Clinical trial NCT02905981
Conditions: Iron-Refractory Iron-Deficiency Anemia
Keywords: IRIDA Triferic soluble ferric pyrophosphate Shohl's solution
Sponsor: Rockwell Medical Technologies, Inc.
Start date: 2017-01-17; Completion date: 2018-03-15
Enrollment: 1 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main purpose is to determine whether Triferic, administered orally with Shohl's solution, is safe and effective for the treatment of iron-refractory iron-deficiency anemia (IRIDA).

Detailed description:
This is an open label, 3-period study assessing the safety, efficacy, and pharmacokinetics of Triferic and Shohl's solution administered orally to patients with IRIDA. A total of 28 patients stratified by 4 age groups (age 0 to \<6 years, age 6 to \<12 years, age 12 to \<18 years, and age \>=18 years) will be studied.

Total participation in the study is between 4 weeks (Period 1) and 12 months (Periods 1, 2, and 3), depending upon how many Periods each patient participates in. Following screening, in Period 1 (iron absorption testing) patients undergo oral iron absorption testing during 3 visits to confirm that they adequately absorb iron from Triferic when it is administered with Shohl's solution ('Triferic responders': patients with a maximal increase from baseline in serum iron concentration \>100 micrograms per deciliter (μg/dL) following an oral Shohl's solution and Triferic dose).

The 'Triferic responders' from Period 1 are then invited to participate in Period 2 (dose titration). The patients will receive Shohl's solution and Triferic orally up to 3 times per day for 4 months, titrated as needed based on laboratory results and patient tolerance, to determine whether their hemoglobin levels respond to this treatment. Period 2 'hemoglobin responders' (patients with an increase from baseline in hemoglobin (Hgb) concentration ≥1.0 grams per deciliter (g/dL) at Visit 9) will be invited to participate in period 3.

In Period 3 patients will receive Shohl's solution and Triferic orally up to 3 times per day for an additional 6 months to determine whether the hemoglobin response observed in Period 2 is sustainable. During Period 3, Shohl's solution and Triferic dose and frequency may continue to be titrated as needed based on laboratory results and patient tolerance.

A follow-up visit will occur approximately 1 week after the last completed Period study visit, regardless of the Period that the patient completes the study.

Arms: arm 1: During 3 consecutive weekly study visits, patients will receive Fer-In- Sol orally 3 milligram iron per kilogram (mg Fe/kg) body weight, Shohl's solution 0.67 millimoles per kilogram (mmol/kg) followed 5 - 15 minutes later by Fer-In- Sol orally 3 mg Fe/kg body weight, and Shohl's solution 0.67 mmol/kg followed 5 - 15 minutes later by Triferic orally 3 mg Fe/kg body weight (respectively). All oral doses will be administered by study personnel at the research center. Blood tests will be conducted following each administration in order to measure iron absorption to see if patients qualify for Period 2. arm 2: Patients who qualified as 'Triferic responders' in Period 1 will participate in Period 2. Patients will be given oral Shohl's solution and Triferic to administer at home 3 times per day, with the dose being titrated higher or lower based on lab results. The initial dose will be the same as Period 1 (Shohl's solution 0.67 mmol/kg followed 5 - 15 minutes later by Triferic orally 3 mg Fe/kg body weight) but may be adjusted during Period 2 based on lab results. Period 2 will involve 5 study visits, scheduled every 4 weeks. At the end of Period 2, blood tests will be performed to determine if patients qualify for Period 3. arm 3: Patients who qualified as 'hemoglobin responders' in Period 2 will participate in Period 3. Patients will continue to take Shohl's solution and Triferic at their titrated dose for an additional six months to confirm that their hemoglobin can be maintained over an extended period of time. The period will be comprised of 3 study visits, scheduled every 8 weeks.
Interventions: intervention 1: Fer-In-Sol intervention 2: Shohl's solution intervention 3: Triferic
Intervention descriptions: intervention 1: Fer-In-Sol is an over-the-counter oral iron supplement. It will be administered during Period 1 at a dose of 3 mg/kg body weight. intervention 2: Shohl's solution will be supplied as 500-milliliter (mL) bottles containing citric acid United States Pharmacopeia (USP) 640 milligrams per 5 milliliters (mg/5 mL) and hydrous sodium citrate USP 490 mg/5 mL. It will be administered during all Periods at a dose of 0.67 mmol/kg body weight. intervention 3: Triferic is an iron salt that is approved by the Food and Drug Administration (FDA) for the maintenance of hemoglobin in patients with end stage kidney disease on hemodialysis. It is experimental in this study because it has not yet been approved for patients with IRIDA. It will be administered during Period 1 at a dose of 3 mg/kg body weight. In Periods 2 and 3 the dose may be adjusted based on lab results.

Protocol documents:
Prot_SAP_000.pdf: 
Rockwell Medical Inc. CONFIDENTIAL/PROPRIETARY 
  
Protocol RMFPC-15 
 
08 March 2017 
 
 
Page 1 
 
Clinical Research Protocol 
 
Triferic (Ferric Pyrophosphate Citrate) Administered Orally with 
Shohl’s Solution for the Treatment of Iron-Refractory Iron-
Deficiency Anemia 
 
IND Number: 
125570 
Protocol Number:  
RMFPC-15 
Version: 
Clinical Phase:  
1.3 
2 
Investigational Drug:  
Triferic (Ferric Pyrophosphate Citrate) 
Indication: 
Iron-Refractory Iron-Deficiency Anemia 
Sponsor Signatory: 
Raymond D Pratt, MD FACP 
 
Chief Medical Officer 
Rockwell Medical Inc. 
Principal Investigator: 
 
 
 
 
Original Protocol Date: 
19 November 2015 
Amendment 1 Date: 
17 December 2015 
Amendment 2 Date: 
21 December 2015 
Amendment 3 Date: 
08 March 2017 
 
 
CONFIDENTIALITY STATEMENT 
Information in this protocol is confidential and should not be disclosed, other than to those directly 
involved in the execution or the ethical review of the study, without written authorization from 
Rockwell Medical. 


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PROTOCOL APPROVAL PAGE 
Study Title: 
Triferic (Ferric Pyrophosphate Citrate) Administered Orally 
with Shohl’s Solution for the Treatment of Iron-Refractory Iron-
Deficiency Anemia 
Protocol 
Number: 
RMFPC-15 
Version: 
1.3 
Date of Issue: 
 
08 March 2017 
Sponsor Name 
and Address: 
 
Rockwell Medical Inc. 
30142 S. Wixom Rd 
Wixom, MI 48393 
 
 
I, the undersigned, have read and approve this protocol and agree on its content. It 
is confirmed that the information and guidance given in this protocol complies with 
scientific principles, the guidelines of Good Clinical Practice, the Declaration of 
Helsinki in the latest relevant version, and the applicable legal and regulatory 
requirements. 
 
 
 
 
 
 
 
Sponsor Signatory:  
 
 
 
Raymond D Pratt, MD FACP 
Chief Medical Officer 
 
(Date) 
 
 


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Protocol RMFPC-15 
 
08 March 2017 
 
 
 
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INVESTIGATOR PROTOCOL AGREEMENT 
Protocol Title: 
Triferic (Ferric Pyrophosphate Citrate) Administered Orally 
with Shohl’s Solution for the Treatment of Iron-Refractory Iron-
Deficiency Anemia 
Protocol Number: RMFPC-15 
Version: 1.3 
 
 
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 FDA regulations, the International Conference on 
Harmonisation (ICH) GCP guidelines, the Declaration of Helsinki, and all 
applicable rules, regulations, and federal, state, and local laws relating to the 
conduct of clinical studies and the protection of human 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 US Food and Drug Administration (FDA), local governing 
regulatory bodies, and IRB/EC inspectors. 
 
 
 
Investigator's Signature 
 
Date 
 
 
 
Print Name 
 
 


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Protocol RMFPC-15 
 
08 March 2017 
 
 
 
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SYNOPSIS 
PROTOCOL TITLE 
Triferic (Ferric Pyrophosphate Citrate) Administered Orally with 
Shohl’s Solution for the Treatment of Iron-Refractory Iron-Deficiency 
Anemia 
PROTOCOL 
NUMBER 
RMFPC-15 
SPONSOR 
Rockwell Medical Inc. 
INVESTIGATIONAL 
PRODUCT 
Triferic® (ferric pyrophosphate citrate) 
STUDY 
OBJECTIVE 
Primary Objective 
The primary objective is to determine whether Triferic, administered 
orally with Shohl’s solution, is safe and effective for the treatment of 
iron-refractory iron-deficiency anemia (IRIDA). 
Secondary Objective 
The secondary objectives are: 
• 
To compare the results of 4-hour iron-absorption tests conducted 
after administration of (i) ferrous sulfate, 3 mg Fe/kg; (ii) Shohl’s 
solution, 0.67 mmol/kg, followed by ferrous sulfate, 3 mg Fe/kg; 
and (iii) Shohl’s solution, 0.67 mmol/kg, followed by Triferic, 3 mg 
Fe/kg 
• 
To determine the effect on hemoglobin concentration of a 4-
month trial of QD-TID oral iron therapy, given as Shohl’s solution, 
0.67 mmol/kg, followed by Triferic, 1 to 3 mg Fe/kg, titrated as 
needed based on laboratory results and patient tolerance 
• 
To determine the sustainability of response to Shohl’s solution 
and Triferic by an additional 6-month trial of QD-TID oral iron 
therapy, given as Shohl’s solution, 0.67 mmol/kg, followed by 
Triferic, 1 to 3 mg Fe/kg, titrated as needed based on laboratory 
results and patient tolerance 
STUDY DESIGN & 
DURATION 
Open-label, three-period study. Following screening, eligible patients 
will undergo oral iron absorption testing during 3 visits during Period 
1. Visit 4 responders will then take Shohl’s solution and Triferic orally 
QD-TID for 4 months, with the dose and frequency titrated as needed 
based on laboratory results and patient tolerance. Visit 9 responders 
will continue treatment for 6 additional months during Period 3. A 
follow-up visit will occur approximately 1 week afterwards. The 


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duration from screening to the last study visit will be approximately 
12 months. 
Study Design Schematic: 
 
NUMBER OF 
PLANNED  
PATIENTS  
A total of 28 patients with IRIDA will be enrolled in this study.  
Patients will be stratified into 4 age groups as follows:    
• 
<6 years 
• 
6 years to <12 years 
• 
12 to <18 years 
• 
≥18 years 
INVESTIGATIONAL 
SITES 
TBD 
PARTICIPATING 
COUNTRIES 
US 
 
PATIENT 
POPULATION 
Adult and pediatric patients with iron-refractory iron-deficiency 
anemia (IRIDA) 
INCLUSION AND 
EXCLUSION 
CRITERIA 
Inclusion Criteria 
1. Adult patients have provided informed consent and have signed 
the informed consent form. For pediatric patients, parents/legal 
guardians of the patient have the ability to understand the 
requirements of the study and have demonstrated a willingness 
to have their child comply with all study procedures by signing the 
informed consent form.  Where applicable, assent of the pediatric 
patient has also been obtained for all study procedures prior to 
any study-related activities. 
2. Patient has a history of congenital hypochromic microcytic 
anemia. 
3. Patient has a mean corpuscular volume (MCV) below the lower 
limit of normal for the clinical laboratory value at screening. 
4. Patient has a serum transferrin saturation ≤15% at screening. 


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5. Patient has a history of no or incomplete response to oral iron 
therapy. 
6. Patient has a history of no or incomplete response to intravenous 
iron administration. 
7. Patient has a history of hepcidin values that are elevated relative 
to the mean value for patients with iron deficiency anemia. 
8. Patient is documented to have homozygous or compound 
heterozygous pathogenic mutations in TMPRSS6.  
9. Patient has appropriate laboratory values for their disease state 
at screening (per investigator judgment). 
10. Patient has no significant abnormal findings on physical 
examination at screening that would preclude participation in the 
study (per investigator judgment). 
11. If the patient is female, she must be pre-pubertal, have had 
documented surgical sterilization ≥2 years prior to screening, or 
be practicing adequate birth control.  All female patients 9 years 
of age and older, and also any who have reached menarche 
before age 9 years, must have a negative serum pregnancy test 
during screening. It is the investigator’s responsibility to 
determine whether the patient has adequate birth control for 
study participation. 
Exclusion Criteria 
A patient will not be eligible for inclusion in the study if any of the 
following criteria apply: 
1. Patient has had IV or oral iron supplements within 2 weeks prior 
to Visit 2. 
2. Patient has had a blood transfusion within 3 months prior to Visit 
2. 
3. Patient is receiving intravenous or oral antibiotics or antifungals 
for any infectious process.  Prophylactic antibiotics administered 
on a regular basis are allowed.  Otherwise-eligible patients may 
be rescreened when they have recovered from any acute 
illnesses. 
4. Patient has a body weight of <11 lbs (5 kg) at screening. 
5. Patient has participated in an investigational drug study within the 
30 days prior to Visit 2. 


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6. Patient has any condition that, in the opinion of the investigator, 
is likely to prevent the patient from complying with or successfully 
completing the protocol. 
EFFICACY 
ENDPOINTS 
Primary Endpoint 
• 
The change from baseline in hemoglobin concentration (Hgb) at 
4 months 
Key Secondary Endpoint 
 
• 
The change from baseline in serum iron and TSAT at 4 months 
Additional Secondary Endpoints  
• 
The change from baseline in Hgb, RBC, MCV, reticulocyte count, 
reticulocyte Hgb (CHr), serum iron, TIBC, ferritin, UIBC, TSAT, 
and soluble transferrin receptor (sTfR) and hepcidin 
concentrations every 4 weeks and at end-of-treatment (EoT) 
• 
The incidence of hemoglobin responders (patients with an 
increase from baseline in Hgb concentration ≥1.0 g/dL) every 4 
weeks and at EoT 
• 
The serum iron Cmax following oral Shohl’s solution 0.67 mmol/kg 
and Triferic 3 mg Fe/kg body weight 
• 
The incidence of Triferic responders (patients with a maximal 
increase from baseline in serum iron concentration >15 µg/dL 
following oral Shohl’s solution 0.67 mmol/kg and Triferic 3 mg 
Fe/kg body weight) 
SAFETY 
ENDPOINTS 
• 
Incidence of treatment-emergent adverse events and serious 
adverse events 
• 
Changes in clinical laboratory tests, vital signs, and weight 
STATISTICAL 
METHODS 
Where appropriate, the normality of data will assessed before 
analysis by using the Shapiro-Wilk test and graphically by evaluating 
histograms and Q-Q plots. Data not normally distributed will be log 
transformed for analysis. Log-transformed data will be back 
transformed for reporting. Normally distributed data will be presented 
as means (±SDs, ±95% confidence intervals (CI), or both), data 
normally distributed after log transformation will be presented as 
geometric means (±95% CI), and non-normally distributed data will 
be presented as medians and ranges. The baseline demographic 
and clinical characteristics of the study population will be presented 
in tabular form. For the primary and key secondary endpoints, a 
summary of results with the estimated effect size and its precision 
will be reported. Differences in changes between baseline and 4-
month and subsequent 6-month measurements will be compared. 


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A study-specific statistical analysis plan (SAP) will be written and 
finalized prior to any lock of the study database. The SAP will give a 
detailed description of the summaries and analyses (primary and 
secondary) that will be performed. 


