Conditions: Chronic Kidney Diseases Iron Deficiency Anemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 206
Healthy volunteers: no

Brief summary:
The objectives of this study are to assess the long-term efficacy and safety of different dose regimens of KRX-0502 in the treatment of iron deficiency anemia (IDA) in adult subjects with non-dialysis dependent chronic kidney disease (CKD).

Detailed description:
This is a Phase 4, 48-week, randomized, open-label, multicenter clinical study comprised of 2 periods: a 24-week Dose Titration Period, followed by a 24-week Dose Maintenance Period. The study will consist of 12 scheduled clinic visits over a period of 48 weeks and additional visits as needed.

Arms:
arm 1: KRX-0502 1 tablet thrice daily (TID) with meals arm 2: KRX-0502 2 tablets twice daily (BID) with the largest 2 daily meals

Interventions: intervention 1: KRX-0502
Intervention descriptions: intervention 1: Oral ferric citrate with meals

Protocol document:
Prot_000.pdf: 
Protocol - Phase 4 Study 402 
Amendment 1 
13 December 2017 
1 
KRX-0502 (FERRIC CITRATE) 
STUDY KRX-0502-402 
A PHASE 4 STUDY OF KRX-0502 (FERRIC CITRATE) 
DOSE REGIMENS IN SUBJECTS WITH NON-DIALYSIS 
DEPENDENT CHRONIC KIDNEY DISEASE AND IRON 
DEFICIENCY ANEMIA: THE COMPASS TRIAL  
IND Number: 120,629 
Protocol History 
Original (version 0.1) 
03 April 2017 
Administrative Letter #1 
25 May 2017 
Amendment 1 
13 December 2017 
Sponsor: 
Keryx Biopharmaceuticals, Inc. 
12th Floor, One Marina Park Drive 
Boston, MA 02210 USA 
This document is a confidential communication of Keryx Biopharmaceuticals, Inc.  Acceptance of 
this document constitutes agreement by the recipient that no unpublished information contained 
herein shall be published or disclosed without prior written approval, except that this document 
may be disclosed to the appropriate Institutional Review Boards under the condition that they keep 
it confidential. 
NCT Number: NCT03236246
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
 
 
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Rationale for Amendment 1: 
This protocol amendment includes changes to eligibility criteria and screening processes that will 
facilitate subject enrollment.  These changes address barriers to enrollment that have been 
identified during study start-up and study conduct, as evidenced by a screen failure rate that, to 
date, has been higher than anticipated.  The adjustments to the inclusion laboratory thresholds for 
eligibility (specifically, estimated glomerular filtration rate [eGFR], hemoglobin [Hgb], and 
serum ferritin), and the allowance to include subjects who require low-dose oral steroid use, are 
clinically appropriate for the target population, and do not add any safety concerns for the 
enrolled subjects. 
This amendment also incorporates the change addressed in Administrative Letter #1, replacing 
the incorrect FACIT Scale questionnaire with the correct FACIT Fatigue Scale questionnaire in 
the appendix, and reflects the FDA approval (on 06 November 2017) for the use of ferric citrate 
as "an iron replacement product indicated for the treatment of iron deficiency anemia in adult 
patients with chronic kidney disease not on dialysis". 
Purposes for Amendment 1: 
The purposes of this amendment are to: 
• Change the lower limit of eGFR for eligibility from >20 to ≥20 mL/min (Inclusion #3). 
• Change the Hgb range for eligibility, from ≥9 and ≤11.0 g/dL, to ≥8.5 and ≤11.5 g/dL  
(Inclusion # 4).   
• Revise the Hgb level for allowing  ESA therapy, or for withdrawing the subject from the 
study if all ESA rescue therapy requirements are not met, from <8.5 to <8.0 g/dL. 
• Raise the serum ferritin eligibility requirement from ≤200 ng/mL to ≤500 ng/mL 
(Inclusion #5). 
• Allow subjects on low-dose oral corticosteroids (eg, ≤5 mg/day prednisone or the relative 
equivalent dose of another corticosteroid) to enter the study (Exclusion #14). 
• Allow re-testing for specific inclusion/exclusion criteria during a re-screening episode, if 
applicable, as well as during the first screening episode. 
• Clarify that Medical Monitor consultation is not required when the Investigator decides to 
re-test or re-screen a subject.  (Note, this is a clarification of initial intent, not a change to 
protocol procedures). 
• Increase the number of clinical sites from approximately 25 to approximately 30. 
• Replace the incorrect FACIT Scale questionnaire with the correct FACIT Fatigue Scale 
questionnaire in Appendix B. 
• Incorporate a description of the FDA approval (on 06 November 2017) for the use of ferric 
citrate as "an iron replacement product indicated for the treatment of iron deficiency anemia 
in adult patients with chronic kidney disease not on dialysis".   
• Revise the Signature Page with the current Study Biostatistician information. 
• Change "Quintiles" to "IQVIATM" to reflect the integration of IMS Health and Quintiles 
under this new organization name. 
For specific examples of changes in text and where the changes are located, see Appendix C.   






Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
 
 
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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for KRX-0502.  I have read the Study 402 
protocol Amendment 1, and agree to conduct the study as outlined.  I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol.  
I understand the protocol and will work according to it, the principles of Good Clinical Practice 
(GCP) (current International Council for Harmonisation [ICH] guidelines), and the Declaration 
of Helsinki (1964), including all amendments up to and including the Brazil revision (2013). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
5 
 
STUDY CONTACT INFORMATION 
 
Medical Monitor (24-hour coverage) 
Immunology & Internal Medicine, 
Medical Strategy & Science 
Therapeutic Science & Strategy Unit 
IQVIATM 
10188 Telesis Court, Suite 400 
San Diego, CA 92121 
Contact directly on mobile phone, for urgent issues: 
Mobile: 
Email: 
The below numbers can be used for 24 hour Urgent Medical Contact if the medical monitor or 
designated coverage cannot be reached: 
Tel. + 1 973 659 6677 
Tel. + 1 570 819 8565 (alternative number) 


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Keryx Biopharmaceuticals, Inc.  
Name of Investigational Product: 
KRX-0502 (ferric citrate) 
Name of Active Ingredient: 
Ferric citrate 
Title of Study:  
A Phase 4 study of KRX-0502 (ferric citrate) dose regimens in subjects with non-dialysis dependent 
chronic kidney disease and iron deficiency anemia:  the COMPASS Trial 
Study center(s):  Multicenter; approximately 30 sites in the United States 
Studied period (years):  
Estimated date first subject enrolled:  3rd Quarter 2017 
Estimated date last subject completed: 2nd Quarter 2019 
Phase of development:  
4 
Objectives:  
The objectives of this study are to assess the long-term efficacy and safety of different dose regimens 
of KRX-0502 in the treatment of iron deficiency anemia (IDA) in adult subjects with non-dialysis 
dependent chronic kidney disease (CKD). 
Methodology:  
This is a 48-week, Phase 4, randomized, open-label, multicenter clinical study comprised of 2 periods: 
a 24-week Dose Titration Period, followed by a 24-week Dose Maintenance Period.  The study will 
consist of 12 scheduled clinic visits over a period of 48 weeks and additional visits as needed. 
Approximately 200 eligible subjects with non-dialysis dependent CKD and IDA will be randomized in 
the study into 1 of 2 active treatment groups: 
• 
Group 1:  KRX-0502 1 tablet thrice daily (TID; total of 3 tablets/day) with meals 
• 
Group 2:  KRX-0502 2 tablets twice daily (BID; total of 4 tablets/day) with the largest 2 daily 
meals 
At Week 12, those subjects with a hemoglobin (Hgb) increase of ≥0.5 g/dL from Baseline and an 
Hgb ≥10 g/dL will maintain the same dose, otherwise their dose will be increased as follows: 
• 
Group 1:  KRX-0502 2 tablets TID (total of 6 tablets/day) with meals 
• 
Group 2:  KRX-0502 3 tablets BID (total of 6 tablets/day) with the largest 2 daily meals 
Number of subjects (planned):  
Two hundred (200) subjects are planned to be randomized 
Diagnosis and main criteria for inclusion:  
Inclusion criteria 
Subjects meeting all of the following inclusion criteria will be randomized in this study: 
1. Age ≥18 years 


Protocol - Phase 4 Study 402 
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13 December 2017 
 
 
 
 
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2. Men and women. Women of childbearing potential must have a negative serum pregnancy test 
at Screening 
3. Estimated glomerular filtration rate ≥20 mL/min and <60 mL/min at Screening 
4. Hgb ≥8.5 g/dL and ≤11.5 g/dL at Screening 
5. Serum ferritin ≤500 ng/mL and transferrin saturation (TSAT) ≤25% at Screening 
6. Serum intact parathyroid hormone ≤600 pg/mL at Screening 
7. Must consume a minimum of 2 meals per day 
8. Willing and able to give written informed consent 
9. Female subjects who are not surgically sterile (by bilateral tubal ligation, bilateral 
oophorectomy, or hysterectomy) or postmenopausal (no menstrual period within 1 year of 
Screening) must agree to use adequate contraception throughout the study and for at least 4 
weeks following their final study visit.  Adequate contraception is defined as: 
• 
Total abstinence from sexual intercourse starting at least 1 complete menstrual cycle 
prior to Screening visit, or  
• 
Having a vasectomized partner, or  
• 
Use of hormonal contraceptives (oral, parenteral, or transdermal) for at least 3 months 
prior to study drug administration or intrauterine contraception/device, or  
• 
Use of a double-barrier method (such as male condom, female condom, diaphragm, 
sponge, or cervical cap together with spermicidal foam/gel/film/suppository) starting 
at Screening  
There is no restriction for female partners of male subjects. 
Exclusion criteria 
Subjects will be excluded if they meet any of the following criteria: 
1. Serum phosphate <3.0 mg/dL at Screening 
2. Liver transaminases (alanine aminotransferase or aspartate aminotransferase) >3× upper 
limit of normal at Screening 
3. Intravenous (IV) iron administered within 4 weeks prior to Screening or during the 
Screening Period 
4. Erythropoiesis-stimulating agents (ESA) administered within 4 weeks prior to Screening 
or during the Screening Period 
5. Blood transfusion within 4 weeks prior to Screening or during the Screening Period 
6. Treatment with any investigational drug within 4 weeks prior to Screening or during the 
Screening Period 
7. Cause of anemia other than iron deficiency anemia of CKD 


Protocol - Phase 4 Study 402 
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13 December 2017 
 
 
 
 
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8. Symptomatic gastrointestinal bleeding within 12 weeks prior to Screening or during the 
Screening Period 
9. Symptomatic inflammatory bowel disease within 12 weeks prior to Screening or during 
the Screening Period 
10. Dialysis within 12 weeks prior to Screening or during the Screening Period, or initiation of 
dialysis planned within 6 months following Screening 
11. Kidney transplant recipient or kidney transplant scheduled within 6 months following 
Screening 
12. Planned surgery or hospitalization (anticipated to last >72 hours) in the 6 months following 
Screening other than dialysis access-related surgery 
13. Requires treatment with myelosuppressive therapy and/or immunosuppressive therapy at 
Screening or during the Screening Period 
14. Requires treatment with oral corticosteroids at Screening or during the Screening Period 
(use of low-dose oral corticosteroids, eg, ≤5 mg/day prednisone or the relative equivalent 
dose of another corticosteroid, is not an exclusion); IV corticosteroids administered within 
2 weeks prior to Screening or during the Screening Period. 
15. Active infection requiring treatment with antibiotics at Screening or during the Screening 
Period 
16. Malignancy except for subjects that have been disease-free for at least 2 years after 
curative therapy or non-melanoma skin cancer regardless of treatment 
17. History of hemochromatosis 
18. Subjects who are pregnant or breast feeding 
19. Active drug or alcohol dependence or abuse (excluding tobacco use or medicinal or 
recreational marijuana use where legal unless there is evidence of abuse) within the 
12 months prior to Screening or evidence of such abuse (in the opinion of the Investigator) 
20. Subjects with known allergic reaction to previous oral iron therapy 
21. Prior treatment with KRX-0502 
22. Any other medical condition that, in the opinion of the Investigator, renders the subject 
unable or unlikely to complete the study or that would interfere with optimal participation 
in the study or produce significant risk to the subject 
Investigational product, dosage and mode of administration:  
KRX-0502 will be supplied as tablets containing 1 g ferric citrate (210 mg of ferric iron).   
Subjects should take KRX-0502 orally with meals or snacks or within 1 hour after their meals or 
snacks.  
Visits need to occur in the morning, non-fasted and subjects instructed to hold KRX-0502 until blood 
is drawn. 


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
 
 
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Laboratory values will be checked at each scheduled visit in a Central Laboratory, and the study drug 
dose may be adjusted in response to these results. When laboratory retesting is necessary, it will be 
done as an unscheduled visit, unless it coincides with a scheduled visit. 
Scheduled Dose Adjustment During the Dose Titration Period (Week 12):  
The starting dose of KRX-0502 during the 24-week Dose Titration Period will be determined at 
Randomization: 
• 
Group 1:  KRX-0502 1 tablet TID with meals 
• 
Group 2:  KRX-0502 2 tablets BID with the largest 2 daily meals 
There will be only one scheduled dose titration step at Week 12.  At Week 12, subjects with an Hgb 
increase of ≥0.5 g/dL from Baseline and an Hgb ≥10.0 g/dL will maintain the same dose; otherwise, 
their dose will be increased to: 
• 
Group 1:  KRX-0502 2 tablets TID with meals 
• 
Group 2:  KRX-0502 3 tablets BID with the largest 2 daily meals 
The maximum dose before Week 12 is the dose determined at randomization, ie, 3 or 4 g/day 
depending on randomized group.  The maximum dose after Week 12 is the dose determined in 
Week 12, ie, 3, 4, or 6 g/day depending on randomized group and dose titration at Week 12.  Only 
subjects who complete the 24-week Dose Titration Period will be eligible to enter the Dose 
Maintenance Period.  During the Dose Maintenance Period, subjects will continue on the dose 
determined during the Dose Titration Period.  The maximum dose is the dose determined in Week 12.  
Unscheduled Dose Titration at Any Time During the Study:  
Unscheduled dose adjustments may be necessary at any point during the study.  The guidance below 
aims to assist the Investigator with decision making about dose modification in the presence of 
laboratory abnormalities or AEs.  Investigators are responsible for evaluating the appropriateness of 
applying these guidelines to any particular clinical situation for an individual subject.  Dose 
interruption refers to holding of the drug, usually for a short term with the intent to resume dosing 
when possible.  To discuss dosing decisions, including extended dose interruption, Investigators should 
contact the Medical Monitor. 
Low serum phosphorus level: 
• 
If serum phosphorus is <2.0 mg/dL, interrupt dosing.  
− Two weeks after interrupting the dose, repeat the laboratory tests: 
 
If serum phosphorus is ≥2.5 mg/dL, resume dosing at the dose prior to the dose 
interruption.  
 
If serum phosphorus is ≥2.0 to <2.5 mg/dL, resume dosing at a reduced dose compared 
to the dose prior to the dose interruption.  
 
If serum phosphorus is <2.0 mg/dL, continue to dose interruption. 
• 
If serum phosphorus is ≥2.0 to <2.5 mg/dL, reduce the KRX-0502 dose by 1 to 3 tablets/day 
without complete dose interruption.  
− Two weeks after reducing the dose, repeat the laboratory tests: 
 
If serum phosphorus is ≥2.5 mg/dL, increase the dose to the dose prior to the dose 
reduction.  
 
If serum phosphorus is ≥2.0 to <2.5 mg/dL, reduce the dose again. 
 
If serum phosphorus is <2.0 mg/dL, interrupt dosing. 


Protocol - Phase 4 Study 402 
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13 December 2017 
 
 
 
 
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• 
Decisions about resuming or increasing dosing and at which dose should take into 
consideration the absolute levels and trends of the serum phosphorus in the context of the prior 
dose changes as well as Hgb and TSAT. 
• 
After resolution of a low serum phosphorus, an attempt should be made to increase the dose to 
the highest dose tolerated prior to the dose interruption or reduction, if supported by the 
Investigator’s clinical judgement. 
Elevated TSAT: 
• 
If TSAT is ≥50%, repeat laboratory tests with care to assure that the blood draw is performed 
before dosing with KRX-0502.  
− If the TSAT is ≥70%, interrupt dosing.  
− If the TSAT is ≥50 and <70%, the response should consider the Hgb level.  
 
If Hgb is ≥12 g/dL, interrupt dosing.  
 
If Hgb is <12 g/dL, reduce the dose.  
− 
If the TSAT is <50%, continue current dose and repeat laboratory tests at the next 
scheduled visit. 
• 
After a dose reduction, repeat laboratory tests at the next scheduled visit. 
• 
Two weeks after interrupting dosing, repeat laboratory tests.  
− If the TSAT is ≥70%, continue dose interruption and check laboratory tests after 2 weeks.  
− If TSAT is <70%, consult the Medical Monitor.  
• 
Decisions about resuming and increasing dosing and at which dose should take into 
consideration the absolute levels and trends of the TSAT and Hgb in the context of the prior 
dose changes, as well as serum phosphorus levels. 
• 
After resolution of an elevated TSAT, an attempt should be made to increase the dose to the 
highest dose tolerated prior to the dose interruption or reduction, if supported by the 
Investigator’s clinical judgement. 
Elevated ferritin: 
An elevated ferritin level alone (ie, ferritin >1000 ng/mL) does not require dose interruption or 
dose reduction because it is a poor indicator of iron stores in patients with CKD.  However, an 
elevated ferritin level should prompt clinical evaluation for inflammation or infection and, in 
review together with the Hgb and TSAT, may lead an Investigator to the decision to interrupt or 
reduce dosing. 
Other laboratory abnormality or AE: 
Another laboratory abnormality or AE may require a dose interruption or reduction.  Upon 
resolution of the laboratory abnormality or AE, the dose should subsequently be resumed and/or 
increased to the highest dose tolerated prior to dose interruption or reduction, if supported by the 
Investigator’s clinical judgement.  
Prohibited Therapies 
The use of IV iron, blood transfusions, phosphate binders other than KRX-0502, oral iron therapy other 
than KRX-0502 as treatment for iron deficiency (multivitamins containing iron are permitted), 
commercial ferric citrate, aluminum-containing therapies, or investigational drugs other than KRX-
0502 will not be permitted at any time during the study (beginning with the Screening visit).  
The use of ESA is also not permitted during the study, except if used in the specifically defined 
scenario of ESA rescue therapy (see Section 9.2.2)  


Protocol - Phase 4 Study 402 
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If a subject receives a dose of IV iron or a blood transfusion, the subject will immediately discontinue 
KRX-0502, complete the Early Termination visit assessments, and exit the study.  Any subject who is 
to receive or has received any prohibited medications other than IV iron or a blood transfusion should 
be discussed with the Medical Monitor as soon as possible to determine the most appropriate course of 
action (see Section 9.2.1 and Section 9.2.2).  
Duration of treatment:  
24-week Dose Titration Period followed by a 24-week Dose Maintenance Period (48 weeks total) 
Reference therapy, dosage and mode of administration:  
Not applicable 
Criteria for evaluation: 
Efficacy: 
Primary endpoint:  
The primary efficacy endpoint is the change in Hgb from Baseline at Week 24.   
Secondary endpoints: 
Secondary endpoints are as follows: 
1. Change in Hgb from Baseline at Week 48 
2. Change in TSAT from Baseline at Weeks 24 and 48 
3. Change in ferritin from Baseline at Weeks 24 and 48 
4. Change in serum phosphate from Baseline at Weeks 24 and 48 
5. Change in scores for Work Productivity and Activity Impairment (WPAI) questionnaire from 
Baseline at Weeks 24 and 48 
6. Change in score of Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale 
from Baseline at Weeks 24 and 48 
7. Number of hospitalizations and duration (days) 
Safety: 
Safety evaluations will be based on the following: 
• 
Incidence, seriousness, intensity, duration, and type of AEs 
• 
Clinically significant changes in the subject’s vital signs and laboratory test results 
Statistical methods: 
Efficacy: 
The change in Hgb from Baseline is the primary endpoint of interest.  Ninety-five percent confidence 
intervals (CI) will be constructed for change from Baseline at Week 24 and change from Baseline at 
Week 48 based on the entire sample and by randomized dose groups.  No imputation will be performed 
for these analyses.   
Additionally, a Mixed Model Repeated Measures model will be fitted to the change from Baseline Hgb 
incorporating all visits at which Hgb is measured for each subject.  Baseline Hgb and randomized dose 
group will be applied as fixed effects, as will time (in weeks) and time-by-dose group interaction.  An 
unstructured within-subject covariance structure will be assumed.  


Protocol - Phase 4 Study 402 
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TSAT, ferritin, and serum phosphorus will be analyzed in a manner similar to the primary endpoint 
stated above.  Changes for the WPAI questionnaire, the FACIT Fatigue Scale, and frequency and 
duration of hospitalizations will be analyzed descriptively. 
Efficacy analyses will be repeated, substituting the dosing sequence groups for the randomized dose 
groups if appropriate, based on the distribution in the 4 dosing sequence groups (3-3, 3-6, 4-4, and 4-6 
tablets/day). The dosing sequence groups will be determined based on actual doses received by each 
subject. 
Safety: 
All safety analyses will be conducted based on the Safety Analysis Set. 
Safety data will include AEs, vital signs, and clinical laboratory measurements.  Observed data will be 
listed by subject and summarized using descriptive statistics overall and by dose group based on the 
Safety Analysis Set.   
AEs will be mapped to preferred term and body system using the Medical Dictionary for Regulatory 
Activities (MedDRA).  AEs that begin after the first administration of study medication or pre-existing 
conditions that worsen after the first dose of study medication are considered treatment-emergent 
adverse events (TEAEs).  The number and percentage of subjects reporting TEAEs will be summarized 
overall and for each randomized dose group by MedDRA system organ class and preferred term, then 
by severity, and by relationship to study treatment.  Drug-related AEs will be considered those that are 
related to study drug based on the Investigator’s assessment.  The number and percentage of subjects 
reporting serious AEs and the number and percentage of subjects reporting AEs leading to treatment 
discontinuation will also be summarized overall and for each dose group by MedDRA system organ 
class and preferred term. 
Vital signs and other clinical and laboratory parameters will be measured at baseline and post-baseline 
visits.  Abnormalities observed in these parameters will be summarized using shift tables for all 
subjects and by randomized dose group. 
Selected safety analyses (including AE analyses) will be repeated substituting the dosing sequence 
groups for the randomized dose groups, if appropriate, based on the distribution of the dosing sequence 
groups. 
Sample Size:  
As this is an open-label Phase 4 study designed to estimate within group changes from Baseline and 
describe time trends of iron parameters in sub-groups of subjects, it is appropriate to conduct a 
precision-based sample size estimation as opposed to a power-based calculation.  The primary endpoint 
of interest is change in Hgb from Baseline at Week 24, for which the standard deviation is estimated as 
0.9 g/dL based on the Week 16 data in a prior Phase 3 study in a similar population (Study 306).   
Assuming a population standard deviation of 0.9 g/dL, with a sample size of 140 subjects, the 95% CI 
for mean change in Hgb from Baseline at Week 24 can be estimated, allowing for a CI half-width of 
0.149 g/dL.  
It is assumed that 30% of the subjects in this study will drop out or be otherwise excluded from the Per 
Protocol population.  Hence, 200 subjects will be randomized to ensure that there will be a sufficient 
number of subjects at the end of the study for the longitudinal analyses.  Based on prior clinical trial 
experience, it is estimated that half of the subjects will stay on their starting dose, and the other half 
will increase their dose after 12 weeks of treatment.  Hence, it is expected that the 4 dosing sequence 
groups that will arise will have approximately equal numbers of subjects (ie, 35 subjects are expected 
in each of the four dosing sequence groups (3-3, 3-6, 4-4, and 4-6 tablets/day). 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
RATIONALE FOR AMENDMENT 1: ...........................................................................................2 
PURPOSES FOR AMENDMENT 1: ..............................................................................................2 
2. 
SYNOPSIS ...................................................................................................................6 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
5. 
INTRODUCTION ......................................................................................................22 
5.1. 
Background .................................................................................................................22 
5.2. 
KRX-0502 (Ferric Citrate) Known Potential Benefits and Risks ..............................23 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................26 
6.1. 
Study Endpoints ..........................................................................................................26 
6.1.1. 
Primary Efficacy Endpoint .........................................................................................26 
6.1.2. 
Secondary Efficacy Endpoint .....................................................................................26 
6.1.3. 
Safety Endpoints .........................................................................................................26 
6.2. 
Study Rationale ...........................................................................................................26 
7. 
INVESTIGATIONAL PLAN .....................................................................................28 
7.1. 
Overall Study Design ..................................................................................................28 
7.2. 
Number of Subjects ....................................................................................................34 
7.3. 
Study Sites ..................................................................................................................34 
7.4. 
Treatment Assignment ................................................................................................34 
7.5. 
Dosing and Dose Adjustment Criteria ........................................................................34 
7.5.1. 
Scheduled Dose Adjustment During the Dose Titration Period .................................35 
7.5.2. 
Unscheduled Dose Adjustments .................................................................................36 
7.6. 
Study Commencement ................................................................................................40 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................42 
8.1. 
Subject Inclusion Criteria ...........................................................................................42 
8.2. 
Subject Exclusion Criteria ..........................................................................................42 
8.3. 
Subject Withdrawal Criteria .......................................................................................44 
8.3.1. 
Discontinuation From Study Drug..............................................................................44 


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8.3.2. 
Discontinuation From Study .......................................................................................44 
8.3.3. 
Deviations From the Protocol .....................................................................................45 
8.4. 
Termination of Study ..................................................................................................45 
9. 
TREATMENT OF SUBJECTS ..................................................................................46 
9.1. 
Description of Study Drug ..........................................................................................46 
9.2. 
Concomitant Medications ...........................................................................................46 
9.2.1. 
Prohibited Therapy .....................................................................................................46 
9.2.2. 
ESA Rescue Therapy ..................................................................................................46 
9.3. 
Treatment Compliance ................................................................................................47 
9.4. 
Randomization and Blinding ......................................................................................47 
10. 
STUDY VISITS AND PROCEDURES .....................................................................48 
10.1. 
Visit 1A (Screening) ...................................................................................................48 
10.1.1. 
Procedures for Visit 1A (Screening) ...........................................................................48 
10.1.1.1. 
Re-testing for Specific Inclusion/Exclusion Criteria ..................................................49 
10.2. 
Visit 1B (Re-screening) ..............................................................................................49 
10.2.1. 
Procedures for Visit 1B (Re-screening) ......................................................................50 
10.2.1.1. 
Screen Failures ............................................................................................................50 
10.3. 
Visit 2 (Randomization/Week 0, Day 1/Baseline) – First Visit of Dose 
Titration Period ...........................................................................................................51 
10.3.1. 
Procedures for Visit 2 .................................................................................................51 
10.4. 
Visits 3 to 8 (Weeks 2 to 20) – Dosing Titration Period ............................................52 
10.4.1. 
Procedures for Visits 3 to 8 ........................................................................................52 
10.5. 
Visit 9 (Week 24) – End of Dose Titration Period .....................................................53 
10.5.1. 
Procedures for Visit 9 .................................................................................................53 
10.6. 
Visits 10 to 12 (Weeks 32 to 48) – Dose Maintenance Period ...................................54 
10.6.1. 
Procedures for Visits 10 and 11 ..................................................................................54 
10.6.2. 
Procedures for Visit 12 (Week 48) and ET Visit ........................................................55 
11. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................56 
11.1. 
Study Drug ..................................................................................................................56 
11.2. 
Study Drug Packaging and Labeling ..........................................................................56 
11.3. 
Administration ............................................................................................................56 
11.4. 
Study Drug Accountability .........................................................................................56 


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11.5. 
Study Drug Storage, Handling, and Disposal .............................................................57 
12. 
ASSESSMENT OF EFFICACY ................................................................................58 
13. 
ASSESSMENT OF SAFETY .....................................................................................59 
13.1. 
Safety Parameters .......................................................................................................59 
13.1.1. 
Demographic/Medical History ...................................................................................59 
13.1.2. 
Vital Signs ..................................................................................................................59 
13.1.3. 
Weight and Height ......................................................................................................59 
13.1.4. 
Laboratory Assessments .............................................................................................59 
13.1.4.2. 
Blood Chemistry .........................................................................................................59 
13.1.4.3. 
Iron Tests ....................................................................................................................59 
13.1.4.4. 
Other Tests ..................................................................................................................60 
13.1.4.5. 
Spot Urine Protein-to-Creatinine Ratio ......................................................................60 
13.1.4.6. 
Frozen Serum Samples ...............................................................................................60 
13.1.4.7. 
Pregnancy Screen ........................................................................................................60 
13.2. 
Adverse and Serious Adverse Events .........................................................................60 
13.2.1. 
Definition of Adverse Events .....................................................................................60 
13.2.1.1. 
Adverse Event .............................................................................................................60 
13.2.1.2. 
Serious Adverse Event ................................................................................................61 
13.2.2. 
Recording Adverse Events/Serious Adverse Events ..................................................62 
13.2.2.1. 
Intensity ......................................................................................................................62 
13.2.2.2. 
Relationship to Study Drug ........................................................................................63 
13.2.2.3. 
Follow-up of Adverse Events .....................................................................................64 
13.2.3. 
Reporting of Serious Adverse Events .........................................................................64 
13.2.4. 
Pregnancy ...................................................................................................................65 
13.3. 
Medical Emergency Unblinding Procedures ..............................................................65 
14. 
CLINICAL PHARMACOLOGY ...............................................................................66 
15. 
STATISTICAL METHODS AND PLANNED ANALYSES ...................................67 
15.1. 
General Considerations ...............................................................................................67 
15.2. 
Determination of Sample Size ....................................................................................67 
15.3. 
Analysis Sets ...............................................................................................................67 
15.3.1. 
Safety Analysis Set .....................................................................................................67 
15.3.2. 
Full Analysis Set .........................................................................................................68 


