treated with ESAs:
Subjects who are being treated with ESAs:
Example 1:
Example 2:
Example 1:
Example 2:
Last ESA dose before SV1 <2w for epoetin alfa, beta, or kappa; 
<4w for darbepoetin alfa; or <8w for epoetin beta pegol
Last ESA dose before SV1 ≥2w for epoetin alfa, beta, or kappa; 
≥4w for darbepoetin alfa; or ≥8w for epoetin beta pegol
*After SV1 and before SV2, ≥2w off of epoetin alfa, beta, or kappa; ≥4w off of darbepoetin alfa; or ≥8w off of epoetin beta pegol


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Akebia Therapeutics, Inc. 
 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
 
Summary of Changes to Protocol Version 1 
 
 
Confidential 
Page 2 of 22 
2 
SPECIFIC CHANGES 
Amendments to the protocol are detailed below, except for editorial changes and minor clarification changes.  If it is necessary to clarify the edits, 
newly added text is identified using bold underlined font and deleted text is identified by strikethrough font. 
Protocol Section 
Text in Version 1 
Changes in Version 2 
Rationale for Change 
Synopsis, overview of 
Study Design,  
Synopsis, Dosage and 
Regimen 
8.2.4, Study Drug 
Administration during the 
Primary Efficacy Period 
(Week 1 to Week 6) 
  
Fixed dose treatment during the 
primary efficacy period will allow a 
dose response relationship to be 
established.  No increase in study drug 
dose is permitted during this period.  
However, if Hb level increases rapidly 
or if the Hb level exceed the desired 
range, the study drug dose can be 
decreased or interrupted following the 
dose adjustment guidelines listed under 
“Dosage and Regimen” (see below). 
The primary efficacy period involves 
fixed-dose treatment to establish a 
dose-response relationship.  No 
increase in study drug dose is permitted 
during this period.  However, if Hb 
levels increase too rapidly or if Hb 
levels exceed the desired range based 
on Hb results from the Week 2 and/or 
Week 4 study visits, the study drug 
dose will be decreased as described 
below. 
 
If the Hb rises rapidly (eg, 
more than 1 g/dL in any 
2-week period), reduce the 
dose by 1 tablet. 
 
If the Hb exceeds 13.0 g/dL, 
interrupt study drug until the 
Hb decreases to 12.5 g/dL or 
below and then resume dosing 
with 1 fewer tablet.   
Fixed dose treatment during the 
primary efficacy period will allow a 
dose response relationship to be 
established.  No increase in study drug 
dose is permitted during this period.  
However, if Hb level increases rapidly 
or if the Hb level exceeds 13.0g/dL the 
study drug dose can be decreased or 
interrupted following the dose 
adjustment guidelines listed under 
“Dosage and Regimen” (see below). 
The primary efficacy period involves 
fixed-dose treatment to establish a 
dose-response relationship.  No 
increase in study drug dose is permitted 
during this period.  However, the dose 
may be decreased or interrupted as 
described below. 
 
If the Hb increases rapidly (eg, 
more than 1 g/dL in any 
2-week period), reduce the 
dose by 1 tablet. 
 
If the Hb exceeds 13.0 g/dL, 
interrupt study drug until the 
Hb decreases to 12.5 g/dL or 
below and then resume dosing 
with 1 fewer tablet 
If dose reduction or interruption is 
recommended based on the central 
laboratory Hb result and protocol-
specified guidelines, the investigative 
site will contact the subject within 1 
To clarify the Hb level at which the dose 
will be interrupted (>13.0 g/dL) 


Akebia Therapeutics, Inc. 
 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
 
Summary of Changes to Protocol Version 1 
 
 
Confidential 
Page 3 of 22 
If dose reduction is recommended 
based on the central laboratory Hb 
result and protocol-specified guidelines, 
the investigative site will contact the 
subject within 1 business day of 
receiving the Hb result from the central 
laboratory.   
business day of receiving the Hb result 
from the central laboratory.   
 
 
Synopsis, Study Duration 
6.2, Study Duration 
 For subjects who were not 
prescribed ESAs prior to study 
entry:  Up to 22 weeks, including 
the eligibility screening period (up 
to 4 weeks), primary efficacy 
period (6 weeks), dose adjustment 
and maintenance period 
(10 weeks), and follow-up period 
(2 weeks) 
 For subjects who were prescribed 
ESAs prior to study entry:  Up to 
29 weeks, including the eligibility 
screening period (up to 11 weeks), 
primary efficacy period (6 weeks), 
dose adjustment and maintenance 
period (10 weeks), and follow-up 
period (2 weeks) 
Note: Subjects who discontinue 
prematurely from the study will 
complete the end-of-treatment Week 16 
visit followed in two weeks by the 
Week 18 visit.   
 For subjects who were not 
prescribed ESAs prior to study 
entry:  Up to 22 weeks, including 
the eligibility screening period (up 
to 4 weeks, with 2 screening 
visits), primary efficacy period 
(6 weeks), dose adjustment and 
maintenance period (10 weeks), 
and follow-up period (2 weeks) 
 For subjects who were prescribed 
ESAs prior to study entry:  Up to 
29 weeks, including the eligibility 
screening period (up to 11 weeks, 
with 3 screening visits), primary 
efficacy period (6 weeks), dose 
adjustment and maintenance 
period (10 weeks), and follow-up 
period (2 weeks) 
Note: Subjects who discontinue 
prematurely from the study or 
permanently discontinue study 
medication will complete the end-of-
treatment Week 16 visit followed in 
two weeks by the Week 18 visit.   
To clarify the number of screening visits 
that subjects will undergo during 
screening. 
To clarify which subjects will participate 
prematurely in end-of-treatment visit 
assessments in alignment with the 
protocol 
Synopsis, Study Duration 
6.2, Study Duration  
7.6.1, Subject Completion 
9.3.2, Laboratory 
Evaluations 
For subjects with Hb >13.0 g/dL at the 
follow-up visit, Hb will be assessed 
every 2 weeks until the Hb <13.0 g/dL. 
Text has been deleted 
Excursions in Hb >13 g/dL occurred in 
only 6 of 138 vadadustat-treated subjects 
and 1 of 94 vadadustat-treated subjects in 
the US Phase 2b NDD-CKD 
(AKB-6548-CI-0007) and Phase 2 
DD-CKD (AKB-6548-CI-0011) studies, 
respectively. In these 2 trials, no 


Akebia Therapeutics, Inc. 
 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
 
Summary of Changes to Protocol Version 1 
 
 
Confidential 
Page 4 of 22 
9.4.9, Week 18 Follow-up 
Visit 
9.5.10, Week 18 Follow-up 
Visit 
elevations in Hb >13 g/dL were observed 
in the follow-up visit performed 4 weeks 
after vadadustat cessation. These 
excursions were not affiliated with any 
adverse events.  
Synopsis, Study Design 
6.1 Study Design 
Subjects will participate in a screening 
period to determine study eligibility. 
Subjects who have recently received 
ESA therapy and otherwise meet 
eligibility criteria will be required to 
washout from ESA therapy prior to 
evaluation of screening Hb.  
Subjects will participate in a screening 
period to determine study eligibility. 
Subjects who have not recently 
received ESA therapy will participate 
in 2 screening visits. Subjects who 
have recently received ESA therapy 
and otherwise meet eligibility criteria 
will be required to washout from ESA 
therapy prior to evaluation of screening 
Hb, and will participate in 3 
screening visits.  
To clarify that the number of screening 
visits is either 2 or 3 depending on 
whether subjects recently received ESA 
therapy.  
Synopsis, Key Inclusion 
Criteria 
6.1, Study Design 
7.2, Inclusion Criteria 
8.4.2, ESAs and Blood 
Transfusion 
9.1, Schedule of Visits 
9.5.1, Screening Visit 1 
Appendix B, Schedule of 
Activities 
Previously, ESA washout periods were 
specified as a 2-week washout for 
short-acting ESAs and an 8-week 
washout for long-acting ESAs 
 
 ESA status and screening Hb that 
meet one of the following criteria:  
- 
For subjects who are not being 
treated with ESAs:  Mean 
Hb <10.0 g/dL; average of 
2 measurements obtained 
during screening.  
- 
For subjects who are being 
treated with ESAs: mean 
Hb <10.0 g/dL; average of 
2 measurements obtained 
during screening after the 
protocol-defined ESA washout 
period (ie, a 2-week washout 
period for short-acting ESA 
Protocol has been updated to specify 
2-week washout period for epoetin alfa, 
epoetin beta, and epoetin kappa, 
4-week washout for darbepoetin alfa, 
and 8-week washout for epoetin beta 
pegol  
Screening visit times in relation to ESA 
washout periods have been specified 
For subjects who are being treated with 
ESAs:  Mean Hb <10.0 g/dL; average 
of 2 measurements obtained during 
screening. These subjects must be off 
ESAs for at least the following 
periods of time prior to screening 
visit 1(refer to Appendix C for 
examples):  
 
2 weeks for epoetin alfa, epoetin 
beta, or epoetin kappa;  
 
4 weeks for darbepoetin alfa;  
A re-evaluation of the published 
literature (eg, Macdougall KI 2002) and 
ongoing discussions with nephrology 
experts in Japan indicated that an 8-week 
washout period for darbepoetin alfa was 
too long, and that a 4-week washout 
period for darbepoetin alfa would be 
optimal. 
 
Text was also edited to clarify ESA 
washout periods for subjects who are and 
are not taking ESAs. 


Akebia Therapeutics, Inc. 
 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
 
Summary of Changes to Protocol Version 1 
 
 
Confidential 
Page 5 of 22 
and an 8-week washout period 
for long-acting ESA) 
 
 
 
8 weeks for epoetin beta pegol.  
For subjects who are being treated with 
ESAs:  Mean Hb <10.0 g/dL; average 
of 2 measurements obtained during 
screening after the protocol-defined 
ESA washout period. These subjects 
must washout ESA therapy for the 
following periods of time during the 
screening period, beginning at 
screening visit 1 and prior to 
screening visit 2 (refer to Appendix C 
for examples): 
 
2 weeks for epoetin alfa, epoetin 
beta, and epoetin kappa;  
 
4 weeks for darbepoetin alfa;  
 
8 weeks for epoetin beta pegol.  
Synopsis, Key Exclusion 
Criteria 
Section 7.3, Exclusion 
Criteria 
Hypo-responsiveness to ESA defined as 
an epoetin equivalent dose >23,000 IU 
per week within the prior 8 weeks 
Hypo-responsiveness to ESA defined 
as any of the following ESA 
treatments within 8 weeks prior to 
screening: (i) intravenous epoetin 
dose ≥3000 units/dose 3 times a week 
(9000 units/week), (ii) intravenous 
darbepoetin alfa dose ≥60 µg once a 
week, (iii) epoetin beta pegol ≥200 µg 
once a month or ≥100 µg once every 
2 weeks as an epoetin equivalent dose 
>23,000 IU per week within the prior 8 
weeks 
The definition of ESA 
hyporesponsiveness was updated to be 
consistent with the 2008 renal anemia 
guidelines provided by the Japanese 
Society of Dialysis Therapy 
Synopsis, Rescue Therapy 
Guidelines 
Section 8.2.6, Rescue 
Therapy Guidelines 
The following rescue therapy 
guidelines are provided to ensure the 
safety of study subjects and to 
standardize the use of rescue in the 
study. 
ESA Rescue Therapy 
In order to standardize the use of ESA 
rescue in the study, the following 
guidelines should be followed. ESA 
rescue therapy may be considered if: 
1) ESA is considered warranted by 
the investigator’s judgment, AND 
Text was updated to clarify that (a) the 
rescue guidelines are in place to 
standardize the use of rescue therapy 
across study sites (b) clarify when a 
confirmatory Hb level <9.0 g/dL will be 
taken and (c) add a provision to initiate 
rescue therapy if clinically indicated by 
the investigator.    


Akebia Therapeutics, Inc. 
 
Protocol No. AKB-6548-CI-0022 
Vadadustat 
 
Summary of Changes to Protocol Version 1 
 
 
Confidential 
Page 6 of 22 
• ESA rescue:  ESA rescue therapy may 
be considered based on the 
investigator’s judgment if a subject: 
-Experiences a clinically significant 
worsening of anemia or symptoms of 
anemia, AND 
-Has a confirmed Hb level <9.0 g/dL If 
a subject has one Hb result <9.0 g/dL, 
the subject should return to the site 
within 1 week for repeat Hb 
measurement through the central 
laboratory.  If the second Hb result is 
also <9.0 g/dL, the subject qualifies for 
initiation of ESA rescue therapy. 
•RBC transfusion:  Investigators should 
use their local institution’s transfusion 
guidelines when determining whether 
to transfuse a study subject. 
Subjects who initiate rescue therapy 
will be required to stop study drug 
treatment and will be discontinued from 
the study.   
 
2) The subject experiences a clinically 
significant worsening of anemia or 
symptoms of anemia, AND 
3) The subject has a confirmed Hb 
level <9.0 g/dL as defined by two 
consecutive Hb levels <9.0 g/dL. The 
investigator may schedule the subject 
to return for an unscheduled visit to 
confirm Hb level <9.0 g/dL prior to 
the subsequent scheduled study visit.  
If clinically indicated, the 
investigator at his/her discretion may 
initiate ESA rescue therapy without a 
confirmatory Hb level <9.0 g/dL if 
the first two criteria above are met. 
Red Blood Cell Transfusions 
Investigators should use their local 
institution’s transfusion guidelines 
when determining whether to transfuse 
a study subject. 
Subjects who initiate either rescue 
therapy, ESA Rescue Therapy or Red 
Blood Cell Transfusion, will be 
required to stop study drug treatment 
and will be discontinued from the 
study.   
Synopsis, Statistical 
Considerations 
The primary analysis will use a linear 
regression analysis to quantify the 
association between vadadustat dose 
and mean change in Hb (ie, to assess 
the vadadustat dose-response 
relationship).  Comparison of each 
vadadustat dose group versus baseline 
will be performed.  All tests of 
significance will be performed using a 
0.05 two-sided significance level. 
[Text shown in the left cell has been 
deleted and replaced with the following 
text] 
An analysis of covariance 
(ANCOVA) model will be used to 
compare change from baseline in Hb 
between the 3 vadadustat dosing 
groups and the placebo group.  The 
model will include treatment 
assignment (3 dosed groups and 1 
Update of statistical approach to primary 
endpoint. Use of ANCOVA instead of 
linear regression is considered more 
appropriate for this dose-finding study. 
For comparison of more than 2 treatment 
groups, with baseline metric as a 
covariate, ANCOVA analysis is a 
common and traditional method to assess 
change from baseline, the primary 
endpoint. This change in statistical 


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placebo group) and baseline Hb 
value as a covariate.  A step-down 
procedure will be used to control the 
overall type I error rate for the 
multiple comparisons.  Testing of the 
highest dose compared with placebo 
will be conducted first.  If and only if 
this comparison is significant, then 
testing will proceed to comparison of 
the next lower dose and placebo, and 
so on.  As a result, no multiplicity 
adjustment will be needed for this 
analysis. 
analysis method does not affect the study 
design. 


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Synopsis, Statistical 
Considerations 
Based on the results from 
Study AKB-6548-CI-0005, the 
expected changes in mean Hb from 
baseline to Week 6 will be 0, 0.5, 0.7, 
and 1.2 g/dL for the placebo, 150 mg, 
300 mg, and 600 mg vadadustat dose 
groups, respectively, with a common 
standard deviation of 0.68 g/dL among 
the 4 treatment groups.  With these 
assumptions, the study will have >85% 
power to detect a non-zero slope in a 
dose-response relationship using linear 
regression analysis and α=0.05, based 
on simulation of 10,000 repetitions 
using SAS® software, Version Number 
9.4. 
[Text shown in the left cell has been 
deleted and replaced with the following 
text] 
The study is powered based on a 
comparison of the highest dose 
vadadustat group (600 mg daily) and 
the placebo group. 
Based on the results from Study 
AKB 6548 CI 0005 that was 
conducted in the United States and 
evaluated vadadustat in patients with 
anemia secondary to NDD-CKD, it is 
assumed that the expected mean Hb 
changes from baseline to Week 6 will 
be approximately 0 mg/dL for the 
placebo group and 1.35 g/dL for the 
highest dose vadadustat group (600 
mg daily). 
Based on the results from Study 
AKB 6548 CI 0011 that was 
conducted in the United States and 
evaluated vadadustat in patients with 
anemia secondary to DD-CKD, it is 
assumed that the common Hb 
standard deviation will be 0.9 g/dL 
across treatment groups.  In 
addition, a dropout rate of 10% is 
assumed.  With these assumptions, 
the study with n=12 subjects per 
group will have >85% power to 
detect the difference between 
treatment group and control group, 
at 2-sided alpha of 0.05. 
The common Hb standard deviation is 
increased from 0.68 to 0.9 g/dL based on 
the US Phase 2 DD-CKD study 
(AKB-6548-CI-0011) to better reflect the 
DD-CKD population. In addition, the 
assumed dropout rate is increased from 0 
to 10%. With these changes in 
assumptions, the study power has 
changed from >95% to >85%. This 
change does not impact study conduct. 
Synopsis, Statistical 
Considerations 
Sponsor and CRO study team personnel 
involved in the preliminary analysis 
will not be involved in the conduct of 
the study after the preliminary analysis.   
Individuals from the sponsor and 
CRO study teams team personnel 
involved in who are unblinded for the 
development and reporting of the 
preliminary analysis will not be 
To clarify that individuals who are 
unblinded during the primary analysis 
will not be involved in study conduct 
following the preliminary analysis. 


