Conditions: Peritoneal Dialysis (PD) Anemia Chronic Kidney Disease
Keywords: Triferic ferric pyrophosphate citrate (FPC) peritoneal dialysis anemia chronic kidney disease
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 30
Healthy volunteers: no

Brief summary:
The main purpose is to determine the pharmacokinetic (PK) profile, maximum concentration (Cmax) and Area Under the Concentration Time Curve (AUC0-t) of Triferic iron administered intraperitoneally in patients with chronic kidney disease on peritoneal dialysis (CKD-5 PD). It is an open label, dose escalation study.

Detailed description:
This is a phase 1, open-label, dose escalation study assessing the pharmacokinetic (PK) profile, maximum concentration (Cmax) and Area Under the Concentration Time Curve (AUC0-t) of Triferic iron administered intraperitoneally in chronic kidney disease patients on peritoneal dialysis (Continuous Cycling Peritoneal Dialysis (CCPD) or Continuous Ambulatory Peritoneal Dialysis (CAPD)).

Screening can be up to 4 weeks, and the enrollment period is approximately one week. There are two treatment (dosing) visits and one follow-up visit during the enrollment period.

At each treatment visit, the patients will be randomly assigned to receive either a single ascending dose of Triferic administered intraperitoneal (IP) during a long (12 hour) peritoneal dialysis dwell or a single 6.6 mg dose of Triferic administered IV over 4 hours. Blood samples will be obtained at defined times over 12 hours to establish the total serum iron PK of IP Triferic as well as the clinical serum iron profile.

The IP dose of the first Cohort will be 5 mg Triferic iron/liter IP. Subsequent Cohort IP doses will be 12.5 mg Triferic iron/liter, and 20 mg Triferic iron/liter, with the final Cohort dose to be determined (TBD). The IV dose will be 6.6. mg for all Cohorts. Six patients will be enrolled in each Cohort, with enrollment in the subsequent (higher dose) Cohort not being initiated until the completion and evaluation of the previous (lower dose) Cohort.

Arms:
arm 1: The patient will receive a single dose of Triferic in the peritoneal dialysis solution (IP) during a long (12 hour) peritoneal dialysis dwell. Each Cohort will receive a different ascending IP dose ( 5 mg/L, 12.5 mg/L, 20 mg/L). Blood samples will be drawn periodically over a 12 hour period for analysis. arm 2: The patient will receive a single 6.6 mg intravenous (IV) dose of Triferic in the over a 4 hour period. All Cohorts will receive the same IV dose. Blood samples will be drawn periodically over a 12 hour period for analysis.

Interventions: intervention 1: Triferic
Intervention descriptions: intervention 1: Triferic is an iron salt that is approved by the FDA for the maintenance of hemoglobin in patients with end stage kidney disease on hemodialysis. It is experimental in this study because it has not yet been approved for patients on chronic peritoneal dialysis.

Protocol document:
Prot_000.pdf: 
 
Clinical Research Protocol 
 
Single Ascending Dose Study of Intraperitoneal Triferic 
(Ferric Pyrophosphate Citrate) in Patients on Chronic 
Peritoneal Dialysis 
 
 
 
IND Number: 
51,290 
 
Protocol Number: 
RMFPC-17 
Version: 
Clinical Phase: 
 
1.0 
 
1 
 
Investigational Drug: 
Triferic (Ferric Pyrophosphate Citrate) 
 
Indication: 
Maintenance of Iron and Hemoglobin in CKD-5PD 
Patients 
 
Sponsor Signatory: 
Raymond D. Pratt, MD FACP 
Chief Medical Officer 
Rockwell Medical, Inc. 
 
Principal Investigator: 
 
 
 
 
 
Original Protocol Date: 
21 November 2016 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
Information in this protocol is confidential and should not be disclosed, other than to those directly 
involved in the execution or the ethical review of the study, without written authorization from 
Rockwell Medical. 
 
 
 
 
 
 
 
 
 
 
 
Confidential/Proprietary 
Page 1 of 56 


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PROTOCOL APPROVAL PAGE 
 
Study Title: 
Single Ascending Dose Study of Intraperitoneal Triferic (Ferric 
Pyrophosphate Citrate) in Patients on Chronic Peritoneal 
Dialysis 
Protocol 
Number: 
RMFPC-17 
Version: 
1.0 
Date of Issue: 
21 November 2016 
Sponsor Name 
and Address: 
Rockwell Medical, Inc. 
30142 S. Wixom Rd 
Wixom, MI 48393 
 
 
 
 
I, the undersigned, have read and approve this protocol and agree on its content. It 
is confirmed that the information and guidance given in this protocol complies with 
scientific principles, the guidelines of Good Clinical Practice, the Declaration of 
Helsinki in the latest relevant version, and the applicable legal and regulatory 
requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor Signatory: 
 
Raymond D. Pratt, MD FACP 
Chief Medical Officer 
(Date) 


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INVESTIGATOR PROTOCOL AGREEMENT 
 
Protocol Title: 
Single Ascending Dose Study of Intraperitoneal Triferic (Ferric 
Pyrophosphate Citrate) in Patients on Chronic Peritoneal 
Dialysis 
Protocol Number: RMFPC-17 
Version: 1.0 
 
 
 
 
By my signature, I 
• Confirm that my staff and I have carefully read and understand this protocol or 
protocol amendment and are thoroughly familiar with the appropriate use of the 
investigational drug described herein. 
• Agree to comply with the conduct and terms of the study specified herein and 
with any other study conduct procedures provided by the Sponsor, Rockwell 
Medical. 
• Agree to assume responsibility for the proper conduct of the study at this site, 
including complying with US Food and Drug Administration (FDA) regulations, 
the International Conference on Harmonisation (ICH) GCP guidelines, the 
Declaration of Helsinki, and all applicable rules, regulations, and federal, state, 
and local laws relating to the conduct of clinical studies and the protection of 
human subjects. 
• Agree not to implement deviations from or changes to the protocol or protocol 
amendments without agreement from the Sponsor and prior submission to and 
written approval (where required) from the Institutional Review Board (IRB) or 
Ethics Committee (EC), except when necessary to eliminate an immediate 
hazard to the subjects, or for administrative aspects of the study (where 
permitted by all applicable regulatory requirements). 
• Agree to onsite monitoring of the case report forms (CRFs) and source 
documents by Rockwell Medical or designee and to onsite inspection of CRFs 
and source documents by appropriate regulatory authorities, including but not 
limited to the FDA, local governing regulatory bodies, and IRB/EC inspectors. 
 
 
 
 
Investigator's Signature 
Date 
 
 
 
 
Print Name 


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SYNOPSIS 
PROTOCOL TITLE 
Single Ascending Dose Study of Intraperitoneal Triferic (Ferric 
Pyrophosphate Citrate) in Patients on Chronic Peritoneal Dialysis 
PROTOCOL NUMBER 
RMFPC-17 
SPONSOR 
Rockwell Medical, Inc. 
INVESTIGATIONAL 
PRODUCT 
Triferic (ferric pyrophosphate citrate) 
STUDY OBJECTIVES 
Primary Objective 
Determine the pharmacokinetic profile, Cmax and AUC0-t of 
Triferic iron administered intraperitoneally in patients with end- 
stage chronic kidney disease on peritoneal dialysis (CKD-5 PD). 
Secondary Objectives 
The secondary objectives are: 
• To determine the dose proportionality of Triferic iron 
administered via peritoneal dialysate 
• To estimate the absolute bioavailability Triferic iron 
administered via peritoneal dialysate 
• To explore the safety of intraperitoneal Triferic administration 
in adult CKD-5 PD patients 
STUDY DESIGN & 
DURATION 
• Open-label, single ascending dose study. 
• Up to 4 Cohorts of 6 patients receiving ascending doses of 
Triferic Intraperitoneally in the PD solution. 
• Patients on Continuous Cycling Peritoneal Dialysis (CCPD) or 
Continuous Ambulatory Peritoneal Dialysis (CAPD). 
• At each treatment visit, the patients will be randomly assigned 
to receive either a single ascending dose of Triferic 
administered IP during a long (12 hr.) peritoneal dialysis dwell 
or a single 6.6 mg dose of Triferic administered IV over 4 hrs. 
• Blood samples will be obtained at defined times over 12 
hours to establish the total serum iron PK of IP Triferic as well 
as the clinical serum iron profile (sFe, ferritin, TIBC and 
TSAT). 
• Peritoneal dialysate samples will be collected prior to and 
after IP Triferic administration for biocompatibility studies. 
• Patients will undergo a follow-up visit approximately 1 week 
after their last dose of study drug. 
• After analysis of data for Cohort 1 and 2, the blood draw 
schedule for the remaining cohorts may be changed to reflect 
the time course of iron absorption and clearance, as well as 
for patient retention. 
• Additional cohorts may be added or a cohort deleted based 
on the serum iron profiles and or safety parameters. 
• Duration of Study: Each Cohort up to 5 weeks including 


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Screening, Treatment and Follow-up. 
Study Design Schematic: 
NUMBER OF 
PLANNED 
SUBJECTS 
Approximately 24 
Patients will be stratified based on PET tests administered within 
6 months of enrollment. Approximately 12 patients with average 
to high transport and 12 with low average to low transport will be 
enrolled. 
INVESTIGATIONAL 
SITE 
Multicenter 
PARTICIPATING 
COUNTRIES 
United States 
PATIENT 
POPULATION 
Stable adults with CKD-5 PD 
INCLUSION AND 
EXCLUSION 
CRITERIA 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for 
inclusion in the study: 
1.  The patient must be able to provide informed consent and 
have personally signed and dated the study written informed 
consent document before completing any study-related 
procedures. 
2.  The patient must be 18-75 years of age inclusive at the time of 
consent. 
3.  The patient must have a diagnosis of End Stage Renal 
Disease and have been on stable Peritoneal Dialysis for at 
least 3 months (CAPD or CCPD) prior to Screening using 
standard PD solution. 
4.  The patient must be in a stable clinical condition during the 
four weeks immediately prior to Screening Period as 
demonstrated by medical history, physical examination and 
laboratory testing. 
5.  The patient must have a blood hemoglobin concentration 
above 9.5 g/dL. 
6.  The patient must have a TIBC of ≥ 175 µg/dL. 


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7.  The patient must not have experienced peritonitis episodes in 
the last 3 months prior to Screening. 
8.  The patient must agree to discontinue all iron preparations for 
14 days prior to Study PD #1/Day 1. 
9.  Female patients must be nonpregnant and not breastfeeding. 
They must either have been amenorrheic for the past year or 
agree to not become pregnant by continuous use of an 
effective birth control method acceptable to the Investigator for 
the duration of their participation in the study. 
 
 
Exclusion Criteria 
Patients will not be eligible for inclusion in the study if any of the 
following criteria apply: 
1.  The patient has had an RBC or whole blood transfusion within 
4 weeks prior to Screening. 
2.  The patient has had administration of IV or oral iron 
supplements (including multivitamins with iron) within 14 days 
prior to Study PD #1/Day 1. 
3.  The patient has known active bleeding from any site (e.g., 
gastrointestinal, hemorrhoidal, nasal, pulmonary, etc.). 
4.  The patient has a living kidney donor identified or living-donor 
kidney transplant scheduled to occur during study 
participation. (Note:  Patients awaiting deceased-donor 
transplant need not be excluded.) 
5.  The patient is scheduled to have a surgical procedure during 
the study. 
6.  The patient has had a hospitalization within the 4 weeks prior 
to Screening (except for vascular access surgery) that, in the 
opinion of the Investigator, confers a significant risk of 
hospitalization during the course of the study. 
7.  The patient has a history of noncompliance with the dialysis 
regimen in the opinion of the Investigator. 
8.  The patient has a known active ongoing inflammatory disorder 
(other than CKD), such as systemic lupus erythematosus, 
rheumatoid arthritis, or other collagen-vascular disease, that 
currently requires systemic anti-inflammatory or 
immunomodulatory therapy. 
9.  The patient has any current febrile illness (e.g., oral 
temperature ≥100.4°F, 38.0°C).  (The patient may 
subsequently become eligible at least 1 week after resolution 
of the illness.) 
10. The patient has known bacterial, tuberculosis, fungal, viral, or 
parasitic infection requiring anti-microbial therapy or 
anticipated to require anti-microbial therapy during the 
patient’s participation in this study. 
11. The patient is known to be positive for HIV, hepatitis B, or 


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hepatitis C (viral testing is not required as part of this protocol). 
12. The patient has cirrhosis of the liver based on histological 
criteria or clinical criteria (e.g., presence of ascites, 
esophageal varices, multiple spider nevi, or history of hepatic 
encephalopathy). 
13. The patient has ALT and/or AST levels consistently greater 
than twice the upper limit of normal at any time during the two 
months prior to Study PD #1/Day 1. 
14. The patient currently has any malignancy other than basal or 
squamous cell skin cancer. 
15. The patient has a history of drug or alcohol abuse within the 6 
months prior to Screening. 
16. The patient participated in an investigational drug study within 
30 days prior to Study PD #1/Day 1. 
17. The patient has any condition that, in the opinion of the 
Investigator, would make it unlikely for the patient to complete 
the study. 
PLANNED 
ANALYSES 
• Pharmacokinetics (PK) of serum iron following Triferic 
administration IP 
• Estimate absolute bioavailability of iron via PD 
o By proportionality of IP (Cmax and AUC0-t) to IV (Cmax and 
AUC0-t) 
o By quantitating iron remaining in the PD solution 
compared to that infused. 
SAFETY ENDPOINTS 
• The incidence of treatment-emergent adverse events (TEAEs) 
and treatment-emergent serious AEs (TESAEs) 
PHARMACOKINETIC 
ENDPOINTS 
The primary PK analysis will be performed on the total serum iron 
(sFe).  Non-compartmental PK parameters will be estimated for 
total serum iron. 
Pharmacokinetic parameters will be determined using all 
appropriate available data from each Cohort. 
The key PK parameters listed below will be calculated for total 
serum iron as data permit and as appropriate. 
The following iron parameters will be determined by obtaining 
blood at various times after Triferic administration: 
• Total serum iron (sFe) 
The key PK parameters listed below will be calculated for total 
serum iron as data permit and as appropriate.  Additional details 
of the PK analysis will be provided in the PK analysis plan. 
Cmax 
The maximum drug concentration in serum 
determined directly from individual 


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concentration-time data 
Tmax 
The observed time to reach maximum concentration 
AUC(0-t) 
The area under the serum concentration-time curve 
from time zero to the time of the last quantified 
concentration, calculated using the linear-up/log- 
down trapezoidal rule 
AUC(0-end) 
The area under the serum concentration-time curve 
from time zero to the end of each study drug 
infusion, calculated using the linear-up/log-down 
trapezoidal rule 
λz 
The terminal phase rate constant, estimated by 
linear regression through the terminal phase of the 
log concentration-time profile 
t½ 
The terminal phase half-life, calculated as: 
t½ = ln(2) 
lz 
AUCinf 
The area under the serum concentration-time curve 
from time zero extrapolated to infinity, calculated 
using the linear-up/log-down trapezoidal rule 
CL or 
CL/F 
Total systemic clearance, calculated as: 
Total Dose/AUClast 