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15.3.3. 
Per Protocol Analysis Set ...........................................................................................68 
15.4. 
Demographics and Baseline Characteristics ...............................................................68 
15.5. 
Subject Accountability ................................................................................................68 
15.6. 
Study Treatment Usage and Compliance ...................................................................68 
15.7. 
Efficacy Analyses .......................................................................................................68 
15.7.1. 
Primary Efficacy Endpoint Analyses ..........................................................................68 
15.7.2. 
Secondary Efficacy Analyses .....................................................................................69 
15.8. 
Safety Analyses ..........................................................................................................69 
15.8.1. 
Vital Signs ..................................................................................................................69 
15.8.2. 
Clinical Laboratory Tests ...........................................................................................69 
15.8.3. 
Adverse Events ...........................................................................................................70 
15.9. 
Other Analyses ............................................................................................................70 
15.10. 
Other Statistical Issues ................................................................................................70 
15.10.1. 
Significance Levels .....................................................................................................70 
15.10.2. 
Multiple Comparisons/Multiplicity ............................................................................70 
15.10.3. 
Missing or Invalid Data ..............................................................................................70 
15.11. 
Interim Analysis ..........................................................................................................71 
16. 
STUDY MANAGEMENT .........................................................................................72 
16.1. 
Study Monitoring ........................................................................................................72 
16.2. 
Audits and Inspections ................................................................................................72 
16.3. 
Electronic Data Capture ..............................................................................................73 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................74 
18. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
CONSIDERATIONS ..................................................................................................75 
18.1. 
Ethics Review .............................................................................................................75 
18.2. 
Ethical Conduct of the Study ......................................................................................75 
18.3. 
Written Informed Consent ..........................................................................................75 
18.4. 
Patient Confidentiality ................................................................................................76 
18.5. 
Study Master File ........................................................................................................76 
18.6. 
Laboratory Accreditation ............................................................................................76 
18.7. 
Independent Medical Monitor ....................................................................................76 
19. 
DATA HANDLING AND RECORDKEEPING .......................................................78 


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19.1. 
Inspection of Records .................................................................................................78 
19.2. 
Retention of Records ..................................................................................................78 
19.3. 
Financial Disclosure ...................................................................................................78 
20. 
PUBLICATION POLICY ..........................................................................................79 
21. 
LIST OF REFERENCES ............................................................................................80 
22. 
APPENDICES ............................................................................................................82 
APPENDIX A. WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT (WPAI) 
QUESTIONNAIRE ....................................................................................................83 
APPENDIX B. FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY 
(FACIT) FATIGUE SCALE QUESTIONNAIRE .....................................................85 
APPENDIX C. AMENDMENT 1 DETAILED SUMMARY OF CHANGES ..........................86 
 


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LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................20 
Table 2: 
Schedule of Assessments ............................................................................................31 
Table 3: 
Scheduled Study Drug Titration After Visit 6 (Week 12) ..........................................36 
 


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LIST OF FIGURES 
Figure 1: 
Study Periods ..............................................................................................................30 
Figure 2: 
KRX-0502 Dosing Algorithm: Serum Phosphorus <2.0 mg/dL ................................38 
Figure 3: 
KRX-0502 Dosing Algorithm: Serum Phosphorus ≥2.0 to<2.5 mg/dL .....................39 
Figure 4: 
KRX-0502 Dosing Algorithm: TSAT ≥50% ..............................................................40 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AM 
Ante meridiem (before midday) 
AST 
Aspartate aminotransferase 
BID 
Twice daily 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CCP 
Complete chemistry profile 
CI 
Confidence interval 
CKD 
Chronic kidney disease 
CRO 
Contract Research Organization 
DAR 
Drug Accountability Record 
DD-CKD 
Dialysis-dependent chronic kidney disease 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated glomerular filtration rate 
ESA 
Erythropoiesis-stimulating agents  
ET 
Early Termination 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FGF23 
Fibroblast growth factor 23 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HCT 
Hematocrit 
Hgb 
Hemoglobin  
ICH 
International Council for Harmonisation 
IDA 
Iron deficiency anemia 
IEC 
Independent Ethics Committee 


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Abbreviation or Specialist Term 
Explanation 
iPTH 
Intact parathyroid hormone 
IRB 
Institutional Review Board 
IV 
Intravenous  
IWRS 
Interactive Web and Voice Response System 
KDIGO 
Kidney Disease:  Improving Global Outcomes 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MMRM 
Mixed Model Repeated Measures 
NDD-CKD 
Non-dialysis dependent chronic kidney disease 
PI 
Principal Investigator 
PP 
Per Protocol 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
sNDA 
Supplemental new drug application 
TEAE 
Treatment-emergent adverse event 
TIBC 
Total iron-binding capacity 
TID 
3 times daily 
TSAT 
Transferrin saturation 
UIBC 
Unsaturated iron-binding capacity 
US 
United States 
WBC 
White blood cell 
WBC differential 
White blood cell types 
WPAI 
Work Productivity and Activity Impairment 
 


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5. 
INTRODUCTION 
5.1. 
Background  
Chronic kidney disease (CKD) affects up to 14.8% of adults in the United States (US) [USRDS 
2016] and markedly increases the risk of premature cardiovascular events [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 [Hgb] <13g/dL for men; <12 g/dL for women), the 
guidelines suggest a trial of iron to increase the Hgb 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 Hgb levels.  When 
prescribing iron therapy, the guidelines recommend to “balance the potential benefits of avoiding 
or minimizing blood transfusions, erythropoiesis-stimulating agents (ESA) therapy, and anemia-
related symptoms against the risks of harm in individual subjects (eg, anaphylactoid and other 
acute reactions, unknown long-term risks).”  
For CKD patients on dialysis iron is usually given intravenously, but oral iron is preferred in 
patients with non-dialysis dependent chronic kidney disease (NDD-CKD) for its convenience 
and low cost.  However, the tolerability and efficacy of currently available oral iron formulations 
is often limited by gastrointestinal side effects, poor adherence to therapy, and poor absorption 
[Drüeke 2012; Cancelo-Hidalgo 2013; Macdougall 2016].  Intravenous (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 in-office 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.  
ESA are another treatment modality for anemia of CKD that is widely used in dialysis-dependent 
chronic kidney disease (DD-CKD) patients but safety concerns due to excess cardiovascular risk 
for ESA resulted in black box warnings in 2007.  Fewer than 1 in 5 patients with NDD-CKD 
currently receive ESA therapy prior to initiating dialysis [Regidor 2011; Miskulin 2013].  
As a result, many patients with NDD-CKD and anemia today are not optimally treated.  For 
instance, the 2016 Annual Report from the United States Renal Data System finds that the 
average Hgb for patients initiating dialysis is only 9.6 g/dL [USRDS 2016].   


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5.2. 
KRX-0502 (Ferric Citrate) Known Potential Benefits and Risks 
Ferric citrate was developed as a phosphate binder because it reacts with the phosphate in the 
gastrointestinal (GI) tract when administered with food, precipitating phosphate as ferric 
phosphate.  The latter is insoluble and excreted in the stool, reducing the amount of phosphate 
that is absorbed from the GI tract and lowering serum phosphorus levels.  In 2014, KRX-0502 
(ferric citrate) was approved in the US for the control of serum phosphorus levels in patients with 
CKD on dialysis.  Additionally, ferric citrate is authorized under different tradenames in Europe, 
Japan, and Taiwan in subjects with DD-CKD, and in Europe for the control of serum phosphorus 
in patients with NDD and DD-CKD. 
Not all of the elemental iron from ferric citrate precipitates with phosphate, and some is absorbed 
in the GI tract, thereby providing iron available for erythropoiesis.  Indeed, the pivotal trial of 
KRX-0502 that gained its FDA approval as a phosphate binder in dialysis patients (Study 304) 
[Lewis 2015] showed that KRX-0502 increases iron stores and reduces IV iron and 
erythropoietin-stimulating agent use while maintaining Hgb.  The observation of this 
well-tolerated iron delivery in dialysis patients prompted the investigation of KRX-0502 as a 
treatment for IDA in NDD-CKD patients.  
KRX-0502 has now shown efficacy in Phase 2 and Phase 3 trials of IDA in NDD-CKD in the 
absence of concomitant ESA and IV iron.  The 2 adequate and well-controlled studies in the 
development program for IDA in NDD-CKD are described below. 
Study 306 [Fishbane 2017] was a pivotal Phase 3 study specifically designed to measure the 
effect of KRX-0502 on IDA in adults with Stage 3 to 5 NDD-CKD.  Eligible patients had been 
intolerant to or had an inadequate response to other oral irons.  The objectives of Study 306 were 
to compare the efficacy and safety of KRX-0502 to placebo as a treatment for IDA in a 16-week, 
randomized, double-blind period, followed by an 8-week, open-label period.  The starting dose 
of KRX-0502 was 3 g/day and titrated up to a maximum of 12 g/day based on Hgb response.  
During the randomized period, the dose was uptitrated by 3 tabs/day every 4 weeks if the Hgb 
increase from baseline was ≤1 g/dL.  The study drug was given with food, and IV iron and ESA 
were prohibited.  The primary endpoint was the proportion of subjects who achieved an increase 
in Hgb of ≥1.0 g/dL at any point from Baseline through Week 16.  During the Randomized 
Period, the average KRX-0502 dose was 5 tabs/day.  The average dose over successive 4 weekly 
intervals during the randomized period was approximately 3.0, 4.8, 6.9, and 7.9 tabs/day.  
Study 204 [Block 2014] was a prior well-controlled Phase 2 study designed to measure the effect 
of KRX-0502 on serum phosphorus and IDA in adults with NDD-CKD.  The objectives of Study 
204 were to compare the efficacy and safety of KRX-0502 to placebo as a treatment for IDA and 
hyperphosphatemia in a 12-week, randomized, double-blind study.  The starting dose of KRX-
0502 was 3 g/day and titrated up to a maximum of 12 g/day based on serum phosphorus levels.  
The study drug was given with food, and IV iron and ESA were prohibited.  The co-primary 
endpoints were the changes from Baseline at Week 12 in TSAT and serum phosphorus levels.  
The average KRX-0502 dose was 5.1 tabs/day.  
In Study 306, the difference in the proportions of subjects with a ≥1 g/dL increase in Hgb 
between the KRX-0502 and placebo groups was 33% (52.1% responders in KRX-0502 vs 19.1% 
in Placebo, p<0.001).  The difference in response rates between KRX-0502 and placebo did not 


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vary across subgroups by age, sex, race, CKD stage, or baseline Hgb.  The analysis of time to 
first Hgb increase of ≥1.0 g/dL from Baseline to Week 16 in Study 306 shows a continuous 
increase in responses over the entire duration of the randomized period and this explains the 
greater increase in Hgb observed in this study compared to Study 204 which had a 4-week 
shorter treatment duration.  In Study 204, the difference in the proportions of subjects with a ≥1 
g/dL increase in Hgb between the KRX-0502 and placebo groups was 24% (41.7% responders in 
KRX-0502 vs 17.4% in Placebo, p=0.002).  
In both studies (Study 204 and Study 306), KRX-0502 treatment resulted in clinically 
meaningful increases in Hgb, with concurrent increases in TSAT and ferritin levels, which were 
statistically significantly different than placebo treatment, where the levels did not increase.  In 
Study 306, the treatment group difference for the LS mean change from Baseline at Week 16 
was 0.84 g/dL for Hgb, 18.4% for TSAT, and 170.3 ng/mL for ferritin (all p<0.001).  
Statistically significant treatment differences were seen after 1 to 2 weeks of treatment. 
KRX-0502 also lowered phosphate levels in both studies.  This was a desired effect in 
Study 204, where subjects were hyperphosphatemic at baseline.  In Study 306, where mean 
baseline phosphate was still in the normal range (4.2 mg/dL), the phosphate reduction was 
modest and phosphate levels rarely went below the lower limit of the normal range (2.5 to 
4.5 mg/dL) 
The IDA development program further includes a supportive study (Study 207), which was a 
small, uncontrolled, pilot study in which the study drug was given without food and at a lower 
dose than in the 2 adequate and well-controlled studies (Studies 306 and 204).  Study 207 was a 
Phase 2, single-arm, open-label study for the treatment of IDA in subjects with Stage 3 to 5 
NDD-CKD.  Subjects were treated for 8 weeks and the primary efficacy endpoint was the change 
in Hgb from Baseline at Week 8.  The starting dose of KRX-0502 was 1 g/day, which could be 
increased to 2 g/day or reduced to 1 g/2 days, depending on the Hgb response by Week 4.  The 
study drug was given without food, and IV iron and ESA were not permitted.  The average 
KRX-0502 dose was 1.2 tabs/day. 
The Hgb change from Baseline at Week 8 demonstrated a non-statistically significant trend 
(0.3 mg/dL, p=0.06).  Increases in TSAT and ferritin were statistically significant with the mean 
change from Baseline at Week 8 in TSAT of 4.4% (p=0.0142) and the mean change from 
Baseline at Week 8 in ferritin of 38.7 ng/mL (p=0.0003).  The changes in Hgb, TSAT, and 
ferritin observed in Study 207 were smaller than those observed in the adequate- and well-
controlled studies but were consistent, considering the shorter treatment duration and lower dose.  
The safety of KRX-0502 has been well characterized.  To date, there have been over 
1900 subjects exposed to KRX-0502 in clinical studies in the 2 development programs for 
hyperphosphatemia in predominantly DD-CKD and for IDA in NDD-CKD.  Four clinical studies 
(1 study in NDD-CKD and 3 in DD-CKD) included treatment for up to 1 year.  KRX-0502 was 
generally well tolerated and showed a similar safety profile in patients with DD-CKD and 
NDD-CKD.  The most frequently reported adverse events (AEs) were in the gastrointestinal 
system (diarrhea, nausea, constipation, vomiting, and discolored feces) and were generally mild 
to moderate in severity.  


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As of 06 November 2017, KRX-0502 (ferric citrate) is approved in the US as "an iron 
replacement product indicated for the treatment of iron deficiency anemia in adult patients with 
chronic kidney disease not on dialysis."   


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6. 
STUDY OBJECTIVES AND PURPOSE 
The objectives of this study are to assess the long-term efficacy and safety of different dose 
regimens of KRX-0502 in the treatment of IDA in adult subjects with NDD-CKD. 
6.1. 
Study Endpoints 
6.1.1. 
Primary Efficacy Endpoint  
The primary efficacy endpoint is the change in Hgb from Baseline at Week 24. 
6.1.2. 
Secondary Efficacy Endpoint 
The secondary endpoints of this study are as follows: 
1. Change in Hgb from Baseline at Week 48 
2. Change in TSAT from Baseline at Weeks 24 and 48 
3. Change in ferritin from Baseline at Weeks 24 and 48 
4. Change in serum phosphate from Baseline at Weeks 24 and 48 
5. Change in scores for Work Productivity and Activity Impairment (WPAI) questionnaire 
from Baseline at Weeks 24 and 48 (see Appendix A) 
6. Change in score of Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue 
Scale from Baseline at Weeks 24 and 48 (see Appendix B) 
7. Number of hospitalizations and duration (days) 
6.1.3. 
Safety Endpoints 
Safety evaluations will be based on the following: 
• Incidence, seriousness, intensity, duration, and type of AEs 
• Clinically significant changes in the subject’s vital signs and laboratory test results. 
6.2. 
Study Rationale  
Previous clinical studies in both the NDD-CKD and DD-CKD populations have demonstrated 
the ability of KRX-0502 to increase Hgb, TSAT, and ferritin, as well as to reduce serum 
phosphate and fibroblast growth factor 23 (FGF23).  In Study 306, this was achieved with 
repeated prompt uptitration of KRX-0502 to optimize the rapidity of the response and spare 
patients who had been intolerant to or had an inadequate response to other oral irons any 
repeated exposure to those agents or treatment initiation with IV iron or ESA.  
The current study has been designed to estimate the effect of different dosing regimens of KRX-
0502 as chronic therapy for IDA in NDD-CKD.  KRX-0502 will be started at 1 of 2 treatment 
regimens (1 tablet 3 times daily [TID] or 2 tablets twice daily [BID]) utilizing a slower titration 
and lower maximal dose relative to the 2 prior adequate and well-controlled studies (Study 306 
and Study 204).  Patients will be observed for a longer duration on treatment than in these prior 
studies to describe longer-term trends of Hgb and iron parameters in the different groups.  Less 


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frequent visits will more closely align with the office visit frequency in routine clinical care.  
Thus, the study will serve to directly inform the real-world management of patients with NDD-
CKD and IDA treated with KRX-0502. 
This Phase 4 study was named the COMPASS trial. The name was chosen to denote that this 
trial is designed to provide additional direction for the use of KRX-0502 in the anticipated “real 
world” setting. The name is not an acronym. 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a 48-week, Phase 4, randomized, open-label, multicenter clinical study, comprised of 
2 periods:  a 24-week Dose Titration Period followed by a 24-week Dose Maintenance Period 
(Figure 1).  The study will consist of approximately 12 scheduled clinic visits over a period of 
48 weeks with additional visits as needed.  There will be a Screening period of up to 21 days.  
Two Hundred (200) eligible subjects with non-dialysis dependent CKD and IDA will be 
randomized in the study into 1 of 2 active treatment groups: 
• Group 1:  KRX-0502 1 tablet TID (total of 3 tablets/day) with meals 
• Group 2:  KRX-0502 2 tablets BID (total of 4 tablets/day) with the largest 2 daily 
meals 
Study drug dose adjustment will occur at Week 12 and will be based upon the Hgb increase 
relative to Baseline and an Hgb threshold.  Those subjects with an Hgb increase of ≥0.5 g/dL 
from Baseline and an Hgb ≥10 g/dL will maintain the same dose as determined at 
Randomization; subjects with an Hgb increase <0.5 g/dL from Baseline (at Randomization) or an 
Hgb <10 g/dL will have their dose of KRX-0502 increased to the following: 
• Group 1:  KRX-0502 2 tablets TID (total of 6 tablets/day) with meals 
• Group 2:  KRX-0502 3 tablets BID (total of 6 tablets/day) with the largest 2 daily 
meals 
Detailed guidance on dosing and dose adjustments is provided in Section 7.5.  
A complete blood count (CBC; including white blood cell [WBC], white blood cell types [WBC 
differential], red blood cell [RBC] count, hematocrit (HCT), Hgb, RBC indices and platelet 
[thrombocyte] count) will be performed at Visit 1A (Screening) and, if applicable, Visit 1B 
(Re-screening); Visit 2 (Randomization); and all subsequent visits. 
A complete chemistry profile (CCP; including sodium, potassium, phosphorus, calcium [adjusted 
for albumin], chloride, carbon dioxide/bicarbonate, glucose, blood urea nitrogen [BUN], 
creatinine, eGFR, aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline 
phosphatase [ALP], total bilirubin, total protein, and albumin) will be performed at Visit 1A 
(Screening) and, if applicable, Visit 1B (Re-screening); Visit 2 (Randomization); and all 
subsequent visits. 
Iron studies (TSAT, ferritin, unsaturated iron-binding capacity [UIBC], total iron-binding 
capacity [TIBC] and serum iron) will be performed at Visit 1A (Screening) and, if applicable, 
Visit 1B (Re-screening); Visit 2 (Randomization); and all subsequent visits. 
FGF23 (intact and C-terminal) testing will be performed at Visit 2 (Randomization), Visit 9 
(Week 24), Visit 12 (Week 48), and the Early Termination (ET) visit. 
Intact parathyroid hormone (iPTH) testing will be performed at Visit 1A (Screening) and, if 
applicable, Visit 1B (Re-screening); Visit 2 (Randomization); Visit 9 (Week 24); Visit 12 (Week 
48); and the ET visit. 


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Subjects should take KRX-0502 orally with meals or snacks or within 1 hour after their meals or 
snacks.  
Visits need to occur in the morning, non-fasted and subjects instructed to hold KRX-0502 until 
blood is drawn.  This is to standardize blood draws to occur at trough levels at least 10 to 12 
hours after last study drug intake on the day before the visit, because iron parameters rise acutely 
in the hours following oral intake [Kobune 2011]. 
A schedule of assessments is presented in Table 2. 
 


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Figure 1: 
Study Periods 
 
BID=twice daily; Hgb=hemoglobin; TID=3 times daily. 
1 g =1 tablet of KRX-0502.  All doses of study drug will be taken with food.  Treatment groups on a BID regimen will be dosed with the 2 largest meals of the 
day.   
Scheduled study drug titration to occur after Visit 6 in Week 12 of Dose Titration Period. 


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Table 2: 
Schedule of Assessments 
 
Screening/ 
Baseline 
Dose Titration Period 
Dose Maintenance Period 
Visit  
1A 
Screening 
Visit  
1B  
Re -Screeninga 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11 
Visit 
12 
ET 
Visit 
Day 
 -21 to -1 
Day 
-21 to-1 
Randomizationb 
W0 (Day 1) 
W2 
±3 d 
W4 
±3 d 
W8 
±5 d 
W12 
±5 d 
W16 
±5 d 
W20 
±5 d 
W24 
±5 d 
W32 
±7 d 
W40 
±7 d 
W48 
±7 d 
 
Informed consentc 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusiond 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical historye  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Vital signsef 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/record 
study drug dose; 
review diaryh 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant non-
drug therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test 
(serum) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBCi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Screening/ 
Baseline 
Dose Titration Period 
Dose Maintenance Period 
Visit  
1A 
Screening 
Visit  
1B  
Re -Screeninga 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11 
Visit 
12 
ET 
Visit 
Day 
 -21 to -1 
Day 
-21 to-1 
Randomizationb 
W0 (Day 1) 
W2 
±3 d 
W4 
±3 d 
W8 
±5 d 
W12 
±5 d 
W16 
±5 d 
W20 
±5 d 
W24 
±5 d 
W32 
±7 d 
W40 
±7 d 
W48 
±7 d 
 
Iron studiesj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete chemistry 
profilek 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
iPTH 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
iFGF23, cFGF23 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Serum for freezing 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Spot urine for 
protein-to-creatinine 
ratio 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
WPAI questionnaire 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
FACIT Fatigue Scale 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Hospitalizations and 
duration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
KRX-0502 dose 
titrationl 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
AE=adverse event; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CBC=complete blood count; cFGF23= C-terminal fibroblast growth factor 23; EOS=End of 
Study; ET=Early Termination; FACIT=Functional Assessment of Chronic Illness Therapy; HCT=hematocrit; Hgb=hemoglobin; iFGF23=intact fibroblast growth factor 23; 
iPTH=intact parathyroid hormone; RBC=red blood cell; TIBC=total iron-binding capacity; UIBC= unsaturated iron-binding capacity; W=week; WBC= white blood cell; WBC 
differential=white blood cell types; WPAI=Work Productivity and Activity Impairment. 
Note: All visits other than screening need to occur in the morning, non-fasted and subjects instructed to hold KRX-0502 until blood is drawn (see Section 7.1), 
a Visit 1B (Re-screening) is optional and may be completed if subject screen fails after first screening and is eligible to be re-screened. 
b Randomization should occur as soon as possible, but no later than 21 days from the date of Screening or Re-screening. All assessments must be performed prior to randomization 
c No more than 7 days before Screening or Re-screening. 


Protocol - Phase 4 Study 402 
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d During Screening and/or Re-screening, subjects may be re-tested for specific inclusion and exclusion criteria that were not met at the initial testing.  If a re-test is conducted, it 
needs to occur within 10 days of Screening (Visit 1A) or Re-screening (Visit 1B) (see Section 10.1.1.1). 
e Significant pre-existing medical conditions prior to receiving first dose of study medication. 
f Includes seated heart rate and blood pressure after at least 5 minutes of rest. 
g AEs will be collected starting at the time of informed consent. 
h Diary will be dispensed at Visit 2 and collected at Visit 12 or ET visit. 
i CBC includes WBC count, WBC differential, RBC count, HCT, Hgb, RBC indices, and platelet (thrombocyte) count. 
j Iron studies includes TSAT, ferritin, UIBC, TIBC, and serum iron. Labs to be drawn as trough levels (see Section 7.1). 
k Complete chemistry profile includes sodium, potassium, phosphorus, calcium, calcium (adjusted for albumin), chloride, carbon dioxide/bicarbonate, glucose, BUN, creatinine, 
eGFR, total protein, albumin, total bilirubin, alkaline phosphatase, AST and ALT. 
l All subjects will be evaluated for dose increase at Week 12; subjects with an Hgb increase <0.5 g/dL from Baseline (randomization) or an Hgb <10 g/dL at Week 12 will have 
their dose increased as described in Section 7.5. 


Protocol - Phase 4 Study 402 
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7.2. 
Number of Subjects 
Approximately 600 adult subjects with NDD-CKD and IDA will be screened to yield 
200 subjects eligible for randomization.  Eligible subjects will be randomized in a 1:1 ratio into 1 
of 2 active treatment groups.  It is expected that each of these treatment groups will have 
70 evaluable subjects at the end of the study (Section 15.2). 
7.3. 
Study Sites 
There will be approximately 30 sites in the US participating in this study.  Each site may 
randomize a maximum of 25 subjects. 
7.4. 
Treatment Assignment 
Following a Screening visit, eligible subjects will be randomized in a 1:1 ratio into the 24-week 
Dose Titration Period.  Subjects who complete the Dose Titration Period will continue treatment 
with KRX-0502 in the 24-week Dose Maintenance Period at the dose determined in the Dose 
Titration Period.  
7.5. 
Dosing and Dose Adjustment Criteria 
KRX-0502 will be supplied as tablets containing 1 g ferric citrate (210 mg of ferric iron).  
Subjects should take KRX-0502 orally with meals or snacks or within 1 hour after their meals or 
snacks.  Subjects on a TID regimen should take their daily dose as equally distributed (with 
meals/snacks throughout the day) as possible, and subjects on a BID regimen should take their 
daily dose with the 2 largest daily meals.  A subject who is randomized to a TID dose regimen 
but eats only 2 meals per day should be instructed to take the third daily dose with a snack.  
Subjects will be instructed to initiate dosing the day after randomization. 
The frequency of dosing (eg, TID and BID) should be maintained.  However, subjects may 
require different dose distributions in a given day due to snacks, missed meals, or a study visit.  
If the subject is receiving the total number of pills per day required by protocol in any 
distribution with meals or snacks, the distribution does not need to be approved by the Medical 
Monitor or Keryx. A KRX-0502 tablet should not be divided.  
Visits need to occur in the morning, non-fasted and subjects instructed to hold KRX-0502 until 
blood is drawn.  On a visit day, the morning dose should be taken after the blood draw with a 
meal or snack or added to the dose with the next meal or snack. 
This is a fixed dose study with 1 scheduled dose titration step at Week 12.  The starting dose is 
determined at Randomization (ie, 3 or 4 g/day depending on randomized group).  The maximum 
dose before Week 12 is the dose determined at Randomization.  The maximum dose after 
Week 12 is the dose determined at Week 12, ie, 3, 4, or 6 g/day depending on the randomized 
group and dose titration at Week 12.  Only subjects who complete the 24-week Dose Titration 
Period will be eligible to enter the Dose Maintenance Period.  During the Dose Maintenance 
Period, subjects will continue on the dose determined during the Dose Titration Period.  The 
maximum dose is the dose determined at Week 12.  


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
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Unscheduled dose adjustments can be made at any time during the study for AEs or abnormal 
laboratories (see Section 7.5.2).  
All dose changes should be based on Central Laboratory values.  Laboratory results will be 
checked at each scheduled visit, and the dose may be adjusted in response to these results.  When 
repeat testing of laboratory values is necessary, it will be done as an unscheduled visit, unless it 
coincides with a scheduled visit.  Repeat laboratory testing to guide KRX-0502 dosing should 
include a CBC, iron studies, and CCP.  The Investigator should contact the subject as soon as 
possible after review of the laboratory results for any scheduled or unscheduled dose 
adjustments.  
Additional information regarding drug-drug interactions is provided in Section 14. 
7.5.1. 
Scheduled Dose Adjustment During the Dose Titration Period 
Scheduled study drug titration will occur in Week 12 and will be based upon the Hgb increase 
relative to Baseline and an Hgb threshold.  The Baseline assessment value is the last non-missing 
value prior to the subject’s first dose of study medication.  If the Week 12 assessment is missing, 
the Hgb increase from Baseline will be assessed based on the first non-missing value after 
Week 12.  
Those subjects with an Hgb increase of ≥0.5 g/dL from Baseline and an Hgb ≥10 g/dL will 
maintain the same dose as determined at Randomization; subjects with an Hgb increase 
<0.5 g/dL from Baseline or an Hgb <10 g/dL will have their dose of KRX-0502 increased as 
shown in Table 3. 
Due to the random variability of Hgb values, if a Hgb level at Visit 6 (Week 12) appears not 
plausible (as defined as more than 1 g/dL difference from the most recent Hgb value obtained in 
the prior 6 weeks), the Investigator may choose to repeat it.  In that case, the Hgb from the repeat 
laboratory draw will determine the dose titration. 
For subjects with a scheduled dose titration, the dose change should begin the day after 
notification.  


