Clinical trial NCT04042324
Conditions: End Stage Renal Disease
Sponsor: Rockwell Medical Technologies, Inc.
Start date: 2019-09-30; Completion date: 2020-01-16
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will investigate the effect of co-administration of Triferic and heparin on the ability to maintain circuit anti-coagulation and iron delivery when compared to control conditions when each treatment is administered via separate routes.

Detailed description:

Arms: arm 1: Patients will receive Triferic 6.75 mg IV over 3 hours into the post-dialyzer blood line (or drip chamber) administered by an infusion pump. Anti-coagulation will be provided by a bolus of heparin administered into the venous return line immediately prior to the initiation of hemodialysis followed by a continuous infusion of heparin using the on-machine infusion pump. The infusion of heparin to be stopped at hour 3 of hemodialysis. arm 2: Patients will receive Triferic 6.75 mg IV plus the appropriate volume of unfractionated heparin for continuous infusion over 3 hours into the pre-dialyzer "heparin line". This mixture will be administered by the on-machine syringe infusion pump for continuous infusion. Anti-coagulation will be provided by a bolus of heparin administered into the venous return line immediately prior to the initiation of hemodialysis followed by a continuous infusion of Triferic + heparin. The infusion of Triferic + heparin will be stopped at hour 3 of hemodialysis. arm 3: Patients will receive no Triferic. Anti-coagulation will be provided by a bolus of heparin administered into the venous return line immediately prior to the initiation of hemodialysis followed by a continuous infusion of heparin via the on-machine syringe pump. The infusion of heparin to be stopped at hour 3 of hemodialysis
Interventions: intervention 1: Triferic intervention 2: Heparin
Intervention descriptions: intervention 1: Triferic (ferric pyrophosphate citrate, FPC), an iron-replacement product, is an iron complex in which iron(III) is bound to pyrophosphate and citrate. intervention 2: Unfractionated heparin (UFH): a common anticoagulant used during hemodialysis treatments.

Protocol documents:
Prot_SAP_000.pdf: 
RMFPC-24 
 
Protocol V1.1 
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12 July 2019 
CONFIDENTIAL 
 
Page 1 of 47 
Clinical Trial Protocol 
A RANDOMIZED 3 PERIOD CROSSOVER STUDY TO INVESTIGATE 
THE EFFECT OF TRIFERIC PLUS HEPARIN INFUSION COMPARED 
TO HEPARIN ALONE ON COAGULATION PARAMETERS IN 
HEMODIALYSIS PATIENTS.  
Protocol Identifying Number: RMFPC-24 
Principal Investigator:  Thomas C Marbury, MD 
Orlando Clinical Research Center 
5055 S. Orange Ave. 
Orlando FL 32809, USA 
Sponsor:  
Rockwell Medical Inc. 
30142 S Wixom Rd  
Wixom MI 48393, USA
Funded by:  
Rockwell Medical Inc. 
USA IND #
051,290
USA NDA # 
206,317 
208,551 
212,860
 
 
This document and the information it contains is the property of Rockwell Medical, Inc. 
and is provided for the sole and exclusive use of Investigators of this clinical investigation.  
The information in this document is privileged and confidential, and may not be disclosed 
unless such disclosure is required by Federal or applicable State Law or Regulations (or 
other applicable law) or unless there is prior written consent from Rockwell Medical, Inc.  
Patient to the foregoing, this information may be disclosed only to those persons involved 
in the clinical investigation who have a need to know, and who share the obligation not to 
further disseminate this information. 


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PROTOCOL APPROVAL PAGE 
 
Protocol Title: 
A Randomized 3 period crossover study to investigate the 
effect of Triferic plus heparin infusion compared to heparin 
alone on coagulation parameters in hemodialysis patients.
 
Protocol 
Number:
 
RMFPC-24 
 
Version: 
 
1.1 
 
Date of Issue: 
 
July 12 2019 
Sponsor Name 
and Address: 
 
Rockwell Medical, Inc. 
30142 S. Wixom Rd 
Wixom, MI 48393 USA 
 
 
 
 
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: 
A Randomized 3 period crossover study to investigate the 
effect of Triferic plus heparin infusion compared to heparin 
alone on coagulation parameters in hemodialysis patients.
Protocol 
Number: 
RMFPC-24 
Version: 1.1 
 
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 EMA guidelines, China Food and Drug 
Administration (CFDA) 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 Patients.  
 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 Patients, 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 EMA, CFDA, local governing regulatory bodies, and IRB/EC 
inspectors. 
 
 
 
Investigator's Signature 
 
Date 
Thomas C Marbury, MD 
 
 
Print Name 
 
 
 


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Table of Contents 
PROTOCOL APPROVAL PAGE .................................................................................................................. 2 
INVESTIGATOR PROTOCOL AGREEMENT .............................................................................................. 3 
LIST OF ABBREVIATIONS........................................................................................................................... 7 
STATEMENT OF COMPLIANCE ................................................................................................................. 8 
PROTOCOL SUMMARY ............................................................................................................................... 9 
SCHEMATIC OF STUDY DESIGN ............................................................................................................. 12 
1 
KEY ROLES .................................................................................................................................... 12 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE.................... 12 
2.1 
Background on Iron Deficiency in Hemodialysis and Treatment with IV Iron ...... 12 
2.2 
Rationale .............................................................................................................. 13 
2.3 
Potential Risks and Benefits ................................................................................ 14 
2.3.1 
Known Potential Risks ......................................................................................... 14 
2.3.2 
Known Potential Benefits ..................................................................................... 15 
3 
OBJECTIVES AND PURPOSE ....................................................................................................... 15 
3.1 
Primary objective.................................................................................................. 15 
3.2 
Secondary objectives ........................................................................................... 15 
4 
STUDY DESIGN AND ENDPOINTS ............................................................................................... 15 
4.1 
Description of the Study Design ........................................................................... 15 
4.2.1 
Primary Endpoint.................................................................................................. 16 
4.2.2 
Secondary Endpoints ........................................................................................... 16 
4.2.3 
SAfety Endpoints.................................................................................................. 17 
5 
STUDY ENROLLMENT AND WITHDRAWAL................................................................................. 17 
5.1 
Inclusion Criteria .................................................................................................. 17 
5.2 
Exclusion Criteria ................................................................................................. 17 
5.3 
Strategies for Recruitment and Retention ............................................................ 18 
5.4 
Participant Withdrawal or termination .................................................................. 18 
5.4.1 
Reasons for Study drug witholding, Withdrawal or Termination .......................... 18 
5.4.2 
Handling of Participant Withdrawals or termination ............................................. 18 
5.5 
Premature Termination or Suspension of Study .................................................. 19 
6 
STUDY AGENT ............................................................................................................................... 19 
6.1 
Study Agent(s) and Control Description .............................................................. 19 
6.1.1 
Acquisition ............................................................................................................ 19 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ........................................... 19 
6.1.3 
Product Storage and Stability .............................................................................. 19 
6.1.4 
TRIFERIC Preparation ......................................................................................... 19 
6.1.5 
Dosing and Administration ................................................................................... 20 
6.1.6 
Route of Administration ........................................................................................ 20 
6.1.7 
Starting Dose and Dose Escalation Schedule ..................................................... 20 
6.1.8 
Dose Adjustments/Modifications/Delays .............................................................. 20 
6.1.9 
Duration of Therapy ............................................................................................. 20 
6.1.10 
Tracking of Dose .................................................................................................. 20 
6.2 
Study agent Accountability Procedures ............................................................... 20 
6.2.1 
Study drug dosing ................................................................................................ 21 
7 
STUDY PROCEDURES AND SCHEDULE ..................................................................................... 21 
7.1 
Study Procedures/Evaluations ............................................................................. 21 
7.1.1 
Study specific procedures .................................................................................... 21 
7.1.2 
Standard of care study procedures ...................................................................... 21 


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7.2 
Laboratory Procedures/Evaluations ..................................................................... 21 
7.2.1 
Clinical Laboratory Evaluations ............................................................................ 21 
7.2.2 
Other Assays or Procedures ................................................................................ 21 
7.2.3 
Specimen Preparation, Handling, and Storage ................................................... 21 
7.2.4 
Specimen Shipment ............................................................................................. 21 
7.3 
Study Schedule .................................................................................................... 22 
7.3.1 
Screening ............................................................................................................. 22 
7.3.2 
Enrollment and Treatment Periods ...................................................................... 22 
7.3.3 
Follow-up Visit ...................................................................................................... 23 
7.3.4 
Final Study Visit or EArly TErmination Visit ......................................................... 23 
7.3.7 
Schedule of Events Table .................................................................................... 24 
7.4 
Justification for Sensitive Procedures .................................................................. 25 
7.5 
Concomitant Medications, Treatments, and Procedures ..................................... 25 
7.5.1 
Precautionary Medications, Treatments, and Procedures ................................... 25 
7.6 
Prohibited or restricted Medications, Treatments, and Procedures ..................... 25 
7.7 
Prophylactic Medications, Treatments, and Procedures ..................................... 25 
7.8 
Rescue Medications, Treatments, and Procedures ............................................. 25 
7.9 
Participant Access to Study Agent At Study Closure ........................................... 25 
8 
ASSESSMENT OF SAFETY ........................................................................................................... 25 
8.1 
Specification of Safety Parameters ...................................................................... 25 
8.1.1 
Definition of Adverse Events (AE)........................................................................ 25 
8.1.2 
Definition of Serious Adverse Events (SAE) ........................................................ 25 
8.1.3 
Definition of Unanticipated Problems (UP) .......................................................... 26 
8.2 
Classification of an Adverse Event ...................................................................... 26 
8.2.1 
Severity of Event .................................................................................................. 27 
8.2.2 
Relationship to Study Agent ................................................................................. 27 
8.2.3 
Expectedness....................................................................................................... 28 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up .................... 28 
8.4 
Reporting Procedures .......................................................................................... 28 
8.4.1 
Adverse Event Reporting ..................................................................................... 28 
8.4.2 
Follow-Up of Adverse events ............................................................................... 29 
8.4.3 
Post study Adverse events .................................................................................. 29 
8.4.4 
Serious Adverse Event Reporting ........................................................................ 29 
8.4.5 
Unanticipated Problem Reporting ........................................................................ 31 
8.4.6 
Events of Special Interest .................................................................................... 31 
8.4.7 
Reporting of Pregnancy ....................................................................................... 31 
8.5 
Clinical laboratory abnormalities .......................................................................... 31 
8.6 
Safety Oversight................................................................................................... 32 
9 
CLINICAL MONITORING ................................................................................................................ 32 
10 
STATISTICAL CONSIDERATIONS ................................................................................................ 33 
10.1 
Statistical and Analytical Plans ............................................................................ 33 
10.2 
Statistical Hypotheses ............................................................................................................ 33 
10.3 
Analysis Datasets .................................................................................................................. 33 
10.4 
Description of Statistical Methods .......................................................................................... 33 
10.4.1 
General Approach ................................................................................................ 33 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) ....................................................... 34 
10.4.3 
Analysis of the Secondary Endpoint(s) ................................................................ 35 
10.4.3.4 
Safety Analyses ................................................................................................... 35 
 
