Conditions: Anemia Dialysis-Dependent Chronic Kidney Disease
Keywords: anemia kidney dialysis-dependent chronic kidney disease CKD DD-CKD renal vadadustat AKB-6548 hypoxia-inducible factor HIF hypoxia-inducible factor prolyl-hydroxylase inhibitor HIF-PHI hyporesponder hyporesponsive epoetin alfa hemoglobin erythropoiesis stimulating agent ESA
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
This is a Phase 2, randomized, open-label study to evaluate vadadustat versus epoetin alfa for the treatment of anemia in subjects with Dialysis-dependent Chronic Kidney Disease (DD-CKD) who are hyporesponsive to erythropoiesis stimulating agents (ESAs.)

Detailed description:

Arms:
arm 1: Vadadustat daily oral dose, adjustable based on Hb level arm 2: Epoetin alfa, dose adjustable based on Hb level, as clinically indicated throughout the study

Interventions: intervention 1: vadadustat intervention 2: epoetin alfa
Intervention descriptions: intervention 1: vadadustat intervention 2: epoetin alfa

Protocol document:
Prot_SAP_000.pdf: 
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Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
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 protect the rights, 
safety, privacy, and well-being of study subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Council on Harmonization Guideline for Good Clinical Practice E6 (R1). 
• 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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Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 8 
LIST OF FIGURES 
Figure 1 
Mechanism of Action of Vadadustat ....................................................................21 
Figure 2 
Schematic of the Study Design .............................................................................28 
 
 


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Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 10 
 on Day 1. Additional information on vadadustat dosing adjustments is 
provided in the study schematic figure and “Dosage and Regimens” below. 
• Epoetin alfa treatment arm: For subjects who are randomized to the epoetin alfa 
treatment arm, the initial dosing regimen in the study (starting from baseline 
[Day 1] visit) will be the same dose that they were receiving during the screening 
period. Epoetin alfa will be administered based on the approved label for adult 
patients with CKD on dialysis. 
Safety Follow-Up Period (Weeks 20 to 24): 
The 4-week safety follow-up period starting at Week 20 will be followed by a post-
treatment safety assessment conducted at Week 24. 
 
Figure.  Schematic of Study Design 
 
Study Duration 
Individual subjects will participate in the study for up to 28 weeks, including a 
screening period of up to 4 weeks, a 20-week treatment period, and a 4-week safety 
follow-up period.  
Inclusion Criteria 
Subjects must meet all the following inclusion criteria to be eligible for study 
participation: 
1. ≥18 years of age 
2. Receiving chronic maintenance in-center hemodialysis (3 times per week) for 
end-stage renal disease for at least 6 months prior to screening 
3. Currently receiving epoetin alfa for anemia 
 
 
 
4. Two Hb measurements (by central lab analysis) between 8.5 and 10 g/dL during 
screening 
5. Administered intravenous supplemental iron per investigative site’s protocol to 
maintain serum ferritin ≥100 ng/mL and transferrin saturation (TSAT) ≥20% 
6. Folate and vitamin B12 measurements ≥ lower limit of normal during screening 
7. Having dialysis adequacy as indicated by K- dialyzer clearance of urea, t- dialysis 
time, V- volume of distribution of urea (Kt/V) >1.2 
8. Understands the procedures and requirements of the study, willing and able to 
comply with all study procedures, and provides written informed consent and 
authorization for protected health information disclosure 


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 11 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not qualify for entry 
into the study: 
1. Anemia due to a cause other than CKD or subjects with active bleeding or recent 
blood loss 
2. History of sickle cell disease, myelodysplastic syndromes, bone marrow fibrosis, 
hematologic malignancy, myeloma, hemolytic anemia, thalassemia, or pure red 
cell aplasia 
3. Red blood cell (RBC) transfusion within 4 weeks prior to or during screening. 
4. Anticipated to recover adequate kidney function to no longer require dialysis 
5. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase 
(SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase 
(SGPT), or total bilirubin >2.0 x upper limit of normal (ULN) during screening.  
Subjects with a history of Gilbert’s syndrome are not excluded 
6. Uncontrolled hypertension (defined as confirmed pre-dialysis systolic blood 
pressure >190 mmHg or diastolic blood pressure >110 mmHg at rest) during 
screening 
7. Severe heart failure during screening (New York Heart Association Class IV) 
8. Acute coronary syndrome (hospitalization for unstable angina or myocardial 
infarction), surgical or percutaneous intervention for coronary, cerebrovascular or 
peripheral artery disease (aortic or lower extremity), surgical or percutaneous 
valvular replacement or repair, sustained ventricular tachycardia, hospitalization 
for heart failure, or stroke within 12 weeks prior to or during screening 
9. History of deep vein thrombosis (DVT) or pulmonary embolism (PE) within 
8 weeks prior to or during screening 
10. History of active malignancy within 2 years prior to or during screening, except 
for treated basal cell carcinoma of skin, curatively resected squamous cell 
carcinoma of skin, or cervical carcinoma in situ 
11. History of hemosiderosis or hemochromatosis 
12. History of prior organ transplantation or scheduled organ transplant (subjects on 
the kidney transplant waiting list or with a history of failed kidney transplant are 
not excluded), or prior hematopoietic stem cell or bone marrow transplant; note 
that corneal transplants and stem cell therapy for knee arthritis are not excluded 
13. History of an acute or chronic infection requiring intravenous antibiotics within 
4 weeks prior to randomization 
14. Hypersensitivity to vadadustat, epoetin alfa, or any of their excipients 
15. 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 
16. Previous participation in this study, previous participation in a Phase 3 study of 
vadadustat, or previous participation in a study with another hypoxia-inducible 
factor prolyl-hydroxylase inhibitor (HIF-PH inhibitor) other than vadadustat 
17. Females subjects who are pregnant or breastfeeding; or female subjects of 
childbearing potential who are unable or unwilling to use an acceptable method 
of contraception 
18. Non-vasectomized male subjects who are unable or unwilling to use an 
acceptable method of contraception 
19. Any other reason, which in the opinion of the investigator, would make the 
subject not suitable for participation in the study 
Retesting and 
Rescreening 
Retesting 
Retesting is defined as repeating laboratory tests within the same Screening Period. 


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 12 
Subjects who initially fail to qualify for the study based on laboratory test results may 
be retested once for each laboratory parameter within the 28-day screening period at 
the investigator’s discretion. 
Rescreening 
Subjects who fail to meet the qualifying criteria for Hb during the initial 28-day 
screening period may be considered for rescreening at the discretion of the investigator 
if it is considered 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 TSAT, ferritin, folate, or vitamin B12 values may be considered for rescreening 
after receiving appropriate replacement therapy. 
Screening is limited to 3 attempts (initial screening and 2 additional rescreening 
attempts). 
Efficacy Endpoints 
The primary endpoint is to evaluate the change in Hb from baseline over time during 
the treatment period.   
Secondary endpoints: 
• 
Proportion of subjects demonstrating incremental increases in Hb from 
baseline over time during the treatment period  
• 
Proportion of subjects with Hb values within the target range of 10.0-
11.0 g/dL during the treatment period 
• 
Proportion of subjects receiving epoetin alfa rescue 
• 
Proportion of subjects receiving RBC transfusion 
• 
Levels of various biomarkers, including C-reactive protein (CRP), hepcidin, 
and vascular endothelial growth factor (VEGF) 
• 
Mean weekly dose of intravenous elemental iron 
• 
Maintenance of iron sufficiency (defined as ferritin ≥100 ng/mL and TSAT 
≥20%). 
• 
Resource utilization 
Safety Endpoints 
Safety endpoints include the following: 
• Hb >12.0 g/dL, >13.0 g/dL, or >14.0 g/dL 
• Hb increase >1.0 g/dL within any 2-week interval or >2.0 g/dL within any 4-week 
interval 
• AEs and SAEs 
• Vital sign measurements and clinical laboratory values 
Dosage and Regimens 
Study drug treatment will aim to maintain Hb level within target range of 10.0 to 
11.0 g/dL.  
Hemoglobin will be monitored throughout the study to determine the dose of study 
medication (vadadustat or epoetin alfa) that subjects should receive. Hb levels can be 
measured more frequently based on investigator’s clinical judgment. 
On Day 1, subjects will withhold dosing until it is confirmed which treatment arm 
(vadadustat or epoetin alfa) they are assigned to. 
Dosing Regimen for the Epoetin Alfa Treatment Arm 
• For subjects who are randomized to the epoetin alfa treatment arm, the initial dosing 
regimen in the study (starting from baseline/Day 1 visit) will be the same dose that 
they were receiving during the screening period. 


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 13 
• Epoetin alfa dose will be administered and titrated as clinically indicated based on 
an individual subject’s central laboratory Hb value and the approved label for adult 
patients with CKD on dialysis. 
Dosing Regimen for the Vadadustat Treatment Arm  
• Vadadustat dosing (Day 1 to Week 20) 
- Starting dose of vadadustat: 
 once daily) starting at 
baseline (Day 1). The first dose of vadadustat will be administered at the 
investigative site after other baseline procedures have been completed. 
- Vadadustat dose will be adjustable from Day 1 to Week 20. The vadadustat 
dose can be up-titrated every 4 weeks or down-titrated more frequently based 
on the target Hb range of 10.0-11.0 g/dL.
 
 
- The vadadustat dose can be titrated (as presented in the “Guidelines for 
Vadadustat Dose Adjustments” below)  
- After the end of vadadustat treatment at Week 20 (or following early 
discontinuation of vadadustat), subjects will resume dosing with epoetin alfa 
(or another ESA), based on the approved label for adult patients with CKD 
on dialysis. 
Guidelines for Vadadustat Dose Adjustments 
Vadadustat dose adjustments will be guided by an interactive web response (IWR) 
system based on the Hb value and programmed Dose Adjustment Algorithms (as 
presented below). 
When adjusting vadadustat dose, investigators should consider Hb rate of rise, rate of 
decline, and the subject’s clinical condition (eg, recent illness, volume depletion, and 
volume overload). In cases of extenuating clinical circumstances, the investigator may 
elect to dose outside the IWR system dosing recommendation to maintain the Hb 
within the target range. In such cases, the clinical circumstances must be documented 
in the subject’s record and IWR system. 
• Do not increase the vadadustat dose more frequently than once every 4 weeks.  
Decreases in vadadustat dose can occur more frequently.  Avoid frequent 
vadadustat dose adjustments.  
• If a dose adjustment is required to maintain Hb within the target range 
(10.0-11.0 g/dL), then increase or decrease the vadadustat dose by 1 tablet. 
• If the Hb decreases below 10.0 g/dL, increase the dose of vadadustat by 1 tablet. 
• If the Hb exceeds 11.0 g/dL, interrupt vadadustat until Hb decreases to 11.0 g/dL or 
less, then resume dosing of vadadustat with 1 fewer tablet.  
NOTE: If subject was on 1 tablet prior to interruption, then resume dosing with 1 
tablet.  
• If the Hb increases rapidly (eg, >1.0 g/dL in any 2-week period or >2.0 g/dL in any 
4-week period), decrease the dose of vadadustat by 1 tablet. 