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TABLE OF CONTENTS 
 
Page 
PROTOCOL APPROVAL PAGE............................................................................... 2 
INVESTIGATOR PROTOCOL AGREEMENT ........................................................... 3 
SYNOPSIS ................................................................................................................ 4 
TABLE OF CONTENTS ............................................................................................ 9 
LIST OF IN-TEXT FIGURES ................................................................................... 12 
ABBREVIATIONS ................................................................................................... 13 
1. INTRODUCTION ............................................................................................... 15 
1.1. Current Therapies/Treatments..............................................................................15 
1.2. Rationale for Development ....................................................................................16 
1.3. Description of Study Drugs....................................................................................17 
1.4. Previous Clinical Experience with Triferic ...........................................................17 
1.5. Rationale for the Current Study ............................................................................19 
1.6. Justification for Dose ..............................................................................................20 
2. STUDY OBJECTIVES ....................................................................................... 21 
2.1. Primary Objective ....................................................................................................21 
2.2. Secondary Objectives ............................................................................................21 
3. INVESTIGATIONAL PLAN ............................................................................... 21 
3.1. Overall Study Design and Plan .............................................................................21 
3.2. Endpoints .................................................................................................................23 
3.2.1. 
Efficacy Endpoints ....................................................................... 23 
3.2.1.1. Primary 23 
3.2.1.2. Secondary ............................................................................. 23 
3.2.2. 
Safety Endpoints .......................................................................... 23 
4. SELECTION OF STUDY POPULATION .......................................................... 24 
4.1. Inclusion Criteria .....................................................................................................24 
4.2. Exclusion Criteria ....................................................................................................25 
4.3. Removal of Patients from Therapy/Premature Discontinuation ......................25 
4.4. Study Discontinuation ............................................................................................26 
5. TREATMENTS .................................................................................................. 26 
5.1. Treatments Administered ......................................................................................26 
5.2. Identity of Investigational Products(s)..................................................................26 
5.2.1. 
Labeling ....................................................................................... 27 
5.2.2. 
Storage and Handling .................................................................. 27 
5.3. Method of Assigning Patients to Treatment Groups .........................................27 
5.3.1. 
Treatment Assignment/Randomization ........................................ 27 


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5.4. Selection and Timing of Dose for Each Patient .................................................27 
5.5. Procedures for Blinding..........................................................................................28 
5.6. Prior and Concomitant Therapy............................................................................28 
5.6.1. 
Prior Therapy ............................................................................... 28 
5.6.2. 
Concomitant Therapy ................................................................... 28 
5.6.3. 
Prohibited Medications ................................................................. 29 
5.7. Treatment Compliance ...........................................................................................29 
5.7.1. 
Study Drug Accountability ............................................................ 29 
6. STUDY ASSESSMENTS AND PROCEDURES ............................................... 29 
6.1. Study Visits ..............................................................................................................29 
6.1.1. 
Screening (Week -4 through Day -1)............................................ 30 
6.1.1.1. Screening Visit (Visit 1) .......................................................... 30 
6.1.2. 
Period 1: Iron Absorption Testing (Visits 2-4, Weeks 1-3) ............ 30 
6.1.2.1. Study Procedures .................................................................. 30 
6.1.2.2. Study Drug ............................................................................. 31 
6.1.3. 
Period 2: Dose Titration (Visits 5-9, Weeks 4-20) ........................ 31 
6.1.4. 
Period 3: Hemoglobin Maintenance (Visits 10-12, Weeks 21-
44) ................................................................................................ 32 
6.1.5. 
Follow-up/Early Termination (Visit 13) ......................................... 33 
6.2. Study Assessments ................................................................................................33 
6.2.1. 
Laboratory Assessments .............................................................. 33 
6.2.1.1. Hepcidin 33 
6.2.1.2. Non-Transferrin-Bound Iron (NTBI) and Labile Plasma Iron 
(LPI) 
33 
6.2.1.3. All Other Laboratory Assessments ........................................ 33 
6.2.1.4. Collecting, Processing, and Shipping Samples ..................... 33 
6.2.2. 
Assessment of Safety .................................................................. 34 
6.2.2.1. Clinical Laboratory Tests ....................................................... 35 
6.2.2.2. Physical Examinations ........................................................... 35 
6.2.2.3. Vital Signs .............................................................................. 35 
7. ADVERSE EVENTS .......................................................................................... 35 
7.1. Definition of an Adverse Event .............................................................................36 
7.2. Definition of a Serious Adverse Event .................................................................36 
7.3. Method, Frequency, and Time Period for Detecting Adverse Events and 
Serious Adverse Events ........................................................................................37 
7.4. Reporting SAEs .......................................................................................................38 
7.4.1. 
Timeframes for Reporting SAEs .................................................. 39 
7.4.2. 
SAE Information to Report ........................................................... 39 
7.4.3. 
Regulatory/Ethics Reporting Requirement ................................... 39 


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7.5. Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs40 
7.6. Documenting AEs ...................................................................................................40 
7.7. Follow-up of AEs .....................................................................................................40 
7.8. Post-study AEs ........................................................................................................41 
8. STATISTICS ..................................................................................................... 42 
8.1. General Considerations .........................................................................................42 
8.2. Determination of Sample Size ..............................................................................42 
8.3. Analysis Populations ..............................................................................................43 
8.4. Patient Disposition ..................................................................................................43 
8.5. Baseline Characteristics ........................................................................................43 
8.6. Concomitant Medications ......................................................................................43 
8.7. Extent of Exposure .................................................................................................43 
8.8. Safety Assessments ...............................................................................................43 
8.8.1. 
Adverse Events ............................................................................ 43 
8.8.2. 
Clinical Laboratory Assessments ................................................. 44 
8.8.3. 
Vital Signs .................................................................................... 44 
8.9. Statistical and Analytical Issues ...........................................................................44 
8.9.1. 
Statistical Analysis Plan ............................................................... 44 
8.9.2. 
Handling of Missing Data ............................................................. 44 
8.9.3. 
Interim Analyses and Data Monitoring ......................................... 44 
8.9.4. 
Criteria for Stopping the Study ..................................................... 44 
9. STUDY ADMINISTRATION .............................................................................. 45 
9.1. Sponsor’s and Investigator’s Responsibilities ....................................................45 
9.2. Sponsor’s Responsibilities ....................................................................................45 
9.2.1. 
GCP Compliance ......................................................................... 45 
9.2.2. 
Regulatory Approval..................................................................... 45 
9.2.3. 
Indemnity/Liability and Insurance ................................................. 45 
9.2.4. 
Protocol Conduct ......................................................................... 46 
9.2.4.1. Protocol Compliance and Protocol Deviations ....................... 46 
9.2.4.2. Protocol Amendments ........................................................... 46 
9.3. Investigator’s Responsibilities ...............................................................................47 
9.3.1. 
GCP Compliance ......................................................................... 47 
9.3.2. 
Protocol Adherence and Investigator Agreement ......................... 47 
9.3.3. 
Documentation and Retention of Records ................................... 47 
9.3.3.1. Case Report Forms ............................................................... 47 
9.3.3.2. Site Visits ............................................................................... 48 
9.3.3.3. Recording, Access and Retention of Source Data ................. 48 
9.3.4. 
Investigator’s Final Report ........................................................... 49 


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9.4. Ethical Considerations ...........................................................................................50 
9.5. Informed Consent ...................................................................................................50 
9.5.1. 
Institutional Review Board or Ethics Committee Approval ........... 50 
9.6. Confidentiality ..........................................................................................................51 
10. DISCLOSURE OF DATA AND PUBLICATION ................................................ 51 
11. REFERENCES .................................................................................................. 52 
APPENDIX 1. TIME AND EVENTS SCHEDULE .................................................... 55 
APPENDIX 2. SERUM IRON PARAMETER SAMPLE COLLECTION 
SCHEDULE, VISITS 2-4 ................................................................................... 56 
APPENDIX 3. SAMPLE HANDLING, STORAGE & SHIPPING.............................. 59 
APPENDIX 4. DETAILED INSTRUCTIONS FOR STUDY DRUG DOSING ............ 60 
APPENDIX 5. STUDY DRUG DOSING SCHEDULES ............................................ 65 
 
LIST OF IN-TEXT TABLES 
 
Page 
Table 1: Summary of Clinical Studies Conducted with Triferic in Adults .................. 17 
Table 2: Time and Events Schedule ........................................................................ 55 
Table 3: Sample Collection Schedule, Visit 2 .......................................................... 56 
Table 4: Sample Collection Schedule, Visit 3 .......................................................... 57 
Table 5: Sample Collection Schedule, Visit 4 .......................................................... 58 
Table 6: Study Drug Dosing, Visit 2 ......................................................................... 65 
Table 7: Study Drug Dosing, Visit 3 ......................................................................... 66 
Table 8: Study Drug Dosing, Visit 4 ......................................................................... 67 
Table 9: Study Drug Dosing, Periods 2 and 3 .......................................................... 68 
 
LIST OF IN-TEXT FIGURES 
 
Page 
Figure 1:  TMPRSS6 Gene Structure and Mutations ............................................... 15 
Figure 2:  Four-hour Oral Iron-absorption Test ........................................................ 20 
Figure 3. Study Design Schematic .......................................................................... 22 
 
 
 
 


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ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine transaminase (SGPT) 
AST 
aspartate transaminase (SGOT) 
ATC 
anatomical therapeutic chemical  
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CHr 
reticulocyte hemoglobin concentration 
CI 
confidence interval 
CKD-5HD 
chronic kidney disease, stage 5, on hemodialysis 
CL/F 
apparent clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
peak serum concentration, observed 
CMRC 
Children’s Memorial Research Center 
CNS 
central nervous system 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CUB 
complement factor CIs/CIr, urchin embryonic growth factor, 
bone morphogenic protein 1 
CV 
cardiovascular 
DNA 
deoxyribonucleic acid 
EC 
ethics committee 
ECG 
electrocardiogram 
ENT 
ear, nose, and throat 
EoT 
end-of-treatment 
EU 
European Union 
FDA 
Food and Drug Administration  
Fe 
iron 
FeSO4 
iron sulfate 
FPC 
Triferic (ferric pyrophosphate citrate) 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HD 
hemodialysis 
Hgb 
hemoglobin concentration 
HIPAA 
Health Insurance Portability and Accountability Act (of 1996) 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IND 
investigational new drug 
IRB 
institutional review board 
IRIDA 
iron-refractory iron-deficiency anemia 


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IV 
Intravenous 
LDLRA 
low density lipoprotein receptor class A 
LPI 
labile plasma iron 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
modified intent-to-treat 
Mr 
relative molecular mass 
MT-2 
matriptase-2 
NA 
North America 
NPO 
nothing by mouth 
NTBI 
non-transferrin-bound iron 
OMIM 
Online Mendelian Inheritance in Man 
PHI 
protected health information 
PK 
pharmacokinetic  
QD 
once daily 
RBC 
red blood cell count 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SEA 
sea urchin sperm protein, enteropeptidase, agrin 
sTfR 
soluble transferrin receptor 
TBD 
to be determined 
TBI 
transferrin-bound iron 
TBV 
total blood volume 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TIBC 
total iron-binding capacity 
TID 
three times daily 
TMPRSS6 
gene encoding matriptase-2 
TSAT 
transferrin saturation 
UIBC 
unsaturated iron-binding capacity 
US 
United States 
USP 
United States pharmacopeia 
WBC 
white blood cell 
WCX-TOF MS 
weak cation exchange chromatography in combination 
with time-of-flight mass spectrometry 
WHO 
World Health Organization 
 
 
 


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1.   
INTRODUCTION 
1.1.   Current Therapies/Treatments 
Iron-refractory iron-deficiency anemia (IRIDA; OMIM 206200) is a rare autosomal-
recessive disorder characterized by iron-deficiency anemia unresponsive to oral iron 
therapy and a delayed, incomplete response to parenteral iron treatment.1-3 Patients 
have a congenital microcytic, hypochromic anemia, low plasma iron and transferrin 
saturation, and a normal or decreased serum ferritin concentration. The mutations 
responsible are in the gene TMPRSS6, which encodes matriptase-2 (MT-2), a type II 
plasma membrane serine protease that cleaves hemojuvelin4 to negatively regulate 
hepcidin, the systemic iron-regulatory protein.2,5,6 Hepcidin acts by binding to and 
inactivating the iron-export protein, ferroportin, preventing the efflux of iron from 
enterocytes, macrophages, and hepatocytes into plasma for transport by transferrin 
to the erythroid marrow and other tissues.7 The TMPRSS6 gene mutations result in 
inappropriately high plasma hepcidin concentrations, leading to obstruction both of 
iron absorption by enterocytes and of iron release from macrophages and 
hepatocytes.1,3 At present, 51 unrelated families with 74 patients with 58 TMPRSS6 
mutations resulting in iron-refractory iron-deficiency anemia have been described.8 
The responsible mutations seem to be sporadic and to lack any specific 
geographical or ethnic distribution. The diversity of the mutations is illustrated 
graphically in Figure 1.6   
Figure 1:  TMPRSS6 Gene Structure and Mutations 
The genomic organization and the corresponding structural domains of matriptase-2 with currently 
identified mutations reported in patients with IRIDA are shown. The missense, nonsense, frame shift 
and splice junction mutations are shown in green, blue, red and purple arrows, respectively. One in-
frame deletion is boxed in gray. The mutations highlighted in red represent those that appear to have 
haploinsufficiency.6 Shown are 42 mutations known at the time of the preparation of this figure; an 
additional 16 mutations have since been reported.8 
Functional studies of the mutations have found considerable variability. The SEA 
(sea urchin sperm protein, enteropeptidase, agrin) and LDLRA (low density 
lipoprotein receptor class A) domains of matriptase-2 are important for trafficking to 
the cell surface while the CUB (complement factor Cls/Clr, urchin embryonic growth 


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factor, bone morphogenic protein 1), LDLRA and serine protease domains are 
required for cleavage of hemojuvelin.4,23-25 
The phenotypic expression of iron-refractory iron-deficiency anemia reflects the 
underlying heterogeneity of the responsible mutations, apparently depending on 
whether hepcidin inhibition is completely or partially abolished.1,2,6,8,22,25 With 
mutations with less hepcidin inhibition, oral iron, with or without ascorbic acid, may 
provide partial correction of the anemia.26-28 While patients heterozygous for 
pathogenic mutations in TMPRSS6 may be more susceptible to the development of 
iron deficiency, expression of the phenotype of iron-refractory iron-deficiency anemia 
requires homozygous or compound heterozygous pathogenic mutations. 
Furthermore, a variety of TMPRSS6 polymorphisms that are not associated with 
iron-refractory iron-deficiency anemia have been reported29, other conditions may 
mimic some features of the disorder30,31, and the diagnosis of congenital microcytic 
anemia is complex.32,33  
In the most severely affected, oral iron therapy is entirely ineffective and the 
response to parenteral iron is delayed and incomplete. The available parenteral iron 
preparations are iron-carbohydrate complexes that must first be taken up and 
processed by reticuloendothelial macrophages to free the iron from the carbohydrate 
for subsequent export via ferroportin. Consequently, parenteral iron treatment is 
unable to circumvent the hepcidin-induced block in iron export and produces only a 
sluggish, partial correction of the microcytic anemia.1,3   
1.2.   Rationale for Development 
Ferric pyrophosphate citrate (Triferic®) can donate iron directly to transferrin without 
first requiring macrophage processing. Consequently, it may provide a means to 
bypass the hepcidin-induced obstruction of ferroportin iron export underlying IRIDA. 
Citrate (given as Shohl’s solution), a tricarboxylic anion, can complex with calcium in 
the proximal gastrointestinal tract, opening intracellular tight junctions and permitting 
paracellular uptake of soluble complexes.12-17 Citrate-induced paracellular 
absorption of aluminum was responsible for increased absorption of aluminum and 
aluminum toxicity in patients with renal failure treated with aluminum citrate for 
control of hyperphosphatemia.13-17 Ferric citrate, recently approved in Japan for 
control of hyperphosphatemia in patients with chronic kidney disease,18 increases 
transferrin saturation and serum ferritin over 12 weeks of administration.19 
In patients with iron-refractory iron-deficiency anemia, we hypothesize that oral co-
administration of Triferic with Shohl’s solution will bypass the hepcidin-mediated 
block of enterocyte iron uptake by permitting paracellular absorption (i) of intact 
Triferic that reaches the proximal duodenum and jejunum, with subsequent direct 
donation of iron to transferrin, and (ii) of iron derived from Triferic. We also will 