10.4.3.5 Pharmacokinetic analyses ..................................................................... 36 


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10.4.4 
Adherence and Retention Analyses..................................................................... 36 
10.4.5 
Planned Interim Analyses .................................................................................... 36 
10.4.7 
 Multiple Comparison/Multiplicity .......................................................................... 36 
10.4.8 
Tabulation of Individual Response Data .............................................................. 36 
10.4.9 
Exploratory Analyses ........................................................................................... 36 
10.5 
Sample Size ......................................................................................................... 36 
10.6 
Measures to Minimize Bias .................................................................................. 36 
10.6.1 
Enrollment/ Randomization/ Masking Procedures ............................................... 36 
10.6.2 
Evaluation of Success of Blinding ........................................................................ 37 
10.6.3 
Breaking the Study Blind/Participant Code .......................................................... 37 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ............................... 37 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ...................................................................... 37 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ........................................................................... 38 
13.1 
Ethical Standard ..................................................................................................................... 38 
13.2 
Institutional Review Board ..................................................................................................... 38 
13.3 
Informed Consent Process .................................................................................. 39 
13.3.1 
Consent/assent and Other Informational Documents Provided to Participants .. 39 
13.3.2 
Consent Procedures and Documentation ............................................................ 39 
13.4 
Participant and data Confidentiality ..................................................................... 39 
13.4.1 
Research Use of Stored Human Samples,Specimens or Data ........................... 39 
13.5 
Future Use of Stored Specimens ......................................................................... 39 
14 
DATA HANDLING AND RECORD KEEPING ................................................................................. 39 
14.1 
Data Collection and Management Responsibilities ............................................. 40 
14.2 
Study Records Retention ..................................................................................... 41 
14.2.1 
Investigators final Report ..................................................................................... 41 
14.3 
Protocol Deviations .............................................................................................. 41 
14.4 
Publication and Data Sharing Policy .................................................................... 41 
15 
STUDY ADMINISTRATION ............................................................................................................. 42 
15.1 
Study Leadership ................................................................................................. 42 
16 
CONFLICT OF INTEREST POLICY ................................................................................................ 42 
17  
LITERATURE REFERENCES ......................................................................................................... 42 
Reference List 
42 
Appendix 1: Protocol Revisions ........................................................................................................... 45 
Appendix 2: Schedule of PK Assessments.......................................................................................... 45 
Appendix 3: Visual Scale for Dialyzer Circuit Clotting ......................................................................... 46 
Appendix 4:  Instructions for administration of heparin + Triferic and Triferic alone. .......................... 46 
 


 
Page 7 of 47 
 
LIST OF ABBREVIATIONS 
 
Abbreviations
Term
ACT 
activated clotting time 
AE 
adverse event 
ALT 
alanine transaminase (SGPT) 
ANCOVA 
analysis of covariance 
Anti-Xa 
heparin anti Xa activity 
aPTT 
activated partial thromboplastin time 
AST 
aspartate transaminase (SGOT) 
BP 
blood pressure 
C 
Celsius 
CAP 
College of American Pathologists 
CBC 
complete blood count 
CFDA 
China Food and Drug Administration 
CFR 
Code of Federal Regulations 
Chem-20 
comprehensive metabolic panel including 20 analytes 
CHr 
reticulocyte hemoglobin 
CI 
confidence interval 
CKD 
chronic kidney disease 
CKD-5HD 
chronic kidney disease stage 5 undergoing chronic hemodialysis 
CLIA 
Clinical Laboratory Improvement Amendments 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
CRO 
contract research organization 
CRP 
C-reactive protein 
EC 
ethics committee 
EoT 
end-of-treatment 
ESA 
erythropoiesis-stimulating agent 
FPC 
ferric pyrophosphate citrate; Triferic 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HD 
hemodialysis 
HDF 
hemodiafiltration 
Hgb 
hemoglobin 
hr 
hour 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IRB 
institutional review board 
IV 
intravenous 
KDOQI 
Kidney Disease Outcomes Quality Initiative 
Kt/V 
dialyzer clearance of urea multiplied by dialysis time, divided by patient’s total body 
water 
LS 
least squares 
MI 
Michigan 
MITT 
modified intent-to-treat 
NIH 
National Institutes of Health 
NKF 
National Kidney Foundation 


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PMAM 
protocol-mandated change in anemia management 
PT 
prothrombin time 
QB 
blood flow rate during dialysis 
RBC 
red blood cell 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SE 
standard error 
SFP 
soluble ferric pyrophosphate, a previous name for FPC 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvate transaminase (ALT) 
Tf 
transferrin 
TIBC 
total iron-binding capacity 
TSAT 
transferrin saturation 
TSATTf 
transferrin saturation based on transferrin value 
TSATUIBC 
transferrin saturation based on UIBC value 
TT 
thrombin time 
UFH 
Unfractionated heparin 
UIBC 
unsaturated iron-binding capacity, calculated as TIBC – total serum iron 
URR 
urea reduction ratio 
US 
United States 
WBC 
white blood cell 
 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with Good Clinical Practice (GCP) as required by the following 
applicable regulations depending on study location and sponsor requirements. 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 
CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
ICH E6 
All key personnel (all individuals responsible for the design and conduct of this trial) have completed 
Human Subjects Protection Training. 
 
 


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PROTOCOL SUMMARY 
Title: 
A Randomized 3 period crossover study to investigate the effect of 
Triferic plus heparin infusion compared to heparin alone on 
coagulation parameters in hemodialysis patients. 
Precis: 
This study will investigate the administration of Triferic intravenously into 
the pre-dialyzer blood line with and without concomitant administration of 
continuous infusion heparin for anticoagulation of the dialyzer circuit. 
Study Design 
Prospective, randomized, three period crossover open label single site 
study. 
Objectives: 
 
To investigate the effect of co-administration of Triferic and heparin on the 
ability to maintain circuit anti-coagulation and iron delivery when compared 
to control conditions when each treatment is administered via separate 
routes.. 
Primary Objectives: 
Investigate if there is a drug-drug interaction between Triferic and 
concomitant administration of continuous dose heparin to anticoagulate the 
dialyzer blood circuit for plasma by measuring Anti-Xa activity 
Secondary Objectives 
Investigate if there is a drug-drug interaction between Triferic and 
continuous heparin on the ability to deliver Triferic iron as measured by the 
serum iron profile pharmacokinetics. 
Investigate the effect of the administration of Triferic and concomitant 
continuous dose heparin on aPTT and TT activity. 
Investigate the effect on dialyzer circuit clotting as measured by a visual 
scale 
Investigate the overall safety profile of Triferic and heparin as measured by, 
targeted adverse events, serious adverse events, number and quantity of 
equired extra heparin bolus doses and standard laboratory analyses 
Study Design: 
Prospective, randomized three period crossover, open-label single site 
study. 
Enrolled patients will be randomized to receive 3 sequential HD treatments 
as shown in the Study Design.  Each treatment will examine a unique 
combination of Triferic and heparin administration.   
Treatment A: Patients will receive Triferic 6.75 mg IV over 3 hours into the 
post-dialyzer blood line (or drip chamber) administered by an 
infusion pump.   Anti-coagulation will be provided by a bolus of 
heparin administered into the venous return line immediately prior 
to the initiation of hemodialysis followed by a continuous infusion 
of heparin using the on-machine infusion pump. The infusion of 
heparin to be stopped at hour 3 of hemodialysis. 


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Treatment B: Patients will receive Triferic 6.75 mg IV plus the appropriate 
volume of unfractionated heparin for continuous infusion over 3 
hours into the pre-dialyzer “heparin line”.  This mixture will be 
administered by the on-machine syringe infusion pump for 
continuous infusion.  Anti-coagulation will be provided by a bolus 
of heparin administererd into the venous return line immediately 
prior to the initiation of hemodialysis followed by a continuous 
infusion of Triferic + heparin. The infusion of Triferic + heparin will 
be stopped at hour 3 of hemodialysis. 
Treatment C: Patients will receive no Triferic. Anti-coagulation will be 
provided by a bolus of heparin administered into the venous 
return line immediately prior to the initiation of hemodialysis 
followed by a continuous infusion of heparin via the on-machine 
syringe pump. The infusion of heparin to be stopped at hour 3 of 
hemodialysis. 
The heparin dose to be utilized will be what the patient normally receives 
during their regular outpatient hemodialysis within the ranges specified 
below:  the heparin dose will be the same at each treatment. 
 
Heparin IV:  25-50 IU/kg IV push then 600-3000 IU/hr X 3 hour 
Triferic IV:  6.75 mg Triferic IV X 3 hour 
Triferic IV + Heparin IV:  25-50 IU/kg UFH IV push, followed by a 
continuous infusion of Triferic 6.75 mg + sufficient volume of 
heparin to meet the patients anti-coagulation requirements.  The 
entire contents of the syringe are programmed to be delivered 
over the first 3 hours of dialysis. 
Safety parameters to be assessed are adverse events, evidence of clotting 
in the dialyzer circuit by visual inspection at intervals, abnormal vital signs, 
and abnormal laboratory analyses (complete blood counts and blood 
chemistries) for this patient population. 
Primary Endpoint 
Anti-Xa activity between Triferic IV + heparin IV infusion mixture compared 
to Heparin IV infusion (Treatment  B vs Treatment C) as measured by the 
AUC0-t for the Anti-Xa concentration vs time.  
Secondary Endpoints 
 
anti-Xa as measured by the AUC0-4 hours between Treatment  B vs C. 
and Treatment A vs B 
 
aPTT as measured by the AUC0-4 hours between Treatment B vs C and 
Treatent A vs B 
 
TT as measured by the AUC0-4 hours between Treatment B vs C and 
Treatent A vs B  . 
 
Iron profile as measured by the sFe Cmax and AUC0-t of Treatment B 
(Triferic +Heparin) versus Treatment A (Triferic IV pre—dialyzer, 
separate heparin infusion). 
Safety Endpoints 
 
The incidence and amount of clotting in the dialyzer circuit by visual 
inspection: Visual Clotting Scale (VCS) 


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 
The incidence of treatment-emergent adverse events (TEAEs), 
including the seriousness, severity, and assessed relatedness to 
anemia management protocol. 
 
