Conditions: Anemia Non-dialysis Dependent Chronic Kidney Disease
Keywords: Anemia kidney non-dialysis dependent chronic kidney disease CKD NDD-CKD renal vadadustat AKB-6548 hypoxia-inducible factor hypoxia-inducible factor (HIF) HIF prolyl-hydroxylase inhibitor (PHI) PHI Japan Japanese Akebia (AKB)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 51
Healthy volunteers: no

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 Non-dialysis Dependent Chronic Kidney Disease (NDD-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: None intervention 2: None

Protocol document:
Prot_000.pdf: 
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Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 2 
1 SIGNATURE PAGES 
1.1 Protocol Approval 
 
 
Medical Research 
Akebia Therapeutics, Inc. 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 3 
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 also protect the 
rights, safety, privacy, and well-being of study subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonization Guidance for Industry, Good Clinical 
Practice E6. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting serious adverse events defined in this protocol. 
• Terms outlined in the Clinical Study Site Agreement. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Phone Number 
Full Address 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 4 
TABLE OF CONTENTS 
1 
SIGNATURE PAGES .................................................................................................. 2 
1.1 
Protocol Approval .................................................................................................... 2 
1.2 
Investigator Agreement ............................................................................................ 3 
TABLE OF CONTENTS ......................................................................................................... 4 
LIST OF TABLES ................................................................................................................... 7 
LIST OF FIGURES ................................................................................................................. 7 
2 
PROTOCOL SYNOPSIS .............................................................................................. 8 
3 
LIST OF ABBREVIATIONS ..................................................................................... 14 
4 
BACKGROUND ........................................................................................................ 16 
4.1 
Proposed Indication of Renal Anemia ................................................................... 16 
4.2 
Available Therapies for Anemia in Patients with CKD ......................................... 17 
4.3 
Hypoxia-Inducible Factor ...................................................................................... 17 
4.4 
Description and Mechanism of Action of Vadadustat ........................................... 18 
4.5 
Summary of Clinical Experience ........................................................................... 19 
4.6 
Ethno-Bridging Data from a Study of Healthy Japanese and Caucasian Volunteers
 ................................................................................................................................ 20 
4.7 
Potential Benefits and Risks ................................................................................... 22 
5 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 22 
5.1 
Primary Objective and Endpoint ............................................................................ 22 
5.2 
Secondary Objectives and Endpoints ..................................................................... 22 
6 
STUDY DESIGN ........................................................................................................ 23 
6.1 
Study Design .......................................................................................................... 23 
6.2 
Study Duration ....................................................................................................... 25 
6.3 
Rationale for Study Design .................................................................................... 25 
6.4 
Dose Justification ................................................................................................... 26 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 27 
7.1 
General Criteria ...................................................................................................... 27 
7.2 
Inclusion Criteria .................................................................................................... 27 
7.3 
Exclusion Criteria ................................................................................................... 27 
7.4 
Retesting and Rescreening ..................................................................................... 29 
7.4.1 
Retesting ............................................................................................................ 29 
7.4.2 
Rescreening ....................................................................................................... 29 
7.5 
Study Completion, Study Termination, and Individual Study Site Termination ... 29 
7.5.1 
Study Completion .............................................................................................. 29 
7.5.2 
Study Termination ............................................................................................. 30 
7.5.3 
Individual Study Site Termination .................................................................... 30 
7.6 
Subject Completion and Individual Subject Discontinuation ................................ 30 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 5 
7.6.1 
Subject Completion ........................................................................................... 30 
7.6.2 
Conditions and Documentation of Individual Subject Study Drug 
Discontinuation .................................................................................................. 30 
7.6.3 
Individual Subject Discontinuation during the Primary Efficacy Period or 
Blinded Dose Adjustment and Data Cleaning Period ....................................... 31 
7.6.4 
Individual Subject Discontinuation during the Open-Label Extension Period . 31 
8 
STUDY DRUGS AND TREATMENT OF SUBJECTS ............................................ 31 
8.1 
Study Drugs ............................................................................................................ 31 
8.1.1 
Formulation ....................................................................................................... 31 
8.1.2 
Storage and Accountability ............................................................................... 32 
8.1.3 
Dispensing of Study Drugs ................................................................................ 32 
8.1.4 
Product Accountability and Destruction ........................................................... 32 
8.2 
Treatment of Subjects ............................................................................................. 33 
8.2.1 
Dosing Instructions ............................................................................................ 33 
8.2.2 
Randomization ................................................................................................... 33 
8.2.3 
Blinding During the Primary Efficacy Period and Breaking the Blind ............. 34 
8.2.4 
Study Drug Administration during the Primary Efficacy Period ...................... 34 
8.2.5 
Study Drug Administration during the Blinded Dose Adjustment and Data 
Cleaning Period ................................................................................................. 35 
8.2.6 
Vadadustat Administration during the Open-Label Extension Period .............. 36 
8.2.7 
Dose Adjustment Guidelines ............................................................................. 36 
8.2.8 
Rescue Therapy Guidelines ............................................................................... 37 
8.2.9 
Oral Iron Supplementation (Information on Allowed Use) .............................. 37 
8.2.10 
Late or Missed Doses ........................................................................................ 37 
8.2.11 
Treatment Compliance ...................................................................................... 38 
8.2.12 
Continuation of Treatment ................................................................................ 38 
8.3 
Prior and Concomitant Therapy ............................................................................. 38 
8.4 
Prohibited Treatments ............................................................................................ 38 
8.4.1 
Investigational Medications ............................................................................... 38 
8.4.2 
ESAs, Intravenous Iron, and Blood Transfusion ............................................... 38 
8.4.3 
Oral Iron Supplementation (Information on Prohibition) ................................. 39 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES ................................ 39 
9.1 
Administrative Procedures ..................................................................................... 39 
9.1.1 
Informed Consent Procedure ............................................................................. 39 
9.1.2 
Documentation of Screen Failures .................................................................... 39 
9.1.3 
Review of Inclusion and Exclusion Criteria ...................................................... 39 
9.1.3.1 
Acceptable Methods of Contraception ......................................................... 39 
9.2 
Study Procedures and Evaluations ......................................................................... 40 
9.2.1 
Clinical Evaluations ........................................................................................... 40 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 6 
9.2.2 
Laboratory Evaluations ..................................................................................... 41 
9.3 
Schedule of Activities ............................................................................................ 42 
9.3.1 
Screening Visit .................................................................................................. 42 
9.3.2 
Baseline Visit (Day 1) ....................................................................................... 43 
9.3.3 
Week 1 Visit ...................................................................................................... 44 
9.3.4 
Week 2 Visit ...................................................................................................... 44 
9.3.5 
Week 4 Visit ...................................................................................................... 44 
9.3.6 
Week 6 Visit ...................................................................................................... 45 
9.3.7 
Week 10 Visit (End-of-treatment visit for the blinded period and early 
withdrawals) ...................................................................................................... 45 
9.3.8 
Week 14 Visit .................................................................................................... 46 
9.3.9 
Week 16 Visit (End-of-treatment visit for the open-label period and early 
withdrawal visit for withdrawals after Week 10 but before Week 16) ............. 46 
9.3.10 
Week 18 Safety Follow-Up Visit (Or 2 Weeks after End-of-Treatment Safety 
Follow-Up Visit) ............................................................................................... 47 
10 
ADVERSE EVENTS .................................................................................................. 47 
10.1 
Definitions .............................................................................................................. 47 
10.1.1 
Adverse Events (AEs) ....................................................................................... 47 
10.1.2 
Serious Adverse Events (SAEs) ........................................................................ 49 
10.2 
Eliciting Adverse Event Information ..................................................................... 50 
10.3 
Reporting ................................................................................................................ 50 
10.3.1 
Reporting Period ................................................................................................ 50 
10.3.2 
Reporting AEs ................................................................................................... 50 
10.3.3 
Reporting SAEs ................................................................................................. 50 
10.3.4 
Relationship to Study Medication ..................................................................... 51 
10.3.5 
Severity .............................................................................................................. 52 
10.3.6 
Follow-Up of Unresolved Events ...................................................................... 52 
10.3.7 
Special Situations .............................................................................................. 52 
10.4 
Exposure In Utero .................................................................................................. 52 
11 
DATA ANALYSIS ..................................................................................................... 53 
11.1 
Primary Endpoint and Sample Size Determination ................................................ 53 
11.2 
Study Populations ................................................................................................... 54 
11.2.1 
Analysis Population for the Safety Analyses .................................................... 54 
11.2.2 
Analysis Populations for the Efficacy Analyses ............................................... 54 
11.3 
Analysis of Demographics and Pretreatment Variables ......................................... 54 
11.4 
Disposition of Subjects ........................................................................................... 54 
11.5 
Efficacy and PD Analyses ...................................................................................... 54 
11.6 
Safety Analyses ...................................................................................................... 55 
11.7 
PK Analyses ........................................................................................................... 55 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 7 
12 
DATA HANDLING AND RECORD KEEPING ...................................................... 55 
12.1 
Case Report Forms (CRFs) .................................................................................... 55 
12.2 
Record Retention .................................................................................................... 56 
13 
QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) ....................... 56 
13.1 
Study Site Monitoring Visits .................................................................................. 56 
13.2 
Protocol Deviations ................................................................................................ 56 
14 
STUDY DISCONTINUATION/INVESTIGATIVE STUDY SITE TERMINATION
 ..................................................................................................................................... 57 
14.1 
Criteria for Premature Termination or Suspension of the Study ............................ 57 
14.2 
Criteria for Premature Termination or Suspension of Investigational Sites .......... 57 
14.3 
Procedures for Premature Termination or Suspension of the Study or 
Investigational Site(s) ............................................................................................. 57 
15 
ETHICS ....................................................................................................................... 57 
15.1 
Ethical Conduct of the Study ................................................................................. 57 
15.2 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) ........... 58 
15.3 
Subject Information and Consent ........................................................................... 58 
15.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .... 58 
15.5 
Subject Confidentiality ........................................................................................... 58 
16 
PUBLICATION OF STUDY RESULTS ................................................................... 59 
17 
REFERENCES ............................................................................................................ 60 
 
LIST OF TABLES 
Table 1: 
Identity of Study Drugs ........................................................................................31 
 
LIST OF FIGURES 
Figure 1 
Mechanism of Action of Vadadustat ....................................................................18 
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) .......21 
Figure 3: 
Overview of Study Design ....................................................................................24 
Figure 4: 
Absolute Change in Hemoglobin (± Standard Error of Mean, g/dL) at Week 6 
Compared to Baseline (Study AKB-6548-CI-0005) ..........................................26 
Figure 5: 
Randomization Scheme of Study Treatment ........................................................33 
Figure 6: 
Algorithm for Dose Reduction or Discontinuation of Study Drug During the Primary 
Efficacy Period ...................................................................................................35 
Figure 7: 
Potential Scenarios for Individual Subject Unblinding ........................................36 
 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 8 
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 Non-Dialysis 
Dependent Chronic Kidney Disease 
Protocol Number 
AKB-6548-CI-0021 
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 non-dialysis dependent chronic kidney disease 
(NDD-CKD) who are not currently being treated with an erythropoiesis-stimulating 
agent (ESA) 
Investigative Sites 
Approximately 25 sites in Japan 
Planned Number of 
Subjects 
Approximately 48 subjects will be enrolled in the study, with 36 subjects receiving 
one of the 3 doses of vadadustat and 12 subjects receiving placebo: 
• 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 (QD) dosing for 6 weeks and the change in hemoglobin 
(Hb) in Japanese subjects with anemia secondary to NDD-CKD; in order 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 QD dosing in Japanese subjects 
with anemia secondary to NDD-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 maintenance period 
Study Design Overview 
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 NDD-CKD.  The study 
will include the following periods: 
• Eligibility screening period (up to 4 weeks) 
• Primary efficacy period (6 weeks; Weeks 1 to 6) 
• Dose adjustment and maintenance period (10 weeks), including the following: 
- Blinded dose adjustment and data cleaning period (4 weeks; Weeks 7 to 10): 
Individual subject data (from screening to Week 6) will be locked and 
individual subject unblinding will take place at the Week 10 visit  
- Open-label extension period (6 weeks; Weeks 11 to 16): Subjects 
randomized to receive vadadustat treatment during the blinded period will 
continue into this period 
• Safety follow-up period (2 weeks; Weeks 17 and 18): Subjects who complete 
participation in the open-label extension period and subjects who discontinue 
early during the blinded study periods will complete the safety follow-up 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 9 
period.  Subjects identified as having received placebo during the Week 10 
unblinding visit will not participate in this safety follow-up period. 
Following the screening period, eligible subjects will be randomized to receive 
blinded study drug treatment during a 6-week primary efficacy period, with subjects 
randomized at a 3:1 ratio to receive vadadustat (150, 300, or 600 mg vadadustat) or 
placebo.  See “Dosage and Regimen” in the synopsis for additional information 
regarding the randomization scheme. 
Fixed-dose treatment during the blinded primary efficacy period will allow a 
dose-response relationship to be established.  However, if Hb levels increase too 
rapidly or if the Hb levels exceed the desired range, the blinded study drug dose can 
be decreased or discontinued (see “Dosage and Regimen” for additional 
information). 
After completing the primary efficacy period, subjects will continue to a 10-week 
dose adjustable maintenance period which will include a 4-week, blinded dose 
adjustment and data cleaning period and a 6-week, open-label extension period.  
Dose can be adjusted during the open-label period to achieve a target Hb of 
10-12 g/dL, and the dose adjustments will be guided by an interactive web response 
(IWR) system based on Hb concentration and programmed dose adjustment 
algorithms (see “Dosage and Regimen” for additional information). 
Individual subject’s study data (from screening to Week 6) will be cleaned and 
locked during the 4-week, blinded, dose adjustment and data cleaning period. 
At the Week 10 visit, treatment assignment will be unblinded on an individual 
subject basis.  Subjects who were randomized to receive placebo will end study 
participation after unblinding at the Week 10 visit.  Subjects who were randomized 
to receive 1 of the 3 vadadustat doses will continue receiving vadadustat during the 
open-label extension period. 
Vadadustat treatment will stop after the extension period has been completed 
(Week 16) and subjects will continue in a 2-week follow-up safety period 
(Week 17-18). 
Study Duration 
Up to 22 weeks, including the eligibility screening period (up to 4 weeks), primary 
efficacy period (6 weeks), blinded dose adjustment and data cleaning period 
(4 weeks), open-label extension period (6 weeks), and safety follow-up period 
(2 weeks). 
Only subjects who are randomized to receive vadadustat will continue in the 
maintenance period and the safety follow-up period. 
Key Inclusion Criteria 
(the complete list is 
provided in the 
protocol) 
• Male and female Japanese subjects (20 years or older) 
• Diagnosis of CKD based on an estimated glomerular filtration rate (eGFR) of 
≤60 mL/min/1.73 m2 (using the 2009 Japanese Society of Nephrology 
equation; Matsuo 2009) 
• Not currently being treated with dialysis and not expected to start dialysis 
within 3 months of screening 
• Hb ≤10.5 g/dL 
• Serum ferritin ≥50 ng/mL 
• Transferrin saturation (TSAT) ≥20% 
• Folate and vitamin B12 ≥lower limit of normal 
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 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 10 
screening; intravenous iron within 4 weeks prior to or during screening; and any 
ESA use within 6 weeks prior to or during screening. 
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 or eGFR 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 B12 values may be considered for rescreening after receiving 
replacement therapy. 
Screening is limited to 3 attempts (initial screening and 2 additional rescreening 
attempts). 
Study Endpoints 
Note that a pre-treatment value for Hb, hematocrit, RBC count, reticulocyte count, 
and iron metabolism markers is defined as the average of 2 values obtained prior to 
treatment, ie, the qualifying screening value 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: 
• Proportion of subjects who achieve target Hb 10-12 g/dL at the end of the 
open-label extension period (Week 16) 
• Mean change in Hb between pre-treatment and the end of the open-label 
extension period (Week 16) 
• Mean change in hematocrit, RBC count, and reticulocyte count from 
pre-treatment to the end of the primary efficacy period (Week 6) and the end of 
the open-label extension period (Week 16) 
• Mean change in iron indices (ie, iron, total iron-binding capacity [TIBC], 
TSAT, ferritin, and hepcidin) from pre-treatment to the end of the primary 
efficacy period (Week 6) and the end of the open-label extension period 
(Week 16) 
• Proportion of subjects with confirmed Hb values <10.0 or >12.0 g/dL from 
pre-treatment to the end of the open-label extension 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 open-label 
extension 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 open-label extension 
period (Week 16) 
• Number of dose adjustments from baseline to the end of the primary efficacy 
period (Week 6) and the end of the open-label extension period (Week 16) 
• Maintenance of iron sufficiency (defined as ferritin ≥50 ng/mL and TSAT 
≥20%) from baseline to the end of the primary efficacy period (Week 6) and 
the end of the open-label extension period (Week 16) 
• Plasma concentration profile of vadadustat and its metabolites using pre-dose 
sample from Week 4 
• Safety assessments, including adverse events, vital signs, electrocardiograms 
(ECGs), and other laboratory assay results (eg, serum chemistry, components 
of the complete blood count [CBC] other than the ones noted above, and 
vascular endothelial growth factor [VEGF]) 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 11 
Dosage and Regimen 
Study drug will be administered on an outpatient basis.  Subjects should take the 
study medication with water or other oral beverage and should be instructed to 
swallow the intact tablet(s).  Subjects may take the study medication with or without 
food. 
Note: Hb will be assessed at the central laboratory and also monitored using 
point-of-care HemoCue®.  Note that the point-of-care HemoCue Hb value will be 
used to determine if the dose of study medication will be adjusted or discontinued. 
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. 
 
The primary efficacy period includes a fixed-dose treatment to establish a 
dose-response relationship.  However, if Hb level increases too rapidly or if the Hb 
levels exceed the desired range, the blinded study drug dose will be decreased or 
discontinued as presented below. 
• Subjects who meet the following criteria for excess Hb response will undergo a 
dose reduction by 1 tablet: 
- 
Hb increase >1 g/dL within any 2-week period, OR 
- 
Hb increase >2 g/dL within any 4-week period, OR 
- 
Hb level >13 g/dL 
• Subjects who meet the following criteria will discontinue study drug: 
- 
Excess Hb response as defined by any of the aforementioned criteria, 
AND 
- 
Current dose 1 tablet OR subject had previously decreased study drug 
dose due to excess Hb response 
Blinded dose adjustment and data cleaning period (Week 7 to 10) 
During this period, data from screening through the Week 6 visit will be cleaned and 
locked in preparation for the Week 10 unblinding visit.  Blinded study drug dosage 
will be adjusted to achieve a target Hb 10-12 g/dL.  Starting at the Week 6 visit, 
adjustments to doses will be guided by an IWR system based on Hb concentration 
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-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 12 
and programmed dose adjustment algorithms.  See the dose adjustment guidelines 
below. 
Open-label extension period (Weeks 11 to 16): 
Subjects who were randomized to receive vadadustat will enter this open-label 
extension period, and vadadustat dosage will continue to be adjusted to achieve a 
target Hb 10-12 g/dL.  Dose adjustments will continue to be guided by an IWR 
system based on Hb concentration and programmed dose adjustment algorithms.  
See the dose adjustment guidelines below. 
Dose adjustment guidelines from Week 7 to Week 16 
The programmed dose adjustment algorithm for blinded study drug (from Week 7 to 
10) and open-label vadadustat (from Week 11 to 16) will follow the dose adjustment 
guidelines listed below to achieve a target Hb of 10-12 g/dL, and will be guided by 
an IWR system.  The point-of-care HemoCue Hb value will be used to determine if 
the dose of study drug will be adjusted. 
• 
Do not increase the dose more frequently than once within any given 
4-week interval.  For example, if a subject’s dose was increased at Week 10 
and the subject remains below the Hb target, the next opportunity to further 
increase the dose would be Week 14.  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 rises 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).  In cases of extenuating clinical 
circumstances, investigators may elect to dose outside the IWR system dosing 
recommendation to maintain the Hb within the target range. 
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: 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 
- 
Exhibits Hb level <9.0 g/dL 
• 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. 
Oral Iron 
Supplementation 
Subjects who are taking oral iron supplementation at baseline should continue their 
oral iron at the same dose throughout their study participation.  Changes to oral iron 
supplementation dose will be considered protocol deviations but will not be 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 13 
considered a reason for subject discontinuation. 
Subjects who are not taking oral iron supplementation at baseline should not start 
oral iron during their study participation. 
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 
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. 
The target enrollment will be approximately 48 subjects for the study with 
12 subjects enrolled in each of the 4 treatment groups.  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. 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 14 
3 LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
BUN 
blood urea nitrogen 
C 
Celsius 
CBC 
complete blood count 
CKD 
chronic kidney disease 
CRF 
case report form 
CRO 
contract research organization 
CV 
cardiovascular 
dL 
deciliter 
DVT 
deep venous thrombosis 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
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 
GFR 
glomerular filtration rate 
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-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 15 
IV 
intravenous(ly) 
IWR 
interactive web response 
JSN 
Japanese Society of Nephrology 
KDIGO 
Kidney Disease Improving Global Outcomes 
kg 
kilogram 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
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) 
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-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 16 
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-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 17 
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. 
A number of 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-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 19 
4.3% of patients on 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 patients with DD-CKD 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.  As a result, 
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. 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 20 
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 
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 recently completed Phase 2b, randomized, double-blind, placebo-controlled study to assess the 
hematologic PD response, safety, and tolerability of oral vadadustat for 20 weeks was performed 
in 210 subjects with anemia associated with NDD-CKD (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.  


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Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 22 
4.7 Potential Benefits and Risks 
Please see the vadadustat Investigator’s Brochure for additional discussion and information for 
the following section. 
Vadadustat offers the potential of flexible oral dosing that is easier to adjust than injectable 
hormone ESAs.  This alternate therapeutic approach may avoid the excursions and fluctuations 
in Hb levels seen with currently available injectable ESAs and provide for a controlled, steady 
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 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 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, all of the acute findings observed at doses less than the maximum tolerated dose (MTD) 
in animals have been shown to be reversible and dose-related.  In addition, most of the findings 
have followed a pattern that would have been predicted based on the known HIF and HIFPH 
biochemistry, pharmacology, and human genetic variations (eg, Chuvash polycythemia).  In the 
completed clinical studies, vadadustat has been generally well-tolerated. 
5 STUDY OBJECTIVES AND ENDPOINTS 
Note that a pre-treatment value for Hb, hematocrit, RBC count, reticulocyte count, and iron 
metabolism markers is defined as the average of 2 values obtained prior to treatment, ie, the 
qualifying screening value 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 Hb in Japanese subjects with anemia 
secondary to NDD-CKD; in order 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 
NDD-CKD during the 6-week, primary efficacy period 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 23 
• To evaluate the effect of dose adjustments and demonstrate the maintenance effect on Hb 
during a 10-week maintenance period 
The endpoints that will be used to assess these objectives include the following: 
• Proportion of subjects who achieve target Hb 10-12 g/dL at the end of the open-label 
extension period (Week 16) 
• Mean change in Hb between pre-treatment and the end of the open-label extension period 
(Week 16) 
• Mean change in hematocrit, RBC count, and reticulocyte count from pre-treatment to the 
end of the primary efficacy period (Week 6) and the end of the open-label extension 
period (Week 16) 
• Mean change in iron indices (ie, iron, total iron-binding capacity [TIBC], TSAT, ferritin, 
and hepcidin) from pre-treatment to the end of the primary efficacy period (Week 6) and 
the end of the open-label extension period (Week 16) 
• Proportion of subjects with confirmed Hb values <10.0 or >12.0 g/dL from pre-treatment 
to the end of the open-label extension 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 open-label extension 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 open-label extension period (Week 16) 
• Number of dose adjustments from baseline to the end of the primary efficacy period 
(Week 6) and the end of the open-label extension period (Week 16) 
• Maintenance of iron sufficiency (defined as ferritin ≥50 ng/mL and TSAT ≥20%) from 
baseline to the end of the primary efficacy period (Week 6) and the end of the open-label 
extension period (Week 16) 
• Plasma concentration profile of vadadustat and its metabolites using pre-dose sample 
from Week 4 
• Safety assessments, including adverse events, vital signs, electrocardiograms (ECGs), 
and other laboratory assay results (eg, serum 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 subjects 
with anemia secondary to NDD-CKD.   


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 24 
The study has a planned enrollment of 48 subjects to be enrolled at approximately 25 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. 
Figure 3: 
Overview of Study Design 
 
 
The study will include the following periods: 
• Eligibility screening period (up to 4 weeks) 
• Primary efficacy period (6 weeks; Weeks 1 to 6) 
• Dose adjustment and maintenance period (10 weeks) include the following: 
- Blinded dose adjustment and data cleaning period (4 weeks; Weeks 7 to 10): Individual 
subject data (from screening to Week 6) will be cleaned and locked and individual 
subject unblinding will take place at the Week 10 visit  
- Open-label extension period (6 weeks; Weeks 11 to 16): Subjects randomized to 
receive vadadustat treatment during the blinded period will continue into this period 
• Safety follow-up period (2 weeks; Weeks 17 and 18): Subjects who complete 
participation in the open-label extension period and subjects who discontinue early 
during the blinded study periods will complete the safety follow-up period.  Subjects 
identified as having received placebo during the Week 10 unblinding visit will not 
participate in this safety follow-up period. 
Subjects will participate in a screening period (4 days to 4 weeks) to determine study eligibility, 
and eligible subjects will be randomized following the screening period. 
Vadadustat 300mg (n=12); 2x150 mg tablets once daily
Placebo (n=4); 2 tablets once daily
Vadadustat 150mg (n=12); 1x150 mg tablet once daily
Placebo (n=4); 1 tablet once daily
4 days - 4 weeks
6 weeks
4 weeks
6 weeks
2 weeks
Screening
Double-blind, fixed-dose, 
primary efficacy period
Open-label, dose-adjustable, 
extension period
Blinded, dose-
adjustable, data 
cleaning period
Safety
follow-up
Individual subject unblinding;
end-of-Treatment (EOT) for subjects receiving placebo
Data cutoff for primary endpoint
Vadadustat 600 mg (n=12);
4 x 150 mg tablets once daily
Placebo (n=4);
4 tablets once daily
Vadadustat 300 mg (n=12);
2 x 150 mg tablets once daily
Placebo (n=4);
2 tablets once daily
Vadadustat 150 mg (n=12);
1 x 150 mg tablet once daily
Placebo (n=4);
1 tablet once daily
(EOT)
(EOT)
(EOT)
(EOT)
(EOT)
(EOT)
g


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 25 
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. 
Blinded 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 levels increase too rapidly or if the Hb levels exceed the desired 
range, the blinded study drug dose can be decreased or discontinued (see Section 8.2.4). 
After completing the primary efficacy period, subjects will continue to a 10-week dose 
adjustment and maintenance period including a 4-week, blinded dose adjustment and data 
cleaning period and a 6-week, open-label extension period (see Sections 8.2.5 and 8.2.6).  Dose 
will be adjusted to achieve a target Hb of 10-12 g/dL, and the dose adjustments will be guided by 
an interactive web response (IWR) system based on Hb concentration and programmed dose 
adjustment algorithms (see Section 8.2.7). 
Individual subject’s study data (from screening to Week 6) will be cleaned and locked during the 
4-week, blinded, dose adjustment period. 
At the Week 10 visit, treatment assignment will be unblinded on an individual subject basis.  
Subjects who were randomized to receive placebo will end study participation after unblinding at 
the Week 10 visit.  Subjects who were randomized to receive 1 of the 3 vadadustat doses will 
continue receiving vadadustat during the 6-week, open-label extension period. 
Vadadustat treatment will stop after the extension period has been completed (Week 16) and 
subjects will continue in a 2-week follow-up safety period (Week 17-18). 
The clinical and safety assessments will be performed as described in Section 9.3 and as listed in 
Appendix A. 
6.2 Study Duration 
Individual subjects will participate in the study for up to 22 weeks, including the eligibility 
screening period (up to 4 weeks), primary efficacy period (6 weeks), blinded dose adjustment 
and data cleaning period (4 weeks), open-label extension period (6 weeks), and safety follow-up 
period (2 weeks). 
Only subjects who are randomized to receive vadadustat will continue in the open-label 
extension period and the safety follow-up period.  Subjects who are randomized to receive 
placebo during the blinded treatment period will discontinue from the study after unblinding at 
Week 10. 
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 NDD-CKD is modeled on a previously completed 
dose-finding study in Caucasian subjects with anemia secondary to NDD-CKD 
(Study AKB-6548-CI-0005). 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 26 
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 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 safe and 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 safe, 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 according to 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
*
*
*
*


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 27 
7 SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 General Criteria 
The study population will consist of male and female Japanese adults aged 20 years or older with 
anemia secondary to NDD-CKD who are not currently being treated with an ESA. 
To be eligible for this study, a subject or their legally acceptable representative must have 
provided valid informed consent and must meet all of the following criteria.  No study 
procedures (including screening tests) may be performed until after the informed consent has 
been legally signed. 
7.2 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for study participation: 
1. Male and female Japanese subjects, aged 20 years or older 
2. Diagnosis of CKD based on an estimated glomerular filtration rate (eGFR) of 
≤60 mL/min/1.73 m2 (using the 2009 Japanese Society of Nephrology equation; Matsuo 
2009) 
3. Not currently being treated with dialysis and not expected to start dialysis within 
3 months of screening 
4. Hemoglobin (Hb) ≤10.5 g/dL during screening 
5. Serum ferritin ≥50 ng/mL during screening 
6. TSAT ≥20% during screening 
7. Folate and vitamin B12 greater than or equal to the lower limit of normal during 
screening 
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. RBC transfusion within 4 weeks prior to or during screening 
4. Intravenous iron within 4 weeks prior to or during screening 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 28 
5. Any ESA use within 6 weeks prior to or during screening (eg, recombinant human 
erythropoietin, darbepoetin alfa, or methoxy polyethylene glycol-epoetin beta) 
6. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), 
alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total 
bilirubin >2.0 x upper limit of normal during screening.  A history of Gilbert’s syndrome 
is not an exclusion criterion. 
7. Uncontrolled hypertension (confirmed diastolic blood pressure >110 mm Hg or systolic 
blood pressure >180 mm Hg) during screening 
8. Body mass index (BMI) >42.0 kg/m2 
9. Severe heart failure during screening (New York Heart Association Class III or IV) 
10. 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 
11. 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 
12. 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 
13. History of deep vein thrombosis (DVT) or pulmonary embolism (PE) requiring active 
treatment within 8 weeks prior to or during screening 
14. History of hemosiderosis or hemochromatosis 
15. History of prior organ transplantation or scheduled organ transplant (subjects on kidney 
transplant wait-list are not excluded), or prior hematopoietic stem cell or bone marrow 
transplant (corneal transplants and stem cell therapy for knee arthritis are not excluded) 
16. 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 
17. Previous participation in a study with vadadustat or another hypoxia-inducible factor 
prolyl-hydroxylase inhibitor 
18. Hypersensitivity to vadadustat, or to any of its excipients 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 29 
19. Females who are pregnant or breast-feeding 
20. Females of childbearing potential who are unable or unwilling to use an acceptable 
method of contraception 
21. Non-vasectomized males who are unable or unwilling to use an acceptable method of 
contraception 
22. 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. 
The screening period can last up to 4 weeks long, with a minimum of 4 days between the last 
qualifying repeat measurement and the baseline visit (Day 1), ie, the screening period window is 
from Day -28 to Day -4. 
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.   
7.4.2 Rescreening  
Subjects who fail to meet the qualifying criteria for Hb or eGFR 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 B12 values may be considered for 
rescreening after receiving replacement therapy. 
If intravenous (IV) iron is used to replete iron stores, the last dose of IV iron must be 
administered at least 4 weeks prior to rescreening. 
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). 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 30 
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 randomized to receive placebo will be considered as having completed the study after 
completing participation in the Week 10 (unblinding) visit. 
A subject randomized to receive vadadustat will be considered as having completed the study 
after completing participation in the Week 18 visit (end of the 2-week safety follow-up period). 
Note that for subjects who discontinue study drug due to an excess Hb response during the 
primary efficacy period, Hb levels will be monitored weekly via lab evaluation until the subject 
no longer exhibits an excess Hb response. 
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 will discontinue study medication for any of the following conditions: 
• Completion of the protocol-defined dosing period (see Appendix A) 
• Meets discontinuation criteria related to excess Hb response during the primary efficacy 
period (defined in Section 8.2.4) 
• Major toxicity considered to be related to study medication 
• Worsening of anemia requiring ESA rescue or blood transfusion 
• Administrative reasons, such as, subject non-compliance or a major protocol violation 
• Upon request of the sponsor or regulatory agency 
• If, in the opinion of the investigator, it is medically necessary, or if it is the wish of the 
subject 
• Study termination (see Section 14) 
Subjects who are taking oral iron supplementation at baseline should continue their oral iron at 
the same dose throughout their study participation.  Changes to oral iron supplementation dose 
will be considered protocol deviations but will not be considered a reason for subject 
discontinuation. 
The investigator must document the primary reason for discontinuation in the appropriate case 
report form (CRF). 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 31 
7.6.3 Individual Subject Discontinuation during the Primary Efficacy Period or Blinded Dose 
Adjustment and Data Cleaning Period 
Subjects discontinuing study medication or withdrawing early from the study during the blinded 
periods should undergo the Week 10 (EOT for blinded period) clinical and laboratory 
assessments within 1 day of stopping study medication, if possible.  Such subjects should also 
complete the 2-week safety follow-up period (see Appendix A).  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. 
7.6.4 Individual Subject Discontinuation during the Open-Label Extension Period 
Only subjects randomized to vadadustat will continue to the open-label extension period.  
Subjects discontinuing vadadustat or withdrawing from the study during the open-label period 
should complete the Week 16 (EOT for open-label period) clinical and laboratory assessments 
within 1 day of stopping study medication, if possible.  Such subjects should also complete the 
2-week safety follow-up period and complete the Week 18 visit assessments (see Appendix A).  
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. 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 32 
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 according to 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 at the baseline visit.  Each bottle will contain 100 tablets of study drug.  
Subjects will be instructed to finish 1 bottle before opening a new bottle. 
Resupply of additional study drug at subsequent 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. 
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 at all times. 
Proper drug accountability includes, but is not limited to: 
• 
Continuously monitoring expiration dates, if expiry date or retest date is provided to the 
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 
immediately. 
During the study, the investigator will be notified of any expiry dates or retest date extensions of 
clinical study material.  If an expiry date notification is received during the study, the 
investigative site must complete all instructions outlined in the notification, including 
segregation of expired clinical study material for return to the sponsor or its designee for 
destruction. 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1) 
 
 
Confidential 
23 May 2016; Page 33 
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 according to 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 other oral 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 exception of the Week 4 visit.  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. 
Figure 5: 
Randomization Scheme of Study Treatment 
 
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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8.2.3 Blinding During the Primary Efficacy Period and Breaking the Blind 
During the blinded periods, all subjects and personnel involved with the conduct and 
interpretation of the study will be blinded to the study drug treatment, including investigators, 
site personnel, site pharmacist, and sponsor’s staff and designees. 
The study blind should be broken for individual subjects after a subject completes the Week 6 
visit and the subject’s data (from screening to Week 6) is cleaned and locked. 
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. 
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.  The applicable standard operating procedure will be followed for 
blind-breaking procedures.  After each subject’s data is cleaned and locked, their individual 
randomization code will be broken to determine eligibility for continuation to the open-label 
extension period. 
8.2.4 Study Drug Administration during the Primary Efficacy Period 
To establish a dose-response relationship, the primary efficacy period includes a blinded 
fixed-dose treatment regimen.  However, if Hb levels increase too rapidly or if the Hb levels 
exceed the desired range, the dose will be decreased or discontinued as presented below (and as 
depicted in Figure 6). 
• Subjects who meet the following criteria for excess Hb response will undergo a dose 
reduction by 1 tablet: 
- Hb level >13 g/dL, OR 
- Hb increase >1 g/dL within any 2-week period, OR 
- Hb increase >2 g/dL within any 4-week period 
• Subjects who meet the following criteria will discontinue study drug: 
- Excess Hb response as defined by any of the aforementioned criteria, AND 
- Current dose of 1 tablet daily OR subject had previously decreased study drug dose 
due to excess Hb response 
Hb will be assessed at the central laboratory and also monitored using point-of-care HemoCue® 
(as listed in Appendix A).  Note that the point-of-care HemoCue Hb value will be used to 
determine if the dose of study medication will be adjusted or discontinued. 
 


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Figure 6: 
Algorithm for Dose Reduction or Discontinuation of Study Drug During the 
Primary Efficacy Period 
 
 
8.2.5 Study Drug Administration during the Blinded Dose Adjustment and Data Cleaning 
Period 
After completing the Week 6 visit, subjects will continue blinded study treatment for an 
additional 4 weeks during which time their data from screening through the Week 6 visit will be 
cleaned and locked.  Individual subjects will be unblinded at their Week 10 visit.  Potential 
scenarios for individual subject unblinding is shown in Figure 7. 
Point-of-care Hb levels will be monitored via HemoCue to determine if the dose of study 
medication will be adjusted (as listed in Appendix A).  Dose adjustments will be guided by an 
IWR system based on Hb concentration and programmed dose adjustment algorithms (see 
Section 8.2.7). 
 