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TABLE OF CONTENTS 
 
 
Page 
 
PROTOCOL APPROVAL PAGE............................................................................... 2 
INVESTIGATOR PROTOCOL AGREEMENT ........................................................... 3 
SYNOPSIS ................................................................................................................ 4 
TABLE OF CONTENTS ............................................................................................ 9 
LIST OF IN-TEXT TABLES ..................................................................................... 13 
LIST OF IN-TEXT FIGURES ................................................................................... 13 
1. INTRODUCTION ............................................................................................... 16 
1.1. Current Therapies/Treatments..............................................................................16 
1.2. Description of Drug .................................................................................................17 
1.3. Previous Clinical Experience with Triferic ...........................................................17 
1.4. Non-Clinical Studies of Peritoneal Administration of Triferic ...........................19 
1.4.1. In-vitro Compatibility Study: ......................................................... 19 
1.4.2. Animal Studies: ............................................................................ 19 
1.4.2.1. Study 1: Intraperitoneal administration of soluble ferric 
pyrophosphate (SFP) in rabbits. ............................................ 19 
1.4.2.2. Study 2: Four week intraperitoneal GLP toxicity study of 
Triferic administered to rats. .................................................. 20 
1.5. Rationale for the Current Study ............................................................................21 
1.6. Justification for Dose ..............................................................................................22 
2. STUDY OBJECTIVES....................................................................................... 22 
2.1. Primary Objective....................................................................................................22 
2.2. Secondary Objectives ............................................................................................22 
3. INVESTIGATIONAL PLAN ............................................................................... 22 
3.1. Overall Study Design and Plan.............................................................................22 
3.2. Endpoints .................................................................................................................23 
3.2.1. Pharmacokinetic Endpoints.......................................................... 23 
3.2.1.1. Primary Endpoints ................................................................. 23 
3.2.1.2. Secondary Endpoints ............................................................ 23 
3.2.2. Safety Endpoints .......................................................................... 24 
4. SELECTION OF STUDY POPULATION .......................................................... 24 
4.1. Inclusion Criteria .....................................................................................................24 
4.2. Exclusion Criteria ....................................................................................................25 
4.3. Removal of Patients from Therapy/Premature Discontinuation ......................26 
5. TREATMENTS .................................................................................................. 26 
5.1. Treatments Administered ......................................................................................26 
5.2. Identity of Investigational Products(s)..................................................................26 


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5.2.1. Labeling ....................................................................................... 27 
5.2.2. Storage and Handling .................................................................. 27 
5.3. Method of Assigning Patients to Treatment Groups .........................................27 
5.3.1. Treatment Assignment/Randomization ........................................ 27 
5.4. Selection of Doses in the Study............................................................................27 
5.5. Selection and Timing of Dose for Each Patient .................................................28 
5.6. Procedures for Blinding..........................................................................................28 
5.7. Procedures for Randomization .............................................................................28 
5.8. Prior and Concomitant Therapy............................................................................28 
5.8.1. Prior Therapy ............................................................................... 28 
5.8.2. Concomitant Therapy................................................................... 28 
5.8.3. Prohibited Medications................................................................. 28 
5.9. Treatment Compliance...........................................................................................28 
5.9.1. Study Drug Accountability ............................................................ 29 
6. STUDY PROCEDURES .................................................................................... 29 
6.1. Study Periods and Procedures .............................................................................29 
6.1.1. Screening Period (Study Day -28 through Study Day -1)............. 29 
6.1.2. Day -1 Enrollment ........................................................................ 30 
6.1.3. Triferic IP (Day 1 or Day 3, depending on randomization) ........... 30 
6.1.4. Triferic 6.6 mg IV/4 hours (Day 1 or Day 3, depending on 
randomization) ............................................................................. 31 
6.1.5. Follow-up (Study Day 5-8) ........................................................... 32 
6.2. Study Measurements and Assessments.............................................................33 
6.2.1. Assessment of Pharmacokinetics ................................................ 33 
6.2.1.1. Total Serum Iron .................................................................... 33 
6.2.1.2. Appropriateness of Iron Parameter Measurements ............... 33 
6.2.1.3. Collecting, Processing, and Shipping Pharmacokinetic 
Samples  ............................................................................... 33 
6.2.2. Assessment of Safety .................................................................. 34 
6.2.2.1. Clinical Laboratory Tests ....................................................... 34 
6.2.2.2. Physical Examinations........................................................... 34 
6.2.2.3. Vital Signs and Weight........................................................... 34 
6.3. Assessment to Proceed to Next Dose Levels ....................................................35 
7. ADVERSE EVENTS.......................................................................................... 35 
7.1. Definition of an Adverse Event .............................................................................35 
7.2. Definition of a Serious Adverse Event .................................................................36 
7.3. Method, Frequency, and Time Period for Detecting Adverse Events and 
Serious Adverse Events ........................................................................................37 
7.4. Reporting Serious Adverse Events ......................................................................37 
7.4.1. Timeframes for Reporting Serious Adverse Events ..................... 38 


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7.4.2. Serious Adverse Event Information to Report .............................. 39 
7.4.3. Regulatory/Ethics Reporting Requirement ................................... 39 
7.5. Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events .......................................................................................................39 
7.6. Documenting Adverse Events ..............................................................................40 
7.7. Follow-up of Adverse Events ................................................................................40 
7.8. Post-study Adverse Events ...................................................................................40 
8. STATISTICS ..................................................................................................... 41 
8.1. General Considerations .........................................................................................41 
8.2. Determination of Sample Size ..............................................................................41 
8.3. Analysis Populations ..............................................................................................41 
8.4. Patient Disposition ..................................................................................................41 
8.5. Baseline Characteristics ........................................................................................41 
8.6. Concomitant Medications ......................................................................................41 
8.7. Extent of Exposure .................................................................................................41 
8.8. Safety Assessments ...............................................................................................42 
8.8.1. Adverse Events ............................................................................ 42 
8.8.2. Clinical Laboratory Assessments ................................................. 42 
8.8.3. Vital Signs .................................................................................... 42 
8.9. Pharmacokinetic Analyses ....................................................................................42 
8.10. Quantitation of Iron Administered ......................................................................43 
8.11. Planned Modeling.................................................................................................43 
8.12. Pharmacogenomics Analyses ............................................................................43 
8.13. Statistical and Analytical Issues .........................................................................44 
8.13.1. Statistical Analysis Plan ............................................................... 44 
8.13.2. Handling of Missing Data ............................................................. 44 
8.13.3. Interim Analyses and Data Monitoring ......................................... 44 
8.13.4. Criteria for Stopping the Study ..................................................... 44 
9. STUDY ADMINISTRATION .............................................................................. 45 
9.1. Sponsor’s and Investigator’s Responsibilities ....................................................45 
9.2. Sponsor’s Responsibilities ....................................................................................45 
9.2.1. GCP Compliance ......................................................................... 45 
9.2.2. Regulatory Approval..................................................................... 45 
9.2.3. Indemnity/Liability and Insurance ................................................. 45 
9.2.4. Protocol Conduct ......................................................................... 45 
9.2.4.1. Protocol Compliance and Protocol Deviations....................... 45 
9.2.4.2. Protocol Amendments ........................................................... 46 
9.3. Investigator’s Responsibilities...............................................................................46 
9.3.1. GCP Compliance ......................................................................... 46 


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9.3.2. Protocol Adherence and Investigator Agreement......................... 46 
9.3.3. Documentation and Retention of Records ................................... 47 
9.3.3.1. Case Report Forms ............................................................... 47 
9.3.3.2. Site Visits............................................................................... 47 
9.3.3.3. Recording, Access and Retention of Source Data................. 48 
9.3.4. Investigator’s Final Report ........................................................... 49 
9.4. Ethical Considerations ...........................................................................................49 
9.5. Informed Consent ...................................................................................................49 
9.5.1. Institutional Review Board or Independent Ethics Committee 
Approval....................................................................................... 49 
9.6. Confidentiality ..........................................................................................................50 
10. DISCLOSURE OF DATA AND PUBLICATION ................................................ 50 
11. REFERENCES .................................................................................................. 52 
APPENDIX 1. TIME AND EVENTS SCHEDULE .................................................... 53 
APPENDIX 2. PHARMACOKINETIC, SERUM IRON PROFILE, AND 
HEPCIDIN SAMPLE COLLECTION SCHEDULE............................................. 54 
APPENDIX 3. PHARMACOKINETIC, SERUM IRON PROFILE, AND 
HEPCIDIN SAMPLE HANDLING...................................................................... 55 
APPENDIX 4. TRIFERIC DOSING SOLUTION PREPARATION............................ 56 


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LIST OF IN-TEXT TABLES 
 
 
Page 
 
Table 1: Summary of Clinical Studies Conducted with Triferic in Adults .................. 17 
Table 2: Compatibility Study Materials ..................................................................... 19 
Table 3: Time and Events Schedule ........................................................................ 53 
Table 4: PK and Serum Iron Profile Sample Collection Schedule............................ 54 
Table 5: Preparation of Triferic PD Dosing Solution................................................. 56 
 
 
 
 
LIST OF IN-TEXT FIGURES 
 
 
Page 
 
Figure 1:  Serum iron concentrations after administration of PD fluid in Rabbits. .... 20 
Figure 2: Total Serum Iron on Day 1 and 26 According to Dose Group.................. 21 
Figure 3:  Study Design Schematic.......................................................................... 23 


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ABBREVIATIONS 
 
AE 
adverse event 
ALT 
alanine transaminase (SGPT) 
AST 
aspartate transaminase (SGOT) 
ATC 
anatomical therapeutic chemical 
AUC 
area under the curve 
AV 
arteriovenous 
BMI 
body mass index 
CAPD 
continuous ambulatory peritoneal dialysis 
CBC 
complete blood count 
CCPD 
Continuous cycling peritoneal dialysis 
CFR 
Code of Federal Regulations 
Chem-20 
standard comprehensive metabolic panel laboratory test 
CKD 
chronic kidney disease 
CKD-5HD 
chronic kidney disease stage 5, hemodialysis-dependent 
CKD-5 PD 
chronic kidney disease stage 5, peritoneal dialysis-dependent 
CL 
total systemic clearance 
Cmax 
peak serum concentration, observed 
CNS 
central nervous system 
CRF 
case report form 
CRP 
C-reactive protein 
CV 
cardiovascular 
D5W 
dextrose 5% in water 
EC 
ethics committee 
ECG 
electrocardiogram 
ENT 
ear, nose, and throat 
ESA 
erythropoiesis-stimulating agent 
FDA 
Food and Drug Administration 
Fe 
Iron 
FPC 
Triferic (ferric pyrophosphate citrate) 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HD 
hemodialysis 
Hgb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act (of 1996) 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICP-MS 
Inductively Coupled Plasma Mass Spectrometry 
IND 
investigational new drug 
IP 
intra-peritoneal 


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IRB 
institutional review board 
IV 
intravenous/intravenously 
Kt/V 
dialyzer clearance of urea multiplied by dialysis time, divided by 
patient’s total body water 
KIDt/V 
online dialyzer clearance measured using ionic dialysance 
multiplied by dialysis time, divided by patient’s total body water 
LPI 
labile plasma iron 
λz 
terminal phase rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
NTBI 
non-transferrin-bound Iron 
PD 
peritoneal dialysis 
PHI 
protected health information 
PK 
pharmacokinetic(s) 
RBC 
red blood cell/red blood cell count 
RE 
reticuloendothelial 
RES 
reticuloendothelial system 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
t½ 
terminal phase half-life 
TBD 
to be determined 
TBI 
transferrin-bound iron 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
Tf 
transferrin 
TIBC 
total iron-binding capacity 
TIBCTf 
total iron-binding capacity based on transferrin 
TIBCUIBC 
total iron-binding capacity based on UIBC 
Tmax 
time to peak serum concentration, observed 
TSAT 
transferrin saturation 
TSATTf 
transferrin saturation based on transferrin 
TSATUIBC 
transferrin saturation based on UIBC 
UIBC 
unsaturated iron-binding capacity 
US 
United States 
USP 
United States Pharmacopeia 
Vz/F 
volume of distribution 
WBC 
white blood cell/white blood cell count 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
 
1.1. 
Current Therapies/Treatments 
 
The goals of iron therapy in adult patients with chronic kidney disease receiving 
chronic dialysis are to avoid depletion of iron stores, prevent iron-restricted 
erythropoiesis and maintain hemoglobin levels while minimizing erythropoiesis- 
stimulating agent (ESA) therapy and avoiding blood transfusions that may sensitize 
patients and limit chances for a kidney transplant1. 
 
Iron supplementation is provided to patients receiving maintenance peritoneal 
dialysis (PD) with intravenous (IV) iron. However, these IV iron products are ferric- 
hydroxide cores within a carbohydrate shell that do not donate iron directly to 
transferrin. Instead, the complexes must first be taken up by reticuloendothelial (RE) 
macrophages that free the iron from the carbohydrate shell for subsequent export 
via ferroportin.  As a result, a considerable portion of the iron derived from these 
iron-carbohydrate complexes is sequestered within macrophages and is not readily 
available for transport to the erythroid marrow for use in hemoglobin synthesis. 
Patients receiving PD generally do not have high flow vascular access. Thus, 
administration of IV iron via peripheral veins can be challenging and may also 
contribute to venous sclerosis. 
 
Compared to hemodialysis (HD) patients, PD patients have less blood loss; 
however, they do require iron supplementation along with ESA administration to 
maintain hemoglobin concentrations.  Currently, PD patients must attend the clinic 
periodically for IV iron administration. If an iron preparation is available for 
intraperitoneal (IP) administration, this would allow patients to receive needed iron 
and avoid the potential risks of IV iron administration including anaphylaxis and 
injection site reactions. 
 
There are no specific guidelines for the administration of iron to PD patients.  Recent 
trends indicate an increase in the use of IV iron in PD patients.  PD patients received 
an average of 1 dose IV iron /month with a mean value of 127 to 151 mg Fe per 
dose.2  Patients receiving PD also have elevated hepcidin concentrations which 
result in the impairment of iron absorption from the duodenum and the release of 
iron from the reticuloendothelial system. This hepcidin elevation impairs the 
utilization of IV iron from stores due to the block of ferroportin, the sole iron 
transporter in macrophages of the RES. 
 
Triferic has been developed as a maintenance iron therapy. Triferic is a form of 
protected iron, and can be added to the PD solution. Triferic can diffuse across the 
peritoneal membrane to the systemic circulation. Triferic administered parenterally 
does not require processing by macrophages, and it donates iron directly to 
transferrin for optimal utilization in erythropoiesis, avoiding sequestration within the 
RES. 


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In adults, Triferic, administered at each HD session via dialysate, has been shown to 
maintain hemoglobin concentrations without increasing iron stores. Triferic does this 
by delivering 5-7 mg of elemental iron with each HD session, the amount typically 
lost as a consequence of retained blood in the dialyzer circuit plus other HD- and 
uremia-associated blood losses. 
 
The safety profile of Triferic in controlled clinical studies is similar to that of patients 
receiving placebo. There were few related adverse events (AEs) and no 
anaphylaxis in over 100,000 individual patient administrations. Safety data are 
included in the approved US package insert and in the Investigator’s Brochure. 
Triferic added to the bicarbonate concentrate for hemodialysis has been approved 
as the first maintenance iron therapy in adult CKD-5HD patients. 
 
1.2. 
Description of Drug 
 
Triferic (ferric pyrophosphate citrate; FPC) is a water-soluble, mixed-ligand iron salt 
in which iron(III) is bound to pyrophosphate and citrate. It has a molecular formula of 
Fe4(C6H4O7)3(H2P2O7)2(P2O7) and a relative molecular weight of approximately 1313 
Da. Triferic solution is a clear, slightly yellow-green sterile solution containing 27.2 
mg iron(III) per 5 mL (5.44 mg iron (III) per mL) filled in low density polyethylene 
(LDPE) ampules. 
 