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8.2.3, Blinding During the 
Study and Breaking the 
Blind 
involved in the conduct of the study 
after the preliminary analysis.   
4.6, Ethno-Bridging Data 
from a Study of Healthy 
Japanese and Caucasian 
Volunteers 
Not applicable 
Vadadustat was generally well 
tolerated in this study. 
Overall safety results from the study was 
added 
4.7, Potential Benefits and 
Risks 
In addition, HIF activation promotes 
iron mobilization through upregulation 
of ferroportin and transferrin and 
downregulation of hepcidin 
(Peyssonnaux 2007).  As a result, 
vadadustat will likely improve iron 
availability and enhance EPO 
responsiveness. 
In addition, HIF activation is 
associated with increased expression 
of promotes iron mobilization through 
upregulation of ferroportin and 
transferrin and downregulation 
decreased expression of hepcidin (Liu 
2012, Peyssonnaux 2007, Tacchini 
1999).  These changes in iron 
biomarkers are consistent with 
enhanced iron mobilization and 
utilization to promote hemoglobin 
synthesis and erythropoiesis As a 
result, vadadustat will likely improve 
iron availability and enhance EPO 
responsiveness.   
Editorial change to accurately quote the 
referenced articles 
6.2, Study Duration 
7.6.1, Subject Completion 
Subjects who discontinue prematurely 
from the study will complete the end-
of-treatment Week 16 visit followed in 
two weeks by the Week 18 visit. 
[Text in the left cell has been deleted 
and replaced with the following text] 
See Section 7.6.3 for subjects who 
discontinue study drug or withdraw 
early from the study. 
To clarify which subjects will participate 
prematurely in end-of-treatment visit 
assessments in alignment with the 
protocol 
6.3, Rationale for Study 
Design 
…completed dose-finding study in 
Caucasian subjects with anemia 
secondary to NDD-CKD… 
…completed dose-finding study in 
Caucasian subjects with anemia 
secondary to NDD-CKD that included 
a majority of Caucasian and 
Black/African American subjects… 
Clarification of the ethnic distribution of 
the subjects who participated in 
Study AKB-6548-CI-0005 
7.6.3, Individual Subject 
Discontinuation 
Subjects discontinuing study drug or 
withdrawing from the study should 
complete the Week 16 (EOT) clinical 
and laboratory assessments within 
Subjects permanently discontinuing 
study drug or withdrawing early from 
the study prior to the Week 16 visit 
should complete the Week 16 (EOT) 
clinical and laboratory assessments 
To clarify which subjects will participate 
prematurely in end-of-treatment visit 
assessments in alignment with the 
protocol 


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1 day of stopping study medication, if 
possible.   
within 1 day of stopping study 
medication, if possible.   
8.1.3, Dispensing of Study 
Drugs 
At the Week 6 visit, sites will collect 
from subjects from all dosing cohorts 
study drug bottles and all remaining 
study drug tablets remaining from the 
primary efficacy period.  Each subject 
will then be provided with 1 bottle of 
vadadustat.  Each bottle will contain 
100 tablets of vadadustat.  Subjects will 
be instructed to finish 1 bottle before 
opening a new bottle. 
Resupply of additional study drug at 
other visits will be dependent on the 
dose level and the number of tablets 
remaining in the subject’s current 
supply at a given study visit. 
To allow for some flexibility in study 
visit scheduling and possible dropped 
doses, sites should ensure that subjects 
have an adequate supply of study 
medication. 
At the Week 6 visit, sites will collect 
from subjects from all dosing cohorts 
study drug bottles and all unused 
remaining study drug tablets remaining 
from dispensed during the primary 
efficacy period.  Each subject will then 
be provided with 1 bottle of vadadustat.  
Each bottle will contain 100 tablets of 
vadadustat.  Subjects will be instructed 
to finish 1 bottle before opening a new 
bottle. 
Resupply of additional study drug at 
other visits as needed will be 
dependent on the dose level and the 
number of tablets remaining in 
the subject’s current supply at a given 
study visit. Subjects will be instructed 
to finish 1 bottle before opening a 
new bottle. 
To allow for some flexibility in study 
visit scheduling and possible dropped 
doses, sites should ensure that subjects 
have an adequate supply of study 
medication. 
Editorial change to clarify the drug 
dispensing and return process. 
8.2.3, Blinding During the 
Study and Breaking the 
Blind 
The applicable standard operating 
procedure will be followed for 
blind-breaking procedures. 
The sentence has been deleted 
Statement is not necessary to be included 
in the protocol as information related to 
SOPs will be addressed in the Trial 
Master File. 
8.2.5, Study Drug 
Administration during the 
Dose Adjustment and 
Maintenance Period 
(Week 7 to Week16) 
Specifically, at the Week 6 visit, sites 
will collect from subjects from all 
dosing cohorts study drug bottles and 
all remaining study drug tablets 
remaining from the primary efficacy 
period.   
Specifically, at the Week 6 visit, sites 
will collect from subjects from all 
dosing cohorts study drug bottles and 
all remaining unused study drug tablets 
remaining dispensed during from the 
primary efficacy period.   
Editorial change to clarify the drug return 
process. 


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8.2.5, Study Drug 
Administration during the 
Dose Adjustment and 
Maintenance Period 
(Week 7 to Week16) 
When adjusting therapy, investigators 
should consider Hb rate of rise, rate of 
decline, and variability as well as the 
subject’s clinical condition (including 
recent illness, volume depletion, and 
volume overload).  In cases of 
extenuating clinical circumstances, 
investigators may elect to dose outside 
the dosing guidelines to maintain the 
Hb within the target range. 
[Text shown in the left cell has been 
deleted and replaced with the following 
text] 
As clinically indicated, the 
investigator may elect to dose outside 
the dose adjustment guidelines. In such 
cases, the clinical circumstances must 
be documented in the subject’s 
record 
The text was updated to mitigate any 
ambiguity or confusion regarding the 
adjustment of therapy. 
8.2.6, Rescue Therapy 
Guidelines 
8.4.2, ESAs and Blood 
Transfusion 
Note: ESAs and RBC transfusions are 
allowed as rescue therapies, please refer 
to Section 8.2.6 for the rescue therapy 
guidelines.  Subjects who initiate rescue 
therapy will be required to stop study 
drug treatment and will be discontinued 
from the study. 
• Prohibitions related to ESA use: See 
Section 9.1 for washout period for 
short-acting ESAs and long-acting 
ESAs.  Subjects may not receive any 
short acting ESA treatment within 2 
weeks of the Hb assessment at 
Screening Visit 2 or any long acting 
ESA treatment within 8 weeks of the 
Hb assessment at Screening Visit 2.  In 
addition, subjects may not receive any 
ESA treatment through the follow up 
period. 
• Prohibitions related to blood 
transfusions: Subjects may not receive 
blood transfusion within 4 weeks prior 
to the screening period and through the 
follow up period. 
Note:  ESAs and RBC transfusions are 
allowed as rescue therapies, please refer 
to Section 8.2.6 for the rescue therapy 
guidelines.  Subjects who initiate rescue 
therapy will be required to stop study 
drug treatment and will be discontinued 
from the study.  See Section 7.6.3 for 
subjects who discontinue study drug 
or withdraw early from the study. 
 
Prohibitions related to ESA use:  
See Section 9.1 for washout 
period for ESAs.   
 
For subjects who are not 
currently being treated with 
ESAs:  
o 
Subjects may not 
receive any ESA during 
the screening, treatment, 
and follow-up study 
periods except in the 
context of ESA rescue 
(see ESA rescue 
guidelines, section 8.2.6). 
 
For subjects who are currently 
being treated with ESAs: 
o 
After screening visit 1 
and prior to screening 
visit 2, subjects must not 
Text was updated to provide additional 
clarification regarding: 
1. When subjects, who discontinue 
early from the study, will participate 
in the end-of-treatment visit 
assessments. 
2. When subjects must be off ESAs 
during the study. 
 


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receive ESAs for at least 
the following time 
periods: 
ESA 
ESA washout 
period 
(Minimum 
duration of 
time without 
ESA treatment 
after SV1 and 
prior to SV2) 
Epoetin alfa 
Epoetin beta 
Epoetin 
kappa 
2 weeks 
Darbepoetin 
alfa 
4 weeks  
Epoetin beta 
pegol 
8 weeks 
 
 
After screening visit 2 and 
through the remaining screening 
period, subjects must not use any 
ESA. Any ESA use during this 
period would result in exclusion 
from the study. 
 
During the treatment and follow-up 
study periods, subjects may not 
receive any ESA except in the context 
of ESA rescue (see ESA rescue 
guidelines, section 8.2.6).  
8.2.9, Compliance with 
Study Drug Dosing 
Subjects will be questioned regarding 
dosing compliance at all study visits 
Subjects will be questioned regarding 
dosing compliance and whether they 
have questions or have experienced 
Editorial change to clarify that dosing 
compliance is to be determined from 


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from Week 1 through Week 16, and 
any missed doses will be recorded. 
Subjects will also be questioned 
regarding the date and time of their last 
dose of study drug prior to the PK 
sample at the Week 4 visit.  The date 
and time of these doses will be 
recorded on the CRF. 
any problems related to the dosing of 
study drug.  The investigator will 
also maintain drug accountability 
logs itemizing vadadustat dispensed 
to and returned from each subject 
during the study.  Treatment 
compliance will be determined from 
these forms along with the subject 
questioning.at all study visits from 
Week 1 through Week 16, and any 
missed doses will be recorded. 
Subjects who miss doses will be 
counseled on the importance of 
treatment compliance. 
Subjects will also be questioned 
regarding the timing of their last dose 
of vadadustat during PK sample 
collection. the date and time of their 
last dose of study drug prior to the PK 
sample at the Week 4 visit.  The date 
and time of these doses will be 
recorded on the CRF. 
discussions with the subject following 
drug accountability. 
9.3.1, Clinical Evaluations 
Not applicable 
Rescue therapy (ESA rescue and 
RBC transfusion) review: Beginning 
with the first post-baseline visit (after 
Day 1) and through the follow-up 
visit, the investigator and study 
personnel will review whether a 
subject received rescue therapy (ESA 
rescue or RBC transfusion). 
This item was added to prompt sites to 
ask about ESA rescue and RBC 
transfusion at each post-baseline visit. 
9.4, Schedule of Activities 
(For Subjects Who Were 
Not Prescribed ESAs Prior 
to Study Entry) 
9.5, Schedule of Activities 
(For Patients Who Were 
Not applicable 
Added the following item to post-
baseline visits: 
Rescue therapy (ESA rescue and 
RBC transfusion) review 
This item was added to prompt sites to 
ask about ESA rescue and RBC 
transfusion at each post-baseline visit. 


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Prescribed ESAs Prior to 
Study Entry) 
Appendix A 
Appendix B 
9.4, Schedule of Activities 
(For Subjects Who Were 
Not Prescribed ESAs Prior 
to Study Entry) 
9.5, Schedule of Activities 
(For Patients Who Were 
Prescribed ESAs Prior to 
Study Entry) 
Appendix A 
Appendix B 
Not applicable 
Relevant sections have been updated to 
include “AE review” at the screening 
and baseline visits. 
 
Section 9.5.1 has been updated to list 
“Demographics, medical…” 
Related footnote has been added to 
Appendix A and Appendix B 
The SAE reporting period has been 
redefined specifically for SAEs related to 
protocol procedures, eg, ESA washout 
during screening. This was done because 
the screening period in this study 
requires withdrawal of ESA therapy in 
the study population of DD-CKD 
patients who are currently using ESAs. 
Section 9.4 and Appendix A were 
updated to ensure that the assessments 
are aligned across these 2 sections. 
Section 9.5 and Appendix B were 
updated to ensure that the assessments 
are aligned across these 2 sections. 
9.2.3.1, Acceptable 
Methods of Contraception 
9.3.2, Laboratory 
Evaluations 
9.4, Schedule of Activities 
(For Subjects Who Were 
Not Prescribed ESAs Prior 
to Study Entry) 
9.5, Schedule of Activities 
(For Patients Who Were 
Prescribed ESAs Prior to 
Study Entry) 
Appendix A 
Appendix B 
Urine pregnancy test performed at 
baseline visit 
Deleted urine pregnancy test 
Added serum pregnancy testing to the 
last scheduled screening visit prior to 
randomization 
A substantial proportion of DD-CKD 
subjects are anuric. Therefore, we 
replaced urine pregnancy testing at 
baseline with a serum pregnancy testing 
at screening. 


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9.3.2, Laboratory 
Evaluations 
9.4.2, Screening Visit 2, 
Appendix A footnote [c] 
9.5.3 Screening Visit 3, 
Appendix B, footnote [c] 
Serum pregnancy tests:  Female 
subjects who are of childbearing 
potential (ie, are not surgically sterile or 
postmenopausal) will participate in 
serum pregnancy tests (to be analyzed 
by the central lab).  The screening 
pregnancy test results must be available 
and must be negative for a subject to 
initiate or continue study drug. 
 
Serum pregnancy tests:  Female 
subjects who are of childbearing 
potential (ie, are not surgically sterile or 
postmenopausal) will participate in 
serum pregnancy tests (to be analyzed 
by the central lab).  The screening 
pregnancy test results must be available 
and must be negative for a subject to 
initiate study drug.  
Note: Additional serum or local urine 
(if possible) pregnancy tests may be 
conducted, as determined by the 
investigator or required by local 
regulations, to establish the absence 
of pregnancy during the study 
Newly added text to section 9.4.2 and 
9.5.3. Text was customized for visit. 
 
Serum pregnancy test for 
females of childbearing potential 
(eligible subjects will be advised 
to use an adequate contraceptive 
method).  The serum pregnancy 
test must be performed within 4-
8 days prior visit 1/Day 1 to 
allow sufficient time to obtain the 
pregnancy test result prior to 
randomization, and the 
screening results must be 
available and must be negative 
before the subject takes the first 
dose of study drug. In the event 
screening visit 3 is >8 days prior 
to Day 1, the subject will be 
asked to return to the study site 
for an unscheduled serum 
pregnancy test to verify 
eligibility prior to Day 1. The 
The timing of the screening pregnancy 
test was changed from baseline to last 
screening visit to ensure the test results 
are available to verify subject eligibility 
prior to randomization and dosing on 
Day 1. 
As an additional precaution to avoid in 
utero exposure to study drug, language 
has been added to remind sites that 
pregnancy testing may be performed 
during the study as determined by 
investigator discretion. 


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serum pregnancy test will be 
analyzed by the central lab.   
10.1.1, Adverse Events 
Not applicable 
Newly added text: 
Kidney Transplantation – During 
this study, some subjects may receive 
a kidney transplant.  These events 
will not be recorded as AEs. 
Clarification is provided that kidney 
transplantation will not be considered an 
AE in this study. 
10.3.1, Reporting Period 
Appendix A, Footnote [b] 
Appendix B, Footnote [b] 
The AE reporting period for a subject 
begins upon receiving the first dose of 
study medication and ends at the final 
protocol-required visit.  In addition, 
SAEs that occur after the 
protocol-defined AE reporting period 
that are considered to be related to the 
study medication should be recorded 
and reported to the sponsor’s medical 
monitor or CRO designee. 
 
The reporting period for all non-
serious AEs and all SAEs not related 
to protocol procedures begins upon 
receiving the first dose of study 
medication and ends at the final 
protocol-required visit. 
SAEs that are assessed by the 
investigator to be related to protocol 
procedures (eg, ESA washout) must 
be reported after signing of the 
informed consent form. 
In addition, SAEs that occur after the 
protocol-defined AE reporting period 
that are considered to be related to the 
study medication should be recorded 
and reported to the sponsor’s medical 
monitor or CRO designee. 
The SAE reporting period has been 
redefined specifically for SAEs related to 
protocol procedures, eg, ESA washout 
during screening. This was done because 
the screening period in this study 
requires withdrawal of ESA therapy in 
the study population of DD-CKD 
patients who are currently using ESAs. 
Appendix A and B were updated to 
reflect the clarification. 
 
10.4, Exposure in Utero 
If any study participant becomes or is 
found to be pregnant while receiving a 
study medication or within 30 days of 
discontinuing the study medication, the 
pregnancy must be recorded on the 
Pregnancy Reporting Form/Exposure In 
Utero Form within 24 hours of 
awareness of the pregnancy and sent to 
the CRO via email or fax, or the 
investigator should call the CRO SAE 
hotline within 24 hours of being made 
If any study participant becomes or is 
found to be pregnant while receiving a 
study medication or within 30 days of 
discontinuing the study medication, the 
pregnancy must be recorded on the 
Pregnancy Reporting Form/Exposure In 
Utero Form within 24 hours of 
awareness of the pregnancy and sent to 
the CRO via email or fax, or the 
investigator should call the CRO SAE 
hotline within 24 hours of being made 
Editorial change to clarify the process for 
reporting pregnancy and its outcome. 