1 tablet
2 tablets
4 tablets
Discontinue
study drug
Decrease to 
1 tablet
Decrease to
3 tablets
Criteria for dose reduction
•
Hemoglobin >13 g/dL, OR
•
Hemoglobin increase >1 g/dL within any 2-week period, OR
•
Hemoglobin increase >2 g/dL within any 4-week period
Discontinue
study drug*
Discontinue
study drug*
Criteria for dose reduction
•
Hemoglobin >13 g/dL, OR
•
Hemoglobin increase >1 g/dL within any 2-week period, OR
•
Hemoglobin increase >2 g/dL within any 4-week period
Study Visit
(Week 1, 2, 4, or 6)
Study Visit
(Week 2, 4, or 6)
*Note: A subject who had previously decreased study drug dose due to an excess Hb response and 
meets the criteria for excess Hb response at a subsequent visit during the primary efficacy period 
(Week 2, 4, or 6) will discontinue study drug


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Figure 7: 
Potential Scenarios for Individual Subject Unblinding 
 
 
8.2.6 Vadadustat Administration during the Open-Label Extension Period 
During the 6-week, open-label extension period, vadadustat dosage will be adjusted to achieve a 
target Hb level of 10-12 g/dL.  Point-of-care Hb will be monitored via HemoCue to determine if 
the dose of study medication will be adjusted (see Appendix A).  Dose adjustments will be 
guided by an IWR system based on Hb concentration and programmed dose adjustment 
algorithms (see Section 8.2.7). 
8.2.7 Dose Adjustment Guidelines 
The programmed dose adjustment algorithm for blinded study drug (from Week 7 to 10) and 
open-label vadadustat (from Week 11 to 16) will follow the dose adjustment guidelines listed 
below to achieve a target Hb of 10-12 g/dL, and will be guided by an IWR system.  The 
point-of-care HemoCue Hb value will be used to determine if the dose of study drug will be 
adjusted. 
• Do not increase the dose more frequently than once within any given 4-week interval.  For 
example, if a subject’s dose was increased at Week 10 and the subject remains below the Hb 
target, the next opportunity to further increase the dose would be Week 14.  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). 
First Patient In
DATA CUT
Vadadustat 150 mg
Placebo
Placebo
UNBLIND
Vadadustat 600 mg
Vadadustat 300 mg
Vadadustat 150 mg
Double-blind, fixed-dose, primary efficacy period (6 weeks)
Open-label, dose-adjustable, extension period (6 weeks)
Randomization
Randomization
Randomization
Randomization
Randomization
Randomization
DATA LOCK
Double-blind, dose-adjustable, data cleaning period (4 weeks)
Adjust as Needed to Achieve Goal Hb 10-12 g/dL
Adjust as Needed to Achieve Goal Hb 10-12 g/dL
Adjust to Goal Hb
Adjust as Needed to Achieve Goal Hb 10-12 g/dL
Adjust to Goal Hb
Adjust as Needed to Achieve Goal Hb 10-12 g/dL


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• 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 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).  In cases of extenuating clinical circumstances, investigators may elect to 
dose outside the IWR system dosing recommendation to maintain the Hb within the target range. 
8.2.8 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: 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 
- Exhibits Hb level <9.0 g/dL 
• 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. 
8.2.9 Oral Iron Supplementation (Information on Allowed Use) 
Subjects who are taking oral iron supplementation at baseline should continue their oral iron at 
the same dose throughout their study participation.  Changes to oral iron supplementation dose 
will be considered protocol deviations but will not be considered a reason for subject 
discontinuation. 
Subjects who are not taking oral iron supplementation at baseline should not start oral iron 
during their study participation (see Section 8.4.3). 
Important: Because of the potential for oral iron to reduce the bioavailability of vadadustat, the 
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. 
8.2.10 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.   


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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. 
Subjects should be questioned regarding dosing compliance and the information should be 
recorded. 
8.2.11 Treatment Compliance 
Subjects will be questioned regarding dosing compliance at all study visits from Week 1 through 
Week 18, 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. 
8.2.12 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 through the course of 
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, Intravenous Iron, and Blood Transfusion 
Subjects may not receive any ESA treatment within 6 weeks prior to the screening period and 
through the safety follow-up period (eg, recombinant human erythropoietin, darbepoetin alfa, or 
methoxy polyethylene glycol-epoetin beta).  See Section 8.2.8 for the rescue therapy guidelines. 
Subjects may not receive intravenous iron or blood transfusion within 4 weeks prior to the 
screening period and through the safety follow-up period.  Use of intravenous iron 
supplementation after Day 1 will be considered a protocol deviation but will not be considered a 
reason for subject discontinuation. 
ESAs and RBC transfusions are allowed as rescue therapies, please refer to Section 8.2.8 for the 
rescue therapy guidelines.  Note that subjects who initiate rescue therapy will be required to stop 
study drug treatment and will be discontinued from the study. 


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8.4.3 Oral Iron Supplementation (Information on Prohibition) 
Subjects who are not taking oral iron supplementation at baseline should not start oral iron 
during study participation.  Use of oral iron supplementation by such subjects will be considered 
a protocol deviation but will not be considered a reason for subject discontinuation. 
See Section 8.2.9 for information on circumstances allowing use of oral iron supplementation. 
9 STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES 
As presented in Appendix A, this study includes the following visits: 
• 
Eligibility screening period (Day -28 to Day -4) 
• 
Baseline visit (Day 1) 
• 
Primary efficacy period (Week 1 ± 1 day, Week 2 ± 1 day, Week 4 ± 3 days, and 
Week 6 ± 3 days) 
• 
Blinded dose adjustment and data cleaning period (Week 10 ± 3 days) 
• 
Open-label extension period (Week 14 ± 3 days and Week 16 ± 3 days) 
• 
Safety follow-up period (Week 18 ± 3 days) 
The following sections describe the procedures to be completed during the study.  Subjects are to 
be assessed by the same investigator or site personnel whenever possible. 
9.1 Administrative Procedures 
9.1.1 Informed Consent Procedure 
Informed consent must be obtained and legally signed prior to a subject entering into the study 
and before any protocol-directed procedures (including screening tests) are performed (see 
Section 15.3). 
9.1.2 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. 
9.1.3 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 9.1.3.1. 
9.1.3.1 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.  


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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.   
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) and at baseline (assessed using urine pregnancy test). 
• 
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 
9.2 Study Procedures and Evaluations 
9.2.1 Clinical Evaluations 
The following clinical evaluations will be conducted during the course of the study.  Detailed 
information regarding the timing of the assessments is presented in Section 9.3 and summarized 
in Appendix A: 
• Demographics and medical history: Relevant medical history (with particular emphasis 
on previous medical conditions that may lead to exclusion) and significant ongoing 
medical conditions or diseases should be documented. 
• Physical examination: Physical examination, including height assessments 
• Weight assessment 
• 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 


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taken prior to blood draws when possible.  The subject should consume no more than a 
light meal or 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. 
• 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. 
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. 
9.2.2 Laboratory Evaluations 
Samples for laboratory assays will be sent to a central laboratory for analysis, with the exception 
of the urine pregnancy test at baseline which will be performed locally.  Detailed instructions for 
the collection, processing, and shipment of laboratory samples will be provided by the sponsor 
and the central laboratory.  The investigator is responsible for reviewing laboratory results for 
clinical significance. 
The following laboratory evaluations will be conducted during the course of the study: 
• Serum and urine pregnancy test: A serum pregnancy test for females of childbearing 
potential will be analyzed by the central lab (screening, Week 10, and Week 16 visits).  A 
urine pregnancy test will be analyzed by the local lab (baseline visit).  The screening and 
baseline pregnancy test results must be available and must be negative for a subject to 
initiate or continue study drug. 
• Coagulation tests: Blood sample will be collected to assess the prothrombin time (PT), 
partial thromboplastin time (PTT), and international normalized ratio (INR). 
• Folate and vitamin B12: Blood sample will be collected to assess folate and Vitamin B12 
levels. 
• HemoCue®: Hb will be monitored via HemoCue point-of-care device to determine if the 
dose of study drug will be adjusted. 


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• 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). 
For subjects who discontinue study drug due to an excess Hb response during the primary 
efficacy period, Hb will be assessed weekly via lab evaluation until the subject no longer 
exhibits an excess Hb response. 
• 
Serum chemistry and eGFR: The serum chemistry will include the following assays: 
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.  eGFR will be calculated from serum creatinine as 
described in Appendix B. 
• Iron indices: Blood samples will be collected to assess serum iron, TIBC, TSAT, ferritin, 
and 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. 
9.3 Schedule of Activities 
The Schedule of Events in Appendix A shows the timing of planned study procedures.  Every 
effort should be made to adhere to this procedure schedule and all assessments should be 
completed at each study visit. 
9.3.1 Screening Visit 
The screening visit must be performed within 28 days prior to dosing and there must be a 
minimum of 4 days between the last qualifying repeat measurement and the baseline visit 
(Day 1). 
After obtaining informed consent and receiving a unique subject identification number, subjects 
will undergo a number of screening activities.  The investigator will maintain a log of subjects 
and indicate who was enrolled or excluded and the reason for exclusion (see Section 9.1.2). 


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At the screening visit, the following activities/procedures will be performed: 
• Review of study inclusion and exclusion criteria 
• Demographics, medical history, and physical examination 
• Weight assessment 
• Vital signs (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
• 12-lead ECG (prior to blood draws when possible and obtained after the subject has been 
resting supine comfortably for approximately 10 minutes) 
• Prior and current medication use 
• 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 Coagulation tests (including prothrombin time, partial thromboplastin time, and 
international normalized ratio) 
o Folate and vitamin B12 levels 
o CBC 
o Serum chemistry and eGFR 
o Iron indices 
9.3.2 Baseline Visit (Day 1) 
There must be a minimum of 4 days between the screening and baseline visits. 
At the baseline visit, the following activities/procedures will be performed: 
• Review of study inclusion and exclusion criteria 
• Vital signs (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
• Recording of any concomitant medication use since screening visit 
• Laboratory procedures: 
o Urine pregnancy test for females of childbearing potential (eligible subjects will 
be advised to use an adequate contraceptive method).  The urine sample will be 
analyzed by the local lab.  The baseline results must be available and must be 
negative before the subject takes the first dose of study drug. 
o CBC 
o Serum chemistry and eGFR 
o Iron indices 
o C-reactive protein 
o VEGF 
• Dispense blinded study drug 
• Review dosing instructions 


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9.3.3 Week 1 Visit 
At the Week 1 visit, 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) 
• AE review 
• Concomitant medication review 
• Hb using HemoCue 
• CBC 
• Subjects should be questioned regarding dosing compliance 
• Review dosing instructions 
9.3.4 Week 2 Visit 
At the Week 2 visit, 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) 
• AE review 
• Concomitant medication review 
• Hb using HemoCue 
• Laboratory procedures: 
o CBC 
o Serum chemistry and eGFR 
o Iron indices 
• Subjects should be questioned regarding dosing compliance 
• Dispense blinded study drug (as necessary) 
• Review dosing instructions and 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 
9.3.5 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 (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
• AE review 
• Concomitant medication review 
• Hb using HemoCue 
• Laboratory procedures: 
o CBC 
o Serum chemistry and eGFR 
o Iron indices 
o Pre-dose PK sample 


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• Record date and time of the last dose of the study that was taken prior to the pre-dose PK 
sample 
• Subjects should be questioned regarding dosing compliance 
• Dispense blinded study drug (as necessary) 
• Review dosing instructions 
9.3.6 Week 6 Visit 
Individual subject data (up to Week 6) will be cleaned and locked after the Week 6 visit.  
Following data lock, individual subject’s randomized treatment assignment will be unblinded 
and the subject will be informed at the Week 10 visit. 
At the Week 6 visit, 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) 
• AE review 
• Concomitant medication review 
• Hb using HemoCue 
• Laboratory procedures: 
o CBC 
o Serum chemistry and eGFR 
o Iron indices 
o C-reactive protein 
o VEGF 
• Subjects should be questioned regarding dosing compliance 
• Dispense blinded study drug (as necessary) 
• Review dosing instructions 
9.3.7 Week 10 Visit (End-of-treatment visit for the blinded period and early withdrawals) 
All enrolled subjects who receive at least 1 dose of blinded study drug should complete the 
Week 10 assessments. 
Subjects who withdraw early from the study prior to the Week 6 visit or permanently discontinue 
study medication prior to the Week 6 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 9.3.10). 
Individual subject data (up to Week 6) will be locked after the Week 6.  Following data lock, 
individual subject’s randomized treatment assignment will be unblinded and the subject will be 
informed at the Week 10 visit.  Subjects who were assigned to receive placebo will discontinue 
from the study at the end of the Week 10 visit, and subjects who were assigned to receive 
vadadustat will continue to the open-label extension period. 
At the Week 10 visit, 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) 
• 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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• AE review (see Section 10.3.6 for follow-up of unresolved events) 
• Concomitant medication review 
• Hb using HemoCue for dose adjustment (not for subjects who discontinue prior to the 
Week 6 visit) 
• Laboratory procedures: 
o Serum pregnancy test for females of childbearing potential (to be analyzed by the 
central lab) 
o CBC 
o Serum chemistry and eGFR 
o Iron indices 
o C-reactive protein 
o VEGF 
• Subjects should be questioned regarding dosing compliance 
• Dispense open-label vadadustat (as necessary) and review dosing instructions (only 
applicable to subjects who are continuing to the open-label extension period) 
9.3.8 Week 14 Visit 
At this visit, 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) 
• AE review 
• Concomitant medication review 
• Hb using HemoCue for dose adjustment 
• CBC 
• Serum chemistry and eGFR 
• Subjects should be questioned regarding dosing compliance 
• Dispense vadadustat (as necessary) 
• Review dosing instructions 
9.3.9  Week 16 Visit (End-of-treatment visit for the open-label period and early withdrawal 
visit for withdrawals after Week 10 but before Week 16) 
All subjects who received at least 1 dose of open-label vadadustat should complete the Week 16 
assessments. 
Subjects who withdraw early from the open-label period 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 9.3.10). 
At the Week 16 visit, 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) 
• 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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• AE review (see Section 10.3.6 for follow-up of unresolved events) 
• Concomitant medication review 
• Laboratory procedures: 
o Serum pregnancy test for females of childbearing potential (to be analyzed by the 
central lab) 
o CBC 
o Serum chemistry and eGFR 
o Iron indices 
o C-reactive protein 
o VEGF 
• Subjects should be questioned regarding dosing compliance 
9.3.10  Week 18 Safety Follow-Up Visit (Or 2 Weeks after End-of-Treatment Safety Follow-Up 
Visit) 
For subjects randomized to vadadustat who complete the open-label extension period, the safety 
visit will be conducted 2 weeks after their end-of-treatment visit (Week 16). 
For subjects who discontinue the study early during the primary efficacy period or the blinded 
dose adjustment and data cleaning period, the safety visit will be conducted 2 weeks after their 
end-of-treatment visit (Week 10). 
At the follow-up visit, 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) 
• AE review (see Section 10.3.6 for follow-up of unresolved events) 
• Concomitant medication review 
• Laboratory procedures: 
o CBC 
o Serum chemistry and eGFR 
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. 


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• 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). 
• 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 


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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). 
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. 
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. 


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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. 
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 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. 
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 


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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 
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. 


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Investigators are encouraged to choose the most plausible cause for the event(s) from the 
following list: medical history, lack of efficacy/worsening of treated condition, study treatment, 
other treatment (concomitant, or previous), withdrawal of study treatment, administration error, 
protocol-related procedure, others (specify). 
10.3.5 Severity 
The investigator will assess each AE as either MILD, MODERATE, or SEVERE using the 
following guidelines to describe the maximum severity of the AE: 
• MILD: Does not interfere with subject's usual function. 
• MODERATE: Interferes to some extent with subject's usual function 
• SEVERE: Interferes significantly with subject's usual function. 
Note that a severe AE is not necessarily a serious AE.  For example, a headache may be severe 
in intensity, but would not be classified as serious unless it met 1 of the criteria for serious events 
listed above. 
10.3.6 Follow-Up of Unresolved Events 
All AEs 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. 


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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 
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 aware of the pregnancy (reference the site manual for 
contact information). 
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. 
• 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 
11.1 Primary Endpoint and Sample Size Determination 
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 NDD-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 EOT visit minus the mean pre-treatment Hb.  
Pre-treatment Hb is defined as the average of 2 Hb values obtained prior to treatment based on 
the qualifying screening Hb value and the Hb value at the baseline visit.  Linear regression 
analysis will be used to calculate the relationship between vadadustat dose and change in Hb. 
The target enrollment will be approximately 48 subjects for the study with 12 subjects enrolled 
in each of the 4 treatment groups. 
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 reasonable to assume 
that 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 


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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. 
11.2 Study Populations 
11.2.1 Analysis Population 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. 
11.2.2 Analysis Populations for the Efficacy Analyses 
The modified intent-to-treat (MITT) population will include all subjects assigned to study 
medication who receive at least 1 dose of study medication and have a pre-treatment average and 
at least one post-baseline measurement.  All efficacy endpoints will be analyzed using the MITT 
population. 
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.   
As sensitivity analyses, efficacy endpoints will also be analyzed using the PP population. 
11.3 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. 
11.4 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. 
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 
For purposes of analysis, a pre-treatment average (defined as the average of 2 samples obtained 
prior to treatment [ie, the qualifying screening value and baseline value]) will be used as the 


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baseline value for Hb and RBC count, and last observation before the first dose of study 
medication will be used as baseline for other parameters. 
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 assess 
the vadadustat dose-response relationship.  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. 
11.6 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, components of the CBC, and VEGF. 
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. 
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. 
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 
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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 
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. 


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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 
assessments. 
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). 


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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 
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 course of 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. 


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The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy.  Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number.  As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (eg, US FDA), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports.  Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process. 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (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 
2007S4-9. 
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. 
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. 
Matsuo S, Imai E, Horio M, et al.  Revised equations for estimated GFR from serum creatinine 
in Japan.  Am J Kidney Dis 2009;53:982-92. 
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. 
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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Appendix A: Schedule of Activities 
Please refer to Section 9.2 for detailed information regarding the study procedures and evaluations, and please refer to Section 9.3 for 
detailed information regarding the activities to be performed at each study visit. 
 
Screening 
Primary efficacy period 
(blinded, fixed-dose treatment) 
(Day 1-Week 6) 
Blinded dose 
adjustment, data 
cleaning period 
(Week 7-10) 
Open-label extension 
period 
(Week 11-16) 
Safety 
Follow-up 
(Week 17-18) 
Study Week 
-4 to 0 
Base 
line 
1 
2 
4 
6 
10 (EOT, Blinded 
Period) 
14 
16 (EOT, 
Open-Label 
Period) 
18 
Study Day 
-28 to -4 
1 
8 
15 
29 
43 
81 
109 
123 
137 
Visit Window (Days) 
 
 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Review inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Individual subject data lock (for subjects 
who complete Week 6) 
 
 
 
 
 
X 
 
 
 
Individual subject unblinding (for 
subjects who complete Week 6) 
 
 
 
 
 
 
X 
 
 
 
Demographics, medical history, physical 
exam, and weight 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram 
X 
 
 
 
 
 
X 
 
X 
 
Adverse event review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy test 
X 
 
 
 
 
 
X 
 
X 
 
Urine pregnancy test 
 
X 
 
 
 
 
 
 
 
 
Coagulation tests 
X 
 
 
 
 
 
 
 
 
 


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Screening 
Primary efficacy period 
(blinded, fixed-dose treatment) 
(Day 1-Week 6) 
Blinded dose 
adjustment, data 
cleaning period 
(Week 7-10) 
Open-label extension 
period 
(Week 11-16) 
Safety 
Follow-up 
(Week 17-18) 
Study Week 
-4 to 0 
Base 
line 
1 
2 
4 
6 
10 (EOT, Blinded 
Period) 
14 
16 (EOT, 
Open-Label 
Period) 
18 
Study Day 
-28 to -4 
1 
8 
15 
29 
43 
81 
109 
123 
137 
Visit Window (Days) 
 
 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Folate and vitamin B12 
X 
 
 
 
 
 
 
 
 
 
Hb using HemoCue® (Week 10 
assessment is not for subjects who 
discontinue prior to Week 6) 
 
 
X 
X 
X 
X 
X 
X 
 
 
Complete blood count, including Hb [a] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry and eGFR 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Iron indices 
X 
X 
 
X 
X 
X 
X 
 
X 
 
C-reactive protein 
 
X 
 
 
 
X 
X 
 
X 
 
VEGF  
 
X 
 
 
 
X 
X 
 
X 
 
PK pre-dose sample (study drug to be 
administered after sample collection) 
 
 
 
 
X 
 
 
 
 
 
Blinded study drug dispensation, as 
necessary 
 
X 
 
X 
X 
X 
 
 
 
 
Blinded study drug dosing 
 
Blinded study drug dosing 
 
 
 
Vadadustat dispensation, as necessary [b] 
 
 
 
 
 
 
X 
X 
 
 
Vadadustat dosing [b] 
 
 
 
 
 
 
 
Open-label vadadustat 
dosing 
 
Study drug compliance check 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: eGFR, estimated glomerular filtration rate; EOT, end of treatment; Hb, hemoglobin; PK, pharmacokinetics; VEGF, vascular endothelial growth 
factor 


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[a] For subjects who discontinue study drug due to an excess Hb response, blood samples will be collected weekly to monitor Hb until the subject no longer 
exhibits an excess Hb response.  The blood samples will be analyzed in a lab.  Point-of-care Hb assessment will not be used for such evaluations. 
[b] Subjects who were randomized to receive vadadustat treatment during the primary efficacy period and complete the Week 10 visit will continue to the 
open-label extension period. 
 
 
 


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Appendix B: Japanese Society of Nephrology 2009 Equation to Calculate eGFR 
The estimated glomerular filtration rate (eGFR) will be calculated from serum creatinine using 
the 2009 Japanese Society of Nephrology Equation (3-variables; Matsuo 2009).   
eGFR (mL/min/1.73 m2) = 194 x (Scr in mg/dL)-1.094 x (Age)-0.287 x (0.739 if female) 


Akebia Therapeutics, Inc. 
Clinical Study Protocol No.:AKB-6548-CI-0021 
Vadadustat 
Annex 1: Study Administrative Structure 
Version number: 1 
 
1 
GLOBAL SPONSOR 
Akebia Therapeutics, Inc. 
245 First Street, Suite 1100 
Cambridge, MA 02142, United States of America 
2 
CONTRACT RESEARCH ORGANIZATION (CRO) 
PAREXEL International 
Kayaba-cho First Building,  
1-17-21 Shinkawa, Chuo-ku,  
Tokyo 104-0033, Japan 
Tel: +81-3-3537-5899 
Fax: +81-3-3552-0451 
Role: Overall management of clinical study in Japan 
3 
SPONSOR REPRESENTATIVE 
 
Clinical Operations 
Akebia Therapeutics, Inc. 
Tel: 
 
4 
PROJECT LEADER IN CRO 
Project Management 
PAREXEL International 
Urban Ace Sannomiya Building, 
4-1-22 Onoe-dori, Chuo-ku,  
Kobe 651-0088, Japan 
Tel: +
 
5 
MEDICAL DIRECTOR 
Medical Research 
Akebia Therapeutics, Inc. 
Tel: 
 
 
Confidential 
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Akebia Therapeutics, Inc. 
Clinical Study Protocol No.:AKB-6548-CI-0021 
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Annex 1: Study Administrative Structure 
Version number: 1 
 
6 
MEDICAL MONITOR 
 
 
PAREXEL International 
Kayaba-cho First Building,  
1-17-21 Shinkawa, Chuo-ku,  
Tokyo 104-0033, Japan 
Tel:
 
7 
MONITOR LEADER 
Clinical Operations Japan 
PAREXEL International 
Urban Ace Sannomiya Building, 
4-1-22 Onoe-dori, Chuo-ku,  
Kobe 651-0088, Japan 
Tel: +
 
Fax: +
 
8 
CENTRALLABORATORY 
8.1 
Central Laboratory Service Provider 
SRL Medisearch Inc. 
Shinjuku I-Land-Tower (10F) 
6-5-1, Nishishinjuku, Shinjuku-ku, 
Tokyo 163-1310, JAPAN 
Tel: +81-3-5324-2602 
8.2 
Central Laboratory 
SRL, Inc 
2-1-1 Nishishinjuku, Shinjuku-ku, 
Tokyo 163-0409, JAPAN 
Tel: +81-3-6279-0900 
8.3 
PK Analysis 
 
Q2 Solutions 
19 Brown Road 
Ithaca, NY 14850 
Tel: 
 
 
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Akebia Therapeutics, Inc. 
Clinical Study Protocol No.:AKB-6548-CI-0021 
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Annex 1: Study Administrative Structure 
Version number: 1 
 
9 
EMERGENCY SAFETY CONTACT 
Emergency Medical Contact and Unblinding Service 
Toll number: +1-978-805-7613 
Toll free number: +1-888-615-2296 
• Country connection number for study site 
− KDDI: 00-539-111 
− NTT: 0034-811-001 
− Softbank Telecom: 00-663-5111 
 
Expedited Reporting Contact of Serious Adverse Events 
 
PAREXEL International 
Kayaba-cho Tower Building, 
1-21-2, Shinkawa, Chuo-ku 
Tokyo, 104-0033, Japan 
Tel: +
 
Fax: +
 
e-mail: 
 
10 AUDITOR 
Akebia Therapeutics, Inc. 
245 First Street, Suite 1100 
Cambridge, MA 02142, United States of America 
 
 
Confidential 
17 June 2016; Page 3 


Akebia Therapeutics, Inc. 
Clinical Study Protocol No.:AKB-6548-CI-0021 
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Annex 2: List of Investigators and Study Sites 
Version number: 1 
 
LIST OF INVESTIGATORS AND STUDY SITES 
Centre address 
Department 
Name of investigator 
Qualifications 
Seikeikai Hospital 
1-1-1, Minamiyasui-cho,  
Sakai-ku, Sakai, Osaka 
590-0064, Japan 
Tel: 072-223-8199 
Kidney Internal Medicine 
 
 
Confidential 
17 June 2016; Page 1 


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Original Protocol (Version 1.1) 
 
 
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CLINICAL PROTOCOL 
 
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 NON-DIALYSIS 
DEPENDENT CHRONIC KIDNEY DISEASE (NDD-CKD) 
 
 
Compound: 
Vadadustat (AKB-6548) 
Protocol Number: 
AKB-6548-CI-0021 
Phase: 
Phase 2 
Status / Date: 
Original protocol (Version 1; 23 May 2016) 
Original protocol (Version 1.1; 22 June 2016) 
 
Sponsor: 
Akebia Therapeutics, Inc. 
245 First Street, Suite 1100 
Cambridge, MA 02142, United States of America 
 
 
 
 
This document contains information that is confidential and proprietary to the Sponsor, Akebia Therapeutics, Inc.  
This information is being provided to you solely for the purpose of evaluating and/or conducting a clinical study 
for the Sponsor.  You may disclose the contents of this document only to study personnel under your supervision, 
the Institutional Review Board, the United States Food and Drug Administration, or duly authorized 
representatives of regulatory agencies for this purpose under the condition that they maintain confidentiality.  The 
contents of this document may not be used in any other clinical study, disclosed to any other person or entity, 
and/or published without the prior written permission of the Sponsor.  The foregoing shall not apply to disclosure 
required by any regulations; however, you will give prompt notice to the Sponsor of any such disclosure. 


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1 SIGNATURE PAGES 
1.1 Protocol Approval 
 
 
 Medical Research 
Akebia Therapeutics, Inc. 
 
 


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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 also protect the rights, 
safety, privacy, and well-being of study subjects in accordance with the following: 
 The ethical principles that have their origin in the Declaration of Helsinki. 
 International Conference on Harmonization Guidance for Industry, Good Clinical 
Practice E6. 
 All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
 Regulatory requirements for reporting serious adverse events defined in this protocol. 
 Terms outlined in the Clinical Study Site Agreement. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Phone Number 
Full Address 


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TABLE OF CONTENTS 
1 
SIGNATURE PAGES .................................................................................................. 2 
1.1 
Protocol Approval .................................................................................................... 2 
1.2 
Investigator Agreement ............................................................................................ 3 
TABLE OF CONTENTS ......................................................................................................... 4 
LIST OF TABLES ................................................................................................................... 7 
LIST OF FIGURES ................................................................................................................. 7 
2 
PROTOCOL SYNOPSIS .............................................................................................. 9 
3 
LIST OF ABBREVIATIONS ..................................................................................... 15 
4 
BACKGROUND ........................................................................................................ 17 
4.1 
Proposed Indication of Renal Anemia ................................................................... 17 
4.2 
Available Therapies for Anemia in Patients with CKD ......................................... 18 
4.3 
Hypoxia-Inducible Factor ...................................................................................... 18 
4.4 
Description and Mechanism of Action of Vadadustat ........................................... 19 
4.5 
Summary of Clinical Experience ........................................................................... 20 
4.6 
Ethno-Bridging Data from a Study of Healthy Japanese and Caucasian Volunteers
 ................................................................................................................................ 21 
4.7 
Potential Benefits and Risks ................................................................................... 23 
5 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 23 
5.1 
Primary Objective and Endpoint ............................................................................ 23 
5.2 
Secondary Objectives and Endpoints ..................................................................... 23 
6 
STUDY DESIGN ........................................................................................................ 24 
6.1 
Study Design .......................................................................................................... 24 
6.2 
Study Duration ....................................................................................................... 26 
6.3 
Rationale for Study Design .................................................................................... 26 
6.4 
Dose Justification ................................................................................................... 27 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 28 
7.1 
General Criteria ...................................................................................................... 28 
7.2 
Inclusion Criteria .................................................................................................... 28 
7.3 
Exclusion Criteria ................................................................................................... 28 
7.4 
Retesting and Rescreening ..................................................................................... 30 
7.4.1 
Retesting ............................................................................................................ 30 
7.4.2 
Rescreening ....................................................................................................... 30 
7.5 
Study Completion, Study Termination, and Individual Study Site Termination ... 30 
7.5.1 
Study Completion .............................................................................................. 30 
7.5.2 
Study Termination ............................................................................................. 31 
7.5.3 
Individual Study Site Termination .................................................................... 31 


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7.6 
Subject Completion and Individual Subject Discontinuation ................................ 31 
7.6.1 
Subject Completion ........................................................................................... 31 
7.6.2 
Conditions and Documentation of Individual Subject Study Drug 
Discontinuation .................................................................................................. 31 
7.6.3 
Individual Subject Discontinuation during the Primary Efficacy Period or 
Blinded Dose Adjustment and Data Cleaning Period ....................................... 32 
7.6.4 
Individual Subject Discontinuation during the Open-Label Extension Period . 32 
8 
STUDY DRUGS AND TREATMENT OF SUBJECTS ............................................ 32 
8.1 
Study Drugs ............................................................................................................ 32 
8.1.1 
Formulation ....................................................................................................... 32 
8.1.2 
Storage and Accountability ............................................................................... 33 
8.1.3 
Dispensing of Study Drugs ................................................................................ 33 
8.1.4 
Product Accountability and Destruction ........................................................... 33 
8.2 
Treatment of Subjects ............................................................................................. 34 
8.2.1 
Dosing Instructions ............................................................................................ 34 
8.2.2 
Randomization ................................................................................................... 34 
8.2.3 
Blinding During the Primary Efficacy Period and Breaking the Blind ............. 35 
8.2.4 
Study Drug Administration during the Primary Efficacy Period ...................... 35 
8.2.5 
Study Drug Administration during the Blinded Dose Adjustment and Data 
Cleaning Period ................................................................................................. 36 
8.2.6 
Vadadustat Administration during the Open-Label Extension Period .............. 37 
8.2.7 
Dose Adjustment Guidelines ............................................................................. 37 
8.2.8 
Rescue Therapy Guidelines ............................................................................... 38 
8.2.9 
Oral Iron Supplementation (Information on Allowed Use) .............................. 38 
8.2.10 
Late or Missed Doses ........................................................................................ 38 
8.2.11 
Treatment Compliance ...................................................................................... 39 
8.2.12 
Continuation of Treatment ................................................................................ 39 
8.3 
Prior and Concomitant Therapy ............................................................................. 39 
8.4 
Prohibited Treatments ............................................................................................ 39 
8.4.1 
Investigational Medications ............................................................................... 39 
8.4.2 
ESAs, Intravenous Iron, and Blood Transfusion ............................................... 39 
8.4.3 
Oral Iron Supplementation (Information on Prohibition) ................................. 39 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES ................................ 40 
9.1 
Administrative Procedures ..................................................................................... 40 
9.1.1 
Informed Consent Procedure ............................................................................. 40 
9.1.2 
Documentation of Screen Failures .................................................................... 40 
9.1.3 
Review of Inclusion and Exclusion Criteria ...................................................... 40 
9.1.3.1 
Acceptable Methods of Contraception ......................................................... 40 
9.2 
Study Procedures and Evaluations ......................................................................... 41 


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9.2.1 
Clinical Evaluations ........................................................................................... 41 
9.2.2 
Laboratory Evaluations ..................................................................................... 42 
9.3 
Schedule of Activities ............................................................................................ 43 
9.3.1 
Screening Visit .................................................................................................. 43 
9.3.2 
Baseline Visit (Day 1) ....................................................................................... 44 
9.3.3 
Week 1 Visit ...................................................................................................... 44 
9.3.4 
Week 2 Visit ...................................................................................................... 45 
9.3.5 
Week 4 Visit ...................................................................................................... 45 
9.3.6 
Week 6 Visit ...................................................................................................... 46 
9.3.7 
Week 10 Visit (End-of-treatment visit for the blinded period and early 
withdrawals) ...................................................................................................... 46 
9.3.8 
Week 14 Visit .................................................................................................... 47 
9.3.9 
Week 16 Visit (End-of-treatment visit for the open-label period and early 
withdrawal visit for withdrawals after Week 10 but before Week 16) ............. 47 
9.3.10 
Week 18 Safety Follow-Up Visit (Or 2 Weeks after End-of-Treatment Safety 
Follow-Up Visit) ............................................................................................... 48 
10 
ADVERSE EVENTS .................................................................................................. 48 
10.1 
Definitions .............................................................................................................. 48 
10.1.1 
Adverse Events (AEs) ....................................................................................... 48 
10.1.2 
Serious Adverse Events (SAEs) ........................................................................ 50 
10.2 
Eliciting Adverse Event Information ..................................................................... 51 
10.3 
Reporting ................................................................................................................ 51 
10.3.1 
Reporting Period ................................................................................................ 51 
10.3.2 
Reporting AEs ................................................................................................... 51 
10.3.3 
Reporting SAEs ................................................................................................. 51 
10.3.4 
Relationship to Study Medication ..................................................................... 52 
10.3.5 
Severity .............................................................................................................. 52 
10.3.6 
Follow-Up of Unresolved Events ...................................................................... 53 
10.3.7 
Special Situations .............................................................................................. 53 
10.4 
Exposure In Utero .................................................................................................. 53 
11 
DATA ANALYSIS ..................................................................................................... 54 
11.1 
Primary Endpoint and Sample Size Determination ................................................ 54 
11.2 
Study Populations ................................................................................................... 54 
11.2.1 
Analysis Population for the Safety Analyses .................................................... 54 
11.2.2 
Analysis Populations for the Efficacy Analyses ............................................... 55 
11.3 
Analysis of Demographics and Pretreatment Variables ......................................... 55 
11.4 
Disposition of Subjects ........................................................................................... 55 
11.5 
Efficacy and PD Analyses ...................................................................................... 55 
11.6 
Safety Analyses ...................................................................................................... 56 


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11.7 
PK Analyses ........................................................................................................... 56 
12 
DATA HANDLING AND RECORD KEEPING ...................................................... 56 
12.1 
Case Report Forms (CRFs) .................................................................................... 56 
12.2 
Record Retention .................................................................................................... 56 
13 
QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) ....................... 57 
13.1 
Study Site Monitoring Visits .................................................................................. 57 
13.2 
Protocol Deviations ................................................................................................ 57 
14 
STUDY DISCONTINUATION/INVESTIGATIVE STUDY SITE TERMINATION
 ..................................................................................................................................... 57 
14.1 
Criteria for Premature Termination or Suspension of the Study ............................ 58 
14.2 
Criteria for Premature Termination or Suspension of Investigational Sites .......... 58 
14.3 
Procedures for Premature Termination or Suspension of the Study or 
Investigational Site(s) ............................................................................................. 58 
15 
ETHICS ....................................................................................................................... 58 
15.1 
Ethical Conduct of the Study ................................................................................. 58 
15.2 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) ........... 58 
15.3 
Subject Information and Consent ........................................................................... 59 
15.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .... 59 
15.5 
Subject Confidentiality ........................................................................................... 59 
16 
PUBLICATION OF STUDY RESULTS ................................................................... 60 
17 
REFERENCES ............................................................................................................ 61 
 
LIST OF TABLES 
Table 1: 
Identity of Study Drugs ........................................................................................32 
 
LIST OF FIGURES 
Figure 1 
Mechanism of Action of Vadadustat ....................................................................19 
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) .......22 
Figure 3: 
Overview of Study Design ....................................................................................25 
Figure 4: 
Absolute Change in Hemoglobin (± Standard Error of Mean, g/dL) at Week 6 
Compared to Baseline (Study AKB-6548-CI-0005) ..........................................27 
Figure 5: 
Randomization Scheme of Study Treatment ........................................................34 
Figure 6: 
Guidelines for Dose Reduction or Discontinuation of Study Drug During the Primary 
Efficacy Period ...................................................................................................36 
Figure 7: 
Potential Scenarios for Individual Subject Unblinding ........................................37 


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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 Non-Dialysis 
Dependent Chronic Kidney Disease 
Protocol Number 
AKB-6548-CI-0021 
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 non-dialysis dependent chronic kidney disease 
(NDD-CKD) who are not currently being treated with an erythropoiesis-stimulating 
agent (ESA) 
Investigative Sites 
Approximately 25 sites in Japan 
Planned Number of 
Subjects 
Approximately 48 subjects will be enrolled in the study, with 36 subjects receiving 
one of the 3 doses of vadadustat and 12 subjects receiving placebo: 
 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 (QD) dosing for 6 weeks and the change in hemoglobin 
(Hb) in Japanese subjects with anemia secondary to NDD-CKD; in order 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 QD dosing in Japanese subjects 
with anemia secondary to NDD-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 maintenance period 
Study Design Overview 
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 NDD-CKD.  The study 
will include the following periods: 
 Eligibility screening period (up to 4 weeks) 
 Primary efficacy period (6 weeks; Weeks 1 to 6) 
 Dose adjustment and maintenance period (10 weeks), including the following: 
- Blinded dose adjustment and data cleaning period (4 weeks; Weeks 7 to 10): 
Individual subject data (from screening to Week 6) will be locked and 
individual subject unblinding will take place at the Week 10 visit  
- Open-label extension period (6 weeks; Weeks 11 to 16): Subjects 
randomized to receive vadadustat treatment during the blinded period will 
continue into this period 
 Safety follow-up period (2 weeks; Weeks 17 and 18): Subjects who complete 


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participation in the open-label extension period and subjects who discontinue 
early during the blinded study periods will complete the safety follow-up 
period.  Subjects identified as having received placebo during the Week 10 
unblinding visit will not participate in this safety follow-up period. 
Following the screening period, eligible subjects will be randomized to receive 
blinded study drug treatment during a 6-week primary efficacy period, with subjects 
randomized at a 3:1 ratio to receive vadadustat (150, 300, or 600 mg vadadustat) or 
placebo.  See “Dosage and Regimen” in the synopsis for additional information 
regarding the randomization scheme. 
Fixed-dose treatment during the blinded primary efficacy period will allow a 
dose-response relationship to be established.  However, if Hb levels increase too 
rapidly or if the Hb levels exceed the desired range, the blinded study drug dose can 
be decreased or discontinued (see “Dosage and Regimen” for additional 
information). 
After completing the primary efficacy period, subjects will continue to a 10-week 
dose adjustable maintenance period which will include a 4-week, blinded dose 
adjustment and data cleaning period and a 6-week, open-label extension period.  
Dose can be adjusted during the open-label period to achieve a target Hb of 
10-12 g/dL, and the dose adjustment guidelines are listed under “Dosage and 
Regimen” (see below). 
Individual subject’s study data (from screening to Week 6) will be cleaned and 
locked during the 4-week, blinded, dose adjustment and data cleaning period. 
At the Week 10 visit, treatment assignment will be unblinded on an individual 
subject basis.  Subjects who were randomized to receive placebo will end study 
participation after unblinding at the Week 10 visit.  Subjects who were randomized 
to receive 1 of the 3 vadadustat doses will continue receiving vadadustat during the 
open-label extension period. 
Vadadustat treatment will stop after the extension period has been completed 
(Week 16) and subjects will continue in a 2-week follow-up safety period 
(Week 17-18). 
Study Duration 
Up to 22 weeks, including the eligibility screening period (up to 4 weeks), primary 
efficacy period (6 weeks), blinded dose adjustment and data cleaning period 
(4 weeks), open-label extension period (6 weeks), and safety follow-up period 
(2 weeks). 
Only subjects who are randomized to receive vadadustat will continue in the 
maintenance period and the safety follow-up period. 
Key Inclusion Criteria 
(the complete list is 
provided in the 
protocol) 
 Male and female Japanese subjects (20 years or older) 
 Diagnosis of CKD based on an estimated glomerular filtration rate (eGFR) of 
≤60 mL/min/1.73 m2 (using the 2009 Japanese Society of Nephrology 
equation; Matsuo 2009) 
 Not currently being treated with dialysis and not expected to start dialysis 
within 3 months of screening 
 Hb ≤10.5 g/dL 
 Serum ferritin ≥50 ng/mL 
 Transferrin saturation (TSAT) ≥20% 
 Folate and vitamin B12 ≥lower limit of normal 
Key Exclusion Criteria 
(the complete list is 
provided in the 
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 


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protocol) 
aplasia; red blood cell (RBC) transfusion within 4 weeks prior to or during 
screening; intravenous iron within 4 weeks prior to or during screening; and any 
ESA use within 6 weeks prior to or during screening. 
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 or eGFR 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 B12 values may be considered for rescreening after receiving 
replacement therapy. 
Screening is limited to 3 attempts (initial screening and 2 additional rescreening 
attempts). 
Efficacy Endpoints 
Note that a pre-treatment value for Hb and RBC count is defined as the average of 
2 values obtained prior to treatment, ie, the qualifying screening value and the 
baseline value. Last observation before the first dose of study medication will be 
used as baseline for other parameters. 
Primary Endpoint: 
 Mean change in Hb levels from pre-treatment to the end of the primary efficacy 
period (Week 6) 
Secondary Endpoints: 
 Proportion of subjects who achieve target Hb 10-12 g/dL at the end of the 
open-label extension period (Week 16) 
 Mean change in Hb between pre-treatment and the end of the open-label 
extension period (Week 16) 
 Mean change in hematocrit, RBC count, and reticulocyte count from 
pre-treatment to the end of the primary efficacy period (Week 6) and the end of 
the open-label extension period (Week 16) 
 Mean change in iron indices (ie, iron, total iron-binding capacity [TIBC], 
TSAT, and ferritin) and hepcidin from pre-treatment to the end of the primary 
efficacy period (Week 6) and the end of the open-label extension period 
(Week 16) 
 Proportion of subjects with confirmed Hb values <10.0 or >12.0 g/dL from 
pre-treatment to the end of the open-label extension 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 open-label 
extension 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 open-label extension 
period (Week 16) 
 Number of dose adjustments from baseline to the end of the primary efficacy 
period (Week 6) and the end of the open-label extension period (Week 16) 
 Maintenance of iron sufficiency (defined as ferritin ≥50 ng/mL and TSAT 
≥20%) from baseline to the end of the primary efficacy period (Week 6) and 
the end of the open-label extension period (Week 16) 
 Plasma concentration profile of vadadustat and its metabolites using pre-dose 
sample from Week 4 
Safety Endpoints 
Safety and tolerability assessments, including adverse events, vital signs, 
electrocardiograms (ECGs), and other laboratory assay results (eg, serum chemistry, 


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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 other oral beverage and should be instructed to 
swallow the intact tablet(s).  Subjects may take the study medication with or without 
food. 
Note: Hb will be assessed at the central laboratory and also monitored using 
point-of-care HemoCue®.  Note that the point-of-care HemoCue Hb value will be 
used to determine if the dose of study medication will be adjusted or discontinued. 
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. 
 
