Clinical trial NCT04707768
Conditions: Anemia Associated With Chronic Kidney Disease (CKD)
Keywords: Anemia Chronic Kidney Disease CKD Hemodialysis Vadadustat Erythropoiesis-stimulating agent (ESA)
Sponsor: Akebia Therapeutics
Start date: 2021-06-18; Completion date: 2023-01-30
Enrollment: 456 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be conducted to demonstrate the efficacy and safety of vadadustat administered three times weekly (TIW) compared to a long-acting erythropoiesis-stimulating agent (ESA) (Mircera®) for the maintenance treatment of anemia in hemodialysis participants.

Detailed description:
Following randomization, there will be 2 periods during the study:

* Conversion and Maintenance Period (Weeks 0 to 52): There will be a primary efficacy evaluation period (Weeks 20 to 26) and a secondary efficacy evaluation period (Weeks 46 to 52).
* Safety Follow-up Period (Early Termination \[ET\] and Follow-Up): post-treatment safety follow-up visit (ET/End of Treatment \[EOT\] +4 weeks) either in person or via telephone.

Arms: arm 1: Participants previously receiving Mircera® received vadadustat for up to 52 weeks with an initial dose of 600 milligrams (mg). arm 2: Participants previously receiving Mircera® received vadadustat for up to 52 weeks with an initial dose of 900 mg. arm 3: Participants will continue to receive Mircera® for up to 52 weeks.
Interventions: intervention 1: Vadadustat intervention 2: Mircera®
Intervention descriptions: intervention 1: oral tablets intervention 2: intravenous administration

Protocol documents:
Prot_000.pdf: 
Akebia Therapeutics, Inc. 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
16 September 2020 
Akebia – Company Confidential 
Page 1 of 69 
  
CLINICAL PROTOCOL 
A RANDOMIZED, OPEN-LABEL, ACTIVE-CONTROLLED STUDY EVALUATING THE 
EFFICACY AND SAFETY OF DOSE CONVERSION FROM A LONG-ACTING 
ERYTHROPOIESIS-STIMULATING AGENT (MIRCERA®) TO THREE TIMES WEEKLY 
ORAL VADADUSTAT FOR THE MAINTENANCE TREATMENT OF ANEMIA IN 
HEMODIALYSIS SUBJECTS 
Compound:  
Vadadustat (AKB-6548) 
Protocol Number:   
AKB-6548-CI-0039 
Regulatory Agency ID Number(s): 
IND: 102,465 
Study Phase:  
Phase 3b 
Protocol Version/Date:   
Original Version 1.0/16 September 2020 
Sponsor: 
Akebia Therapeutics, Inc. 
245 First Street 
Cambridge, MA 02142 
United States of America 
This document contains information that is confidential and proprietary to the Sponsor, Akebia 
Therapeutics, Inc. This information is being provided to you solely for the purpose of evaluating 
and/or conducting a clinical study for the Sponsor. You may disclose the contents of this 
document only to study personnel under your supervision, the Institutional Review Board, the 
United States Food and Drug Administration, or duly authorized representatives of regulatory 
agencies for this purpose under the condition that they maintain confidentiality. The contents of 
this document may not be used in any other clinical study, disclosed to any other person or 
entity, and/or published without the prior written permission of the Sponsor. The foregoing 
shall not apply to disclosure required by any regulations; however, you will give prompt notice 
to the Sponsor of any such disclosure.  
 
 
 
 
 
NCT Number: NCT04707768
This NCT number has been applied to the document for purposes of posting on Clinicaltrials.gov


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 2 of 69 
  
SIGNATURE PAGES 
Protocol Approval 
Name and Title 
Signature and Date 
 MD 
Senior Vice President of Research and 
Development and Chief Medical Officer 
 
Director, Clinical Operations 
 
 MD 
Vice President, Drug Safety and 
Pharmacovigilance 
 
 PhD 
Senior Director, Biostatistics 
 
PhD 
Senior Director, Clinical Pharmacology 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 3 of 69 
  
Investigator Agreement 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and 
other product information provided by the sponsor. I agree to conduct this study in accordance 
with the requirements of this protocol and also protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following:  
• The ethical principles that have their origin in the Declaration of Helsinki.  
• International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use Guidance for Industry, Good Clinical Practice E6.  
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.  
• Regulatory requirements for reporting SAEs defined in this protocol.  
• Terms outlined in the Clinical Study Site Agreement.  
I will make a copy of the protocol and any amendments available to all study personnel under 
my supervision for the conduct of the study. I will discuss the materials with them to ensure that 
they are fully informed and understand this study and are able to comply. 
 
 
 
______________________________ 
 
__________________________ 
Principal Investigator Name (printed) 
 
Signature 
______________________________ 
Date 
 
 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 4 of 69 
  
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................4 
 PROTOCOL SUMMARY ........................................................................................................9 
1.1 
Synopsis ...............................................................................................................................9 
1.2 
Schema ...............................................................................................................................14 
1.3 
Schedule of Activities ........................................................................................................15 
 LIST OF ABBREVIATIONS .................................................................................................18 
 INTRODUCTION ..................................................................................................................21 
3.1 
Study Rationale ..................................................................................................................21 
3.2 
Background ........................................................................................................................21 
3.3 
Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors .................................................22 
3.4 
Summary of Clinical Experience .......................................................................................23 
3.5 
Risk/Benefit Assessment ...................................................................................................27 
3.5.1 
Known Potential Risks .................................................................................................27 
3.5.2 
Known Potential Benefits ............................................................................................28 
3.5.3 
Overall Benefit: Risk Conclusion ................................................................................28 
 OBJECTIVES AND ENDPOINTS ........................................................................................29 
4.1 
Primary Objective ..............................................................................................................29 
4.2 
Primary Efficacy Endpoint ................................................................................................29 
4.3 
Secondary Efficacy Endpoint ............................................................................................29 
4.4 
Other Endpoints .................................................................................................................29 
4.5 
Safety Endpoints ................................................................................................................29 
4.6 
Primary Safety Endpoint ....................................................................................................29 
4.7 
Secondary Safety Endpoints ..............................................................................................29 
4.8 
Pharmacokinetic/Pharmacodynamic Endpoints .................................................................30 
 
 
 STUDY DESIGN ...................................................................................................................30 
5.1 
Overall Design ...................................................................................................................30 
5.2 
Scientific Rationale for Study Design ................................................................................30 
5.3 
Justification for Dose .........................................................................................................31 
5.4 
End of Study Definition .....................................................................................................32 
5.5 
Number of Study Sites .......................................................................................................32 
5.6 
Subject Input on Study Design ..........................................................................................32 
 STUDY POPULATION .........................................................................................................33 
6.1 
Inclusion Criteria ...............................................................................................................33 
6.2 
Exclusion Criteria ..............................................................................................................33 
6.3 
Screen Failures and Retesting/Rescreening .......................................................................34 
 STUDY INTERVENTION ....................................................................................................35 
7.1 
Study Intervention(s) Administration ................................................................................35 
7.1.1 
Study Intervention Description ....................................................................................35 
PP
D


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 5 of 69 
  
7.1.2 
Dosing and Administration ..........................................................................................35 
7.1.3 
Study Medication Stopping Rules for Liver Function Test Changes ..........................36 
7.2 
Preparation/Handling/Storage/Accountability ...................................................................37 
7.2.1 
Acquisition and Accountability ...................................................................................37 
7.2.2 
Formulation, Appearance, Packaging and Labeling ....................................................37 
7.2.3 
Product Storage and Stability.......................................................................................37 
7.2.4 
Preparation ...................................................................................................................37 
7.3 
Measures to Minimize Bias: Randomization and Blinding ...............................................37 
7.4 
Study Intervention Compliance .........................................................................................38 
7.5 
Concomitant Therapy.........................................................................................................38 
7.5.1 
Erythropoiesis-stimulating Agents...............................................................................38 
7.5.2 
Iron Supplementation and Phosphate Binders .............................................................38 
7.5.3 
OATP1B1/1B3 Substrates (eg, Statins) .......................................................................39 
7.5.4 
Sulfasalazine, Other Breast Cancer Resistance Protein Substrates, and 
Probenecid ..................................................................................................................39 
7.5.5 
Rescue Medicine ..........................................................................................................39 
 
Red Blood Cell Transfusion ...................................................................................39 
 
Erythropoiesis-stimulating Agent Use ...................................................................39 
 DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..............................................................................40 
8.1 
Discontinuation of Study Intervention ...............................................................................40 
8.1.1 
Temporary Interruption of Study Drug ........................................................................40 
8.1.2 
Permanent Discontinuation of Study Medication ........................................................40 
8.1.3 
Withdrawal of Consent ................................................................................................40 
8.1.4 
Entire Study Termination .............................................................................................41 
8.1.5 
Individual Study Site Termination ...............................................................................41 
8.1.6 
Lost to Follow-Up ........................................................................................................41 
 STUDY ASSESSMENTS AND PROCEDURES ..................................................................42 
9.1 
General Study Periods........................................................................................................42 
9.1.1 
Screening, Enrollment and/or Randomization .............................................................42 
 
Informed Consent...................................................................................................42 
9.1.2 
Treatment Period ..........................................................................................................42 
9.1.3 
End of Treatment Visit.................................................................................................42 
9.1.4 
Safety Follow-up ..........................................................................................................42 
9.2 
Clinical Assessments .........................................................................................................42 
9.2.1 
Medical History, Demographics, and Physical Examination ......................................42 
9.2.2 
Vital Sign Measurements .............................................................................................43 
9.2.3 
Dialysis Adequacy .......................................................................................................43 
9.2.4 
Dialysis Treatment .......................................................................................................43 
9.3 
Efficacy Assessments .........................................................................................................43 
9.4 
Laboratory and Other Assessments ...................................................................................43 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 6 of 69 
  
9.5 
Subject Reported Outcome Assessments ...........................................................................45 
9.6 
Pharmacodynamic Assessments ........................................................................................46 
9.7 
Pharmacogenomic Assessments ........................................................................................46 
 
 
 
 
 
 
 
 
 
 
9.10 
Safety and Other Assessments ...........................................................................................47 
9.10.1 
Adverse Event Assessments ........................................................................................47 
9.10.2 
Concomitant Medication Recording ............................................................................47 
9.10.3 
Therapeutic Phlebotomy ..............................................................................................47 
9.11 
Adverse Events and Serious Adverse Events ....................................................................47 
9.11.1 
Definitions of Adverse Events and Serious Adverse Events .......................................47 
 
Adverse Events ......................................................................................................47 
 
Serious Adverse Events .........................................................................................50 
9.11.2 
Classification of an Adverse Event ..............................................................................51 
 
Severity of Event ....................................................................................................51 
 
Relationship to Study Intervention ........................................................................51 
 
Expectedness ..........................................................................................................52 
9.11.3 
Time Period and Frequency for Event Assessment and Follow-up .............................52 
9.11.4 
Adverse Event Reporting .............................................................................................52 
9.11.5 
Reporting Period ..........................................................................................................52 
9.11.6 
Reporting Adverse Events ...........................................................................................52 
9.11.7 
Serious Adverse Event Reporting ................................................................................52 
9.11.8 
Events of Special Interest.............................................................................................53 
9.11.9 
Follow-up of Unresolved Events .................................................................................53 
9.11.10 
Reporting of Pregnancy ...............................................................................................54 
9.12 
Special Situations ...............................................................................................................54 
9.12.1 
Treatment of Overdose ................................................................................................55 
 STATISTICAL CONSIDERATIONS ...................................................................................56 
10.1 
Statistical Hypotheses ........................................................................................................56 
10.2 
Sample Size Determination ................................................................................................56 
10.3 
Populations for Analyses ...................................................................................................56 
10.4 
Missing Data ......................................................................................................................56 
10.5 
Statistical Analyses ............................................................................................................56 
10.5.1 
General Considerations ................................................................................................56 
10.5.2 
Analysis of Primary Efficacy Endpoint(s) ...................................................................57 
 
Sensitivity Analyses of Primary Efficacy Endpoint Screening .............................57 
10.5.3 
Analysis of Secondary Efficacy Endpoint(s) ...............................................................58 
 
 
PPD
PPD


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 7 of 69 
  
10.5.5 
Safety Analyses ............................................................................................................58 
10.5.6 
Analysis of Adverse Events .........................................................................................58 
10.5.7 
Remaining Safety Endpoints........................................................................................58 
10.5.8 
Baseline Descriptive Statistics .....................................................................................59 
 
Analysis of Demographic and Pretreatment Variables ..........................................59 
 
Disposition of Subjects ..........................................................................................59 
10.6 
Additional Assessments .....................................................................................................59 
10.6.1 
Concomitant Medications ............................................................................................59 
 
 
10.6.3 
Pharmacokinetic Assessments .....................................................................................60 
10.6.4 
Pharmacodynamic Assessments ..................................................................................60 
 
 
 
 
10.6.7 
Sub-Group Analyses ....................................................................................................60 
 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .........61 
11.1 
Ethical Conduct of the Study .............................................................................................61 
11.2 
IRB and Ethics Committees ...............................................................................................61 
11.3 
Informed Consent Process .................................................................................................61 
11.4 
Financial Disclosure ...........................................................................................................62 
11.5 
Confidentiality and Data Privacy .......................................................................................62 
11.6 
Data Handling and Record Keeping ..................................................................................62 
11.6.1 
Data Collection and Management Responsibilities .....................................................62 
11.6.2 
Study Records Retention ..............................................................................................62 
11.7 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ................63 
11.8 
Study Discontinuation and Closure ...................................................................................63 
11.8.1 
Criteria for Premature Termination or Suspension of the Study .................................63 
11.8.2 
Criteria for Premature Termination or Suspension of Study Sites ..............................63 
11.8.3 
Criteria for Premature Termination or Suspension of the Study or Study Sites ..........64 
11.9 
Future Use of Stored Specimens and Data ........................................................................64 
11.10 Key Roles, Committees and Study Governance ................................................................64 
11.11 Safety Oversight.................................................................................................................64 
11.12 Quality Assurance and Quality Control .............................................................................65 
11.12.1 
Clinical Monitoring ......................................................................................................65 
11.12.2 
Protocol Deviations ......................................................................................................65 
 PUBLICATION OF STUDY RESULTS ...............................................................................66 
 REFERENCES .......................................................................................................................67 
LIST OF TABLES 
Table 1 
Schedule of Activities ............................................................................................15 
Table 2 
Treatment-emergent Adverse Events Occurring at ≥5% Incidence in Vadadustat-
treated Subjects ......................................................................................................26 
PPD
PPD


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 8 of 69 
  
Table 3 
Protocol Required Laboratory Assessments ..........................................................45 
 
LIST OF FIGURES 
Figure 1 
Study Schema.........................................................................................................14 
 
 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 9 of 69 
  
 
 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Synopsis 
Protocol Title 
A Randomized, Open-label, Active-controlled Study Evaluating the Efficacy and 
Safety of Dose Conversion from a Long-acting Erythropoiesis-stimulating Agent 
(Mircera®) to Three Times Weekly Oral Vadadustat for the Maintenance 
Treatment of Anemia in Hemodialysis Subjects 
Protocol Number 
AKB-6548-CI-0039 
Phase of Development  
3b 
Indication 
Anemia associated with chronic kidney disease (CKD) 
Investigational Product 
Vadadustat; 300 mg tablets  
Reference Therapy, as 
applicable 
Methoxy polyethylene glycol-epoetin beta (Mircera), F. Hoffman-La 
Roche Ltd. 
Study Population  
The study population will consist of subjects ≥18 years of age and 
receiving chronic, outpatient in-center hemodialysis three times weekly 
(TIW), requiring erythropoiesis-stimulating agent (ESA) treatment and 
are on maintenance treatment currently receiving Mircera and with mean 
of 2 Screening hemoglobin (Hb) values between 8.5 and 11.0 g/dL 
(inclusive). 
Number of Study Sites 
Approximately 50 investigative sites in the United States (US) at outpatient 
hemodialysis center. 
Planned Number of Subjects 
Approximately 450 subjects. 
Rationale  
During prior clinical trials, vadadustat has demonstrated dose proportional 
pharmacokinetic (PK) and dose dependent pharmacodynamics (PD). Vadadustat 
showed dose-dependent increases in erythropoietin (EPO) concentrations in 
Phase 1 and Phase 2 studies. The changes in EPO have been accompanied by an 
increase in reticulocytes and Hb as well as increases in total iron binding capacity 
(TIBC) and decreases in hepcidin and ferritin. Overall, the safety profile for 
vadadustat has been acceptable and has supported further development. Akebia is 
developing vadadustat as a treatment for anemia associated with CKD in adult 
patients. The development program to date included a number of phase 1, 2, and 
3 clinical trials in both populations. A majority of trials studied once daily (QD) 
dosing. TIW dosing is supported by an earlier completed clinical trial involving 
TIW dosing and PK-PD modelling data. The rationale for this trial is to obtain 
safety and efficacy data that supports DD-CKD patients switching from Mircera 
to vadadustat TIW. 
Primary Objectives 
The primary objective of the study is to demonstrate the efficacy and safety of 
vadadustat administered TIW compared to long acting ESA (Mircera) for the 
maintenance treatment of anemia in hemodialysis subjects. 
Efficacy Endpoints 
Primary: 
• 
Primary efficacy endpoint is mean change in Hb between Baseline 
(average pretreatment Hb) and the primary evaluation period (average 
Hb from Weeks 20 to 26, inclusive). 
Secondary: 
Secondary efficacy endpoint is mean change in Hb between Baseline 
(average pretreatment Hb) and the secondary evaluation period (average 
Hb from Weeks 46 to 52, inclusive). 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 10 of 69 
  
Other Endpoints 
• 
Proportion of subjects having a Hb value within the target range (10.0 to 
11.0 g/dL) during the primary evaluation period (Weeks 20 to 26). 
• 
Proportion of subjects having a Hb value within the target range (10.0 to 
11.0 g/dL) during the secondary evaluation period (Weeks 46 to 52). 
Safety Endpoints 
• 
Treatment-emergent adverse events (AEs) and Serious Adverse Events 
(SAEs).  
• 
Proportion of subjects receiving red blood cell (RBC) transfusions from 
Baseline to Week 26 
• 
Proportion of subjects receiving RBC transfusions from after Week 26 
to Week 52. 
• 
Proportion of subjects with Hb >11.0, Hb >12.0, >13.0, or >14.0 g/dL. 
• 
Proportion of subjects with Hb <7.0, <8.0, <9.0, or <10.0 g/dL. 
• 
Proportion of subjects with Hb increase >1.0 g/dL within any 2-week 
interval or >2.0 g/dL within any 4-week interval. 
PK/PD Endpoints 
The PK endpoints include the following: 
• 
Maximum observed concentration (Cmax)  
• 
Pre-dose trough concentration (Ctau) 
The PD endpoints include the following: 
• 
EPO 
• 
Reticulocyte count 
• 
Markers of iron metabolism (including iron, ferritin, total iron binding 
capacity [TIBC]). 
 
 
 
Methodology (study design) 
A multi-center, randomized, open-label, active-controlled study of the efficacy 
and safety of conversion from long-acting ESA (Mircera) to vadadustat TIW for 
the maintenance treatment of anemia in hemodialysis patients. Following a 
Screening period of up to 8 weeks (56 days), subjects who meet all inclusion and 
none of the exclusion criteria, Mircera will be discontinued and subjects will be 
randomized 1:1:1 to vadadustat 600 mg TIW, vadadustat 900 mg TIW, or to 
remain on Mircera according to the dialysis center’s protocol. 
Randomization will be stratified by dialysis organization: 
Following randomization, there will be 2 periods during the study: 
• 
Conversion and Maintenance Period (Weeks 0 to 52): conversion to 
vadadustat TIW or to remain on Mircera (Weeks 0 to 20). There will be 
a primary efficacy evaluation period (Weeks 20 to 26) and a secondary 
efficacy evaluation period (Weeks 46 to 52). 
• 
Safety Follow-up Period (Early Termination [ET] and Follow-
Up): post-treatment safety follow up visit (ET/End of Treatment 
[EOT] +4 weeks) either in person or via telephone. 
Study Duration 
Individual subjects will participate in the study for up to 64 weeks, including a 
Screening Period of up to 8 weeks, a 52-week Treatment Period and a 4-week 
Safety Follow-Up Period. 
Key Inclusion and 
Exclusion Criteria 
Subjects must meet the following inclusion criteria: 
1. ≥18 years of age. 
2. Receiving chronic, outpatient in-center hemodialysis TIW for end-stage 
kidney disease for at least 12 weeks prior to Screening Visit (SV)1. 
3. Currently maintained on Mircera (≤250 µg/month) with at least 2 doses 
PPD


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 11 of 69 
  
received within 8 weeks prior to SV2.  
4. Mean screening Hb between 8.5 and 11.0 g/dL (inclusive), as determined 
by the average of 2 Hb values measured by the central laboratory at least 
4 days apart between SV1 and SV2. 
5. Serum ferritin ≥100 ng/mL and transferrin saturation (TSAT) ≥20% during 
Screening. 
6. Folate and vitamin B12 measurements ≥ lower limit of normal during 
Screening. 
 
Subjects must not meet any of the following exclusion criteria: 
1. Anemia due to a cause other than CKD (e.g., sickle cell disease, 
myelodysplastic syndromes, bone marrow fibrosis, hematologic 
malignancy, myeloma, hemolytic anemia, thalassemia, or pure red cell 
aplasia). 
2. Clinically meaningful bleeding event in opinion of investigator within 
8 weeks prior to Baseline. 
3. RBC transfusion within 8 weeks prior to Baseline. 
4. Having received any doses of darbepoetin alfa (Aranesp®) within the past 4 
weeks prior to Baseline. 
5. Having any epoetin alfa (Epogen®) within the past 1 week prior to 
Baseline. 
6. Anticipated to discontinue hemodialysis during the study. 
7. Judged by the Investigator that the subject is likely to need rescue therapy 
(ESA administration or RBC transfusion) immediately after enrollment in 
the study. 
8. History of chronic liver disease (e.g., chronic infectious hepatitis, chronic 
autoimmune liver disease, cirrhosis or fibrosis of the liver).  
9. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic 
transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic 
pyruvic transaminase (SGPT), or total bilirubin >2 x upper limit of normal 
(ULN) during Screening. Subjects with a history of Gilbert’s syndrome are 
not excluded. 
10. Current uncontrolled hypertension as determined by the Investigator that 
would contraindicate the use of an ESA. 
11. Acute coronary syndrome (hospitalization for unstable angina or 
myocardial infarction), surgical or percutaneous intervention for coronary, 
cerebrovascular or peripheral artery disease (aortic or lower extremity), 
surgical or percutaneous valvular replacement or repair, sustained 
ventricular tachycardia, hospitalization for heart failure (HF) or New York 
Heart Association Class IV HF, or stroke within 12 weeks prior to or 
during Screening. 
12. History of new, active or recurrent malignancy within 2 years prior to and 
during Screening or currently receiving treatment or suppressive therapy 
for cancer. Subjects with treated basal cell carcinoma of skin, curatively 
resected squamous cell carcinoma of skin, or treated cervical carcinoma 
in situ are not excluded. 
13. History of deep vein thrombosis or pulmonary embolism within 12 weeks 
prior to or during Screening 
14. History of hemosiderosis or hemochromatosis. 
15. History of prior organ transplantation (subjects with a history of failed 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 12 of 69 
  
kidney transplant or corneal transplants are not excluded). 
16. Scheduled organ transplant from a living donor and subjects on the kidney 
transplant wait-list who are expected to receive a transplant within 
6 months.  
17. History of a prior hematopoietic stem cell or bone marrow transplant (stem 
cell therapy for knee arthritis is not excluded). 
18. Known hypersensitivity to vadadustat, Mircera, or any of their excipients. 
19. Use of an investigational medication or participation in an investigational 
study within 30 days or 5 half-lives of the investigational medication 
(whichever is longer), prior to Screening (subjects may participate in 
another concurrent study only if that study is a non-interventional, 
observational investigation). 
20. Current exposure to any hypoxia-inducible factor prolyl-hydroxylase (HIF-
PH) inhibitor or prior exposure to vadadustat. 
21. Subjects with bilateral native nephrectomy. 
22. Noncompliance with dialysis session attendance defined as missing more 
than 1 dialysis session within 8 weeks prior to Baseline. 
23. Active Severe Acute Respiratory Syndrome-Related Coronavirus (SARS-
CoV-2) during Screening. 
24. Females who are pregnant or breastfeeding during Screening or are 
planning to become pregnant and breastfeeding during the study period, 
and for 30 days after the final study drug administration. 
25. Women of childbearing potential who are unable or unwilling to use 2 
acceptable methods of contraception* starting at Screening, throughout the 
study period and for 45 days after the final study drug administration. 
26. Female subjects of childbearing potential who plan to donate ova during 
the study, and for 30 days after the last dose of study drug. 
27. Non-vasectomized male subjects who are unable or unwilling to use an 
acceptable method of contraception* from time of first dose of study drug 
until 30 days after the last dose of the study drug.  
28. Male subjects who plan to donate sperm during the study and for at least 
30 days after the last dose of study drug. 
29. Any other reason, which in the opinion of the Investigator, would make the 
subject not suitable for participation in the study. 
*Acceptable forms of contraception include: 
• 
Established use of oral, injected or implanted hormonal methods of 
contraception 
• 
Placement of an intrauterine device or intrauterine system 
• Barrier methods of contraception: condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository. 
Safety Oversight 
An Independent Data Monitoring Committee (IDMC) will be established to 
review and discuss the available study data as subjects are enrolled and followed. 
The IDMC will meet approximately twice per year throughout the course of the 
study. The IDMC will be unblinded and will include, at a minimum 2 physicians 
and a biostatistician. The discussions of the IDMC will include a review of key 
safety data (i.e., AEs, vital sign measurements, and laboratory assessments).  
Hepatic cases will be adjudicated by a hepatic panel of experts.  
Statistical considerations 
The primary efficacy endpoint is defined as the mean change in Hb between 
Baseline (average pretreatment Hb) and the primary evaluation period (average 
Hb from Weeks 20 to 26, inclusive). 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 13 of 69 
  
a. General analysis plan 
b. Rationale for number 
of subjects 
The primary analysis of the primary endpoint will use the randomized population. 
Analysis of covariance (ANCOVA) with multiple imputation for missing data 
will be used to calculate the 95% confidence interval (CI) of the difference in 
mean change in Hb from baseline to the primary evaluation period between the 
vadadustat group and Mircera® control group, with a randomization stratification 
factor and Baseline Hb as covariates.  
Noninferiority of vadadustat will be established if the lower limit of this 
CI is ≥ -0.75 g/dL. 
A hierarchical testing scheme will be used to correct for the multiplicity 
of the 2 comparisons of the primary efficacy endpoint: comparison 
between vadadustat TIW 600 mg versus Mircera and comparison 
between vadadustat TIW 900 mg versus Mircera . 
• 
Step 1: comparison between vadadustat TIW 900 mg versus. 
Mircera  
If the noninferiority of vadadustat is established in step 1, then 
move to the step 2; 
• 
Step 2: comparison between vadadustat TIW 600 mg versus Mircera 
For the primary efficacy analysis, it will be assumed that the difference 
in mean change from Baseline in Hb for vadadustat will be the same as 
the active control, Mircera, and the common standard deviation for the 
mean change from Baseline will be assumed to be 1.2 g/dL. The 
noninferiority margin of -0.75 g/dL will be used (for vadadustat minus 
Mircera). With the 1:1:1 randomization ratio of vadadustat 600 mg TIW, 
vadadustat 900 mg TIW, and Mircera, approximately 150 subjects in 
each arm, the noninferiority test will have >90% power with 
consideration of a 30% drop out rate. 
In addition to the final analysis which will take place when all subjects 
have completed study and will include all data collected, the 26-week 
efficacy and safety data may be summarized after the last patient 
completes the primary efficacy period (Week 26). As the study conduct 
and final analyses of primary efficacy endpoint will not be modified by 
this analysis, no alpha adjustment is proposed. The decision about 
whether this 26-week analysis would be conducted and details about the 
analysis will be described in the statistical analysis plan (SAP). 
 