1.3. 
Previous Clinical Experience with Triferic 
 
Table 1: Summary of Clinical Studies Conducted with Triferic in Adults 
 
Protocol 
Number 
Country 
(# sites) 
Study Design and Phase 
Treatment Groups 
Number of 
Subjects 
/Treatment 
Duration 
SFP-8 
US 
1 site 
Phase 1/2, single-dose PK 
in CKD-5HD patients 
Triferic 2 µM 
Placebo 
12 
6 individual HD 
sessions 
SFP-9 
US 
1 site 
Phase 1, single dose in 
healthy volunteers 
Triferic mg IV: 
2.5 mg/4 hr 
5.0 mg/4 hr 
7.5 mg/4 hr 
10 mg/4 hr 
15 mg/12 hr 
20 mg/12 hr 
Placebo 
48 
Single ascending 
dose 
FPC-12 
US 
1 site 
Phase 1, two sequential 
doses in healthy volunteers 
Triferic 6 mg IV 
over 3 hrs 
Triferic 35 µg/kg IV 
push 
12 
2 days (1 dose per 
day) 


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Protocol 
Number 
Country 
(# sites) 
Study Design and Phase 
Treatment Groups 
Number of 
Subjects 
/Treatment 
Duration 
FPC-16 
US 
1 Site 
Phase 1, 3 period crossover 
Preliminary BE study 
Triferic 2 µM (110 
µg/L) via HD 
Triferic 6.6mg/3 hr 
IV pre-dialyzer 
Triferic 6.6 mg/3 hr 
post dialyzer 
13 
3 day (1 dose/day) 
SFP-1 
US 
1 site 
Phase 2, randomized, 
open-label, parallel group, 
placebo-controlled, 
dose escalation 
Triferic iron µg/L 
dialysate: 
0, 20, 40, 80 and 
120 
24 
27 weeks 
Monthly dose 
escalation 
SFP-2 
US 
29 sites 
Phase 2, randomized, 
double-blind, parallel group, 
placebo-controlled, 
dose escalation 
Triferic iron µg/L 
dialysate: 
0, 50, 100, 120 and 
150 
136 
26 weeks 
SFP-3 
US 
2 sites 
Phase 2, randomized 
double-blind, crossover 
Triferic 130 µg/L 
(food grade) 
Triferic 130 µg/L 
(GMP) 
33 
2X2 weeks 
NIH-FP-01 
US 
23 sites 
Phase 2, randomized, 
double-blind, parallel group, 
placebo-controlled 
Triferic 2 µM (110 
µg/L) 
Placebo 
108 
36 weeks 
NIH-FP-01 
Addendum 
US 
1 site 
Phase 2, randomized, 
double-blind, parallel group, 
placebo-controlled 
Triferic 2 µM (110 
µg/L) 
Placebo 
11 
36 weeks 
SFP-4-RC 
NA 
44 sites 
Phase 3, randomized, 
single-blind, parallel group, 
placebo-controlled 
Triferic 2 µM (110 
µg/L) 
Placebo 
305 
Up to 48 weeks 
SFP-4-OL 
NA 
38 sites 
Phase 3, open-label 
extension 
Triferic 2 µM (110 
µg/L) 
207 
24 weeks or a total 
of 72 weeks 
SFP-5-RC 
NA 
41 sites 
Phase 3, randomized, 
single-blind, parallel group, 
placebo-controlled 
Triferic 2 µM (110 
µg/L) 
Placebo 
294 
Up to 48 weeks 
SFP-5-OL 
NA 
37 sites 
Phase 3, open-label 
extension 
Triferic 2 µM (110 
µg/L) 
214 
24 weeks or a total 
of 72 weeks 
SFP-6-RC 
NA 
51 sites 
Phase 3, randomized, 
double-blind, crossover, 
placebo-controlled 
Triferic 2 µM (110 
µg/L) 
Placebo 
718 
2X2 weeks 
SFP-6-OL 
NA 
34 sites 
Phase 3, open-label 
extension 
Triferic 2 µM (110 
µg/L) 
310 
48 weeks 
  NA=North America  
 


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1.4. 
Non-Clinical Studies of Peritoneal Administration of Triferic 
 
1.4.1. 
In-vitro Compatibility Study: 
 
The compatibility study was designed to evaluate the physical compatibility and 
stability of Triferic added to dextrose and icodextrin containing peritoneal dialysate 
solutions over a 30 day time period. 
 
The compatibility study was performed on two different peritoneal dialysis solutions. 
Dianeal contains dextrose as an osmotic agent and Extraneal contains icodextrin as 
an osmotic agent. All peritoneal dialysis fluids are non-pyrogenic, contain no 
bacteriostatic or antimicrobial agents and are packaged in polyvinyl chloride 
containers. A summary of the study conditions are listed in Table 2. 
 
Table 2: Compatibility Study Materials 
 
mEq/L 
Dextrose 
g/dL 
Icodextrin 
g/dL 
Triferic 
pH 
Na 
Ca 
Mg 
Cl 
Lactate 
Dianeal 1.5% 
1.5 
10 mg Fe/2 L 
50 mg Fe/2L 
5.2 
132 
3.5 
0.5 
96 
40 
Dianeal 4.5% 
4.5 
10 mg Fe/2 L 
50 mg Fe/2L 
5.2 
132 
3.5 
0.5 
96 
40 
Extraneal 7.5% 
7.5 
10 mg Fe/2 L 
50 mg Fe/2L 
5.0 
132 
3.5 
0.5 
96 
40 
 
Triferic was compatible with all PD solutions at 5 mg/L and 25 mg/L ferric iron 
concentrations.  All testing over the 30 day period indicated stability of Triferic in PD 
solutions. The iron concentrations and pyrophosphate concentrations were stable at 
target for up to 30 days. 
1.4.2. 
Animal Studies: 
 
1.4.2.1. 
Study 1:  Intraperitoneal administration of soluble ferric 
pyrophosphate (SFP) in rabbits. 
 
The results of Study 1 demonstrated that SFP (5 mg Fe/L in 2.5% Dianeal) was 
absorbed from the peritoneum resulting in an increase in in serum Fe from 139.6 ± 
20.1 µg/dL to 195.4 ± 28.9 µg/dL after 30 minutes. Concomitantly, the TSAT 
increased from 53.2% to 73.1% over the same time interval (refer to 
 
Figure 1).  Results at 2 hours were similar to the results at 30 minutes indicating a 
continued transfer of iron from peritoneum to blood. 


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Figure 1:  Serum iron concentrations after administration of PD fluid in 
Rabbits. 
 
 
1.4.2.2. 
Study 2:  Four week intraperitoneal GLP toxicity study of Triferic 
administered to rats. 
 
Study 2 evaluated the toxicity and toxicokinetics of Triferic when administered to 
iron-replete rats for four weeks as three weekly intraperitoneal doses via a targeted 
1-hour infusion.  Reversibility of toxicity was evaluated during a four-week recovery 
period following the final dose Triferic, and effects on serum iron parameters were 
evaluated. The study was conducted under GLP conditions. Three (3) different 
concentrations of Triferic iron in 1.5% Dianeal PD fluid were studied and compared 
to a control group receiving 1.5% Dianeal alone. 
 
Results: 
 
Rats tolerated intraperitoneal doses of Triferic three times a week for four weeks at 
all dose levels (i.e., at up to 450 µg Fe/kg).  There were no clinical signs of toxicity 
and no effects on body weight gain (growth), food consumption, or hematology, 
coagulation, clinical chemistry, or urinalysis parameters. Administration of Triferic 
did not produce macroscopic pathologic findings or affect organ weights at necropsy. 
The only findings were swellings in the area of the subcutaneous access port and 
entanglement of the catheter tip in the omentum and/or abdominal fat, which were 
present in all groups, including the vehicle control group. 
 
No test article-related findings were present in this study. The majority of histologic 
findings were confined to the region of the treatment site, in addition to immediately 
adjacent tissues (omentum and/or testicular/ovarian adipose tissue).  Findings 
included chronic active inflammation of the peritoneum and adjacent fascia, variable 
stages of fibroplasia/fibrosis, and neovascularization. These findings are consistent 
with a foreign body reaction secondary to catheter/port placement and were 
recorded collectively as “mixed cell inflammation” with severity grades reflecting the 
density of the inflammatory infiltrate, amount and maturity of fibrosis, and/or degree 
of tissue involvement. Findings were relatively localized to the region of the 
treatment site with only rare incidences of distant involvement of the peritoneum or 
omentum. No dose-related increases in incidence or severity of any of the findings 


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were noted. Findings at the treatment sites of the recovery groups were similar in 
incidence and severity, as compared to the main study groups. 
 
Toxicokinetic Findings 
 
Intraperitoneal administration of Triferic increased total serum iron concentration in a 
dose-related manner, and the effects were similar in both sexes and after the first 
and last doses. At Triferic dose levels of 50, 150, and 450 µg Fe/kg, baseline- 
adjusted AUC values increased proportionally with dose level after the first dose 
(162, 489, and 1450 h*µg/dL, respectively) and somewhat less than proportionally 
after the last dose (142, 362, and 778 h*µg/dL, respectively). 
 
Transferrin saturation also increased in parallel with total serum iron concentration, 
reaching peak values of 55%, 65%, and 88%, respectively, after the first dose and 
51%, 71%, and 78%, respectively, after the last dose. Toxicokinetic findings indicate 
that Cmax is reached between 1 and 3 hours and returns to baseline by 8-10 hours 
after the start of the infusion at the first and last study period as shown in Figure 2. 
The rapid clearance of iron is similar to that observed after the dialytic infusion of 
Triferic iron and the IV infusion of Triferic to healthy volunteers (t½ ≅1.7 hr). 
Figure 2:  Total Serum Iron on Day 1 and 26 According to Dose Group 
Dose 50 µg/kg 
5 mg Fe/L PD Fluid 
Dose 150 µg/kg 
15 mg Fe/L PD Fluid 
450 µg/kg 
45 mg Fe/L PD Fluid 
 
 
 
 
 
 
 
 
 
 
 
Conclusions: 
 
This GLP peritoneal toxicology study demonstrated that Triferic administered in 
peritoneal dialysis fluid is able to cross the peritoneal membrane and donate iron to 
the systemic circulation in rats. Triferic demonstrated no adverse effects on 
peritoneal or omental histopathology.  The toxicokinetic analysis demonstrated a 
dose proportional absorption of Triferic iron which was essentially unchanged after 
30 days of repeated administration. The results of this study support administration 
of Triferic via the peritoneal dialysate in humans. 
1.5. 
Rationale for the Current Study 
 
Peritoneal dialysis patients have need of a convenient and safer alternative to IV iron 
for the management of their anemia. This study will examine different doses of 
Triferic administered via the PD fluid to assess the transfer of iron to the systemic 
circulation. 


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1.6. 
Justification for Dose 
 
The doses chosen for this study are within the range studied in the GLP peritoneal 
toxicity study and are expected to result in sufficient mass transfer of iron from 
peritoneum to the circulation. 
 
2. 
STUDY OBJECTIVES 
 
2.1. 
Primary Objective 
 
Determine the pharmacokinetic profile, Cmax and AUC0-t of Triferic administered 
intraperitoneally. 
 
2.2. 
Secondary Objectives 
 
The secondary objectives are: 
• To determine the dose proportionality of Triferic iron administered via peritoneal 
dialysate 
• Estimate absolute bioavailability of iron via PD 
o By proportionality of IP (Cmax and AUC0-t) to IV (Cmax and AUC0-t) 
 
o By quantitating iron remaining in PD the PD solution compared to that 
infused corrected To explore the safety of intraperitoneal Triferic 
administration in adult CKD-5 PD patients 
• To investigate the safety of intraperitoneal Triferic administration in adult CKD-5 
PD patients 
 
3. 
INVESTIGATIONAL PLAN 
 
3.1. 
Overall Study Design and Plan 
 
This is a Phase 1, open-label, single ascending dose study to assess the safety and 
pharmacokinetics of Triferic administered via PD to iron-replete adult end-stage 
renal disease patients on maintenance peritoneal dialysis (CKD-5PD). 
Approximately 24 patients will be studied. 
 
Patients will be screened within 28 days of Baseline. All patients must provide 
informed consent to enter Screening.  Patients will be advised to discontinue all iron 
supplements including multivitamins with iron. The study will be conducted as an 
outpatient study.  Patients will attend the clinic for two (2) 12 hour treatment periods 
with a 48 hour interval between test article administrations. Patients will be 
randomly assigned to receive either a single dose of Triferic in the peritoneal dialysis 
solution or a single IV dose of Triferic 6.6 mg over a 4 hour period. 


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Patients begin a long dwell time (12 hours) from approximately 08:00 to 20:00 hours 
on each day of dosing. After completion of PK measurements patient resume their 
usual dialysis prescription until the next scheduled administration of test article. 
 
A follow-up assessment will be conducted within 1 week after the last administration 
of test article to assess safety parameters. 
 
 
 
Figure 3:  Study Design Schematic 
 
 
 
3.2. 
Endpoints 
 
3.2.1. 
Pharmacokinetic Endpoints 
 
3.2.1.1. 
Primary Endpoints 
 
This is an exploratory PK study.  The primary objective is to characterize the PK of 
Triferic iron following PD administration. This will be done by assessing the mean 
absolute Cmax, AUC0-t, AUC0-end and AUCinf of serum iron obtained with 
administration of Triferic via PD and IV. Additional parameters to be determined 
may include Tmax, CL, λz, and t½. 
 
3.2.1.2. 
Secondary Endpoints 
 
The secondary endpoints are as follows: 
• Dose proportionality of Triferic iron will be determined using the Cmax and AUC 
parameters for serum iron. 
• The mass balance of iron absorbed from the PD fluid will be determined by two 
methods: 
o The absolute bioavailability of iron from Triferic administered 
via PD. 


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o The difference in mass of Triferic iron in the PD fluid infused 
 
 
and removed at the end of the dwell will be measured to 
determine the mass balance. 
3.2.2. 
Safety Endpoints 
 
The safety endpoints are as follows: 
• The incidence of treatment-emergent AEs (TEAEs) and treatment-emergent 
serious AEs (TESAEs) 
 
4. 
SELECTION OF STUDY POPULATION 
 
A total of 18 completed subjects will be required if only 3 doses are studied. Up to 30 
completed subjects may be required if two additional cohorts are needed after 
assessment of safety and tolerability of planned doses. Depending on the safety 
profile the study may be terminated at the discretion of the Sponsor after the first 
cohort has completed the study.  Doses may be changed depending on the PK or 
safety results, to be assessed after each cohort completes the study.  The Sponsor 
may change the times for the PK draws after cohort 1 or 2 have completed for 
patient convenience and compliance. 
 
