Conditions: Anemia, Iron Deficiency Hyperphosphatemia Renal Insufficiency, Chronic Renal Anemia Disease Progression Cardiovascular Iron
Keywords: ferric citrate
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 289
Healthy volunteers: no

Brief summary:
A 9-month randomized, double-blind, placebo-controlled study to compare the effect of fixed dose ferric citrate versus placebo in patients with advanced chronic kidney disease (eGFR ≤20 ml/min/1.73m2) on the composite endpoint of time to initiation of maintenance dialysis or all-cause mortality.

Detailed description:
This multicenter, randomized, double-blind, placebo-controlled clinical trial is being conducted to determine the effect of ferric citrate on the time to a composite endpoint of initiation of maintenance dialysis or all-cause mortality in patients with non-dialysis dependent, advanced CKD. Up to 400 subjects will be randomized in 1:1 ratio to receive either ferric citrate or matching placebo. All subjects will initiate dosing at 2 tablets per meal or snacks, up to 3 times per day (maximum of 6 tablets per day). The dose of ferric citrate/placebo will only be adjusted based on safety and/or tolerability. Given the double-blind design of this trial, investigators will be instructed to not prescribe commercial Auryxia to either study arm. Study visits during the treatment period are to be conducted as part of routine scheduled clinical encounters. Standard of care local laboratory results will be collected however no study specific laboratory tests other than a pregnancy test in women of child-bearing potential will be required.

Arms:
arm 1: Supplied as tablets for oral administration containing 1 gram ferric citrate (210 milligrams of ferric iron). Administered orally with meals or snacks. arm 2: Tablets, matching in color and size to ferric citrate.

Interventions: intervention 1: Ferric Citrate 1 GM Oral Tablet [AURYXIA] intervention 2: Placebo
Intervention descriptions: intervention 1: All subjects will be instructed to take study drug (ferric citrate or placebo) at a fixed dose of 2 tablets per meal or snacks, up to three times per day. The maximum dose is 6 tablets per day. No additional tablets (beyond a total of 6 per day) should be taken. Tablets should not be crushed or chewed. intervention 2: All subjects will be instructed to take study drug (ferric citrate or placebo) at a fixed dose of 2 tablets per meal or snacks, up to three times per day. The maximum dose is 6 tablets per day. No additional tablets (beyond a total of 6 per day) should be taken. Tablets should not be crushed or chewed.

Protocol document:
Prot_000.pdf: 
USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 1 of 54 
  
 
 
CLINICAL PROTOCOL 
Ferric Citrate for the Prevention of Renal Failure in Adults with Advanced Chronic 
Kidney Disease (FRONTIER)  
 
Compound:  
 
 
 
Ferric Citrate (KRX-0502) 
Protocol Number:   
 
 
USRC-2021-002 
Regulatory Agency ID Number(s):  
IND: 157400 
Protocol Version / Date:   
 
 
Original Version 5.0/dated 28JUL2022 
Investigator-Sponsor: 
 
 
US Renal Care, Inc.  
 
 
 
 
 
 
5851 Legacy Circle, Suite 900 
 
 
 
 
 
 
Plano, TX 75024 
 
 
 
 
 
 
United States of America 
 
This document contains information that is confidential and proprietary to the Investigator-
Sponsor, USRC, Inc. This information is being provided to you solely for the purpose of 
evaluating and/or conducting a clinical study for the Investigator-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 Investigator-Sponsor. The foregoing shall not apply to disclosure required by any 
regulations; however, you will give prompt notice to the Investigator-Sponsor of any such 
disclosure.  


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 2 of 54 
  
SIGNATURE PAGES  
 
Protocol Approval 
 
Name and Title 
Signature and Date 
Geoffrey A Block, MD 
SVP, Clinical Research/Medical Monitor  
 
Martha Block, RN, CCRP 
VP, Clinical Research 
 
Stephanie Brillhart, MSCI 
Director, Regulatory Affairs 
 
Mark Danese, PhD 
Principle Biostatistician, Outcomes Insights 
 
 
 
 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 3 of 54 
  
 
Investigator Agreement 
I confirm that I have read and that I understand this protocol, the current Investigator Brochure, 
and other product information provided by the Investigator-Sponsor. I agree to conduct this study 
in accordance with the requirements of this protocol and to make a reasonable effort to complete 
the study within the timelines.  I further agree to protect the rights, safety, privacy, and well-
being of study subjects in accordance with the following:  
• The ethical principles that have their origin in the Declaration of Helsinki.  
• International Council for Harmonization of Technical Requirements for Pharmaceuticals 
for Human Use Guidance for Industry, Good Clinical Practice E6 (R2).  
• Good Clinical Practice (GCP) including the archiving of essential documents 
• The Institutional Review Board (IRB) requirements 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.  
• Regulatory requirements for reporting serious adverse events defined in this protocol.  
• Terms outlined in the Clinical Study Site Agreement.  
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 
 
 
 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 4 of 54 
  
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................7 
 PROTOCOL SUMMARY ........................................................................................................8 
1.1 
Synopsis ...............................................................................................................................8 
1.2 
Schema ...............................................................................................................................11 
1.3 
Schedule of Activities ........................................................................................................12 
 LIST OF ABBREVIATIONS .................................................................................................14 
 INTRODUCTION ..................................................................................................................16 
3.1 
Study Rationale ..................................................................................................................16 
3.2 
Background ........................................................................................................................16 
3.2.1 
Iron Deficiency Anemia ...............................................................................................16 
3.2.2 
Hyperphosphatemia .....................................................................................................17 
3.3 
Risk/Benefit Assessment ...................................................................................................18 
3.3.1 
Known Potential Risks .................................................................................................18 
3.3.2 
Known Potential Benefits ............................................................................................19 
3.3.3 
Overall Benefit: Risk Conclusion ................................................................................19 
 OBJECTIVES AND ENDPOINTS ........................................................................................19 
4.1 
Study Objectives ................................................................................................................19 
4.1.1 
Primary Objective ........................................................................................................19 
4.1.2 
Secondary Objective ....................................................................................................19 
4.2 
Study Endpoints .................................................................................................................20 
4.2.1 
Primary Endpoint .........................................................................................................20 
4.2.2 
Secondary Endpoints ...................................................................................................20 
4.2.3 
Exploratory Endpoints .................................................................................................20 
 STUDY DESIGN ...................................................................................................................20 
5.1 
Overall Design ...................................................................................................................20 
5.1.1 
Replacement of Participants ........................................................................................21 
5.2 
Scientific Rationale for Study Design ................................................................................21 
5.3 
Justification for Dose .........................................................................................................22 
5.4 
End of Study Definition .....................................................................................................22 
5.5 
Number of Study Sites .......................................................................................................22 
 STUDY POPULATION .........................................................................................................22 
6.1 
Inclusion Criteria ...............................................................................................................22 
6.2 
Exclusion Criteria ..............................................................................................................23 
6.3 
Screen Failures ...................................................................................................................23 
 STUDY INTERVENTION ....................................................................................................24 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 5 of 54 
  
7.1 
Study Intervention(s) Administration ................................................................................24 
7.1.1 
Study Intervention Description ....................................................................................24 
7.1.2 
Dosing and Administration ..........................................................................................24 
7.1.2.1 
Dose Adjustment ....................................................................................................24 
7.2 
Preparation/Handling/Storage/Accountability ...................................................................26 
7.2.1 
Acquisition and Accountability ...................................................................................26 
7.2.2 
Formulation, Appearance, Packaging and Labeling ....................................................27 
7.2.3 
Product Storage and Stability.......................................................................................27 
7.3 
Measures to Minimize Bias: Randomization and Blinding ...............................................27 
7.3.1 
Randomization .............................................................................................................27 
7.3.2 
Blinding........................................................................................................................27 
7.4 
Study Intervention Compliance .........................................................................................28 
7.5 
Concomitant Therapy.........................................................................................................28 
7.5.1 
Phosphate Lowering Therapy ......................................................................................28 
7.5.2 
Iron Supplementation ...................................................................................................28 
7.5.3 
Erythropoiesis-Stimulating Agents (ESAs) or Packed Red Blood Cell (PRBC) 
Transfusion .................................................................................................................29 
7.5.4 
Prohibited Medications/Procedures .............................................................................29 
7.5.5 
Permitted therapy .........................................................................................................29 
7.5.6 
Potential Drug-Drug Interactions .................................................................................29 
 DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..............................................................................30 
8.1 
Discontinuation of Study Drug ..........................................................................................30 
8.1.1 
Temporary Interruption of Study Drug ........................................................................30 
8.1.2 
Permanent Discontinuation of Study Drug ..................................................................31 
8.2 
Withdrawal from Study......................................................................................................31 
8.3 
Lost to Follow-Up ..............................................................................................................32 
 STUDY ASSESSMENTS AND PROCEDURES ..................................................................32 
9.1 
General Study Periods........................................................................................................32 
9.1.1 
Screening, Enrollment, and/or Randomization ............................................................32 
9.1.2 
Treatment Period ..........................................................................................................33 
9.1.3 
End of Treatment (EOT) Visit .....................................................................................33 
9.1.4 
Long Term/ Safety Follow-up .....................................................................................33 
9.2 
Clinical Assessments .........................................................................................................33 
9.2.1 
Medical History and Demographics ............................................................................33 
9.2.2 
Vital Sign Measurement ..............................................................................................34 
9.3 
Efficacy Assessments .........................................................................................................34 
9.4 
Laboratory and Other Assessments ...................................................................................34 
9.5 
Safety and Other Assessments ...........................................................................................35 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 6 of 54 
  
9.5.1 
Concomitant Medication Recording ............................................................................35 
9.5.2 
Adverse Event Assessment ..........................................................................................36 
9.6 
Adverse Events and Serious Adverse Events ....................................................................37 
9.6.1 
Definitions of Adverse Events and Serious Adverse Events .......................................37 
9.6.1.1 
Adverse Events ......................................................................................................37 
9.6.1.2 
Serious Adverse Events .........................................................................................37 
9.6.2 
Classification of an Adverse Event ..............................................................................39 
9.6.2.1 
Severity of Event ....................................................................................................39 
9.6.2.2 
Relationship to Study Intervention ........................................................................39 
9.6.2.3 
Expectedness ..........................................................................................................40 
9.6.3 
Time Period and Frequency for Event Assessment and Follow-up .............................40 
9.6.4 
Reporting Adverse Events ...........................................................................................40 
9.6.5 
Reporting Period ..........................................................................................................40 
9.6.6 
Serious Adverse Event Reporting ................................................................................41 
9.6.7 
Follow-up of Unresolved Events .................................................................................42 
9.6.8 
Reporting of Pregnancy ...............................................................................................42 
9.7 
Special Situations ...............................................................................................................42 
 STATISTICAL CONSIDERATIONS ...................................................................................43 
10.1 
Sample Size Determination ................................................................................................43 
10.2 
Populations for Analyses ...................................................................................................44 
10.3 
Missing Data ......................................................................................................................44 
10.4 
Statistical Analyses ............................................................................................................44 
10.4.1 
General Considerations ................................................................................................44 
10.4.2 
Analysis of Primary Endpoint(s) .................................................................................44 
10.4.3 
Analysis of Secondary Endpoint(s) .............................................................................45 
10.4.4 
Tertiary/Exploratory Endpoint(s) .................................................................................45 
10.4.5 
Safety Analyses ............................................................................................................45 
10.4.5.1 
Analysis of Adverse Events ...................................................................................45 
10.4.6 
Baseline Descriptive Statistics .....................................................................................46 
10.4.7 
Planned Interim Analyses ............................................................................................46 
10.4.8 
Sensitivity Analyses .....................................................................................................46 
10.4.9 
Sub-Group Analyses ....................................................................................................46 
 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .........46 
11.1 
Ethical Conduct of the Study .............................................................................................46 
11.2 
IRB and Ethics Committees ...............................................................................................47 
11.3 
Informed Consent Process .................................................................................................47 
11.4 
Financial Disclosure ...........................................................................................................47 
11.5 
Confidentiality and Data Privacy .......................................................................................48 
11.6 
Data Handling and Record Keeping ..................................................................................48 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 7 of 54 
  
11.6.1 
Data Collection and Management Responsibilities .....................................................48 
11.6.2 
Study Records Retention ..............................................................................................48 
11.7 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ................49 
11.8 
Study Discontinuation and Closure ...................................................................................49 
11.8.1 
Criteria for Premature Termination or Suspension of the Study .................................49 
11.8.2 
Criteria for Premature Termination or Suspension of Study Sites ..............................50 
11.8.3 
Criteria for Premature Termination or Suspension of the Study or Study Sites ..........50 
11.9 
Safety Oversight.................................................................................................................50 
11.10 Quality Assurance and Quality Control .............................................................................50 
11.10.1 
Clinical Monitoring ......................................................................................................50 
11.10.2 
Protocol Deviations ......................................................................................................51 
 PUBLICATION OF STUDY RESULTS ...............................................................................51 
 REFERENCES .......................................................................................................................53 
LIST OF TABLES 
Table 1. Schedule of Activities ......................................................................................................12 
Table 2. Typical Quarterly Laboratory Assessments .....................................................................35 
 
LIST OF FIGURES 
Figure 1. Study Schema .................................................................................................................11 
 
 
 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 8 of 54 
  
 
 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Synopsis 
Protocol Title 
Ferric Citrate for the Prevention of Renal Failure in Adults with 
Advanced Chronic Kidney Disease (FRONTIER) 
Protocol Number 
USRC-2021-002 
Investigational Product 
Auryxia (Ferric Citrate-KRX-0502) 
Reference Therapy, as applicable 
Matching Placebo 
Study Population  
The study population will consist of adult subjects ≥18 years old with 
a diagnosis of non-dialysis dependent (NDD) advanced chronic 
kidney disease (CKD)  
Number of Study Sites 
Multicenter, up to 25 sites in the United States (US)  
Planned Number of Subjects 
Up to 400 subjects will be randomized 1:1 to receive either ferric 
citrate or matching placebo 
Primary Objective/Endpoint 
To determine the effect of ferric citrate on the time to a composite 
endpoint of initiation of maintenance dialysis or all-cause mortality 
compared to placebo in adult patients with advanced CKD. 
Secondary Objectives/Endpoints 
• Time to first hospitalization event reported as a serious adverse 
event (SAE) (excluding disease-related hospitalization [e.g., dialysis 
access placement, dialysis initiation, kidney transplant] and elective 
procedures) 
• Component of Primary – Time to Initiation of Maintenance Dialysis 
• Component of Primary – Time to All-Cause Mortality 
Methodology (study design) 
Multicenter, randomized, double-blind, placebo-controlled clinical 
trial to determine the effect of ferric citrate on the time to a composite 
endpoint of initiation of maintenance dialysis or all-cause mortality in 
patients with NDD, advanced CKD. Subjects will be randomized in 
1:1 ratio to receive either ferric citrate or matching placebo. All 
subjects will initiate dosing at 2 tablets per meal or snacks, up to 
3 times per day (maximum of 6 tablets/day). The dose of ferric 
citrate/placebo will only be adjusted based on safety/tolerability. 
Given the double-blind design of this trial, investigators will be 
instructed to not prescribe commercial Auryxia to either study arm. 
The study will be considered completed when all randomized subjects 
have completed their final study visit (Month 9 or EOT) and 30-day 
safety follow-up visit. Study visits during the treatment period are to 
be conducted as part of routine scheduled clinical encounters.  
Standard of care local laboratory results will be collected, including 
the monitoring of phosphorus and iron indices (TSAT and ferritin) at 
quarterly intervals. A pregnancy test in women of child-bearing 
potential will be required.  
Study Duration 
Each subject will be followed for a treatment period of approximately 
9 months plus an additional 30-day safety follow-up period. 
Key Inclusion and Exclusion Criteria 
Inclusion Criteria 
1. Adult patients ≥18 years old. 
2. Diagnosis of NDD advanced CKD, regardless of etiology.  
Advanced CKD is defined as at least one local laboratory 
determined estimated glomerular filtration rate (eGFR) ≤20 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 9 of 54 
  
ml/min/1.73m2 (calculated per any commonly used method 
or equation for estimating eGFR) within 90 days of Day 1. 
3. Most recent transferrin saturation (TSAT) ≤45% within 45 
days of Day 1.  
4. Most recent serum phosphate is ≥3.0 mg/dL within 45 days 
of Day 1. 
5. Most recent ferritin ≤500 ng/mL within 45 days of Day 1.  
6. Women of child-bearing potential must have a negative 
serum or urine pregnancy test within 30 days prior to Day1 
procedures. Can be performed on Day 1 if prior to any Day 1 
procedures.  Results must be available prior to the 1st dose 
of study drug.  
7. Understands the procedures and requirements of the study 
and provides written informed consent and authorization for 
protected health information disclosure. 
 