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examine the effects of oral co-administration of conventional ferrous sulfate (FeSO4) 
with Shohl’s solution. 
1.3.   Description of Study Drugs 
Ferric pyrophosphate citrate (Triferic®; Rockwell Medical, Wixom, MI) 
[Fe4(C6H5O7)3(P2O7)3] is a low-molecular-weight iron salt (Mr 1313). It is currently 
approved as an iron-replacement therapy that is added to the dialysate and 
administered during hemodialysis in adult patients with hemodialysis-dependent 
chronic kidney disease. Food-grade soluble ferric pyrophosphate11 is widely used to 
fortify milk drinks and infant formula. Triferic has a neutral to slightly salty taste when 
administered orally. Triferic administered orally may be diluted with water or simple 
sugar syrup (in a maximum dilution ratio of up to 1:2 Triferic:sugar), but dilution is 
not necessary. If needed, Triferic may be administered orally using an oral 
medication syringe. After several patients have been enrolled in the study, we plan 
to develop an appropriate dose form for oral use and storage.   
Citrate (as Shohl’s solution, e.g., Oracit®; CMP Pharma, Farmville, NC) is a buffer of 
sodium citrate and citric acid that is used for prolonged treatment of children with 
cystinuria and some forms of renal tubular acidosis.20,21 Citrate administered orally 
may be diluted with water or simple sugar syrup (in a maximum dilution ratio of up to 
1:2 Citrate:sugar), but dilution is not necessary. The dosing of citrate for all US sites 
will be as Oracit. However, if Oracit is not available (e.g., in the European Union 
(EU), if the protocol is amended to include EU sites), any brand of Shohl’s solution 
that contains sodium citrate may be used based on local availability.  
Ferrous sulfate (Fer-In-Sol®, Mead Johnson, Glenview, IL) is available over-the-
counter as an iron supplement. 
1.4.   Previous Clinical Experience with Triferic 
Table 1: Summary of Clinical Studies Conducted with Triferic in Adults 
Protocol 
Number 
Country  
(# sites) 
Study Design and Phase 
Treatment 
Groups 
Patient N 
Treatment 
Duration 
SFP-8 
US 
1 site 
Phase ½, single-dose, PK in 
CKD-5HD patients 
Triferic 2 µM 
Placebo 
12 
6 individual HD 
sessions  
SFP-9 
US 
1 site 
Phase 1, single dose in 
healthy volunteers 
 
Triferic mg IV: 
2.5 mg/4 hr 
5.0 mg/4 hr 
48 
Single Ascending 
Dose 


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Protocol 
Number 
Country  
(# sites) 
Study Design and Phase 
Treatment 
Groups 
Patient N 
Treatment 
Duration 
7.5 mg/4 hr 
10 mg/4 hr 
15 mg/12 hr 
20 mg/12 hr 
Placebo 
 
 
FPC-12 
US 
1 site 
Phase 1, two single 
sequential doses in healthy 
volunteers 
Triferic: 
6 mg IV/3 hr 
35 µg/kg IV push 
12 
Two single 
sequential doses 
SFP-1 
US 
1 site 
Phase 2, randomized, open-
label parallel group 
Placebo-controlled 
Dose escalation 
Triferic iron µg/L 
dialysate: 
0, 20, 40, 80 and 
120 
 
24 
27 weeks 
Monthly dose 
escalation 
SFP-2 
US 
29 sites 
Phase 2, randomized, double-
blind, parallel group 
Placebo-controlled 
Dose escalation 
Triferic iron µg/L 
dialysate: 
0, 50, 100, 120 
and 150 
 
136 
26 weeks 
SFP-3 
US 
2 sites 
Phase 2, double-blind 
Crossover 
Triferic 130 µg/L  
(food grade) 
Triferic 130 µg/L  
(GMP) 
33 
2X2 weeks 
NIH-FP-01 
US 
23 sites 
Phase 2, randomized, double-
blind, parallel group 
Placebo-controlled 
Triferic 2 µM (110 
µg/L) 
Placebo 
108 
36 weeks 
NIH-FP-01 
Addendum 
US 
Phase 2, randomized, double-
blind, parallel group 
Triferic 2 µM (110 
µg/L) 
11 


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Protocol 
Number 
Country  
(# sites) 
Study Design and Phase 
Treatment 
Groups 
Patient N 
Treatment 
Duration 
1 site 
Placebo-controlled 
Placebo 
36 weeks 
SFP-4-RC 
NA 
44 sites 
Phase 3, randomized, double-
blind, parallel group 
Placebo-controlled 
Triferic 2 µM (110 
µg/L) 
Placebo 
305 
Up to 48 weeks 
SFP-4-OL 
NA 
38 sites 
Phase 3, open-label extension 
Triferic 2 µM (110 
µg/L) 
207 
24 weeks or a total 
of 72 weeks 
SFP-5-RC 
NA 
41 sites 
Phase 3, randomized, double-
blind, parallel group 
Placebo-controlled 
 
Triferic 2 µM (110 
µg/L) 
Placebo 
294 
Up to 48 weeks 
SFP-5-OL 
NA 
37 sites 
Phase 3, open-label extension 
Triferic 2 µM (110 
µg/L) 
214 
24 weeks or a total 
of 72 weeks 
SFP-6-RC 
NA 
51 sites 
Phase 3, double-blind 
Crossover 
Placebo-controlled 
Triferic 2 µM (110 
µg/L) 
Placebo 
718 
2X2 weeks 
SFP-6-OL 
NA 
34 sites 
Phase 3, open-label extension 
Triferic 2 µM (110 
µg/L) 
310 
48 weeks 
NA=North America 
1.5.   Rationale for the Current Study 
The current study is designed to determine whether Triferic, given with Shohl’s 
solution, is safe and effective for the treatment of IRIDA.  
First, the results of 4-hour oral iron-absorption tests (see Figure 2) conducted after 
administration of (i) FeSO4, 3 mg Fe/kg; (ii) Shohl’s solution, 0.67 mmol/kg, followed 
by FeSO4, 3 mg Fe/kg; and (iii) Shohl’s solution, 0.67 mmol/kg, followed by Triferic, 
3 mg Fe/kg will be compared. 
Then, “Triferic responders” (patients with increases of >15 µg/dL in serum iron 
following oral administration of Shohl’s solution 0.67 mmol/kg and Triferic 3 mg 


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Fe/kg) will undergo up to 10 months of treatment with Triferic, given with Shohl’s 
solution, to determine whether this treatment can increase the Hgb concentration by 
at least 1 g/dL after 4 months (termed “hemoglobin responders”) and whether any 
increase can be sustained for an additional 6 months. The 4-month initial duration of 
the trial, corresponding to a period during which the entire population of circulating 
red blood cells normally would be replaced, should provide sufficient time for 
increased iron absorption from Triferic to improve the circulating hemoglobin 
concentration. 
 
Figure 2:  Four-hour Oral Iron-absorption Test 
Oral iron absorption curves in de novo iron-deficient children (Group II) and in iron-deficient 
nonresponders (Group III: iron-deficient children who received prolonged course of therapeutic iron 
without correction of anemia). An elevated iron absorption curve was present in 24 of 25 Group II 
patients. A flat iron absorption curve was present in 1 of 25 Group II and 6 of 6 Group III patients. 
Gross et al.34 
1.6.   Justification for Dose 
The oral doses of FeSO4 and Triferic in this study are based on the 1-3 mg Fe/kg 
usual recommended range for treatment of iron deficiency anemia in both children 
and adults.36 
The oral dose of Shohl’s solution, 0.67 mmol, has been chosen based on the dose 
of Shohl’s solution used for treatment of pediatric patients with cystinuria over a 
period of two years, i.e., 0.67 mmol given three times daily for a total daily dose of 2 
mmol per day.20, 21 Administration of Shohl’s solution has been reported to raise 


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gastric pH to 3.80–3.94 over a period of 7 hours.35 An elevated gastric pH would be 
expected to decrease transcellular iron absorption from FeSO4 but the extent, if any, 
to which this decrease might be offset by increased paracellular uptake will be 
determined in these studies.  
2.   
STUDY OBJECTIVES 
2.1.   Primary Objective 
The primary objective is to determine whether Triferic, administered orally with 
Shohl’s solution, is safe and effective for the treatment of iron-refractory iron-
deficiency anemia (IRIDA). 
2.2.   Secondary Objectives 
The secondary objectives are: 
• To compare the results of 4-hour iron-absorption tests conducted after 
administration of (i) ferrous sulfate, 3 mg Fe/kg; (ii) Shohl’s solution, 0.67 
mmol/kg, followed by ferrous sulfate, 3 mg Fe/kg; and (iii) Shohl’s solution, 0.67 
mmol/kg, followed by Triferic, 3 mg Fe/kg 
• To determine the effect on hemoglobin concentration of a 4-month trial of QD-
TID oral iron therapy, given as Shohl’s solution, 0.67 mmol/kg, followed by 
Triferic, 1 to 3 mg Fe/kg, titrated as needed based on laboratory results and 
patient tolerance 
• To determine the sustainability of response to Shohl’s solution and Triferic by an 
additional 6-month trial of QD-TID oral iron therapy, given as Shohl’s solution, 
0.67 mmol/kg, followed by Triferic, 1 to 3 mg Fe/kg, titrated as needed based on 
laboratory results and patient tolerance 
3.   
INVESTIGATIONAL PLAN 
3.1.   Overall Study Design and Plan 
This is a Phase 2, open-label, 3-period study assessing the safety, efficacy, and 
pharmacokinetics of Triferic and Shohl’s solution administered orally to patients with 
IRIDA.  A total of 28 patients stratified by 4 age groups (age 0 to <6 years, age 6 to 
<12 years, age 12 to <18 years, and age >=18 years) will be studied.   
All patients who meet inclusion and exclusion criteria regardless of age at 
presentation will be considered for study participation.  There are only a limited 
number of patients with IRIDA in the US (estimated to be less than 30 total patients), 
and they have no other options available to improve their anemia.  Given the rarity of 
the diagnosis and the presentation of patients at an early age (typically <2 years), 
this study represents a minimal risk for tolerability and a positive benefit to risk 


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assessment for patients of all ages. The dose regimen of Shohl’s solution has 
demonstrated long term safety in pediatric patients with renal tubular acidosis and 
cystinuria, and the iron form in Triferic has been used as a food additive and 
supplement to provide nutritional iron.   
The study design schematic is shown in Figure 3 below. 
Following screening, in Period 1, patients will undergo oral iron absorption testing 
during 3 visits to confirm that they adequately absorb iron from Triferic when it is 
administered with Shohl’s solution.  The order in which the different treatment visits 
are scheduled during Period 1 will be determined by the site. 
In Period 2 (dose titration), Period 1 “Triferic responders” (patients with a maximal 
increase from baseline in serum iron concentration >15 µg/dL following an oral 
Shohl’s solution and Triferic dose) will receive Shohl’s solution and Triferic orally up 
to 3 times per day for 4 months, titrated as needed based on laboratory results and 
patient tolerance, to determine whether their hemoglobin levels respond to this 
treatment. 
In Period 3 (hemoglobin maintenance), Period 2 “hemoglobin responders” (patients 
with an increase from baseline in Hgb concentration ≥1.0 g/dL at Visit 9) will receive 
Shohl’s solution and Triferic orally up to 3 times per day for an additional 6 months to 
determine whether the hemoglobin response observed in Period 2 is sustainable. 
During Period 3, Shohl’s solution and Triferic dose and frequency may continue to 
be titrated as needed based on laboratory results and patient tolerance. 
A follow-up visit will occur approximately 1 week afterwards. The duration from 
screening to the last study visit will be approximately 12 months. 
Figure 3. 
Study Design Schematic 
Blood samples will be obtained at various times specified in Appendices 1 and 2 to 
analyze for changes in CBC, reticulocyte count, the reticulocyte hemoglobin 
concentration (CHr), the serum iron profile (serum iron, ferritin, transferrin TSAT, 


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TIBC, and UIBC), other serum iron parameters (TBI [optional], NTBI, and LPI), and 
soluble transferrin receptor (sTfR) and hepcidin concentrations. 
Patients will be also monitored for safety parameters, including AEs, clinical 
laboratory parameters, and vital signs during the study. 
If any of Visits 2-4 are interrupted and the patient and parent/guardian (if applicable) 
agree, a repeat visit can be performed provided that the total blood volume drawn 
does not exceed the maximum allowable (refer to Appendix 2; if the patient is 
between body weight categories, use the lower weight category).  The repeat visit 
should be performed at least 48 hours after the interrupted visit but no later than 1 
month.  If an enrolled patient cannot attend a study visit, the study visit can be 
rescheduled to take place no later than 1 month after the missed visit. 
3.2.   Endpoints 
3.2.1.   
Efficacy Endpoints 
3.2.1.1.   
Primary 
The primary efficacy endpoint is: 
• The change from baseline in hemoglobin concentration at 4 months 
3.2.1.2.   
Secondary 
The key secondary efficacy endpoint is:  
• The change from baseline in serum iron and TSAT at 4 months 
Additional secondary efficacy endpoints are:  
• The change from baseline in Hgb, RBC, MCV, reticulocyte count, CHr, serum 
iron, TIBC, ferritin, UIBC, TSAT, and sTfR and hepcidin concentrations every 4 
weeks and at end-of-treatment (EoT) 
• The incidence of hemoglobin responders (patients with an increase from baseline 
in Hgb concentration ≥1.0 g/dL) every 4 weeks and at EoT 
• The serum iron Cmax following oral Shohl’s solution 0.67 mmol/kg and Triferic 3 
mg Fe/kg body weight 
• The incidence of Triferic responders (patients with a maximal increase from 
baseline in serum iron concentration >15 µg/dL following oral Shohl’s solution 
0.67 mmol/kg and Triferic 3 mg Fe/kg body weight) 
3.2.2.   
Safety Endpoints 
The safety endpoints are: 
• Incidence of treatment-emergent adverse events and serious adverse events 
• Changes in clinical laboratory tests, vital signs, and weight. 


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4.   
SELECTION OF STUDY POPULATION 
4.1.   Inclusion Criteria 
A patient will be eligible for inclusion in the study only if all of the following criteria 
are met: 
1. Adult patients have provided informed consent and have signed the informed 
consent form. For pediatric patients, parents/legal guardians of the patient have 
the ability to understand the requirements of the study and have demonstrated a 
willingness to have their child comply with all study procedures by signing the 
informed consent form.  Where applicable, assent of the pediatric patient has 
also been obtained for all study procedures prior to any study-related activities. 
2. Patient has a history of congenital hypochromic microcytic anemia. 
3. Patient has a mean corpuscular volume (MCV) below the lower limit of normal for 
the clinical laboratory value at screening. 
4. Patient has a serum transferrin saturation ≤15% at screening. 
5. Patient has a history of no or incomplete response to oral iron therapy. 
6. Patient has a history of no or incomplete response to intravenous iron 
administration. 
7. Patient has a history of hepcidin values that are elevated relative to the mean 
value for patients with iron deficiency anemia. 
8. Patient is documented to have homozygous or compound heterozygous 
pathogenic mutations in TMPRSS6.  
9. Patient has appropriate laboratory values for their disease state at screening (per 
investigator judgment). 
10. Patient has no significant abnormal findings on physical examination at screening 
that would preclude participation in the study (per investigator judgment). 
11. If the patient is female, she must be pre-pubertal, have had documented surgical 
sterilization ≥2 years prior to screening, or be practicing adequate birth control.  
All female patients 9 years of age and older, and also any who have reached 
menarche before age 9 years, must have a negative serum pregnancy test 
during screening. It is the investigator’s responsibility to determine whether the 
patient has adequate birth control for study participation. 