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 14 
Dosing Instructions 
Vadadustat 
Subjects assigned to the vadadustat arm will discontinue epoetin alfa and take 
vadadustat once daily for 20 weeks. All subjects will start with 
 
administered once daily). 
 
 
On Day 1, subjects will take their first dose of vadadustat at the investigative site after 
other baseline procedures have been completed. Thereafter, vadadustat will be taken 
once daily in the dialysis centers or on an outpatient basis.  Subjects may take 
vadadustat with or without food. The full dose should be taken at approximately the 
same time each day.  The subject should be instructed to take any oral iron 
supplements (including multivitamins containing iron), iron containing phosphate 
binders, or any medication containing iron at least 2 hours before or 2 hours after 
taking the vadadustat dose. 
Epoetin alfa 
Epoetin alfa will be administered based on the approved label for adult patients with 
CKD on dialysis. 
Iron Supplementation 
Investigators should prescribe iron supplementation (intravenous, oral, or intradialytic) 
as needed and maintain ferritin ≥100 ng/mL and TSAT ≥20%. 
Important: Because of the potential for oral iron to decrease the bioavailability of 
vadadustat, vadadustat should not be administered concurrently with an oral iron 
supplement (including multivitamins containing iron), iron containing phosphate 
binders, or any medications containing iron. The subject should be instructed to take 
any of these medications at least 2 hours before or 2 hours after taking the dose of 
vadadustat. 
Rescue Therapy 
Guidelines 
Hemoglobin levels will be monitored throughout the study at scheduled visits and can 
be measured more frequently based on investigator’s clinical judgment. 
Rescue therapy with RBC transfusion or epoetin alfa are allowed, but not required 
during the treatment period. The following rescue therapy guidelines are provided to 
ensure the safety of study subjects and to standardize the use of rescue in the study.  In 
cases of extenuating clinical circumstances, the investigator may elect to dose outside 
the rescue therapy guidelines to maintain the Hb within the target range. In such cases, 
the clinical circumstances should be documented in the subject’s record. 
1. Red Blood Cell Transfusion: Investigators should use their investigative site’s 
transfusion guidelines when determining whether to transfuse a study subject. In 
general, in the event of an acute or severe loss of blood, RBC transfusion should be 
administered as clinically indicated. In less severe instances but where there may be 
worsening of anemia or moderate to severe symptoms of anemia, RBC transfusions 
are permitted based on investigator’s clinical judgment. Study drug (vadadustat or 
epoetin alfa) may be continued during the transfusion period. 
2. Epoetin Alfa Rescue Therapy: Starting at Week 6, subjects in both treatment arms 
will be allowed (although not required) to have their Hb rescued with epoetin alfa.  
When possible, a subject on vadadustat should be on maximum dose of vadadustat 
for 2 weeks prior to epoetin alfa rescue. Epoetin alfa rescue therapy should be 
administered based on the approved US product label for adult patients with CKD 
on dialysis.  
To qualify for epoetin alfa rescue therapy, each of the following conditions must be 
fulfilled.   
NOTE: Epoetin alfa rescue therapy should be stopped when Hb is ≥9.0 g/dL. 
- The subject has experienced a clinically significant worsening of their 
anemia or symptoms of anemia (eg, fatigue, weakness, shortness of breath, 
chest pain, confusion, or dizziness) compared to baseline 


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 15 
- The subject’s Hb is confirmed to be <9.0 g/dL 
- The Hb level decreased >0.5 g/dL from baseline 
- Reducing the risk of alloimmunization or transfusion-related risks or both is 
a goal 
• For the epoetin alfa treatment arm: 
In addition to meeting the rescue criteria noted above, dosing and administration 
of epoetin alfa rescue therapy should be based on the approved label for adult 
patients with CKD on dialysis. 
• For the vadadustat treatment arm: 
Epoetin alfa rescue may not be considered until the next study visit if a subject’s 
current vadadustat dose can be increased (ie, if the subject’s last vadadustat dose 
increase was at least 4 weeks earlier and the subject is currently receiving a 
vadadustat dose of 600 mg/day or less, then vadadustat dose can be increased by 
1 tablet to maintain Hb within the target range of 10.0-11.0 g/dL). 
NOTE: Vadadustat must be temporarily interrupted during epoetin alfa rescue 
therapy. After epoetin alfa rescue therapy is completed, vadadustat should be 
resumed and adjusted per the dose adjustment guidelines (see “Dosage and 
Regimens”).   
A minimum interval must be observed prior to restarting vadadustat after the last 
dose of rescue medication, and treatment may be resumed 2 days after last dose 
of epoetin alfa rescue.   
Therapeutic 
phlebotomy 
If a subject’s Hb exceeds 14.0 g/dL or the rate of rise of Hb raises concern to the 
investigator, the subject may be phlebotomized based on the investigator’s clinical 
judgment. The method of phlebotomy will be in accordance with the investigative 
site’s standard clinical practice. 
Study Completion, 
Subject Completion, 
Discontinuation of 
Study Drug, or 
Withdrawal from the 
Study 
NOTE: The need for rescue therapy does not constitute study completion and is not a 
criterion for subject withdrawal from the study or permanent discontinuation of study 
drug (vadadustat or epoetin alfa). 
NOTE: Subjects who permanently discontinue study drug or discontinue prematurely 
from the study will complete the end-of-treatment (EOT) (Week 20) visit assessments 
and should participate in the 4-week safety follow-up period and the Week 24 visit 
assessments. 
Study Completion 
The study will be considered completed after all enrolled subjects have completed 
study participation, and the adverse event reporting period has been completed for each 
enrolled subject. 
Subject Completion 
A subject will be considered as having completed the study after completing 
participation in the Week 24 visit (end of the 4-week follow-up period). 
Discontinuation of Study Drug 
During the study, it is anticipated that subjects may interrupt study drug (vadadustat or 
epoetin alfa) for any of the following reasons: 
• Unacceptable toxicity or drug intolerability 
• Adverse event 
• Missed dialysis visit 
• Investigator’s discretion 
• Other reasons 


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 16 
Unless contraindicated, treatment should be resumed wherever possible and routinely 
considered at every visit following study drug interruption. 
Subjects may permanently discontinue study drug (vadadustat or epoetin alfa) for any 
of the following reasons: 
• Unacceptable toxicity or drug intolerability  
• Investigator’s discretion 
• Subject withdraws consent  
• Subject becomes pregnant 
• Receipt of kidney transplant 
• Other reasons 
Study Termination/ 
Individual Study Site 
Termination 
The entire study may be suspended or terminated by the sponsor for safety or other 
unanticipated reasons or upon request of regulatory agencies. If this occurs, prompt 
notification will be given to investigators, Institutional Review Boards (IRBs), and 
regulatory authorities in accordance with regulatory requirements. 
The investigator must notify the sponsor if the study is terminated by the investigator 
or the IRB at the site. If the investigator, IRB, or sponsor decides to terminate or 
suspend the study conduct at an investigative site for safety, non-enrollment, non-
compliance with the protocol, or other unanticipated reasons, the above parties will be 
promptly notified. 
Statistical 
Considerations 
This study is exploratory in nature, designed to evaluate the change in Hb from 
baseline over time during the treatment period. No formal statistical testing will be 
performed.   
Summary statistics (mean, median, standard deviation [SD], range, proportion and 
95% confidence intervals when appropriate) will be provided, by treatment groups for 
primary and secondary endpoints.   
Sample Size 
Determination 
About 50 subjects (n=25 per treatment arm) are planned for randomization in the 
study. 
Sample size has been determined to reflect the exploratory nature of this study.  
Internal Safety 
Assessment  
An internal Safety Monitoring Committee (SMC) will review safety data on a regular 
basis, throughout the course of the study. The details of the SMC will be outlined in a 
study-specific safety monitoring plan. 


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Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 18 
kg 
kilogram 
Kt/V  
k- dialyzer clearance of urea, t- dialysis time, V- volume of distribution of urea 
MedDRA 
Medical Dictionary for Regulatory Activities 
µM 
micromolar 
MMC 
microcrystalline cellulose 
mg 
milligram 
mL 
milliliter 
NDD-CKD 
non-dialysis dependent chronic kidney disease 
ng 
nanogram 
PD 
pharmacodynamics(s) 
PE 
pulmonary embolism 
PHD 
prolyl 4-hydroxylase domain 
PRCA 
pure red cell aplasia 
PK 
pharmacokinetic(s) 
RBC 
red blood cell 
SAE 
serious adverse event 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
SMC 
Safety Monitoring Committee 
SV1 
screening visit 1 
SV2 
screening visit 2 
TEAE 
treatment-emergent AE 
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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Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 20 
themselves may be causative of the increased frequency of adverse 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 studies have led to changes in prescribing information and 
clinical practice guidelines. In the US, the mortality and CV risks associated with ESAs are 
outlined in a black-box warning in the prescribing information of ESAs with a recommendation 
to use the lowest dose possible to avoid transfusions. 
The risks associated with currently available recombinant ESAs highlight the need for novel 
therapies that may potentially minimize or avoid such risks and slow CKD progression. 
4.3 
Hypoxia-Inducible Factor and Hypoxia-Inducible Factor Prolyl-Hydroxylase 
Inhibitors 
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 
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.   