Exclusion Criteria 
1. Patients who, in the opinion of the Investigator, have acute 
kidney injury rather than CKD. 
2. Patients with planned/imminent maintenance dialysis, or that 
are anticipated to begin maintenance dialysis within 8 weeks 
from Screening, in the opinion of the Investigator.  
3. A known allergy or intolerance to ferric citrate or any of its 
constituents. 
4. Hypersensitivity reaction to previous oral iron therapy. 
5. History of hemochromatosis or iron overload syndrome (e.g., 
hereditary sideroblastic anemia, thalassemia, polycythemia 
vera). 
6. Active malignancy requiring current treatment except for 
non-melanoma skin cancer regardless of treatment. 
7. Active drug or alcohol dependence or abuse (excluding 
tobacco use or use of medical or recreational marijuana) 
within the 12 months prior to Screening or evidence of such 
abuse, in the opinion of the Investigator. 
8. Limited life expectancy (<6 months) in the opinion of the 
Investigator. 
9. Females who are known to be pregnant or are breast-feeding 
during Screening or are planning to become pregnant and 
breastfeeding during the study period.    
10. Evidence of a clinically active infection requiring antibiotics 
at Randomization.  
11. Unable to comply with study requirements or in the opinion 
of the Investigator, not clinically stable to participate in the 
study. 
12. Use of an investigational medication or participation in an 
investigational study within 30 days prior to Day 1.  
13. Patients with a scheduled date for living donor kidney 
transplant  
 
Safety Monitoring 
All Serious Adverse Events (SAEs) will be collected. Adverse Events 
of Special Interest (AESI) (iron overload and hypophosphatemia) will 
also be collected.  


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 10 of 54 
  
Statistical considerations 
a. 
General analysis plan 
 
b. Rationale for number of 
subjects 
The primary endpoint is the time to a composite endpoint of initiation of 
maintenance dialysis or all-cause mortality.  The primary endpoint will be 
analyzed by Cox-proportional hazards regression model. Hazards ratios and 
corresponding 95% confidence intervals will be presented.  
 
The sample size for this study is driven by the primary endpoint, initiation of 
maintenance dialysis or all-cause mortality and is based on the observed data 
from the pilot study using nearly identical inclusion and exclusion criteria.  The 
observed rate of the primary composite endpoint in the pilot study (all-cause 
mortality, maintenance dialysis or kidney transplant) for patients in the standard 
of care arm was 0.94 events per person-year of follow up.   The observed 
hazard ratio was 0.42 (58% relative risk reduction, p=0.002) for the primary 
composite endpoint when comparing ferric citrate treated patients versus usual 
care.  
 
Assuming 1 year recruitment and 0.75 years of follow up (9 months) for each 
individual and a hazard ratio of 0.60 (40% relative risk reduction), a sample size 
of 400 patients (200 per arm) provides 90% power with a 2-sided alpha p 
<0.05.  Assuming a hazard ratio of 0.50 (50% relative risk reduction), a sample 
size of 225 patients provides 90% power with a 2-sided alpha p<0.05.  
 
 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 11 of 54 
  
1.2 
Schema 
Figure 1. Study Schema 
 
 
 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 12 of 54 
  
1.3 
Schedule of Activities 
Table 1. Schedule of Activities 
Study Period 
 
Treatment 
Periodb, c 
 
 
 
Follow-upd 
Study Month/ Day 
Screeninga 
Randomization 
D1/ 
Baseline 
Month 3 
(D90) 
Month 6 
(D180) 
Month 9 
(D270) EOT 
Month 10 
(EOS) 
(Day 300) 
Visit 
1 
 
2 
3 
4 
5 
6 
Visit Window (days) 
-45 
-8 
0 
±30 
±30 
±30 
±7 
Visit Type 
In-Person 
 
In-person  
 In-person 
or virtual 
In-person 
or virtual 
In-person 
virtual 
General and Clinical Assessments 
Informed Consent 
X 
 
 
 
 
 
 
Review inclusion/exclusion 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical Historyk 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Vital Signse 
X 
 
X 
 
X 
X 
 
Height and Weightf 
 
 
X 
 
X 
X 
 
Laboratory Assessments as Available per Standard of Care 
Pregnancy test g 
X 
 
 
 
 
Serum Chemistry  
Xa 
 
 
X 
X 
Xi 
 
CBC  
Xa 
 
 
X 
X 
Xi 
 
eGFR 
Xa 
 
 
X 
X 
Xi 
 
Other laboratory assessmentsh 
Xa 
 
 
X 
X 
Xi 
 
Serum Phosphorus 
Xa 
 
 
X 
X 
Xi 
 
Iron indices  
Xa 
 
 
X 
X 
Xi 
 
Safety Assessments 
Concomitant medication reviewj 
X 
 
X 
X 
X 
X 
 
PRBC transfusions and/or dialysis access 
procedures 
X 
===================================================================== 
Adverse Events of Special Interestn 
 
 
==================================================== 
SAE Assessmentl 
 
 
==================================================== 
Endpoint Assessmento 
 
 
 
X 
X 
X 
X 
Study intervention 
Study drug prescription/provide study drugm 
 
X 
Xp 
X 
X 
 
 
Study drug accountabilityq 
 
 
 
 
X 
X 
 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 13 of 54 
  
 
Study Period 
 
Treatment 
Periodb, c 
 
 
 
Follow-upd 
Study Month/ Day 
Screeninga 
Randomization 
D1/ 
Baseline 
Month 3 
(D90) 
Month 6 
(D180) 
Month 9 
(D270) EOT 
Month 10 
(EOS) 
(Day 300) 
Visit 
1 
 
2 
3 
4 
5 
6 
Visit Window (days) 
-45 
-8 
0 
±30 
±30 
±30 
±7 
Visit Type 
In-Person 
 
In-person  
 In-person 
or virtual 
In-person 
or virtual 
In-person 
virtual 
CBC: complete blood count; D: Day; eGFR: estimated glomerular filtration rate; EOT: end of treatment; ET: early termination; PRBC: packed red blood cell; PTH: parathyroid 
hormone; SAE: serious adverse event; SOC: standard of care; TSAT: transferrin saturation. 
A: Laboratory Assessments used for screening eligibility must be within 45 days prior to Day 1 with the exception of eGFR which must be within 90 days of Day 1. The 
screening visit may be conducted as part of a routine scheduled clinical encounter.   
B: 
Study visits are scheduled to occur every 90 days +/-30 days during the treatment period and are anticipated to be conducted as part of a routine scheduled clinical 
encounter.  
C: 
Virtual visits may be conducted via telephone or electronic format (i.e., zoom call) and will be documented in source documents.  
D: Subjects will conclude the study with a follow-up virtual visit 30 days after their last dose of study drug to assess for SAEs and vital status. 
E:  Vital signs will include systolic blood pressure, diastolic blood pressure, and resting heart rate. These may be captured using data from the subject’s clinical encounter. If 
SOC vital signs are collected prior to signing of informed consent at the screening visit, those vital signs may be captured and do not need to be repeated.   
F:  Both height and weight will be collected at the Day 1 visit.  Height may be self-reported. Weight only will be collected during the treatment period and may be captured 
using data from the clinical encounter.   
G: Serum or urine pregnancy test (women of childbearing potential) must be done at any point within 30 days of Day 1. Can be performed on Day 1 if prior to any Day 1 
procedures.  Results must be available prior to the 1st dose of study drug.  
H: Other laboratory assessments include urine chemistry, hepatic panel, magnesium, cystatin-C and PTH if available (section 9.4, Table 2).  
I.      The most recent laboratory assessments prior to EOT will be utilized  
J.      Routine concomitant medications will be assessed at each in-person visit (Screening, Day 1, Month 9). Concomitant medications of interest will be assessed at Screening   
at then at each subsequent study visit (see Section 9.5.1).  
K.     Targeted medical history (refer to section 9.2.1) 
L.     Collection begins at initiation of study drug treatment (1st dose of study drug) and continues through the follow-up visit. Refer to Section 9.5.2.   
M.    Prescription for study drug must be sent to USRC Rx Pharmacy for processing at time of randomization to ensure on-time delivery prior to Day 1.  Refill prescriptions or 
changes to prescription will be sent to the pharmacy as needed.  Dispensing will be a minimum of 3 months supply.   
N.     Collection begins at initiation of study drug treatment (1st dose of study drug) and continues through the follow-up visit. Refer to Section 9.5.2.   
O.     Endpoint assessment includes initiation of dialysis, vital status (alive or decreased), transplant, and hospitalization. Any subject who either receives a kidney transplant or 
initiates maintenance dialysis, and has not withdrawn consent from study participation, will have a vital status check performed at 30-days following the relevant event.  
P.     If there are delays related to shipment from the USRC Rx pharmacy, study drug will be provided to subjects within 12 days of the Day 1 visit. 
Q.    Study drug accountability is performed at in-person visits only. 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 14 of 54 
  
 
 LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition 
AE 
adverse event 
BL 
Baseline 
CKD 
chronic kidney disease 
CONSORT 
Consolidated Standards of Reporting Trials 
CRO 
contract research organization 
DD 
dialysis-dependent 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOT 
end of treatment 
ESA 
erythropoiesis-stimulating agent 
ET 
early termination 
FDA 
(United States) Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
HR 
hazard ratio 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDA 
iron deficiency anemia 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
Intravenous 
KDIGO 
Kidney Disease: Improving Global Outcomes 
KFRE 
Kidney Failure Risk Equation 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDD 
non-dialysis-dependent 
RBC 
Red Blood Cell 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 15 of 54 
  
Abbreviation or Term 
Definition 
PP 
per protocol 
QC 
quality control 
SAE 
serious adverse event 
SoA 
Schedule of Activities 
SOC 
standard of care 
TEAE 
treatment-emergent adverse event 
TSAT 
transferrin saturation 
US 
United States 
USRDS 
United States Renal Data System 
 
 
 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 16 of 54 
  
 INTRODUCTION 
This is a multicenter, randomized, double-blind, placebo-controlled clinical trial to determine the 
effect of ferric citrate on time to a composite endpoint of initiation of maintenance dialysis or all-
cause mortality compared to placebo in adult patients with advanced chronic kidney disease 
(CKD).  This study is funded by Akebia Therapeutics, Inc.  
3.1 
Study Rationale 
Ferric citrate is an iron-based phosphate binder and has been extensively studied for the 
treatment of hyperphosphatemia in subjects with dialysis-dependent chronic kidney disease 
(DD-CKD) and for the treatment of iron deficiency anemia (IDA) in subjects with non-
dialysis-dependent chronic kidney disease (NDD-CKD). Epidemiological evidence suggests that 
patients with CKD are at greater risk of adverse outcomes due to higher incidence of anemia in 
this population. The severity of anemia is directly related to the occurrence of cardiovascular 
events in this patient population. A pilot randomized trial of ferric citrate compared to standard 
of care in 200 subjects with advanced CKD showed that subjects treated with ferric citrate 
demonstrated significant changes in laboratory values associated with improvements in anemia 
and iron. Additionally, this pilot study demonstrated a clinically significant reduction in the risk 
of the composite endpoint of death, dialysis, or transplantation in patients randomized to ferric 
citrate. [Block 2019].   It has been recommended by a KDIGO Conference Report that there is a 
priority need to study the effects of iron repletion in those without overt anemia.  This study is 
being conducted in a population of patients chosen purposefully to reflect the broad 
characteristics of individuals with advanced CKD and is not restricted only to those with iron 
deficiency nor hyperphosphatemia.   
This study is being conducted to determine if ferric citrate will delay the progression of advanced 
CKD to kidney failure requiring maintenance dialysis or death, compared to placebo in adult 
patients with advanced CKD. 
3.2 
Background 
3.2.1 
Iron Deficiency Anemia 
CKD affects up to 14.9% of adults in the United States (US) [USRDS 2020] and markedly 
increases the risk of premature cardiovascular events [McCullough 2021, Foley 2005]. Anemia is 
a common complication of CKD, and is associated with mortality and cardiovascular events, 
even after accounting for CKD stage and other cardiovascular risk factors, including 
albuminuria, diabetes mellitus, smoking, and hypercholesterolemia [Kovesdy 2006]. 
International clinical practice guidelines for anemia in CKD by the Kidney Disease: Improving 
Global Outcomes (KDIGO) 2012 anemia work group recommend evaluation for and resolution 
of correctable causes of anemia in subjects with CKD and anemia [KDIGO 2012]. While the 
anemia of CKD is multifactorial in origin, 60% to 73% of persons with estimated glomerular 
filtration rate (eGFR) <60 mL/min/1.73 m2 are iron-deficient [Fishbane 2009]. Therefore, in 
persons with CKD and anemia (hemoglobin [Hb] <13 g/dL for men; <12 g/dL for women), the 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 17 of 54 
  
