Clinical trial NCT04080908
Conditions: Anemia
Sponsor: NYU Langone Health
Start date: 2020-01-15; Completion date: 2021-10-19
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Ferumoxytol injection (Feraheme®) is a parenteral form of iron supplementation that is FDA-approved for treatment of iron deficiency anemia. Ferumoxytol injection achieves iron repletion in fewer doses (2) when compared with other available injectable iron formulations (5-6) available at NYU Langone Health, and thus may be useful to reduce travel burden and expedite full iron repletion in patients with iron deficiency. Iron-deficiency anemia is common in patients after placement of a ventricular assist device (VAD) for treatment of end-stage heart disease. This is a pilot study to test the feasibility of iron repletion with ferumoxytol injection in 20 eligible subjects with laboratory evidence of iron deficiency after placement of a VAD.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Ferumoxytol injection
Intervention descriptions: intervention 1: Two doses of ferumoxytol injection will be administered intravenously 3-8 days apart.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
Open Label Single Arm Pilot Study to Assess Feasibility and Safety of 
Iron Repletion With Feraheme in Iron Deficient Patients With Durable 
Ventricular Assist Device Support   
NCT Number: 
NCT04080908 
Study Number: 
19-00866 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
August 15, 2022 
 
 


 
 
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Tool Revision History: 
 
Version Number 
Version Date 
Summary of Revisions Made 
0.9 
22 April 2019 
Original version 
1.0 
15 July 2019 
Minor edits pre IRB submission 
1.1 
12 August 2019 
Initial IRB review 
1.2  
03 August 
2022 
Removing Claudia Gidea, MD 
 
 


 
 
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STUDY TITLE: OPEN-LABEL SINGLE-ARM PILOT STUDY TO ASSESS 
FEASIBILITY AND SAFETY OF IRON REPLETION WITH FERAHEME IN IRON-
DEFICIENT PATIENTS WITH DURABLE VENTRICULAR ASSIST DEVICE SUPPORT 
 
 
Principal Investigator: 
 
Stuart Katz, MD MS 
Department of Medicine, Leon H. Charney Division of Cardiology 
530 First Avenue, Skirball 9R, New York, NY. 10016 
stuart.katz@nyumc.org 
212-263-3946 
Additional Investigators: 
 
Shaline Rao, MD 
Department of Medicine, Leon H. Charney Division of Cardiology 
530 First Avenue, Skirball 9R, New York, NY. 10016 
shaline.rao@nyumc.org 
646-501-0119 
Alex Reyentovich, MD 
Department of Medicine, Leon H. Charney Division of Cardiology 
530 First Avenue, Skirball 9R, New York, NY. 10016 
Alex.reyentovich@nyumc.org 
646-501-0119 
Tajinderpal Saraon, MD 
Department of Medicine, Leon H. Charney Division of Cardiology 
530 First Avenue, Skirball 9R, New York, NY. 10016 
Tajinderpal.saraon@nyumc.org 
646-501-0119 
NYULMC Study Number: 
S19-00866 
Funding Sponsor:  
AMAG Pharmaceuticals, Inc. 
1100 Winter Street 
Waltham, MA 02451 
617-498-3300 
IND/IDE Number:  
Not applicable 
Regulatory Sponsor:  
Not applicable 
Study Product: 
Ferumoxytol injection (Ferumoxytol injection ®) 
Study Product Provider:  
AMAG Pharmaceuticals, Inc. 
1100 Winter Street 
Waltham, MA 02451 
617-498-3300 
ClinicalTrials.gov 
Number                 
 
 
Initial version: 
12 august 2019 
Amended: 
03 August 2022 
Amended: 
 
 


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Statement of Compliance 
 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any other applicable 
US government research regulations, and institutional research policies and procedures. The International 
Conference on Harmonisation (“ICH”) Guideline for Good Clinical Practice (“GCP”) (sometimes referred to 
as “ICH-GCP” or “E6”) will be applied only to the extent that it is compatible with FDA and DHHS regulations. 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the sponsor and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel 
involved in the conduct of this study have completed Human Subjects Protection Training. 
 