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
36 
 
 
  
 
Table 3: 
Scheduled Study Drug Titration After Visit 6 (Week 12) 
Study Drug Titration at Week 12 
Group 1 (starting dose: 1 tablet TID with meals) 
 
Hgb increase ≥0.5 g/dL from Baseline and 
an Hgb ≥10 g/dL  
No change 
 
Hgb increase <0.5 g/dL from Baseline or 
an Hgb <10 g/dL 
2 tablets TID (total of 6 tablets/day) with meals 
Group 2 (starting dose: 2 tablets BID with mealsa) 
 
Hgb increase ≥0.5 g/dL from Baseline and 
an Hgb ≥10 g/dL 
No change  
 
Hgb increase <0.5 g/dL from Baseline or 
an Hgb <10 g/dL 
3 tablets BID (total of 6 tablets/day) with mealsa 
BID=twice daily; Hgb=hemoglobin; TID=3 times daily. The baseline assessment value is the last non-missing value 
prior to the subject’s first dose of study medication. 
a Dose to be taken with the largest 2 daily meals 
7.5.2. 
Unscheduled Dose Adjustments 
Unscheduled dose adjustments may be necessary at any point during the study.  Below guidance 
and the dosing algorithms depicted in Figure 2, Figure 3, and Figure 4 aim to assist the 
Investigator with decision making about dose modification in the presence of laboratory 
abnormalities or AEs.  They are not intended to define a standard of care, nor should they be 
interpreted as prescribing an exclusive course of management.  Investigators are responsible for 
evaluating the appropriateness of applying these guidelines to any particular clinical situation for 
an individual subject.  Dose interruption refers to holding of the drug, usually for a short term 
with the intent to resume dosing when possible.  To discuss dosing decisions, including extended 
dose interruption, Investigators should contact the Medical Monitor. 
• Serum phosphorus <2.5 mg/dL: 
• If serum phosphorus is <2.0 mg/dL, interrupt dosing.  
− Two weeks after interrupting the dose, repeat the laboratory tests: 
 If serum phosphorus is ≥2.5 mg/dL, resume dosing at the dose prior to the 
dose interruption.  
 If serum phosphorus is ≥2.0 to <2.5 mg/dL, resume dosing at a reduced dose 
compared to the dose prior to the dose interruption.  
 If serum phosphorus is <2.0, continue dose interruption. 
• If serum phosphorus is ≥2.0 to <2.5 mg/dL, reduce the KRX-0502 dose by 1 to 
3 tablets/day without complete dose interruption.  
− Two weeks after reducing the dose, repeat the laboratory tests: 
 If serum phosphorus is ≥2.5 mg/dL, increase the dose to the dose prior to the 
dose reduction.  


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
37 
 
 
  
 
 If serum phosphorus is ≥2.0 to <2.5 mg/dL, reduce the dose again. 
 If serum phosphorus is <2.0 mg/dL, interrupt dosing. 
• Decisions about resuming or increasing dosing and at which dose should take into 
consideration the absolute levels and trends of the serum phosphorus in the context of 
the prior dose changes as well as Hgb and TSAT. 
• After resolution of a low serum phosphorus, an attempt should be made to increase 
the dose to the highest dose tolerated prior to the dose interruption or reduction, if 
supported by the Investigator’s clinical judgement. 
TSAT ≥50%: 
• If TSAT is ≥50%, repeat laboratory tests with care to assure that the blood draw is 
performed before dosing with KRX-0502.  
− If the repeat TSAT is ≥70%, interrupt dosing.  
− If the repeat TSAT is ≥50 and <70%, the response should consider the Hgb level.  
 If Hgb is ≥12 g/dL, interrupt dosing.  
 If Hgb is <12 g/dL, reduce the dose.  
− If the repeat TSAT is <50%, continue current dose and repeat laboratory tests at 
the next scheduled visit. 
• After a dose reduction, repeat laboratory tests at the next scheduled visit. 
• Two weeks after interrupting dosing, repeat laboratory tests.  
− If the repeat TSAT is ≥70%, continue dose interruption and repeat laboratory tests 
after 2 weeks.  
− If TSAT is <70%, consult the Medical Monitor.  
• Decision about resuming and increasing dosing and at which dose should take into 
consideration the absolute levels and trends of the TSAT and Hgb in the context of 
the prior dose changes, as well as serum phosphorus levels. 
• After resolution of an elevated TSAT, an attempt should be made to increase the dose 
to the highest dose tolerated prior to the dose interruption or reduction, if supported 
by the Investigator’s clinical judgement. 
Elevated ferritin: 
An elevated ferritin level alone (ie, ferritin >1000 ng/mL) does not require dose interruption or 
dose reduction because it is a poor indicator of iron stores in patients with CKD.  However, an 
elevated ferritin level should prompt clinical evaluation for inflammation or infection and, in 
review together with the Hgb and TSAT, may lead an Investigator to the decision to interrupt or 
reduce dosing. 


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Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
41 
 
 
  
 
Form (eCRF) completion and serious adverse event (SAE) reporting, and overall responsibilities, 
including those for drug accountability and Study Master File maintenance. 


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
42 
 
 
  
 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
Subject eligibility should be reviewed and documented by an appropriately qualified member of 
the Investigator’s study team before subjects are included in the study. 
Subjects must meet all of the following inclusion criteria to be eligible to participate in this 
study:  
1. Age ≥18 years 
2. Men and women. Women of childbearing potential must have a negative serum 
pregnancy test at Screening 
3. eGFR ≥20 mL/min and <60 mL/min at Screening 
4. Hgb ≥8.5 g/dL and ≤11.5 g/dL at Screening 
5. Serum ferritin ≤500 ng/mL and TSAT ≤25% at Screening 
6. Serum iPTH ≤600 pg/mL at Screening 
7. Must consume a minimum of 2 meals per day 
8. Willing and able to give written informed consent 
9. Female subjects who are not surgically sterile (by bilateral tubal ligation, bilateral 
oophorectomy, or hysterectomy) or postmenopausal (no menstrual period within 1 year 
of Screening) must agree to use adequate contraception throughout the study and for at 
least 4 weeks following their final study visit.  Adequate contraception is defined as: 
a. Total abstinence from sexual intercourse starting at least 1 complete menstrual cycle 
prior to Screening visit, or 
b. Having a vasectomized partner, or  
c. Use of hormonal contraceptives (oral, parenteral, or transdermal) for at least 3 months 
prior to study drug administration or intrauterine contraception/device, or  
d. Use of a double-barrier method (such as male condom, female condom, diaphragm, 
sponge, or cervical cap together with spermicidal foam/gel/film/suppository) starting 
at Screening  
There is no restriction for female partners of male subjects. 
8.2. 
Subject Exclusion Criteria 
Subjects will be excluded if they meet any of the following criteria: 
1. Serum phosphate <3.0 mg/dL at Screening 
2. Liver transaminases (ALT or AST) >3× upper limit of normal at Screening 
3. IV iron administered within 4 weeks prior to Screening or during the Screening Period 
4. ESA administered within 4 weeks prior to Screening or during the Screening Period 
5. Blood transfusion within 4 weeks prior to Screening or during the Screening Period 


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
43 
 
 
  
 
6. Treatment with any investigational drug within 4 weeks prior to Screening or during the 
Screening Period 
7. Cause of anemia other than iron deficiency anemia of CKD 
8. Symptomatic gastrointestinal bleeding within 12 weeks prior to Screening or during the 
Screening Period 
9. Symptomatic inflammatory bowel disease within 12 weeks prior to Screening or during 
the Screening Period 
10. Dialysis within 12 weeks prior to Screening or during the Screening Period, or initiation 
of dialysis planned within 6 months following Screening 
11. Kidney transplant recipient or kidney transplant scheduled within 6 months following 
Screening 
12. Planned surgery or hospitalization (anticipated to last >72 hours) in the 6 months 
following Screening other than dialysis access-related surgery 
13. Requires treatment with myelosuppressive therapy and/or immunosuppressive therapy at 
Screening or during the Screening Period 
14. Requires treatment with oral corticosteroids at Screening or during the Screening Period 
(use of low-dose oral corticosteroids, eg, ≤5 mg/day prednisone or the relative equivalent 
dose of another corticosteroid, is not an exclusion); IV corticosteroids administered 
within 2 weeks prior to Screening or during the Screening Period. 
15. Active infection requiring treatment with antibiotics at Screening or during the Screening 
Period 
16. Malignancy except for subjects that have been disease-free for at least 2 years after 
curative therapy or non-melanoma skin cancer regardless of treatment 
17. History of hemochromatosis 
18. Subjects who are pregnant or breast feeding 
19. Active drug or alcohol dependence or abuse (excluding tobacco use or medicinal or 
recreational marijuana use where legal unless there is evidence of abuse) within the 
12 months prior to Screening or evidence of such abuse (in the opinion of the 
Investigator) 
20. Subjects with known allergic reaction to previous oral iron therapy 
21. Prior treatment with KRX-0502 
22. Any other medical condition that, in the opinion of the Investigator, renders the subject 
unable or unlikely to complete the study or that would interfere with optimal participation 
in the study or produce significant risk to the subject 


Protocol - Phase 4 Study 402 
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13 December 2017 
 
 
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8.3. 
Subject Withdrawal Criteria 
8.3.1. 
Discontinuation From Study Drug 
Discontinuation from study drug is defined as a permanent termination of treatment with 
KRX-0502.  Subjects may be discontinued from the study drug at any time for any of the 
following reasons: 
• Adverse event 
• Lack of efficacy (see Section 9.2.2) 
• Pregnancy 
• Withdrawal by subject 
• Other 
If at any time during the course of the study, in the opinion of the Investigator, the subject may 
no longer safely participate due to a change in medical status (eg, experiences an AE, becomes 
pregnant), the subject must be discontinued from the study drug.  
Whenever study drug is discontinued prematurely, Keryx and the Medical Monitor must be 
notified.  The subject should return for the ET visit and exit the study. 
8.3.2. 
Discontinuation From Study 
Subjects may discontinue from the study for the following reasons: 
• Discontinuation from study drug (see Section 8.3.1) 
• Subject withdrawal of consent 
• Lost to follow-up 
• Study drug non-compliance 
• Investigator judgment 
• Use of certain prohibited therapies (see Section 9.2.1 and Section 9.2.2) 
• Start of chronic dialysis or kidney transplantation 
• Death 
• Sponsor termination of study 
• Other 
The Investigator should inquire about the reason for withdrawal, request the subject to return all 
unused investigational product, request the subject to return for a final ET Visit as soon as 
possible to undergo the assessments specified for the visit, and follow-up with the subject 
regarding any unresolved AEs.  For ETs that occur on or after the day of study drug initiation, 
every effort should be made to document the subject’s outcome, regardless of cause.  Whenever 
a subject is discontinued prematurely, Keryx and the Medical Monitor must be notified. 


Protocol - Phase 4 Study 402 
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13 December 2017 
 
 
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8.3.3. 
Deviations From the Protocol 
A protocol deviation is defined as an event where the Investigator or site personnel do not 
conduct the study according to the investigational plan or the Study Site Investigator agreement.  
Protocol deviations are neither encouraged nor allowed unless there are special circumstances.  
The Sponsor or the Medical Monitor will not grant waivers for eligibility criteria.   
Investigators are required to obtain prior approval from the Sponsor or the Medical Monitor 
before initiating deviations from the investigational plan or protocol, except where necessary to 
protect the life or physical well-being of a subject in an emergency.  Such approval will be 
documented in writing and maintained in study files.  Prior approval is generally not expected in 
situations where unforeseen circumstances are beyond the Investigator’s control, (eg, subject did 
not attend scheduled follow-up visit or clinical sample lost by laboratory); however, the event is 
still considered a deviation. 
Keryx will not assume responsibility or liability for any unauthorized deviation from, or change 
to the protocol. 
The Per Protocol (PP) population will exclude subjects with major protocol deviations.  Details 
of the criteria for exclusion from the PP population will be provided in the Statistical Analysis 
Plan (SAP). 
8.4. 
Termination of Study 
Throughout the course of the study, the Investigator shall make every effort to maintain the 
enrollment rate of appropriate subjects at a level previously determined by Keryx as reasonable.  
Should the enrollment rate lag or significant numbers of clearly non-evaluable subjects be 
entered, the Sponsor may elect to terminate the study.  
The Sponsor also has the right at any time to terminate the study at specific sites for subject 
safety, non-adherence to the protocol, unavailability of Investigators or study staff for monitoring 
visits, or administrative reasons. 


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
The term “study drug” refers to KRX-0502 (ferric citrate).  All subjects will be initiated on a 
fixed dose of KRX-0502 as determined at Randomization. 
Study drug titration will occur at Week 12 as described in Section 7.5. 
9.2. 
Concomitant Medications 
All prescription and over-the-counter medications taken at Visit 1A (Screening) and thereafter 
must be noted on the eCRF as confirmed with the subject. 
9.2.1. 
Prohibited Therapy 
Administration of any of the following therapies to subjects enrolled in the study starting with 
the Screening visit is not permitted: 
1. IV iron 
2. Blood transfusion 
3. ESA with exception specified in Section 9.2.2  
4. Oral iron therapy other than KRX-0502 as treatment for iron deficiency (multivitamins 
containing iron are permitted) 
5. Phosphate binder other than KRX-0502 
6. Commercial ferric citrate 
7. Aluminum-containing therapies 
8. Investigational drug other than the KRX-0502 
If a subject receives a dose of IV iron or a blood transfusion (items 1 and 2 listed above), the 
subject will immediately discontinue study drug, complete the ET Visit assessments, and exit the 
study.   
If a subject is to receive or has received any prohibited medication listed under items 3 to 8 
above, the subject should be discussed with the Medical Monitor as soon as possible to 
determine the most appropriate course of action.  
9.2.2. 
ESA Rescue Therapy 
ESA use is not permitted during the study. The exception is a scenario in which all of the 
following conditions for ESA rescue therapy are met: 
1. A subject has had 2 consecutive Hgb values of <8.0 g/dL more than 3 days apart. 
2. The Investigator decides to treat the subject with ESA as per standard of care. 
3. The Investigator deems it appropriate for the subject to continue in the study. 
4. The subject continues in the study on study drug.  


Protocol - Phase 4 Study 402 
Amendment 1 
 
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Any subject who is to receive or has received ESA therapy regardless of whether its use 
constitutes permitted ESA rescue therapy or not should be discussed with the Medical Monitor as 
soon as possible to decide whether the subject may remain in the study. 
Subjects who received ESA during the study and who remain in the study will be excluded from 
the PP analysis set. Subgroup analyses will be conducted for these subjects. 
Subjects who have had 2 consecutive Hgb values of <8.0 g/dL more than 3 days apart but do not 
meet the other criteria of ESA rescue therapy should complete the ET visit and discontinue from 
the study.  
9.3. 
Treatment Compliance 
Study personnel will instruct the subjects on the correct number of tablets to take each day with 
their meals or snacks.  Subjects will be given a diary to record daily drug intake.  Subjects will 
be instructed to return with their bottle(s) of medication and their diary at each visit so that 
compliance may be assessed. 
9.4. 
Randomization and Blinding 
As described in Section 7.2, in this open-label study, eligible subjects will be randomized 1:1 to 
1 of the 2 KRX-0502 groups with approximately 100 subjects per group: 
• Group 1:  KRX-0502 1 tablet TID (total of 3 tablets/day) with meals 
• Group 2:  KRX-0502 2 tablets BID (total of 4 tablets/day) with the largest 2 daily 
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10. 
STUDY VISITS AND PROCEDURES 
10.1. 
Visit 1A (Screening) 
Iron-deficient anemic subjects with NDD-CKD who have an Hgb ≥8.5 g/dL and ≤11.5 g/dL will 
be approached to participate in this study.  Subjects must sign an informed consent form prior to 
the initiation of any study-related activities and must qualify based on all inclusion criteria 
(Section 8.1) and exclusion criteria (Section 8.2) to be eligible for this study.  Visit 1 (Screening) 
must occur within 7 days of signing the informed consent form.  
To be eligible for the study, the test results from Visit 1A must include an Hgb ≥8.5 g/dL and 
≤11.5 g/dL, serum ferritin ≤500 ng/mL, TSAT ≤25%, iPTH ≤600 pg/mL, and a negative serum 
pregnancy test (if applicable).  The subject must also meet all other eligibility criteria.  The 
subject, if eligible, will then be instructed to proceed to Randomization (W0, Day 1).  Subject 
randomization should occur as soon as possible, but no later than 21 days from the date of 
Visit 1A (Screening). 
10.1.1. 
Procedures for Visit 1A (Screening)  
• Obtain informed consent form (no more than 7 days before Screening) 
• Review and record inclusion and exclusion criteria including but not limited to the 
following:  
− Confirming subject has not been administered IV iron, ESA, or blood transfusions 
in the last 4 weeks prior to Screening 
• Obtain clinically significant medical history (pre-existing medical conditions 
including ongoing signs and symptoms) 
• Obtain demographic information 
• List current medications 
• Instruct subject to stop any oral iron treatment (multivitamin containing iron is 
permitted) and oral phosphate binder 
• Instruct subject about non-permitted medications (Section 9.2.1) 
• List current non-drug therapies 
• Record weight and height 
• Record vital signs (seated heart rate and blood pressure after at least 5 minutes of 
rest) 


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• Obtain blood samples: 
− CBC 
− Iron studies 
− CCP 
− iPTH 
− Serum pregnancy test for women of childbearing potential 
• Record AEs since signing informed consent and ensure that no recent event has 
impacted the subject’s ability to participate in the study 
• Enroll subject using Interactive Web and Voice Response System (IWRS) to obtain 
unique subject number based on site number and sequential screening order of subject 
• Schedule next visit 
At this and each subsequent visit, the Investigator will ensure that the procedures used for blood 
collection and processing are completed in accordance with guidelines provided in this protocol 
(see Section 7.1 for instructions on timing of trough blood draws).  All laboratory samples will 
be sent to the Sponsor-designated Central Laboratory.  The Central Laboratory will provide all 
materials and procedures for the collection of laboratory samples sent to the Central Laboratory. 
It is the Investigator’s decision, in consultation with the Medical Monitor if needed, to re-test or 
re-screen a subject.  A subject will maintain the original screening ID for re-testing or re-
screening. 
10.1.1.1. Re-testing for Specific Inclusion/Exclusion Criteria  
During screening and/or re-screening (if applicable), subjects may be re-tested for specific 
inclusion and exclusion criteria that were not met at the initial testing.  If a re-test is conducted, it 
needs to occur within 10 days of Screening (Visit 1A) or Re-screening (Visit 1B).  For example, 
a subject with a TSAT above the eligibility threshold may be re-tested after discontinuation of an 
oral iron medication that the subject received up to the Screening visit, or, a subject with a 
phosphorus level below the eligibility threshold may be retested after discontinuation of an oral 
phosphate binders that the subject received up to the Screening visit.  Retesting for an iron 
parameter should be done by retesting all iron studies, retesting for phosphorus should be done 
for phosphorus only.  The results from the second test should be used to assess eligibility.  
However, results from both the first test and the second test should be recorded in the eCRF. 
10.2. 
Visit 1B (Re-screening) 
Depending on the reason for screen failure, subjects may be re-screened for study entry at least 
2 weeks after their original screen failure date.  Re-screening will include re-evaluation of all 
inclusion and exclusion criteria.  


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10.2.1. 
Procedures for Visit 1B (Re-screening) 
• Obtain informed consent form (no more than 7 days before Re-screening) 
• Review and record inclusion and exclusion criteria including but not limited to the 
following:  
− Confirming subject has not been administered IV iron, ESA, or blood transfusions 
in the last 4 weeks prior to Screening 
• Obtain clinically significant medical history (pre-existing medical conditions 
including ongoing signs and symptoms) 
• Obtain demographic information 
• List current medications 
• Instruct subject to stop any oral iron treatment (multivitamin containing iron is 
permitted) and oral phosphate binder 
• Instruct subject about non-permitted medications (Section 9.2.1) 
• List current non-drug therapies 
• Record weight and height 
• Record vital signs (seated heart rate and blood pressure after at least 5 minutes of 
rest) 
• Obtain blood samples: 
− CBC 
− Iron studies 
− CCP 
− iPTH 
− Serum pregnancy test for women of childbearing potential 
• Record AEs since signing informed consent and ensure that no recent event has 
impacted the subject’s ability to participate in the study 
• Enroll subject using previously obtained unique subject number assigned by IWRS 
• Schedule next visit  
Retesting for specific inclusion/exclusion criteria may be conducted during re-screening, as 
detailed in Section 10.1.1.1.  
10.2.1.1. Screen Failures 
After screening (i.e. a maximum of 21 days after the Screening visit), subjects who do not meet 
all the inclusion and exclusion criteria will be considered screen failures.  Screen failure eCRFs 
will be completed and the subject’s screen failure status will be captured on the appropriate log. 


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10.3. 
Visit 2 (Randomization/Week 0, Day 1/Baseline) – First Visit of Dose 
Titration Period 
Randomization should occur within 3 weeks after Screening.  Prior to randomizing a subject into 
the study, it should be verified that the subject still meets all eligibility criteria, and did not 
develop an intercurrent issue, start a prohibited medication, or require hospitalization since 
Screening.  If the subject is not eligible, the subject will be considered a screen failure. 
On the first visit of the 24-week Dose Titration Period, eligible subjects will be randomized in a 
1:1 ratio to receive 1 of 2 dosing regimens of KRX-0502.   
The starting dose of study drug is determined at Randomization as described in Section 9.4. 
The site will contact the IWRS for randomization for each subject at Visit 2 (Randomization) at 
which time the randomization number will be assigned by the IWRS. 
Subjects who consume only 2 meals a day and who are randomized to the TID dosing group 
should be instructed to take the third daily dose with a snack. 
10.3.1. 
Procedures for Visit 2 
• Review and record inclusion/exclusion criteria confirming that the subject meets all 
eligibility criteria 
• Record weight 
• Record vital signs 
• Record AEs (ensure that AEs have not impacted the subject’s ability to participate in 
the study) 
• Record hospitalizations and duration (ensure that the hospitalization has not impacted 
the subject’s ability to participate in the study) 
• Record changes in concomitant medications or non-drug therapies 
• Instruct subject about non-permitted medications (see Section 9.2.1 and Section 9.2.2) 
• Obtain blood samples: 
− CBC 
− CCP 
− Iron studies  
− iPTH 
− FGF23 (intact and C-terminal) 
− Serum sample for freezing 
• Obtain spot urine for protein-to-creatinine ratio 
• Administer FACIT Fatigue Scale  
• Administer the WPAI questionnaire 


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• Assign randomization number through IWRS 
• Dispense study drug and diary and instruct on use of diary 
• Instruct subjects on the number of tablets to take each day and how they are to be 
taken with meals or snacks (see Section 7.5) 
• Schedule next visit for AM and instruct subject to hold KRX-0502 on visit day until 
blood is drawn (see Section 7.1) 
Additional information regarding drug-drug interactions is provided in Section 14.  For dosing 
and dose adjustment criteria, see Section 7.5. 
10.4. 
Visits 3 to 8 (Weeks 2 to 20) – Dosing Titration Period 
During the Dose Titration Period, Hgb will guide dose titration at Visit 6 (Week 12).  Provided 
the subject’s increase in Hgb from Baseline is <0.5 g/dL or Hgb <10 g/dL, the subject’s dose will 
be increased at this visit as described in Section 7.5.  If a subject’s Hgb increase from Baseline is 
≥0.5 g/dL and Hgb >10 g/dL, the subject’s dose will not be titrated. 
The maximum dose of study drug will be 3 or 4 tablets/day up to Visit 6 (Week 12), and the 
maximum dose thereafter will be the dose determined by the dose titration at Week 12.  At any 
time, the Investigator can reduce, interrupt, or discontinue the dose of study drug due to an AE or 
other safety reason.  If there are any questions regarding titration of the dose of KRX-0502, the 
Investigator should contact the Medical Monitor.  For additional guidance, refer to Section 7.5. 
If an unscheduled dose reduction or interruption is necessary due to a laboratory abnormality or 
an AE, upon resolution of the laboratory abnormality or AE the dose should be resumed and/or 
subsequently increased to the highest dose tolerated prior to dose reduction or interruption, if 
supported by the Investigator’s clinical judgement.  
Visits need to occur in the morning, non-fasted and subjects instructed to hold KRX-0502 until 
blood is drawn.  The morning dose can be taken after the blood draw with a snack or with the 
next meal. 
It is expected that dose adjustments will be communicated via telephone to the subject as soon as 
possible after receipt of laboratory values to ensure the longest possible amount of time on the 
new dose prior to the next scheduled visit. 
10.4.1. 
Procedures for Visits 3 to 8 
• Record vital signs 
• Review laboratory results from previous visit 
• Record AEs  
• Record hospitalizations and duration 
• Record changes in concomitant medications and non-drug therapies 
• Review whether any non-permitted medications were administered since the last visit 
and instruct subject about non-permitted medications (see Section 9.2.1 and 
Section 9.2.2) 


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• Obtain blood samples: 
− CBC (every visit) 
− Iron studies (every visit) 
− CCP (every visit)  
• Record study drug dosing, review diary, and assess study drug compliance 
• Dispense study drug 
• Schedule next visit for AM and instruct subject to hold KRX-0502 on visit day until 
blood is drawn (see Section 7.1) 
• At Visit 6 (Week 12), assess the subject for scheduled dose titration (see Section 7.5.1 
and Table 3).  If necessary, notify the subject (via telephone) as soon as possible 
following receipt of laboratory results to titrate study drug dose  
For dosing and dose adjustment criteria, see Section 7.5.  
10.5. 
Visit 9 (Week 24) – End of Dose Titration Period 
Visit 9 (Week 24) is the final visit of the Dose Titration Period for all subjects. 
Only subjects who complete Visit 9 (Week 24) on study drug will enter the Dose Maintenance 
Period. 
10.5.1. 
Procedures for Visit 9 
• Record weight 
• Record vital signs 
• Review laboratory results from previous visit 
• Record AEs  
• Record hospitalizations and duration 
• Record changes in concomitant medication and non-drug therapies 
• Review whether any non-permitted medications were administered since the last visit 
and instruct subject about non- permitted medications (see Section 9.2.1 and 
Section 9.2.2) 
• Obtain blood samples: 
− CBC 
− CCP 
− Iron studies 
− iPTH 
− FGF23 (intact and C-terminal) 


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− Serum sample for freezing 
• Record study drug dosing, review diary, and assess study drug compliance 
• Dispense study drug 
• Administer WPAI questionnaire 
• Administer FACIT Fatigue Scale  
• Schedule next visit for AM and instruct subject to hold KRX-0502 on visit day until 
blood is drawn (see Section 7.1) 
For dosing and dose adjustment criteria, see Section 7.5.  
10.6. 
Visits 10 to 12 (Weeks 32 to 48) – Dose Maintenance Period 
Only subjects who complete the 24-week Dose Titration Period will be eligible to enter the Dose 
Maintenance Period following Week 24. 
During the Dose Maintenance Period, subjects will continue on the dose determined during the 
Dose Titration Period.  There will be no scheduled dose adjustment other than that on Week 12.  
If an unscheduled dose reduction or interruption is necessary due to an AE or abnormal 
laboratory value, the dose may be subsequently increased back to the previous dose upon 
resolution of the event/laboratory abnormality. 
Instructions for unscheduled dose interruption (Section 7.5.2) and reduction, dose resumption, 
and dose increase (Section 7.5), as the case may be, apply also to the Dose Maintenance Period. 
If an unscheduled dose reduction or interruption is necessary due to an AE or an abnormal 
laboratory value, upon resolution of the laboratory abnormality or AE the dose should be 
resumed and/or subsequently increased to the highest dose tolerated prior to dose reduction or 
interruption, if supported by the Investigator’s clinical judgement. 
Visits need to occur in the morning, non-fasted and subjects instructed to hold KRX-0502 until 
blood is drawn. The morning dose can be taken after the blood draw with a snack or with the 
next meal. 
10.6.1. 
Procedures for Visits 10 and 11 
• Record vital signs 
• Review laboratory results from previous visit 
• Record AEs 
• Record changes in concomitant medications or non-drug therapies 
• Review whether any non-permitted medications were administered since the last visit 
(see Section 9.2.1 and Section 9.2.2) 
• Instruct subject about non-permitted medications (see Section 9.2.1 and Section 9.2.2) 
• Record hospitalizations and duration 
• Obtain blood samples: 


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− CBC (every visit) 
− CCP (every visit) 
− Iron studies (every visit) 
• Record study drug dosing, review diary, and assess study drug compliance (every 
visit) 
• Dispense study drug 
• Schedule next visit for AM and instruct subject to hold KRX-0502 until blood is 
drawn (see Section 7.1) 
For dosing and dose adjustment criteria, see Section 7.5.  
10.6.2. 
Procedures for Visit 12 (Week 48) and ET Visit 
• Record weight 
• Record vital signs 
• Review laboratory results from previous visit 
• Record AEs 
• Record hospitalizations and duration 
• Review whether any non-permitted medications were administered since the last visit 
(see Section 9.2.1 and Section 9.2.2) 
• Record changes in concomitant medication and non-drug therapies 
• Obtain blood samples: 
− CBC 
− CCP 
− Iron studies 
− iPTH  
− FGF23 (intact and C-terminal) 
− Serum sample for freezing 
• Record study drug dosing, review diary, and assess study drug compliance 
• Collect study drug and diary 
• Administer WPAI questionnaire  
• Administer FACIT Fatigue Scale  


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11. 
STUDY DRUG MATERIALS AND MANAGEMENT 
11.1. 
Study Drug 
KRX-0502 (ferric citrate) will be supplied as tablets containing 1g ferric citrate (210 mg of ferric 
iron). 
11.2. 
Study Drug Packaging and Labeling 
KRX-0502 will be supplied to subjects in bottles of 200 tablets.  The following information will 
be provided on the label:   
• protocol number 
• Sponsor name and address 
• compound/code/name of investigational drug 
• number of tablets  
• Investigational New Drug statement 
• instructions for use and storage  
• blank space for site number, subject number, and date opened  
• lot number  
• expiration date 
Study personnel will instruct the subjects on the correct number of tablets to take with their 
meals or snacks.  Subjects will be instructed to return with their bottle(s) of medication at each 
visit so that compliance may be assessed.  Unused medication will be re-dispensed to the 
subjects at the end of each visit.  When needed, a new bottle of medication will also be dispensed 
to ensure that the subjects have enough medication to last until their next visit. 
KRX-0502 packaging will be labeled to indicate that the drug is to be used only for 
investigational purposes and is to be kept out of the reach of children. 
11.3. 
Administration 
Keryx or its official designee will supply study drug.  The study drug is to be prescribed by only 
the Investigator or his/her designee.  Under no circumstances will the Investigator allow the 
study drug to be used other than as directed by the protocol without prior Keryx approval. 
Subjects will be instructed to return all unused study drug to the Investigator at each visit or upon 
discontinuation of participation (for any reason). 
11.4. 
Study Drug Accountability 
Keryx or its official designee will supply a Drug Accountability Record (DAR) to the Principal 
Investigator (PI).  The PI and his/her designee must maintain the DAR or a suitable site 
substitute for this record.  The site will complete the DAR with dates and quantities of all drug 
shipments received from Keryx or its official designee, as well as the dates and quantities of all 


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drug supplies returned to Keryx or its official designee.  The DAR must be made available for 
inspection by authorized representatives of Keryx, its official designee, and the FDA or 
appropriate regulatory authorities. 
Study personnel are responsible for the accountability of used and unused study drug.  
11.5. 
Study Drug Storage, Handling, and Disposal 
All study drug, used and unused, must be stored in the original containers in a secure area at the 
study site (eg, locked cabinet or pharmacy) protected from light and moisture.  Storage 
temperature should be between 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C 
to 30°C (59°F to 86°F).  Temperature excursions out of this range should be promptly reported to 
Keryx for determination of product use and recording of any necessary protocol deviations.  
Upon completion of the study, the PI must return all used containers and unused drugs to Keryx 
or its official designee for destruction. 