guidelines suggest a trial of iron to increase the Hb if transferrin saturation (TSAT) is ≤30% and 
serum ferritin is ≤500 ng/mL. 
The goals of iron therapy are to avoid iron storage depletion, to prevent impairment of 
erythropoiesis due to iron deficiency, and to help achieve and maintain target Hb levels. When 
prescribing iron therapy, the guidelines recommend to “balance the potential benefits of avoiding 
or minimizing blood transfusions, erythropoiesis-stimulating agent (ESA) therapy, and 
anemia-related symptoms against the risks of harm in individual subjects (e.g., anaphylactoid 
and other acute reactions, unknown long-term risks)” [Van Wyck 2000, KDIGO 2012]. 
For CKD patients on dialysis, iron is usually given intravenously, but oral iron is preferred in 
patients with NDD-CKD for its convenience and low cost. However, the tolerability and efficacy 
of currently available oral iron formulations is often limited by gastrointestinal (GI) side effects, 
poor adherence to therapy, and poor absorption [Drüeke 2012; Cancelo-Hidalgo 2013; 
Macdougall 2016]. IV iron use remains low in persons with NDD-CKD [Wetmore 2015]. 
Anaphylactoid and other acute reactions are infrequent but potentially life-threatening 
complications of IV iron treatment [Wang 2015]. These risks have resulted in black box 
warnings, or Warnings and Precautions. IV iron administration requires additional safety 
measures for administration, resulting in higher personnel costs and more time required for these 
therapies. The long-term safety of IV iron administration has also not been established, and there 
are concerns that patients may be exposed to increased oxidative stress and greater vulnerability 
to infections [Macdougall 2016]. Further, IV iron administration can be burdensome for patients, 
requiring visits to clinics or infusion centers. 
ESAs are another treatment modality for anemia of CKD that are widely used in DD-CKD 
patients but safety concerns due to excess cardiovascular risk for ESAs resulted in black box 
warnings in 2007.  
3.2.2 
Hyperphosphatemia 
In healthy individuals, phosphate is primarily eliminated by the kidneys, which effectively 
regulate phosphate balance and blood phosphate concentration. With decreasing kidney function, 
and other changes associated with CKD, there is a marked decrease in phosphorus excretion in 
the urine, leading to hyperphosphatemia. Hyperphosphatemia contributes to bone disease, 
vascular calcification, cardiovascular events, and mortality [Martin and Gonzalez 2011]. 
Restriction of dietary phosphate is usually not sufficient to control hyperphosphatemia in patients 
with DD-CKD; therefore, these patients are treated with orally administered phosphate binders 
which effectively bind dietary phosphate and facilitate fecal elimination rather than intestinal 
absorption. However, different phosphate binders differ in their safety profile, and all pose a high 
pill burden [Salusky 2006]. Specific safety or cost concerns with existing phosphate binders 
resulted in a persistent high level of unmet need for patients with hyperphosphatemia, which 
resulted in the development of ferric citrate as a phosphate binder in patients with DD-CKD.  
Ferric citrate reduces intestinal phosphate absorption by precipitating phosphate in the intestine. 
The ferric iron from ferric citrate reacts with the phosphorus in the GI tract and precipitates as 
ferric phosphate or ferrous phosphate. The latter are insoluble and are excreted in the stool. 
Citrate is absorbed, potentially alleviating the metabolic acidosis that occurs in patients with 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 18 of 54 
  
renal failure. Ferric citrate is approved for the control of serum phosphorus levels in adult 
patients with CKD on dialysis. 
3.3 
Risk/Benefit Assessment 
3.3.1 
Known Potential Risks 
A thorough summary of the risks of ferric citrate is provided in the Investigator Brochure. 
(Edition 14, 10 March 2020).  The main source of information on the safety of ferric citrate in 
humans comes from two main datasets. One dataset, the risks Pooled Safety Set – 
Hyperphosphatemia, is based on the integrated data from four completed studies (Studies 304, 
305, PBB00101, and 201). These studies involved subjects with DD-CKD treated for 
hyperphosphatemia with ferric citrate for up to 1 year at dosages of up to 12 g/day. In these four 
studies, a total of 557 subjects received ferric citrate, 149 subjects received active control and 
111 subjects received placebo. 
The second dataset, the Pooled Safety Set – IDA, is based on the integrated data from 3 studies 
(Studies 306, 204, and 207). These studies involved 405 unique subjects (excluding 9 subjects 
treated in Study 204 and Study 306) with NDD-CKD IDA. In these 3 studies, 301 received ferric 
citrate (including 81 subjects treated with placebo in the Randomized Period and ferric citrate in 
the Extension Period of Study 306 and excluding 2 subjects treated with ferric citrate in Study 
204 and Study 306) and 188 received placebo (excluding 1 subject treated with placebo in Study 
204 and Study 306). 
In the hyperphosphatemia pooled safety set, the incidence of subjects who experienced at least 
one treatment-emergent adverse event (TEAE) was lower in the all ferric citrate group (77.5%) 
compared with subjects on active control (89.3%). The most common TEAEs in subjects 
receiving ferric citrate were diarrhea (20.8%), discolored feces (19.4%), and nausea (11.1%). 
The most common TEAEs in subjects receiving active control were vomiting (14.8%), nausea 
(14.1%), diarrhea (14.1%), dyspnea (13.4%), vascular access complication (11.4%), hypotension 
(10.7%), and cough (10.1%).   
In the IDA pooled safety set in the randomized periods, the incidence of subjects who 
experienced at least 1 TEAE was higher among subjects who received ferric citrate (75.3%) than 
among subjects who received placebo (61.7%).  The most common TEAEs in subjects receiving 
ferric citrate were discolored feces (21.6%), diarrhea (20.5%), constipation (18.4%), nausea 
(9.5%), hyperkalemia (5.3%), and abdominal pain (4.7%). The most common TEAEs in subjects 
receiving placebo were diarrhea (12.2%), constipation (10.1%), and nausea (4.3%).   
Iron accumulation is a potential risk of long-term treatment with ferric citrate or other 
iron-containing medicinal products. Continued excessive iron uptake can lead to iron deposition 
in body tissues and ultimately to organ damage. To prevent excessive iron accumulation, 
laboratory iron measures will be monitored regularly, and the ferric citrate, oral or IV iron dose 
will be adjusted in response to sustained elevations of TSAT.  


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 19 of 54 
  
3.3.2 
Known Potential Benefits 
The ability of ferric citrate to lower serum phosphorus in adult patients with CKD on dialysis 
was demonstrated in Study KRX-0502-304. In that pivotal study, the efficacy of ferric citrate for 
controlling serum phosphorus levels was similar to that of calcium acetate and/or sevelamer 
carbonate, and better than that of placebo. 
Study KRX-0502-204 was a 12-week, double-blind, placebo-controlled study. 
Study KRX-0502-306 was a 24-week study consisting of a 16-week, randomized, double-blind, 
placebo-controlled, efficacy period followed by an 8-week, open-label, safety extension period in 
which all subjects remaining in the study, including those in the placebo group, received ferric 
citrate. Both studies showed reduction in serum phosphorus levels with ferric citrate treatment 
compared with placebo. In addition, the efficacy of ferric citrate for the treatment of IDA was 
demonstrated in 2 controlled studies in adult subjects with CKD not on dialysis. 
Ferric citrate’s potential benefits are supported by its approval for use in the US for the control of 
serum phosphorus levels in adult patients with CKD on dialysis, and for the treatment of IDA in 
adult patients with CKD not on dialysis.   
3.3.3 
Overall Benefit: Risk Conclusion 
No significant change in the safety profile of ferric citrate has been identified in post-marketing 
surveillance. A recent study demonstrated that treatment with ferric citrate significantly improves 
anemia in subjects with advanced CKD without the routine use of supplemental iron or ESAs. 
The results of the study suggest that treatment with ferric citrate can improve clinical outcomes 
for these subjects, is safe, and potentially beneficial [Block 2019]. The risk-benefit profile of 
ferric citrate in the treatment of adult patients with CKD remains favorable in the commercial 
setting. 
 
OBJECTIVES AND ENDPOINTS 
4.1 
Study Objectives 
4.1.1 
Primary Objective 
To determine the effect of ferric citrate on the time to a composite endpoint of initiation of 
maintenance dialysis or all-cause mortality compared to placebo in adult patients with advanced 
CKD. 
4.1.2 
Secondary Objective 
To evaluate the impact of ferric citrate on time to all-cause hospitalization and individual 
components of the primary endpoint. 
 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 20 of 54 
  
4.2 
Study Endpoints 
4.2.1 
Primary Endpoint 
Time to a composite endpoint of initiation of maintenance dialysis or all-cause mortality  
4.2.2 
Secondary Endpoints  
Secondary endpoints include: 
1. Time to first hospitalization event reported as a serious adverse event (SAE) 
(excluding disease-related hospitalization [e.g., dialysis access placement, dialysis 
initiation, kidney transplant] and elective procedures) 
2. Component of Primary – Time to Initiation of Maintenance Dialysis 
3. Component of Primary – Time to All-Cause Mortality 
4.2.3 
Exploratory Endpoints  
Exploratory endpoints include: 
1. Annualized hospital days prior to initiating maintenance dialysis  
2. Receipt of kidney transplant prior to initiating maintenance dialysis  
3. Cumulative utilization of rescue therapy for anemia including (individually, [ESA, 
intravenous iron, RBC transfusion]) prior to initiating maintenance dialysis  
4. Time to a composite of death, dialysis, or kidney transplant  
 STUDY DESIGN 
5.1 
Overall Design 
This is an investigator-initiated multicenter, randomized, double-blind, placebo-controlled, 
pragmatic clinical trial in patients with advanced CKD to determine the effect of ferric citrate 
versus matching placebo on the time to a composite endpoint of maintenance dialysis or all-
cause mortality.  
Subjects who meet all inclusion and none of the exclusion criteria will be randomized in a 1:1 
ratio (stratified by site and eGFR) to receive either ferric citrate or matching placebo. All 
subjects will receive a fixed dose of 2 tablets orally taken with meals or snacks up to 3 times per 
day.  The maximum daily dose is 6 tablets/day. Subjects will remain on study drug for up to 9 
months followed by an additional 30-day safety follow-up period. Study drug will be stopped for 
subjects who initiate maintenance dialysis or receive a kidney transplant. Subjects who undergo 
maintenance dialysis or receive a kidney transplant will be removed from study with no follow-
up visit, however, these subjects will have a vital status check (to ascertain mortality) performed 
at 30-days following the relevant event. 
 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 21 of 54 
  
The study periods are: 
• Screening Period: Up to 45 days prior to Day 1. Standard of Care (SOC) laboratory 
collection permitted up to 45 days (up to 90 days for eGFR) prior to Day 1.  
• Treatment Period: Up to 9 months  
• Safety follow-up Period: 30 days after EOT 
 
Each randomized subject will complete 5 study visits (2 in-person and 3 phone/virtual or in-
person). In-person study visits should attempt to coincide with routine standard of care office 
visits and relevant clinical data from such standard of care visits (including assessments for 
possible endpoint events or adverse events) will be collected and entered into the electronic case 
report form (eCRF). Standard of care (SOC) laboratory assessments as ordered by the primary 
nephrologist will be utilized. Iron status and serum phosphate collection and monitoring will be 
required as part of the SOC laboratory assessments.   Laboratory assessments captured in the 
eCRF other than a screening pregnancy test for women of child-bearing potential and non-SOC 
iron and serum phosphorus labs, will utilize local laboratory results.   
 
Study drug is not intended to be used as a treatment for either serum phosphorus or iron 
repletion.  Management of serum phosphorus and iron sufficiency will be directed at the 
discretion of the treating physician and/or Investigator independent of study drug with the 
exception of protocol required safety adjustments of study drug.  The prescribed dose of study 
drug will be adjusted only in the event of a safety or tolerability concern (as described in Section 
7.1.2.1). Investigators will be instructed not to prescribe commercial ferric citrate (Auryxia) to 
any study participant; however, all other phosphate lowering therapy or iron repletion therapy 
may be prescribed at the discretion of the PI according to local standard of care.  
Subjects may or may not be prescribed phosphate-lowering or iron-repletion therapy prior to Day 
1; however, if a subject is receiving commercial ferric citrate (Auryxia), it must be stopped at or 
prior to Day 1.  
5.1.1 
Replacement of Participants  
Subjects who sign the informed consent form (ICF) and are randomized but do not receive the 
study intervention may be replaced at the discretion of the Investigator or Investigator-Sponsor. 
Subjects who sign the ICF and are randomized, receive any dose of the study intervention, and 
then subsequently withdraw, or are withdrawn or discontinued from the study, will not be 
replaced. 
5.2 
Scientific Rationale for Study Design 
A pilot randomized trial of ferric citrate in patients with advanced CKD demonstrated that, as 
compared to standard of care therapy, patients randomized to ferric citrate showed a significant 
reduction in progression to maintenance dialysis (p=0.001) as well as a significantly lower 
incidence of the composite endpoint of death, dialysis, or transplant (p=0.002).  In addition, 
compared with usual care, ferric citrate treated subjects had significantly fewer annualized 
hospitalization admissions and fewer days in the hospital.  [Block, 2019, Figure 4].  
 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 22 of 54 
  
 
 
5.3 
Justification for Dose 
The prescribed dose of study drug will be a fixed dose of 2 tablets orally taken with meals or 
snacks up to 3 times per day.  The maximum daily dose is 6 tablets/day.  This is the dose of 
ferric citrate that was utilized in the pilot randomized trial demonstrating clinical benefit on time 
to dialysis as described in Section 5.2, and has an established safety profile as it is the approved 
starting dose for the treatment of iron-deficiency anemia in patients with chronic kidney disease 
[Auryxia USPI 2021]. 
5.4 
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Schedule of 
Activities (SoA) (Section 1.3). 
The end of the study will be considered complete after all randomized subjects have completed 
their final study visit (Month 9 or EOT) and 30-day safety follow-up visit. 
Any subject who either receives a kidney transplant or initiates maintenance dialysis, and has not 
withdrawn consent from study participation, will have a vital status check performed at 30-days 
following the relevant event. The vital status check will ascertain the subject’s mortality (alive 
vs. deceased). 
5.5 
Number of Study Sites 
Up to 25 investigative sites in the US.  
 STUDY POPULATION 
6.1 
Inclusion Criteria 
1. Adult patients ≥18 years old. 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 23 of 54 
  
2. Diagnosis of NDD advanced CKD, regardless of etiology.  Advanced CKD is defined as 
at least one local laboratory determined estimated glomerular filtration rate (eGFR) ≤20 
ml/min/1.73m2 (calculated per any commonly used method or equation for estimating 
eGFR) within 90 days of Day 1. 
3. Most recent transferrin saturation (TSAT) ≤45% within 45 days of Day 1.  
4. Most recent serum phosphate is ≥3.0 mg/dL within 45 days of Day 1. 
5. Most recent ferritin ≤500 ng/mL within 45 days of Day 1.  
6. Women of child-bearing potential must have a negative serum or urine pregnancy test 
within 30 days prior to Day 1 procedures. Can be performed on Day 1 if prior to any Day 
1 procedures.  Results must be available prior to the 1st dose of study drug.  
7. Understands the procedures and requirements of the study and provides written informed 
consent and authorization for protected health information disclosure. 
 