 


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Table of Contents 
 
STATEMENT OF COMPLIANCE ................................................................................................................ III 
LIST OF ABBREVIATIONS........................................................................................................................ VII 
PROTOCOL SUMMARY .............................................................................................................................. 8 
SCHEMATIC OF STUDY DESIGN ............................................................................................................. 11 
 .................................................................................................................................................................... 11 
 .................................................................................................................................................................... 12 
1 
KEY ROLES ....................................................................................................................................... 13 
2 
INTRODUCTION, BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ..................... 13 
2.1 
BACKGROUND INFORMATION AND RELEVANT LITERATURE .............................................................. 14 
2.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL AGENT ............................................................ 14 
2.2.1 
Clinical Data to Date .............................................................................................................. 14 
2.2.2 
Dose Rationale (if applicable) ............................................................................................... 14 
2.3 
RATIONALE .................................................................................................................................. 15 
2.4 
POTENTIAL RISKS & BENEFITS ...................................................................................................... 15 
2.4.1 
Known Potential Risks ........................................................................................................... 15 
2.4.2 
Known Potential Benefits ...................................................................................................... 16 
3 
OBJECTIVES AND PURPOSE ......................................................................................................... 16 
3.1 
PRIMARY OBJECTIVE .................................................................................................................... 16 
3.2 
SECONDARY OBJECTIVES ............................................................................................................. 16 
4 
STUDY DESIGN AND ENDPOINTS .................................................................................................. 17 
4.1 
DESCRIPTION OF STUDY DESIGN .................................................................................................. 17 
4.2 
STUDY ENDPOINTS....................................................................................................................... 17 
4.2.1 
Primary Study Endpoints ....................................................................................................... 17 
4.2.2 
Secondary Study Endpoints .................................................................................................. 17 
4.2.3 
Exploratory Endpoints ........................................................................................................... 17 
5 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................................. 17 
5.1 
INCLUSION CRITERIA .................................................................................................................... 17 
5.2 
EXCLUSION CRITERIA ................................................................................................................... 17 
5.3 
VULNERABLE SUBJECTS ............................................................................................................... 18 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION .......................................................................... 18 
5.5 
DURATION OF STUDY PARTICIPATION ............................................................................................ 18 
5.6 
TOTAL NUMBER OF PARTICIPANTS AND SITES ................................................................................ 18 
5.7 
PARTICIPANT WITHDRAWAL OR TERMINATION ................................................................................ 18 
5.7.1 
Reasons for Withdrawal or Termination ................................................................................ 18 
5.7.2 
Handling of Participant Withdrawals or Termination ............................................................. 19 
5.8 
PREMATURE TERMINATION OR SUSPENSION OF STUDY .................................................................. 19 
6 
STUDY AGENT (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE ETC.) AND/OR PROCEDURAL 
INTERVENTION ......................................................................................................................................... 19 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION .............................................................................. 19 
6.1.1 
Acquisition ............................................................................................................................. 20 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ............................................................ 20 
6.1.3 
Product Storage and Stability ................................................................................................ 21 
6.1.4 
Preparation ............................................................................................................................ 21 
6.1.5 
Dosing and Administration .................................................................................................... 21 
6.1.6 
Route of Administration ......................................................................................................... 21 
6.1.7 
Dose Adjustments/Modifications/Delays ............................................................................... 21 