The primary efficacy period includes a fixed-dose treatment to establish a 
dose-response relationship.  However, if Hb level increases too rapidly or if the Hb 
levels exceed the desired range, the blinded study drug dose will be decreased or 
discontinued as presented below. 
 Subjects who meet the following criteria for excess Hb response will undergo a 
dose reduction by 1 tablet: 
- 
Hb increase >1 g/dL within any 2-week period, OR 
- 
Hb increase >2 g/dL within any 4-week period, OR 
- 
Hb level >13 g/dL 
 Subjects who meet the following criteria will discontinue study drug: 
- 
Excess Hb response as defined by any of the aforementioned criteria, 
AND 
- 
Current dose 1 tablet OR subject had previously decreased study drug 
dose due to excess Hb response 
Blinded dose adjustment and data cleaning period (Week 7 to 10) 
During this period, data from screening through the Week 6 visit will be cleaned and 
locked in preparation for the Week 10 unblinding visit.  Blinded study drug dosage 
will be adjusted to achieve a target Hb 10-12 g/dL.  Starting at the Week 6 visit, 
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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adjustments to doses will be based on the dose adjustment guidelines listed below. 
Open-label extension period (Weeks 11 to 16): 
Subjects who were randomized to receive vadadustat will enter this open-label 
extension period, and vadadustat dosage will continue to be adjusted to achieve a 
target Hb 10-12 g/dL.  Dose adjustments will continue to be based on the dose 
adjustment guidelines listed below. 
Dose adjustment guidelines from Week 7 to Week 16 
The dose adjustment for blinded study drug (from Week 7 to 10) and open-label 
vadadustat (from Week 11 to 16) will follow the dose adjustment guidelines listed 
below to achieve a target Hb of 10-12 g/dL.  The point-of-care HemoCue Hb value 
will be used to determine if the dose of study drug will be adjusted. 
 
Do not increase the dose more frequently than once within any given 
4-week interval.  For example, if a subject’s dose was increased at Week 10 
and the subject remains below the Hb target, the next opportunity to further 
increase the dose would be Week 14.  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 rises 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).  In cases of extenuating clinical 
circumstances, investigators may elect to dose outside the dosing guidelines to 
maintain the Hb within the target range. 
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: 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 
- 
Exhibits Hb level <9.0 g/dL 
 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. 
Oral Iron 
Supplementation 
Subjects who are taking oral iron supplementation at baseline should continue their 
oral iron at the same dose throughout their study participation.  Changes to oral iron 
supplementation dose will be considered protocol deviations but will not be 
considered a reason for subject discontinuation. 
Subjects who are not taking oral iron supplementation at baseline should not start 


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oral iron during their study participation. 
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 
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. 
The target enrollment will be approximately 48 subjects for the study with 
12 subjects enrolled in each of the 4 treatment groups.  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. 
 


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3 LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
BUN 
blood urea nitrogen 
C 
Celsius 
CBC 
complete blood count 
CKD 
chronic kidney disease 
CRF 
case report form 
CRO 
contract research organization 
CV 
cardiovascular 
dL 
deciliter 
DVT 
deep venous thrombosis 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
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 
GFR 
glomerular filtration rate 
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 


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IRB 
institutional review board 
IV 
intravenous 
JSN 
Japanese Society of Nephrology 
KDIGO 
Kidney Disease Improving Global Outcomes 
kg 
kilogram 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
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) 
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 
 


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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). 


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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. 
A number of 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- proteins.  When HIF- is stabilized, it travels to the 
nucleus of the cell, where it binds to the protein HIF-β (Figure 1).  Dimerized HIF- 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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protein and other proteins.  Therefore, stabilization of HIF proteins leads to an increased 
production of EPO and mobilization of iron to the bone marrow, increasing Hb and RBC 
production.  Inhibitors of HIF-PH enzymes (such as vadadustat) decrease the degradation of 
HIFs thus mimicking physiological conditions at low oxygen levels.   
Figure 1 
Mechanism of Action of Vadadustat 
 
a. 
Normoxia: HIF-PH hydroxylates HIF-α (high level of hydroxylation depicted by 4 arrows), targeting HIF-α for 
degradation in a VHL (von Hippel-Lindau)-dependent manner, and leading to low levels of HIF-α. 
b. 
Hypoxia: HIF-PH activity is decreased (1 dashed arrow).  Stabilized HIF-α travels to the cell nucleus, dimerizes 
with HIF-β, and binds to hypoxia response elements (HREs) that control various target genes, including 
activation of the EPO gene leading to increased production of EPO protein. 
c. 
By inhibiting HIF-PH activity, vadadustat mimics the physiological effects of hypoxia, leading to increased 
production of EPO protein and mobilization of iron in the bone marrow, subsequently increasing the level of Hb 
and RBC production. 
Adapted from Bigham 2014 
 
4.4 
Description and Mechanism of Action of Vadadustat 
Vadadustat works by inhibiting PHD enzymes (Figure 1), leading to stabilization and increased 
levels of HIF-, and improved production of Hb and RBCs, while maintaining normal levels of 
EPO in patients. 
Vadadustat has compelling clinical data with several potential safety and efficacy advantages 
over current injectable recombinant ESA therapy for the treatment of renal anemia: 
 Vadadustat significantly increases and maintains Hb levels in CKD patients with anemia: 
We have successfully completed two Phase 2 trials in patients with non-dialysis 
dependent chronic kidney disease (NDD-CKD) which demonstrated that vadadustat 
significantly increased Hb levels.  In the first study (AKB-6548-CI-0005), vadadustat 
was shown to raise Hb in a dose-dependent manner compared to baseline and across all 
treatment arms (p < 0.0001).  In the second Phase 2b study (AKB-6548-CI-0007), 
vadadustat effectively increased Hb while minimizing Hb excursions  13.0 g/dL.  Only 
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


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4.3% of patients on 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 patients with DD-CKD 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-.  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.  As a result, 
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. 


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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 
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 recently completed Phase 2b, randomized, double-blind, placebo-controlled study to assess the 
hematologic PD response, safety, and tolerability of oral vadadustat for 20 weeks was performed 
in 210 subjects with anemia associated with NDD-CKD (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.  


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Within each dose cohort assignment, subjects were randomized at a 3:1 ratio to receive either 
vadadustat (n=6) or placebo (n=2). 
Brief Overview of Study Results 
Based on the study results, the PK and PD of vadadustat are similar in healthy Caucasian and 
Japanese subjects with no ethnic factors identified.  The mean plasma concentration versus time 
plot for vadadustat is shown in Figure 2.  Although there is a slight increase in the EPO exposure 
in Japanese subjects at the highest dose (600 mg); this increase is not clinically meaningful.  The 
mean reticulocyte concentrations in subjects of both ethnicities is also similar.  EPO levels 
following vadadustat dosing were within normal physiologic range, at a concentration below 
EPO receptor saturation, and substantially lower than EPO levels following ESA dosing. 
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) 
 
 


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4.7 Potential Benefits and Risks 
Please see the vadadustat Investigator’s Brochure for additional discussion and information for 
the following section. 
Vadadustat offers the potential of flexible oral dosing that is easier to adjust than injectable 
hormone ESAs.  This alternate therapeutic approach may avoid the excursions and fluctuations 
in Hb levels seen with currently available injectable ESAs and provide for a controlled, steady 
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 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 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, all of the acute findings observed at doses less than the maximum tolerated dose (MTD) 
in animals have been shown to be reversible and dose-related.  In addition, most of the findings 
have followed a pattern that would have been predicted based on the known HIF and HIFPH 
biochemistry, pharmacology, and human genetic variations (eg, Chuvash polycythemia).  In the 
completed clinical studies, vadadustat has been generally well-tolerated. 
5 STUDY OBJECTIVES AND ENDPOINTS 
Note that a pre-treatment value for Hb, hematocrit, RBC count, reticulocyte count, and iron 
metabolism markers is defined as the average of 2 values obtained prior to treatment, ie, the 
qualifying screening value 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 Hb in Japanese subjects with anemia 
secondary to NDD-CKD; in order 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 
NDD-CKD during the 6-week, primary efficacy period 


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 To evaluate the effect of dose adjustments and demonstrate the maintenance effect on Hb 
during a 10-week maintenance period 
The efficacy endpoints that will be used to assess these objectives include the following: 
 Proportion of subjects who achieve target Hb 10-12 g/dL at the end of the open-label 
extension period (Week 16) 
 Mean change in Hb between pre-treatment and the end of the open-label extension period 
(Week 16) 
 Mean change in hematocrit, RBC count, and reticulocyte count from pre-treatment to the 
end of the primary efficacy period (Week 6) and the end of the open-label extension 
period (Week 16) 
 Mean change in iron indices (ie, iron, total iron-binding capacity [TIBC], TSAT, and 
ferritin) and hepcidin from pre-treatment to the end of the primary efficacy period 
(Week 6) and the end of the open-label extension period (Week 16) 
 Proportion of subjects with confirmed Hb values <10.0 or >12.0 g/dL from pre-treatment 
to the end of the open-label extension 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 open-label extension 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 open-label extension period (Week 16) 
 Number of dose adjustments from baseline to the end of the primary efficacy period 
(Week 6) and the end of the open-label extension period (Week 16) 
 Maintenance of iron sufficiency (defined as ferritin ≥50 ng/mL and TSAT ≥20%) from 
baseline to the end of the primary efficacy period (Week 6) and the end of the open-label 
extension 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, serum 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 subjects 
with anemia secondary to NDD-CKD.   


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The study has a planned enrollment of 48 subjects to be enrolled at approximately 25 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. 
Figure 3: 
Overview of Study Design 
 
 
The study will include the following periods: 
 Eligibility screening period (up to 4 weeks) 
 Primary efficacy period (6 weeks; Weeks 1 to 6) 
 Dose adjustment and maintenance period (10 weeks) include the following: 
- Blinded dose adjustment and data cleaning period (4 weeks; Weeks 7 to 10): Individual 
subject data (from screening to Week 6) will be cleaned and locked and individual 
subject unblinding will take place at the Week 10 visit  
- Open-label extension period (6 weeks; Weeks 11 to 16): Subjects randomized to 
receive vadadustat treatment during the blinded period will continue into this period 
 Safety follow-up period (2 weeks; Weeks 17 and 18): Subjects who complete 
participation in the open-label extension period and subjects who discontinue early 
during the blinded study periods will complete the safety follow-up period.  Subjects 
identified as having received placebo during the Week 10 unblinding visit will not 
participate in this safety follow-up period. 
Subjects will participate in a screening period (4 days to 4 weeks) to determine study eligibility, 
and eligible subjects will be randomized following the screening period. 
Vadadustat 300mg (n=12); 2x150 mg tablets once daily
Placebo (n=4); 2 tablets once daily
Vadadustat 150mg (n=12); 1x150 mg tablet once daily
Placebo (n=4); 1 tablet once daily
4 days - 4 weeks
6 weeks
4 weeks
6 weeks
2 weeks
Screening
Double-blind, fixed-dose, 
primary efficacy period
Open-label, dose-adjustable, 
extension period
Blinded, dose-
adjustable, data 
cleaning period
Safety
follow-up
Individual subject unblinding;
end-of-Treatment (EOT) for subjects receiving placebo
Data cutoff for primary endpoint
Vadadustat 600 mg (n=12);
4 x 150 mg tablets once daily
Placebo (n=4);
4 tablets once daily
Vadadustat 300 mg (n=12);
2 x 150 mg tablets once daily
Placebo (n=4);
2 tablets once daily
Vadadustat 150 mg (n=12);
1 x 150 mg tablet once daily
Placebo (n=4);
1 tablet once daily
(EOT)
(EOT)
(EOT)
(EOT)
(EOT)
(EOT)
g


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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. 
Blinded 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 levels increase too rapidly or if the Hb levels exceed the desired 
range, the blinded study drug dose can be decreased or discontinued (see Section 8.2.4). 
After completing the primary efficacy period, subjects will continue to a 10-week dose 
adjustment and maintenance period including a 4-week, blinded dose adjustment and data 
cleaning period and a 6-week, open-label extension period (see Sections 8.2.5 and 8.2.6).  Dose 
will be adjusted to achieve a target Hb of 10-12 g/dL, and dose adjustments will be based on 
dose adjustment guidelines (see Section 8.2.7). 
Individual subject’s study data (from screening to Week 6) will be cleaned and locked during the 
4-week, blinded, dose adjustment period. 
At the Week 10 visit, treatment assignment will be unblinded on an individual subject basis.  
Subjects who were randomized to receive placebo will end study participation after unblinding at 
the Week 10 visit.  Subjects who were randomized to receive 1 of the 3 vadadustat doses will 
continue receiving vadadustat during the 6-week, open-label extension period. 
Vadadustat treatment will stop after the extension period has been completed (Week 16) and 
subjects will continue in a 2-week follow-up safety period (Week 17-18). 
The clinical and safety assessments will be performed as described in Section 9.3 and as listed in 
Appendix A. 
6.2 Study Duration 
Individual subjects will participate in the study for up to 22 weeks, including the eligibility 
screening period (up to 4 weeks), primary efficacy period (6 weeks), blinded dose adjustment 
and data cleaning period (4 weeks), open-label extension period (6 weeks), and safety follow-up 
period (2 weeks). 
Only subjects who are randomized to receive vadadustat will continue in the open-label 
extension period and the safety follow-up period.  Subjects who are randomized to receive 
placebo during the blinded treatment period will discontinue from the study after unblinding at 
Week 10. 
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 NDD-CKD is modeled on a previously completed 
dose-finding study in Caucasian subjects with anemia secondary to NDD-CKD 
(Study AKB-6548-CI-0005). 
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 


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Study AKB-6548-CI-0005 was adequate to establish a statistically significant dose-response 
relationship (as shown in Figure 4).  An additional 10-week 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 safe and 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 safe, 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 according to 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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7 SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 General Criteria 
The study population will consist of male and female Japanese adults aged 20 years or older with 
anemia secondary to NDD-CKD who are not currently being treated with an ESA. 
To be eligible for this study, a subject or their legally acceptable representative must have 
provided valid informed consent and must meet all of the following criteria.  No study 
procedures (including screening tests) may be performed until after the informed consent has 
been legally signed. 
7.2 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for study participation: 
1. Male and female Japanese subjects, aged 20 years or older 
2. Diagnosis of CKD based on an estimated glomerular filtration rate (eGFR) of 
≤60 mL/min/1.73 m2 (using the 2009 Japanese Society of Nephrology equation; Matsuo 
2009) 
3. Not currently being treated with dialysis and not expected to start dialysis within 
3 months of screening 
4. Hemoglobin (Hb) ≤10.5 g/dL during screening 
5. Serum ferritin ≥50 ng/mL during screening 
6. TSAT ≥20% during screening 
7. Folate and vitamin B12 greater than or equal to the lower limit of normal during 
screening 
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. RBC transfusion within 4 weeks prior to or during screening 
4. Intravenous iron within 4 weeks prior to or during screening 


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5. Any ESA use within 6 weeks prior to or during screening (eg, recombinant human 
erythropoietin, darbepoetin alfa, or methoxy polyethylene glycol-epoetin beta) 
6. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), 
alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total 
bilirubin >2.0 x upper limit of normal during screening.  A history of Gilbert’s syndrome 
is not an exclusion criterion. 
7. Uncontrolled hypertension (confirmed diastolic blood pressure >110 mm Hg or systolic 
blood pressure >180 mm Hg) during screening 
8. Body mass index (BMI) >42.0 kg/m2 
9. Severe heart failure during screening (New York Heart Association Class III or IV) 
10. 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 
11. 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 
12. 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 
13. History of deep vein thrombosis (DVT) or pulmonary embolism (PE) requiring active 
treatment within 8 weeks prior to or during screening 
14. History of hemosiderosis or hemochromatosis 
15. History of prior organ transplantation or scheduled organ transplant (subjects on kidney 
transplant wait-list are not excluded), or prior hematopoietic stem cell or bone marrow 
transplant (corneal transplants and stem cell therapy for knee arthritis are not excluded) 
16. 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 
17. Previous participation in a study with a hypoxia-inducible factor prolyl-hydroxylase 
inhibitor, other than vadadustat, within 90 days prior to screening 
18. Hypersensitivity to vadadustat, or to any of its excipients 


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19. Females who are pregnant or breast-feeding 
20. Females of childbearing potential who are unable or unwilling to use an acceptable 
method of contraception 
21. Non-vasectomized males who are unable or unwilling to use an acceptable method of 
contraception 
22. 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. 
The screening period can last up to 4 weeks long, with a minimum of 4 days between the last 
qualifying repeat measurement and the baseline visit (Day 1), ie, the screening period window is 
from Day -28 to Day -4. 
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.   
7.4.2 Rescreening  
Subjects who fail to meet the qualifying criteria for Hb or eGFR 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 B12 values may be considered for 
rescreening after receiving replacement therapy. 
If intravenous (IV) iron is used to replete iron stores, the last dose of IV iron must be 
administered at least 4 weeks prior to rescreening. 
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). 


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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 randomized to receive placebo will be considered as having completed the study after 
completing participation in the Week 10 (unblinding) visit. 
A subject randomized to receive vadadustat will be considered as having completed the study 
after completing participation in the Week 18 visit (end of the 2-week safety follow-up period). 
Note that for subjects who discontinue study drug due to an excess Hb response during the 
primary efficacy period, Hb levels will be monitored weekly via lab evaluation until the subject 
no longer exhibits an excess Hb response. 
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 will discontinue study medication for any of the following conditions: 
 Completion of the protocol-defined dosing period (see Appendix A) 
 Meets discontinuation criteria related to excess Hb response during the primary efficacy 
period (defined in Section 8.2.4) 
 Major toxicity considered to be related to study medication 
 Worsening of anemia requiring ESA rescue or blood transfusion 
 Administrative reasons, such as, subject non-compliance or a major protocol violation 
 Upon request of the sponsor or regulatory agency 
 If, in the opinion of the investigator, it is medically necessary, or if it is the wish of the 
subject 
 Study termination (see Section 14) 
Subjects who are taking oral iron supplementation at baseline should continue their oral iron at 
the same dose throughout their study participation.  Changes to oral iron supplementation dose 
will be considered protocol deviations but will not be considered a reason for subject 
discontinuation. 
The investigator must document the primary reason for discontinuation in the appropriate case 
report form (CRF). 


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7.6.3 Individual Subject Discontinuation during the Primary Efficacy Period or Blinded Dose 
Adjustment and Data Cleaning Period 
Subjects discontinuing study medication or withdrawing early from the study during the blinded 
periods should undergo the Week 10 (EOT for blinded period) clinical and laboratory 
assessments within 1 day of stopping study medication, if possible.  Such subjects should also 
complete the 2-week safety follow-up period (see Appendix A).  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. 
7.6.4 Individual Subject Discontinuation during the Open-Label Extension Period 
Only subjects randomized to vadadustat will continue to the open-label extension period.  
Subjects discontinuing vadadustat or withdrawing from the study during the open-label period 
should complete the Week 16 (EOT for open-label period) clinical and laboratory assessments 
within 1 day of stopping study medication, if possible.  Such subjects should also complete the 
2-week safety follow-up period and complete the Week 18 visit assessments (see Appendix A).  
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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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 according to 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 at the baseline visit.  Each bottle will contain 100 tablets of study drug.  
Subjects will be instructed to finish 1 bottle before opening a new bottle. 
Resupply of additional study drug at subsequent 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. 
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 at all times. 
Proper drug accountability includes, but is not limited to: 
 
Continuously monitoring expiration dates, if expiry date or retest date is provided to the 
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 
immediately. 
During the study, the investigator will be notified of any expiry dates or retest date extensions of 
clinical study material.  If an expiry date notification is received during the study, the 
investigative site must complete all instructions outlined in the notification, including 
segregation of expired clinical study material for return to the sponsor or its designee for 
destruction. 


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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 according to 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 other oral 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 exception of the Week 4 visit.  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. 
Figure 5: 
Randomization Scheme of Study Treatment 
 
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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8.2.3 Blinding During the Primary Efficacy Period and Breaking the Blind 
During the blinded periods, all subjects and personnel involved with the conduct and 
interpretation of the study will be blinded to the study drug treatment, including investigators, 
site personnel, site pharmacist, and sponsor’s staff and designees. 
The study blind should be broken for individual subjects after a subject completes the Week 6 
visit and the subject’s data (from screening to Week 6) is cleaned and locked. 
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. 
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.  The applicable standard operating procedure will be followed for 
blind-breaking procedures.  After each subject’s data is cleaned and locked, their individual 
randomization code will be broken to determine eligibility for continuation to the open-label 
extension period. 
8.2.4 Study Drug Administration during the Primary Efficacy Period 
To establish a dose-response relationship, the primary efficacy period includes a blinded 
fixed-dose treatment regimen.  However, if Hb levels increase too rapidly or if the Hb levels 
exceed the desired range, the dose will be decreased or discontinued as presented below (and as 
depicted in Figure 6). 
 Subjects who meet the following criteria for excess Hb response will undergo a dose 
reduction by 1 tablet: 
- Hb level >13 g/dL, OR 
- Hb increase >1 g/dL within any 2-week period, OR 
- Hb increase >2 g/dL within any 4-week period 
 Subjects who meet the following criteria will discontinue study drug: 
- Excess Hb response as defined by any of the aforementioned criteria, AND 
- Current dose of 1 tablet daily OR subject had previously decreased study drug dose 
due to excess Hb response 
Hb will be assessed at the central laboratory and also monitored using point-of-care HemoCue® 
(as listed in Appendix A).  Note that the point-of-care HemoCue Hb value will be used to 
determine if the dose of study medication will be adjusted or discontinued. 
 


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Figure 6: 
Guidelines for Dose Reduction or Discontinuation of Study Drug During the 
Primary Efficacy Period 
 
 
8.2.5 Study Drug Administration during the Blinded Dose Adjustment and Data Cleaning 
Period 
After completing the Week 6 visit, subjects will continue blinded study treatment for an 
additional 4 weeks during which time their data from screening through the Week 6 visit will be 
cleaned and locked.  Individual subjects will be unblinded at their Week 10 visit.  Potential 
scenarios for individual subject unblinding is shown in Figure 7. 
Point-of-care Hb levels will be monitored via HemoCue to determine if the dose of study 
medication will be adjusted (as listed in Appendix A).  Dose adjustments will be based on dose 
adjustment guidelines (see Section 8.2.7). 
 
1 tablet
2 tablets
4 tablets
Discontinue
study drug
Decrease to 
1 tablet
Decrease to
3 tablets
Criteria for dose reduction
•
Hemoglobin >13 g/dL, OR
•
Hemoglobin increase >1 g/dL within any 2-week period, OR
•
Hemoglobin increase >2 g/dL within any 4-week period
Discontinue
study drug*
Discontinue
study drug*
Criteria for dose reduction
•
Hemoglobin >13 g/dL, OR
•
Hemoglobin increase >1 g/dL within any 2-week period, OR
•
Hemoglobin increase >2 g/dL within any 4-week period
Study Visit
(Week 1, 2, 4, or 6)
Study Visit
(Week 2, 4, or 6)
*Note: A subject who had previously decreased study drug dose due to an excess Hb response and 
meets the criteria for excess Hb response at a subsequent visit during the primary efficacy period 
(Week 2, 4, or 6) will discontinue study drug


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Figure 7: 
Potential Scenarios for Individual Subject Unblinding 
 
 
8.2.6 Vadadustat Administration during the Open-Label Extension Period 
During the 6-week, open-label extension period, vadadustat dosage will be adjusted to achieve a 
target Hb level of 10-12 g/dL.  Point-of-care Hb will be monitored via HemoCue to determine if 
the dose of study medication will be adjusted (see Appendix A).  Dose adjustments will be based 
on dose adjustment guidelines (see Section 8.2.7). 
8.2.7 Dose Adjustment Guidelines 
Dose adjustment of blinded study drug (from Week 7 to 10) and open-label vadadustat (from 
Week 11 to 16) will follow the dose adjustment guidelines listed below to achieve a target Hb of 
10-12 g/dL.  The point-of-care HemoCue Hb value will be used to determine if the dose of study 
drug will be adjusted. 
 Do not increase the dose more frequently than once within any given 4-week interval.  For 
example, if a subject’s dose was increased at Week 10 and the subject remains below the Hb 
target, the next opportunity to further increase the dose would be Week 14.  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 rises rapidly (eg, more than 1 g/dL in any 2-week period), reduce the dose by 
1 tablet. 
First Patient In
DATA CUT
Vadadustat 150 mg
Placebo
Placebo
UNBLIND
Vadadustat 600 mg
Vadadustat 300 mg
Vadadustat 150 mg
Double-blind, fixed-dose, primary efficacy period (6 weeks)
Open-label, dose-adjustable, extension period (6 weeks)
Randomization
Randomization
Randomization
Randomization
Randomization
Randomization
DATA LOCK
Double-blind, dose-adjustable, data cleaning period (4 weeks)
Adjust as Needed to Achieve Goal Hb 10-12 g/dL
Adjust as Needed to Achieve Goal Hb 10-12 g/dL
Adjust to Goal Hb
Adjust as Needed to Achieve Goal Hb 10-12 g/dL
Adjust to Goal Hb
Adjust as Needed to Achieve Goal Hb 10-12 g/dL


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 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).  In cases of extenuating clinical circumstances, investigators may elect to 
dose outside the dosing guidelines to maintain the Hb within the target range. 
8.2.8 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: 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 
- Exhibits Hb level <9.0 g/dL 
 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. 
8.2.9 Oral Iron Supplementation (Information on Allowed Use) 
Subjects who are taking oral iron supplementation at baseline should continue their oral iron at 
the same dose throughout their study participation.  Changes to oral iron supplementation dose 
will be considered protocol deviations but will not be considered a reason for subject 
discontinuation. 
Subjects who are not taking oral iron supplementation at baseline should not start oral iron 
during their study participation (see Section 8.4.3). 
Important: Because of the potential for oral iron to reduce the bioavailability of vadadustat, the 
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. 
8.2.10 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. 


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Subjects should be questioned regarding dosing compliance and the information should be 
recorded. 
8.2.11 Treatment Compliance 
Subjects will be questioned regarding dosing compliance at all study visits from Week 1 through 
Week 18, 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. 
8.2.12 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 through the course of 
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, Intravenous Iron, and Blood Transfusion 
Subjects may not receive any ESA treatment within 6 weeks prior to the screening period and 
through the safety follow-up period (eg, recombinant human erythropoietin, darbepoetin alfa, or 
methoxy polyethylene glycol-epoetin beta).  See Section 8.2.8 for the rescue therapy guidelines. 
Subjects may not receive intravenous iron or blood transfusion within 4 weeks prior to the 
screening period and through the safety follow-up period.  Use of intravenous iron 
supplementation after Day 1 will be considered a protocol deviation but will not be considered a 
reason for subject discontinuation. 
ESAs and RBC transfusions are allowed as rescue therapies, please refer to Section 8.2.8 for the 
rescue therapy guidelines.  Note that subjects who initiate rescue therapy will be required to stop 
study drug treatment and will be discontinued from the study. 
8.4.3 Oral Iron Supplementation (Information on Prohibition) 
Subjects who are not taking oral iron supplementation at baseline should not start oral iron 
during study participation.  Use of oral iron supplementation by such subjects will be considered 
a protocol deviation but will not be considered a reason for subject discontinuation. 
See Section 8.2.9 for information on circumstances allowing use of oral iron supplementation. 


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9 STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES 
As presented in Appendix A, this study includes the following visits: 
 
Eligibility screening period (Day -28 to Day -4) 
 
Baseline visit (Day 1) 
 
Primary efficacy period (Week 1 ± 1 day, Week 2 ± 1 day, Week 4 ± 3 days, and 
Week 6 ± 3 days) 
 
Blinded dose adjustment and data cleaning period (Week 10 ± 3 days) 
 
Open-label extension period (Week 14 ± 3 days and Week 16 ± 3 days) 
 
Safety follow-up period (Week 18 ± 3 days) 
The following sections describe the procedures to be completed during the study.  Subjects are to 
be assessed by the same investigator or site personnel whenever possible. 
9.1 Administrative Procedures 
9.1.1 Informed Consent Procedure 
Informed consent must be obtained and legally signed prior to a subject entering into the study 
and before any protocol-directed procedures (including screening tests) are performed (see 
Section 15.3). 
9.1.2 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. 
9.1.3 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 9.1.3.1. 
9.1.3.1 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 


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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) and at baseline (assessed using urine pregnancy test). 
 
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 
9.2 Study Procedures and Evaluations 
9.2.1 Clinical Evaluations 
The following clinical evaluations will be conducted during the course of the study.  Detailed 
information regarding the timing of the assessments is presented in Section 9.3 and summarized 
in Appendix A: 
 Demographics and medical history: Relevant medical history (with particular emphasis 
on previous medical conditions that may lead to exclusion) and significant ongoing 
medical conditions or diseases should be documented. 
 Physical examination: Physical examination, including height assessments 
 Weight assessment 
 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 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 


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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. 
 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. 
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. 
9.2.2 Laboratory Evaluations 
Samples for laboratory assays will be sent to a central laboratory for analysis, with the exception 
of the urine pregnancy test at baseline which will be performed locally.  Detailed instructions for 
the collection, processing, and shipment of laboratory samples will be provided by the sponsor 
and the central laboratory.  The investigator is responsible for reviewing laboratory results for 
clinical significance. 
The following laboratory evaluations will be conducted during the course of the study: 
 Serum and urine 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) and urine pregnancy tests (to be analyzed by the local 
lab).  The screening and baseline pregnancy test results must be available and must be 
negative for a subject to initiate or continue study drug. 
 Coagulation tests: Blood sample will be collected to assess the prothrombin time (PT), 
partial thromboplastin time (PTT), and international normalized ratio (INR). 
 Folate and vitamin B12: Blood sample will be collected to assess folate and Vitamin B12 
levels. 
 HemoCue®: Hb will be monitored via HemoCue point-of-care device to determine if the 
dose of study drug will be adjusted. 
 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). 


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For subjects who discontinue study drug due to an excess Hb response during the primary 
efficacy period, Hb will be assessed weekly via lab evaluation until the subject no longer 
exhibits an excess Hb response. 
 