6.2 
Exclusion Criteria 
1. Patients who, in the opinion of the Investigator, have acute kidney injury rather than 
CKD. 
2. Patients with planned/imminent maintenance dialysis, or that are anticipated to begin 
maintenance dialysis within 8 weeks from Screening, in the opinion of the Investigator.   
3. A known allergy or intolerance to ferric citrate or any of its constituents. 
4. Hypersensitivity reaction to previous oral iron therapy. 
5. History of hemochromatosis or iron overload syndrome (e.g., hereditary sideroblastic 
anemia, thalassemia, polycythemia vera). 
6. Active malignancy requiring current treatment except for non-melanoma skin cancer 
regardless of treatment. 
7. Active drug or alcohol dependence or abuse (excluding tobacco use or use of medical or 
recreational marijuana) within the 12 months prior to Screening or evidence of such 
abuse, in the opinion of the Investigator. 
8. Limited life expectancy (<6 months) in the opinion of the Investigator. 
9. Females who are known to be pregnant or are breast-feeding during Screening or are 
planning to become pregnant and breastfeeding during the study period.    
10. Evidence of a clinically active infection requiring antibiotics at Randomization.  
11. Unable to comply with study requirements or in the opinion of the Investigator, not 
clinically stable to participate in the study. 
12. Use of an investigational medication or participation in an investigational study within 30 
days prior to Day 1.  
13. Patients with a scheduled date for receipt of living donor kidney transplant. 
 
6.3 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 24 of 54 
  
requirements.  Minimal information includes informed consent, demography, eligibility criteria 
and screen failure details, including screening laboratory results. 
Subjects who fail to qualify for the study may be considered for rescreening at the discretion of 
the Investigator, if it is considered that the subject’s status has changed, and the subject may now 
qualify for the study. A new informed consent is required to be signed prior to every rescreening. 
Rescreened subjects will be assigned a new screening number.  
Any subject who is randomized to study intervention but does not receive study drug will be 
considered an early termination.  
 
STUDY INTERVENTION 
7.1 
Study Intervention(s) Administration  
7.1.1 
Study Intervention Description 
Ferric citrate will be supplied as tablets for oral administration containing 1 g ferric citrate 
(210 mg of ferric iron).    
Placebo will be supplied as tablets, matching in color and size to ferric citrate. 
Subjects should take the assigned study drug orally with meals or snacks or within 1 hour before 
or after their meals or snacks.   
Missed doses should not be taken if greater than 1 hour from meals.  
7.1.2 
Dosing and Administration 
Study drug is not intended to be used as a treatment for either serum phosphorus or iron 
repletion.  Management of serum phosphorus and iron sufficiency will be directed at the 
discretion of the treating physician and/or Investigator independent of study drug with the only 
restriction being that subjects cannot be prescribed commercial Auryxia (ferric citrate).   
Subjects will be randomized in a 1:1 ratio to receive either ferric citrate or placebo. All subjects 
will be instructed to take study drug at a fixed dose of 2 tablets per meal or snacks, up to three 
times per day. The maximum dose is 6 tablets/day.  No additional tablets (beyond a total of 
6/day) should be taken. Tablets should not be crushed or chewed. 
Every effort will be made to provide study drug to subjects at the Day 1 visit.  If there are delays 
related to shipment from the USRC Rx pharmacy, study drug will be provided to subjects within 
12 days of the Day 1 visit.  Dosing will begin upon receipt of study drug with the next 
meal/snack.  This would not be considered a protocol deviation.  
7.1.2.1 
Dose Adjustment 
No titration of study drug will be performed other than for issues of tolerability or safety. 
It is expected that the Investigator will monitor serum phosphorus and iron indices per generally 
recognized standard of care for individuals with advanced CKD.  The monitoring of iron indices 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 25 of 54 
  
and serum phosphate is required at least every 3 months and failure to monitor these parameters 
will be considered a protocol deviation. 
Required dose adjustments for low serum phosphorus are as follows: 
• If serum phosphorus is <3.0 mg/dL captured by a single value, the study drug, and any 
other prescribed phosphate lowering therapy, should be temporarily held until such time 
as serum phosphorus is ≥3.0 mg/dL at which time study drug may be resumed at a dose 
that is approximately equivalent to 50% of the previous total daily dose.  The reduction in 
dose relative to meals or snacks is at the discretion of the investigator as long as it 
represents a total dose reduction of 50%. Repeat assessment of serum phosphorus will be 
at the discretion of the Investigator. This assessment must occur at the next scheduled 
visit (which may be up to three months), or it may also be performed earlier. Other 
prescribed phosphate lowering therapy may be resumed per investigator discretion when 
serum phosphorus is ≥3.0 mg/dL. 
Required dose adjustments for high TSAT are as follows: 
• If TSAT is >45% and ≤50%, captured by a single laboratory value, the study drug should 
be reduced by 1 tablet per meal or snack (reduce the dose by the equivalent of 50%). Any 
other prescribed oral or IV iron therapy should be stopped.  
 
If TSAT is >50%, captured by a single laboratory value, the study drug, and any other 
prescribed oral or IV iron therapy, should be temporarily held until such time as TSAT is 
≤50% (captured by a single laboratory value) at which time study drug may be resumed 
at a dose that is equivalent to 50% of the previous total daily dose.  The reduction in dose 
relative to meals or snacks is at the discretion of the investigator as long as it represents a 
total dose reduction of 50%.  Repeat assessment of iron indices will be at the discretion 
of the Investigator. This assessment must occur at the next scheduled visit (which may be 
up to three months), or it may also be performed earlier.  
 
If after a 50% reduction in total daily dose of study drug, the TSAT is >50%, the study 
drug should be temporarily held. Subsequent study visits including the Follow Up visit 
(Visit 6) should continue to be conducted as per the SoA (regardless of study drug 
administration). When TSAT is ≤50%, study drug may be resumed. Other prescribed oral 
or IV iron therapy may be resumed per investigator discretion when TSAT is ≤45%.  
 
Required dose adjustments for high ferritin are as follows: 
• If serum ferritin is >500 ng/mL, captured by a single laboratory value, the study drug, and 
any other prescribed oral or IV iron therapy, should be temporarily held until such time as 
ferritin is ≤500 ng/mL (captured by a single laboratory value) at which time study drug 
may be resumed at a dose that is equivalent to 50% of the current total daily dose.  The 
reduction in dose relative to meals or snacks is at the discretion of the investigator as long 
as it represents a total dose reduction of 50%. Repeat assessment of iron indices will be at 
the discretion of the Investigator. This assessment must occur at the next scheduled visit 
(which may be up to three months), or it may also be performed earlier.  


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 26 of 54 
  
 
• If after a 50% reduction in total daily dose of study drug, the serum ferritin is >500 
ng/mL, the study drug should be temporarily held.  Subsequent study visits including the 
Follow Up visit (Visit 6) should continue to occur per the SoA (regardless of study drug 
administration). When serum ferritin is ≤500 ng/mL, study drug may be resumed. Other 
prescribed oral or IV iron therapy may be resumed per investigator discretion when 
ferritin is ≤500 ng/mL.    
Both TSAT and ferritin laboratory values must be within ranges defined above prior to 
resumption of study drug.   
Study drug may be titrated downward at any time during the treatment period at the discretion of 
the Investigator for adverse reactions determined to be related to study drug. 
There is no minimum allowable dose of study drug, and the Investigator has discretion to 
resume dosing up to 6 tablets/day based on subject acceptance when possible (and when 
TSAT, ferritin, and phosphorus values are within protocol-defined ranges).    
All dose adjustments should be captured in the subject specific source documentation and the 
eCRF.  
7.2 
Preparation/Handling/Storage/Accountability 
7.2.1 
Acquisition and Accountability 
Akebia Therapeutics will supply study drug to a centralized pharmacy known as USRC Clinical 
Pharmacy, LLC (USRC Rx), under temperature-controlled conditions. The central pharmacy will 
maintain the study level accountability and distribution records and will store the study drug 
under controlled temperature conditions.  Investigator-Sponsor or its official designee will 
supply study drug from USRC Rx to the clinical sites. Please refer to the pharmacy manual for 
further information.  
The Investigator or site designee will be responsible for maintaining accurate study drug patient 
level accountability, storage, destruction and/or return records for study drug that is received 
from the central pharmacy. All study drug that is received from the central pharmacy must be 
kept under controlled temperature in a secure, locked location in which access is limited until 
dispensed to the individual subject.   
All unused and/or partially used study drug will be returned by the study subject for destruction 
at the investigational site in accordance with its policies and procedures. Records of disposal will 
be documented and maintained. No unused study drug may be disposed of until fully accounted 
for by the Investigator-Sponsor or designee. Empty containers may be disposed of in accordance 
with local procedures after fully accounted for by Investigator-Sponsor or designee. 
The use of study drug for any reason other than as directed by the protocol is not permitted.   
Refer to Section 7.4 for additional details on assessment of treatment compliance.  


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 27 of 54 
  
7.2.2 
Formulation, Appearance, Packaging and Labeling 
Blinded study drug, (ferric citrate 1g tablets or matching placebo) will be supplied to USRC Rx 
in high-density polyethylene bottles. Each bottle will contain 200 tablets.  
The unassigned study drug supply will be stored at the USRC Rx in its original packaging. Upon 
subject randomization and notification to USRC Rx, study drug may be dispensed to meet a 3-9 
month supply need (per site discretion) and re-supplied as required in advance of in-person or 
telephone study visits.   
Labeling from the manufacturer will be in accordance with current GMP requirements.  The 
USRC Rx will generate an additional label specific to this research protocol which will not 
obscure the manufacturers label.   
7.2.3 
Product Storage and Stability 
Please consult the Pharmacy Manual for details on storage and temperature monitoring 
procedures and managing temperature excursions.   
7.3 
Measures to Minimize Bias: Randomization and Blinding 
7.3.1 
Randomization 
Eligible subjects will be stratified by site and by eGFR (above or equal to/below 15 
ml/min/1.73m2) randomized in a 1:1 ratio to receive either ferric citrate or matching placebo. 
eGFR can be calculated using any commonly used method or equation for estimating eGFR.  
7.3.2 
Blinding 
This is a randomized, double-blind, placebo-controlled study.  Treatment assignment will be 
done through a validated electronic system. The Investigator-Sponsor, Investigator, and study 
teams will not be aware of which treatment will be assigned next.  
In case of an emergency, the Investigator has responsibility for determining if unblinding of a 
subject’s treatment assignment is warranted. The Investigator must consult with the Medical 
Monitor prior to unblinding of a subject’s treatment assignment. Subject safety must always be 
the first consideration in making such a determination. All unblinding requests should be 
generated within the EDC system. If it is not possible to access the EDC system, the study-
specific unblinding request form can be used.  If a subject’s treatment assignment is unblinded, 
the Investigator-Sponsor must be notified within 24 hours after breaking the blind. Emergency 
unblinding procedure details will be provided in the Pharmacy manual. The date and reason that 
the blind was broken must be recorded in the source documentation and eCRF, as applicable.  
Unblinding a subject’s treatment assignment by the Investigator or study site personnel under 
any other circumstances (except as noted above) will be considered a protocol deviation.  
If a subject’s treatment assignment is unblinded, they will be considered an early termination. 
The subject will permanently discontinue study drug. The subject will be followed as per 
instructions in Section 8.1.2.  


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 28 of 54 
  
7.4 
Study Intervention Compliance 
Study personnel will instruct the subjects and caregivers on the correct number of tablets to take 
each day with their meals or snacks. Subjects will be instructed to return with their bottle(s) of 
study drug at each in-person visit so that compliance may be assessed. Unused study drug will be 
re-dispensed to the subject at the end of each in-person visit.  
Throughout the study, subjects will be questioned regarding dosing compliance and whether they 
have questions or have experienced any problems related to the dosing of study drug. The 
Investigator or designee will also maintain study drug accountability itemizing all study drug 
dispensed to and returned from each subject during the study. Treatment compliance will be 
determined from these logs and subject questioning.  
Subjects who miss doses will be counseled on the importance of compliance. Subjects will not be 
withdrawn from the study for reasons related to study drug compliance. 
7.5 
Concomitant Therapy 
7.5.1 
Phosphate Lowering Therapy 
Investigators may continue or newly prescribe non-Auryxia phosphate lowering therapy as 
needed throughout the study to maintain serum phosphorus according to the local community 
standard.  
Commercial Auryxia may not be prescribed to any subject for the duration of the study.  See 
Section 7.5.4 
In the event of an adverse event of special interest (serum phosphorus <2.5 mg/dL), the 
Investigator must review other prescribed phosphate-lowering therapies and make adjustments 
accordingly. Additionally, in the event of a serum phosphorus <3.0 mg/dL, other prescribed 
phosphate lowering therapy may also require adjustment as per Section 7.1.2.1. 
All changes in phosphate-lowering therapy will be captured in source documentation and in the 
eCRF. 
7.5.2 
Iron Supplementation  
Investigators may continue or newly prescribe iron supplementation (IV, oral) as needed 
throughout the study to maintain ferritin and TSAT according to the local community standard 
with the exception of protocol required safety changes in study drug as outlined in Section 
7.1.2.1.  
In the event of an adverse event of special interest (iron overload), the Investigator must review 
other prescribed iron supplementation (IV and oral) and make adjustments accordingly. 
Additionally, in the event of elevated iron indices (TSAT >45% or ferritin >500 ng/mL), other 
prescribed oral or IV iron therapy may also require adjustment as per Section 7.1.2.1.  
All changes in iron supplementation therapy will be captured in source documentation and in the 
eCRF. 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 29 of 54 
  
7.5.3 
Erythropoiesis-Stimulating Agents (ESAs) or Packed Red Blood Cell (PRBC) 
Transfusion 
There are no restrictions on the use of ESA and dose adjustments may be made at the discretion 
of the Investigator. All changes in ESA therapy will be captured in source documentation and in 
the eCRF 
Receipt of RBC transfusions will be captured in source documentation and in the eCRF.  
• Subjects who receive repeated red blood cell transfusions during the study may need to 
temporarily hold study drug. For the purpose of the study, “repeated blood transfusion” 
will be defined as receipt of >4 units of red blood cells within any 6-month period of 
time. Prior to study drug hold please contact the medical monitor. If study drug is 
permanently discontinued, subsequent study visits including the Follow Up visit (Visit 6) 
should occur per the SoA.  
7.5.4 
Prohibited Medications/Procedures 
Potentially eligible subjects may or may not be receiving phosphate-lowering or iron-repletion 
therapy prior to Day 1; however, if a subject is receiving commercial ferric citrate (Auryxia), it 
must be stopped at or prior to Day 1.  
Prescription of commercial Auryxia is prohibited for all subjects at any time after Day 1/Baseline 
in the study.  All other therapies may be administered per SOC.  Receipt of commercial Auryxia 
for longer than 4 consecutive weeks during trial participation will be considered a protocol 
deviation.  If the Investigator is unwilling to discontinue commercial Auryxia, study drug should 
be discontinued, and the subject should continue to be followed per the SoA including the 
Follow Up Visit (Visit 6).  
Since ferric citrate will be administered to 50% of subjects, standard drug-drug interactions 
reported in the Auryxia package insert approved by the Food and Drug Administration (FDA) in 
the US shall be followed. [Auryxia USPI 2021]. 
7.5.5 
Permitted therapy 
There are no restrictions on use of any concomitant medications other than that identified in 
Section 7.5.4 
7.5.6 
Potential Drug-Drug Interactions 
An interaction with ferric citrate is known to occur with doxycycline and ciprofloxacin. If 
prescribed, doxycycline should be taken at least 1 hour before study drug and ciprofloxacin 
should be taken at least 2 hours before or after study drug. 
The following drugs, by drug category, did not show an interaction with ferric citrate:   
• Antibiotics: levofloxacin.   
• Anticoagulants/antiplatelets: aspirin, clopidogrel, and warfarin.   
• Antidiabetics: glimepiride and sitagliptin.   