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6.1.8 
Duration of Therapy ............................................................................................................... 21 
6.1.9 
Tracking of Dose ................................................................................................................... 21 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ............................................................................. 22 
7 
STUDY PROCEDURES AND SCHEDULE ....................................................................................... 22 
7.1 
STUDY PROCEDURES/EVALUATIONS ............................................................................................. 22 
7.1.1 
Study Specific Procedures .................................................................................................... 22 
7.1.2 
Standard of Care Study Procedures ..................................................................................... 23 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ................................................................................... 23 
7.3 
STUDY SCHEDULE ........................................................................................................................ 23 
7.3.1 
Screening .............................................................................................................................. 23 
7.3.2 
Enrollment/Baseline .............................................................................................................. 23 
7.3.3 
Final Study Visit ..................................................................................................................... 24 
7.3.4 
Withdrawal/Early Termination Visit........................................................................................ 24 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES .................................................... 24 
8 
ASSESSMENT OF SAFETY ............................................................................................................. 24 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................................... 24 
8.1.1 
Definition of Adverse Events (AE) ......................................................................................... 25 
8.1.2 
Definition of Serious Adverse Events (SAE) ......................................................................... 25 
8.1.3 
Definition of Unanticipated Problems (UP) ............................................................................ 25 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ....................................................................................... 26 
8.2.1 
Severity of Event ................................................................................................................... 26 
8.2.2 
Relationship to Study Agent .................................................................................................. 26 
8.2.3 
Expectedness ........................................................................................................................ 27 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP .................................... 27 
8.4 
REPORTING PROCEDURES – NOTIFYING THE IRB .......................................................................... 28 
8.4.1 
Adverse Event Reporting ...................................................................................................... 28 
8.4.2 
Serious Adverse Event Reporting ......................................................................................... 28 
8.4.3 
Unanticipated Problem Reporting ......................................................................................... 28 
8.4.4 
Reporting of Pregnancy ......................................................................................................... 28 
8.5 
REPORTING PROCEDURES – NOTIFYING THE STUDY SPONSOR ...................................................... 29 
8.6 
STUDY HALTING RULES ................................................................................................................ 29 
9 
STATISTICAL CONSIDERATIONS .................................................................................................. 29 
9.1 
STATISTICAL AND ANALYTICAL PLANS (SAP) ................................................................................. 29 
9.2 
STATISTICAL HYPOTHESES ........................................................................................................... 29 
9.3 
ANALYSIS DATASETS .................................................................................................................... 30 
9.4 
DESCRIPTION OF STATISTICAL METHODS ...................................................................................... 30 
9.4.1 
General Approach ................................................................................................................. 30 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ........................................................................ 30 
9.4.3 
Analysis of the Secondary Endpoint(s) ................................................................................. 30 
9.4.4 
Safety Analyses ..................................................................................................................... 31 
9.5 
SAMPLE SIZE ............................................................................................................................... 31 
10 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................. 31 
11 
QUALITY ASSURANCE AND QUALITY CONTROL ....................................................................... 32 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................. 32 
12.1 
ETHICAL STANDARD ..................................................................................................................... 32 
12.2 
INSTITUTIONAL REVIEW BOARD ..................................................................................................... 32 
12.3 
INFORMED CONSENT PROCESS .................................................................................................... 32 
12.3.1 
Consent/Assent and Other Informational Documents Provided to Participants ............... 32 
12.3.2 
Consent Procedures and Documentation ......................................................................... 33 
12.4 
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................................... 33 
13 
DATA HANDLING AND RECORD KEEPING ................................................................................... 34 


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13.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .............................................................. 34 
13.2 
STUDY RECORDS RETENTION ....................................................................................................... 35 
13.3 
PROTOCOL DEVIATIONS ............................................................................................................... 35 
13.4 
PUBLICATION AND DATA SHARING POLICY ..................................................................................... 35 
14 
STUDY FINANCES ............................................................................................................................ 36 
14.1 
FUNDING SOURCE ........................................................................................................................ 36 
14.2 
COSTS TO THE PARTICIPANT ......................................................................................................... 36 
14.3 
PARTICIPANT REIMBURSEMENTS OR PAYMENTS ............................................................................ 36 
15 
CONFLICT OF INTEREST POLICY .................................................................................................. 36 
16 
REFERENCES ................................................................................................................................... 37 
 
 
 
 
 


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List of Abbreviations 
 
 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTSI 
Clinical Translational Science Institute 
DHHS 
Department of Health and Human Services 
FDA 
Food and Drug Administration 
FWA 
Federal-wide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NYULH 
New York University Langone Health 
OHRP 
Office for Human Research Protections 
OHSR 
Office of Human Subjects Research 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
US 
United States 
VAD 
Ventricular Assist Device 
 
 