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aware of the pregnancy (reference the 
site manual for contact information). 
aware of the pregnancy (reference the 
site manual for contact information). 
10.4, Exposure in Utero 
Not applicable 
The Pregnancy Reporting 
Form/Exposure In Utero Form must 
be completed with all known 
information regarding the pregnancy 
at the time of 
reporting.  Investigative site 
personnel will update the form with 
additional information regarding the 
pregnancy and the outcome of the 
pregnancy as it becomes available 
until the outcome of the pregnancy is 
reported. 
To clarify procedure for reporting 
pregnancy and its outcome. 
10.4, Exposure in Utero 
Neonates should be followed the first 
four weeks after birth. 
[The text shown in the left cell has been 
deleted and the following text has been 
added] 
 
Neonates should be followed through 
gestational age of 46 weeks. 
Specification of follow-up period for 
neonates based on gestational age to 
account for the possibility of premature 
births. 


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Section 11 
See deleted/added text in the cell below 
See deleted/added text in the cell below 
Update of statistical approach to primary 
endpoint. Use of ANCOVA instead of 
linear regression is considered more 
appropriate for this dose-finding study. 
 
The common Hb standard deviation is 
increased from 0.68 to 0.9 g/dL based on 
the US Phase 2 DD-CKD study (CI-
0011) to better reflect the DD-CKD 
population. In addition, the assumed 
dropout rate is increased from 0 to 10%. 
With these changes in assumptions, the 
study power has changed from >95% to 
>85%. This change does not impact 
study conduct.  
This cell refers to the item in the above row. Rationale for change is provided in the row above in the far right cell. 
Text added to Section 11: 
An overview of the statistical approach to the primary endpoint and safety analyses are provided below.  The details of the planned analysis of the 
primary endpoint as well as the planned analyses of secondary endpoints, PK, PD, and safety will be documented in the statistical analysis plan 
(SAP). 
Section 11.1 Primary Endpoint – Mean Change in Hb from Pre-treatment to the End of the Primary Efficacy Period (Week 6) 
The primary objective of this study is to evaluate the dose-response relationship between oral vadadustat once daily dosing for 6 weeks and the 
change in Hb in Japanese subjects with anemia secondary to DD-CKD; in order to define the starting dose for use in Phase 3 clinical studies in 
Japan.   
The primary endpoint is the mean change in Hb from pre-treatment to the end of the primary efficacy period (Week 6). Pre-treatment Hb is defined 
as the average of 3 Hb values obtained prior to treatment based on the 2 qualifying screening Hb value and the Hb value at the baseline visit.   
Section 11.2 Primary Efficacy Analysis and Sample Size Determination 
An analysis of covariance (ANCOVA) model will be used to compare change from pre-treatment in Hb between the 3 vadadustat dosing groups and 
the placebo group. The model will include treatment assignment (3 dosed groups and 1 placebo group) and pre-treatment Hb value as a covariate. A 
step-down procedure will be used to control the overall type I error rate for the multiple comparisons. Testing of the highest dose compared with 
placebo will be conducted first. If and only if this comparison is significant, then testing will proceed to comparison of the next lower dose and 
placebo, and so on. As a result, no multiplicity adjustment will be needed for this analysis. 
The study is powered based on a comparison of the highest dose vadadustat group (600 mg daily) and the placebo group. 


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Based on the results from Study AKB-6548-CI-0005 that was conducted in the United States and evaluated vadadustat in patients with anemia 
secondary to NDD CKD, it is assumed that the expected mean Hb changes from pre-treatment to Week 6 will be approximately 0 mg/dL for the 
placebo group and 1.35 g/dL for the highest dose vadadustat group (600 mg daily). 
Based on the results from Study AKB 6548 CI 0011 that was conducted in the United States and evaluated vadadustat in patients with anemia 
secondary to DD-CKD, it is assumed that the common Hb standard deviation will be 0.9 g/dL across treatment groups. In addition, a dropout rate of 
10% is assumed. With these assumptions, the study with n=12 subjects per group will have >85% power to detect the difference between treatment 
group and control group, at 2-sided alpha of 0.05. 
Text deleted from Section 11: 
The primary objective of this study is to quantify the dose-response relationship between oral vadadustat once daily dosing for 6 weeks and change in 
Hb in Japanese subjects with DD-CKD in order to define the starting dose for use in Phase 3 clinical studies in Japan.   
Change in Hb is defined as the Hb measured at the Week 6 visit minus the mean pre-treatment Hb.  Note that a pre-treatment average value for Hb 
is defined as the average of 3 values obtained prior to dosing, ie, the 2 qualifying screening values and the baseline value.   
Linear regression analysis will be used to calculate the relationship between vadadustat dose and change in Hb. 
The primary analysis will use a linear regression analysis to quantify the association between vadadustat dose and mean change in Hb (ie, to assess 
the vadadustat dose-response relationship).  Comparison of each vadadustat dose group versus will be performed.  All tests of significance will be 
performed using a 0.05 two-sided significance level. 
Based on the results from Study AKB-6548-CI-0005 that was conducted in the United States and evaluated vadadustat in patients with anemia 
secondary to NDD-CKD, the expected mean Hb changes from baseline to Week 6 will be 0, 0.5, 0.7, and 1.2 g/dL for the placebo, 150 mg, 300 mg, and 
600 mg vadadustat dose groups, respectively, with a common standard deviation of 0.68 g/dL among the 4 treatment groups.  With these 
assumptions, the study will have >85% power to detect a non-zero slope in a dose-response relationship using linear regression analysis and α=0.05, 
based on simulation of 10,000 repetitions using SAS® software, Version Number 9.4. 
11.4.1, Analysis 
Populations for the Safety 
Analyses 
The intent-to-treat (ITT) population 
will include all subjects assigned to 
study medication who receive at least 1 
dose of study medication.  All safety 
analyses will be performed using the 
ITT population. 
The intent-to-treat (ITT) safety 
population is defined as will include all 
enrolled subjects assigned to study 
medication who receive at least 1 dose 
of study medication.  The safety 
population will be based on the 
actual treatment that patients 
received. All safety analyses will be 
performed using the ITT safety 
population. 
The various study populations were 
defined. 
11.4.2, Analysis 
Populations for the 
Efficacy Analyses 
The modified intent-to-treat (MITT) 
population will include subjects who 
receive at least 1 dose of study 
medication, have a pre-treatment Hb 
The modified intent-to-treat (MITT) 
population is defined as all 
randomized subjects who receive at 
least 1 dose of study medication, have a 
The various study populations were 
defined. 


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Summary of Changes to Protocol Version 1 
 
 
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average defined as the average of the 
qualifying screening value and the 
baseline value, and at least one post-
baseline Hb measurement. 
The per-protocol (PP) population will 
consist of the subjects in the MITT 
population who have completed the 
study and have efficacy data through 
Week 6, have a study medication 
compliance of ≥80%, and do not have 
any major protocol deviations. 
pre-treatment Hb average defined as the 
average of the qualifying screening 
value and the baseline value, and at 
least one post-baseline Hb 
measurement. The MITT population 
will be based on the treatment to 
which patients are randomized. 
 
The per-protocol (PP) population will 
consist of the subjects in the MITT 
population who have completed the 
study and have efficacy data through 
Week 6, have a study medication 
compliance of ≥80%, and do not have 
any major protocol deviations expected 
to significantly affect the primary 
efficacy endpoint.  Subjects with 
major protocol deviations expected to 
significantly affect the primary 
efficacy endpoint will be identified 
and documented prior to data 
unblinding. 
11.5 Efficacy and PD 
Analyses 
The entire set of efficacy outcomes will 
be defined in the statistical analysis 
plan (SAP).  In addition to the primary 
endpoint analysis defined above, the 
following efficacy endpoints will also 
be assessed: 
• Actual values and change (absolute 
and percent) from baseline in Hb, HCT, 
RBC count, and reticulocyte count 
(both absolute and percent) 
• Actual values and change (absolute 
and percent) from baseline in iron, 
TIBC, TSAT, ferritin (both absolute 
and percent), and hepcidin 
This section has been deleted 
Editorial revision to focus protocol on 
statistical approach to primary efficacy 
analysis. Details related to all planned 
analyses will be provided in the 
statistical analyses plan as mentioned in 
the newly added paragraph at the 
beginning of Section 11. 


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Changes from baseline of efficacy and 
PD parameters will be summarized 
using descriptive statistics by treatment 
groups and each scheduled assessment, 
and results will be displayed using box 
lots. 
Linear regression analysis will be 
performed for Hb change from baseline 
to Week 6, to quantify the association 
between vadadustat dose and mean 
change in Hb (ie, to assess the 
vadadustat dose response relationship)..  
Comparison of each vadadustat dose 
group versus baseline will be 
performed.  All tests of significance 
will be performed using a 0.05 two 
sided significance level.  Similar 
analysis will be performed for change 
from baseline to Week 6 of reticulocyte 
count (both absolute and percent), 
hematocrit, and RBC count. 
Also, similar linear regression analysis 
will be performed for change from 
baseline to Week 6 of the iron indices 
(ie, iron, TIBC, ferritin, and TSAT) and 
hepcidin will be evaluated. 
All tests of significance will be 
performed using a 0.05 two sided 
significance level. 
11.7, Safety Analyses 
The following variables are the safety 
endpoints: adverse events, vital signs, 
ECGs, components of the CBC, and 
VEGF. 
The following variables are the safety 
endpoints: adverse events, vital signs, 
ECGs, and laboratory parameters 
components of the CBC, and VEGF. 
Editorial revision 
11.7, PK Analyses 
At the Week 4 visit, pre-dose plasma 
concentrations of vadadustat and its 
metabolites will be obtained to evaluate 
for accumulation of study medication. 
This section has been deleted 
Editorial revision to focus protocol on 
statistical approach to primary efficacy 
analysis. Details related to all planned 
analyses will be provided in the 


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Protocol No. AKB-6548-CI-0022 
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Summary of Changes to Protocol Version 1 
 
 
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statistical analyses plan as mentioned in 
the newly added paragraph at the 
beginning of Section 11. 
18, Appendices 
Appendix C: Definitions of ESA Status Inclusion Criteria and ESA Washout Period, was added to provide additional clarity 
regarding when subjects are to washout ESA therapy.  
 
 
 
ESA use
ESA washout*
SV1
SV2
SV3
Baseline Visit
ESA use
ESA washout
ESA use
ESA washout
SV1
SV2
No prior ESA use
Baseline Visit
No ESA washout required
SV1
SV2
Baseline Visit
No ESA washout required
ESA use
ESA washout*
SV1
SV2
SV3
Baseline Visit
Subjects who are not being treated with ESAs:
Subjects who are being treated with ESAs:
Example 1:
Example 2:
Example 1:
Example 2:
Last ESA dose before SV1 <2w for epoetin alfa, beta, or kappa; 
<4w for darbepoetin alfa; or <8w for epoetin beta pegol
Last ESA dose before SV1 ≥2w for epoetin alfa, beta, or kappa; 
≥4w for darbepoetin alfa; or ≥8w for epoetin beta pegol
*After SV1 and before SV2, ≥2w off of epoetin alfa, beta, or kappa; ≥4w off of darbepoetin alfa; or ≥8w off of epoetin beta pegol


.. ~Akebia 
tt.:... 
T H E R A P E U T I C S 
NOTE TO FILE 
Protocol Number: AKB-6548-CI-0022 
Akebia Therapeutics, Inc . 
245 First Street, Suite 1100 
Cambridge, MA 02142 
T: +1 617.871 .2098 F: +1 617.871.2099 
www.akebia.com 
Protocol Title: Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Dose-Finding Study to Assess the Efficacy, Safety, Pharmacokinetics, and 
Pharmacodynamics ofVadadustat in Japanese Subjects with Anemia 
Secondary to Chronic Kidney Disease (DD-CKD) 
Protocol Section: 9.1 - Schedule of Events, Appendix B - Schedule of Activities 
for Subjects Who Were Prescribed ESAs Prior to Study Entry (ESA Washout 
is Required) 
Subject: Clarification regarding administrative errors 
Date: 16-Dec-2016 
This is to confirm that the below editorial changes will made to the English version 
of protocol AKB-6548-CI-0022 (v.2.0, 23Nov2016) at the time of the next 
protocol amendment. Please note that these edits were made in the Japanese 
version of the protocol. 
Section 9.1 - Schedule of Events: Day 42 will be updated to Day -42. 
o 
~or subjects who were prescribed CQAAtin alfa. eppetin beta. and epru;tin kappa prior 
to study entry, the screening '\isits must be performed within 6 weeks (Day 42 to 
Day 0) prior to dosing on Day 1. There \\rill be a 2-week ESA washout period 
between screening visit 1 and screening visit 2, in addition, screening visit 2 after the 
~-wk ESA washout; screening visit 3 should be ~4 days from screening '\isit 2; and 
baseline "Visit (Day 1) should be~ days from screening visit 3. 
Appendix B: Schedule of Activities for Subjects who were Prescribed ESAs 
Prior to Study Entry (ESA Washout is Required): A [c] will be added after 
Serum Pregnancy test in the Schedule of Events. 


\ .&.;..., ............... ., a..u.u 
RBC transfusion) 
review 
Serum pregnancy 
x 
x 
t.est 
Iron indices 
x 
x 
Folate and 
y 
[b] SAEs that are deemed by the investigator to be related to protocol procedures (U. ESA washout) must be reported after signing of the informed cODllent 
form. The reporting period for all no11-serious AEs md all SAEs 11ot related to protocol procedures begi!IS upoo receivUig the fast dose of study medicatio11 
md mds at the fmal protocol-required visit. 
[c] In the e\·e11t sc:n1enillg \'Wt 3 is >8 days prior to Day 1, the subject will be asked to retum to the study site for a11 Ullscheduled serum pregi:uwcy test to verify 
eligibility prior to Da}i 1. 
Printed Name: 
 
Role: 
 
Date: 
16-Dec-2016 


 
 
 
 
Akebia Therapeutics, Inc. 
245 First Street, Suite 1100 
Cambridge, MA 02142 
T: +1 617.871.2098 F: +1 617.871.2099  
www.akebia.com 
 
NOTE TO FILE  
 
 
Protocol Number:  AKB-6548-CI-0022 
 
Protocol Title: Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Finding 
Study to Assess the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Vadadustat in 
Japanese Subjects with Anemia Secondary to Dialysis Dependent Chronic Kidney Disease 
 
Subject: Administrative errors in Protocol Version 2.0 and Summary of Changes (SOC)  
 
Date: 03 February 2017 
 
 
This is to clarify that the following administrative errors were noted in Protocol version 2.0 and the 
corresponding Summary of Changes (SOC) document, dated 23 November 2016. 
 
• 
The following highlighted text the protocol synopsis, protocol section 11.2, and the SOC, is 
incorrect: “mg/dL” should be “g/dL” 
o 
Based on the results from Study AKB-6548-CI-0005 that was conducted in the United States and 
evaluated vadadustat in patients with anemia secondary to NDD-CKD, it is assumed that the expected 
mean Hb changes from baseline to Week 6 will be approximately 0 mg/dL for the placebo group and 
1.35 g/dL for the highest dose vadadustat group (600 mg daily), with a common standard deviation of 
0.68 g/dL across treatment groups.   
 