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 30 of 54 
  
• Antihyperlipidemics: atorvastatin, fluvastatin, and pravastatin.   
• Antihypertensives: amlodipine, diltiazem, enalapril, losartan, metoprolol, and 
propranolol.   
• Cardiac glycoside: digoxin.   
• Vitamin D analogs: calcitriol and doxercalciferol.   
Consider separation of the timing of the administration of study drug with drugs where a 
reduction in their bioavailability would have a clinically significant effect on safety or efficacy. 
The duration of separation depends upon the absorption characteristics of the medication 
concomitantly administered, such as the time to reach peak systemic levels and whether the drug 
is an immediate release or an extended-release product. Consider monitoring clinical responses 
or blood levels of concomitant medications that have a narrow therapeutic range. 
 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL  
8.1 
Discontinuation of Study Drug 
8.1.1 
Temporary Interruption of Study Drug 
Discontinuation from study drug is different from discontinuation from the study, and remaining 
study procedures will be completed as indicated by the study protocol. The Investigator is 
strongly encouraged to resume study drug as soon as the reason for temporary interruption is 
over.  Reasons for temporary discontinuation of study drug include: 
• Drug-related AEs per the Investigator’s discretion 
• Unforeseen circumstances per the Investigator’s discretion 
• Serum phosphorus <3.0 mg/dL 
• TSAT is >50%  
• Ferritin >500 ng/mL  
• Repeated red blood cell transfusions (>4 units of red blood cells within any 6-month 
period of time). See Section 7.5.3. 
• Significant elevation in liver enzymes (SGOT and/or SGPT) >3X ULN or pancreatic 
enzymes (amylase and/or lipase) >2X ULN or elevation in total bilirubin >2X ULN, 
without an identifiable alternate etiology. Study drug should not be resumed prior to 
discussion with Medical Monitor.   
 
The study drug may be restarted when the reason for temporary discontinuation is resolved. If 
study drug is temporarily discontinued due to elevations in iron indices, both TSAT and ferritin 
laboratory values must be within protocol-defined ranges prior to resumption of study drug.   
The data to be collected at the time of study drug discontinuation should be in accordance with 
the SoA. 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 31 of 54 
  
8.1.2 
Permanent Discontinuation of Study Drug  
Subjects are free to withdraw from taking study drug at any time upon request.  Subjects who 
permanently discontinue study drug will be asked to continue study participation (either by in 
person visits or by allowing access to medical records) in accordance with the SoA, through 
completion of the study. The endpoint assessment will be considered the End of Study date. 
 
If a subject declines to continue study visits and withdraws consent to be followed, the subject is 
an early termination, and NO endpoint assessment will be performed. The subject’s early 
termination date will be considered the End of Study date. 
 
An Investigator may discontinue study drug or withdraw a subject from the study for the 
following reasons: 
• Pregnancy 
• Significant study intervention non-compliance  
• If any clinically significant AE, laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the subject 
• Iron overload supported by liver biopsy, magnetic resonance imaging and persistent 
elevations in TSAT or ferritin 
• If the TSAT remains >50%; Refer to Section 7.1.2.1   
• If the ferritin remains >500 ng/mL; Refer to Section 7.1.2.1   
• If the serum phosphorus remains <3.0 mg/dL; Refer to Section 7.1.2.1 
• Investigator-Sponsor decision 
• Lost to follow-up 
 
The reason for study drug discontinuation will be recorded in source documentation and in the 
eCRF.  
8.2 
Withdrawal from Study 
Subjects are free to withdraw from participation in the study at any time upon request. Reasons 
for withdrawal from the study includes: 
• Withdrawal of consent from study participant. 
• Subjects who initiate maintenance dialysis. 
• Subjects who receive a kidney transplant.  
Subjects who initiate maintenance dialysis or who receive a kidney transplant, but have not 
withdrawn consent from study participation, will have a vital status check performed at 30-days 
following the relevant event. Vital status (alive vs. deceased) will be ascertained using available 
methods (e.g., phone call, in-person interaction, medical record, dialysis facility records, public 
records). 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 32 of 54 
  
Subjects who withdraw their consent will discontinue study drug and be considered an early 
termination. The reason for subject discontinuation or withdrawal from the study will be 
recorded in source documentation and in the eCRF. The early termination date will be 
considered the End of Study date.  
8.3 
Lost to Follow-Up 
A subject will be considered lost to follow-up if he or she fails to return for 2 consecutive 
scheduled in-person or phone visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a subject fails to be available for a required study visit: 
• The site will attempt to contact the subject 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 (a minimum of 3 documented telephone calls, or 
e-mails or certified letter to subject’s listed address). These contact attempts should be 
documented in the subject’s medical record or source documentation.  
• 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. 
• Available methods (e.g., phone call, in-person interaction, medical records, dialysis 
facility records, public records) will be used to attempt to ascertain dialysis status, 
transplant status, and vital status for all subjects deemed lost to follow-up. This ensures 
that the data set(s) produced as an outcome of the study is/are as comprehensive as 
possible. 
 
STUDY ASSESSMENTS AND PROCEDURES 
9.1 
General Study Periods 
9.1.1 
Screening, Enrollment, and/or Randomization 
Written informed consent must be obtained prior to the subject entering the study and before 
protocol-directed procedures are performed. Study visits are intended to coincide with the 
standard of care (SOC) nephrology visit. Initial informed consent discussion, in most cases, will 
occur at a SOC visit.  
• The Screening period will be a maximum of 45 days in duration.  It is defined as the 
period of 45 days prior to Day 1 (Baseline). Local laboratory assessments used for 
eligibility must be within 45 days prior to Day 1, with the exception of eGFR which must 
be within 90 days of Day 1 
 
If found eligible (and informed consent has been obtained), the subject will be randomized.  
Dosing will begin on Day 1. 
 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 33 of 54 
  
The Screening laboratory values will be defined as the most recent local laboratory assessments 
obtained prior to Day 1 (within 45 days) with the exception of eGFR which must be within 90 
days of Day 1. 
 
9.1.2 
Treatment Period 
The treatment period of this study includes the following visits: 
• Baseline/Day 1 Visit  
• Treatment Period: 270 days (9 months) 
 
Each randomized subject will complete 5 study visits during the Treatment Period (2 in-person 
and 3 telephone/virtual or in-person). Study visits during the treatment period are intended to be 
conducted as part of routine scheduled clinical encounters. 
 
Every attempt should be made to complete all study visits within the window as outlined in the 
SoA. If a visit is missed, the reason for the missed visit should be documented in the source 
chart.   
 
The monitoring of iron indices and serum phosphate is required at least every 3 months and 
failure to monitor these parameters will be considered a protocol deviation. 
9.1.3 
End of Treatment Visit  
Subjects completing study treatment will undergo a final in-person visit at Month 9 according to 
the SoA (Section 1.3).  
9.1.4 
Month 10/End of Study (EOS)  
There is a 30-day safety follow-up visit after the Month 9 visit which will be performed via a 
telephone call/virtual visit.  
Any subject who either receives a kidney transplant or initiates maintenance dialysis, and has not 
withdrawn consent from study participation, will have a vital status check (alive or deceased) 
performed at 30-days following the relevant event.  
9.2 
Clinical Assessments 
The following clinical assessments will be conducted during the study, according to the SoA 
(Section 1.3). 
9.2.1 
Medical History and Demographics  
• Medical History and Demographics: Targeted medical history and demographic 
information will be collected. Targeted medical history will include an assessment of 
relevant medical history with particular emphasis on medical conditions that may lead to 
exclusion. Significant ongoing medical conditions or diseases should be documented.  


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 34 of 54 
  
Only the starting year of a condition will be required (e.g., not month or day). For 
conditions that may have multiple occurrences (e.g., myocardial infarction), only the year 
of the most recent event will be captured.  
• Targeted relevant surgical history will be captured.  
• The primary cause of CKD, current transplant status and current dialysis access (if 
applicable), will be collected.  
9.2.2 
Vital Sign Measurement 
Heart rate, blood pressure, and weight may be collected from data available in the clinical 
encounter for in-person visits.  
Height may be collected either from data available in the clinical record or from subject self-
reported height. Height will be collected at Baseline/Day 1 only.  
9.3 
Efficacy Assessments 
The primary endpoint is the time to a composite endpoint of initiation of maintenance dialysis or 
all-cause mortality. It will be considered as confirmatory evidence of efficacy.  
9.4 
Laboratory and Other Assessments 
Laboratory assays will be conducted by each sites’ local laboratory. Given the requirement for 
all subjects to have advanced NDD-CKD it is anticipated that Investigators will collect the 
laboratory assessments described in the SoA at intervals no less frequent than quarterly.  All 
Investigators will receive protocol specific training regarding the anticipated laboratory 
assessment schedule. Routine laboratory values, as required in the SoA, will be documented in 
the source documentation and eCRF.  
Results of these laboratory assays will be reviewed by the primary treating nephrologist, 
Investigator, or designee as a part of routine SOC. 
Investigators or their designee are required to acknowledge and review the local laboratory test 
results, however, they will not be required to provide independent assessment of SOC laboratory 
test results with regard to their ‘clinical significance’ or to direct intervention (except as noted 
below). Review of the laboratory parameters should be captured in the subject source 
documentation.  
Phosphorus and Iron Indices 
Collection and evaluation of phosphorus and iron indices (TSAT and ferritin) must be 
performed and reviewed at an interval no less than quarterly. Failure to monitor these 
parameters is considered an important protocol deviation. 
In all instances in which phosphorus and iron indices are collected, the Investigator must 
independently review these results to assess clinical significance and determine whether study 
drug dose changes or temporary discontinuation are required. Timely review of the laboratory 
assessments by the Investigator or designee is anticipated. Appropriate documentation of clinical 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 35 of 54 
  
significance and any resulting dose adjustments will be documented in the subject source 
documentation and eCRF.   
In the event the Investigator determines that a specific quarterly assessment of phosphorus and 
iron indices (TSAT and ferritin) is outside SOC, a study-specific lab kit will be provided by the 
sponsor and used to collect blood for assessment of TSAT, ferritin, and phosphorus by a central 
laboratory. Central laboratory details are provided in a laboratory information sheet.  
Blood or urine 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 or urine pregnancy test will be performed according to the SoA 
(Section 1.3) for females of childbearing potential. These results must be available and must 
be negative before the subject takes the first dose of study drug.  Additional serum or urine 
pregnancy tests may be conducted throughout the study at the discretion of the Investigator to 
establish the absence of pregnancy during the study.  
 
Table 2 
 Typical Quarterly Laboratory Assessments  
Hematology 
Iron Indices 
Serum Chemistry 
Complete Blood Count 
 
Ferritin* 
TSAT* 
Total iron 
Total iron binding capacity 
Phosphorus* 
Calcium 
Renal Panel (sodium, potassium, 
bicarbonate, chloride, BUN, 
creatinine, glucose) 
Hepatic Panel (albumin, AST, ALT 
total bilirubin, ALP, total protein) 
Magnesium  
eGFR 
Additional Laboratory Tests 
Urine Tests  
PTH 
Cystatin-C 
 
Urine albumin or protein; creatinine 
ratio  
ALP: alkaline phosphatase; AST: aspartate aminotransferase; ALT: alanine aminotransferase; BUN: blood urea nitrogen; 
eGFR: estimated glomerular filtration rate; PTH: parathyroid hormone; TSAT: transferrin saturation.  
*Assessment required at a frequency of no less than quarterly (90 days). 
 
9.5 
Safety and Other Assessments 
9.5.1 
Concomitant Medication Recording 
Routine concomitant medications (name, indication for use, route, start and stop dates), including 
prescription and over the counter medications will be collected at Screening, Day 1, and Month 
9.   
Concomitant medications of interest will be captured beginning at Screening and then at each 
subsequent study visit.  
The concomitant medications of interest include: 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 36 of 54 
  
• Erythropoietin Stimulating Agents (ESA) 
• All forms of oral or IV iron excluding oral iron in multivitamins 
• All phosphate-lowering therapy 
• HIF-Stabilizers 
For medications of interest, the name, indication, dose, route of administration, frequency and 
start/stop date will be collected and captured in the source documentation and in the eCRF.  
Blood Transfusions will be captured and recorded in the source and eCRF.  
9.5.2 
Adverse Event Assessment 
Auryxia (ferric citrate) is approved by the FDA for use as an oral iron replacement product in 
adult patients with NDD-CKD and iron deficiency at doses up to 12 tablets per day which is 
100% (2 times) greater than the maximum dose allowed in this clinical study. 
The safety profile of ferric citrate in the NDD-CKD population has been described by the FDA 
in the Auryxia USPI and by Akebia Therapeutics, Inc. in the Investigators Brochure.   
As such, adverse events will only be collected in the following instances: 
If they meet the definition of an SAE (see Section 9.6.1.2) or meet the requirements for reporting 
as an IND safety report. If there is any doubt whether the information constitutes an AE or SAE, 
please contact the Medical Monitor for discussion. 
Adverse Events of Special Interest: 
• If an event of iron overload occurs it will be captured as an adverse event of special 
interest. Iron overload is defined as any liver biopsy findings or MRI imaging consistent 
with this diagnosis in the setting of persistent TSAT >45%. In the event of an adverse 
event of special interest, the Investigator must review other prescribed iron 
supplementation (IV and oral) and make adjustments in accordance with Section 7.1.2.1.  
• If a clinically significant episode of hypophosphatemia occurs it will be captured as 
adverse events of special interest. Clinically significant hypophosphatemia is defined as 
serum phosphorus <2.5 mg/dL. In the event of an adverse event of special interest, the 
Investigator must review other prescribed phosphate-lowering therapies and make 
adjustments in accordance with Section 7.1.2.1. 
Subjects will be followed for protocol required SAEs and AEs of special interest until the final 
required protocol visit or until all drug-related toxicities and AEs have resolved (or are 
considered chronic/stable), whichever is later.  


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 37 of 54 
  
9.6 
Adverse Events and Serious Adverse Events 
9.6.1 Definitions of Adverse Events and Serious Adverse Events 
9.6.1.1 
Adverse Events 
As defined by the Code of Federal Regulations section 312.32 an adverse event (AE) is any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related.  
An AE may include 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. 
AEs therefore may include the following:  
• All AEs, whether suspected to be causally related to study drug or otherwise 
• All AEs secondary to any medication overdose, medication error, abuse, withdrawal, 
sensitivity, or toxicity 
• Illnesses apparently unrelated to study drug, including the worsening of a pre-existing 
illness 
• Injury or accidents.  
• 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.  
 