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Protocol Summary 
Title 
Open-Label Single-Arm Pilot Study To Assess Feasibility and Safety of Iron 
Repletion with Feraheme® Injection in Iron-Deficient Patients with Durable 
Ventricular Assist Device Support 
Short Title 
Ferumoxytol injection in VAD patients 
Brief Summary 
Ferumoxytol injection (Feraheme®) is a parenteral form of iron 
supplementation that is FDA-approved for treatment of iron deficiency 
anemia. Ferumoxytol injection achieves iron repletion in fewer doses (2) 
when compared with other available injectable iron formulations (5-6) 
available at NYU Langone Health, and thus may be useful to reduce travel 
burden and expedite full iron repletion in patients with iron deficiency. Iron-
deficiency anemia is common in patients after placement of a ventricular 
assist device (VAD) for treatment of end-stage heart disease. This is a pilot 
study to test the feasibility of iron repletion with ferumoxytol injection in 20 
eligible subjects with laboratory evidence of iron deficiency after placement of 
a VAD.  
Phase 
Phase 4 
Objectives 
Primary Objective: To assess feasibility of iron-repletion with ferumoxytol 
injection administered according to FDA-approved prescribing instructions 
(initial 510 mg dose followed by a second 510 mg dose 3 to 8 days later, each 
dose infused over at least 15 minutes while the patient is in a reclined or semi-
reclined position) in iron-deficient patients with durable VAD support. 
 
Secondary Objective: To assess safety of ferumoxytol injection in iron-deficient 
patients with durable ventricular assist device support. 
 
Exploratory Objectives: To characterize the clinical response to ferumoxytol 
injection from chart review of the medical record (biomarkers of iron stores 
(serum ferritin and transferrin saturation), hemoglobin level, six-minute walk 
distance, bleeding episodes and hospitalizations). 
Methodology 
Open-label single-arm pilot study will assess feasibility and safety of iron 
repletion with ferumoxytol injection.  


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Endpoint 
Primary Feasibility Outcome: Proportion of subjects who complete 
ferumoxytol injection therapy according to the study protocol. 
 
Primary Safety Outcome: Incidence of treatment related adverse events 
 
Other Exploratory Outcomes based on clinically available data obtained by 
review of the medical record: 
• 
Change from pre-treatment baseline in serum ferritin 1-24 weeks 
after ferumoxytol injection therapy 
• 
Change from pre-treatment baseline in transferrin saturation 1-24 
weeks after ferumoxytol injection therapy 
• 
Change from pre-treatment baseline in hemoglobin level 1-24 weeks 
after ferumoxytol injection therapy 
• 
Change from pre-treatment baseline in 6-minute walk distance 1-24 
weeks after ferumoxytol injection therapy 
 
Study Duration 
Total anticipated duration of study (subject accrual, completion of study 
therapy and assessments, data analysis, manuscript preparation) is 18 
months. 
Participant Duration 
Six months including three study visits over about two weeks, and data 
extraction from medical record for up to six months after ferumoxytol 
injection. 
Duration of IP 
administration 
Two doses of ferumoxytol injection will be administered intravenously 3-8 
days apart. 
Population 
Adult subjects with stable clinical status after clinically-indicated VAD 
placement and iron deficiency anemia will be enrolled 
Study Sites 
NYULH is the only clinical site for enrollment and study procedures 
Number of participants 
20 subjects from the NYULH VAD program will be enrolled 
Description of Study 
Agent/Procedure 
Ferumoxytol injection will be administered to eligible subjects according to 
FDA-approved prescribing information. Two doses of ferumoxytol injection  
will be administered: an initial 510 mg dose followed by a second 510 mg 
dose 3 to 8 days later, each dose given as an intravenous infusion in 50-200 
mL 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP 
while the subject is in a reclined or semi-reclined position. 
Reference Therapy 
There is no reference therapy for this study 
Key Procedures 
The only study procedures are the administration of IP. Other data will be 
collected from clinical information in the medical record. 