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4.2.   Exclusion Criteria 
A patient will not be eligible for inclusion in the study if any of the following criteria 
apply: 
1. Patient has had IV or oral iron supplements within 2 weeks prior to Visit 2. 
2. Patient has had a blood transfusion within 3 months prior to Visit 2. 
3. Patient is receiving intravenous or oral antibiotics or antifungals for any infectious 
process.  Prophylactic antibiotics administered on a regular basis are allowed.  
Otherwise-eligible patients may be rescreened when they have recovered from 
any acute illnesses. 
4. Patient has a body weight of <11 lbs (5 kg) at screening. 
5. Patient has participated in an investigational drug study within the 30 days prior 
to Visit 2. 
6. Patient has any condition that, in the opinion of the investigator, is likely to 
prevent the patient from complying with or successfully completing the protocol. 
4.3.   Removal of Patients from Therapy/Premature Discontinuation 
A patient will be discontinued from the study for the following medical or 
administrative reasons: 
• Occurrence of a TEAE that represents an unacceptable risk to the patient and 
when continued participation in the investigational study is not warranted, in the 
judgment of the investigator.  The investigator must follow the patient until the AE 
resolves or satisfactorily stabilizes; 
• Occurrence of a TEAE of grade ≥3 (Common Terminology Criteria for Adverse 
Events [CTCAE] v4.0) that the investigator determines to be related to the study 
drug (Shohl’s solution or Triferic).  The investigator must follow the patient until 
the AE resolves or satisfactorily stabilizes; 
• Pregnancy;  
• Initiation of a prohibited concomitant therapy without medical monitor or sponsor 
approval; and/or 
• Patient request. 
The investigator may discontinue individual patients from the study at any time.  
Patients may voluntarily withdraw at any time. If possible, patients who are 
withdrawn should complete a Follow-up visit.  
Patients who withdraw or are withdrawn prior to Visit 2 will be considered screen 
failures and will be replaced. 


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4.4.   Study Discontinuation 
After 5 patients have completed Period 1, if none of them is a Triferic responder (i.e., 
no patient has a serum iron Cmax that is >15 g/dL higher than the Hr 0 serum iron 
concentration following oral Shohl’s solution 0.67 mmol/kg and Triferic 3 mg Fe/kg 
body weight), then Rockwell Medical will consider discontinuing the study. 
In addition, after 5 patients have completed Period 2, if none of them is a 
hemoglobin responder (i.e., no patient has a Visit 9 Hgb concentration that is ≥1 
g/dL higher than the Visit 5 Hgb concentration), then Rockwell Medical will consider 
discontinuing the study. 
5.   
TREATMENTS 
5.1.   Treatments Administered  
Study drug for Visits 2-4 will be administered by qualified study personnel only in 
accordance with the procedures described in this protocol. The order in which the 
different treatment visits are scheduled during Period 1 will be determined by the 
site.  For Periods 2-3, study drugs should be self-administered by the patient, or 
alternatively by the patient’s parent or guardian if the patient is unable to do so. 
Ferrous sulfate (Fer-In-Sol®, Mead Johnson, Glenview, IL) will be administered at a 
dose of 3 mg Fe/kg. When administered in conjunction with Shohl’s solution, the 
dose will be given 5-15 minutes after the dose of Shohl’s solution. 
Citrate (as Shohl’s solution, e.g., Oracit®; CMP Pharma, Farmville, NC) will be 
administered at 0.67 mmol/kg. 
Ferric pyrophosphate citrate (Triferic®; Rockwell Medical, Wixom, MI) will be 
administered at a dose of 3 mg Fe/kg, 5-15 minutes after the dose of Shohl’s 
solution. 
At each of Visits 5, 7, 9, 10, and 11, sufficient Shohl’s solution and Triferic to provide 
at least 60 days of dosing will be dispensed to the patient. On study visit days, 
patients should not take their Shohl’s solution and Triferic doses until after the study 
visit. Patients are to stop taking Shohl’s solution and Triferic after Visit 12. 
5.2.   Identity of Investigational Products(s) 
Triferic is supplied as either a sterile 5-mL ampule or sterile 50-mL ampule, both 
containing 5.44 mg/mL of iron in water.  Each 5-mL ampule contains 27.2 mg of 
Triferic iron and each 50-mL ampule contains 272 mg of Triferic iron. 
Citrate (as Shohl’s solution, e.g., Oracit®; CMP Pharma, Farmville, NC) is supplied 
as 500-mL bottles containing citric acid USP 640 mg/5 mL and hydrous sodium 
citrate USP 490 mg/5 mL. Oracit will be used for dosing in the US. Other 


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commercially-available preparations of Shohl’s solution that contain sodium citrate 
may also be used (e.g., in the EU, if the protocol is amended to add EU sites) if 
Oracit is not available. 
Ferrous sulfate (Fer-In-Sol®, Mead Johnson, Glenview, IL) is supplied as 50-mL 
bottles containing 15 mg Fe/mL. 
5.2.1.   
Labeling 
Triferic study drug packaging will bear a label that meets applicable laws for an 
investigational drug, which includes, but is not limited to, the following information: 
• Federal law statement 
• Protocol number 
• Lot number 
• Dosing instructions 
• Storage information 
 
Shohl’s solution and Fer-In-Sol bottles will be supplied in their currently-available 
commercial presentations. 
 
5.2.2.   
Storage and Handling 
Prior to being dispensed, all study drugs will be kept in a locked area with limited 
access.  
Triferic ampules will be stored protected from light in an aluminum pouch at 
controlled room temperature (20 to 25C [68 to 77F]; excursions will be permitted 
to 15-30C [59 to 86F] [See USP Controlled Room Temperature]). 
Shohl’s solution and Fer-In-Sol bottles will be stored at 15-30C [59 to 86F]. 
All study drugs should be kept out of reach of children. 
 
5.3.   Method of Assigning Patients to Treatment Groups 
5.3.1.   
Treatment Assignment/Randomization 
The study is open-label and all patients will be treated in the sequence indicated in 
Section 3.1.  Consequently, randomization is not required. 
 
5.4.   Selection and Timing of Dose for Each Patient  
For Visits 2-4, in order to help control for the diurnal variation in serum iron 
parameters, each treatment will be administered at approximately the same time 


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each day per patient.  The order in which the different treatment visits are scheduled 
during Period 1 will be determined by the site. 
During Periods 2 and 3, it is recommended that the patients take the Shohl’s solution 
and Triferic orally at least one hour before or two hours after meals. Initially, the 
dose of study drug will be Shohl’s solution 0.67 mmol/kg followed by Triferic 3 mg/kg 
3x/day.  
However, if the patient experiences adverse events related to either the Shohl’s 
solution or Triferic, study drug may be withheld for up to 7 days if needed and then 
resumed 3x/day with Shohl’s solution being dosed at 0.67 mmol/kg and Triferic 
being dosed at 1/3 of the most recent previous dose.  
If the adverse event recurs, study drug may be withheld for up to 7 days if needed 
and then resumed with a decreased frequency of dosing. The frequency of dosing 
may be decreased from 3x/day to 1x/day.  
If a dose of Shohl’s solution and Triferic has been well-tolerated for at least 7 days, if 
the dose frequency is less than 3x/day it may be increased by 1x/day if needed 
based on Hgb concentrations and serum iron parameters. If a dose of Shohl’s 
solution and Triferic has been well-tolerated for at least 7 days, if the Triferic dose 
being administered at less than 3 mg/kg, then the dose may be increased by 1 
mg/kg per dose if needed based on Hgb concentrations and serum iron parameters. 
See Appendices 4 and 5 for details regarding study drug dosing. 
5.5.   Procedures for Blinding   
 
 
This is an open-label study; no blinding is required. 
5.6.   Prior and Concomitant Therapy  
5.6.1.   
Prior Therapy 
All prescription and non-prescription medications (including multivitamins) taken at 
screening and/or within 14 days prior to Visit 2 (whichever is earlier) will be 
documented in source documents and the case report form (CRF) (based on patient 
report and/or medical records). The date of screening is considered to be the date 
that the first study-related screening assessment is performed. 
5.6.2.   
Concomitant Therapy 
All prescription and non-prescription medications taken over the course of study 
participation must be documented in the source documents and CRF.   


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5.6.3.   
Prohibited Medications 
Oral and IV iron products are prohibited from 2 weeks prior to Visit 2 until all blood 
samples have been collected after the Follow-up/Early Termination Visit.  This 
includes oral multivitamins containing iron. 
Blood transfusions are prohibited from 3 months prior to Visit 2. If a patient requires 
transfusion after enrollment in the study, they should first be discontinued from the 
study and then transfused. Follow-up/Early Termination Visit procedures may occur 
prior to or after the blood transfusion. 
Aluminum-containing compounds (e.g., Maalox®, Alternagel®, Alu-Cap®, 
Dialume®, Amphojel®, Alu-Tab®, Aloh-Gel®, etc.) are prohibited from Day 1 of the 
study through the date of the patient’s last dose of Shohl’s solution. 
5.7.   Treatment Compliance 
The site is responsible for documenting compliance with study drug administration. 
5.7.1.   
Study Drug Accountability 
Study drug will be administered in accordance with the procedures of this protocol.  
Only authorized site personnel may supply study drug and only patients enrolled in 
the study may receive study drug, in accordance with applicable regulatory 
requirements.  
Drug accountability information collected may include but is not limited to:  
• Receipt of study drug (date and quantity); 
• Storage temperature log; 
• Dispensation of study drug (date, quantity, and patient number); 
• Return of study drug (date, quantity, and patient number); and 
• Initials of individual dispensing study drug 
At the conclusion of a site’s participation in the study, all unused investigational drug 
shall be returned to Rockwell or destroyed upon Rockwell’s request unless 
otherwise instructed by Rockwell.  A copy of the reconciled drug inventory record will 
be provided to Rockwell or its designee, and the original will be retained at the site. 
6.   
STUDY ASSESSMENTS AND PROCEDURES 
6.1.   Study Visits 
The study should be conducted as much as possible according to the time and 
events schedule in Appendix 1 (Table 2).  


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6.1.1.   
Screening (Week -4 through Day -1) 
6.1.1.1.   
Screening Visit (Visit 1) 
The Screening Visit (Visit 1) should be conducted within 28 days prior to Visit 2.  The 
date of screening is considered to be the date that the first study-related screening 
assessment is performed.  The following procedures will be performed at screening:   
• For adult patients, obtain informed consent. For pediatric patients, obtain 
informed consent from parent(s)/legal guardian(s) and assent (where applicable) 
from the patient. This must be done prior to any study procedures, including 
asking patients to discontinue any prohibited medications; 
• Assign study-specific patient number; 
• Record patient demographics and medical history; 
• Record current medications; 
• Record height and weight; 
• Record vital signs (blood pressure, pulse, temperature); 
• Perform a physical examination; 
• Perform serum pregnancy test (for all female patients 9 years of age or older, 
and also any who have reached menarche prior to age 9 years); 
• Collect venous blood for isolation and storage of genomic DNA, if patient has not 
previously had TMPRSS6 sequencing done; 
• Collect venous blood for hematology, reticulocyte count, reticulocyte hemoglobin 
concentration (CHr), chemistry, the serum iron profile, and sTfR and hepcidin 
concentrations. For pediatric patients, results from up to 30 days prior to 
screening may be used for determination of eligibility; 
• Confirm patient meets all eligibility criteria; and 
• Schedule next study visit (Visit 2). Remind the patient that they should be NPO 
except for water after midnight prior to Visit 2. 
 
6.1.2.   
Period 1: Iron Absorption Testing (Visits 2-4, Weeks 1-3) 
6.1.2.1.   
Study Procedures  
The following procedures are to be completed during Visits 2-4: 
• Assess and record AEs since last study visit; 
• Assess and record medications;  
• Collect vital signs (blood pressure, pulse, and temperature);  
• Collect blood for serum iron parameters (serum iron, TSAT, TBI [optional], NTBI, 
and LPI) within 30 minutes prior to the oral iron dose;  
• Administer study drug (see Section 6.1.2.2 below, and also Appendices 4 and 5); 


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• Collect blood for serum iron parameters at 1 hr, 2 hr, and 4 hr following the oral 
iron dose per Appendix 2, Tables 3, 4, and 5 for Visits 2, 3, and 4, respectively; 
• Assess and record AEs; and 
• Schedule the patient for their next study visit to take place in approximately 1 
week. Remind the patient that they should be NPO except for water after 
midnight prior to each visit. 
It is recommended that sixty (60) minutes after each oral iron dose during Period 1, 
patients may eat a non-meat breakfast (note: dairy is permitted, but eggs, seafood, 
and other meats are not); and they may resume a normal diet after collection of the 
4-hr blood samples.  
Following dosing with oral Shohl’s solution 0.67 mmol/kg and Triferic 3 mg Fe/kg 
body weight, serum iron Cmax should be compared to the Hr 0 serum iron 
concentration. If the serum iron Cmax is >15 g/dL higher than the Hr 0 serum iron 
concentration, the patient is designated a “Triferic responder” and will proceed to 
Period 2. If not, the patient will proceed to the early termination visit to occur 
approximately 1 week after Visit 4. 
6.1.2.2.   
Study Drug  
Study drug for Visits 2-4 will be as follows: 
• oral FeSO4, 3 mg Fe/kg body weight 
• oral Shohl’s solution, 0.67 mmol/kg body weight, followed after 5-15 minutes by 
oral FeSO4, 3 mg Fe/kg body weight  
• oral Shohl’s solution, 0.67 mmol/kg body weight, followed after 5-15 minutes by 
oral Triferic (ferric pyrophosphate citrate), 3 mg Fe/kg body weight 
The order in which the different treatment visits are scheduled during Period 1 will be 
determined by the site.  Please see Appendices 4 and 5 for details of study drug 
dosing.  
 
 
6.1.3.   
Period 2: Dose Titration (Visits 5-9, Weeks 4-20) 
The following procedures are to be completed during Visits 5-9: 
• Assess and record AEs since last study visit; 
• Assess and record medications;  
• Collect vital signs (blood pressure, pulse, temperature) and weight;  
• Perform a brief, targeted physical examination (Visit 5 only); 
• Collect venous blood for hematology, reticulocyte count, CHr, chemistry, the 
serum iron profile, and sTfR and hepcidin concentrations;  
• Collect study drug and perform compliance assessment (Visits 6-9 only); 


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• Dispense study drug and dosing syringes and/or dosing cups (Visits 5, 7, and 9 
only), and provide instruction on study drug storage and dosing (see Appendices 
4 and 5); and 
• Schedule the patient for their next study visit to take place in approximately 1 
month (Visits 5-8) or 2 months (Visit 9). Remind the patient that they should be 
NPO except for water after midnight prior to each visit, and they should not take 
any study drug on visit days until after their visit. 
 
Following Visit 9, the patient’s Visit 9 hemoglobin level should be compared to the 
Visit 5 hemoglobin level. If the Visit 9 hemoglobin level is ≥1 g/dL higher than the 
Visit 5 level, the patient is designated a “hemoglobin responder” and will proceed to 
Period 3. If not, the patient will proceed to the early termination visit to occur within 
approximately 1 week after Visit 9. 
 
6.1.4.   
Period 3: Hemoglobin Maintenance (Visits 10-12, Weeks 21-44) 
The following procedures are to be completed during Visits 10-12: 
• Assess and record AEs since last study visit; 
• Assess and record medications;  
• Collect vital signs (blood pressure, pulse, temperature) and weight;  
• Perform a brief, targeted physical examination (Visit 10 only); 
• Collect venous blood for hematology, reticulocyte count, CHr, chemistry, the 
serum iron profile, and sTfR and hepcidin concentrations;  
• Collect study drug and perform compliance assessment; 
• Dispense study drug (Visits 10 and 11 only) and dosing syringes and/or dosing 
cups, and provide instruction on study drug storage and dosing (see Appendices 
4 and 5); and 
• At the conclusion of Visits 10 and 11, schedule the patient for their next study 
visit to take place in approximately 2 months. Additional unscheduled visits at 
weeks 24, 32, and 40 may be performed at the discretion of the investigator for 
assessments of Hgb and/or the serum iron profile to further titrate the dose of 
study drug. Remind the patient that they should be NPO except for water after 
midnight prior to each visit, and they should not take any study drug on visit days 
until after their visit. At the conclusion of Visit 12, advise the patient not to take 
any more study drug, and schedule the patient for the follow-up visit to take place 
in approximately 1 week. 
 