Serum chemistry and eGFR: The serum chemistry will include the following assays: 
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.  eGFR will be calculated from serum creatinine as 
described in Appendix B. 
 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. 
9.3 Schedule of Activities 
The Schedule of Events in Appendix A shows the timing of planned study procedures.  Every 
effort should be made to adhere to this procedure schedule and all assessments should be 
completed at each study visit. 
9.3.1 Screening Visit 
The screening visit must be performed within 28 days prior to dosing and there must be a 
minimum of 4 days between the last qualifying repeat measurement and the baseline visit 
(Day 1). 
After obtaining informed consent and receiving a unique subject identification number, subjects 
will undergo a number of screening activities.  The investigator will maintain a log of subjects 
and indicate who was enrolled or excluded and the reason for exclusion (see Section 9.1.2). 
At the screening visit, the following activities/procedures will be performed: 
 Review of study inclusion and exclusion criteria 


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 Demographics, medical history, and physical examination 
 Weight assessment 
 Vital signs (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
 Prior and current medication use 
 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 Folate and vitamin B12 levels 
o CBC 
o Serum chemistry and eGFR 
o Iron indices 
9.3.2 Baseline Visit (Day 1) 
There must be a minimum of 4 days between the screening and baseline visits. 
At the baseline visit, the following activities/procedures will be performed: 
 Review of study inclusion and exclusion criteria 
 Vital signs (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
 12-lead ECG (prior to blood draws when possible and obtained after the subject has been 
resting supine comfortably for approximately 10 minutes) 
 Recording of any concomitant medication use since screening visit 
 Laboratory procedures: 
o Urine pregnancy test for females of childbearing potential (eligible subjects will 
be advised to use an adequate contraceptive method).  The urine sample will be 
analyzed by the local lab.  The baseline results must be available and must be 
negative before the subject takes the first dose of study drug. 
o Coagulation tests (including prothrombin time, partial thromboplastin time, and 
international normalized ratio) 
o CBC 
o Serum chemistry and eGFR 
o Iron indices 
o Hepcidin 
o C-reactive protein 
o VEGF 
 Dispense blinded study drug 
 Review dosing instructions 
9.3.3 Week 1 Visit 
At the Week 1 visit, 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) 


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 AE review 
 Concomitant medication review 
 Hb using HemoCue 
 CBC 
 Subjects should be questioned regarding dosing compliance 
 Review dosing instructions 
9.3.4 Week 2 Visit 
At the Week 2 visit, 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) 
 AE review 
 Concomitant medication review 
 Hb using HemoCue 
 Laboratory procedures: 
o CBC 
o Serum chemistry and eGFR 
o Iron indices 
 Dispense blinded study drug (as necessary) 
 Subjects should be questioned regarding dosing compliance 
 Review dosing instructions and 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 
9.3.5 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 (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
 AE review 
 Concomitant medication review 
 Hb using HemoCue 
 Laboratory procedures: 
o CBC 
o Serum chemistry and eGFR 
o Iron indices 
o Pre-dose PK sample 
 Record date and time of the last dose of the study that was taken prior to the pre-dose PK 
sample 
 Dispense blinded study drug (as necessary) 
 Subjects should be questioned regarding dosing compliance 
 Review dosing instructions 


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9.3.6 Week 6 Visit 
Individual subject data (up to Week 6) will be cleaned and locked after the Week 6 visit.  
Following data lock, individual subject’s randomized treatment assignment will be unblinded 
and the subject will be informed at the Week 10 visit. 
At the Week 6 visit, 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) 
 AE review 
 Concomitant medication review 
 Hb using HemoCue 
 Laboratory procedures: 
o CBC 
o Serum chemistry and eGFR 
o Iron indices 
o Hepcidin 
o C-reactive protein 
o VEGF 
 Dispense blinded study drug (as necessary) 
 Subjects should be questioned regarding dosing compliance 
 Review dosing instructions 
9.3.7 Week 10 Visit (End-of-treatment visit for the blinded period and early withdrawals) 
All enrolled subjects who receive at least 1 dose of blinded study drug should complete the 
Week 10 assessments. 
Subjects who withdraw early from the study prior to the Week 6 visit or permanently discontinue 
study medication prior to the Week 6 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 9.3.10). 
Individual subject data (up to Week 6) will be locked after the Week 6.  Following data lock, 
individual subject’s randomized treatment assignment will be unblinded and the subject will be 
informed at the Week 10 visit.  Subjects who were assigned to receive placebo will discontinue 
from the study at the end of the Week 10 visit, and subjects who were assigned to receive 
vadadustat will continue to the open-label extension period. 
At the Week 10 visit, 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) 
 AE review (see Section 10.3.6 for follow-up of unresolved events) 
 Concomitant medication review 
 Laboratory procedures: 
o Hb using HemoCue for dose adjustment (not for subjects who discontinue prior to 
the Week 6 visit) 
o CBC 
o Serum chemistry and eGFR 


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o Iron indices 
o Hepcidin 
o C-reactive protein 
o VEGF 
 Dispense open-label vadadustat (as necessary; only applicable to subjects who are 
continuing to the open-label extension period) 
 Subjects should be questioned regarding dosing compliance 
 Review dosing instructions (only applicable to subjects who are continuing to the 
open-label extension period) 
9.3.8 Week 14 Visit 
At this visit, 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) 
 AE review 
 Concomitant medication review 
 Hb using HemoCue for dose adjustment 
 CBC 
 Serum chemistry and eGFR 
 Dispense vadadustat (as necessary) 
 Subjects should be questioned regarding dosing compliance 
 Review dosing instructions 
9.3.9  Week 16 Visit (End-of-treatment visit for the open-label period and early withdrawal 
visit for withdrawals after Week 10 but before Week 16) 
All subjects who received at least 1 dose of open-label vadadustat should complete the Week 16 
assessments. 
Subjects who withdraw early from the open-label period 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 9.3.10). 
At the Week 16 visit, 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) 
 AE review (see Section 10.3.6 for follow-up of unresolved events) 
 Concomitant medication review 
 Laboratory procedures: 
o Serum pregnancy test for females of childbearing potential (to be analyzed by the 
central lab) 
o CBC 
o Serum chemistry and eGFR 
o Iron indices 
o Hepcidin 


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o C-reactive protein 
o VEGF 
 Subjects should be questioned regarding dosing compliance 
9.3.10  Week 18 Safety Follow-Up Visit (Or 2 Weeks after End-of-Treatment Safety Follow-Up 
Visit) 
For subjects randomized to vadadustat who complete the open-label extension period, the safety 
visit will be conducted 2 weeks after their end-of-treatment visit (Week 16). 
For subjects who discontinue the study early during the primary efficacy period or the blinded 
dose adjustment and data cleaning period, the safety visit will be conducted 2 weeks after their 
end-of-treatment visit (Week 10). 
At the follow-up visit, 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) 
 AE review (see Section 10.3.6 for follow-up of unresolved events) 
 Concomitant medication review 
 Laboratory procedures: 
o CBC 
o Serum chemistry and eGFR 
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. 


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 Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test). 
 Laboratory abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they are associated with an already 
reported clinical event.  Laboratory abnormalities associated with a clinical event 
reported as an AE (eg, elevated liver enzymes in a subject with jaundice) should be 
described under ‘Comments’ on the report of the clinical event rather than reported as 
separate AEs. 
The following guidelines are to be used when reporting AEs for this study: 
Medical Diagnoses – Whenever possible, a medical diagnosis term should be used to report AEs 
instead of signs and symptoms due to a common etiology, as determined by qualified medical 
study staff.  For example, pneumonia should be the reported AE term, instead of fever, dyspnea, 
etc., when the diagnosis has been established.  Signs and symptoms should be reported as event 
terms only when the medical diagnosis remains unknown, and revised to a medical diagnosis 
term once it has been established. 
Procedures – Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as AEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE.  For example, an acute 
appendicitis that begins during the AE reporting period should be reported as the AE and the 
resulting appendectomy noted under “Comments.” 
Pre-planned therapeutic procedures not associated with a new medical condition or worsening 
pre-existing condition should not be reported as AEs. 
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: 


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 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). 
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. 
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 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. 
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 
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. 


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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). 
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 


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 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 
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 aware of the pregnancy (reference the site manual for 
contact information). 
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 


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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. 
 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 
11.1 Primary Endpoint and Sample Size Determination 
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 NDD-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 EOT visit minus the mean pre-treatment Hb.  
Pre-treatment Hb is defined as the average of 2 Hb values obtained prior to treatment based on 
the qualifying screening Hb value and the Hb value at the baseline visit.  Linear regression 
analysis will be used to calculate the relationship between vadadustat dose and change in Hb. 
The target enrollment will be approximately 48 subjects for the study with 12 subjects enrolled 
in each of the 4 treatment groups. 
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 reasonable to assume 
that 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. 
11.2 Study Populations 
11.2.1 Analysis Population 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. 


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11.2.2 Analysis Populations for the Efficacy Analyses 
The modified intent-to-treat (MITT) population for Hb or RBC count will include subjects who 
receive at least 1 dose of study medication, have a pre-treatment average defined as the average 
of the qualifying screening value and the baseline value, and at least one post-baseline 
measurement. The MITT population for other parameters will include subjects who receive at 
least 1 dose of study medication, have at least one pre-treatment value, and at least one 
post-baseline 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.   
As sensitivity analyses, efficacy endpoints will also be analyzed using the PP population. 
11.3 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. 
11.4 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. 
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 
For purposes of analysis, a pre-treatment average (defined as the average of 2 samples obtained 
prior to treatment [ie, the qualifying screening value and baseline value]) will be used as the 
baseline value for Hb and RBC count, and last observation before the first dose of study 
medication will be used as baseline for other parameters. 
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 assess 
the vadadustat dose-response relationship.  Similar analysis will be performed for change from 
baseline to Week 6 of reticulocyte count (both absolute and percent), hematocrit, and RBC count. 


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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. 
11.6 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, components of the CBC, and VEGF. 
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. 
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. 
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 


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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 
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 
assessments. 
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. 


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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 
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. 


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Vadadustat 
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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 course of 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 
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. 


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Vadadustat 
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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 
2007S4-9. 
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. 
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. 
Matsuo S, Imai E, Horio M, et al.  Revised equations for estimated GFR from serum creatinine 
in Japan.  Am J Kidney Dis 2009;53:982-92. 
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. 
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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Appendix A: Schedule of Activities 
Please refer to Section 9.2 for detailed information regarding the study procedures and evaluations, and please refer to Section 9.3 for 
detailed information regarding the activities to be performed at each study visit. 
 
Screening 
Primary efficacy period 
(blinded, fixed-dose treatment) 
(Day 1-Week 6) 
Blinded dose 
adjustment, data 
cleaning period 
(Week 7-10) 
Open-label extension 
period 
(Week 11-16) 
Safety 
Follow-up 
(Week 17-18) 
Study Week 
-4 to 0 
Base 
line 
1 
2 
4 
6 
10 (EOT, Blinded 
Period) 
14 
16 (EOT, 
Open-Label 
Period) 
18 
Study Day 
-28 to -4 
1 
8 
15 
29 
43 
71 
99 
113 
127 
Visit Window (Days) 
 
 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Review inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Individual subject data lock (for subjects 
who complete Week 6) 
 
 
 
 
 
X 
 
 
 
Individual subject unblinding (for 
subjects who complete Week 6) 
 
 
 
 
 
 
X 
 
 
 
Demographics, medical history, physical 
exam, and weight 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram 
 
X 
 
 
 
 
 
 
 
 
Adverse event review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
X 
 
Urine pregnancy test 
 
X 
 
 
 
 
 
 
 
 
Coagulation tests 
 
X 
 
 
 
 
 
 
 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1.1) 
 
 
Confidential 
22 June 2016; Page 64 
 
Screening 
Primary efficacy period 
(blinded, fixed-dose treatment) 
(Day 1-Week 6) 
Blinded dose 
adjustment, data 
cleaning period 
(Week 7-10) 
Open-label extension 
period 
(Week 11-16) 
Safety 
Follow-up 
(Week 17-18) 
Study Week 
-4 to 0 
Base 
line 
1 
2 
4 
6 
10 (EOT, Blinded 
Period) 
14 
16 (EOT, 
Open-Label 
Period) 
18 
Study Day 
-28 to -4 
1 
8 
15 
29 
43 
71 
99 
113 
127 
Visit Window (Days) 
 
 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Folate and vitamin B12 
X 
 
 
 
 
 
 
 
 
 
Hb using HemoCue® (Week 10 
assessment is not for subjects who 
discontinue prior to Week 6) 
 
 
X 
X 
X 
X 
X 
X 
 
 
Complete blood count, including Hb [a] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry and eGFR 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Iron indices 
X 
X 
 
X 
X 
X 
X 
 
X 
 
Hepcidin 
 
X 
 
 
 
X 
X 
 
X 
 
C-reactive protein 
 
X 
 
 
 
X 
X 
 
X 
 
VEGF  
 
X 
 
 
 
X 
X 
 
X 
 
PK pre-dose sample (study drug to be 
administered after sample collection) 
 
 
 
 
X 
 
 
 
 
 
Blinded study drug dispensation, as 
necessary 
 
X 
 
X 
X 
X 
 
 
 
 
Blinded study drug dosing 
 
Blinded study drug dosing 
 
 
 
Vadadustat dispensation, as necessary [b] 
 
 
 
 
 
 
X 
X 
 
 
Vadadustat dosing [b] 
 
 
 
 
 
 
 
Open-label vadadustat 
dosing 
 
Study drug compliance check 
 
 
X 
X 
X 
X 
X 
X 
X 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1.1) 
 
 
Confidential 
22 June 2016; Page 65 
Abbreviations: eGFR, estimated glomerular filtration rate; EOT, end of treatment; Hb, hemoglobin; PK, pharmacokinetics; VEGF, vascular endothelial growth 
factor 
[a] For subjects who discontinue study drug due to an excess Hb response, blood samples will be collected weekly to monitor Hb until the subject no longer 
exhibits an excess Hb response.  The blood samples will be analyzed in a lab.  Point-of-care Hb assessment will not be used for such evaluations. 
[b] Subjects who were randomized to receive vadadustat treatment during the primary efficacy period and complete the Week 10 visit will continue to the 
open-label extension period. 
 
 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 1.1) 
 
 
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22 June 2016; Page 66 
Appendix B: Japanese Society of Nephrology 2009 Equation to Calculate eGFR 
The estimated glomerular filtration rate (eGFR) will be calculated from serum creatinine using 
the 2009 Japanese Society of Nephrology Equation (3-variables; Matsuo 2009).   
eGFR (mL/min/1.73 m2) = 194 x (Scr in mg/dL)-1.094 x (Age)-0.287 x (0.739 if female) 


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Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 2) 
 
 
Confidential 
19 July 2016; Page 2 
1 SIGNATURE PAGES 
1.1 Protocol Approval 
 
 
 
Akebia Therapeutics, Inc. 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 2) 
 
 
Confidential 
19 July 2016; Page 3 
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 also protect the 
rights, safety, privacy, and well-being of study subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonization Guidance for Industry, Good Clinical 
Practice E6. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting serious adverse events defined in this protocol. 
• Terms outlined in the Clinical Study Site Agreement. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Phone Number 
Full Address 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 2) 
 
 
Confidential 
19 July 2016; Page 4 
TABLE OF CONTENTS 
1 
SIGNATURE PAGES .................................................................................................. 2 
1.1 
Protocol Approval .................................................................................................... 2 
1.2 
Investigator Agreement ............................................................................................ 3 
TABLE OF CONTENTS ......................................................................................................... 4 
LIST OF TABLES ................................................................................................................... 7 
LIST OF FIGURES ................................................................................................................. 7 
2 
PROTOCOL SYNOPSIS .............................................................................................. 9 
3 
LIST OF ABBREVIATIONS ..................................................................................... 15 
4 
BACKGROUND ........................................................................................................ 17 
4.1 
Proposed Indication of Renal Anemia ................................................................... 17 
4.2 
Available Therapies for Anemia in Patients with CKD ......................................... 18 
4.3 
Hypoxia-Inducible Factor ...................................................................................... 18 
4.4 
Description and Mechanism of Action of Vadadustat ........................................... 19 
4.5 
Summary of Clinical Experience ........................................................................... 20 
4.6 
Ethno-Bridging Data from a Study of Healthy Japanese and Caucasian Volunteers
 ................................................................................................................................ 21 
4.7 
Potential Benefits and Risks ................................................................................... 23 
5 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 23 
5.1 
Primary Objective and Endpoint ............................................................................ 23 
5.2 
Secondary Objectives and Endpoints ..................................................................... 23 
6 
STUDY DESIGN ........................................................................................................ 24 
6.1 
Study Design .......................................................................................................... 24 
6.2 
Study Duration ....................................................................................................... 26 
6.3 
Rationale for Study Design .................................................................................... 26 
6.4 
Dose Justification ................................................................................................... 27 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 28 
7.1 
General Criteria ...................................................................................................... 28 
7.2 
Inclusion Criteria .................................................................................................... 28 
7.3 
Exclusion Criteria ................................................................................................... 28 
7.4 
Retesting and Rescreening ..................................................................................... 30 
7.4.1 
Retesting ............................................................................................................ 30 
7.4.2 
Rescreening ....................................................................................................... 30 
7.5 
Study Completion, Study Termination, and Individual Study Site Termination ... 30 
7.5.1 
Study Completion .............................................................................................. 30 
7.5.2 
Study Termination ............................................................................................. 31 
7.5.3 
Individual Study Site Termination .................................................................... 31 


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7.6 
Subject Completion and Individual Subject Discontinuation ................................ 31 
7.6.1 
Subject Completion ........................................................................................... 31 
7.6.2 
Conditions and Documentation of Individual Subject Study Drug 
Discontinuation .................................................................................................. 31 
7.6.3 
Individual Subject Discontinuation during the Primary Efficacy Period or 
Blinded Dose Adjustment and Data Cleaning Period ....................................... 31 
7.6.4 
Individual Subject Discontinuation during the Open-Label Extension Period . 32 
8 
STUDY DRUGS AND TREATMENT OF SUBJECTS ............................................ 32 
8.1 
Study Drugs ............................................................................................................ 32 
8.1.1 
Formulation ....................................................................................................... 32 
8.1.2 
Storage and Accountability ............................................................................... 32 
8.1.3 
Dispensing of Study Drugs ................................................................................ 33 
8.1.4 
Product Accountability and Destruction ........................................................... 33 
8.2 
Treatment of Subjects ............................................................................................. 34 
8.2.1 
Dosing Instructions ............................................................................................ 34 
8.2.2 
Randomization ................................................................................................... 34 
8.2.3 
Blinding During the Primary Efficacy Period and Breaking the Blind ............. 34 
8.2.4 
Study Drug Administration during the Primary Efficacy Period ...................... 35 
8.2.5 
Study Drug Administration during the Blinded Dose Adjustment and Data 
Cleaning Period ................................................................................................. 36 
8.2.6 
Vadadustat Administration during the Open-Label Extension Period .............. 37 
8.2.7 
Dose Adjustment Guidelines ............................................................................. 37 
8.2.8 
Rescue Therapy Guidelines ............................................................................... 38 
8.2.9 
Oral Iron Supplementation (Information on Allowed Use) .............................. 38 
8.2.10 
Late or Missed Doses ........................................................................................ 38 
8.2.11 
Treatment Compliance ...................................................................................... 39 
8.2.12 
Continuation of Treatment ................................................................................ 39 
8.3 
Prior and Concomitant Therapy ............................................................................. 39 
8.4 
Prohibited Treatments ............................................................................................ 39 
8.4.1 
Investigational Medications ............................................................................... 39 
8.4.2 
ESAs, Intravenous Iron, and Blood Transfusion ............................................... 39 
8.4.3 
Oral Iron Supplementation (Information on Prohibition) ................................. 39 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES ................................ 40 
9.1 
Administrative Procedures ..................................................................................... 40 
9.1.1 
Informed Consent Procedure ............................................................................. 40 
9.1.2 
Documentation of Screen Failures .................................................................... 40 
9.1.3 
Review of Inclusion and Exclusion Criteria ...................................................... 40 
9.1.3.1 
Acceptable Methods of Contraception ......................................................... 40 
9.2 
Study Procedures and Evaluations ......................................................................... 41 


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9.2.1 
Clinical Evaluations ........................................................................................... 41 
9.2.2 
Laboratory Evaluations ..................................................................................... 42 
9.3 
Schedule of Activities ............................................................................................ 43 
9.3.1 
Screening Visit .................................................................................................. 43 
9.3.2 
Baseline Visit (Day 1) ....................................................................................... 44 
9.3.3 
Week 1 Visit ...................................................................................................... 44 
9.3.4 
Week 2 Visit ...................................................................................................... 45 
9.3.5 
Week 4 Visit ...................................................................................................... 45 
9.3.6 
Week 6 Visit ...................................................................................................... 46 
9.3.7 
Week 10 Visit (End-of-treatment visit for the blinded period and early 
withdrawals) ...................................................................................................... 46 
9.3.8 
Week 14 Visit .................................................................................................... 47 
9.3.9 
Week 16 Visit (End-of-treatment visit for the open-label period and early 
withdrawal visit for withdrawals after Week 10 but before Week 16) ............. 47 
9.3.10 
Week 18 Safety Follow-Up Visit (Or 2 Weeks after End-of-Treatment Safety 
Follow-Up Visit) ............................................................................................... 48 
10 
ADVERSE EVENTS .................................................................................................. 48 
10.1 
Definitions .............................................................................................................. 48 
10.1.1 
Adverse Events (AEs) ....................................................................................... 48 
10.1.2 
Serious Adverse Events (SAEs) ........................................................................ 50 
10.2 
Eliciting Adverse Event Information ..................................................................... 51 
10.3 
Reporting ................................................................................................................ 51 
10.3.1 
Reporting Period ................................................................................................ 51 
10.3.2 
Reporting AEs ................................................................................................... 51 
10.3.3 
Reporting SAEs ................................................................................................. 51 
10.3.4 
Relationship to Study Medication ..................................................................... 52 
10.3.5 
Severity .............................................................................................................. 52 
10.3.6 
Follow-Up of Unresolved Events ...................................................................... 53 
10.3.7 
Special Situations .............................................................................................. 53 
10.4 
Exposure In Utero .................................................................................................. 53 
11 
DATA ANALYSIS ..................................................................................................... 54 
11.1 
Primary Endpoint and Sample Size Determination ................................................ 54 
11.2 
Study Populations ................................................................................................... 54 
11.2.1 
Analysis Population for the Safety Analyses .................................................... 54 
11.2.2 
Analysis Populations for the Efficacy Analyses ............................................... 55 
11.3 
Analysis of Demographics and Pretreatment Variables ......................................... 55 
11.4 
Disposition of Subjects ........................................................................................... 55 
11.5 
Efficacy and PD Analyses ...................................................................................... 55 
11.6 
Safety Analyses ...................................................................................................... 56 


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11.7 
PK Analyses ........................................................................................................... 56 
12 
DATA HANDLING AND RECORD KEEPING ...................................................... 56 
12.1 
Case Report Forms (CRFs) .................................................................................... 56 
12.2 
Record Retention .................................................................................................... 56 
13 
QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) ....................... 57 
13.1 
Study Site Monitoring Visits .................................................................................. 57 
13.2 
Protocol Deviations ................................................................................................ 57 
14 
STUDY DISCONTINUATION/INVESTIGATIVE STUDY SITE TERMINATION
 ..................................................................................................................................... 57 
14.1 
Criteria for Premature Termination or Suspension of the Study ............................ 58 
14.2 
Criteria for Premature Termination or Suspension of Investigational Sites .......... 58 
14.3 
Procedures for Premature Termination or Suspension of the Study or 
Investigational Site(s) ............................................................................................. 58 
15 
ETHICS ....................................................................................................................... 58 
15.1 
Ethical Conduct of the Study ................................................................................. 58 
15.2 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) ........... 58 
15.3 
Subject Information and Consent ........................................................................... 59 
15.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .... 59 
15.5 
Subject Confidentiality ........................................................................................... 59 
16 
PUBLICATION OF STUDY RESULTS ................................................................... 60 
17 
REFERENCES ............................................................................................................ 61 
 
LIST OF TABLES 
Table 1: 
Identity of Study Drugs ........................................................................................32 
 
LIST OF FIGURES 
Figure 1 
Mechanism of Action of Vadadustat ....................................................................19 
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) .......22 
Figure 3: 
Overview of Study Design ....................................................................................25 
Figure 4: 
Absolute Change in Hemoglobin (± Standard Error of Mean, g/dL) at Week 6 
Compared to Baseline (Study AKB-6548-CI-0005) ..........................................27 
Figure 5: 
Randomization Scheme of Study Treatment ........................................................34 
Figure 6: 
Guidelines for Dose Reduction or Discontinuation of Study Drug During the Primary 
Efficacy Period ...................................................................................................36 
Figure 7: 
Potential Scenarios for Individual Subject Unblinding ........................................37 


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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 Non-Dialysis 
Dependent Chronic Kidney Disease 
Protocol Number 
AKB-6548-CI-0021 
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 non-dialysis dependent chronic kidney disease 
(NDD-CKD) who are not currently being treated with an erythropoiesis-stimulating 
agent (ESA) 
Investigative Sites 
Approximately 25 sites in Japan 
Planned Number of 
Subjects 
Approximately 48 subjects will be enrolled in the study, with 36 subjects receiving 
one of the 3 doses of vadadustat and 12 subjects receiving placebo: 
• 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 (QD) dosing for 6 weeks and the change in hemoglobin 
(Hb) in Japanese subjects with anemia secondary to NDD-CKD; in order 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 QD dosing in Japanese subjects 
with anemia secondary to NDD-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 maintenance period 
Study Design Overview 
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 NDD-CKD.  The study 
will include the following periods: 
• Eligibility screening period (up to 4 weeks) 
• Primary efficacy period (6 weeks; Weeks 1 to 6) 
• Dose adjustment and maintenance period (10 weeks), including the following: 
- Blinded dose adjustment and data cleaning period (4 weeks; Weeks 7 to 10): 
Individual subject data (from screening to Week 6) will be locked and 
individual subject unblinding will take place at the Week 10 visit  
- Open-label extension period (6 weeks; Weeks 11 to 16): Subjects 
randomized to receive vadadustat treatment during the blinded period will 
continue into this period 
• Safety follow-up period (2 weeks; Weeks 17 and 18): Subjects who complete 


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participation in the open-label extension period and subjects who discontinue 
early during the blinded study periods will complete the safety follow-up 
period.  Subjects identified as having received placebo during the Week 10 
unblinding visit will not participate in this safety follow-up period. 
Following the screening period, eligible subjects will be randomized to receive 
blinded study drug treatment during a 6-week primary efficacy period, with subjects 
randomized at a 3:1 ratio to receive vadadustat (150, 300, or 600 mg vadadustat) or 
placebo.  See “Dosage and Regimen” in the synopsis for additional information 
regarding the randomization scheme. 
Fixed-dose treatment during the blinded primary efficacy period will allow a 
dose-response relationship to be established.  However, if Hb levels increase too 
rapidly or if the Hb levels exceed the desired range, the blinded study drug dose can 
be decreased or discontinued (see “Dosage and Regimen” for additional 
information). 
After completing the primary efficacy period, subjects will continue to a 10-week 
dose adjustable maintenance period which will include a 4-week, blinded dose 
adjustment and data cleaning period and a 6-week, open-label extension period.  
Dose can be adjusted during the open-label period to achieve a target Hb of 
10-12 g/dL, and the dose adjustment guidelines are listed under “Dosage and 
Regimen” (see below). 
Individual subject’s study data (from screening to Week 6) will be cleaned and 
locked during the 4-week, blinded, dose adjustment and data cleaning period. 
At the Week 10 visit, treatment assignment will be unblinded on an individual 
subject basis.  Subjects who were randomized to receive placebo will end study 
participation after unblinding at the Week 10 visit.  Subjects who were randomized 
to receive 1 of the 3 vadadustat doses will continue receiving vadadustat during the 
open-label extension period. 
Vadadustat treatment will stop after the extension period has been completed 
(Week 16) and subjects will continue in a 2-week follow-up safety period 
(Week 17-18). 
Study Duration 
Up to 22 weeks, including the eligibility screening period (up to 4 weeks), primary 
efficacy period (6 weeks), blinded dose adjustment and data cleaning period 
(4 weeks), open-label extension period (6 weeks), and safety follow-up period 
(2 weeks). 
Only subjects who are randomized to receive vadadustat will continue in the 
maintenance period and the safety follow-up period. 
Key Inclusion Criteria 
(the complete list is 
provided in the 
protocol) 
• Male and female Japanese subjects (20 years or older) 
• Diagnosis of CKD based on an estimated glomerular filtration rate (eGFR) of 
≤60 mL/min/1.73 m2 (using the 2009 Japanese Society of Nephrology 
equation; Matsuo 2009) 
• Not currently being treated with dialysis and not expected to start dialysis 
within 3 months of screening 
• Hb ≤10.5 g/dL 
• Serum ferritin ≥50 ng/mL 
• Transferrin saturation (TSAT) ≥20% 
• Folate and vitamin B12 ≥lower limit of normal 
Key Exclusion Criteria 
(the complete list is 
provided in the 
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 


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protocol) 
aplasia; red blood cell (RBC) transfusion within 4 weeks prior to or during 
screening; intravenous iron within 4 weeks prior to or during screening; and any 
ESA use within 6 weeks prior to or during screening. 
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 or eGFR 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 B12 values may be considered for rescreening after receiving 
replacement therapy. 
Screening is limited to 3 attempts (initial screening and 2 additional rescreening 
attempts). 
Efficacy Endpoints 
Note that a pre-treatment value for Hb and RBC count is defined as the average of 
2 values obtained prior to treatment, ie, the qualifying screening value and the 
baseline value. Last observation before the first dose of study medication will be 
used as baseline for other parameters. 
Primary Endpoint: 
• Mean change in Hb levels from pre-treatment to the end of the primary efficacy 
period (Week 6) 
Secondary Endpoints: 
• Proportion of subjects who achieve target Hb 10-12 g/dL at the end of the 
open-label extension period (Week 16) 
• Mean change in Hb between pre-treatment and the end of the open-label 
extension period (Week 16) 
• Mean change in hematocrit, RBC count, and reticulocyte count from 
pre-treatment to the end of the primary efficacy period (Week 6) and the end of 
the open-label extension period (Week 16) 
• Mean change in iron indices (ie, iron, total iron-binding capacity [TIBC], 
TSAT, and ferritin) and hepcidin from pre-treatment to the end of the primary 
efficacy period (Week 6) and the end of the open-label extension period 
(Week 16) 
• Proportion of subjects with confirmed Hb values <10.0 or >12.0 g/dL from 
pre-treatment to the end of the open-label extension 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 open-label 
extension 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 open-label extension 
period (Week 16) 
• Number of dose adjustments from baseline to the end of the primary efficacy 
period (Week 6) and the end of the open-label extension period (Week 16) 
• Maintenance of iron sufficiency (defined as ferritin ≥50 ng/mL and TSAT 
≥20%) from baseline to the end of the primary efficacy period (Week 6) and 
the end of the open-label extension period (Week 16) 
• Plasma concentration profile of vadadustat and its metabolites using pre-dose 
sample from Week 4 
Safety Endpoints 
Safety and tolerability assessments, including adverse events, vital signs, 
electrocardiograms (ECGs), and other laboratory assay results (eg, chemistry, 


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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 other oral beverage and should be instructed to 
swallow the intact tablet(s).  Subjects may take the study medication with or without 
food. 
Note: Hb will be assessed at the central laboratory and also monitored using 
point-of-care HemoCue®.  Note that the point-of-care HemoCue Hb value will be 
used to determine if the dose of study medication will be adjusted or discontinued. 
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. 
 
The primary efficacy period includes a fixed-dose treatment to establish a 
dose-response relationship.  However, if Hb level increases too rapidly or if the Hb 
levels exceed the desired range, the blinded study drug dose will be decreased or 
discontinued as presented below. 
• Subjects who meet the following criteria for excess Hb response will undergo a 
dose reduction by 1 tablet: 
- 
Hb increase >1 g/dL within any 2-week period, OR 
- 
Hb increase >2 g/dL within any 4-week period, OR 
- 
Hb level >13 g/dL 
• Subjects who meet the following criteria will discontinue study drug: 
- 
Excess Hb response as defined by any of the aforementioned criteria, 
AND 
- 
Current dose 1 tablet OR subject had previously decreased study drug 
dose due to excess Hb response 
Blinded dose adjustment and data cleaning period (Week 7 to 10) 
During this period, data from screening through the Week 6 visit will be cleaned and 
locked in preparation for the Week 10 unblinding visit.  Blinded study drug dosage 
will be adjusted to achieve a target Hb 10-12 g/dL.  Starting at the Week 6 visit, 
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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adjustments to doses will be based on the dose adjustment guidelines listed below. 
Open-label extension period (Weeks 11 to 16): 
Subjects who were randomized to receive vadadustat will enter this open-label 
extension period, and vadadustat dosage will continue to be adjusted to achieve a 
target Hb 10-12 g/dL.  Dose adjustments will continue to be based on the dose 
adjustment guidelines listed below. 
Dose adjustment guidelines from Week 7 to Week 16 
The dose adjustment for blinded study drug (from Week 7 to 10) and open-label 
vadadustat (from Week 11 to 16) will follow the dose adjustment guidelines listed 
below to achieve a target Hb of 10-12 g/dL.  The point-of-care HemoCue Hb value 
will be used to determine if the dose of study drug will be adjusted. 
• 
Do not increase the dose more frequently than once within any given 
4-week interval.  For example, if a subject’s dose was increased at Week 10 
and the subject remains below the Hb target, the next opportunity to further 
increase the dose would be Week 14.  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 rises 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).  In cases of extenuating clinical 
circumstances, investigators may elect to dose outside the dosing guidelines to 
maintain the Hb within the target range. 
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: 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 
- 
Exhibits Hb level <9.0 g/dL 
• 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. 
Oral Iron 
Supplementation 
Subjects who are taking oral iron supplementation at baseline should continue their 
oral iron at the same dose throughout their study participation.  Changes to oral iron 
supplementation dose will be considered protocol deviations but will not be 
considered a reason for subject discontinuation. 
Subjects who are not taking oral iron supplementation at baseline should not start 


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oral iron during their study participation. 
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 
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. 
The target enrollment will be approximately 48 subjects for the study with 
12 subjects enrolled in each of the 4 treatment groups.  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. 
 


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3 LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
BUN 
blood urea nitrogen 
C 
Celsius 
CBC 
complete blood count 
CKD 
chronic kidney disease 
CRF 
case report form 
CRO 
contract research organization 
CV 
cardiovascular 
dL 
deciliter 
DVT 
deep venous thrombosis 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
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 
GFR 
glomerular filtration rate 
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 


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IRB 
institutional review board 
IV 
intravenous 
JSN 
Japanese Society of Nephrology 
KDIGO 
Kidney Disease Improving Global Outcomes 
kg 
kilogram 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
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) 
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-0021 
Vadadustat 
Original Protocol (Version 2) 
 
 
Confidential 
19 July 2016; Page 17 
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-0021 
Vadadustat 
Original Protocol (Version 2) 
 
 
Confidential 
19 July 2016; Page 18 
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. 
A number of 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-0021 
Vadadustat 
Original Protocol (Version 2) 
 
 
Confidential 
19 July 2016; Page 20 
4.3% of patients on 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 patients with DD-CKD 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.  As a result, 
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. 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 2) 
 
 
Confidential 
19 July 2016; Page 21 
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 
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 recently completed Phase 2b, randomized, double-blind, placebo-controlled study to assess the 
hematologic PD response, safety, and tolerability of oral vadadustat for 20 weeks was performed 
in 210 subjects with anemia associated with NDD-CKD (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.  


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Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 2) 
 
 
Confidential 
19 July 2016; Page 23 
4.7 Potential Benefits and Risks 
Please see the vadadustat Investigator’s Brochure for additional discussion and information for 
the following section. 
Vadadustat offers the potential of flexible oral dosing that is easier to adjust than injectable 
hormone ESAs.  This alternate therapeutic approach may avoid the excursions and fluctuations 
in Hb levels seen with currently available injectable ESAs and provide for a controlled, steady 
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 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 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, all of the acute findings observed at doses less than the maximum tolerated dose (MTD) 
in animals have been shown to be reversible and dose-related.  In addition, most of the findings 
have followed a pattern that would have been predicted based on the known HIF and HIFPH 
biochemistry, pharmacology, and human genetic variations (eg, Chuvash polycythemia).  In the 
completed clinical studies, vadadustat has been generally well-tolerated. 
5 STUDY OBJECTIVES AND ENDPOINTS 
Note that a pre-treatment value for Hb, hematocrit, RBC count, reticulocyte count, and iron 
metabolism markers is defined as the average of 2 values obtained prior to treatment, ie, the 
qualifying screening value 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 Hb in Japanese subjects with anemia 
secondary to NDD-CKD; in order 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 
NDD-CKD during the 6-week, primary efficacy period 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 2) 
 
 
Confidential 
19 July 2016; Page 24 
• To evaluate the effect of dose adjustments and demonstrate the maintenance effect on Hb 
during a 10-week maintenance period 
The efficacy endpoints that will be used to assess these objectives include the following: 
• Proportion of subjects who achieve target Hb 10-12 g/dL at the end of the open-label 
extension period (Week 16) 
• Mean change in Hb between pre-treatment and the end of the open-label extension period 
(Week 16) 
• Mean change in hematocrit, RBC count, and reticulocyte count from pre-treatment to the 
end of the primary efficacy period (Week 6) and the end of the open-label extension 
period (Week 16) 
• Mean change in iron indices (ie, iron, total iron-binding capacity [TIBC], TSAT, and 
ferritin) and hepcidin from pre-treatment to the end of the primary efficacy period 
(Week 6) and the end of the open-label extension period (Week 16) 
• Proportion of subjects with confirmed Hb values <10.0 or >12.0 g/dL from pre-treatment 
to the end of the open-label extension 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 open-label extension 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 open-label extension period (Week 16) 
• Number of dose adjustments from baseline to the end of the primary efficacy period 
(Week 6) and the end of the open-label extension period (Week 16) 
• Maintenance of iron sufficiency (defined as ferritin ≥50 ng/mL and TSAT ≥20%) from 
baseline to the end of the primary efficacy period (Week 6) and the end of the open-label 
extension 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 subjects 
with anemia secondary to NDD-CKD.   