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Statistical Analysis 
The null hypothesis for the primary feasibility objective is that 75% of the 
subjects will successfully complete ferumoxytol injection  treatment as per 
study protocol. 20 subjects will provide >80% power (one-tailed alpha=0.05) 
to detect <40% successful completion of ferumoxytol injection treatment.  
 
Chi-Square analysis will be used to compare the observed proportion of 
successful completion of ferumoxytol injection treatment with the null 
hypothesis of 0.75. Statistical significance will be inferred for one-tailed p-
value <0.05. 
 
Descriptive analysis techniques will be used to characterize clinical 
characteristics of the study participants, and incidence of adverse events and 
change in secondary exploratory outcomes. Center and variability of 
continuous variables will be presented as means (SD) when they follow a 
normal distribution and as medians and interquartile range otherwise. Log 
transformation will be applied on variables with skewed distribution 
 
 
 
 


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Schematic of Study Design 
 
 
 
Schedule of Assessments 
 
Visit Name 
Screening 
 
First Dose Ferumoxytol injection  
Second Dose Ferumoxytol injection  
(3-8 days after first dose) 
Visit Number 
1 
2 
3 
Study Week (±7days)* 
0 
0-2 
1-3 
Informed consent 
X 
 
 
Screening Evaluation  
X 
 
 
Medical History 
X 
X 
X 
Bleeding/Blood 
Transfusion 
History 
X 
X 
X 


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Vital Signs 
X 
X 
X 
Cardiovascular exam 
X 
X 
X 
VAD settings 
X 
X 
X 
Ferumoxytol 
injection  
Administration* 
 
X 
X 
Infusion Monitoring 
 
X 
X 
AE monitoring  
 
X 
X 
Concomitant Meds 
X 
X 
X 
 
*Ferumoxytol injection will be administered according to FDA-approved prescribing instructions 3-8 days apart 
 


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1 Key Roles 
Principal Investigator: 
 
Stuart Katz, MD MS 
Department of Medicine, Leon H. Charney Division of Cardiology 
530 First Avenue, Skirball 9R, New York, NY. 10016 
stuart.katz@nyumc.org 
212-263-3946 
Additional Investigators: 
 
Shaline Rao, MD 
Department of Medicine, Leon H. Charney Division of Cardiology 
530 First Avenue, Skirball 9R, New York, NY. 10016 
shaline.rao@nyumc.org 
646-501-0119 
Alex Reyentovich, MD 
Department of Medicine, Leon H. Charney Division of Cardiology 
530 First Avenue, Skirball 9R, New York, NY. 10016 
Alex.reyentovich@nyumc.org 
646-501-0119 
Claudia Gidea, MD 
Department of Medicine, Leon H. Charney Division of Cardiology 
530 First Avenue, Skirball 9R, New York, NY. 10016 
Claudia.gidea@nyumc.org 
646-501-0119 
Tajinderpal Saraon, MD 
Department of Medicine, Leon H. Charney Division of Cardiology 
530 First Avenue, Skirball 9R, New York, NY. 10016 
Tajinderpal.saraon@nyumc.org 
646-501-0119 
 
 
 
2 Introduction, Background Information and Scientific Rationale 
 


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2.1 Background Information and Relevant Literature 
Ventricular assist devices (VADs) are surgically implantable pumps used to support circulation of blood in patients with advanced heart failure.1 
Approximately 2500-3000 VADs are implanted annually in the US.2 Iron-deficiency anemia is common in patients with VADs due to high 
prevalence of pre-operative chronic anemia associated with advanced heart failure, surgical blood loss during implantation, mandatory chronic 
aspirin and warfarin therapy to reduce risk of device thrombosis, and increased risk of gastrointestinal bleeding after placement of the VAD.3 
Chronic iron-deficiency may contribute to reduced functional capacity in these patients.4  
 
Erythropoiesis stimulating agents are contraindicated in patients with VADs due to increased risk of device thrombosis.5 Oral iron therapy is poorly 
tolerated, and is not likely to be effective for repletion of iron stores due to poor gastrointestinal iron absorption in the heart failure population.6 In 
the NYU VAD program, nine patients with iron-deficiency anemia have previously received clinical treatment with intravenous formulations of iron 
(iron sucrose or ferric gluconate) with no reported adverse effects. 
 