4.1. 
Inclusion Criteria 
 
Patients must meet all of the following criteria to be eligible for inclusion in the study: 
 
1.  The patient must be able to provide informed consent and have personally 
signed and dated the study written informed consent document before 
completing any study-related procedures. 
2.  The patient must be 18-75 years of age inclusive at the time of consent. 
3.  Have a diagnosis of End Stage Renal Disease and have been on stable 
Peritoneal Dialysis for at least 3 months (CAPD or CCPD) prior to Screening 
using standard PD solution. 
4.  Be in a stable clinical condition during the four weeks immediately prior to 
Screening Period as demonstrated by medical history, physical examination and 
laboratory testing 
5.  Have a blood hemoglobin concentration above 9.5 g/dL. 
6.  Have a TIBC of ≥ 175 µg/dL. 
7.  Have not experienced peritonitis episodes in the last 3 months prior to Screening. 
8.  The patient must agree to discontinue all iron preparations for 14 days prior to 
Study PD #1/Day 1. 
9.  Female patients must be nonpregnant and not breastfeeding. They must either 
have been amenorrheic for the past year or agree to not become pregnant by 
continuous use of an effective birth control method acceptable to the Investigator 
for the duration of their participation in the study. 


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4.2. 
Exclusion Criteria 
 
Patients will not be eligible for inclusion in the study if any of the following criteria 
apply: 
 
1.  The patient has had an RBC or whole blood transfusion within 4 weeks prior to 
Screening. 
 
2.  The patient has had administration of IV or oral iron supplements (including 
multivitamins with iron) within 14 days prior to Study PD #1/Day 1. 
 
3.  The patient has known active bleeding from any site (e.g., gastrointestinal, 
hemorrhoid, nasal, pulmonary, etc.). 
 
4.  The patient has a living kidney donor identified or living-donor kidney transplant 
scheduled to occur during study participation. (Note:  Patients awaiting 
deceased-donor transplant need not be excluded.) 
 
5.  The patient is scheduled to have a surgical procedure during the study. 
 
6.  The patient has had a hospitalization within the 4 weeks prior to Screening 
(except for vascular access surgery) that, in the opinion of the Investigator, 
confers a significant risk of hospitalization during the course of the study. 
 
7.  The patient has a history of noncompliance with the dialysis regimen in the 
opinion of the Investigator. 
 
8.  The patient has a known ongoing inflammatory disorder (other than CKD), such 
as systemic lupus erythematosus, rheumatoid arthritis, or other collagen-vascular 
disease, that currently requires systemic anti-inflammatory or immunomodulatory 
therapy. 
 
9.  The patient has any current febrile illness (e.g., oral temperature ≥100.4°F, 
38.0°C).  (Patients may subsequently become eligible at least 1 week after 
resolution of the illness.) 
 
10. The patient has known bacterial, tuberculosis, fungal, viral, or parasitic infection 
requiring anti-microbial therapy or anticipated to require anti-microbial therapy 
during the patient’s participation in this study. 
 
11. The patient is known to be positive for HIV, hepatitis B, or hepatitis C (viral 
testing is not required as part of this protocol). 
 
12. The patient has cirrhosis of the liver based on histological criteria or clinical 
criteria (e.g., presence of ascites, esophageal varices, multiple spider nevi, or 
history of hepatic encephalopathy). 
 
13. The patient has ALT and/or AST levels consistently greater than twice the upper 
limit of normal at any time during the two months prior to Study PD #1/Day 1. 


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14. The patient currently has any malignancy other than basal or squamous cell skin 
 
 
cancer. 
 
15. The patient has a history of drug or alcohol abuse within the 6 months prior to 
Screening. 
 
16. The patient participated in an investigational drug study within 30 days prior to 
Study PD #1/Day 1. 
 
17. The patient has any condition that, in the opinion of the Investigator, would make 
it unlikely for the patient to complete the study. 
 
4.3. 
Removal of Patients from Therapy/Premature Discontinuation 
 
A patient will be discontinued from the study for the following medical or 
administrative reasons: 
• Occurrence of a treatment-emergent AE (TEAE) that represents an unacceptable 
risk to the patient and when continued participation in the investigational study is 
not warranted, in the judgment of the Investigator. The Investigator must follow 
the patient until the TEAE resolves or satisfactorily stabilizes; 
• Pregnancy; 
• Initiation of a prohibited concomitant therapy without medical monitor or Sponsor 
approval; and/or 
• Patient request. 
 
The Investigator may discontinue individual patients from the study at any time. 
Patients may voluntarily withdraw at any time. If possible, patients who are 
withdrawn should complete a Follow-up visit. 
 
Patients who withdraw or are withdrawn after enrollment will not be replaced under 
this protocol. Patients who withdraw or are withdrawn prior to enrollment will be 
considered screen failures and will be replaced. 
 
5. 
TREATMENTS 
 
5.1. 
Treatments Administered 
 
Triferic will be administered by qualified study personnel only in accordance with the 
procedures described in this protocol. 
 
5.2. 
Identity of Investigational Products(s) 
 
Triferic is supplied as sterile 5 mL or 50 mL ampules containing 5.44 mg/mL of iron 
in water for injection. The actual content of Triferic iron from the COA will be used to 
calculate the dose to be administered. 


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5.2.1. 
Labeling 
 
Study drug packaging will bear a label that meets applicable laws for an 
investigational drug, which includes, but is not limited to, the following information: 
• Federal law statement 
• Protocol number 
• Lot number 
• Storage information 
5.2.2. 
Storage and Handling 
 
All study drugs will be kept in a locked area with limited access. 
 Triferic ampules will be stored protected from light in an aluminum pouch at 
controlled room temperature (20° to 25°C [68° to 77°F]; excursions will be permitted 
to 15° to 30°C [59° to 86°F] [See USP Controlled Room Temperature]). 
 
5.3. 
Method of Assigning Patients to Treatment Groups 
 
5.3.1. 
Treatment Assignment/Randomization 
 
This is a multiple period cohort study.  Each patient within a cohort will be 
randomized to receive either a single dose of Triferic in the peritoneal dialysis 
solution, or a single IV dose of Triferic 6.6 mg over a 4 hour period. The anticipated 
doses of Triferic IP are: 
 
Cohort 1: Triferic 5 mg/L in peritoneal dialysis solution 
Cohort 2: Triferic 12.5 mg/L in peritoneal dialysis solution 
Cohort 3: Triferic 20 mg/L in peritoneal dialysis solution 
Cohort 4: Triferic XX mg/L in peritoneal dialysis solution depending on the results 
from previous cohorts iron profiles and safety findings. The IP dose of Triferic in 
Cohort 4 may be higher or lower than the proposed doses in Cohorts 2 and 3 and 
will be determined by the Sponsor after consultation with the study investigators. 
 
Cohort 5: (If needed) Triferic XX mg/L in peritoneal dialysis solution depending on 
the results from previous cohorts iron profiles and safety findings. The IP dose of 
Triferic in Cohort 5 may be higher or lower than the proposed doses in Cohorts 2, 3 
and 4 and will be determined by the Sponsor after consultation with the study 
investigators. 
 
See Appendix 4: Triferic Dosing Solution Preparation. 
 
5.4. 
Selection of Doses in the Study 
 
The rationale for the doses chosen in this study has been presented in Section 1.5. 
This is an exploratory study to determine the dose range and PK of Triferic 
administered IP to adult patients with CKD-5 PD. The doses chosen are within the 


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range of those studies in the rat GLP toxicology study and have been found to not 
induce any local toxicity and are lower than doses that are well tolerated. 
 
5.5. 
Selection and Timing of Dose for Each Patient 
 
Each treatment will be administered starting at approximately 8 AM on the applicable 
study day for each patient. 
 
5.6. 
Procedures for Blinding 
 
This is an open-label study, no blinding is required. 
 
5.7. 
Procedures for Randomization 
 
The order of administration of test article will be determined by a pre-prepared 
randomization table. 
 
5.8. 
Prior and Concomitant Therapy 
 
5.8.1. 
Prior Therapy 
 
All prescription and non-prescription medications (including multivitamins and oral 
and IV iron products) taken within 28 days prior to Study PD #1/Day 1 will be 
documented in source documents and the case report form (CRF) (based on patient 
report and/or medical records). 
 
Red blood cell and whole blood transfusions are prohibited from 4 weeks prior to 
Screening and during the study.  The date of Screening is considered to be the date 
that the first study-related Screening assessment is performed. Should a patient 
require a red blood cell or whole blood transfusion during the study, they will be 
removed from participation. 
 
5.8.2. 
Concomitant Therapy 
 
All prescription and non-prescription medications taken from 28 days prior to Study 
PD #1/Day 1 to Follow-up must be documented in the source documents and CRF. 
 
5.8.3. 
Prohibited Medications 
 
Oral and IV iron products are prohibited from 14 days prior to Study PD #1/Day 1 
until all blood samples have been collected for each subject at Study PD #2. This 
includes oral multivitamins containing iron. 
 
5.9. 
Treatment Compliance 
 
Because this is a parenteral administration study, the site is responsible for 
documenting compliance with study drug administration. 


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5.9.1. 
Study Drug Accountability 
 
Study drug will be administered in accordance with the procedures of this protocol. 
Only authorized site personnel may supply or administer study drug and only 
patients enrolled in the study may receive study drug, in accordance with applicable 
regulatory requirements. 
 
Drug accountability information collected may include but is not limited to: 
• Receipt of study drug (date and quantity); 
• Storage temperature log; 
• Dispensation of study drug (date, quantity, and patient number); 
• Return of study drug (date, quantity, and patient number); 
• Initials of individual dispensing study drug; and 
• Compliance assessment. 
At the conclusion of a site’s participation in the study, all unused investigational drug 
shall be returned to Rockwell or destroyed upon Rockwell’s request unless 
otherwise instructed by Rockwell.  A copy of the reconciled drug inventory record will 
be provided to Rockwell or its designee, and the original will be retained at the site. 
 
6. 
STUDY PROCEDURES 
 
6.1. 
Study Periods and Procedures 
 
A time and events schedule is provided in Appendix 1 (Table 3). 
Screening will occur on Study Day -28 through Study Day -1. 
The first dose of study drug will be administered on Day 1. The second dose of 
study drug will be administered on Day 3. The Follow-up visit is expected to occur 
within 1 week following Day 3. 
 
Please note that for any visit, if the visit is missed, or if the patient shows up too late 
to begin PD at 8 AM and/or the Triferic infusion is interrupted for more than 15 
minutes, then the visit may be rescheduled to occur within the next 30 days. If 
Triferic was being administered, the administration should be discontinued and PK 
and serum iron profile samples should be drawn immediately, and no further PK or 
serum iron profile samples should be collected for that day. 
 
6.1.1. 
Screening Period (Study Day -28 through Study Day -1) 
 
The Screening Visit (Day -28) should be conducted within 28 days prior to admission 
to the clinical research center (Study Day -1).  The date of Screening is considered 
to be the date that the first study-related screening assessment is performed. The 
following procedures will be performed at Screening: 
• Obtain informed consent from the patient (must be done prior to any study 
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• Assign study-specific patient number 
• Record patient demographics and medical history 
• Record all current medications, and also record any other medications taken 
within 28 days prior to Study PD #1/Day 1 
• Record the date of the patient’s last RBC or whole blood transfusion 
• Record height and weight 
• Record vital signs (blood pressure, pulse, and temperature) 
• Perform a physical examination 
• Record ECG 
• Collect laboratory samples (including hematology, Chem-14, CRP, pregnancy 
test (if applicable) and the serum iron profile) if not available within the last 30 
days. 
• Confirm patient meets all assessable eligibility criteria 
• Schedule the next study visit (clinical research center admission Day -1) to occur 
within 28 days after Screening. Provide instruction to patients to discontinue any 
prohibited medications such as oral iron supplements and multivitamins with iron. 
6.1.2. 
Day -1 Enrollment 
• Assess and record medical conditions 
• Record medications 
• Perform a final review of inclusion/exclusion criteria and enroll eligible patients 
into the study 
• Schedule the next visit for administration of test article. 
6.1.3. 
Triferic IP (Day 1 or Day 3, depending on randomization) 
 
The exact time (clock time) of infusion start and stop as well as each blood sample 
collection must be recorded. 
 
PRE-DIALYSIS 
• The site pharmacist will prepare the peritoneal dialysis solution under aseptic 
conditions (Appendix 4: Triferic Dosing Solution Preparation) at the appropriate 
dose for the cohort. 
• Retain a 50 mL sample of PD fluid for analysis of iron content. 
• Weigh the bag of dialysate after removal of the baseline 50 mL sample and 
record to the nearest gram. 
• Record vital signs (blood pressure and pulse) within 10 minutes of starting PD. 
• Collect a serum iron profile (sFe, ferritin, TIBC, and TSAT) to be sent to the 
clinical laboratory, a time = 0 PK blood sample, and a hepcidin sample at 
approximately 8 AM (within 5 minutes prior to the start of PD) as indicated in 
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• The patient will drain the PD fluid from the abdomen and infuse the PD fluid 
containing Triferic according to their standard routine. 
• Weigh the patient after the dialysis fluid is drained and prior to infusing the PD 
fluid with test article. 
• The following samples will be collected from the drained baseline bag of PD fluid 
that does not contain Triferic: 
o 50 mL to send to the lab for a cell count and differential 
o 50 mL to be stored according to the instructions in Appendix 
4 for analysis of fluid iron content, and 
o Six (6) 15-mL samples to be frozen at -80 for future analysis. 
DURING DIALYSIS 
• Collect blood samples for PK and serum iron profile as indicated in Appendix 2 
(PK, Serum Iron Profile, and Hepcidin Sample Collection Schedule). 
• Record vital signs (blood pressure, pulse) every 2 hours during PD. 
• Assess and record AEs 
• At the end of the 12 hour dwell, the patient will drain the PD fluid and cap off or 
infuse the next bag of PD solution per their standard routine. 
• Weigh the drained peritoneal dialysis solution and record to the nearest gram. 
• The following samples will be collected from the drained bag of PD fluid that 
contains Triferic: 
o 50 mL to send to the lab for a cell count and differential 
o 50 mL to be stored according to the instructions in Appendix 
4 for analysis of fluid iron content, and 
o Six (6) 15-mL samples to be frozen at -80 for future analysis. 
• Remind patients to continue not to take any prohibited medications, such as oral 
iron supplements and multivitamins with iron. 
• Schedule the next visit. 
6.1.4. 
Triferic 6.6 mg IV/4 hours (Day 1 or Day 3, depending on 
randomization) 
 
PRE-DIALYSIS 
• Assess and record AEs 
• Record medications 
• Insert an IV in a peripheral vein and keep open with an infusion of D5/W. 
• The patient should then drain the PD fluid from the abdomen and infuse standard 
PD fluid according to their usual routine. 
• Weigh the patient after the dialysis fluid is drained and prior to infusing the 
standard PD fluid. 
• The following samples will be collected from the drained baseline bag of PD fluid 
that does not contain Triferic: 


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o 50 mL to send to the lab for a cell count and differential 
o 50 mL to be stored according to the instructions in Appendix 
4 for analysis of fluid iron content, and 
o Six (6) 15-mL samples to be frozen at -80 for future analysis. 
• Record vital signs (blood pressure and pulse) within 10 minutes of starting PD. 
• Collect a serum iron profile (sFe, ferritin, TIBC, and TSAT) to be sent to the 
clinical laboratory, a time=0 PK blood sample, and a t = 0 hepcidin sample at 
approximately 8 AM (within 5 minutes prior to the start of PD) as indicated in 
Appendix 3. 
DURING DIALYSIS 
• Begin the patient’s usual PD at approximately 08:00. 
• At the same time that PD is started, begin administration of Triferic 6.6 mg 
intravenously over 4 hours. See Appendix 4 for details of the preparation of 
Triferic dosing solutions. The rate of infusion should be adjusted to complete the 
infusion of 6.6 mg Triferic iron over 4 hours. Record the actual start time and stop 
time of the Triferic IV infusion. 
• Collect blood samples for PK and serum iron profile as indicated in Appendix 2 
(PK, Serum Iron Profile, and Hepcidin Sample Collection Schedule). 
• Record vital signs (blood pressure, pulse) every 2 hours during PD. 
• Assess and record AEs. 
• At the end of the infusion, drain the PD fluid and reinfuse new fluid per the 
patient’s usual routine. 
• The following samples will be collected from the drained bag of PD fluid: 
o 50 mL to send to the lab for a cell count and differential 
o 50 mL to be stored according to the instructions in Appendix 
4 for analysis of fluid iron content, and 
o Six (6) 15-mL samples to be frozen at -80 for future analysis. 
• Confirm the scheduling next visit. 
6.1.5. 
Follow-up (Study Day 5-8) 
 
NOTE: Patients who are discontinued or withdraw from this study prior to Follow-up 
are to have Follow-up procedures and evaluations performed at the time of 
discontinuation or withdrawal. 
The following assessments are to be completed during Follow-up: 
• Assess and record AEs 
• Record concomitant medications 
• Physical exam 
• Record vital signs (blood pressure, pulse, and temperature) 
• Collect safety laboratory samples (including hematology, Chem-14, the serum 
iron profile) if required to assess AEs 


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• Discharge patient from the study 
6.2. 
Study Measurements and Assessments 
 
PK samples will be prepared and shipped to a central bioanalytical laboratory for 
analysis of the total serum iron profile. 
Safety laboratory samples (including serum 
chemistry, hematology, pregnancy CRP, and serum iron profile) will be sent to a 
central clinical laboratory.  Dosing solution samples will be sent to a central 
bioanalytical laboratory for analysis. Baseline and post-dose PD fluid samples will 
be sent to the central clinical laboratory for analysis of cell count and differential. 
Hepcidin samples will be analyzed by Mass Spectroscopy at the laboratory of Dorine 
Swinkels (Hepcidinalysis.com). 
 