9.6.1.2 
Serious Adverse Events 
Each AE is to be classified by the Investigator as serious or nonserious.  An AE that meets one 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. 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 38 of 54 
  
Serious may also include any other event that the Investigator and Investigator-Sponsor judges to 
be serious. If there is any doubt whether the information constitutes an AE or SAE, the 
information is to be treated as an SAE. 
Life-threatening – Any event in which the subject was at risk of death at the time of the event; 
‘life-threatening’ does not refer to an event which hypothetically might have caused death if it 
were more severe. 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 (e.g., 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. 
 
The following guidelines are to be used when reporting SAEs for this study:  
 
Medical Diagnoses – Whenever possible, a medical diagnosis term should be used to report 
SAEs instead of signs and symptoms due to a common etiology, as determined by qualified 
medical study staff. 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 SAEs. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE. For example, when a subject 
is hospitalized for an acute appendicitis that begins during the SAE reporting period, appendicitis 
should be reported as the SAE and the resulting appendectomy noted in the narrative.  
 
Pre-planned therapeutic procedures or surgeries not associated with a new medical condition or 
worsening pre-existing condition should not be reported as SAEs.  
 
The only procedures to be captured include the placement of dialysis access (e.g., Arteriovenous 
Graft or Fistula [AVG/ AVF], Peritoneal Dialysis [PD] Catheters, Central Venous Catheters 
[CVC]).  Diagnostic procedures (e.g., x-rays, ultrasounds, echocardiograms) are not required to 
be captured. 
 
Transplantation – It is anticipated that subjects may receive a kidney transplant during this 
study. Kidney transplant will be captured as a Study Endpoint and will not be recorded as an 
SAE. Adverse events resulting in prolongation of hospitalization during the index kidney 
transplant will be captured as an SAE. Subjects will discontinue study drug following receipt of a 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 39 of 54 
  
kidney, other solid organ, hematopoietic stem cell or bone marrow transplant. Receipt of a 
kidney transplant will be considered an exception to the requirement for a 30-day safety follow 
up period, however any subject who receives a kidney transplant, and has not withdrawn consent 
from study participation, will have a vital status check performed at 30-days following the 
kidney transplant.  
 
Dialysis Initiation - It is anticipated that subjects may initiate maintenance dialysis during this 
study. Dialysis initiation will be captured as a Study Endpoint and will not be recorded as an 
SAE. Hospitalization days will be recorded in the eCRF and adverse events resulting in 
prolongation of hospitalization during the index dialysis initiation will be captured as additional 
SAEs. Subjects will discontinue study drug following initiation of dialysis.  Initiation of dialysis 
will be considered an exception to the requirement for a 30-day safety follow up period, however 
any subject who initiates maintenance dialysis, and has not withdrawn consent from study 
participation, will have a vital status check performed at 30-days following the initiation of 
maintenance dialysis.  
9.6.2 Classification of an Adverse Event 
9.6.2.1 
Severity of Event 
The Investigator will assess each SAE as either mild, moderate, or severe using the following 
guidelines to describe the maximum severity of the SAE: 
• Mild: Does not interfere with subject's usual function.  Clinical or diagnostic observation 
only; no intervention indicted. 
• Moderate: Interferes to some extent with subject's usual function.  Requires minimal, 
local, or noninvasive medical intervention/medication. 
• Severe: Interferes significantly with subject's usual function. Disabling, medically 
significant but not immediately life-threatening; may include hospitalization or 
prolongation of hospitalization indicated.  
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 at least 1 of the criteria for serious 
events listed above. 
9.6.2.2 
Relationship to Study Intervention 
The causal relationship of the AE to study drug will be assessed by both the Investigator and the 
Investigator-Sponsor.   
The assessment of causal relationship to study drug should be evidence-based, and not based on 
the premise that all AEs are possibly causally related to study drug until proven otherwise.   
Examples of evidence that would suggest a causal relationship between the study drug and the 
AE include the occurrence of an AE that is uncommon and known to be strongly associated with 
drug exposure (e.g., angioedema, hepatic injury, and Stevens-Johnson syndrome) or an AE that 
is uncommon in the population exposed to the drug. 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 40 of 54 
  
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 study 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 study drug and/or there is no reasonable possibility that the study drug caused the AE. 
This assessment includes situations where the AE is related to other factors such as the 
subject’s clinical state, other therapeutic interventions, or concomitant drugs administered 
to the subject. 
Default assessments using the ‘related’ category without supportive evidence for a causal 
relationship to study drug is generally uninformative and do not contribute meaningfully to the 
development of the safety profile of the drug or to subject protection. 
9.6.2.3 
Expectedness 
The Investigator or Investigator-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 is not consistent with the risk information previously described for the 
study intervention as described in the current Investigators Brochure. 
9.6.3 Time Period and Frequency for Event Assessment and Follow-up 
The Investigator is to report all SAE’s either directly observed or spontaneously reported by the 
study subject. In addition, each study subject will be questioned about SAEs at each visit 
following initiation of study drug treatment. 
9.6.4 Reporting Adverse Events  
Non-serious AEs (with the exception of Adverse Events of Special Interest in Section 9.5.2) will 
not be collected in source documents or reported in the eCRF.  
All SAEs will be collected in source documents and reported in the eCRF. 
All Adverse Events of Special Interest will be collected in the source documents and reported in 
the eCRF. 
9.6.5 Reporting Period 
SAE and Adverse Events of Special Interest collection will begin from initiation of study drug 
treatment through the 30-day follow-up visit. Subjects will be followed for protocol required 
SAEs and Adverse Events of Special Interest until the final required protocol visit or until all 
drug-related toxicities and Adverse Events of Special Interest and SAEs have resolved (or are 
considered chronic/stable), whichever is later.  


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 41 of 54 
  
9.6.6 
Serious Adverse Event Reporting 
Any SAE, regardless of causal relationship, must be reported to the Investigator-Sponsor within 
24 hours after the Investigator or designee becomes aware of the SAE. Compliance with this 
time requirement is essential so that the Investigator-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 awareness; 
• The date of report; 
• Name of the reporter; 
• Name of the suspected medicinal product, if applicable;  
• 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). If the event meets serious 
criteria and it is not possible to access the EDC system, a study-specific paper SAE Report Form 
should be sent to the Investigator-Sponsor via email (research@usrenalcare.com) within 24 
hours of being made aware of the SAE. 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 Investigator-
Sponsor by updating the electronic eCRF with the new information or by submitting a study-
specific 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. The subject should be observed 
and monitored carefully until the condition resolves or stabilizes.  
All deaths are to be thoroughly investigated and reported. Autopsy reports and death certificates 
are to be obtained, if possible, and summarized as appropriate. 
The Investigator-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 Investigator is 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 Investigator-Sponsor and any SAEs occurring at their investigative site which meet the 
reporting requirements of the IRB. 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 42 of 54 
  
9.6.7 Follow-up of Unresolved Events 
All reportable SAEs 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 (e.g., until a final report is 
completed for that subject). 
In addition, all SAEs assessed by the Investigator as related to the study drug 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. 
9.6.8 Reporting of Pregnancy 
A pregnancy in a female subject must be confirmed by a positive serum or urine test (β-human 
chorionic gonadotropin). 
Female subjects should interrupt study drug if they think they are pregnant. The study drug 
should be immediately discontinued once the pregnancy of a female study subject has been 
confirmed. The study drug can be resumed once a negative pregnancy test is confirmed. 
If any study subject becomes or is found to be pregnant while receiving study drug or within 
30 days of discontinuing the study drug, the pregnancy must be recorded on the study-specific 
paper Pregnancy Reporting Form within 24 hours of awareness of the pregnancy.  
The study-specific paper Pregnancy Reporting 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 until completion of the pregnancy. 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 drug should also be 
reported. 
• In the case of a live birth, the “normality” of the newborn can be assessed at time of birth. 
9.7 
Special Situations 
Certain safety events, called ‘Special Situations’, that occur in association with study drug may 
require reporting. These Special Situations include, but are not limited to, the following: 
• Overdose of the medicinal product 
o Ferric citrate overdose - Accidental ingestion and resulting overdose of 
iron-containing products is a leading cause of fatal poisoning in children under 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 43 of 54 
  
6 years of age. In case of accidental overdose, call a physician or poison control 
center immediately. Advise subjects of the risks to children and to keep ferric 
citrate out of the reach of children. 
An overdose of iron can lead to iron toxicity. Iron toxicity can be classified as corrosive or 
cellular. Ingested iron can have an extremely corrosive effect on the GI mucosa, which can 
manifest as nausea, vomiting, abdominal pain, hematemesis, and diarrhea; patients may become 
hypovolemic because of significant fluid and blood loss. Cellular toxicity occurs with the 
absorption of excessive quantities of ingested iron. Severe overdose causes impaired oxidative 
phosphorylation and mitochondrial dysfunction, which can result in acidosis and cellular death. 
The liver is one of the organs most affected by cellular iron toxicity, but other organs such as the 
heart, kidneys, lungs, and the hematologic systems may also be impaired. With chronic iron 
overload, the deposit of iron into visceral organs can cause organ dysfunction due to siderosis 
[Spanierman 2010].  
Acute intoxication is most commonly reported in children ingesting large quantities of ferrous 
sulfate or chewable vitamins with iron; thus, ferric citrate must be kept out of the reach of 
children unless administered under a pediatric clinical study protocol. 
An overdose of iron in pregnant women may carry a risk for spontaneous abortion, gestational 
diabetes, and fetal malformation. 
Special situations should be collected whether they result in an SAE or not. Special situations 
with associated SAE should also be reported on the corresponding SAE forms, following 
applicable SAE process. 
 STATISTICAL 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, 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 and by time point/time 
period, as appropriate. 
10.1 
Sample Size Determination 
The sample size for this study is driven by the primary endpoint, initiation of maintenance 
dialysis or all-cause mortality and is based on the observed data from the pilot study using nearly 
identical inclusion and exclusion criteria.  The observed rate of the primary composite endpoint 
in the pilot study (all-cause mortality, maintenance dialysis or kidney transplant) for patients in 
the standard of care arm was 0.94 events per person-year of follow up.  The observed hazard 
ratio was 0.42 (58% relative risk reduction, p=0.002) for the primary composite endpoint when 
comparing ferric citrate treated patients versus usual care.  
 
Assuming 1 year recruitment and 0.75 years of follow up (9 months) for each individual and a 
hazard ratio of 0.60 (40% relative risk reduction), a sample size of 400 patients (200 per arm) 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 44 of 54 
  
provides 90% power with a 2-sided alpha p <0.05.  Assuming a hazard ratio of 0.50 (50% 
relative risk reduction), a sample size of 225 patients provides 90% power with a 2-sided alpha 
p<0.05.  
 
10.2 
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 one or more doses of 
study drug. This population will be analyzed based upon the randomized treatment. 
• Safety population: defined as all subjects who received at least one dose of study drug. This 
population will be analyzed based upon the actual treatment received. 
• Per protocol population: defined as all randomized subjects who received study drug 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. 
10.3 
Missing Data 
Discontinuation from study intervention is different from discontinuation from the study, and 
remaining study procedures will be completed as indicated by the study protocol unless the 
subject withdraws consent for participation in the study.  
All data pertaining to the primary and secondary endpoints collected at any point during the 
study, both during study drug treatment and post-study drug treatment discontinuation, will be 
used for the primary analysis of the endpoints and its individual components. 
Unless stated otherwise in the Statistical Analysis Plan, missing data for all other endpoints will 
not be imputed and the analysis will be based on observed data.   
10.4 
Statistical Analyses 
10.4.1 
General Considerations 
Data summaries for categorical variables such as SAEs will use descriptive statistics including 
number of subjects, and proportions. Data summaries for continuous variables such as laboratory 
parameters will use descriptive statistics for mean, standard deviation, median, minimum, and 
maximum. Within-group changes from baseline for continuous parameters will be assessed. 
10.4.2 
Analysis of Primary Endpoint(s) 
The primary endpoint is the time to composite endpoint of initiation of maintenance dialysis or 
all-cause mortality. It will be considered as confirmatory evidence of efficacy. The primary 
endpoint will be analyzed by Cox-proportional hazards regression model. HRs and 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 45 of 54 
  
corresponding 95% confidence intervals will be presented for the primary endpoint (initiation of 
maintenance dialysis or all-cause mortality.   
10.4.3 
Analysis of Secondary Endpoint(s) 
For the below secondary endpoints, Cox-proportional hazard regression model or competing risk 
analyses will be conducted. HRs and corresponding 95% confidence intervals will be presented.  
• Time to first event hospitalization reported as a SAE (excluding disease-related 
hospitalization [e.g., fistula replacement, dialysis initiation, kidney transplant] and 
elective procedures),  
• Component of Primary – time to initiation of maintenance dialysis 
• Component of Primary – time to all-cause mortality 
 
A full description of the analyses performed on secondary endpoints will be provided in the 
statistical analysis plan. A pre-specified process for identifying hospitalization events to be 
included in the analysis of the hospitalization secondary endpoint will be used. 
 
10.4.4 
Tertiary/Exploratory Endpoint(s) 
A full description of the analyses performed on exploratory endpoints will be provided in the 
statistical analysis plan. Exploratory endpoints include: 
• Rate of hospitalizations and rate of hospitalization days prior to initiating maintenance 
dialysis  
• Receipt of kidney transplant prior to initiating maintenance dialysis  
• Cumulative dose over time of rescue therapy for anemia including (individually, [ESA, 
intravenous iron, RBC transfusion]) prior to initiating maintenance dialysis  
10.4.5 
Safety Analyses 
10.4.5.1 
Analysis of Adverse Events  
All analyses of safety data will use the safety population. 
SAEs and Adverse Events of Special Interest will be summarized using the number and 
percentage for all subjects in the safety population. 
All SAEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
classification. Treatment-emergent SAEs will be summarized by system organ class and 
preferred term (PT) for each treatment group. SAEs will also be summarized by their maximum 
severity. 
Summaries will also be provided for the following types of SAEs: 
• 
Related SAEs (including all categories for relationship to study drug other than 
“Unrelated”, as determined by the Investigator) 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 46 of 54 
  
10.4.6 
Baseline Descriptive Statistics 
Descriptive statistics will be generated for demographic and pretreatment variables for the 
randomized population defined in Section 10.2. 
Medical history terms will be summarized for each treatment group based on the randomized 
population. 
10.4.7 
Planned Interim Analyses 
No formal interim analysis is planned.  
10.4.8 
Sensitivity Analyses 
Sensitivity analyses will be conducted to explore the robustness of the primary endpoint analysis. 
Full details of the sensitivity analyses will be described in the statistical analysis plan but may 
include analyses such as those related to compliance with study drug (per-protocol analysis) or 
excluding endpoint events occurring within 8 weeks of study start.  
10.4.9 
Sub-Group Analyses 
Analyses of the primary, secondary, and exploratory endpoints may be performed in subgroups 
with more details to be included in the final SAP, including: 
• eGFR within 3 months of Screening: 
o ≥15 to ≤20 ml/min/1.73 m2 
o <15 ml/min/1.73 m2 
• 4-variable Kidney Failure Risk Equation (KFRE) score [Tangri 2011] within 3 months of 
Screening: 
o ≥20% 
o <20% over 2 years 
 
 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 Harmonization (ICH) E6 (R2) guideline on Good Clinical Practice (GCP), and 
applicable local regulatory requirements and laws.  