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6.1.5.   
Follow-up/Early Termination (Visit 13) 
The following procedures are to be completed during the Follow-up/Early 
Termination visit: 
• Assess and record AEs since last study visit; 
• Assess and record concomitant medications;  
• Collect vital signs (blood pressure, pulse, temperature) and weight; 
• Collect blood for hematology, chemistry, the serum iron profile, and a serum 
pregnancy test (if applicable);  
• Collect the reticulocyte count, CHr, and sTfR and hepcidin concentrations only if 
not collected within the previous 30 days; 
• Collect any remaining study drug and perform compliance assessment if 
applicable; and 
• Discharge patient from the study. 
 
6.2.   Study Assessments 
Serum samples for hepcidin, and the Visits 2-4 serum iron parameters (NTBI, and 
LPI) will be prepared and shipped to Hepcidinanalysis.com according to the 
instructions in Appendix 3. All other laboratory samples will be sent to the site-
specific local clinical laboratory. 
6.2.1.   
Laboratory Assessments 
6.2.1.1.   
Hepcidin 
The assay for hepcidin has been validated and will be performed on serum samples 
by weak cation exchange chromatography in combination with time-of-flight mass 
spectrometry (WCX-TOF MS) on a Microflex LT MALDI-TOF mass spectrometer 
(Bruker Daltonics). 
6.2.1.2.   
Non-Transferrin-Bound Iron (NTBI) and Labile Plasma Iron (LPI) 
The assays for NTBI and LPI will be performed on serum samples by 
Hepcidinanalysis.com using a validated method. 
6.2.1.3.   
All Other Laboratory Assessments 
All of the other laboratory assessments are routine tests and will be performed by 
the site-specific local clinical laboratory. 
6.2.1.4.   
Collecting, Processing, and Shipping Samples 
Blood samples for serum iron parameters (serum iron, TSAT, TBI [optional], NTBI, 
and LPI) at Visits 2-4 will be collected as outlined in the Sample Collection Schedule 


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in Appendix 2.  An indwelling venous catheter may be inserted for the collection of 
blood samples if deemed necessary by the investigator.  Approximately 3.5-5 mL of 
whole blood will be collected for each blood draw (1-2 mL blood may be collected 
instead for smaller patients by syringe and transferred to pediatric vacutainer tubes 
to avoid exceeding maximum blood collection limits).  The total volume of blood 
collected from each patient will be dependent upon the age and weight of the patient 
and will be collected in accordance with the limits for blood sampling in Appendix 2 
(if the patient is between body weight categories, the lower weight category should 
be used). 
Blood samples for serum iron parameters at Visits 2-4 will be collected in serum 
separator tubes with clot activator at the following nominal time points (actual blood 
sampling times must be recorded in the source documents and CRF) as described 
in Appendix 2 (if the patient is between body weight categories, the lower weight 
category should be used): pre-dose (within 30 minutes before dosing), and 1, 2, and 
4 hours after each oral iron dose at Visits 2-4.  The time points are listed in the blood 
sampling schedule for Visits 2-4 (Table 3-5) according to patient body weight.  
Additional clinical blood samples can be collected as long as the total volume of 
blood does not exceed the volumes recommended by the CMRC tables for the 
maximum allowable blood draws 
(http://www.ucdmc.ucdavis.edu/clinicaltrials/studytools/documents/Blood_Draws_Ma
ximum_Allowable.doc).   
Blood samples for DNA sequencing and for the analysis of and hepcidin will be 
processed as described in Appendix 3. All other samples will be processed per the 
site-specific local clinical laboratory requirements. 
6.2.2.   
Assessment of Safety 
Safety assessments will include the following: 
• AEs and SAEs, both reported and observed; 
• Clinical laboratory tests; 
• Changes in physical examinations; 
• Vital sign measurements (blood pressure, pulse, temperature) and weight. 


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6.2.2.1.   
Clinical Laboratory Tests 
All blood samples other than those for DNA sequencing, NTBI, LPI, and hepcidin will 
be analyzed by the site’s local licensed clinical laboratory.  For pediatric patients, 
recent (within 30 days of screening) tests are sufficient for determining study 
eligibility. For all patients, TMPRSS6 sequencing results obtained at any time prior to 
enrollment may be used for determination of eligibility. The clinical laboratory tests 
that may be conducted at local labs are as follows: 
• Hematology: complete blood count with platelet count, white blood cell (WBC) 
count and WBC differential. 
• Blood Chemistry:  routine Chemistry 20 analysis 
• Serum Iron Profile:  serum iron, ferritin, transferrin, TSAT, and TIBC.  Optional 
TBI and UIBC if laboratory can perform that test. 
• Other: reticulocyte count, CHr, and sTfR. 
The investigator is responsible for determining whether out-of-range laboratory 
values are clinically significantly changed or not.  If the investigator determines that 
additional laboratory examinations are needed for a patient in screening, then the 
patient is not considered eligible for the study until such values are considered 
clinically stable. All clinically significantly changed values of enrolled patients will be 
followed until resolution or stabilization.   
6.2.2.2.   
Physical Examinations 
A physical examination will be performed during the screening period any time prior 
to Visit 2 and will consist of assessments of the following: skin, ENT (ears, nose, and 
throat), head, eyes, lungs/chest, heart, abdomen, musculoskeletal, extremities, and 
neurologic. Brief, targeted physical examinations will be performed at Visits 5 and 
10. 
6.2.2.3.   
Vital Signs 
Vital signs will include supine or sitting blood pressure (mm Hg), heart rate (beats 
per minute [bpm]), and tympanic or oral temperature.  A consistent body position 
(supine or sitting) should be used for all routine vital sign assessments. Vital sign 
measurements will be collected at specified intervals as per Section 6.1 and 
Appendix 1. 
7.   
 ADVERSE EVENTS 
The investigator is responsible for the detection and documentation of events 
meeting the definition of an adverse event (AE) or serious adverse event (SAE) as 
provided in this protocol.   


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7.1.   Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this product. 
An AE can therefore be any unfavorable and unintended sign (including a clinically 
significant abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the 
medicinal product. Adverse events will be recorded on the adverse events CRF from 
the start of the first dose of oral iron (FeSO4) through the end of study participation 
or 7 days after the last dose of oral iron (FeSO4 or Triferic), whichever is later. Pre-
treatment-emergent medical conditions will be captured on the medical history CRF, 
unless they meet seriousness criteria (Section 7.2). 
An AE does include any: 
• Exacerbation of a pre-existing illness; 
• Increase in frequency or intensity of a pre-existing episodic event or condition; 
• Condition detected or diagnosed after the start of study drug administration even 
though it may have been present prior to the start of the study; or 
• Continuous persistent disease or symptoms present at baseline that worsen 
following the start of the study. 
Symptoms associated with a disease not previously reported by the patient will be 
recorded as an AE. 
An AE does not include a/an: 
• Medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, 
transfusion). Rather, the underlying condition that leads to the procedure is the 
AE that should be reported, unless the condition did not worsen during the study; 
• Pre-existing diseases or conditions present or detected at the start of the study 
that do not worsen; 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for cosmetic elective surgery, social and/or convenience 
admissions). 
7.2.   Definition of a Serious Adverse Event 
Any SAE that occurs from the date of Screening to the date of the Follow-up visit or 
7 days after the last dose of Triferic, whichever is later, will be reported on an SAE 
report form. For enrolled patients, SAEs are also recorded on the AE CRF page. An 
SAE is any AE occurring at any dose that results in any of the following outcomes: 
a. Death; 
b. A life-threatening AE; 


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• 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. 
7.3.   Method, Frequency, and Time Period for Detecting Adverse 
Events and Serious Adverse Events 
At appropriate intervals, patients should be assessed for AEs and SAEs.  After the 
patient has had an opportunity to spontaneously mention any problems, the 
investigator should inquire about AEs by asking a non-leading question such as the 
following: 


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1. “How are you feeling?” 
2. “Have you had any medical problems since your last assessment/visit?” 
3. “Have you taken any new medicines since your last assessment/visit?” 
7.4.   Reporting SAEs  
CONTACT THE MEDICAL MONITOR BY PHONE, EMAIL, OR FAX (1 866 250 
5488) WITHIN THE TIMEFRAME SPECIFIED IN SECTION 7.4.1 TO NOTIFY 
ROCKWELL MEDICAL OF ANY SAEs. 
All SAEs (related and unrelated) will be recorded from the time of the Screening visit 
until the date of the Follow-up visit or 7 days following the last dose of Triferic, 
whichever is later. Any SAEs considered possibly, probably, or definitely related to 
the investigational product and discovered by the investigator or site personnel at 
any interval after completion of the study should also be reported. All SAEs must be 
reported to Rockwell Medical within 48 hours of the site’s first awareness of the 
event. If the SAE is fatal or life-threatening, it must be reported to Rockwell Medical 
within 24 hours of the site’s first awareness of the event.  The investigator must 
complete, sign and date the SAE pages, verify the accuracy of the information 
recorded on the SAE pages with the corresponding source documents, and send a 
copy by fax (1 866 250 5488) or email to Rockwell Medical. 
At a minimum, the event name, the reporter’s name and contact information, and the 
patient’s study identifier must be provided at the time of the initial report. Optimally, a 
description of the event and the investigator’s preliminary assessment of causality 
would also be provided. Additional follow-up information, if required or available, 
should be sent to Rockwell Medical within 48 hours of receipt. Follow-up information 
should be provided using a follow up SAE report, and the follow-up SAE report 
should be placed with the original report in the appropriate section of the CRF/study 
file. 
The investigator is encouraged to discuss with Rockwell Medical any AEs for which 
the issue of seriousness is unclear or questioned. 
Rockwell Medical is responsible for notifying the relevant regulatory authorities of 
certain events. Multiple inquiries between Rockwell Medical and the study site may 
be necessary for report preparation. 
It is the Principal Investigator’s responsibility to notify the Institutional Review Board 
(IRB), 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 Safety Reports) that occur during any 
clinical trials of Triferic. Each site is responsible for notifying their IRB, EC or the 
relevant local regulatory authority of these additional SAEs. 


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7.4.1.   
Timeframes for Reporting SAEs 
Prompt notification to Rockwell Medical regarding SAEs is essential so that ethical 
and regulatory responsibilities and legal obligations can be satisfied.  The 
investigator must report SAEs according to the following time frames:      
• Death or Life-Threatening Event: 
o Initial notification must be sent to Rockwell Medical within 24 hours of the 
investigational site learning of the death or life-threatening event 
(regardless of causality).   
o Complete SAE information (i.e., all SAE pages) must be sent to Rockwell 
Medical within 48 hours.  
o Follow-up information must be sent to Rockwell Medical within 48 hours of 
receipt of the information by the investigational site.  
• All other SAEs  
o Complete SAE information (i.e., all SAE pages) must be sent to Rockwell 
Medical within 48 hours of site study personnel learning of the event. 
o Follow-up information must be sent to Rockwell Medical within 48 hours of 
receipt of the information by the investigational site.  
7.4.2.   
SAE Information to Report 
All information available regarding an SAE must be submitted in the timeframes 
indicated in Section 7.4.1.  At a minimum, SAE reports must contain the patient’s 
study identifier, the SAE term, and the name of the person reporting the event to 
Rockwell Medical.  Optimally, a description of the event and the investigator’s 
preliminary assessment of causality would also be provided. 
The investigator must record all relevant information regarding an AE/SAE in the 
applicable sections of the CRF.  It is not acceptable for the investigator to send 
photocopies of the patient’s medical records in lieu of completion of the 
appropriate AE/SAE pages.  However, there may be instances when copies of 
medical records for certain cases are requested by Rockwell Medical.  If medical 
records are submitted to Rockwell Medical then all patient personal identifiers must 
be completely and thoroughly redacted prior to submission. Each page of medical 
records should be labeled with the patient’s study identifier. 
7.4.3.   
Regulatory/Ethics Reporting Requirement  
The investigator, or responsible person according to local requirements, must 
comply with the applicable local regulatory requirements related to the reporting of 
SAEs to regulatory authorities and the IRB/EC. 


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7.5.   Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as AEs 
Clinically significant abnormal laboratory findings or other abnormal assessments 
that are associated with a diagnosis, unless judged by the investigator as more 
severe than expected for the patient's condition, or that are present or detected 
before study drug administration and do not worsen after study drug administration, 
should not be reported as AEs. Instead, the diagnosis with which they are 
associated should be assessed for whether it constitutes an AE, and reported 
accordingly. For example, if a patient experiences leukocytosis or hypoxia 
associated with a diagnosis of pneumonia, it is not necessary to report these in 
addition to reporting the pneumonia unless they are more severe than expected. 
If not known to be associated with a diagnosis, abnormal laboratory findings (e.g., 
clinical chemistry, hematology, and urinalysis) or other abnormal assessments (e.g., 
ECGs, 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 
7.1, Definition of an Adverse Event), and reported as SAEs if they meet the criteria 
for seriousness (Section 7.2, Definition of an SAE). 
The investigator should exercise his or her medical and scientific judgment in 
deciding whether an abnormal laboratory finding or other abnormal assessment is 
clinically significant. 
7.6.   Documenting AEs 
Adverse events, including SAEs, will be recorded on the adverse events CRF from 
the start of the first dose of oral iron (FeSO4) through the end of study participation 
or 7 days after the last dose of oral iron (FeSO4 or Triferic), whichever is later. Pre-
treatment-emergent medical conditions will be captured on the medical history CRF, 
unless they meet seriousness criteria (Section 7.2). 
Any SAE that occurs from the date of Screening to the Follow-up visit or 7 days after 
the last dose of oral iron, whichever is later, will be reported on an SAE report form. 
For enrolled patients, SAEs are also recorded on the AE CRF page.   
The investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the adverse event and/or SAE. 
7.7.   Follow-up of AEs 
After the initial AE report, the investigator is required to proactively follow each 
patient and provide further information to Rockwell Medical on the patient’s 
condition.  All AEs documented at a previous visit/contact that are designated as 
ongoing will be reviewed at subsequent visits/contacts. 


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All AEs that are ongoing at the conclusion of the patient’s participation will be 
followed up until resolution, until the condition stabilizes, or until the patient is lost to 
follow-up.  The appropriate AE/SAE source document and CRF page(s) will be 
updated.  If a patient dies during participation in the study or during the 7 days 
following the patient’s last dose of oral iron, a copy of any post-mortem findings, 
including histopathology, should be obtained, if available, and forwarded to Rockwell 
Medical. 
7.8.   Post-study AEs 
Investigators are not obligated to actively seek new AEs or SAEs that begin after the 
Follow-up visit or 7 days after the last dose of oral iron, whichever is later. The 
investigator should notify Rockwell Medical of any SAEs that begin following study 
completion only if the event is considered related to study drug.          