6.2.1. 
Assessment of Pharmacokinetics 
 
The primary PK assessment for each dose level will be determined from samples 
obtained during PD # 1 and PD #2 for each Cohort. 
 
The PK samples will be obtained according to the schedule in Appendix 2 and will 
be analyzed for the iron profile at each time point. 
 
The following serum iron profile values will be measured by the central clinical 
laboratory at the time points indicated in Appendices 1 and 2: 
• Total serum iron 
• Ferritin 
• TIBC 
• TSAT 
6.2.1.1. 
Total Serum Iron 
The PK of administered Triferic iron will be assessed by measuring total serum iron. 
Total serum iron will be measured using a validated Inductively Coupled Plasma 
Mass Spectrometry (ICP-MS) method. 
 
6.2.1.2. 
Appropriateness of Iron Parameter Measurements 
The determination of total serum iron by ICP-MS has been developed and validated. 
Previous studies have demonstrated the concordance of sFe with transferrin bound 
 iron for Triferic administered parenterally.  The autoanalyzer method has a lower 
limit of detection of 5 µg/dL and the ICP-MS assay has a lower limit of detection of 
0.2 µg/dL. 
6.2.1.3. 
Collecting, Processing, and Shipping Pharmacokinetic Samples 
 
Blood samples for PK analysis will be collected as outlined in the PK, Serum Iron 
Profile and Hepcidin Sample Collection Schedule in Appendix 2.  An indwelling 
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necessary by the investigator.  Approximately 10 mL of whole blood will be collected 
for each blood draw.  Including the safety laboratory tests, the total volume collected 
from each patient will be less than 200mL. 
 
Blood samples will be collected in serum separator tubes with clot activator at the 
nominal time points listed in Appendix 2. Actual blood sampling times must be 
recorded in the source documents and CRF. 
 
Blood samples will be drawn and processed for serum as described in Appendix 3. 
 
6.2.2. 
Assessment of Safety 
 
Safety assessments will include the following: 
• AEs and SAEs, both reported and observed; 
• Clinical laboratory tests; 
• Changes in physical examinations; 
• Vital sign measurements (blood pressure, pulse, and temperature). 
6.2.2.1. 
Clinical Laboratory Tests 
 
All routine and safety blood samples will be analyzed by the site’s local licensed 
clinical laboratory.  The clinical laboratory tests that will be conducted at a clinical 
laboratory are as follows: 
• Hematology: complete blood count with platelet count, white blood cell (WBC) 
count and WBC differential. 
• Blood Chemistry:  routine Chem-14 analysis, serum pregnancy test, and CRP 
(Screening only). 
• Serum Iron Profile:  sFe, ferritin, TIBC, and TSAT. 
The Investigator is responsible for determining whether out-of-range laboratory 
values are clinically significantly changed or not.  If the Investigator determines that 
additional laboratory examinations are needed for a patient in screening, then the 
patient is not considered eligible for the study until such values are considered 
clinically stable. All clinically significantly changed values of enrolled patients will be 
followed until resolution or stabilization. 
 
6.2.2.2. 
Physical Examinations 
 
Physical examinations will consist of assessments of the following: skin, ENT (ears, 
nose, and throat), head, eyes, lungs/chest, heart, abdomen, musculoskeletal, 
extremities, and neurologic. 
 
6.2.2.3. 
Vital Signs and Weight 
 
Vital signs will include blood pressure (mm Hg), heart rate (beats per min), and 
temperature (Screening and Follow-up).  Blood pressure and heart rate 


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measurements will be obtained in the same position (supine or sitting) and in the 
same arm when possible, after being supine or sitting for at least 5 minutes. 
 
6.3. 
Assessment to Proceed to Next Dose Levels 
 
The safety findings, serum iron, and iron profile will be reviewed at the conclusion of 
each cohort and prior to escalating the dose. 
 
Stopping criteria for any dose level: 
• Onset of nausea, vomiting, diarrhea or changes in sensorium in at least 1 
patient receiving FPC IP. 
• Evidence for metabolic acidosis in at least 1 patient receiving FPC IP. 
• Evidence for peritoneal irritation as manifest by abdominal pain with 
tenderness in greater than 1 patient receiving FPC IP. 
• Increase in cell count indicative of peritoneal inflammation in greater than 1 
patient receiving FPC IP. 
• A serious adverse event deemed possibly related in any patient receiving 
FPC IP. 
 
 
 
7. 
ADVERSE EVENTS 
 
The Investigator is responsible for the detection and documentation of events 
meeting the definition of an AE or SAE as provided in this protocol. 
 
7.1. 
Definition of an Adverse Event 
 
An AE is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this product. 
 
An AE can therefore be any unfavorable and unintended sign (including a clinically 
significant abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the 
medicinal product. Adverse events will be recorded on the AE CRF from the start of 
the first dose of Triferic through the end of study participation or 7 days after the last 
dose of Triferic, whichever is later. Pre-treatment-emergent medical conditions will 
be captured on the medical history CRF, unless they meet seriousness criteria 
(Section 7.2). 
 
An AE does include any: 
• Exacerbation of a pre-existing illness; 
• Increase in frequency or intensity of a pre-existing episodic event or condition; 
• Condition detected or diagnosed after the start of study drug administration even 
though it may have been present prior to the start of the study; or 


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• Continuous persistent disease or symptoms present at baseline that worsen 
following the start of the study. 
Symptoms associated with a disease not previously reported by the patient will be 
recorded as an AE. 
 
An AE does not include a/an: 
• Medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, 
transfusion). Rather, the underlying condition that leads to the procedure is the 
AE that should be reported, unless the condition did not worsen during the study; 
• Pre-existing diseases or conditions present or detected at the start of the study 
that do not worsen; 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for cosmetic elective surgery, social and/or convenience 
admissions). 
7.2. 
Definition of a Serious Adverse Event 
 
Any SAE that occurs from the date of Screening to the date of the Follow-up visit or 
7 days after the last dose of Triferic, whichever is later, will be reported on an SAE 
report form. For enrolled patients, SAEs are also recorded on the AE CRF page. An 
SAE is any AE occurring at any dose that results in any of the following outcomes: 
 
a.  Death; 
 
b.  A life-threatening AE; 
• NOTE: Life-threatening means that the patient was, in the view of the 
investigator, at immediate risk of death from the event as it occurred. 
This definition does not include an event that, had it occurred in a more 
severe form, might have caused death. 
 
c.  Inpatient hospitalization or prolongation of an existing hospitalization; 
• NOTE: Hospitalization for elective treatment of a pre-existing condition 
that did not worsen during the study is not considered an AE or SAE. 
• NOTE: Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization, or otherwise meets seriousness 
criteria, the event is an SAE. 
• NOTE: “Inpatient” hospitalization means the patient has been formally 
admitted to a hospital for medical reasons. This may or may not be 
overnight.  It does not include presentation at a casualty or emergency 
room. 
 
d.  A disability/incapacity; 
• NOTE: The term disability means a substantial disruption of a person’s 
ability to conduct normal life functions.  This definition is not intended 
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uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
accidental trauma (e.g., sprained ankle) that may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 
 
e.  A congenital anomaly in the offspring of a patient who received drug; or 
 
f. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
• Medical and scientific judgment should be used in deciding whether 
prompt reporting is appropriate in this situation. 
 
7.3. 
Method, Frequency, and Time Period for Detecting Adverse 
Events and Serious Adverse Events 
 
At appropriate intervals, patients should be assessed for AEs and SAEs. After the 
patient has had an opportunity to spontaneously mention any problems, the 
Investigator should inquire about AEs by asking a non-leading question such as the 
following: 
 
18. “How are you feeling?” 
 
19. “Have you had any medical problems since your last assessment/visit?” 
 
20. “Have you taken any new medicines since your last assessment/visit?” 
 
7.4. 
Reporting Serious Adverse Events 
 
CONTACT THE MEDICAL MONITOR BY PHONE, EMAIL, OR FAX (1 866 250 
5488) WITHIN THE TIMEFRAME SPECIFIED IN SECTION 7.4.1 TO NOTIFY 
ROCKWELL MEDICAL OF ANY SAEs. 
 
All SAEs (related and unrelated) will be recorded from the time of the Screening visit 
until the date of the Follow-up visit or 7 days following the last dose of Triferic, 
whichever is later. Any SAEs considered possibly, probably, or definitely related to 
the investigational product and discovered by the Investigator or site personnel at 
any interval after completion of the study should also be reported. All SAEs must be 
reported to Rockwell Medical within 48 hrs (24 hrs for deaths and life-threatening 
events) of the site’s first awareness of the event. The Investigator must complete, 
sign and date the SAE pages, verify the accuracy of the information recorded on the 
SAE pages with the corresponding source documents, and send a copy by fax (1 
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At a minimum, the event name, a reporter’s name and contact information, the name 
of the suspected investigational product and patient identifiers, a description of the 
event and the Investigator’s preliminary assessment of causality must be provided at 
the time of the initial report. Additional follow-up information, if required or available, 
should be sent to Rockwell Medical within 48 hrs of receipt. Follow-up information 
should be provided using a follow up SAE report, and the follow-up SAE report 
should be placed with the original report in the appropriate section of the CRF/study 
file. 
 
The Investigator is encouraged to discuss with Rockwell Medical any AEs for which 
the issue of seriousness is unclear or questioned. 
 
Rockwell Medical is responsible for notifying the relevant regulatory authorities of 
certain events. Multiple inquiries between Rockwell Medical and the study site may 
be necessary for report preparation. 
 
It is the Principal Investigator’s responsibility to notify the Institutional Review Board 
(IRB), Independent Ethics Committee (IEC) or the relevant local regulatory authority 
of all SAEs that occur at his or her site. Investigators will also be notified of all 
unexpected, serious, drug-related events (7- and 15-Day Safety Reports) that occur 
during any clinical trials. Each site is responsible for notifying their IRB, IEC or the 
relevant local regulatory authority of these additional SAEs. 
 
7.4.1. 
Timeframes for Reporting Serious Adverse Events 
 
Prompt notification to Rockwell Medical regarding SAEs is essential so that ethical 
and regulatory responsibilities and legal obligations can be satisfied. The 
Investigator must report SAEs according to the following time frames: 
• Death or Life-Threatening Event: 
o Initial notification must be sent to Rockwell Medical within 24 hrs of the 
investigational site learning of the death or life-threatening event (regardless 
of causality). 
o Complete SAE information (i.e., all SAE pages) must be sent to Rockwell 
Medical within 48 hrs. 
o Follow-up information must be sent to Rockwell Medical within 48 hrs of 
receipt of the information by the investigational site. 
• All Other SAEs 
o Complete SAE information (i.e., all SAE pages) must be sent to Rockwell 
Medical within 48 hrs of site study personnel learning of the event. 
o Follow-up information must be sent to Rockwell Medical within 48 hrs of 
receipt of the information by the investigational site. 


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7.4.2. 
Serious Adverse Event Information to Report 
 
 
 
All information available regarding an SAE must be submitted in the timeframes 
indicated in Section 7.4.1. At a minimum, SAE reports must contain the patient’s 
study identifier, the SAE term, and the name of the person reporting the event to 
Rockwell Medical.  Optimally, the initial report will also include the onset date, 
relationship to study drug, and a brief narrative of the event. 
 
The Investigator must record all relevant information regarding an AE/SAE in the 
applicable sections of the CRF.  It is not acceptable for the investigator to send 
photocopies of the patient’s medical records in lieu of completion of the 
appropriate AE/SAE pages. However, there may be instances when copies of 
medical records for certain cases are requested by Rockwell Medical.  If medical 
records are submitted to Rockwell Medical then all patient personal identifiers must 
be completely and thoroughly redacted prior to submission. Each page of medical 
records should be labeled with the patient’s study identifier. 
 
7.4.3. 
Regulatory/Ethics Reporting Requirement 
 
The Investigator, or responsible person according to local requirements, must 
comply with the applicable local regulatory requirements related to the reporting of 
SAEs to regulatory authorities and the IRB/EC. 
 
7.5. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events 
 
Clinically significant abnormal laboratory findings or other abnormal assessments 
that are associated with a diagnosis, unless judged by the investigator as more 
severe than expected for the patient's condition, or that are present or detected 
before study drug administration and do not worsen after study drug administration, 
should not be reported as AEs. Instead, the diagnosis with which they are 
associated should be assessed for whether it constitutes an AE, and reported 
accordingly. For example, if a patient experiences leukocytosis or hypoxia 
associated with a diagnosis of pneumonia, it is not necessary to report these in 
addition to reporting the pneumonia unless they are more severe than expected. 
 
If not known to be associated with a diagnosis, abnormal laboratory findings (e.g., 
clinical chemistry or hematology) or other abnormal assessments (e.g., ECGs or 
vital signs) that are judged by the Investigator as clinically significant must be 
recorded as AEs or SAEs if they meet the definition of an AE (Section 7.1, Definition 
of an Adverse Event), and also reported as SAEs if they meet the criteria for 
seriousness (Section 7.2, Definition of an SAE). 
 
The Investigator should exercise his or her medical and scientific judgment in 
deciding whether an abnormal laboratory finding or other abnormal assessment is 
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7.6. 
Documenting Adverse Events 
 
Adverse events, including SAEs, will be recorded on the AE CRF from the start of 
the first dose of Triferic through the end of study participation or 7 days after the last 
dose of Triferic, whichever is later. Pre-treatment-emergent medical conditions will 
be captured on the medical history CRF, unless they meet seriousness criteria 
(Section 7.2). 
 