The number and quantity of additional heparin bolus doses by 
treatment 
 
The change from baseline to end-of-treatment (EoT) in laboratory 
assessments. 
Population: 
Patients ≥18 years of age with end stage kidney disease receiving chronic 
hemodialysis (CKD-5HD). 
Phase:
I/II 
Number of Sites: 
1 site 
Countries 
US 
Description of Study 
Agent(s) : 
Triferic IV:  
Triferic (ferric pyrophosphate citrate, FPC), an iron-replacement product, is 
an iron complex in which iron(III) is bound to pyrophosphate and citrate. 
Triferic will be supplied as liquid luer-lock ampules containing 6.75 mg of 
Fe/4.5 ml and will be administered directly into the post-dialyzer blood line 
via a separate infusion pump at a rate to deliver the entire contents over 3 
hours. 
Triferic IV + Heparin: 
Triferic can be mixed with heparin to provide a mixture containing both 
agents.  The heparin dose to be administered by continuous infusion should 
be drawn up in a syringe.  The syringe should then be connected to the 
LDPE luer-lock ampule containing Triferic and the contents withdrawn.  The 
total volume to be administered is noted and the on-machine syringe pump 
is programmed to deliver the entire contents over 3 hours. 
Heparin IV Standard Dose Protocol: 
Unfractionated heparin 25 – 50 IU/kg administered as an IV bolus into the 
venous blood line immediately prior to the start of hemodialysis followed by 
a continuous infusion of 600-3000 IU/hr X 3 hours (per referring 
hemodialysis unit protocol). 
Study Duration:
4 week 
Participant Duration:
1 week 


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SCHEMATIC OF STUDY DESIGN 
 
1 
KEY ROLES 
Sponsor Medical Monitor 
Raymond D Pratt, MD 
Chief Medical Officer 
Rockwell Medical Inc. 
Principal Investigator 
Thomas C Marbury , MD 
Orlando Clinical Research Center 
5055 S Orange Ave. 
Orlando FL 32809, USA 
Clinical Laboratory 
Orlando Regional Medical Center Clinical Lab
1414 Kuhl Ave 
Orlando, FL  32806 
Contract Research Organization 
Data Management 
Statistical analysis 
Mdical Writing-clinical study report 
Innovative Analytics, Inc. 
161 E. Michigan Ave 
Kalamazoo, MI 49007, USA 
Pharmacokinetic analysis 
Pharmacokinetic analysis report 
Nuventra, Inc. 
2525 Meridian Parkway 
Suite 280 
Durham NC 27713, USA 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE  
 
2.1 
BACKGROUND ON IRON DEFICIENCY IN HEMODIALYSIS AND 
TREATMENT WITH IV IRON  
Chronic kidney disease (CKD) is a worldwide public health concern with an increasing incidence and 
prevalence, and is accompanied by poor outcomes and high healthcare costs. (National Kidney 
Foundation [NKF] Kidney Disease Outcomes Quality Initiative [KDOQI] 2002)  Patients with CKD develop 
anemia primarily due to deficient production of erythropoietin by the diseased kidneys, as well as iron 
deficiency1.  Anemia commonly contributes to poor quality of life in patients with CKD2.  The appropriate 


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treatment of anemia is important; in addition to reduced quality of life, anemia is associated with fatigue, 
left ventricular hypertrophy and other deleterious consequences, and correction of anemia has been 
associated with improved quality of life, morbidity, and survival in uremic patients3.  
Treatment with erythropoiesis stimulating agents (ESAs) can lead to rapid depletion of iron stores and 
functional iron deficiency due to stimulated erythropoiesis.  Iron deficiency is further exacerbated by iron 
losses that are particularly high in hemodialysis patients: up to 15 to 25 mL of whole blood are lost with 
each dialysis treatment (approximately 60 mL per week) as a result of retention of blood in the dialyzer 
and tubing, frequent phlebotomy for blood testing and excessive gastrointestinal blood loss4.   
Oral iron supplements are often either not sufficiently effective or not tolerated in a significant proportion 
of patients due to associated gastrointestinal adverse events.  Thus, oral iron frequently fails to maintain 
adequate iron stores in hemodialysis patients, particularly those on ESA5;6.  The anemia working group of 
the NKF KDOQI concluded that oral iron is unlikely to maintain iron stores, and most hemodialysis 
patients will require intravenous (IV) iron on a regular basis to achieve and maintain target hemoglobin 
levels7. 
IV iron is associated with acute toxicity, thought to be related at least in part to the carbohydrate moiety 
and/or release of labile iron.  IV iron administration is well recognized to be associated with anaphylactoid 
reactions, other hypersensitivity reactions, and profound hypotension8. The other recognized acute 
adverse reactions from IV iron administration such as nausea, vomiting, cramps, back pain, and chest 
pain, are likely attributable to free or labile iron liberated from the iron complex9.  Labile iron effects may 
also be associated with increased oxidative stress and inflammation10. 
Theoretically, IV iron may also increase the risk of infections via two potential mechanisms.  The uptake 
of iron carbohydrate complexes from the circulation is by the same phagocytic cells (macrophages) in the 
reticuloendothelial system (liver, spleen and lymph nodes) that act as scavengers to pick up bacteria or 
foreign substances in the circulation; their function can be theoretically overwhelmed by the handling of 
the iron complexes, thereby predisposing to infections.  In addition, while in the circulation, iron can 
potentially serve as a nutrient for the microorganisms.   
Repeated administration of IV iron over prolonged periods of time can result in the accumulation of iron in 
storage sites, as reflected by persistently elevated ferritin levels11.  Over prolonged periods of time, this 
has the potential to cause toxic effects associated with iron overload, including liver damage, 
atherosclerosis, and heart disease.   All IV iron compounds are known to increase ferritin levels. 
2.2 
RATIONALE  
Triferic (ferric pyrophosphate citrate, or FPC), an iron-replacement product, is an iron complex in which 
iron(III) is bound to pyrophosphate and citrate12.  Triferic does not require processing by macrophages, 
and it donates iron directly to transferrin for optimal utilization in erythropoiesis, avoiding sequestration 
within reticuloendothelial system macrophages13. Additional information regarding Triferic may be found 
in the Investigator’s Brochure14 (IB) v10.0 (2018). 
 
The amount of iron Triferic delivered via HD at the approved dose of 2 M (110 g Fe/L) was 
determined by PK parameters to be 6.75 mg Fe/HD. 
 
The amount of iron delivered IV into the pre-dialyzer blood line is 6.75 mg. 
 


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Rationale for the Current Study 
Hemodialysis requires some form of anticoagulation to prevent clotting in the dialyzer circuit.  
Unfractionated heparin (UFH) has been the long time standard to provide anticoagulation15. UFH is 
typically administered as a bolus dose of 25 to 50 IU/kg at the initiation of hemodialysis followed by a 
continuous infusion via the on-machine syringe (heparin) pump of 600-3000 IU/hour16.  Alternately UFH 
or low molecular weight heparins (LMWH) can be administered as a single IV bolus predialysis followed 
by an additional bolus if needed.  This mode of administration does not require use of the on-machine 
syringe (heparin) pump.  Anticoagulation within the dialysis circuit is monitored by visual observation of 
the dialyzer and drip chambers.  The UFH dose needs to be individually determined and may be variable 
depending on the underlying comorbidities17-19.   
Triferic can be administered to HD patients via the dialysate or intravenously into the pre- or post-dialyzer 
blood lines.  This can be accomplished by using an accessory infusion pump, or in the case where the 
patient is receiving intermittent bolus heparin using the on-machine infusion pump.  
The current study will investigate the administration of the admixture of Triferic + heparin during 
hemodialysis in those patients who are receiving heparin as a continuous infusion during HD.  Triferic has 
no effect on the anti-coagulant effects of UFH and LMWH when mixed together (data on file: Rockwell 
Medical Inc).  Macromolecular iron has been previously administered to patients with continuous infusion 
heparin20.   
The test administration will be Treatment B to assess the impact of the Triferic + heparin mixture on the 
ability to maintain adequate anticoagulation of the dialyzer circuit and administration of Triferic iron.   The 
Control arms will compare heparin continuous infusion alone (Treatment C) and Heparin administered via 
constant infusion with Triferic administered into the post-dialyzer blood line by a separate infusion pump 
(without heparin admixture -Treatment A). 
Justification for Dose 
Triferic at 2 µM iron (110 g Fe/L) final concentration in hemodialysate was shown to provide 6.75 mg 
iron per dialysis and is the approved dialysate concentration in the United States21.   
2.3 
POTENTIAL RISKS AND BENEFITS  
 
2.3.1 KNOWN POTENTIAL RISKS  
Triferic is generally well-tolerated.  In controlled clinical studies, the safety profile is similar to patients 
receiving placebo treatment.  The most common adverse reactions leading to treatment discontinuation 
included headache, asthenia, dizziness, constipation, nausea, hypersensitivity reactions, intradialytic 
hypotension, pruritus, and pyrexia.  Adverse reactions reported in the treatment extension periods were 
similar to those observed in the randomized clinical studies.  
Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-
threatening and fatal, have been reported in patients receiving parenteral iron products. Patients may 
present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Patients 
receiving IV iron should be monitored for signs and symptoms of hypersensitivity during and after 
hemodialysis until clinically stable. 


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Personnel and therapies should be immediately available for the treatment of serious hypersensitivity 
reactions. 
Adverse events in controlled clinical trials of Triferic were mild to moderate in severity.  The pattern of AE 
was similar between Triferic and placebo treated patients.  There were no events of anaphylaxis in 
controlled trials. Since product launch, over 600,000 individual doses of Triferic have been administered 
via HD and IV with no reported hypersensitivity or anaphylaxis.    
Anticoagulation is required to prevent clotting of the dialyzer circuit.  The use of continuous dose heparin 
administered via the on-machine infusion pump has been demonstrated to be safe and effective in 
preventing clots from forming in the dialyzer circuit.   
Triferic has been demonstarated to be compatible with unfractionated heparin in an in-vitro study. This 
study will examine the effect of administering an admixture of Triferic and heparin on the coagulation 
parameters and iron delivery during infusion of the mixture.   
2.3.2 KNOWN POTENTIAL BENEFITS  
Triferic administered at each dialysis treatment can maintain hemoglobin concentrations without 
increasing body iron stores as measured by serum ferritin concentrations22.  In one clinical study, patients 
receiving Triferic over 9 months required 35% less erythropoiesis stimulating agents (ESA) than patients 
receiving placebo23. 
3 
OBJECTIVES AND PURPOSE 
To investigate the co-administration of Triferic and heparin on the ability to maintain circuit anti-
coagulation and iron delivery when compared to control conditions when each treatment is administered 
via separate routes. 
3.1 
PRIMARY OBJECTIVE 
Investigate if there is a drug-drug interaction between Triferic and concomitant administration of 
continuous dose heparin to anticoagulate the dialyzer blood circuit for plasma by measuring Anti-Xa 
activity. 
3.2 
SECONDARY OBJECTIVES 
Investigate if there is a drug-drug interaction between Triferic and continuous heparin on the ability to 
deliver Triferic iron as measured by the serum iron profile pharmacokinetics. 
Investigate the effect of the administration of Triferic and concomitant continuous dose heparin on aPTT 
and TT activity. 
Investigate the overall safety profile of Triferic and heparin as measured by, targeted adverse events, 
serious adverse events, number and quantity of equired extra heparin bolus doses and standard 
laboratory analyses. 
4 
STUDY DESIGN AND ENDPOINTS 
 
4.1 
DESCRIPTION OF THE STUDY DESIGN 


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This is a prospective, single-center, open-label, three period crossover clinical trial investigating the 
delivery of Triferic IV with continuous heparin infusion compared to control delivery of heparin and Triferic 
by different routes.  (Figure 1).    
A total of 12 chronic hemodialysis patients will be enrolled.  Patients will be randomized to one of three 
treatment periods and will cross over to the other two periods according to a pre-defined randomization 
sequence. There is one day between crossover periods which is  sufficient to prevent carryover effects of 
heparin and Triferic due to their short half-lives. 
Figure 1:  RMFPC-24 Study Design Schematic 
 
 
Coagulation parameters (anti-Xa activity, aPTT and TT) will be measured at specified intervals for 8 hours 
to include the 4 hours hemodialysis and 4 hours post HD. 
Serum iron profile will be obtained at specified times for 8 hours to assess delivery of Triferic iron.  
Safety parameters to be assessed are the visual evaluation of clotting in the dialyzer circuit, targeted 
adverse events, abnormal vital signs, and abnormal laboratory analyses (complete blood counts and 
blood chemistries including liver function tests) for this patient population. 
4.2.1 PRIMARY ENDPOINT 
 
Anti-Xa activity between Triferic IV + heparin IV infusion mixture compared to Heperin IV infusion 
(Treatment  B vs Treatment C) as measured by the AUC0-t for the Anti-Xa concentration vs time. 
4.2.2 SECONDARY ENDPOINTS 
 
anti-Xa as measured by the AUC0-4 hours between Treatment  B vs C. and Treatment A vs B 
 
aPTT as measured by the AUC0-4 hours between Treatment B vs C and Treatent A vs B 
 TT as measured by the AUC0-4 hours between Treatment B vs C. and Trreatment A vs B 


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 Iron profile as measured by the sFe Cmax and AUC0-t of Treatment B (Triferic + Heparin) versus 
Treatment A (Triferic IV post-dialyzer, separate heparin bolus + infusion). 
4.2.3 SAFETY ENDPOINTS 
 
The incidence and amount of clotting in the dialyzer circuit by visual inspection: Visual Clotting 
Scale (VCS) 
 
The incidence of treatment-emergent adverse events (TEAEs), including the seriousness, 
severity, and assessed relatedness to anemia management protocol. 
 