 
 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 14 of 69 
  
1.2 
Schema 
Figure 1 
Study Schema 
 
 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 15 of 69 
  
 
1.3 
Schedule of Activities  
Table 1 
Schedule of Activities 
Study Period 
Screening 
Treatment (Conversion and Maintenance) 
 
Safety 
Follow-upa 
Visit Type 
SV1 
SV2 
BL 
 
Primary Efficacy 
Evaluation 
 
Secondary Efficacy 
Evaluation 
Week 
-8 to 0 
0 
2 
4 
6 
8 
12 
16 
20 
24 
26 
30 
34 
38 
42 
46 
50 
52 (EOT) 
/ETb 
56 
(EOT or ET 
+4 weeks) 
Visit Window (Days) 
 
 
±3 
±5 
±3 
±5 
±3 
+7 
General and Clinical Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E Criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examc 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments f 
Pregnancy Testg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-Reactive Protein 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
CBC without differentialh 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CBC with differential  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Iron Indicesi 
X  
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Chemistry 
X  
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
Liver Function Testsj 
X  
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lipid Panelk 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Reticulocyte count 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Coagulation Tests l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Erythropoietin 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
PGx and future biospecimen 
researchn 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Dialysis Assessments 
Dialysis Adequacy o 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Dialysis Access Type 
 
 
X 
Document any change to dialysis access type during Treatment Period 
X 
Safety Assessments 
PPD
PPD


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 16 of 69 
  
Study Period 
Screening 
Treatment (Conversion and Maintenance) 
 
Safety 
Follow-upa 
Visit Type 
SV1 
SV2 
BL 
 
Primary Efficacy 
Evaluation 
 
Secondary Efficacy 
Evaluation 
Week 
-8 to 0 
0 
2 
4 
6 
8 
12 
16 
20 
24 
26 
30 
34 
38 
42 
46 
50 
52 (EOT) 
/ETb 
56 
(EOT or ET 
+4 weeks) 
Visit Window (Days) 
 
 
±3 
±5 
±3 
±5 
±3 
+7 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transfusions and ESA Rescue  
 
 
 
Document any transfusions or ESA rescue during Treatment Period 
 
Therapeutic Phlebotomy 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Assessments and Procedures 
Concomitant Medicine Review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vadadustat Dispensing p 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vadadustat Reconciliation 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vadadustat Medication Dosing 
 
 
X 
TIW dosing 
 
Mircera Dosing 
 
 
X 
Dosing according to the dialysis center’s protocol 
 
Iron Supplementation 
 
 
As needed to maintain ferritin ≥100 ng/mL and TSAT ≥20%  
As needed IV iron dosing according to the dialysis center’s protocol 
 
PK Sampling 
PK Evaluation (Vadadustat dosing 
arm only)q 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BL: baseline; CBC: complete blood count; EOT: end-of-treatment; ESA: 
erythropoiesis-stimulating agent; ET: early termination; 
; Hb: hemoglobin; HDL: high density lipoprotein; 
I/E: inclusion/exclusion; 
 LDL: low density lipoprotein; 
 PGx: pharmacogenomics; PK: pharmacokinetic; SGOT: serum glutamic oxaloacetic transaminase; SGPT: serum glutamic pyruvic transaminase; 
SV1: Screening visit 1; SV2: Screening visit 2; TIBC: total iron binding capacity; TIW: three times weekly; TSAT: transferrin saturation; 
. 
a. The safety follow-up period includes the EOT visit and follow-up visit (4 weeks after EOT). 
b. Subjects who permanently discontinue study medication prior to study completion will not continue in the study. These subjects are to have their ET visit at the time of permanently 
discontinuing study medication and perform a 4-week safety follow-up after ET visit. 
c. During the Treatment period, an abbreviated physical examination may be performed at the discretion of the investigator, as clinically indicated. 
d. Pre-dialysis vital signs including temperature, heart rate, blood pressure, respiratory rate, and weight. Dry weight will be collected for all subjects.  
e. 
 
f. If blood is collected on a hemodialysis day, the blood draw should be completed before dialysis occurs. Subjects may be retested for iron indices, serum chemistry, and liver function tests. 
g. Serum pregnancy will be tested in women of childbearing potential at SV2. Additional serum or local urine pregnancy tests may be conducted throughout the study as determined by the 
investigator to establish the absence of pregnancy during the study. If positive at SV2, the subject is not eligible to enter the study. If a subject becomes pregnant during the study, the subject 
must permanently discontinue study medication. 
h. For eligibility, 2 Hb values measured by the central laboratory during Screening (SV1, SV2 or retest) must be between 8.5 and 11.0 g/dL (inclusive). 
i. Iron indices: ferritin, iron, TIBC, and TSAT. 
j. Liver function tests: total bilirubin, ALP, ALT/SGPT, AST/SGOT, and LDH. 
k. Lipids: total cholesterol, LDL, HDL, and triglycerides. 
l. The coagulation tests prothrombin time, partial thromboplastin time, and international normalized ratio will be performed for unscheduled visits only. 
 
n. Optional additional blood samples will be collected for PGx and future biospecimen research for consenting subjects only.  
o. Most recent dialysis adequacy assessment. 
p. Subjects will be provided with a supply of vadadustat at the Baseline visit and will be resupplied at subsequent visits as needed. Refer to the study drug dispensing instructions for further 
details.  
PPD
PPD
PPD
PPD
PPD
PPD


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 17 of 69 
  
Study Period 
Screening 
Treatment (Conversion and Maintenance) 
 
Safety 
Follow-upa 
Visit Type 
SV1 
SV2 
BL 
 
Primary Efficacy 
Evaluation 
 
Secondary Efficacy 
Evaluation 
Week 
-8 to 0 
0 
2 
4 
6 
8 
12 
16 
20 
24 
26 
30 
34 
38 
42 
46 
50 
52 (EOT) 
/ETb 
56 
(EOT or ET 
+4 weeks) 
Visit Window (Days) 
 
 
±3 
±5 
±3 
±5 
±3 
+7 
q. Vadadustat PK samples will be taken predose (within 60 minutes) and 0.5 hours  ±5 minutes, 1, 2 and 3 hours ±10 minutes postdose.   


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 18 of 69 
  
 
LIST OF ABBREVIATIONS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under concentration-time curve 
BCRP 
breast cancer resistance protein 
β-HCG 
β-human chorionic gonadotropin 
Cmax 
maximum observed concentration 
Ctau 
pre-dose trough concentration 
CERA 
Continuous Erythropoietin Receptor Activator 
CI 
confidence interval 
CKD 
chronic kidney disease 
CRF 
case report form 
CRO 
Contract Research Organization 
CSR 
clinical study report 
CV 
cardiovascular 
DD 
dialysis-dependent 
DILI 
drug-induced liver injury 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
End of Treatment 
EPO 
erythropoietin 
ESA 
erythropoiesis-stimulating agent 
ET 
Early Termination 
EU 
European Union 
 
 
FBR 
future biospecimen research 
PPD


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 19 of 69 
  
Abbreviation 
Definition 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practices 
Hb 
hemoglobin 
HF 
heart failure 
HIF 
hypoxia-inducible factor 
HIF-PHs 
hypoxia-inducible factor prolyl-hydroxylases 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
mRNA 
messenger ribonucleic acid 
MTPC 
Mitsubishi Tanabe Pharma Corporation 
NDD 
non-dialysis-dependent 
OAT 
organic anion transporter 
PD 
pharmacodynamic 
 
 
 
 
PGx 
pharmacogenomic 
PHD 
prolyl 4-hydroxylase domains 
PK 
pharmacokinetic 
PP 
per protocol 
PT 
preferred term 
QC 
quality control 
QD 
once daily 
PPD
PPD


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 20 of 69 
  
Abbreviation 
Definition 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome-Related Coronavirus 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SmPC 
Summary of Product Characteristics 
SoA 
Schedule of Activities 
SOC 
system organ class 
SOP 
Standard Operating Procedures 
SV1 
Screening Visit 1 
SV2 
Screening Visit 2 
TIBC 
total iron binding capacity 
TIW 
three times weekly 
TSAT 
transferrin saturation 
UGT 
UDP-glucuronosyltransferase 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
 
 
 
 
PPD


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 21 of 69 
  
 
INTRODUCTION 
This is an open-label, active-controlled, sponsor-blinded study to determine the safety and 
efficacy of dose conversion from a long-acting erythropoiesis-stimulating agent (ESA) (Mircera) 
to three times weekly (TIW) oral vadadustat dosing for the maintenance treatment of anemia in 
hemodialysis subjects 
3.1 
Study Rationale 
During prior clinical trials, vadadustat has demonstrated dose proportional pharmacokinetic (PK) 
and dose-dependent pharmacodynamics (PD). Vadadustat showed dose-dependent increases in 
erythropoietin (EPO) concentrations in Phase 1 and Phase 2 studies. The changes in EPO have 
been accompanied by an increase in reticulocytes and hemoglobin (Hb) as well as increases in 
total iron binding capacity (TIBC) and decreases in hepcidin and ferritin. Overall, the safety 
profile for vadadustat has been acceptable and has supported further development. 
Akebia is developing vadadustat as a treatment for anemia associated with chronic kidney 
disease (CKD) in adult patients. The development program to date included a number of phase 1, 
2, and 3 clinical trials in both populations. A majority of trials studied once daily (QD) dosing. 
TIW dosing is supported by an earlier completed clinical trial involving TIW dosing and PK-PD 
modelling data.  
The rationale for this trial is to obtain additional safety and efficacy data that supports dialysis-
dependent (DD)-CKD patients switching from Mircera to vadadustat TIW. 
3.2 
Background 
Chronic kidney disease, defined as the presence of kidney damage or a decreased level of kidney 
function, is a major public health problem worldwide. Globally, CKD is estimated to affect 
between 8% to 16% of the population (Jha 2013; KDIGO 2013). At the most advanced stages of 
CKD, end-stage kidney disease, patients require chronic dialysis, or kidney transplantation to 
sustain life. Chronic kidney disease is not only a cause of end-stage kidney disease, but is also a 
significant risk factor for cardiovascular (CV) disease, infection, cancer, and mortality 
(Iseki 2007). 
The prevalence and severity of renal anemia in CKD increases as renal function deteriorates 
(Di Iorio 2007; Stauffer 2014). As CKD progresses, the combined effect of decreased red blood 
cell (RBC) production from lower EPO signaling, increased rate of RBC destruction, and 
reduced iron availability to the bone marrow results in the increased prevalence and severity of 
anemia (Pergola 2016). Anemia is defined by hemoglobin (Hb) is less than 13.0 g/dL in men or 
less than 12.0 g/dL in women (KDIGO 2012). Three principal factors contribute to the 
development of anemia as CKD progresses:  
• Peritubular fibroblasts, a type of cell in the kidney, are designed to sense the amount of 
oxygen carried by the blood. These cells produce and secrete EPO to adjust the production of 
RBCs by the bone marrow and maintain circulating oxygen levels at normal physiologic 
levels. As kidney disease progresses, the number of peritubular fibroblasts is reduced and 
EPO production and secretion is significantly decreased, leading to a reduction in RBC 
production (Iseki 2007; Nurko 2006).  


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 22 of 69 
  
• On average, the RBCs in CKD patients have a shorter lifespan (approximate lifespan of 
70 days) compared with the RBCs in healthy people (approximate lifespan of 90 to 120 days) 
(Ly 2004; Nurko 2006). Such a condition requires increased RBC production in CKD 
patients to maintain normal physiologic levels.  
• The availability of iron to the bone marrow is impaired. Iron is a required component in the 
formation of Hb, and is essential for the transport of oxygen to the tissues of the body. 
The main impact of anemia on organ function is reduced oxygen delivery to tissues leading to a 
constellation of symptoms including fatigue, shortness of breath, and exercise intolerance 
(Finkelstein 2019). In these patients, compensatory changes occur in cardiac structure and 
function including an increase in cardiac output and the development of left ventricular 
hypertrophy and eventually the development of heart failure (HF, Metivier 2000). Other 
consequences from anemia in CKD patients include impaired cognitive function, sleep disorders, 
and depressed immune function which can impact the quality of life in patients 
(Iseki 2007; NICE 2011). Overall, anemia contributes to a poorer prognosis in patients with 
CKD (Iseki 2007; Nurko 2006). 
Anemia associated with CKD has been treated with ESAs, blood transfusions, and iron 
supplementation. The risks associated with ESAs, including an increased risk of death and CV 
events (Besarab 1998; Drüeke 2006; Pfeffer 2009a; Pfeffer 2009b; Singh 2006), highlight the 
need for additional therapies that might minimize or avoid these risks when compared to 
currently available recombinant protein-based ESAs. Therefore, the unmet medical need for the 
treatment of anemia in DD-CKD patients remains high. To fulfill this unmet need, the vadadustat 
clinical program is focused on developing an orally active therapeutic agent for the treatment of 
anemia in patients with CKD. 
3.3 
Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors 
Please see the vadadustat Investigator’s Brochure for additional discussion and information for 
the following section. 
Vadadustat is a synthetic, orally bioavailable, small molecule being developed as an inhibitor of 
hypoxia-inducible factor prolyl-hydroxylases (HIF-PHs) for the treatment of anemia associated 
with CKD. HIF-PH enzymes are also referred to as prolyl 4-hydroxylase domains (PHDs), of 
which the 2 most commonly expressed isoforms are PHD2 and PHD3. Vadadustat inhibits PHD2 
and PHD3. The inhibition of PHD2 and PHD3 stabilizes hypoxia-inducible factor (HIF)-2α and 
HIF-1α, which in turn stimulates the production of EPO. In vivo animal efficacy and messenger 
ribonucleic acid (mRNA) data indicate that vadadustat induces the production of EPO from both 
renal and extra-renal sites (liver and brain), and this increase in EPO results in an increase in 
RBC production in the bone marrow. In clinical studies, vadadustat has been shown to facilitate 
iron homeostasis by decreasing hepcidin and increasing transferrin levels in healthy adult male 
subjects and male and female CKD patients. This enables iron transport mechanisms that should 
enhance the terminal steps of erythropoiesis. Vadadustat may offer the potential of flexible oral 
dosing that provides a more gradual and reliable means of titration than injectable hormones. 
Therefore, vadadustat is being developed as an alternative to the existing protein hormone ESAs. 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 23 of 69 
  
3.4 
Summary of Clinical Experience 
Please see the vadadustat Investigator Brochure for additional discussion and information for 
the following section. 
The efficacy, safety, tolerability, PK, and PD profiles of vadadustat have been characterized in 
15 completed Phase 1 studies in healthy subjects including 1 ethno-bridging study in Caucasian 
and Japanese subjects, 1 completed Phase 1 study in subjects undergoing chronic hemodialysis, 
3 completed Phase 2a studies in NDD-CKD subjects, 1 completed Phase 2b study in NDD-CKD 
subjects, and 1 completed Phase 2 study in DD-CKD subjects. The United States (US) Phase 2a 
studies evaluated Stages 3, 4, and 5 CKD (not on dialysis) subjects in a single-dose PK study, a 
multi-dose, 28-day, open-label, dose escalation pilot study, and a randomized, double-blind, 
placebo-controlled study with 5 different dose groups dosed for 42 days. The US Phase 2b, 
randomized, double-blind, placebo-controlled study evaluated Stages 3, 4, and 5 CKD 
(pre-dialysis) dosed for 20 weeks. The Japanese Phase 2, randomized, double-blind, 
placebo-controlled study evaluated Stages 3, 4, and 5 CKD (pre-dialysis) dosed for 16 weeks. 
The US Phase 2 open-label study evaluated DD-CKD subjects on chronic hemodialysis dosed 
for 16 weeks. The Japanese Phase 2, randomized, double-blind, placebo-controlled study 
evaluated DD-CKD subjects on chronic hemodialysis dosed for 16 weeks. In the studies 
completed to date, a total of 1011 subjects have received vadadustat, including 553 healthy 
subjects, 450 subjects with CKD, and 8 subjects with hepatic impairment. Four additional Phase 
3 studies from Akebia’s co-development partner, Mitsubishi Tanabe Pharma Corporation 
(MTPC) have been conducted in Japan with NDD-CKD and DD-CKD subjects. As of 
18 Aug 2019, a total of 379 subjects have received vadadustat. Two of these studies (J02 and 
J04) have been completed and the clinical study reports (CSRs) are final. The other 2 studies 
(J01 and J03) have reported 24-week primary efficacy and safety data and CSRs for the 24-week 
data are final. The clinical conduct for the 52-weeks of treatment (J01 and J03) has been 
completed and CSRs are pending. One pharmacological study in 61 healthy subjects has also 
been completed (J05). 
Vadadustat has shown dose-dependent increases in EPO concentrations in Phase 1 and Phase 2a 
studies. The changes in EPO have been accompanied by an increase in reticulocytes and Hb as 
well as increases in TIBC and decreases in hepcidin and ferritin. Data from Japan Phase 3 studies 
in NDD-CKD and DD-CKD subjects and post-hoc analyses of the US Phase 2 DD-CKD study 
indicate the potential for an association between higher baseline ESA dose and a lower Hb 
response among subjects converted from ESA to vadadustat. Overall, the safety profile for 
vadadustat has been acceptable and has supported further development. Vadadustat has 
demonstrated consistent bioavailability with area under concentration-time curve (AUC) and 
maximum observed concentration (Cmax) in Phase 1 and Phase 2 studies covering the dose range 
of 80 to 1200 mg after single administration and 500 to 900 mg after repeated daily 
administration for 10 days. The plasma half-life of vadadustat had a modest increase in subjects 
with NDD-CKD and DD-CKD. Despite the longer half-life in the CKD group, vadadustat 
plasma concentrations are not expected to accumulate with repeated QD or TIW administration.  
Vadadustat is extensively metabolized and its metabolites are eliminated from the body by dual 
routes of excretion (both renal and fecal). The urinary excretion of vadadustat and its metabolites 
has been shown to be less than 60% in healthy human subjects. In a clinical study conducted to 
evaluate the effect of hemodialysis on the exposures to vadadustat, hemodialysis did not have an 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 24 of 69 
  
effect on the exposures of vadadustat or its metabolites. Given its short half-life and the dual 
routes of elimination, vadadustat is unlikely to accumulate in patients with CKD.  
Multiple doses of up to 900 mg daily for up to 10 days and single doses of 1200 mg have been 
examined in healthy subjects. Vadadustat demonstrated dose-proportional PK and 
dose-dependent serum EPO concentrations that returned to baseline levels with treatment 
cessation. A higher incidence of adverse events (AEs) in the gastrointestinal System Organ Class 
(SOC) – nausea, diarrhea, abdominal pain, dyspepsia – was observed in groups treated with 700, 
900, or 1200 mg compared with lower vadadustat doses or placebo. Most AEs were mild to 
moderate, short-lived (1 or 2 days), and assessed as unrelated by investigators. No AEs led to 
study withdrawal, and no serious adverse events (SAEs) were reported in healthy subjects. No 
clinically meaningful changes or abnormalities in vital signs, safety laboratory studies, or 
electrocardiogram (ECG) parameters were reported. 
A 16-week, open-label, multicenter, Phase 2 study evaluated vadadustat in 94 subjects receiving 
chronic hemodialysis previously maintained on epoetin alfa and intravenous (IV) iron from the 
3 months prior to Screening. Epoetin alpha was discontinued and subjects were assigned to 1 of 
3 vadadustat dose cohorts:  300 mg QD, 450 mg QD, or 450 mg TIW. Dosing was fixed for the 
first 8 weeks; for the subsequent 8 weeks dose was adjusted from 150 to 600 mg according to Hb 
response based upon a dose adjustment algorithm. Sixty-nine of the 94 subjects completed the 
study. The primary endpoint was the mean Hb concentration change from pre-treatment average 
(Screening Visit 1 [SV1], Screening Visit 2 [SV2], and Baseline Visit) to mid-study 
(Weeks 7 to 8) and end-of-study (Weeks 15 to 16) and was analyzed using observed Hb values 
(no imputation for missing data). No statistically significant mean change in Hb from pre-
treatment average was observed for either of the 2 time points for any of the three treatment 
groups. 
Among subjects randomized to an initial dose of 300 mg QD, 450 mg QD, or 450 mg TIW, 
0% (0 of 30), 3% (1 of 33), and 19% (6 of 31) of subjects withdrew from the study due to 
worsening anemia, respectively. In a sensitivity analysis using last observation carried forward 
for the primary efficacy endpoint, no significant mean change in Hb from pre-treatment levels 
was observed in the 300 mg daily dosing group. At Weeks 15 to 16, modest, statistically 
significant mean decreases were observed in the 450 mg daily and 450 mg TIW dosing groups. 
In a post-hoc univariate analysis of baseline characteristics, higher pre-baseline epoetin alfa dose 
was associated with a decrease in mean Hb at Weeks 7 to 8 and Weeks 15 to 16 in the dosing 
cohorts. Subjects who discontinued the study due to worsening anemia had a higher mean 
pre-baseline epoetin alfa dose compared with subjects who discontinued due to other reasons or 
subjects who completed the study. 
A total of 34 Akebia studies spanning Phase 1 through 3 have been completed or are ongoing. In 
the studies completed to date (Phase 1 and 2 studies), a total of 1011 subjects have received 
vadadustat, including 553 healthy subjects, 450 subjects with CKD, and 8 subjects with hepatic 
impairment. In 4 ongoing Phase 3 studies, 7237 subjects have received study medication 
(vadadustat or comparator).  
Generally, in completed vadadustat studies with healthy subjects, there were a low number of 
AEs. The most frequently reported AEs in healthy subjects were in gastrointestinal disorders 
(nausea, diarrhea, abdominal pain, flatulence, dyspepsia) and nervous system disorders 
(headache, dizziness). The majority of the events were mild to moderate in severity. There were 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 25 of 69 
  
no SAEs, deaths, or withdrawals due to AEs.
 