Any SAE that occurs from the date of Screening to the Follow-up visit or 7 days after 
the last dose of Triferic, whichever is later, will be reported on an SAE report form. 
For enrolled patients, SAEs are also recorded on the AE CRF page. 
 
The Investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE and/or SAE. 
 
7.7. 
Follow-up of Adverse Events 
 
After the initial AE report, the Investigator is required to proactively follow each 
patient and provide further information to Rockwell Medical on the patient’s 
condition. All AEs documented at a previous visit/contact that are designated as 
ongoing will be reviewed at subsequent visits/contacts. 
 
All AEs that are ongoing at the conclusion of the patient’s participation will be 
followed up until resolution, until the condition stabilizes, or until the patient is lost to 
follow-up.  The appropriate AE/SAE source document and CRF page(s) will be 
updated.  If a patient dies during participation in the study or during the 7 days 
following the patient’s last dose of Triferic, a copy of any post-mortem findings, 
including histopathology, should be obtained, if available, and forwarded to Rockwell 
Medical. 
 
7.8. 
Post-study Adverse Events 
 
Investigators are not obligated to actively seek new AEs or SAEs that begin more 
than 7 days after the last dose of Triferic. The Investigator should notify Rockwell 
Medical of any SAEs that begin following study completion only if the event is 
considered related to study drug. 


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8. 
STATISTICS 
 
8.1. 
General Considerations 
 
A total sample size of approximately 24 patients is planned. The total sample of 24 
patients should provide enough information for an analysis of the PK and dose 
proportionality of Triferic iron administered via PD and IV. 
 
8.2. 
Determination of Sample Size 
 
A total of up to 24 adult patients with CKD-5HD will be enrolled in this study. The 
sample size was determined empirically. One half (12 patients) will be CAPD and 
one half will be CCPD patients. 
 
8.3. 
Analysis Populations 
 
Two analysis populations will be defined as follows: 
• PK Population will include all enrolled patients who receive at least 1 dose of 
study drug and have sufficient PK samples (a sample at end of administration 
and at least 3 samples during the elimination phase) to include in the PK 
assessments. 
• Safety Population will include all enrolled patients who received at least 1 dose 
of study drug. 
 
The analyses of disposition, baseline characteristics, and exposure will be 
performed for the Safety Population. The PK analyses will be performed for the PK 
population. All safety analyses will be performed for the Safety Population. 
 
8.4. 
Patient Disposition 
 
Patient disposition will be summarized for the Safety Population. 
 
8.5. 
Baseline Characteristics 
 
Baseline characteristics will be summarized for the Safety Population. 
 
8.6. 
Concomitant Medications 
 
Concomitant medications will be categorized by World Health Organization (WHO) 
classification (Anatomical Therapeutic Chemical classification system [ATC] levels 1- 
4) and drug name and summarized by number and percentage of patients for the 
Safety Population. 
 
8.7. 
Extent of Exposure 
 
Exposure will be calculated for the Safety Population. 


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8.8. 
Safety Assessments 
 
8.8.1. 
Adverse Events 
 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The frequency of treatment-emergent AEs will be calculated for each 
body system, by preferred term, by treatment, for number of patients and percentage 
reporting the event. The severity of the AEs and the relationship to the study drug 
will be summarized for each body system and preferred term by treatment. 
Withdrawals due to AEs will be summarized for each body system and preferred 
term by treatment. 
 
Withdrawals from the study due to AEs will be summarized. 
 
Narratives will be presented for all deaths, SAEs and patients withdrawn due to AEs. 
 
8.8.2. 
Clinical Laboratory Assessments 
 
With the exception of the PK analyses for total serum iron, all hematology and 
chemistry results (including serum iron profiles and hepcidin) will be summarized for 
the Safety Population and follow-up values will be summarized separately where 
applicable. 
 
8.8.3. 
Vital Signs 
 
Changes from baseline at each time point will be summarized for the Safety 
Population. 
 
8.9. 
Pharmacokinetic Analyses 
 
The primary PK analysis will be performed on the total serum iron values. 
 
PK parameters will be derived using non-compartmental methods employing 
WinNonlin® Phoenix version 6.3 or later (Pharsight Corp, Mountain View, CA).  The 
following PK parameters will be estimated for serum iron as data permit and as 
appropriate: 
 
Cmax 
The maximum drug concentration in serum 
determined directly from individual 
concentration-time data 
Tmax 
The observed time to reach maximum concentration 
AUC(0-t) 
The area under the serum concentration-time curve 
from time zero to the time of the last quantified 
concentration, calculated using the linear-up/log- 
down trapezoidal rule 
AUC(0-end) 
The area under the serum concentration-time curve 
from time zero to the end of each study drug 
infusion, calculated using the linear-up/log-down 
trapezoidal rule 


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λz 
The terminal phase rate constant, estimated by 
linear regression through the terminal phase of the 
log concentration-time profile 
t½ 
The terminal phase half-life, calculated as: 
t½ = ln(2) 
lz 
AUCinf 
The area under the serum concentration-time curve 
from time zero extrapolated to infinity; calculated 
using the linear-up/log-down trapezoidal rule 
CL or 
CL/F 
Systemic clearance calculated as: 
Total Dose/AUClast 
Individual PK parameters for total serum iron will be summarized with descriptive 
statistics. Pharmacokinetic parameters including the maximum observed serum 
concentration (Cmax), time to Cmax (Tmax), the area under the serum concentration 
versus time curve from time 0 (pre-dose) to the last quantified time point (AUC0-t), 
the area under the serum concentration versus time curve from time 0 (pre-dose) to 
the end of each study drug infusion (AUC0-end), AUC from time 0 (pre-dose) to time 
infinity (AUCinf), the elimination rate constant (lz), the total systemic clearance (CL or 
CL/F), and elimination half-life (t½) will be calculated as data permit and as 
appropriate using non-compartmental analyses. 
 
8.10.  Quantitation of Iron Administered 
 
An estimate of the amount of iron transferred from the PD solution to the circulation 
will be obtained in two different analyses. 
 
a)  The Cmax and AUC0-t for sFe at each dose level compared to the Cmax and 
AUC0-t for the Triferic IV administration will be used to calculate the 
relative bioavailability of Triferic iron during the PD period. 
 
b)  A sample of the initial dosing solution and the final PD drainage will be 
analyzed for iron content using ICP-MS. The difference between the 
dosing solution and the final drainage (corrected for volume effects) is a 
direct measure of Triferic iron absorbed during the PD dwell. 
 
8.11.  Planned Modeling 
 
Pharmacokinetic results from this study for total serum iron may be used to develop 
a model to provide a method to estimate PK parameters for Triferic. 
 
A population PK model may be used to combine all data for a PK estimate for the full 
population. 
 
8.12.  Pharmacogenomics Analyses 
 
None are planned. 


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8.13.  Statistical and Analytical Issues 
 
8.13.1. 
Statistical Analysis Plan 
 
A statistical analysis plan (SAP) will be written and finalized prior to any lock of the 
study database. The SAP will give a detailed description of the summaries and 
analyses (primary and secondary) that will be performed and clearly describe when 
these analyses will take place. Included in the SAP will be adjustments for 
covariates, and handling of dropouts and missing data points. 
 
8.13.2. 
Handling of Missing Data 
 
Missing data will not be replaced or imputed. All analyses will use available data 
only. 
 
8.13.3. 
Interim Analyses and Data Monitoring 
 
No interim analysis is planned. 
 
8.13.4. 
Criteria for Stopping the Study 
 
The study can be stopped at any time if any of the following circumstances occurs: 
• An SAE occurring during Triferic administration and considered related to study 
drug; 
• Signs of possible hypersensitivity during infusion of study drug as evidenced by 
any of the following, that is not consistent with the patient’s ongoing medical 
history: 
o Hypotension,  respiratory  difficulty,  angioedema,  generalized  pruritis  and 
flushing; 
• Signs of potential iron toxicity as evidenced by any of the following, that is not 
consistent with the patient’s ongoing medical history: 
o GI:  Nausea, vomiting, diarrhea and abdominal pain; 
o CV: Decreased cardiac output leading to hypoperfusion and shock; 
o Metabolic: Acute metabolic acidosis; or 
o CNS: Depressed sensorium; 
• Serum iron levels ≥500 µg/mL regardless of symptomology; or 
• Hepatic injury as evidenced by any acute combination of elevated bilirubin, AST 
or ALT levels. 
 
If any of these events occurs, a safety review committee will review the entire 
study’s safety data before a decision is made to terminate the study. 


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9.       STUDY ADMINISTRATION 
 
9.1.    Sponsor’s and Investigator’s Responsibilities 
 
This study will be conducted in accordance with current applicable regulations, ICH 
and local ethical and legal requirements. 
 
9.2.    Sponsor’s Responsibilities 
 
9.2.1.        GCP Compliance 
 
Rockwell Medical and any third party to whom aspects of the study management or 
monitoring  have  been  delegated  will  undertake  their  roles  for  this  study  in 
compliance with all applicable regulations and ICH GCP Guideline E6. 
Visits to investigator sites will be conducted by representatives of Rockwell Medical 
to  inspect  study  data,  patients’  medical  records  and  CRFs  in  accordance  with 
current GCP and the respective local and national government regulations and 
guidelines. Records and data may additionally be reviewed by auditors, or by 
regulatory authorities. 
9.2.2.        Regulatory Approval 
 
Rockwell Medical will ensure that local Regulatory Authority and IRB/EC 
requirements are met at each site prior to releasing investigational product for 
shipment to the study site. 
9.2.3.        Indemnity/Liability and Insurance 
 
Rockwell Medical will ensure that suitable insurance coverage is in place prior to the 
start of the study. 
9.2.4.        Protocol Conduct 
 
9.2.4.1.     Protocol Compliance and Protocol Deviations 
 
Except for a change that is intended to eliminate an apparent immediate hazard to a 
study patient, the protocol shall be conducted as specified.  Any such change must 
be reported immediately to Rockwell Medical and to the IRB according to the 
applicable IRB/EC policy. 
The Investigator must notify the IRB of any and all protocol deviations according to 
the applicable IRB/EC policy. Protocol ‘waivers’ will not be granted. 
Written documentation of all protocol deviations must be kept in the study center file 
and  provided  to  Rockwell  Medical.    Examples  of  possible  protocol  deviations 
include, but are not limited to: 
•  Failure to obtain required informed consent, 
•  Failure to collect, report or file AE reports, 
•  Performance of an unapproved study procedure, 
•  Performance of research at an unapproved location, 


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•  Failure to file protocol modifications, and 
•  Failure to adhere to an approved protocol. 
9.2.4.2.     Protocol Amendments 
 
All protocols and amendments will be prepared by Rockwell Medical. If it becomes 
necessary to issue a protocol amendment during the course of the study, Rockwell 
Medical (or designee) will notify the investigators and collect a documented 
Investigator Agreement to the amendment. 
All protocol amendments must be submitted to the IRB/EC for review and approval 
must be obtained prior to implementation.  However, immediate implementation of a 
protocol amendment may be necessary if the nature of the amendment concerns the 
safety of patients and is required to be implemented on an urgent basis to protect 
the safety of patients.  Any such immediate implementation of protocol amendments 
must be agreed to in advance and in writing by Rockwell.  Hard copy documentation 
of IRB/EC approval must be forwarded to Rockwell. 
If an amendment significantly alters the study design, increases potential risk to the 
patient or otherwise affects statements in the informed consent form (ICF), the ICF 
will be revised accordingly and submitted to the IRB/EC for review and approval. 
The approved ICF will be used to obtain informed consent from new patients prior to 
enrollment and must be used to re-obtain informed consent from patients already 
enrolled if they are potentially affected by the amendment and wish to continue 
participation. 
9.3.    Investigator’s Responsibilities 
 
9.3.1.        GCP Compliance 
 
The Investigator must undertake to perform the study in accordance with ICH GCP 
Guideline E6 and the applicable regulatory requirements. 
It is the investigator’s responsibility to ensure that adequate time and appropriate 
resources are available at the study site prior to commitment to participate in this 
study. The Investigator should also be able to estimate or demonstrate a potential 
for recruiting the required number of suitable patients within the agreed recruitment 
period. 
If the patient has a primary physician the Investigator should, with the patient’s 
consent, inform them of the patient’s participation in the trial. 
9.3.2.        Protocol Adherence and Investigator Agreement 
 
The Investigator must adhere to the protocol as detailed in this document. The 
Investigator will be responsible for enrolling only those patients who have met 
protocol eligibility criteria. The Investigators will be required to sign an Investigator 
Agreement to confirm acceptance and willingness to comply with the study protocol. 
It is the Investigator’s responsibility to communicate with their local IRB to ensure 
accurate and timely information is provided at all times during the study. In particular 
the appropriate approvals must be in place prior to recruitment, notification of any 


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SAEs during the study must take place and the IRB must be informed of study 
completion. 
9.3.3.        Documentation and Retention of Records 
 
9.3.3.1.     Case Report Forms 
 
Case report forms (CRFs) will be supplied by the sponsor or its designee and should 
be handled in accordance with instructions from Rockwell Medical. 
In accordance with the US 21 CFR 312.62, a CRF, whether paper or electronic, 
must be completed for each patient enrolled in the study.  All data collected for each 
study patient will be recorded on CRFs provided or approved by Rockwell Medical. 
CRFs need not be completed by the Investigator, but all entries in CRFs are the 
responsibility of the investigator and entry of CRF data must be made under the 
supervision of the Investigator.  The Investigator is responsible for ensuring the 
accuracy, completeness, legibility (if paper), and timeliness of all data reported in the 
CRFs and all required reports for each study patient.      The Investigator is also 
responsible  for  maintaining  any  source  documentation  related  to  the  study, 
including, but not limited to, any operative reports, laboratory results, radiographic 
films, ECG tracings, and computer discs, files or tapes. The Investigator must retain 
a copy of all CRFs. 
9.3.3.2.     Site Visits 
 
Study Initiation, Monitoring and Closeout Visits 
Representatives of Rockwell Medical will perform a number of on-site visits to the 
study center, from prior to initiation of the study at the site until after the study has 
been completed.  These visits will include but not be limited to review of the site for 
adequacy to conduct the trial, review of study data, CRFs, and supportive source 
documents, and drug accountability. 
Throughout the course of the study, Rockwell Medical representatives will also make 
frequent contacts with the investigator and designated site personnel.  As part of the 
data review it is expected that source documents (e.g., hospital records, office 
records) will be made available for review by Rockwell Medical.   The study 
documents may also be similarly evaluated by auditors representing Rockwell 
Medical.  For these purposes, the Investigator will make CRFs, source documents 
and study files available when requested. 
The study will be terminated and the study center will be closed when all completed 
original CRFs have been collected, all data discrepancies resolved, and drug 
accountability has been reconciled.  It will be the responsibility of the Investigator to 
notify the IRB/EC that the study has been completed. 
Rockwell Medical has the right to terminate the study for non-adherence to protocol, 
unavailability of the Investigator or his or her study staff for Rockwell Medical or its 
representatives, or for administrative reasons, at any time.  In that event, Rockwell 
Medical will notify the Investigator in writing that the study is to be discontinued.  The 


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Investigator  will  comply  with  Rockwell  Medical’s  written  instructions  for  study 
discontinuation, which will include the following: 
•  Date discontinuation will occur, 
•  Rationale for discontinuation, 
•  Instructions on how discontinuation is to be performed, 
•  Instructions for patients participating in the study, and 
•  Instructions for retention of study documents. 
In addition to monitoring by Rockwell Medical or its designees, the study may be 
audited by representatives of the U.S. Food and Drug Administration (FDA) or other 
applicable regulatory agencies, who will also be allowed access to study documents. 
The Investigator should immediately notify Rockwell Medical of any proposed or 
scheduled audits with any regulatory authorities. 
9.3.3.3.     Recording, Access and Retention of Source Data 
 