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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.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 22 
• 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 
studies, vadadustat has demonstrated improved iron mobilization as reflected by a decrease 
in hepcidin and ferritin levels and an increase in total iron binding capacity (TIBC). 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 INNO2VATE clinical studies in DD-CKD patients. 
• Differentiated safety profile: Vadadustat’s 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 or excursions or both (McCullough 2013). The incidence of CV adverse 
events on vadadustat as compared with ESAs will be assessed in the global Phase 3 clinical 
studies. 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. 
To date, the efficacy, safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) 
profiles of vadadustat have been characterized in 10 completed Phase 1 studies (9 studies in 
healthy volunteers and one study in subjects undergoing chronic hemodialysis), 3 completed 
Phase 2a studies in NDD-CKD subjects, one Phase 2b study in NDD-CKD, and one Phase 2 
study in subjects with DD-CKD. In these studies, vadadustat was administered to 548 subjects, 
including 200 healthy subjects, 106 subjects with DD-CKD, and 242 subjects with NDD-CKD. 
Key findings from two Phase 2 clinical studies of vadadustat in NDD-CKD and DD-CKD are 
presented below. 
Study AKB-6548-CI-0007 
This was a double-blind, randomized, placebo-controlled study evaluating the efficacy and safety 
of vadadustat over 20 weeks of dosing in 210 subjects (n=138 received vadadustat and 
n=72 received placebo) with CKD GFR categories 3-5 (Pergola 2016). Subjects were enrolled 
into 1 of 3 groups and randomized (2:1) to once daily vadadustat or placebo: 
• Group 1: ESA naïve with Hb ≤10.5 g/dL 


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 23 
• Group 2: Previously treated with ESA with hemoglobin ≤10.5 g/dL 
• Group 3: Actively treated with ESA with Hb ≥9.5 and ≤12.0 g/dL 
The primary endpoint was the percent of subjects with either a mean Hb of ≥11.0 g/dL or an 
increase in Hb by ≥1.2 g/dL from baseline.  
At baseline, the mean age was 66 years, about 75% of subjects had diabetes mellitus, and the 
mean estimated GFR (eGFR) was 25 mL/min/1.73 m2. The results from the study demonstrated 
that about 54.9% of vadadustat-treated subjects compared to 10.3% of placebo-treated subjects 
met the primary endpoint (p=0.0001). Only 4.4% of subjects in the vadadustat group had Hb 
excursion ≥13.0 g/dL. Group 3 placebo-treated subjects experienced a decline in the mean Hb 
within the first 2 weeks, whereas subjects randomized to vadadustat maintained a stable Hb 
throughout the study. Increases in Hb in the vadadustat group were associated with an increase in 
reticulocytes and TIBC, and a decrease in serum hepcidin and ferritin. There was no difference 
between the vadadustat and placebo groups in vascular endothelial growth factor (VEGF) levels 
during the study.   
Vadadustat was generally well-tolerated, and the number of subjects who experienced at least 
one treatment-emergent AE (TEAE) in the vadadustat and placebo groups was comparable 
(74.6% versus 73.6%, respectively). More subjects experienced SAEs in the vadadustat group 
than in the placebo group (23.9% and 15.3%, respectively). This difference was primarily due to 
a greater incidence of renal-related SAEs in the vadadustat treatment group (vadadustat 9.4% 
versus placebo 2.8%), however, the number of subjects requiring dialysis (an objective measure 
of the severity of renal disease) was similar in the 2 treatment groups (vadadustat 8.0% versus 
placebo 9.7%). In addition, no trends in serum creatinine levels were observed between the 
vadadustat and placebo groups. Overall, the number of AEs for renal and urinary disorders was 
balanced (vadadustat 14.5% versus placebo 13.9%). Therefore, the disparity in renal SAEs was 
likely related to variability in reporting between investigators. Of the commonly reported events 
(reported in ≥5% of subjects in either treatment group), diarrhea, nausea, hyperkalemia, and 
hypertension were reported more frequently in the vadadustat than the placebo group. There 
were 3 deaths among the vadadustat-treated subjects (3/138; 2.2%). 
Study AKB-6548-CI-0011 
This was a multi-center, open-label, 16-week trial to assess the Hb response, safety, and 
tolerability of vadadustat in subjects with DD-CKD.  The trial enrolled 94 subjects receiving 
hemodialysis (Hb level from 9 to 12 g/dL), who were maintained on ESAs prior to study entry.  
Subjects were converted from ESA to vadadustat, and assigned to 1 of 3 dose cohorts: 300 mg 
once daily; 450 mg once daily; or 450 mg three times weekly. For each dose cohort, the mean Hb 
level at study entry was compared to the average at Weeks 7 and 8, and to the average at 
Weeks 15 and 16. During the first 8 weeks of this study, subjects remained on the prescribed 
starting dose, or decreased if necessary to control Hb. Beginning at Week 8, the dose of 
vadadustat could be increased or decreased to maintain Hb levels as needed. Intravenous (IV) 
iron use was allowed.  
The underlying demographics and profile of these CKD subjects were well-balanced across the 
3 cohorts, and reflective of the DD-CKD population in the United States as reported in the 
literature.  At baseline, the mean age was 58 years, average time on dialysis was 4.6 years, and 
the most common cause of end-stage renal disease was diabetes mellitus and/or hypertension.  


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
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Page 24 
Baseline Hb levels were similar (10.4 to 10.6 g/dL) in all 3 cohorts and the serum ferritin levels 
indicated that the subjects were iron replete at study entry and throughout the study. 
The trial achieved its primary endpoint of maintaining stable Hb levels over 16 weeks, across all 
3 cohorts converting from ESAs to vadadustat. Consistent with previous studies, all three starting 
dose regimens improved iron mobilization, as reflected by increases in TIBC and serum iron, and 
decreases in serum ferritin and hepcidin levels. Only one subject in the 300 mg once daily 
starting dose cohort had a single hemoglobin excursion to 13.1 g/dL.  
Vadadustat was generally well-tolerated across the 3 treatment groups. There were no apparent 
differences in the type or frequency of the AEs that were reported across the 3 dosing groups.  
The type and frequency of SAEs were consistent with events that have been described in patients 
with DD-CKD with multiple comorbidities. No SAEs were reported by the investigators as 
related to vadadustat. No deaths, strokes, or transient ischemic attacks were reported. 
Summary 
Overall, oral administration of vadadustat has been well tolerated in clinical studies. The 
frequency and types of SAEs in Akebia-sponsored trials (Phase 1 and 2) have been consistent 
with those expected in a population with chronic renal failure. The most commonly reported AEs 
included nausea and diarrhea, and generally, these events have been mild to moderate in severity, 
non-serious, and resolved on vadadustat therapy. In some cases, these AEs lead to 
discontinuation of vadadustat therapy.   
Vadadustat has also demonstrated a clear and consistent dose-response pattern in both PK and 
PD with sequential increases in EPO, reticulocytes, and Hb. The hematologic response has been 
accompanied by dose-responsive increase in iron mobilization (ie, decreases in hepcidin and 
ferritin, and an increase in TIBC). Together, these effects have stimulated an increase in 
reticulocytes and Hb, and such a combination of effects indicates that vadadustat increases 
erythropoiesis through a coordinated response. Furthermore, this is achieved with a modest 
increase in the daily peak level of EPO, which returns to baseline prior to the subsequent dose (in 
a manner that mimics the physiologic diurnal response in healthy individuals).  
Vadadustat is eliminated from the body by dual routes (renal and fecal), 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.  
Furthermore, in a clinical study conducted to evaluate the effect of hemodialysis on the 
exposures to vadadustat, the hemodialysis procedure did not impact the exposures of vadadustat 
or its metabolites, indicating that vadadustat can be administered irrespective of the dialysis 
session. 
Collectively, these data support the ongoing clinical development of vadadustat as an orally 
bioavailable agent for the treatment of anemia secondary to CKD, and the safety and efficacy of 
vadadustat in subjects with DD-CKD and NDD-CKD are currently being evaluated in global 
Phase 3 studies (PRO2TECT-Correction, PRO2TECT-Conversion, INNO2VATE-Correction, and 
INNO2VATE-Conversion; ClinicalTrials.gov Identifier: NCT02648347, NCT02680574, 
NCT02865850, and NCT02892149, respectively). 


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 25 
4.6 
Potential Benefits and Risks 
Please see the vadadustat Investigator’s Brochure for additional information. 
Vadadustat offers the potential of flexible oral dosing that is easier to titrate than injectable 
hormone ESAs. The enhancement in the normal diurnal variation in EPO concentration without 
continuous elevation of EPO levels may avoid the overshoots 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 the suggestion from US Food and Drug Administration (US FDA) that 
fluctuations in Hb concentrations, rapidly increasing Hb levels, and overshoots of the target level 
are associated with an increased risk of CV events (Unger 2007; Unger 2010).  
In addition, HIF activation is associated with increased expression of ferroportin and transferrin 
and decreased expression of hepcidin (Liu 2012; Peyssonnaux 2007; Tacchini 1999). These 
changes in iron biomarkers are consistent with enhanced iron mobilization and utilization to 
promote hemoglobin synthesis and erythropoiesis. In the Phase 1b multiple-ascending-dose 
study (AKB-6548-CI-0002), a prominent effect on iron metabolism was noted with the dosing of 
vadadustat, including a dose responsive increase in TIBC, and decreases in hepcidin and ferritin.  
A similar pattern was observed in the Phase 2a and Phase 2b studies AKB-6548-CI-0003, 
AKB-6548-CI-0004, AKB-6548-CI-0005, AKB-6548-CI-0007, and AKB-6548-CI-0011. 
In preclinical safety studies, the main findings originated from an exaggerated pharmacological 
response, including increased erythropoiesis and hematocrit, and at high doses, blood 
hyperviscosity. These findings were reproducible across species and studies, were 
dose-dependent and showed reversibility.  
In the completed clinical studies, vadadustat has been generally well-tolerated with no apparent 
differences among various dose groups and control groups, and consistent with the expected 
safety profile based on the evaluated patient populations. The AEs most frequently assessed by 
investigators as related to vadadustat and which occurred more frequently in subjects who 
received vadadustat versus placebo are nausea and diarrhea. Generally, these events have been 
mild to moderate in severity, non-serious, and resolved on vadadustat therapy, although these 
events led to discontinuation of vadadustat in some subjects. 
4.7 
DD-CKD Patients Hyporesponsive to ESAs 
Although renal anemia in patients undergoing chronic hemodialysis treatment is generally 
treated with ESAs and iron supplements, there is a significant proportion of such patients who 
cannot achieve the target Hb range or they require persistently high doses of ESA to achieve the 
Hb target (Luo 2016). Such hyporesponsiveness to ESAs has been shown to be associated with 
poor patient outcomes, including higher mortality and a greater rate of missed hemodialysis 
treatments (Brookhart 2010; Inrig 2012; Kainz 2010; Kalantar–Zadeh 2009; Kilpatrick 2008; 
Luo 2016; McCullough 2013; Okazaki 2014; Weinhandl 2011). Moreover, because missed 
dialysis treatments frequently result in hospitalizations, it is likely that ESA hyporesponsiveness 
also has economic implications for health insurers and taxpayers beyond the management of a 
patient’s anemia. 
The mechanisms underlying ESA hyporesponsiveness have not been delineated, but various 
factors have been associated with a diminished response to ESAs including inflammatory 
response (eg, increased levels of the inflammatory biomarkers hepcidin and C-reactive protein 
[CRP]), iron deficiency (absolute or functional), inadequate vitamin D, an impaired nutritional 