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 47 of 54 
  
11.2 
IRB and Ethics Committees 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, (e.g., recruitment 
advertisements, if applicable) from the IRB/IEC. All correspondence with the IRB/IEC will be 
retained in the Investigator File. Copies of IRB/IEC approvals will be forwarded to the 
Investigator-Sponsor/Investigator or its designee.  
In case of a substantial protocol amendment, the Investigator-Sponsor/Investigator will obtain 
approval from responsible Regulatory Authorities before implementation.  
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects. In that 
event, the investigator will notify the IRB/IEC and the Investigator-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 and answer all 
questions regarding this study. Prior to any study-related procedures being performed on the 
subject, the informed consent form (ICF) will be reviewed, signed, and dated by the subject or 
their legally acceptable representative, as well as the person who administered the informed 
consent, and any other signatories, according to local requirements. Informed consent may be 
obtained using an electronic consent process (e-consent) following all applicable ICH/GCP and 
IRB guidelines and regulations.  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/IEC 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/IEC and the Investigator-Sponsor before use.  
11.4 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor-Investigator with sufficient, accurate 
financial information, as requested, to allow the Sponsor-Investigator 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. 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 48 of 54 
  
11.5 
Confidentiality and Data Privacy 
All parties will ensure protection of subject personal data and will not include subject names on 
any Investigator-Sponsor forms, reports, publications, or in any other disclosures, except where 
required by law. In case of data transfer, the Investigator-Sponsor will maintain high standards of 
confidentiality and protection of subject personal data. 
The Investigator/Investigator-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 Investigator-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 
Investigator-Sponsor requires the Investigator to permit its monitor or designee’s monitor, 
representatives from any regulatory authority (e.g., FDA), the Investigator-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, electrocardiogram 
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. 
11.6 
Data Handling and Record Keeping 
11.6.1 
Data Collection and Management Responsibilities 
This study will utilize an electronic data capture (EDC) system to manage data collection during 
this trial that is fully Code of Federal Regulations 21 part 11 compliant. An EDC system contains 
certain functionality including, but not limited to, a graphical user interface to help facilitate data 
entry, a data validation element to check user data, and a reporting function. eCRFs available 
through this system are required and will be completed for each randomized subject.  
Any form of data from the electronic system are the sole property of the Investigator-Sponsor 
and will not be made available in any form to third parties, except for authorized representatives 
of the Investigator-Sponsor or appropriate regulatory authorities, without written permission 
from the Investigator-Sponsor.  
The Investigator has ultimate responsibility for the accuracy, authenticity, and timely collection 
and reporting of all clinical, safety, and laboratory data entered in the eCRF or any other data 
collection forms.  
In most cases, the source documents are contained in the subject’s chart at the hospital or the 
physician's office. In these cases, data collected on the eCRFs will match the data in those charts.  
11.6.2 
Study Records Retention 
To enable evaluations and/or audits from regulatory authorities or the Investigator-Sponsor, the 
Investigator agrees to keep records, including the identity of all participating subjects (sufficient 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 49 of 54 
  
information to link records (e.g., eCRFs 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 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 Investigator-Sponsor will be prospectively 
notified. The study records will be transferred to a designee acceptable to the Investigator-
Sponsor, such as another Investigator, another institution, or to the Investigator-Sponsor. The 
Investigator will obtain Investigator-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 (e.g., 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 Investigator-
Sponsor will be informed immediately.  
In addition, the Investigator will inform the Investigator-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 Investigator-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 Investigator-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 early termination 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 Investigator-Sponsor reserves the right to discontinue the study for other valid 
administrative reasons. If the study has been suspended or terminated, prompt notification will 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 50 of 54 
  
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 
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 Investigator-Sponsor if the trial is terminated by the Investigator 
or the IRB at the site. If the Investigator, IRB, or Investigator-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 Investigator-Sponsor elects to terminate or suspend the study or the 
participation of an investigational study site, a study-specific procedure for early termination or 
suspension will be provided by the Investigator-Sponsor; the procedure will be followed by 
applicable study sites during the course of termination or study suspension.  
11.9 
Safety Oversight 
Subject safety will be monitored through collection of SAEs. 
11.10 Quality Assurance and Quality Control 
The Investigator-Sponsor will verify that the clinical trial is conducted, and data are documented 
(recorded), and reported in compliance with the protocol, ICH GCP, and applicable regulatory 
requirements (e.g., Good Laboratory Practices [GLP], Good Manufacturing Practices [GMP]).  
Each clinical site will perform ongoing internal quality management review of their study 
conduct, data documentation and completion. 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 Investigator-Sponsor, and inspection by local and regulatory authorities. 
11.10.1 
Clinical Monitoring 
During study conduct, the Investigator-Sponsor or its agent will conduct periodic on-site or 
remote monitoring visits to ensure that the protocol and GCP are being followed. The 
Investigator-Sponsor or designee will review source documents to confirm that the data recorded 
on the eCRFs is accurate. The Investigator/institution will allow the Investigator-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 Investigator-
Sponsor or companies working with or on behalf of the Investigator-Sponsor, and/or review by 
the IRB, and/or to inspection by appropriate regulatory authorities.  


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 51 of 54 
  
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.  
11.10.2 
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 
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.  
For the purposes of this protocol, deviations requiring notification to the Investigator-Sponsor 
are defined as any subject who:  
• Entered into the study even though they did not satisfy entry criteria  
• Received wrong treatment or incorrect dose  
• Received excluded concomitant treatment, including commercial Auryxia  
• Does not discontinue prescribed phosphate-lowering therapy or oral/IV iron therapy in 
response to low phosphorus or elevated iron indices, per Section 7.1.2.1  
• Does not receive quarterly monitoring of serum phosphorus and iron indices (with 
documented Investigator review).  
When one of these deviations from the protocol is identified for an individual subject, the 
Investigator or designee must ensure the Investigator-Sponsor is notified. If the Investigator 
determines that the deviation impacts the safety of a subject, the Investigator must contact the 
Investigator-Sponsor immediately. The Investigator-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 provided to the Investigator-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 Investigator-Sponsor and the Investigator 
and/or the Investigator’s institution. The Investigator-Sponsor will have the opportunity to 
review and approve all proposed abstracts, manuscripts, or presentations regarding this study 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 52 of 54 
  
prior to submission for publication/presentation. Any information identified by the Investigator-
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.  


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 53 of 54 
  
 REFERENCES 
Auryxia United States Prescribing Information 2021 
Auryxia USPI. Keryx Biopharmaceuticals, Inc. One Marina Park Drive, 12
th Floor, Boston, MA 
02210, USA. Issued 03/2021 Rev 7.0. 
Block 2019 
Block GA, Block MS, Smits G, et al. A Pilot Randomized Trial of Ferric Citrate Coordination 
Complex for the Treatment of Advanced CKD. JASN 2019;30:1495–504. 
Cancelo-Hidalgo 2013 
Cancelo-Hidalgo MJ, Castelo-Branco C, Palacios S, et al. Tolerability of different oral iron 
supplements: a systematic review. Curr Med Res Opin 2013;29(4):291–303. 
Drüeke 2012 
Drüeke TB, Parfrey PS. Summary of the KDIGO guideline on anemia and comment: reading 
between the (guide)line(s). Kidney Int 2012;82(9):952-60. 
Fishbane 2009 
Fishbane S, Pollack S, Feldman HI, Joffe MM. Iron indices in chronic kidney disease in the 
National Health and Nutritional Examination Survey 1988-2004. Clin J Am Soc Nephrol 
2009;4(1):57-61. 
Foley 2005 
Foley RN1, Murray AM, Li S, et al. Chronic Kidney Disease and the Risk for Cardiovascular 
Disease, Renal Replacement, and Death in The United States Medicare Population, 1998 to 
1999. J Am Soc Nephrol 2005; 6(2):489-95. 
KDIGO 2012 
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 
Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. 
Kidney inter., Suppl. 2013;3: 1-150. 
Kovesdy 2006 
Kovesdy CP, Trivedi BK, Kalantar-Zadeh K, Anderson JE. Association of anemia with 
outcomes in men with moderate and severe chronic kidney disease. Kidney Int 2006;69(3):560- 
4. 


USRC Kidney Research 
 
 
 
Original Version 5.0 
28JUL2022 
Protocol No USRC-2021-002 
 
 
USRC– Company Confidential  
 
Page 54 of 54 
  
Macdougall 2016 
Macdougall IC, Bircher AJ, Eckardt KU, et al. Iron management in chronic kidney disease: 
conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies 
Conference. Kidney Int. 2016 Jan;89(1):28-39. 
Martin and Gonzalez 2011 
Martin KJ and Gonzalez EA. Prevention and Control of Phosphate 
Retention/Hyperphosphatemia in CKD-MBD: What Is Normal, When to Start, and How to 
Treat? Clin J Am Soc Nephrol. (2011) 6:440-6. 
Salusky 2006 
Salusky IB. A new era in phosphate binder therapy: What are the options? Kidney Int. 
(2006) 70:S10-15. 
Spanierman 2010 
Spanierman, C. Iron Toxicity in Emergency Medicine. Available at: 
http://emedicine.medscape.com/article/815213-overview. As of 16 March 2010.  
Tangri 2011 
Tangri N, Stevens LA, Griffith J, et al. A predictive model for progression of chronic kidney 
disease to kidney failure. JAMA. (2011) (15): 1553-9. 
USRDS 2020 
United States Renal Data System. 2020 USRDS annual data report: epidemiology of kidney 
disease in the United States. National Institutes of Health, National Institute of Diabetes and 
Digestive and Kidney Diseases, Bethesda, MD, 2020.  
Wang 2015 
Wang C, Graham DJ, Kane RC, et al. Comparative risk of anaphylactic reactions associated with 
intravenous iron products. JAMA. 2015 Nov 17;314(19):2062-8. 
Wetmore 2015 
Wetmore JB, Peng Y, Monda KL, et al. Trends in anemia management practices in patients 
receiving hemodialysis and peritoneal dialysis: a retrospective cohort analysis. Am J Nephrol. 
2015;41(4-5):354-61. 

SAP_001.pdf: 
USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
1 
Version 2.0 20MAR2024 
 
 
 
Statistical Analysis Plan 
 
Ferric Citrate for the Prevention of Renal Failure in 
Adults with Advanced Chronic Kidney Disease  
(USRC 2021-002) 
“FRONTIER” 
 
Document Version: V 2.0 
Document Date: 20MAR2024 
 
Prepared by: 
USRC Kidney Research, LLC 
 
 
 
 
 
 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
2 
Version 2.0 20MAR2024 
 
 
 
Approvals: 
Name: Geoffrey A. Block, MD 
Date: 
Role: USRC, SVP Clinical Research 
(Signature) 
 
 
 
 
 
 
 
Name: Gerard Smits, PhD 
Date: 
Role: Statistician 
(Signature) 
 
 
 
 
 
 
 
Name: Martha Block, RN, CCRP 
Date: 
Role: USRC, VP Clinical Research 
(Signature) 
 
 
 
 
 
 
 
Name: Stephanie Brillhart, MSCI 
Date: 
Role: USRC, Director Regulatory Affairs  
(Signature) 
 
 
 
 
 
 
 
 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
3 
Version 2.0 20MAR2024 
Table of Contents 
1. 
ABBREVIATIONS .................................................................................................................... 4 
2. 
INTRODUCTION ..................................................................................................................... 6 
2.1. 
Overview of Trial Design ................................................................................................ 6 
3. 
STATISTICAL CONSIDERATIONS ............................................................................................. 7 
3.1. 
Sample Size ................................................................................................................... 7 
3.2. 
Populations for Analyses ............................................................................................... 8 
3.3. 
Missing or Incorrect Data .............................................................................................. 8 
3.4. 
Statistical Analyses ........................................................................................................ 9 
3.4.1. 
General Considerations ........................................................................................... 9 
3.4.2. 
Baseline Characteristics ........................................................................................... 9 
3.4.3. 
Protocol Deviations ............................................................................................... 10 
3.4.4. 
Analysis of Primary Endpoints ............................................................................... 10 
3.4.5. 
Analysis of Secondary Endpoints ........................................................................... 11 
3.4.6. 
Tertiary Endpoint(s) ............................................................................................... 11 
3.4.7. 
Subgroup analyses ................................................................................................. 11 
3.5. 
Study attrition and disposition .................................................................................... 12 
3.6. 
Safety Analyses ............................................................................................................ 12 
3.6.1. 
Analysis of Adverse Events .................................................................................... 12 
3.6.2. 
Safety Sub-Group Analyses .................................................................................... 13 
3.7. 
Planned Interim Analyses ............................................................................................ 13 
3.8. 
Sensitivity / Exploratory Analyses ................................................................................ 13 
4. 
REFERENCES ........................................................................................................................ 14 
5. 
SELECT TABLE SHELLS .......................................................................................................... 15 
 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
4 
Version 2.0 20MAR2024 
1. ABBREVIATIONS 
Abbreviation or Term 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ASCVD 
Atherosclerotic cardiovascular disease 
CHF 
Congestive heart failure 
CKD 
Chronic kidney disease 
eGFR 
Estimated Glomerular Filtration Rate 
EOT 
End of treatment 
ESA 
Erythropoiesis-stimulating agent 
IV 
Intravenous 
KFRE 
Kidney Failure Risk Equation  
MedDRA 
Medical Dictionary for Regulatory Activities  
PP 
Per protocol 
PT 
Preferred term 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SOC 
Standard of care 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
5 
Version 2.0 20MAR2024 
Abbreviation or Term 
Definition 
TSAT 
Transferrin saturation 
 
 
 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
6 
Version 2.0 20MAR2024 
2. INTRODUCTION 
This statistical analysis plan (SAP) contains definitions of analysis sets and statistical methods 
for the planned analyses in protocol USRC-2021-002 (Version 5.0, 28JUL2022). 
2.1. Overview of Trial Design 
This is an investigator-initiated multicenter, randomized, double-blind, placebo-controlled, 
pragmatic clinical trial in patients with advanced chronic kidney disease (CKD) to determine the 
effect of ferric citrate versus placebo on the time to a composite endpoint of initiation of 
maintenance dialysis or all-cause mortality. Secondary objectives of this trial are to evaluate the 
impact of ferric citrate on time to all-cause hospitalization and individual components of the 
primary endpoint. 
The study periods are: 
• Screening Period: Up to 45 days prior to Day 1. Standard of Care (SOC) laboratory 
collection permitted up to 45 days (up to 90 days for estimated glomerular filtration rate 
[eGFR]) prior to Day 1.  
• Treatment Period: Up to 9 months  
• Safety follow-up Period: 30 days after end of treatment (EOT) 
Subjects will be stratified by site and by eGFR (above or equal to/below 15 ml/min/1.73m2) 
randomized in a 1:1 ratio to receive either ferric citrate or matching placebo.  
All subjects will receive a fixed dose of two tablets orally taken with meals or snacks up to three 
times per day. The maximum daily dose is six tablets. Subjects will remain on study drug for up 
to 9 months followed by an additional 30-day safety follow-up period. Study drug will be 
stopped for subjects who initiate maintenance dialysis or receive a kidney transplant. Subjects 
who undergo maintenance dialysis or receive a kidney transplant will be removed from study 
with no follow-up visit, however, these subjects will have a vital status check (to ascertain 
mortality) performed 30-days following the relevant event. 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
7 
Version 2.0 20MAR2024 
Each randomized subject will complete five study visits (2 in-person and three phone/virtual or 
in-person). Study visits during the treatment period will be conducted as part of routine 
scheduled clinical encounters. Standard of care local laboratory results will be collected, 
including the monitoring of phosphorus and iron indices (TSAT and ferritin) at quarterly 
intervals. 
Management of serum phosphorus and iron sufficiency will be directed at the discretion of the 
treating physician and/or Investigator independent of study drug with the exception of protocol 
required safety adjustments of study drug. There is no minimum allowable dose of study drug, 
and the prescribed dose of study drug will be adjusted only in the event of a safety or 
tolerability concern.  
3. STATISTICAL CONSIDERATIONS 
Data collected throughout the study will be summarized in tables with descriptive statistics and 
listed in by-subject listings. Missing information will be summarized by counts for each variable. 
Continuous variables will be summarized using number of subjects with data, mean, standard 
deviation, median, first and third quartile, 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 and by time point/time 
period, as appropriate. 
3.1. Sample Size  
The sample size for this study is driven by the primary endpoint, initiation of maintenance 
dialysis or all-cause mortality and is based on the observed data from the pilot study (Block, 
2019) using nearly identical inclusion and exclusion criteria. The observed rate of the primary 
composite endpoint in the pilot study (all-cause mortality, maintenance dialysis or kidney 
transplant) for patients in the standard of care arm was 0.94 events per person-year of follow 
up. The observed hazard ratio was 0.42 (58% relative risk reduction, p=0.002) for the primary 
composite endpoint when comparing ferric citrate treated patients versus usual care.  