 
vital signs, or ECGs.  
In completed Phase 2 studies, the most frequently reported AEs in subjects with CKD were in 
gastrointestinal disorders (nausea, diarrhea, vomiting), CV disorders (hypertension, hypotension, 
coronary artery disease), renal disorders (renal failure chronic, renal failure acute), infections and 
infestations (gastroenteritis, urinary tract infection, pneumonia), and metabolism and nutrition 
disorders (hyperkalemia, fluid overload).  
The INNO2VATE program is the global phase 3 clinical development program comprised of 
2 studies in subjects with DD-CKD in which vadadustat and the comparator ESA, darbepoetin 
alpha, were studied. In this program, vadadustat was titrated up or down from a starting dose of 
300 mg according to Hb response. The primary safety endpoint of the INNO2VATE program 
was a MACE endpoint and vadadustat demonstrated non-inferiority to darbepoetin alpha in this 
regard.  
Of the 2 studies which made up the INNO2VATE program, the safety data most relevant to this 
program is the preliminary safety data from Study CI-6548-0017, a study that demonstrated the 
efficacy and safety of vadadustat compared with darbepoetin alfa for the maintenance treatment 
of anemia in subjects with DD-CKD. The Conversion and Maintenance Period of this study was 
from Weeks 0 to 52: conversion to study drug for maintaining Hb (Weeks 0 to 23), primary 
efficacy period (Weeks 24 to 36), and secondary efficacy period (Weeks 40 to 52). 
One thousand seven hundred and seventy-seven subjects were enrolled in the vadadustat arm of 
Study CI-6548-0017 of which 1768 received vadadustat. Based on these preliminary data, the 
overall incidence of TEAEs was similar between the vadadustat (88.3%) and darbepoetin 
(89.3%) comparator arm. Common TEAEs (≥5% for vadadustat-treated subjects) are as below:  
PPD


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 26 of 69 
  
Table 2 
Treatment-emergent Adverse Events Occurring at ≥5% Incidence in 
Vadadustat-treated Subjects 
Preferred Term 
Vadadustat 
N = 1768  
n (%) 
Darbepoetin Alfa 
N = 1769 
n (%) 
Any TEAEs 
1562 (88.3) 
1580 (89.3) 
Diarrhoea 
230 (13.0) 
178 (10.1) 
Pneumonia 
195 (11.0) 
172 (9.7) 
Hypertension 
187 (10.6) 
244 (13.8) 
Headache 
160 (9.0) 
135 (7.6) 
Hyperkalaemia 
160 (9.0) 
191 (10.8) 
Fluid overload 
156 (8.8) 
173 (9.8) 
Fall 
150 (8.5) 
159 (9.0) 
Nausea 
149 (8.4) 
134 (7.6) 
Hypotension 
146 (8.3) 
141 (8.0) 
Vomiting 
120 (6.8) 
124 (7.0) 
Urinary tract infection 
110 (6.2) 
117 (6.6) 
Arteriovenous fistula thrombosis 
106 (6.0) 
78 (4.4) 
Cough 
99 (5.6) 
121 (6.8) 
Dialysis related complication 
99 (5.6) 
122 (6.9) 
Upper respiratory tract infection 
99 (5.6) 
112 (6.3) 
Arteriovenous fistula site complication 
94 (5.3) 
120 (6.8) 
Dyspnoea 
92 (5.2) 
119 (6.7) 
Hypoglycaemia 
92 (5.2) 
78 (4.4) 
Nasopharyngitis 
92 (5.2) 
84 (4.7) 
Pain in extremity 
91 (5.1) 
117 (6.6) 
Source: Table 14.3.1.2.1.  Study CI-6548-0017 
Drug-related TEAEs were more frequently reported in the vadadustat treatment group (9.6%) 
than in the darbepoetin alfa treatment group (3.8%). Compared to the 5.3% incidence of 
Gastrointestinal disorders SOC in the vadadustat treatment group (with the most common 
TEAEs being diarrhea [2.2%] and nausea [1.5%]), there was a 0.2% incidence of 
Gastrointestinal disorders SOC with darbepoetin alpha. With the exception of Gastrointestinal 
disorders SOC, the incidence of drug-related TEAEs is similar between subjects treated with 
vadadustat (4.2%) and darbepoetin alfa (3.7%). 
There were 266 (15.0%) and 276 (15.6%) subjects that experienced TEAEs resulting in death in 
the vadadustat and darbepoetin alfa treatment groups, respectively. The most frequent TEAEs by 
PT resulting in death were similar between both treatment groups, and included cardiac arrest 
(2.0% and 2.1%), septic shock (1.3% and 1.2%), and cardio-respiratory arrest (1.2% and 1.3%) 
for the vadadustat and darbepoetin alfa treatment groups, respectively.  
In the vadadustat treatment group, all deaths due to TEAEs were considered unrelated. In the 
darbepoetin alfa treatment group, only 1 death due to TEAE of acute MI was considered related. 
The TEAEs that resulted in death were similar across both treatment groups. 
In addition to Study CI-6548-0017, Study CI-6548-0025, a Phase 2, randomized, open-label 
study to evaluate vadadustat for the treatment of anemia in hemodialysis subjects converting 
from epoetin alfa therapy, has recently completed the active patient phase but summary efficacy 
and data are not available at this time. Subjects who were randomized to vadadustat were treated 
QD from Day 1 to Week 12 and if Week 12 criteria were met, then vadadustat was administered 
TIW from Weeks 12 to 20. Dose levels of vadadustat administered in this study include 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 27 of 69 
  
150, 300, 450, 600, 750 and 900 mg QD or TIW. One hundred twenty-nine subjects were 
randomized to vadadustat and 36 subjects were randomized to epoetin. All randomized subjects 
received at least one dose of study drug. Of the randomized subjects, 60.5% of subjects in the 
vadadustat group and 88.9% of subjects in the epoetin group completed treatment and 76.7% of 
subjects in the vadadustat group and 94.4% of subjects in the epoetin group completed the study. 
Overall, taking into account the entire vadadustat clinical development program, the safety 
profile to date supports the ongoing clinical development of vadadustat as an orally bioavailable 
agent for the treatment of anemia associated with CKD. 
3.5 
Risk/Benefit Assessment 
Please see the vadadustat Investigator’s Brochure for additional discussion and information for 
the following section. 
3.5.1 
Known Potential Risks 
Trials of injectable ESAs in patients with anemia secondary to NDD-CKD or DD-CKD have 
demonstrated an increased risk of CV events associated with higher Hb targets 
(Besarab 1998; Pfeffer 2009a; Singh 2006). Post-hoc analyses performed by the Food and Drug 
Administration (FDA) and others have shown an association between these adverse outcomes 
and supraphysiologic serum EPO levels and/or Hb oscillations and overshoots 
(McCullough 2013; Unger 2010).   
In vadadustat nonclinical safety studies, the main findings originated from an exaggerated 
pharmacological response that results in increased erythropoiesis, polycythemia, blood 
hyperviscosity, and the formation of fibrin thrombi in multiple organs. Early mortality noted in 
the mouse and rat and moribundity in the dog were due to the sequelae associated with 
polycythemia. These findings were reproducible across species and studies, dose-dependent and 
showed reversibility. Dose-limiting toxicity in the exploratory toxicology studies was due to 
hemoglobinuric nephropathy (rat) and emesis associated with body weight loss (dog). 
In completed Phase 1 clinical studies of vadadustat in healthy subjects, there were low numbers 
of treatment-emergent AEs. The most frequently reported AEs were in the gastrointestinal 
disorders (i.e., nausea, diarrhea, abdominal pain, flatulence, dyspepsia) and nervous system 
disorders (i.e., headache, dizziness) SOC.  The majority of AEs were mild to moderate in 
severity.  
The most frequently reported AEs in completed Phase 2 studies of NDD- and DD-CKD subjects 
were in the following SOCs: gastrointestinal disorders (nausea, diarrhea, vomiting), 
CV disorders (hypertension, hypotension, coronary artery disease), renal disorders (renal failure 
chronic, renal failure acute), infections and infestations (gastroenteritis, urinary tract infection, 
pneumonia), and metabolism and nutrition disorders (hyperkalemia, fluid overload).  Four deaths 
occurred in the completed Phase 2 clinical studies.  
An important identified risk of hepatotoxicity associated with vadadustat therapy has been 
confirmed. There have been reports of drug-induced liver injury (DILI) possibly or probably 
related to vadadustat including one case of Hy's Law probably related to vadadustat. All subjects 
recovered without sequelae. 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 28 of 69 
  
An important identified risk of drug-drug interactions with some statins has been confirmed 
based on the results of clinical studies and have resulted in the following dose restrictions in 
subjects taking vadadustat and concomitant statins: the maximum recommended daily dose of 
rosuvastatin is 10 mg, and the maximum recommended daily dose of simvastatin is 20 mg.  
Review of the Phase 3 safety data did not identify any safety signal for myopathy and/or 
rhabdomyolysis.   
Other non-important identified risks include abdominal pain, headache, and increased blood uric 
acid.  
3.5.2 
Known Potential Benefits 
In studies to date, once-daily oral doses of vadadustat increased mean Hb with fewer excursions 
above the target range of 10.0 to 11.0 g/dL when compared with darbepoetin alfa. In addition, 
serum EPO levels remained well below those reported with ESAs in the literature. As a result, 
there is the potential for the investigational drug vadadustat to provide an effective and safe 
therapeutic option for the treatment of renal anemia. 
In addition, vadadustat may enhance iron absorption, transport, and utilization. Phase 1 and 
Phase 2 studies have demonstrated a consistent dose-dependent increase in TIBC and decrease in 
ferritin and hepcidin. Mechanistic studies have demonstrated that HIF stabilization 
downregulates the iron absorption inhibitor hepcidin, and upregulates the iron-mobilizing 
regulators ferroportin and transferrin (and its receptor) (Peyssonnaux 2007). Potential clinical 
benefits include enhanced erythropoiesis and decreased exogenous iron requirements. 
3.5.3 
Overall Benefit: Risk Conclusion 
DD-CKD and associated anemia are serious chronic conditions with significant morbidity and 
mortality due to the underlying disease as well as associated conditions (including diabetes and 
cardiovascular diseases including hypertension). Subjects enrolled in this study will be receiving 
chronic, outpatient in-center hemodialysis TIW, requiring maintenance ESA treatment.   
The currently known risks of vadadustat most relevant to the study population are those 
associated with long-term vadadustat treatment in DD-CKD patients as measured in 
Study CI-6548-0017. In this study, the overall safety profile was similar to that of darbepoetin 
alpha. The overall incidence of TEAEs was similar between the vadadustat treatment group 
(88.3%) and darbepoetin comparator group (89.3%). The most common TEAEs (> 10%) in the 
vadadustat treatment group were diarrhoea, pneumonia and hypertension. 
Drug-related TEAEs were more frequently reported in the vadadustat treatment group (9.6%) 
than in the darbepoetin alfa treatment group (3.8%). With the exceptional of Gastrointestinal 
disorders SOC (with the most common TEAEs being diarrhea [2.2%] and nausea [1.5%]), the 
incidence of drug related TEAEs was similar between subjects treated with vadadustat (4.2% and 
darbepoetin alfa (3.7%). 
Adverse events of special interest (AESI, see Section 9.11.8) for vadadustat are malignancy 
including renal cell carcinoma (also see Section 9.11.1.2), elevation in ALT or AST >3 times 
ULN (also see Section 9.11.1.1), hepatotoxicity, worsening of hypertension, pulmonary 
hypertension, thrombotic events, congestive heart failure and adrenal disorders. 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 29 of 69 
  
This study will evaluate efficacy and safety of different vadadustat dosing strategies in 
hemodialysis subjects converting from ESAs to further characterize the optimal vadadustat 
regimen, with an emphasis on TIW dosing in hemodialysis patients. This will be the first study in 
which DD-CKD subjects will receive vadadustat as TIW treatment from the onset of treatment, 
will receive TIW doses for more than 20 weeks or receive doses > 900 mg of vadadustat. In 
addition, this will be first study in which vadadustat will be studied against Mircera. 
In studies to date, QD oral doses of vadadustat increased mean Hb with fewer excursions above 
the target range of 10.0 to 11.0 g/dL when compared with darbepoetin alfa. The results of the 
global Phase 3 clinical development program have confirmed that vadadustat in oral daily doses 
between 150 – 600 mg is non-inferior to darbepoetin alpha with respect to achieving and 
maintaining target Hb concentrations. Potential clinical benefits include enhanced erythropoiesis 
and decreased exogenous iron requirements. 
Based on the totality of available information for vadadustat in the proposed patient population, 
the benefits outweigh the risks for the proposed study. 
 
OBJECTIVES AND ENDPOINTS 
4.1 
Primary Objective 
To demonstrate the efficacy and safety of vadadustat administered TIW compared to long acting 
ESA (Mircera) for the maintenance treatment of anemia in hemodialysis subjects. 
4.2 
Primary Efficacy Endpoint 
Mean change in Hb between Baseline (average pretreatment Hb) and the primary evaluation 
period (average Hb from Weeks 20 to 26, inclusive). 
4.3 
Secondary Efficacy Endpoint 
Mean change in Hb between Baseline (average pretreatment Hb) and the secondary evaluation 
period (average Hb from Weeks 46 to 52, inclusive). 
4.4 
Other Endpoints 
Other endpoints include the following: 
• Proportion of subjects having a Hb value within the target range (10.0 to 11.0 g/dL) during 
the primary evaluation period (Weeks 20 to 26). 
• Proportion of subjects having a Hb value within the target range (10.0 to 11.0 g/dL) during 
the secondary evaluation period (Weeks 46 to 52). 
4.5 
Safety Endpoints 
4.6 
Primary Safety Endpoint 
Treatment-emergent AEs and treatment-emergent SAEs.  
4.7 
Secondary Safety Endpoints 
Secondary endpoints include the following: 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 30 of 69 
  
• Proportion of subjects receiving RBC transfusions from Baseline to Week 26. 
• Proportion of subjects receiving RBC transfusions from after Week 26 to Week 52. 
• Proportion of subjects with Hb >11.0, Hb >12.0, >13.0, or >14.0 g/dL. 
• Proportion of subjects with Hb <7.0, <8.0, <9.0, or <10.0 g/dL. 
• Proportion of subjects with Hb increase >1.0 g/dL within any 2-week interval or >2.0 
g/dL within any 4-week interval. 
4.8 
Pharmacokinetic/Pharmacodynamic Endpoints 
The PK parameters include the following: 
• Cmax 
• Ctau 
The PD endpoints include the following: 
• Erythropoietin (EPO) 
• Reticulocyte count 
• Markers of iron metabolism (including iron, ferritin, TIBC) 
 
 
 
 
 
STUDY DESIGN 
5.1 
Overall Design 
This is a multi-center, randomized, open-label, active-controlled study of the efficacy and safety 
of conversion from long-acting ESA (Mircera) to vadadustat TIW for the maintenance treatment 
of anemia in hemodialysis patients. Following a Screening period of up to 8 weeks (56 days), 
subjects who meet all inclusion and none of the exclusion criteria will be randomized 1:1:1 to 
vadadustat 600 mg TIW, vadadustat 900 mg TIW, or to remain on Mircera according to the 
dialysis center’s protocol. 
Randomization will be stratified by dialysis organization: 
Following randomization, there will be 2 periods during the study: 
• Conversion and Maintenance Period (Weeks 0 to 52): conversion to vadadustat TIW 
or to remain on Mircera (Weeks 0 to 20). There will be a primary efficacy evaluation 
period (Weeks 20 to 26) and a secondary efficacy evaluation period (Weeks 46 to 52). 
• Safety Follow-up Period (Early Termination [ET] and Follow-Up): post-treatment 
safety follow up visit (ET/End of Treatment [EOT] +4 weeks) either in person or via 
telephone. 
5.2 
Scientific Rationale for Study Design 
This study will evaluate the efficacy and safety of dose conversion from a long-acting ESA 
(Mircera) to TIW vadadustat for the maintenance of treatment of anemia in hemodialysis 
patients. Numerous studies have demonstrated that hemodialysis subjects requiring higher ESA 
PP
D


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 31 of 69 
  
doses to treat their anemia have a higher burden of comorbidities, a more inflammatory state, and 
a greater risk of adverse outcomes (Besarab 1998; Parfrey 2005; Unger 2010). As described 
above (Section 3.4) in a Phase 2 hemodialysis study (CI-0011), a post-hoc analysis suggested 
higher pre-baseline ESA doses were associated with lower observed mean Hb levels. Subjects on 
higher pre-baseline ESA doses may benefit from a higher starting dose of vadadustat after initial 
conversion from ESAs.  
In this study, Mircera was chosen as an active comparator as it is a long-acting Continuous EPO 
Receptor Activator (CERA) and therefore can be administered less frequently than short- and 
middle-acting ESAs, while maintaining equivalent efficacy for the treatment of anemia in 
patients with CKD (Biggar, 2017; Davey, 2018; Mircera USPI 2018; Palmer, 2014). Patients 
receiving CERA required less frequent ESA administration, demonstrated smaller decreases in 
Hb levels, and were less likely to require an ESA dose during hospitalization. Overall, CERA 
showed comparable clinical performance to shorter-acting ESAs while reducing dose frequency 
in CKD patients receiving hemodialysis (Davey et al, 2018). 
This is particularly relevant in the current medical and regulatory climate given the accumulating 
study findings that resulted in the FDA revising the prescribing information for the currently 
marketed ESAs. These study results indicate an increased risk of death and adverse CV events, 
such as stroke and HF, particularly when using ESAs to achieve a higher Hb concentration. In 
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. While no similar major warnings exist in the European Union (EU) Summary 
of Product Characteristics (SmPC), there is caution suggested with use of ESAs, and 
recommendation to keep Hb levels below 12.0 g/dL. Clinical practice guidelines (Locatelli 2013) 
recommend that risk factors for stroke and malignancy should also be taken into account when 
making treatment decisions to use ESAs for the treatment of anemia. 
5.3 
Justification for Dose 
In this trial, 2 different vadadustat starting doses will be explored. The starting doses of 
vadadustat will be 600 mg TIW and 900 mg TIW in subjects converting from Mircera. The dose 
range for titration is 300 to 1200 mg TIW. Vadadustat 750 and 900 mg QD as titration doses are 
being studied in an ongoing Phase 2b trial in DD-CKD subjects and as fixed doses in an ongoing 
Phase 1b trial, DD-CKD subjects. In prior studies, there was minimal accumulation of vadadustat 
with repeated dosing of up to 900 mg. Given that the half-life of vadadustat in dialysis patients is 
approximately 8 to 10 hours and the interval between doses will be a minimum of 48 hours 
(approximately 5 times the half-life), it is expected that during TIW dosing, vadadustat will be 
eliminated from the systemic circulation without accumulation before the subsequent dose. 
Therefore, the exposures with 1200 mg single dose is likely to be similar to 1200 mg TIW. 
Further, per total weekly dosing, 1200 mg TIW (3600 mg/week) is a lower dosing regimen 
compared to 900 mg QD (6300 mg/week). The starting doses and the proposed vadadustat 
Dosing and Dose Algorithm (Appendix 1) in this study are designed to maintain Hb in a 
predictable and controlled manner while minimizing abrupt increases or excessive rises in Hb 
levels. Based on plasma concentrations and PD measures from previously conducted clinical 
studies with vadadustat, a population PK/PD model was developed. Using this model and the 
proposed dosing algorithm, simulations were carried out to evaluate the effects of different 
starting doses and the resulting Hb responses to support the dosing rationale. Results of the 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 32 of 69 
  
simulations indicated that the starting doses of 300 and 450 mg QD along with the proposed 
dosing algorithm are optimal to maintain Hb levels of 10.0 to 11.0 g/dL in the US and 10.0 to 
12.0 g/dL outside of the US while minimizing excessive rises. The daily dose of 300 mg equates 
to a weekly dose of 2,100 mg. That weekly dose would equate to 700 mg TIW. The daily dose of 
450 mg equates to a weekly dose of 3,150 mg. That weekly dose would equate to 1050 mg TIW. 
For dosing simplicity, a single dose strength of 300 mg is being used in this study. Therefore, 
600 mg TIW (maximum weekly dosing of 1800) and 900 mg TIW (maximum weekly dosing of 
2700 mg) were selected as starting doses for this study. 
Hb monitoring, a dose adjustment algorithm (Section 7.1.2 and Appendix 1), and phlebotomy 
will be implemented to mitigate the potential risk of a rapid Hb rise, as follows: 
• Hb measurements are scheduled at least every 2 weeks to Week 8 and thereafter every 
4 weeks. 
• The dose adjustment algorithm will target a narrow Hb range, 10.0 to 11.0 g/dL. 
• The protocol specifies that phlebotomy may be considered in the setting of high Hb levels 
(>14.0 g/dL) or a high Hb rate of rise, based on the investigator’s judgment. 
5.4 
End of Study Definition 
Study Completion 
The study will be considered completed after all randomized subjects have completed their final 
study visit (Week 52/or ET and Safety Follow-Up at Week 56).  
Subject Completion 
A subject will be considered as having completed the study after completion of their final study 
visit (Week 52, Safety Follow-Up at Week 56). 
5.5 
Number of Study Sites 
Approximately 50 investigative sites in the US at outpatient hemodialysis center. 
5.6 
Subject Input on Study Design 
No subject input was obtained on the study design. 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 33 of 69 
  
 
STUDY POPULATION 
6.1 
Inclusion Criteria 
Subjects must meet the following inclusion criteria: 
1. ≥18 years of age. 
2. Receiving chronic, outpatient in-center hemodialysis TIW for end-stage kidney disease 
for at least 12 weeks prior to SV1. 
3. Currently maintained on Mircera (≤250 µg/month) with at least 2 doses received within 8 
weeks prior to SV2. 
4. Mean screening Hb between 8.5 and 11.0 g/dL (inclusive), as determined by the average 
of 2 Hb values measured by the central laboratory at least 4 days apart between SV1 and 
SV2. 
5. Serum ferritin ≥100 ng/mL and transferrin saturation (TSAT) ≥20% during Screening. 
6. Folate and vitamin B12 measurements ≥ lower limit of normal during Screening. 
6.2 
Exclusion Criteria 
Subjects must not meet any of the following exclusion criteria: 
1. Anemia due to a cause other than CKD (e.g., sickle cell disease, myelodysplastic 
syndromes, bone marrow fibrosis, hematologic malignancy, myeloma, hemolytic anemia, 
thalassemia, or pure red cell aplasia). 
2. Clinically meaningful bleeding event in opinion of investigator within 8 weeks prior to 
Baseline. 
3. RBC transfusion within 8 weeks prior to Baseline. 
4. Having received any doses of darbepoetin alfa (Aranesp®) within 4 weeks prior to 
Baseline. 
5. Having received any doses of epoetin alfa (Epogen®) within 1 week prior to Baseline. 
6. Anticipated to discontinue hemodialysis during the study. 
7. Judged by the Investigator that the subject is likely to need rescue therapy (ESA 
administration or RBC transfusion) immediately after enrollment in the study. 
8. History of chronic liver disease (e.g., chronic infectious hepatitis, chronic autoimmune 
liver disease, cirrhosis or fibrosis of the liver).  
9. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), 
alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), or total 
bilirubin >2 x upper limit of normal (ULN) during Screening. Subjects with a history of 
Gilbert’s syndrome are not excluded. 
10. Current uncontrolled hypertension as determined by the Investigator that would 
contraindicate the use of an ESA. 
11. Acute coronary syndrome (hospitalization for unstable angina or myocardial infarction), 
surgical or percutaneous intervention for coronary, cerebrovascular or peripheral artery 
disease (aortic or lower extremity), surgical or percutaneous valvular replacement or 
repair, sustained ventricular tachycardia, hospitalization for HF or New York Heart 
Association Class IV HF, or stroke within 12 weeks prior to or during Screening. 
12. History of new, active or recurrent malignancy within 2 years prior to and during 
Screening or currently receiving treatment or suppressive therapy for cancer. Subjects 
with treated basal cell carcinoma of skin, curatively resected squamous cell carcinoma of 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 34 of 69 
  
skin, or treated cervical carcinoma in situ are not excluded. 
13. History of deep vein thrombosis or pulmonary embolism within 12 weeks prior to or 
during Screening. 
14. History of hemosiderosis or hemochromatosis. 
15. History of prior organ transplantation (subjects with a history of failed kidney transplant 
or corneal transplants are not excluded). 
16. Scheduled organ transplant from a living donor and subjects on the kidney transplant 
wait-list who are expected to receive a transplant within 6 months.  
17. History of a prior hematopoietic stem cell or bone marrow transplant (stem cell therapy 
for knee arthritis is not excluded). 
18. Known hypersensitivity to vadadustat, Mircera, or any of their excipients. 
19. Use of an investigational medication or participation in an investigational study within 
30 days or 5 half-lives of the investigational medication (whichever is longer), prior to 
Screening (subjects may participate in another concurrent study only if that study is a 
non-interventional, observational investigation). 
20. Current exposure to any HIF-PH inhibitor or prior exposure to vadadustat. 
21. Subjects with bilateral native nephrectomy. 
22. Noncompliance with dialysis session attendance defined as missing more than 1 dialysis 
session within 8 weeks prior to Baseline. 
23. Active Severe Acute Respiratory Syndrome-Related Coronavirus (SARS-CoV-2) during 
Screening. 
24. Females who are pregnant or breastfeeding during Screening or are planning to become 
pregnant and breastfeeding during the study period, and for 30 days after the final study 
drug administration. 
25. Women of childbearing potential who are unable or unwilling to use 2 acceptable 
methods of contraception* starting at Screening, throughout the study period and for 45 
days after the final study drug administration. 
26. Female subjects of childbearing potential who plan to donate ova during the study, and 
for 30 days after the last dose of study drug. 
27. Non-vasectomized male subjects who are unable or unwilling to use an acceptable 
method of contraception* from time of first dose of study drug until 30 days after the last 
dose of the study drug.  
28. Male subjects who plan to donate sperm during the study and for at least 30 days after the 
last dose of study drug. 
29. Any other reason, which in the opinion of the Investigator, would make the subject not 
suitable for participation in the study. 
*Acceptable forms of contraception include: 
• Established use of oral, injected or implanted hormonal methods of contraception 
• Placement of an intrauterine device or intrauterine system 
• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository. 
6.3 
Screen Failures and Retesting/Rescreening 
Subjects who fail to qualify for the study based on laboratory tests may be considered for 
rescreening at the discretion of the Investigator if it is considered that the subject’s status has 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 35 of 69 
  
changed, and the subject may now qualify for the study. Screening is limited to 3 attempts (initial 
Screening and 2 additional rescreening attempts). A new informed consent is required to be 
signed prior to every rescreening. Rescreened subjects should be assigned a new subject number. 
Subjects who initially fail to qualify for the study based on laboratory test results may be retested 
once for each laboratory parameter within the 8-week Screening Period, per Investigator 
discretion. 
 