 
 
 
Printed Name: _____________________________________ Role: Clinical Project Manager 
 
 
 
 
Signature: _________________________________________ Date: _________________________  
 

SAP_001.pdf: 
Akebia Therapeutics, Inc. 
AKB-6548-CI-0022 
Statistical Analysis Plan 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 0.1 
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Page 1 of 47 
PAREXEL International 
Akebia Therapeutics, Inc. 
AKB-6548-CI-0022 
PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, DOSE-
FINDING STUDY TO ASSESS THE EFFICACY, SAFETY, PHARMACOKINETICS, 
AND PHARMACODYNAMICS OF VADADUSTAT IN JAPANESE SUBJECTS 
WITH ANEMIA SECONDARY TO DIALYSIS-DEPENDENT CHRONIC KIDNEY 
DISEASE (DD-CKD) 
Statistical Analysis Plan 
PAREXEL Project Number: 231352 
Status; Date: 
Version 1; 23 June 2017 (Original SAP) 
Version 2; 15 August 2017 
NCT Number: NCT03054350
This NCT number has been applied to the document for 
purposes of posting on clinicaltrials.gov 


Akebia Therapeutics, Inc.
AKB-6548-CI-0022
Statistical Analysis Plan 
SPONSOR SIGNATURE PAGE 
Approved by: 
 
, Biostatistics 
Akebia Therapeutics, Inc. 
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Page 2 of 47 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 0.1 
Effective Date:  25 Nov 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 3 of 47 
 
PAREXEL SIGNATURE PAGE 
 
 
 
This document has been approved and signed electronically on the final page by the 
following: 
 
 
 
Signatory 
Author  
 
Project Role: Biostatistics Lead  
 
Signatory 
Reviewer 
 
 
Project Role: Biostatistics Reviewer 
 
Project Role: Primary Statistical Programmer 
 
Project Role: MWS Reviewer 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 0.1 
Effective Date:  25 Nov 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 4 of 47 
TABLE OF CONTENTS 
 
1 
INTRODUCTION ....................................................................................................... 7 
2 
STUDY OBJECTIVES ............................................................................................... 7 
2.1 Primary Objective and Endpoint .......................................................................... 7 
2.2 Secondary Objectives and Endpoints ................................................................... 7 
3 
INVESTIGATIONAL PLAN ..................................................................................... 8 
3.1 Overall Study Design and Plan ............................................................................. 8 
3.2 Efficacy and Safety Variables ............................................................................ 10 
3.2.1 Efficacy and PD Variables ........................................................................ 10 
3.2.2 Safety Variables ........................................................................................ 10 
3.2.3 PK Variables ............................................................................................. 11 
4 
STATISTICAL METHODS ..................................................................................... 11 
4.1 Data Quality Assurance ...................................................................................... 11 
4.2 General Presentation Considerations .................................................................. 11 
4.3 Study Subjects .................................................................................................... 12 
4.3.1 Disposition of Subjects ............................................................................. 12 
4.3.2 Protocol Deviations ................................................................................... 12 
4.4 Analysis Populations .......................................................................................... 13 
4.4.1 Analysis Population for the Safety Analyses ............................................ 13 
4.4.2 Analysis Populations for the Efficacy Analyses ....................................... 13 
4.4.3 Analysis Population for the PK Analysis.................................................. 14 
4.5 Demographic and Other Baseline Characteristics .............................................. 14 
4.6 Treatment Compliance ........................................................................................ 14 
4.7 Efficacy Evaluation ............................................................................................ 15 
4.7.1 Analysis and Data Conventions ................................................................ 15 
4.7.1.1 Multi-center Studies .................................................................... 15 
4.7.1.2 Adjustments for Covariates ......................................................... 15 
4.7.1.3 Handling of Missing Data ........................................................... 15 
4.7.1.4 Multiple Comparisons/Multiplicity ............................................. 16 
4.7.1.5 Preliminary (6-Week) Analysis ................................................... 16 
4.7.1.6 Examination of Subgroups .......................................................... 16 
4.7.2 Primary Efficacy Variable – Mean Change in Hb from Pre-treatment to 
the End of the Primary Efficacy Period (Week 6) .................................... 16 
4.7.2.1 Summary of actual value and change in Hb at week 6 ............... 17 
4.7.2.2 Summary of actual value and change in Hb from baseline to week 
6 and beyond .......................................................................................... 17 
4.7.2.3 Summary of excess Hb response from baseline to week 6 and 
beyond .................................................................................................... 18 
4.7.3 Secondary Efficacy Variables ................................................................... 18 
4.7.4 Exploratory Efficacy Variable .................................................................. 22 
4.8 Safety Evaluation ................................................................................................ 22 
4.8.1 Extent of Exposure .................................................................................... 22 
4.8.2 Adverse Events ......................................................................................... 22 
4.8.3 Deaths, Serious Adverse Events, and Other Significant Adverse Events. 25 
4.8.4 Clinical Laboratory Evaluation ................................................................. 25 


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4.8.4.1 Liver function abnormality .......................................................... 25 
4.8.4.2 Serum and urine pregnancy tests ................................................. 25 
4.8.4.3 Coagulation tests ......................................................................... 26 
4.8.4.4 Folate and vitamin B12 ............................................................... 26 
4.8.4.5 Complete Blood Count (CBC) .................................................... 26 
4.8.4.6 Hemoglobin ................................................................................. 27 
4.8.4.7 Chemistry .................................................................................... 27 
4.8.4.8 C-reactive protein and Vascular Endothelial Growth Factor 
(VEGF) .................................................................................................. 27 
4.8.4.9 Laboratory Abnormalities ........................................................ 28 
4.8.5 Vital Signs, Physical Findings and Other Observations Related to Safety28 
4.8.5.1 Vital Signs and Dry Weight ........................................................ 28 
4.8.5.2 12-lead ECG ................................................................................ 29 
4.8.5.3 Physical Examination and Weight Assessment ........................... 29 
4.8.6 Safety Monitoring (Independent Data Monitoring Committee [IDMC], 
Data Monitoring Committee [DMC], Data and Safety Monitoring Board 
[DSMB]) ................................................................................................... 30 
4.9 Other Analyses .................................................................................................... 30 
4.9.1 PK Analysis .............................................................................................. 30 
4.9.2 Treatment-Emergent Outliers analysis ..................................................... 30 
4.10 
Determination of Sample Size .................................................................. 31 
4.11 
Changes in the Conduct of the Study or Planned Analysis ...................... 31 
5 
REFERENCES .......................................................................................................... 32 
6 
Statistical Analysis Plan Amendment 1 .................................................................... 33 
6.1 Modifications and changes ................................................................................. 33 
6.1.1 Rationale for the amendment .................................................................... 33 
6.1.2 Global Changes ......................................................................................... 33 
6.1.3 Specific changes........................................................................................ 33 
6.1.3.1 Section 4.7.2.2 Summary of actual value and change in Hb from 
baseline to week 6 and beyond, page 17, ............................................... 35 
6.1.3.2 Urine albumin-to-creatinine ratio (uACR) .................................. 42 
6.1.3.3 Section 4.8.6 Hemoglobin, page 27, ........................................... 42 
 
 


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Statistical Analysis Plan 
 
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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
CBC 
complete blood count 
CI 
confidence interval 
CRP 
C-reactive protein 
DD-CKD 
dialysis dependent chronic kidney disease 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
eGFR 
estimated glomerular filtration rate 
EOT 
end-of-treatment 
ESA 
erythropoiesis-stimulating agent 
Hb 
hemoglobin 
ITT 
intent-to-treat 
IV 
Intravenous 
LOCF 
last observation carried forward 
LS mean 
least-squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
modified intent-to-treat 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PT 
preferred term 
Q1 
1st quartile 
Q3 
3rd quartile 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SMQ 
standardised MedDRA queries 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TIBC 
total iron binding capacity 
TSAT 
transferrin saturation 
TTR 
time in therapeutic range 
uACR 
urine albumin-to-creatinine ratio 
VEGF 
vascular endothelial growth factor 
 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
CONFIDENTIAL 
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Project Document Effective Date: Date of last signature 
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1 
INTRODUCTION 
This study is a Phase 2 clinical study to assess the dose-response relationship between 
oral vadadustat once daily dosing for 6 weeks and the change in hemoglobin (Hb) in 
Japanese subjects with anemia secondary to dialysis dependent chronic kidney disease 
(DD-CKD); in order to define the starting dose for use in Phase 3 clinical studies in Japan. 
 
This Statistical Analysis Plan (SAP) defines the preliminary and final statistical analyses 
for the clinical study report for this study.  This should be read in conjunction with the 
study protocol that provides all necessary background information and rationale for the 
current study and its design. 
 
The pharmacokinetic data will be separately obtained from vendor to keep blindness of 
the study. 
 
This SAP is based upon the following study documents: 
• Study Protocol, Version 2 (November 23, 2016) 
• electronic Case Report Form (eCRF), Version 2.0 (January 27 2017) 
• Protocol Deviation Specification Form, Version 2.0 (February 07, 2017) 
 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective and Endpoint 
The primary objective of this study is to assess the dose-response relationship between 
oral vadadustat once daily dosing for 6 weeks and the change in Hb in Japanese subjects 
with anemia secondary to DD-CKD; this is to define the starting dose for use in Phase 3 
clinical studies in Japan. 
The primary endpoint that will be used to assess this objective is the mean change in 
Hb levels from pre-treatment to the end of the primary efficacy period (Week 6).  Pre-
treatment Hb is defined as the average of 3 Hb values obtained prior to treatment based 
on 2 qualifying screening Hb values and the Hb value at the baseline visit (Day 1). 
 
2.2 
Secondary Objectives and Endpoints 
The secondary objectives of this study are:  
•                                                                                                                                                 
To assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics 
(PD) of oral vadadustat once daily dosing in Japanese subjects with anemia 
secondary to DD-CKD during the 6-week, primary efficacy period 
• To evaluate the effect of dose adjustments and demonstrate the maintenance 
effect on Hb during a 10-week dose-adjustment and maintenance period 
• To assess the time to reach the target Hb range from baseline 
 


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The secondary endpoints that will be used to assess these objectives include the 
following: 
• Time to reach target Hb level of 10.0-12.0 g/dL from baseline visit (Day 1) 
• Mean Hb levels at the end of the primary efficacy period (Week 6) and at the end 
of the dose adjustment and maintenance period (Week 16) 
• Proportion of subjects who achieve target Hb 10.0-12.0 g/dL at the end of the 
dose adjustment and maintenance period (Week 16) 
• Mean change in Hb between pre-treatment and the end of the dose adjustment and 
maintenance period (Week 16) 
• Mean change in hematocrit, red blood cell (RBC) count, and reticulocyte count 
from baseline to the end of the primary efficacy period (Week 6) and the end of 
the dose adjustment and maintenance period (Week 16) 
• Mean change in iron indices (i.e., iron, total iron-binding capacity [TIBC], 
transferrin saturation [TSAT], and ferritin) and hepcidin from baseline to the end 
of the primary efficacy period (Week 6) and the end of the dose adjustment and 
maintenance period (Week 16) 
• Proportion of subjects requiring rescue with RBC transfusion from baseline to the 
end of the primary efficacy period (Week 6) and the end of the dose adjustment 
and maintenance period (Week 16) 
• Proportion of subjects requiring rescue with erythropoiesis-stimulating agents 
(ESAs) from baseline to the end of the primary efficacy period (Week 6) and the 
end of the dose adjustment and maintenance period (Week 16) 
• Number of dose adjustments from baseline to the end of the dose adjustment and 
maintenance period (Week 16) 
• Plasma concentration profile of vadadustat and its metabolites using pre-dose 
sample from Week 4 
 
The safety endpoints that will be used to assess these objectives include the following: 
• Safety assessments, including adverse events (AEs), vital signs, 
electrocardiograms (ECGs), and other laboratory assay results (eg, chemistry, 
components of the complete blood count [CBC] other than the ones noted above, 
and vascular endothelial growth factor [VEGF]) 
 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a Phase 2, randomized, double-blind, placebo-controlled, dose-finding study to 
assess the efficacy, safety, tolerability, PK, and PD of orally administered vadadustat in 
Japanese subjects with anemia secondary to DD-CKD.  The study does not include a pre 
specified male to female ratio. 
Approximately 48 subjects will be enrolled at approximately 35 sites in Japan.  
 There will be around 12 subjects enrolled in each of the 4 treatment groups . Please see 
the protocol section 8.2.2 for information regarding the randomization scheme.  


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An overview of the study design is presented in Figure 1. 
 
Figure 1: Overview of Study Design 
 
 
The study will include the following periods: 
• Eligibility screening period (up to 4 weeks) 
- Up to 4 weeks for subjects who were not prescribed ESAs prior to study entry 
(Day -28 to Day 0) 
- Up to 6 weeks for subjects who were prescribed epoetin alfa, epoetin beta, and 
epoetin kappa prior to study entry (Day -42 to Day 0) 
- Up to 8 weeks for subjects who were prescribed darbepoetin alfa prior to study 
entry (Day -56 to Day 0) 
- Up to 11 weeks for subjects who were prescribed epoetin beta pegol prior to 
study entry (Day -77 to Day 0) 
• Primary efficacy period (6 weeks; Weeks 1 to 6) 
• Dose adjustment and maintenance period (10 weeks; Weeks 7 to 16) 
• Follow-up period (2 weeks; Weeks 17 and 18) 
Subjects will participate in a screening period to determine study eligibility.  Subjects 
who have not recently received ESA therapy will participate in 2 screening visits.  
Subjects who have recently received ESA therapy and otherwise meet eligibility criteria 


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will be required to washout from ESA therapy prior to evaluation of screening Hb, and 
will participate in 3 screening visits. 
Eligible subjects will be randomized following the screening period using a central 
randomization system.  Subjects will be randomized 1:1:1 to receive 1, 2, or 4 tablets at 
their baseline visit (Day 1).  Within each tablet-count group, subjects will be randomized 
3:1 to receive vadadustat (150, 300, or 600 mg vadadustat) or placebo.   
Study drug treatment will be administered during a 6-week primary efficacy period.  See 
the protocol section 8.2.4 for information on study drug administration. The primary 
efficacy period includes fixed-dose treatment to establish a dose-response relationship.  
However, if Hb level increase rapidly or if the Hb levels exceeds 13.0 g/dL, the study 
drug dose can be decreased or interrupted (see the protocol section 8.2.4). 
After completing the primary efficacy period, subjects will continue to a 10-week dose 
adjustment and maintenance period (see the protocol section 8.2.5). Subjects receiving 
placebo will be switched to vadadustat, and study drug dose will be adjusted to achieve a 
target Hb of 10.0-12.0 g/dL based on dose adjustment guidelines (see the protocol section 
8.2.5). 
Vadadustat treatment will stop after the dose adjustment and maintenance period has 
been completed (Week 16) and subjects will continue in a 2-week follow-up period 
(Week 17-18). 
For subjects who were not being treated with ESAs, the clinical and safety assessments 
will be performed as described in the protocol section 9.4 and as listed in the protocol  
Appendix A.  For subjects who were being treated with ESAs prior to study entry, the 
clinical and safety assessments will be performed as described in the protocol section 9.5 
and as listed in the protocol Appendix B. 
 
3.2 
Efficacy and Safety Variables 
3.2.1 Efficacy and PD Variables 
The following variable is the primary efficacy variable: 
• 
Change from pre-treatment in Hb at Week 6. 
 
The following efficacy endpoints will also be analyzed: 
• 
Actual values and change (absolute and percent) from baseline in Hb, hematocrit, 
RBC count, and reticulocyte count (both absolute and percent) 
• 
Actual values and change (absolute and percent) from baseline in iron, TIBC, TSAT, 
ferritin, and hepcidin 
 
3.2.2 Safety Variables 
The following variables are the safety endpoints: 
• 
AEs 
• 
Vital signs 
• 
ECGs 
• 
Laboratory parameters 


Akebia Therapeutics, Inc. 
 
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3.2.3 PK Variables 
The following variables are the PK variable: 
• 
Pre-dose plasma concentrations of vadadustat at the Week 4 visit 
• 
Pre-dose plasma concentrations of vadadustat’s metabolites at the Week 4 visit 
 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently 
checked for consistency, integrity and in accordance with standard PAREXEL 
procedures. 
 
4.2 
General Presentation Considerations 
Pre-treatment Hb is defined as the average of 3 Hb values obtained prior to treatment 
based on most recently 2 qualifying screening Hb values and the Hb value at the baseline 
visit (Day 1). ‘Pre-treatment’ for other variables is defined as the last available pre-
treatment assessment.  In general, this is the value at the Baseline Visit.  ‘End of 
Treatment (EOT)’ is defined as the assessment on the EOT form labeled as ‘Week 16 
Visit’, even if other values closer to Day 113 are available. For the analysis purpose, only 
actual visit will be used and hence EOT will be presented as “Week 16”. In the summary 
table, EOT of early withdrawal will not be counted but only be displayed in the listing for 
reference purpose.  ‘Treatment Day’ will be calculated relative to start of dosing at 
Baseline Visit (i.e. Treatment Day = Assessment Date - Baseline Visit Date + 1).   
 
Continuous data will be summarized in terms of the mean, standard deviation (SD), 
median, minimum, maximum and number of observations, unless otherwise stated.  The 
minimum and maximum will be reported to the same number of decimal places as the 
raw data recorded in the database.  The mean and median will be reported to one more 
decimal place than the raw data recorded in the database.  The SD will be reported to two 
more decimal places than the raw data recorded in the database.  In general, the 
maximum number of decimal places reported shall be four for any summary statistic. 
 
Categorical data will be summarized in terms of the number of subjects providing data at 
the relevant time point (n), frequency counts and percentages.  Any planned collapsing of 
categories will be detailed in the SAP text and the data displays.   
 
Percentages will be presented to one decimal place. Percentages will not be presented for 
zero counts.  Percentages will be calculated using n as the denominator.  If sample sizes 
are small, the data displays will show the percentages, but any textual report will describe 
frequencies only.   
 


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Changes from baseline in categorical data will be summarized using shift tables where 
appropriate. 
 
P-values greater than or equal to 0.001, in general, will be presented to three decimal 
places.  P-values less than 0.001 will be presented as “<0.001”. 
 
Confidence intervals will be presented to one more decimal place than the raw data. 
 
All report outputs will be produced using SAS® version 9.3 or a later version in a secure 
and validated environment.  All report outputs will be provided to the Sponsor in a single 
Microsoft Word 2010 [Version 14.0] document. 
 
4.3 
Study Subjects 
4.3.1 Disposition of Subjects 
A clear accounting of the disposition of all subjects who enter the study will be provided, 
from screening to study completion. 
 
The summary of the following subject disposition will be presented. 
• 
A summary of the number of subjects randomized, the number and percentage of 
subjects treated (with at least one dose of study medication) and the number and 
percentage of subjects completed through Week 6 Visit and discontinued by Week 6 
Visit by treatment group and overall (Analysis population: All Subjects 
Randomized).  For final analysis, a summary of the number and percentage of 
subjects completed Week 18 Visit and discontinued from the study by treatment 
group and overall will be provided (Analysis population: All Subjects Randomized).  
Withdrawals from the study will also be summarized by major reason. 
 
By-subject listings of eligibility details, randomization details, visit dates and 
withdrawal/study completion details (including reason for discontinuation and duration of 
treatment prior to discontinuation) will be provided. 
 
4.3.2 Protocol Deviations 
Major protocol deviations are defined as those deviations from the protocol likely to have 
an impact on the perceived efficacy and/or safety of study treatments.  The impact of 
major protocol deviations on the efficacy and/or safety results will be evaluated prior to 
unblinding to determine which data and/or subjects, if any, to exclude from the analysis 
populations (see Section 4.4), 
 
Protocol deviations and any action to be taken regarding the exclusion of subjects or 
affected data from specific analyses will be determined in the Protocol Deviation 
Specification document 20170207 version 2.0.  
 