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state, hyperthyroidism, low dialysis adequacy, and underlying illnesses or infections (Ganz 2016; 
Icardi 2013; Inrig 2011; Kalantar-Zadeh 2003; Lee 2003; Locatelli 2006; Lopez-Gomez 2008; 
Luo 2016; Movilli 2001). 
Unlike ESAs, clinical studies of vadadustat have demonstrated correction and maintenance of Hb 
with improved iron mobilization following vadadustat administration as reflected by a decrease 
in hepcidin and ferritin levels and an increase in TIBC (Studies AKB–6548–CI–0003, 
AKB-6548-CI-0004, AKB-6548-CI-0005, AKB-6548-CI-0007, and AKB-6548-CI-0011; 
Haase 2015; Haase 2016b; Pergola 2016).  In addition, post ad hoc analysis of results from 
Studies AKB-6548-CI-0007 and AKB-6548-CI-0011 demonstrated that the Hb response and 
vadadustat dose requirement for Hb maintenance were independent of the level of baseline 
markers of systemic inflammation (ie, CRP and hepcidin) and were not correlated with a 
patient’s prior ESA dose (Haase 2016a; Haase 2016c).  Thus, vadadustat may offer a new 
treatment option for this underserved patient population. 
The ongoing, global, Phase 3 open-label, randomized trial evaluating vadadustat versus 
darbepoetin alfa in patients with DD-CKD (INNO2VATE-Conversion; ClinicalTrials.gov 
Identifier: NCT02892149), allows the inclusion of subjects who could be characterized as ESA 
hyporesponsive, among a broader range of subjects who would not be characterized as ESA 
hyporesponsive. 
The present study is designed to specifically assess the ability of vadadustat to increase the Hb 
concentration in subjects with anemia secondary to DD-CKD who are hyporesponsive to ESAs. 
 


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Subjects who meet all inclusion and none of the exclusion criteria will be randomly allocated 
(1:1 ratio) using the interactive web response (IWR) system to participate in either the vadadustat 
or epoetin alfa treatment arm. Permuted block randomization will be used to assign subjects to 
treatment. 
Study Treatment Period (Baseline [Day 1] to Week 20): 
Study drug treatment will aim to maintain Hb level within target range of 10.0 to 11.0 g/dL. 
• Vadadustat treatment arm: Subjects who are randomized to the vadadustat treatment arm 
will discontinue epoetin and will initiate vadadustat dosing at 
 on Day 1.  
Additional information on vadadustat dosing adjustments is provided in Section 8.3.5. 
• Epoetin alfa treatment arm: Subjects who are randomized to the epoetin alfa treatment arm 
will continue to receive epoetin alfa at the same dose that they were receiving during the 
screening period. Epoetin alfa dose can be titrated as clinically indicated; and additional 
information is provided in Section 8.3.4. 
Safety Follow-Up Period (Weeks 20 to 24): 
The 4-week safety follow-up period starting at Week 20 will be followed by a post-treatment 
safety assessment conducted at Week 24. 
Internal Safety Assessment 
An internal Safety Monitoring Committee (SMC) will review safety data on a regular basis, 
throughout the course of the study. The details of the SMC will be outlined in a study-specific 
safety monitoring plan. 
6.2 
Rationale for Study Design 
The primary objective of this study is to evaluate the ability of vadadustat to increase the Hb 
concentration in subjects with anemia secondary to DD-CKD who are hyporesponsive to ESAs.  
In this study, epoetin alfa has been chosen as an active comparator as it is marketed and available 
globally, has an extensive safety profile, and has been the standard of care in many hemodialysis 
centers, including DaVita dialysis centers in the US. Since the study will be conducted mostly at 
DaVita dialysis centers in the US, a single active comparator epoetin alfa has been selected, 
thereby reducing variability and simplifying trial logistics.  
In a previous study (AKB-6548-CI-0011), subjects with DD-CKD who were directly switched 
from ESA to vadadustat achieved stable levels of Hb over 16 weeks. This study also 
demonstrated improvement of iron mobilization, as reflected by increases in TIBC and serum 
iron, and decreases in serum ferritin and hepcidin levels.  
The present study is to apply a similar design to switch subjects from their current dose of ESA 
to vadadustat. Subjects who are randomized to the direct switching arm will have an initial 
vadadustat dose of 
, with the flexibility of increasing or decreasing the dose level 
based on Hb response, which will be closely monitored throughout the study.  
The study design also includes a comprehensive vadadustat dose adjustment guideline and 
epoetin alfa rescue algorithm to ensure Hb can be maintained within the target range of 
10.0-11.0 g/dL (see Sections 8.3.5 and 8.3.10). 


Akebia Therapeutics, Inc.  
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6.3 
Dose Justification 
To date, vadadustat has been evaluated in patients with DD-CKD and NDD-CKD.  In the present 
Phase 2, open-label, study of ESA hyporesponsive subjects, an initial dose of
 along with 
a dose range of 
, is planned.   
 
 
 
 
 
 
 
 
 
 
 
 
In the ongoing, global, Phase 3 open-label, randomized trial evaluating vadadustat versus 
darbepoetin alfa in subjects with DD-CKD (INNO2VATE-Conversion; ClinicalTrials.gov 
Identifier: NCT02892149), 
 
 
 
 
 


Akebia Therapeutics, Inc.  
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Vadadustat demonstrated dose-proportional PK and achieved serum EPO concentrations that are 
considered physiologic and below exposures achieved with injectable ESAs. A higher incidence 
of gastrointestinal AEs (e.g., nausea, diarrhea, abdominal pain) was observed in groups treated 
with 
 compared with lower vadadustat doses or placebo. Most AEs 
were mild, short-lived (1 or 2 days), and assessed as unrelated by investigators. No AEs led to 
study withdrawal, and no serious AEs were reported. In addition, there were no clinically 
meaningful changes or abnormalities in vital signs, safety laboratory studies, or ECG parameters.  
In addition, the mean anticipated maximum concentration observed (Cmax)and area under the 
curve (AUC) at steady state for the 750 mg once daily dose are expected to be approximately 
20% higher than those seen with the 600 mg once daily dose, previously tested in DD-CKD and 
NDD-CKD patient populations.  
 
A vadadustat dosing algorithm designed to maintain Hb in a predictable and controlled manner 
while minimizing abrupt increases or excessive rises in Hb levels is being utilized in the global 
Phase 3 studies. In the present study, frequent Hb monitoring and use of the vadadustat dosing 
algorithm will be implemented to mitigate the potential risk of a rapid Hb rise.  Furthermore, the 
protocol specifies that phlebotomy may be considered in the setting of high Hb levels (>14 g/dL) 
or a high Hb rate of rise, based on the Investigator’s judgment. Lastly, the Phase 2b NDD-CKD 
study (CI-0007) demonstrated that cessation of treatment resulted in prompt reduction in mean 
Hb to baseline values. 
 
Given that vadadustat only results in physiologic increases in erythropoietin―as opposed to 
pharmacologic increases following administration of recombinant ESAs―it is anticipated that 
the beneficial effect of HIF stabilization with vadadustat will be related to improvements in iron 
mobilization to the bone marrow and promotion of erythropoiesis, if observed in this ESA 
hyporesponsive patient population. Conversely, to minimize the possibility for sudden declines 
in Hb in the vadadustat treatment arm, frequent Hb monitoring, and guidance for rescue therapy 
(Epoetin Alfa Rescue Therapy and/or Red Blood cell transfusions) are provided. 


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8. Acute coronary syndrome (hospitalization for unstable angina or myocardial infarction), 
surgical or percutaneous intervention for coronary, cerebrovascular or peripheral artery 
disease (aortic or lower extremity), surgical or percutaneous valvular replacement or repair, 
sustained ventricular tachycardia, hospitalization for heart failure, or stroke within 12 weeks 
prior to or during screening 
9. History of deep vein thrombosis (DVT) or pulmonary embolism (PE) within 8 weeks prior to 
or during screening 
10. History of active malignancy within 2 years prior to or during screening, except for treated 
basal cell carcinoma of skin, curatively resected squamous cell carcinoma of skin, or cervical 
carcinoma in situ 
11. History of hemosiderosis or hemochromatosis 
12. History of prior organ transplantation or scheduled organ transplant (subjects on the kidney 
transplant wait-list or with a history of failed kidney transplant are not excluded), or prior 
hematopoietic stem cell or bone marrow transplant; note that corneal transplants and stem 
cell therapy for knee arthritis are not excluded 
13. History of an acute or chronic infection requiring intravenous antibiotics within 4 weeks 
prior to randomization 
14. Hypersensitivity to vadadustat, epoetin alfa, or any of their excipients 
15. 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 
16. Previous participation in this study, previous participation in a Phase 3 study of vadadustat, 
or previous participation in a study with another hypoxia-inducible factor prolyl-hydroxylase 
inhibitor (HIF-PH inhibitor) other than vadadustat 
17. Females subjects who are pregnant or breastfeeding; or female subjects of childbearing 
potential who are unable or unwilling to use an acceptable method of contraception (see 
Section 9.2.4) 
18. Non-vasectomized male subjects who are unable or unwilling to use an acceptable method of 
contraception (see Section 9.2.4) 
19. Any other reason, which in the opinion of the investigator, would make the subject not 
suitable for participation in the study 
7.4 
Retesting and Rescreening 
7.4.1 
Retesting  
Retesting is defined as repeating laboratory tests within the same Screening Period. 
All screening laboratory tests, including any repeat measurements, must be performed within the 
28-day screening window with a minimum of 4 days between the last qualifying repeat 
measurement and the baseline visit on Day 1 (see Section 9.1). 


Akebia Therapeutics, Inc.  
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Subjects who initially fail to qualify for the study based on laboratory test results may have their 
laboratory value retested once for each laboratory parameter within the 28-day 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 (see Section 7.4.2). 
For eligibility purposes, if Hb at screening visit 1 (SV1) is 10.0 to 10.5 g/dL, 1 retest complete 
blood count (CBC) should be performed prior to SV2.  If the retest Hb is ≥10.0 g/dL, the subject 
should not proceed with SV2.  If the Hb at SV1 is >10.5 g/dL, the subject should not proceed 
with any further screening procedures at that time. 
7.4.2 
Rescreening  
Subjects who fail to meet the qualifying criteria for Hb may be considered for rescreening 
outside of the initial 28-day screening period at the discretion of the investigator, if it is 
considered 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 appropriate 
replacement therapy. 
Screening is limited to 3 attempts (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 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. If this occurs, prompt notification will be given 
to investigators, Institutional Review Boards (IRBs), and regulatory authorities in accordance 
with regulatory requirements. 
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. 
The investigator must notify the sponsor if the study is terminated by the investigator or the IRB 
at the site.  If the investigator, IRB, or sponsor decides to terminate or suspend the study conduct 
at an investigative site for safety, non-enrollment, non-compliance with the protocol, or other 
unanticipated reasons, the above parties will be promptly notified. 