Ferumoxytol injection (Feraheme®) is FDA-approved to treat iron deficiency anemia in adult patients, but there are no published data for 
ferumoxytol injection or any other FDA-approved intravenous iron preparations in VAD patients with iron deficiency anemia.7 This pilot study is 
being proposed to assess feasibility and safety of iron repletion with ferumoxytol injection  in VAD patients with iron deficiency. 
2.2 Name and Description of the Investigational Agent  
Ferumoxytol injection will be administered to eligible subjects according to FDA-approved prescribing information. Two doses of ferumoxytol 
injection will be administered: an initial 510 mg dose followed by a second 510 mg dose 3 to 8 days later, each dose given as an intravenous 
infusion in 50-200 mL 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP while the subject is in a reclined or semi-reclined 
position. 
2.2.1 Clinical Data to Date 
Ferumoxytol injection has been demonstrated to be safe and effective in the treatment of iron deficiency anemia and is FDA-approved for 
treatment of iron deficiency in adult patients with chronic kidney disease. 
 
The pharmacokinetic (PK) behavior of ferumoxytol injection has been examined in healthy subjects and in patients with CKD stage 5D on 
hemodialysis. Ferumoxytol injection exhibited dose-dependent, capacity-limited elimination from plasma with a half-life of approximately 15 hours 
in humans. The clearance (CL) was decreased by increasing the dose of ferumoxytol injection. Volume of distribution (Vd) was consistent with 
plasma volume, and the mean maximum observed plasma concentration (Cmax) and terminal half-life (t1/2) values increased with dose. The 
estimated values of CL and Vd following two 510 mg doses of ferumoxytol injection administered intravenously within 24 hours were 69.1 mL/hr 
and 3.16 L, respectively. The Cmax and time of maximum concentration (tmax) were 206 mcg/mL and 0.32 hr, respectively. Rate of infusion had 
no influence on ferumoxytol injection PK parameters. No gender differences in Ferumoxytol injection  PK parameters were observed. Ferumoxytol 
injection is not removed by hemodialysis. 
2.2.2 Dose Rationale (if applicable)  
The dosing regimen will be identical to the FDA-approved prescribing information. 


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2.3 Rationale 
Ferumoxytol injection has been demonstrated to be safe and effective in the treatment of iron deficiency anemia and is FDA-approved for treatment 
of iron deficiency in adult patients with chronic kidney disease with or without requirement for chronic dialysis. Chronic kidney disease is common in 
the VAD population, but there are no previous data to demonstrate the safety and feasibility of the regimen described in the FDA-approved 
prescribing information. 
2.4 Potential Risks & Benefits 
2.4.1 Known Potential Risks 
Ferumoxytol injection has been demonstrated to be safe and effective in the treatment of iron deficiency anemia and is FDA-approved for 
treatment of iron deficiency in adult patients with chronic kidney disease. The most common adverse reactions (≥ 2%) following the administration 
of Ferumoxytol injection are diarrhea, nausea, dizziness, hypotension, constipation, and peripheral edema. Fatal and serious hypersensitivity 
reactions including anaphylaxis have occurred in patients receiving ferumoxytol injection. In clinical studies predominantly in patients with CKD, 
serious hypersensitivity reactions were reported in 0.2% (3/1,726) of subjects receiving Ferumoxytol injection. Other adverse reactions potentially 
associated with hypersensitivity (e.g., pruritus, rash, urticaria or wheezing) were reported in 3.7% (63/1,726) of these subjects. In other trials 
excluding patients with Stages 4 and 5 CKD, moderate to severe hypersensitivity reactions were reported in 2.6% (26/1,014) of patients treated 
with ferumoxytol injection. Severe adverse reactions of clinically significant hypotension have been reported in the post-marketing experience. In 
clinical studies, hypotension was reported in 1.9% (33/1,726) of subjects, including three patients with serious hypotensive reactions. The following 
additional serious adverse reactions have been reported from the post-marketing experience with ferumoxytol injection : tachycardia/rhythm 
abnormalities, angioedema, ischemic myocardial events, congestive heart failure, pulse absent, and cyanosis. This safety information is derived 
from studies in patients with chronic kidney disease with or without dialysis requirement. The dosing and route of administration used in this study 
are consistent with the FDA-approved prescribing information for this drug. There is no reason to suspect that VAD patients with iron deficiency 
are at greater risk for adverse effects of ferumoxytol injection when compared with completed clinical trials and post-marketing experience in 
chronic kidney disease patients. 
 