STUDY INTERVENTION 
7.1 
Study Intervention(s) Administration  
7.1.1 
Study Intervention Description 
A multi-center, randomized, open-label, active-controlled study of the efficacy and safety of 
conversion from long-acting ESA (Mircera) to vadadustat TIW for the maintenance treatment of 
anemia in hemodialysis patients. Following a Screening period of up to 8 weeks (56 days), 
subjects who meet all inclusion and none of the exclusion criteria, Mircera will be discontinued 
and subjects will be randomized 1:1:1 to vadadustat 600 mg TIW, vadadustat 900 mg TIW, or to 
remain on Mircera according to the dialysis center’s protocol. 
Randomization will be stratified by dialysis organization: 
The minimum dose of vadadustat will be 300 mg TIW and the maximum dose will be 1200 mg 
TIW.   
Following randomization, there will be 2 periods during the study: 
• Conversion and Maintenance Period (Weeks 0 to 52): conversion to vadadustat TIW or to 
remain on Mircera (Weeks 0 to 20). There will be a primary efficacy evaluation period 
(Weeks 20 to 26) and a secondary efficacy evaluation period (Weeks 46 to 52). 
• Safety Follow-up Period (ET and Follow-Up): post-treatment safety follow up visit 
(ET/EOT +4 weeks) either in person or via telephone. 
7.1.2 
Dosing and Administration 
The aim is to achieve and maintain Hb levels within the target range of 10.0 to 11.0 g/dL 
inclusive, while targeting the middle of the range and minimizing excursions outside the target 
range. 
Dosing will be initiated at Baseline and the first dose of vadadustat will be administered at the 
hemodialysis unit after other Baseline procedures have been completed. Thereafter, vadadustat is 
anticipated to be administered at the hemodialysis unit. Subjects may take vadadustat with or 
without food and will be instructed to swallow the tablet(s) whole. Subjects are to take 
vadadustat at roughly the same time each day. 
Mircera will be administered IV at the hemodialysis unit based on according to the dialysis 
center’s protocol. 
Note: For all subjects, it is recommended that no additional ESA doses will be administered after 
SV2 after the subject has met all eligibility criteria and before Baseline. For all subjects, it is 
required that a minimum of 14 days be observed between the last dose of Mircera and the 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 36 of 69 
  
Baseline visit. If an ESA other than Mircera was administered during the Screening period, the 
subject will be a screen failure. 
After discussion with the Medical Monitor, screening may be extended for an additional 2 to 
4 weeks based on subject’s Hb level or Hb trajectory or based on timing of last Mircera dose 
given during Screening and the Baseline visit. 
For subjects who are randomized to the Mircera treatment arm, the initial dosing regimen in the 
study (starting from Baseline) will be according to the dialysis center’s protocol. The timing of 
randomization should align with next anticipated dose of Mircera. 
Study Drug Guidelines for Dose Adjustment 
Dose adjustments will be guided by central laboratory Hb concentrations throughout the study to 
determine if vadadustat or Mircera doses will be adjusted, interrupted, or maintained. Mircera 
dosing will be based on standard of care laboratory measures according to the dialysis center’s 
protocol. 
Guidelines for vadadustat dose adjustment are as follows (see Appendix 1): 
• Dose adjustments are based on the Investigator’s clinical discretion, incorporating the 
protocol guidance below as well as the subject’s current Hb level, trajectory, and 
variability; symptoms; CV risk; and other features of his/her clinical condition(s). 
• If a dose increase or decrease is required to achieve and maintain Hb levels within the 
target range of 10.0 to 11.0 g/dL inclusive, dose is adjusted by 1 dose level 
(vadadustat 300 mg). 
• A one-time dose increase after the first 2 weeks of dosing after randomization is 
allowed. Thereafter, in general, do not increase the dose more frequently than once 
every 4 weeks. 
o A subject’s dose may be increased by 1 dose level (300 mg TIW) if the 
subject has a decline in Hb ≥0.5 g/dL from Baseline in the first 2-week period 
(the initial period from Baseline to Week 2 following conversion from 
Mircera) and if Hb is <10.0 g/dL. 
• Reduce the dose in the setting of a rapid rise in Hb (defined as >1.0 g/dL in any 
2-week period or >2.0 g/dL in any 4-week period).  
• Reduce the dose in the setting of Hb >11.0 g/dL.  
• Interrupt the dose in the setting of a Hb >12.0 g/dL until Hb value falls below 
11.0 g/dL. After Hb falls below 11.0 g/dL, restart study drug at a lower dose.  
The minimum dose of vadadustat will be 300 mg TIW (1 tablet TIW) and the maximum dose 
will be 1200 mg TIW. Subjects whose dose of vadadustat is interrupted due to elevated Hb will 
continue in the study. Unless contraindicated, treatment will be resumed whenever possible and 
assessed at every visit following study drug interruption. 
Mircera will be administered as standard of care. Dose adjustments will be made according to the 
dialysis center’s protocol. 
7.1.3 Study Medication Stopping Rules for Liver Function Test Changes 
Vadadustat must be permanently discontinued if a subject meets 1 of the following criteria:  
• ALT or AST >3x ULN and total bilirubin >2x ULN 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 37 of 69 
  
• ALT or AST >3x ULN and international normalized ratio (INR) >1.5 
• ALT or AST >8x ULN 
• ALT or AST remains >5x ULN over 2 weeks (re-challenge generally should be avoided 
with ALT or AST >5x ULN unless there are no other good therapeutic options) 
• ALT or AST >3x ULN with symptoms (e.g., fatigue, nausea, vomiting, right upper 
quadrant pain, fever, rash) or eosinophilia 
See Section 9.11 for reporting requirements related to a subject being permanently discontinued 
based on meeting the laboratory abnormalities listed above. 
7.2 
Preparation/Handling/Storage/Accountability 
7.2.1 
Acquisition and Accountability 
Vadadustat for oral administration will be provided and shipped by the Sponsor.  
The investigator or designated study personnel will be responsible for preparing vadadustat for 
dispensing to the subject and for vadadustat supply accountability. 
Mircera will be supplied by the dialysis unit which will be also responsible for mircera supply 
accountability. 
Refer to the Pharmacy Manual for additional details. 
7.2.2 
Formulation, Appearance, Packaging and Labeling 
Vadadustat will be provided as 300 mg oval, yellow tablets debossed with “VDT” on 1 side and 
“300” on the other side for oral administration. The tablets will be packaged in high-density 
polyethylene bottles with child-resistant closures, polypropylene liner, and induction seal. 
Labeling will be in accordance with current Good Manufacturing Practices (GMP) and local 
regulatory requirements. 
7.2.3 
Product Storage and Stability 
Vadadustat should be stored per the investigational labels. Please consult the Pharmacy Manual 
for details on storage and managing temperature excursions. 
7.2.4 
Preparation 
Not applicable. 
7.3 
Measures to Minimize Bias: Randomization and Blinding 
Subjects will be randomized 1:1:1 to vadadustat 600 mg TIW, vadadustat 900 mg TIW, or to 
remain on Mircera.   
Randomization will be stratified by dialysis organization: 
This will be an open-label study. Treatment assignment will be done through a validated 
electronic  system. The Investigator, Sponsor, and contract research organization (CRO) study 
teams will not be aware of which treatment will be assigned next. Treatments will be 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 38 of 69 
  
administered in an open-label fashion. The sponsor and CRO study teams will be blinded to ‘by 
treatment’ aggregated analyses except for the unblinded statistician.   
7.4 
Study Intervention Compliance 
Subjects will take the dose of study drug on dialysis days. If a dose is forgotten, the missed dose 
will not be replaced. 
Subjects will be questioned on whether they have experienced any problems related to the dosing 
of study medication.  
7.5 
Concomitant Therapy 
7.5.1 Erythropoiesis-stimulating Agents 
Co-administration of any ESA with vadadustat is prohibited. In the setting of ESA rescue 
therapy, the initial dose of ESA rescue therapy may be administered on the same day as the last 
vadadustat dose prior to vadadustat dose interruption (Section 7.5.5.2) if deemed medically 
necessary at the discretion of the Investigator. Guidelines for ESA administration as rescue 
therapy are provided in Section 7.5.5.2. All efforts will be made to avoid inadvertent 
administration of ESAs resulting from adherence to ESA hemodialysis center protocols (e.g., 
ESA protocols for patients on hemodialysis). If ESA is inadvertently administered to subjects 
actively receiving vadadustat treatment, vadadustat treatment will be stopped and the event will 
be reported as a protocol deviation.  
For all subjects, it is required that a minimum period as outlined below be observed between the 
last dose of ESA administered during Screening and Randomization visit:  
• 
2 days after last dose of epoetin alpha. 
• 
7 days after last dose of darbepoetin alfa. 
• 
14 days after last dose of methoxy polyethylene glycol-epoetin beta (Mircera). 
7.5.2 Iron Supplementation and Phosphate Binders 
Investigators will prescribe iron supplementation (IV, oral or intradialytic) as needed throughout 
the study to maintain ferritin and TSAT according to the Schedule of Activities (SoA) 
(Section 1.3). The use of iron-based phosphate binders (e.g., ferric citrate) is permitted. 
Important: Subjects already receiving oral iron supplementation as part of their treatment plan 
may continue their current treatment regimen. Because of the potential for oral iron and 
phosphate binders to reduce the bioavailability of vadadustat, the trial medication is not to be 
administered concurrently with an oral iron supplement (including multivitamins containing 
iron), iron-containing phosphate binders, non-iron-containing phosphate binders, or any oral 
medications containing iron.  
Subjects will be instructed to take any non-iron-containing phosphate binders with a meal at least 
2 hours before or 1 hour after the dose of vadadustat. Subjects will be instructed to take 
iron-containing supplements and phosphate binders at least 1 hour after the dose of vadadustat. 
Investigators will prescribe IV iron as needed with dosing according to the dialysis center’s 
protocol. Iron supplementation details will be captured in the appropriate electronic case report 
form (eCRF). 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 39 of 69 
  
7.5.3 OATP1B1/1B3 Substrates (eg, Statins) 
Investigators should adjust the dose of these concomitant medication as follows: 
• Simvastatin, maximum daily dose of 20 mg. 
• Rosuvastatin, maximum daily dose of 10 mg. 
7.5.4 Sulfasalazine, Other Breast Cancer Resistance Protein Substrates, and Probenecid 
Exposures to sulfasalazine (moderately) and mesalamine (mildly) were increased with 
co-administration of vadadustat based on a study in healthy adults. In subjects taking vadadustat, 
sulfasalazine and other clinically relevant substrates of the breast cancer resistance protein 
(BCRP) transporter (e.g., sulfasalazine, methotrexate, mitoxantrone, imatinib, irinotecan, 
lapatinib, topotecan, tenofovir, glecaprevir, pibrentasir, or sofosbuvir), caution should be taken 
during the study. 
Probenecid, an inhibitor of UDP-glucuronosyltransferase (UGT) and the organic anion 
transporter (OAT)1/3 transporters, increased vadadustat area under the curve and is prohibited 
during the study 
7.5.5 Rescue Medicine 
To ensure the safety of subjects and to standardize the use of rescue in the study, rescue therapy 
guidelines are provided. 
 
Red Blood Cell Transfusion 
Investigators will use their local institution’s transfusion guidelines when determining whether to 
transfuse a study subject. In general, in the event of an acute or severe loss of blood, a RBC 
transfusion will be administered as clinically indicated. In less severe instances but where there 
may be worsening of anemia or moderate to severe symptoms of anemia, RBC transfusions are 
permitted at the discretion of the Investigator given medical necessity. Study drug may be 
continued during the transfusion period. 
Reasons for RBC transfusion will be captured in the appropriate eCRF. 
 
Erythropoiesis-stimulating Agent Use 
ESA Rescue administration will be allowed when medically necessary at the discretion of the 
Investigator or if a subject is hospitalized. In the setting of ESA rescue therapy, the initial dose of 
ESA rescue therapy may be administered on the same day as the last vadadustat dose prior to 
vadadustat dose interruption if deemed medically necessary at the discretion of the investigator. 
In general, ESA rescue will be allowed in subjects with Hb <9.0 g/dL, and ESA rescue will be 
stopped when Hb ≥9.5 g/dL. ESA therapy will be administered using an approved ESA and 
dosing as per the local institution’s guidelines and per the approved product label.   
While receiving ESA therapy, subjects randomized to vadadustat must temporarily interrupt 
vadadustat. A minimum interval will be observed prior to restarting vadadustat after the last dose 
of ESA, and treatment will be resumed after the following minimum intervals: 
• 2 days after last dose of epoetin alfa  


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 40 of 69 
  
• 7 days after last dose of darbepoetin alfa  
• 14 days after last dose of methoxy polyethylene glycol-epoetin beta (Mircera) 
Following ESA administration, vadadustat will be resumed at the same dose as previously used 
or one dose higher and adjusted according to the dose adjustment algorithms (Section 7.1.2 and 
Appendix 1) at the discretion of the Investigator.  
Reasons for ESA Rescue use will be captured in the appropriate eCRF. 
 
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL  
8.1 
Discontinuation of Study Intervention 
8.1.1 
Temporary Interruption of Study Drug 
During the study, a subject may interrupt vadadustat for any of the following reasons: 
• AE 
• Missed hemodialysis visit 
• Investigator’s discretion 
• Rapid rise in Hb (defined in Section 7.1.2)  
• Hb above 11.0 g/dL 
• ESA use  
Unless contraindicated, treatment will be resumed whenever possible and assessed at every visit 
following study drug interruption. 
8.1.2 
Permanent Discontinuation of Study Medication 
Subjects who permanently discontinue study medication prior to study completion will not 
continue in the study. These subjects are to have their ET visit at the time of permanently 
discontinuing study medication and perform a 4-week safety follow-up after ET visit.  
Subjects may permanently discontinue study medication for any of the following reasons: 
• AE  
• Investigator’s discretion 
• Subject withdrawal of consent  
• Lack of efficacy 
• Lost to follow up despite reasonable efforts by the Investigator to locate the subject 
• Death  
• Other reasons (pregnancy, kidney transplantation, specific reasons to be documented by 
the Investigator) 
Lack of efficacy is defined as an inadequate response to vadadustat in the Investigator's opinion.  
Subjects who undergo a solid organ (including kidney), hematopoietic stem cell, or bone marrow 
transplantation will have vadadustat permanently discontinued. 
8.1.3 
Withdrawal of Consent 
All subjects have the right to withdraw their consent from further participation in the trial at any 
time without prejudice. Subjects cannot withdraw consent for use of data already collected as 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 41 of 69 
  
part of the trial, but only for future participation. The investigator can also discontinue a 
subject’s participation in the trial at any time if medically necessary.  
Withdrawal of consent is a critical trial event and, therefore, should be approached with the same 
degree of importance and care as is used in initially obtaining informed consent. The reasons for 
a subject’s intended withdrawal need to be completely understood, documented, and managed to 
protect the rights of the subject and the integrity of the trial. 
Details on the withdrawal of consent from the pharmacogenomic (PGx) assessment and/or 
optional future biospecimen research (FBR) substudy are provided in the informed consent form 
(ICF). 
8.1.4 Entire Study Termination 
The entire study may be suspended or terminated by the Sponsor for safety or other 
unanticipated reasons or upon request of regulatory agencies. Criteria for premature termination 
or suspension of the study are detailed in Section 11.8.1. 
8.1.5 Individual Study Site Termination 
Study participation may be suspended or terminated at an individual investigational site for 
various reasons. Criteria and procedures for premature termination or suspension of an 
investigational site are detailed in Section 11.8.2. 
8.1.6 Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she is unable to be contacted by the study 
site staff.  
 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site will attempt to contact the subject and reschedule the missed visit and counsel 
the subject on the importance of maintaining the assigned visit schedule and ascertain if 
the subject wishes to and/or should continue in the study. 
• Before a subject is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject‘s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical record 
or study file.  
• Should the subject continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
• For subjects who are lost to follow-up, the investigator may search publicly available 
records to ascertain survival status. This ensures that the data set(s) produced as an 
outcome of the study is/are as comprehensive as possible. 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 42 of 69 
  
 
STUDY ASSESSMENTS AND PROCEDURES 
9.1 
General Study Periods 
9.1.1 
Screening, Enrollment and/or Randomization 
 
Informed Consent 
Informed consent must be obtained prior to the subject entering into the study and before any 
protocol-directed procedures are performed (including Screening activities). Additionally, 
subjects may be asked to provide a separate, optional consent to obtain and store a blood 
sample(s) for future research. 
This study includes 2 screening visits (SV1 and SV2). 
9.1.2 
Treatment Period 
The treatment period of this study includes the following visits: 
• A Baseline/randomization visit 
• A 52-week treatment period 
9.1.3 
End of Treatment Visit 
Subjects completing the study will undergo a final Week 52 EOT visit according to the SoA 
(Section 1.3). 
9.1.4 
Safety Follow-up 
The safety follow-up will be conducted 4 weeks after the EOT visit, or 4 weeks after the last 
dose of study medication for ET. 
9.2 
Clinical Assessments 
The following clinical evaluations will be conducted during the course of the study. If the 
evaluations will occur on a hemodialysis day, the clinical evaluations should be completed 
before dialysis, if applicable. 
9.2.1 
Medical History, Demographics, and Physical Examination 
Medical history, demographic information, and physical examination (including height) will be 
collected according to the SoA (Section 1.3). Relevant medical history (with particular emphasis 
on previous medical conditions that may lead to exclusion) and significant ongoing medical 
conditions or diseases should be documented.   
During the Treatment period, an abbreviated physical examination should be performed at the 
discretion of the investigator, as clinically indicated. 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 43 of 69 
  
9.2.2 
Vital Sign Measurements 
Predialysis temperature, heart rate, blood pressure, respiratory rate, and weight will be assessed 
in the seated position after 5 minutes of rest prior to blood draws. For blood pressure, a total of 
2 measurements at intervals of at least 2 minutes will be performed. Measurements will be taken 
prior to scheduled blood draws when possible.  
Dry weight will be collected for all subjects per site standard of care according to the SoA 
(Section 1.3).  
9.2.3 
Dialysis Adequacy 
Dialysis adequacy, as available from local collection, will be recorded in the eCRF. 
9.2.4 
Dialysis Treatment 
Hemodialysis vascular access type use at baseline; and changes in renal replacement therapy 
(from in-center hemodialysis) throughout the trial. 
9.3 
Efficacy Assessments 
The primary efficacy endpoint is mean change in Hb between Baseline (average pretreatment 
Hb) and the primary evaluation period (average Hb from Weeks 20 to 26, inclusive). Laboratory 
evaluations of Hb levels will be conducted according to the SoA (Section 1.3) and are described 
in Section 9.4. 
9.4 
Laboratory and Other Assessments 
The following safety and other assessments will be conducted during the course of the study, 
according to the SoA (Section 1.3).  
Samples for laboratory assays will be sent to a central laboratory for analysis. Detailed 
instructions for the collection, processing, and shipment of laboratory samples will be provided 
by the sponsor and the central laboratory. If blood is collected on a hemodialysis day, blood 
draws should be done prior to dialysis, if applicable. The investigator is responsible for 
reviewing laboratory results for clinical significance. 
Blood samples will be collected for the following laboratory evaluations listed below and will be 
conducted during the course of the study. For details regarding the timing of these assessments 
refer to Section 1.3. 
• Pregnancy Test: A serum pregnancy test will be performed according to the timepoints in the 
SoA (Section 1.3) for females of childbearing potential. Additional serum or local urine (if 
possible) pregnancy tests may be conducted throughout the study in sufficient number, as 
determined by the investigator to establish the absence of pregnancy during the study. These 
results must be available and must be negative before the subject takes the first dose of study 
medication. 
• PK Evaluations (samples to be drawn only for subjects randomized to vadadustat): Plasma 
samples for PK evaluation will be collected to analyze for both the parent compound 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 44 of 69 
  
(vadadustat) and its metabolites. Collection time points for PK will be obtained according to 
the SoA (Section 1.3). Vadadustat should be dosed prior to the start of dialysis. The predose 
PK sample should be collected as close to the same time as the serum chemistry sample. 
Blood samples will be collected and processed according to the Operations/Laboratory 
Manual. The actual date and time of the PK sample collection will be recorded in the eCRF. 
Additionally, the time of the dose of trial medication will be recorded in the eCRF and the 
start and stop time of the dialysis session will be recorded in the eCRF. The date and time of 
dose and PK samples will be recorded in eCRF.  
o After processing into plasma, aliquots will be placed into appropriately labeled tubes and 
will be placed in a freezer set at −70°C or −20°C, unless otherwise instructed in the 
Operations/Laboratory Manual. All plasma samples will be shipped to the bioanalytical 
laboratory for analysis. Information will be provided in the Operations/Laboratory 
Manual. 
• Laboratory Evaluations: Blood samples for laboratory analysis will be obtained according to 
the SoA (Section 1.3) and are specified in Table 3. 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 45 of 69 
  
Table 3 
Protocol Required Laboratory Assessments 
Complete Blood Count 
Iron Indices 
Serum Chemistry 
Hb 
hematocrit 
RBC 
MCV 
MCH 
MCHC 
platelets 
RDW 
Differential WBC 
• Neutrophils 
• Lymphocytes 
• Monocytes 
• Eosinophils 
• Basophils 
Ferritin 
Iron 
TIBC 
TSAT 
Sodium 
Potassium 
Bicarbonate 
Chloride 
Calcium 
Magnesium 
Phosphorus 
Glucose 
Creatinine 
BUN 
CPK 
Uric acid 
Albumin 
Total Protein 
Lipid Profile 
Total cholesterol 
LDL 
HDL 
Trigylcerides 
Liver Function Tests 
Additional Laboratory Tests 
Total bilirubin 
ALP 
ALT/SGPT 
AST/SGOT 
LDH 
 
β-HCG 
Reticulocyte counta 
Folate 
Vitamin B12 
CRP 
Erythropoietin 
 
Coagulation Testsb 
PT 
PTT 
INR 
β-HCG: beta human chorionic gonadotropin; ALP: alkaline phosphatase; ALT: alanine aminotransferase; 
AST: aspartate aminotransferase; BUN: blood urea nitrogen; CPK: creatine phosphokinase; CRP: C-reactive 
protein; Hb: hemoglobin; HDL: high density lipoprotein; INR: international normalized ration; LDH: lactate 
dehydrogenase; LDL: low density lipoprotein; MCH: mean corpuscular hemoglobin; MCHC: mean corpuscular 
hemoglobin concentration; MCV: mean corpuscular volume; PT: prothrombin time; PTT: partial thromboplastin 
time; RBC: red blood cell; RDW: red blood cell distribution; SGOT: serum glutamic-oxaloacetic transaminase; 
SGPT: serum glutamic-pyruvic transaminase; TIBC: total iron-binding capacity; TSAT: transferrin saturation; 
VEGF: vascular endothelial growth factor; WBC: white blood cell. 
a. An automated reticulocyte count should include both absolute and percent 
b. The coagulation tests will be performed for unscheduled visits only. 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD
PP
D


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 46 of 69 
  
 
  
 
 
9.6 
Pharmacodynamic Assessments 
Blood samples for EPO, reticulocytes, and iron indices (ferritin, iron, TIBC, and TSAT) analysis 
will be collected according to the SoA (Section 1.3). Blood samples will be collected and 
processed according to the Operations/Laboratory Manual. For all PD sampling, the time of the 
previous dose of trial medication is to be recorded in the eCRF and the timing of administration 
of trial medication and the start and stop time of the dialysis session will be recorded in the 
eCRF. 
9.7 
Pharmacogenomic Assessments 
9.7.1 
Pharmacogenomic Samples 
A separate informed consent will be required to authorize the collection of PGx samples. PGx 
samples will be collected from consenting subjects according to the SoA (Section 1.3). Blood 
samples will be collected and processed according to the Operations/Laboratory manual. The 
date and time of samples collected for PGx analysis will be recorded. All PGx samples will be 
shipped to the PGx laboratory for analysis. Information will be provided in the 
Operations/Laboratory Manual. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PP
D
PP
D


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 47 of 69 
  
 
 
 
 
 
 
 
 
 
 