The number and quantity of additional heparin bolus doses by treatment 
 
The change from baseline to end-of-treatment (EoT) in laboratory assessments. 
 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
INCLUSION CRITERIA 
1. Adult hemodialysis patients ≥18 years of age. 
2. Signed informed consent to participate in the study. 
3. Stable on hemodialysis prescription for ≥3 months. 
4. Hemoglobin concentration >9.5 g/dL. 
5. Serum TSAT ≥20%. 
6. Able to receive continuous heparin infusion as their anticoagulation protocol. 
7. Receiving hemodialysis via AV fistula or graft. 
8. Able to receive hemodialysis for 4 hours at each session over the duration of the treatment periods. 
 
5.2 
EXCLUSION CRITERIA 
1. Active bleeding disorder (GI, skin, nasal…) 
2. Receiving hemodialysis via catheter. 
3. Receiving heparin free dialysis. 
4. Receiving low molecular weight heparin as sole anti-coagulation for dialysis. 
5. Receiving IV iron within 2 weeks of the first on-study hemodialysis treatment. 
6. Receiving oral anti-coagulants or anti-platelet agents. 
7. Any other condition, that in the opinion of the investigator would not allow completion of the 3 
hemodialysis treatments in the study. 
 


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5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Patients will be recruited from hemodialysis centers in the local area.  
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
Patients may withdraw from the study at any time for any reason.  Patients who withdraw prior to 
completion of the three study periods will be replaced to ensure a balanced sequence design is 
completed.   
5.4.1 REASONS FOR STUDY DRUG WITHOLDING, WITHDRAWAL OR 
TERMINATION 
Safety monitoring of enrolled patients will be ongoing during the study.  The Investigator is responsible for 
guarding the patient’s welfare and can discontinue study drug administration at any time that this action 
appears to be in the patient’s best interest.  
The rationale for all decisions to permanently discontinue test drugs and/or discontinue a patient from the 
study must be documented.  A patient may choose to have study drug withheld or discontinue from the 
study at any time and for any reason. 
There is no provision for study drug withholding.  Patients who cannot continue in the study for any 
reason must be withdrawn and will be replaced. 
Study drug must be permanently withdrawn (patient must be discontinued from the study) if: 
 
Patient has a serious adverse event that is due to study drug. 
1. Systemic and/or serious infection such as bacteremia or fungemia.  
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
Possible reasons for discontinuing a patient from the study include the following: 
 
Death 
 
Adverse event 
 
Withdrawal of consent 
 
Permanent discontinuation of study drug 
 
Lost to follow-up 
 
Investigator’s discretion 
 
Sponsor’s discretion 
 
Other (kidney transplant, patient changed dialysis clinics, patient moved, pregnancy, etc.) 
Discontinued patients will be replaced.  
If the reason for withdrawal is an adverse event, the patient will be followed until the event resolves or 
stabilizes, as defined in the adverse event reporting section of this protocol. 
In accordance with legal requirements and International Conference on Harmonization-Good Clinical 
Practice (ICH-E6) guidelines, all patients are free to withdraw from participating in this study at any time 
and for whatever reason, specified or unspecified, and without prejudice. In addition, Rockwell Medical 
retains the right to end the study at any time if the study cannot be carried out as agreed upon in the 
protocol. In the case of premature termination or suspension of the study, Rockwell Medical or its 


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representative will promptly inform the investigator/institutions and regulatory authorities of the 
termination or suspension and the reason for the termination. It is the responsibility of the Investigator, 
however, to notify the IRB or local Ethics Committee in the case of premature termination/suspension. 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
Should the study be terminated or suspended, all administration of study drug will stop and patients will 
return to the direction of their nephrologist. 
6 
STUDY AGENT 
 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
 
6.1.1 ACQUISITION 
Triferic for administration IV will be provided in 5 mL LDPE luer-lock ampules containing 6.75 mg Triferic 
iron in 4.5 mL water for injection.   
Unfractionated heparin will be provided by the investigative site for administration as IV bolus and 
continuous infusion. 
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
Triferic is a pale yellow-green liquid. 
Triferic for IV adminsitrateion will be labeled as an investigative drug. 
Unfractionated heparin will retain its FDA-approved labeling and will not include study-specific labeling. 
6.1.3 PRODUCT STORAGE AND STABILITY 
All drugs will be kept in a secured area with limited access.  
Triferic ampules for IV use will be stored protected from light at controlled room temperature (20 to 25C 
[68 to 77F] in the provided packages until use; excursions will be permitted to 15 to 30C [59 to 86F]. 
Heparin products must be stored according to their product labeling. 
6.1.4 TRIFERIC PREPARATION 
For Treatment A, the Triferic for IV administration should be drawn up into a syringe of appropriate 
volume by connecting the syringe tip to the luer connector and withdrawing the contents of the ampule. 
The syringe containing Triferic will be mounted on a separate infusion pump and programmed to deliver 
the 4.5 mL contents over 3 hours into the post-dialyzer blood line (or drip chamber).  The UFH will be 
infused during the first 3 hours of hemdialysis via the on-machine syringe pump into the pre-dialyzer 
blood line. 
For Treatment B, the UFH dose to be administered by continuous infusion should be drawn up in a 
syringe.  The syringe should then be connected to the LDPE luer-lock ampule containing Triferic and the 
contents withdrawn.  The syringe containing Triferic + heparin will be mounted on the on-machine syringe 
pump and programmed to deliver the entire contents over 3 hours via the pre-dialyzer blood line. 


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For Treatment C, the UFH dose to be administered by continuous infusion should be drawn up in a 
syringe and infused over the first 3 hours of hemodialysis via the heparin pump into the pre-dialyzer blood 
line. 
A detailed description of dosing solution preparation is included in APPENDIX 4. 
6.1.5 DOSING AND ADMINISTRATION 
Doses of Triferic and heparin will be delivered according to the sequence to which patients have been 
assigned. 
6.1.6 ROUTE OF ADMINISTRATION 
See section 6.1.4. 
6.1.7 STARTING DOSE AND DOSE ESCALATION SCHEDULE 
All heparin doses are fixed at the patients standard dose of heparin to maintain circuit anticoagulation. 
Triferic doses are fixed at 6.75 mg Triferic iron via IV infusion. 
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
No Triferic dose adjustments are allowed. 
Heparin may be adjusted if visible clots are observed in the arterial drip chamber at any time.  Extra 
heparin can be administered in boluses of 200 to 400 U if required. 
6.1.9 DURATION OF THERAPY 
The study will encompass three sequential hemodialysis treatments. 
6.1.10 TRACKING OF DOSE 
This is a parenteral dosing study.  The investigative site will be responsible for tracking all study drugs 
and dosing. 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
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, time, quantity, and subject number); 
 
Return or destruction of study drug (date, quantity, and subject number);  


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 
Initials of individual dispensing study drug; and 
 
Compliance assessment as outlined in Section 6.1.10. 
At the conclusion of a site’s participation in the study, all unused drug shall be returned to the Sponsor or 
destroyed upon the Sponsor’s request unless otherwise instructed by the Sponsor.  A copy of the 
reconciled drug inventory record will be provided to the Sponsor or its designee, and the original will be 
retained at the site. 
6.2.1 STUDY DRUG DOSING 
Triferic will be dosed as described in Section 6.1.4.   
Heparin will be administered according to the study periods described in Section 6.1.4. 
7 
STUDY PROCEDURES AND SCHEDULE 
 
7.1 
STUDY PROCEDURES/EVALUATIONS 
 
7.1.1 STUDY SPECIFIC PROCEDURES  
All procedures for the study are described in Section 7.3. 
7.1.2 STANDARD OF CARE STUDY PROCEDURES  
All other patient requirements for medication administration will be administered according to the patients 
standard hemodialysis prescription as determined by their referring nephrologist. 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 CLINICAL LABORATORY EVALUATIONS  
A schedule of laboratory assessments is presented in Section 7.3.7.   
7.2.2 OTHER ASSAYS OR PROCEDURES 
None 
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
Hematology:  All specimens should be collected in 2.0 mL K2EDTA tubes (BD# 367841 or equivalent). 
Coagulation: All specimens should be collected in 2.7 mL BD # 363083 tubes or equivalent. 
Chemistry (including iron profile):  All specimens should be collected in 3.5-mL clot activator, serum 
separator vacutainer tubes (BD# 367983 or equivalent). 
7.2.4 SPECIMEN SHIPMENT 


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All laboratory specimens for the hematology, coagulation and iron profile assessments are to be shipped 
to the local laboratory within 24 hours after collection.   
7.3 
STUDY SCHEDULE 
 
7.3.1 SCREENING 
Patients will be recruited from local hemodialysis centers and will sign an informed consent document and 
will undergo the following procedures: 
 
Eligibility evaluation 
 
Demographics and medical history (including current heparin prescription) 
 
Height and pre-/post-dialysis weight 
 
Vital signs (blood pressure, pulse, and temperature) 
 
Physical exam 
 
ECG 
 
Pregnancy test (if applicable) 
 
Serum chemistry (Chem-14) 
 
Hematology and coagulation profile 
 
C-reactive protein 
 
Serum iron profile (total serum iron, ferritin, TIBC, TSAT, transferrin) 
  
7.3.2 ENROLLMENT AND TREATMENT PERIODS 
Prior to the first Treatment Period (HD Day 1): 
 
Ascertain the patient meets all inclusion criteria and none of the exclusion criteria. 
 
Determine the UFH loading dose and  infusion dose for each patient depending on their previous 
UFH history ascertained at Screening. 
 
Determine the randomization allocation to a specific sequence from the randomization schedule 
prepared by Innovative Analytics. 
For each of the Treatment Periods (HD Days 1, 3, 5), the following study procedures will be performed: 
 
Prepare the UFH and Triferic according to the treatment assignments: 
Treatment A:  Triferic infusion post-dialyzer; UFH via continuous infusion pre-dialyzer  
 
UFH: Prepare the syringe containing UFH for continuous infusion via the pre-dialyzer heparin 
line. 
 