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12. 
ASSESSMENT OF EFFICACY  
The primary efficacy endpoint is the change in Hgb from Baseline at Week 24. 
The secondary endpoints for this study are as follows: 
1. Change in Hgb from Baseline at Week 48 
2. Change in TSAT from Baseline at Weeks 24 and 48 
3. Change in ferritin from Baseline at Weeks 24 and 48 
4. Change in serum phosphate from Baseline at Weeks 24 and 48 
5. Change in scores of WPAI questionnaire from Baseline at Weeks 24 and 48 
6. Change in FACIT Fatigue Scale from Baseline at Weeks 24 and 48 
7. Number of hospitalizations and duration (days) 
 


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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety Parameters 
13.1.1. 
Demographic/Medical History 
Subject demographic and clinically significant medical history information will be collected at 
Visit 1A (Screening) and, if applicable, Visit 1B (Re-screening). 
13.1.2. 
Vital Signs 
Vital signs (seated heart rate and blood pressure after at least 5 minutes of rest) will be recorded 
at Visit 1A (Screening) and, if applicable, Visit 1B (Re-screening); Visit 2 (Randomization); and 
all subsequent visits. 
13.1.3. 
Weight and Height 
Subject weight and height will be measured at Visit 1A (Screening) and, if applicable, Visit 1B 
(Re-screening).  Weight will also be measured at Visit 2 (Randomization), Visit 9 (Week 24), 
Visit 12 (Week 48), and ET Visit. 
13.1.4. 
Laboratory Assessments 
All laboratory values for this study will be determined by a Sponsor-designated Central 
Laboratory.  The Central Laboratory will provide all materials and procedures for the collection 
of laboratory samples to be sent to the Central Laboratory.  Decisions regarding study drug 
dosing should be based on Central Laboratory test results only.  If local laboratory tests are 
conducted as part of routine care and there are discrepancies between the Central Laboratory and 
local laboratory test results, the Investigator should use their clinical judgment and consult the 
Medical Monitor as needed.   
Only Central Laboratory test results will be used for statistical analyses. 
13.1.4.1. Hematology 
A CBC (WBC count, WBC differential, RBC count, HCT, Hgb, RBC indices, platelet 
[thrombocyte] count) will be performed at Visit 1A (Screening) and, if applicable, Visit 1B 
(Re-screening); Visit 2 (Randomization); and all subsequent visits. 
13.1.4.2. Blood Chemistry 
A CCP (sodium, potassium, phosphorus, calcium, calcium [adjusted for albumin], chloride, 
carbon dioxide/bicarbonate, glucose, BUN, creatinine, eGFR, AST, ALT, ALP, total bilirubin, 
total protein, and albumin) will be performed at Visit 1A (Screening) and, if applicable, Visit 1B 
(Re-screening); Visit 2 (Randomization); and all subsequent visits 
13.1.4.3. Iron Tests 
Iron studies (TSAT, ferritin, UIBC, TIBC, and serum iron) will be performed at Visit 1 A 
(Screening) and, if applicable, Visit 1B (Re-screening); Visit 2 (Randomization); and all 
subsequent visits. 


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13.1.4.4. Other Tests 
FGF23 (intact and C-terminal) will be performed at Visit 2 (Randomization), Visit 9 (Week 24), 
Visit 12 (Week 48), and the ET visit. 
iPTH will be performed at Visit 1A (Screening) and, if applicable, Visit 1B (Re-Screening); 
Visit 2 (Randomization); Visit 9 (Week 24); Visit 12 (Week 48); and the ET visit. 
13.1.4.5. Spot Urine Protein-to-Creatinine Ratio 
Spot urine protein-to-creatinine ratio will be measured at Visit 2 (Randomization) 
13.1.4.6. Frozen Serum Samples 
For subjects that provide informed consent specifically for collection of serum samples for 
freezing, serum samples will be obtained at Visit 2 (Randomization), Visit 9 (Week 24), Visit 12 
(Week 48), and the ET visit.  The serum samples obtained will be frozen for future analysis of 
biomarkers of CKD.  One candidate biomarker is Klotho for which efforts are underway to 
develop a better standard assay [Hu 2013].  Thus, the testing is deferred.  The future analysis will 
only be for biomarkers of CKD such as Klotho, there will be no genetic testing done with the 
frozen specimens at any point. 
13.1.4.7. Pregnancy Screen 
Serum pregnancy test for all women of childbearing potential will be performed at Visit 1A 
(Screening) and, if applicable, Visit 1B (Re-screening).  Post-menopausal women must be 
amenorrheic for at least 12 months to be considered of non-childbearing potential. 
13.2. 
Adverse and Serious Adverse Events 
13.2.1. 
Definition of Adverse Events 
All AEs spontaneously reported by the subject and/or in response to an open question from the 
study personnel or revealed by observation, regardless of treatment group or suspected causal 
relationship to the study drug, will be recorded on the AE eCRF. 
13.2.1.1. Adverse Event 
An AE is any untoward medical occurrence in a subject or clinical study subject administered a 
medicinal (investigational) product and which does not necessarily have a causal relationship 
with the study treatment. 
An AE can therefore be any unfavorable and unintended sign (eg, an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product.  Any worsening of a pre-existing condition 
that is temporally associated with the use of the study drug (ie, occurs after the first dose of study 
drug) is also considered an AE and should be captured as “worsening” of the pre-existing 
condition. 


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13.2.1.2. Serious Adverse Event 
The definitions and reporting requirements to which full adherence will be ensured during the 
conduct of the study are:  1) ICH Guidelines for Clinical Safety Data Management, Definitions 
and Standards for Expedited Reporting Topic E2A; 2) Code of Federal Regulations 312.12 IND 
Safety Reporting.  
The Investigator or the Sponsor may determine the seriousness of an AE based on the criteria 
below.  
An AE is considered serious if at least one of the following conditions apply: 
• Death:  An AE that results in the death of a subject.  The cause of death or AE that 
resulted in a fatal outcome should be recorded and reported as the SAE 
• Life-threatening:  An AE that places the subject in the view of the Investigator or the 
Sponsor, at immediate risk of death from the event as it occurred (ie, this does not 
include an event that, had it occurred in a more severe form, might have caused 
death). 
• Disability/Incapacity:  An AE that results in a persistent or significant 
disability/incapacity or substantial disruption of the subject’s ability to conduct 
normal life functions. 
• Hospitalization/Prolongation of Hospitalization:  An AE that results in subject 
hospitalization or prolongation of an existing hospitalization.  Hospitalization refers 
to admission of a subject to a hospital for any length of time. 
The following instances do not constitute hospitalization for the purposes of SAE 
reporting: 
− Routine treatment or monitoring of the studied indication, not associated with any 
worsening in the baseline condition  
− Elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing of the informed 
consent 
− Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above and not resulting in a hospital admission for 
patient care 
− Social reasons and respite care in the absence of any worsening in the patient’s 
baseline condition 
• Congenital anomaly/birth defect:  A fixed, permanent impairment established at or 
before birth in the offspring of a study subject 
• Important Medical Event:  Medical and scientific judgment should be exercised in 
determining whether an event is an important medical/medically significant event.  
An important medical event may not result in death, be life-threatening, or require 
hospitalization.  However, if it is determined that the event may jeopardize the subject 
and/or may require intervention to prevent one of the other outcomes listed in the 


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SAE definition provided above, the important medical event should be reported as 
serious/SAE.  Examples of such events are intensive treatment in an emergency room 
for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization 
13.2.2. 
Recording Adverse Events/Serious Adverse Events 
All AEs/SAEs will be collected for all randomized subjects from the date informed consent was 
signed to completion of the study or to the last administration of study drug or the 
Investigator/subject decision to discontinue treatment, whichever occurs later.  Subjects will be 
followed for a 28-day follow-up period that begins with completion of the study or after the last 
administration of study drug, or after the Investigator/subject decision to discontinue treatment, 
whichever occurs later. 
An SAE that occurs during the 28-day follow-up period must be collected regardless of 
relationship to study drug.  
Any SAE reported to the Investigator following completion of the 28-day follow-up period must 
be promptly reported to the study’s Sponsor if it is considered “related” by the Investigator.   
The AE term should be reported in standard medical terminology when possible.  For each AE, 
the Investigator will evaluate and report the following: 
• Seriousness  
• Relationship to study drug  
• Action taken with the study drug  
• Onset date  
• Ongoing or resolution date  
• Outcome 
• Intensity (if applicable)  
For all AEs, the Investigator must pursue and obtain information adequate to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
(Section 13.2.1.2) requiring immediate action. 
Changes in laboratory values, blood pressure, and pulse need not be reported as AEs.  However 
abnormal values that are deemed clinically significant, lead to discontinuation of administration 
of study drug, or constitute an SAE must be reported and recorded as an AE.  
13.2.2.1. Intensity 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal day-to-day 
activities) 
• Severe (incapacitating, with inability to perform normal day-to-day activities) 


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It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 13.2.1.2.  An AE of severe intensity 
may not be considered serious if it does not meet any of the seriousness criteria listed in 
Section 13.2.1.2. 
13.2.2.2. Relationship to Study Drug 
An Investigator who is licensed in medicine must make the determination of causal relationship 
to the study drug for each AE.  
The Investigator should use his/her knowledge of the patient, the circumstances surrounding the 
event, and an evaluation of any potential alternative causes to determine whether an AE is 
considered unrelated or related to study drug.   
The following factors should be taken into consideration for determination of relationship to 
study drug: 
• Temporal relationship of event onset to the initiation of study drug 
• Course of the event, considering the effects of dose reduction 
• The effects of study drug discontinuation or re-introduction (if applicable) 
• Known association of the AE to ferric citrate therapy or with similar treatments 
• Known association of the AE with the disease under study 
• Presence of risk factors for the AE in the subject or use of concomitant medications 
known to be associated with the AE 
• Presence of non-treatment-related factors that are anticipated or known to be 
associated with the occurrence of the AE (eg, conditions associated with the progress 
of the underlying disease) 
Unrelated:  The AE is considered “unrelated” to ferric citrate (study drug) if: 
• there is evidence that clearly indicates an alternative explanation, 
• the subject has not received study drug, 
• the timing of the exposure to study drug and the onset of the AE are not reasonably 
associated in time, or  
• other facts, evidence or arguments exist that suggest an alternative cause or 
explanation 
Related: The AE is considered “related” to ferric citrate (study drug) if: 
• administration of study drug and the AE are considered reasonably associated in time,  
• the AE could be explained by exposure to study drug or by other causes, or no 
alternative has been identified,  


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• there is biological plausibility for the causal relationship between the AE and the 
study drug, and 
• there is no alternative cause identified for the AE to occur. 
13.2.2.3. Follow-up of Adverse Events 
There should be routine follow-up of AEs in all subjects.  Appropriate diagnostic tests should be 
performed and therapeutic measures, as medically indicated and per standard of care, should be 
instituted.  Appropriate consultation and follow-up evaluations should be carried out.  
All SAEs and related AEs will be followed until the event is resolved, clinically stable, or 
otherwise explained by the Investigator (eg, returned to baseline, is chronic/irreversible).  
After the 28-day follow-up period, only unresolved SAEs should be followed at least every 
4 weeks until they resolve, improve to baseline level (for “worsening of a pre-existing 
condition”), or are clinically stable and chronic/irreversible.  
Any related SAE occurring after the 28-day follow-up period should be followed at least every 
4 weeks until it is resolved, clinical stable, or otherwise explained by the Investigator (eg, has 
returned to baseline, is chronic/irreversible) 
The Medical Monitor or Sponsor may specify a longer period of follow-up time for AEs if 
required to assure the safety of the subject.  
13.2.3. 
Reporting of Serious Adverse Events 
All SAEs must be reported on the AE eCRF to the study Sponsor within 24 hours of becoming 
aware of the SAE.   
The Sponsor will notify all Investigators of all reportable SAEs that are unexpected per 
Investigator’s Brochure and considered related to the study drug.  This notification will be in the 
form of an expedited safety report.  Upon receiving such notices, the Investigator must review 
and retain the notice with other study-related documentation. 
For all SAEs, the Investigator is obligated to pursue and provide information to the study 
Sponsor.  In addition, the Investigator may be requested by the study Sponsor to obtain specific 
information in an expedited manner.  This information may be more detailed than that captured 
on the AE eCRF.  In general, this will include a description of the AE in sufficient detail to allow 
for a complete medical assessment of the case and independent determination of possible causal 
relationship.  Information on other possible causes such as concomitant medications and 
concurrent illnesses must be provided as applicable. 
The Investigator, Sponsor, and Institutional Review Board (IRB) will determine if the informed 
consent requires revision.  The Investigator will comply with the IRB or the Independent Ethics 
Committee (IEC) procedures for reporting any other safety information. 
Suspected serious adverse reactions and other significant safety issues reported from the study 
shall be reported to the relevant regulatory authorities by the study Sponsor in full adherence to 
the guidelines and regulations. 


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13.2.4. 
Pregnancy 
All pregnancies must be reported and recorded on Keryx’s pregnancy form.  Pregnancy itself is 
not regarded as an AE unless there is an AE associated with the pregnancy and/or pregnancy 
outcome and a suspicion that the study drug may have caused or have been associated with this 
AE. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous 
abortions/miscarriages should also be reported and handled as SAEs.  Elective abortions without 
complications should not be recorded as AEs. 
13.3. 
Medical Emergency Unblinding Procedures 
This is an open-label study. 


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14. 
CLINICAL PHARMACOLOGY 
An interaction with KRX-0502 was seen with doxycycline and ciprofloxacin.  Doxycycline 
should be taken at least 1 hour before KRX-0502.  Ciprofloxacin should be taken at least 2 hours 
before or after KRX-0502. 
The following drugs, by drug category, did not show an interaction with KRX-0502: 
• Antibiotics:  levofloxacin 
• Anticoagulants/antiplatelets:  aspirin, clopidogrel, and warfarin 
• Antidiabetics:  sitagliptin 
• Antihyperlipidemics:  atorvastatin, fluvastatin and pravastatin 
• Antihypertensives:  amlodipine, enalapril, metoprolol, and propranolol 
• Cardiac glycoside:  digoxin 
• Vitamin D analogues:  calcitriol and doxercalciferol 
Consider separation of the timing of the administration of KRX-0502 with drugs where a 
reduction in their bioavailability would have a clinically significant effect on safety or efficacy.  
Monitor blood levels of concomitant medications that have a narrow therapeutic range. 


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15. 
STATISTICAL METHODS AND PLANNED ANALYSES 
15.1. 
General Considerations 
All statistical analyses will be performed using Version 9.4 or later of Statistical Analysis 
Software (SAS®). 
Data summaries will use descriptive statistics (number of subjects [n], mean, standard deviation 
[SD], median, minimum, and maximum) for continuous variables and frequency and percentage 
for categorical and ordinal variables.  If there are missing values, the number missing will be 
presented but without a percentage.   All data collected will be included in by-subject data 
listings. 
15.2. 
Determination of Sample Size 
Because this is an open-label Phase 4 study designed to estimate within-group changes from 
Baseline and describe time trends of iron parameters in sub-groups of subjects, it is appropriate 
to conduct a precision-based sample size estimation as opposed to a power-based calculation.  
The primary endpoint of interest is change in Hgb from Baseline at Week 24.  The SD for that 
endpoint is estimated as 0.9 g/dL based on the Week 16 data in a prior Phase 3 study in a similar 
population (Study 306).   
Assuming a population SD of 0.9 g/dL, with a sample size of 140 subjects, the 95% confidence 
intervals (CIs) for mean change in Hgb from Baseline to Week 24 can be estimated, allowing for 
a of CI half-width of 0.149 g/dL.  
It is assumed that 30% of the subjects in this study will drop out or be otherwise excluded from 
the PP population.  Hence, 200 subjects will be randomized to ensure that there will be sufficient 
subjects at the end of the study for the longitudinal analyses (ie, 70 evaluable subjects in each 
randomized treatment group).  Based on prior clinical trial experience, it is estimated that half of 
the subjects will stay on their starting dose, and the other half will increase their dose after 12 
weeks of treatment.  Hence, it is expected that the 4 dosing sequence groups that will arise will 
have approximately equal numbers of subjects (ie, 35 subjects are expected in each of the four 
dosing sequence groups (3-3, 3-6, 4-4, and 4-6 tablets/day). 
The proposed sample size and the sizes of the sub-groups of interest are deemed sufficient for the 
analyses proposed below including the longitudinal analyses. 
15.3. 
Analysis Sets 
15.3.1. 
Safety Analysis Set 
All subjects who are randomized and take at least 1 dose of study medication will be included in 
the Safety Analysis Set.  Safety analyses will be based on the medication that was actually 
dispensed to each subject. 


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15.3.2. 
Full Analysis Set 
All subjects who are randomized, take at least 1 dose of study medication, and have at least 1 
post-randomization efficacy measurement will be included in the Full Analysis Set (FAS).  
Analyses of the FAS will be based on each subject’s randomized assigned dose group.  
15.3.3. 
Per Protocol Analysis Set 
The PP Analysis Set will include all subjects in the FAS who meet the study eligibility 
requirements and have no major protocol deviations that affect the validity of the efficacy 
measurements.  Protocol violations that may result in exclusion from the PP Analysis Set will 
include, but may not be limited to: violations of entry criteria deemed to impact efficacy results, 
usage of prohibited medications deemed to impact efficacy results, and lack of compliance with 
study medication to an extent that is deemed to impact efficacy results. The SAP will include 
specific criteria for exclusion from the PP analysis set. 
15.4. 
Demographics and Baseline Characteristics 
Demographic data and baseline characteristics for the FAS, PP, and Safety Analysis Sets will be 
summarized overall and by dose group using descriptive statistics.  These data include sex, age 
(years), race/ethnicity, weight (kg), height (cm), and calculated body mass index.  Baseline 
characteristics include baseline Hgb, eGFR, TSAT, ferritin, and phosphorus.  The baseline value 
is the last non-missing value observed prior to the first dose of study medication date/time. 
15.5. 
Subject Accountability 
Frequencies and percentages will be displayed for the number of subjects screened, failed 
screening, randomized, completed the study, and dropped out from the study, overall and by dose 
group.  Similarly, the number and percentage of subjects in each analysis set will be summarized. 
15.6. 
Study Treatment Usage and Compliance 
Study treatment usage will be assessed based on the numbers of tablets dispensed and returned.  
Percent compliance will be calculated and analyzed using descriptive statistics.  Percent 
compliance is defined as the ratio of the number of actual study medication tablets taken to the 
number of study medication tablets that should have been taken during the dosing period 
multiplied by 100. 
15.7. 
Efficacy Analyses 
All efficacy analyses will be performed based on both the FAS and the PP analysis sets.  The PP 
analyses will be considered primary and the FAS analyses will be considered as sensitivity 
analyses to assess the impact of subject exclusions. 
15.7.1. 
Primary Efficacy Endpoint Analyses 
The change in Hgb from Baseline is the primary endpoint of interest.  Ninety-five percent CIs 
will be constructed for change from Baseline at Week 24 and change from Baseline at Week 48 
based on the entire sample and by randomized dose groups.  No imputation will be performed for 
these analyses.  


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15.7.2. 
Secondary Efficacy Analyses 
A Mixed Model Repeated Measures (MMRM) model will be fitted to the change from Baseline 
Hgb incorporating all visits at which Hgb is measured for each subject.  Baseline Hgb and 
randomized dose group will be applied as fixed effects, as will time (in weeks) and time-by-dose 
group interaction.  An unstructured within-subject covariance structure will be assumed. 
The MMRM model is one approach to obtain treatment effect estimates in the presence of 
missing data.  As a sensitivity analysis to MMRM fitted to observed-case data, missing Hgb data 
will be imputed using multiple imputation (MI) methods described in Section 15.10.3. 
TSAT, ferritin, and serum phosphorus will be analyzed in a manner similar to the primary 
endpoint stated above.   
Changes in scores for the WPAI questionnaire and the FACIT Fatigue Scale, and frequency of 
hospitalizations and hospital days will be analyzed descriptively.  
Efficacy analyses will be repeated, substituting the dosing sequence groups for the randomized 
dose groups if appropriate, based on the distribution in the 4 dosing sequence groups (3-3, 3-6, 4-
4, and 4-6 tablets/day).  The dosing sequence groups will be determined based on actual doses 
received by each subject. 
15.8. 
Safety Analyses 
All safety analyses will be conducted based on the Safety Analysis Set. 
Safety data will include AEs, vital signs, and clinical laboratory measurements.  Observed data 
will be listed by subject and summarized using descriptive statistics overall and by dose group 
based on the Safety Analysis Set.  Selected safety analyses (including AE analyses) will be 
repeated substituting the dosing sequence groups for the randomized dose groups, if appropriate, 
based on the distribution in the 4 dosing sequence groups. 
15.8.1. 
Vital Signs 
Vital signs (seated heart rate and blood pressure after at least 5 minutes of rest) will be 
summarized as changes from Baseline and will be classified as low, normal, or high based on 
reference ranges pre-specified in the SAP.  Vital sign abnormalities will be summarized using 
shift tables for all subjects and by randomized dose group. 
15.8.2. 
Clinical Laboratory Tests 
Clinical and laboratory parameters will be measured at baseline and post-baseline visits.  Each 
continuous laboratory variable will be summarized as changes from Baseline for all subjects and 
by randomized dose group. 
Laboratory data will also be classified as low, normal, or high relative to the parameter’s 
reference range for a population with CKD stage 3 to 5.  Laboratory abnormalities for all 
subjects and for each dose group will also be summarized using shift tables. 


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15.8.3. 
Adverse Events 
AEs will be mapped to preferred term and body system using the Medical Dictionary for 
Regulatory Activities (MedDRA).  AEs that begin after the first administration of study 
medication or a pre-existing condition that worsens after the first dose of study medication are 
considered treatment-emergent adverse events (TEAEs).  The number and percentage of subjects 
reporting TEAEs will be summarized overall and for each randomized dose group by MedDRA 
system organ class and preferred term, then by severity, and by relationship to study treatment.  
The number and percentage of subjects reporting serious AEs and the number and percentage of 
subjects reporting AEs leading to treatment discontinuation will also be summarized overall and 
for each randomized dose group by MedDRA system organ class and preferred term.  
15.9. 
Other Analyses 
Concomitant medications will be coded using the World Health Organization Drug Dictionary.  
A by-subject listing of concomitant medications will include all medications taken during the 
study regardless of the timing for the start of the medication.  All medications started prior to the 
administration of study drug will be included in the data but will be identified as prior in the 
listing.  Only the continuing/ongoing concomitant medication use will be summarized for all 
subjects and by randomized dose group. 
15.10. 
Other Statistical Issues 
15.10.1. 
Significance Levels 
Unless otherwise specified, all tests will be 2 tailed using a 0.05 level of significance.  All CIs 
will be 2-sided 95% CIs.   
15.10.2. 
Multiple Comparisons/Multiplicity 
No multiplicity adjustments are required for this Phase 4 trial. 
15.10.3. 
Missing or Invalid Data 
Subjects who discontinue will not be replaced.  To the extent possible, attempts will be made to 
minimize the amount of missing data through measures planned in the study conduct.  However, 
if missing data are present, they will be handled as follows. 
As the primary longitudinal analysis, only available data will be analyzed using the MMRM 
model described above.  This model implicitly adjusts for missing data through a variance-
covariance structure.   
As a sensitivity analysis, missing endpoint information will be imputed via an MI linear 
regression approach.  A total of 10 imputed datasets will be generated, and the MMRM analyses 
will be carried out on each imputed dataset; the analyses results will be combined across the 10 
datasets using the standard techniques for multiple imputed datasets to yield overall dose group 
comparisons based on the imputed data. 


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15.11. 
Interim Analysis 
When all subjects complete their Week 24 visit, an interim analysis will be conducted based on 
an interim database lock for all subject data through Week 24 visit.  As this is a long-term open 
label Phase 4 trial, it is considered appropriate to conduct a descriptive interim analysis for the 
primary endpoint (Hgb) and key secondary endpoints (TSAT and ferritin) based on cleaned data 
through Week 24 using the methods described above including CIs and MMRM analyses.  
Further details regarding the interim analysis will be provided in the SAP.  


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16. 
STUDY MANAGEMENT 
16.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of Keryx will 
visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Keryx or its representatives.  This 
will be documented in a Clinical Study Agreement between Keryx and the 
Investigator. 
During the study, a monitor from Keryx or representative will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the Investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm proper storage of study drug. 
• Review drug accountability logs. 
• Confirm that the investigational team is adhering to the protocol, data are being 
accurately recorded in the eCRFs, and study drug accountability checks are being 
performed. 
• Perform source data verification.  This includes a comparison of the data in the 
eCRFs with the subject’s medical records at the hospital or practice, and other records 
relevant to the study.  This will require direct access to all original records for each 
subject (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to Keryx. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Keryx and those SAEs that met criteria for reporting 
have been forwarded to the IRB. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
16.2. 
Audits and Inspections 
Authorized representatives of Keryx, a regulatory authority, an IEC or an IRB may visit the site 
to perform audits or inspections, including source data verification.  The purpose of a Keryx 
audit or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, GCP guidelines of the ICH, and any 
applicable regulatory requirements.  The Investigator should contact Keryx immediately if 
contacted by a regulatory agency about an inspection. 


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16.3. 
Electronic Data Capture 
Keryx will provide the study sites with secure access to, and training on, the Electronic Data 
Capture application sufficient to permit study site personnel to enter or correct information in the 
eCRFs on the subjects for which they are responsible. 
An eCRF will be completed for each enrolled study subject. It is the Investigator's responsibility 
to ensure the accuracy, completeness, clarity and timeliness of the data reported in the subject’s 
eCRF. Source documentation supporting the eCRF data will indicate the subject’s participation 
in the study and will document the dates and details of study procedures, AEs, other observations 
and subject status. 
The Investigator or designated representative, will complete the eCRF as soon as possible after 
information is collected. 
The audit trail entry will show the user’s identification information and the date and time of any 
correction.  The Investigator will provide formal approval of all the information in the eCRFs, 
including any changes made to the eCRFs, to endorse the final submitted data for the subjects for 
whom the Investigator is responsible. 
Keryx will retain the eCRF data and corresponding audit trails.  A copy of the final archival 
eCRF in the form of a compact disc or other electronic media will be placed in the Investigators 
study file. 


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17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, Keryx may conduct 
a quality assurance audit.  Please see Section 16.2 for more details regarding the audit process. 
 