9.10 
Safety and Other Assessments 
9.10.1 
Adverse Event Assessments 
AE collection will begin from time of signing of the Informed Consent Form (ICF) through 
Safety Follow-up Visit. The investigator and study personnel will review each subject’s 
laboratory and clinical evaluation findings and query the subject directly regarding AEs (see 
Section 9.11.1.1). Subjects must be followed for AEs until the final required protocol visit or 
until all drug-related toxicities and SAEs have resolved (or are considered chronic/stable), 
whichever is later. 
9.10.2 
Concomitant Medication Recording 
All medications (both prescription and non-prescription, and including vitamins, herbals, 
topicals, inhaled, and intranasal), taken during the screening period and throughout the study, 
ending at the final protocol required visit, should be recorded on the appropriate eCRF. At each 
study visit, subjects will be asked whether they have started or discontinued any medication 
since their previous study visit. This includes single-use or as-needed medication use. All 
medications and treatments, including vitamin supplements, over-the-counter medications and 
oral herbal preparations must be recorded in the eCRFs. Heparin injections or saline flushes, are 
not required to be recorded unless relevant for an AE or SAE, however other concomitant 
medications administered in the dialysis unit will be recorded. In addition, the ESA, blood 
transfusion, and iron treatment regimen prior to randomization and date of last dose will be 
recorded.  
9.10.3 
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 study site’s standard clinical practice. 
9.11 
Adverse Events and Serious Adverse Events 
9.11.1 
Definitions of Adverse Events and Serious Adverse Events 
 
Adverse Events 
For the purposes of this study, an AE is any untoward medical occurrence (including an 
abnormal laboratory finding) that occurs in the protocol-specified AE reporting period; the event 
does not necessarily have a causal relationship with that treatment or usage.  
P
P
D


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 48 of 69 
  
An AE includes medical conditions, signs, and symptoms not previously observed in the subject 
that emerge during the protocol-specified AE reporting period, including signs or symptoms 
associated with pre-existing underlying conditions that were not present prior to the AE reporting 
period. In addition, any worsening of a pre-existing condition that occurs during the protocol-
specified AE reporting period is also considered an AE and will be captured as “worsening” of 
pre-existing condition 
AEs therefore include the following:  
• All AEs, whether suspected to be causally related to study medication or otherwise 
• All AEs secondary to any medication overdose, medication error, abuse, withdrawal, 
sensitivity, or toxicity 
• Illnesses apparently unrelated to study medication, 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 and 
dyspnea, when the diagnosis has been established. Signs and symptoms should be reported as 
event terms only when the medical diagnosis remains unknown, and revised to a medical 
diagnosis term once it has been established. 
Procedures – Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as AEs. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE. For example, an acute 
appendicitis that begins during the AE reporting period should be reported as the AE and the 
resulting appendectomy noted under ‘Comments’. 
Pre-planned therapeutic procedures not associated with a new medical condition or worsening 
pre-existing condition should not be reported as AEs. 
Device related events (failures/malfunctions) should not be reported as AEs; however, the 
etiology or complication associated with the device failure/malfunction should be reported if it 
meets the definition of an AE. 
Pre-existing Conditions – In this study, a pre-existing condition (i.e., a disorder present before 
the AE reporting period started and noted on the pretreatment medical history/physical 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 49 of 69 
  
examination form) should not be reported as an AE unless the condition worsens or episodes 
increase in frequency during the AE reporting period. 
Abnormal Test Findings – All laboratory test results will be reviewed by the Investigator. The 
Investigator will utilize his/her judgment in determining if out-of-range laboratory values are 
clinically significant and will denote this using the abbreviation “CS” on the laboratory report for 
source documentation. Laboratory tests that are labeled as clinically significant should be 
reported as AEs, either separately or as part of a description of a symptomatic AE. If there are 
significant changes in a laboratory report from a previous visit that are determined to be 
clinically significant, these should also be reported as AEs. Any abnormal laboratory value 
which requires treatment or further diagnostic testing and/or results in discontinuation from study 
should be reported as an AE. An expected laboratory abnormality from a condition that is part of 
the medical history is not considered clinically significant for the purposes of the study unless it 
represents a worsening of the condition. 
Abnormalities in ALT, AST, and Total Bilirubin – Abnormalities in ALT, AST, and total 
bilirubin should be reported to the Sponsor’s Medical Monitor or CRO designee within 24 hours 
of awareness as an SAE with ‘other medically important event’ criteria selected, if the following 
conditions are met: 
• New elevation in ALT or AST >3 x ULN 
If new elevations in ALT or AST >3 x ULN, without an elevation of total serum bilirubin >2 x 
ULN are identified, the following steps are to be taken: 
• Temporary discontinuation of study medication; 
• Repeat testing of ALT, AST, alkaline phosphatase (ALP), and total bilirubin, to be 
completed within 48 to 72 hours to confirm the abnormalities and to determine trend; 
• Study medication should not be resumed until monitoring indicates abnormalities have 
resolved or are stable. 
Details on the management of subjects with other ALT and AST abnormalities are further 
described in Section 7.1.3.   
Worsening of Anemia – In this study, it is possible that some subjects may experience a 
worsening of anemia. As the primary endpoint of this study assesses Hb response, worsening of 
anemia is captured as part of this efficacy parameter. Worsening of anemia should not be 
considered an AE unless the worsening of anemia is associated with a cause other than the 
subject’s CKD. 
Transplantation – During this long-term study, it is anticipated that some subjects may receive 
a kidney transplant. These events will not be recorded as AEs. Subjects will discontinue study 
medication for receipt of a kidney, other solid organ, hematopoietic stem cell or bone marrow 
transplant and should continue with the SoA and safety assessments as described in 
Section 8.1.2. 
Malignancy – During this long-term study, some subjects may develop a newly diagnosed 
malignancy or a recurrence of a malignancy. At the discretion of the Investigator, these subjects 
may continue study medication. For reporting of AEs of malignancy, see Section 9.11.1.2. 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 50 of 69 
  
 
Serious Adverse Events 
Each AE is to be classified by the Investigator as SERIOUS or NONSERIOUS. An AE that 
meets 1 or more of the following criteria/outcomes is classified as serious: 
• Death 
• Life-threatening (see below for definition) 
• In-patient hospitalization or prolongation of existing hospitalization (see paragraph below 
on hospitalization) 
• Persistent or significant disability/incapacity (see paragraph below on disability) 
• Congenital anomaly/birth defect 
• Is considered a medically important event not meeting the above criteria, but which may 
jeopardize a subject, or may require medical or surgical intervention to prevent one of the 
criteria listed in this definition. 
In addition to the above criteria for classifying AEs as serious, the following situation will also 
be classified as serious for purposes of this study:  
• Malignancies – Newly diagnosed malignancies or a recurrence of a malignancy should be 
reported as an SAE with the seriousness criterion “medically important” if no other 
seriousness criteria are met. However, if a subject develops basal cell carcinoma of skin, 
squamous cell carcinoma of skin, or cervical carcinoma in situ during the study, or has 
worsening of these events from Baseline, the Investigator will determine if the event is 
reported as an AE or SAE. 
Serious also includes any other event that the Investigator or Sponsor judges to be serious. If 
there is any doubt whether the information constitutes an AE or SAE, the information is to be 
treated as an SAE. 
Life-threatening – Any event in which the subject was at immediate 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. 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 51 of 69 
  
9.11.2 
Classification of an Adverse Event 
 
Severity of Event 
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. 
 
Relationship to Study Intervention 
The causal relationship of the AE to vadadustat or Mircera will be assessed by both the 
Investigator and the Sponsor.   
The assessment of causal relationship to study medication should be evidence-based, and not 
based on the premise that all AEs are possibly causally related to study medication until proven 
otherwise.   
Examples of evidence that would suggest a causal relationship between the study medication and 
the AE include the occurrence of an AE that is uncommon and known to be strongly associated 
with drug exposure (eg, angioedema, hepatic injury, and Stevens-Johnson syndrome) or an AE 
that is uncommon in the population exposed to the drug. 
The causal relationship of the AE is assessed using a binary system, and AEs are classified as 
either ‘related’ or ‘unrelated’; 
• Related: There is ‘reasonable possibility’ that the drug caused the AE. The AE follows a 
reasonable temporal sequence from the time of drug administration. There is supportive 
evidence (facts) to suggest a possible causal relationship, irrespective of the degree of 
certainty between the observed AE and the drug. 
• Unrelated: An AE does not follow a reasonable temporal sequence from administration of 
the product and/or there is no reasonable possibility that the drug caused the AE. This 
assessment includes situations where the AE is related to other factors such as the 
subject’s clinical state, other therapeutic interventions, or concomitant drugs administered 
to the subject. 
Default assessments using the ‘related’ category without supportive evidence for a causal 
relationship to study medication is generally uninformative and do not contribute meaningfully 
to the development of the safety profile of the drug or to subject protection. 
Investigators are encouraged to choose the most plausible cause for the event(s) from the 
following list: medical history, lack of efficacy/worsening of treated condition, study medication, 
other treatment (concomitant, or previous), withdrawal of study medication, administration error, 
protocol-related procedure, others (specify). 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 52 of 69 
  
 
Expectedness 
The Sponsor will be responsible for determining whether an AE is expected or unexpected. An 
AE will be considered unexpected if the nature, severity, or frequency of the event exceeds the 
risk information previously described for the study intervention as described in the current 
Investigator’s Brochure. 
9.11.3 
Time Period and Frequency for Event Assessment and Follow-up 
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. 
9.11.4 
Adverse Event Reporting 
9.11.5 Reporting Period 
AE collection will begin from time of signing of the Informed Consent Form (ICF) through 
Safety Follow-up Visit. 
In addition, any AE that occurs subsequent to the AE reporting period that the investigator 
assesses as related to the study medication should also be reported as an AE. 
9.11.6 Reporting Adverse Events 
All AEs (serious and non-serious) are to be reported on the AE eCRFs. 
9.11.7 
Serious Adverse Event Reporting 
Any SAE, regardless of causal relationship, must be reported to the Sponsor’s Medical Monitor 
or CRO designee within 24 hours after the Investigator becomes aware of the SAE. Compliance 
with this time requirement is essential so that the Sponsor may comply with its regulatory 
obligations. 
The initial SAE report should be completed as fully as possible but should contain, at a minimum: 
• Subject number/ID, sex, and age/date of birth 
• The date of report 
• Name of the reporter 
• Name of the suspected medicinal product 
• A description of the event, including event term(s), seriousness criteria, and a clinical 
summary of the event 
• Causality assessment. 
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 EDC system. The Investigator 
must provide an assessment of causality (relationship to study drug) for all events reported at the 
time of the report. If the event meets serious criteria and it is not possible to access the EDC 
system, a paper SAE Report Form should be sent to the CRO via email or fax, or the Investigator 
will call the CRO SAE hotline within 24 hours of being made aware of the SAE (reference the 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 53 of 69 
  
site manual for contact information). When the EDC system becomes available, the SAE 
information must be entered within 24 hours of the system becoming available. 
The Investigator must report follow-up information relating to an SAE to the Sponsor’s Medical 
Monitor or CRO designee within 24 hours of awareness updating the electronic eCRF with the 
new information or by submitting a paper SAE Report Form in the event that the EDC is not 
available. When the EDC system becomes available, the SAE information must be entered 
within 24 hours. The subject should be observed and monitored carefully until the condition 
resolves or stabilizes. 
All deaths are to be thoroughly investigated and reported. Autopsy reports and/or death 
certificates are to be obtained, if possible. 
The Sponsor and/or its designee are responsible for reporting SAEs to all applicable regulatory 
agencies and the central ethics committees within the required timeline. 
The Investigators are responsible for submitting required safety information to their local 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) as per local 
regulations. This information includes, but is not limited to, any safety alert letter received from 
the Sponsor and any SAEs occurring at their investigative site. 
9.11.8 
Events of Special Interest 
The following are considered to be AESIs for this study: 
• malignancy including renal cell carcinoma (see Section 9.11.1.2) 
• elevation in ALT or AST >3 x ULN (see Section 9.11.1.2) 
• hepatotoxicity 
• worsening of hypertension 
• pulmonary hypertension 
• thrombotic events 
• congestive HF 
• adrenal disorders 
Reporting and classification of these events as SAEs (see Section 9.11.1.2) will be as per usual 
practice. 
9.11.9 Follow-up of Unresolved Events 
All AEs should be followed until they are resolved or the Investigator assesses them as chronic 
or stable or the subject’s participation in the trial ends (i.e., until a final report is completed for 
that subject). 
In addition, all SAEs and those nonserious events assessed by the Investigator as related to the 
study medication should continue to be followed even after the subject's participation in the trial 
is over. Such events should be followed until they resolve or until the Investigator assesses them 
as “chronic” or “stable”. Resolution of such events is to be documented on the appropriate eCRF. 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 54 of 69 
  
9.11.10 
Reporting of Pregnancy 
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 subject 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 in the validated electronic system within 24 hours of 
awareness of the pregnancy or the investigator will call the CRO SAE hotline within 24 hours of 
being made aware of the pregnancy. 
Pregnancy during this time frame of the female partner of a male subject should also be reported.  
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 classification as an SAE 
(i.e., spontaneous abortion, stillbirth, neonatal death within 1 month of birth, or congenital 
anomaly [including an aborted fetus]), the investigator will also follow the procedures for 
reporting an SAE within 24 hours of awareness. A pregnancy in and of itself is not considered an 
AE; however, unexpected complications are considered AEs. 
Additional information about pregnancy outcomes follows: 
• Note that “spontaneous abortion” includes miscarriage and missed abortion. 
• All neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, any infant death after 1 month that the investigator 
assesses as related or unrelated to the in utero exposure to the 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. 
9.12 
Special Situations 
Certain safety events, called ‘Special Situations’, that occur in association with study 
medication(s) may require reporting. These Special Situations include, but are not limited to, the 
following: 
• Medication error involving the medicinal product (with or without subject exposure to the 
sponsor’s medicinal product [e.g., name confusion]) 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 55 of 69 
  
• Drug-drug interaction. 
• Overdose (see Section 9.12.1) 
Special situations should be reported on the Special Situations eCRF whether they result in an 
AE/SAE or not. Special situations with associated AE/SAE should also be reported on the 
corresponding AE/SAE forms, following applicable AE or SAE process. 
9.12.1 
Treatment of Overdose 
Overdose of the medicinal product is a category of Special Situations: 
• Mircera overdose – The United States Prescribing Information (USPI) should be referenced 
for information on Mircera overdosing.   
• Vadadustat overdose - There is no known antidote for vadadustat.  In cases of suspected 
overdose, subjects should be treated per standard medical practice based on the investigator’s 
judgment and dose delays, reductions, or discontinuation may be implemented as necessary. 
Withholding subsequent vadadustat doses immediately after a vadadustat overdose should be 
strongly considered. 
Note: Chronic overdosage with vadadustat may result in excessive production of RBCs and 
polycythemia.  Polycythemia can be potentially life threatening and may result in severe 
thrombosis and death (known as hyperviscosity syndrome).  If hyperviscosity syndrome is 
observed, vadadustat should be discontinued and standard treatment for polycythemic 
hyperviscosity syndrome should be initiated (i.e., phlebotomy). 
• Suspected abuse/misuse of the medicinal product 
• Inadvertent or accidental exposure to the medicinal product 
Overdose should be reported on the Special Situations eCRF whether it results in an AE/SAE or 
not. Overdose with associated AE/SAE should also be reported on the corresponding AE/SAE 
forms, following the applicable AE or SAE process. 
 
 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 56 of 69 
  
 
STATISTICAL CONSIDERATIONS 
10.1 
Statistical Hypotheses 
Not applicable. 
10.2 
Sample Size Determination 
For the primary efficacy analysis, it will be assumed that the difference in mean change from 
Baseline in Hb for vadadustat will be the same as the active control, Mircera, and the common 
standard deviation for the mean change from Baseline will be assumed to be 1.2 g/dL. The 
noninferiority margin of -0.75 g/dL will be used (for vadadustat minus Mircera). With the 
1:1:1 randomization ratio of vadadustat 600 mg TIW, vadadustat 900 mg TIW, and Mircera, 
approximately 150 subjects in each arm, the noninferiority test will have >90% power with 
consideration of a 30% drop out rate.  
10.3 
Populations for Analyses 
The following analysis populations will be used in this study: 
• Randomized population: defined as all randomized subjects. 
• Full analysis population: defined as randomized subjects receiving 1 or more doses of study 
medication and had at least one post-dose Hb assessment. This population will be analyzed 
based upon the randomized treatment. 
• Per protocol (PP) population: defined as all randomized subjects who received study 
medication during the primary evaluation period, had at least 1 Hb assessments during the 
primary evaluation period, and have no protocol deviations affecting the primary endpoint 
analyses. Protocol deviations leading to exclusion from the PP population will be specified 
prior to database lock on a blinded basis and recorded in a separate document. 
• Safety population: defined as all subjects who received at least 1 dose of study medication. 
This population will be analyzed based upon the actual treatment received. Subjects who 
received in error some vadadustat and some mircera (excluding rescue therapy) will be 
classified by the more frequently received drug. 
Efficacy analyses will utilize the randomized, full analysis, and PP populations while safety 
analyses will utilize the safety population. 
10.4 
Missing Data 
It is expected that some subjects will discontinue prior to Week 52. The reasons for any missing 
data will be summarized by treatment arm. Missing Hb values in the primary and secondary 
evaluation period will be imputed using multiple imputation methods. 
10.5 
Statistical Analyses 
10.5.1 
General Considerations 
Data collected throughout the study will be summarized using descriptive statistics and listed in 
by-subject listings. Continuous variables will be summarized using number of subjects with data, 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 57 of 69 
  
mean, standard deviation, median, minimum, and maximum. For categorical variables, the 
number and percentage of subjects in each category will be tabulated. Summaries will be 
provided by treatment group within appropriate analysis populations (as defined in Section 10.3) 
and by time point/time period, as appropriate. 
For Hb, Baseline will be calculated as the average of the last 2 central laboratory Hb 
measurements of samples taken at or prior to the date of first dose. For other parameters, unless 
otherwise specified, Baseline will be defined as the last available value prior to the first dose of 
study medication. 
The primary efficacy endpoint as well as the secondary and all other efficacy endpoints will be 
summarized using descriptive statistics by treatment group, as well as by study visit and/or 
analysis period as appropriate. Mean values of Hb as well as selected other efficacy parameters 
will be plotted across study visits/periods by treatment group. 
Hb values will be assessed through the central laboratory for dose adjustments, efficacy and 
safety evaluations. 
10.5.2 
Analysis of Primary Efficacy Endpoint(s) 
The primary efficacy endpoint is defined as the mean change in Hb between Baseline (average 
pretreatment Hb) and the primary evaluation period (average Hb from Weeks 20 to 26, 
inclusive). 
The primary analysis of the primary endpoint will use the randomized population. Analysis of 
covariance (ANCOVA) with multiple imputation for missing data will be used to calculate the 
95% confidence interval (CI) of the difference in mean change in Hb from baseline to the 
primary evaluation period between the vadadustat groups and Mircera® control group, with the 
randomization stratification factor and Baseline Hb as covariates. 
Noninferiority of vadadustat will be established if the lower limit of this CI is ≥-0.75 g/dL. 
A hierarchical testing scheme will be used to correct for the multiplicity of the 2 comparisons of 
the primary efficacy endpoint: comparison between vadadustat TIW 600 mg versus Mircera and 
comparison between vadadustat TIW 900 mg versus Mircera. 
• 
Step 1: comparison between vadadustat TIW 900 mg versus Mircera  
If the noninferiority of vadadustat is established in step 1, then move to the step 2; 
• 
Step 2: comparison between vadadustat TIW 600 mg versus Mircera 
 
Sensitivity Analyses of Primary Efficacy Endpoint Screening 
The following sensitivity analyses will be conducted if necessary:  
• Primary analysis will be repeated using the full analysis population. 
• Primary analysis will be repeated using the PP population with the actual treatment received. 
• Primary analysis will be repeated with imputation of data which may have been affected by a 
subject’s having received any form of rescue (transfusion or ESA). Details are provided in 
the statistical analysis plan (SAP). 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 58 of 69 
  
• Primary analysis will be repeated with method of mixed model for repeated measures 
(MMRM). 
10.5.3 
Analysis of Secondary Efficacy Endpoint(s) 
Mean change in Hb between Baseline (average pretreatment Hb) and the secondary evaluation 
period (average Hb from Weeks 46 to 52, inclusive) will be analyzed using the same 
methodology as specified for the primary efficacy endpoint. Sensitivity analyses similar to those 
of the primary efficacy endpoint will be performed and details will be provided in the SAP. 
10.5.4 
Exploratory Endpoint(s) 
A full description of the analyses performed on exploratory endpoints will be provided in the 
SAP. 
10.5.5 
Safety Analyses 
All analyses of safety data will use the safety population. 
10.5.6 Analysis of Adverse Events 
AEs 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 Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent and post-treatment AEs will be summarized by SOC and preferred terms 
(PT) for each treatment group.  
Summaries will also be provided for the following types of AEs: 
• SAEs 
• Related AEs (including all categories for relationship to study medication other than 
“Unrelated”, as determined by the investigator) 
• AEs leading to early discontinuation of study medication. 
10.5.7 Remaining Safety Endpoints 
The analysis of the safety endpoints will be detailed in the SAP: The analysis of proportion of 
subjects with Hb >11.0, Hb >12.0, Hb>13.0, or >14.0 g/dL post-Baseline will classify a subject 
as a “yes” if: 
• Any value Hb >11.0 g/dL at any time after Day 1 
• Any value Hb >12.0 g/dL at any time after Day 1 
• Any value Hb >13.0 g/dL at any time after Day 1 
• Any value Hb >14.0 g/dL at any time after Day 1 
• Any value Hb <7.0 g/dL at any time after Day 1 
• Any value Hb <8.0 g/dL at any time after Day 1 
• Any value Hb <9.0 g/dL at any time after Day 1 
• Any value Hb <10.0 g/dL at any time after Day 1 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 59 of 69 
  
The analysis of proportion of subjects with any Hb increase >1.0 g/dL within any 2-week 
interval or >2.0 g/dL within any 4-week interval post-Baseline will classify a subject as a “yes” 
if at least 1 of the following criteria at any point after Day 1 is met: 
• Hb increase >1.0 g/dL within any 2-week interval 
• Hb increase >2.0 g/dL within any 4-week interval. 
Subjects with no available data post-Baseline will be excluded from this analysis. All 
other subjects will be classified to the “no” category. 
Observed values of continuous and categorical parameters and changes from Baseline for 
continuous parameters to each study visit will be summarized descriptively for vital signs and 
clinical laboratory results.  
10.5.8 
Baseline Descriptive Statistics 
 
Analysis of Demographic and Pretreatment Variables 
Descriptive statistics will be generated for demographic and pretreatment variables for each 
treatment group based on randomized population. 
Medical history terms will be coded using the MedDRA and summarized by SOC and PT for 
each treatment group. 
 
Disposition of Subjects 
The number and percentage of subjects randomized and included in each analysis population will 
be summarized by treatment and overall. Reasons for excluding subjects from the analysis 
populations will be presented in a by-subject listing. 
The number of randomized subjects who completed study medication treatment discontinued 
from study medication early, and completed or discontinued from the study and reasons for 
discontinuation will be summarized by treatment group and overall. 
10.6 Additional Assessments 
10.6.1 Concomitant Medications 
Prior and concomitant medications will be coded using World Health Organization Drug 
dictionary. 
Prior medications will be defined as any medications that were taken before the date of the first 
dose of study medication. Concomitant medications will be defined as any medications taken at 
any time from the date of the first dose of study medication through the date of the last dose of 
the study medication. 
 
 
 
PPD


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 60 of 69 
  
10.6.3 Pharmacokinetic Assessments 
Plasma concentrations will be summarized descriptively by dose and analyte, as specified in the 
SoA (Section 1.3). PK parameters will be summarized descriptively by analyte and dose. 
10.6.4 Pharmacodynamic Assessments 
The observed and change from Baseline/Day 1 values of all PD (EPO, reticulocytes, and iron 
indices) assessments will be summarized using descriptive statistics.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
10.6.7 
Sub-Group Analyses 
Analyses of the primary efficacy endpoint and secondary efficacy endpoints will also be 
performed for subgroups based on the following: 
• Age 
• Sex 
• Race 
• Stratification factor: Dialysis Organization 
PPD
PPD


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 61 of 69 
  
 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
11.1 
Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical Principles 
for Medical Research Involving Human Subjects, adopted by the General Assembly of the World 
Medical Association (2013).  
In addition, the study will be conducted in accordance with the protocol, the International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) E6 guideline on Good Clinical Practice (GCP), and applicable local regulatory 
requirements and laws.  
11.2 
IRB and Ethics Committees 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, ICFs, and other relevant documents, (e.g., recruitment advertisements, if 
applicable) from the IRB/EC. All correspondence with the IRB/EC will be retained in the 
investigator File. Copies of IRB/EC approvals will be forwarded to the sponsor or its designee.  
In case of substantial protocol amendment, the sponsor will obtain approval from responsible 
Regulatory Authorities before implementation.  
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects. In that 
event, the investigator will notify the IRB/EC and the sponsor in writing immediately after the 
implementation.  
11.3 
Informed Consent Process 
The investigator or designee will explain the nature of the study to the subject or their legally 
acceptable representative, and answer all questions regarding this study. Prior to any 
study-related screening procedures being performed on the subject, the informed consent 
statement will be reviewed and signed and dated by the subject or their legally acceptable 
representative, the person who administered the informed consent and any other signatories 
according to local requirements. A copy of the signed ICF will be given to the subject and the 
original will be placed in the subject’s medical record. An entry must also be made in the 
subject’s dated source documents to confirm that informed consent was obtained prior to any 
study-related procedures and that the subject received a signed copy.  
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor, auditor, regulatory authorities and/or IRB/Ethics Committees and 
other applicable individuals upon request.  
The ICFs will be in compliance with ICH GCP, local regulatory requirements, and legal 
requirements. The ICFs used in this study, and any changes made during the course of the study, 
will be prospectively approved by both the IRB/EC and the sponsor before use.  