Administer the priming bolus of heparin into the post-dialyzer blood line port. 
 
Mount the syringe containing heparin on the on-machine syringe pump and program the pump to 
deliver the UFH over 3 hours of the 4 hour dialysis period. 
 
Triferic:  The volume of Triferic to be administered is 4.5 mL via a separate infusion pump into the 
post-dialyzer blood line (or drip chamber). The administration rate is 1.5 mL/hour for 3 hours. 
 
Prepare the solution by withdrawing 4.5 mL Triferic IV solution in a 10 mL syringe.   
 
Inject 0.25 mL of the solution into the connecting tubing in order to displace the air present in the 
line prior to initiating blood flow. 


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 
Mount the syringe on the infusion pump. 
 
Start infusion and administer over 3 hours of the 4 hour HD session. 
 
Keep all Triferic solutions protected from light until use. 
 
Treatment B:  UFH + Triferic admixture 
 
UFH + Triferic: Prepare the syringe containing UFH for continuous infusion via the pre-dialyzer 
heparin line by removing the required volume of UFH into a 10 mL syringe.  In the same syringe, 
attach the Triferic luer lock ampule to the syringe and remove the contents (4.5 mL).  Mix the 
contents by inverting and rotating the syringe until the solution has a uniform appearance. 
 
Note the final volume of the Triferic + heparin. 
 
Attach the syringe containing Triferic and heparin to the pre-dialyzer heparin line and mount the 
syringe on the on-machine “heparin pump”. 
 
Administer the priming bous of heparin into the post-dialyzer blood line port. 
 
Program the syringe pump to deliver the entire contents of the syringe over 3 hours of the 4 hour 
HD session. 
 
Keep all Triferic solutions protected from light until use. 
 Treatment C:  UFH via continuous infusion pre-dialyzer  
 
UFH: Prepare the syringe containing UFH for continuous infusion via the pre-dialyzer heparin 
line. 
 
Administer the priming bous of heparin into the post-dialyzer blood line port. 
 
Mount the syringe containing heparin on the machine syringe pump and program the pump to 
deliver the UFH over 3 hours of the 4 hour dialysis period. 
In addition to the study drug administration noted above, the following procedures will be performed at 
each treatment visit (HD Days 1, 3, and 5): 
 
Blood sampling for pharmacokinetic analysis (serum total iron, ferritin, TIBC, TSAT, transferrin): t 
= 0, 1, 2, 3, 4, 5, 6, 7, 8 hr 
 
Blood sample for coagulation studies (Anti-Xa, aPTT, TT): t = 0, 0.08, 0.5, 1, 2, 3, 4, 5, 6, 7, 8 hr 
 
Dialyzer visual scale 
 
Adverse events 
 
Concomitant medications 
Visual Dialysis Circuit Clottiing Scale:  Assessment of visible clotting to be assessed at 1 hour intervals 
during dialysis (Appendix 3). 
7.3.3 FOLLOW-UP VISIT 
Patients who complete the study or withdraw prior to completion will undergo a follow up evaluation within 
1 week.  The evaluation may be done by phone contact to assess any adverse events that may have 
occurred or medications that were administered after completion of the final hemodialysis treatment.   
7.3.4 FINAL STUDY VISIT OR EARLY TERMINATION VISIT 
See Section 7.3.3. 


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7.3.7 SCHEDULE OF EVENTS TABLE 
 
Assessments 
Screening 
Treatment A  
Treatment  B 
Treatment C 
Follow Upf 
Visit #
1
2
3
4
5
Target study day
-28 to -1
1
3
5
8
Informed consent
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history
X
Height and pre- and post-
HD weighta
X 
 
 
 
 
Vital signs
X
Physical examination
X
ECG
X
Serum pregnancy test 
(if applicable)
X 
 
 
 
 
Hematologyb
X
Chem-14, CRPb
X
Serum iron profileb,c 
X 
 
 
 
 
Heparin HD Rx
X
Enrollment in study
X
Randomized Triferic 
Administrationd
 
FPC 6.75 mg IV Post-
dialyzer
FPC 6.75 mg IV Pre-
dialyzer +heparin
 
 
Heparin Administration 
 
 Heparin Bolus + Heparin 
IV infusion
Heparin Bolus + 
Heparin IV infusion
Heparin Bolus + 
Heparin IV infusion
 
PK samplese
X
X
X
aPTT anti-Xa, TT 
collectione
X 
X 
X 
X 
 
Dialyzer circuit clotting 
visual scaleg
 
X 
X 
X 
 
Discharge from study
X
Adverse events
X
X
X
X
Medications
X
X
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, TSAT and transferrin), and pregnancy test samples 
will be analyzed by the local clinical laboratory. Hematology and Chem-14 required only if not performed within 1 month prior to screening 
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 Section 7.3.2 for instructions on the preparation and dosing of Triferic. 
e See Appendix 2 for the schedule for obtaining PK samples. PK samples will be sent to and analyzed by the local clinical laboratory. See Appendix 3 for 
instructions on the handling of the PK samples. 
f 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. 
g See Appendix 4 for the Dialyzer circuit clotting visual scale 
 


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7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
All procedures in this study are standard of care. 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  
All prescription and non-prescription medications (including multivitamins and oral and IV iron products) 
taken during the study are standard care.  
7.5.1 PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
None. 
7.6 
PROHIBITED OR RESTRICTED MEDICATIONS, TREATMENTS, AND 
PROCEDURES  
Patients may not receive IV or oral iron from the first day of screening until after completion of the final 
Treatment Period. 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
None. 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
None. 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
Triferic will be available for commercial use by dialysis units at the conclusion of this study. 
 
8 
ASSESSMENT OF SAFETY 
 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
The safety endpoints are: 
 
The visual scale for dialyzer circuit clotting at t=0, 1, 2, 3 and 4 hours. 
 
The incidence of all treatment-emergent adverse events (TEAEs) attributed to anemia 
management protocol, including the seriousness, severity, and assessed relatedness to Triferic 
or standard anemia management. 
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse events attributed to Triferic or standard anemia management will be collected starting with the 
first study drug administration during the treatment period as described in the protocol section on the 
collection and reporting of adverse events.  
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 


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Any SAE that occurs from the first day of site participation to the end of study participation 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 to include experiences of relatively 
minor medical significance such as 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. 
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
An unanticipated problem is any event not listed in the Research Investigators Brochure that does not 
meet the definition of an AE or SAE.  Examples include HD machine malfunctions or other events that 
may occur during the study but are not related to study drug. 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 


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8.2.1 SEVERITY OF EVENT 
The Investigator must categorize the severity of each AE related to anemia management according to the 
following guidelines.   
Mild: 
The patient is aware of signs or symptoms but is able to perform activities of daily living. 
Moderate: 
The event is sufficiently discomforting to the patient that it interferes with the patient’s performance of 
activities of daily living. 
Severe: 
Due to the event, the patient is unable to perform activities of daily living. 
8.2.2 RELATIONSHIP TO STUDY AGENT 
The relationship of each AE to the anemia management treatment administration will be assessed by the 
Investigator after careful consideration, and according to the following guidelines.  
No, Not Related: 
This category is applicable to those AEs that are clearly due to extraneous causes (concurrent drugs, 
environment, etc.) and do not meet the criteria for drug relationship listed under UNLIKELY, POSSIBLY, 
PROBABLY, AND DEFINITELY RELATED. 
Unlikely Related: 
This category applies to those AEs that are judged to be unlikely to be related to the study drug 
administration.  An AE may be considered to be UNLIKELY RELATED when it meets at least two (2) of 
the following criteria: 
a) 
It does not follow a reasonable temporal sequence from administration of the study drug. 
b) 
It could readily have been produced by the patient’s clinical state, environmental or toxic factors, 
or other modes of therapy administered to the subject. 
c) 
It does not follow a known or expected response pattern to the study drug. 
d) 
It does not reappear or worsen when the study drug is re-administered. 
Possibly Related: 
This category applies to those AEs that are judged to be perhaps related to the study drug administration.  
An AE may be considered POSSIBLY RELATED when it meets at least one (1) of the following criteria: 
a) 
It follows a reasonable temporal sequence from administration of the study drug. 
b) 
It could not readily have been produced by the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient. 
c) 
It follows a known or expected response pattern to the study drug. 


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Probably Related: 
This category applies to those AEs that are felt with a high degree of certainty to be related to the study 
drug administration.  An AE may be considered PROBABLY RELATED if it meets at least two (2) of the 
following criteria: 
a) 
It follows a reasonable temporal sequence from administration of the study drug. 
b) 
It could not be reasonably explained by the known characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the patient. 
c) 
It disappears or decreases on cessation or reduction in study drug dose.  There are exceptions 
when an AE does not disappear upon discontinuation of the drug, yet drug relatedness clearly exists 
(e.g., bone marrow depression, fixed drug eruptions, tardive dyskinesia, etc.). 
d) 
It follows a known or expected response pattern to the study drug. 
Definitely Related: 
This category applies to those AEs that are incontrovertibly related to study drug administration.  An AE 
may be assigned to this category if it meets at least the first three (3) of the following criteria: 
a) 
It follows a reasonable temporal sequence from administration of the study drug. 
b) 
It could not be reasonably explained by the known characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the patient. 
c) 
It disappears or decreases on cessation or reduction in study drug dose.  There are exceptions 
when an AE does not disappear upon discontinuation of the drug, yet drug relatedness clearly exists 
(e.g., bone marrow depression, fixed drug eruptions, tardive dyskinesia, etc.). 
d) 
It follows a known or expected response pattern to the study drug. 
e) 
It reappears or worsens when the study drug is re-administered. 
8.2.3 EXPECTEDNESS  
Adverse events listed in any ESA or Iron  product labeling are considered expected.  All other SAEs 
considered by the investigator to be associated or related to the anemia management drugs are 
considered unexpected and should be reported as such. 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
 
At appropriate intervals, patients should be assessed for AEs and SAEs.   
All SAEs (related and unrelated) will be recorded from the first day of site participation until the end of 
study participation.  AEs will be recorded from the first day of site participation to end of study 
participation. 
8.4 
REPORTING PROCEDURES 
 