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 2) 
 
 
Confidential 
19 July 2016; Page 25 
The study has a planned enrollment of 48 subjects to be enrolled at approximately 25 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. 
Figure 3: 
Overview of Study Design 
 
 
The study will include the following periods: 
• Eligibility screening period (up to 4 weeks) 
• Primary efficacy period (6 weeks; Weeks 1 to 6) 
• Dose adjustment and maintenance period (10 weeks) include the following: 
- Blinded dose adjustment and data cleaning period (4 weeks; Weeks 7 to 10): Individual 
subject data (from screening to Week 6) will be cleaned and locked and individual 
subject unblinding will take place at the Week 10 visit  
- Open-label extension period (6 weeks; Weeks 11 to 16): Subjects randomized to 
receive vadadustat treatment during the blinded period will continue into this period 
• Safety follow-up period (2 weeks; Weeks 17 and 18): Subjects who complete 
participation in the open-label extension period and subjects who discontinue early 
during the blinded study periods will complete the safety follow-up period.  Subjects 
identified as having received placebo during the Week 10 unblinding visit will not 
participate in this safety follow-up period. 
Subjects will participate in a screening period (4 days to 4 weeks) to determine study eligibility, 
and eligible subjects will be randomized following the screening period. 
Vadadustat 300mg (n=12); 2x150 mg tablets once daily
Placebo (n=4); 2 tablets once daily
Vadadustat 150mg (n=12); 1x150 mg tablet once daily
Placebo (n=4); 1 tablet once daily
4 days - 4 weeks
6 weeks
4 weeks
6 weeks
2 weeks
Screening
Double-blind, fixed-dose, 
primary efficacy period
Open-label, dose-adjustable, 
extension period
Blinded, dose-
adjustable, data 
cleaning period
Safety
follow-up
Individual subject unblinding;
end-of-Treatment (EOT) for subjects receiving placebo
Data cutoff for primary endpoint
Vadadustat 600 mg (n=12);
4 x 150 mg tablets once daily
Placebo (n=4);
4 tablets once daily
Vadadustat 300 mg (n=12);
2 x 150 mg tablets once daily
Placebo (n=4);
2 tablets once daily
Vadadustat 150 mg (n=12);
1 x 150 mg tablet once daily
Placebo (n=4);
1 tablet once daily
(EOT)
(EOT)
(EOT)
(EOT)
(EOT)
(EOT)
g


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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. 
Blinded 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 levels increase too rapidly or if the Hb levels exceed the desired 
range, the blinded study drug dose can be decreased or discontinued (see Section 8.2.4). 
After completing the primary efficacy period, subjects will continue to a 10-week dose 
adjustment and maintenance period including a 4-week, blinded dose adjustment and data 
cleaning period and a 6-week, open-label extension period (see Sections 8.2.5 and 8.2.6).  Dose 
will be adjusted to achieve a target Hb of 10-12 g/dL, and dose adjustments will be based on 
dose adjustment guidelines (see Section 8.2.7). 
Individual subject’s study data (from screening to Week 6) will be cleaned and locked during the 
4-week, blinded, dose adjustment period. 
At the Week 10 visit, treatment assignment will be unblinded on an individual subject basis.  
Subjects who were randomized to receive placebo will end study participation after unblinding at 
the Week 10 visit.  Subjects who were randomized to receive 1 of the 3 vadadustat doses will 
continue receiving vadadustat during the 6-week, open-label extension period. 
Vadadustat treatment will stop after the extension period has been completed (Week 16) and 
subjects will continue in a 2-week follow-up safety period (Week 17-18). 
The clinical and safety assessments will be performed as described in Section 9.3 and as listed in 
Appendix A. 
6.2 Study Duration 
Individual subjects will participate in the study for up to 22 weeks, including the eligibility 
screening period (up to 4 weeks), primary efficacy period (6 weeks), blinded dose adjustment 
and data cleaning period (4 weeks), open-label extension period (6 weeks), and safety follow-up 
period (2 weeks). 
Only subjects who are randomized to receive vadadustat will continue in the open-label 
extension period and the safety follow-up period.  Subjects who are randomized to receive 
placebo during the blinded treatment period will discontinue from the study after unblinding at 
Week 10. 
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 NDD-CKD is modeled on a previously completed 
dose-finding study in Caucasian subjects with anemia secondary to NDD-CKD 
(Study AKB-6548-CI-0005). 
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 


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Study AKB-6548-CI-0005 was adequate to establish a statistically significant dose-response 
relationship (as shown in Figure 4).  An additional 10-week 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 safe and 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 safe, 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 according to 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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7 SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 General Criteria 
The study population will consist of male and female Japanese adults aged 20 years or older with 
anemia secondary to NDD-CKD who are not currently being treated with an ESA. 
To be eligible for this study, a subject or their legally acceptable representative must have 
provided valid informed consent and must meet all of the following criteria.  No study 
procedures (including screening tests) may be performed until after the informed consent has 
been legally signed. 
7.2 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for study participation: 
1. Male and female Japanese subjects, aged 20 years or older 
2. Diagnosis of CKD based on an estimated glomerular filtration rate (eGFR) of 
≤60 mL/min/1.73 m2 (using the 2009 Japanese Society of Nephrology equation; Matsuo 
2009) 
3. Not currently being treated with dialysis and not expected to start dialysis within 
3 months of screening 
4. Hemoglobin (Hb) ≤10.5 g/dL during screening 
5. Serum ferritin ≥50 ng/mL during screening 
6. TSAT ≥20% during screening 
7. Folate and vitamin B12 greater than or equal to the lower limit of normal during 
screening 
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. RBC transfusion within 4 weeks prior to or during screening 
4. Intravenous iron within 4 weeks prior to or during screening 


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5. Any ESA use within 6 weeks prior to or during screening (eg, recombinant human 
erythropoietin, darbepoetin alfa, or methoxy polyethylene glycol-epoetin beta) 
6. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), 
alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total 
bilirubin >2.0 x upper limit of normal during screening.  A history of Gilbert’s syndrome 
is not an exclusion criterion. 
7. Uncontrolled hypertension (confirmed diastolic blood pressure >110 mm Hg or systolic 
blood pressure >180 mm Hg) during screening 
8. Body mass index (BMI) >42.0 kg/m2 
9. Severe heart failure during screening (New York Heart Association Class III or IV) 
10. 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 
11. 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 
12. 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 
13. History of deep vein thrombosis (DVT) or pulmonary embolism (PE) requiring active 
treatment within 8 weeks prior to or during screening 
14. History of hemosiderosis or hemochromatosis 
15. History of prior organ transplantation or scheduled organ transplant (subjects on kidney 
transplant wait-list are not excluded), or prior hematopoietic stem cell or bone marrow 
transplant (corneal transplants and stem cell therapy for knee arthritis are not excluded) 
16. 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 
17. Previous participation in a study with a hypoxia-inducible factor prolyl-hydroxylase 
inhibitor, other than vadadustat, within 90 days prior to screening 
18. Hypersensitivity to vadadustat, or to any of its excipients 


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19. Females who are pregnant or breast-feeding 
20. Females of childbearing potential who are unable or unwilling to use an acceptable 
method of contraception 
21. Non-vasectomized males who are unable or unwilling to use an acceptable method of 
contraception 
22. 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. 
The screening period can last up to 4 weeks long, with a minimum of 4 days between the last 
qualifying repeat measurement and the baseline visit (Day 1), ie, the screening period window is 
from Day -28 to Day -4. 
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.   
7.4.2 Rescreening  
Subjects who fail to meet the qualifying criteria for Hb or eGFR 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 B12 values may be considered for 
rescreening after receiving replacement therapy. 
If intravenous (IV) iron is used to replete iron stores, the last dose of IV iron must be 
administered at least 4 weeks prior to rescreening. 
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). 


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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 randomized to receive placebo will be considered as having completed the study after 
completing participation in the Week 10 (unblinding) visit. 
A subject randomized to receive vadadustat will be considered as having completed the study 
after completing participation in the Week 18 visit (end of the 2-week safety follow-up period). 
Note that for subjects who discontinue study drug due to an excess Hb response during the 
primary efficacy period, Hb levels will be monitored weekly via lab evaluation until the subject 
no longer exhibits an excess Hb response. 
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 will discontinue study medication for any of the following conditions: 
• Completion of the protocol-defined dosing period (see Appendix A) 
• Meets discontinuation criteria related to excess Hb response during the primary efficacy 
period (defined in Section 8.2.4) 
• Major toxicity considered to be related to study medication 
• Worsening of anemia requiring ESA rescue or blood transfusion 
• Administrative reasons, such as, subject non-compliance or a major protocol violation 
• Upon request of the sponsor or regulatory agency 
• If, in the opinion of the investigator, it is medically necessary, or if it is the wish of the 
subject 
• Study termination (see Section 14) 
The investigator must document the primary reason for discontinuation in the appropriate case 
report form (CRF). 
7.6.3 Individual Subject Discontinuation during the Primary Efficacy Period or Blinded Dose 
Adjustment and Data Cleaning Period 
Subjects discontinuing study medication or withdrawing early from the study during the blinded 
periods should undergo the Week 10 (EOT for blinded period) clinical and laboratory 
assessments within 1 day of stopping study medication, if possible.  Such subjects should also 
complete the 2-week safety follow-up period (see Appendix A).  For subjects who discontinue 


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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. 
7.6.4 Individual Subject Discontinuation during the Open-Label Extension Period 
Only subjects randomized to vadadustat will continue to the open-label extension period.  
Subjects discontinuing vadadustat or withdrawing from the study during the open-label period 
should complete the Week 16 (EOT for open-label period) clinical and laboratory assessments 
within 1 day of stopping study medication, if possible.  Such subjects should also complete the 
2-week safety follow-up period and complete the Week 18 visit assessments (see Appendix A).  
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. 
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 according to the Pharmacy Manual.  A 
min-max thermometer is preferred for this study. 


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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 at the baseline visit.  Each bottle will contain 100 tablets of study drug.  
Subjects will be instructed to finish 1 bottle before opening a new bottle. 
Resupply of additional study drug at subsequent 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. 
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 at all times. 
Proper drug accountability includes, but is not limited to: 
• 
Continuously monitoring expiration dates, if expiry date or retest date is provided to the 
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 
immediately. 
During the study, the investigator will be notified of any expiry dates or retest date extensions of 
clinical study material.  If an expiry date notification is received during the study, the 
investigative site must complete all instructions outlined in the notification, including 
segregation of expired clinical study material for return to the sponsor or its designee for 
destruction. 
Prior to investigative site closure and at appropriate intervals during the study, a representative 
from the sponsor will perform clinical study material accountability and reconciliation. 


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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 according to 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 other oral 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 exception of the Week 4 visit.  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. 
Figure 5: 
Randomization Scheme of Study Treatment 
 
8.2.3 Blinding During the Primary Efficacy Period and Breaking the Blind 
During the blinded periods, all subjects and personnel involved with the conduct and 
interpretation of the study will be blinded to the study drug treatment, including investigators, 
site personnel, site pharmacist, and sponsor’s staff and designees. 
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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The study blind should be broken for individual subjects after a subject completes the Week 6 
visit and the subject’s data (from screening to Week 6) is cleaned and locked. 
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. 
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.  The applicable standard operating procedure will be followed for 
blind-breaking procedures.  After each subject’s data is cleaned and locked, their individual 
randomization code will be broken to determine eligibility for continuation to the open-label 
extension period. 
8.2.4 Study Drug Administration during the Primary Efficacy Period 
To establish a dose-response relationship, the primary efficacy period includes a blinded 
fixed-dose treatment regimen.  However, if Hb levels increase too rapidly or if the Hb levels 
exceed the desired range, the dose will be decreased or discontinued as presented below (and as 
depicted in Figure 6). 
• Subjects who meet the following criteria for excess Hb response will undergo a dose 
reduction by 1 tablet: 
- Hb level >13 g/dL, OR 
- Hb increase >1 g/dL within any 2-week period, OR 
- Hb increase >2 g/dL within any 4-week period 
• Subjects who meet the following criteria will discontinue study drug: 
- Excess Hb response as defined by any of the aforementioned criteria, AND 
- Current dose of 1 tablet daily OR subject had previously decreased study drug dose 
due to excess Hb response 
Hb will be assessed at the central laboratory and also monitored using point-of-care HemoCue® 
(as listed in Appendix A).  Note that the point-of-care HemoCue Hb value will be used to 
determine if the dose of study medication will be adjusted or discontinued. 
 


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Figure 6: 
Guidelines for Dose Reduction or Discontinuation of Study Drug During the 
Primary Efficacy Period 
 
 
8.2.5 Study Drug Administration during the Blinded Dose Adjustment and Data Cleaning 
Period 
After completing the Week 6 visit, subjects will continue blinded study treatment for an 
additional 4 weeks during which time their data from screening through the Week 6 visit will be 
cleaned and locked.  Individual subjects will be unblinded at their Week 10 visit.  Potential 
scenarios for individual subject unblinding is shown in Figure 7. 
Point-of-care Hb levels will be monitored via HemoCue to determine if the dose of study 
medication will be adjusted (as listed in Appendix A).  Dose adjustments will be based on dose 
adjustment guidelines (see Section 8.2.7). 
 
1 tablet
2 tablets
4 tablets
Discontinue
study drug
Decrease to 
1 tablet
Decrease to
3 tablets
Criteria for dose reduction
•
Hemoglobin >13 g/dL, OR
•
Hemoglobin increase >1 g/dL within any 2-week period, OR
•
Hemoglobin increase >2 g/dL within any 4-week period
Discontinue
study drug*
Discontinue
study drug*
Criteria for dose reduction
•
Hemoglobin >13 g/dL, OR
•
Hemoglobin increase >1 g/dL within any 2-week period, OR
•
Hemoglobin increase >2 g/dL within any 4-week period
Study Visit
(Week 1, 2, 4, or 6)
Study Visit
(Week 2, 4, or 6)
*Note: A subject who had previously decreased study drug dose due to an excess Hb response and 
meets the criteria for excess Hb response at a subsequent visit during the primary efficacy period 
(Week 2, 4, or 6) will discontinue study drug


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Figure 7: 
Potential Scenarios for Individual Subject Unblinding 
 
 
8.2.6 Vadadustat Administration during the Open-Label Extension Period 
During the 6-week, open-label extension period, vadadustat dosage will be adjusted to achieve a 
target Hb level of 10-12 g/dL.  Point-of-care Hb will be monitored via HemoCue to determine if 
the dose of study medication will be adjusted (see Appendix A).  Dose adjustments will be based 
on dose adjustment guidelines (see Section 8.2.7). 
8.2.7 Dose Adjustment Guidelines 
Dose adjustment of blinded study drug (from Week 7 to 10) and open-label vadadustat (from 
Week 11 to 16) will follow the dose adjustment guidelines listed below to achieve a target Hb of 
10-12 g/dL.  The point-of-care HemoCue Hb value will be used to determine if the dose of study 
drug will be adjusted. 
• Do not increase the dose more frequently than once within any given 4-week interval.  For 
example, if a subject’s dose was increased at Week 10 and the subject remains below the Hb 
target, the next opportunity to further increase the dose would be Week 14.  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 rises rapidly (eg, more than 1 g/dL in any 2-week period), reduce the dose by 
1 tablet. 
First Patient In
DATA CUT
Vadadustat 150 mg
Placebo
Placebo
UNBLIND
Vadadustat 600 mg
Vadadustat 300 mg
Vadadustat 150 mg
Double-blind, fixed-dose, primary efficacy period (6 weeks)
Open-label, dose-adjustable, extension period (6 weeks)
Randomization
Randomization
Randomization
Randomization
Randomization
Randomization
DATA LOCK
Double-blind, dose-adjustable, data cleaning period (4 weeks)
Adjust as Needed to Achieve Goal Hb 10-12 g/dL
Adjust as Needed to Achieve Goal Hb 10-12 g/dL
Adjust to Goal Hb
Adjust as Needed to Achieve Goal Hb 10-12 g/dL
Adjust to Goal Hb
Adjust as Needed to Achieve Goal Hb 10-12 g/dL


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• 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).  In cases of extenuating clinical circumstances, investigators may elect to 
dose outside the dosing guidelines to maintain the Hb within the target range. 
8.2.8 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: 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 
- Exhibits Hb level <9.0 g/dL 
• 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. 
8.2.9 Oral Iron Supplementation (Information on Allowed Use) 
Subjects who are taking oral iron supplementation at baseline should continue their oral iron at 
the same dose throughout their study participation.  Changes to oral iron supplementation dose 
will be considered protocol deviations but will not be considered a reason for subject 
discontinuation. 
Subjects who are not taking oral iron supplementation at baseline should not start oral iron 
during their study participation (see Section 8.4.3). 
Important: Because of the potential for oral iron to reduce the bioavailability of vadadustat, the 
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. 
8.2.10 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. 


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Subjects should be questioned regarding dosing compliance and the information should be 
recorded. 
8.2.11 Treatment Compliance 
Subjects will be questioned regarding dosing compliance at all study visits from Week 1 through 
Week 18, 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. 
8.2.12 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 through the course of 
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, Intravenous Iron, and Blood Transfusion 
Subjects may not receive any ESA treatment within 6 weeks prior to the screening period and 
through the safety follow-up period (eg, recombinant human erythropoietin, darbepoetin alfa, or 
methoxy polyethylene glycol-epoetin beta).  See Section 8.2.8 for the rescue therapy guidelines. 
Subjects may not receive intravenous iron or blood transfusion within 4 weeks prior to the 
screening period and through the safety follow-up period.  Use of intravenous iron 
supplementation after Day 1 will be considered a protocol deviation but will not be considered a 
reason for subject discontinuation. 
ESAs and RBC transfusions are allowed as rescue therapies, please refer to Section 8.2.8 for the 
rescue therapy guidelines.  Note that subjects who initiate rescue therapy will be required to stop 
study drug treatment and will be discontinued from the study. 
8.4.3 Oral Iron Supplementation (Information on Prohibition) 
Subjects who are not taking oral iron supplementation at baseline should not start oral iron 
during study participation.  Use of oral iron supplementation by such subjects will be considered 
a protocol deviation but will not be considered a reason for subject discontinuation. 
See Section 8.2.9 for information on circumstances allowing use of oral iron supplementation. 


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9 STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES 
As presented in Appendix A, this study includes the following visits: 
• 
Eligibility screening period (Day -28 to Day -4) 
• 
Baseline visit (Day 1) 
• 
Primary efficacy period (Week 1 ± 1 day, Week 2 ± 1 day, Week 4 ± 3 days, and 
Week 6 ± 3 days) 
• 
Blinded dose adjustment and data cleaning period (Week 10 ± 3 days) 
• 
Open-label extension period (Week 14 ± 3 days and Week 16 ± 3 days) 
• 
Safety follow-up period (Week 18 ± 3 days) 
The following sections describe the procedures to be completed during the study.  Subjects are to 
be assessed by the same investigator or site personnel whenever possible. 
9.1 Administrative Procedures 
9.1.1 Informed Consent Procedure 
Informed consent must be obtained and legally signed prior to a subject entering into the study 
and before any protocol-directed procedures (including screening tests) are performed (see 
Section 15.3). 
9.1.2 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. 
9.1.3 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 9.1.3.1. 
9.1.3.1 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 


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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) and at baseline (assessed using urine pregnancy test). 
• 
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 
9.2 Study Procedures and Evaluations 
9.2.1 Clinical Evaluations 
The following clinical evaluations will be conducted during the course of the study.  Detailed 
information regarding the timing of the assessments is presented in Section 9.3 and summarized 
in Appendix A: 
• Demographics and medical history: Relevant medical history (with particular emphasis 
on previous medical conditions that may lead to exclusion) and significant ongoing 
medical conditions or diseases should be documented. 
• Physical examination: Physical examination, including height assessments 
• Weight assessment 
• 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 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 


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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. 
• 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. 
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. 
9.2.2 Laboratory Evaluations 
Samples for laboratory assays will be sent to a central laboratory for analysis, with the exception 
of the urine pregnancy test at baseline which will be performed locally.  Detailed instructions for 
the collection, processing, and shipment of laboratory samples will be provided by the sponsor 
and the central laboratory.  The investigator is responsible for reviewing laboratory results for 
clinical significance. 
The following laboratory evaluations will be conducted during the course of the study: 
• Serum and urine 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) and urine pregnancy tests (to be analyzed by the local 
lab).  The screening and baseline pregnancy test results must be available and must be 
negative for a subject to initiate or continue study drug. 
• Coagulation tests: Blood sample will be collected to assess the prothrombin time (PT), 
partial thromboplastin time (PTT), and international normalized ratio (INR). 
• Folate and vitamin B12: Blood sample will be collected to assess folate and Vitamin B12 
levels. 
• HemoCue®: Hb will be monitored via HemoCue point-of-care device to determine if the 
dose of study drug will be adjusted. 
• 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). 


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For subjects who discontinue study drug due to an excess Hb response during the primary 
efficacy period, Hb will be assessed weekly via lab evaluation until the subject no longer 
exhibits an excess Hb response. 
• Chemistry and eGFR: 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.  eGFR will be calculated from serum 
creatinine as described in Appendix B.  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. 
9.3 Schedule of Activities 
The Schedule of Events in Appendix A shows the timing of planned study procedures.  Every 
effort should be made to adhere to this procedure schedule and all assessments should be 
completed at each study visit. 
9.3.1 Screening Visit 
The screening visit must be performed within 28 days prior to dosing and there must be a 
minimum of 4 days between the last qualifying repeat measurement and the baseline visit 
(Day 1). 
After obtaining informed consent and receiving a unique subject identification number, subjects 
will undergo a number of screening activities.  The investigator will maintain a log of subjects 
and indicate who was enrolled or excluded and the reason for exclusion (see Section 9.1.2). 
At the screening visit, the following activities/procedures will be performed: 
• Review of study inclusion and exclusion criteria 


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• Demographics, medical history, and physical examination 
• Weight assessment 
• Vital signs (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
• Prior and current medication use 
• 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 Folate and vitamin B12 levels 
o CBC 
o Chemistry and eGFR 
o Iron indices 
9.3.2 Baseline Visit (Day 1) 
There must be a minimum of 4 days between the screening and baseline visits. 
At the baseline visit, the following activities/procedures will be performed: 
• Review of study inclusion and exclusion criteria 
• Vital signs (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
• 12-lead ECG (prior to blood draws when possible and obtained after the subject has been 
resting supine comfortably for approximately 10 minutes) 
• Recording of any concomitant medication use since screening visit 
• Laboratory procedures: 
o Urine pregnancy test for females of childbearing potential (eligible subjects will 
be advised to use an adequate contraceptive method).  The urine sample will be 
analyzed by the local lab.  The baseline results must be available and must be 
negative before the subject takes the first dose of study drug. 
o Coagulation tests (including prothrombin time, partial thromboplastin time, and 
international normalized ratio) 
o CBC 
o Chemistry and eGFR 
o Iron indices 
o Hepcidin 
o C-reactive protein 
o VEGF 
• Dispense blinded study drug 
• Review dosing instructions 
9.3.3 Week 1 Visit 
At the Week 1 visit, 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) 


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• AE review 
• Concomitant medication review 
• Hb using HemoCue 
• CBC 
• Subjects should be questioned regarding dosing compliance 
• Review dosing instructions 
9.3.4 Week 2 Visit 
At the Week 2 visit, 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) 
• AE review 
• Concomitant medication review 
• Hb using HemoCue 
• Laboratory procedures: 
o CBC 
o Chemistry and eGFR 
o Iron indices 
• Dispense blinded study drug (as necessary) 
• Subjects should be questioned regarding dosing compliance 
• Review dosing instructions and 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 
9.3.5 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 (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
• AE review 
• Concomitant medication review 
• Hb using HemoCue 
• Laboratory procedures: 
o CBC 
o Chemistry and eGFR 
o Iron indices 
o Pre-dose PK sample 
• Record date and time of the last dose of the study that was taken prior to the pre-dose PK 
sample 
• Dispense blinded study drug (as necessary) 
• Subjects should be questioned regarding dosing compliance 
• Review dosing instructions 


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9.3.6 Week 6 Visit 
Individual subject data (up to Week 6) will be cleaned and locked after the Week 6 visit.  
Following data lock, individual subject’s randomized treatment assignment will be unblinded 
and the subject will be informed at the Week 10 visit. 
At the Week 6 visit, 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) 
• AE review 
• Concomitant medication review 
• Hb using HemoCue 
• Laboratory procedures: 
o CBC 
o Chemistry and eGFR 
o Iron indices 
o Hepcidin 
o C-reactive protein 
o VEGF 
• Dispense blinded study drug (as necessary) 
• Subjects should be questioned regarding dosing compliance 
• Review dosing instructions 
9.3.7 Week 10 Visit (End-of-treatment visit for the blinded period and early withdrawals) 
All enrolled subjects who receive at least 1 dose of blinded study drug should complete the 
Week 10 assessments. 
Subjects who withdraw early from the study prior to the Week 6 visit or permanently discontinue 
study medication prior to the Week 6 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 9.3.10). 
Individual subject data (up to Week 6) will be locked after the Week 6.  Following data lock, 
individual subject’s randomized treatment assignment will be unblinded and the subject will be 
informed at the Week 10 visit.  Subjects who were assigned to receive placebo will discontinue 
from the study at the end of the Week 10 visit, and subjects who were assigned to receive 
vadadustat will continue to the open-label extension period. 
At the Week 10 visit, 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) 
• AE review (see Section 10.3.6 for follow-up of unresolved events) 
• Concomitant medication review 
• Laboratory procedures: 
o Hb using HemoCue for dose adjustment (not for subjects who discontinue prior to 
the Week 6 visit) 
o CBC 
o Chemistry and eGFR 


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o Iron indices 
o Hepcidin 
o C-reactive protein 
o VEGF 
• Dispense open-label vadadustat (as necessary; only applicable to subjects who are 
continuing to the open-label extension period) 
• Subjects should be questioned regarding dosing compliance 
• Review dosing instructions (only applicable to subjects who are continuing to the 
open-label extension period) 
9.3.8 Week 14 Visit 
At this visit, 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) 
• AE review 
• Concomitant medication review 
• Hb using HemoCue for dose adjustment 
• CBC 
• Chemistry and eGFR 
• Dispense vadadustat (as necessary) 
• Subjects should be questioned regarding dosing compliance 
• Review dosing instructions 
9.3.9  Week 16 Visit (End-of-treatment visit for the open-label period and early withdrawal 
visit for withdrawals after Week 10 but before Week 16) 
All subjects who received at least 1 dose of open-label vadadustat should complete the Week 16 
assessments. 
Subjects who withdraw early from the open-label period 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 9.3.10). 
At the Week 16 visit, 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) 
• AE review (see Section 10.3.6 for follow-up of unresolved events) 
• Concomitant medication review 
• Laboratory procedures: 
o Serum pregnancy test for females of childbearing potential (to be analyzed by the 
central lab) 
o CBC 
o Chemistry and eGFR 
o Iron indices 
o Hepcidin 


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o C-reactive protein 
o VEGF 
• Subjects should be questioned regarding dosing compliance 
9.3.10  Week 18 Safety Follow-Up Visit (Or 2 Weeks after End-of-Treatment Safety Follow-Up 
Visit) 
For subjects randomized to vadadustat who complete the open-label extension period, the safety 
visit will be conducted 2 weeks after their end-of-treatment visit (Week 16). 
For subjects who discontinue the study early during the primary efficacy period or the blinded 
dose adjustment and data cleaning period, the safety visit will be conducted 2 weeks after their 
end-of-treatment visit (Week 10). 
At the follow-up visit, 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) 
• AE review (see Section 10.3.6 for follow-up of unresolved events) 
• Concomitant medication review 
• Laboratory procedures: 
o CBC 
o Chemistry and eGFR 
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. 


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• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test). 
• Laboratory abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they are associated with an already 
reported clinical event.  Laboratory abnormalities associated with a clinical event 
reported as an AE (eg, elevated liver enzymes in a subject with jaundice) should be 
described under ‘Comments’ on the report of the clinical event rather than reported as 
separate AEs. 
The following guidelines are to be used when reporting AEs for this study: 
Medical Diagnoses – Whenever possible, a medical diagnosis term should be used to report AEs 
instead of signs and symptoms due to a common etiology, as determined by qualified medical 
study staff.  For example, pneumonia should be the reported AE term, instead of fever, dyspnea, 
etc., when the diagnosis has been established.  Signs and symptoms should be reported as event 
terms only when the medical diagnosis remains unknown, and revised to a medical diagnosis 
term once it has been established. 
Procedures – Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as AEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE.  For example, an acute 
appendicitis that begins during the AE reporting period should be reported as the AE and the 
resulting appendectomy noted under “Comments.” 
Pre-planned therapeutic procedures not associated with a new medical condition or worsening 
pre-existing condition should not be reported as AEs. 
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: 


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• 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). 
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. 
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 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. 
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 
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 
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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). 
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 


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• 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 
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 aware of the pregnancy (reference the site manual for 
contact information). 
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 
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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. 
• 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 
11.1 Primary Endpoint and Sample Size Determination 
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 NDD-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 EOT visit minus the mean pre-treatment Hb.  
Pre-treatment Hb is defined as the average of 2 Hb values obtained prior to treatment based on 
the qualifying screening Hb value and the Hb value at the baseline visit.  Linear regression 
analysis will be used to calculate the relationship between vadadustat dose and change in Hb. 
The target enrollment will be approximately 48 subjects for the study with 12 subjects enrolled 
in each of the 4 treatment groups. 
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 reasonable to assume 
that 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. 
11.2 Study Populations 
11.2.1 Analysis Population 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 
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11.2.2 Analysis Populations for the Efficacy Analyses 
The modified intent-to-treat (MITT) population for Hb or RBC count will include subjects who 
receive at least 1 dose of study medication, have a pre-treatment average defined as the average 
of the qualifying screening value and the baseline value, and at least one post-baseline 
measurement. The MITT population for other parameters will include subjects who receive at 
least 1 dose of study medication, have at least one pre-treatment value, and at least one 
post-baseline 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.   
As sensitivity analyses, efficacy endpoints will also be analyzed using the PP population. 
11.3 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. 
11.4 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. 
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 
For purposes of analysis, a pre-treatment average (defined as the average of 2 samples obtained 
prior to treatment [ie, the qualifying screening value and baseline value]) will be used as the 
baseline value for Hb and RBC count, and last observation before the first dose of study 
medication will be used as baseline for other parameters. 
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 assess 
the vadadustat dose-response relationship.  Similar analysis will be performed for change from 
baseline to Week 6 of reticulocyte count (both absolute and percent), hematocrit, and RBC 
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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. 
11.6 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, components of the CBC, and VEGF. 
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. 
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. 
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, 


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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 
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 
assessments. 
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.  


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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 
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 


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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 course of 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 
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 


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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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Appendix A: Schedule of Activities 
Please refer to Section 9.2 for detailed information regarding the study procedures and evaluations, and please refer to Section 9.3 for 
detailed information regarding the activities to be performed at each study visit. 
 
Screening 
Primary efficacy period 
(blinded, fixed-dose treatment) 
(Day 1-Week 6) 
Blinded dose 
adjustment, data 
cleaning period 
(Week 7-10) 
Open-label extension 
period 
(Week 11-16) 
Safety 
Follow-up 
(Week 17-18) 
Study Week 
-4 to 0 
Base 
line 
1 
2 
4 
6 
10 (EOT, Blinded 
Period) 
14 
16 (EOT, 
Open-Label 
Period) 
18 
Study Day 
-28 to -4 
1 
8 
15 
29 
43 
71 
99 
113 
127 
Visit Window (Days) 
 
 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Review inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Individual subject data lock (for subjects 
who complete Week 6) 
 
 
 
 
 
X 
 
 
 
Individual subject unblinding (for 
subjects who complete Week 6) 
 
 
 
 
 
 
X 
 
 
 
Demographics, medical history, physical 
exam, and weight 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram 
 
X 
 
 
 
 
 
 
 
 
Adverse event review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
X 
 
Urine pregnancy test 
 
X 
 
 
 
 
 
 
 
 
Coagulation tests 
 
X 
 
 
 
 
 
 
 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 2) 
 
 
Confidential 
19 July 2016; Page 64 
 
Screening 
Primary efficacy period 
(blinded, fixed-dose treatment) 
(Day 1-Week 6) 
Blinded dose 
adjustment, data 
cleaning period 
(Week 7-10) 
Open-label extension 
period 
(Week 11-16) 
Safety 
Follow-up 
(Week 17-18) 
Study Week 
-4 to 0 
Base 
line 
1 
2 
4 
6 
10 (EOT, Blinded 
Period) 
14 
16 (EOT, 
Open-Label 
Period) 
18 
Study Day 
-28 to -4 
1 
8 
15 
29 
43 
71 
99 
113 
127 
Visit Window (Days) 
 
 
±1 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
Folate and vitamin B12 
X 
 
 
 
 
 
 
 
 
 
Hb using HemoCue® (Week 10 
assessment is not for subjects who 
discontinue prior to Week 6) 
 
 
X 
X 
X 
X 
X 
X 
 
 
Complete blood count, including Hb [a] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry and eGFR 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Iron indices 
X 
X 
 
X 
X 
X 
X 
 
X 
 
Hepcidin 
 
X 
 
 
 
X 
X 
 
X 
 
C-reactive protein 
 
X 
 
 
 
X 
X 
 
X 
 
VEGF  
 
X 
 
 
 
X 
X 
 
X 
 
PK pre-dose sample (study drug to be 
administered after sample collection) 
 
 
 
 
X 
 
 
 
 
 
Blinded study drug dispensation, as 
necessary 
 
X 
 
X 
X 
X 
 
 
 
 
Blinded study drug dosing 
 
Blinded study drug dosing 
 
 
 
Vadadustat dispensation, as necessary [b] 
 
 
 
 
 
 
X 
X 
 
 
Vadadustat dosing [b] 
 
 
 
 
 
 
 
Open-label vadadustat 
dosing 
 
Study drug compliance check 
 
 
X 
X 
X 
X 
X 
X 
X 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 2) 
 
 
Confidential 
19 July 2016; Page 65 
Abbreviations: eGFR, estimated glomerular filtration rate; EOT, end of treatment; Hb, hemoglobin; PK, pharmacokinetics; VEGF, vascular endothelial growth 
factor 
[a] For subjects who discontinue study drug due to an excess Hb response, blood samples will be collected weekly to monitor Hb until the subject no longer 
exhibits an excess Hb response.  The blood samples will be analyzed in a lab.  Point-of-care Hb assessment will not be used for such evaluations. 
[b] Subjects who were randomized to receive vadadustat treatment during the primary efficacy period and complete the Week 10 visit will continue to the 
open-label extension period. 
 
 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 2) 
 
 
Confidential 
19 July 2016; Page 66 
Appendix B: Japanese Society of Nephrology 2009 Equation to Calculate eGFR 
The estimated glomerular filtration rate (eGFR) will be calculated from serum creatinine using 
the 2009 Japanese Society of Nephrology Equation (3-variables; Matsuo 2009).   
eGFR (mL/min/1.73 m2) = 194 x (Scr in mg/dL)-1.094 x (Age)-0.287 x (0.739 if female) 


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Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 2 
1 SIGNATURE PAGES 
1.1 Protocol Approval 
 
 
 
Akebia Therapeutics, Inc. 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 3 
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 also protect the 
rights, safety, privacy, and well-being of study subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonization Guidance for Industry, Good Clinical 
Practice E6. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting serious adverse events defined in this protocol. 
• Terms outlined in the Clinical Study Site Agreement. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Phone Number 
Full Address 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 4 
TABLE OF CONTENTS 
1 
SIGNATURE PAGES .................................................................................................. 2 
1.1 
Protocol Approval .................................................................................................... 2 
1.2 
Investigator Agreement ............................................................................................ 3 
TABLE OF CONTENTS ......................................................................................................... 4 
LIST OF TABLES ................................................................................................................... 7 
LIST OF FIGURES ................................................................................................................. 7 
2 
PROTOCOL SYNOPSIS .............................................................................................. 8 
3 
LIST OF ABBREVIATIONS ..................................................................................... 14 
4 
BACKGROUND ........................................................................................................ 16 
4.1 
Proposed Indication of Renal Anemia ................................................................... 16 
4.2 
Available Therapies for Anemia in Patients with CKD ......................................... 17 
4.3 
Hypoxia-Inducible Factor ...................................................................................... 17 
4.4 
Description and Mechanism of Action of Vadadustat ........................................... 18 
4.5 
Summary of Clinical Experience ........................................................................... 19 
4.6 
Ethno-Bridging Data from a Study of Healthy Japanese and Caucasian Volunteers
 ................................................................................................................................ 20 
4.7 
Potential Benefits and Risks ................................................................................... 22 
5 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 22 
5.1 
Primary Objective and Endpoint ............................................................................ 22 
5.2 
Secondary Objectives and Endpoints ..................................................................... 22 
6 
STUDY DESIGN ........................................................................................................ 24 
6.1 
Study Design .......................................................................................................... 24 
6.2 
Study Duration ....................................................................................................... 25 
6.3 
Rationale for Study Design .................................................................................... 25 
6.4 
Dose Justification ................................................................................................... 26 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 26 
7.1 
General Criteria ...................................................................................................... 26 
7.2 
Inclusion Criteria .................................................................................................... 27 
7.3 
Exclusion Criteria ................................................................................................... 27 
7.4 
Retesting and Rescreening ..................................................................................... 29 
7.4.1 
Retesting ............................................................................................................ 29 
7.4.2 
Rescreening ....................................................................................................... 29 
7.5 
Study Completion, Study Termination, and Individual Study Site Termination ... 29 
7.5.1 
Study Completion .............................................................................................. 29 
7.5.2 
Study Termination ............................................................................................. 30 
7.5.3 
Individual Study Site Termination .................................................................... 30 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 5 
7.6 
Subject Completion and Individual Subject Discontinuation ................................ 30 
7.6.1 
Subject Completion ........................................................................................... 30 
7.6.2 
Conditions and Documentation of Individual Subject Study Drug 
Discontinuation .................................................................................................. 30 
7.6.3 
Individual Subject Discontinuation ................................................................... 30 
8 
STUDY DRUGS AND TREATMENT OF SUBJECTS ............................................ 31 
8.1 
Study Drugs ............................................................................................................ 31 
8.1.1 
Formulation ....................................................................................................... 31 
8.1.2 
Storage and Accountability ............................................................................... 31 
8.1.3 
Dispensing of Study Drugs ................................................................................ 31 
8.1.4 
Product Accountability and Destruction ........................................................... 32 
8.2 
Treatment of Subjects ............................................................................................. 33 
8.2.1 
Dosing Instructions ............................................................................................ 33 
8.2.2 
Randomization ................................................................................................... 33 
8.2.3 
Blinding During the Study and Breaking the Blind .......................................... 33 
8.2.4 
Study Drug Administration during the Primary Efficacy Period (Week 1 to 
Week 6) ............................................................................................................. 34 
8.2.5 
Study Drug Administration during the Dose Adjustment and Maintenance 
Period (Week 7 to Week 16) ............................................................................. 34 
8.2.6 
Rescue Therapy Guidelines ............................................................................... 35 
8.2.7 
Oral Iron Supplementation (Information on Allowed Use) .............................. 36 
8.2.8 
Late or Missed Doses ........................................................................................ 36 
8.2.9 
Treatment Compliance ...................................................................................... 36 
8.2.10 
Continuation of Treatment ................................................................................ 36 
8.3 
Prior and Concomitant Therapy ............................................................................. 36 
8.4 
Prohibited Treatments ............................................................................................ 37 
8.4.1 
Investigational Medications ............................................................................... 37 
8.4.2 
ESAs, Intravenous Iron, and Blood Transfusion ............................................... 37 
8.4.3 
Oral Iron Supplementation (Information on Prohibition) ................................. 37 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES ................................ 37 
9.1 
Administrative Procedures ..................................................................................... 38 
9.1.1 
Informed Consent Procedure ............................................................................. 38 
9.1.2 
Documentation of Screen Failures .................................................................... 38 
9.1.3 
Review of Inclusion and Exclusion Criteria ...................................................... 38 
9.1.3.1 
Acceptable Methods of Contraception ......................................................... 38 
9.2 
Study Procedures and Evaluations ......................................................................... 39 
9.2.1 
Clinical Evaluations ........................................................................................... 39 
9.2.2 
Laboratory Evaluations ..................................................................................... 40 
9.3 
Schedule of Activities ............................................................................................ 41 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 6 
9.3.1 
Screening Visit .................................................................................................. 41 
9.3.2 
Baseline Visit (Day 1) ....................................................................................... 42 
9.3.3 
Week 2 Visit ...................................................................................................... 42 
9.3.4 
Week 4 Visit ...................................................................................................... 43 
9.3.5 
Week 6 Visit ...................................................................................................... 43 
9.3.6 
Week 8, 10, 12, 14 Visits .................................................................................. 44 
9.3.7 
Week 16 Visit (end-of-treatment visit for subjects who complete the dose 
adjustment and maintenance period or for subjects who withdraw prematurely 
from the study prior to Week 16) ...................................................................... 44 
9.3.8 
Week 18 Follow-Up Visit (or 2 weeks after end-of-treatment follow-up visit) 45 
10 
ADVERSE EVENTS .................................................................................................. 45 
10.1 
Definitions .............................................................................................................. 45 
10.1.1 
Adverse Events (AEs) ....................................................................................... 45 
10.1.2 
Serious Adverse Events (SAEs) ........................................................................ 47 
10.2 
Eliciting Adverse Event Information ..................................................................... 48 
10.3 
Reporting ................................................................................................................ 48 
10.3.1 
Reporting Period ................................................................................................ 48 
10.3.2 
Reporting AEs ................................................................................................... 48 
10.3.3 
Reporting SAEs ................................................................................................. 48 
10.3.4 
Relationship to Study Medication ..................................................................... 49 
10.3.5 
Severity .............................................................................................................. 50 
10.3.6 
Follow-Up of Unresolved Events ...................................................................... 50 
10.3.7 
Special Situations .............................................................................................. 50 
10.4 
Exposure In Utero .................................................................................................. 50 
11 
DATA ANALYSIS ..................................................................................................... 51 
11.1 
Primary Endpoint and Sample Size Determination ................................................ 51 
11.2 
Study Populations ................................................................................................... 52 
11.2.1 
Analysis Population for the Safety Analyses .................................................... 52 
11.2.2 
Analysis Populations for the Efficacy Analyses ............................................... 52 
11.3 
Analysis of Demographics and Pretreatment Variables ......................................... 52 
11.4 
Disposition of Subjects ........................................................................................... 52 
11.5 
Efficacy and PD Analyses ...................................................................................... 52 
11.6 
Safety Analyses ...................................................................................................... 53 
11.7 
PK Analyses ........................................................................................................... 53 
12 
DATA HANDLING AND RECORD KEEPING ...................................................... 53 
12.1 
Case Report Forms (CRFs) .................................................................................... 53 
12.2 
Record Retention .................................................................................................... 54 
13 
QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) ....................... 54 
13.1 
Study Site Monitoring Visits .................................................................................. 54 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 7 
13.2 
Protocol Deviations ................................................................................................ 55 
14 
STUDY DISCONTINUATION/INVESTIGATIVE STUDY SITE TERMINATION
 ..................................................................................................................................... 55 
14.1 
Criteria for Premature Termination or Suspension of the Study ............................ 55 
14.2 
Criteria for Premature Termination or Suspension of Investigational Sites .......... 55 
14.3 
Procedures for Premature Termination or Suspension of the Study or 
Investigational Site(s) ............................................................................................. 55 
15 
ETHICS ....................................................................................................................... 56 
15.1 
Ethical Conduct of the Study ................................................................................. 56 
15.2 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) ........... 56 
15.3 
Subject Information and Consent ........................................................................... 56 
15.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .... 56 
15.5 
Subject Confidentiality ........................................................................................... 57 
16 
PUBLICATION OF STUDY RESULTS ................................................................... 57 
17 
REFERENCES ............................................................................................................ 58 
 