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 35 
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 
NOTE: The need for rescue therapy does not constitute study completion and are not criteria for 
subject withdrawal from the study or permanent discontinuation of study drug (vadadustat or 
epoetin alfa). 
7.6.1 
Subject Completion 
A subject will be considered as having completed the study after completing participation in the 
Week 24 visit (end of the 4-week safety follow-up period). 
7.6.2 
Individual Subject Study Drug Discontinuation or Individual Subject 
Discontinuation 
The investigator must document the primary reason for temporary or permanent study drug 
discontinuation on the case report form (CRF). For subjects who discontinue study drug, the 
investigator should resume treatment based on standard of care and clinical judgment. 
7.6.2.1 Interruption of Study Drug by Individual Subjects 
Subjects who interrupt their study drug (vadadustat or epoetin alfa) after receiving the first dose 
on Day 1 and prior to completion of the study, should continue with the Schedule of Activities 
and safety assessments through Week 20, and should complete the 4-week safety follow-up 
period and the Week 24 visit assessments (see Appendix A). 
During the study, it is anticipated that subjects may interrupt their study drug for any of the 
following reasons: 
• Unacceptable toxicity or drug intolerability 
• Investigator’s discretion 
• Adverse event 
• Missed dialysis visit 
• Other reasons 
7.6.2.2 Permanent Discontinuation of Study Drug by Individual Subjects 
NOTE:  Subjects who permanently discontinue study drug (after randomization and prior to 
completion of the study drug treatment period) will complete the end-of-treatment (EOT) 
(Week 20) visit assessments within 1 day of stopping study drug (if possible), and should 
complete the 4-week safety follow-up period and the Week 24 visit assessments. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. 


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Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 37 
8.2.2 
Dispensing Procedures for Vadadustat 
The site pharmacist or designated study personnel will be responsible for preparing study drugs 
for dispensation, and will maintain an investigational medication distribution form itemizing all 
study drugs dispensed to and returned from each subject during the study. 
At the baseline (Day 1) visit, subjects who are randomized to the vadadustat treatment arm will 
be provided with 1 bottle of vadadustat. Each bottle of vadadustat will contain 100 tablets of 
vadadustat (150 mg/tablet). 
Subjects should be instructed to bring unused vadadustat and empty bottles to each study visit for 
product accountability. Subjects will be instructed to finish 1 bottle before opening a new bottle. 
Empty bottles will be collected at the study visits. Previously dispensed bottles (whether opened 
or unopened) with remaining tablets may be re-dispensed to the subject during the dosing phase 
of the study. 
Resupply of additional vadadustat at subsequent visits will be managed via the IWR system and 
will be dependent on the current dose level of vadadustat and the number of tablets remaining in 
the subject’s current vadadustat supply at a given study visit.   
8.2.3 
Product Accountability and Destruction 
Vadadustat accountability should be an ongoing process throughout the study. Vadadustat 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 should be maintained that accurately reflect the drug accountability throughout the 
study. 
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, or destruction, and copies will be sent to the sponsor or 
designee. 


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 38 
All unused 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 in accordance with 
local procedures. 
8.3 
Treatment of Subjects 
Study drug treatment will aim to maintain Hb level within target range of 10.0 to 11.0 g/dL. 
8.3.1 
Randomized Treatment Group Assignments 
Subjects will be randomly allocated (1:1 ratio) via the IWR system to participate in either the 
vadadustat treatment arm or the epoetin alfa treatment arm. On Day 1, subjects will withhold 
dosing until it is confirmed which treatment arm (vadadustat or epoetin alfa) they are assigned to. 
8.3.2 
Blinding During the Study 
This is an open-label study and will not involve any blinding procedures. 
8.3.3 
Measurement of Hemoglobin Levels for Dose Adjustment Consideration 
Hemoglobin values will be measured by a central laboratory. Study drug treatment will aim to 
maintain Hb level within target range of 10.0 to 11.0 g/dL. Hemoglobin will be monitored 
throughout the study to determine the dose of study medication (vadadustat or epoetin alfa) that 
subjects should receive. Refer to Section 8.3.5. Hb levels can be measured more frequently based 
on investigator’s clinical judgment. 
If dose adjustment is recommended based on Hb value and protocol-specified guidelines, dosing 
instructions can be provided to the subject during the next dialysis session at the investigative 
site (or dialysis center) or during an unscheduled site visit within 3 business days after receiving 
the Hb result from the central laboratory. If scheduling the subject within this time frame is not 
possible, dosing instructions will be provided to the subject over the telephone. 
8.3.4 
Dosing Regimen for the Epoetin Alfa Treatment Arm 
For subjects who are randomized to the epoetin alfa treatment arm, the initial dosing regimen in 
the study (starting from baseline [Day 1] visit) will be the same dose that they were receiving 
during the screening period. 
Epoetin alfa dose will be administered and titrated as clinically indicated based on an individual 
subject’s central lab Hb value and the approved label for adult patients with CKD on dialysis. 


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 39 
8.3.5 
Dosing Regimen for the Vadadustat Treatment Arm and Guidelines for 
Vadadustat Dose Adjustment 
Subjects assigned to the vadadustat arm will discontinue epoetin alfa and take vadadustat once 
daily for 20 weeks. 
The following dosing regimen are for subjects who are randomized to the vadadustat treatment 
arm: 
• Vadadustat dosing (Day 1 to Week 20) 
- Starting dose of vadadustat: 
 once daily) starting at 
baseline/Day 1. The first dose of vadadustat will be administered at the investigative 
site after other baseline procedures have been completed. Thereafter, vadadustat will 
be taken once daily in the dialysis centers or on an outpatient basis. 
- The vadadustat dose can be up-titrated every 4 weeks or down-titrated more 
frequently based on the target Hb range of 10.0-11.0 g/dL.   
- 
 
 
- Dosing instructions: Subjects should be instructed to swallow intact tablet(s) of 
vadadustat with water or another beverage. Subjects may take vadadustat with or 
without food.  The full dose should be taken at approximately the same time each 
day.  The subject should be instructed to take any oral iron supplements (including 
multivitamins containing iron), iron containing phosphate binders, or any medication 
containing iron at least 2 hours before or 2 hours after taking the vadadustat dose. 
- After the end of vadadustat treatment at Week 20 (or following early discontinuation 
of vadadustat), subjects will resume dosing with epoetin alfa (or another ESA), based 
on the approved label for adult patients with CKD on dialysis. 
Guidelines for Vadadustat Dose Adjustments 
Vadadustat dose adjustments will be guided by an IWR system based on the Hb value and 
programmed Dose Adjustment Algorithms (as presented below). 
When adjusting vadadustat dose, investigators should consider Hb rate of rise, rate of decline, 
and the subject’s clinical condition (eg, recent illness, volume depletion, and volume overload).  
In cases of extenuating clinical circumstances, the investigator may elect to dose outside the 
IWR system dosing recommendation to maintain the Hb within the target range. In such cases, 
the clinical circumstances must be documented in the subject’s record and IWR system. 
• Do not increase the vadadustat dose more frequently than once every 4 weeks.  Decreases in 
vadadustat dose can occur more frequently. Avoid frequent vadadustat dose adjustments.  
• If a dose adjustment is required to maintain Hb within the target range (10.0-11.0 g/dL), then 
increase or decrease the vadadustat dose by 1 tablet. 
• If the Hb decreases below 10.0 g/dL, increase the dose of vadadustat by 1 tablet. 
• If the Hb exceeds 11.0 g/dL, interrupt vadadustat until Hb decreases to 11.0 g/dL or less, then 
resume dosing of vadadustat with 1 fewer tablet.  


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 40 
NOTE: If subject was on 1 tablet prior to interruption, then resume dosing with 1 tablet. 
• If the Hb increases rapidly (eg, >1.0 g/dL in any 2-week period or >2.0 g/dL in any 4-week 
period), and a subject is not receiving epoetin alfa, decrease the dose of vadadustat by 
1 tablet. 
8.3.6 
Late or Missed Doses of Study Drug Treatment 
Subjects on vadadustat should be instructed to take the study drug at approximately the same 
time each day. If a dose is forgotten, subjects should be instructed to take the dose as soon as 
they remember during the same day. If a forgotten dose is not remembered on the same day, the 
subject should skip the dose and resume the normal dosing schedule the following day. Subjects 
should not double-up on missed doses. 
Epoetin alfa dose (including handling of late or missed dose) should be administered as clinically 
indicated based on an individual subject’s Hb value and the approved label for adult patients 
with CKD on dialysis. 
8.3.7 
Compliance with Vadadustat Treatment 
Subjects will be questioned regarding dosing compliance and whether they have questions or 
have experienced any problems related to vadadustat dosing. The investigator will also maintain 
drug accountability logs itemizing vadadustat dispensed to and returned from each subject during 
the study. Treatment compliance will be determined from these forms along with the subject 
questioning. 
Subjects who miss doses will be counseled on the importance of compliance. 
NOTE: At the Week 2 and Week 18 visits, subjects in the vadadustat treatment arm should be 
reminded and instructed to hold their vadadustat dose on the day of the Week 4 and Week 20 
visits (respectively). This is because a blood sample for PK analysis will be collected on the day 
of the Week 4 and Week 20 visits before the vadadustat dose is administered at the investigative 
site.  
Subjects will also be questioned regarding the timing of their last dose of vadadustat during PK 
sample collection at the Day 1 visit and Week 4 and Week 20 visits. The date and time of these 
doses should be recorded. 
8.3.8 
Continuation of Study Drug Treatment 
Subjects in the vadadustat treatment arm will not receive vadadustat past the treatment period of 
approximately 20 weeks. Subjects in the vadadustat treatment arm who complete Week 20, or 
discontinue early, will resume dosing with epoetin alfa (or another ESA) at Week 20 after all 
EOT procedures are completed. 
8.3.9 
Iron Supplementation (Information on Allowed Use) 
Investigators should prescribe iron supplementation (intravenous, oral, or intradialytic) as needed 
and maintain ferritin ≥100 ng/mL and TSAT ≥20%. The duration, dosage, and frequency of use 
of supplemental iron should be recorded. 
Important: Because of the potential for oral iron to decrease the bioavailability of vadadustat, 
vadadustat should not be administered concurrently with an oral iron supplements (including 