8.4.1 ADVERSE EVENT REPORTING  


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Adverse events, including SAEs, will be recorded on the adverse events CRF through the end of study 
participation.  
Any SAE that occurs from the first day of site participation to the end of study participation will be reported 
on an SAE report form. 
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 adverse event 
and/or SAE. 
8.4.2 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 or its designee 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 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 or its designee. 
8.4.3 POST STUDY ADVERSE EVENTS 
Investigators are not obligated to actively seek new AEs or SAEs that begin after the end of study 
participation. The investigator should notify Rockwell Medical of any SAEs that begin following study 
completion only if the event is considered related to study drug 
8.4.4 SERIOUS ADVERSE EVENT REPORTING  
REPORT ALL SAEs WITHIN THE TIMEFRAMES SPECIFIED TO NOTIFY ROCKWELL MEDICAL OF 
ANY SAEs. 
All SAEs (related and unrelated) will be recorded from the first day of site participation until the end of 
study participation. 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 or its designee 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 to Rockwell Medical or its designee at 
the specified facsimile number or email address (TBD). 
At a minimum, the event name, a reporter’s name and contact information, the name of the suspected 
investigational product and subject 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 or its designee 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 the Medical Monitor (TBD) any AEs for which the issue of 
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The designated CRO and Rockwell Medical are responsible for notifying the relevant regulatory 
authorities of certain events. Multiple inquiries with the study site may be necessary for report 
preparation. 
It is the Principal Investigator’s responsibility to notify the Institutional Review Board (IRB), Ethics 
Committee (EC) 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 
Expedited Safety Reports) that occur during any clinical trials. Each site is responsible for notifying their 
IRB, EC or the relevant local regulatory authority of these additional SAEs. 
Timeframes for Reporting SAEs 
Prompt notification 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 or its designee within 24 hr 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 or its designee 
within 48 hr.  
o 
Follow-up information must be sent to Rockwell Medical or its designee within 48 hr 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 or its designee 
within 48 hr of site study personnel learning of the event. 
o 
Follow-up information must be sent to Rockwell Medical or its designee within 48 hr of receipt of 
the information by the investigational site.  
SAE Information to Report 
All information available regarding an SAE must be submitted in the timeframes indicated above.  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 or its designee.  Please note that relationship to study 
drug/causality is very important and optimally should be included in the initial report as it may impact 
expedited regulatory reporting requirements for 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 or its designee, 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. 
Regulatory/Ethics Reporting Requirement 


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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. 
8.4.5 UNANTICIPATED PROBLEM REPORTING  
All unanticipated problems occurring during the study should be discussed with the Medical Monitor to 
determine the need for reporting events. 
8.4.6 EVENTS OF SPECIAL INTEREST  
8.4.6.1 
DEFINITION OF HYPERSENSITIVITY/ANAPHYLAXIS 
For the purposes of this study, hypersensitivity reactions, including anaphylaxis/ anaphylactoid reactions, 
are defined as the acute onset (within minutes to one hour after exposure to study drug) of an illness 
characterized by either or both of the following:  
(1) Involvement of the skin, mucosal tissue, or both (e.g., generalized hives, pruritus, or flushing; or 
swollen lips-tongue-uvula), or  
(2) Thoraco-lumbar back pain not known to be caused by any factor other than possible hypersensitivity 
reaction,  
AND either or both of the following:  
(Α) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory 
flow, hypoxemia), or  
(Β) Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, 
incontinence). 
Possible events of anaphylaxis/anaphylactoid reaction will be reviewed and assessed by the Sponsor and 
Investigator as to whether or not the event was indeed a hypersensitivity reaction and related to study 
drug using the above proposed definition.   
8.4.7 REPORTING OF PREGNANCY  
If any patient is found to be pregnant, they will not be permitted to participate in the study.  Any verified 
pregnancy after initial exposure to study drug in a patient on study must be immediately reported to the 
Investigator and in turn to Rockwell Medical or its designee per study reporting procedures, and the 
patient must discontinue study drug administration.  Pregnancy during the study period will be reported 
and followed until final resolution (i.e., delivery or early termination).  Any treatment-emergent birth defect 
or congenital anomaly will be reported to Rockwell Medical or its designee per study reporting procedures 
immediately as an SAE. 
8.5 
CLINICAL LABORATORY ABNORMALITIES  
If not known to be associated with a diagnosis, abnormal laboratory findings (e.g., clinical chemistry, 
hematology, and urinalysis) or other abnormal assessments (e.g., 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 
adverse event (Section 8.1.1, Definition of an Adverse Event), and reported as SAEs if they meet the 
criteria for seriousness (Section 8.1.2, Definition of an SAE). 


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The investigator should exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. 
8.6 
SAFETY OVERSIGHT 
There is no Data Safety Monitoring Board required for this study.  The oversight of safety reporting and 
assessment is the responsibility of the Sponsor and the Medical Monitor. 
9 
CLINICAL MONITORING 
Representatives of Rockwell Medical, in conjunction with Study Monitor(s) representing Rockwell, will 
perform a number of on-site visits to the study center.  Prior to commencement of the study, 
representatives of Rockwell will visit the study center to assure adequacy of facilities to conduct the 
protocol, and to discuss with the Investigator the general obligations regarding studies with investigational 
new drugs.  This visit will be documented in a report.  In some cases, for example when the study center 
has recently participated in a clinical trial in conjunction with Rockwell Medical, the Pre-Study Qualification 
visit may be waived according to applicable standard operating procedures. 
Upon satisfactory receipt of all necessary documentation (including, but not limited to, an allowed IND, an 
executed Clinical Trials Agreement, and IRB/EC approval of the protocol and informed consent form), 
Rockwell or its designated monitor(s) will arrange for all study material to be delivered to the study center 
and for the scheduling of a mutually convenient appointment for a Study Initiation visit.  Patient entry must 
not begin until this initiation visit has been completed.  At this meeting, all personnel expected to be 
involved in the conduct of the study should undergo an orientation to include review of the study protocol, 
instruction for CRF completion, and overall responsibilities including those for drug accountability and 
study file maintenance.  This visit will be documented in a report. 
Throughout the course of the study, Rockwell Medical’s and/or its designated monitor(s) will make 
frequent contacts with the Investigator.  Study Monitors representing Rockwell will visit study centers 
periodically throughout the trial for routine monitoring visits.  The Study Monitor will review CRFs to verify 
that they are accurate, complete and verifiable from source documents.  They will also verify the rights 
and well-being of the study patients are protected and that the study conduct is in compliance with the 
currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirements.  
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 or its designee monitor(s).  The study and its monitors may also 
be similarly evaluated by auditors representing Rockwell.  For these purposes, the Investigator will make 
CRFs, source documents and study files available when requested.  A report will be generated for each 
monitoring visit. 
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.  In 
accordance with applicable standard operating procedures (Rockwell or contracted vendor), a closeout 
visit may be scheduled, during which Rockwell or its representative will review all informed consents, 
CRFs, drug accountability records, and other study-related documents.  Rockwell or its representative will 
hold a final meeting with the Investigator and study staff to explain procedures for record retention, 
publication policy, site audit notification, and financial disclosure.  A final letter to the site will record the 
events of this closeout visit.  Study-closure activities will be documented in a report.  It will be the 
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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 or its designee monitoring personnel, or for 
administrative reasons, at any time.  In that event, Rockwell or its designee will notify each Investigator in 
writing that the study is to be discontinued.  The Investigator will comply with Rockwell’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 or its designees, the study may be audited by representatives of the 
US FDA, EMA, CFDA or other applicable regulatory agencies, who will also be allowed access to study 
documents.  The Investigator should immediately notify the Clinical Research Department at Rockwell or 
its designee of any proposed or scheduled audits with any regulatory authorities. 
10 
STATISTICAL CONSIDERATIONS  
 
10.1 STATISTICAL AND ANALYTICAL PLANS 
A formal statistical analysis plan for the analysis of primary and secondary endpoints will be prepared and 
completed prior to database lock. 
10.2 STATISTICAL HYPOTHESES 
The primary endpoint in this study is the difference between Period B and Period C for anti-Xa activity.   
 
Ho:  The AUC0-t anti-Xa is not different between the Heparin infusion period (Period C) and the 
Triferic +heparin infusion (Period B); 
 
Ha:  The AUC0-t anti-Xa is different between the Heparin infusion period (Period C) and the Triferic 
+ heparin infusion (Period B). 
10.3 ANALYSIS DATASETS 
The primary analysis dataset for this study will be based on patients who complete all 3 study periods.   
The Safety population dataset will include all randomized patients.  The primary safety analysis of interest 
is the comparison of safety parameters during the randomized treatment period. 
10.4 DESCRIPTION OF STATISTICAL METHODS 
 
10.4.1 GENERAL APPROACH 
 


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A pharmacokinetic analysis plan (PKAP) describing the analytical methodology will be completed prior to 
commencing analysis of the data. 
Summary descriptive statistics will be calculated for all parameters by treatment group; natural logarithmic 
transformations will be performed prior to the statistical analysis of the parameters. For categorical 
variables, the frequency and percentage in each category will be reported.  Percentages will be based on 
the number of patients in the analysis population for whom there are non-missing data, unless otherwise 
specified. For continuous variables, number of available observations (n), arithmetic mean, 95% 
confidence interval about the arithmetic mean, standard deviation [], minimum, median and maximum 
will be reported. 
Unless otherwise stated, all summaries will be presented by treatment group.  Unless otherwise specified, 
baseline data presentations will be based on the primary analysis dataset and safety analyses will be 
based on the Safety population. 
The statistical test to be used to determine equivalence of test to reference will be a two one-sided t-test 
(TOST) that requires a 90% confidence interval of the ratio of the geometric means obtained from a 
mixed effects model with sequence, period and treatment as fixed effects and patient (sequence) as a 
random effect, to be within the boundaries of 0.8 to 1.25. 
Test of significance will be based on 5%, one-sided (α=0.05) 
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The primary analysis will compare anti-Xa activity between the Triferic + heparin (Treatment B) and 
Control heparin (Treatments A andC) as measured by the AUC0-t. 
To investigate the drug-drug interaction between Triferic and concomitant administration of heparin, a 
mixed effects linear analysis of variance (ANOVA) model will be fit to the log-transformed parameters 
(AUC0-t for anti-Xa). Effects associated with treatment sequence, period, and treatment will be considered 
fixed; effects associated with patient (within each treatment sequence) will be considered random.  
Point estimates corresponding 90% confidence intervals (CI) will be derived from the differences in model 
least-squares means for the pairwise treatment comparisons of interest (B-A and B-C) using the residual 
error from the ANOVA mean square error (). The log-transformed point and interval estimates will be 
exponentiated (back transformed) to obtain estimates for the geometric mean (GLSM) ratio along with the 
90% CI for the GLSM ratios (B:A and B:C).  Confidence intervals that fall entirely with the range of 0.8 to 
1.25 will indicate no interaction between Triferic and concomitant administration of heparin. 
An estimate of the within-subject coefficient of variation (%) for each log-transformed parameter will 
be calculated based on the log-normal distribution as follows: 
  % =  −1 × 100 
where  if the residual error from the ANOVA model described above.  
In addition to descriptive summary statistics, the GM, 95% confidence interval about the geometric mean 
and between-patient coefficients of variation (%) will be calculated for the log-transformed parameters. 
The % will be calculated as follows: 


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   % =  −1 × 100 
where  is the standard deviation of the log-transformed data.  
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
The secondary efficacy endpoints are: 
• 
The aPTT and TT time comparisons between the Triferic + heparin (Treatment B) and Control 
heparin (Treatment C) as measured by the AUC0-t. 
• 
The sFe comparison between treatment periods (Treatment B  vs Treatment A) as measured by 
Cmax and AUC0-t. 
• 
The aPTT and TT time comparisons between the Triferic + heparin (Treatment B) and Control 
heparin (Treatment C) as measured by the AUC0-4. 
• 
The aPTT and TT time comparisons between the Triferic + heparin (Treatment A) and Control 
heparin (Treatment C) as measured by the AUC0-4. 
10.4.3.1 
SECONDARY EFFICACY ENDPOINT 
Similar analyses will be conducted that will mirror the approach used for the primary analysis described in 
section 10.4.2. For these analyses, the mixed effects linear ANOVA model will be the same as the 
primary analysis to fit the log-transformed parameters (AUC0-t for anti-Xa; AUC0-t for aPTT; AUC0-t for TT; 
AUC0-t and Cmax for sFe;). Point estimates corresponding 90% CI will be reported from the differences in 
model for the pairwise treatment comparisons. The GM ratio along with the 90% CI for the GM ratios will 
be reported. 
10.4.3.2 
SECONDARY EFFICACY ENDPOINTS  
• 
anti-Xa as measured by the AUC0-4 hours between Treatment  B vs C. 
• 
aPTT as measured by the AUC0-4 hours between Treatment B vs C 
• 
Number of aPTT measurements between 0.08 hr and 4 hours that are <1.5 X baseline (t=0) or 
>2.5 X baseline (t=0) 
 
10.4.3.3 
SAFETY ANALYSES 
Demographics and safety analyses will be presented using descriptive statistics. 
The following safety endpoints will be summarized and compared among the three treatment groups: 
 
The visual dialyzer circuit clotting scale score from start of dialysis to the end of dialysis at 1 hour 
intervals. 
 