Protections Against Risk: 
 
To minimize risk, all procedures will be performed in clinically stable participants who meet eligibility criteria under the direct supervision of the 
principal investigators and other research personnel with appropriate training and licensure. All study procedures are performed at the NYU 
Clinical Translational Science Institute Clinical Research Center located within Bellevue Hospital with immediate access to emergency support 
equipment and personnel in the event of deterioration in clinical status.  
 
Participant risks are also minimized by the following protections described in the study protocol: 
• 
Study entry criteria to exclude potential participants at greater risk of adverse events 
• 
Administration of ferumoxytol injection according to the FDA-approved prescribing information 
• 
Active monitoring for potential treatment related adverse effects and other adverse events 
• 
Pre-specified criteria for participant withdrawal to protect participant safety 
• 
Pre-specified criteria for study termination or suspension to protect participant safety 
 


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It is important to note that VAD patients with iron deficiency not enrolled in this study will be referred for standard of care treatment with other FDA-
approved intravenous iron formulations that have comparable safety profiles to ferumoxytol injection. Accordingly, the risks related to drug infusion 
during participation in this study are no different than risk related to standard of care, and may actually be lower since ferumoxytol requires only 
two infusions, whereas other commonly used preparations require 5-6 infusions. 
2.4.2 Known Potential Benefits 
Ferumoxytol injection has been demonstrated to be safe and effective in the treatment of iron deficiency anemia and is FDA-approved for 
treatment of iron deficiency in adult patients with chronic kidney disease with or without dialysis requirement. A summary of the findings of the 
three major efficacy trials is presented in the table below.7 
 
 
3 Objectives and Purpose 
The proposed pilot study will provide preliminary feasibility and safety data to guide design of future clinical trials of ferumoxytol injection therapy in 
the VAD population. 
3.1 Primary Objective 
To assess feasibility of iron-repletion with ferumoxytol injection (initial 510 mg dose followed by a second 510 mg dose 3 to 8 days later, each 
dose infused over at least 15 minutes while the patient is in a reclined or semi-reclined position) in iron-deficient patients with durable ventricular 
assist device support. 
3.2 Secondary Objectives 
To assess safety of ferumoxytol injection administration in iron-deficient patients with durable ventricular assist device support. 
 
To determine the effects of ferumoxytol injection on biomarkers of iron stores (serum ferritin and transferrin saturation), hemoglobin level, and six 
minute walk distance when compared with pre-treatment baseline. 


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4 Study Design and Endpoints 
4.1 Description of Study Design 
Open-label single-arm pilot study will assess feasibility and safety of iron repletion of ferumoxytol injection. Total anticipated duration of study 
(subject accrual, completion of study therapy and assessments, data analysis, manuscript preparation) is 18 months. 
4.2 Study Endpoints 
4.2.1 Primary Study Endpoints 
The null hypothesis for the primary feasibility objective is that 75% of the subjects will successfully complete ferumoxytol injection treatment as per 
study protocol. 
 