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18. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
CONSIDERATIONS 
18.1. 
Ethics Review 
The Investigator must obtain IRB approval for the investigation.  A copy of written IRB approval 
or favorable opinion of the protocol, informed consent form, and advertising (if applicable) must 
be provided to Keryx prior to initiation of the study.  Initial IRB approval and all materials 
approved by the IRB for this study including the patient consent form and recruitment materials 
must be maintained by the Investigator and made available for inspection.  The PI is responsible 
for informing the IRB of any amendment to the protocol in accordance with local requirements.  
The protocol must be re-approved by the IRB or IEC upon receipt of amendments and annually, 
as local regulations require. 
The Investigator is responsible for obtaining continued review of the clinical research or 
submitting periodic progress reports, in accordance with applicable regulations, at intervals not 
exceeding 1 year or otherwise specified by the IRB.  Keryx must be supplied with written 
documentation of continued review of the clinical research.  The Investigator must promptly 
inform their IRB of all SAEs or other safety information reported from Keryx/CRO in 
accordance with applicable laws and regulations.  
18.2. 
Ethical Conduct of the Study 
This study will be conducted in compliance with all U.S.  FDA regulations including 21 CFR, 
Parts 11, 50, 54, 56, and 312, as well as other guidelines for GCP, and applicable local regulatory 
requirements and laws.  This study will also comply with the Declaration of Helsinki, ICH/GCP 
and all subsequent international agreements for subjects’ rights and safety.  This study will 
receive IRB approval prior to its commencement at each study site. 
The clinical database at the Sponsor-designated Clinical Research Organization complies with 
the regulation in 21 CFR Part 11. 
18.3. 
Written Informed Consent 
The study personnel shall obtain written informed consent from each subject prior to performing 
any study assessments.  The consent form must be approved by Keryx and the IRB according to 
the IRB’s requirements.  The consent must also indicate that, by signature, the subject permits 
access to relevant medical records by designated auditors and representatives of the Regulatory 
Authority.  This document must be written in a language understandable to an individual with an 
eighth grade education.  The consent form must be written and explained in the subject’s primary 
language.  Subjects must be given time to consider the information fully and be encouraged to 
ask questions about their study participation.  The Investigator must also inform the subject that 
s/he is free to refuse to enter the study and to withdraw from the study at any time, for any 
reason, and that such refusal will not compromise the care s/he is rendered.  All consent forms 
must be signed and dated by the study personnel and the subject.  For subjects not qualified to 
give legal consent, written consent must be obtained from the next of kin or legal guardian.  A 
copy of the signed document will be given to the subject, and the Investigator will retain the 
original with the subject files. 


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18.4. 
Patient Confidentiality 
Keryx will preserve the confidentiality of subjects taking part in this study.  Keryx, its official 
designee, the IRB, and the FDA will use records from the study only in connection with this 
research project.  These medical records will not be disclosed to any other parties and will 
otherwise be kept completely confidential.  In the event of subject names inadvertently appearing 
on study documentation, this information will not be entered into the computer database for the 
study.  Representatives of Keryx will seek access to clinical information only after the subject or 
subject’s legal guardian so has given approval to do. 
The study will comply with Health Insurance Portability and Accountability Act. 
18.5. 
Study Master File 
All study correspondence and administrative documentation (eg, protocol, consent form, and 
IRB information) should be filed by the Investigator in an organized and easily retrievable 
manner for review during monitoring, an audit, or an inspection.  This Investigator Site File will 
be open for inspection by monitors, to ensure that all relevant documents are present and easily 
retrievable.   
18.6. 
Laboratory Accreditation 
Laboratories used for analysis of samples required for this protocol must show evidence of 
adequate licensure or accreditation.  A copy of the accreditation certificate(s) for all laboratories 
will be provided for retention in the Investigator Site File. 
18.7. 
Independent Medical Monitor 
The Sponsor delegates the responsibility of medical monitoring to a contracted Medical Monitor.  
Contact information for the Medical Monitor is provided in the Study Contacts page (see 
page 4). 
The Medical Monitor will be available 24 hours per day to provide assistance for 
• Interpretation of protocol and eligibility criteria,  
• Dosing decisions (see Section 7.5),  
• Discussion of any subject who is to receive or has received ESA therapy (see 
Section 9.2.2),  
• Discussion of any subject who is to receive or has received prohibited therapy (see 
Section 9.2.1), 
• Questions regarding AEs,  
• Discussion of any subject with extended dose interruption, and 
• Discussion or notification regarding any subject who is considered for or has 
undergone study drug discontinuation or study discontinuation (see Section 8.3.1 and 
Section 8.3.2).  
The medical care of a subject remains the sole responsibility of the Investigator.  


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In case a subject has to be withdrawn from the trial, the Medical Monitor will be informed 
immediately, who will then inform the Sponsor.   


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19. 
DATA HANDLING AND RECORDKEEPING 
19.1. 
Inspection of Records 
Keryx will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study.  The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, DARs, subject charts and study source documents, and 
other records relative to study conduct. 
19.2. 
Retention of Records 
The PI must maintain all documentation relating to the study for a period of 2 years after the last 
marketing application approval or, if not approved, 2 years following the discontinuance of the 
test article for investigation.  If it becomes necessary for Keryx or the Regulatory Authority to 
review any documentation relating to the study, the Investigator must permit access to such 
records. 
If the Investigator relocates, retires, or for any reason withdraws from the study, Keryx should be 
prospectively notified.  The study records must be transferred to an acceptable designee.  The 
Investigator must retain Keryx’s written permission before disposing of any records, even if 
retention requirements have been met. 
19.3. 
Financial Disclosure 
By signing this protocol, the Investigator agrees to provide Keryx accurate financial information 
to allow Keryx to submit complete and accurate certification and disclosure statements as 
required by the US FDA regulations (21 CFR Part 54).  The Investigator further agrees to 
provide this information on a Financial Disclosure/Certification Form that is provided by the 
Keryx.  The Investigator will update this information if there are any relevant changes during the 
conduct of the study and for 1 year after completion of the study.  This requirement also extends 
to sub-investigators. 


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20. 
PUBLICATION POLICY 
Individual subject medical information obtained as a result of this study is to be considered 
confidential, and disclosure to third parties other than the FDA or regulatory authorities and/or 
other persons or organizations designated by Keryx is prohibited.  Any medical information may 
be provided to the subject’s personal physician or to appropriate medical personnel responsible 
for the subject’s care.  Additionally, data generated from this study are to be provided, upon 
request, to FDA auditors, and Keryx’s monitors, as well as to the local IRB.  Subject 
confidentiality is to be further assured by utilizing subject identification code numbers to identify 
subject data.  
Primary data resulting from all centers participating in this study are to be published as 1 or 
2 articles following Good Publication Practices including ICMJE authorship criteria [Graf 2009; 
Battisti 2015].  After submission of the primary data, Keryx may produce publications 
addressing secondary analyses, post-hoc analyses and/or sub-analyses following all good 
publication practices.  Additionally, individual centers may request permission from Keryx to 
submit manuscripts addressing secondary analyses, post-hoc analyses and/or sub-analyses.  In 
this case, Keryx will be granted a period of 60 days to review all final drafts and make 
suggestions. 


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21. 
LIST OF REFERENCES 
Battisti 2015 
Battisti WP, Wager E, Baltzer L, et al. Good Publication Practice for Communicating Company-
Sponsored Medical Research: GPP3. Ann Intern Med 2015;163:461-464. 
Block 2014 
Block GA, Fishbane S, Rodriguez M, et al. A 12-week, double-blind, placebo-controlled trial of 
ferric citrate for the treatment of iron deficiency anemia and reduction of serum phosphate in 
patients with CKD Stages 3-5. Am J Kidney Dis 2015;65(5):728-36. 
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. 
Fishbane 2017 
Fishbane S, Block GA, Loram L, et al. Effects of ferric citrate in patients with nondialysis-
dependent CKD and iron deficiency anemia. J Am Soc Nephrol 2017; Jan 12. pii: 
ASN.2016101053. doi: 10.1681/ASN.2016101053. [Epub ahead of print]. 
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; 16(2):489-95. 
Graf 2009 
Graf C, Battisti WP, Bridges D, et al. For the International Society for Medical Publication 
Professionals. Good publication practice for communicating company sponsored medical 
research: the GPP2 guidelines. BMJ 2009;339:b4330.  
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. 
Hu 2013 
Hu MC, Kuro M, Moe OW. Klotho and Chronic Kidney Disease. Contrib Nephrol 
2013;180:7-63. 


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
81 
 
 
  
 
Kobune 2011 
Kobune M, Miyanishi K, Takada K, Kawano Y, Nagashima H, Kikuchi S, et al. Establishment of 
a simple test for iron absorption from the gastrointestinal tract. Int J Hematol 2011;93:715-719. 
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. 
Lewis 2015 
Lewis JB, Sika M, Koury MJ, et al. Ferric citrate controls phosphorus and delivers iron in 
patients on dialysis. J Am Soc Nephrol 2015;26(2):493-503. 
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. 
Miskulin 2013 
Miskulin DC, Zhou J, Tangri N, et al. Trends in anemia management in US hemodialysis 
patients 2004-2010. BMC Nephrol. 2013 Dec 1;14:264. 
Regidor 2011 
Regidor D, McClellan WM, Kewalramani R, Sharma A, Bradbury BD. Changes in 
erythropoiesis-stimulating agent (ESA) dosing and haemoglobin levels in US non-dialysis 
chronic kidney disease patients between 2005 and 2009. Nephrol Dial Transplant. 2011 May; 
26(5):1583-91.  
USRDS 2016 
United States Renal Data System. 2016 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, 2016. 
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.  
 


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
82 
 
 
  
 
22. 
APPENDICES 
Appendix A 
Work Productivity and Activity Impairment (WPAI) Questionnaire  
Appendix B 
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale 
Questionnaire  
Appendix C  Amendment 1 Detailed Summary of Changes  
 


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
83 
 
 
  
 
APPENDIX A. WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
(WPAI) QUESTIONNAIRE 
Work Productivity and Activity Impairment Questionnaire: 
Specific Health Problem V2.0 (WPAI:SHP) 
 
The following questions ask about the effect of your Anemia associated with Chronic Kidney 
Disease on your ability to work and perform regular activities.  Please fill in the blanks or circle 
a number, as indicated. 
 
1.  Are you currently employed (working for pay)?  
_____ NO ___ YES 
 
 
If NO, check “NO” and skip to question 6. 
 
The next questions are about the past seven days, not including today. 
 
2. During the past seven days, how many hours did you miss from work because of problems 
associated with your Anemia associated with Chronic Kidney Disease?  Include hours you 
missed on sick days, times you went in late, left early, etc., because of your Anemia 
associated with Chronic Kidney Disease.  Do not include time you missed to participate in 
this study. 
 
_____ HOURS 
 
3. During the past seven days, how many hours did you miss from work because of any other 
reason, such as vacation, holidays, time off to participate in this study? 
 
_____HOURS 
 
4. During the past seven days, how many hours did you actually work? 
 
_____HOURS  (If “0”, skip to question 6.) 
 
5. During the past seven days, how much did your Anemia associated with Chronic Kidney 
Disease affect your productivity while you were working?   
 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as usual.  
If Anemia associated with Chronic Kidney Disease affected your work only a little, choose a low 
number.  Choose a high number if Anemia associated with Chronic Kidney Disease affected your 
work a great deal.   


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
84 
 
 
  
 
Consider only how much Anemia associated with Chronic Kidney Disease  
affected productivity while you were working 
Anemia 
associated with 
Chronic Kidney 
Disease had no 
effect on my 
work 
 
 
 
 
 
 
 
 
 
 
 
Anemia associated 
with Chronic 
Kidney Disease 
completely 
prevented me from 
working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
 
6. During the past seven days, how much did your Anemia associated with Chronic Kidney 
Disease affect your ability to do your regular daily activities, other than work at a job?   
 
By regular activities, we mean the usual activities you do, such as work around the house, 
shopping, childcare, exercising, studying, etc.  Think about times you were limited in the 
amount or kind of activities you could do and times you accomplished less than you would 
like.  If Anemia associated with Chronic Kidney Disease affected your activities only a little, 
choose a low number.  Choose a high number if Anemia associated with Chronic Kidney 
Disease affected your activities a great deal.   
 
Consider only how much anemia associated with chronic kidney disease affected your ability to 
do your regular daily activities, other than work at a job 
Anemia 
associated with 
Chronic Kidney 
Disease had no 
effect on my 
daily activities 
 
 
 
 
 
 
 
 
 
 
 
Anemia associated 
with Chronic 
Kidney Disease 
completely 
prevented me from 
doing my daily 
activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
WPAI:SHP  V2.0 (US English)      
Reilly MC, Zbrozek AS, Dukes E: The validity and reproducibility of a work productivity and activity impairment measure.  
PharmacoEconomics 1993; 4(5):353-365. 
 


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
85 
 
 
  
 
APPENDIX B. FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS 
THERAPY (FACIT) FATIGUE SCALE QUESTIONNAIRE 
FACIT-Fatigue Scale (Version 4) 
 
 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
 
Not 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
 
 
 
HI7 
I feel fatigued...................................................................... 
0 
1 
 
2 
 
3 
4 
 
HI12 
I feel weak all over ............................................................. 
0 
1 
2 
3 
4 
 
An1 
I feel listless (“washed out”)............................................... 
0 
1 
2 
3 
4 
 
An2 
I feel tired ........................................................................... 
0 
1 
2 
3 
4 
 
An3 
I have trouble starting things because I am tired ................ 
0 
1 
2 
3 
4 
 
An4 
I have trouble finishing things because I am tired.............. 
0 
1 
2 
3 
4 
 
An5 
I have energy ...................................................................... 
0 
1 
2 
3 
4 
 
An7 
I am able to do my usual activities ..................................... 
0 
1 
2 
3 
4 
 
An8 
I need to sleep during the day............................................. 
0 
1 
2 
3 
4 
 
An12 
I am too tired to eat............................................................. 
0 
1 
2 
3 
4 
An14 
I need help doing my usual activities ................................. 
0 
1 
2 
3 
4 
An15 
I am frustrated by being too tired to do the things I want 
to do .................................................................................... 
0 
 
1 
 
2 
3 
4 
An16 
I have to limit my social activity because I am tired.......... 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
English (Universal) 
16 November 2007 
Copyright 1987, 1997 
Page 1 of 1 
 


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
86 
 
 
  
 
APPENDIX C. AMENDMENT 1 DETAILED SUMMARY OF CHANGES 
Purpose:  Change the lower limit of eGFR for eligibility from >20 to ≥20 mL/min 
(Inclusion #3). 
The primary change occurs in Section 8.1, Subject Inclusion Criteria:  
Formerly 
read: 
3.  eGFR >20 mL/min and <60 mL/min at Screening 
Now 
reads: 
3.  eGFR ≥20 mL/min and <60 mL/min at Screening 
Section 2, Synopsis, also contains this change.   
Purpose:  Change the Hgb range for eligibility, from ≥9 and ≤11.0 g/dL, to ≥8.5 and 
≤11.5 g/dL  (Inclusion # 4). 
The primary change occurs in Section 8.1, Subject Inclusion Criteria: 
Formerly 
read: 
4.  Hgb ≥9.0 g/dL and ≤11.0 g/dL at Screening 
Now 
reads: 
4.  Hgb ≥8.5 g/dL and ≤11.5 g/dL at Screening 
Sections that also contain this change are: 
• Section 2, Synopsis 
• Section 10.1, Visit 1A (Screening) 
Purpose:  Revise the Hgb level for allowing ESA therapy, or for withdrawing the subject 
from the study if all ESA rescue therapy requirements are not met, from <8.5 to 
<8.0 g/dL. 
The change occurs in Section 9.2.2, ESA Rescue Therapy 
Formerly 
read: 
ESA use is not permitted during the study. The exception is a scenario in 
which all of the following conditions for ESA rescue therapy are met: 
1.  A subject has had 2 consecutive Hgb values of <8.5 g/dL more than 3 days 
apart. 
2.  … 
Subjects who have had 2 consecutive Hgb values of <8.5 g/dL more than 3 
days apart but do not meet the other criteria of ESA rescue therapy should 
complete the ET visit and discontinue from the study.  


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
87 
 
 
  
 
Now 
reads: 
ESA use is not permitted during the study. The exception is a scenario in 
which all of the following conditions for ESA rescue therapy are met: 
1.  A subject has had 2 consecutive Hgb values of <8.0 g/dL more than 3 days 
apart. 
2.  … 
Subjects who have had 2 consecutive Hgb values of <8.0 g/dL more than 3 
days apart but do not meet the other criteria of ESA rescue therapy should 
complete the ET visit and discontinue from the study.  
Purpose:  Raise the serum ferritin eligibility requirement from ≤200 ng/mL to 
≤500 ng/mL (Inclusion #5). 
The primary change occurs in Section 8.1, Subject Inclusion Criteria 
Formerly 
read: 
5.  Serum ferritin ≤200 ng/mL and TSAT ≤25% at Screening 
Now 
reads: 
5.  Serum ferritin ≤500 ng/mL and TSAT ≤25% at Screening 
Sections that also contain this change are: 
• Section 2, Synopsis 
• Section 10.1, Visit 1A (Screening) 
Purpose:  Allow subjects on low-dose oral corticosteroids (eg, ≤5 mg/day prednisone or 
the relative equivalent dose of another corticosteroid) to enter the study (Exclusion #14). 
The primary change occurs in Section 8.2, Subject Exclusion Criteria 
Formerly 
read: 
14.  Requires treatment with oral corticosteroids at Screening or during the 
Screening Period; IV corticosteroids administered within 2 weeks prior to 
Screening or during the Screening Period. 
Now 
reads: 
14.  Requires treatment with oral corticosteroids at Screening or during the 
Screening Period (use of low-dose oral corticosteroids, eg, ≤5 mg/day 
prednisone or the relative equivalent dose of another corticosteroid, is 
not an exclusion); IV corticosteroids administered within 2 weeks prior to 
Screening or during the Screening Period. 
Section 2, Synopsis, also contains this change.   


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
88 
 
 
  
 
Purpose:  Allow re-testing for specific inclusion/exclusion criteria during a re-screening 
episode, if applicable, as well as during the first screening episode. 
The primary change occurs in Section 10.1.1.1, Re-testing for Specific 
Inclusion/Exclusion Criteria 
Formerly 
read: 
10.1.1.1  Retesting for Specific Inclusion/Exclusion Criteria During 
Screening 
During the first screening episode, subjects may be re-tested for specific 
inclusion and exclusion criteria that were not met at the initial testing.  Re-test 
may occur within 10 days of the original screening date.   
Now 
reads: 
10.1.1.1  Re-testing for Specific Inclusion/Exclusion Criteria  
During screening and/or re-screening (if applicable), subjects may be re-
tested for specific inclusion and exclusion criteria that were not met at the 
initial testing.  If a re-test is conducted, it needs to occur within 10 days of 
Screening (Visit 1A) or Re-screening (Visit 1B).   
Sections also affected by this change are: 
• Table 2: Schedule of Assessments (footnote d) 
• Section 10.1.1, Procedures for Visit 1A (Screening) 
• Section 10.2.1, Procedures for Visit 1B (Re-screening)  
Purpose:  Clarify that Medical Monitor consultation is not required when the Investigator 
decides to re-test or re-screen a subject.  (Note, this is a clarification of initial intent, not a 
change to protocol procedures). 
The change occurs in 10.1.1, Procedures for Visit 1A (Screening) 
Formerly 
read: 
It is the Investigator’s decision, in consultation with the Medical Monitor, to 
re-test or re-screen a subject.  There may only be 1 re-testing or re-screening 
for a subject.  A subject will maintain the original screening ID for re-testing 
or re-screening. 
Now 
reads: 
It is the Investigator’s decision, in consultation with the Medical Monitor if 
needed, to re-test or re-screen a subject.  A subject will maintain the original 
screening ID for re-testing or re-screening.   
Purpose:  Increase the number of clinical sites from approximately 25 to approximately 
30. 
The primary change occurs in 7.3, Study Sites: 
Formerly 
read: 
There will be approximately 25 sites in the US participating in this study.  
Each site may randomize a maximum of 25 subjects. 


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
89 
 
 
  
 
Now 
reads: 
There will be approximately 30 sites in the US participating in this study.  
Each site may randomize a maximum of 25 subjects. 
Section 2, Synopsis, also contains this change.   
Purpose:  Replace the incorrect FACIT Scale questionnaire with the correct FACIT 
Fatigue Scale questionnaire in Appendix B. 
The primary change occurs in Appendix B, Functional Assessment of Chronic Illness 
Therapy (FACIT) Fatigue Scale Questionnaire: 
This change required the deletion of 3 pages of the FACIT scale and replacement of 1 
page; these changes are not shown here for brevity/clarity.   
Purpose:  Incorporate a description of the FDA approval (on 06 November 2017) for the 
use of ferric citrate as "an iron replacement product indicated for the treatment of iron 
deficiency anemia in adult patients with chronic kidney disease not on dialysis". 
The primary change occurs in Section 5.2, KRX-0502 (Ferric Citrate) Known Potential 
Benefits and Risks: 
Formerly 
read: 
Based on these data, Keryx submitted a sNDA for treatment of IDA in NDD-
CKD to the FDA in January 2017. 
Now 
reads: 
As of 06 November 2017, KRX-0502 (ferric citrate) is approved in the US 
as "an iron replacement product indicated for the treatment of iron 
deficiency anemia in adult patients with chronic kidney disease not on 
dialysis." 
Section 5.1, Background is also affected by this change.   
Purpose:  Revise the Signature Page with the current Study Biostatistician information. 
The change occurs on the Protocol Signature Page:  
Formerly 
read: 
 
PROMETRIKA, LLC  
Cambridge, MA 
Now 
reads: 
Biostatistics 
IQVIATM 
United States 


Protocol - Phase 4 Study 402 
Amendment 1 
 
13 December 2017 
 
 
90 
 
 
  
 
Purpose:  Change "Quintiles" to "IQVIATM" to reflect the integration of IMS Health and 
Quintiles under this new organization name. 
The change occurs on the Study Contact Information page:  
Formerly 
read: 
 
 
Immunology & Internal Medicine, 
Medical Strategy & Science 
Therapeutic Science & Strategy Unit 
QuintilesIMS 
10188 Telesis Court, Suite 400 
San Diego, CA 92121 
Contact directly on mobile phone, for urgent issues: 
Mobile:  
 
Email:  
 
Now 
reads: 
 
 
Immunology & Internal Medicine, 
Medical Strategy & Science 
Therapeutic Science & Strategy Unit 
IQVIATM 
10188 Telesis Court, Suite 400 
San Diego, CA 92121 
Contact directly on mobile phone, for urgent issues: 
Mobile:  
 
Email:  
 
 
 
 

SAP_001.pdf: 
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Statistical Analysis Plan - Protocol No. KRX-0502-402 
Keryx Biopharmaceuticals, Inc 
April 4, 2019 
Page 1 of64 
STATISTICAL ANALYSIS PLAN 
VERSION: 1.1 
DATE OF PLAN: 
04-Apr-2019 
BASED ON: 
Protocol No. KRX-0502-402, Version 0.1, Date: 03-APR-2017, Amendment 1 13-DEC-2017: 
"A Phase 4 Study ofKRX-0502 (Ferric Citrate) Dose Regimens in Subjects with Non-Dialysis 
Dependent Chronic Kidney Disease and Iron Deficiency Anemia: the COMPASS Trial" 
Document: 
Author: 
CRF Date: 06-FEB-2018 
STUDY DRUG: 
KRX-0502 (FERRIC CITRATE) 
SPONSOR: 
Keryx Biopharmaceuticals, Inc. 
12th Floor, One Marina Park Drive 
Boston, MA 02210 USA 
\\quintiles. n et\e nterp rise \a p ps \sasd ata \sasb \sas \Ke ryx\KRX-
0502\Bi ostatistics \Documentation \SAP\ 
 
Version Number: 
1.1 
NCT Number: NCT03236246
This NCT number has been applied to the document for
purposes of posting on Clinicaltrials.gov


-=IMSHeollh& 
-=: Ouinti'-s.,.. now 
IQVIA'" 
Statistical Analysis Plan - Protocol No. KRX-0502-402 
SIGNATURE PAGE 
This document has been prepared and/or reviewed by: 
 
Biostatistician II 
Biostatistics, IQVIA 
Biostatistics, IQVIA 
Akebia Therapeutics, 
Cambridge, MA 
Signature 
Signature 
Keryx Biopharmaceuticals, Inc 
April 4, 2019 
Page 2 of64 
Date 
Date 
Document: 
\\qui nti I es. n et\e nterprise \a pps \sa sd ata \sas b \sas \Keryx\KRX-
0502\B i ostatistics \Documentation \SAP\ 
Author: 
 
Version Number: 
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~ 
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Statistical Analysis Plan - Protocol No. KRX-0502-402 
Keryx Biopharmaceuticals, Inc 
April 4, 2019 
Page 3 of64 
MODIFICATION HISTORY 
Unique 
Identifier 
for this 
Version 
l.O 
I.I 
Document: 
Author: 
Date of the 
Significant Changes from Previous 
Document Version 
Author 
Authorized Version 
l3NOV20189 
Not Applicable - First Version 
04APR2019 
Updated based on Sponsor Comments of the 
TLFs produced in the Dry Run. 
Added additional description of analysis for 
Permitted ESA Rescue Therapy Subgroup. 
Updated Table 3 to be consistent with text in 
Efficacy sections. 
Updated section 5.l to include specific data 
that will be used for publication purposes 
and to clarify the 24-Week analysis will be 
done at the end of the study. 
Updated section 6.5.4 to expand visit 
windows for all visits. 
Updated section 6.3 to add the modified Per 
Protocol Analysis Set. 
Updated section 9.6 based on additional 
analysis described in the SAP that is not 
discussed in the protocol. 
\\quintiles.net\enterprise\apps\sasdata\sasb\sas\Keryx\KRX-
0502\Biostatistics\Documentation\SAP\ 
 