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8.   
STATISTICS  
8.1.   General Considerations 
A total sample size of approximately 28 patients is planned. Where appropriate, the 
normality of data will be assessed before analysis by using the Shapiro-Wilk test and 
graphically by evaluating histograms and Q-Q plots. Data not normally distributed 
will be log transformed for analysis. Log-transformed data will be back transformed 
for reporting. Normally distributed data will be presented as means (±SDs, ±95% 
confidence intervals (CI), or both), data normally distributed after log transformation 
will be presented as geometric means (±95% CI), and non-normally distributed data 
will be presented as medians and ranges. The baseline demographic and clinical 
characteristics of the study population will be presented in tabular form. For the 
primary and key secondary endpoints, a summary of results with the estimated 
effect size and its precision will be reported. Differences in changes between 
baseline and 4-month and subsequent 6-month measurements will be compared. 
8.2.   Determination of Sample Size 
The overall goal of this project is to test the primary study hypothesis that QD-TID 
administration of Shohl’s solution, 0.67 mmol/kg, followed by Triferic, 1 to 3 mg 
Fe/kg, will produce a sustained increase in hemoglobin concentration of ≥1 g/dL in 
80% of patients with IRIDA (termed “hemoglobin responders”). Given that the total 
number of patients with IRIDA currently reported is only about 75 individuals, for the 
purpose of sample size calculation for this trial, we determine the number of patients 
that would need to be examined to determine if the true proportion of hemoglobin 
responders is within ±10% of our estimate with a 90% confidence interval. Then 
= (1.6452 x 0.8 x 0.2)/0.12 
= 43.4 
where n is the unadjusted sample size for an unlimited population, Zα/2 is value of the 
normal distribution at α/2, p* is the hypothesized proportion of hemoglobin 
responders, and E is the level of precision. Because the population of patients with 
iron-refractory iron-deficiency anemia currently reported is only about 75 individuals, 
the sample size is adjusted by 
nadj = Nn/(N+n-1) 
= (75 x 43.4)/(75 + 43.4 - 1) 
= 27.6 
2
*
*
2
2
)
1(
E
p
p
Z
n
−




=



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Accordingly, our sample size estimate for this trial is 28 patients. If our estimate that 
80% of patients is an appreciable overestimate, then the need to revise this estimate 
should become evident early during the course of the trial. 
8.3.   Analysis Populations 
Two analysis populations will be defined as follows: 
• MITT Population will include all enrolled patients who receive at least 1 dose of 
study drug and have at least one Hgb assessment following Visit 5. 
• Safety Population will include all randomized patients who received at least 
1 dose of study drug. 
The analyses of baseline characteristics will be performed for the Safety Population.  
All efficacy analyses will be performed for the MITT Population. All safety analyses 
will be performed for the Safety Population. 
8.4.   Patient Disposition 
Patient disposition will be summarized by Safety Population and for the 4 age strata. 
8.5.   Baseline Characteristics 
Baseline characteristics will be summarized for the Safety Population and for the 4 
age strata. 
8.6.   Concomitant Medications 
Concomitant medications will be categorized by World Health Organization (WHO) 
classification (ATC levels 1-4) and drug name and summarized by number and 
percentage of patients for the Safety Population. 
8.7.   Extent of Exposure 
Exposure will be calculated for the Safety Population and for the 4 age strata. 
8.8.   Safety Assessments 
8.8.1.   
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 14.1 or later. The frequency of treatment-emergent AEs will be 
calculated for each body system, by preferred term, by treatment, for number of 
patients and percentage reporting the event. The severity of the AEs and the 
relationship to the study drug will be summarized for each body system and 
preferred term by treatment. Withdrawals due to AEs will be summarized for each 
body system and preferred term by treatment. Adverse events will also be 
summarized by sex, age stratum (<6 years, 6 to <12 years, 12 to <18 years, ≥18 
years) and race (white and nonwhite).  


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If more than 1 patient experiences an AE grade ≥3 (CTCAE v4.0) that is considered 
related to study drug by the investigator, then a complete review of all AEs in the 
study will be initiated.  During any such review, no new patients will be enrolled in 
the study until a determination concerning the AEs is completed.  
Narratives will be presented for all deaths, SAEs and patients withdrawn due to AEs.  
8.8.2.   
Clinical Laboratory Assessments 
All clinical laboratory assessments will be summarized for the Safety Population. 
Baseline, time point, and Follow-up values will be summarized separately.  Changes 
from baseline will be summarized by age group. 
8.8.3.   
Vital Signs 
Vital signs will be reported by each individual component.  Changes from baseline at 
each time point will be summarized. 
8.9.   Statistical and Analytical Issues 
8.9.1.   
Statistical Analysis Plan 
A study-specific statistical analysis plan (SAP) will be written and finalized prior to 
any lock of the study database. The SAP will give a detailed description of the 
summaries and analyses (primary and secondary) that will be performed and clearly 
describe when these analyses will take place. Included in the SAP will be 
adjustments for covariates, and handling of dropouts and missing data points. 
8.9.2.   
Handling of Missing Data  
Missing data will not be replaced or imputed.  All analyses will use available data 
only. 
8.9.3.   
Interim Analyses and Data Monitoring 
An interim analysis will be performed after approximately 5 patients have been 
studied to assess the frequency of hemoglobin responders at Visit 9.  Should the 
proportion of hemoglobin responders be too high or too low, the protocol may be 
amended to change the targeted sample size for the remainder of the study.   
8.9.4.   
Criteria for Stopping the Study 
The study can be stopped at any time if any of the following circumstances occurs: 
• An SAE occurring during Triferic administration and considered related to study 
drug; 
• Signs of potential iron toxicity in 1 or more patients in any cohort as evidenced by 
any of the following, that is not consistent with the patients’ ongoing medical 
history: 


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• GI:  Nausea, vomiting, diarrhea and abdominal pain; 
• CV: Decreased cardiac output leading to hypoperfusion and shock; 
• Metabolic:  Acute metabolic acidosis; or 
• CNS: Depressed sensorium; 
• Serum iron levels 500 µg/dL regardless of symptomology; or 
• Hepatic injury as evidenced by any acute combination of elevated bilirubin, AST 
or ALT levels. 
If any of these events occurs, enrollment may be suspended and a safety review 
committee will review the entire study’s safety data before a decision is made to 
resume enrollment or terminate the study. 
9.   
STUDY ADMINISTRATION 
9.1.   Sponsor’s and Investigator’s Responsibilities 
This study will be conducted in accordance with current applicable regulations, ICH 
and local ethical and legal requirements. 
9.2.   Sponsor’s Responsibilities 
9.2.1.   
GCP Compliance 
Rockwell Medical and any third party to whom aspects of the study management or 
monitoring have been delegated will undertake their roles for this study in 
compliance with all applicable regulations and ICH GCP Guideline E6. 
Visits to investigator sites will be conducted by representatives of Rockwell Medical 
to inspect study data, patients’ medical records and CRFs in accordance with 
current GCP and the respective local and national government regulations and 
guidelines. Records and data may additionally be reviewed by auditors, or by 
regulatory authorities. 
9.2.2.   
Regulatory Approval 
Rockwell Medical will ensure that local Regulatory Authority and IRB/EC 
requirements are met at each site prior to releasing investigational product for 
shipment to the study site. 
9.2.3.   
Indemnity/Liability and Insurance 
Rockwell Medical will ensure that suitable insurance coverage is in place prior to the 
start of the study.  


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9.2.4.   
Protocol Conduct 
9.2.4.1.   
Protocol Compliance and Protocol Deviations 
Except for a change that is intended to eliminate an apparent immediate hazard to a 
study patient, the protocol shall be conducted as specified.  Any such change must 
be reported immediately to Rockwell Medical and to the IRB/EC according to the 
applicable IRB/EC policy. 
The investigator must notify the IRB/EC of any and all protocol deviations according 
to the applicable IRB/EC policy. Protocol waivers will not be granted.  
Written documentation of all protocol deviations must be kept in the study center file 
and provided to Rockwell Medical.  Examples of possible protocol deviations 
include, but are not limited to:  
• Failure to obtain required informed consent,  
• Failure to collect, report or file AE reports,  
• Performance of an unapproved study procedure,  
• Performance of research at an unapproved location, 
• Failure to file protocol modifications, and 
• Failure to adhere to an approved protocol.  
9.2.4.2.   
Protocol Amendments 
All protocols and amendments will be prepared by Rockwell Medical. If it becomes 
necessary to issue a protocol amendment during the course of the study, Rockwell 
Medical (or designee) will notify the investigators and collect a documented 
Investigator Agreement to the amendment. 
All protocol amendments must be submitted to the IRB/EC for review and approval 
must be obtained prior to implementation.  However, immediate implementation of a 
protocol amendment may be necessary if the nature of the amendment concerns the 
safety of patients and is required to be implemented on an urgent basis to protect 
the safety of patients.  Any such immediate implementation of protocol amendments 
must be agreed to in advance and in writing by Rockwell.  Hard copy documentation 
of IRB/EC approval must be forwarded to Rockwell. 
If an amendment significantly alters the study design, increases potential risk to the 
patient or otherwise affects statements in the informed consent form (ICF) and 
assent form, the ICF and assent form must be revised accordingly and submitted to 
the IRB/EC for review and approval.  The approved ICF and assent form must be 
used to obtain informed consent/assent from new patients/legal guardians prior to 
enrollment and must be used to re-obtain informed consent/assent from 
patients/legal guardians already enrolled if they are potentially affected by the 
amendment and wish to continue participation. 


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9.3.   Investigator’s Responsibilities 
9.3.1.   
GCP Compliance 
The investigator must undertake to perform the study in accordance with ICH GCP 
Guideline E6 and the applicable regulatory requirements.  
It is the investigator’s responsibility to ensure that adequate time and appropriate 
resources are available at the study site prior to commitment to participate in this 
study. The investigator should also be able to estimate or demonstrate a potential for 
recruiting the required number of suitable patients within the agreed recruitment 
period. 
If the patient has a primary physician the investigator should, with the patient’s 
consent, inform them of the patient’s participation in the trial. 
9.3.2.   
Protocol Adherence and Investigator Agreement 
The investigator must adhere to the protocol as detailed in this document. The 
investigator will be responsible for enrolling only those patients who have met 
protocol eligibility criteria. The investigators will be required to sign an Investigator 
Agreement to confirm acceptance and willingness to comply with the study protocol. 
It is the investigator’s responsibility to communicate with their local IRB/EC to ensure 
accurate and timely information is provided at all phases during the study. In 
particular the appropriate approvals must be in place prior to recruitment, notification 
of any SAEs during the study must take place and the IRB/EC must be informed of 
study completion. 
9.3.3.   
Documentation and Retention of Records 
9.3.3.1.   
Case Report Forms 
Case report forms (CRFs) will be supplied by Rockwell Medical and should be 
handled in accordance with instructions from Rockwell Medical. 
In accordance with the U.S. 21 CFR 312.62, a CRF, whether paper or electronic, 
must be completed for each patient enrolled in the study.  All data collected for each 
study patient will be recorded on CRFs provided or approved by Rockwell Medical.   
CRFs need not be completed by the investigator, but all entries in CRFs are the 
responsibility of the investigator and entry of CRF data must be made under the 
supervision of the investigator.  The investigator is responsible for ensuring the 
accuracy, completeness, legibility (if paper), and timeliness of all data reported in the 
CRFs and all required reports for each study patient.    The investigator is also 
responsible for maintaining any source documentation related to the study, 
including, but not limited to, any operative reports, laboratory results, radiographic 
films, tracings, and computer discs, files or tapes. The investigator must retain a 
copy of all CRFs.  


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9.3.3.2.   
Site Visits 
Study Initiation, Monitoring and Closeout Visits 
Representatives of Rockwell Medical will perform a number of on-site visits to the 
study center, from prior to initiation of the study at the site until after the study has 
been completed.  These visits will include but not be limited to review of the site for 
adequacy to conduct the trial, review of study data, CRFs, and supportive source 
documents, and drug accountability. 
Throughout the course of the study, Rockwell Medical representatives will also make 
frequent contacts with the investigator and designated site personnel.  As part of the 
data review it is expected that source documents (e.g., hospital records, office 
records) will be made available for review by Rockwell Medical.  The study 
documents may also be similarly evaluated by auditors representing Rockwell 
Medical.  For these purposes, the investigator will make CRFs, source documents 
and study files available when requested.   
At fulfillment of study enrollment, each investigator will be notified in writing by 
Rockwell Medical.  The study will be terminated and the study center will be closed 
when all completed original CRFs have been collected, all data discrepancies 
resolved, and drug accountability has been reconciled.  It will be the responsibility of 
the investigator to notify the IRB/EC that the study has been completed. 
Rockwell Medical has the right to terminate the study for non-adherence to protocol, 
unavailability of the investigator or his or her study staff for Rockwell Medical or its 
representatives, or for administrative reasons, at any time.  In that event, Rockwell 
Medical will notify each investigator in writing that the study is to be discontinued.  
The investigator will comply with Rockwell Medical’s written instructions for study 
discontinuation, which will include the following:   
• Date discontinuation will occur, 
• Rationale for discontinuation, 
• Instructions on how discontinuation is to be performed, 
• Instructions for patients participating in the study, and 
• Instructions for retention of study documents. 
In addition to monitoring by Rockwell Medical or its designees, the study may be 
audited by representatives of the U.S. Food and Drug Administration (FDA) or other 
applicable regulatory agencies, who will also be allowed access to study documents.  
The investigator should immediately notify Rockwell Medical of any proposed or 
scheduled audits with any regulatory authorities. 
9.3.3.3.   
Recording, Access and Retention of Source Data 
All records of this clinical study must be retained by the investigator, including, but 
not limited to, the following: 
• Protocol and all protocol amendments, 


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• All signed versions of the Statement of Investigator, Form FDA 1572, 
• All drug accountability records, 
• All IRB/EC approvals, correspondence and reports, 
• Signed and dated informed consent/assent forms for each patient, 
• Completed CRFs for each patient, 
• Copies of any other material distributed to patients, 
• Any advertisements for this study, 
• The investigator’s final report to the IRB/EC, and 
• Source documents pertaining to the study, including, but not limited to, any 
operative reports, laboratory results, radiographic films, tracings, and computer 
discs, files or tapes. 
The period of time these documents must be maintained is governed by US law and, 
when applicable, non-US regulations.  All records are to be retained by the 
investigator for a minimum of two (2) years after the FDA has approved the use of 
Triferic for the treatment of IRIDA, or after Rockwell Medical has notified the 
investigator in writing that all investigations of the drug have been discontinued.  
However, because of international regulatory requirements, Rockwell Medical may 
request retention for a longer period of time.  Therefore, Rockwell Medical or its 
designee will inform the investigator when these documents may be destroyed.  The 
investigator must obtain written approval from Rockwell Medical prior to destruction 
of any records. 
The investigator must advise Rockwell Medical in writing if the records are to be 
moved to a location other than the investigator’s archives.  If the investigator leaves 
the institution or study center, the records shall be transferred to an appropriate 
designee, at the study center, who assumes the responsibility for record retention.  
Notice of such transfer shall be documented in writing and provided to Rockwell 
Medical. 
In the event of accidental loss or destruction of any study records, the investigator 
will immediately notify Rockwell Medical in writing.  Rockwell Medical or its designee 
must be notified in writing at least 30 days prior to the intended date of disposal of 
any study records related to this protocol. 
9.3.4.   
Investigator’s Final Report 
Shortly after completion of the investigator’s participation in the study, the 
investigator will submit a written report to Rockwell Medical.  This report may be a 
copy of the investigator’s end-of-study report to their IRB/EC, which will include, but 
not be limited to, notification that the study has concluded, the number of patients 
enrolled/ treated, and the number of adverse and serious AEs that occurred during 
the study.  The report to the IRB/EC will be consistent with the applicable IRB/EC 
regulations and time frames. 