Protocol deviations will be summarized as following: 
 


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A summary of the number and percentage of subjects with a protocol deviation by 
treatment group and overall and by type of deviation and by period including primary 
period and dose adjustment and maintence period.Randomized subjects will be analyzed  
A by-subject listing of protocol deviations will be provided. 
 
4.4 
Analysis Populations 
Upon database release, protocol deviation and analysis population outputs will be 
produced and will be sent to Sponsor for review. An analysis population classification 
meeting will be arranged to discuss the outputs and to decide which subjects and/or 
subject data will be excluded from certain analyses. Decisions made regarding the 
exclusion of subjects and/or subject data from analyses will be made prior to unblinding 
and will be documented and approved by Sponsor.   
 
The following summary of analysis population will be provided: 
 
• 
A summary of the number and percentage of subjects allocated to each analysis 
population by treatment group and overall (Analysis population: All Subjects 
Randomized) 
 
A by-subject listing of analysis population details will be provided.  This listing will be 
presented by treatment group and include: site, subject identifier, inclusion/exclusion flag 
for each population and reason for exclusion from each population. All subjects 
randomized will appear on this listing. 
 
4.4.1 Analysis Population for the Safety Analyses 
The safety summaries and analyses will be based on the safety population.  The safety 
population is defined as all enrolled subjects who receive at least 1 dose of study 
medication.  In the event that a subject is allocated the incorrect study treatment as per 
the study randomization list, subjects will be summarized and analyzed ‘as treated’ i.e. by 
allocated treatment group. 
 
4.4.2 Analysis Populations for the Efficacy Analyses 
The efficacy summaries and analyses will be based on the modified intent-to-treat 
(MITT) population. The MITT population is defined as all randomized subjects who 
have received at least 1 dose of study medication and have a pre-treatment Hb average 
defined as the average of the most recently 2 qualifying screening value and the baseline 
value, and at least one post-baseline Hb measurement. The post-baseline Hb 
measurement will exclude the withdrawal Hb and follow-up Hb measurements for 
discontinued patients. In the event that a subject is allocated the incorrect study treatment 
as per the study randomization list, subjects will be summarized and analyzed ‘as 
randomized’ i.e. by randomized treatment group.   
 


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For the efficacy variables, sensitivity analyses will be performed on the per-protocol 
(PP) population to assess the robustness of the study conclusions to the choice of 
analysis population.  The PP population is defined as the subjects in the MITT population 
who have completed the study and have efficacy data through Week 6, have a study 
medication compliance of ≥80%, and do not have any major protocol deviations expected 
to significantly affect the primary efficacy endpoint.  Subjects with major protocol 
deviations expected to significantly affect the primary efficacy endpoint will be identified 
and documented prior to data unblinding.   
 
4.4.3 Analysis Population for the PK Analysis 
The PK summaries and analyses will be based on the pharmacokinetics (PK) 
population.  The PK population is defined as all subjects in the safety population who 
have a pre-dose PK sample at Week 4. Subjects will be summarized and analyzed by 
actual treatment group. 
 
4.5 
Demographic and Other Baseline Characteristics 
The demographic and other baseline characteristics will be summarized for the MITT and 
safety populations.  The following summaries will be provided: 
 
• 
A summary of demographic variables (e.g. age, gender, weight, height and body 
mass index [BMI]) by treatment group and all subjects. 
• 
A summary of other relevant variables (e.g. etiology of CKD and smoking status) by 
treatment group and all subjects. 
• 
A summary of relevant medical and surgical history by treatment group and all 
subjects. 
• 
A summary of relevant medical history by treatment group and all subjects. 
• 
A summary of prior and concomitant medications within 30 days prior to the first 
study drug dose up to and including Week 6 by treatment group and overall. 
• 
For the final analysis, a summary of concomitant medications after Week 6 will be 
provided. 
 
Age will be calculated as the number of complete years between a subject's birth date and 
the date of informed consent. 
 
By-subject listings of demographic data and other baseline characteristics (as summarized 
above) will be provided. 
 
4.6 
Treatment Compliance 
The treatment compliance will be summarized for the MITT and safety population.  The 
following summary will be provided. 
 
• 
A summary of the treatment compliance measures (i.e. ≥80% compliance and <80%) 
by treatment group and study visit. 


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A by-subject listing of treatment compliance data will be provided. 
 
4.7 
Efficacy Evaluation 
4.7.1 Analysis and Data Conventions 
This study is designed to test for dose-response relationship.  An analysis of covariance 
(ANCOVA) model will be used to compare absolute change from pre-treatment in Hb 
between the 3 vadadustat dosing groups and the placebo group.  The model will include 
treatment assignment (3 dosed groups and one placebo group) and pre-treatment Hb 
value as a covariate.  A step-down procedure will be used to control the overall type I 
error rate for the multiple comparisons.  Testing of the highest dose compared with 
placebo will be conducted first.  If and only if this comparison is significant, then testing 
will proceed to comparison of the next lower dose and placebo, and so on.  Therefore, no 
multiplicity adjustment will be needed for this analysis. 
 
A linear regression dose-response modeling will be performed as a secondary analysis. 
 
Y = 𝛽0 + 𝛽𝑑𝑜𝑠𝑒𝑋 
 
where Y is change in Hb and X is vadadustat dose.  βxs are parameters of the model.  β0 is 
intercept and βdose is slope, respectively. 
 
The null hypothesis for the dose response will be that the regression coefficient of slope 
parameter is zero.  The alternative hypothesis will be that the regression coefficient is not 
zero.  Symbolically, this is expressed as follows: 
 
𝐻0: 𝛽𝑑𝑜𝑠𝑒= 0 
𝐻1: 𝛽𝑑𝑜𝑠𝑒≠0 
 
This hypothesis will be tested using a 0.05 two-sided significance level. 
 
4.7.1.1 Multi-center Studies 
Not Applicable.  Analysis of center effect is not planned. 
 
4.7.1.2 Adjustments for Covariates 
The primary efficacy analysis will be adjusted for the pre-treatment measure of primary 
efficacy variable. 
 
An ‘unadjusted’ sensitivity analysis will be performed to assess the robustness of the 
study conclusion. 
 
4.7.1.3 Handling of Missing Data 
For the MITT population analyses for the primary efficacy variable, the Last Observation 
Carried Forward (LOCF) approach will be used to impute missing data for primary 
efficacy analysis. 


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Subjects who underwent dose reduction before week 6 will not 
be analyzed differently from subjects who did not undergo dose reduction. This means 
we will use the actual Hb at week 6 for all subjects except the missing data, which will be 
carried from the last Hb before week 6 and after baseline. 
 
• If a Baseline value is missing, the last value prior to baseline will be carried forward 
to the Baseline value but not to further values during the treatment period. 
• For post-Baseline assessments, hemoglobin measurements at end of treatment and 
follow-up visits are not carried  forward. Other than that, the most recent post-
baseline assessments to the primary evaluation period (week 6 will be carried forward 
. Baseline and pre-Baseline values will not be carried forward to the post-Baseline 
visits. 
 
For the secondary endpoint analyses, data will be used as observed and no imputation 
method will be used. 
 
4.7.1.4 Multiple Comparisons/Multiplicity 
Analysis of one primary variable [Change in Hb] and one time point of primary interest 
[Week 6 visit] has been defined for this study.  Though 3 pairwise comparison between 
placebo and dosed group is planned, step-down procedure will be used to control the 
overall type I error rate.  The secondary variables defined are intended to provide 
supportive evidence relating to the primary objective and no labeling claims are intended.  
Though one preliminary analysis is planned before the final analysis, primary analysis 
will not be changed.  Therefore no adjustments for multiplicity are required. 
 
4.7.1.5 Preliminary (6-Week) Analysis 
After all subject performed assessment of the Week 6 Visit, preliminary analysis will be 
performed.  As the study conduct and final analysis will not be modified by this analysis, 
no alpha adjustment is proposed. It is expected that this 6-week data  
will be identical for the preliminary analysis and the final analysis of the complete dataset.  
Any changes between the preliminary analysis and the final analysis will be documented. 
The preliminary analysis will be performed by the independent unblinded team. All data 
through the cutoff date of the last subject randomized who completes week 6 will be 
analyzed. Blinding of blinded team and investigators will be maintained to prevent 
potential bias. 
 
4.7.1.6 Examination of Subgroups 
Not Applicable.  No subgroup analysis is planned. 
 
4.7.2 Primary Efficacy Variable – Mean Change in Hb from Pre-treatment to the 
End of the Primary Efficacy Period (Week 6) 
The primary variable for the assessment of efficacy is the change from pre-treatment to 
Week 6 in Hb (g/dL).  Change in Hb is defined as the Hb measured at the Week 6 visit 


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minus the mean pre-treatment Hb.  Pre-treatment Hb is defined as the average of 3 Hb 
values obtained prior to treatment based on 2 qualifying screening Hb values and the Hb 
value at the baseline visit (Day 1). If screening visit are not performed for some clinical 
consideration, pre-treatment HB will be calculated as average of available screening HB 
values and baseline visit without any screening visit imputation.  e.g. if only one 
qualifying screening HB values available in the screening period, then Pre-treatment Hb 
is calculated as the average of 2 Hb values : only 1 qualifying screening Hb values and 
the Hb value at the baseline visit (Day 1). 
 
For the primary analysis, the LOCF approach will be used to impute missing data.   
 
4.7.2.1 Summary of actual value and change in Hb at week 6  
 
The primary analysis population for efficacy will be MITT population.  The following 
summary will be provided: 
• 
A summary of actual value of Hb by treatment group at baseline and week 6. A 
summary of the change (absolute and percent) from pre-treatment average in Hb by 
treatment group at week 6.  1st and 3rd quartiles (Q1, Q3) as well as the mean, SD, 
median, minimum, maximum and number of observations will be shown.  P values 
for overall comparison and treated groups vs. placebo on change from pre-treatment 
will also be presented.  
• 
A waterfall plot for absolute Hb change from pre-treatment average for each 
treatment group at week 6. 
 
The effect of treatment in terms of the change from pre-treatment to Week 6 in Hb will 
be analyzed using a one-way analysis of covariance (ANCOVA). The statistical model 
will assess the main effect of treatment, adjusted for pre-treatment average. Least-squares 
(LS) means for each treatment and their 95% confidence intervals (CIs) will be presented.  
Three post-hoc pairwise comparison, i.e., Placebo vs 150 mg, placebo vs 300 mg, and 
placebo vs 600 mg, will be done. Unadjusted one-way analysis of variance (ANOVA) 
will be performed for sensitivity. 
 
The simple linear regression between the change from pre-treatment to Week 6 in Hb and 
dose will be calculated. The regression coefficients and their standard errors, p-values of 
test of regression parameters and their 95%CIs will be presented. The test of slope 
parameter will be used to evaluate dose response relationship. 
 
As sensitivity analyses, efficacy endpoints will also be analyzed using the PP population. 
 
A by-subject listing of actual values and change (absolute and percent) from baseline in 
Hb will be provided. 
 
4.7.2.2 Summary of actual value and change in Hb from baseline to week 6 and beyond 
 
The analysis population for efficacy will be MITT and PP population. The following 
summary will be provided: 


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• 
A summary of actual value of Hb by treatment group and study visits.  1st and 3rd 
quartiles (Q1, Q3) as well as the mean, SD, median, minimum, maximum and 
number of observations will be shown.  Summary of pre-treatment average will also 
be presented. 
• 
A summary of the change (absolute and percent) from baseline in Hb by treatment 
group and study visits. 
• 
A plot showing the mean Hb value over time within each treatment group. 95% CI of 
these means will be shown as error bar and sample size in each group at each time 
point will be shown. 
• 
Plots of individual profile of Hb values over time within each treatment group. 
• 
Box plots of absolute Hb changes for each treatment group from pre-treatment study 
average to week 6. 
• 
Box plots of absolute Hb changes for each treatment group from pre-treatment study 
average to week 16  
 
 
A by-subject listing of actual values and change (absolute and percent) from baseline in 
Hb will be provided. 
 
4.7.2.3 Summary of excess Hb response from baseline to week 6 and beyond 
 
The analysis population for efficacy will be MITT and PP population. The following 
summary will be provided: 
• A summary of subject with three excess Hb criteria: Hb>13 g/dL, Hb>12 g/dL to 
13 g/dL and >1 g/dL increment in a 2-week period will be provided by treatment 
group on 2-week basis starting from baseline to week 18. In addition, the period 
starting from baseline to week 16, primary efficacy period (baseline to week 6) 
and dose adjustment and maintenance period (week 7 to week 16) will also be 
presented within three excess HB criteria. 
 
 
4.7.3 Secondary Efficacy Variables 
The analysis population for efficacy will be MITT and PP population.   
 
Change from baseline visit to Week 6 in HB (g/dL). 
The following summaries will be provided: 
• 
A summary of actual value of Hb by treatment group at baseline and week 6. A 
summary of the change (absolute and percent) from baseline in Hb by treatment 
group at week 6.  1st and 3rd quartiles (Q1, Q3) as well as the mean, SD, median, 
minimum, maximum and number of observations will be shown.  P values for overall 
comparison and treated groups vs. placebo on change from baseline will also be 
presented.  
• 
The effect of treatment in terms of the change from pre-treatment to Week 6 in Hb 
will be analyzed using a one-way analysis of covariance (ANCOVA). The statistical 
model will assess the main effect of treatment, adjusted for Baseline. Least-squares 
(LS) means for each treatment and their 95% confidence intervals (CIs) will be 


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presented.  Three post-hoc pairwise comparison, i.e., Placebo vs 150 mg, placebo vs 
300 mg, and placebo vs 600 mg, will be done. Unadjusted one-way analysis of 
variance (ANOVA) will be performed for sensitivity. 
• 
The simple linear regression between the change from Baseline to Week 6 in Hb and 
dose will be calculated. The regression coefficients and their standard errors, p-
values of test of regression parameters and their 95%CIs will be presented. The test 
of slope parameter will be used to evaluate dose response relationship. 
• 
A waterfall plot for absolute Hb change from baseline for each treatment group at 
week 6. 
• 
A summary of the number and percentage of subjects who achieved a ≥1 g/dL 
increase in Hb from baseline average will be provided by treatment group. 
 
Time to reach target Hb level 
Time to reach target Hb level of 10.0-12.0 g/dL from baseline is defined for subjects with 
Hb <10.0 g/dL at the baseline visit as following: 
First post-treatment assessment date with value of Hb ≥10.0 and ≤12.0 g/dL – the 
baseline visit date +1. If target Hb level is not achieved, last Hb assessment date will be 
used as censored date. 
 
A summary of time to reach target Hb level will be provided for subjects with Hb 
<10.0 g/dL at the baseline visit by treatment group. 
 
 
A by-subject listing will be provided. 
 
Hb within target Range 
A summary of the number and percentage of subjects within target Hb 10-12 g/dL at the 
end of the dose adjustment and maintenance period (Week 16) will be provided by 
treatment group. 
 
The number and percentage of subjects above / within / below target range who are 
maintained within the target range at their previous visit after Week 6 will be provided by 
treatment group. 
 
The effect of treatment in terms of the proportion of subjects within target Hb level at 
Week 6 will be analyzed using Fisher’s exact test.  Three post-hoc pairwise comparison, 
i.e., placebo vs 150 mg, placebo vs 300 mg, and placebo vs 600 mg, will be done. 
 
A by-subject listing will be provided. 
 
Increase in Hb from pre-treatment average 
A summary of the cumulative number and percentage of subjects who achieved a ≥1 g/dL 
increase in Hb from pre-treatment average will be provided by treatment group. In 
addition, the cumulative proportion of subjects within target range will be displayed 
graphically from baseline visit to follow up visit by treatment group. 
 


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The effect of treatment in terms of the proportion of subjects who achieved a ≥1 g/dL 
increase in Hb from pre-treatment average will be analyzed using Fisher’s exact test.  
Three post-hoc pairwise comparison, i.e., Placebo vs 150 mg, placebo vs 300 mg, and 
placebo vs 600 mg, will be done. 
 
Hematocrit, RBC count, and reticulocyte count (CBC) 
Hematocrit, RBC count, and reticulocyte count (both absolute and percent) will be 
analyzed as secondary efficacy variables. 
 
The following summaries will be provided: 
• 
A summary of hematocrit, RBC count, and reticulocyte count (both absolute and 
percent) by treatment group and time point.  1st and 3rd quartiles (Q1, Q3) as well as 
the mean, SD, median, minimum, maximum and number of observations will be 
presented. 
• 
A summary of the change (absolute and percent) from baseline in hematocrit, RBC 
count, and reticulocyte count (both absolute and percent) by treatment group and 
time point. 
• 
Box plots of absolute changes from baseline in hematocrit, RBC count, and 
reticulocyte count for each treatment group at each post-treatment time point. 
 
The effect of treatment in terms of the change from baseline to Week 6 in hematocrit and 
RBC count and reticulocyte count (both absolute and percent) will be analyzed using 
ANCOVA.  The statistical model will assess the main effect of treatment, adjusted for 
baseline measurement.  LS-means for each treatment and their 95% CIs will be presented.  
Three post-hoc pairwise comparison, i.e., Placebo vs 150 mg, placebo vs 300 mg, and 
placebo vs 600 mg, will be done.  Unadjusted ANOVA will be performed for sensitivity. 
 
A by-subject listing of hematocrit, RBC count, and reticulocyte count (both absolute and 
percent) will be provided by treatment group. 
 