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April 4, 2019 
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TABLE OF CONTENTS 
1. 
List Of Abbreviations ............................................................................................................................. 8 
2. 
Introduction ........................................................................................................................................ 11 
3. 
Study Objectives and Endpoints ......................................................................................................... 12 
3.1. 
Study Objectives ..................................................................................................................... 12 
3.2. 
Study Endpoints ..................................................................................................................... 12 
3.2.1. 
Primary Endpoint ................................................................................................................... 12 
3.2.2. 
Secondary Endpoints ............................................................................................................. 12 
3.2.3. 
Safety Endpoints .................................................................................................................... 13 
4. 
Study Design ........................................................................................................................................ 14 
4.1. 
Summary of Study Design ...................................................................................................... 14 
4.2. 
Definition of Study Drugs ....................................................................................................... 14 
4.3. 
Sample Size Considerations ................................................................................................... 14 
4.3.1. 
Sample Size Justifications ...................................................................................................... 14 
4.3.2. 
Sample Size Re-estimation ..................................................................................................... 15 
4.4. 
Randomization ....................................................................................................................... 15 
4.5. 
Clinical Assessments .............................................................................................................. 15 
5. 
Planned Analyses ................................................................................................................................ 18 
5.1. 
24-Week Analysis .................................. .................................. ~ ............................................... 18 
5.2. 
Final Analysis .......................................................................................................................... 19 
5.3. 
Ad Hoc Analysis ...................................................................................................................... 19 
5.4. 
Chronic Kidney Disease Biomarker Analysis .......................................................................... 19 
6. 
General Considerations for Data Analyses and Handling ................................................................... 20 
6.1. 
Data Collection, Processing and Reporting ............................................................................ 20 
6.2. 
Data Presentation Conventions ............................................................................................. 21 
6.3. 
Analysis Sets ........................................................................................................................... 22 
6.3.1. 
Screened Subjects .................................................................................................................. 22 
6.3.2. 
Screen Failures ....................................................................................................................... 22 
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6.3.3. 
Safety Analysis Set ................................................................................................................. 22 
6.3.4. 
Full Analysis Set ...................................................................................................................... 22 
6.3.5. 
Per Protocol Analysis Set ....................................................................................................... 23 
6.3.6. 
Modified Per Protocol Analysis Set ......... ............................................................................... 23 
6.4. 
Baseline Definition .......................................................................... ....................................... 24 
6.5. 
Derived and Transformed Data .............................................................................................. 24 
6.5.1. 
Baseline Age ........................................................................................................................... 24 
6.5.2. 
Study Day ·················---········································································································· 24 
6.5.3. 
Change from Baseline ............................................................................................................ 25 
6.5.4. 
Visit Windows ........................................................................................................................ 25 
6.6. 
Handling of Missing Data ....................................................................................................... 27 
6.6.1. 
Missing Efficacy Endpoints ............................................................................................... ....... 27 
6.6.2. 
Missing Start and Stop Dates for Prior and Concomitant Medications and Medical 
Conditions .................... ....................................................................................................................... 27 
6.6.3. 
Missing Start and Stop Dates for Adverse Events .................................................................. 27 
6.6.4. 
Missing CKD Initial Diagnosis Date ......................................................................................... 27 
7. 
Study Population ................................................................................................................................. 29 
7.1. 
Subject Disposition ............... .................................................................................................. 29 
7.1.1. 
Discontinuation from Study for Use of Prohibited Therapies ............................................... 30 
7.1.2. 
Discontinuation from Study Drug .......................................................................................... 31 
7 .2. 
Protocol Deviations ................................................................................................................ 31 
7 .3. 
Demographic and Other Baseline Characteristics ................................................................. 31 
7.4. 
Medical History and Medical Conditions Present at Entry .................................................... 34 
7.5. 
Prior and Concomitant Medications and Non-Drug Therapies .............................................. 34 
8. 
Efficacy ................................................................................................................................................ 36 
8.1. 
General Considerations .......................................................................................................... 36 
8.2. 
Primary Efficacy Analysis ........................................................................................................ 37 
8.3. 
Secondary Efficacy Analyses .................................................................................................. 38 
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8.4. 
Subgroup Analyses ................................................................................................................. 40 
9. 
Safety and Tolerability ........................................................................................................................ 42 
9.1. 
Overall Summary of Tolerability ............................................................................................ 42 
9.2. 
Adverse Event Summary Tables ............................................................................................. 43 
9.2.1. 
Summaries of All Treatment Emergent Adverse Events ........................................................ 43 
9.2.2. 
Missing and Partial AE Start Dates ......................................................................................... 44 
9.2.3. 
Summaries of Serious Adverse Events (SAE), Adverse Event Dropouts, and Death .............. 45 
9.3. 
Total Duration of Therapy, Maximum Daily Dose, Final Daily Dose of Study Medication, and 
Compliance ............................................................................................................................................. 46 
9.3.1. 
Total Duration of Exposure Calculation ................................................................................. 46 
9.3.2. 
Compliance Calculation ......................................................................................................... 47 
9.4. 
Routine Laboratory Data ........................................................................................................ 51 
9.5. 
Vital Signs ............................................................................................................................... 53 
9.6. 
Summary of Changes from Protocol-Specified Analyses ....................................................... 54 
10. 
References .............................................................................................................................. 56 
11. 
Appendix ................................................................................................................................ 57 
11.1. 
Work Productivity and Activity Impairment (WPAI) Questionnaire ...................................... 57 
Specific Health Problem V2.0 (WPAI:SHP)* ..................................................................................... 57 
11.2. 
WPAI :SHP QuestionnaireV2.0 ................................................................................................ 59 
11.3. 
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale (Version 4) ........... 61 
11.4. 
FACIT-Fatigue Subscale Scoring ............................................................................................. 62 
11.4.1. 
Handling Missing Items on FACIT Fatigue Subscale ............................................................. 63 
11.5. 
Tables, Listings and Figures .................................................................................................... 64 
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April 4, 2019 
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LIST OF TABLES 
Table 1: 
List of Abbreviations .................................................................................................... 8 
Table 2: 
Visit Windows (Days) ................................................................................................ 25 
Table 3: 
Analysis Method and Analysis Set for Special Focus Efficacy Endpoints ............. .35 
Table 4: 
Criteria for Potentially Clinically Significant Laboratory Results 
............. 53 
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1. 
LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this statistical analysis plan. 
Table 1: 
Abbreviation 
ADaM 
AE 
ALP 
ALT 
ANCOVA 
AST 
ATC 
BID 
BMI 
bpm 
BUN 
CBC 
CCP 
CI 
CKD 
cm 
CRF 
CRO 
CSR 
CTCAE 
DD-CKD 
DILi 
dL 
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Abbreviations and Special Terms 
Term 
Analysis data model 
Adverse Event 
Alkaline Phosphatase 
Alanine Aminotransferase 
Analysis of Covariance 
Aspartate Aminotransferase 
Anatomical therapeutic chemical 
Twice Daily 
Body mass index 
Beats per minute 
Blood Urea Nitrogen 
Complete Blood Count 
Complete Chemistry Profile 
Confidence Interval 
Chronic Kidney Disease 
Centimeter 
Case Report Form 
Clinical Research Organization 
Clinical Study Report 
Common Terminology Criteria for Adverse Event 
Dialysis-Dependent Chronic Kidney Disease 
Drug Induced Liver Injury 
Deciliter 
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Abbreviation 
eCRF 
EDC 
eGFR 
ESA 
ET 
FACIT 
FAS 
FGF23 
g 
HCT 
Hgb 
IDA 
iPTH 
IV 
IWRS 
kg 
L 
LSM 
MedDRA 
MEq 
MORD 
mg 
mm 
ml 
ML 
mmHg 
MMRM 
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Term 
Electronic Case Report Form 
Electronic Data Capture 
Estimated Glomerular Filtration Rate 
E:iythropoiesis-Stimulating Agents 
Early Termination 
Functional Assessment of Chronic Illness Therapy 
Full Analysis Set 
Fibroblast growth factor 23 
Gram 
Hematocrit 
Hemoglobin 
Iron deficiency anemia 
Intact parathyroid hormone 
Intravenous 
Interactive Web and Voice Response System 
Kilogram 
Liter 
Least square mean 
Medical Dictionary for Regulatory Activities Terminology 
Milliequivalents 
Modification of Diet in Renal Disease 
Milligram 
Minute 
Milliliter 
Maximum likelihood 
Millimeters of mercury 
Mixed Model Repeated Measures 
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Statistical Analysis Plan - Protocol No. KRX-0502-402 
Abbreviation 
mPP 
N 
NDD-CKD 
ng 
pp 
PT 
Ql 
Q3 
RBC 
REML 
SAE 
SAP 
SAS 
SD 
SDTM 
soc 
TEAE 
TIBC 
TID 
TLF 
TSAT 
UIBC 
ULN 
WBC 
WHO 
WPAI 
yr 
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Term 
Modified Per Protocol 
Total Sample Size 
Non-Dialysis Dependent Chronic Kidney Disease 
Nano gram 
Per Protocol 
Preferred term 
First quartile 
Third quartile 
Red Blood Cell 
Residual Maximum Likelihood 
Serious Adverse Event 
Statistical Analysis Plan 
Statistical Analysis System 
Standard Deviation 
Standard Data Tabulation Model 
System organ class 
Treatment emergent adverse event 
Total iron binding capacity 
3 times daily 
Tables, listings and figures 
Transferrin saturation 
Unsaturated iron-binding capacity 
Upper Limit of Normal 
White Blood Cell Count 
World Health Organization 
Work Productivity and Activity Impairment 
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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the specifics of the statistical 
analyses to be performed for the planned 24-Week and final analyses for this study based on 
Protocol KRX-0502-402. The data displays to be included in the Clinical Study Report (CSR) 
for Protocol KRX-0502-402 are described in the document, KRX-502-402 Phase IV TLFs 
Shells. 
Protocol Revision Chronology: 
Protocol 
DD-MMM-YYYY 
Description 
Version 0.1 
03-APR-2017 
Original 
Amendment 1 
l 3-Dec-2017 
Changes to eligibility criteria and screening 
processes that will facilitate subject enrollment. 
Incorporate the correct F ACIT Fatigue Scale. 
This SAP was developed in accordance with ICH E9 guideline. All decisions regarding an 
analysis, as defined in this SAP document, will be made prior to Database Freeze/Lock of the 
study data. Further information can be found in the protocol. 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
The objectives of this study are to assess the long-term efficacy and safety of different dose 
regimens ofKRX-0502 in the treatment of iron deficiency anemia (IDA) in adult subjects with 
non-dialysis dependent chronic kidney disease (NDD-CKD) 
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoint 
The primary efficacy endpoint is the change in hemoglobin (Hgb) from Baseline at Week 24. 
3.2.2. 
Secondary Endpoints 
The secondary endpoints of this study are as follows: 
1. Change in Hgb from Baseline at Week 48 
2. Time from randomization to first increase from Baseline Hgb of at least 0.5 g/dL 
3. Change in transferrin saturation (TSA T) from Baseline at Weeks 24 and 48 
4. Change in ferritin from Baseline at Weeks 24 and 48 
5. Change in serum phosphate from Baseline at Weeks 24 and 48 
6. Change in estimated glomerular filtration rate (eGFR) from Baseline at Weeks 24 and 48 
7. Change in bicarbonate from baseline at Weeks 24 and 48 
8. Change in intact parathyroid (iPTH) from baseline at Weeks 24 and 48 
9. Change in C-terminal fibroblast growth factor 23 (FGF 23) from baseline at Weeks 24 
and48 
10. Change in intact fibroblast growth factor from baseline at Weeks 24 and 48 
11. Change in score for Work Productivity and Activity Impairment (WP Al) questionnaire 
adapted for anemia associated with chronic kidney disease from Baseline at Weeks 24 
and 48 (A copy of the questionnaire is in Section 11.1.) 
12. Change in score on the FACIT Fatigue Scale (Version 4) from Baseline at Weeks 24 and 
48 (A copy of the questionnaire is in Section 11.3.) 
13. Number of hospitalizations and duration (days) 
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3.2.3. 
Safety Endpoints 
Safety evaluations are based on the following: 
• Incidence, seriousness, intensity, duration, and type of AEs 
• Clinically significant changes in laboratory test results and vital signs 
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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is a 48-week, Phase 4, randomized, open-label, multicenter clinical study, comprised of 2 
periods: a 24-Week Dose Titration Period followed by a 24-Week Dose Maintenance Period. 
The study will consist of approximately 12 scheduled clinic visits over a period of 48 weeks with 
additional visits as needed. There will be a Screening period of up to 21 days. Two Hundred 
(200) eligible subjects with non-dialysis dependent CKD and IDA will be randomized in the 
study into 1 of 2 active treatment groups: 
• 
Group 1: KRX-0502 1 tablet TID (total of 3 tablets/day) with meals 
• 
Group 2: KRX-0502 2 tablets BID (total of 4 tablets/day) with the largest 2 daily meals 
A scheduled study drug dose adjustment will occur at Week 12 based upon the Hgb increase 
relative to Baseline and an Hgb threshold. Those subjects with an Hgb increase of;::0.5 g/dL 
from Baseline and Hgb ;::IO g/dL will maintain the same dose as determined at Randomization; 
subjects with an Hgb increase <0.5 g/dL from Baseline (at Randomization) or Hgb <10 g/dL will 
have their dose ofKRX-0502 increased to the following: 
• 
Group 1: KRX-0502 2 tablets TID (total of 6 tablets/day) with meals 
• 
Group 2: KRX-0502 3 tablets BID (total of 6 tablets/day) with the largest 2 daily meals 
Unscheduled dose adjustments can be made at any time during the study for adverse events 
(AEs) or abnormal laboratories. The unscheduled dose adjustments may involve a sequence of 
dose decreases, interruptions, no changes and/or increases based on various laboratory test 
results. (See the Test product, dose and mode of administration section of the Synopsis in this 
SAP and Section 7.5.2 of the protocol for details.) 
4.2. 
Definition of Study Drugs 
The term "study drug" refers to KRX-0502 (ferric citrate). 
4.3. 
Sample Size Considerations 
4.3.1. 
Sample Size Justifications 
Because this is an open-label Phase 4 study designed to estimate within-group changes from 
Baseline and describe time trends of iron parameters in subgroups of subjects, it is appropriate to 
conduct a precision-based sample size estimation as opposed to a power-based calculation. The 
primary endpoint of interest is change in Hgb from Baseline at Week 24. The standard deviation 
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(SD) for that endpoint is estimated as 0.9 g/dL based on the Week 16 data in a prior Phase 3 
study in a similar population (Keryx Study KRX-0502-306). 
Assuming a population SD of 0.9 g/dL, with a sample size of 140 subjects, the 95% confidence 
intervals (Cis) for mean change in Hgb from Baseline to Week 24 can be estimated, allowing for 
a CI half-width of 0.149 g/dL. 
It is assumed that 30% of the subjects in this study will drop out or be otherwise excluded from 
the PP population. Hence, 200 subjects will be randomized to ensure that there will be sufficient 
subjects at the end of the study for the longitudinal analyses (i.e., 70 evaluable subjects in each 
randomized treatment group). Based on prior clinical trial experience, it is estimated that half of 
the subjects will stay on their starting dose, and the other half will increase their dose after 12 
weeks of treatment. Hence, it is expected that the 4 dosing sequence groups that will arise will 
have approximately equal numbers of subjects (i.e., 35 subjects are expected in each of the four 
dosing sequence groups (3-3, 3-6, 4-4, and 4-6 tablets/day). 
The proposed sample size and the sizes of the subgroups of interest are deemed sufficient for the 
analyses proposed below including the longitudinal analyses. 
4.3.2. 
Sample Size Re-estimation 
Not Applicable. 
4.4. 
Randomization 
In this open-label study, eligible subjects will be randomized 1:1 to one of the two KRX-0502 
starting dose groups with approximately 100 subjects per group: 
• 
Group 1: KRX-0502 1 tablet TID (total of 3 tablets/day) with meals 
• 
Group 2: KRX-0502 2 tablets BID (total of 4 tablets/day) with the largest 2 daily meals 
4.5. 
Clinical Assessments 
The complete schedule of assessments for this study is presented in Table 2 of the protocol. 
Data from the central laboratory will be used for efficacy and safety analyses including analyses 
for supportive and exploratory endpoints. The following laboratory evaluations will be 
performed at the central laboratory: 
• 
A complete blood count (CBC); including white blood cell (WBC), white blood cell 
types (WBC differential), red blood cell (REC] count, hematocrit (HCT), Hgb, REC 
indices and platelet (thrombocyte]) count will be performed at Visit lA (Screening) and, 
if applicable, Visit 1 B (Re-screening); Visit 2 (Randomization); and all subsequent visits. 
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• 
A complete chemistry profile (CCP); including sodium, potassium, phosphorus, calcium, 
calcium adjusted for albumin, chloride, carbon dioxide/bicarbonate, glucose, blood urea 
nitrogen [BUN], creatinine, estimated glomerular filtration rate ( eGFR) based on the 
Modification of Diet in Renal Disease (MDRD) Study equation, aspartate 
aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALP], 
total bilirubin, total protein, and albumin) will be performed at Visit IA (Screening) and, 
if applicable, Visit IB (Re-screening); Visit 2 (Randomization); and all subsequent visits. 
• 
Iron studies (TSAT, ferritin, transferrin, unsaturated iron-binding capacity [UIBC], total 
iron-binding capacity [TIBC] and serum iron) will be performed at Visit IA (Screening) 
and Visit 1 B (Re-screening), if applicable, Visit 2 (Randomization); and all subsequent 
visits. 
• 
FGF23 (intact and C-terminal) testing will be performed at Visit 2 (Randomization), Visit 
9 (Week 24), Visit 12 (Week 48), and the Early Termination (ET) visit. 
• 
Intact parathyroid hormone (iPTH) testing will be performed at Visit IA (Screening) and 
if applicable, Visit lB (Re-screening); Visit 2 (Randomization); Visit 9 (Week 24); Visit 
12 (Week 48); and the ET visit. 
The laboratory parameters used in the assessment of efficacy are: 
• 
Hgb, 
• 
TSAT, 
• 
Ferritin and 
• 
Serum phosphate 
The schedule for the additional efficacy assessments is as follows: 
• 
Work Productivity and Activity Impairment (WPAI) Questionnaire and FACIT Fatigue 
Scale Questionnaire will be administered at Visit 2 (Randomization); Visit 9 (Week 24); 
Visit 12 (Week 48); and the ET visit. 
• 
Number of hospitalizations and duration (days) will be assessed at each visit. 
In addition to the laboratory assessments listed above, the safety assessments schedule includes 
the following: 
• 
AEs will be collected starting at the time of informed consent. 
• 
Vital signs (seated heart rate and blood pressure after at least 5 minutes of rest) will be 
recorded at Visit IA (Screening) and, if applicable Visit 1 B (Re-screening); Visit 2 
(Randomization); and all subsequent visits. 
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• 
Weight and height will be measured at Visit lA (Screening) and, if applicable, Visit 1B 
(Re-screening). Weight will also be measured at Visit 2 (Randomization), Visit 9 (Week 
24), Visit 12 (Week 48), and ET Visit. 
• 
Spot urine protein-to-creatinine ratio will be measured at Visit 2 (Randomization). 
• 
Serum pregnancy test for all women of childbearing potential will be performed at Visit 
IA (Screening) and, if applicable, Visit lB (Re-screening). 
Further, serum samples that will be frozen for future analysis of biomarkers of CKD will be 
obtained at Visit 2 (Randomization), Visit 9 (Week 24), Visit 12 (Week 48), and the ET visit 
from only those subjects who provided informed consent specifically for their collection. 
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5. 
PLANNED ANALYSES 
The following analyses are planned for this trial: 
• 
A 24-Week Analysis (to be performed after all Screening and Dose Titration Period data 
are available for all subjects) 
• 
The Final Analysis (to be performed after Database lock, based on data from the entire 
study). 
There will be two analyses; a 24-Week analysis after all subjects complete the 24-Week Dose 
Titration Period or have been withdrawn from the study and a Final analysis after all subjects 
either complete or have been withdrawn from the 48-Week study. Both analyses will be done at 
the end of the study. 
Additionally, a "snapshot" of the data for the 24-Week analysis will be presented for publication. 
This publication will be based on clean data through Week 24 for key safety and efficacy 
measurements. This will be referred to as the "24-Week analysis snapshot". 
5.1. 
24-Week Analysis 
The 24-Week analysis will be based on the data for all visits up to and including the Week 24 
visit, (i.e. it will cover the Dose Titration Period). Data for screen failure subjects will not be 
cleaned for this analysis. 
Data for this analysis are the data for those subjects who completed the Week 24 visit or had 
Early Termination from the study prior to Week 24. This will be done at the end of the study. 
The 24-Week analysis snapshot will be used for a publication. The subset of data will be cleaned 
and summarized in an abstract after all subjects have completed the 24-Week Dose Titration 
Period or have been withdrawn from the study. The following variables will be summarized: 
Efficacy analyses for hemoglobin, transferrin saturation, ferritin, serum phosphorus, and 
estimated glomerular filtration rate ( eGFR) will be analyzed using a MMRM model. 
Additionally, hemoglobin, intact parathyroid hormone (iPTH), C-Terminal fibroblast 
growth factor 23, and intact fibroblast growth factor 23 will be analyzed using an 
ANCOV A model. Analyses will use the modified PP Analysis Set. 
Summary statistics for safety analyses, including demographic, baseline characteristics, 
adverse events, and hematology, chemistry and miscellaneous laboratory tests will be 
performed. Analyses will use the Safety Analysis Set and modified PP Analysis Set 
(demographics and baseline characteristics only). 
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5.2. 
Final Analysis 
The final analysis will be based on the full set of cleaned data for all visits up to and including 
the Week 48 visit (i.e. it will cover the Dose Titration Period and the Dose Maintenance Period). 
Data for this analysis are the data for those subjects who completed the Week 48 visit or had 
Early Termination from the study prior to Week 48. 
Some tables, listings and figures produced for the final analysis will display statistics for both the 
Dose Titration and the Dose Maintenance treatment periods. 
5.3. 
Ad Hoc Analysis 
There is no ad hoc analysis planned. If an ad hoc analysis is deemed necessary, the SAP will be 
updated accordingly. 
5.4. 
Chronic Kidney Disease Biomarker Analysis 
Analyses for the CKD biomarkers from the frozen samples are not covered in this SAP. The 
analyses and report will be specified in an addendum to the final analysis report. 
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6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
Data management will transfer the raw data that were recorded in the eCRF and those data sets 
from external vendors that contain data to be used in the analyses to Biostatistics for creating the 
Study Data Tabulation Model (SDTM) and Analysis Data Model (ADaM) datasets. These 
derived datasets will be created using (SAS®) software. All data analyses will be conducted and 
summary tables generated using SAS version 9.4 or above. 
6.1. 
Data Collection, Processing and Reporting 
Keryx will provide the study sites with secure access to, and training on, the Electronic Data 
Capture (EDC) application sufficient to permit study site personnel to enter or correct 
information in the eCRFs on the subjects for which they are responsible. Creation and validation 
of the clinical database, entry and management of data, and transfer of central laboratory data 
will be maintained by the Contract Research Organization (CRO) and conducted in accordance 
with 21 CFR Part 11 [1] and the Guidance for Industry on Computerized Systems Used in 
Clinical Investigations [2].1. U.S. Department of Health and Human Services, Food and Drug 
Administration. 21 CFR Part 11.2. U.S. Department of Health and Human Services, Food and 
Drug Administration. Computerized Systems Used in Clinical Investigations, May 2007. 
An eCRF will be completed for each enrolled study subject. Data processed at the central 
laboratory will be transferred electronically. It is the Investigator's responsibility to ensure the 
accuracy, completeness, clarity and timeliness of the data reported in the subject's eCRF. Source 
documentation supporting the eCRF data will indicate the subject's participation in the study and 
will document the dates and details of study procedures, AEs, other observations and subject 
status. The Investigator or designated representative, will complete the eCRF as soon as possible 
after information is collected. 
Where corrections to an eCRF are needed after the eCRF has been submitted to EDC, the 
Investigator or appropriate staff member will have to respond with the correct answer. The audit 
trail entry will show the user's identification information and the date and time of any correction. 
Details of the data correction (query) process will be specified in the Data Management Plan. 
The Investigator will provide formal approval of all the information in the eCRFs, including any 
changes made to the eCRFs, to endorse the final submitted data for the subjects for whom the 
Investigator is responsible. CRFs will be completed for all subjects enrolled to study. 
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6.2. 
Data Presentation Conventions 
Unless otherwise stated, all analyses will be performed using SAS® Version 9.4 or higher. 
The following formats apply to all tables, figures and listings: 
1. p-values will be presented with 3 decimals; p-values that are less than 0.001 will be 
presented as <0.001. If the rounded result is a value of 1.000, it will be displayed as 
>0.999. All date information in listings will be presented using 9 character alphanumeric 
formats (e.g., 01JAN2008). 
2. Continuous data will be summarized using descriptive statistics: number of observations 
(n), mean, standard deviation (SD), median, 25th and 75th percentiles, minimum, and 
maximum. Given that the 25th and 75th percentiles are the 1st and 3rd quartiles, 
respectively, they will be labelled as Ql and Q3, respectively. 
3. Unless otherwise specified, in summary tables of continuous variables, the minimum and 
maximum values will be displayed to the same number of decimal places as the raw data, 
the mean and median will be presented to one extra decimal place compared to the raw 
data, and the standard deviation and coefficient of variation will be displayed to two extra 
decimal places compared to the raw data. 
4. Frequencies and percentages will be used to summarize categorical (discrete) data. If 
there are missing values, the number missing will be presented. 
5. Percentages will be based on the non-missing values. Presentations of categorical data 
will generally suppress percentages for items where the count is zero in order to draw 
attention to the nonzero counts. 
6. Unless otherwise stated, confidence intervals, when presented, will be constructed at the 
two-sided 95% level. 
7. For binomial variables, the confidence intervals will be constructed using the normal 
approximation without continuity correction due to the relatively large sample size. 
8. Wherever possible, data will be decimal aligned. 
9. Some laboratory values may be reported as <x, <=x, >x, or >=x due to the limits of 
detection for a specific assay, where xis the lower or upper limit of detection. For 
analysis purposes, these values will be treated as x, and for the listings they will be 
transcribed as from the raw data. (e.g., <x, <=x, >x, or >=x). 
10. The listings that display Study Day will have its numeric value, with 'Day' appended as a 
prefix and a suffix (if applicable) that is: 
• 
F, if Study Day is the subject's first study medication dose date, 
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• 
L, if Study Day is the subject's last study medication dose date and 
• 
P, if Study Day is after the subject's last study medication dose date. 
The derivation of study day is outlined in section 6.5.2. 
11. In the listings, any subject who is a 'protocol permitted ESA rescue therapy user' will be 
identified with an asterisk. 
6.3. 
Analysis Sets 
Keryx's agreement and authorization of subjects included/excluded from each analysis set will 
be obtained prior to the 24-Week Analysis snapshot and the Final Analysis database lock. 
6.3.1. 
Screened Subjects 
A screened subject is a person who signs an informed consent form, attends a Screening visit and 
is assigned a screening ID in IWRS. 
6.3.2. 
Screen Failures 
Subjects who do not meet all the inclusion and exclusion criteria will be considered screen 
failures. Depending on the reason for screen failure, subjects may be re-screened for study entry 
at least 2 weeks after their original screen failure date. A subject can be rescreened only once and 
informed consent must be obtained no more than 7 days before the rescreening. Re-screening 
will include re-evaluation of all inclusion and exclusion criteria. During screening and/or re-
screening (if applicable), subjects may be re-tested for specific inclusion and exclusion criteria 
that were not met at the initial testing. If a re-test is conducted, it needs to occur within 10 days 
of Screening (Visit lA) or Re-screening (Visit lB). 
6.3.3. 
Safety Analysis Set 
All subjects who take at least I dose of study medication will be included in the Safety Analysis Set. 
The Safety Analysis Set will be used in the assessment and reporting of safety data. 
The only study medication to be used is KRX-502. Therefore, treatment groups for the safety 
analyses will be based on the starting dose of KRX-502 to which subjects were randomized, 
irrespective of the dose used during the study. 
6.3.4. 
Full Analysis Set 
All subjects who are randomized, take at least 1 dose of study medication and have at least 1 
post-randomization efficacy measurement and have the corresponding baseline data will be 
included in the Full Analysis Set (FAS). 
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6.3.5. 
Per Protocol Analysis Set 
The Per Protocol (PP) Analysis Set will include all subjects in the FAS who have no major 
protocol deviations that affect the validity of the efficacy measurements (see section 7.2) and 
have not received additional treatment that affect the validity of the efficacy measurements. 
The following criteria exclude a subject from the PP Analysis Set: 
• 
Receive red blood cell transfusions within 4 weeks prior to screening or at any time during 
the study. 
• 