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9.4.   Ethical Considerations 
This study will be conducted under a US Investigational New Drug (IND) Application.  
All applicable US regulations governing human subject protection must be followed.  
All ethical and regulatory requirements necessary to comply with the principles of 
Good Clinical Practice (GCP) for the conduct and monitoring of clinical investigations 
must be followed.  
9.5.   Informed Consent 
A copy of the proposed ICF and assent form documents should be submitted to 
Rockwell Medical for review and comment prior to submission to the reviewing 
IRB/EC.  The ICF/assent forms 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 consenting a patient.  Authorization to use or disclose 
Personal Health Information (PHI) in accordance with requirements of the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA) should be covered in 
the ICF/assent form or in a separate document to be signed by the patient.  
The investigator will be responsible for obtaining written informed consent from the 
parent(s)/legal guardian(s) of potential patients and assent from potential patients 
(where applicable) prior to any study-specific screening and entry into the study.  
The research study will be completely explained to each prospective study patient.  
The investigator or designee must explain that the patient is free to refuse to enter 
the study, and free to withdraw from it at any time for any reason. 
9.5.1.   
Institutional Review Board or Ethics Committee Approval 
In accordance with 21 CFR Parts 50 and 56, the investigator agrees to provide the 
appropriate IRB/EC with all appropriate material, including a copy of the protocol, 
ICF, and any proposed advertisement for the study prior to the start of the study.   
The proposed ICF and any proposed advertisement must also be agreed to by 
Rockwell Medical.  The site may not begin consenting, screening or enrolling 
patients until the investigator has obtained IRB/EC approval of the protocol and 
ICF/assent form and Rockwell Medical has received documentation of each.   
The investigator will supply to Rockwell Medical a list of the names, professions, and 
affiliations of IRB/EC members to demonstrate compliance with membership 
requirements.  If the investigator or a sub-investigator is a routine voting member of 
the IRB/EC, Rockwell Medical will be provided with a statement from the IRB/EC 
that the investigator/sub-investigator 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. 
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. 


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Any significant changes or revisions in the study protocol or any changes that may 
alter patient risk must be approved by Rockwell Medical (and may require FDA/other 
regulatory agency review and/or approval) and must be approved in writing by the 
IRB/EC prior to implementation.  The investigator must also receive a written notice 
of approval from Rockwell Medical prior to initiating the revised changes to the study 
protocol.  A protocol change intended to eliminate an apparent immediate hazard 
may be implemented immediately, provided that Rockwell Medical is immediately 
notified and an amendment is subsequently provided by Rockwell Medical and 
approved by the IRB/EC. 
It is the investigator's obligation to maintain an IRB/EC correspondence file, to 
provide copies of all documents to Rockwell Medical, and to make this available for 
review by Rockwell Medical or its designated representatives as part of the study 
monitoring process. 
9.6.   Confidentiality 
All US-based investigational sites and laboratories or entities providing support for 
this study, must, where applicable, comply with HIPAA. An investigational site that is 
not a Covered Entity, as defined by HIPAA, must provide documentation of this fact 
to Rockwell Medical. 
10.   DISCLOSURE OF DATA AND PUBLICATION 
All information obtained as a result of this study or during the conduct of this study 
will be regarded as confidential.  All unpublished information relating to this drug or 
to the operations of Rockwell Medical, including clinical indications, formula, 
methods of manufacture, and any other related scientific data provided to or 
developed by the investigator, is confidential and shall remain the sole property of 
Rockwell Medical.  The investigator agrees to use the information for the purpose of 
carrying out this study and for no other purpose, unless prior written permission from 
Rockwell Medical is obtained.  Rockwell Medical has full ownership of the CRFs and 
database resulting from this study. 
The investigator agrees that results from this study may be used by Rockwell 
Medical for purposes of domestic and international new drug registration, for 
publication, and to inform medical and pharmaceutical professionals.  Regulatory 
authorities will be notified of the investigator’s name, address, qualifications, and 
extent of involvement. 
 
 


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not always iron-refractory iron deficiency anaemia. Br J Haematol 2015; 169: 
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32. Donker AE, Raymakers RA, Vlasveld LT et al. Practice guidelines for the 
diagnosis and management of microcytic anemias due to genetic disorders of 
iron metabolism or heme synthesis. Blood 2014; 123: 3873-86; quiz 4005. 
33. Hershko C, Camaschella C. How I treat unexplained refractory iron deficiency 
anemia. Blood 2014; 123: 326-333. 
34. Gross SJ, Stuart MJ, Swender PT, Oski FA. Malabsorption of iron in children 
with iron deficiency. J Pediatr 1976; 88: 795-799. 
35. Hauptfleisch JJ, Payne KA. An oral sodium citrate-citric acid non-particulate 
buffer in humans. Br J Anaesth 1996; 77: 642-644. 
36. Brittenham GM. Chapter 34: Disorders of iron homeostasis: iron deficiency and 
overload. In: Hoffman R, Benz EJ, Shattil SJ et al., eds. Hematology: Basic 
Principles and Practice. New York: Elsevier, 2013:437-449. 
37. Kirschbaum BB, Schoolwerth AC. Acute aluminum toxicity associated with oral 
citrate and aluminum-containing antacids. Am J Med Sci 1989; 297: 9-11. 
38. Martin RB. Citrate binding of Al3+ and Fe3+. J Inorg Biochem 1986; 28: 181-
187. 
39. Salusky IB, Foley J, Nelson P, Goodman WG. Aluminum accumulation during 
treatment with aluminum hydroxide and dialysis in children and young adults 
with chronic renal disease. N Engl J Med 1991; 324: 527-531. 
40. US FDA. Guidance for industry. E6 Good Clinical Practice: Consolidated 
Guidance. Federal Register 1997; 62: 25691-22570. 
41. Allen Jr LV. Formulations-Shohl's Solution, Modified (Albright’s Solution). 
International Journal of Pharmaceutical Compounding 2005; 9: 316. 
 
 
 
 
 


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APPENDIX 1. TIME AND EVENTS SCHEDULE 
Table 2: Time and Events Schedule 
Assessments 
Screen 
Period 1: Iron 
Absorption Testing 
Period 2: Dose Titration§ 
Period 3: Hemoglobin  
Maintenance§ 
Follow-
up 
Visit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Target study week* 
-4 to -1 
1 
2 
3 
4 
8 
12 
16 
20 
28 
36 
44 
45 
Informed consent/ 
patient assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weighta 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
DNA samplec 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyb,c 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reticulocyte count, 
CHr, and sTfR and 
hepcidind 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
(X)d 
Chemistryb,c  
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Serum iron profileb,c 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum iron, TSAT, TBI, 
NTBI, and LPIe 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
(if applicable)b,c  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Enroll patient§ 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
Administer study drug 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Dispense study drug 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 
 
Collect study drug and 
assess compliance 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
(X) 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
§ Period 1 Triferic responders will progress to Period 2. Period 2 Hgb responders will progress to Period 3. During Period 3, additional unscheduled visits at weeks 
24, 32, and 40 may be performed at the discretion of the investigator for assessments of Hgb and/or the serum iron profile to further titrate the dose of study drug. 
* A visit window of ±1 week is permitted for each study visit; however, study visits 3-5 and 13 should occur at least 2 days after the previous study visit. 
a Height will be recorded at Screening Visit only. 
b All blood draws for pediatric patients to use pediatric tubes. Blood draws for adult patients may use standard adult tubes. 
c For pediatric patients, hematology, chemistry, and serum iron profile results from up to 30 days prior to screening may be used for determination of eligibility. For 
all patients, TMPRSS6 sequencing results obtained at any time prior to enrollment may be used for determination of eligibility. 
d Collect only if not obtained within the previous 30 days. 
e See Appendix 2, Tables 3, 4, and 5 for the schedule for obtaining these serum iron parameter samples at Visits 2, 3, and 4, respectively. 


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APPENDIX 2. SERUM IRON PARAMETER SAMPLE COLLECTION SCHEDULE, VISITS 2-4 
Table 3: Sample Collection Schedule, Visit 2 
Body weight (kg) 
5 
6 
7 
8 
9 
10 
11-15 
16-20 
21-25 
>25 
Body weight (lbs) 
11 
13.2 
15.4 
17.6 
19.8 
22 
24.2-33 
35.2-44 
46.2-55 
>55 
Total blood volume (mL) 
400 
480 
560 
640 
720 
800 
880-
1200 
1280 
1600 
1680 
2000 
>2000 
Maximum allowable volume (mL) in one blood 
draw (2.5% TBV) 
10 
12 
14 
16 
18 
20 
22-30 
32-40 
42-50 
>50 
Total (clinical + research) maximum allowable 
volume (mL) in a 30-day period 
20 
24 
28 
32 
36 
40 
44-60 
64-80 
84-100 
>100 
Nominal Time hr§ 
Serum Iron Parameter Collection Schedule for Visit 2  
0 
a† 
a† 
a† 
a† 
a 
a 
a 
a 
a 
a 
1 
a† 
a† 
a† 
a† 
a† 
a† 
a 
a 
a 
a 
2 
a† 
a† 
a† 
a 
a 
a 
a 
a 
a 
a 
4 
a† 
a† 
a† 
a† 
a† 
a† 
a 
a 
a 
a 
Total Blood Draw for Visit 2 (mL) 
4 
4 
4 
6.5 
11 
11 
14 
14 
14 
14 
§ The time of the 3 mg Fe/kg oral dose (as FeSO4) is time 0. Sample collection for the 0-hr nominal time point should occur within 30 minutes prior to the iron dose. 
 
† For patients <9 kg (19.8 lb), 1 mL blood may be drawn using a syringe and put into a 2.5 - 3.5 mL serum separator tube (e.g., BD #367983 [gold top] or Vacuette #454243 [red cap 
with white ring, non-ridged]) to remain within collection volume limits. For patients 9 - ≤10 kg (22 pounds), 2 mL blood may be drawn and put into a 2.5 - 3.5 mL serum separator tube 
to remain within collection volume limits. Tubes may also be underfilled at additional time points if needed for any patient to remain within collection volume limits. 
a Collect samples for assessment of serum iron, TSAT, TBI, NTBI, and LPI. Process according to the instructions in Appendix 3.  
 
 


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Table 4: Sample Collection Schedule, Visit 3 
Body weight (kg) 
5 
6 
7 
8 
9 
10 
11-15 
16-20 
21-25 
>25 
Body weight (lbs) 
11 
13.2 
15.4 
17.6 
19.8 
22 
24.2-33 
35.2-44 
46.2-55 
>55 
Total blood volume (mL) 
400 
480 
560 
640 
720 
800 
880-
1200 
1280 
1600 
1680 
2000 
>2000 
Maximum allowable volume (mL) in one 
blood draw (2.5% TBV) 
10 
12 
14 
16 
18 
20 
22-30 
32-40 
42-50 
>50 
Total (clinical + research) maximum allowable 
volume (mL) in a 30-day period 
20 
24 
28 
32 
36 
40 
44-60 
64-80 
84-100 
>100 
Nominal Time hr§ 
Serum Iron Parameter Collection Schedule for Visit 3  
0 
a† 
a† 
a 
a 
a 
a 
a 
a 
a 
a 
1 
a† 
a† 
a† 
a† 
a† 
a† 
a 
a 
a 
a 
2 
a† 
a† 
a 
a 
a 
a 
a 
a 
a 
a 
4 
a† 
a† 
a† 
a† 
a† 
a† 
a 
a 
a 
a 
Total Blood Draw for Visit 3 (mL) 
4 
4 
11 
11 
11 
11 
14 
14 
14 
14 
Total Blood Draw Visits 2 + 3 (mL) 
8 
8 
15 
17.5 
22 
22 
28 
28 
28 
28 
§ The time of the 3 mg Fe/kg oral dose (as FeSO4) is time 0. At Visit 3, the iron dose should occur approximately 5 minutes after administration of Shohl’s solution, 0.67 mmol/kg. 
Sample collection for the 0-hr nominal time point should occur within 30 minutes prior to the iron dose. 
 
† For patients <9 kg (19.8 lb), 1 mL blood may be drawn using a syringe and put into a 2.5 - 3.5 mL serum separator tube (e.g., BD #367983 [gold top] or Vacuette #454243 [red cap 
with white ring, non-ridged]) to remain within collection volume limits. For patients 9 - ≤10 kg (22 pounds), 2 mL blood may be drawn and put into a 2.5 - 3.5 mL serum separator tube 
to remain within collection volume limits. Tubes may also be underfilled at additional time points if needed for any patient to remain within collection volume limits. 
a Collect samples for assessment of serum iron, TSAT, TBI, NTBI, and LPI. Process according to the instructions in Appendix 3.  
 
 
 


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Table 5: Sample Collection Schedule, Visit 4 
Body weight (kg) 
5 
6 
7 
8 
9 
10 
11-15 
16-20 
21-25 
>25 
Body weight (lbs) 
11 
13.2 
15.4 
17.6 
19.8 
22 
24.2-33 
35.2-44 
46.2-55 
>55 
Total blood volume (mL) 
400 
480 
560 
640 
720 
800 
880-
1200 
1280 
1600 
1680 
2000 
>2000 
Maximum allowable volume (mL) in one 
blood draw (2.5% TBV) 
10 
12 
14 
16 
18 
20 
22-30 
32-40 
42-50 
>50 
Total (clinical + research) maximum allowable 
volume (mL) in a 30-day period 
20 
24 
28 
32 
36 
40 
44-60 
64-80 
84-100 
>100 
Nominal Time hr§ 
Serum Iron Parameter Collection Schedule for Visit 4  
0 
a† 
a 
a 
a 
a 
a 
a 
a 
a 
a 
1 
a† 
a† 
a† 
a† 
a† 
a† 
a 
a 
a 
a 
2 
a 
a 
a 
a 
a 
a 
a 
a 
a 
a 
4 
a† 
a† 
a† 
a† 
a† 
a† 
a 
a 
a 
a 
Total Blood Draw for Visit 4 (mL) 
6.5 
11 
11 
11 
11 
11 
14 
14 
14 
14 
Total Blood Draw Visits 2 + 3 + 4 (mL) 
14.5 
19 
26 
28.5 
33 
33 
42 
42 
42 
42 
§ The time of the 3 mg Fe/kg oral dose (as Triferic, ferric pyrophosphate citrate) is time 0. At Visit 4, the iron dose should occur approximately 5 minutes after administration of Shohl’s 
solution, 0.67 mmol/kg. Sample collection for the 0-hr nominal time point should occur within 30 minutes prior to the iron dose. 
 
† For patients <9 kg (19.8 lb), 1 mL blood may be drawn using a syringe and put into a 2.5 - 3.5 mL serum separator tube (e.g., BD #367983 [gold top] or Vacuette #454243 [red cap 
with white ring, non-ridged]) to remain within collection volume limits. For patients 9 - ≤10 kg (22 pounds), 2 mL blood may be drawn and put into a 2.5 - 3.5 mL serum separator tube 
to remain within collection volume limits. Tubes may also be underfilled at additional time points if needed for any patient to remain within collection volume limits.  
a Collect samples for assessment of serum iron, TSAT, TBI, NTBI, and LPI. Process according to the instructions in Appendix 3.  
 


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APPENDIX 3. SAMPLE HANDLING, STORAGE & SHIPPING 
Supplies for the Study 
2.5 - 3.5-mL serum separator vacutainer tubes (pediatric) and 5-mL serum separator 
vacutainer tubes (adults) 
3-mL syringes for blood sampling 
Screw-top plastic sample transport tubes 
Sample Collection and Processing Instructions 
a) Serum iron, TSAT, TBI: follow the site-specific local clinical laboratory 
requirements. 
b) NTBI, and LPI samples: After allowing the samples to clot at controlled room 
temperature (22°C nominal temperature) for 30 minutes, separate the serum by 
centrifuging at controlled room temperature at 1500xg for 10 minutes. Gently 
transfer into plastic sample transport tubes. Store frozen at -80C until shipped to 
Hepcidinanalysis.com on dry ice for analysis of NTBI and LPI.  
c) Hepcidin samples: After allowing the samples to clot at controlled room 
temperature (22°C nominal temperature) for 30 minutes, separate the serum by 
centrifuging at controlled room temperature (22°C nominal temperature) at 
1500xg for 10 minutes and gently transfer two 400-µL aliquots into plastic sample 
transport tubes.  Store aliquot #1 frozen at -80C until shipped to 
Hepcidinanalysis.com on dry ice. Store aliquot #2 frozen at -80C until shipped 
as directed by Rockwell Medical. 
d) CHr samples: follow the site-specific local clinical laboratory requirements. 
e) sTfR samples: follow the site-specific local clinical laboratory requirements. 
f) DNA samples: TBD 
g) All other samples: follow the site-specific local clinical laboratory requirements. 
 