Iron indices and hepcidin 
Iron indices (i.e., iron, TIBC, TSAT, and ferritin) and hepcidin will be analyzed as 
secondary efficacy variables. 
 
The following summaries will be provided: 
• 
A summary of iron indices and hepcidin by treatment group and time point 
• 
A summary of the change (absolute and percent) from baseline in iron indices and 
hepcidin by treatment group and time point 
• 
Box plots of absolute changes from baseline in iron indices and hepcidin for each 
treatment group at each post-treatment time point 
 
A by-subject listing of iron indices and hepcidin will be provided by treatment group. 
 
Rescue therapy & ESA administration  
Initiation of rescue therapy will be analyzed. 
 


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The following Rescue therapy summaries will be provided: 
• 
A summary of the number and percentage of subjects requiring rescue with RBC 
transfusion from baseline to the end of the primary efficacy period (Week 6) and the 
end of the dose adjustment and maintenance period (Week 16) 
• 
A summary of the number and percentage of subjects requiring rescue with ESAs 
from baseline to the end of the primary efficacy period (Week 6) and the end of the 
dose adjustment and maintenance period (Week 16) An ESA rescue is defined to 
fulfill the following 4 criteria simultaneously: 
1. ESA administration, and 
2. ESA administered because the subject experienced a clinically significant 
worsening of their anemia or symptoms of anemia,  and 
3. ESA administered because the subject's Hb level is <9.0 g/dL, and 
4. Subjects’ reason for early study withdrawal is because of “Worsening of 
anemia requiring ESA rescue or blood transfusion”. 
 
The following ESA administration summaries will be provided: 
 
• 
A summary of the number and percentage of subjects requiring administration with 
ESAs from baseline to the end of the primary efficacy period (Week 6) and the end 
of the dose adjustment and maintenance period (Week 16) 
 
The effect of treatment in terms of the proportion of subjects requiring RBC transfusion / 
ESAs administration will be analyzed using Fisher’s exact test. Three post-hoc pairwise 
comparison, i.e., Placebo vs 150 mg, placebo vs 300 mg, and placebo vs 600 mg, will be 
done. 
 
By-subject listings of rescue therapies and ESA administration will be provided by 
treatment group. 
 
Average Daily Dose 
A summary of Average Daily Dose by treatment group and visit will be presented with  
1st and 3rd quartiles (Q1, Q3) as well as the mean, SD, median, minimum, maximum and 
number of observations.  
 
Dose adjustment 
A overview summary of the number of dose adjustments from baseline to the end of the 
dose adjustment and maintenance period (Week 16) will be provided. 
 
A summary of the number of dose adjustments by visit from baseline to the end of the 
dose adjustment and maintenance period (Week 16) will be provided. 
 
A by-subject listing of dose adjustment with HB change will be provided by treatment 
group. The three flags of HB change will be presented as follows: 
• HB>13 g/dL at any time of study 
• HB >12 g/dL to 13 g/dL at dose adjustment and maintenance period only  
• HB increase >1 g/dL over 2 weeks at any time of study. 


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4.7.4 Exploratory Efficacy Variable 
Time in Therapeutic Range (TTR) for Hb from week 6 to week 20 
The half-time interpolation method will be used to calculate TTR for Hb.  The total time 
of follow-up with Hb in target range of 10.0 to 12.0 g/dL is divided by the total time. 
Half the time between two tests is allocated to the first Hb value, and half to the second 
Hb value.  
 
A summary of TTR for Hb will be provided by treatment group. 
 
A by-subject listing of TTR for Hb will be provided by treatment group 
 
4.8 
Safety Evaluation 
All safety summaries and analyses will be based upon the safety population as defined in 
Section 4.4. 
 
4.8.1 Extent of Exposure  
The extent of exposure will be summarized for the safety population.  The following 
summary will be provided. 
• 
A summary of the treatment duration (e.g. End Date of Administration - Start date of 
Administration +1) by treatment group and study visits. 
 
A by-subject listing of start, end and duration of treatment will be provided. 
 
4.8.2 Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 19.0.   
 
Treatment-emergent adverse events (TEAEs) will be tabulated and are defined as those 
AEs that either start or worsen in severity on or after the date/time of first dose of study 
treatment and on or before the final protocol required visit.  In general, it is Week 18 
Visit and 14 days after the date of last dose of study treatment. The TEAEs are defined as 
those adverse events that started after first injection up to 14 days post-last dose.   
 
Where AEs dates are missing or partially missing, AEs will be assumed to be treatment-
emergent, unless there is clear evidence (through comparison of partial dates) to suggest 
that the AE started prior to the first dose of study treatment or more than 14 days after the 
last dose of study treatment.   
Partial AE start dates will be imputed as follows: 


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Statistical Analysis Plan 
 
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CONFIDENTIAL 
Project Document Version No. 0.1 
Effective Date:  25 Nov 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
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1. If the year (and month and day) is unknown, the date will be imputed as the date of 
first intake of study treatment if this is possible (i.e., the event end date is not prior to 
treatment start date). 
2. If the month and day is unknown then: 
a. If the year matches the first dose date, then impute the month and day of the 
first dose date. 
b. If the year is earlier than the first dose date or the first dose date is not available 
(subject is not dosed) and matches the year of informed consent date, then impute 
the month and day of the informed consent date; 
c. Otherwise, assign January 1. 
3. If the day is unknown then: 
a. If the month and year match the first dose date, then impute the day of the first 
dose date. 
b. If the month and year are earlier than the first dose date or the first dose date is 
not available (subject is not dosed) and matches the month and year of the 
informed consent date, then impute the day of the informed consent date; 
c.Otherwise, assign ‘1’. 
Partial AE stop dates will be imputed as follows: 
1. If the year is unknown, the date will not be imputed and will be assigned a missing 
value. 
2. If the month is unknown, then assign December. 
3. If the day is unknown, then assign the last day of the month.  
For all other settings (eg. year missing, but day and month available etc.), imputation 
strategies will be reviewed and decided in the ongoing data cleaning and sponsor 
meetings.   
If the start and/or stop dates of medications other than study treatments are missing or 
partially missing, the dates will be compared as far as possible with the date of first study 
treatment administration.  
If not specified, observed data approach will be performed. 
 
The AE will be summarized using MedDRA system organ class (SOC) and preferred 
term (PT).  All AE summaries will provide the number of subjects reporting at least one 
AE and the total number of events reported.  The following summaries will be provided: 
 
• 
A summary of the number and percentage of subjects reporting at least one TEAE, 
drug-related TEAE, TEAE leading to withdrawal, serious adverse event (SAE), drug-
related SAE, SAE leading to withdrawal and death by treatment group. 
• 
A summary of the number and percentage of subjects reporting a TEAE by treatment 
group, SOC, and PT 


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Statistical Analysis Plan 
 
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• 
A summary of the number and percentage of subjects reporting a drug-related TEAE 
by treatment group, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a treatment-emergent 
SAE by treatment group, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a SAE  during the 
screening period Assessed as Related to Protocol Procedures by treatment group, 
SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a drug-related 
treatment-emergent SAE by treatment group, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a drug-related TEAE 
leading to withdrawal by treatment group, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a TEAE leading to 
withdrawal by treatment group, SOC, and PT 
• 
A summary of the most common TEAEs by treatment group and PT (reported by 
>10% of subjects in any treatment group) 
• 
A summary of the number and percentage of subjects reporting a TEAE by treatment 
group, severity, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a TEAE by treatment 
group, relationship, SOC, and PT 
 
AE summaries will be ordered alphabetically for SOC, and PT within SOC. 
 
For each subject and each AE, the worst severity recorded will be attributed and used in 
the by-severity summaries.  Similarly, the worst causality (most related to treatment) will 
be attributed and used in the by-causality summaries.  If severity or causality is missing, 
data will be treated as observed. 
 
A by-subject listing of all AEs (including non-treatment-emergent events) 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), date of onset, date of 
resolution, duration, severity, seriousness, action taken, outcome and causality.  
 
The following AEs are defined as AEs of special interest.  Summaries of the number and 
percentage of subjects reporting the following AEs will be provided. 
• 
PT: “hyperkalemia” (MedDRA 10020646) or “blood potassium increased” 
(MedDRA 10005725) 
• 
PT:  “hyperuricaemia” (MedDRA 10020903) or “blood uric acid level increased” 
(MedDRA 10022891) 
• 
PT: “Hypertension” (MedDRA 10020772) or “Blood pressure increased” (MedDRA 
10005750) or “Blood pressure systolic  increased” (MedDRA 10005760) or “Blood 
pressure diastolic increased” (MedDRA 10005739) or “Blood pressure ambulatory 
increased” (MedDRA 10005732) or “Blood pressure inadequately controlled” 
(MedDRA 10051128) or “Accelerated hypertension” (MedDRA 10000358) or 
“Essential hypertension” (MedDRA 10015488) or “Diastolic hypertension” 
(MedDRA 10012758) or “Systolic hypertension” (MedDRA 10042957) or 
“Malignant hypertension” (MedDRA 10025600) 


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Statistical Analysis Plan 
 
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• 
Standardised MedDRA Query (SMQ): “Cholestasis and jaundice of hepatic origin” 
(SMQ 20000009) or “Drug related hepatic disorders – severe events only” (SMQ 
20000007) or “Liver related investigations, signs and symptoms” (SMQ 20000008) 
• 
Standardised MedDRA Query (SMQ): “Ischaemic heart disease” (SMQ 20000043) 
• 
SMQ: “Central nervous system haemorrhages and cerebrovascular conditions” (SMQ 
20000061) 
• 
SMQ: “Embolic and thrombotic events” (SMQ 20000081)  
• 
SMQ: “Cardiac failure” (SMQ 20000004)  
• 
SMQ: “Retinal disorders” (SMQ 20000158, narrow) 
 
Serious adverse events that occur during the screening period and are assessed by the 
investigator as related to study procedures will be tabulated separately from treatment-
emergent serious adverse events. 
 
4.8.3 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
Other significant AEs are those AEs reported as leading to withdrawal from study.  The 
summaries of SAEs and AEs leading to withdrawal from study are described in section 
4.8.2. 
 
A summary of the number and percentage of deaths during the study will be provided by 
treatment group. 
 
A summary of the number and percentage of subjects Adverse Events Leading to Death 
by treatment group, severity, SOC and PT 
 
A by-subject listing of all deaths that occurred during the study will be provided. 
 
4.8.4 Clinical Laboratory Evaluation 
4.8.4.1 Liver function abnormality  
A summary of Liver function abnormality by visit will be provided by treatment group. 
Any subject with at least one of the following liver function abnormalities is summarized: 
• ALT ≥2x and <3x ULN 
• AST ≥2x and <3x ULN 
• Bilirubin ≥2x and <3x ULN 
• ALT ≥3x ULN 
• AST ≥3x ULN 
• Bilirubin ≥3x ULN 
 
4.8.4.2 Serum and urine pregnancy tests 
Serum pregnancy test for females of childbearing potential will be performed at the 
screening visit and will be used for subject’s inclusion / exclusion.  Urine pregnancy test 
will be performed at the baseline visit and used for subject’s initiation of study drug.  
Additional pregnancy tests may be conducted during the study to establish the absence of 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
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CONFIDENTIAL 
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pregnancy based on the investigator’s clinical judgment or as required by local 
regulations. 
 
 
A by-subject listing of serum and urine pregnancy tests will be provided. 
 
4.8.4.3 Coagulation tests 
Coagulation tests will be performed at the baseline visit.  The following variables will be 
analyzed. 
• 
prothrombin time 
• 
partial thromboplastin time 
• 
international normalized ratio 
 
A summary of baseline coagulation test results will be provided by treatment group. 
 
A by-subject listing of coagulation tests will be provided. 
 
4.8.4.4 Folate and vitamin B12 
Folate and vitamin B12 tests will be performed at the screening visit and will be used for 
subject’s inclusion / exclusion. 
 
 
A by-subject listing of folate and vitamin B12 tests will be provided. 
 
 
4.8.4.5 Complete Blood Count (CBC) 
The following components of the CBC are described in Efficacy / PD analysis section. 
• 
Hb 
• 
Hematocrit 
• 
RBC count 
• 
Automated Reticulocyte Count (both absolute and percent). 
 
The following components of the CBC will be analyzed: 
• 
Mean Corpuscular Volume 
• 
Mean Corpuscular Hb 
• 
Mean Corpuscular Hb Concentration 
• 
Red Cell Distribution Width 
• 
White Blood Cell count with differential (neutrophils, bands, lymphocytes, 
monocytes, eosinophils, and basophils) 
• 
Platelets 
 
The following summaries will be provided: 
• 
A summary of each component of the CBC by treatment group and time point 
• 
A summary of the change from baseline in each component of the CBC by treatment 
group and time point 
 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
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CONFIDENTIAL 
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Project Document Effective Date: Date of last signature 
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A by-subject listing of CBC will be provided by treatment group. 
 
4.8.4.6 Hemoglobin 
The following Hb analyses will be performed for safety analysis section: 
• 
A summary of the number and percentage of subjects with Hb increase > 1.0 g/dL in 
any 2-week interval by treatment group 
 
4.8.4.7 Chemistry  
The following laboratory parameters will be analyzed: 
• 
Sodium 
• 
Potassium 
• 
Bicarbonate 
• 
Chloride 
• 
Calcium 
• 
Phosphorus 
• 
Glucose 
• 
Creatinine 
• 
Blood Urea Nitrogen 
• 
Creatine Phosphokinase 
• 
Uric Acid 
• 
Albumin 
• 
Total Protein 
• 
Total Bilirubin 
• 
Alkaline Phosphatase 
• 
Alanine Aminotransferase (ALT) 
• 
Aspartate Aminotransferase (AST) 
• 
Lactate Dehydrogenase 
• 
Total cholesterol 
 
The following summaries will be provided: 
• 
A summary of Chemistry by treatment group and time point 
• 
A summary of the change (absolute and percent) from baseline in Chemistry by 
treatment group and time point 
 
 
A by-subject listing of Chemistry will be provided by treatment group. 
 
 
4.8.4.8 C-reactive protein and Vascular Endothelial Growth Factor (VEGF) 
The following summaries will be provided: 
• 
A summary of C-reactive protein (CRP) ,VEGF and total cholesterol by treatment 
group and time point 
• 
A summary of the change (absolute and percent) from baseline in CRP ,VEGF and 
total cholesterol by treatment group and time point 
 
The effect of treatment in terms of the change from baseline to Week 6 in CRP , VEGF 
and total cholesterol will be analyzed using ANCOVA.  The statistical model will assess 


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Statistical Analysis Plan 
 
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the main effect of treatment, adjusted for baseline measurement.  Three post-hoc pairwise 
comparison, i.e., placebo vs 150 mg, placebo vs 300 mg, and placebo vs 600 mg, will be 
done.  Unadjusted ANOVA will be performed for sensitivity. 
 
A by-subject listing of CRP and VEGF will be provided by treatment group. 
 
4.8.4.9 Laboratory Abnormalities  
 
A summary of the number and percentage of subjects experiencing abnormal values by 
selected laboratory parameter with over with over CTCAE v.4.0 grade 3, treatment group 
and period will be presented. 
 
 The following parameter will be analyzed: 
• 
Albumin 
• 
Alkaline Phosphatase 
• 
Calcium 
• 
Creatine Kinase 
• 
Glucose 
• 
Phosphate 
• 
Potassium 
• 
Protein 
• 
Sodium 
• 
Alanine Aminotransferase 
• 
Aspartate 
• 
Aminotransferase 
• 
Bilirubin 
• 
Leukocytes 
• 
Lymphocytes 
• 
Neutrophils 
• 
Platelets 
• 
Activated Partial 
• 
Thromboplastin Time 
• 
Prothrombin Time 
 
4.8.5 Vital Signs, Physical Findings and Other Observations Related to Safety 
4.8.5.1 Vital Signs and Dry Weight 
The following variables of vital signs will be analyzed: 
• 
Blood Pressure (Systolic / Diastolic) 
• 
Heart Rate 
• 
Respiratory Rate 
• 
Body Temperature 
 
A summary table of subjects with blood pressure measured values after baseline visit will 
be provided by treatment group (Note: two categories of potential outlier for systolic 
blood pressure are >=160 mmHg and <180 mmHg, >=180 mmHg; two categories of 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 0.1 
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Project Document Effective Date: Date of last signature 
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potential outlier for diastolic blood pressure are >=100 mmHg and <110 mmHg, >=110 
mm/Hg) as well as subjects with increment from baseline (Note: two categories of 
potential outlier for systolic blood pressure increasing from baseline are >=20 mmHg and 
<40 mmHg, >=40 mmHg; two categories of potential outlier for diastolic blood pressure 
are >=10 mmHg and <20 mmHg, >=20 mmHg). 
 
A summary table of subjects with heart rate measured values after baseline visit (two 
categories of potential outlier: >=100 beats/min and <120 beats/min, >=120 beats/min) 
will be provided by treatment group as well as subjects with increment from baseline 
(two categories of potential outlier: >=20 beats/min and <30 beats/min, >=30 beats/min) 
 
The following summaries will be also provided: 
• 
A summary of each vital sign parameter and dry weight by treatment group and time 
point. 
• 
A summary of the change (absolute and percent) from baseline in each vital sign 
parameter by treatment group and time point. 
 
Any findings of treatment-emergent vital sign and dry weight abnormalities will be 
handled as adverse event and reported in AE tables / listings. 
 