Receive ESAs (permitted or non-permitted) within 4 weeks prior to screening or at any time 
during the study. 
• 
Receive IV Iron within 4 weeks prior to screening or at any time during the study. 
• 
Pregnancy during screening or at any time during the study. 
• 
Overall drug compliance< 50% i.e., from randomization to the Week 48 Visit date or to 
Early Termination date (whichever is earlier). (See section 7.4.1 Compliance Calculation) 
• 
Major violations of eligibility criteria as determined by review prior to database lock. 
The PP analysis set will be used for the 24-Week and Final analyses. 
6.3.6. 
Modified Per Protocol Analysis Set 
The modified Per Protocol (mPP) Analysis Set will include all subjects in the FAS who have no 
important, i.e., major protocol deviations that affect the validity of the efficacy measurements 
(see section 7.2). 
The following criteria exclude a subject from the mPP Analysis Set: 
• 
Receive red blood cell transfusions within 4 weeks prior to screening or at any time during 
the study. 
• 
Receive ESAs (permitted or non-permitted) within 4 weeks prior to screening or at any time 
during the study. 
• 
Receive IV Iron within 4 weeks prior to screening or at any time during the study. 
• 
Pregnancy during screening or at any time during the study. 
• 
Major violations of eligibility criteria as determined by review prior to the snapshot. 
The mPP analysis set will be used for the 24-Week analysis snapshot only. The only difference 
between the PP and mPP is the mPP analysis set is not considering compliance as a criterion for 
exclusion. 
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6.4. 
Baseline Definition 
The baseline value for each variable, except age, for the 24-Week analysis and the final analysis 
is the last non-missing value observed prior to administration of the first dose of study 
medication, irrespective of whether it was a scheduled visit, or unscheduled visit or retest 
observation. 
Unless otherwise indicated, measurements taken on the same day as the first dose are considered 
to have been taken prior to the first dose. 
Each subject's first dose of study medication is prescribed to be consumed on the next day after 
the Date of Randomization. Because the actual date that the subject takes the first dose may 
differ from what was prescribed the actual start date will be recorded in the eCRF. 
First Dose Date= Study Medication Actual Start Date recorded in the eCRF. 
6.5. 
Derived and Transformed Data 
6.5.1. 
Baseline Age 
Baseline Age (years) will be calculated as 
the integer part of [ (date of informed consent - date of birth + 1) I 3 65 .25]. 
CKD Initial Diagnosis Age (years) will be calculated as 
the integer part of [(CKD initial diagnosis date - date of birth+ 1) I 365.25], 
where the CKD initial diagnosis date is imputed using the rule in section 6.6.4, if it contains any 
missing parts. 
6.5.2. 
Study Day 
If the date of interest occurs on or after randomization date and on or before treatment end date, 
then study day will be calculated as 
(date of interest - date ofrandomization) + 1. 
If the date of interest occurs prior to randomization date, then study day will be calculated as 
(date of interest - date of randomization). 
If the date of interest occurs after treatment end date, then study day will be calculated as 
(date of interest - treatment end date) + 1. 
In this study, there is no Study Day 0 and Study Day 1 is the subject's Randomization Day. 
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6.5.3. 
Change from Baseline 
Change from baseline is calculated as 
(post-baseline result- baseline result). 
If either the baseline or the post-baseline result is missing, the change from baseline and 
percentage change from baseline are both set to missing. 
6.5.4. 
Visit Windows 
Except for the Randomization Visit, which is designated as Study Day 1, all originally planned 
visits given in the protocol schedule of assessments from the Screening visit (Visit lA) through 
the End of Study visit (Visit 12: Week 48) have a specified visit window. The table below gives 
the window for each of these visits. 
During the first screening episode, subjects may be re-tested for specific inclusion and exclusion 
criteria that were not met at the initial testing. The re-test must take place within 10 days of the 
original screening date. Subjects who do not meet all the eligibility criteria within 21 days of the 
screening visit are considered screen failures. 
Depending on the reason for screen failure, subjects may be re-screened for study entry at least 2 
weeks after their original screen failure date. Subjects who are to be re-screened must give 
informed consent again no more than 7 days prior to rescreening. 
Table 2: 
Visit Windows (Study Days) 
Relative Target 
Analysis Visit 
Day 
Visit Number: Visit Name 
Name 
(Study Day) 
Visit IA: Screening• 
Screening 
-14 
Visit 1 A: Retest" 
Screening 
-9· 
Visit I B: Rescreenb 
Screening 
-14b 
Visit lB: Retestb 
Screening 
-9· 
Visit 2: Randomization 
Baseline 
1 
Visit 3: Week 2 
Week2 
15 
Visit 4: Week 4 
Week4 
29 
Visit 5: Week 8 
Week8 
57 
Visit 6: Week 12 
Week 12 
85 
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Relative Target 
Analysis Visit 
Day 
Visit Window 
Visit Number: Visit Name 
Name 
(Study Day) 
(Study Day Interval) 
Visit 7: Week 16 
Week 16 
113 
[100, 127] 
Visit 8: Week 20 
Week20 
141 
[128, 155] 
Visit 9: Week 24 
Week24 
169 
[156, 197] 
Visit 10: Week 32 
Week32 
225 
[198, 253] 
Visit 11: Week 40 
Week40 
281 
[254, 309] 
Visit 12: Week 48 
Week48 
337 
>309 
Visit Early Termination: Early 
Early Termination 
Termination (ET) c 
•Any retest for specific inclusion and exclusion criteria that were not met at the initial testing may occur within 10 
days of the original screening date. Therefore, the visit window, including start and end dates, for the retest is the 
same visit window as that for the original screening visit. A subject can have only 1 retest based on the original 
screening results. 
b Visit window for the rescreen visit has a study day interval relative to Day 1, equivalent to that for the original 
screening visit but because rescreening of a subject must be at least 14 days after the subject's original screen 
failure date the actual start and end dates on a subject's Screening Visit window and the Re-Screening Visit 
window differ. A subject can have only 1 retest based on the re-screening results. Any retest for specific inclusion 
and exclusion criteria that were not met at re-screening may occur within 10 days of the re-screening date. 
c Early Termination visits may fall within a visit window corresponding to a planned study visit. If this is the case, 
the ET visit will be labeled and summarized with the analysis visit name corresponding to the visit window. 
Multiple assessments may occur within the same window for a variety of reasons, for example, 
assessments to determine ifthe study drug dose should be adjusted. While there is only one 
planned scheduled dose adjustment, unscheduled dose adjustments for a subject may be 
necessary at any time during the study. 
The protocol includes guidance on making dosing adjustments which are dependent on specific 
central laboratory results. Laboratory values will be checked at each scheduled visit and the 
study drug dose may be adjusted in response to these results. When laboratory retesting is 
necessary, it will be done as an unscheduled visit, unless it coincides with a scheduled visit. 
Given the time lag in obtaining lab results and communicating the desired dose adjustment to the 
subject via telephone the time that the new prescription is to start and the subsequent follow-up 
blood draws for testing may or may not be in a single window for an originally planned visit 
given in the protocol's schedule of assessments. There may be multiple assessments falling in the 
same window and multiple assessments related to a single event may be taken during the 
window for more than one scheduled visit. 
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Additionally, when a subject discontinues from the study, the assessments made at the Early 
Termination visit may fall within a window for one of the originally planned visits given in the 
protocol's schedule of assessments. 
When multiple assessments occur within the same window, the one whose date of assessment is 
the largest study day in the window will be considered as the observed assessment value for that 
scheduled visit study day. 
6.6. 
Handling of Missing Data 
6.6.1. 
Missing Efficacy Endpoints 
Subjects who discontinue will not be replaced. If efficacy endpoint data are missing, they will 
not be imputed. 
Mixed models will be used to analyze the repeated measures data for visits up to and including 
Week 24 and Week 48. The Mixed Model Repeated Measures (MMRM) models described in 
section 8.2 implicitly adjust for missing data under the assumption of missing at random. 
6.6.2. 
Missing Start and Stop Dates for Prior and Concomitant Medications and 
Medical Conditions 
Prior and concomitant medication missing start and stop dates will be imputed in accordance 
with the rules specified in section 7.5. Imputed dates will only be used to determine whether a 
medication is concomitant or not. 
The rules for imputing medical history and medical conditions start and stop dates to identify 
those present at entry are equivalent to the rules given in section 7 .5 for prior and concomitant 
medications, respectively. 
6.6.3. 
Missing Start and Stop Dates for Adverse Events 
Missing stop dates for adverse events will not be imputed. Missing start dates for adverse events 
will be imputed in accordance with the rules specified in section 9.2.2. Imputed dates will only 
be used to determine whether an adverse event is treatment emergent or not. 
6.6.4. 
Missing CKD Initial Diagnosis Date 
If the year part of the CKD diagnosis date is missing, it will not be imputed and CKD Initial 
Diagnosis Age (years) will be missing. If the year part of the CKD diagnosis date is not missing 
and either the month or day is missing, then the missing part of the date will be imputed as 
follows for the analysis: 
• If the month is missing, then the month will be imputed as January. 
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• If the day is missing, then the day will be imputed as 01. 
The imputed CKD diagnosis date will be concatenated with subject number and other subject 
characteristics on some of the by subject listings. 
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7. 
STUDY POPULATION 
7.1. 
Subject Disposition 
Keryx Biopharmaceuticals, Inc 
April 4, 2019 
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Each subject who provided informed consent will be accounted for in this study. 
A table displaying the number and percentage ofrandomized subjects in each analysis set by 
starting dose treatment group and the two treatment groups combined will be provided for the 
24-Week Analysis and the Final Analysis. For the Final analysis, this table will also include 
these counts and percentages on subjects who enter the Dose Maintenance Period, as there may 
be subjects who do not return after the Dose Titration Period, i.e., after their Week 24 visit. 
A summary of subject accountability by treatment period and treatment group will also be 
presented. The summary will include the number of subjects screened, number of screen failures, 
number of subjects randomized, number subjects that were randomized but did not receive a 
dose of study drug and the number of subjects and percentage of randomized subjects in the 
Safety, Full and Per Protocol/modified Per Protocol analysis sets. 
The subject disposition table for the 24-Week Analysis will display statistics for the Dose 
Titration Period. The subject disposition table for the Final Analysis will display statistics for the 
48-Week treatment period (i.e. both the Dose Titration and the Dose Maintenance treatment 
periods). 
These tables will display by treatment group and overall the number and percentage of 
randomized subjects with each of the following two statuses at the end of the specific treatment 
period: 
• 
Completed the treatment period; 
• 
Discontinued from the study. 
The number and percentage of those who discontinued the study during the treatment period will 
be displayed by reason for non-completion. 
One of the following 15 reasons for non-completion should have been recorded in the eCRF for 
each subject who did not complete the study: 
• 
Discontinuation from study drug 
• 
Subject withdrawal of consent 
• 
Lost to follow-up 
• 
Study drug non-compliance 
• 
Investigator judgment 
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• 
Prohibited Therapy 
• 
Start of chronic dialysis or kidney transplantation 
• 
Death 
• 
Sponsor termination of study 
• 
Protocol violation 
• 
Adverse event 
• 
Pregnancy 
• 
Administrative reasons 
• 
Two consecutive Hgb values of< 8.0 g/dL (< 8.5 g/dL per original protocol) and patient 
does not qualify for ESA Rescue Therapy 
• 
Other 
A by subject listing, showing the subject disposition information, including the analysis set flags 
for all screened subjects, sorted by subject number within treatment group will be produced. For 
the Final analysis only, ifthere are less than 3 subjects in the 'Permitted' ESA Rescue Therapy 
subgroup, a separate disposition listing for only those subjects will be provided instead of a table. 
7.1.1. 
Discontinuation from Study for Use of Prohibited Therapies 
A table displaying the number and percentage of subjects in the Safety analysis set who 
discontinued the study with use of each of the following prohibited therapies as the primary 
reason will be provided: 
• 
IV iron 
• 
Blood transfusion 
• 
ESA with the exception ofESA Rescue Therapy under the conditions permitted by 
protocol. 
• 
Oral iron therapy other than KRX-0502 as treatment for iron deficiency except for 
multivitamins containing iron 
• 
Phosphate binder other than KRX-0502 
• 
Commercial ferric citrate 
• 
Aluminum-containing therapies 
• 
Investigational drug other than the KRX-0502 
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The statistics in this table will be shown for each of the starting dose treatment groups and the 
two treatment groups combined. 
7.1.2. 
Discontinuation from Study Drug 
A table will display the number and percentage of subjects in the Safety Analysis set whose 
primary reason for discontinuation of treatment with the study drug was as follows: 
• 
Adverse event 
• 
Two consecutive Hgb below 8.0 g/d.L (below 8.5 g/dL per original protocol) more than 3 
days apart and subject does not qualify for ESA Rescue Therapy 
• 
Pregnancy 
• 
Withdrawal by subject 
• 
Other 
The statistics will be displayed by starting dose treatment group and the two treatment groups 
combined for the Dose Titration treatment period and the Dose Maintenance treatment period. 
7 .2. 
Protocol Deviations 
Protocol deviations (PDs) will be collected on a PD log. 
Protocol deviations will be reviewed by the Keryx Team, and their status confirmed by the time 
that all data are cleaned for the 24-Week analysis and the Final Analysis. 
Section 6.3.5 lists PDs that affect the validity of the efficacy measurements and result in 
exclusion of subjects from the PP Analysis Set. 
A listing of PDs for subjects who are excluded from the PP analysis set will be generated. 
7.3. 
Demographic and Other Baseline Characteristics 
Baseline demographic and other baseline characteristics for subjects in the PP analysis and 
Safety analysis sets will be summarized by starting dose group and these two treatment groups 
combined, as well as by dosing sequence group, using descriptive statistics and by subject 
listings of these data will be presented by starting dose group. In addition, comparable summary 
tables and by subject listings will be provided for the subgroup of FAS who received ESA rescue 
therapy under the conditions permitted by the protocol given that there will be efficacy analyses 
performed for this subgroup. For the Final analysis only, if the subgroup includes less than 3 
subjects, by subject listings of the data for these subjects will be provided instead of tables. 
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Note, no comparisons of the baseline demographic and other baseline characteristics between 
treatment groups are carried out for this study. 
The demographic characteristics include: 
• 
Age (years) 
• 
Age Category 
• 
Sex 
• 
Ethnicity 
• 
Race 
• 
Weight (kg) 
• 
Height (cm) 
• 
Body Mass Index (BMI kg/m2) 
Age (years) is the Baseline Age derived using the expression in section 6.5.1. 
Age Category is this calculated value, Age (years), categorized into the groups: 
• 
< 65 years 
• 
~ 65 years 
Race is recorded in the eCRF by choosing all of the following classifications that apply: 
• 
Asian 
• 
Black/African-American 
• 
White/Caucasian 
• 
American Indian or Alaska Native 
• 
Native Hawaiian or Other Pacific Islander 
• 
Unknown 
• 
Other 
The subjects' choices will be summarized to show the number and percentage of subjects in the 
following categories for each of the starting dose groups and these two treatment groups 
combined: 
• 
Asian Only 
• 
Black/African-American Only 
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• 
White/Caucasian Only 
• 
American Indian or Alaska Native Only 
• 
Native Hawaiian or Other Pacific Islander Only 
• 
More Than One Race 
• 
Unknown 
• 
Other 
Only those categories with at least 1 subject will be displayed in the Baseline Demographic 
tables. 
Subjects with more than 1 of the 5 categories, Asian, Black/African-American, White/Caucasian, 
American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander selected on the 
eCRF Demography page are to be counted in the "Multiple" category. 
Calculate Baseline BMI using the expression below where the values for weight and height 
values are baseline values. 
BMI (kg/m2) =[Weight (kg)] I [height (m)]2. 
Since height and weight are recorded in inches and pounds, respectively, note that 
Weight (kg)= Weight (lb)/2.2046 
Height (m) = 0.0254*height (in). 
Round weight and height to one decimal place before calculating BMI and round BMI to one 
decimal place. 
Descriptive statistics of the following CKD characteristics will be presented in a table separate 
from the other characteristics: 
• 
Age (years) at CKD Diagnosis 
• 
CKD Primary Cause 
• 
Baseline CKD Stage 
Age at CKD Diagnosis is the CKD initial diagnosis age derived using the expression in section 
6.5.1. 
Other baseline characteristics include: 
• 
Work Productivity and Activity Impairment Scores (See section 11.2 for scoring 
instructions.) 
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o Percent work time missed due to anemia associated with CKD 
o Percent impairment while working due to anemia associated with CKD 
o 
Percent overall work impairment due to anemia associated with CKD 
o Percent activity impairment due to anemia associated with CKD 
• 
FACIT-Fatigue Subscale Score (See section 11.4 for scoring instructions.) 
• 
Number of hospitalizations 
• 
Duration of hospitalization stay (days) 
• 
The baseline evaluation for the following parameters reported by the central laboratory: 
o Hemoglobin (Hgb) 
o Estimated glomerular filtration rate ( eGFR) 
o eGFR category: <30, 30 - 44, and >=45 ml/min/1.73m2 
o Transferrin saturation (TSAT) 
o Ferritin 
o Phosphorus, i.e., serum phosphate 
o Intact parathyroid hormone (iPTH) 
o Intact Fibroblast growth factor 23 (iFGF23 
o C-terminal Fibroblast growth factor 23 (cFGF23) 
o 
Spot urine protein-to-creatinine ratio 
Descriptive statistics of the laboratory parameters will be displayed in conventional units. 
7.4. 
Medical History and Medical Conditions Present at Entry 
No table showing the number and percentage of subjects who had each medical history condition 
coded to MedDRA version 20.0 system order class (SOC) and preferred term (PT) or by subject 
data listings will be presented. The missing start and stop dates will be imputed as described in 
section 6.6.2 and included in the ADaM dataset. 
7.5. 
Prior and Concomitant Medications and Non-Drug Therapies 
All prescription and over-the-counter medications and non-drug therapies used by subjects at 
Visit IA (Screening) and thereafter through the last study visit will be recorded in the eCRF. 
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WHO-DD version 01Jun2017 B2 format will be used to code the medications. Non-drug 
therapies will not be coded. 
Prior medications and therapies are defined as any that were started and stopped prior to the date 
the subject used the first dose of the study drug. Concomitant medications and therapies are 
defined as any that were started or were ongoing on or after the study drug first dose date up to 
and including the last study visit date. 
No by subject data listings or tables showing the prior or concomitant medications recorded in 
the eCRF will be presented. 
Incomplete start and/or stop dates for the medications and therapies recorded in the eCRF will be 
imputed as follows: 
• If either the start of medication or other therapy date is completely missing, or the 
month and/or year of the start date is missing, the start date will be set to the first dose 
date. 
• If only the day is missing, the day will be set to the first day of the month except if the 
start month is the same as the first dose month. If the latter is true, the start day will be 
set to the first dose day. 
• If stop date is completely missing, it will be assumed that use of the medication is 
ongoing, and it will be classified as a concomitant medication with a missing stop date. 
• If stop date is partially missing, then impute as the latest possible date given date parts 
that are not missing. (I.e., if only day is missing then impute as last day of the given 
month and if month and day are missing then impute as Dec. 31st of the given year. 
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8. 
EFFICACY 
8.1. 
General Considerations 
Efficacy analyses will be based on the PP Analysis Set data for the 24-Week and Final analyses 
(mPP Analysis Set for 24-Week analysis snapshot). Additionally, efficacy of the study drug in 
the FAS subgroup of subject who received rescue therapy under the conditions specified in 
section 9.2.2 of protocol will be assessed. 
Table 3 lists the efficacy endpoints of special focus for the 24-Week Analysis snapshot and the 
24-Week and Final Analyses showing the analysis method and analysis set to be used in 
assessing them. See section 8.2 for any special conditions to be explored for implementation of 
the analysis method or alternatives that will necessitate implementation of an alternative method. 
Table 3: Analysis Method and Analysis Set for Special Focus Efficacy Endpoints 
24-Week Analysis 
Final Analysis 
Efficacy 
(Study Period: Dose 
(Study Period: 
Parameter 
Titration Period) 
Entire Study) 
Hgb 
Change from 
Change from 
Baseline to Week 24 • 
Baseline to Week 48 
Hgb 
Change from Baseline at 
Change from 
Week24 
Baseline at Week 48 
Hgb 
Time from 
Not Applicable 
Randomization to First 
Increase from Baseline 
Hgb >= 0.5 g/dL 
TSAT, ferritin, 
Change from Baseline to 
Change from 
phosphate, 
Week24 
Baseline to Week 48 
bicarbonate, eGFR 
PTH, c-terminal 
Change from Baseline to 
Change from 
and intact FGF-23 
Week24 
Baseline to Week 48 
FACIT score 
Change from baseline at 
Change from 
Week24 
Baseline to Week 48 
WPAI 
Change from Baseline to 
Change from 
Week24 
Baseline to Week 48 
Hospitalizations 
Number and Duration 
Number and Duration 
(days) 
(days) 
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Analysis 
Method 
MMRM 
ANCOVA 
Kaplan-
Meier 
MMRM 
ANCOVA 
Descriptive 
Descriptive 
Descriptive 
Analysis Set 
ppl 
pp! 
Completers 
pp! 
pp! 
pp! 
ppl 
pp! 
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Hgb, TSAT, 
Change from Baseline to 
Change from 
MMRM 
FAS subjects 
ferritin, phosphate 
Week24 
Baseline to Week 48 
who received 
permitted 
Change from 
ESARescue 
Baseline to Week 24 
Therapy 
Hgb, TSAT, 
Change from 
MMRM 
PP Dosing 
ferritin, phosphate 
Baseline to Week 48 
sequence 
groups 
Change from 
Baseline to Week 24 
* Hgb change from baseline to Week 24 is the primary endpoint. 
1The analysis set used will either be the modified PP Analysis Set (24-Week Analysis snapshot) or PP Analysis Set 
(24-Week and Final Analysis). 
8.2. 
Primary Efficacy Analysis 
The primary efficacy endpoint is change from Baseline Hgb value at Week 24. A two-sided 
95% confidence interval will be constructed for the mean change from Baseline in Hgb at 
Week 24 for each of the starting dose treatment groups, for subjects in the PP/mPP analysis set. 
Results obtained using the Mixed Model Repeated Measures (MMRM) model will be used to 
construct the confidence intervals. The SAS procedure PROC MIXED with method specified as 
residual maximum likelihood (REML) will be used to fit the model and obtain the least squares 
mean, the associated standard error and two-sided 95% confidence interval for each treatment. 
Under an assumption that the missing observations are missing at random, change from baseline 
Hgb at Week 24 will be analyzed by using a MMRM model with an intercept term, baseline Hgb 
as a covariate, starting dose treatment group effect, visit, visit by starting dose treatment group 
interaction, baseline Hgb by visit interaction and a random error term. 
For the MMRM model, the Kenward-Roger method for approximating the denominator degrees 
of freedom and correcting for bias in the estimated variance-covariance of the fixed effects will 
be used. This will be achieved by specifying the DDFM = KR option in the MODEL statement 
within PROC MIXED. An unstructured variance-covariance matrix will be used to model the 
within-subject covariance. If the unstructured covariance configuration results in a lack of 
convergence, then the following variance-covariance matrix will be used, in the order listed 
below, stopping with the first that converges: 
• 
Heterogeneous Toeplitz 
• 
Heterogeneous first-order autoregressive 
• 
Heterogeneous compound symmetry 
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If all variance-covariance matrices selected fail to converge, variance components will be used as 
the next attempt at convergence. 
To check the model assumption regarding normality for residuals and to detect potential outliers 
a normal probability plot of residuals and a plot of the residuals versus the fitted values will be 
used. If necessary, transformations and/or dropping of outliers to obtain data that meet the model 
assumptions will be implemented. 
A table displaying, by visit and starting dose, the descriptive statistics for Hgb and the change 
from Baseline Hgb, the least squares mean (LSM) change from Baseline Hgb obtained using the 
MMRM described above and the corresponding 95% confidence interval of the mean change 
from baseline Hgb for each starting dose treatment group and these two groups combined will be 
presented for the 24-Week Analysis. 
8.3. 
Secondary Efficacy Analyses 
For the Final Analysis, the secondary efficacy endpoint, change from Baseline Hgb at Week 48 
will be assessed in the same manner, using data for all visits up to and including the Week 48 
visit, as described in section 8.2 for the Week 24 visit. 
The 95% Cl for the mean change from baseline will be obtained for each of the following 
secondary efficacy endpoints by using an MMRM: 
1. Change in transferrin saturation (TSAT) from Baseline at Weeks 24 and 48 
2. Change in ferritin from Baseline at Weeks 24 and 48 
3. Change in serum phosphate from Baseline at Weeks 24 and 48 
4. Change in eGFR from Baseline to Weeks 24 and 48 
5. Change in bicarbonate from Baseline to Weeks 24 and 48 
The same type statistics as described in Section 8.2 for Hgb will also be provided for the 
endpoints listed above where the change from Baseline to Week 24 results and the change from 
Baseline to Week 48 results will be presented in tables for the 24-Week analysis and the Final 
analysis, respectively. 
Ninety-five percent Cls will be constructed for mean change from Baseline Hgb at Week 24 and 
mean change from Baseline Hgb at Week 48 based on the data for the PP analysis subjects who 
complete their Week 24 visit and data for the PP analysis subjects who complete their Week 48 
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visit, respectively, by starting dose treatment group and these two groups combined. The 
parametric analysis of covariance (ANCOVA) model for change from baseline in Hgb at Week 
24 and at Week 48 with an intercept term, baseline Hgb as a covariate, starting dose treatment 
group effect, and a random error will be used to obtain the least squares mean (LSM), the 
associated standard error and associated 95% confidence intervals. To check the model 
assumption regarding normality for residuals and to detect potential outliers a normal probability 
plot ofresiduals and a plot of the residuals versus the fitted values will be used. If necessary, 
transformations and/or dropping of outliers to obtain data that meet these assumptions will be 
implemented. 
Intact parathyroid hormone (iPTH), C-terminal fibroblast growth factor 23 and intact fibroblast 
growth factor 23 are only measured at Randomization Day, Week 24 and Week 48. Therefore, 
the type of ANCOVA model as described above for change for Baseline Hgb in the PP/mPP 
analysis subjects who complete the Week 24 visit and those who complete the Week 48 visit will 
be used to obtain the 95% confidence intervals for the means of the following: 
1. Change in intact parathyroid hormone (iPTH) from Baseline to Weeks 24 and 48 
2. Change in C-terminal fibroblast growth factor 23 from Baseline to Weeks 24 and 48 
3. Change in intact fibroblast growth factor 23 from Baseline to Weeks 24 and 48. 
Box plots over time of the observed value and the change from Baseline for each of the efficacy 
parameters, Hgb, TSAT, ferritin and serum phosphate will be provided. The box plots will be 
constructed based on observations made during the window of time designated for each visit 
given in section 6.5.4. If there are visits that are out of window, a scatter plot of the in-window 
and out of window observations will be used along with the box plots to explore the question of 
the stability of Hgb, TSAT, ferritin and serum phosphate during treatment with the study 
medication. 
The Kaplan-Meier estimator of the survival function of time from randomization to first increase 
from Baseline Hgb of at least 0.5 g/dL for each of the two starting dose treatment groups will be 
obtained. The Kaplan-Meier plot of the functions for the two starting doses will be presented on 
a single figure. 
A table will be presented that shows for the PP/mPP analysis set by treatment group the 
following for the event, time from randomization to first increase from Baseline Hgb of at least 
0.5 g/dL, during the Dose Titration Period: 
• 
Estimated median time in days; 
• 
Number and percentage of subjects who had at least one event; 
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• 
Number and percentage of subjects with time to the event censored (Censoring occurs if a 
subject does not have the event prior to either completing the Week 24 visit or 
discontinuing from the study prior to the Week 24 visit.). 
Tables displaying descriptive statistics will be provided for the Week 24 analysis and the Final 
analysis for the following secondary efficacy endpoints: 
• 
Change in FACIT Fatigue Scale from Baseline at Weeks 24 and 48; 
• 
Change in WPAI questionnaire specific health problem score from Baseline at Weeks 24 
and48 
where the change from Baseline at Week 24 results and the change from Baseline at Week 48 
results will be presented in tables for the 24-Week analysis and the Final analysis, respectively. 
Descriptive statistics will also be provided for the number of hospitalizations and duration of 
hospital stay in days during the Dose Titration Period and the entire study for the 24-Week 
Analysis and Final Analysis, respectively. 
8.4. 
Subgroup Analyses 
For the 24-Week analysis, the change from baseline at Week 24 in Hgb, TSA T, ferritin, and 
phosphorus will be assessed for subjects who received 'Permitted' ESA therapy during the Dose 
Titration Period. For the Final analysis, the change from baseline at Week 24 and at Week 48 in 
Hgb, TSAT, ferritin, and phosphorus will be assessed for subjects who received 'Permitted' ESA 
therapy during the study. 
Data in the Full Analysis Set for this subgroup of subjects will be used for the analyses. If at 
least 30 subjects are in the subgroup descriptive statistics and the two-sided 95% confidence 
intervals for the mean change from Baseline will be obtained as described in section 8.2 for the 
change from Baseline Hgb. If this subgroup includes at least 3 subjects but less than 30 subjects, 
only descriptive statistics will be presented for each of the starting dose treatment groups. For the 
Final analysis only, ifless than 3 subjects are in the subgroup by subject listings of disposition, 
demographics, and laboratory tests (hematology, chemistry, urine chemistry, and miscellaneous) 
will be provided instead of summary tables. 
It is expected that after the planned dose titration at Week 12 there will be about 35 subjects in 
each of the 4 dosing sequence groups, 
(Starting Dose Group Daily Dose (pills/day) - Week 12 Titrated Daily Dose (pills/day), i.e.: 
• 
3 pills/day- 3 pills/day, 
• 
3 pills/day- 6 pills/day, 
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For the Final analysis, additional subgroup analyses will be conducted for change from baseline 
in Hgb, TSAT, ferritin, and phosphorus in these dosing sequence groups. The 95% confidence 
interval for the mean change from baseline for each dosing sequence will be obtained by using 
dosing sequence rather than starting dose treatment group in the MMRM model described in 
section 8.2. Each subject's dosing sequence group will be based on the actual dose prescribed at 
baseline and the Week 12 dose titration assignment. If the subgroups include at least 3 subjects 
but less than 30 subjects, the MMRM analysis will not be performed and only descriptive 
statistics will be presented. For the Final analysis only, ifthere are less than 3 subjects in any 
subgroup, only by subject listings will be provided instead of tables. 
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9. 
SAFETY AND TOLERABILITY 
Safety and tolerability evaluation will be included in the 24-Week Analysis and the Final 
Analysis. 
The safety data includes adverse events, vital signs and clinical laboratory measurements. 
Adverse events that begin after the first administration of study medication or pre-existing 
conditions that worsen after the first dose of study medication are considered TEAEs. If, based 
upon the data recorded in the eCRF and/or the procedure for imputing the start date given in 
section 9 .2.2, it is not possible to classify an AE as treatment emergent or not, then classify the 
AE as a TEAE. 
For the 24-Week Analysis, since any table, listing or figure produced will only include statistics 
based upon the Screening period and Dose Titration treatment period: 
• 
No adverse event that starts or worsens after the Week 24 visit date will be included in 
summaries of TEAEs and 
• 
In calculating the subject months of study drug exposure only those days of treatment prior 
to the Week 24 visit will be counted since subjects are to delay taking their study drug on the 
day of planned site visits until after the site visit. 
For the Final Analysis, all observations up to and including those for the Week 48 visit date will be 
included in identifying TEAEs and calculating subject months of study drug exposure. 
9.1. 
Overall Summary of Tolerability 
An overall summary of tolerability table by treatment group and the two treatment groups 
combined for all subjects in the Safety Analysis Set will be produced. 