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 41 
multivitamins containing iron), iron containing phosphate binders, or any medications containing 
iron.  Subjects should be instructed to take any of these medications at least 2 hours before or 
2 hours after taking the dose of vadadustat. 
8.3.10 
Rescue Therapy Guidelines 
Hemoglobin levels will be monitored throughout the study at scheduled visits and can be 
measured more frequently based on investigator’s clinical judgment. 
Rescue therapy with RBC transfusion or epoetin alfa are allowed, but not required during the 
treatment period. The following rescue therapy guidelines are provided to ensure the safety of 
study subjects and to standardize the use of rescue in the study. In cases of extenuating clinical 
circumstances, the investigator may elect to dose outside the rescue therapy guidelines to 
maintain the Hb within the target range. In such cases, the clinical circumstances should be 
documented in the subject’s record. 
• RBC transfusion: Investigators should use their investigative site’s transfusion guidelines 
when determining whether to transfuse a study subject.  In general, in the event of an acute or 
severe loss of blood, RBC transfusion should be administered as clinically indicated. In less 
severe instances but where there may be worsening of anemia or moderate to severe 
symptoms of anemia, RBC transfusions are permitted based on the investigator’s clinical 
judgment. Study drug (vadadustat or epoetin alfa) may be continued during the RBC 
transfusion period. 
• Epoetin alfa rescue therapy: Starting at Week 6, subjects in both treatment arms will be 
allowed (although not required) to have their Hb rescued with epoetin alfa. When 
possible, a subject on vadadustat should be on maximum dose of vadadustat for 2 weeks 
prior to epoetin alfa rescue. Epoetin alfa rescue therapy should be administered based on 
the approved US product label for adult patients with CKD on dialysis. 
- To qualify for epoetin alfa rescue therapy, each of the following conditions must be 
fulfilled.   
NOTE: Epoetin alfa rescue therapy should be stopped when Hb is ≥9.0 g/dL. 
• 
The subject has experienced a clinically significant worsening of their anemia or 
symptoms of anemia (eg, fatigue, weakness, shortness of breath, chest pain, 
confusion, or dizziness) compared to baseline 
• 
The subject’s Hb is confirmed to be <9.0 g/dL 
• 
The Hb level decreased >0.5 g/dL from baseline 
• 
Reducing the risk of alloimmunization or transfusion-related risks or both is a 
goal 
- For the epoetin alfa treatment arm: 
• 
In addition to meeting the rescue criteria noted above, dosing and administration 
of epoetin alfa rescue therapy should be based on the approved label for adult 
patients with CKD on dialysis. 


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 42 
- For the vadadustat treatment arm: 
• 
Epoetin alfa rescue may not be considered until the next study visit if a subject’s 
current vadadustat dose can be increased (ie, if the subject’s last vadadustat dose 
increase was at least 4 weeks earlier and the subject is currently receiving a 
vadadustat dose of 600 mg/day or less, then vadadustat dose can be increased by 
1 tablet to maintain Hb within the target range of 10.0-11.0 g/dL). 
NOTE: vadadustat must be temporarily interrupted during epoetin alfa rescue 
therapy. After epoetin alfa rescue therapy is completed, vadadustat should be 
resumed and adjusted per the dose adjustment guidelines (Section 8.3.5). 
A minimum interval must be observed prior to restarting vadadustat after the last 
dose of rescue medication, and treatment may be resumed 2 days after last dose of 
epoetin alfa rescue.   
8.3.11 
Therapeutic Phlebotomy 
If a subject’s Hb exceeds 14.0 g/dL or the rate of rise of Hb raises concern to the investigator, the 
subject may be phlebotomized based on the investigator’s clinical judgment. The method of 
phlebotomy will be in accordance with the investigative site’s guidelines and standard clinical 
practice. 
8.4 
Prior and Concomitant Therapy 
8.4.1 
General 
All medications (except those routinely administered as part of the dialysis procedure or flushes 
used for routine catheter maintenance) taken within 30 days prior to Day 1 and through the final 
study visit should be recorded on the appropriate CRF. In addition, ESA history will be recorded 
in the 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 on the appropriate CRF.   
8.4.2 
Erythropoiesis-Stimulating Agents 
Subjects are prohibited from taking non-protocol ESAs starting from the screening period and 
through Week 20, unless the subject permanently discontinues study treatment. 
Epoetin alfa rescue therapy is allowed as presented in Section 8.3.10. 
8.4.3 
RBC Transfusion, Epoetin Alfa Rescue Therapy, Iron Supplementation, and 
Therapeutic Phlebotomy 
Use of epoetin alfa rescue therapy, iron supplementation, and therapeutic phlebotomy within 
30 days prior to Day 1 will be recorded. 
Receipt of RBC transfusion, epoetin alfa rescue therapy, iron supplementation, and therapeutic 
phlebotomy during the study will be recorded. 


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 43 
NOTE: RBC transfusion within 4 weeks prior to or during screening is a study exclusion 
criterion. 
8.4.4 
Dialysis Treatment and Renal Replacement Therapy 
Information on dialysis treatment, including dialysis vascular access type, dialysis adequacy, and 
history of and changes in renal replacement therapies, will be recorded. 
8.4.5 
Investigational Medications 
Study subjects should not have received any investigational medication or participated in an 
investigational study within 30 days or 5 half-lives of the investigational medication (whichever 
is longer), prior to screening.  In addition, subjects should not have participated in a study with 
another HIF-PH inhibitor other than vadadustat. 
Subjects should not take another investigational medication while participating in this study. 


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Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
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Page 45 
9.2.2 
Informed Consent 
Informed consent must be obtained and legally signed prior to a subject’s entry into the study 
and before any protocol-directed procedures (including screening tests) are performed (see 
Section 15.3). After providing informed consent and receiving a unique subject identification 
number, subjects will undergo various screening activities. Additionally, subjects will be asked 
to provide separate written informed consent for the collection and storage of a blood sample for 
future genetic analyses. 
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. 
9.2.4 
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 drug. In addition, 
men must not donate sperm during the study and for at least 90 days after the last dose of study 
drug. 
Acceptable methods of contraception are defined as follows: 
• Female subjects must be surgically sterile or postmenopausal (no menses for at least 1 year) 
• Female subjects of childbearing potential (ie, are not surgically sterile or postmenopausal) 
must have negative pregnancy test results (see Section 9.3.2 for information on pregnancy 
tests) 
• 
Female subjects of childbearing potential (ie, are not surgically sterile or postmenopausal) 
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 drug 
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 drug 
o Intrauterine contraceptive device starting at the screening visit, throughout the study, and 
for 30 days after the last dose of study drug 


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Clinical Protocol 
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o Double-barrier method (such as male condom, female condom, diaphragm, sponge, or 
cervical cap together with spermicidal foam, gel, film, or suppository) starting at the 
screening visit, throughout the study, and for 30 days after the last dose of study drug. 
9.2.5 
Randomization 
Subjects who meet all inclusion and none of the exclusion criteria will be randomly allocated 
(1:1 ratio) using the IWR system to participate in either the vadadustat or epoetin alfa treatment 
arm. Permuted block randomization will be used to assign subjects to treatment. 
9.3 
Study Procedures and Evaluations 
9.3.1 
Clinical and Safety Assessments 
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. Clinical evaluations should be completed prior to dialysis on the day of the visit, if 
applicable.   
• 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 measurement. After the 
screening period, an abbreviated, symptom-directed physical examination may be performed 
based on investigator’s clinical judgment. 
• Dry weight, dialysis adequacy, and dialysis treatment review: Dry weight will be recorded.  
Dialysis adequacy (measured as Kt/V), as available from local collection, will be recorded.  
Dialysis treatment will be reviewed including frequency of dialysis and vascular access type 
(eg, arteriovenous fistula, arteriovenous graft, and venous catheter). 
• Vital signs: Vital signs will include blood pressure, heart rate, respiratory rate, and body 
temperature.  Blood pressure and heart rate will be collected in the seated position after 
5 minutes of rest. Vital signs should be collected prior to blood draws, when possible. 
• 12-lead electrocardiography (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 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 


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information is provided in Section 10 and follow-up of unresolved AEs, 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. See Section 8.4 for additional information. 
9.3.2 
Laboratory Evaluations 
Samples for laboratory assays will be sent to a central laboratory for analysis (unless noted 
otherwise).  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: 
• Pregnancy test(s): Female subjects of childbearing potential (ie, are not surgically sterile or 
postmenopausal) must participate in pregnancy test(s). 
- A serum pregnancy test should be performed within 4 to 8 days prior to the baseline 
(Day 1) visit to allow sufficient time to obtain the pregnancy test results prior to 
randomization on Day 1. The results must be available and negative before the 
subject initiates study drug. 
- If the serum pregnancy test takes place more than 8 days prior to Day 1, then one of 
the following tests should be conducted: 
• 
Subjects who produce urine will participate in a urine pregnancy test on Day 1.  
The results must be available and negative before the subject initiates study drug. 
• 
Subjects who cannot produce urine will be asked to return to the study site within 
4 to 8 days prior to Day 1 for an unscheduled serum pregnancy test. The results 
must be available and negative before the subject initiates study drug. 
- Serum pregnancy test samples will be analyzed by the central lab and urine 
pregnancy test samples will be analyzed by the local lab. 
- 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.   
• CBC: A CBC with differential will be performed at the baseline (Day 1) visit and at the 
Week 20 (or EOT) visit. At the other visits including the screening visits, a CBC without 
differential will be performed. CBC with differential will include: 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, lymphocytes, 
monocytes, eosinophils, and basophils), and platelets.   
Hemoglobin will be monitored throughout the study to determine the dose of study 
medication (vadadustat or epoetin alfa) that subjects should receive. Refer to Section 8.3.5 
Hb levels can be measured more frequently based on investigator’s clinical judgment. 
• Reticulocyte count: An automated reticulocyte count (both absolute and percent) will be 
performed. 