All records of this clinical study must be retained by the Investigator, including, but 
not limited to, the following: 
•  Protocol and all protocol amendments, 
•  All signed versions of the Statement of Investigator, Form FDA 1572, 
•  All drug accountability records, 
•  All IRB/EC approvals, correspondence and reports, 
•  Signed and dated informed consent forms for each patient, 
•  Completed CRFs for each patient, 
•  Copies of any other material distributed to patients, 
•  Any advertisements for this study, 
•  The Investigator’s final report to the IRB/EC, and 
•  Source documents pertaining to  the  study, including, but not limited to, any 
operative reports, laboratory results, radiographic films, tracings, and computer 
discs, files or tapes. 
The period of time these documents must be maintained is governed by US law and, 
when applicable, non-US regulations.   All records are to be retained by the 
Investigator for a minimum of two (2) years after the FDA has approved the new 
drug application, or after Rockwell Medical has notified the investigator in writing that 
all investigations of the drug have been discontinued.   However, because of 
international regulatory requirements, Rockwell Medical may request retention for a 
longer period of time.  Therefore, Rockwell Medical or its designee will inform the 
Investigator when these documents may be destroyed.  The Investigator must obtain 
written approval from Rockwell Medical prior to destruction of any records. 
The Investigator must advise Rockwell Medical in writing if the records are to be 
moved to a location other than the Investigator’s archives.  If the Investigator leaves 
the institution or study center, the records shall be transferred to an appropriate 


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designee, at the study center who assumes the responsibility for record retention. 
Notice of such transfer shall be documented in writing and provided to Rockwell 
Medical. 
In the event of accidental loss or destruction of any study records, the Investigator 
will immediately notify Rockwell Medical in writing.  Rockwell Medical or its designee 
must be notified in writing at least 30 days prior to the intended date of disposal of 
any study records related to this protocol. 
9.3.4.        Investigator’s Final Report 
 
Shortly  after  completion  of  the  Investigator’s  participation  in  the  study,  the 
Investigator will submit a written report to Rockwell Medical.  This report may be a 
copy of the Investigator’s end-of-study report to their IRB, which will include, but not 
be limited to, notification that the study has concluded, the number of patients 
enrolled/ treated, and the number of AEs and SAEs that occurred during the study. 
The report to the IRB will be consistent with the applicable IRB regulations and time 
frames. 
9.4.    Ethical Considerations 
 
This study will be conducted under a US Investigational New Drug (IND) Application. 
All applicable US regulations governing human subject protection must be followed. 
All ethical and regulatory requirements necessary to comply with the principles of 
GCP for the conduct and monitoring of clinical investigations must be followed. 
9.5.    Informed Consent 
 
A copy of the proposed ICF should be submitted to Rockwell Medical for review and 
comment prior to submission to the reviewing IRB.  The ICF must be approved by 
the IRB and contain all elements required by all applicable federal, state, local, and 
institutional regulations or requirements prior to consenting a patient.  Authorization 
to   use   or   disclose   Personal   Health   Information   (PHI)   in   accordance   with 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA) should be covered in the ICF or in a separate document to be signed by the 
patient. 
The Investigator will be responsible for obtaining written informed consent from the 
potential subjects prior to any study-specific screening and entry into the study.  The 
research study will be completely explained to each prospective study subject.  The 
Investigator or designee must explain that the subject is free to refuse to enter the 
study, and free to withdraw from it at any time for any reason. 
9.5.1.        Institutional Review Board or Independent Ethics Committee 
Approval 
 
In accordance with 21 CFR Parts 50 and 56, the Investigator agrees to provide the 
appropriate IRB with all appropriate material, including a copy of the protocol, ICF, 
and any proposed advertisement for the study prior to the start of the study. 
The proposed ICF and any proposed advertisement must also be agreed to by 
Rockwell  Medical.    The  site  may  not  begin  consenting,  screening  or  enrolling 


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patients until the Investigator has obtained IRB approval of the protocol and ICF and 
Rockwell Medical has received documentation of each. 
The Investigator will supply to Rockwell Medical a list of the names, professions, and 
affiliations of IRB members to demonstrate compliance with membership 
requirements.  If the Investigator or a sub-investigator is a routine voting member of 
the IRB, Rockwell Medical will be provided with a statement from the IRB that the 
Investigator/sub-investigator  did  not  and  will  not  vote  on  any  IRB  decisions 
pertaining to this clinical investigation. 
During the course of the study, the Investigator shall make timely and accurate 
reports to the IRB on the progress of the trial, at intervals not exceeding one year, as 
well as satisfying any other local IRB regulations regarding reporting. Furthermore, 
at the completion or early termination of the study, a final report should be made to 
the IRB by the Investigator within the applicable IRB time frames. 
Any significant changes or revisions in the study protocol or any changes that may 
alter patient risk must be approved by Rockwell Medical (and may require FDA/other 
regulatory agency review and/or approval) and must be approved in writing by the 
IRB prior to implementation.  The Investigator must also receive a written notice of 
approval from Rockwell Medical prior to initiating the revised changes to the study 
protocol.   A protocol change intended to eliminate an apparent immediate hazard 
may be implemented immediately, provided that Rockwell Medical is immediately 
notified and an amendment is subsequently provided by Rockwell Medical and 
approved by the IRB. 
It is the Investigator's obligation to maintain an IRB correspondence file, to provide 
copies of all documents to Rockwell Medical, and to make this available for review 
by  Rockwell  Medical  or  its  designated  representatives  as  part  of  the  study 
monitoring process. 
9.6.    Confidentiality 
 
All US-based investigational sites and laboratories or entities providing support for 
this study, must, where applicable, comply with HIPAA. An investigational site that is 
not a Covered Entity, as defined by HIPAA, must provide documentation of this fact 
to Rockwell Medical. 
 
10.     DISCLOSURE OF DATA AND PUBLICATION 
 
All information obtained as a result of this study or during the conduct of this study 
will be regarded as confidential.  All unpublished information relating to this drug or 
to  the  operations  of  Rockwell  Medical,  including  clinical  indications,  formula, 
methods of manufacture, and any other related scientific data provided to or 
developed by the Investigator, is confidential and shall remain the sole property of 
Rockwell Medical.  The Investigator agrees to use the information for the purpose of 
carrying out this study and for no other purpose, unless prior written permission from 
Rockwell Medical is obtained.  Rockwell Medical has full ownership of the CRFs and 
database resulting from this study. 


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The  Investigator agrees  that  results from  this  study may be  used  by Rockwell 
Medical for purposes of domestic and international new drug registration, for 
publication, and to inform medical and pharmaceutical professionals.  Regulatory 
authorities will be notified of the Investigator’s name, address, qualifications, and 
extent of involvement. 


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11. REFERENCES 
 
 
Reference List 
 
 
(1)  III. Clinical practice recommendations for anemia in chronic kidney disease in 
children. Am J Kidney Dis 2006;47:S86-108. 
 
(2)  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;41:354-361. 


 
 
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APPENDIX 1. TIME AND EVENTS SCHEDULE 
 
Table 3: Time and Events Schedule 
 
Assessments 
Screening 
Enrollment 
Triferic  PD 
Triferic 
6.6 mg Fe IV 
Follow-up* 
Visit # 
1 
2 
3/4 
3/4 
5 
Target study day 
-28 to -1 
-3 to -1 
1/3 
1/3 
5 to 8 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
X 
Demographics 
X 
Medical history 
X 
X 
Height and weighta 
X 
X 
X 
X 
Vital signsf 
X 
X 
X 
X 
Physical examination 
X 
X 
ECG 
X 
Serum pregnancy test 
(if applicable) 
X 
Hematologyb 
X 
X 
Chem-14, CRPb 
X 
X 
Serum iron profileb,c 
X 
X 
X 
X 
Hepcidin 
X 
X 
Enrollment in study 
X 
Triferic administration PDd 
X 
Triferic administration IVd 
X 
PK samplese (total serum iron profile) 
X 
X 
50 mL PD fluid for cell 
count/differential 
X 
X 
50 mL PD fluid for iron content 
X 
X 
6 15-mL PD fluid for future analysis 
X 
X 
Weight of PD fluid 
X 
X 
Discharge from study 
X 
Adverse events 
X 
X 
X 
Medications 
X 
X 
X 
X 
X 
* A visit window of ±5 days will be permitted for the follow-up visit. 
a Height is measured at Visit 1 (Screening) only. 
b Hematology, Chem-14, CRP (Visit 1/Screening only), the serum iron profile (total serum iron, ferritin, TIBC, and TSAT), and pregnancy test samples will be 
analyzed by a central clinical laboratory. 
c If an SAE occurs during or within 30 min after any Triferic infusion, a serum iron profile will be obtained as soon as the SAE is recognized. 
d See Appendix 4 for instructions on the preparation and dosing of Triferic. 
e See Appendix 2 for the schedule for obtaining PK, serum iron profile, and hepcidin samples. See Appendix 3 for instructions on the handling of the PK, serum 
iron profile, and hepcidin samples. 
fVitals include blood pressure and pulse.  Temperature is to be recorded at Screening and Follow-up only. 
 


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APPENDIX 2. PHARMACOKINETIC, SERUM IRON PROFILE, AND HEPCIDIN 
SAMPLE COLLECTION SCHEDULE 
 
At each time point marked with an “X” in Table 3 below, collect one (1) 7.5 mL 
sample using serum separator tubes; to be used for the PK, serum iron profile, and 
hepcidin analyses (see Appendix 3) 
 
Table 4: PK, Serum Iron Profile, and Hepcidin Sample Collection Schedule 
 
Nominal Time 
Hrs. 
Triferic IP 
Triferic 6.6 mg Fe 
IV/4 Hrs. 
0 
Xa,b,c 
Xa,b,c 
0.5 
Xa,b 
Xa,b 
1 
Xa,b 
Xa,b 
1.5 
Xa,b 
Xa,b 
2 
Xa,b 
Xa,b 
3 
Xa,b 
Xa,b 
4 
Xa,b 
Xa,b 
6 
Xa,b 
Xa,b 
8 
Xa,b 
Xa,b 
10 
Xa,b 
Xa,b 
12 
Xa,b 
Xa,b 
 
a PK sample 
b Serum iron profile sample 
c Hepcidin sample 
See Appendix 3 for PK, serum iron profile, and hepcidin sample processing, storage, and shipping instructions. 


 
 
Rockwell Medical, Inc. 
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21 November 2016 
 
APPENDIX 3. PHARMACOKINETIC, SERUM IRON PROFILE, AND HEPCIDIN 
SAMPLE HANDLING 
 
Supplies for the Study 
 
7.5-mL clot activator serum separator vacutainer tubes 
 
1.0 -2.0-mL screw top plastic sample transport tubes 
 
PK, Serum iron Profile, and Hepcidin Sample Collection and Processing 
Instructions 
 
a)  Collect the 1 X 7.5 mL tubes and allow toclot for at least 10 minutes at room 
temperature. 
b)  Spin the tubes at 4,000 X g for 15 minutes 
c)  Separate the serum from the 7.5 mL tube and transfer 1000 µL aliquots into 2 
labeled screw top plastic sample transport tubes (aliquots #1 and #2). 
a. 
For the t = 0 (Baseline) sample only, transfer an additional 1000 µL 
aliquot into a labeled screw top plastic sample transport tube 
(Aliquot #3) for the hepcidin analysis, and store Aliquot #3 at -70 to 
-80°C until shipment. For all other time points, skip this step and 
proceed with step (d) below. 
 d)  Transfer any remaining serum into another transport tube. Keep tubes on ice 
until they are placed in the freezer. Store all aliquots frozen at -20°C until they 
are shipped (with the exception of the hepcidin aliquot, which should be stored at 
-70 to -80°C until shipment). 
e)  On completion of sample collections, ship aliquot #1 to the central bioanalytical 
lab frozen on dry ice for assessment of the total serum iron PK profile. 
f) On completion of sample collections, ship aliquot #2 to the central clinical lab for 
analysis of the serum iron profile (total serum iron, ferritin, TIBC and TSAT). 
g)  On completion of sample collections, ship aliquot #3 to hepcidinanalysis.com 
frozen on dry ice for analysis of the baseline hepcidin. 
h)  Store any remaining aliquots frozen until completion of the study or until directed 
by the Sponsor or designee to ship to the laboratories or destroy. 
 
 
PK Sample Shipping Instructions 
 
Included in site instructions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 4. TRIFERIC DOSING SOLUTION PREPARATION 
 
Triferic dosing solutions may be prepared up to 24 hrs prior to planned infusion start times. 
All pre-prepared solutions should be stored at controlled room temperature and protected 
from light until use. 
PD fluids containing Dextrose or Icodextrin may be used for this study.  For dextrose 
containing PD fluid any dextrose concentration is permissible according to the patient’s 
usual PD prescription. 
 
Triferic PD Dosing Solution Preparation for Cohorts 1 - 3 
• For each patient, prepare the Triferic PD dosing solution by adding the appropriate 
amount of Triferic solution to each 2L bag of PD fluid. 
•   Draw up the required amount under aseptic conditions and add to 2 L PD solution using 
a syringe and aseptic technique.  Mix the bag to disperse. 
•   Retain one (1) 50-mL aliquot of each PD fluid (containing Triferic) in polypropylene 
screw-cap tubes and store at approximately 4°C for dosing solution analysis. 
•   Weigh each PD bag after removal of the dosing solution aliquot to the nearest gram 
(gm.) 
•   Keep all Triferic solutions protected from light until use. 
 
 
 
Table 5: Preparation of Triferic PD Dosing Solution 
 
Dose 
Volume Triferic* 
(5.44 mg/mL) 
Final Concentration 
Mg Fe/L 
10 mg Fe/2L 
1.85 mL 
5 mg/L 
25 mg Fe/2L 
4.60 mL 
12.5 mg/L 
40 mg Fe/2L 
7.35 mL 
20 mg/L 
*use the COA for Triferic batch for exact iron concentration to determine the volume 
required. 
 