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 62 of 69 
  
11.4 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information, as requested, to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
11.5 
Confidentiality and Data Privacy 
All parties will ensure protection of subject personal data and will not include subject names on 
any sponsor forms, reports, publications, or in any other disclosures, except where required by 
law. In case of data transfer, the sponsor will maintain high standards of confidentiality and 
protection of subject personal data. 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (e.g., FDA), the sponsor’s designated auditors, and the appropriate IRBs to 
review the subject’s original medical records (source data or documents), including, but not 
limited to, laboratory test result reports, ECG reports, admission and discharge summaries for 
hospital admissions occurring during a subject’s study participation, and autopsy reports. Access 
to a subject’s original medical records requires the specific authorization of the subject as part of 
the informed consent process.  
Copies of any subject source documents that are provided to the sponsor will have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s eCRF).  
11.6 
Data Handling and Record Keeping 
11.6.1 
Data Collection and Management Responsibilities 
Data handling and record keeping are detailed in the Pharmacy Manual.  
11.6.2 
Study Records Retention 
To enable evaluations and/or audits from regulatory authorities or the sponsor, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, e.g., case report forms (CRFs) and hospital records), all original signed ICFs, 
copies of all eCRFs, SAE forms, source documents, detailed records of drug disposition, and 
adequate documentation of relevant correspondence (e.g., letters, meeting minutes, and 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 63 of 69 
  
telephone calls reports). The records will be retained by the investigator according to the ICH, 
local regulations, or as specified in the Clinical Study Agreement, whichever is longer.  
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement and relocation), the sponsor will be prospectively notified. The 
study records will be transferred to a designee acceptable to the sponsor, such as another 
investigator, another institution, or to the sponsor. The investigator will obtain sponsor’s written 
permission before disposing of any records, even if retention requirements have been met.  
11.7 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
Competent Authority, or if the investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of the investigational product, the sponsor will 
be informed immediately.  
In addition, the investigator will inform the sponsor immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP, defined as a breach that will likely affect the 
safety or physical or mental integrity of subjects or the scientific value of the trial, that comes to 
the attention of the investigator.  
11.8 
Study Discontinuation and Closure 
The sponsor reserves the right to discontinue the study prior to inclusion of the intended number 
of subjects, but intends only to exercise this right for valid scientific or administrative reasons. 
After such a decision, the investigator will contact all participating subjects within a time period 
specified by the sponsor to inform them of the decision to discontinue the study.  
11.8.1 
Criteria for Premature Termination or Suspension of the Study 
The following criteria may result in either temporary suspension or ET of the study:  
• New information regarding the safety or efficacy of the study drug that indicates a change 
in the known risk/benefit profile for the compound, such that the risk/benefit is no longer 
acceptable for subjects participating in the study  
• Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises subject safety  
• Request from regulatory agencies 
 
The sponsor reserves the right to discontinue the study for other valid administrative reasons. If 
the study has been suspended or terminated, prompt notification will be given to investigators, 
IRBs, and regulatory authorities in accordance with regulatory requirements.  
11.8.2 
Criteria for Premature Termination or Suspension of Study Sites 
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 64 of 69 
  
termination. Advanced notice is not required if the study is stopped due to safety concerns. If the 
Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
Investigator and subsequently provide written instructions for study termination. If the study has 
been suspended or terminated, prompt notification will be given to Investigators, IRBs, and 
regulatory authorities in accordance with regulatory requirements. 
A study site may be terminated prematurely or suspended if the study site (including the 
investigator) is found to be in significant violation of GCP, protocol, contractual agreement, or is 
unable to ensure adequate performance of the study.  
The investigator will notify the sponsor if the trial is terminated by the investigator or the IRB at 
the site. If the investigator, IRB, or sponsor decides to terminate or suspend the trial conduct at a 
particular study site for safety, non-enrollment, non-compliance with the protocol, or other 
unanticipated reasons, the above parties will be promptly notified.  
11.8.3 
Criteria for Premature Termination or Suspension of the Study or Study Sites 
In the event that the sponsor elects to terminate or suspend the study or the participation of an 
investigational study site, a study-specific procedure for ET or suspension will be provided by 
the sponsor; the procedure will be followed by applicable study sites during the course of 
termination or study suspension.  
11.9 
Future Use of Stored Specimens and Data 
With the subject’s approval and as approved by local IRBs, de-identified biological samples will 
be stored at the biorepository with the same goal as the sharing of data with the biorepository. 
These samples could be used to research the causes of anemia in subjects receiving hemodialysis 
in CKD, its complications and other conditions for which individuals with anemia in subjects 
receiving hemodialysis in CKD are at increased risk, and to improve treatment. The 
biorepository will also be provided with a code-link that will allow linking the biological 
specimens with the phenotypic data from each subject, maintaining the blinding of the identity of 
the subject. 
During the conduct of the study, an individual subject can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed.  
When the study is completed, access to study data and/or samples will be provided through the 
biorepository. 
11.10 Key Roles, Committees and Study Governance 
Not applicable. 
11.11 Safety Oversight 
An Independent Data Monitoring Committee (IDMC) will be established to review and discuss 
the available study data as subjects are enrolled and followed. The IDMC will meet 
approximately twice per year throughout the course of the study. The IDMC will be unblinded 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 65 of 69 
  
and will include, at a minimum, 2 physicians and a biostatistician. The discussions of the IDMC 
will include a review of key safety data (i.e., AEs, vital sign measurements, and laboratory 
assessments).  
AEs and laboratory changes suggestive of possible effects on the liver will be reviewed and 
adjudicated by a hepatic panel of experts.  
11.12 Quality Assurance and Quality Control 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements (e.g., Good Laboratory Practices [GLP], GMP).  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. 
11.12.1 
Clinical Monitoring 
During study conduct, the sponsor or its agent will conduct periodic monitoring visits to ensure 
that the protocol and GCP are being followed. The monitors will review source documents to 
confirm that the data recorded on the eCRFs is accurate. The investigator/institution will allow 
the sponsor’s monitors or designees and appropriate regulatory authorities direct access to source 
documents to perform this verification.  
The study site may also be subject to Quality Assurance audits performed by the sponsor or 
companies working with or on behalf of the sponsor, and/or review by the IRB, and/or to 
inspection by appropriate regulatory authorities.  
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.  
11.12.2 
Protocol Deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring the 
study is conducted in accordance with the procedures and evaluations described in this protocol 
and must protect the rights, safety, and welfare of subjects. The investigator should not 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 66 of 69 
  
implement any deviation from, or changes of, the protocol, unless it is necessary to eliminate an 
immediate hazard to trial subjects. 
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.  
For the purposes of this protocol, deviations requiring notification to sponsor are defined as any 
subject who:  
• Entered into the study even though they did not satisfy entry criteria.  
• Developed withdrawal criteria during the study and not withdrawn.  
• Received wrong treatment or incorrect dose.  
• Received excluded concomitant treatment.  
 
When one of these deviations from the protocol is identified for an individual subject, the 
investigator or designee must ensure the sponsor is notified. If the investigator determines that 
the deviation impacts the safety of a subject, the investigator must contact the sponsor 
immediately. The sponsor will follow-up with the investigator, as applicable, to assess the 
deviation and the possible impact to the safety and/or efficacy of the subject to determine subject 
continuation in the study.  
The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be filed in the 
Investigator Site Files and will be the provided to the sponsor and maintained within the Trial 
Master File.  
Note: Other deviations outside of the categories defined above that are required to be reported by 
the IRB/IEC in accordance with local requirements will be reported, as applicable.  
 
PUBLICATION OF STUDY RESULTS 
No publication or disclosure of study results will be permitted, except under the terms and 
conditions of a separate, written agreement between sponsor and the investigator and/or the 
investigator’s institution. The sponsor will have the opportunity to review and approve all 
proposed abstracts, manuscripts, or presentations regarding this study prior to submission for 
publication/presentation. Any information identified by the sponsor as confidential will be 
deleted prior to submission.  
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including: Section II - “Ethical Considerations 
in the Conduct and Reporting of Research” of the Uniform Requirements for Manuscripts 
Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, established by 
the International Committee of Medical Journal Editors.  


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 67 of 69 
  
 
REFERENCES 
Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low 
hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. 
N Engl J Med 1998;339(9):584-90. 
Biggar P, Kim GH. Treatment of renal anemia: Erythropoiesis stimulating agents and beyond. 
Kidney Res Clin Pract 2017;36:209–23. 
Davey AJ, Stennett AK, Lee C, et al. Dialysis provider’s transition to methoxy polyethylene 
glycol-epoetin beta for anemia in patients with in-center hemodialysis. Nephrology News & 
Issues July 2018.  
Di Iorio B, Cirillo M, Bellizzi V, Stellato D, De Santo NG. Prevalence and correlates of anemia 
and uncontrolled anemia in chronic hemodialysis patients – The Campania Dialysis Registry. Int 
J Antif Organs 2007;30(4):325-33. 
Drüeke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with 
chronic kidney disease and anemia. N Engl J Med 2006;355(20):2071-84. 
Finkelstein FO and Finkelstein SH. The Impact of Anemia Treatment on Health-Related Quality 
of Life in Patients With Chronic Kidney Disease in the Contemporary Era. Adv Chronic Kidney 
Dis 2019;26(4):250-52. 
Iseki K and Kohagura K. Anemia as a risk factor for chronic kidney disease. Kidney Int 
2007;Suppl 72:S4-9. 
Jha V, Garcia-Garcia G, Iseki K, et al.  Chronic kidney disease: global dimension and 
perspectives. Lancet 2013;382(9888): 260-72.  
KDIGO CKD Working Group. KDIGO clinical practice guideline for the evaluation and 
management of chronic kidney disease. Kidney Int Suppl 2013;3(1): 1-150. 
KDIGO.  KDIGO clinical practice guideline for anemia in chronic kidney disease.  Kidney Int 
(2012) 2(4):1-64.  Available 
at: http://www2.kidney.org/professionals/kdoqi/guidelines_ckd/p4_class_g1.htm 
Locatelli F, Bárány P, Covic A, et al. Kidney Disease: Improving Global Outcomes guidelines 
on anaemia management in chronic kidney disease: a European Renal Best Practice position 
statement. Nephrol Dial Transplant 2013;28(6):1346-59. 
Ly J, Marticrena R, Donnelly S. Red blood cell survival in chronic renal failure. Am J Kidney 
Dis 2004;44(4):715-9. 
McCullough PA, Barnhart HX, Inrig JK, et al. Cardiovascular toxicity of epoetin-alfa in patients 
with chronic kidney disease. Am j Nephrol 2013;37 (6): 549-58. 
Metivier F, Marchais SJ, Guerin AP, Pannier B, London GM. Pathophysiology of anaemia: focus 
on the heart and blood vessels. Nephrol Dial Transplant 2000;15 Suppl 3: 14-8. 
Mircera package insert. 
2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125164s078lbl.pdf. Accessed 
August 11 2020. 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 68 of 69 
  
NICE. Anaemia management in people with chronic kidney disease. National Institute for 
Health and Care Excellence 2011:1-39. 
Nurko S. Anemia in chronic kidney disease: causes, diagnosis, treatment. Cleve Clin J Med 
2006;73(3):289-97. 
Palmer SC, Saglimbene V, Mavridis D, et al. Erythropoiesis‐stimulating agents for anaemia in 
adults with chronic kidney disease: a network meta‐analysis. Cochrane Database Syst Rev 
2014;(12):CD010590. 
Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D. Double-blind comparison 
of full and partial anemia correction in incident hemodialysis patients without symptomatic heart 
disease. J Am Soc Nephrol 2005;16(7):2180-9. 
Pergola PE, Spinowitz BS, Hartman CS, et al. Vadadustat, a novel oral HIF stabilizer, provides 
effective anemia treatment in nondialysis-dependent chronic kidney disease. Kidney Int 
2016;90:1115-22. 
Peyssonnaux C, Zinkernagel AS, Schuepbach RA, et al. Regulation of iron homeostasis by the 
hypoxia-inducible transcription factors (HIFs). J Clin Invest 2007;117(7):1926-32. 
Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of ESA in type 2 diabetes and chronic kidney 
disease. N Engl J Med 2009a;361(21):2019-32. 
Pfeffer MA, Burdmann EA, Chen CY, et al. Baseline characteristics in the Trial to Reduce 
Cardiovascular Events With Aranesp Therapy (TREAT). Am J Kidney Dis 2009b;54(1):59-69. 
Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney 
disease. N Engl J Med 2006;355(20):2085-98. 
Stauffer ME and Fan T. Prevalence of anemia in chronic kidney disease in the United States. 
PLoS One 2014;9(1): e84943. 
Unger EF, Thompson AM, Blank MJ, Temple R. Erythropoiesis-stimulating agents - Time for a 
reevaluation. N Engl J Med 2010;362(3):189-92. 


Akebia Therapeutics, Inc. 
 
 
Version # 1.0 
Protocol No. AKB-6548-CI-0039 
 
16 September 2020 
Akebia – Company Confidential 
Page 69 of 69 
  
PPD

SAP_001.pdf: 
Statistical Analysis Plan
Protocol No. AKB-6548-CI-0039   
 Akebia Therapeutics, Inc.
STATISTICAL ANALYSIS PLAN
This document contains information that is confidential and proprietary to the Sponsor, 
Akebia Therapeutics, Inc. This information is being provided to you solely for the purpose 
of evaluating and/or conducting a clinical study for the Sponsor. You may disclose the 
contents of this document only to study personnel under your supervision, the Institutional 
Review Board, the United States Food and Drug Administration, or duly authorized 
representatives of regulatory agencies for this purpose under the condition that they 
maintain confidentiality. The contents of this document may not be used in any other 
clinical study, disclosed to any other person or entity, and/or published without the prior 
written permission of the Sponsor. The foregoing shall not apply to disclosure required by 
any regulations; however, you will give prompt notice to the Sponsor of any such disclosure. 
Firma Clinical Research Confidential and Proprietary
Page 1 of 54
A Randomized, Open-label, Active-controlled Study Evaluating 
the Efficacy and Safety of Dose Conversion from a Long-acting 
Erythropoiesis-stimulating Agent (Mircera®) to Three Times 
Weekly Oral Vadadustat for the Maintenance Treatment of 
Anemia in Hemodialysis Subjects
Vadadustat (AKB-6548)
AKB-6548-CI-0039
102,465
Phase 3b
Akebia Therapeutics, Inc.
245 First Street
Cambridge, MA 02142
United States of America
Firma Clinical Research
221 Schilling Circle, Suite 1888
Hunt Valley, MD 21031
21 July 2022/Version 1.0
Protocol:
Compound: 
Protocol Number: 
US IND Number: 
Phase: 
Sponsor:
Author:
Initial SAP Date: 
Amendment #1:
31 October 31, 2022/Version 1.1
 
 
 
 
 
NCT Number: NCT04707768 
This NCT number has been applied to the document for purposes of posting on Clinicaltrials.gov
PPD


Statistical Analysis Plan
Protocol No. AKB-6548-CI-0039   
 Akebia Therapeutics, Inc.
Firma Clinical Research Confidential and Proprietary
Page 2 of 54
Signature Page
 MD, PhD
Akebia Therapeutics, Inc
Senior Medical Director, Clinical 
Development
Signature
Date
 PhD
Akebia Therapeutics, Inc
Vice President, Biometrics
Signature
Date
PhD
Lead Statistician
Firma Clinical Research, LLC
Signature
Date
ign
g ature
Date

	
Signature
Date


ign
g ature
Date


PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 3 of 54 
 
REVISION HISTORY 
 
Version 
Version Date 
Author 
Summary of Changes Made 
1.0 
21Jul2022 
 
Initial 
1.1 
31Oct2022 
 
Sections 6.11.2 and 6.11.3 
Removed the hierarchical 
testing. The treatment 
comparison is based on the 
combined vadadustat dosing 
group vs. Mircera for both 
primary and secondary 
efficacy endpoints. The 
comparisons between 
vadadustat 900 mg TIW vs. 
Mircera and vadadustat 600 
mg TIW vs. Mircera are the 
sensitivity analyses.    
 
 
PPD
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 4 of 54 
 
Table of Contents 
 
1. 
Introduction ................................................................................................................. 9 
2. 
Study Objectives ......................................................................................................... 9 
2.1 
Primary Objective ................................................................................................ 9 
3. 
Study Design ............................................................................................................... 9 
3.1 
Overview .............................................................................................................. 9 
3.2 
Study Population ................................................................................................ 11 
3.3 
Sample Size Determination ................................................................................ 11 
3.4 
Study Medication Stopping Rules ...................................................................... 11 
3.5 
Measures to Minimize Bias: Randomization and Blinding ............................... 12 
4. 
Analysis Population .................................................................................................. 12 
5. 
Endpoints .................................................................................................................. 13 
5.1 
Primary Efficacy Endpoint ................................................................................. 13 
5.2 
Secondary Efficacy Endpoint ............................................................................. 13 
5.3 
Other Efficacy Endpoints ................................................................................... 13 
5.4 
Primary Safety Endpoints................................................................................... 14 
5.5 
Secondary Safety Endpoints............................................................................... 14 
5.6 
Other Safety Endpoints ...................................................................................... 14 
 
 
6. 
Statistical Methodology and Analyses ...................................................................... 14 
6.1 
General Considerations ...................................................................................... 14 
6.2 
Visit and Analysis Time Period Classification .................................................. 15 
6.3 
Handling of Missing Values ............................................................................... 17 
6.4 
Week 26 analysis ................................................................................................ 18 
6.5 
Subject Disposition ............................................................................................ 18 
6.6 
Protocol Deviations ............................................................................................ 19 
6.7 
Demographic and Baseline Characteristics ........................................................ 19 
6.8 
Medical History .................................................................................................. 19 
6.9 
Prior and Concomitant Medications ................................................................... 20 
6.10 Study Drug Dosing and Compliance .................................................................. 20 
6.11 Efficacy Analyses ............................................................................................... 21 
6.11.1 Primary Estimand........................................................................................ 21 
6.11.2 Primary Efficacy Analyses ......................................................................... 21 
6.11.2.1 
Sensitivity Analyses of the Primary Efficacy Endpoint ...................... 22 
6.11.3 Secondary Efficacy Analyses ..................................................................... 23 
6.11.4 Other Efficacy Analyses ............................................................................. 23 
6.11.4.1 
Hb value within the target range .......................................................... 23 
6.11.4.2 
Endpoints Related to Iron .................................................................... 24 
6.11.4.3 
Other Laboratory Parameters ............................................................... 24 
6.11.4.4 
Definition of Rescue ............................................................................ 24 
6.11.4.4.1 Analysis of Rescue ........................................................................ 25 
PP
D


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 5 of 54 
 
6.11.4.4.2 RBC Transfusion ........................................................................... 25 
6.11.4.4.3 ESA Rescue ................................................................................... 25 
6.12 Safety Analyses .................................................................................................. 26 
6.12.1 Adverse Events ........................................................................................... 26 
6.12.2 Laboratory Data .......................................................................................... 27 
6.12.2.1 
Hb-related Safety Endpoints ................................................................ 27 
6.12.2.2 
Liver Function Abnormality ................................................................ 28 
6.12.2.3 
Other Laboratory Safety Endpoints ..................................................... 29 
6.12.3 Physical Examination.................................................................................. 29 
6.12.4 Vital Signs ................................................................................................... 29 
 
 
 
 
 
 
 
 
 
6.14 Subgroup Analyses ............................................................................................. 32 
7. 
Changes to protocol-planned analyses ...................................................................... 33 
8. 
References ................................................................................................................. 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix E. Adverse Events of Special Interest (AESI) ............................................. 51 
 
PPD
P
P
D


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 6 of 54 
 
List of Abbreviations and Definitions 
The following abbreviations and specialist terms are used in this document. 
Abbreviation 
Definition 
AE  
adverse event  
AESI  
adverse event of special interest  
ALP  
alkaline phosphatase  
ALT  
alanine aminotransferase  
ARCRS 
American Renal Clinical Research Services 
AST  
aspartate aminotransferase  
ANCOVA  
analysis of covariance  
BMI 
body mass index 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CI  
confidence interval  
CKD  
chronic kidney disease  
CPK 
creatine phosphokinase 
CRO 
contract research organization 
CRP 
C-reactive protein 
CV 
cardiovascular 
DBP 
diastolic blood pressure 
DILI  
drug-induced liver injury  
eCRF  
electronic case report form  
EOT  
end of treatment  
EPO  
erythropoietin  
ESA  
erythropoiesis-stimulating agent  
ET  
early termination  
  
  
FAS 
full analysis population 
FCS 
fully conditional specification 
Hb  
hemoglobin  
HDL 
high density lipoprotein 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 7 of 54 
 
Abbreviation 
Definition 
HF 
heart failure 
INR  
international normalized ratio  
IV  
intravenous  
  
  
MAR 
missing at random 
MedDRA  
Medical Dictionary for Regulatory Activities  
MMRM  
mixed model repeated measures  
MNAR 
missing not at random 
LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
LLD 
lower limits of detection 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCS 
mental health composite score 
MCV 
mean corpuscular volume 
PCS 
physical health composite score 
PEP 
primary efficacy period 
  
  
  
  
PP  
per protocol  
PT  
preferred term  
RBC  
red blood cell  
RDW 
red blood cell distribution width 
SAE  
serious adverse event  
SAP  
statistical analysis plan  
SBP 
systolic blood pressure 
SD 
standard deviation 
SE 
standard error 
SEP 
secondary efficacy period 
PPD
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 8 of 54 
 
Abbreviation 
Definition 
SF-12 
12-Item Short Form Survey 
SGPT  
serum glutamic pyruvic transaminase  
SOC  
system organ class  
TEAE 
treatment-emergent adverse event 
TFL 
table, listing, figure 
TIBC  
total iron binding capacity  
TIW  
three times weekly  
TSAT  
transferrin saturation  
ULN  
upper limit of normal  
US  
United States  
USRC 
U.S. Renal Care 
  
  
WBC 
white blood cell 
 
 
 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 9 of 54 
 
1. INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical analysis methods that will be used to analyze, and report results for Akebia 
Protocol AKB-6548-CI-0039.   
This SAP is based on the final study protocol, version 1.0 (dated 16 September 2020). 
Details of study design, conduct and data collection are described in the study protocol, 
the electronic case report form (eCRF), and general eCRF completion guidelines. The 
specifications of tables, figures, and data listings are  included in a separate document 
(i.e., TFL shells).  
If the analyses described in the protocol differs from those in this SAP, the analysis 
methods described in the SAP prevail.  
 
2. STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
To demonstrate the efficacy and safety of vadadustat administered three times weekly 
(TIW) compared to long-acting ESA (Mircera) for the maintenance treatment of anemia 
in hemodialysis subjects. 
 
3. STUDY DESIGN 
3.1 
OVERVIEW 
This is a multi-center, randomized, open-label, active-controlled study of the efficacy and 
safety of conversion from long-acting ESA (Mircera) to vadadustat TIW for the 
maintenance treatment of anemia in hemodialysis patients. Following a Screening period 
of up to 8 weeks (56 days), subjects who meet all inclusion and none of the exclusion 
criteria will be randomized 1:1:1 to vadadustat 600 mg TIW, vadadustat 900 mg TIW, or 
to remain on Mircera according to the dialysis center’s protocol. The planned number of 
subjects are 450 at approximately 60 investigative sites in the United States (US) at 
outpatient hemodialysis centers. 
Randomization will be stratified across dialysis organization: USRC (U.S. Renal Care), 
ARCRS (American Renal Clinical Research Services), and Frenova (Frenova Renal 
Research). 
Following randomization there will be 2 periods during the study: 
x Conversion and Maintenance Period (Weeks 0 to 52): conversion to vadadustat 
TIW or to remain on Mircera (Weeks 0 to 20). There will be a primary efficacy 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 10 of 54 
 
evaluation period (Weeks 20 to 26) and a secondary efficacy evaluation period 
(Weeks 46 to 52). 
x Safety Follow-up Period (Early Termination [ET] and Follow-Up): post-
treatment safety follow-up visit (ET/End of Treatment [EOT] +4 weeks) either in 
person or via telephone. 
End of Study: 
x Study Completion  
The study will be considered completed after all randomized subjects have 
completed their final study visit (Week 52/or ET and Safety Follow-Up at Week 
56).  
x Subject Completion  
Completion of treatment: A subject will be considered as having completed the 
study treatment after completion of their study treatment through Week 52. 
Completion of study: A subject will be considered as having completed the study 
after completion of their study treatment through Week 52 and the safety follow-
up visit. 
 