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
8 
Version 2.0 20MAR2024 
Assuming 1 year recruitment and 0.75 years of follow up (9 months) for each individual and a 
hazard ratio of 0.60 (40% relative risk reduction), a sample size of 400 patients (200 per arm) 
provides 90% power with a 2-sided alpha p <0.05.  Assuming a hazard ratio of 0.50 (50% 
relative risk reduction), a sample size of 225 patients provides 90% power with a 2-sided alpha 
p<0.05. 
3.2. 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 one or more doses of 
study drug. This population will be analyzed based upon the randomized treatment. 
• Safety population: defined as all subjects who received at least one dose of study drug. 
This population will be analyzed based upon the actual treatment received. 
• Per protocol (PP) population: defined as full analysis subjects who received a non-zero 
dose of study medication at least 70% of their time in study and have no protocol 
deviations affecting the primary endpoint analyses. This population will be analyzed 
based upon the treatment received.  
Any subject who is randomized to study intervention but does not receive study drug will be 
considered an early termination.  
3.3. Missing or Incorrect Data 
Discontinuation from study intervention is different from discontinuation from the study, and 
remaining study procedures will be completed as indicated by the study protocol unless the 
subject withdraws consent for participation in the study. The date of vital status for all patients 
who early term will be capped at 37 days post the early termination date. For all patients who 
complete the study through 9 months, the 10-month follow-up safety visit date will be capped 
at 307 days post study drug Day 1.       


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
9 
Version 2.0 20MAR2024 
All data pertaining to the primary and secondary endpoints collected at any point during the 
study, both during study drug treatment and post-study drug treatment discontinuation, will be 
used for the primary analysis of the endpoints and its individual components. 
3.4. Statistical Analyses 
3.4.1. General Considerations 
Data summaries for categorical variables such as serious adverse events (SAEs) and adverse 
events of special interest (AESI) will use descriptive statistics including incidence for subjects 
with, as well as counts for number of events. Data summaries for continuous variables such as 
laboratory parameters will use descriptive statistics for mean, standard deviation, median, first 
and third quartiles, minimum, and maximum. Change from baseline will be calculated, with the 
addition of a 95% confidence interval. Within-group and between group changes from baseline 
for continuous parameters will be assessed.  
3.4.2. Baseline Characteristics 
Descriptive statistics will be generated for demographic and pretreatment variables for the 
safety population defined in the protocol. 
Medical history terms will be summarized by treatment group in the safety population. This will 
include: 
• Congestive heart failure, defined as systolic or diastolic dysfunction, heart failure with 
reduced ejection fraction, or heart failure with preserved ejection fraction 
• Diabetes, defined as type I or type II 
• Atherosclerotic cardiovascular disease, defined as coronary artery disease, angioplasty, 
stent, myocardial infarction, cerebrovascular accident, or transient ischemic attack  
• Hypertension 
• Peripheral vascular disease defined as amputation or artery revascularization, stent, or 
angioplasty 
• Dyslipidemia 
• Anemia 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
10 
Version 2.0 20MAR2024 
• Secondary Hyperparathyroidism 
• COVID-19 infection 
3.4.3. Protocol Deviations 
Important protocol deviations will be summarized for the full analysis population. For the 
purposes of this protocol, important deviations are defined as any subject who:  
• Entered the study even though they did not satisfy entry criteria  
• Received wrong treatment or incorrect dose (i.e., patient not stopping IP when protocol 
required, patient not decreasing IP when serum phosphorus and iron indices indicate)  
• Received excluded concomitant treatment, including commercial Auryxia  
• Does not discontinue prescribed phosphate-lowering therapy or oral/IV iron therapy in 
response to low phosphorus or elevated iron indices, per Section 7.1.2.1  
• Does not receive quarterly monitoring of serum phosphorus and iron indices (with 
documented Investigator review). 
A listing of subjects with important protocol deviations will be provided. 
3.4.4. Analysis of Primary Endpoints 
The primary endpoint is the time to composite endpoint of initiation of maintenance dialysis or 
all-cause mortality. A statistically significant hazard ratio less than 1 will be considered as 
confirmatory evidence of efficacy. The primary endpoint will be analyzed, based on the full 
analysis set, by Cox-proportional hazards regression model, with covariates included age, 
diabetes, atherosclerotic cardiovascular disease (ASCVD), congestive heart failure (CHF), and 
eGFR. The proportionality assumption of the model will be examined. HRs and corresponding 
95% confidence intervals will be presented for the primary endpoint (initiation of maintenance 
dialysis or all-cause mortality). Analyses will be performed using the per protocol population as 
supportive. 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
11 
Version 2.0 20MAR2024 
3.4.5. Analysis of Secondary Endpoints 
For the secondary endpoints listed below, Cox-proportional hazards model, using the same 
covariates as for the primary endpoint analysis, will be based on the full analysis set. Hazard 
ratios and corresponding 95% confidence intervals will be presented.  
• Time to first event hospitalization reported as a SAE (excluding disease-related 
hospitalization [e.g., fistula replacement, dialysis initiation, kidney transplant] and 
elective procedures),  
• Component of Primary – time to initiation of maintenance dialysis 
• Component of Primary – time to all-cause mortality 
Analyses will be performed using the per protocol population as supportive. 
3.4.6. Tertiary Endpoint(s) 
Tertiary endpoints include: 
• Annualized rate of hospitalizations, incidence of hospitalizations, and proportion of days 
hospitalized prior to initiating maintenance dialysis  
• Receipt of kidney transplant prior to experiencing a primary endpoint event  
• Annualized incidence of receipt and cumulative dose of therapy for anemia including 
(individually, [ESA, intravenous iron, RBC transfusion]) prior to initiating maintenance 
dialysis 
• Time to RBC transfusion 
3.4.7. Subgroup analyses 
Data will be analyzed within the following subgroups of interest, as appropriate: 
• eGFR within 3 months of Screening: 
o ≥15 to ≤20 ml/min/1.73 m2 
o <15 ml/min/1.73 m2 
• Diabetes versus Non-diabetic patients  
• 3-variable Kidney Failure Risk Equation (KFRE) score [Tangri 2011] within 3 months of 
Screening: 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
12 
Version 2.0 20MAR2024 
o ≥20% over 2 years 
o <20% over 2 years 
• Per protocol subsets using thresholds of 50%, 60%, and 80% of time on study that a 
subject received a non-zero dose of study medication.  
3.5. Study attrition and disposition 
We will summarize study attrition by treatment group, including patients randomized, received 
study drug, and completed. We will identify those who ended the study due to study endpoint 
(death, initiation of maintenance dialysis, transplant), adverse event, withdrawal of consent, 
lost to follow up, investigator decision, and all other reasons. 
3.6. Safety Analyses 
Hypotheses are not provided for safety outcomes. Observed measures of the following 
biochemical results will be reported at each visit and change from baseline at each visit: serum 
phosphorus, ferritin, TSAT, hemoglobin, and eGFR. Additionally, for hemoglobin and serum 
phosphorus, the proportion of patients within clinical standard of care range, using last on 
treatment value will be reported. 
3.6.1. Analysis of Adverse Events 
Analyses of safety data will use the safety population and will only be conducted for SAEs, 
related SAEs, AESI, and laboratory values.  
Adverse Events of Special Interest: 
• Iron overload is defined as any liver biopsy findings or MRI imaging consistent with this 
diagnosis in the setting of persistent TSAT >45%. 
• Clinically significant hypophosphatemia, defined as serum phosphorus <2.5 mg/dL. 
No statistical inference testing will be done for adverse events. 
AE analyses, by subject incidence and event counts, will be summarized by preferred terms, 
within system organ class, by number and percentage for all subjects in the safety population. 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
13 
Version 2.0 20MAR2024 
All SAEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA). All verbatim 
terms will be reconciled to preferred terms by the Medical Monitor. Treatment-emergent SAEs 
will be summarized by system organ class and preferred term (PT) for each treatment group. 
SAEs will also be summarized by their maximum severity. 
A summary and listing of all deaths and cause of death will be provided overall and by 
treatment group. 
3.6.2. Safety Sub-Group Analyses 
There are no safety subgroup analyses planned. If appropriate, selected safety analyses may be 
conducted using the subgroups from the primary analyses defined above. 
3.7. Planned Interim Analyses 
There are no planned interim analyses for this study. 
3.8. Sensitivity / Exploratory Analyses 
Primary and secondary endpoint analysis using the mITT population may be conducted using 
the percentage of time on study a subject received a non-zero dose of study drug as a 
covariate. 
 
. 
 
 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
14 
Version 2.0 20MAR2024 
4. REFERENCES 
1. Block G.A., Block M.S., Smits G, Mehta R, Isakova T, Wolf M, Chertow G.M. A Pilot Randomized 
Trial of Ferric Citrate Coordination Complex for the Treatment of Advanced CKD. JASN 
2019;30:1495-1504. 
2. Tangri N, Stevens LA, Griffith J, et al. A predictive model for progression of chronic kidney 
disease to kidney failure. JAMA. (2011) (15): 1553-9. 
 
 
 
 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
15 
Version 2.0 20MAR2024 
5. SELECT TABLE SHELLS 
Table X:  Selected Demographic, Clinical, and Laboratory Characteristics at baseline 
Variable 
Ferric Citrate 
Placebo 
Significance 
eGFR<15 (%) 
 
 
 
Age (mean year) 
 
 
 
 
Male (%) 
 
 
 
 
Race (%) 
Black 
 
 
 
 
White 
 
 
 
 
Other 
 
 
 
Ethnicity (n, %) 
Hispanic 
 
 
 
 
Non-Hispanic 
 
 
 
CKD Cause (%) 
Diabetes 
 
 
 
 
Hypertension 
 
 
 
 
Glomerular 
disease 
 
 
 
 
Polycystic 
disease 
 
 
 
 
Other 
 
 
 
Comorbidity, % 
 
 
 
 
ASCVD 
 
 
 
 
Congestive Heart 
Failure 
 
 
 
 
Diabetes 
 
 
 
 
Hypertension 
 
 
 
 
Peripheral vascular 
disease 
 
 
 
 
Cerebrovascular 
disease 
 
 
 
 
Secondary 
hyperparathyroidism 
 
 
 
 
Dyslipidemia 
 
 
 
 
Anemia 
 
 
 
 
Transplant status, % 
 
 
 
 
Listed or Referred 
 
 
 
 
Kidney Failure Risk 
Equation 
 
 
 
 
Laboratory (mean±SD) 
 
 
 
 
Creatinine 
 
 
 
 
eGFR, ml/min per 
1.73m2 
 
 
 
 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
16 
Version 2.0 20MAR2024 
Ferritin, ng/ml 
 
 
 
 
TSAT 
 
 
 
 
Phosphorus 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes:  Therapies and laboratory values estimated during the screening period, prior to Day 1 
of the study. Values to be provided as mean (standard deviation) or proportion (count) as 
appropriate. 
 
Abbreviations:  TSAT, transferrin saturation   
 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
17 
Version 2.0 20MAR2024 
Table X:  Primary Outcome Measures 
 
 
 
 
 
 
 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
18 
Version 2.0 20MAR2024 
Table X:  Secondary Outcome Measures 
 
 
 
 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
19 
Version 2.0 20MAR2024 
Table X:  All Adverse Events  
Type of AE 
Ferric Citrate  
(n, % with event) 
Placebo  
(n, % with event) 
Serious AEs 
 
 
Related Serious AEs 
 
 
Adverse Events of Special 
Interest (AESI) 
 
 
Abbreviations: AE, adverse event.  
 
 
 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
20 
Version 2.0 20MAR2024 
Table X:  Specific Adverse Events  
System Organ Class 
Serious AE 
Related Serious AE 
Ferric Citrate  
(n, % with 
event) 
Placebo  
(n, % with 
event) 
Ferric Citrate  
(n, % with 
event) 
Placebo  
(n, % with 
event) 
Blood and lymphatic 
system 
 
 
 
 
Cardiac disorders 
 
 
 
 
Endocrine disorders 
 
 
 
 
Eye Disorders 
 
 
 
 
GI disorders 
 
 
 
 
General 
 
 
 
 
Hepatobiliary 
 
 
 
 
Immune System 
 
 
 
 
Infections and 
infestations 
 
 
 
 
Injury (poisoning) 
 
 
 
 
Metabolism 
 
 
 
 
Musculoskeletal 
 
 
 
 
Neoplasms 
 
 
 
 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
21 
Version 2.0 20MAR2024 
Nervous system 
 
 
 
 
Psychiatric 
 
 
 
 
Renal and urinary 
 
 
 
 
Reproductive 
 
 
 
 
Respiratory 
 
 
 
 
Skin 
 
 
 
 
Vascular 
 
 
 
 
All Others 
 
 
 
 
Abbreviations: AE, adverse event.  
 
 
 


USRC Kidney Research 
 
 
Statistical Analysis Plan 
 
22 
Version 2.0 20MAR2024 
Additional tables and figures without specific table or figure shells: 
Study Disposition Table 
Consented 
Screened 
 
Screen Failures 
Early Terminations 
 
Reasons for ET (including endpoints) 
Completed 9 months 
 
Endpoints 
Safety Follow-Up (10 months)