The number and quantity of additional heparin bolus administered by treatment. 
 
The incidence of all treatment-related, treatment-emergent adverse events (AEs), including the 
seriousness, severity, and assessed relatedness to study drug. 


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 
The number and percentage of patients permanently discontinued from study drug treatment due 
to treatment-emergent AEs. 
 
10.4.3.4 PHARMACOKINETIC ANALYSES 
 
Noncompartmental pharmacokinetic analysis of serum iron concentrations will be conducted  
 
Iron profile as measured by the sFe Cmax and AUC0-t Treatment B (Triferic + Heparin) vs 
Treatment A (Triferic IV post-dialyzer) will be analyzed as described in Section 10.4.2. 
10.4.4 ADHERENCE AND RETENTION ANALYSES 
A summary of any dropouts and reasons will be provided in the clinical study report. 
10.4.5 PLANNED INTERIM ANALYSES  
No interim analyses are planned. 
10.4.5.1 
SAFETY REVIEW 
Safety reviews are the responsibility of the Sponsor and will occur at the time of annual reporting to 
regulatory agencies unless otherwise required. 
10.4.5.2 
EFFICACY REVIEW 
There will be no interim efficacy review. 
10.4.6 ADDITIONAL SUB-GROUP ANALYSES 
Sub-groups of age and sex, will be analyzed where indicated by the data. 
10.4.7 MULTIPLE COMPARISON/MULTIPLICITY 
Not applicable. 
10.4.8 TABULATION OF INDIVIDUAL RESPONSE DATA 
All tabulations of individual responses will be included in the data listings. 
10.4.9 EXPLORATORY ANALYSES 
Additional post-hoc analyses may be conducted after analysis of the primary, secondary and safety 
results.  
10.5 SAMPLE SIZE 
The samples size has been estimated empirically..   
10.6 MEASURES TO MINIMIZE BIAS 
 
10.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 


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This is an open-label randomized, 3 period crossover study.  All treatment arms utilize heparin in various 
permutations of administration; two of the treatment arms utilize Triferic.   
10.6.2 EVALUATION OF SUCCESS OF BLINDING  
N/A 
10.6.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE 
This is an open label study.  All patients and study personnel have knowledge of the treatments 
administered. 
If the protocol is revised, protocol amendments will be prepared and approved by Rockwell.  All protocol 
amendments must be submitted to the IRB/EC for review and approval must be obtained prior to 
implementation.  However, as discussed in Section 14.3, 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 Medical or its designee. 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
In accordance with the applicable regulations a case report form (CRF), whether paper or electronic, must 
be completed for eachpatient enrolled in the study.  CRFs are an integral part of the trial and subsequent 
reports.  All data collected for each study patient will be recorded on CRFs provided or approved by 
Rockwell.   
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.  CRF 
completion may be formally delegated to other study personnel.  However, Rockwell Medical or its 
designee must be informed in writing of the name of such persons and the scope of their authority.  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.  It is the obligation of the 
Investigator to review each page of the CRFs and to sign the designated and appropriate CRFs as the 
study's authority.  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, 
tracings, and computer discs, files or tapes.  
If using paper source documents, they must be completed legibly, preferably with black ballpoint pen.  A 
correction should be made by striking through the incorrect entry with a single line and entering the 
correct information adjacent to the incorrect entry.  The correction must be initialed and dated by the 
person making the correction.  Erasure or the use of correction fluid or film is unacceptable. 
For each study subject, the completed CRFs must be promptly reviewed, and required pages signed and 
dated by the Investigator.  The Investigator must retain a copy of all CRFs. 
12 
QUALITY ASSURANCE AND QUALITY CONTROL 
All CRF entries will be monitored and subject to verification against source documents during routine 
monitoring visits by Rockwell Medical personnel or their designees. 


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13 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
 
13.1 ETHICAL STANDARD  
This study is a Phase I/II study involving both investigational products (Triferic IV) and approved 
therapeutic agents (UFH). All applicable regulations governing human patient protection for the study 
location must be followed.  All ethical and regulatory requirements necessary to comply with the principles 
of Good Clinical Practice (GCP) for the conduct and monitoring of clinical investigations must be followed.  
To ensure ethical conduct of this clinical study, Investigators will be expected to adhere to basic principles 
provided from generally recognized guidelines such the Belmont Report and the International Ethical 
Guidelines for Biomedical Research Involving Human Subjects.  Participants must have provided written 
informed consent to document their voluntary participation in this study.  Updated safety information will 
be provided to the Investigators, Institutional Review Boards (IRBs)/Ethics Committees (ECs) and 
patients as necessary in order that they may consider relevant and emerging information that could affect 
their willingness to continue participation in this study. 
13.2 INSTITUTIONAL REVIEW BOARD  
In accordance with the Food and Drug Law in each locality the Investigator agrees to provide the 
appropriate Institutional Review Board (IRB)/Ethics Committee (EC) with all appropriate material, 
including a copy of the protocol, informed consent form (ICF), and any proposed advertisement for the 
study prior to the start of the study.   
The proposed informed consent form (ICF) and any proposed advertisement must also be agreed to by 
Rockwell Medical.  A copy of the IRB/EC approval letter of the protocol and the ICF must be supplied to 
Rockwell Medical or its designee prior to consenting any patients for the study.  A copy of the IRB/EC 
approval letter of any protocol amendments and any advertisements must be supplied to Rockwell 
Medical or its designee prior to implementing these documents.  The study may not begin screening or 
enrolling patients until the Investigator has obtained IRB/EC approval of the protocol and ICF and 
Rockwell Medical or its designee has received a hardcopy documentation of each.   
The Investigator will supply to Rockwell Medical or its designee a list of the names, professions, and 
affiliations of IRB/EC members to demonstrate compliance with membership requirements.  If the 
Investigator or a subinvestigator is a routine voting member of the IRB/EC, Rockwell Medical or its 
designee will be provided with a statement from the IRB/EC that the Investigator/subinvestigator did not 
and will not vote on any IRB/EC decisions pertaining to this clinical investigation.   
During the course of the study, the Investigator shall make timely and accurate reports to the IRB/EC on 
the progress of the trial, at intervals not exceeding one year, as well as satisfying any other local IRB/EC 
regulations regarding reporting.  Copies of all reports to and correspondence with and from the IRB/EC 
must be provided to Rockwell or its designee.  Furthermore, at the completion or early termination of the 
study, a final report should be made to the IRB/EC by the Investigator within the applicable IRB/EC time 
frames.  A copy of this report will be provided to Rockwell or its designee. 
Any significant changes or revisions in the study protocol or any changes that may alter patient risk must 
be approved by Rockwell (and may require CFDA/other regulatory agency review and/or approval) and 
must be approved in writing by the IRB/EC prior to implementation (see Section 13.2 for protocol 
amendments).  The Investigator must also receive a written notice of approval from Rockwell prior to 


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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 is immediately notified and 
an amendment is subsequently provided by Rockwell and approved by the IRB/EC. 
It is the Investigator's obligation to maintain an IRB/EC correspondence file, and to make this available for 
review by Rockwell or its designated representatives as part of the study monitoring process. 
13.3 INFORMED CONSENT PROCESS  
 
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO PARTICIPANTS 
A copy of the proposed patient information document should be submitted to Rockwell Medical or its 
designee for review and comment prior to submission to the reviewing IRB/EC.  The patient information 
document must be approved by the IRB/EC and contain all elements required by all applicable federal, 
state, local, and institutional regulations or requirements prior to study initiation.   
The proposed patient information document must contain a full explanation of the purpose and nature of 
the study, a description of the procedures, the possible advantages, risks, and a statement of 
confidentiality of patient study records,an explanation of whom to contact about the research, the patient’s 
rights, compensation, and notification that participation is voluntary and refusal will involve no penalty or 
loss of medical benefits.  These requirements are in accordance with the US Code of Federal Regulations 
(CFR) as detailed in the 21CFR50.25 and the Declaration of Helsinki.  The patient information document 
should also indicate that access to relevant medical records by Rockwell Medical and/or its duly 
appointed agent and by representatives of the Food and Drug Administration (FDA) or other applicable 
regulatory agency may be required and informs patients that their data may to be used in publications. 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
See Section 13.3.1. 
13.4 PARTICIPANT AND DATA CONFIDENTIALITY  
All investigational sites and laboratories or entities providing support for this study, must, where 
applicable, comply with all applicable data protection and patient confiendtiality regulations in force at the 
time of study initiation.   
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES,SPECIMENS OR DATA 
Data collected for this study will be analyzed and stored by the Sponsor.  No blood or serum sample 
retention is part of this study.   
All data collected is anonomized and may be provided to investigators for additional analysis upon 
acceptance of a protocol for data analysis. 
13.5 FUTURE USE OF STORED SPECIMENS  
N/A 
 
14 
DATA HANDLING AND RECORD KEEPING  


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14.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
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,  
 
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 patient, 
 
Any advertisements for this study, 
 
The Investigator’s final report to the IRB/EC, 
 
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 Investigator must advise Rockwell 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 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 or its 
designee. 
In the event of accidental loss or destruction of any study records, the Investigator will immediately notify 
Rockwell Medical or its designee 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. 
The laboratory facility intended to be used for analysis of clinical laboratory samples required by this 
protocol must provide evidence of adequate licensure or accreditation.  Reference values and/or normal 
ranges for the test results must be provided.  Rockwell or its designee must be notified immediately in 
writing of any changes occurring in reference values during the course of the study. 
Local and central laboratories used in the study may be asked to provide the following or its local 
equivalent: 
 
College of American Pathologist (CAP) accreditation, and/or 
 
Clinical Laboratory Improvement Amendments (CLIA) accreditation, 
 
Listing of laboratory normal reference values (for all protocol required tests), 
 
Laboratory license, 


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 
Curriculum vita of laboratory director may also be requested. 
14.2 STUDY RECORDS RETENTION  
The period of time these documents must be maintained is governed by US law and, when applicable, 
non-US regulations.  Some countries require these documents to be maintained for 15 years or longer.  
All records are to be retained by the Investigator for a minimum of two (2) years after the approval of a 
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 may request retention for a longer period of time.  Therefore, Rockwell or its 
designee will inform the Investigator when these documents may be destroyed.  The Investigator must 
obtain written approval from Rockwell prior to destruction of any records. 
14.2.1 INVESTIGATORS 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. 
14.3 PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or MOP requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
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 the Sponsor 
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 the 
Sponsor.  Examples of possible protocol deviations include, but are not limited to:  
 
Failure to provide required patient information,  
 
Failure to collect, report or file AE reports,  
 
Performance of an unapproved study procedure,  
 
Performance of research at an unapproved location, 
 
Failure to file protocol modifications, and 
 
Failure to adhere to an approved protocol.  
14.4 PUBLICATION AND DATA SHARING POLICY 


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 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 or its designee is 
obtained.  Rockwell Medical has full ownership of the CRFs and database resulting from this study. 
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. 
Data from the study will be made available under the regulations in force at each country participating in 
the study.  Final study data wil be posted to the Clinicaltrials.gov website according to requirements in 
force at the time of completion of the CSR.   
15 
STUDY ADMINISTRATION 
 
15.1 STUDY LEADERSHIP 
This study in under the leadership of Rockwell Medical Inc.  Rockwell Medical is responsible for 
coordination of study design, execution, monitoring, data mangagement, analysis and reporting. Rockwell 
Medical may designate certain activities to contract research organizations (CRO) as needed. 
 