See site instructions for further details on sample collection, processing, and 
shipping, particularly for pediatric samples. 
 
 


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APPENDIX 4. DETAILED INSTRUCTIONS FOR STUDY DRUG DOSING 
Note: For Visits 2-4, study drugs should only be administered by qualified site 
personnel. For Periods 2-3, study drugs should be self-administered by the patient, 
or alternatively by the patient’s parent or guardian if the patient is unable to do so. 
 
Materials required:  
1-, 3-, 5-, and 10-mL medication dosing syringes 
30-mL graduated plastic medication dosing cups 
 
Procedure: 
Fer-In-Sol (Visit 2, 3, or 4) 
1. Shake the bottle of Fer-In-Sol well.  
2. Determine the volume of Fer-In-Sol to be dosed (see Appendix 5, Table 6).  
3. Select the most appropriate dosing device (1-, 3-, 5-, or 10-mL medication dosing 
syringe; or 30-mL graduated plastic medication dosing cup) based on the volume to 
be dosed and the age of the patient. 
4. Dispense the correct amount of Fer-In-Sol according to Appendix 5, Table 6. If the 
Fer-In-Sol is to be administered via syringe, draw up the indicated volume of Fer-In-
Sol in the appropriate syringe. If the Fer-In-Sol is to be administered via dosing cup, 
pour the indicated volume of Fer-In-Sol into a dosing cup. 
5. Administer the Fer-In-Sol. For dosing via syringe, dispense the Fer-In-Sol slowly 
towards the patient’s inner cheek. For dosing via dosing cup, have the patient drink 
all of the contents of the cup.  
 
 


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Shohl’s Solution Followed by Fer-In-Sol (Visit 2, 3, or 4) 
1. Determine the volume of Shohl’s solution to be dosed (see Appendix 5, Table 7).  
2. Select the most appropriate dosing device (1-, 3-, 5-, or 10-mL medication dosing 
syringe; or 30-mL graduated plastic medication dosing cup) based on the volume to 
be dosed and the age of the patient. 
3. Dispense the correct amount of Shohl’s solution according to Appendix 5, Table 7. 
If the Shohl’s solution is to be administered via syringe, draw up the indicated 
volume of Shohl’s solution in the appropriate syringe. If the Shohl’s solution is to be 
administered via dosing cup, pour the indicated volume of Shohl’s solution into a 
dosing cup. 
4. Administer the Shohl’s solution. For dosing via syringe, dispense the Shohl’s 
solution slowly towards the patient’s inner cheek. For dosing via dosing cup, have 
the patient drink all of the contents of the cup.  
5. Shake the bottle of Fer-In-Sol well.  
6. Determine the volume of Fer-In-Sol to be dosed (see Appendix 5, Table 7).  
7. Select the most appropriate dosing device (1-, 3-, 5-, or 10-mL medication dosing 
syringe; or 30-mL graduated plastic medication dosing cup) based on the volume to 
be dosed and the age of the patient. 
8. 5-15 minutes after the dose of Shohl’s solution, dispense the correct amount of 
Fer-In-Sol according to Appendix 5, Table 7. If the Fer-In-Sol is to be administered 
via syringe, draw up the indicated volume of Fer-In-Sol in the appropriate syringe. If 
the Fer-In-Sol is to be administered via dosing cup, pour the indicated volume of 
Fer-In-Sol into a dosing cup. 
9. Administer the Fer-In-Sol. For dosing via syringe, dispense the Fer-In-Sol slowly 
towards the patient’s inner cheek. For dosing via dosing cup, have the patient drink 
all of the contents of the cup.  
 
 


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Shohl’s Solution Followed by Triferic (Visit 2, 3, or 4) 
1. Determine the volume of Shohl’s solution to be dosed (see Appendix 5, Table 8).  
2. Select the most appropriate dosing device (1-, 3-, 5-, or 10-mL medication dosing 
syringe; or 30-mL graduated plastic medication dosing cup) based on the volume to 
be dosed and the age of the patient. 
3. Dispense the correct amount of Shohl’s solution according to Appendix 5, Table 8. 
If the Shohl’s solution is to be administered via syringe, draw up the indicated 
volume of Shohl’s solution in the appropriate syringe. If the Shohl’s solution is to be 
administered via dosing cup, pour the indicated volume of Shohl’s solution into a 
dosing cup. 
4. Administer the Shohl’s solution. For dosing via syringe, dispense the Shohl’s 
solution slowly towards the patient’s inner cheek. For dosing via dosing cup, have 
the patient drink all of the contents of the cup.  
5. Determine the volume of Triferic to be dosed (see Appendix 5, Table 8).  
6. Select the most appropriate dosing device (1-, 3-, 5-, or 10-mL medication dosing 
syringe; or 30-mL graduated plastic medication dosing cup) based on the volume to 
be dosed and the age of the patient. 
7. Open the Triferic ampule(s) by twisting off the plastic top. Use a new ampule(s) 
for each dose. 
8. 5-15 minutes after the dose of Shohl’s solution, dispense the correct amount of 
Triferic according to Appendix 5, Table 8. If the Triferic is to be administered via 
syringe, draw up the indicated volume of Triferic in the appropriate syringe. If the 
Triferic is to be administered via dosing cup, pour the indicated volume of Triferic 
into a dosing cup. 
9. Administer the Triferic. For dosing via syringe, dispense the Triferic slowly 
towards the patient’s inner cheek. For dosing via dosing cup, have the patient drink 
all of the contents of the cup.  
 
 


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Periods 2-3, Shohl’s Solution Followed by Triferic 
For Periods 2 and 3, each time study drug is dispensed and each time the 
investigator puts the patient on a different dose of Triferic, site personnel should: 
1. Determine the volume of Shohl’s solution and Triferic to be dosed (see Appendix 
5, Table 9).  
2. Select the most appropriate dosing device(s) (1-, 3-, 5-, or 10-mL medication 
dosing syringe; or 30-mL graduated plastic medication dosing cup) based on the 
volumes to be dosed and the age of the patient. 
3. Show the patient (and/or the patient’s parent or guardian, if appropriate) the 
volumes of Shohl’s solution and Triferic to be dosed for each administration on the 
dosing device(s). 
4. Write down the volumes of Shohl’s solution and Triferic to be dosed for each 
administration on the Study Drug Administration Sheet and provide this to the patient 
(and/or the patient’s parent or guardian, if appropriate). 
5. Provide the patient with enough study drug (Shohl’s solution and Triferic) and 
dosing devices to last until the next time the patient is scheduled to be dispensed 
study drug. 
 
The Study Drug Administration Sheet will include the following instructions: 
1. Check the Study Drug Administration Sheet for the amount of Shohl’s solution to 
be dosed and how many times per day it should be dosed.  
2. If the Shohl’s solution is to be given by syringe, draw up the correct volume of 
Shohl’s solution into the syringe. If the Shohl’s solution is to be given by dosing cup, 
pour the correct amount of Shohl’s solution into a dosing cup(s). 
3. For dosing via syringe, dispense the Shohl’s solution slowly towards your inner 
cheek. For dosing via dosing cup, drink all of the contents of the cup(s).  
4. Check the Study Drug Administration Sheet for the amount of Triferic to be dosed 
and how many times per day it should be dosed. 
5. Open the needed number of Triferic ampules by twisting off the plastic top. Use 
new ampules for each dose. 
6. 5-15 minutes after the dose of Shohl’s solution, give yourself the correct amount 
of Triferic. If the Triferic is to be given by syringe, draw up the correct volume of 
Triferic into the syringe. If the Triferic is to be given by dosing cup, pour the correct 
amount of Triferic into a dosing cup(s). 


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7. For dosing via syringe, dispense the Triferic solution slowly towards your inner 
cheek. For dosing via dosing cup, drink all of the contents of the cup(s).  
8. If you have side effects from either the Shohl’s solution or the Triferic, be sure to 
tell your study doctor. Your study doctor may be able to adjust the dose of your 
study medication so that it is less bothersome to you.  
9. You may stop taking the study medication any time you want. Please tell the study 
doctor if you stop taking the study medication and why. 
 
 


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APPENDIX 5. STUDY DRUG DOSING SCHEDULES 
Ferrous sulfate (Fer-In-Sol®, Mead Johnson, Glenview, IL; 15 mg Fe(II)/mL) will be 
administered at a dose of 3 mg Fe/kg at two visits during Period 1. When given in 
conjunction with Shohl’s solution, the dose will be given 5-15 minutes after the dose 
of Shohl’s solution. 
Citrate (as Shohl’s solution, e.g., Oracit®; CMP Pharma, Farmville, NC; hydrous 
sodium citrate 490 mg/5 mL and citric acid 640 mg/5 mL; 1 mmol citrate/mL) will be 
administered at 0.67 mmol/kg at two visits during Period 1. 
Ferric pyrophosphate citrate (Triferic®; Rockwell Medical, Wixom, MI; 5.44 mg 
Fe(III)/mL) will be administered at a dose of 3 mg Fe/kg at one visit during Period 1, 
5-15 minutes after the dose of Shohl’s solution. 
Fer-In-Sol  
Fer-In-Sol should be administered at a dose of 3 mg Fe/kg body weight according to 
the following table. If the patient is between body weight categories, use the lower 
weight category.    The dose may be rounded down to the nearest whole mL.  
Table 6: Study Drug Dosing  
Weight 
(kg) 
Fer-In-Sol 
(mL) 
5.0 
1.0 
6.0 
1.2 
7.0 
1.4 
8.0 
1.6 
9.0 
1.8 
10.0 
2.0 
11.0 
2.2 
12.0 
2.4 
13.0 
2.6 
14.0 
2.8 
15.0 
3.0 
20.0 
4.0 
25.0 
5.0 
30.0 
6.0 
35.0 
7.0 
40.0 
8.0 
45.0 
9.0 
50.0 
10 
55.0 
11 
60.0 
12 
65.0 
13 
70.0 
14 
75.0 
15 
80.0 
16 
85.0 
17 
90.0 
18 
95.0 
19 
≥100.0 
20 


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Shohl’s Solution Followed by Fer-In-Sol 
Shohl’s solution (1 mmol citrate/mL) will be administered at a dose of 0.67 mmol/kg 
body weight followed 5-15 minutes later by Fer-In-Sol administered at a dose of 3 
mg Fe/kg body weight according to the following table. If the patient is between body 
weight categories, use the lower weight category.    The dose may be rounded down 
to the nearest whole mL. 
Table 7: Study Drug Dosing 
Weight 
(kg) 
Shohl’s 
Solution 
(mL) 
Fer-In-Sol 
(mL) 
5.0 
3.4 
1.0 
6.0 
4.0 
1.2 
7.0 
4.7 
1.4 
8.0 
5.4 
1.6 
9.0 
6.0 
1.8 
10.0 
6.7 
2.0 
11.0 
7.4 
2.2 
12.0 
8.0 
2.4 
13.0 
8.7 
2.6 
14.0 
9.4 
2.8 
15.0 
10 
3.0 
20.0 
13 
4.0 
25.0 
17 
5.0 
30.0 
20 
6.0 
35.0 
24 
7.0 
40.0 
27 
8.0 
45.0 
30 
9.0 
50.0 
34 
10 
55.0 
37 
11 
60.0 
40 
12 
65.0 
44 
13 
70.0 
47 
14 
75.0 
50 
15 
80.0 
54 
16 
85.0 
57 
17 
90.0 
60 
18 
95.0 
64 
19 
≥100.0 
67 
20 
 
 
 


Rockwell Medical Inc. CONFIDENTIAL/PROPRIETARY 
  
Protocol RMFPC-15 
 
08 March 2017 
 
 
 
Page 67 of 68 
Version 1.3 
Shohl’s Solution Followed by Triferic 
Shohl’s solution (1 mmol citrate/mL) will be administered at a dose of 0.67 mmol/kg 
body weight followed 5-15 minutes later by Triferic administered at a dose of 3 mg 
Fe/kg body weight according to the following table. If the patient is between body 
weight categories, use the lower weight category.  The dose may be rounded down 
to the nearest whole mL. 
Table 8: Study Drug Dosing 
Weight 
(kg) 
Shohl’s 
Solution 
(mL) 
Triferic 
(mL) 
5.0 
3.4 
2.8 
6.0 
4.0 
3.3 
7.0 
4.7 
3.9 
8.0 
5.4 
4.4 
9.0 
6.0 
5.0 
10.0 
6.7 
5.5 
11.0 
7.4 
6.1 
12.0 
8.0 
6.6 
13.0 
8.7 
7.2 
14.0 
9.4 
7.7 
15.0 
10 
8.3 
20.0 
13 
11 
25.0 
17 
14 
30.0 
20 
17 
35.0 
24 
19 
40.0 
27 
22 
45.0 
30 
25 
50.0 
34 
28 
55.0 
37 
30 
60.0 
40 
33 
65.0 
44 
36 
70.0 
47 
39 
75.0 
50 
41 
80.0 
54 
44 
85.0 
57 
47 
90.0 
60 
50 
95.0 
64 
52 
≥100.0 
67 
55 
 
 
 


Rockwell Medical Inc. CONFIDENTIAL/PROPRIETARY 
  
Protocol RMFPC-15 
 
08 March 2017 
 
 
 
Page 68 of 68 
Version 1.3 
Periods 2 and 3 
During Periods 2 and 3, Shohl’s solution (1 mmol citrate/mL) will be administered 3x 
per day at a dose of 0.67 mmol/kg body weight followed 5-15 minutes later by 
Triferic according to the following table. If the patient is between body weight 
categories, use the lower weight category.  The dose may be rounded down to the 
nearest whole mL. 
Initially, the dose of study drug will be Shohl’s solution 0.67 mmol/kg followed by 
Triferic 3 mg/kg 3x/day. However, the Triferic dose may be titrated to 2 mg/kg or 1 
mg/kg if needed. In addition, the number of doses of study drug may be decreased 
to 2x/day or 1x/day. 
Table 9: Study Drug Dosing, Periods 2 and 3 
Weight 
(kg) 
Shohl’s 
Solution 
(mL) 
Triferic 
3 mg/kg 
(mL) 
Triferic 
2 mg/kg 
(mL) 
Triferic  
1 mg/kg 
(mL) 
5.0 
3.4 
2.8 
1.8 
0.9 
6.0 
4.0 
3.3 
2.2 
1.1 
7.0 
4.7 
3.9 
2.6 
1.3 
8.0 
5.4 
4.4 
2.9 
1.5 
9.0 
6.0 
5.0 
3.3 
1.7 
10.0 
6.7 
5.5 
3.7 
1.8 
11.0 
7.4 
6.1 
4.0 
2.0 
12.0 
8.0 
6.6 
4.4 
2.2 
13.0 
8.7 
7.2 
4.8 
2.4 
14.0 
9.4 
7.7 
5.1 
2.6 
15.0 
10 
8.3 
5.5 
2.8 
20.0 
13 
11 
7.4 
3.7 
25.0 
17 
14 
9.2 
4.5 
30.0 
20 
17 
11 
5.5 
35.0 
24 
19 
13 
6.4 
40.0 
27 
22 
15 
7.4 
45.0 
30 
25 
17 
8.3 
50.0 
34 
28 
18 
9.2 
55.0 
37 
30 
20 
10 
60.0 
40 
33 
22 
11 
65.0 
44 
36 
24 
12 
70.0 
47 
39 
26 
13 
75.0 
50 
41 
28 
14 
80.0 
54 
44 
29 
15 
85.0 
57 
47 
31 
16 
90.0 
60 
50 
33 
17 
95.0 
64 
52 
35 
17 
≥100.0 
67 
55 
37 
18