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• Coagulation tests: Blood sample will be collected to assess the prothrombin time, partial 
thromboplastin time, and international normalized ratio (INR). 
• Folate and vitamin B12: Blood sample will be collected to assess folate and vitamin B12 
levels. 
• C-reactive protein: Blood sample will be collected to assess CRP. 
• Serum chemistry: Blood sample will be collected to assess sodium, potassium, bicarbonate, 
chloride, calcium, magnesium, phosphorus, glucose, creatinine, blood urea nitrogen, creatine 
phosphokinase, uric acid, albumin, and total protein. 
• Liver function tests: Blood sample will be collected to assess total bilirubin, alkaline 
phosphatase, ALT/SGPT, AST/SGOT, and lactate dehydrogenase. 
• Iron indices: Blood samples will be collected to assess the following indices: ferritin, iron, 
TIBC, and TSAT. 
• Lipid panel: Blood sample will be collected to assess total cholesterol, low density 
lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides. 
• PK evaluations (for subjects in the vadadustat treatment arm): Plasma samples will be 
analyzed for vadadustat and its metabolites.  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. 
• Additional biomarkers: Blood samples for additional biomarker analysis (eg, hepcidin and 
VEGF) will be collected. 
• Erythropoietin: Blood samples for analysis of EPO levels will be collected. 
• Exploratory analyses: Additional blood samples may be collected for exploratory analyses of 
biomarkers (eg, factors relating to the activation of the HIF pathway). Subjects will also be 
asked to provide optional written informed consent to obtain and store a blood sample for 
future genetic analyses. 
9.3.3 
Procedures Related to Study Drug Treatments 
• Epoetin alfa dosing (for epoetin alfa treatment arm only): See Section 8.3.4 for additional 
information. 
• Epoetin alfa dose reduction (for vadadustat treatment arm only): See Section 8.3.5 for 
additional information. 
• Vadadustat dosing (for vadadustat treatment arm only): See Section 8.3.5 for additional 
information. 
• Vadadustat drug dispensation (for vadadustat treatment arm only): See Section 8.2.2 for 
additional information. 
• Review vadadustat dosing instructions (for vadadustat treatment arm only): See Section 8.3.5 
for additional information. 
• Vadadustat drug reconciliation (for vadadustat treatment arm only): See Section 8.2.2 for 
additional information. 


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• Review vadadustat dosing compliance (for vadadustat treatment arm only): Subjects will be 
questioned regarding dosing compliance.  See Section 8.3.7 for additional information. 
• Resuming dosing with epoetin alfa (or another ESA) (for vadadustat treatment arm only): 
See Section 8.3.5 for additional information. 
• Recording of use of rescue therapy (RBC transfusions and epoetin alfa rescue therapy): See 
Section 8.3.10 for additional information. 
• Recording of use of supplemental iron: See Section 8.3.9 for additional information. 
• Recording of use of therapeutic phlebotomy: See Section 8.3.11 for additional information. 
9.4 
Schedule of Activities 
The Schedule of Events in Appendix A shows the timing of planned study procedures. 
Subjects will take study drug per their treatment randomization.  
Every effort should be made to adhere to this procedure schedule and the planned assessments 
should be completed at each study visit. 
NOTE: If possible, study visits should be scheduled on the day of the first hemodialysis session 
of the week to allow for the turnaround time for central lab Hb values (and dose adjustment as 
needed) before the end of the workweek. 
9.4.1 
Screening Visits 
Screening visits must be performed within 4 weeks prior to dosing on Day 1 and the last 
screening visit must be completed at least 4 days before dosing starts on Day 1 to allow for 
laboratory test results to be available prior to initiation of study drug. 
For eligibility purposes, if Hb at SV1 is 10.0 to 10.5 g/dL, 1 retest CBC should be performed 
prior to SV2.  If the retest Hb is ≥10.0 g/dL, the subject should not proceed with SV2.  If the Hb 
at SV1 is >10.5 g/dL, the subject should not proceed with any further screening procedures at 
that time. 
Subjects will continue their epoetin alfa dosing regimen during the screening period. 
At SV1, the following activities/procedures will be performed: 
• Signing of informed consent  
• In addition, subjects may be asked during screening or at any study visit thereafter to provide 
optional written informed consent to obtain and store a blood sample for future genetic 
analyses.  
• Review of study inclusion and exclusion criteria 
• Review acceptable methods of contraception 
• Vital signs 
• Laboratory procedures (if blood samples are collected on a day of dialysis, blood draws 
should be done prior to dialysis, if applicable): 
o CBC 
o Iron indices 
• Epoetin alfa dosing will continue 


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Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
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At SV2, the following activities/procedures will be performed: 
• Review of study inclusion and exclusion criteria 
• Review acceptable methods of contraception 
• Demographics, medical history, and physical examination 
• Vital signs 
• Review of concomitant medications 
• Laboratory procedures (if blood samples are collected on a day of dialysis, blood draws 
should be done prior to dialysis, if applicable): 
o Serum pregnancy test (see Section 9.3.2 for additional information) 
o CBC 
o Folate and vitamin B12 levels 
o Serum chemistry 
o Liver function tests 
• Epoetin alfa dosing will continue 
9.4.2 
Baseline Visit (Day 1) 
There must be a minimum of 4 days between the last screening visit and the baseline visit. 
On Day 1, blood sample collection and other baseline procedures should be completed prior to 
dosing with study drug (vadadustat or epoetin alfa). On Day 1, study drug will be administered at 
the investigative site, and may be administered prior to or during the dialysis session.  
At the baseline visit, the following activities/procedures will be performed: 
• Review of study inclusion and exclusion criteria 
• Review acceptable methods of contraception 
• Subject randomization 
• Dry weight and dialysis treatment review 
• Dialysis adequacy (from dialysis performed during screening) 
• Vital signs 
• 12-lead ECG (ECGs should be completed prior to blood draws when possible and should be 
obtained after the subject has been resting supine comfortably for approximately 10 minutes; 
ECG may be completed and reviewed by the investigator on Day 1 or if needed for 
scheduling reasons [eg, dialysis treatment is scheduled for early morning of Day 1], the ECG 
can be completed and reviewed up to 1-3 days prior to Day 1) 
• AE review 
• Recording of any concomitant medication use since screening visit 
• Laboratory procedures (if blood samples are collected on a day of dialysis, blood draws 
should be done prior to dialysis, if applicable): 
o Urine pregnancy test (see Section 9.3.2 for additional information) 
o CBC with differential 
o Reticulocyte count 
o Coagulation tests 
o C-reactive protein 
o Serum chemistry 
o Liver function tests 


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Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
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o Iron indices 
o Lipid panel 
o Sample for PK analysis (vadadustat treatment arm only; the sample will be collected 
between 30 minutes to 1 hour after vadadustat administration either prior to or during 
dialysis; the time of the vadadustat dose, the PK sample collection time, and the start and 
stop times of the dialysis session will be documented) 
o Biomarkers 
o Sample for erythropoietin measurement 
o Sample for exploratory analyses 
• Subjects in epoetin alfa treatment arm will continue to receive epoetin alfa 
• For subjects in the vadadustat treatment arm only: 
o Initiate vadadustat dosing 
o Vadadustat drug dispensation 
o Review vadadustat dosing instructions 
• Review use of rescue therapy (RBC transfusions and epoetin alfa rescue therapy) 
• Review use of iron supplementation 
9.4.3 
Week 2, 4, 6, 8, 10, 12, 14, 16, and 18 Visits 
At the Week 2 and Week 18 visits, subjects in the vadadustat treatment arm should be reminded 
and instructed to hold their vadadustat dose on the day of the Week 4 and Week 20 visits 
(respectively), as blood sample for PK analysis will be collected on the day of the Week 4 and 
Week 20 visits prior to vadadustat administration at the investigative site. 
The following activities/procedures will be performed at the visits on Week 2, 4, 6, 8, 10, 12, 14, 
16, and 18, unless noted otherwise: 
• Review acceptable methods of contraception 
• Dry weight and dialysis treatment review 
• Dialysis adequacy (Week 8 only) 
• Vital signs 
• AE review 
• Concomitant medication review 
• Laboratory procedures (if blood samples are collected on a day of dialysis, blood draws 
should be done prior to dialysis, if applicable): 
o CBC  
o Reticulocyte count (Weeks 4, 8, 12, and 16 only) 
o C-reactive protein (Week 8 only) 
o Serum chemistry (Weeks 4, 8, and 16 only) 
o Liver function tests (Weeks 4, 8, and 16 only) 
o Iron indices (Weeks 8 and 16 only) 
o 2 samples for PK analyses (Week 4 only; vadadustat treatment arm only; the first sample 
will be collected prior to vadadustat administration and the second sample will be 
collected at least 15 minutes post dialysis. If post dialysis collection is not possible, the 
second PK sample will be collected at least 3 hours after vadadustat administration. The 
time of the last dose of vadadustat taken prior to the PK sampling, as well as the timing 
of the PK sample collection, will be documented) 


Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
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o Biomarkers (Week 8 only) 
o Sample for erythropoietin measurement (Weeks 8 and 16 only) 
o Sample for exploratory analyses (Week 8 only) 
• Subjects in epoetin alfa treatment arm will continue to receive epoetin alfa 
• For subjects in the vadadustat treatment arm only: 
o Vadadustat dosing 
o Vadadustat drug dispensation (Weeks 4, 8, 12, 16, and other visits as applicable) 
o Review vadadustat dosing instructions 
o Vadadustat drug reconciliation (Weeks 4, 8, 12, 16, and other visits as applicable) 
o Review vadadustat dosing compliance 
• Review use of rescue therapy (RBC transfusions and epoetin alfa rescue therapy) 
• Review use of iron supplementation 
• Review use of therapeutic phlebotomy 
9.4.4 
Week 20 Visit (End-of-Treatment) 
On the day of the Week 20 visit, the vadadustat dose will be taken at the investigative site after a 
blood sample for PK analysis has been collected. 
At the Week 20 visit, the following activities/procedures will be performed: 
• Review acceptable methods of contraception 
• Dry weight and dialysis treatment review 
• Dialysis adequacy 
• Vital signs 
• AE review 
• Concomitant medication review 
• Laboratory procedures (if blood samples are collected on a day of dialysis, blood draws 
should be done prior to dialysis, if applicable): 
o CBC with differential 
o Reticulocyte count 
o C-reactive protein 
o Serum chemistry 
o Liver function tests 
o Iron indices 
o Lipid panel 
o 2 samples for PK analyses (vadadustat treatment arm only; the first sample will be 
collected prior to vadadustat administration and the second sample will be collected at 
least 15 minutes post dialysis. If post dialysis collection is not possible, the second 
sample will be collected at least 3 hours after vadadustat administration. The time of the 
last dose of vadadustat taken prior to the PK sampling, as well as the timing of the PK 
sample collection, will be documented) 
o Biomarkers 
o Sample for erythropoietin measurement 
o Sample for exploratory analyses 
• Subjects in epoetin alfa treatment arm will continue to receive epoetin alfa 