A plot showing the mean blood pressure over time within each treatment group.  95% CI 
of these means will be shown as error bar and sample size in each group at each time 
point will be shown.  
 
A by-subject listing of vital sign parameter with reference ranges will be provided. 
 
4.8.5.2 12-lead ECG 
The following variables will be analyzed at the Baseline Visit: 
• 
Heart rate 
• 
PR interval 
• 
QT interval 
• 
QRS interval 
• 
QTc (corrected) 
• 
Overall result 
 
A summary of each ECG parameter will be provided by treatment group. 
 
A by-subject listing of 12-lead ECG results will be provided. 
 
4.8.5.3 Physical Examination and Weight Assessment 
Physical Examination and Weight Assessment will be performed at the Screening Visit 
and used for subject’s inclusion / exclusion.  Weight and height will be reported in 
demographic tables and listings. 
 


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Statistical Analysis Plan 
 
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4.8.6 Safety Monitoring (Independent Data Monitoring Committee [IDMC], Data 
Monitoring Committee [DMC], Data and Safety Monitoring Board [DSMB])  
Not applicable.  No change of study conduct based on preliminary analysis result is 
planned. 
 
4.9 
Other Analyses 
4.9.1 PK Analysis 
The following summary will be provided: 
• 
The summary of pre-dose plasma concentrations of vadadustat and its metabolites at 
Week 4 Visit by treatment group. 
• 
Box plots of pre-dose plasma concentrations of vadadustat and its metabolites at 
Week 4 Visit by treatment group. 
• 
Dose-normalized box plots of pre-dose plasma concentrations of vadadustat and its 
metabolites at Week 4 Visit by treatment group. 
 
Concentrations below the limit of quantification (BLQ) will be replaced by the 0 for the 
calculation of descriptive statistics. So concentration contains BLQ values are treated as 0 
for all summary statistics except geometric mean and its related parameters.  
 
By-subject listings of pre-dose plasma concentrations of vadadustat and its metabolites 
will be provided by treatment group. 
4.9.2 Treatment-Emergent Outliers analysis 
 
The purpose of this analysis is to identify the treatment Emergent outliers by each 
prescribed dose at each period. The definition of prescribed doses is the subjects with 
latest dose amount at planned visit when dose change. e.g. if at Week 2 with dose 600 mg 
and dose reduced to 450 mg at week 4, then visit of prescribed dose for VADA 450 was 
assigned to Week 4. 
However, if subject had dose reduction on 150 mg or had interruption of study 
medication, the prescribed dose will be considered as 0 mg. 
 
Only treatment-emergent outliers will be counted but outliers at the baseline and 
screening visits will be excluded. 
 
The following summary will be provided: 
• The summary of subjects with prescribed Dose by treatment group and time point 
• The summary of subjects with prescribed Dose by Above/Within/Below the target 
Hb Range and  treatment group 
 
In addition, the below components will be analyzed by primary efficacy period and dose 
adjustment and maintenance period for all subjects and for subjects with non-elevated 
values at baseline: 
 
• Non-elevated at baseline definition for each component 


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o Systolic Blood Pressure <140 mmHg 
o Diastolic Blood Pressure<90 mmHg 
o Heart Rate <100 bpm 
o Potassium<4 mEq/L 
 
The following component with following criteria will be applied. 
• Systolic Blood Pressure  
o Any SBP >=160 to <180 mmHg 
o Any SBP >=180 mmHg 
o Any SBP increase from baseline >=20 to <40 mmHg 
o Any SBP increase from baseline >=40 mmHg 
• Diastolic Blood Pressure 
o Any DBP >=100 to <110 mmHg 
o Any DBP >=110 mmHg 
o Any DBP increase from baseline >=10 to <20 mmHg 
o Any DBP increase from baseline >=20 mmHg 
• Heart Rate 
o Any pulse >=100 to <120 bpm 
o Any pulse >=120 bpm 
o Any pulse increase from baseline >=20 to <30 bpm 
o Any pulse increase from baseline >=30 bpm 
• Potassium 
o Any Potassium >5.5 to 6.0 mEq/L 
o Any Potassium >6.0 to 6.5 mEq/L 
o Any Potassium >6.5 mEq/L 
o Any Potassium increase from baseline >0.5 to 1.0 
o Any Potassium increase from baseline >1.0 to 1.5 mEq/L 
o Any Potassium increase from baseline > 1.5 mEq/L 
 
4.10 Determination of Sample Size 
The target enrollment will be approximately 48 subjects for the study with around 
12 subjects enrolled in each of the 4 treatment groups. 
The study is powered based on a comparison of the highest dose vadadustat group 
(600 mg daily) and the placebo group.  Based on the results from Study AKB-6548-CI-
0005 that was conducted in the United States and evaluated vadadustat in patients with 
anemia secondary to DD-CKD, it is assumed that the expected mean Hb changes from 
baseline to Week 6 will be approximately 0 mg/dL for the placebo group and 1.35 g/dL 
for the highest dose vadadustat group (600 mg daily), with a common standard deviation 
of 0.68 g/dL across treatment groups.  With these assumptions, the study with n=12 
subjects per group will have >95% power to detect the difference between treatment 
group and control group, at 2-sided alpha of 0.05. 
 
4.11 Changes in the Conduct of the Study or Planned Analysis 
Not Applicable. 


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Statistical Analysis Plan 
 
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5 
REFERENCES 
Not Applicable. 
 
 


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AKB-6548-CI-0022 
Statistical Analysis Plan 
 
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6 
Statistical Analysis Plan Amendment 1 
6.1 
Modifications and changes 
6.1.1 Rationale for the amendment 
The purpose of this amendment is to reflect the change for the efficacy endpoints 
and also illustrate more details from analysis perspective. 
• The main changes includes: 
• Efficacy related: 
o Additional  by-subject listing of dose adjustment with HB change with 
different HB cutoff point at dose adjustment and maintenance period  will 
be provided 
• Safety related: 
o Additional Secondary analysis for change from baseline to Week 6 in HB  
was added 
o Additional description for treatment emergent outlier analysis. 
o Separate  ESA administration summaries and ESA rescue summaries will 
be provided: 
• Other: 
o Keep consistent with mock of shell and remove duplicates description in 
the SAP. 
6.1.2 Global Changes 
None 
6.1.3 Specific changes 
Change#1 
Section 3.2.1 Efficacy and PD Variable, page 10, 
The following efficacy endpoints will also be analyzed: 
• 
Actual values and change (absolute and percent) from pre-treatment in Hb, 
hematocrit, RBC count, and reticulocyte count (both absolute and percent) 
• 
Actual values and change (absolute and percent) from pre-treatment in iron, TIBC, 
TSAT, ferritin, and hepcidin 
Has been changed to: 
The following efficacy endpoints will also be analyzed: 
• 
Actual values and change (absolute and percent) from baseline in Hb, hematocrit, 
RBC count, and reticulocyte count (both absolute and percent) 
• 
Actual values and change (absolute and percent) from baseline in iron, TIBC, TSAT, 
ferritin, and hepcidin 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
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Change#2 
Section 4.3.2 Protocol Deviation, page 12, 
A summary of the number and percentage of subjects with a protocol deviation by treatment 
group and overall and by type of deviation and by preiod (Analysis population: All Subjects 
Randomized) . 
Has been changed to: 
A summary of the number and percentage of subjects with a protocol deviation by 
treatment group and overall and by type of deviation and by period including primary 
period and dose adjustment and maintence period.Randomized subjects will be analyzed  
 
Change#3 
Section 4.4.2 Analysis Populations for the Efficacy Analyses, page 13, 
The efficacy summaries and analyses will be based on the modified intent-to-treat 
(MITT) population. The MITT population is defined as all randomized subjects who 
have received at least 1 dose of study medication and have a pre-treatment Hb average 
defined as the average of the most recently 2 qualifying screening value and the baseline 
value, and at least one post-baseline Hb measurement.  
Has been changed to: 
The efficacy summaries and analyses will be based on the modified intent-to-treat 
(MITT) population. The MITT population is defined as all randomized subjects who 
have received at least 1 dose of study medication and have a pre-treatment Hb average 
defined as the average of the most recently 2 qualifying screening value and the baseline 
value, and at least one post-baseline Hb measurement. The post-baseline Hb 
measurement will exclude the withdrawal Hb and follow-up Hb measurements for 
discontinued patients. 
Change#4 
Section 4.5 4.5 Demographic and Other Baseline Characteristics, page 14, 
The demographic and other baseline characteristics will be summarized for the MITT and 
safety populations.  The following summaries will be provided: 
 
• 
A summary of demographic variables (e.g. age, gender, weight, height and body 
mass index [BMI]) by treatment group and all subjects. 
• 
A summary of other relevant variables (e.g. etiology of CKD and smoking status) by 
treatment group and all subjects. 
• 
A summary of relevant medical history by treatment group and all subjects. 
• 
A summary of prior and concomitant medications within 30 days prior to the first 
study drug dose up to and including Week 6 by treatment group and overall. 
For the final analysis, a summary of concomitant medications after Week 6 will be 
provided. 


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Has been changed to: 
The demographic and other baseline characteristics will be summarized for the MITT and 
safety populations.  The following summaries will be provided: 
 
• 
A summary of demographic variables (e.g. age, gender, weight, height and body 
mass index [BMI]) by treatment group and all subjects. 
• 
A summary of other relevant variables (e.g. etiology of CKD and smoking status) by 
treatment group and all subjects. 
• 
A summary of relevant medical and surgical history by treatment group and all 
subjects. 
• 
A summary of relevant medical history by treatment group and all subjects. 
• 
A summary of prior and concomitant medications within 30 days prior to the first 
study drug dose up to and including Week 6 by treatment group and overall. 
For the final analysis, a summary of concomitant medications after Week 6 will be 
provided. 
 
Change#5 
Section 4.7.2.1 Summary of actual value and change in Hb at week 6, page 17, 
The primary analysis population for efficacy will be MITT population.  The following 
summary will be provided: 
• 
A summary of actual value of Hb by treatment group at baseline and week 6. A 
summary of the change (absolute and percent) from baseline in Hb by treatment 
group at week 6.  1st and 3rd quartiles (Q1, Q3) as well as the mean, SD, median, 
minimum, maximum and number of observations will be shown.  P values for overall 
comparison and treated groups vs. placebo on change from baseline will also be 
presented.  
• 
A waterfall plot for absolute Hb change from baseline for each treatment group at 
week 6. 
Has been changed to: 
The following summary will be provided: 
• 
A summary of actual value of Hb by treatment group at baseline and week 6. A 
summary of the change (absolute and percent) from pre-treatment average in Hb by 
treatment group at week 6.  1st and 3rd quartiles (Q1, Q3) as well as the mean, SD, 
median, minimum, maximum and number of observations will be shown.  P values 
for overall comparison and treated groups vs. placebo on change from pre-treatment 
will also be presented.  
• 
A waterfall plot for absolute Hb change from pre-treatment average for each 
treatment group at week 6. 
 
Change#6 
6.1.3.1 Section 4.7.2.2 Summary of actual value and change in Hb from baseline to 
week 6 and beyond, page 17, 
 


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• 
Box plots of absolute Hb changes for each treatment group from post-treatment study 
average to week 6. 
• 
Box plots of absolute Hb changes for each treatment group from post-treatment study 
average to week 16  
 
Has been changed to: 
• 
Box plots of absolute Hb changes for each treatment group from pre-treatment study 
average to week 6. 
• 
Box plots of absolute Hb changes for each treatment group from pre-treatment study 
average to week 16  
 
Change#7 
Section 4.7.2.3 Summary of excess Hb response from baseline to week 6 and beyond, 
page 18, 
The analysis population for efficacy will be MITT and PP population. The following 
summary will be provided: 
A summary of subject with three excess Hb criteria: Hb>13 g/dL, Hb>13 g/dL to 13 g/dL 
and >1 g/dL increment in a 2-week period will be provided by treatment group on 2-week 
basis starting from baseline to week 18. In addition, the period starting from baseline to 
week 16, primary efficacy period (baseline to week 6) and dose adjustment and 
maintenance period (week 7 to week 16) will also be presented within three excess HB 
criteria. 
 
Has been changed to: 
 
The analysis population for efficacy will be MITT and PP population. The following 
summary will be provided: 
A summary of subject with three excess Hb criteria: Hb>13 g/dL, Hb>12 g/dL to 13 g/dL 
and >1 g/dL increment in a 2-week period will be provided by treatment group on 2-week 
basis starting from baseline to week 18. In addition, the period starting from baseline to 
week 16, primary efficacy period (baseline to week 6) and dose adjustment and 
maintenance period (week 7 to week 16) will also be presented within three excess HB 
criteria. 
Change#8 
Section 4.7.3 Secondary Efficacy Variables, page 18, 
The analysis population for efficacy will be MITT and PP population.   
Has been changed to: 
The analysis population for efficacy will be MITT and PP population.   
 
Change from baseline visit to Week 6 in HB (g/dL). 
The following summaries will be provided: 


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Statistical Analysis Plan 
 
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• 
A summary of actual value of Hb by treatment group at baseline and week 6. A 
summary of the change (absolute and percent) from baseline in Hb by treatment 
group at week 6.  1st and 3rd quartiles (Q1, Q3) as well as the mean, SD, median, 
minimum, maximum and number of observations will be shown.  P values for overall 
comparison and treated groups vs. placebo on change from baseline will also be 
presented.  
• 
The effect of treatment in terms of the change from pre-treatment to Week 6 in Hb 
will be analyzed using a one-way analysis of covariance (ANCOVA). The statistical 
model will assess the main effect of treatment, adjusted for Baseline. Least-squares 
(LS) means for each treatment and their 95% confidence intervals (CIs) will be 
presented.  Three post-hoc pairwise comparison, i.e., Placebo vs 150 mg, placebo vs 
300 mg, and placebo vs 600 mg, will be done. Unadjusted one-way analysis of 
variance (ANOVA) will be performed for sensitivity. 
• 
The simple linear regression between the change from Baseline to Week 6 in Hb and 
dose will be calculated. The regression coefficients and their standard errors, p-
values of test of regression parameters and their 95%CIs will be presented. The test 
of slope parameter will be used to evaluate dose response relationship. 
• 
A waterfall plot for absolute Hb change from baseline for each treatment group at 
week 6. 
A summary of the number and percentage of subjects who achieved a ≥1 g/dL increase in 
Hb from baseline average will be provided by treatment group. 
Change#9 
Section 4.7.3 Secondary Efficacy Variables, page 19, 
Increase in Hb from pre-treatment average 
A summary of the number and percentage of subjects who achieved a ≥1 g/dL increase in 
Hb from pre-treatment average will be provided by treatment group. 
Has been changed to: 
Increase in Hb from pre-treatment average 
A summary of the cumulative number and percentage of subjects who achieved a ≥1 g/dL 
increase in Hb from pre-treatment average will be provided by treatment group. In 
addition, the cumulative proportion of subjects within target range will be displayed 
graphically from baseline visit to follow up visit by treatment group. 
 
Change#10 
Section 4.7.3 Secondary Efficacy Variables, page 20, 
Hematocrit, RBC count, and reticulocyte count  
Hematocrit, RBC count, and reticulocyte count (both absolute and percent) will be 
analyzed as secondary efficacy variables. 
 
The following summaries will be provided: 
• 
A summary of hematocrit, RBC count, and reticulocyte count (both absolute and 
percent) by treatment group and time point.  1st and 3rd quartiles (Q1, Q3) as well as 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
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CONFIDENTIAL 
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Page 38 of 47 
the mean, SD, median, minimum, maximum and number of observations will be 
presented. 
• 
A summary of the change (absolute and percent) from baseline in hematocrit, RBC 
count, and reticulocyte count (both absolute and percent) by treatment group and 
time point. 
Box plots of absolute changes from baseline in hematocrit, RBC count, and reticulocyte 
count (both absolute and percent) for each treatment group at each post-treatment time 
point. 
Has been changed to: 
Hematocrit, RBC count, and reticulocyte count (CBC) 
Hematocrit, RBC count, and reticulocyte count (both absolute and percent) will be 
analyzed as secondary efficacy variables. 
The following summaries will be provided: 
• 
A summary of hematocrit, RBC count, and reticulocyte count (both absolute and 
percent) by treatment group and time point.  1st and 3rd quartiles (Q1, Q3) as well as 
the mean, SD, median, minimum, maximum and number of observations will be 
presented. 
• 
A summary of the change (absolute and percent) from baseline in hematocrit, RBC 
count, and reticulocyte count (both absolute and percent) by treatment group and 
time point. 
Box plots of absolute changes from baseline in hematocrit, RBC count, and reticulocyte 
count for each treatment group at each post-treatment time point. 
Change#11 
Section 4.7.3 Secondary Efficacy Variables, page 20, 
 
Rescue therapy  
Initiation of rescue therapy will be analyzed. 
 
The following summaries will be provided: 
• 
A summary of the number and percentage of subjects requiring rescue with RBC 
transfusion from baseline to the end of the primary efficacy period (Week 6) and the 
end of the dose adjustment and maintenance period (Week 16) 
• 
A summary of the number and percentage of subjects requiring rescue with ESAs 
from baseline to the end of the primary efficacy period (Week 6) and the end of the 
dose adjustment and maintenance period (Week 16) 
 
 
The effect of treatment in terms of the proportion of subjects requiring rescue with RBC 
transfusion / ESAs will be analyzed using Fisher’s exact test.  Three post-hoc pairwise 
comparison, i.e., Placebo vs 150 mg, placebo vs 300 mg, and placebo vs 600 mg, will be 
done. 
 