Figure 1. Study Schema 
  
 
Dosing will be initiated at Baseline and the first dose of vadadustat will be administered 
at the hemodialysis unit after other Baseline procedures have been completed. Subjects 
randomized to vadadustat may take vadadustat with or without food and will be 
instructed to swallow the tablet(s) whole. Subjects are to take vadadustat at roughly the 
same time each day. 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 11 of 54 
 
Mircera assigned subjects will be administered IV Mircera at the hemodialysis unit 
according to the dialysis center’s protocol.  
Dose adjustments will be guided by central laboratory Hb concentrations throughout the 
study to determine if vadadustat or Mircera doses will be adjusted, interrupted, or 
maintained. Mircera dosing will be based on standard of care laboratory measures 
according to the dialysis center’s protocol. Vadadustat dose adjustment will be based on 
the guidelines in the protocol Section 7.1.2. 
The minimum dose of vadadustat will be 300 mg TIW (1 tablet TIW) and the maximum 
dose will be 1200 mg TIW. Subjects whose dose of vadadustat is interrupted due to 
elevated Hb will continue in the study. Unless contraindicated, treatment will be resumed 
whenever possible and assessed at every study visit following study drug interruption. 
Clinical evaluations will be conducted during the course of the study based on the 
schedule of activities in the protocol Table 1. If the evaluations will occur on a 
hemodialysis day, the clinical evaluations should be completed before dialysis, if 
applicable. 
3.2 
STUDY POPULATION 
The study population will consist of subjects greater than or equal to 18 years of age who 
are receiving chronic, outpatient in-center hemodialysis three times weekly (TIW), 
requiring erythropoiesis-stimulating agent (ESA) treatment and are on maintenance 
treatment with Mircera. Study subjects will also be required to have a mean Screening 
hemoglobin (Hb), based on 2 results, between 8.5 and 11.0 g/dL (inclusive). 
3.3 
SAMPLE SIZE DETERMINATION 
For the primary efficacy analysis, it is assumed that the difference in mean change from 
Baseline in Hb for vadadustat will be the same as the active control, Mircera, and the 
common standard deviation for the mean change from Baseline will be assumed to be 1.2 
g/dL. The noninferiority margin of -0.75 g/dL will be used (for vadadustat minus 
Mircera). With the 1:1:1 randomization ratio of vadadustat 600 mg TIW, vadadustat 900 
mg TIW, and Mircera, and approximately 150 subjects in each arm, the noninferiority 
test will have >90% power with consideration of a 30% drop out rate.  
3.4 
STUDY MEDICATION STOPPING RULES 
Vadadustat must be permanently discontinued if a subject meets 1 of the following 
criteria:  
x ALT or AST >3x ULN and total bilirubin >2x ULN  
x ALT or AST >3x ULN and international normalized ratio (INR) >1.5  
x ALT or AST >8x ULN  
x ALT or AST remains >5x ULN over 2 weeks (re-challenge generally should be 
avoided with ALT or AST >5x ULN unless there are no other good therapeutic 
options)  


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 12 of 54 
 
x ALT or AST >3x ULN with symptoms (e.g., fatigue, nausea, vomiting, right 
upper quadrant pain, fever, rash) or eosinophilia  
x undergo a solid organ (including kidney), hematopoietic stem cell, or bone 
marrow transplantation 
3.5 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
This will be an open-label study. Treatment assignment will be done through a validated 
electronic system by block randomization with a block size of 6. Treatments will be 
administered in an open-label fashion. The sponsor study team will be blinded to ‘by 
treatment’ aggregated analyses except for the unblinded statistician. This will be detailed 
in a separate document of “Blinding Plan”.  
In addition, the study involves the use of an Independent Data Monitoring Committee 
(IDMC), and an identical schedule of visits, procedures, and assessments for all treatment 
groups in order to reduce the potential bias.  An external independent group of unblinded 
biostatisticians and programmers will provide the support to IDMC.   
 
4. ANALYSIS POPULATION 
The following analysis populations will be used in this study: 
x Randomized population: defined as all randomized subjects. This population will 
be analyzed based upon the randomized treatment. This is the Intention to Treat 
(ITT) population. 
x Full analysis population (FAS): defined as randomized subjects receiving 1 or 
more doses of study medication and had at least one post-dose Hb assessment. 
This population will be analyzed based upon the randomized treatment. 
x Per protocol (PP) population: defined as all randomized subjects who received 
study medication during the primary evaluation period, had at least 1 Hb 
assessments during the primary evaluation period, and have no important protocol 
deviations affecting the primary endpoint analyses, i.e., up to Week 26. This 
population will be analyzed based upon the actual treatment received. Protocol 
deviations leading to exclusion from the PP population will be specified prior to 
database lock on a blinded basis and recorded in a separate document. 
x Safety population: defined as all subjects who received at least 1 dose of study 
medication. This population will be analyzed based upon the actual treatment 
received. Subjects who received in error some vadadustat and some Mircera 
(excluding rescue therapy) will be classified by the more frequently received 
drug. 
Efficacy analyses will utilize the randomized/ITT, full analysis (FAS), and PP 
populations while safety analyses will utilize the safety population.  


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 13 of 54 
 
 
5. ENDPOINTS 
5.1 
PRIMARY EFFICACY ENDPOINT 
Mean change in Hb between Baseline (average of the last 2 available pretreatment Hb) 
and the primary evaluation period (average Hb from Weeks 20 to 26, inclusive). 
5.2 
SECONDARY EFFICACY ENDPOINT 
Mean change in Hb between Baseline (average of the last 2 available pretreatment Hb) 
and the secondary evaluation period (average Hb from Weeks 46 to 52, inclusive).  
5.3 
OTHER EFFICACY ENDPOINTS 
Other endpoints include the following: 
x Proportion of subjects having a Hb value within the target range (10.0 to 11.0 
g/dL) during the primary evaluation period (Weeks 20 to 26). 
x Proportion of subjects having a Hb value within the target range (10.0 to 11.0 
g/dL) during the secondary evaluation period (Weeks 46 to 52). 
x Proportion of subjects having average Hb value within the target range (10.0 to 
11.0 g/dL) during the primary evaluation period (Weeks 20 to 26)   
x Proportion of subjects having average Hb value within the target range (10.0 to 
11.0 g/dL) during the secondary evaluation period (Weeks 46 to 52)  
x Mean change from baseline and percentage change from baseline in the primary 
efficacy period (PEP) and secondary efficacy period (SEP) for iron-related 
parameters  
x Proportion of subject receiving rescue by analysis periods.  
x Proportion of subjects receiving RBC transfusions by analysis periods. 
x Proportion of subjects receiving ESA medication by analysis periods. 
x Time to first rescue by narrow and broad (include any rescue, ESA, and RBC 
respectively) 
x Proportion of subjects who received any IV iron therapy by analysis period) 
x Mean weekly IV dose elemental iron by analysis period and route of 
administration  
x Mean change in serum glucose and lipid parameters between Baseline and the 
PEP (Weeks 20 to 26) and SEP (Weeks 46 to 52) 
x Mean change in iron metabolism (including iron, hepcidin, ferritin, transferrin 
saturation [TSAT], total iron binding capacity [TIBC]) between Baseline and the 
PEP (Weeks 20 to 26) and SEP (Weeks 46 to 52) 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 14 of 54 
 
5.4 
PRIMARY SAFETY ENDPOINTS 
Treatment-emergent adverse events (TEAEs) and Treatment-emergent Serious Adverse 
Events (SAEs). 
5.5 
SECONDARY SAFETY ENDPOINTS 
Secondary endpoints include the following: 
x Proportion of subjects with Hb >11.0, Hb >12.0, >13.0, or >14.0 g/dL. 
x Proportion of subjects with Hb <7.0, <8.0, <9.0, or <10.0 g/dL. 
x Proportion of subjects with Hb increase >1.0 g/dL within any 2-week interval or 
>2.0 g/dL within any 4-week interval.  
5.6 
OTHER SAFETY ENDPOINTS 
Safety will also be evaluated by the following assessments: 
x Laboratory test results 
x Vital signs 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
6. STATISTICAL METHODOLOGY AND ANALYSES 
6.1 
GENERAL CONSIDERATIONS 
Data collected throughout the study will be summarized using descriptive statistics and 
listed in by-subject listings. Continuous variables will be summarized using number of 
subjects with data, mean, standard deviation (SD), median, minimum, and maximum. For 
categorical variables, the number and percentage of subjects in each category will be 
tabulated. Summaries will be provided by treatment group and for vadadustat treatment 
groups combined within appropriate analysis populations, and by time point/time period, 
as appropriate.  
For Hb, Baseline will be calculated as the average of the last 2 central laboratory Hb 
measurements of samples taken at or prior to the first dose. For blood pressure, baseline 
will be calculated as the average of the blood pressure within same visit, and then select 
PP
D


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 15 of 54 
 
the last available results on or prior to the first dose. For other parameters, unless 
otherwise specified, Baseline will be defined as the last available value prior to the first 
dose of study medication. 
The primary efficacy endpoint as well as the secondary and all other efficacy endpoints 
will be summarized using descriptive statistics by treatment group, and by analysis visit 
and/or analysis period as appropriate. Mean values of Hb and selected other efficacy 
parameters will be plotted across analysis visits/periods by treatment group. 
Hb values will be assessed through the central laboratory for dose adjustments, efficacy, 
and safety evaluations. 
If the central laboratory uses assays that have lower limits of detection (LLD), all 
laboratory results below the LLD will be imputed with the LLD. Results reported as 
greater than a value (i.e., “> value”) will be imputed as 1.5 x that value. 
Mircera will be converted to IV epoetin equivalent unit per kilogram per week 
(U/kg/week) as 1:220. The conversion has been derived from published literature 
(Paganini, 1995; Kaufman1998Levin, 2008Wright2015) and input from clinical experts. 
Study days are defined as follows: 
 
Study Day = [Event date – First dosing date + 1], if on or after first dosing date 
 
 
 
[Event date – First dosing date], if before first dosing date. 
Note that with the definition above, days of “0” will not be used. As such, the study day 
can be interpreted as the number of days before or after first day of dosing. Event date 
refers to the date associated with the result being summarized. In some cases, this is the 
date of an assessment or measurement; in other cases, this is the onset date of an adverse 
or outcome event. 
If the subject numbers, combined over two treatment groups, in one of the strata are less 
than 30, the strata will be combined with the next large strata for efficacy and safety 
analyses.   
6.2 
VISIT AND ANALYSIS TIME PERIOD CLASSIFICATION 
All assessments will be mapped to the corresponding analysis visit (i.e., target week) 
based on study day, including unscheduled visits. Table 1 is a general window for each 
visit based on the protocol. Table 2 will be applied for less frequent assessments such as 
 C-Reactive Protein (CRP), Complete Blood 
Count (CBC) with differential, Serum Chemistry, Lipid Panel, Reticulocyte count, 
Biomarkers, Erythropoietin and Dialysis Adequacy. All other assessments will apply to 
the analysis window from Table 1. 
If more than one Hb assessment is available in a post-baseline analysis period (i.e., PEP 
or SEP), then all results will be used to calculate the average of Hb. But if more than one 
record is available in same day, the last assessment (i.e., at most one record per day) will 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 16 of 54 
 
be used to calculate the average. For other assessments, if more than one assessment is 
available in each window, the assessment which is closest to the target day will be used 
for analysis. If the assessments are equally close, the last assessment will be used.  
Table 1. 
Classification of Assessments at Every Visit (General) 
Analysis Time Period 
Visit 
Target Day 
Analysis Window 
Baseline 
Screening Visit 1 
- 
- 
Screening Visit 2 
- 
- 
Baseline 
Day 1 
<=Day 1 (prior to first dose)a 
Week 2-6 
Week 2 
Day 14 
Day 1 (post dose) – 21 
Week 4 
Day 28 
Day 22 – 35 
Week 6 
Day 42 
Day 36 – 49 
Week 8-16 
Week 8 
Day 56 
Day 50 – 70 
Week 12 
Day 84 
Day 71 – 98 
Week 16 
Day 112 
Day 99 – 126 
Primary Efficacy 
Period (PEP) 
(Weeks 20-26) 
Week 20 
Day 140 
Day 127 – 154 
Week 24 
Day 168 
Day 155 – 175 
Week 26 
Day 182 
Day 176 – 196 
Week 30-42 
Week 30 
Day 210 
Day 197 – 224 
Week 34 
Day 238 
Day 225 – 252 
Week 38 
Day 266 
Day 253 – 280 
Week 42 
Day 294 
Day 281 – 308 
Secondary Efficacy 
Period (SEP) 
(Weeks 46-52) 
Week 46 
Day 322 
Day 309 – 336 
Week 50 
Day 350 
Day 337 – 357 
Week 52 
Day 364 
Day 358 – 378 or ET/EOT 
assessment date + 15 days 
Safety Follow-upb 
Follow-up 
ET/EOT assessment 
date + 28 days 
>= ET/EOT assessment  
date + 15 days 
a If patient has no first dose date, day 1 will be the randomization date. 
b for Vital Sign, Dialysis Access Type, and Therapeutic Phlebotomy 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 17 of 54 
 
Table 2. 
Classification of Assessments for Selected Assessment 
Analysis Time Period 
Visit 
Target Day 
Analysis Window 
Baseline 
Screening Visit 1 
- 
- 
Screening Visit 2 
- 
- 
Baseline 
Day 1 
<=Day 1 (prior to first dose)a 
Week 2-6 
Week 4 
Day 28 
Day 1 (post dose) – 49 
Week 8-16 
Week 12 
Day 84 
Day 50 – 126 
Primary Efficacy 
Period (PEP) 
(Weeks 20-26) 
Week 26 
Day 182 
Day 127 – 196 
Secondary Efficacy 
Period (SEP) 
(Weeks 46-52) 
Week 52 
Day 364 
Day 309 – 378 or ET/EOT 
assessment date + 15 days 
a If patient has no first dose date, day 1 will be the randomization date. 
6.3 
HANDLING OF MISSING VALUES 
Missing data will be handled using a procedure specific to each variable and particular 
analysis as described in the sections relevant to each endpoint. If no method for missing 
data is discussed, descriptive analyses will be based upon observed data without 
imputation. Appendix B describes the general approaches to be used for missing data. 
The algorithms for imputation of partial dates are applied based on following manner. 
Adverse Event Onset 
x If date is completely missing, date is set to date of first dose. 
x If year is present and month and day are missing or year and day are present, and 
month is missing: 
o If year = year of first dose, then set month and day to month and day of 
first dose. 
o If year < year of first dose, then set month and day to December 31. 
o If year > year of first dose, then set month and day to January 1. 
x If month and year are present and day is missing:  
o If year = year of first dose: 
x month = month of first dose, then set day to day of first dose date. 
x month < month of first dose, then set day to last day of month. 
x month > month of first dose, then set day to first day of month. 
o If year < year of first dose, then set day to last day of month. 
o If year > year of first dose, then set day to first day of month. 
x 
For all other cases, set date to date of first dose. 
Adverse Event End Date 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 18 of 54 
 
x If year is present and month and day are missing or year and day are present and 
month is missing, set end month and day to December 31. 
x If month and year are present and day is missing, set the day to last day of the 
month. 
x If fatal event, date is set to minimum of imputed end date and death date. 
x For all other cases, set date to missing. 
 
Concomitant Medication Start Date 
x If start date is completely missing, start date is the date of informed consent 
except for the records that medication end date precedes date of informed consent. 
x If start year is present and month and day are missing or year and day are present 
and month is missing, set start month and day to January 1. 
x If start year and month are present and day is missing, set start day to 1st day of 
month. 
Concomitant Medication End Date 
x If end date is completely missing, end date is the last available date in the study.  
x If end year is present and month and day are missing or year and day are present 
and month is missing, set end month and day to December 31. 
x If end year and month are present and day is missing, set end day to last day of 
the month. 
The imputed dates must be logical, ensuring that no end date is after database lock or 
death or before the start date. 
6.4 
WEEK 26 ANALYSIS 
The protocol mentioned that a formal week 26 analysis for the primary efficacy endpoint 
(the 2 comparisons between the vadadustat groups and Micera with hierarchical testing) 
may be conducted after the last patient completes the primary efficacy period (Week 
26).Because of the complete response letter received in March 2022 from FDA regarding 
the Vadadustat NDA 215192 , Akebia decided not to conduct this week 26 analysis. 
6.5 
SUBJECT DISPOSITION 
The number and percentage of subjects randomized and included in each analysis 
population will be summarized by treatment group and overall. Reasons for excluding 
subjects from the analysis populations will be presented in a by-subject listing. 
The number of randomized subjects who completed study medication treatment, 
discontinued from study medication early, and completed or discontinued from the study 
and reasons for discontinuation will be summarized by treatment group and overall.  
Time to study treatment discontinuation will be estimated using the Kaplan-Meier 
product-limit method and log rank test as described in Appendix A. Subject completed 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 19 of 54 
 
study treatment will be censored at date of study completion. The hazard ratio and 
corresponding 95% confidence interval for the comparison of vadadustat to and Mircera 
control group will be estimated using a Cox proportional hazards model, with treatment 
group, randomization stratification factor (dialysis organization), and baseline Hb as 
covariates. Kaplan-Meier plot of time to study treatment discontinuation will be 
provided. 
6.6 
PROTOCOL DEVIATIONS 
Definitions of important and non-important protocol deviations will be described in a 
master Protocol Deviation log file, including those protocol deviations leading to 
exclusion from the PP populations. These will be specified prior to database lock on a 
blinded basis. 
Protocol deviations will be summarized in the randomized population as the number and 
percentage of subjects with a protocol deviation by treatment group and overall. A by 
subject listing of protocol deviations, indicating those exclusionary from the PP 
population, will be provided. 
6.7 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
The following item will be summarized by treatment group and overall based on 
randomized population: 
Demographic variables: age, age group 1 (<65 years, >=65 years), age group 2 (>=18-64 
years, >=65-84 years, >=85 years), sex, ethnicity, race, height, pre- and post-dialysis 
weight, body mass index (BMI) 
BMI (kg/m2) = weight (kg)/(height (m))at Screening V2 
Baseline characteristics: stratification factor (Dialysis organization), Mircera monthly 
dose amount, Baseline IV/Oral iron dose use (mg/week), Kt/V result, history of diabetes 
mellitus, cardiovascular disease, retinal disorder, statin used, systolic blood pressure 
(SBP), diastolic blood pressure (DBP) and heart rate.  
Baseline Laboratory Measurements: Hb, hepcidin, iron indices (ferritin, TSAT, TIBC, 
serum iron), serum glucose, lipid profile (total cholesterol, low-density lipoprotein 
(LDL), high-density lipoprotein (HDL), triglycerides) and CRP.  
Continuous variables will be summarized as descriptive statistics. Categorical variables 
will be summarized by using number and percentage. 
6.8 
MEDICAL HISTORY 
Medical history terms will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA), and the number and percent of subjects with medical history will 
be summarized by system organ class (SOC) and preferred terms (PT) for each treatment 
group and overall based on the safety population. 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 20 of 54 
 
Etiology of CKD and dialysis history will be summarized by treatment group and overall 
based on safety population. 
6.9 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior and concomitant medications will be coded using World Health Organization Drug 
dictionary (WHO DD). Data collected from eCRF page “Prior and Concomitant 
Medications” and “ESA Administration” will be included and summarized for each 
treatment group and overall based on the safety population. Anti-Hypertensive 
Medications will be summarized for each analysis period by treatment group and overall 
based on the safety population. 
Prior medications will be defined as any medications that were taken 30 days prior to 
SV1 to before the first dose of study medication. Concomitant medications will be 
defined as any medications taken on or after first dose of study medication. 
6.10 STUDY DRUG DOSING AND COMPLIANCE 
Due to  differences in data collection  between the two treatment groups, the calculated 
compliance rate for a given time period will be derived differently for each treatment 
group: 
Compliance rate for vadadustat group (%) = (treatment duration in the given time 
period (+ 7/3, if the treatment duration in the give time period is not multiple of 7 
days)– number of missed dose during the given time period*7/3)/(treatment duration 
in the given time period (+ 7/3, if the treatment duration in the give time period is not 
multiple of 7 days))*100.  
Any tablet is taken in a day will be considered compliant for that day. 
Compliance rate for Mircera group (%) = Sum of minimum (treatment duration of the 
dosing record + the dosing frequency for the exposure, treatment duration up to the 
start date -1 of the next dosing record) during the give time period/(treatment duration 
in the given time period + the dosing frequency of the last dosing record in the given 
time period for the exposure)*100.  
Total duration (week) of dose exposure and interruption will be provided by treatment 
group for safety population. 
The following summary will be provided by treatment group for both safety population 
and FAS as well: 
x Study Treatment Compliance Rates by analysis period 
x Average weekly dose by analysis period 
x Number of subjects who took vadadustat by dose level and by analysis visit 
x Maximum increase in dose amount of Mircera by analysis period 
x Study treatment modifications and discontinuations 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 21 of 54 
 
6.11 EFFICACY ANALYSES 
The general approach for analysis of continuous outcomes will be analysis of covariance 
(ANCOVA) with multiple imputation for missing data or mixed models for repeated 
measurements (MMRM) on observed data.  
For binary variables, the general approach will be Mantel-Haenszel estimation of risk 
difference stratified by dialysis organization with or (without) multiple imputation for 
handling missing data [Mantel, 1959]. 
6.11.1 
Primary Estimand 
The primary estimand defining the treatment effect of interest in this trial uses the 
treatment policy strategy specified in the ICH E9 (R1) Addendum [FDA 2021]. In this 
trial, the research question is to compare the assignment of Mircera to vadadustat, 
regardless of intercurrent events. The primary analysis will be performed in the 
randomized population in accordance with intent-to-treat. This means the analysis will 
include individuals who never received treatment, discontinued treatment, were rescued 
with any therapy, and withdrew consent. The estimate of the treatment effect of interest 
will be the one regardless of whether the intercurrent event occurred. 
The primary estimand for this trial is defined by the following components: 
x Treatment: vadadustat with rescue therapy as needed versus Mircera with rescue 
therapy as needed    
x Population: randomized population. 
x Variable: change in Hb from Baseline (average pretreatment Hb) to the primary 
evaluation period (average Hb from Weeks 20 to 26, inclusive). 
x Intercurrent event: never received treatment, discontinued treatment, rescued with 
any therapy or withdrew consent. 
x Population-level summary: difference in mean change in Hb from baseline to the 
primary evaluation period between the vadadustat groups and Mircera control 
group. 
6.11.2 
Primary Efficacy Analyses 
The primary efficacy endpoint is defined as the mean change in Hb between Baseline 
(average pretreatment Hb) and the primary evaluation period (average Hb from Weeks 20 
to 26, inclusive). 
The primary analysis of the primary endpoint will use the randomized population with 
imputation of data. All intercurrent events will be handled by treatment policy strategy 
(Section 6.11.1).  Unobserved data after intercurrent events, including Hb outcomes and 
any covariates to be used in the models, will be imputed with the randomized treatment 
group to which the subject was randomized using multiple imputation under fully 
conditional specification (FSC) method as described in Appendix B. Data up to 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 22 of 54 
 
scheduled visit of week 26 will be included in the primary efficacy analyses. Analysis of 
covariance (ANCOVA) as described in Appendix A will be used to calculate the LS 
mean (SE) by treatment group and LS mean difference (SE), 95% confidence intervals 
(CI) of the difference in mean change in Hb from baseline to the primary evaluation 
period between the vadadustat groups and Mircera control group, with the randomization 
stratification factor (Dialysis organization) and Baseline Hb as covariates.  
Treatment comparisons will be performed between the vadadustat and Mircera groups. 
Subjects in the vadadustat starting dose groups of 600 mg or 900 mg TIW will have their 
doses adjusted to maintain Hb levels of 10.0 to 11.0 g/dL following the protocol’s dosing 
algorithm.  
x Noninferiority of vadadustat will be established if the lower limit of 2-sided CI is 
greater or equal to -0.75 g/dL for combined vadadustat dosing groups minus 
Mircera. 
If the lower limit of the 2-sided 95% confidence interval for the difference between the 
mean Hb change from baseline to Weeks 20 to 26 in the vadadustat group and the mean 
Hb change from baseline in the Mircera group is above zero, superiority will have been 
established and the finding will be interpreted as providing evidence of a greater change 
from baseline in Hb for vadadustat relative to the control arm. Because the same 95% 
confidence interval is used to the superiority test, no adjust of multiplicity is needed. 
6.11.2.1 Sensitivity Analyses of the Primary Efficacy Endpoint 
To assess the robustness of the findings from the primary analysis, the following 
sensitivity analyses will be conducted: 
x Primary analysis will be repeated using the FAS population. 
x Primary analysis will be repeated using the PP population with the actual 
treatment received. 
x Primary analysis will be repeated with imputation of data which may have been 
affected by the intercurrent events. All per-visit Hb values within four weeks of 
administration of rescue therapy (narrow or broad-on-treatment defined in Section 
6.11.4.4) or after EOT visit will be set as missing prior to imputation. 
x Primary analysis will be repeated with method of mixed model for repeated 
measures (MMRM) based on observed data only. The MMRM model as 
described in Appendix A will include baseline Hb, stratification factor (dialysis 
organization), treatment group, analysis period (throughout 26-weeks), treatment-
by-analysis time period interaction, baseline-by-analysis time period interaction 
as covariate.  
x Tipping point analyses will be performed to assess the effect of the missing data. 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 23 of 54 
 
x Primary analysis will be repeated for the vadadustat 900 mg TIW starting dose 
group vs. Mircera and the vadadustat 600 mg starting dose group vs. Mircera as 
exploratory analyses. 
6.11.3 
Secondary Efficacy Analyses 
The study has one secondary efficacy endpoint which will be analyzed formally only if 
the primary analysis meets the noninferiority margin.  
Mean change in Hb between Baseline (average pretreatment Hb) and the secondary 
evaluation period (average Hb from Weeks 46 to 52, inclusive) will be analyzed using the 
same methodology as specified for the primary efficacy endpoint. Evaluation of the 
average change in Hb will employ the approach described for the primary endpoint 
assessing Weeks 46 to 52 instead of Weeks 20 to 26.  
Sensitivity analyses analogous to those performed for the primary efficacy endpoint will 
be repeated to assess mean change in Hb from Baseline to Weeks 46 to 52. For 
ANCOVA models, the analysis period of Weeks 46 to 52 will replace the analysis period 
of Weeks 20 to 26, and for MMRM, the models will be extended to include analysis 
period up to week 52. The analysis will be repeated for the vadadustat 900 mg TIW 
starting dose group vs. Mircera and vadadustat 600 mg starting dose group vs. Mircera as 
exploratory analyses.  
After the non-inferiority for both primary and key secondary endpoints have been 
established, If the lower limit of the 2-sided 95% confidence interval for the difference 
between the mean Hb change from baseline to Weeks 20 to 26 in the vadadustat group 
and the mean Hb change from baseline in the Mircera group is above zero, superiority 
will have been established and the finding will be interpreted as providing evidence of a 
greater change from baseline in Hb for vadadustat relative to the control arm. Because the 
same 95% confidence interval is used to the superiority test, no adjustment for 
multiplicity is needed. 
6.11.4 
Other Efficacy Analyses 
Except for specifying the analysis population, other efficacy endpoint analyses will be 
performed using the randomized analysis population.  
6.11.4.1 Hb value within the target range 
All subjects will be defined as either being in target range (10.0 to 11.0 g/dL) in Weeks 
20 through 26 (“yes”) or not (“no”), based on at least one Hb value meeting the target 
range during the visit windows in Weeks 20 through 26. This analysis includes the 
observed Hb values only.  
The same criterion will be used based on the average Hb value during the visit windows 
in Weeks 20 through 26. To ensure uniformity across all analyses, the missing binary 
outcomes will be computed from the imputed complete dataset in the primary analysis.  