LIST OF TABLES 
Table 1: 
Identity of Study Drugs ........................................................................................31 
 
LIST OF FIGURES 
Figure 1 
Mechanism of Action of Vadadustat ....................................................................18 
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) .......21 
Figure 3: 
Overview of Study Design ....................................................................................24 
Figure 4: 
Absolute Change in Hemoglobin (± Standard Error of Mean, g/dL) at Week 6 
Compared to Baseline (Study AKB-6548-CI-0005) ..........................................26 
Figure 5: 
Randomization Scheme of Study Treatment ........................................................33 
 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 8 
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 Non-Dialysis 
Dependent Chronic Kidney Disease 
Protocol Number 
AKB-6548-CI-0021 
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 non-dialysis dependent chronic kidney disease 
(NDD-CKD) who are not currently being treated with an erythropoiesis-stimulating 
agent (ESA) 
Investigative Sites 
Approximately 25 sites in Japan 
Planned Number of 
Subjects 
Approximately 48 subjects will be enrolled in the study, with 36 subjects receiving 
one of the 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 (QD) dosing for 6 weeks and the change in hemoglobin 
(Hb) in Japanese subjects with anemia secondary to NDD-CKD; in order 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 QD dosing in Japanese subjects 
with anemia secondary to NDD-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  
Study Design Overview 
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 NDD-CKD. 
The study will include the following periods: 
• Eligibility screening period (up to 4 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). 
Following the screening period, eligible subjects will be randomized to receive 
blinded study drug treatment during a 6-week primary efficacy period, with subjects 
randomized at a 3:1 ratio to receive vadadustat (150, 300, or 600 mg vadadustat) or 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 9 
placebo.  See “Dosage and Regimen” in the synopsis for additional information 
regarding the randomization scheme. 
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 levels increase too rapidly or if the Hb levels exceed the 
desired range, the study drug dose can be decreased or interrupted (see “Dosage and 
Regimen” for additional information). 
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 
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). 
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.  In addition, 
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. 
Key Inclusion Criteria 
(the complete list is 
provided in the 
protocol) 
• Male and female Japanese subjects (20 years or older) 
• Diagnosis of CKD based on an estimated glomerular filtration rate (eGFR) of 
≤60 mL/min/1.73 m2 (using the 2009 Japanese Society of Nephrology 
equation; Matsuo 2009) 
• Not currently being treated with dialysis and not expected to start dialysis 
within 3 months of screening 
• Hb ≤10.5 g/dL 
• Serum ferritin ≥50 ng/mL 
• Transferrin saturation (TSAT) ≥20% 
• Folate and vitamin B12 ≥ lower limit of normal 
• For subjects who are receiving oral iron supplementation, the dose of oral iron 
supplementation must be stable for at least 28 days prior to the screening 
period. For subjects who are not receiving oral iron supplementation, no iron 
supplementation may have been ingested for at least 28 days prior to the 
screening 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; intravenous iron within 4 weeks prior to or during screening; and any 
ESA use within 6 weeks prior to or during screening. 
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 or eGFR 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 B12 values may be considered for rescreening after receiving 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 10 
replacement therapy. 
Screening is limited to 3 attempts (initial screening and 2 additional rescreening 
attempts). 
Efficacy and 
Pharmacokinetic 
Endpoints 
Note that a pre-treatment value for Hb is defined as the average of 2 values obtained 
prior to treatment, ie, the qualifying screening value 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 10.0-12.0 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, 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) 
• Maintenance of iron sufficiency (defined as ferritin ≥50 ng/mL and TSAT 
≥20%) from baseline to the end of the primary efficacy period (Week 6) and 
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 
Safety Endpoints 
Safety and tolerability 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 other oral 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 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 11 
tablet-count group, subjects will be randomized 3:1 to receive vadadustat or placebo 
as shown 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.   
 
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. 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 at Week 6 
and the subject remains below the Hb target, the next opportunity to further 
increase the dose would be Week 10.  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 rises 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. 
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-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 12 
• 
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).  In cases of extenuating clinical 
circumstances, investigators may elect to dose outside the dosing guidelines to 
maintain the Hb within the target range. 
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 
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: 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 
• 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. 
Oral Iron 
Supplementation 
Subjects who are receiving a stable dose of oral iron supplementation for at least 
28 days prior to the screening period should continue their oral iron supplementation 
at the same dose through the primary efficacy period (through Week 6).  Changes to 
oral 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 adjust oral iron supplementation as 
needed for subjects with ferritin <100 ng/mL and TSAT <20%, and the iron dose 
will be selected at the investigator’s discretion. 
Subjects who are not receiving oral iron supplementation at the beginning of the 
screening period should not start oral iron supplementation through the primary 
efficacy period (through Week 6). Initiation of oral 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 oral iron supplementation for subjects with ferritin <100 ng/mL and 
TSAT <20%, and the iron dose 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 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 13 
after the dose of study drug. 
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. 
The target enrollment will be approximately 48 subjects for the study with 
12 subjects enrolled in each of the 4 treatment groups.  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. 
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 sponsor and CRO study team personnel. 
Subjects and sites will not be unblinded to treatment allocation. 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. 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. 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 14 
3 LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
BUN 
blood urea nitrogen 
C 
Celsius 
CBC 
complete blood count 
CKD 
chronic kidney disease 
CRF 
case report form 
CRO 
contract research organization 
CV 
cardiovascular 
dL 
deciliter 
DVT 
deep venous thrombosis 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
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 
GFR 
glomerular filtration rate 
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 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 15 
IRB 
institutional review board 
IV 
intravenous 
JSN 
Japanese Society of Nephrology 
KDIGO 
Kidney Disease Improving Global Outcomes 
kg 
kilogram 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
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) 
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-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 16 
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-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 17 
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. 
A number of 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-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 19 
4.3% of patients on 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.  As a result, 
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. 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 20 
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 
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 recently completed Phase 2b, randomized, double-blind, placebo-controlled study to assess the 
hematologic PD response, safety, and tolerability of oral vadadustat for 20 weeks was performed 
in 210 subjects with anemia associated with NDD-CKD (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.  


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Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 22 
4.7 Potential Benefits and Risks 
Please see the vadadustat Investigator’s Brochure for additional discussion and information for 
the following section. 
Vadadustat offers the potential of flexible oral dosing that is easier to adjust than injectable 
hormone ESAs.  This alternate therapeutic approach may avoid the excursions and fluctuations 
in Hb levels seen with currently available injectable ESAs and provide for a controlled, steady 
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 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 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, all of the acute findings observed at doses less than the maximum tolerated dose (MTD) 
in animals have been shown to be reversible and dose-related.  In addition, most of the findings 
have followed a pattern that would have been predicted based on the known HIF and HIFPH 
biochemistry, pharmacology, and human genetic variations (eg, Chuvash polycythemia).  In the 
completed clinical studies, vadadustat has been generally well-tolerated. 
5 STUDY OBJECTIVES AND ENDPOINTS 
Note that a pre-treatment value for Hb is defined as the average of 2 values obtained prior to 
treatment, ie, the qualifying screening value 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 Hb in Japanese subjects with anemia 
secondary to NDD-CKD; in order 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 
NDD-CKD during the 6-week, primary efficacy period 


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Protocol No. AKB-6548-CI-0021 
Vadadustat 
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05 August 2016 Page 23 
• 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) 
• 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) 
• Maintenance of iron sufficiency (defined as ferritin ≥50 ng/mL and TSAT ≥20%) from 
baseline to the end of the primary efficacy period (Week 6) and 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]) 


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Protocol No. AKB-6548-CI-0021 
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Original Protocol (Version 3) 
 
 
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05 August 2016 Page 24 
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 subjects 
with anemia secondary to NDD-CKD. 
The study has a planned enrollment of 48 subjects to be enrolled at approximately 25 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. 
Figure 3: 
Overview of Study Design 
 
 
 
The study will include the following periods: 
• Eligibility screening period (up to 4 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) 
Subjects will participate in a screening period (4 days to 4 weeks) to determine study eligibility, 
and eligible subjects will be randomized following the screening period. 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 25 
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 levels increase 
too rapidly or if the Hb levels exceed the desired range, 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). 
The clinical and safety assessments will be performed as described in Section 9.3 and as listed in 
Appendix A. 
6.2 Study Duration 
Individual subjects will participate in the study for 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). 
 
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.  In addition, 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. 
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 NDD-CKD is modeled on a previously completed 
dose-finding study in Caucasian subjects with anemia secondary to NDD-CKD 
(Study AKB-6548-CI-0005). 
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. 


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Protocol No. AKB-6548-CI-0021 
Vadadustat 
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Confidential 
05 August 2016 Page 26 
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 safe and 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 safe, 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 according to 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. 
7 SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 General Criteria 
The study population will consist of male and female Japanese adults aged 20 years or older with 
anemia secondary to NDD-CKD who are not currently being treated with an ESA. 
-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-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 27 
To be eligible for this study, a subject or their legally acceptable representative must have 
provided valid informed consent and must meet all of the following criteria.  No study 
procedures (including screening tests) may be performed until after the informed consent has 
been legally signed. 
7.2 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for study participation: 
1. Male and female Japanese subjects, aged 20 years or older 
2. Diagnosis of CKD based on an estimated glomerular filtration rate (eGFR) of 
≤60 mL/min/1.73 m2 (using the 2009 Japanese Society of Nephrology equation; Matsuo 
2009) 
3. Not currently being treated with dialysis and not expected to start dialysis within 
3 months of screening 
4. Hemoglobin (Hb) ≤10.5 g/dL during screening 
5. Serum ferritin ≥50 ng/mL during screening 
6. TSAT ≥20% during screening 
7. Folate and vitamin B12 greater than or equal to the lower limit of normal during 
screening 
8. For subjects who are receiving oral iron supplementation, the dose of oral iron 
supplementation must be stable for at least 28 days prior to the screening period. For 
subjects who are not receiving oral iron supplementation, no iron supplementation may 
have been ingested for at least 28 days prior to the screening period. 
9. Understands the procedures and requirements of the study and provides written informed 
consent and authorization for protected health information disclosure 
7.3 Exclusion Criteria 
Subjects 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. RBC transfusion within 4 weeks prior to or during screening 
4. Intravenous iron within 4 weeks prior to or during screening 


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Vadadustat 
Original Protocol (Version 3) 
 
 
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05 August 2016 Page 28 
5. Any ESA use within 6 weeks prior to or during screening (eg, recombinant human 
erythropoietin, darbepoetin alfa, or methoxy polyethylene glycol-epoetin beta) 
6. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), 
alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total 
bilirubin >2.0 x upper limit of normal during screening.  A history of Gilbert’s syndrome 
is not an exclusion criterion. 
7. Uncontrolled hypertension (confirmed diastolic blood pressure >110 mm Hg or systolic 
blood pressure >180 mm Hg) during screening 
8. Body mass index (BMI) >42.0 kg/m2 
9. Severe heart failure during screening (New York Heart Association Class III or IV) 
10. 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 
11. 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 
12. 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 
13. History of deep vein thrombosis (DVT) or pulmonary embolism (PE) requiring active 
treatment within 8 weeks prior to or during screening 
14. History of hemosiderosis or hemochromatosis 
15. History of prior organ transplantation or scheduled organ transplant (subjects on kidney 
transplant wait-list are not excluded), or prior hematopoietic stem cell or bone marrow 
transplant (corneal transplants and stem cell therapy for knee arthritis are not excluded) 
16. 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 
17. Previous participation in a study with a hypoxia-inducible factor prolyl-hydroxylase 
inhibitor, other than vadadustat, within 90 days prior to screening 
18. Hypersensitivity to vadadustat, or to any of its excipients 


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19. Females who are pregnant or breast-feeding 
20. Females of childbearing potential who are unable or unwilling to use an acceptable 
method of contraception 
21. Non-vasectomized males who are unable or unwilling to use an acceptable method of 
contraception 
22. 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. 
The screening period can last up to 4 weeks long, with a minimum of 4 days between the last 
qualifying repeat measurement and the baseline visit (Day 1), ie, the screening period window is 
from Day -28 to Day -4. 
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.   
7.4.2 Rescreening  
Subjects who fail to meet the qualifying criteria for Hb or eGFR 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 B12 values may be considered for 
rescreening after receiving replacement therapy. 
If intravenous (IV) iron is used to replete iron stores, the last dose of IV iron must be 
administered at least 4 weeks prior to rescreening. 
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). 


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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:  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.  In addition, 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. 
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 will discontinue study medication for any of the following conditions: 
• Completion of the protocol-defined dosing period (see Appendix A) 
• Worsening of anemia requiring ESA rescue or blood transfusion 
• Unacceptable toxicity or drug intolerability 
• Investigator discretion 
• Subject withdrawal of consent 
• Subject becomes pregnant 
• 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 discontinuing study medication or withdrawing from the study 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 Appendix A).  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. 


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Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
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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. 
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 according to 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.  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 from each subject the study drug bottle 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. 


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Protocol No. AKB-6548-CI-0021 
Vadadustat 
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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. 
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 at all times. 
Proper drug accountability includes, but is not limited to: 
• 
Continuously monitoring expiration dates, if expiry date or retest date is provided to the 
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 
immediately. 
During the study, the investigator will be notified of any expiry dates or retest date extensions of 
clinical study material.  If an expiry date notification is received during the study, the 
investigative site must complete all instructions outlined in the notification, including 
segregation of expired clinical study material for return to the sponsor or its designee for 
destruction. 
Prior to investigative site closure and at appropriate intervals during the study, a representative 
from the sponsor will perform clinical study material accountability and reconciliation. 
At the end of the study, the investigator will retain all original documentation regarding clinical 
study material accountability, return, and/or destruction, and copies will be sent to the sponsor 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 according to local 
procedures. 


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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 other oral 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 exception of the Week 4 visit.  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. 
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 (Section 11.1). Sponsor and CRO study team personnel involved in 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. 
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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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.  The applicable standard operating procedure will be followed for 
blind-breaking procedures.   
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, 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.   
 
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. 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. 
 
8.2.5 Study Drug Administration during the Dose Adjustment and Maintenance Period 
(Week 7 to Week 16) 
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 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 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 at Week 6 and the subject remains below the Hb 
target, the next opportunity to further increase the dose would be Week 10.  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. 


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• 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 rises 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).  In cases of extenuating clinical circumstances, investigators may elect to 
dose outside the dosing guidelines to maintain the Hb within the target range. 
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. 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). 
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: 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. 


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8.2.7 Oral Iron Supplementation (Information on Allowed Use) 
Subjects who are receiving a stable dose of oral iron supplementation for at least 28 days prior to 
the screening period should continue their oral iron supplementation at the same dose through the 
primary efficacy period (through Week 6).  Changes to oral 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 adjust oral iron 
supplementation as needed for subjects with ferritin <100 ng/mL and TSAT is <20%, and the 
iron dose will be selected at the investigator’s discretion. 
Subjects who are not receiving oral iron supplementation at the beginning of the screening period 
should not start oral iron supplementation through the primary efficacy period (through Week 6) 
(see Section 8.4.3). Initiation of oral 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 oral iron supplementation 
for subjects with ferritin is <100 ng/mL and TSAT is <20%, and the iron dose 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. 
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. 
Subjects should be questioned regarding dosing compliance and the information should be 
recorded. 
8.2.9 Treatment Compliance 
Subjects will be questioned regarding dosing compliance at all study visits 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. 
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 through the course of 
study participation should be recorded on the appropriate case report form. 


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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, Intravenous Iron, and Blood Transfusion 
Subjects may not receive any ESA treatment within 6 weeks prior to the screening period and 
through the follow-up period (eg, recombinant human erythropoietin, darbepoetin alfa, or 
methoxy polyethylene glycol-epoetin beta).  See Section 8.2.6 for the rescue therapy guidelines. 
Subjects may not receive intravenous iron or blood transfusion within 4 weeks prior to the 
screening period and through the follow-up period.  Use of intravenous iron supplementation 
after Day 1 will be considered a protocol deviation but will not be considered a reason for 
subject discontinuation. 
ESAs and RBC transfusions are allowed as rescue therapies, please refer to Section 8.2.6 for the 
rescue therapy guidelines.  Note that subjects who initiate rescue therapy will be required to stop 
study drug treatment and will be discontinued from the study. 
8.4.3 Oral 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 oral iron supplementation through 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 
As presented in Appendix A, this study includes the following visits: 
• 
Eligibility screening period (Day -28 to Day -4) 
• 
Primary efficacy period (from Day 1 to the Week 6 visit) 
- Baseline visit (Day 1) 
- Week 2 ± 1 day 
- Week 4 ± 3 days 
- Week 6 ± 3 days 
• 
Dose adjustment and maintenance period (after the Week 6 visit to the Week 16 visit) 
- Week 8 visit ± 3 days 
- Week 10 visit ± 3 days 


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- Week 12 visit ± 3 days 
- Week 14 ± 3 days 
- Week 16 ± 3 days 
• 
Follow-up period (after the Week 16 visit to the Week 18 visit) 
- Week 18 ± 3 days 
The following sections describe the procedures to be completed during the study.  Subjects are to 
be assessed by the same investigator or site personnel whenever possible. 
9.1 Administrative Procedures 
9.1.1 Informed Consent Procedure 
Informed consent must be obtained and legally signed prior to a subject entering into the study 
and before any protocol-directed procedures (including screening tests) are performed (see 
Section 15.3). 
9.1.2 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. 
9.1.3 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 9.1.3.1. 
9.1.3.1 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. 


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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) and at baseline (assessed using urine pregnancy test). 
• 
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 
9.2 Study Procedures and Evaluations 
9.2.1 Clinical Evaluations 
The following clinical evaluations will be conducted during the course of the study.  Detailed 
information regarding the timing of the assessments is presented in Section 9.3 and summarized 
in Appendix A: 
• Demographics and medical history: Relevant medical history (with particular emphasis 
on previous medical conditions that may lead to exclusion) and significant ongoing 
medical conditions or diseases should be documented. 
• Physical examination: Physical examination, including height assessments 
• Weight assessment 
• 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 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 


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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. 
• 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. 
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. 
9.2.2 Laboratory Evaluations 
Samples for laboratory assays will be sent to a central laboratory for analysis, with the exception 
of the urine pregnancy test at baseline which will be performed locally.  Detailed instructions for 
the collection, processing, and shipment of laboratory samples will be provided by the sponsor 
and the central laboratory.  The investigator is responsible for reviewing laboratory results for 
clinical significance. 
The following laboratory evaluations will be conducted during the course of the study: 
• Serum and urine 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) and urine pregnancy tests (to be analyzed by the local 
lab).  The screening and baseline pregnancy test results must be available and must be 
negative for a subject to initiate or continue study drug. 
• Coagulation tests: Blood sample will be collected to assess the prothrombin time (PT), 
partial thromboplastin time (PTT), and international normalized ratio (INR). 
• Folate and vitamin B12: Blood sample will be collected to assess folate and Vitamin B12 
levels. 
• 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). 
For subjects with Hb>13.0 g/dL at the follow-up visit, CBC will be assessed every 2 
weeks until the Hb<13.0 g/dL. 


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• Chemistry and eGFR: 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.  eGFR will be calculated from serum 
creatinine as described in Appendix B.  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. 
9.3 Schedule of Activities 
The Schedule of Events in Appendix A shows the timing of planned study procedures.  Every 
effort should be made to adhere to this procedure schedule and all assessments should be 
completed at each study visit. 
9.3.1 Screening Visit 
The screening visit must be performed within 28 days prior to dosing and there must be a 
minimum of 4 days between the last qualifying repeat measurement and the baseline visit 
(Day 1). 
After obtaining informed consent and receiving a unique subject identification number, subjects 
will undergo a number of screening activities.  The investigator will maintain a log of subjects 
and indicate who was enrolled or excluded and the reason for exclusion (see Section 9.1.2). 
At the screening visit, the following activities/procedures will be performed: 
• Review of study inclusion and exclusion criteria 
• Demographics, medical history, and physical examination 
• Weight assessment 
• Vital signs (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 


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• Prior and current medication use 
• 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 Folate and vitamin B12 levels 
o CBC 
o Chemistry and eGFR 
o Iron indices 
9.3.2 Baseline Visit (Day 1) 
There must be a minimum of 4 days between the screening and baseline visits. 
At the baseline visit, the following activities/procedures will be performed: 
• Review of study inclusion and exclusion criteria 
• Vital signs (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
• 12-lead ECG (prior to blood draws when possible and obtained after the subject has been 
resting supine comfortably for approximately 10 minutes) 
• Recording of any concomitant medication use since screening visit 
• Laboratory procedures: 
o Urine pregnancy test for females of childbearing potential (eligible subjects will 
be advised to use an adequate contraceptive method).  The urine sample will be 
analyzed by the local lab.  The baseline results must be available and must be 
negative before the subject takes the first dose of study drug. 
o Coagulation tests (including prothrombin time, partial thromboplastin time, and 
international normalized ratio) 
o CBC 
o Chemistry and eGFR 
o Iron indices 
o Hepcidin 
o C-reactive protein 
o VEGF 
• Dispense one bottle of study drug 
• Review dosing instructions 
9.3.3 Week 2 Visit 
At the Week 2 visit, 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) 
• AE review 
• Concomitant medication review 
• Laboratory procedures: 
o CBC 


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o Chemistry and eGFR 
o Iron indices 
• 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 obtained from this visit demonstrates excess Hb response, contact 
subject for dose reduction (Section 8.2.4) 
9.3.4 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 (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
• AE review 
• Concomitant medication review 
• Laboratory procedures: 
o CBC 
o Chemistry and eGFR 
o Iron indices 
o Pre-dose PK sample 
• Record date and time of the last dose of the study that was taken prior to the pre-dose PK 
sample 
• 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 
• If central lab Hb result obtained from this visit demonstrates excess Hb response, contact 
subject for dose reduction (Section 8.2.4) 
9.3.5 Week 6 Visit 
At the Week 6 visit, 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) 
• AE review 
• Concomitant medication review 
• Laboratory procedures: 
o CBC 
o Chemistry and eGFR 
o Iron indices 


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o Hepcidin 
o C-reactive protein 
o VEGF 
• Collect study bottle and all remaining study drug tablets remaining from the primary 
efficacy period 
• Dispense one bottle of vadadustat 
• 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) 
9.3.6 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) 
• AE review 
• Concomitant medication review 
• Laboratory procedures: 
o CBC 
o Chemistry and eGFR 
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) 
9.3.7 Week 16 Visit (end-of-treatment visit for subjects who complete the dose adjustment and 
maintenance period or for subjects who withdraw prematurely from the study prior to 
Week 16) 
All subjects should complete the Week 16 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 9.3.8). 
At the Week 16 visit, 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) 
• AE review (see Section 10.3.6 for follow-up of unresolved events) 
• Concomitant medication review 
• Laboratory procedures: 


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o Serum pregnancy test for females of childbearing potential (to be analyzed by the 
central lab) 
o CBC 
o Chemistry and eGFR 
o Iron indices 
o Hepcidin 
o C-reactive protein 
o VEGF 
• Subjects should be questioned regarding dosing compliance 
9.3.8  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, 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 (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
• AE review (see Section 10.3.6 for follow-up of unresolved events) 
• Concomitant medication review 
• Laboratory procedures: 
o CBC 
o Chemistry and eGFR 
• 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. 
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. 


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• Illnesses apparently unrelated to study drug, including the worsening of a pre-existing 
illness (see paragraph below on Pre-existing Conditions). 
• Injury or accidents.  Note that if a medical condition is known to have caused the injury 
or accident (eg, a fall secondary to dizziness), the medical condition (dizziness) and the 
accident (fall) should be reported as 2 separate AEs. 
• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test). 
• Laboratory abnormalities that require clinical intervention or further investigation 
(beyond ordering a repeat [confirmatory] test) unless they are associated with an already 
reported clinical event.  Laboratory abnormalities associated with a clinical event 
reported as an AE (eg, elevated liver enzymes in a subject with jaundice) should be 
described under ‘Comments’ on the report of the clinical event rather than reported as 
separate AEs. 
The following guidelines are to be used when reporting AEs for this study: 
Medical Diagnoses – Whenever possible, a medical diagnosis term should be used to report AEs 
instead of signs and symptoms due to a common etiology, as determined by qualified medical 
study staff.  For example, pneumonia should be the reported AE term, instead of fever, dyspnea, 
etc., when the diagnosis has been established.  Signs and symptoms should be reported as event 
terms only when the medical diagnosis remains unknown, and revised to a medical diagnosis 
term once it has been established. 
Procedures – Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as AEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE.  For example, an acute 
appendicitis that begins during the AE reporting period should be reported as the AE and the 
resulting appendectomy noted under “Comments.” 
Pre-planned therapeutic procedures not associated with a new medical condition or worsening 
pre-existing condition should not be reported as AEs. 
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 


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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). 
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. 
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. 


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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. 
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 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. 
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, or the investigator should call the CRO SAE 
hotline within 24 hours of being made aware of the pregnancy (reference the site manual for 
contact information). 
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. 
• 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 
11.1 Primary Endpoint and Sample Size Determination 
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 NDD-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 EOT visit minus the mean pre-treatment Hb.  
Pre-treatment Hb is defined as the average of 2 Hb values obtained prior to treatment based on 
the qualifying screening Hb value and the Hb value at the baseline visit.  Linear regression 
analysis will be used to calculate the relationship between vadadustat dose and change in Hb. 
The target enrollment will be approximately 48 subjects for the study with 12 subjects enrolled 
in each of the 4 treatment groups. 
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 reasonable to assume 
that 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® 
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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. 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. 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. 
11.2 Study Populations 
11.2.1 Analysis Population 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. 
11.2.2 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 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.   
As sensitivity analyses, efficacy endpoints will also be analyzed using the PP population. 
11.3 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. 
11.4 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. 
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) 


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• Actual values and change (absolute and percent) from baseline in iron, TIBC, TSAT, 
ferritin (both absolute and percent), and hepcidin 
For purposes of analysis, a pre-treatment average (defined as the average of 2 samples obtained 
prior to treatment [ie, the qualifying screening value and baseline value]) will be used as the 
baseline value for Hb, and last observation before the first dose of study medication will be used 
as baseline for other parameters. 
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 assess 
the vadadustat dose-response relationship.  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. 
11.6 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, components of the CBC, and VEGF. 
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. 
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. 
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. 


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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 
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. 


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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 
assessments. 
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. 


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15 ETHICS 
15.1 Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical Principles 
for Medical Research Involving Human Subjects, adopted by the General Assembly of the World 
Medical Association (2013). 
In addition, the study will be conducted in accordance with the protocol, the ICH 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 
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 course of 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. 


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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 
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. 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
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Original Protocol (Version 3) 
 
 
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05 August 2016 Page 58 
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 
2007S4-9. 
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. 
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. 
Matsuo S, Imai E, Horio M, et al.  Revised equations for estimated GFR from serum creatinine 
in Japan.  Am J Kidney Dis 2009;53:982-92. 
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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Protocol No. AKB-6548-CI-0021 
Vadadustat 
Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 59 
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. 
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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05 August 2016 Page 60 
Appendix A: Schedule of Activities 
Please refer to Section 9.2 for detailed information regarding the study procedures and evaluations, and please refer to Section 9.3 for 
detailed information regarding the activities to be performed at each study visit. 
 
Screening 
Primary efficacy period  
(Day 1-Week 6) 
Dose adjustment and maintenance period 
(Week 7-16) 
Follow-up 
(Week 17-18 
Study Week 
-4 to 0 
Base 
line 
2 
4 
6 
8 
10 
12 
14 
16 (EOT) 
18 
Study Day 
-28 to -4 
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 
 
 
 
 
 
 
 
 
 
 
Demographics, medical 
history, physical exam, and 
weight 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram 
 
X 
 
 
 
 
 
 
 
 
 
Adverse event review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
 
X 
 
Urine pregnancy test 
 
X 
 
 
 
 
 
 
 
 
 
Coagulation tests 
 
X 
 
 
 
 
 
 
 
 
 
Folate and vitamin B12 
X 
 
 
 
 
 
 
 
 
 
 
Complete blood count, 
including Hb [a] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry and eGFR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
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Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 61 
 
Screening 
Primary efficacy period  
(Day 1-Week 6) 
Dose adjustment and maintenance period 
(Week 7-16) 
Follow-up 
(Week 17-18 
Study Week 
-4 to 0 
Base 
line 
2 
4 
6 
8 
10 
12 
14 
16 (EOT) 
18 
Study Day 
-28 to -4 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
Visit Window (Days) 
 
 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Iron indices 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Hepcidin 
 
X 
 
 
X 
 
 
 
 
X 
 
C-reactive protein 
 
X 
 
 
X 
 
 
 
 
X 
 
VEGF  
 
X 
 
 
X 
 
 
 
 
X 
 
PK pre-dose sample (study 
drug to be administered after 
sample collection) 
 
 
 
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 
 
Based on Hb results from the 
visits noted, dose reduction 
for excess Hb response as 
needed according to 
guidelines (Section 8.2.4) 
 
 
X 
X 
 
 
 
 
 
 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
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Original Protocol (Version 3) 
 
 
Confidential 
05 August 2016 Page 62 
 
Screening 
Primary efficacy period  
(Day 1-Week 6) 
Dose adjustment and maintenance period 
(Week 7-16) 
Follow-up 
(Week 17-18 
Study Week 
-4 to 0 
Base 
line 
2 
4 
6 
8 
10 
12 
14 
16 (EOT) 
18 
Study Day 
-28 to -4 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
Visit Window (Days) 
 
 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Based on Hb results from the 
visits noted, dose adjustment 
to achieve target Hb 10.0-12.0 
g/dL as needed according to 
guidelines (Section 8.2.5) 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Abbreviations: eGFR, estimated glomerular filtration rate; EOT, end of treatment; Hb, hemoglobin; PK, pharmacokinetics; VEGF, vascular endothelial growth 
factor 
[a] 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. 
 