16 
CONFLICT OF INTEREST POLICY 
Each Investigator is required to provide financial disclosure statements or certifications to Rockwell 
Medical or its designee prior to study initiation.  In accordance with the US 21CFR54 and other non-US 
regulations, Investigators and all sub-investigators are required to disclose all financial interests in 
Rockwell Medical in order to permit complete and accurate certification statements in an application for 
marketing authorization.  This includes compensation affected by the outcome of a clinical study, 
significant equity interest in Rockwell Medical, and proprietary interest in the tested product.  The 
Investigators must promptly update this information if any relevant changes occur during the course of the 
investigation and over the period of one year following completion of the investigation. 
17  
LITERATURE REFERENCES  
 
Reference List 
 
 
(1)  
Erslev AJ. Erythropoietin. N Engl J Med 1991;324:1339-1344. 
 
(2)  
KDIGO Anemia Work Group. KDIGO Clinical practice guideline for anemia in Chronic 
Kidney Disease. Kidney Int Suppl 2012;2:279-335. 


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(3)  
Levin NW. Quality of life and hematocrit level. Am J Kidney Dis 1992;20:16-20. 
 
(4)  
Lindsay RM, Burton JA, King P, Davidson JF, Boddy K, Kennedy AC. The measurement 
of dialyzer blood loss. Clin Nephrol 1973;1:24-28. 
 
(5)  
Silverberg DS, Iaina A, Peer G et al. Intravenous iron supplementation for the treatment 
of the anemia of moderate to severe chronic renal failure patients not receiving dialysis. Am J Kidney Dis 
1996;27:234-238. 
 
(6)  
Wingard RL, Parker RA, Ismail N, Hakim RM. Efficacy of oral iron therapy in patients 
receiving recombinant human erythropoietin. Am J Kidney Dis 1995;25:433-439. 
 
(7)  
Horl WH. Iron therapy for renal anemia: how much needed, how much harmful? Pediatr 
Nephrol 2007;22:480-489. 
 
(8)  
Wang C, Graham DJ, Kane RC et al. Comparative Risk of Anaphylactic Reactions 
Associated With Intravenous Iron Products. JAMA 2015;314:2062-2068. 
 
(9)  
Van Wyck DB. Labile iron: manifestations and clinical implications. J Am Soc Nephrol 
2004;15 Suppl 2:S107-S111. 
 
(10)  
Salahudeen AK, Oliver B, Bower JD, Roberts LJ. Increase in plasma esterified F2-
isoprostanes following intravenous iron infusion in patients on hemodialysis. Kidney Int 2001;60:1525-
1531. 
 
(11)  
Rostoker G, Vaziri ND. Iatrogenic iron overload and its potential consequences in 
patients on hemodialysis. Presse Med 2017;46:e312-e328. 
 
(12)  
Gupta A, Pratt R, Mishra B. Physicochemical characterization of ferric pyrophosphate 
citrate. Biometals 2018;31:1091-1099. 
 
(13)  
Pratt R, Handelman GJ, Edwards TE, Gupta A. Ferric pyrophosphate citrate: interactions 
with transferrin. Biometals 2018;31:1081-1089. 
 
(14)  
Rockwell Medical Inc. Investigator's Brochure Triferic (Ferric Pyrophosphate Citrate) 
V10.0. October 1, 2018. 
 
(15)  
Farrell PC, Ward RA, Schindhelm K, Gotch F. Precise anticoagulation for routine 
hemodialysis. J Lab Clin Med 1978;92:164-176. 
 
(16)  
Cronin RE, Reilly RF. Unfractionated heparin for hemodialysis: still the best option. 
Semin Dial 2010;23:510-515. 
 
(17)  
Kessler M, Moureau F, Nguyen P. Anticoagulation in Chronic Hemodialysis: Progress 
Toward an Optimal Approach. Semin Dial 2015;28:474-489. 
 
(18)  
Kaneva K, Bansal V, Hoppensteadt D, Cunanan J, Fareed J. Variations in the circulating 
heparin levels during maintenance hemodialysis in patients with end-stage renal disease. Clin Appl 
Thromb Hemost 2013;19:449-452. 
 
(19)  
Ward RA. Heparinization for routine hemodialysis. Adv Ren Replace Ther 1995;2:362-
370. 


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(20)  
Granolleras C, Zein A, Oules R, Branger B, Fourcade J, Shaldon S. Continuous 
administration of intravenous iron during haemodialysis. Nephrol Dial Transplant 1997;12:1007-1008. 
 
(21)  
Rockwell Medical Inc. Triferic (Ferric Pyrophosphate Citrate) US Package Insert.  2018.  
Ref Type: Pamphlet 
 
(22)  
Fishbane SN, Singh AK, Cournoyer SH et al. Ferric pyrophosphate citrate (Triferic) 
administration via the dialysate maintains hemoglobin and iron balance in chronic hemodialysis patients. 
Nephrol Dial Transplant 2015;30:2019-2026. 
 
(23)  
Gupta A, Lin V, Guss C, Pratt R, Ikizler TA, Besarab A. Ferric pyrophosphate citrate 
administered via dialysate reduces erythropoiesis-stimulating agent use and maintains hemoglobin in 
hemodialysis patients. Kidney Int 2015;88:1187-1194. 


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 Appendix 1: Protocol Revisions 
 
Version
Date
Significant Revisions 
1.1 
07/12/2019 
Corrected Clinical Laboratory 
Harmonized the figures with text
 
 
 
Appendix 2: Schedule of PK Assessments 
HEPARIN INFUSION PROTOCOL: 
Nominal T=0:  Draw baseline coagulation and serum iron profiles 
T=0 Administer UFH IV push at the patients usual bolus dose and start continuous infusion heparin at the 
usual rate to be administered over 3 hours of dialysis 
Triferic + heparin: mix together and administer at a rate to infuse the entire volume over 3 hours. 
Draw bloods from the arterial blood line port during HD; Post HD draw from peripheral vein or indwelling 
needle. 
Nom Time 
(Min) 
NomTime 
(hr.) 
Coag. 
Profile 
Serum Fe 
Profile 
Syringe 
Volume 
Calc Hep 
Inf Rate 
IU/hr
0
0
X 
X 
X 
 
5
0.08
X 
 
X 
 
30
0.5
X 
 
X 
X 
60
1
X 
X 
X 
X 
120
2
X 
X 
X 
X 
180
3
X 
X 
X 
X 
240
4
X 
X 
 
 
300
5
X 
X 
 
 
360
6
X 
X 
 
 
420
7
X 
X 
 
 
480
8
X 
X 
 
 
 
 
BLOOD DRAWS: 
Coag: BD 363083 2.7 mL blue top citrate tube: 12 X 2.7 X 3=108 mL 
aPTT, anti-Xa and PT  
sFe Profile: BD 367983 3.5 mL SST tube:  10 X 3.5 X3 = 105 mL 
 
sFe, TIBC, TSAT, Ferritin 


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Appendix 3: Visual Scale for Dialyzer Circuit Clotting 
 
 
 
Appendix 4:  Instructions for administration of heparin + Triferic and 
Triferic alone. 
PROTOCOL FOR TRIFERIC INFUSION WITH HEPARIN  
1. Heparin: Aseptically draw total treatment amount of heparin into the 10 mL syringe 
2. Remove needle 
3. Obtain  plastic  ampule of Triferic: wipe the tip with alcohol, open by twisting the top, hold the ampule 
vertically, screw the tip of the inverted syringe into the neck of the ampule, raise the ampule so that it 
is upside down. Draw Triferic solution into the syringe and invert to mix. 
2. CAUTION: Air should not be injected into the plastic ampule prior to drawing out the Triferic solution. 
Doing so may result in leakage of solution through the luer lock.  


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3. Unscrew the tip of the syringe from the luer lock in the neck of the ampule 
4. Inject ~0.25 to 0.4 mL of the solution into the heparin line in order to displace the saline present in the 
line. 
5. Mount the syringe on the heparin pump  
6. Start the heparin + Triferic infusion and program the pump to administer the entire volume. 
7. Set heparin infusion pump to end 1 hour before end of dialysis treatment, or as per unit policy for 
heparin infusion. 
(Note: for a 4 hour hemodialysis treatment, heparin infusion is usually given over the first 3 hours and 
Triferic would be infused concurrently with heparin over the first 3 hours of treatment) 
 PROTOCOL FOR TRIFERIC INFUSION WITHOUT HEPARIN  
1. Obtain  plastic ampule of Triferic: wipe the tip with alcohol, open by twisting the top, hold the ampule 
vertically, screw the tip of the inverted syringe into the neck of the ampule, raise the ampule so that it 
is upside down. Draw Triferic solution into the syringe.  
8. CAUTION: Air should not be injected into the plastic ampule prior to drawing out the Triferic solution. 
Doing so may result in leakage of solution through the luer lock.  
9. Unscrew the tip of the syringe from the luer lock in the neck of the ampule 
10. Inject an amount of the Triferic equal to the priming volume of the administration line (~0.25 to 0.4 
mL) in order to displace the saline present in the line 
11. Mount the syringe on the infusion pump  
12. Start infusion and administer over 3 hours of the dialysis session into the post dialyzer blood line (or 
drip chamber). 
PROTOCOL FOR HEPARIN INFUSION WITHOUT TRIFERIC  
1. Heparin: Aseptically draw total treatment amount of heparin into the 10 mL syringe 
2. Inject the priming bolus of heparin into the venous blood line 
3. Remove the needle and mount the syringe on the heparin pump  
4. Start the heparin and program the pump to administer the entire volume. 
5. Set heparin infusion pump to end 1 hour before end of dialysis treatment, or as per unit policy for 
heparin infusion. 
6. (Note: for a 4 hour hemodialysis treatment, heparin infusion is usually given over the first 3 hours and 
Triferic would be infused concurrently with heparin over the first 3 hours of treatment)