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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. 
Kidney Transplantation – A kidney transplant will not be recorded as an AE. Subjects who 
discontinue study drug because of receipt of a kidney transplant should continue with the 
Schedule of Activities (Appendix A). 
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.  
Investigators will utilize their 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 


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which requires treatment or further diagnostic testing 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 (or medical director) or contract 
research organization (CRO) designee within 24 hours of awareness as a serious adverse event 
(SAE) with ‘other medically important event’ criterion selected, if the following conditions are 
met: 
• New elevation in ALT or AST >3 times ULN, with or without an elevation of total serum 
bilirubin >2 times ULN, AND 
• No other reason was identified that explains the increased ALT/AST with or without an 
increased bilirubin (eg, viral hepatitis, acute liver disease). 
If new elevations in ALT or AST >3 times ULN, with or without an elevation of total serum 
bilirubin >2 times ULN are identified, the following steps are to be taken: 
• Temporary discontinuation of 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 (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 or incapacity (see paragraph below on Disability)  
• Congenital anomaly or 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. For example, drug-induced hepatitis that resolved without evidence of hepatic 
failure would not be considered life threatening, even though drug-induced hepatitis of a more 
severe nature can be fatal. 
Hospitalization – Hospitalization is defined as an overnight admission with observation of a 
minimum of 24 hours. A hospitalization planned before the start of the study for a pre-existing 
condition that has not worsened during the AE reporting period does not constitute an SAE 
unless an untoward event occurs related to the procedure (eg, elective hospitalization for a total 
knee replacement due to a preexisting condition of osteoarthritis of the knee that has not 
worsened during the course of the study). 
Disability – Defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
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 CRF. 
10.3.3 
Reporting SAEs 
Any SAE, regardless of causal relationship, must be reported to the sponsor’s medical monitor 
(or 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 identification number, sex, age, and date of birth 
• Date of report 


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• Name of the reporter 
• Name of the suspected medicinal product 
• Description of the event, including event term(s), seriousness criteria, and a clinical summary 
of the event 
• Causality assessment 
Information about all SAEs (either initial or follow-up information) should be collected and 
recorded in English on the electronic SAE Report Form within the electronic data capture (EDC) 
system. The investigator must assess the relationship to each specific component of the study 
treatment.  If the event meets serious criteria and it is not possible to access the EDC system, a 
paper SAE Report Form should be sent to the CRO via email or fax within 24 hours of being 
made aware of the SAE (reference the site manual for contact information). When the EDC 
system becomes available, the SAE information must be entered within 24 hours of the system 
becoming available. 
The investigator must report follow-up information relating to an SAE to the sponsor’s medical 
monitor (or medical director) or CRO designee within 24 hours of awareness by updating the 
electronic CRF with the new information or by submitting a paper SAE Report Form (only if the 
EDC is not available). When the EDC system becomes available, the SAE information must be 
entered within 24 hours. The subject should be observed and monitored carefully until the 
condition resolves or stabilizes. 
All deaths are to be thoroughly investigated and reported. Autopsy reports are to be obtained, if 
possible, and sent to the CRO via email or fax. 
The sponsor or its designee are responsible for reporting SAEs to all applicable regulatory 
agencies and the central ethics committees within the required timeline. 
The investigators are responsible for submitting required safety information to their local IRB 
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 investigator should provide causality assessment with the initial SAE report 
within 24 hours of becoming aware of the event. 
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 


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(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 or 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 study ends (ie, until a final report is completed for 
that subject). 
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 
study 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. 
10.4 
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 
subject 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 


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Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
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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: 
• 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. 
10.5 
Special Situations  
Certain safety events, called ‘Special Situations’, that occur in association with study drug(s) 
may require reporting. These Special Situations include, but are not limited to, the following:  
• Overdose of the study drug  
• Suspected abuse or misuse of the study drug 
• Inadvertent or accidental exposure to the study drug 
• Medication error involving the study drug (with or without subject exposure to the sponsor’s 
study drug, eg, name confusion)  
• Drug-drug interaction involving the study drug 
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. 


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Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
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The number of randomized subjects who completed the study, discontinued early from study 
drug, completed or discontinued from the study, and reasons for discontinuation will be 
summarized by treatment group and overall. 
11.5 
Missing Data 
It is expected that few subjects will discontinue follow-up for epoetin alfa use. The reasons for 
any missing data will be summarized by treatment arm. The primary analysis will be based upon 
observed data without imputation. 
11.6 
Efficacy Analyses 
This study is exploratory in nature, designed to evaluate the change in Hb from baseline over 
time during the treatment period. No formal statistical testing will be performed.   
Summary statistics (mean, median, standard deviation [SD], range, proportion and 95% 
confidence intervals when appropriate) will be provided, by treatment groups for primary and 
secondary endpoints.    
11.7 
Safety Analyses 
Adverse events will be summarized using the number and percentage of subjects with AEs for 
all subjects in the safety population. 
All AEs will be coded using MedDRA. Treatment-emergent and post-treatment AEs will be 
summarized by System Organ Class and Preferred Term for each treatment group. Adverse 
events will also be summarized by their maximum severity. 
Summaries will also be provided for the following types of AEs: 
• SAEs 
• Related AEs, as determined by the investigator 
• AEs leading to early discontinuation of study drug 
The safety endpoint of Hb changes will be summarized using descriptive statistics with 2-sided 
confidence intervals calculated using the methods used for the secondary efficacy endpoints. 


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Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 67 
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Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 68 
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Akebia Therapeutics, Inc.  
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 69 
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Akebia Therapeutics, Inc. 
 
 
 
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 71 
Study Period 
Screening 
Study Treatment Period 
Safety Follow-Up 
Visit 
SV1 
SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Week 
Week -4 to Day -4 
Baseline/
Day 1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
14 
Week 
16 
Week 
18 
Week 20 
(EOT) 
[8] 
Week 24 
(follow-up) 
Complete blood count (CBC) 
X 
X 
X (CBC 
with diff) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X (CBC 
with diff) 
X 
Reticulocyte count 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Coagulation tests 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Folate and vitamin B12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
C-reactive protein 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
Serum chemistry 
 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
Liver function tests 
 
X 
X 
 
X  
 
X 
 
 
 
X 
 
X 
X 
Iron indices 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
Lipid panel 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Pharmacokinetics (vadadustat 
treatment arm only) [4] 
 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
Biomarkers 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
X 
Erythropoietin 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Exploratory analyses 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Procedures related to study drug treatment 
 
Epoetin alfa dosing (epoetin alfa 
treatment arm) [5] 
X 
Vadadustat dosing (vadadustat 
treatment arm) [6] 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vadadustat drug dispensation 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Review vadadustat dosing 
instructions 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vadadustat drug reconciliation 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Review vadadustat dosing 
compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


Akebia Therapeutics, Inc. 
 
 
 
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 72 
Study Period 
Screening 
Study Treatment Period 
Safety Follow-Up 
Visit 
SV1 
SV2 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Week 
Week -4 to Day -4 
Baseline/
Day 1 
Week 
2 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12 
Week 
14 
Week 
16 
Week 
18 
Week 20 
(EOT) 
[8] 
Week 24 
(follow-up) 
Resume epoetin alfa dosing (or 
another ESA) after EOT with 
vadadustat (vadadustat treatment 
arm) [7] 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Review use of rescue therapy 
(RBC transfusions and epoetin 
alfa rescue therapy) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review use of iron 
supplementation 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review use of therapeutic 
phlebotomy 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: diff, differential; EOT, end-of-treatment visit; ESA, erythropoiesis-stimulating agent; SV1, screening visit 1; SV2, screening visit 2 
[1] Written informed consent will be obtained prior to performing any study procedures. During screening or at any study visit thereafter, subjects will also be 
asked to provide optional written informed consent to obtain and store a blood sample for future genetic analyses.  
[2] On Day 1, subjects will withhold dosing until it is confirmed which treatment arm (vadadustat or epoetin alfa) they are assigned to.  
[3] Baseline dialysis adequacy will be reported from dialysis performed during screening. 
[4] The first sample will be collected prior to vadadustat administration and the second sample will be collected at least 15 minutes post dialysis. If post dialysis 
collection is not possible, the second sample will be collected at least 3 hours after vadadustat administration. The time of the last dose of vadadustat taken prior 
to the PK sampling, as well as the timing of the PK sample collection, will be documented. 
[5] Subjects randomized to the epoetin alfa arm will take the same dose of epoetin alfa they took during screening. During the study, the dose will be 
administered by site staff in the clinic on dialysis days. The dose may be titrated as clinically indicated based on the subject’s central lab Hb value and the 
approved label for adult patients with CKD on dialysis. 
[6] Subjects randomized to the vadadustat arm will discontinue their epoetin alfa and take their first dose of vadadustat in the clinic. During the study, subjects 
will self administer their assigned dose of vadadustat at approximately the same time each day (refer to Section 8.3.5). The dose will be titrated in accordance 
with the protocol dosing guidelines for vadadustat (Section 8.3.5). On days when PK samples are collected, subjects will administer their dose of vadadustat in 
the clinic. See foot note 4 above. 
[7] After the end of vadadustat treatment at Week 20 (or following early discontinuation of vadadustat), subjects will resume dosing with epoetin alfa (or another 
ESA) based on the approved label for adult patients with CKD on dialysis and the investigative site’s standard of care.  
[8] In the event a subject discontinues early from the study prior to Week 20, the assessments listed under Week 20 (EOT) visit should be completed within 1 day 
of study discontinuation, followed by participation in a 4-week safety follow-up period, and a safety follow-up visit (which will include the assessments listed 
under Week 24 [follow-up] visit). 


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Akebia Therapeutics, Inc. 
Clinical Protocol 
Protocol No. AKB-6548-CI-0018 
 Version Amendment 1 (18 Jul 2017) 
 
 
Confidential 
Page 74 
5. In order to limit enrollment of subjects who may require adjustment of their baseline ESA 
dose or transfusion in the near term, inclusion criteria #4 was expanded to include 
subjects with a Hb between 8.5 and 10 g/dl.  
6. To be consistent with the vadadustat Phase 3 program, requirements for serum ferritin 
levels were lowered to ≥100 ng/mL from ≥200 ng/mL throughout the document, and 
exclusion criteria #9 and #10 regarding histories for DVT and active malignancies, 
respectively, were modified.   
7. A clarification that an Akebia internal Safety Monitoring Committee (SMC) will review 
safety on an ongoing basis was added.  
8. This amendment also includes administrative clarifications.