 
 
 


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Protocol No. AKB-6548-CI-0021 
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Original Protocol (Version 3) 
 
 
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Appendix B: Japanese Society of Nephrology 2009 Equation to Calculate eGFR 
The estimated glomerular filtration rate (eGFR) will be calculated from serum creatinine using 
the 2009 Japanese Society of Nephrology Equation (3-variables; Matsuo 2009).   
eGFR (mL/min/1.73 m2) = 194 x (Scr in mg/dL)-1.094 x (Age)-0.287 x (0.739 if female) 


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Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
Confidential 
Page 2 
1 
SIGNATURE PAGES 
1.1 
Protocol Approval 
 
 
 
Akebia Therapeutics, Inc. 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
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Page 3 
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 also protect the 
rights, safety, privacy, and well-being of study subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonization Guidance for Industry, Good Clinical 
Practice E6. 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting serious adverse events defined in this protocol. 
• Terms outlined in the Clinical Study Site Agreement. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Phone Number 
Full Address 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
Confidential 
Page 4 
TABLE OF CONTENTS 
1 
SIGNATURE PAGES .................................................................................................. 2 
1.1 
Protocol Approval .................................................................................................... 2 
1.2 
Investigator Agreement ............................................................................................ 3 
TABLE OF CONTENTS ......................................................................................................... 4 
LIST OF TABLES ................................................................................................................... 7 
LIST OF FIGURES ................................................................................................................. 7 
2 
PROTOCOL SYNOPSIS .............................................................................................. 8 
3 
LIST OF ABBREVIATIONS ..................................................................................... 14 
4 
BACKGROUND ........................................................................................................ 16 
4.1 
Proposed Indication of Renal Anemia ................................................................... 16 
4.2 
Available Therapies for Anemia in Patients with CKD ......................................... 17 
4.3 
Hypoxia-Inducible Factor ...................................................................................... 17 
4.4 
Description and Mechanism of Action of Vadadustat ........................................... 18 
4.5 
Summary of Clinical Experience ........................................................................... 19 
4.6 
Ethno-Bridging Data from a Study of Healthy Japanese and Caucasian Volunteers
 ................................................................................................................................ 20 
4.7 
Potential Benefits and Risks ................................................................................... 22 
5 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 22 
5.1 
Primary Objective and Endpoint ............................................................................ 22 
5.2 
Secondary Objectives and Endpoints ..................................................................... 22 
6 
STUDY DESIGN ........................................................................................................ 24 
6.1 
Study Design .......................................................................................................... 24 
6.2 
Study Duration ....................................................................................................... 25 
6.3 
Rationale for Study Design .................................................................................... 25 
6.4 
Dose Justification ................................................................................................... 26 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 26 
7.1 
General Criteria ...................................................................................................... 26 
7.2 
Inclusion Criteria .................................................................................................... 27 
7.3 
Exclusion Criteria ................................................................................................... 27 
7.4 
Retesting and Rescreening ..................................................................................... 29 
7.4.1 
Retesting ............................................................................................................ 29 
7.4.2 
Rescreening ....................................................................................................... 29 
7.5 
Study Completion, Study Termination, and Individual Study Site Termination ... 30 
7.5.1 
Study Completion .............................................................................................. 30 
7.5.2 
Study Termination ............................................................................................. 30 
7.5.3 
Individual Study Site Termination .................................................................... 30 
7.6 
Subject Completion and Individual Subject Discontinuation ................................ 30 


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7.6.1 
Subject Completion ........................................................................................... 30 
7.6.2 
Conditions and Documentation of Individual Subject Study Drug 
Discontinuation .................................................................................................. 30 
7.6.3 
Individual Subject Discontinuation ................................................................... 30 
8 
STUDY DRUGS AND TREATMENT OF SUBJECTS ............................................ 31 
8.1 
Study Drugs ............................................................................................................ 31 
8.1.1 
Formulation ....................................................................................................... 31 
8.1.2 
Storage and Accountability ............................................................................... 31 
8.1.3 
Dispensing of Study Drugs ................................................................................ 31 
8.1.4 
Product Accountability and Destruction ........................................................... 32 
8.2 
Treatment of Subjects ............................................................................................. 33 
8.2.1 
Dosing Instructions ............................................................................................ 33 
8.2.2 
Randomization ................................................................................................... 33 
8.2.3 
Blinding During the Study and Breaking the Blind .......................................... 33 
8.2.4 
Study Drug Administration during the Primary Efficacy Period (Week 1 to 
Week 6) ............................................................................................................. 34 
8.2.5 
Study Drug Administration during the Dose Adjustment and Maintenance 
Period (Week 7 to Week 16) ............................................................................. 34 
8.2.6 
Rescue Therapy Guidelines ............................................................................... 35 
8.2.7 
Oral Iron Supplementation (Information on Allowed Use) .............................. 36 
8.2.8 
Late or Missed Doses ........................................................................................ 36 
8.2.9 
Treatment Compliance ...................................................................................... 36 
8.2.10 
Continuation of Treatment ................................................................................ 37 
8.3 
Prior and Concomitant Therapy ............................................................................. 37 
8.4 
Prohibited Treatments ............................................................................................ 37 
8.4.1 
Investigational Medications ............................................................................... 37 
8.4.2 
ESAs, Intravenous Iron, and Blood Transfusion ............................................... 37 
8.4.3 
Oral Iron Supplementation (Information on Prohibition) ................................. 37 
9 
STUDY PROCEDURES AND SCHEDULE OF ACTIVITIES ................................ 37 
9.1 
Schedule of Activities ............................................................................................ 37 
9.2 
Administrative Procedures ..................................................................................... 38 
9.2.1 
Informed Consent Procedure ............................................................................. 38 
9.2.2 
Documentation of Screen Failures .................................................................... 38 
9.2.3 
Review of Inclusion and Exclusion Criteria ...................................................... 38 
9.2.3.1 
Acceptable Methods of Contraception ......................................................... 38 
9.3 
Study Procedures and Evaluations ......................................................................... 39 
9.3.1 
Clinical Evaluations ........................................................................................... 39 
9.3.2 
Laboratory Evaluations ..................................................................................... 40 
9.4 
Schedule of Activities ............................................................................................ 41 


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9.4.1 
Screening Visit .................................................................................................. 41 
9.4.2 
Baseline Visit (Day 1) ....................................................................................... 42 
9.4.3 
Week 2 Visit ...................................................................................................... 43 
9.4.4 
Week 4 Visit ...................................................................................................... 43 
9.4.5 
Week 6 Visit ...................................................................................................... 44 
9.4.6 
Week 8, 10, 12, 14 Visits .................................................................................. 44 
9.4.7 
Week 16 Visit (end-of-treatment visit for subjects who complete the dose 
adjustment and maintenance period or for subjects who withdraw prematurely 
from the study prior to Week 16) ...................................................................... 45 
9.4.8 
Week 18 Follow-Up Visit (or 2 weeks after end-of-treatment follow-up visit) 45 
10 
ADVERSE EVENTS .................................................................................................. 46 
10.1 
Definitions .............................................................................................................. 46 
10.1.1 
Adverse Events (AEs) ....................................................................................... 46 
10.1.2 
Serious Adverse Events (SAEs) ........................................................................ 49 
10.2 
Eliciting Adverse Event Information ..................................................................... 49 
10.3 
Reporting ................................................................................................................ 49 
10.3.1 
Reporting Period ................................................................................................ 50 
10.3.2 
Reporting AEs ................................................................................................... 50 
10.3.3 
Reporting SAEs ................................................................................................. 50 
10.3.4 
Relationship to Study Medication ..................................................................... 51 
10.3.5 
Severity .............................................................................................................. 51 
10.3.6 
Follow-Up of Unresolved Events ...................................................................... 51 
10.3.7 
Special Situations .............................................................................................. 52 
10.4 
Exposure In Utero .................................................................................................. 52 
11 
DATA ANALYSIS ..................................................................................................... 53 
11.1 
Primary Endpoint – Mean Change in Hb from Pre-treatment to the End of the 
Primary Efficacy Period (Week 6) ......................................................................... 53 
11.2 
Primary Efficacy Analysis and Sample Size Determination .................................. 53 
11.3 
Preliminary (6-Week) Analysis .............................................................................. 54 
11.4 
Study Populations ................................................................................................... 54 
11.4.1 
Analysis Population for the Safety Analyses .................................................... 54 
11.4.2 
Analysis Populations for the Efficacy Analyses ............................................... 54 
11.5 
Analysis of Demographics and Pretreatment Variables ......................................... 54 
11.6 
Disposition of Subjects ........................................................................................... 55 
11.7 
Safety Analyses ...................................................................................................... 55 
12 
DATA HANDLING AND RECORD KEEPING ...................................................... 55 
12.1 
Case Report Forms (CRFs) .................................................................................... 55 
12.2 
Record Retention .................................................................................................... 55 
13 
QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) ....................... 56 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
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Protocol Version 4 
 
 
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13.1 
Study Site Monitoring Visits .................................................................................. 56 
13.2 
Protocol Deviations ................................................................................................ 56 
14 
STUDY DISCONTINUATION/INVESTIGATIVE STUDY SITE TERMINATION
 ..................................................................................................................................... 56 
14.1 
Criteria for Premature Termination or Suspension of the Study ............................ 57 
14.2 
Criteria for Premature Termination or Suspension of Investigational Sites .......... 57 
14.3 
Procedures for Premature Termination or Suspension of the Study or 
Investigational Site(s) ............................................................................................. 57 
15 
ETHICS ....................................................................................................................... 57 
15.1 
Ethical Conduct of the Study ................................................................................. 57 
15.2 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) ........... 57 
15.3 
Subject Information and Consent ........................................................................... 58 
15.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP .... 58 
15.5 
Subject Confidentiality ........................................................................................... 58 
16 
PUBLICATION OF STUDY RESULTS ................................................................... 59 
17 
REFERENCES ............................................................................................................ 60 
 
LIST OF TABLES 
Table 1: 
Identity of Study Drugs ........................................................................................31 
 
LIST OF FIGURES 
Figure 1 
Mechanism of Action of Vadadustat ....................................................................18 
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) .......21 
Figure 3: 
Overview of Study Design ....................................................................................24 
Figure 4: 
Absolute Change in Hemoglobin (± Standard Error of Mean, g/dL) at Week 6 
Compared to Baseline (Study AKB-6548-CI-0005) ..........................................26 
Figure 5: 
Randomization Scheme of Study Treatment ........................................................33 
 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
Confidential 
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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 Non-Dialysis 
Dependent Chronic Kidney Disease 
Protocol Number 
AKB-6548-CI-0021 
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 non-dialysis dependent chronic kidney disease 
(NDD-CKD) who are not currently being treated with an erythropoiesis-stimulating 
agent (ESA) 
Investigative Sites 
Approximately 25 sites in Japan 
Planned Number of 
Subjects 
Approximately 48 subjects will be enrolled in the study, with 36 subjects receiving 
one of the 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 (QD) dosing for 6 weeks and the change in hemoglobin 
(Hb) in Japanese subjects with anemia secondary to NDD-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 QD dosing in Japanese subjects 
with anemia secondary to NDD-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  
Study Design Overview 
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 NDD-CKD. 
The study will include the following periods: 
• Eligibility screening period (up to 4 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). 
Following the screening period, eligible subjects will be randomized to receive 
blinded study drug treatment during a 6-week primary efficacy period, with subjects 
randomized at a 3:1 ratio to receive vadadustat (150, 300, or 600 mg vadadustat) or 
placebo.  See “Dosage and Regimen” in the synopsis for additional information 
regarding the randomization scheme. 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
Confidential 
Page 9 
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 
13.0 g/dL, the study drug dose can be decreased or interrupted (see “Dosage and 
Regimen” for additional information). 
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 
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). 
Note:  Subjects who discontinue prematurely from the study or permanently 
discontinue study drug 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) 
• Diagnosis of CKD based on an estimated glomerular filtration rate (eGFR) of 
≤60 mL/min/1.73 m2 (using the 2009 Japanese Society of Nephrology 
equation; Matsuo 2009) 
• Not currently being treated with dialysis and not expected to start dialysis 
within 3 months of screening 
• Hb ≤10.5 g/dL 
• Serum ferritin ≥50 ng/mL 
• Transferrin saturation (TSAT) ≥20% 
• Folate and vitamin B12 ≥ lower limit of normal 
• For subjects who are receiving oral iron supplementation, the dose of oral iron 
supplementation must be stable for at least 28 days prior to the screening 
period.  For subjects who are not receiving oral iron supplementation, no iron 
supplementation may have been ingested for at least 28 days prior to the 
screening 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; intravenous iron within 4 weeks prior to or during screening; and any 
ESA use within 6 weeks prior to or during screening. 
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 or eGFR 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). 


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Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
Confidential 
Page 10 
Efficacy and 
Pharmacokinetic 
Endpoints 
Note that a pre-treatment value for Hb is defined as the average of 2 values obtained 
prior to treatment, ie, the qualifying screening value 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 10.0-12.0 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, 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) 
• Maintenance of iron sufficiency (defined as ferritin ≥50 ng/mL and TSAT 
≥20%) from baseline to the end of the primary efficacy period (Week 6) and 
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 
Safety Endpoints 
Safety and tolerability 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. 
 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
Confidential 
Page 11 
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 at Week 6 
and the subject remains below the Hb target, the next opportunity to further 
increase the dose would be Week 10.  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.   
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-0021 
Vadadustat 
Protocol Version 4 
 
 
Confidential 
Page 12 
• 
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).  In cases of extenuating clinical 
circumstances, investigators may elect to dose outside the dosing guidelines to 
maintain the Hb within the target range. 
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 
To standardize the use of ESA rescue therapy 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 2 criteria listed above 
are met. 
 RBC Transfusion 
Investigators should use their local institution’s transfusion guidelines when 
determining whether to transfuse a study subject. 
Subjects who initiate rescue therapy (ESA rescue therapy or RBC transfusion), will 
be required to stop study drug treatment and will be discontinued from the study (see 
“Study Duration”). 
Oral Iron 
Supplementation 
Subjects who are receiving a stable dose of oral iron supplementation for at least 
28 days prior to the screening period should continue their oral iron supplementation 
at the same dose through the primary efficacy period (through Week 6).  Changes to 
oral 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 adjust oral iron supplementation as 
needed for subjects with ferritin <100 ng/mL and TSAT <20%, and the iron dose 
will be selected at the investigator’s discretion. 
Subjects who are not receiving oral iron supplementation at the beginning of the 
screening period should not start oral iron supplementation through the primary 
efficacy period (through Week 6).  Initiation of oral iron supplementation during the 
primary efficacy period will be considered a protocol deviation but will not be 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
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considered a reason for subject discontinuation.  After the Week 6 visit, 
investigators should prescribe oral iron supplementation for subjects with ferritin 
<100 ng/mL and TSAT <20%, and the iron dose 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.  Therefore, no multiplicity adjustment will be needed 
for this analysis. 
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), 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. 
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 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 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. 
 


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Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
Confidential 
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3 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
BUN 
blood urea nitrogen 
C 
Celsius 
CBC 
complete blood count 
CKD 
chronic kidney disease 
CRF 
case report form 
CRO 
contract research organization 
CV 
cardiovascular 
dL 
deciliter 
DVT 
deep venous thrombosis 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
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 
GFR 
glomerular filtration rate 
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 
IV 
intravenous 


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Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
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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) 
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 
 


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Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
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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-0021 
Vadadustat 
Protocol Version 4 
 
 
Confidential 
Page 17 
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


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4.3% of patients on 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. 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
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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 
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.  


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Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
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4.7 
Potential Benefits and Risks 
Please see the vadadustat Investigator’s Brochure for additional discussion and information for 
the following section. 
Vadadustat offers the potential of flexible oral dosing that is easier to adjust than injectable 
hormone ESAs.  This alternate therapeutic approach may avoid the excursions and fluctuations 
in Hb levels seen with currently available injectable ESAs and provide for a controlled, steady 
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 Hb 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 HIFPH 
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 value for Hb is defined as the average of 2 values obtained prior to 
treatment, ie, the qualifying screening value 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 Hb in Japanese subjects with anemia 
secondary to NDD-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 
NDD-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 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
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• To assess the time to reach the target Hb range from baseline 
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) 
• 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) 
• Maintenance of iron sufficiency (defined as ferritin ≥50 ng/mL and TSAT ≥20%) from 
baseline to the end of the primary efficacy period (Week 6) and 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]) 


Akebia Therapeutics, Inc. 
Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
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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 subjects 
with anemia secondary to NDD-CKD. 
The study has a planned enrollment of 48 subjects to be enrolled at approximately 25 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. 
Figure 3: 
Overview of Study Design 
 
 
 
The study will include the following periods: 
• Eligibility screening period (up to 4 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) 
Subjects will participate in a screening period (4 days to 4 weeks) to determine study eligibility, 
and eligible subjects will be randomized following the screening period. 


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Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
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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 level exceeds 13.0 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). 
The clinical and safety assessments will be performed as described in Section 9.4 and as listed in 
Appendix A. 
6.2 
Study Duration 
Individual subjects will participate in the study for 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). 
Note:  Subjects who discontinue prematurely from the study or permanently discontinue study 
drug will complete the end-of-treatment (Week 16) visit followed in two weeks by the Week 18 
visit (see Section 7.6.3). 
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 NDD-CKD is modeled on a previously completed 
dose-finding study in subjects with anemia secondary to NDD-CKD that included mostly 
Caucasian and Black/African American subjects (Study AKB-6548-CI-0005). 
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. 


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Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
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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 according to 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. 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
General Criteria 
The study population will consist of male and female Japanese adults aged 20 years or older with 
anemia secondary to NDD-CKD who are not currently being treated with an ESA. 
-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-0021 
Vadadustat 
Protocol Version 4 
 
 
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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, aged 20 years or older 
2. Diagnosis of CKD based on an estimated glomerular filtration rate (eGFR) of 
≤60 mL/min/1.73 m2 (using the 2009 Japanese Society of Nephrology equation; Matsuo 
2009) 
3. Not currently being treated with dialysis and not expected to start dialysis within 
3 months of screening 
4. Hemoglobin (Hb) ≤10.5 g/dL during screening 
5. Serum ferritin ≥50 ng/mL during screening 
6. TSAT ≥20% during screening 
7. Folate and vitamin B12 greater than or equal to the lower limit of normal during 
screening 
8. For subjects who are receiving oral iron supplementation, the dose of oral iron 
supplementation must be stable for at least 28 days prior to the screening period.  For 
subjects who are not receiving oral iron supplementation, no iron supplementation may 
have been ingested for at least 28 days prior to the screening period. 
9. Understands the procedures and requirements of the study and provides written informed 
consent and authorization for protected health information disclosure 
7.3 
Exclusion Criteria 
Subjects 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. RBC transfusion within 4 weeks prior to or during screening 
4. Intravenous iron within 4 weeks prior to or during screening 


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Protocol No. AKB-6548-CI-0021 
Vadadustat 
Protocol Version 4 
 
 
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5. Any ESA use within 6 weeks prior to or during screening (eg, recombinant human 
erythropoietin, darbepoetin alfa, or methoxy polyethylene glycol-epoetin beta) 
6. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), 
alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total 
bilirubin >2.0 x upper limit of normal during screening.  A history of Gilbert’s syndrome 
is not an exclusion criterion. 
7. Uncontrolled hypertension (confirmed diastolic blood pressure >110 mm Hg or systolic 
blood pressure >180 mm Hg) during screening 
8. Body mass index (BMI) >42.0 kg/m2 
9. Severe heart failure during screening (New York Heart Association Class III or IV) 
10. 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 
11. 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 
12. 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 
13. History of deep vein thrombosis (DVT) or pulmonary embolism (PE) requiring active 
treatment within 8 weeks prior to or during screening 
14. History of hemosiderosis or hemochromatosis 
15. History of prior organ transplantation or scheduled organ transplant (subjects on kidney 
transplant wait-list are not excluded), or prior hematopoietic stem cell or bone marrow 
transplant (corneal transplants and stem cell therapy for knee arthritis are not excluded) 
16. 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 
17. Previous participation in a study with a hypoxia-inducible factor prolyl-hydroxylase 
inhibitor, other than vadadustat, within 90 days prior to screening 
18. Hypersensitivity to vadadustat, or to any of its excipients 


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19. Females who are pregnant or breast-feeding 
20. Females of childbearing potential who are unable or unwilling to use an acceptable 
method of contraception 
21. Non-vasectomized males who are unable or unwilling to use an acceptable method of 
contraception 
22. 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. 
The screening period can last up to 4 weeks long, with a minimum of 4 days between the last 
qualifying repeat measurement and the baseline visit (Day 1), ie, the screening period window is 
from Day -28 to Day -4. 
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. 
For eligibility purposes, if the Hb measured at the screening visit is >10.5 g/dL and <11.0 g/dL, 
Hb level can be retested once at the investigator’s discretion.  The subject should not be retested 
if the Hb level measured at the screening visit is ≥11.0 g/dL. 
Retesting within the screening period does not constitute rescreening; however, if retesting falls 
outside of the screening period, it should be considered a rescreen (see Section 7.4.2).   
7.4.2 Rescreening  
Subjects who fail to meet the qualifying criteria for Hb or eGFR 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. 
If intravenous (IV) iron is used to replete iron stores, the last dose of IV iron must be 
administered at least 4 weeks prior to rescreening. 
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. 


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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:  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 (see Section 7.6.3).   
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 will discontinue study medication for any of the following conditions: 
• Completion of the protocol-defined dosing period (see Appendix A) 
• Worsening of anemia requiring ESA rescue or blood transfusion 
• Unacceptable toxicity or drug intolerability 
• Investigator discretion 
• Subject withdrawal of consent 
• Subject becomes pregnant 
• 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 medication or withdrawing early from the study prior 
to the Week 16 visit should complete the Week 16 (end-of-treatment) clinical and laboratory 
assessments within 1 day of stopping study medication, if possible.  Such subjects should also 


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complete the 2-week follow-up period and complete the Week 18 visit assessments (see 
Appendix A).  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. 
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 according to 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. 


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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 
immediately. 
During the study, the investigator will be notified of any expiry dates or retest date extensions of 
clinical study material.  If an expiry date notification is received during the study, the 
investigative site must complete all instructions outlined in the notification, including 
segregation of expired clinical study material for return to the sponsor or its designee for 
destruction. 
Prior to investigative site closure and at appropriate intervals during the study, a representative 
from the sponsor will perform clinical study material accountability and reconciliation. 
At the end of the study, the investigator will retain all original documentation regarding clinical 
study material accountability, return, and/or destruction, and copies will be sent to the sponsor 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 


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by the sponsor’s monitor or designee.  Empty containers may be disposed of according to 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. 
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. 
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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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 
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 Week 16) 
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 at Week 6 and the subject remains below the Hb 
target, the next opportunity to further increase the dose would be Week 10.  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). 


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• 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 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 “Rescue Therapy Guidelines” below; Section 8.2.6). 
8.2.6 Rescue Therapy Guidelines 
• ESA Rescue Therapy 
To standardize the use of ESA rescue therapy 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 2 criteria listed above are met. 
• RBC Transfusion 
Investigators should use their local institution’s transfusion guidelines when determining 
whether to transfuse a study subject. 


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Subjects who initiate rescue therapy (either ESA rescue therapy or RBC transfusion) will be 
required to stop study drug treatment and will be discontinued from the study (see Section 7.6.3). 
8.2.7 Oral Iron Supplementation (Information on Allowed Use) 
Subjects who are receiving a stable dose of oral iron supplementation for at least 28 days prior to 
the screening period should continue their oral iron supplementation at the same dose through the 
primary efficacy period (through Week 6).  Changes to oral 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 adjust oral iron 
supplementation as needed for subjects with ferritin <100 ng/mL and TSAT is <20%, and the 
iron dose will be selected at the investigator’s discretion. 
Subjects who are not receiving oral iron supplementation at the beginning of the screening period 
should not start oral iron supplementation through the primary efficacy period (through Week 6) 
(see Section 8.4.3).  Initiation of oral 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 oral iron supplementation 
for subjects with ferritin is <100 ng/mL and TSAT is <20%, and the iron dose 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. 
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. 
Subjects should be questioned regarding dosing compliance and the information should be 
recorded. 
8.2.9 Treatment Compliance 
Subjects will be questioned regarding dosing compliance and whether they have questions or 
have experienced any problems related to 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 questioning of the subject. 
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. 


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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, Intravenous Iron, and Blood Transfusion 
Subjects may not receive any ESA treatment within 6 weeks prior to the screening period and 
through the follow-up period (eg, recombinant human erythropoietin, darbepoetin alfa, or 
methoxy polyethylene glycol-epoetin beta).  See Section 8.2.6 for the rescue therapy guidelines. 
Subjects may not receive intravenous iron or blood transfusion within 4 weeks prior to the 
screening period and through the follow-up period.  Use of intravenous iron supplementation 
after Day 1 will be considered a protocol deviation but will not be considered a reason for 
subject discontinuation. 
ESAs and RBC transfusions are allowed as rescue therapies, please refer to Section 8.2.6 for the 
rescue therapy guidelines.  Note that 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). 
8.4.3 Oral 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 oral iron supplementation through 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 Activities 
As presented in Appendix A, this study includes the following visits: 
• 
Eligibility screening period (Day -28 to Day -4) 
• 
Primary efficacy period (from Day 1 to the Week 6 visit) 
- Baseline visit (Day 1) 


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- Week 2 ± 1 day 
- Week 4 ± 3 days 
- Week 6 ± 3 days 
• 
Dose adjustment and maintenance period (after the Week 6 visit to the Week 16 visit) 
- Week 8 visit ± 3 days 
- Week 10 visit ± 3 days 
- Week 12 visit ± 3 days 
- Week 14 ± 3 days 
- Week 16 (or end-of-treatment) ± 3 days 
• 
Follow-up period (after the Week 16 visit to the Week 18 visit) 
- Week 18 ± 3 days 
The following sections describe the procedures to be completed during the study.  Subjects are to 
be assessed by the same investigator or site personnel whenever possible. 
9.2 
Administrative Procedures 
9.2.1 Informed Consent Procedure 
Informed consent must be obtained and legally signed prior to a subject entering into 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.   


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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) and at baseline (assessed using urine pregnancy test). 
• 
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.  Detailed information 
regarding the timing of the assessments is presented in Section 9.4 and summarized in 
Appendix A: 
• 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 
• Weight assessment 
• 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 


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taken prior to blood draws when possible.  The subject should consume no more than a 
light meal or 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 the Day 1 visit) and through the follow-up visit, the investigator 
and study site 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. 
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, except for the 
baseline urine pregnancy test which will be analyzed locally.  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 and urine 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) and urine pregnancy tests (to be analyzed by the local 
lab).  The screening and baseline pregnancy test results must be available and must be 
negative for a subject to initiate or continue study drug.  Additional pregnancy tests may 
be conducted during the study to establish the absence of pregnancy based on the 
investigator’s clinical judgment or as required by local regulations. 
• 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. 
• Urine albumin-to-creatinine ratio (uACR):  A random urine spot sample will be collected 
to provide the uACR.  Subjects should refrain from heavy exercise 24 hours before the 
test. 
• 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). 
• Chemistry and eGFR:  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.  eGFR will be calculated from serum 
creatinine as described in Appendix B.  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. 
9.4 
Schedule of Activities 
The Schedule of Events in Appendix A shows the timing of planned study procedures.  Every 
effort should be made to adhere to this procedure schedule and all assessments should be 
completed at each study visit. 
9.4.1 Screening Visit 
The screening visit must be performed within 28 days prior to dosing and there must be a 
minimum of 4 days between the last qualifying repeat measurement and the baseline visit 
(Day 1). 


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After obtaining informed consent and receiving a unique subject identification number, subjects 
will undergo 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 the screening visit, the following activities/procedures will be performed: 
• Signing of informed consent 
• Review of study inclusion and exclusion criteria 
• Demographics, medical history, and physical examination 
• Weight assessment 
• Vital signs (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
• Prior and current medication 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 Folate and vitamin B12 levels 
o CBC 
o Chemistry and eGFR 
o Iron indices 
9.4.2 Baseline Visit (Day 1) 
There must be a minimum of 4 days between the screening and baseline visits. 
At the baseline visit, the following activities/procedures will be performed: 
• Review of study inclusion and exclusion criteria 
• Vital signs (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
• 12-lead ECG (prior to blood draws when possible and obtained after the subject has been 
resting supine comfortably for approximately 10 minutes) 
• AE review 
• Recording of any concomitant medication use since screening visit 
• Laboratory procedures: 
o Urine pregnancy test for females of childbearing potential (eligible subjects will 
be advised to use an adequate contraceptive method).  The urine sample will be 
analyzed by the local lab.  The baseline results must be available and must be 
negative before the subject takes the first dose of study drug. 
o Coagulation tests (including prothrombin time, partial thromboplastin time, and 
international normalized ratio) 
o Urine albumin-to-creatinine ratio (uACR through random urine spot sample) 
o CBC 
o Chemistry and eGFR 
o Iron indices 
o Hepcidin 
o C-reactive protein 


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o VEGF 
• Dispense one bottle of study drug 
• Review dosing instructions 
9.4.3 Week 2 Visit 
At the Week 2 visit, 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) 
• AE review 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Concomitant medication review 
• Laboratory procedures: 
o CBC 
o Chemistry and eGFR 
o Iron indices 
• 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 or interruption 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 obtained from this visit demonstrates excess Hb response, contact 
subject for dose reduction (Section 8.2.4) 
9.4.4 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 (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
• AE review 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Concomitant medication review 
• Laboratory procedures: 
o CBC 
o Chemistry and eGFR 
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) 
• Dispense study drug (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 reduction or interruption if central lab Hb result demonstrates excess Hb 
response 
• If central lab Hb result obtained from this visit demonstrates excess Hb response, contact 
subject for dose reduction (Section 8.2.4) 
9.4.5 Week 6 Visit 
At the Week 6 visit, 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) 
• AE review 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Concomitant medication review 
• Laboratory procedures: 
o CBC 
o Chemistry and eGFR 
o Iron indices 
o Hepcidin 
o C-reactive protein 
o VEGF 
• Collect study bottle and all remaining study drug tablets remaining from the primary 
efficacy period 
• Dispense one bottle of vadadustat 
• Subjects should be questioned regarding dosing compliance 
• Review dosing instructions and remind subjects that they may be contacted by telephone 
to discuss dose adjustment or interruption 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) 
9.4.6 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) 
• AE review 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Concomitant medication review 
• Laboratory procedures: 
o CBC 
o Chemistry and eGFR 
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 


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• 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 16 Visit (end-of-treatment visit for subjects who complete the dose adjustment 
and maintenance period or for subjects who withdraw prematurely from the study 
prior to Week 16) 
All subjects should complete the Week 16 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 9.4.8). 
At the Week 16 visit, 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) 
• AE review (see Section 10.3.6 for follow-up of unresolved events) 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Concomitant medication review 
• Laboratory procedures: 
o Serum pregnancy test for females of childbearing potential (to be analyzed by the 
central lab) 
o CBC 
o Chemistry and eGFR 
o Iron indices 
o Hepcidin 
o C-reactive protein 
o VEGF 
• Subjects should be questioned regarding dosing compliance 
9.4.8  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 (heart rate and blood pressure should be assessed in a seated position after 
5 minutes of rest and prior to blood draws) 
• AE review (see Section 10.3.6 for follow-up of unresolved events) 
• Rescue therapy (ESA rescue and RBC transfusion) review 
• Concomitant medication review 
• Laboratory procedures: 
o CBC 
o Chemistry and eGFR 


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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). 
• Laboratory abnormalities that require clinical intervention or further investigation (beyond 
ordering a repeat [confirmatory] test) unless they are associated with an already reported 
clinical event.  Laboratory abnormalities associated with a clinical event reported as an AE 
(eg, elevated liver enzymes in a subject with jaundice) should be described under 
‘Comments’ on the report of the clinical event rather than reported as separate AEs. 
The following guidelines are to be used when reporting AEs for this study: 
Medical Diagnoses – Whenever possible, a medical diagnosis term should be used to report AEs 
instead of signs and symptoms due to a common etiology, as determined by qualified medical 
study staff.  For example, pneumonia should be the reported AE term, instead of fever, dyspnea, 
etc., when the diagnosis has been established.  Signs and symptoms should be reported as event 
terms only when the medical diagnosis remains unknown, and revised to a medical diagnosis 
term once it has been established. 
Procedures – Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as AEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE.  For example, an acute 
appendicitis that begins during the AE reporting period should be reported as the AE and the 
resulting appendectomy noted under “Comments.” 


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Pre-planned therapeutic procedures not associated with a new medical condition or worsening 
pre-existing condition should not be reported as AEs. 
Pre-existing 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). 
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. 
Renal-Related Events – Some subjects will experience a progression of their CKD during the 
study as part of the natural course of the disease.  In addition, the study population is prone to 
experience acute, transient loss of kidney function of different etiologies, sometimes 
concomitantly complicated by progression of CKD. 


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To ensure consistent reporting of renal events, the following guidelines are to be used when 
reporting a renal-related AE: 
• The following situations should always be reported as SAEs with the respective 
seriousness criteria selected (see Section 10.1.2): 
o Progression of CKD leading to chronic dialysis:  Subjects who undergo transition 
to chronic maintenance dialysis should be reported using the verbatim SAE term 
of “progression to end-stage renal disease” (ESRD) and the additional seriousness 
criterion “chronic dialysis” 
o Any medical event requiring transient acute dialysis:  Subjects who undergo 
transient acute dialysis should be reported using the verbatim SAE term reflecting 
the indication for the dialysis.  Examples of verbatim AE terms include 
hyperkalemia, volume overload, acute kidney injury, and uremia.  The additional 
seriousness criterion “acute dialysis” should be selected. 
o Kidney transplantation:  Subject receiving a kidney transplant should be reported 
using the verbatim SAE term “Progression to ESRD”, with the additional serious 
criterion of “kidney transplant” selected. 
• The following situations will be reported as SAEs if they meet seriousness criteria 
(see Section 10.1.2); otherwise, they should be reported as AEs: 
o Acute kidney injury not requiring dialysis – The reported AE term should reflect 
the etiology for the impairment of the renal function.  Non-specific AE terms such 
as “Decreased eGFR” or “Increased creatinine” should be avoided whenever the 
underlying etiology is known. 
 Examples of verbatim AE terms for prerenal impairment include 
hypovolemia, hepatorenal syndrome, and heart failure 
 Examples of verbatim AE terms for intrarenal impairment include acute 
tubular necrosis, acute interstitial nephritis, and glomerulonephritis 
 Examples of verbatim AE terms for postrenal impairment include 
hydronephrosis, pelvicaliectasis, and urinary tract obstruction 
o Progression of CKD not requiring dialysis – If permanent loss of renal function 
due to underlying CKD has occurred, the reported AE term should reflect the 
underlying etiology.  Non-specific terms such as “Decreased eGFR,” “Increased 
creatinine,” or “Worsening CKD” should be avoided whenever the underlying 
etiology is known.  Examples of verbatim AE terms include worsening lupus 
nephritis, worsening diabetic kidney disease, and worsening glomerulonephritis. 
o Medical conditions related to CKD that occur without acute kidney injury or 
progression of CKD – If there is no decline in kidney function, the medical 
complication of CKD itself should be reported.  AE terms such as “Progression of 
CKD” or “Acute Kidney Injury,” should be avoided when there is no decline in 
kidney function.  Examples of AE terms include edema and hyperkalemia. 


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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 or 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.  The following events are considered medically important 
events for this patient population: 
o Chronic dialysis 
o Acute dialysis 
o Kidney transplantation 
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. 
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. 


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10.3.1 Reporting Period 
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. 
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 
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. 


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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). 
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. 


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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 
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). 
Pregnancy during this time frame of the female partner of a male subject should also be reported. 
The Pregnancy Reporting Form/Exposure in Utero Form must be completed with all known 
information regarding the pregnancy at the time of reporting.  Investigative site personnel will 
update the form with additional information regarding the pregnancy and the outcome of the 
pregnancy as it becomes available until the outcome of the pregnancy is reported. 
The investigator will follow the subject (or female partner of a male subject) until completion of 
the pregnancy.  If the outcome of the pregnancy meets the criteria for 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: 


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• 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, 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 change in Hb in Japanese subjects with anemia 
secondary to NDD-CKD, 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 2 Hb values obtained 
prior to treatment based on the qualifying screening Hb value and the Hb value at the baseline 
visit.   
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.  Therefore, no multiplicity adjustment 
will be needed for this analysis. 
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 


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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.  
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. 
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 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 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. 
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 


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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. 
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 


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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 
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 
assessments. 
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. 


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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) 
If 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 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 
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. 


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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 
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. 


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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. 
Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in 
Japan. Am J Kidney Dis 2009;53:982-92. 
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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Appendix A:  Schedule of Activities 
Please refer to Section 9.3 for detailed information regarding the study procedures and evaluations, and please refer to Section 9.4 for 
detailed information regarding the activities to be performed at each study visit. 
 
Screening 
Primary efficacy period  
(Day 1-Week 6) 
Dose adjustment and maintenance period 
(Week 7-16) 
Follow-up 
(Week 17-18) 
Study Week 
-4 to 0 
Base 
line 
2 
4 
6 
8 
10 
12 
14 
16 (EOT) 
18 
Study Day 
-28 to -4 
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 
 
 
 
 
 
 
 
 
 
Demographics, medical 
history, physical exam, and 
weight 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead electrocardiogram 
 
X 
 
 
 
 
 
 
 
 
 
Adverse event review 
 
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 
Concomitant medication 
review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
 
X 
 
Urine pregnancy test 
 
X 
 
 
 
 
 
 
 
 
 
Coagulation tests 
 
X 
 
 
 
 
 
 
 
 
 
Folate and vitamin B12 
X 
 
 
 
 
 
 
 
 
 
 


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Screening 
Primary efficacy period  
(Day 1-Week 6) 
Dose adjustment and maintenance period 
(Week 7-16) 
Follow-up 
(Week 17-18) 
Study Week 
-4 to 0 
Base 
line 
2 
4 
6 
8 
10 
12 
14 
16 (EOT) 
18 
Study Day 
-28 to -4 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
Visit Window (Days) 
 
 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Urine albumin to creatinine 
ratio 
 
X 
 
 
 
 
 
 
 
 
 
Complete blood count, 
including Hb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry and eGFR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Iron indices 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Hepcidin 
 
X 
 
 
X 
 
 
 
 
X 
 
C-reactive protein 
 
X 
 
 
X 
 
 
 
 
X 
 
VEGF  
 
X 
 
 
X 
 
 
 
 
X 
 
PK pre-dose sample (study 
drug to be administered after 
sample collection) 
 
 
 
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 
 


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Screening 
Primary efficacy period  
(Day 1-Week 6) 
Dose adjustment and maintenance period 
(Week 7-16) 
Follow-up 
(Week 17-18) 
Study Week 
-4 to 0 
Base 
line 
2 
4 
6 
8 
10 
12 
14 
16 (EOT) 
18 
Study Day 
-28 to -4 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
Visit Window (Days) 
 
 
±1 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
Based on Hb results from the 
visits noted, dose reduction for 
excess Hb response as needed 
according to guidelines 
(Section 8.2.4) 
 
 
X 
X 
 
 
 
 
 
 
 
Based on Hb results from the 
visits noted, dose adjustment to 
achieve target Hb 
10.0-12.0 g/dL as needed 
according to guidelines 
(Section 8.2.5) 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Abbreviations:  eGFR, estimated glomerular filtration rate; EOT, end of treatment; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; 
PK, pharmacokinetics; RBC, red blood cells; VEGF, vascular endothelial growth factor 
 
 
 
 


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Appendix B:  Japanese Society of Nephrology 2009 Equation to Calculate eGFR 
The estimated glomerular filtration rate (eGFR) will be calculated from serum creatinine using 
the 2009 Japanese Society of Nephrology Equation (3-variables; Matsuo 2009).   
eGFR (mL/min/1.73 m2) = 194 x (Scr in mg/dL)-1.094 x (Age)-0.287 x (0.739 if female) 

SAP_001.pdf: 
Akebia Therapeutics, Inc. 
AKB-6548-CI-0021 
Statistical Analysis Plan 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 1.0 
Effective Date:  25 Nov 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 1 of 27 
PAREXEL International 
Akebia Therapeutics, Inc. 
AKB-6548-CI-0021 
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 NON-DIALYSIS DEPENDENT CHRONIC 
KIDNEY DISEASE (NDD-CKD) 
Statistical Analysis Plan 
PAREXEL Project Number: 230644 
NCT Number: NCT03054337
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0021 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 1.0 
Effective Date:  25 Nov 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 2 of 27 
 
SPONSOR SIGNATURE PAGE 
 
 
 
 
Approved by:  
_________________________ 
 
_______________ 
 
 
 
 
 
 
Date 
 
 Biostatistics 
 
 
Akebia Therapeutics, Inc. 
 
 
 
 
 
 
 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0021 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 1.0 
Effective Date:  25 Nov 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 3 of 27 
 
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-0021 
Statistical Analysis Plan 
 
TP-GDO-WW-016-04 
CONFIDENTIAL 
Project Document Version No. 1.0 
Effective Date:  25 Nov 15 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 4 of 27 
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 ............................................................................................. 10 
4 
STATISTICAL METHODS ..................................................................................... 10 
4.1 Data Quality Assurance ...................................................................................... 10 
4.2 General Presentation Considerations .................................................................. 10 
4.3 Study Subjects .................................................................................................... 11 
4.3.1 Disposition of Subjects ............................................................................. 11 
4.3.2 Protocol Deviations ................................................................................... 12 
4.4 Analysis Populations .......................................................................................... 12 
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.................................................. 13 
4.5 Demographic and Other Baseline Characteristics .............................................. 13 
4.6 Treatment Compliance ........................................................................................ 14 
4.7 Efficacy Evaluation ............................................................................................ 14 
4.7.1 Analysis and Data Conventions ................................................................ 14 
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 ............................................. 15 
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 ............... 16 
4.7.2.2 Summary of actual value and change in Hb from baseline to week 
6 and beyond .......................................................................................... 17 
4.7.3 Secondary Efficacy Variables ................................................................... 17 
4.7.4 Exploratory Efficacy Variable .................................................................. 20 
4.8 Safety Evaluation ................................................................................................ 20 
4.8.1 Extent of Exposure .................................................................................... 20 
4.8.2 Adverse Events ......................................................................................... 20 
4.8.3 Deaths, Serious Adverse Events, and Other Significant Adverse Events. 22 
4.8.4 Clinical Laboratory Evaluation ................................................................. 22 
4.8.4.1 Serum and urine pregnancy tests ................................................. 22 
4.8.4.2 Coagulation tests ......................................................................... 23 


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4.8.4.3 Folate and vitamin B12 ............................................................... 23 
4.8.4.4 Urine albumin-to-creatinine ratio (uACR) .................................. 23 
4.8.4.5 Complete Blood Count (CBC) .................................................... 23 
4.8.4.6 Hemoglobin ................................................................................. 24 
4.8.4.7 Chemistry and estimated glomerular filtration rate (eGFR) ....... 24 
4.8.4.8 C-reactive protein and Vascular Endothelial Growth Factor 
(VEGF) .................................................................................................. 25 
4.8.5 Vital Signs, Physical Findings and Other Observations Related to Safety25 
4.8.5.1 Vital Signs ................................................................................... 25 
4.8.5.2 12-lead ECG ................................................................................ 26 
4.8.5.3 Physical Examination and Weight Assessment ........................... 26 
4.8.6 Safety Monitoring (Independent Data Monitoring Committee [IDMC], 
Data Monitoring Committee [DMC], Data and Safety Monitoring Board 
[DSMB]) ................................................................................................... 26 
4.9 Other Analyses .................................................................................................... 26 
4.9.1 PK Analysis .............................................................................................. 26 
4.10 
Determination of Sample Size .................................................................. 27 
4.11 
Changes in the Conduct of the Study or Planned Analysis ...................... 27 
5 
REFERENCES .......................................................................................................... 27 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CBC 
complete blood count 
CI 
confidence interval 
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 
NDD-CKD 
non-dialysis dependent chronic kidney disease 
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 
SMQ 
standardised MedDRA queries 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TIBC 
total iron binding capacity 
TSAT 
transferrin saturation 
VEGF 
vascular endothelial growth factor 
 


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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 non-dialysis dependent chronic kidney 
disease (NDD-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 4 (December 15, 2016) 
• electronic Case Report Form (eCRF), Version 3.0 (October 6, 2016) 
• Protocol Deviation Specification Form, Version 1.0 (September 29, 2016) 
 
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 NDD-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 2 Hb values obtained prior to treatment based 
on the qualifying screening Hb value and the Hb value at the baseline visit. 
 