Triferic 6.6 mg IV Dosing Solution Preparation for IV Infusion 
• Withdraw 1.52 mL Triferic solution under aseptic conditions 
• Add to 250 mL D5/W and mix 
• Administer via peripheral IV at 50 mL/hr via calibrated pump for 4 hours 
• Keep all Triferic solutions protected from light 

SAP_001.pdf: 
Rockwell Medical 
Pharmacokinetic Analysis Plan 
RMFPC-17 
 
 
 
Pharmacokinetic Analysis Plan 
June 26, 2017 
Study RMFPC-17 
 
 
 
 
 
 
 
Title: 
Single Ascending Dose Study of Intraperitoneal Triferic 
(Ferric Pyrophosphate Citrate) in Patients on Chronic 
Peritoneal Dialysis 
Sponsor: 
Rockwell Medical 
30142 S. Wixom Rd 
Wixom, MI 48393 
Prepared by: 
Scott Brantley, PhD 
Associate Director, Pharmacokinetics 
Nuventra, Inc. 
2525 Meridian Parkway, Suite 280 
Durham, NC  27713 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
Page 1 of 10 


Rockwell Medical 
Pharmacokinetic 
 Plan 
RMFPC-17 
 
 
DOCUMENT APPROVAL  
 
 
 
 
 
Single 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Author Approval: 
 
 
 
 
 
 
 
 
 
Management 
(Ferric Pyrophosphate 
 in 
 
 
 
 
 
 
 
 
 
Date 
Date 
Date 
 
 
 
 
 
Page 2 of10 


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Rockwell  Medical  
Pharmacokinetic Analysis  Plan 
RMFPC-17 
 
 
DOCUMENT APPROVAL PAGE 
 
Pharmacokinetic Analysis Plan 
 
 
Single  Ascending Dose Study of Intraperitoneal Triferic (Ferric  Pyrophosphate Citrate) in 
Patients on Chronic  Peritoneal  Dialysis 
 
Sponsor Approval: 
 
 
 
 
 
 
Raymond  D. Pratt, MD, FACP 
Chief  Medical  Officer 
Rockwell Medical 
 
Date 
 
 
 
Author Approval: 
 
 
 
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Date 
 
 
 
 
Management  Approval: 
 
 
 
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onclinical and Clinical  Pharmacology  
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
Page 2 of 10 


Rockwell Medical 
Pharmacokinetic Analysis Plan 
RMFPC-17 
Confidential 
Page 3 of 10 
 
 
 
 
 
1.  Introduction 
 
This Pharmacokinetic Analysis Plan describes the analysis and reporting of the pharmacokinetic 
(PK) results for Study RMFPC-17.  This is a Phase 1, open-label, single ascending dose study to 
assess the safety and pharmacokinetics of Triferic administered via peritoneal dialysate (PD) to 
iron-replete adult end-stage renal disease patients on maintenance peritoneal dialysis (CKD- 
5PD).  Approximately 24 patients will be studied. 
 
 
2.  Objectives 
 
The objectives of this study relevant to the pharmacokinetic analysis plan are as follows: 
 
• Primary 
 
o To determine the pharmacokinetic profile, Cmax and AUC0-t, of Triferic iron 
administered intraperitoneally (IP). 
 
• Secondary 
 
o To determine the dose proportionality of Triferic iron administered via PD. 
 
o Estimate absolute bioavailability of iron via PD 
 
▪ By proportionality of IP (Cmax and AUC0-t) to intravenous (IV) (Cmax 
and AUC0-t). 
 
▪ By quantitating iron remaining in the PD solution compared to that 
infused corrected. 


Rockwell Medical 
Pharmacokinetic Analysis Plan 
RMFPC-17 
Confidential 
Page 4 of 10 
 
 
 
 
3.  Endpoints 
 
• Primary 
 
o Assess the mean absolute Cmax, AUC0-t, AUC0-end, and AUCinf of total serum 
iron, as data permits and as appropriate.  Additional parameters to be 
determined may include Tmax, CL, λz, and t½. 
 
• Secondary 
 
o Dose proportionality of Triferic iron will be determined using the Cmax and 
AUC parameters for serum iron. 
 
o The mass balance of iron absorbed from the PD fluid will be determined by 
two methods: 
 
▪ The absolute bioavailability of iron from Triferic administered via PD. 
 
▪ The difference in mass of Triferic iron in the PD fluid infused and 
removed at the end of the dwell will be measured to determine the 
mass balance. 
 
 
4.  Study Design 
 
This is a Phase 1, open-label, single ascending dose study to assess the safety and 
pharmacokinetics of Triferic administered via PD to iron-replete adult end-stage renal disease 
patients on maintenance peritoneal dialysis (CKD-5PD).  Approximately 24 patients will be 
studied. 
 
Patients will be screened within 28 days of Baseline. All patients must provide informed consent 
to enter Screening.  Patients will be advised to discontinue all iron supplements including 
multivitamins with iron.  The study will be conducted as an outpatient study.  Patients will attend 
the clinic for two (2) 12 hour treatment periods with a 48 hour interval between test article 
administrations.  Patients will be randomly assigned to receive either a single dose of Triferic in 
the PD solution or a single IV dose of Triferic 6.6 mg over a 4 hour period. 
 
Patients begin a long dwell time (12 hours) from approximately 08:00 to 20:00 hours on each 
day of dosing.  After completion of PK measurements patient resume their usual dialysis 
prescription until the next scheduled administration of test article. 
 
A follow-up assessment will be conducted within 1 week after the last administration of test 
article to assess safety parameters. 


Rockwell Medical 
Pharmacokinetic Analysis Plan 
RMFPC-17 
Confidential 
Page 5 of 10 
 
 
 
 
Figure 1 
Study Design Schematic 
 
 
 
 
5.  Pharmacokinetic Sample Collection 
 
Blood samples will be collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hr post dose 
following drug administration on Day 1 and Day 3 (Figure 1). 
 
 
6.  Bioanalytical Methods 
 
6.1. 
Clinical Laboratory 
 
Total serum iron, TSAT, total iron binding capacity (TIBC), and ferritin values will be 
determined by the clinical laboratory using established methods on the Roche COBAS platform 
using a Gen2 Fe assay.  Under acidic conditions, iron is liberated from transferrin.  Lipemic 
samples are clarified by the detergent.  Ascorbate reduces the released Fe3+ ions to Fe2+ ions 
which then react with FerroZine to form a colored complex.  The color intensity is directly 
proportional to the iron concentration and can be measured photometrically.  The quantification 
range for the assay is 5 – 1000 µg/dL. 
 
6.2. 
Bioanalytical Laboratory 
 
6.2.1. 
Total Serum Iron 
Total serum iron will be measured using ICP-MS at QPS laboratories (Gronigan, The 
Netherlands) using a validated serum assay. 
 
6.2.2. 
Serum Hepcidin 
Hepcidin samples will be analyzed by Mass Spectroscopy at the laboratory of Dorine Swinkels 
(www.hepcidinanalysis.com). 


Rockwell Medical 
Pharmacokinetic Analysis Plan 
RMFPC-17 
Confidential 
Page 6 of 10 
 
 
 
 
7.  Pharmacokinetic Population 
 
The PK Population will include all enrolled subjects who receive at least 1 dose of study drug 
and have sufficient PK samples (a sample at the end of administration and at least 3 samples 
during the elimination phase) to include in the PK assessments. 
 
 
8.  Pharmacokinetic Analyses 
 
8.1. 
Noncompartmental Pharmacokinetic Analysis 
 
All pharmacokinetic analysis and reporting will be performed according to applicable Nuventra 
SOPs and protocol specifications.  Programming of tables, figures, and listings will be performed 
by Nuventra using R version 3.3.1 or later (R Foundation for Statistical Computing, Vienna, 
Austria).  Pharmacokinetic parameters will be calculated by Nuventra using Phoenix® 
WinNonlin® 6.3 or later (Certara USA, Inc. (Princeton, NJ)) using actual sampling times. 
 
The measured serum iron profile parameters and associated endpoints for PK analyses (“serum 
iron endpoints”) comprise the following: 
 
• Total serum iron (sFe) 
 
Additional serum iron endpoints will be summarized by treatment: 
 
• Transferrin saturation (TSAT) 
 
• Total iron-binding capacity (TIBC) 
 
• Serum ferritin 
 
• Serum hepcidin 
 
Listings of serum iron endpoints by subject and treatment with nominal blood sample collection 
times, as well as derived actual sampling times will be provided.  Serum iron endpoint data will 
be tabulated and summarized using descriptive statistics (including N, mean, SD, CV%, median, 
minimum, maximum, and geometric mean) for each treatment. 
 
Figures of the time course of individual serum iron endpoints will be presented on linear and 
semi-logarithmic scales, as appropriate.  Figures illustrating the time course of mean/median 
serum iron endpoints for each treatment will be overlaid and presented for relevant comparisons 
on linear and semi-logarithmic scales, as appropriate.  In addition, overlay plots of individual 
serum iron endpoint profiles will be generated for all subjects by treatment. 
 
All serum iron endpoints and PK parameters for total serum iron will be summarized, as 
described above, using actual concentrations. 


Rockwell Medical 
Pharmacokinetic Analysis Plan 
RMFPC-17 
Confidential 
Page 7 of 10 
 
 
 
 
The following pharmacokinetic parameters will be estimated for total serum iron, as appropriate 
and as data permit: 
 
Cmax 
The maximum drug concentration in serum determined directly from individual 
concentration-time data 
Tmax 
The observed time to reach maximum concentration 
Tlast 
The observed time of the last quantified concentration 
AUClast 
The area under the serum concentration-time curve from time-zero to the time of the 
last quantified concentration; calculated using the linear-up/log-down trapezoidal 
rule 
AUC(0-end) 
The area under the serum concentration time curve from time zero to the end of the 
study drug infusion, calculated using the linear-up/log-down trapezoidal rule 
AUCinf 
Area under the concentration-time curve from time-zero extrapolated to infinity, 
calculated as: 
AUC inf = AUClast + Clast 
λz 
where Clast is the last quantified concentration in the terminal elimination phase. 
λz 
The terminal phase rate constant; estimated by linear regression through the terminal 
phase of the log concentration-time profile 
t½ 
The terminal phase half-life calculated as: 
t½ = ln(2) 
λz 
CL 
Clearance after intravenous administration, calculated as: 
CL =   Dose 
AUCinf 
CL/F 
Clearance after extravascular administration, calculated as: 
CL =   Dose 
AUCinf 
F 
Bioavailability, calculated as: 
F = AUCinf  IP * DoseIV 
AUCinf  IV 
DoseIP 
Note that the abbreviations and definitions listed above may differ slightly from the protocol in the phrasing; however, the 
equations and methods used to generate these parameters do not differ from the protocol. 
 
 
No value for λz, AUCinf, t½, or CL will be reported for cases that do not exhibit a terminal log 
linear phase in the concentration versus time profile.  PK parameters will be calculated for 
subjects with detectable concentrations for at least 4 time points.  Additional PK parameters may 
be calculated, as necessary, to fully characterize the PK profiles of total iron. 
 
Individual PK parameters will be listed by subject and treatment.  Summary statistics of PK 
parameters will be tabulated by treatment.  The following summary statistics will be presented 
for PK parameters:  arithmetic mean, CV%, SD of the arithmetic mean, median, minimum, 


Rockwell Medical 
Pharmacokinetic Analysis Plan 
RMFPC-17 
Confidential 
Page 8 of 10 
 
 
 
 
maximum, N, geometric mean, and CV% of the geometric mean.  Tmax and Tlast will be presented 
as median, minimum, and maximum. 
 
8.2. 
Quantitation of Iron Administered 
 
An estimate of the amount of iron transferred from the PD solution to the circulation will be 
obtained in two different analyses: 
 
• The Cmax and AUC0-t for sFe at each dose level compared to the Cmax and AUC0-t for the 
Triferic IV administration will be used to calculate the relative bioavailability of Triferic 
iron during the PD period. 
• A sample of the initial dosing solution and the final PD drainage will be analyzed for iron 
content using ICP-MS (conducted by the bioanalytical lab).  The difference between the 
dosing solution and the final drainage (corrected for volume effects) is a direct measure 
of Triferic iron absorbed during the PD dwell. 
 
 
9.  Imputation of BLQ values 
 
For calculation of mean concentrations and generation of mean concentration time profiles, all 
below the limit of quantification (BLQ) values will be set to zero except when an individual 
BLQ falls between two quantifiable values, in which case it will be treated as missing data. 
 
For the pharmacokinetic analysis and individual concentration vs time plots, a concentration that 
is BLQ is assigned a value of zero if it occurs in a profile before the first measurable 
concentration.  If a BLQ value occurs after a measurable concentration in a profile and is 
followed by a value above the lower limit of quantification, then the BLQ is treated as missing 
data.  If a BLQ value occurs at the end of the collection interval (after the last quantifiable 
concentration) it is treated as missing data.  If two BLQ values occur in succession after Cmax, the 
profile is deemed to have terminated at the first BLQ value and any subsequent concentrations 
are omitted from pharmacokinetic calculations. 
 
In circumstances where alternative approaches to handling BLQ data are necessary, the relevant 
modifications will be appropriately documented in the final PK Report. 
 
 
10.Significant Figures 
 
Significant figures for concentrations and PK parameters, with the exception of Tmax, will be 
generally reported as 3 significant figures.  All associated summary statistics for these 
parameters will also be reported to 3 significant figures with the exception of N which will be 
reported as an integer.  Tmax will be reported to 2 decimal places. 


Rockwell Medical 
Pharmacokinetic Analysis Plan 
RMFPC-17 
Confidential 
Page 9 of 10 
 
 
 
 
 
11.  Tables, Listings, and Figures 
 
Lists of Tables, Figures, Listings, and Appendices to be generated with the analyses are provided 
below.  Additional Listings, Tables, and Figures may be generated, as necessary, to fully 
characterize and explore the available data. 
 
Note: Text in parenthesis is for clarification purposes, and may not appear in the TLF caption 
 
11.1. List of Tables 
 
• Subject Demographics and Baseline Characteristics 
 
• Subject Accountability Table 
 
• Absolute Total Iron Data and Summary Statistics by Sample Collection Time, Cohort, and 
Route of Administration 
 
• Absolute Total Iron Data and Summary Statistics by Sample Collection Time, Cohort, and 
Route of Administration (Clinical Laboratory Data) 
 
• Transferrin Saturation Data and Summary Statistics by Sample Collection Time, Cohort, and 
Route of Administration 
 
• Total Iron Binding Capacity Data and Summary Statistics by Sample Collection Time, 
Cohort, and Route of Administration 
 
• Serum Ferritin Data and Summary Statistics by Sample Collection Time, Cohort, and Route 
of Administration 
 
• Serum Hepcidin Data and Summary Statistics by Visit and Cohort 
 
• Noncompartmental Pharmacokinetic Parameters for Total Iron by Cohort and Route of 
Administration 
 
• Noncompartmental Pharmacokinetic Parameters for Total Iron by Cohort and Route of 
Administration (Clinical Laboratory Data) 


Rockwell Medical 
Pharmacokinetic Analysis Plan 
RMFPC-17 
Confidential 
Page 10 of 10 
 
 
 
 
11.2. List of Figures 
 
• Mean Total Iron vs Time by Cohort with Route of Administration Overlaid 
 
• Mean Total Iron vs Time by Route of Administration with Cohorts Overlaid 
 
• Overlay Plot of Individual Subject Total Iron vs Time with Data Separated by Cohort and 
Route of Administration 
 
• Mean Total Iron vs Time by Cohort with Route of Administration Overlaid (Clinical 
Laboratory Data) 
 
• Mean Total Iron vs Time by Route of Administration with Cohorts Overlaid (Clinical 
Laboratory Data) 
 
• Overlay Plot of Individual Subject Total Iron vs Time with Data Separated by Cohort and 
Route of Administration (Clinical Laboratory Data) 
 
11.3. Listings and Appendices 
 
• Listing of Total Iron Data for Noncompartmental Analysis 
 
• Listing of Total Iron Data for Noncompartmental Analysis (Clinical Laboratory Data) 
 
• Listing of Transferrin Saturation Data 
 
• Listing of Total Iron-binding Capacity Data 
 
• Listing of Ferritin Data 
 
• Listing of Hepcidin Data 
 
• Individual Subject Total Serum Iron vs Time Plots with Route of Administration Overlaid 
 
• Individual Subject Total Serum Iron vs Time Plots with Route of Administration Overlaid 
(Clinical Laboratory Data) 
 
• Individual λz Plots for Total Iron Noncompartmental Analysis