By-subject listings of rescue therapies will be provided by treatment group. 
Has been changed to: 


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AKB-6548-CI-0022 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
CONFIDENTIAL 
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Effective Date:  25 Nov 15 
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Related to:  SOP-GDO-WW-019 
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Rescue therapy & ESA administration  
Initiation of rescue therapy will be analyzed. 
 
The following Rescue therapy summaries will be provided: 
• 
A summary of the number and percentage of subjects requiring rescue with RBC 
transfusion from baseline to the end of the primary efficacy period (Week 6) and the 
end of the dose adjustment and maintenance period (Week 16) 
• 
A summary of the number and percentage of subjects requiring rescue with ESAs 
from baseline to the end of the primary efficacy period (Week 6) and the end of the 
dose adjustment and maintenance period (Week 16). An ESA rescue is defined to 
fulfill the following 4 criteria simultaneously:  
 
1. ESA administration, and 
2. ESA administered because the subject experienced a clinically significant 
worsening of their anemia or symptoms of anemia,  and 
3. ESA administered because the subject's Hb level is <9.0 g/dL, and 
4. Subjects’ reason for early study withdrawal is because of “Worsening of anemia 
requiring ESA rescue or blood transfusion”. 
 
 
The following ESA administration summaries will be provided: 
 
• 
A summary of the number and percentage of subjects requiring administration with 
ESAs from baseline to the end of the primary efficacy period (Week 6) and the end 
of the dose adjustment and maintenance period (Week 16) 
 
The effect of treatment in terms of the proportion of subjects requiring rescue with RBC 
transfusion / ESAs will be analyzed using Fisher’s exact test.  Three post-hoc pairwise 
comparison, i.e., Placebo vs 150 mg, placebo vs 300 mg, and placebo vs 600 mg, will be 
done. 
 
By-subject listings of rescue therapies and ESA administration will be provided by 
treatment group. 
 
Change#12 
Section 4.7.3 Secondary Efficacy Variables, page 21, 
A by-subject listing of dose adjustment will be provided by treatment group. 
Has been changed to: 
 
A by-subject listing of dose adjustment with HB change will be provided by treatment 
group. The three flags of HB change will be presented as follows:  
• HB>13 g/dL at any time of study 
• HB >12 g/dL to 13 g/dL at dose adjustment and maintenance period only  
HB increase >1 g/dL over 2 weeks at any time of study. 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 0.1 
Effective Date:  25 Nov 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 40 of 47 
 
Change#13 
Section 4.7.4 Exploratory Efficacy Variable, page 22, 
Time in Therapeutic Range (TTR) for Hb from week 6 to week 20 
The half-time interpolation method will be used to calculate TTR for Hb.  The total time 
of follow-up with Hb in target range of 10.0 to 12.0 g/dL is divided by the total time. 
Half the time between two tests is allocated to the first Hb value, and half to the second 
Hb value.  
A summary of subject above, within or below the target Hb range (10-12) by visit will be 
provided by treatment group. Similarly, a summary of subject on 150/300/450/600 mg of 
vadadustat by visit will be provided by three different target Hb range (above, within or 
below). 
Has been changed to: 
Time in Therapeutic Range (TTR) for Hb from week 6 to week 20 
The half-time interpolation method will be used to calculate TTR for Hb.  The total time 
of follow-up with Hb in target range of 10.0 to 12.0 g/dL is divided by the total time. 
Half the time between two tests is allocated to the first Hb value, and half to the second 
Hb value.  
Change#14 
Section 4.8.2 Adverse Events, page 24, 
The AE will be summarized using MedDRA system organ class (SOC) and preferred 
term (PT).  All AE summaries will provide the number of subjects reporting at least one 
AE and the total number of events reported.  The following summaries will be provided: 
 
• 
A summary of the number and percentage of subjects reporting at least one TEAE, 
drug-related TEAE, TEAE leading to withdrawal, serious adverse event (SAE), drug-
related SAE, SAE leading to withdrawal and death by treatment group. 
• 
A summary of the number and percentage of subjects reporting a TEAE by treatment 
group, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a drug-related TEAE 
by treatment group, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a treatment-emergent 
SAE by treatment group, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a drug-related 
treatment-emergent SAE by treatment group, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a drug-related TEAE 
leading to withdrawal by treatment group, SOC, and PT 
• 
A summary of the most common TEAEs by treatment group and PT (reported by 
>10% of subjects in any treatment group) 
• 
A summary of the number and percentage of subjects reporting a TEAE by treatment 
group, severity, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a TEAE by treatment 
group, relationship, SOC, and PT 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 0.1 
Effective Date:  25 Nov 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 41 of 47 
 
AE summaries will be ordered alphabetically for SOC, and PT within SOC. 
Has been changed to: 
 
The AE will be summarized using MedDRA system organ class (SOC) and preferred 
term (PT).  All AE summaries will provide the number of subjects reporting at least one 
AE and the total number of events reported.  The following summaries will be provided: 
 
• 
A summary of the number and percentage of subjects reporting at least one TEAE, 
drug-related TEAE, TEAE leading to withdrawal, serious adverse event (SAE), drug-
related SAE, SAE leading to withdrawal and death by treatment group. 
• 
A summary of the number and percentage of subjects reporting a TEAE by treatment 
group, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a drug-related TEAE 
by treatment group, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a treatment-emergent 
SAE by treatment group, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a SAE  during the 
screening period Assessed as Related to Protocol Procedures by treatment group, 
SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a drug-related 
treatment-emergent SAE by treatment group, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a drug-related TEAE 
leading to withdrawal by treatment group, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a TEAE leading to 
withdrawal by treatment group, SOC, and PT 
• 
A summary of the most common TEAEs by treatment group and PT (reported by 
>10% of subjects in any treatment group) 
• 
A summary of the number and percentage of subjects reporting a TEAE by treatment 
group, severity, SOC, and PT 
• 
A summary of the number and percentage of subjects reporting a TEAE by treatment 
group, relationship, SOC, and PT 
 
AE summaries will be ordered alphabetically for SOC, and PT within SOC. 
Change#15 
Section 4.8.4.1 Liver function abnormality, page 25, 
A summary of Liver function abnormality during the study will be provided by treatment 
group 
Has been changed to: 
A summary of Liver function abnormality by visit  will be provided by treatment group. 
Change#16 
Section 4.8.4.5 Urine albumin to creatine ratio (uACR), page 26, 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 0.1 
Effective Date:  25 Nov 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 42 of 47 
 
6.1.3.2 Urine albumin-to-creatinine ratio (uACR) 
Urine albumin-to-creatinine ratio (uACR) will be evaluated at baseline visit. 
 
A by-subject listing of uACR will be provided. 
Has been changed to: 
This section has been removed. 
Change#18 
Section 4.8.4.6 Complete Blood Count (CBC), page 26, 
The following summaries will be provided: 
• 
A summary of each component of the CBC by treatment group and time point 
• 
A summary of the change from baseline in each component of the CBC by treatment 
group and time point 
• 
A summary of the number and percentage of subjects experiencing abnormal values 
by component of CBC, treatment group and time point. 
 
Has been changed to: 
The following summaries will be provided: 
• 
A summary of each component of the CBC by treatment group and time point 
• 
A summary of the change from baseline in each component of the CBC by treatment 
group and time point 
 
Change#19 
6.1.3.3 Section 4.8.6 Hemoglobin, page 27, 
 
The following Hb analyses will be performed for safety analysis section: 
• 
A summary of the number and percentage of subjects with any Hb > 12.0 g/dL by 
treatment group 
• 
A summary of the number and percentage of subjects with any Hb > 13.0 g/dL by 
treatment group 
• 
A summary of the number and percentage of subjects with Hb increase > 1.0 g/dL in 
any 2-week interval by treatment group 
 
Has been changed to: 
The following Hb analyses will be performed for safety analysis section: 
• 
A summary of the number and percentage of subjects with Hb increase > 1.0 g/dL in 
any 2-week interval by treatment group 
Change#20 
Section 4.8.4.8 Chemistry, page 26, 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
CONFIDENTIAL 
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Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 43 of 47 
The following laboratory parameters will be analyzed: 
• 
Sodium 
• 
Potassium 
• 
Bicarbonate 
• 
Chloride 
• 
Calcium 
• 
Phosphorus 
• 
Glucose 
• 
Creatinine 
• 
Blood Urea Nitrogen 
• 
Creatine Phosphokinase 
• 
Uric Acid 
• 
Albumin 
• 
Total Protein 
• 
Total Bilirubin 
• 
Alkaline Phosphatase 
• 
Alanine Aminotransferase (ALT) 
• 
Aspartate Aminotransferase (AST) 
• 
Lactate Dehydrogenase 
• 
Total cholesterol 
• 
Estimated Glomerular Filtration Rate (eGFR) (calculated from serum creatinine) 
 
The following summaries will be provided: 
• 
A summary of Chemistry and eGFR by treatment group and time point 
• 
A summary of the change (absolute and percent) from baseline in Chemistry and 
eGFR by treatment group and time point 
• 
A summary of the number and percentage of subjects experiencing abnormal values 
by laboratory parameter, treatment group and time point 
The following treatment-emergent laboratory test abnormalities of interest will be 
summarized 
•Subjects experiencing at least 1 potassium > upper limit of normal 
•Subjects experiencing at least 1 uric acid > upper limit of normal 
•Subjects experiencing at least 1 ALT or AST > upper limit of normal 
•Subjects experiencing at least 1 ALT or AST > 2x upper limit of normal 
•Subjects experiencing at least 1 ALT or AST > 3x upper limit of normal 
 
A summary table of subjects with potassium measured values after baseline visit will be 
provided by treatment group (Note: three categories of potential outlier: >5.5 mEq/L and 
<=6.0 mEq/L, >6.0 mEq/L and <=6.5 mEq/L, >6.5 mEq/L) as well as subjects with 
increment from baseline (Note: three categories of potential outlier: >0.5 mEq/L and 
<=1.0 mEq/L, >1.0 mEq/L and <=1.5 mEq/L, >1.5 mEq/L) . 
 
Has been changed to: 
The following laboratory parameters will be analyzed: 
• 
Sodium 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
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• 
Potassium 
• 
Bicarbonate 
• 
Chloride 
• 
Calcium 
• 
Phosphorus 
• 
Glucose 
• 
Creatinine 
• 
Blood Urea Nitrogen 
• 
Creatine Phosphokinase 
• 
Uric Acid 
• 
Albumin 
• 
Total Protein 
• 
Total Bilirubin 
• 
Alkaline Phosphatase 
• 
Alanine Aminotransferase (ALT) 
• 
Aspartate Aminotransferase (AST) 
• 
Lactate Dehydrogenase 
• 
Total cholesterol 
• 
Estimated Glomerular Filtration Rate (eGFR) (calculated from serum creatinine) 
 
The following summaries will be provided: 
• 
A summary of Chemistry and eGFR by treatment group and time point 
• 
A summary of the change (absolute and percent) from baseline in Chemistry and 
eGFR by treatment group and time point 
• 
A summary of the number and percentage of subjects experiencing abnormal values 
by laboratory parameter, treatment group and time point 
 
Change#21 
Section 4.8.4.9 C-reactive protein and Vascular Endothelial Growth Factor (VEGF), page 
28, 
The following summaries will be provided: 
• 
A summary of C-reactive protein (CRP) and VEGF by treatment group and time 
point 
• 
A summary of the change (absolute and percent) from baseline in CRP and VEGF by 
treatment group and time point 
 
The effect of treatment in terms of the change from baseline to Week 6 in CRP , total 
cholesterol and VEGF will be analyzed using ANCOVA.  The statistical model will 
assess the main effect of treatment, adjusted for baseline measurement.  Three post-hoc 
pairwise comparison, i.e., placebo vs 150 mg, placebo vs 300 mg, and placebo vs 600 mg, 
will be done.  Unadjusted ANOVA will be performed for sensitivity. 
 
A by-subject listing of CRP and VEGF will be provided by treatment group. 
 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 0.1 
Effective Date:  25 Nov 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 45 of 47 
Has been changed to: 
The following summaries will be provided: 
• 
A summary of C-reactive protein (CRP) ,VEGF and total cholesterol by treatment 
group and time point 
• 
A summary of the change (absolute and percent) from baseline in CRP ,VEGF and 
total cholesterol by treatment group and time point 
 
The effect of treatment in terms of the change from baseline to Week 6 in CRP , VEGF 
and total cholesterol will be analyzed using ANCOVA.  The statistical model will assess 
the main effect of treatment, adjusted for baseline measurement.  Three post-hoc pairwise 
comparison, i.e., placebo vs 150 mg, placebo vs 300 mg, and placebo vs 600 mg, will be 
done.  Unadjusted ANOVA will be performed for sensitivity. 
 
Change#22 
Section 4.8.4.9 Laboratory Abnormalities, page 28, 
New section was added. 
Has been changed to: 
selected laboratory parameter with over with over CTCAE v.4.0 grade 3, treatment group 
and period will be presented. 
 
 The following parameter will be analyzed: 
• 
Albumin 
• 
Alkaline Phosphatase 
• 
Calcium 
• 
Creatine Kinase 
• 
Glucose 
• 
Phosphate 
• 
Potassium 
• 
Protein 
• 
Sodium 
• 
Alanine Aminotransferase 
• 
Aspartate 
• 
Aminotransferase 
• 
Bilirubin 
• 
Leukocytes 
• 
Lymphocytes 
• 
Neutrophils 
• 
Platelets 
• 
Activated Partial 
• 
Thromboplastin Time 
• 
Prothrombin Time 
Change#23 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 0.1 
Effective Date:  25 Nov 15 
Project Document Effective Date: Date of last signature 
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Page 46 of 47 
Section 4.8.5.1 Vital Signs, page 28, 
The following variables will be analyzed: 
• 
Blood Pressure (Systolic / Diastolic) 
• 
Heart Rate 
• 
Respiratory Rate 
• 
Body Temperature 
 
The following summaries will be provided: 
• 
A summary of each vital sign parameter by treatment group and time point. 
• 
A summary of the change (absolute and percent) from baseline in each vital sign 
parameter by treatment group and time point. 
 
Any findings of treatment-emergent vital sign abnormalities will be handled as adverse 
event and reported in AE tables / listings. 
Has been changed to: 
The following variables will be analyzed: 
• 
Blood Pressure (Systolic / Diastolic) 
• 
Heart Rate 
• 
Respiratory Rate 
• 
Body Temperature 
 
The following summaries will be provided: 
• 
A summary of each vital sign parameter by treatment group and time point. 
• 
A summary of the change (absolute and percent) from baseline in each vital sign 
parameter by treatment group and time point. 
 
Any findings of treatment-emergent vital sign abnormalities will be handled as adverse 
event and reported in AE tables / listings. 
A plot showing the mean blood pressure over time within each treatment group.  95% CI 
of these means will be shown as error bar and sample size in each group at each time 
point will be shown 
Change#24 
Section 4.9.2 Treatment-Emergent Outliers analysis , 
This is newly added section in SAP amendment. 
Has been changed to: 
The purpose of this analysis is to identify the treatment Emergent outliers by each 
prescribed dose at each period. The definition of prescribed doses is the subjects with 
latest dose amount at planned visit when dose change. e.g. if at Week 2 with dose 600 mg 
and dose reduced to 450 mg at week 4, then visit of prescribed dose for VADA 450 was 
assigned to Week 4. 
However, if subject had dose reduction on 150 mg or had interruption of study 
medication, the prescribed dose will be considered as 0 mg. 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0022 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
CONFIDENTIAL 
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Project Document Effective Date: Date of last signature 
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Page 47 of 47 
 
Only treatment-emergent outliers will be counted but outliers at the baseline and 
screening visits will be excluded. 
 
The following components will be analyzed by primary efficacy period and dose 
adjustment and maintenance period for all subjects and normotensive at baseline: 
 
• Normotensive at baseline definition for each interested component 
o Systolic Blood Pressure <140 mmHg 
o Diastolic Blood Pressure<90 mmHg 
o Heart Rate <100 bpm 
o Potassium<4 mEq/L 
 
The following component with following criteria will be applied. 
• Systolic Blood Pressure  
o Any SBP >=160 to <180 mmHg 
o Any SBP >=180 mmHg 
o Any SBP increase from baseline >=20 to <40 mmHg 
o Any SBP increase from baseline >=40 mmHg 
• Diastolic Blood Pressure 
o Any DBP >=100 to <110 mmHg 
o Any DBP >=110 mmHg 
o Any DBP increase from baseline >=10 to <20 mmHg 
o Any DBP increase from baseline >=20 mmHg 
• Heart Rate 
o Any pulse >=100 to <120 bpm 
o Any pulse >=120 bpm 
o Any pulse increase from baseline >=20 to <30 bpm 
o Any pulse increase from baseline >=30 bpm 
• Potassium 
o Any Potassium >5.5 to 6.0 mEq/L 
o Any Potassium >6.0 to 6.5 mEq/L 
o Any Potassium >6.5 mEq/L 
o Any Potassium increase from baseline >0.5 to 1.0 
o Any Potassium increase from baseline >1.0 to 1.5 mEq/L 
o Any Potassium increase from baseline > 1.5 mEq/L 
Normotensive at baseline of Systolic Blood Pressure with are defined as and following 
criteria will be applied 
 


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