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 24 of 54 
 
The proportion of subjects within target range will be calculated, 95% CI for the 
proportions will be reported along with the difference in proportions as well as the odds 
ratio; a Mantel-Haenszel method stratified by dialysis organization will be used to 
calculate the 95% CI for the statistics of treatment comparison. 
Noninferiority will be evaluated using a 2-sided CI for the difference in proportions. 
Noninferiority will have been established if the lower limit of the CI is above -15%.  
If the lower limit of the 2-sided CI for the difference in proportions is above zero, 
superiority will have been established and the finding will be interpreted as providing 
evidence of a higher proportion of subjects being within the target range for vadadustat 
relative to the control arm. 
Secondary evaluation period (Weeks 46 through 52) will be analyzed using the same 
method. 
6.11.4.2 Endpoints Related to Iron 
Mean change from baseline and percentage change from baseline are presented for 
hepcidin, ferritin, TIBC, serum iron, and TSAT, ANCOVA model will be used for 
treatment comparisons with respect to mean change from baseline in the PEP and SEP.  
The proportion of subjects who received any iron therapy and the mean weekly dose of 
elemental iron will be summarized by route of administration, analysis periods, and 
treatment groups. The calculation of mean IV (or Oral) weekly dose will include subjects 
with iron administration and will count only weeks in which a subject was still being 
followed in the denominator. For proportion of subjects who received each (or both) of 
the relevant routes of elemental iron, 95% CI for the proportions will be reported along 
with the difference in proportions as well as the odds ratio; a Mantel-Haenszel method 
stratified by dialysis organization will be used to calculate the 95% CI for the statistics of 
treatment comparison. For mean weekly dose of elemental iron, ANCOVA model will be 
used for treatment comparisons.  
6.11.4.3 Other Laboratory Parameters 
Mean changes from baseline in PEP and SEP will be summarized by treatment group for 
serum glucose and lipid parameters – including total cholesterol, LDL, HDL, and 
triglycerides. ANCOVA model will be used for treatment comparisons. 
6.11.4.4 Definition of Rescue 
The eCRF collects reasons for ESA medication and RBC transfusion. An Event is 
considered as rescue only when the event occurred between first dose date to permanent 
study treatment discontinuation. The series of rescue definitions are defined as follows: 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 25 of 54 
 
x Narrow:  
o For RBC transfusion, when “Low Hemoglobin” is the reason indicated on the 
eCRF. 
o For ESA medication: 
 Vadadustat arm: the reason of ESA usage is the subject’s Hb less than 
9.0 g/dL. 
 Mircera arm: two scenarios are defined as below: 
i. the reason of other ESA or Mircera usage is the subject’s Hb 
less than 9.0 g/dL or Mircera dose increase at least 50%. 
ii. the reason of other ESA or Mircera usage is the subject’s Hb 
less than 9.0 g/dL or Mircera dose increase at least 100%. 
x Broad:  
o Any RBC transfusion. 
o For ESA medication: 
 Vadadustat arm: any ESA usage. 
 Mircera arm: two scenarios are defined as below: 
i. Any other ESA usage, or Mircera usage due to the subject’s 
Hb less than 9.0 g/dL or Mircera dose increase at least 50%. 
ii. Any other ESA usage, or Mircera usage due to the subject’s 
Hb less than 9.0 g/dL or Mircera dose increase at least 100%. 
6.11.4.4.1 
Analysis of Rescue  
The number and percentage of subjects receiving rescue by rescue type, treatment group 
and analysis period will be summarized. Confidence interval will be 95% CI for these 
proportions  along with the difference in proportions as well as the odds ratio. A Mantel-
Haenszel test stratified by the dialysis organization will be used to calculate the 95% CI 
for the statistics of treatment comparison. 
Time to first rescue therapy administration by narrow and broad definitions separately 
will be estimated using the Kaplan-Meier product-limit method and log rank test. 
Subjects without events will be censored at last dose date. The hazard ratio and 
corresponding 95% CI for the comparison of vadadustat to Mircera will be estimated 
using a Cox proportional hazards model, with treatment group, randomization 
stratification factor (dialysis organization), and baseline Hb as covariates. Kaplan-Meier 
plots of time to first rescue will be provided. 
6.11.4.4.2 
RBC Transfusion 
The same analyses of any rescue will be performed for RBC transfusion by narrow and 
broad separately. 
6.11.4.4.3 
ESA Rescue 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 26 of 54 
 
The same analyses of any rescue will be performed for RBC transfusion by narrow and 
broad separately. In addition, the increases in dose relative to last dose will be 
characterized in three categories by percentage increase: <50%, ≥50% and <100%, and 
≥100%. Subjects will be presented by their maximum category of increase within each 
analysis periods. 
6.12 SAFETY ANALYSES 
All analyses of the safety data will be summarized by treatment group and overall based 
on the safety population unless otherwise specified. 
6.12.1 
Adverse Events 
A treatment-emergent adverse event (TEAE) is one that begins or worsens after treatment 
initiation. TEAEs will be summarized using the number and percentage of subjects with 
TEAEs for all subjects in the safety population.  
All AEs will be coded by MedDRA. The MedDRA version used for reporting this study 
will be described in a footnote on AE related outputs. TEAEs will be summarized by 
SOC and PT for each treatment group. All TEAE summaries will provide the number of 
subjects reporting at least 1 TEAE. TEAE summaries will be ordered by decreasing 
pooled percentage for SOC, and PT within SOC. 
An overall summary table will show number of subjects with at least 1 of each of the 
following: 
x TEAE 
x Drug-related TEAE 
x Severe TEAE 
x Treatment-emergent SAE 
x Drug-related treatment-emergent SAE 
x TEAE leading to withdrawal of study drug 
x Drug-related TEAE leading to withdrawal of study drug 
x Fatal TEAE 
x All Deaths: Any deaths reported during the study no matter whether deaths are 
caused by TEAEs 
Summaries by SOC and PT will be provided for the following types of TEAEs: 
x TEAE 
x TEAE by severity 
x Drug-related TEAEs (including all categories for relationship to study medication 
other than “Unrelated”, as determined by the investigator) 
x Treatment-emergent serious adverse event (SAE) 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 27 of 54 
 
x Drug-related treatment-emergent SAE 
x TEAEs leading to withdrawal of study drug 
x Drug-related TEAE leading to withdrawal of study drug 
x Fatal TEAE 
x Adverse events of special interest (AESI) listed on Appendix E 
A summary by treatment group and PT will be presented for TEAEs reported by at least 
5% of subjects in either treatment group. 
TEAEs will be summarized by 1) worst severity, and 2) worst causality by SOC and PT. 
For each subject and each PT, the worst severity recorded will be used in the by-severity 
summaries. Similarly, the worst causality (most related to treatment) attributed will be 
used in the by-causality summaries. If severity or causality is missing, data will be 
imputed to the worst category. 
Treatment-emergent SAEs and deaths will be summarized by treatment group and 
overall, including the number and percentage for subject with Treatment-emergent SAEs, 
number of deaths (all causes, resulting from adverse events). Summary by SOC and PT 
will include subjects affected by Treatment-emergent SAEs, occurrence (all, causally 
related to treatment), number of death (all causes), and deaths causally related to 
treatment. 
A by-subject listing of all TEAEs will be provided. This listing will be presented by 
treatment group and will include center, subject identifier, age, sex, race, AE (SOC, PT, 
and verbatim term), study day of onset, study day of resolution, duration, severity, 
seriousness, relationship to the study medication, action taken, outcome and causality.  
A by-subject listing of all Aes happening before first dose date will be provided.  
6.12.2 
Laboratory Data 
6.12.2.1 Hb-related Safety Endpoints 
Hb-related safety endpoints will be defined using data from the central laboratory.  No 
imputation will be performed for missing data. For each endpoint in Table 3, the 
proportion of the study group who satisfy the definition and 95% CI for these proportions 
will be reported along with the difference in proportions as well as the odds ratio; a 
Mantel-Haenszel method stratified by the dialysis organization will be used to calculate 
the 95% CI for the statistics of treatment comparison. 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 28 of 54 
 
Table 3. 
Hb-related Safety Endpoints from First Dose Date to Last Visit 
Variable 
Criterion for “Yes” 
Hb >11.0 g/dL 
Any Hb >11.0 g/dL at any time after Day 1 
Hb >12.0 g/dL  
Any Hb >12.0 g/dL at any time after Day 1 
Hb >13.0 g/dL  
Any Hb >13.0 g/dL at any time after Day 1 
Hb >14.0 g/dL 
Any Hb >14.0 g/dL at any time after Day 1 
Hb<7.0 g/dL 
Any Hb <7.0 g/dL at any time after Day 1 
Hb<8.0 g/dL 
Any Hb <8.0 g/dL at any time after Day 1 
Hb<9.0 g/dL 
Any Hb <9.0 g/dL at any time after Day 1 
Hb<10.0 g/dL 
Any Hb <10.0 g/dL at any time after Day 1 
Hb increase >1.0 g/dL 
within any 2-week interval 
Difference between 2 Hb values within any 2 weeks >1.0 g/dL after Day 1 
Hb increase >2.0 g/dL 
within any 4-week interval 
Difference between 2 Hb values within any 4 weeks >2.0 g/dL after Day 1 
Note: Subjects without any post-baseline data will be excluded from this analysis.  
6.12.2.2 Liver Function Abnormality 
A summary of liver function abnormalities by analysis period will be provided. Any 
subject with at least 1 of the following liver function abnormalities will be summarized: 
x Alanine aminotransferase (ALT) >2x and <=3x upper limit of normal (ULN) 
x ALT >3x and <=5x ULN;  
x ALT >5x and <=10x ULN;  
x ALT >10x ULN 
x Aspartate aminotransferase (AST) >2x and <=3x ULN;  
x AST >3x and <=5x ULN; 
x AST >5x and <=10x ULN;  
x AST >10x ULN 
x Total bilirubin >2x and <=3x ULN;  
x Total bilirubin >3x ULN 
In addition, a table will summarize the occurrence of events that satisfy the following 
criteria of liver injury:  
x (ALT or AST >3x ULN and <=5x ULN) and total bilirubin >2x ULN; 
x (ALT or AST >5x ULN and <=10x ULN) and total bilirubin >2x ULN; 
x ALT or AST >10x ULN and total bilirubin >2x ULN  


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 29 of 54 
 
6.12.2.3 Other Laboratory Safety Endpoints 
Descriptive statistics for laboratory values (in US conventional and SI units) and changes 
from baseline at each analysis visit will be summarized for the following laboratory 
parameters collected in the study including but not limited to the following: 
x Complete blood count (CBC): Hb, hematocrit, red blood cell (RBC), MCV, 
MCH, MCHC, platelets, RDW, white blood cell (WBC) with differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), reticulocyte count  
x Serum chemistry: sodium, potassium, bicarbonate, chloride, calcium, magnesium, 
phosphorus, glucose, creatinine, BUN, CPK, uric acid, albumin, total protein 
x Liver function tests: Total bilirubin, ALP, ALT/SGPT, AST/SGOT, LDH 
x Iron indices: Iron, ferritin, TSAT, TIBC 
x Lipid Profile: Total cholesterol, LDL, HDL, Triglycerides 
x CRP 
x EPO 
A summary of the number and percentage of subjects experiencing clinically significant 
values for the following parameter definitions will be presented by analysis period: 
x Potassium >6.0 mmol/L 
6.12.3 
Physical Examination 
With only the Date of Assessment collected (if performed) on the physical examination 
in the eCRF, no output is planned for it. If there are clinically significant abnormal 
findings, details can be found in the listings of medical history or adverse event.  
6.12.4 
Vital Signs 
For blood pressure, a total of 2 measurements at intervals of at least 2 minutes will be 
performed. For change from baseline related summaries, the average of the blood 
pressure within the same visit will be calculated as the results for the visit. For the 
individual value criteria, an individual result will be used instead of the average.  
Descriptive statistics for vital signs (systolic blood pressure, diastolic blood pressure, 
heart rate, respiratory rate, temperature, weight (pre-dialysis and post-dialysis)) and their 
change from baseline will be provided by each analysis visit. 
The number and percentage of subjects experiencing the following findings by analysis 
periods will be provided: 
x SBP >=180 mmHg 
x SBP >=160 mmHg 
x DBP >=110 mmHg  
x SBP or DBP: Increase from baseline >=20 mmHg 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 30 of 54 
 
x Meet Both/Either Criteria  
o SBP >=160 mmHg and increase from baseline >=20 mmHg 
o DBP >=110 mmHg and increase from baseline >=20 mmHg 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
  
 
 
  
 
 
 
. 
PPD
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 31 of 54 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P
P
D


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 32 of 54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.14 SUBGROUP ANALYSES 
The same analyses of the primary efficacy endpoint and secondary efficacy endpoint will 
also be performed for subgroups based on the following. Subgroup analyses will be 
performed only if the total number of outcomes in a stratum, combined over the two 
treatment groups, is at least 30. 
x Dialysis organization [USRC (U.S. Renal Care), ARCRS (American Renal 
Clinical Research Services), Frenova (Frenova Renal Research)] 
x Age (<65 years, >=65 years) 
x Sex (Male, Female) 
x Race (White, Black, All others) 
x Baseline Hb (<10.0 g/dL, >=10.0 g/dL) 
 
 
 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 33 of 54 
 
7. CHANGES TO PROTOCOL-PLANNED ANALYSES 
Removed the hierarchical testing scheme for both primary and secondary efficacy 
endpoints. Treatment comparisons will be performed between vadadustat (combining the 
2 randomized groups with starting dose of 600mg and 900mg) and Mircera groups. 
Subjects in the vadadustat starting dose groups of 600 mg or 900 mg TIW will have their 
doses adjusted to maintain Hb levels of 10.0 to 11.0 g/dL following the protocol’s dosing 
algorithm. The subgroup analysis with different starting dose with vadadustat vs. Mircera 
will be considered as exploratory analyses.  
 
 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 34 of 54 
 
8. REFERENCES 
Clopper, C. J., and Pearson, E. S. (1934). “The Use of Confidence or Fiducial Limits 
Illustrated in the Case of the Binomial.” Biometrika 26:404–413. 
FACIT Administration and Scoring Guidelines: http://www.ser.es/wp-
content/uploads/2015/03/FACIT-F_INDICE.pdf 
FDA Guidance for Industry: ‘Non-inferiority Clinical Trials’ March 2010. Available at: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/non-
inferiority-clinical-trials 
Food and Drug Administration E9(R1) Statistical Principles for Clinical Trials: 
Addendum: Estimands and Sensitivity Analysis in Clinical Trials Guidance for Industry. 
2021. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/e9r1-statistical-principles-clinical-trials-addendum-estimands-and-sensitivity-
analysis-clinical 
Functional Assessment of Cancer Therapy – Anemia (FACT-An): 
https://www.facit.org/measures/FACT-An 
Levin NW, Fishbane S, Cañedo FV, et al. Intravenous methoxy polyethylene glycol-
epoetin beta for haemoglobin control in patients with chronic kidney disease who are on 
dialysis: a randomised non-inferiority trial (MAXIMA). Lancet 2007; 370:1415-21. 
Erratum in: Lancet 2008; 371:386. 
Hays RD, Kallich JD, Mapes DL, Coons SJ, Carter WB. Development of the kidney 
disease quality of life (KDQOL)instrument. Qual Life Res 1994, Oct;3(5):329-38 
Hays RD, Kallich JD, Mapes DL, Coons SJ, Carter WB. Kidney Disease Quality of Life 
Short Form (KDQOL-SFTM). A Manual for Use and Scoring. Ver. 1.3. Santa Monica: 
RAND; 1997. p. 7994  
Mantel N, Haenszel W. Statistical aspects of analysis of data from retrospective studies 
of disease. J Natl Cancer Inst 1959; 22:719–48 
Paganini EP, Eschbach JW, Lazarus JM, et al. Intravenous versus subcutaneous dosing of 
epoetin alfa in hemodialysis patients. Am J Kidney Dis 1995; 6:331-40. 
Ware JE Jr, Kosinski M, Keller SD. How to Score the SF-12 Physical and Mental Health 
Summary Scales (3rd ed. Boston: The Health Institute, New England Medical Center, 
1998. 
 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 35 of 54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       
 
 
 
 
 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 36 of 54 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
   
 
 
 
 
  
 
 
 
 
 
 
 
     
 
     
 
 
 
 
 
 
     
 
     
 
 
 
 
 
 
 
 
 
zardratio 'Cox proportional hazard' TRT; 
RUN; 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 37 of 54 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 38 of 54 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
     
     
 
    
  
 
    
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
            
 
 
P
P
D


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 39 of 54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For efficacy endpoints of having average Hb value in the target range in Weeks 20-26 
and Weeks 46-52, these endpoints are binary; they will be analysed according to the 
Mantel-Haenszel estimate of stratified risk differences. These binary outcome measures 
will be computed from the continuous imputed data which will serve as the input data set 
for the computation of the estimate of risk difference. The code for this analysis is 
provided as below. 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 40 of 54 
 
B.3. Tipping Point Sensitivity Analysis for Missing Data 
This multiple imputation model for the primary efficacy model described above assumes 
that data in both treatment arms are missing at random (MAR) and would therefore 
follow the trend of observed data. The tipping point analysis assesses the effect of 
potential deviations from this assumption and explores the consequences of assuming that 
data in the vadadustat arm are missing not at random (MNAR) (i.e., subjects in the 
vadadustat arm with missing outcome are assumed to have a lower Hb values than 
subjects in the Mircera arm). The specific steps are as follows: 
1. The missing information on Hb in the vadadustat arm will be multiply imputed using 
a shift parameter S applied to lower the mean Hb values in that arm. Missing data in 
the Mircera arm will continue to be imputed assuming MAR, using the same code as 
for the primary efficacy analysis subset to the Mircera arm.  
2. The multiply imputed data will be analysed using PROC MIANALYZE to obtain an 
estimated treatment effect and its associated 95% CI.  
3. Steps 1 and 2 will then be repeated. The shift parameter S starts from 0, which 
corresponds to the primary efficacy analysis with no shift effect and decreased by 0.1 
in each step until the analysis reaches the “tipping point” (i.e., lower limit of CI <       
-0.75), the point at which the effect of vadadustat is no longer noninferior to that of 
Mircera. The more the tipping point diverges from the observed data, the more robust 
the conclusion based on primary efficacy analysis.   
         
                   
 
 
 
 
 
 
                 
                  
 
 
      
 
 
 
 
 
 
 
 
B.4. Random Seed Specification  
Assigned seeds in proc mi for multiple imputations will be generated randomly from a 
master seed 65480039. The SAS code and the generated seed numbers are listed below. 
  
 
 
   
 
     
 
PPD
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 41 of 54 
 
          
 
          
 
       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 42 of 54 
 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 43 of 54 
 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 44 of 54 
 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
Firma Clinical Research Confidential and Proprietary 
Page 45 of 54 
 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 46 of 54 
 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 47 of 54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
Firma Clinical Research Confidential and Proprietary 
Page 48 of 54 
 
 
 
 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
Firma Clinical Research Confidential and Proprietary 
Page 49 of 54 
 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
Firma Clinical Research Confidential and Proprietary 
Page 50 of 54 
 
PPD


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 51 of 54 
 
Appendix E. Adverse Events of Special Interest (AESI) 
The following items will be presented as AESI. 
x Worsening of Hypertension: Hypertension MedDRA SMQ Narrow 
x Hepatotoxicity: Drug related hepatic disorders Comprehensive SMQ broad 
x Pulmonary Hypertension: Pulmonary Hypertension SMQ narrow 
x Adrenal disorder: high-level group term (HLGT) Adrenal gland disorders not elsewhere 
classified (NEC), high-level term (HLT) Adrenal cortex tests 
x Malignancies: Malignant or unspecified tumors MedDRA SMQ broad  
x Congestive heart failure: Cardiac failure MedDRA SMQ Narrow  
x Adverse event preferred terms used in key queries from FDA briefing document for 
Roxadustat are listed below: 
Medical Topic 
PT Term 
Thrombosis 
Cerebral infarction 
 
Embolic cerebral infarction 
 
Ischaemic stroke 
 
Cerebellar infarction 
 
Lacunar stroke 
 
Embolic stroke 
 
Brain stem stroke 
 
Lacunar infarction 
 
Thrombosis in device 
 
Arteriovenous fistula thrombosis  
 
Arteriovenous graft thrombosis  
 
Vascular access site thrombosis  
 
Vascular graft thrombosis 
 
Graft thrombosis 
 
Shunt thrombosis 
 
Acute myocardial infarction  
 
Myocardial infarction 
 
Deep vein thrombosis  
 
Thrombosis 
 
Atrial thrombosis 
 
Peripheral artery thrombosis  
 
Subclavian vein thrombosis  
 
Brachiocephalic vein thrombosis  


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 52 of 54 
 
Medical Topic 
PT Term 
 
Subclavian artery thrombosis  
 
Vena cava thrombosis  
 
Thrombophlebitis superficial  
 
Arterial thrombosis  
 
Thrombophlebitis 
 
Jugular vein thrombosis 
 
Venous thrombosis 
 
Pelvic venous thrombosis  
 
Venous thrombosis limb 
 
Cardiac ventricular thrombosis 
 
Intracardiac thrombus 
Device/shunt thrombosis/occlusion/malfunction/Stenosis  Thrombosis in device  
 
Arteriovenous fistula thrombosis  
 
Arteriovenous graft thrombosis  
 
Vascular access site thrombosis  
 
Vascular graft thrombosis  
 
Medical device site thrombosis  
 
Device occlusion 
 
Arteriovenous fistula occlusion  
 
Vascular access site occlusion  
 
Vascular access complication  
 
Vascular access malfunction  
 
Arteriovenous graft site stenosis  
 
Shunt occlusion 
 
Shunt malfunction 
 
Vascular graft stenosis  
 
Anastomotic stenosis 
 
Vascular access site complication  
 
Vascular graft occlusion 
Device/shunt thrombosis 
Thrombosis in device  
 
Arteriovenous fistula thrombosis  
 
Arteriovenous graft thrombosis  
 
Vascular access site thrombosis  
 
Vascular graft thrombosis 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 53 of 54 
 
Medical Topic 
PT Term 
 
Graft thrombosis 
 
Shunt thrombosis 
 
Medical device site thrombosis  
 
Device related thrombosis  
 
Injection site thrombosis 
Seizure FDA 
Epilepsy 
 
Epileptic encephalopathy  
 
Seizure 
 
Generalised tonic-clonic seizure  
 
Idiopathic partial epilepsy 
 
Partial seizures 
 
Tonic convulsion 
Stroke 
Cerebral infarction 
 
Embolic cerebral infarction  
 
Ischaemic stroke  
 
Cerebellar infarction 
 
Lacunar stroke 
 
Embolic stroke 
 
Brain stem stroke 
 
Lacunar infarction  
 
Cerebrovascular accident  
 
Haemorrhagic stroke 
 
Brain stem haemorrhage 
Sepsis/septic shock 
Device related sepsis  
 
Enterococcal sepsis  
 
Sepsis 
 
Urosepsis  
 
Streptococcal sepsis  
 
Pseudomonal sepsis  
 
Staphylococcal sepsis  
 
Septic shock 
 
Sepsis syndrome  
 
Biliary sepsis 
 
Bacterial sepsis 


 
 
 
Statistical Analysis Plan 
Protocol No. AKB-6548-CI-0039                                                                             Akebia Therapeutics, Inc. 
 
 
Firma Clinical Research Confidential and Proprietary 
Page 54 of 54 
 
Medical Topic 
PT Term 
 
Fungal sepsis  
 
Citrobacter sepsis  
 
Listeria sepsis  
 
Abdominal sepsis  
 
Septic encephalopathy  
 
Escherichia sepsis