The following statistics for the set of treated subjects will be displayed in this table: 
• 
Subject months of study drug exposure descriptive statistics 
• 
Number and percentage of subjects with treatment emergent adverse events (TEAEs) 
• 
Number of TEAEs 
• 
Number and percentage of subjects with serious adverse events (SAEs) 
• 
Number and percentage of subjects with serious TEAEs 
• 
Number and percentage of subjects requiring a dose alteration due to adverse events 
• 
Number and percentage of subjects discontinuing the study due to adverse events 
• 
Number and percentage of subjects who died 
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Another table displaying the same statistics by dosing sequence will be produced. 
Subject months of drug exposure = 
total number of days of treatment for each subject summed over all subjects divided by 30.4375 
total duration of exposure in days for each subject summed over all subjects divided by 30.4375 
See section 9.3 for the procedure used to calculate each subject's total duration of exposure 
(days) in this study. 
To determine the number of adverse events, count all unique events reported at the preferred 
term level. Multiple events with the same preferred term are considered unique if the event onset 
dates are different. 
9.2. 
Adverse Event Summary Tables 
Adverse events will be mapped to system organ class (SOC) and preferred term (PT) using 
MedDRA version 20.0. 
An adverse event subject data listing providing a complete disclosure of adverse events as 
recorded in the CRF will be produced for each of the starting dose treatment groups. 
To determine the number of adverse events, count all unique events reported at the preferred 
term level. Multiple events with the same preferred term are considered unique, if the event onset 
dates are different. 
9.2.1. 
Summaries of All Treatment Emergent Adverse Events 
The summaries described below will be provided for the 24-Week Analysis and the Final 
Analysis. 
1. The number and percentage of subjects with TEAEs will be summarized by MedDRA 
system organ class and preferred term within each starting dose treatment group and all 
treated subjects without regard to severity (intensity) or relationship to study drug. The 
SOCs will appear in descending order of number of subjects in the two treatment groups, 
i.e., all treated subjects, with at least one TEAE mapped to the SOC. The PTs within 
each SOC will appear in descending order of number of subjects in the two treatment 
groups with at least one TEAE mapped to the PT within that SOC 
2. A table summarizing TEAE by intensity will be produced. The table will display the 
number and percentage of subjects with TEAEs summarized by MedDRA system organ 
class, preferred term, intensity level within each starting dose treatment group and all 
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treated subjects. The SOCs and PTs will appear in the same order as in the table 
described in #1 above. 
3. A table summarizing TEAE by relationship to study drug will be produced. This table 
will display the number and percentage of subjects with TEAEs summarized by 
MedDRA SOC, PT and relationship to study drug within each starting dose treatment 
group and all treated subjects. The SOCs and PTs will appear in the same order as in the 
table described in #1 above. 
4. Tables as described in #1 , #2 and #3 above where, instead of the summaries for the two 
starting dose treatment groups, summaries are presented for the four dosing sequence 
treatment groups, Starting Dose Group Daily Dose (pills/day)- Week 12 Titrated Daily 
Dose (pills/day), i.e., 3 pills/day - 3 pills/day, 3 pills/day - 6 pills/day, 4 pills/day - 4 
pills/day and 4 pills/day - 6 pills/day. 
5. Tables displaying the number and percentage of subjects reporting serious AEs and the 
number and percentage of subjects reporting AEs leading to treatment discontinuation for 
all treated subjects and for each randomized dose group by MedDRA system organ class 
and pref erred term. 
Severity (Intensity on the eCRF) is classified as mild, moderate or severe where these categories 
denote increasing intensity, respectively. TEAEs starting after the first dose of study drug with a 
missing intensity will be classified as severe. If a subject has more than one TEAE within the 
same SOC/ PT, the AE with the worst case intensity will be used in the corresponding intensity 
summanes. 
The only relationships of AE to study drug used in this study are "unrelated" and "related". An 
AE's relationship to study drug is based on the Investigator's assessment. TEAEs with the 
relationship to study drug missing will be classified as "related" to study drug. If a subject has 
more than one AE within the same SOC and PT, the AE with the worst case relationship to study 
drug will be used in the corresponding relationship summaries. 
9.2.2. 
Missing and Partial AE Start Dates 
Completely missing or partially missing AE start (onset) dates will be imputed as follows: 
• If onset date is completely missing, onset date is set to date of first dose. 
• If (year is present and month and day are missing) or (year and day are present and month 
is missing): 
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o If year = year of first dose, then set month and day to month and day of first dose 
o If year < year of first dose, then set month and day to December 31st 
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o If year > year of first dose, then set month and day to January 1st 
• If month and year are present and day is missing: 
o If year=year of first dose and 
• 
if month = month of first dose then set day to day of first dose date 
• 
if month < month of first dose then set day to last day of month 
• 
if month > month of first dose then set day to 1st day of month 
o if year < year of first dose then set day to last day of month 
o if year > year of first dose then set day to 1st day of month 
• 
For all other cases, set onset date to date of first dose 
Note, adverse event listings will display start and end dates as collected, not imputed. 
9.2.3. 
Summaries of Serious Adverse Events (SAE), Adverse Event Dropouts, and 
Death 
For the 24-Week Analysis and the Final Analysis the number and percentage of subjects with 
serious treatment emergent AEs reported will be summarized by MedDRA system organ class 
and preferred term within each starting dose group and all treated subjects without regard to 
intensity or relationship to study drug. The SOCs will appear in descending order of number of 
subjects in the two treatment groups combined, i.e., all treated subjects, with at least one SAE 
mapped to the SOC. The PTs within each SOC will appear in descending order of number of 
subjects in the two treatment groups combined with at least one SAE mapped to the PT within 
that SOC. 
The same types of tables as described for SAEs will be produced for: 
o 
TEAEs leading to treatment discontinuation and 
o 
TEAEs leading to deaths 
A by subject adverse events listing will be produced to support these three tables. The list for the 
24-Week Analysis will show all AEs for subjects who had at least one SAE or had treatment 
discontinued due to a TEAE or had a TEAE that led to death during the Dose Titration Period by 
starting dose group and subject number with the subject's AEs listed in chronological order of 
AE start date. Similarly, the list for the Final Analysis will be produced to show the AEs for 
subjects who experienced the same types of AEs either in the Dose Titration or Dose 
Maintenance period. 
A listing of all adverse events of each deceased subject will be produced. 
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9.3. 
Total Duration of Therapy, Maximum Daily Dose, Final Daily Dose 
of Study Medication, and Compliance 
For the 24-Week Analysis, a table will be provided that shows the descriptive statistics for 
subject's total duration of exposure in days, average and maximum daily dose attained, final 
daily dose taken, and the number and percentage of subjects with overall compliance during the 
Dose Titration Period in the two categories, < 50% and >==50%, by starting dose treatment 
groups and for the four dose sequence treatment groups. 
A by subject listing for exposure, dosing and compliance will be provided for support in 
determining members of the PP Analysis set for the Final analysis. 
For the Final Analysis, a table will be provided corresponding to that described for the 24-Week 
Analysis except that along with the descriptive statistics for the Dose Titration Period those for 
the Dose Maintenance Period and the entire study will be included. The Final Analysis listing 
will include the data for all visits within the study and total duration of exposure at Week 48 and 
overall compliance for the entire study along with the other variables on the listing produced for 
the 24-Week Analysis. 
9.3.1. 
Total Duration of Exposure Calculation 
A subject's total duration of exposure in days is the total number of days that the subject was 
prescribed to be taking more than zero pills per day. 
For this study, duration of exposure in days for a subject is defined as the subject's first dose date 
minus last dose date plus lday minus the number of days that the subject was using a prescribed 
study drug interruption, i.e., using a dose of zero pills per day as prescribed. 
For the Dose Titration Period a subject's: 
duration of exposure (days) during the Dose Titration Period 
([minimum of the subject's Week 24 visit date and date oflast dose in the period] - first dose 
date+ 1 day) 
-
L~=l ([actual stop date]i - [actual start date]i + 1) 
where i denotes the i1h time during the Dose Titration Period that the subject was prescribed zero 
pills per day, the ith actual start date and ith actual stop date are the first and last dates that the 
subject was taking zero pills during the period for which the ith prescription of zero pills per day 
was in effect. 
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For the Dose Maintenance Period a subject's: 
duration of exposure (days) during the Dose Maintenance Period 
(last dose date - Dose Maintenance Period first dose date + 1) 
- L7=1 ([actual stop date]i - [actual start date Ji + 1) 
where i denotes the i1h time during the Dose Maintenance Period that the subject was prescribed 
zero pills per day, the ith actual start date and ith actual stop date are the first and last dates that 
the subject was taking zero pills during the period for which the ith prescription of zero pills per 
day was in effect. 
Total duration of exposure (days) for the entire study 
Total duration of exposure (days) during the Dose Titration Period 
+ 
Total duration of exposure (days) during the Dose Maintenance Period. 
Note: Duration of exposure in months= duration of exposure in days divided by 30.4375. 
9.3.2. 
Compliance Calculation 
A subject's compliance to treatment during a specific time period expressed as a percentage is 
equal to 100 times the amount of study drug taken by the subject during the specific time period 
divided by the amount that was prescribed to be taken by the subject during the specific time 
period. 
The number of pills recorded in the eCRF drug accountability pages as the number of pills 
dispensed and/or the number of pills returned at each site visit are based on a count of the 
physical pills in the bottle(s) dispensed and/or returned during the visit, respectively. 
A subject's prescription may be changed at any time during the course of this study based on 
adverse events or certain laboratory test results observed or reported at any scheduled visit or any 
unscheduled visit. Additionally, it is planned that each subject will get the study drug dose 
titrated at the scheduled Week 12 visit. The prescribed amount to be taken starting after the 
scheduled Week 12 visit will depend on the Week 12 Hgb value. 
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The results of some laboratory tests will be required to make the decision regarding each study 
drug prescription during the study but these results will not be immediately available to the site 
on the visit day. Therefore, it may not be possible to confirm the number of pills actually in the 
bottle at the time that a new dose is prescribed to start. (Instructions with respect to a prescribed 
dose change may be delivered via telephone.) 
The general expression for calculating a subject's compliance(%) over a specific time period X, 
amount of study drug taken during the specific time period,X 
100*~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 
amount of study drug prescribed to be taken during the specific time period,X 
using the drug accountability data recorded in the eCRF is expressed as 
100 
(#of pills dispensed at start of period X - #of pills returned at end of the period X) 
* 
(#days in period X) * (#pills prescribed to be taken per day during the period X) 
This expression for compliance will take one of three forms depending on the number of dose 
adjustments made between two successive site visits, i.e., zero, one or m greater than one dose 
adjustments. 
To define compliance(%) for these three cases, the following notation and assumptions are 
made: 
• 
Let the subscript k 2: 2 denote the site visit number where: 
k = 2 for the Randomization Visit, i.e., Visit 2 in the Schedule of Assessments (See 
protocol section 7 Table 2.); 
k = 3 for the subject's next site visit, scheduled or unscheduled, after Visit 2; 
k = 4 for the subject's next site visit, scheduled or unscheduled, after Visit(k = 3); 
k = 5 for the subject's next site visit, scheduled or unscheduled, after Visit(k=4); 
k = j for the subject's next site visit, scheduled or unscheduled, after Visit(k= j-t). 
• 
First dose on a new prescription issued on date of site visit is to be taken on the day after 
the site visit. E.g., a subject's 1st bottle of pills is dispensed on the Date of Visit 2 but the 
first pill is prescribed to be taken on the day after Visit 2. 
• 
In general, because visits should be scheduled to occur in the morning, non-fasted and 
subjects are instructed to hold study drug until blood is drawn, assume that pills 
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consumed on the date of a site visit are at the dose level last prescribed before the site 
visit. 
To calculate compliance between any two successive site visits one of the three cases described 
below are applicable. 
Case 1: 
Zero dose adjustments were prescribed to start during the period between last date study drug 
was dispensed which was Visitck-1), and the date of the current visit, which is Visit (k). 
Compliance(%)= 
100 times (#pills dispensed at Visitck-1) - #pills returned at Visit(k)) 
divided by 
([#pills prescribed to be taken on the day of Visitck-1)] + {[date of Visit(k)- 1 day 
- date of Visitck-1)] times [#pills prescribed to be taken per day on 1 day after 
date of Visit(k-1) thru the day before Visit(k)]} ), 
where if day of Visitck-1) is day of Randomization, 
then[# pills prescribed to be taken on the day of Visit(k-1)] = 0 
Case 2: 
Only one dose adjustment was made during the period between last date study drug dispensed 
which was Visit(k-1) and the date of the current visit at which study drug was returned, which is 
Visit(k). 
Compliance (%) = 
100 times (#pills dispensed at Visitck-I) - #pills returned at Visit(k)) 
divided by 
([date new dose was prescribed to start- date ofVisit(k-1)] times[# pills prescribed to be 
taken per day starting on date of Visit (k-1) thru the day before the new dose was 
prescribed to start], 
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[date ofVisit(k)- date the new dose was prescribed to start] times [total# pills 
prescribed to be taken per day starting on date the new dose was prescribed to 
start thru the day before the Visit(k)]) 
where if date of Visitck-1) is date of Randomization, 
then let date ofVisitck-1) = { 1 +date of Visit(k-1)} 
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Case 3: 
A total of m > 1 dose adjustments were made during the period between last date study drug was 
dispensed which was Visit (k-1), and the date of the current visit at which study drug was 
returned, which is Visit(k), 
Compliance (%) = 
100 times (#pills dispensed at Visit (k -1) - #pills returned at Visit (k)) 
divided by 
([prescribed start date at dose level for dose adjustment #1- date of Visit(k-1)] times[# 
pills prescribed to be taken per day starting on date of Visit (k- 1) thru the day dose 
adjustment # 1 was prescribed to start] 
plus 
[the sum over i for i = 1 to (m -1) of {date new dose# (i+ 1) was prescribed to 
start- date new dose# i was prescribed to start] times [#pills prescribed to be 
taken per day starting on date that new dose # i was prescribed to start thru the 
day before the new dose # (i+ 1) was prescribed to start}] 
plus 
[date of day before Visit(k) -date new dose# m was prescribed to start] times 
[total# pills prescribed to be taken per day starting on date the new dose# m was 
prescribed to start thru the day before the Visit(k) ]), 
where if date of Visit(k-1) is date of Randomization, 
then let date ofVisitck-1) = {1 +date ofVisit(k-1)} 
Special Case: 
Missing Value for Number of Pills Returned and/or Number of Pills Dispensed 
• 
For all three cases, Case 1, Case 2 and Case 3 described above: 
o If(# pills returned at Visit(k)) is a missing value then Number of Pills Used 
Since Last Visit and Compliance Since Last Visit will be missing. 
o If(# pills dispensed at Visit(k- 1)) is a missing value, 
let (#pills dispensed at Visit(k- 1)) = #pills dispensed at Visit(n), where n is 
the largest site visit number less than k - 1 where (# pills dispensed at 
Visit(n)) is a non-missing value and 
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calculate compliance(%) using Visit(k - 1)) = Visit(n), where n is the 
largest site visit number less thank - 1 where (#pills dispensed at 
Visit(n)) is a non-missing value. 
Compliance Over Period Spanning More Than Two Consecutive Site Visits: 
To calculate compliance for any period X that spans more than the period between two 
consecutive site visits note that the numerator in the expression, 
Compliance (%) = 
amount of study drug taken during the specific time period,X 
100*~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 
amount of study drug prescribed to be taken during the specific time period,X 
is 100 times L :=3 (#pills dispensed at Visit(k- 1) - #pills returned at Visit(k)), where n 
-1 is the number of site visits the subject had during the period X and the denominator is 
n I (the number of pills prescribed to be taken from Visit(k 
k=3 
- 1) thru the day before Visit(k)) 
where (the number of pills prescribed to be taken from Visit(k -
1) thru the day before Visit(k) 
is the denominator of the expression given above for Case 1, Case 2 or Case 3 depending on the 
number of dose adjustments between Visit(k - 1) and Visit(k) . 
9.4. 
Routine Laboratory Data 
Tables for three groups oflaboratory parameters, hematology, clinical chemistry and urine 
chemistry will be provided. All laboratory tests will be listed. Laboratory test results for all 
subjects in the safety analysis set will be summarized using descriptive statistics. For the 
continuous laboratory parameters descriptive statistics will be displayed for the actual values and 
for the change in value from baseline to each scheduled post-baseline visit. Tables and listings 
for the 24-Week Analysis will only display statistics for visits during the Dose Titration period. 
Tables for the Final Analysis will show those visits during the Dose Maintenance period in 
addition to the Baseline visit but listings for the Final Analysis will be based on observations 
over the entire study. 
Subject's laboratory results for the following laboratory parameters: 
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• 
Ferritin 
• 
TSAT 
• 
Hemoglobin 
• 
Serum Phosphorous 
are of special interest. Their values will be classified as low or where relevant one of its sub-
categories, normal, or high or where relevant one of its sub-categories given the range of values 
used to identify clinically meaningful abnormalities in a patient with CKD. 
The thresholds for potentially significant abnormalities are based upon Common Terminology 
Criteria for Adverse Events v4.0 (CTCAE) grades and/or clinically meaningful abnormalities in 
a CKD stage 3- 4 patient. The thresholds are listed in Table 4 below. Table 4 also includes these 
categories for impaired liver function, i.e., the categories of total bilirubin, ALT and AST as 
related to identification of potential Hy's Law cases. 
Shift tables, for the laboratory parameters of special interest will be produced showing the 
number and percentage of subjects with Baseline result in each of the categories, low or where 
relevant the sub-categories of low, normal and high or where relevant the sub-categories of high, 
whose result at the post-baseline visit is in each of these categories. The shift tables will be 
provided by starting dose group and the two treatment groups combined. A by subject listing by 
visit of the subject's values with their classification relative to potentially significant abnormality 
for each laboratory parameter of special interest will be provided. 
By subject listings for every laboratory parameter collected will be provided. Each value will be 
identified in the by subject listings as being low, normal or high based on the central laboratory 
reference ranges. For the Final analysis only, ifless than 3 subjects received permitted ESA 
rescue therapy, comparable by subject listings will be provided for this FAS subgroup. 
An additional by subject listing by starting dose will be provided of subjects who have a total 
serum bilirubin value > 2x ULN. This listing will include the date of first elevated bilirubin; an 
indicator for ALT >3xULN and an indicator for AST >3xULN along with the baseline 
identifying characteristic variables that are displayed on all other by subject listings. 
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Table 4: Clinical Laboratory Potentially Clinically Significant 
Criteria 
Parameter 
Threshold (Low 
Low Criterion 
High Criterion 
Criterion/ High 
(Subcategories) 
(Subcategories) 
Criterion) 
Iron Parameter (unit) 
Ferritin (ng/mL) 
Clinical 
NA 
High 1: > 500 to 1000, 
High 2: > 1000 
Transferrin saturation 
Clinical 
NA 
High 1: >=SO to <70 
(%) 
High 2: > =70 
Hematology 
Hemoglobin (g/dL) 
CTCAE grade 3 /Clinical 
< 8.0 
> 13 
Chemistry 
Phosphorous (mg/dL) 
CTCAE grade 2 /Clinical 
Low 1: :<:2.0 to <2.5, 
> 9.0 
Low2: < 2.0 
Liver Function 
Hy's Law (Impaired Liver 
CTCAE grade 2 /DILi* 
NA 
High 1: ALT or AST> 3 x ULN to 5 x 
Function) 
ULN 
High 2: ALT or AST >5 x ULN 
Total serum bilirubin value 
DILI* 
NA 
> 2xULN 
*DILi = Drug Induced Liver Injury 
9.5. 
Vital Signs 
No tables of descriptive statistics or by subject listings for the vital signs, i.e., seated systolic and 
diastolic blood pressures (mmHg), heart rate (bpm) and weight, values and change from baseline 
will be presented. 
Each value's classification of low, normal or high based on the parameter's central laboratory 
reference range and the following clinical significance and CTCAE classifications will be 
included in an ADaM dataset: 
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• 
Diastolic Blood Pressure < 50 rnrnHg, Systolic Blood Pressure < 80 rnrnHg (based on 
clinical significance), 
• 
Diastolic Blood Pressure 2'.:100 mmHg, Systolic Blood Pressure 2'.:160 rnrnHg (based on 
CTCAE grade 3) 
• 
Pulse< 55 beats/min, Pulse> 110 beats/min (based on clinical significance). 
9.6. 
Summary of Changes from Protocol-Specified Analyses 
• 
The protocol states that "All subjects who are randomized and take at least 1 dose of study 
medication will be included in the Safety Analysis Set." However, the Safety Analysis Set 
is being defined as the set of all subjects who receive at least one dose of study 
medication, to allow for the highly unlikely possibility that some subject (s) may receive 
a dose of medication prior to being randomized. 
• 
The protocol did not discuss the potential for an ad hoc analysis. The analysis is 
acknowledged in this SAP and more details will be added to an amended SAP if an 
analysis is performed. 
• 
The protocol did not discuss the modified Per Protocol Analysis Set. This analysis set is 
described in section 6.3.6 and is used for the 24-Week analysis snapshot only. 
• 
The SAP describes analyses for the following secondary efficacy endpoints which were 
not included in the protocol: 
o 
Time from randomization to first hemoglobin increase of2'.: 0.5 g/dL from 
Baseline. 
o 
Change from the baseline value for each of the following: 
• 
eGFR 
• 
serum bicarbonate 
• 
intact parathyroid hormone 
• 
C-terminal fibroblast growth factor 23 
• 
intact fibroblast growth factor 
o Inclusion of box and scatter plots over time of the observed value and the change 
from Baseline for each of the iron parameter efficacy variables, TSAI and ferritin 
to explore the question of their stability over time on treatment. 
• 
The protocol specified analyses of vital signs is not included in the SAP, since no related 
safety concerns are anticipated. 
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• 
The protocol states that all efficacy analyses will be performed based on both the FAS 
and the PP/mPP analysis sets, however only the PP/mPP analyses sets will be considered. 
Subjects are excluded from the PP/mPP analysis sets due to confounders of efficacy and 
thus the FAS is not appropriate for efficacy analyses. The FAS will be used for the 
efficacy analysis for the 'Permitted' ESA Rescue Therapy subgroup. 
• 
The protocol did not include the baseline by visit interaction term in the efficacy model. 
This interaction term is included in the SAP and will be included in the model. 
• 
Missing endpoint observations will not be imputed using a multiple imputation (Ml) 
linear regression approach for use in an additional sensitivity analysis as specified in the 
protocol sections 15.7.2 and 15.10.3. 
• 
The protocol discusses an Interim Analysis after all subjects have completed the 24-Week 
Visit or Early Termination Visit. This analysis will no longer be performed. Instead, a 24-
Week analysis snapshot will be performed. A selective group of data (disposition, 
demographic, laboratory test, and adverse events) will be cleaned and presented in a 
publication. The 24-Week analysis and Final analysis will be done at the end of the study. 
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10. 
REFERENCES 
Reilly MC, Zbrozek AS, Dukes E: The validity and reproducibility of a work productivity and 
activity impairment measure. PharmacoEconomics 1993; 4(5):353-365. 
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale (Version 4), 
http://www.facit.org/FACITOrg/Questionnaires. 
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11. 
APPENDIX 
11.1. 
Work Productivity and Activity Impairment (WP AI) Questionnaire 
Specific Health Problem V2.0 (WP AI:SHP)* 
The following questions ask about the effect of your Anemia associated with Chronic Kidney 
Disease on your ability to work and perform regular activities. Please fill in the blanks or circle 
a number, as indicated. 
1. Are you currently employed (working for pay)? 
NO 
YES 
If NO, check "NO" and skip to question 6. 
The next questions are about the past seven days, not including today. 
2. During the past seven days, how many hours did you miss from work because of problems 
associated with your Anemia associated with Chronic Kidney Disease? Include hours you 
missed on sick days, times you went in late, left early, etc., because of your Anemia 
associated with Chronic Kidney Disease. Do not include time you missed to participate in 
this study. 
HOURS 
3. During the past seven days, how many hours did you miss from work because of any other 
reason, such as vacation, holidays, time off to participate in this study? 
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HOURS 
4. During the past seven days, how many hours did you actually work? 
HOURS (If "O '', skip to question 6.) 
5. During the past seven days, how much did your Anemia associated with Chronic Kidney 
Disease affect your productivity while you were working? 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully as usual. 
If Anemia associated with Chronic Kidney Disease affected your work only a little, choose a low 
number. Choose a high number if Anemia associated with Chronic Kidney Disease affected your 
work a great deal 
Consider only how much Anemia associated with Chronic Kidney Disease 
affected productivity while you were working 
Anemia 
Anemia associated 
associated with 
with Chronic 
Chronic Kidney 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Kidney Disease 
Disease had no 
completely 
effect on my 
prevented me from 
work 
working 
CIRCLE A NUMBER 
6. 
During the past seven days, how much did your Anemia associated with Chronic Kidney 
Disease affect your ability to do your regular daily activities, other than work at a job? 
By regular activities, we mean the usual activities you do, such as work around the house, 
shopping, childcare, exercising, studying, etc. Think about times you were limited in the 
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amount or kind of activities you could do and times you accomplished less than you would 
like. If Anemia associated with Chronic Kidney Disease affected your activities only a little, 
choose a low number. Choose a high number if Anemia associated with Chronic Kidney 
Disease affected your activities a great deal. 
Consider only how much anemia associated with chronic kidney disease affected your ability to 
do your regular daily activities, other than work at a job 
Anemia 
associated with ---------------- ---
Anemia associated 
Chronic Kidney 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Disease had no 
effect on my 
daily activities 
CIRCLE A NUMBER 
with Chronic 
Kidney Disease 
completely 
prevented me from 
doing my daily 
activities 
*Reilly MC, Zbrozek AS, Dukes E: The validity and reproducibility of a work productivity and 
activity impairment measure. PharmacoEconomics 1993; 4(5):353-365. 
11.2. 
WPAI:SHP QuestionnaireV2.0 
The instructions given by REILLY ASSOCIATES Health Outcomes Research at 
http://www.reillyassociates.net/WPAI Scoring.html and inserted below will be used to score the 
WPAI:SHP questionnaires completed by each subject. Questions 1, 2, 3, 4,5, and 6 in those 
instructions correspond to the questions with the same number in the questionnaire given above that 
subjects will complete during this study. 
WP AI outcomes are expressed as impairment percentages, with higher numbers indicating greater 
impairment and less productivity, i.e., worse outcomes, as follows: 
Questions: 
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1 = currently employed 
2 =hours missed due to specified problem 
3 = hours missed other reasons 
4 = hours actually worked 
5 = degree problem affected productivity while working 
6 = degree problem affected regular activities 
Scores: 
Multiply scores by 100 to express in percentages. 
Percent work time missed due to problem: Q2/(Q2+Q4) 
Percent impairment while working due to problem: Q5/10 
Percent overall work impairment due to problem:Q2/(Q2+Q4)+((1-(Q2/(Q2+Q4)))x(Q5/10)] 
Percent activity impairment due to problem: Q6/10 
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11.3. 
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue 
Scale (Version 4) 
Below is a List of statements that other people with your illness have said are imp01tant. Please 
circle or mark one number per line to indicate your response as it applies to the Past 7 days. 
Not 
A little 
Some-
Quite 
Very 
at all 
bit 
what 
a bit 
much 
Hl7 
I feel fatigued ...................................................................... 
0 
1 
2 
3 
4 
I feel weak all over ............................................................. 
0 
1 
2 
3 
4 
Hill 
I feel listless ("washed out") ............................................... 
0 
1 
2 
3 
4 
.. ,, 
I feel tired ........................................................................ 
0 
1 
2 
3 
4 
,,.., 
I have trouble starting things because I am tired ................ 
0 
1 
2 
3 
4 
..... 
I have trouble finishing things because I am tired .............. 
0 
1 
2 
3 
4 
.... 
I have energy ...................................................................... 
0 
1 
2 
3 
4 
-
I am able to do my usual activities ..................................... 
0 
1 
2 
3 
4 
,,,, 
I need to sleep during the day ............................................. 
0 
1 
2 
3 
4 
... 
I am too tired to eat ............................................................. 
0 
1 
2 
3 
4 
,,,,, 
I need help doing my usual activities ................................. 
0 
1 
2 
3 
4 
,,,,. 
I am frustrated by being too tired to do the things I want 
0 
1 
2 
3 
4 
NllS 
to do 
I have to limit my social activity because I am tired .......... 
0 
1 
2 
3 
4 
An16 
English (Universal) 
Copyright 1987, 1997 
16 November 2007 Page 1 of 1 
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11.4. 
FACIT-Fatigue Subscale Scoring 
The instructions for the FACIT-Fatigue Subscale Scoring Guidelines (Version 4) below were 
copied from the link to FA CIT-Fatigue: Functional Assessment of Chronic Illness Therapy-
Fatigue; a 13-item F ACIT Fatigue Scale Scoring and Interpretation found at 
http://www.facit.org/F ACITOrg/Questiorrnaires. These instructions for scoring will be used as 
described below and ifless than 7 of the 13 FACIT Fatigue Subscale items are missing the Total 
Score will be missing. 
Instructions:* 
1. Record answers in "item response" column. If missing, mark with an X 
2. Perform reversals as indicated, and sum individual items to obtain a score. 
3. Multiply the sum of the item scores by the number of items in the subscale, 
then divide by the 
number of items answered. This produces the subscale score. 
4. The higher the score, the better the QOL. 
Subscale 
FATIGUE 
SUBSCALE 
Score range: 0-52 
Item Code 
HI7 
HI12 
Anl 
An2 
An3 
An4 
An5 
An7 
An8 
Anl2 
Anl4 
Anl5 
Anl6 
Reverse item? 
4 
4 
4 
4 
4 
4 
0 
+ 
0 
+ 
4 
4 
4 
4 
4 
Item response 
Sum individual item scores: 
Item Score 
---
Multiply by 13: __ _ 
Divide by number of items answered: 
=Fatigue Subscale score 
*See the instructions related to missing data in F ACIT subscales within the F ACIT Administration and 
Scoring Guidelines on the F ACIT.org website. 
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Handling Missing Items on FACIT Fatigue Subscale 
Negatively stated items are reversed by subtracting the response from "4". After 
reversing proper items, all subscale items are summed to a total, which is the 
subscale score. For all FACIT scales and symptom indices, the higher the score 
the better the QOL. 
If there are missing items, sub scale scores can be prorated. This is done by 
multiplying the sum of the sub scale by the number of items in the sub scale, then 
dividing by the number of items actually answered. This can be done by using the 
formula below: 
Prorated subscale score = [Sum of item scores] x [N of items in subscale] D D [N 
of items answered] 
When there are missing data, prorating by subscale in this way is acceptable as 
long as more than 50% of the items were answered (i.e, more than 7 of the 13 
FACIT Fatigue Subscale items). 
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See the document, KRX-502-402 Phase IV TLFs Shells_vl.1_03APR2019 for a list of the 
tables, listings and figures that will be produced for this study. In addition to the shell for each 
table, listing and figure, this document will include a section which describes the conventions to 
which the TLFs discussed in this SAP will adhere. 
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