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 NDD-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 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 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 (ie, 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 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) 
• Maintenance of iron sufficiency (defined as ferritin ≥50 ng/mL and TSAT ≥20%) 
from baseline to the end of the primary efficacy period (Week 6) and 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 NDD-CKD.   
The study has a planned enrollment of 48 subjects to be enrolled at approximately 
25 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 1. 


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Figure 1: Overview of Study Design 
 
 
The study will include the following periods: 
• Eligibility screening period (up to 4 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) 
Subjects will participate in a screening period (4 days to 4 weeks) to determine study 
eligibility, and 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 the protocol section 8.2.2 for information regarding the randomization 
scheme. 
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 level 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). 


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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). 
The clinical and safety assessments will be performed as described in the protocol section 
9.3 and as listed in the protocol Appendix A. 
 
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 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 
 
3.2.2 Safety Variables 
The following variables are the safety endpoints: 
• 
AEs 
• 
Vital signs 
• 
ECGs 
• 
Laboratory parameters 
 
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’ of Hb is defined as the average of 2 Hb values obtained prior to treatment 
based on the qualifying screening Hb value and the Hb value at the Baseline Visit.  ‘Pre-


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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.  ‘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.   
 
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 


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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 investigated by 
assessing the robustness of the study results and conclusions to the choice of analysis 
population (see Section 4.4), both including and excluding data potentially affected by 
major protocol deviations. 
 
Protocol deviations and any action to be taken regarding the exclusion of subjects or 
affected data from specific analyses will be determined in Protocol Deviation 
Specification document.  
 
The protocol deviation will be summarized as following: 
 
• 
A summary of the number and percentage of subjects with a protocol deviation by 
treatment group and overall and by type of deviation (Analysis population: All 
Subjects Randomized) 
 
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) 
 


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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 qualifying screening value and the baseline value, and at 
least one post-baseline Hb measurement.  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.   
 
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 


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• 
A summary of other relevant variables (e.g. estimated Glomerular Filtration Rate 
[eGFR] at baseline, CKD stage, 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. 
 
Age will be calculated as the number of complete years between a subject's birth date and 
the date of informed consent. 
 
Definitions of eGFR and CKD stage are described in section 4.8.4.7. 
 
CKD stage will be determined by eGFR at baseline: 
CKD stage 
eGFR (mL/min/1.73m2) 
1 
90+ 
2 
60 - 89 
3a 
45 - 59 
3b 
30 - 44 
4 
15 - 29 
5 
< 15 
 
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 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. 
 
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 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 


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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 = 𝛽𝛽0 + 𝛽𝛽𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑋𝑋 
 
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: 
 
𝐻𝐻0: 𝛽𝛽𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑= 0 
𝐻𝐻1: 𝛽𝛽𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑≠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 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.  Hence no adjustments for multiplicity are required. 
 


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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 
minus the mean pre-treatment Hb.  Pre-treatment Hb is defined as the average of 2 Hb 
values obtained prior to treatment based on the qualifying screening Hb value and the Hb 
value at the baseline visit. 
 
For the primary analysis, the LOCF approach will be used to impute missing data.  
Complete-case analysis will be performed for sensitivity at the scheduled Week 6 visit. 
 
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 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. 
 
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. 


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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: 
• 
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 from baseline for each treatment group at each 
post-treatment study visit 
 
A by-subject listing of actual values and change (absolute and percent) from baseline in 
Hb will be provided. 
 
4.7.3 Secondary Efficacy Variables 
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. 
 
Kaplan-Meier failure (cumulative incidence) plot will be presented for the time to reach 
target Hb level by treatment group. 
 


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Statistical Analysis Plan 
 
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A by-subject listing will be provided. 
 
Hb within target level 
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 number and percentage of subjects who achieved a ≥1 g/dL increase in 
Hb from pre-treatment average will be provided by treatment group. 
 
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 
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 (both absolute and percent) 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 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 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0021 
Statistical Analysis Plan 
 
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CONFIDENTIAL 
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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 (ie, 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 
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. 
 
Dose adjustment 
A 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 by-subject listing of dose adjustment will be provided by treatment group. 
 


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Statistical Analysis Plan 
 
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Maintenance of iron sufficiency 
A summary of maintenance of iron sufficiency (defined as ferritin ≥50 ng/mL and TSAT 
≥20%) from baseline to the end of the primary efficacy period (Week 6) and the end of 
the dose adjustment and maintenance period (Week 16) will be provided. 
 
The effect of treatment in terms of the proportion of subjects who maintain iron 
sufficiency will be analyzed using Fisher’s exact test for week 6 only.  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 of iron sufficiency will be provided by treatment group. 
 
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 treatment duration 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 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0021 
Statistical Analysis Plan 
 
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CONFIDENTIAL 
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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. 
 
Where 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.   
 
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 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, causality, 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. 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0021 
Statistical Analysis Plan 
 
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• 
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) 
• 
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) 
• 
Standardised MedDRA Query (SMQ): “Central nervous system haemorrhages and 
cerebrovascular conditions” (SMQ 20000061) 
• 
Standardised MedDRA Query (SMQ): “Embolic and thrombotic events” (SMQ 
20000081)  
• 
Standardised MedDRA Query (SMQ): “Cardiac failure” (SMQ 20000004)  
• 
Standardised MedDRA Query (SMQ): “Retinal disorders” (SMQ 20000158, narrow) 
 
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 by-subject listing of all deaths that occurred during the study will be provided. 
 
4.8.4 Clinical Laboratory Evaluation 
4.8.4.1 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 
pregnancy based on the investigator’s clinical judgment or as required by local 
regulations. 
 
A summary of subjects with any positive pregnancy test results will be provided by 
treatment group. 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0021 
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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A by-subject listing of serum and urine pregnancy tests will be provided. 
 
4.8.4.2 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. 
 
4.8.4.3 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 summary of folate and vitamin B12 will be provided by treatment group. 
 
A by-subject listing of folate and vitamin B12 tests will be provided. 
 
4.8.4.4 Urine albumin-to-creatinine ratio (uACR) 
Urine albumin-to-creatinine ratio (uACR) will be evaluated at baseline visit. 
 
A summary of uACR will be provided by treatment group. 
 
A by-subject listing of uACR 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: 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0021 
Statistical Analysis Plan 
 
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CONFIDENTIAL 
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• 
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. 
 
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 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 any Hb > 14.0 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 
 
4.8.4.7 Chemistry and estimated glomerular filtration rate (eGFR) 
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 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0021 
Statistical Analysis Plan 
 
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CONFIDENTIAL 
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• 
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 
 
The eGFR will be calculated from serum creatinine by following formula: 
eGFR(mL/min/1.73m2)
= 194 × (Scr in mg/dL)−1.094 × (Age)−0.287 × (0.739 if female) 
 
A by-subject listing of Chemistry and eGFR 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) 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 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. 
 
4.8.5 Vital Signs, Physical Findings and Other Observations Related to Safety 
4.8.5.1 Vital Signs 
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. 
 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0021 
Statistical Analysis Plan 
 
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CONFIDENTIAL 
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Any findings of treatment-emergent vital sign abnormalities will be handled as adverse 
event and reported in AE tables / listings. 
 
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. 
 
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. 
 
By-subject listings of pre-dose plasma concentrations of vadadustat and its metabolites 
will be provided by treatment group. 
 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0021 
Statistical Analysis Plan 
 
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4.10 Determination of Sample Size 
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 
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. 
 
5 
REFERENCES 
Not Applicable. 


Akebia Therapeutics, Inc. 
AKB-6548-Cl-002 I 
P AREXEL International 
Akebia Therapeutics, Inc. 
AKB-6548-CI-002 l 
Statistical Analysis Plan 
PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED DOSE-
FINDING STUDY TO ASSESS THE EFFlCACY. SAFETY PHARMACOKINETICS, 
AND PHARMACODYNAMICS OF VADADUSTAT IN JAPANESE SUBJECTS 
WITH ANEMIA SECONDARY TO NON-DIALYSIS DEPENDENT CHRONlC 
KIDNEY DISEASE (NDD-CKD) 
Statistical Analysis Plan 
P AREXEL Project Number: 230644 
Status; Date: 
TP-GDO-WW-016-04 
Effective Date: 25 Nov 15 
Related to: SOP-GDO-WW-019 
Version 1; 08 March 2017 (Original SAP) 
Version 2; 15 May 2017 
CONFIDENTIAL 
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Akebia Therapeutics, Inc. 
AKB-6548-CI-002 l 
SPONSOR SIGNATURE PAGE 
Approved by: 
Statistical Analysis Plan 
Biostatistics 
Akebia Therapeutics, Inc. 
TP-GDO-WW-016-04 
Effective Date: 25 Nov 15 
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Akebia Therapeutics, Inc. 
AKB-6548-CI-0021 
Statistical Analysis Plan 
PAREXELSIGNATUREPAGE 
This document has been approved and signed electronically on the final page by the 
following: 
Author 
Reviewer 
TP-GDO-WW-016-04 
Effective Date: 25 Nov 15 
Related to: SOP-GDO-WW-019 
Signatory -
Project Role: Biostatistics Lead 
Signatory -
Project Role: Biostatistics Reviewer 
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-
Project Role: MWS Reviewer 
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Akebia Therapeutics, Inc. 
AKB-6548-CI-0021 
TABLE OF CONTENTS 
Statistical Analysis Plan 
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 .............................................................................................. 10 
4 
STATISTICAL METHODS ...................................................................................... 10 
4.1 Data Quality Assurance ....................................................................................... 10 
4.2 General Presentation Considerations ................................................................... 10 
4.3 Study Subjects ..................................................................................................... 11 
4.3 .1 Disposition of Subjects .............................................................................. 11 
4.3.2 Protocol Deviations ................................................................................... 12 
4.4 Analysis Populations ........................................................................................... 12 
4.4.l 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 .................................................. 13 
4.5 Demographic and Other Baseline Characteristics ............................................... 13 
4.6 Treatment Compliance ........................................................................................ 14 
4. 7 Efficacy Evaluation ............................................................................................. J 4 
4.7.1 Analysis and Data Conventions ................................................................. 14 
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 ................ 16 
4.7.2.2 Summary of actual value and change in Hb from baseline to week 
6 and beyond ........................................................................................... 17 
4.7.3 Secondary Efficacy Variables ................................................................... 17 
4.7.4 Exploratory Efficacy Variable ................................................................... 20 
4.8 Safety Evaluation ................................................................................................ 21 
4.8.1 Extent of Exposure .................................................................................... 21 
4.8.2 Adverse Events .......................................................................................... 21 
4.8.3 Deaths, Serious Adverse Events, and Other Significant Adverse Events .23 
4.8.4 Clinical Laboratory Evaluation ................................................................. 24 
4.8.4.l Serum and urine pregnancy tests ................................................. 24 
4.8.4.2 Coagulation tests .......................................................................... 24 
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Akebia Therapeutics, Inc. 
AKB-6548-CI-0021 
Statistical Analysis Plan 
4.8.4.3 Folate and vitamin B12 ................................................................ 24 
4.8.4.4 Urine albumin-to-creatinine ratio (uACR) ................................... 25 
4.8.4.5 Complete Blood Count (CBC) ..................................................... 25 
4.8.4.6 Hemoglobin .................................................................................. 25 
4.8.4.7 Chemistry and estimated glomerular filtration rate (eGFR) ........ 26 
4.8.4.8 C-reactive protein and Vascular Endothelial Growth Factor 
(VEGF) ................................................................................................... 26 
4.8.5 Vital Signs, Physical Findings and Other Observations Related to Safety27 
4.8.5.1 Vital Signs .................................................................................... 27 
4.8.5.2 12-lead ECG ................................................................................. 27 
4.8.5.3 Physical Examination and Weight Assessment ........................... 28 
4.8.6 Safety Monitoring (Independent Data Monitoring Committee [IDMC], 
Data Monitoring Committee [DMC], Data and Safety Monitoring Board 
[DSMB]) .................................................................................................... 28 
4.9 Other Analyses .................................................................................................... 28 
4.9.1 PK Analysis ............................................................................................... 28 
4.10 
Determination of Sample Size ................................................................... 28 
4.11 
Changes in the Conduct of the Study or Planned Analysis ....................... 28 
5 
REFERENCES ........................................................................................................... 29 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CBC 
complete blood count 
CI 
confidence interval 
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 
NDD-CKD 
non-dialysis dependent chronic kidney disease 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic( s) 
pp 
per protocol 
PT 
preferred term 
QI 
1st quartile 
Q3 
3rd quartile 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SMQ 
standardised MedDRA queries 
soc 
system organ class 
TEAE 
treatment-emergent adverse event 
TIBC 
total iron binding capacity 
TSAT 
transferrin saturation 
VEGF 
vascular endothelial growth factor 
Statistical Analysis Plan 
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1 
INTRODUCTION 
Statistical Analysis Plan 
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 non-dialysis dependent chronic kidney 
disease (NDD-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 4 (December 15, 2016) 
• 
electronic Case Report Form (eCRF), Version 3.0 (October 6, 2016) 
• 
Protocol Deviation Specification Form, Version 1.0 (September 29, 2016) 
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 NDD-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 2 Hb values obtained prior to treatment based 
on the qualifying screening Hb value and the Hb value at the baseline visit. 
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 NDD-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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Statistical Analysis Plan 
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 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 (ie, 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 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) 
• 
Maintenance of iron sufficiency (defined as ferritin 2:50 ng/mL and TSAT 2:20%) 
from baseline to the end of the primary efficacy period (Week 6) and 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 NDD-CKD. 
The study has a planned enrollment of 48 subjects to be enrolled at approximately 
25 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 1. 
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Statistical Analysis Plan 
Figure 1: Overview of Study Design 
V 
s t (n=l2) 
4 tablets once dally (600 mg) or 
Placebo (n=4) 
Vadadust t 
4 tablet• once dall 
Initial dose: 4 tablets (600 mg)• 
...--~~~~--'--~~~~~-
Va a 
stat (n=12) 
2 tablets once dally (300 mg) or 
Placebo (n=4) 
VadadMstat 
2 tablets once dally 
Initial dose: 2 tablets (300 mg)• 
~~~~--+-~~~~~---~~~~~---
i.:.===s..,.ta..._t (n=12) 
1 tablet once dally (150 mg) or 
Placebo (n=4) 
Vadadustat 
1 tablet once dally 
Initial dose: 1 tablet (150 mg) 
--~~~~--~~~~~~-
j 4 days -4 weeks I 
&weeks 
10weeks 
I zweeks I 
Screening 
Primary efficacy period 
Dose adjustment and maintenance period 
Safety 
follow-up 
• For subjects who develop an excess ill! response during the primary efficacy period, the number of tablets of 
study drug will be decreased (see Section 8.2.4). For these subjects, the number of tablets of 
d s 
initiated 
at the Week 6 visit will be lower than indicated. 
The study will include the following periods: 
• 
Eligibility screening period (up to 4 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) 
Subjects will participate in a screening period (4 days to 4 weeks) to determine study 
eligibility, and eligible subjects will be randomized following the screening period. 
Using a central randomization system, subjects will be randomized 1: 1: I 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 the protocol section 8.2.2 for information regarding the randomization 
scheme. 
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 level 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). 
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Statistical Analysis Plan 
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). 
The clinical and safety assessments will be performed as described in the protocol section 
9.3 and as listed in the protocol Appendix A. 
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 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 
3.2.2 Safety Variables 
The following variables are the safety endpoints: 
• 
AEs 
• 
Vital signs 
• 
ECGs 
• 
Laboratory parameters 
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' ofHb is defined as the average of 2 Hb values obtained prior to treatment 
based on the qualifying screening Hb value and the Hb value at the Baseline Visit. 'Pre-
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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 EQT form labeled as 'Week 16 Visit', even if other values closer to 
Day 113 are available. '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. 
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 
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Statistical Analysis Plan 
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 Protocol Deviation 
Specification document 20170207 version 2.0. 
The protocol deviation will be summarized as following: 
• 
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 (Analysis 
population: All Subjects Randomized) 
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 
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Statistical Analysis Plan 
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 qualifying screening value and the baseline value, and at 
least one post-baseline Hb measurement. 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. 
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 2'.: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 
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• 
A summary of other relevant variables (e.g. estimated Glomerular Filtration Rate 
[eGFR] at baseline, CKD stage, 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. 
Age will be calculated as the number of complete years between a subject's birth date and 
the date of informed consent. 
Definitions of eGFR and CKD stage are described in section 4.8.4.8. 
CKD 
·11 b d 
· db 
GFR t baseline: 
stage w1 
e etermme 
1y e 
a 
CKD stage 
eGFR (mL/min/l. 73m2) 
1 
90+ 
2 
60 - 89 
3a 
45 - 59 
3b 
30-44 
4 
15 - 29 
5 
< 15 
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. 
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 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 
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Statistical Analysis Plan 
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. 
where Y is change in Hb and X is vadadustat dose. Pxs are parameters of the model. Po is 
intercept and Pdose 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: 
Ho: f3dose = 0 
H1: f3dose * 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. 
• 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. 
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4. 7 .1.4 Multiple Comparisons/Multiplicity 
Statistical Analysis Plan 
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. Hence 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 
minus the mean pre-treatment Hb. Pre-treatment Hb is defined as the average of 2 Hb 
values obtained prior to treatment based on the qualifying screening Hb value and the Hb 
value at the baseline visit. 
For the primary analysis, the LOCF approach will be used to impute missing data. 
Complete-case analysis will be performed for sensitivity at the scheduled Week 6 visit. 
4. 7.2.1 Summary of actual value and change in Hb at week 6 
The primary analysis population for efficacy will be MITT and PP 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 (Ql, 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. 
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Statistical Analysis Plan 
• 
A waterfall plot for absolute Hb change from baseline 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 
(ANOV A) 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: 
• 
A summary of actual value of Hb by treatment group and study visits. 1st and 3rd 
quartiles (QI, 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 from baseline for each treatment group at each 
post-treatment study visit to week 6 
• 
Box plots of absolute Hb changes from baseline for each treatment group at each 
post-treatment study visit to week 16 
A by-subject listing of actual values and change (absolute and percent) from baseline in 
Hb will be provided. 
4.7.3 
Secondary Efficacy Variables 
The analysis population for efficacy will be MITT and PP population. 
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Time to reach target Hb Range 
Statistical Analysis Plan 
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 :'.Sl2.0 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. 
Kaplan-Meier failure (cumulative incidence) plot will be presented for the time to reach 
target Hb level 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 I within I 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 number and percentage of subjects who achieved a ~1 g/dL increase in 
Hb from pre-treatment average will be provided by treatment group. 
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 
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. 151 and 3rd quartiles (Ql, Q3) as well as 
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Statistical Analysis Plan 
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 
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 
ANCOV A. 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 (ie, 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 therap y 
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 I ESAs will be analyzed using Fisher's exact test. Three post-hoc pairwise 
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Statistical Analysis Plan 
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. 
Average Daily Dose 
A summary of Average Daily Dose by treatment group and visit will be presented with 
1st and 3rd quartiles (QI, 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 will be provided by treatment group. 
Maintenance ofiron sufficiency 
A summary of maintenance of iron sufficiency (defined as ferritin 2::50 ng/mL and TSA T 
2::20%) from baseline to the end of the primary efficacy period (Week 6) and the end of 
the dose adjustment and maintenance period (Week 16) will be provided. 
The effect of treatment in terms of the proportion of subjects who maintain iron 
sufficiency will be analyzed using Fisher's exact test for week 6 only. 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 of iron sufficiency will be provided by treatment group. 
4.7.4 Exploratory Efficacy Variable 
Time in Therapeutic Range a'TR) 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 
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4.8 
Safety Evaluation 
Statistical Analysis Plan 
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 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 and concomitant medication start dates will be imputed as follows: 
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: 
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Statistical Analysis Plan 
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 and concomitant medication 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 
• 
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, relatationship, SOC and PT 
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Statistical Analysis Plan 
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) 
• 
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) 
• 
Standardised MedDRA Query (SMQ): "Central nervous system haemorrhages and 
cerebrovascular conditions" (SMQ 20000061) 
• 
Standardised MedDRA Query (SMQ): "Embolic and thrombotic events" (SMQ 
20000081) 
• 
Standardised MedDRA Query (SMQ): "Cardiac failure" (SMQ 20000004) 
• 
Standardised MedDRA Query (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. 
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. 
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Statistical Analysis Plan 
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 during the study will be provided by treatment 
group. 
Any subject with at least one of the following liver function abnormalities is summarized: 
• 
ALT 2:2x and <3x ULN 
• 
AST 2:2x and <3x ULN 
• 
Bilirubin 2:2x and <3x ULN 
• 
ALT 2:3x ULN 
• 
AST 2:3x ULN 
• 
Bilirubin 2:3x 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 I 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 
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 I exclusion. 
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A by-subject listing of folate and vitamin B12 tests will be provided. 
4.8.4.5 Urine albumin-to-creatinine ratio (uACR) 
Statistical Analysis Plan 
Urine albumin-to-creatinine ratio (uACR) will be evaluated at baseline visit. 
A summary of uACR will be provided by treatment group. 
A by-subject listing ofuACR will be provided. 
4.8.4.6 Complete Blood Count (CBC) 
The following components of the CBC are described in Efficacy I 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 
• 
A summary of the number and percentage of subjects experiencing abnormal values 
by component of CBC, treatment group and time point. 
A by-subject listing of CBC will be provided by treatment group. 
4.8.4.7 Hemoglobin 
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 any Hb > 14.0 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 
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4.8.4.8 Chemistry and estimated glomerular filtration rate (eGFR) 
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 
Statistical Analysis Plan 
• 
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 
The eGFR will be calculated from serum creatinine by following formula: 
eGFR(mL/min/1.73m2) = 194x(Scr in mg/dL)-L094x(Age)-0·287 x(0.739 if female) 
A by-subject listing of Chemistry and eGFR will be provided by treatment group. 
4.8.4.9 C-reactive protein and Vascular Endothelial Growth Factor (VEGF) 
The following summaries will be provided: 
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Statistical Analysis Plan 
• 
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 and 
VEGF will be analyzed using ANCOV A. 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 ANOV A will be performed for sensitivity. 
A by-subject listing of CRP and VEGF will be provided by treatment group. 
4.8.5 Vital Signs, Physical Findings and Other Observations Related to Safety 
4.8.5.1 Vital Signs 
The following variables will be analyzed: 
• 
Blood Pressure (Systolic I 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 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 
• Q RS 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. 
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Statistical Analysis Plan 
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 I exclusion. Weight and height will be reported in 
demographic tables and listings. 
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. 
By-subject listings of pre-dose plasma concentrations of vadadustat and its metabolites 
will be provided by treatment group. 
4.10 Determination of Sample Size 
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 
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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S 
REFERENCES 
Not Applicable. 
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Statistical Analysis Plan 
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Akebia Therapeutics, Inc. 
 
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Statistical Analysis Plan 
 
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Page 1 of 38 
 
PAREXEL International 
Akebia Therapeutics, Inc. 
AKB-6548-CI-0021 
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 NON-DIALYSIS DEPENDENT CHRONIC 
KIDNEY DISEASE (NDD-CKD) 
Statistical Analysis Plan 
PAREXEL Project Number: 230644 
 
 
Status; Date: 
Version 1; 08 March 2017 (Original SAP) 
Version 2; 15 May 2017 
Version 3; 24 Jul 2017 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0021 
Statistical Analysis Plan 
 
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SPONSOR SIGNATURE PAGE 
 
 
 
 
Approved by:  
_________________________ 
 
_______________ 
 
 
 
 
 
 
Date 
 
 Biostatistics 
 
 
Akebia Therapeutics, Inc. 
 
 
 
 
 
 
 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0021 
Statistical Analysis Plan 
 
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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-0021 
Statistical Analysis Plan 
 
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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 ............................................................................................. 10 
4 
STATISTICAL METHODS ..................................................................................... 10 
4.1 Data Quality Assurance ...................................................................................... 10 
4.2 General Presentation Considerations .................................................................. 10 
4.3 Study Subjects .................................................................................................... 11 
4.3.1 Disposition of Subjects ............................................................................. 11 
4.3.2 Protocol Deviations ................................................................................... 12 
4.4 Analysis Populations .......................................................................................... 12 
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.................................................. 13 
4.5 Demographic and Other Baseline Characteristics .............................................. 13 
4.6 Treatment Compliance ........................................................................................ 14 
4.7 Efficacy Evaluation ............................................................................................ 14 
4.7.1 Analysis and Data Conventions ................................................................ 14 
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 ............... 16 
4.7.2.2 Summary of actual value and change in Hb from baseline to week 
6 and beyond .......................................................................................... 17 
4.7.3 Secondary Efficacy Variables ................................................................... 18 
4.7.4 Exploratory Efficacy Variable .................................................................. 21 
4.8 Safety Evaluation ................................................................................................ 21 
4.8.1 Extent of Exposure .................................................................................... 21 
4.8.2 Adverse Events ......................................................................................... 21 
4.8.3 Deaths, Serious Adverse Events, and Other Significant Adverse Events. 24 
4.8.4 Clinical Laboratory Evaluation ................................................................. 24 
4.8.4.1 Liver function abnormality .......................................................... 24 
4.8.4.2 Serum and urine pregnancy tests ................................................. 24 


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4.8.4.3 Coagulation tests ......................................................................... 25 
4.8.4.4 Folate and vitamin B12 ............................................................... 25 
4.8.4.5 Urine albumin-to-creatinine ratio (uACR) .................................. 25 
4.8.4.6 Complete Blood Count (CBC) .................................................... 25 
4.8.4.7 Chemistry and estimated glomerular filtration rate (eGFR) ....... 26 
4.8.4.8 C-reactive protein and Vascular Endothelial Growth Factor 
(VEGF) .................................................................................................. 27 
4.8.5 Vital Signs, Physical Findings and Other Observations Related to Safety27 
4.8.5.1 Vital Signs ................................................................................... 27 
4.8.5.2 12-lead ECG ................................................................................ 27 
4.8.5.3 Physical Examination and Weight Assessment ........................... 28 
4.8.6 Safety Monitoring (Independent Data Monitoring Committee [IDMC], 
Data Monitoring Committee [DMC], Data and Safety Monitoring Board 
[DSMB]) ................................................................................................... 28 
4.9 Other Analyses .................................................................................................... 28 
4.9.1 PK Analysis .............................................................................................. 28 
4.9.2 Treatment-Emergent Outliers analysis ..................................................... 28 
4.10 
Determination of Sample Size .................................................................. 29 
4.11 
Changes in the Conduct of the Study or Planned Analysis ...................... 30 
5 
REFERENCES .......................................................................................................... 30 
5.1 Statistical Analysis Plan Amendment 3 .............................................................. 30 
5.1.1 Modifications and changes ....................................................................... 30 
5.1.1.1 Rationale for the amendment ................................................... 30 
5.1.1.2 Global Changes .......................................................................... 30 
5.1.1.3 Specific changes ......................................................................... 30 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CBC 
complete blood count 
CI 
confidence interval 
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 
NDD-CKD 
non-dialysis dependent chronic kidney disease 
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 
SMQ 
standardised MedDRA queries 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TIBC 
total iron binding capacity 
TSAT 
transferrin saturation 
VEGF 
vascular endothelial growth factor 
 


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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 non-dialysis dependent chronic kidney 
disease (NDD-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 4 (December 15, 2016) 
• electronic Case Report Form (eCRF), Version 3.0 (October 6, 2016) 
• Protocol Deviation Specification Form, Version 1.0 (September 29, 2016) 
 
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 NDD-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 2 Hb values obtained prior to treatment based 
on the qualifying screening Hb value and the Hb value at the baseline visit. 
 
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 NDD-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 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 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 (ie, 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 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) 
• Maintenance of iron sufficiency (defined as ferritin ≥50 ng/mL and TSAT ≥20%) 
from baseline to the end of the primary efficacy period (Week 6) and 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 NDD-CKD.   
The study has a planned enrollment of 48 subjects to be enrolled at approximately 
25 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 1. 


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Figure 1: Overview of Study Design 
 
 
The study will include the following periods: 
• Eligibility screening period (up to 4 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) 
Subjects will participate in a screening period (4 days to 4 weeks) to determine study 
eligibility, and 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 the protocol section 8.2.2 for information regarding the randomization 
scheme. 
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 level 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). 


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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). 
The clinical and safety assessments will be performed as described in the protocol section 
9.3 and as listed in the protocol Appendix A. 
 
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 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 
 
3.2.2 Safety Variables 
The following variables are the safety endpoints: 
• 
AEs 
• 
Vital signs 
• 
ECGs 
• 
Laboratory parameters 
 
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’ of Hb is defined as the average of 2 Hb values obtained prior to treatment 
based on the qualifying screening Hb value and the Hb value at the Baseline Visit.  ‘Pre-


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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.  ‘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.   
 
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 


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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 Protocol Deviation 
Specification document 20170207 version 2.0.  
 
The protocol deviation will be summarized as following: 
 
• 
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 (Analysis 
population: All Subjects Randomized) 
 
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 


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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 qualifying screening value and the baseline value, and at 
least one post-baseline Hb measurement.  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.   
 
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 


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• 
A summary of other relevant variables (e.g. estimated Glomerular Filtration Rate 
[eGFR] at baseline, CKD stage, 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. 
 
Age will be calculated as the number of complete years between a subject's birth date and 
the date of informed consent. 
 
Definitions of eGFR and CKD stage are described in section 4.8.4.7. 
 
CKD stage will be determined by eGFR at baseline: 
CKD stage 
eGFR (mL/min/1.73m2) 
1 
90+ 
2 
60 - 89 
3a 
45 - 59 
3b 
30 - 44 
4 
15 - 29 
5 
< 15 
 
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. 
 
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 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 


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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 = 𝛽𝛽0 + 𝛽𝛽𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑋𝑋 
 
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: 
 
𝐻𝐻0: 𝛽𝛽𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑= 0 
𝐻𝐻1: 𝛽𝛽𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑≠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. 
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. 
 


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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.  Hence 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 
minus the mean pre-treatment Hb.  Pre-treatment Hb is defined as the average of 2 Hb 
values obtained prior to treatment based on the qualifying screening Hb value and the Hb 
value at the baseline visit. 
 
For the primary analysis, the LOCF approach will be used to impute missing data.  
Complete-case analysis will be performed for sensitivity at the scheduled Week 6 visit. 
 
4.7.2.1 Summary of actual value and change in Hb at week 6  
 
The primary analysis population for efficacy will be MITT and PP 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 


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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. 
 
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: 
• 
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 from baseline for each treatment group at each 
post-treatment study visit to week 6  
• 
Box plots of absolute Hb changes from baseline for each treatment group at each 
post-treatment study visit to week 16  
 
A by-subject listing of actual values and change (absolute and percent) from baseline in 
Hb will be provided. 
 


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4.7.3 Secondary Efficacy Variables 
The analysis population for efficacy will be MITT and PP population.   
Time to reach target Hb Range 
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. In addition, the cumulative proportion of subjects within target range 
will be displayed graphically from baseline visit to follow up visit 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. 
 
 
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. 
 
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 
Hematocrit, RBC count, and reticulocyte count (both absolute and percent) will be 
analyzed as secondary efficacy variables. 
 
The following summaries will be provided: 


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• 
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 (both absolute and percent) 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 (ie, 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. 
 
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:  
 


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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 with 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. 
 
Maintenance of iron sufficiency 
A summary of maintenance of iron sufficiency (defined as ferritin ≥50 ng/mL and TSAT 
≥20%) from baseline to the end of the primary efficacy period (Week 6) and the end of 
the dose adjustment and maintenance period (Week 16) will be provided. 
 
The effect of treatment in terms of the proportion of subjects who maintain iron 
sufficiency will be analyzed using Fisher’s exact test for week 6 only.  Three post-hoc 


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pairwise comparison, i.e., Placebo vs 150 mg, placebo vs 300 mg, and placebo vs 600 mg, 
will be done. 
 
A by-subject listing of iron sufficiency will be provided by treatment group. 
 
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 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 


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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 and concomitant medication start dates will be imputed as follows: 
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: 
 


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• 
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 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, relatationship, 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” 


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(MedDRA 10012758) or “Systolic hypertension” (MedDRA 10042957) or 
“Malignant hypertension” (MedDRA 10025600) 
• 
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) 
• 
Standardised MedDRA Query (SMQ): “Central nervous system haemorrhages and 
cerebrovascular conditions” (SMQ 20000061) 
• 
Standardised MedDRA Query (SMQ): “Embolic and thrombotic events” (SMQ 
20000081)  
• 
Standardised MedDRA Query (SMQ): “Cardiac failure” (SMQ 20000004)  
• 
Standardised MedDRA Query (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. 
 
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.  


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Additional pregnancy tests may be conducted during the study to establish the absence of 
pregnancy based on the investigator’s clinical judgment or as required by local 
regulations. 
 
A by-subject listing of serum and urine pregnancy tests will be provided. 
 
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 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. 
 
4.8.4.6 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 
 


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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. 
 
A by-subject listing of CBC will be provided by treatment group. 
 
 
4.8.4.7 Chemistry and estimated glomerular filtration rate (eGFR) 
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 eGFR will be calculated from serum creatinine by following formula: 
eGFR(mL/min/1.73m2)
= 194 × (Scr in mg/dL)−1.094 × (Age)−0.287 × (0.739 if female) 
 
A by-subject listing of Chemistry and eGFR will be provided by treatment group. 


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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) 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 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. 
 
4.8.5 Vital Signs, Physical Findings and Other Observations Related to Safety 
4.8.5.1 Vital Signs 
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.  
 
 
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 


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• 
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. 
 
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. 


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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 for subjects with non-elevated 
values at baseline: 
 
• Non-elevated at baseline definition for each 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 
 
4.10 Determination of Sample Size 
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 


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Statistical Analysis Plan 
 
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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. 
 
5 
REFERENCES 
Not Applicable. 
 
5.1 
Statistical Analysis Plan Amendment 3 
5.1.1 Modifications and changes 
5.1.1.1 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 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. 
5.1.1.2 Global Changes 
None 
5.1.1.3 Specific changes 
Change#1 
Section 4.7.1.3 Handling of Missing Data, page 15, 


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For the MITT population analyses for the primary efficacy variable, the Last Observation 
Carried Forward (LOCF) approach will be used to impute missing data. 
Has been changed to: 
For the MITT population analyses for the primary efficacy variable, the Last Observation 
Carried Forward (LOCF) approach will be used to impute missing data. 
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. 
 
Change#2 
Section 4.7.3 Secondary Efficacy Variables, page 18, 
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. 
 
Kaplan-Meier failure (cumulative incidence) plot will be presented for the time to reach 
target Hb level by treatment group. 
Has been changed to: 
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. 
 
Change#3 
Section 4.7.3 Secondary Efficacy Variables, page 18, 
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. 
Has been changed to: 
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 


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AKB-6548-CI-0021 
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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. 
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. 
 
Change#4 
Section 4.7.3 Secondary Efficacy Variables, page 18, 
 
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: 
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:  
 


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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#5 
Section 4.7.3 Secondary Efficacy Variables, page 20, 
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. 
 
Change#6 
Section 4.8.2 Adverse Events, page 21, 
Partial AE stop dates and concomitant medication will be imputed as follows: 
Has been changed to: 
Partial AE stop dates will be imputed as follows: 
 
Change#7 
Section 4.8.4.1 Liver function abnormality, page 24, 


Akebia Therapeutics, Inc. 
 
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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#8 
Section 4.8.4.5 Urine albumin-to-creatinine ratio (uACR), page 28, 
Urine albumin-to-creatinine ratio (uACR) will be evaluated at baseline visit. 
A summary of uACR will be provided by treatment group. 
A by-subject listing of uACR will be provided. 
Has been changed to: 
Urine albumin-to-creatinine ratio (uACR) will be evaluated at baseline visit. 
A by-subject listing of uACR will be provided. 
 
Change#9 
Section 4.8.4.7 Hemoglobin, page 25, 
4.8.4.7 Hemoglobin 
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 any Hb > 14.0 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: 
This section has been removed. 
 
Change#10 
Section 4.8.4.8 Chemistry and estimated glomerular filtration rate (eGFR), page 26, 
The following laboratory parameters will be analyzed: 
• 
Sodium 
• 
Potassium 
• 
Bicarbonate 
• 
Chloride 
• 
Calcium 
• 
Phosphorus 


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• 
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 
Has been changed to: 
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) 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0021 
Statistical Analysis Plan 
 
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• 
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#11 
Section 4.8.5.1 Vital Signs, page 27, 
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. 


Akebia Therapeutics, Inc. 
 
AKB-6548-CI-0021 
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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#12 
Section 4.9.1 PK Analysis, page 27, 
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. 
Has been changed to: 
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. 
 
Change#13 
Section 4.9.2 Treatment-Emergent Outliers analysis , 
This is newly added section in SAP amendment v3.0. 
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. 
 
Only treatment-emergent outliers will be counted but outliers at the baseline and 
screening visits will be excluded. 
 


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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