4.2.2 Secondary Study Endpoints 
Primary Safety Endpoint: The incidence of treatment-related adverse events 
 
4.2.3 Exploratory Endpoints 
• 
Change from pre-treatment baseline in serum ferritin 2-24 weeks after ferumoxytol injection therapy 
• 
Change from pre-treatment baseline in transferrin saturation 2-24 weeks after ferumoxytol injection therapy 
• 
Change from pre-treatment baseline in hemoglobin level 2-24 weeks after ferumoxytol injection therapy 
• 
Change from pre-treatment baseline in 6-minute walk distance 2-24 weeks after ferumoxytol injection therapy 
5 Study Enrollment and Withdrawal 
5.1 Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
• 
Age >18 years 
• 
Status post placement of durable ventricular assist device with stable clinical status for >30days 
• 
Hemoglobin >6 g/dL AND <13 g/dL (men) or <12 g/dL (women) within last 90 days 
• 
Serum ferritin <100 ng/mL OR Serum ferritin 100-299 ng/mL with transferrin saturation <20% within last 90 days 
• 
Able and willing to provide written informed consent 
 
5.2 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study: 
• 
Known hypersensitivity to Ferumoxytol injection  or other intravenous iron preparation 


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• 
History of anaphylaxis 
• 
Treatment with erythropoiesis stimulating agent or intravenous iron in last 3 months 
• 
Renal failure on hemodialysis 
• 
Respiratory failure on mechanical ventilation 
• 
Disabling Stroke 
• 
Ventricular assist device thrombosis 
• 
Evidence of active gastrointestinal bleeding or other active blood loss 
• 
Hospitalization <30 days 
• 
Pregnant or breastfeeding women 
 
5.3 Vulnerable Subjects 
There will be no vulnerable subjects enrolled in this study. 
 
5.4 Strategies for Recruitment and Retention 
Study participants will be recruited from the population of 40-50 VAD patients followed at NYULH. These patients are followed by a dedicated 
multidisciplinary VAD team at regular intervals as outpatients. Assessment of iron deficiency anemia and 6-minute walk testing are standard of 
care during follow-up in these patients, and iron-deficient patients are routinely referred for intravenous iron infusions as part of standard clinical 
care. Participation in the study differs from clinical care only in the formulation of intravenous iron and the location of the iron infusion. Clinical staff 
in the outpatient VAD clinic will assess patient interest in participation in the study and will inform study personnel. Trained study personnel will 
obtain consent in a private quiet setting at the NYU CTSI at a time of clinical stability. 
 
5.5 Duration of Study Participation 
The study will require active participation at three visits conducted over 1-3 weeks. The screening visit and first injection of study drug may occur 
on the same day. Clinical data from the medical record will be reviewed and entered in the research database for 6 months. There are no study 
procedures other than data collection from medical record after completion of the two visits for study drug infusion. 
 
5.6 Total Number of Participants and Sites  
 
Recruitment will end when 20 participants are enrolled. It is expected that 20 participants will be enrolled in order to produce 20 evaluable 
participants. 
5.7 Participant Withdrawal or Termination 
5.7.1 Reasons for Withdrawal or Termination 
 


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Participants are free to withdraw from participation in the study at any time upon request. An investigator may terminate participation in the study 
if: 
• 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation occurs such that continued participation in 
the study would not be in the best interest of the participant 
• 
The participant meets an exclusion criterion (either newly developed or not previously recognized) that precludes further study 
participation 
• 
The participant is not able to return for the second dose of ferumoxytol within 15 days of the first dose. 
 
5.7.2 Handling of Participant Withdrawals or Termination 
 
Withdrawn or terminated participants will be followed for extraction of clinical data from the medical record for 6 months with participant 
permission. Since the primary outcome is feasibility, there will be no replacement of withdrawn subjects. 
5.8 Premature Termination or Suspension of Study 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written notification, documenting the 
reason for study suspension or termination, will be provided by the principal investigator. If the study is prematurely terminated or suspended, the 
PI will promptly inform the IRB and will provide the reason(s) for the termination or suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
 
6 Study Agent (Study drug, device, biologic, vaccine etc.) and/or Procedural Intervention  
6.1 Study Agent Description 
Ferumoxytol injection, an iron replacement product, is a non-stoichiometric magnetite (superparamagnetic iron oxide) coated with polyglucose 
sorbitol carboxymethylether. The overall colloidal particle size is 17-31 nm in diameter. The chemical formula of ferumoxytol injection is 
Fe5874O8752­ C11719H18682O9933Na414 with an apparent molecular weight of 750 kDa. 
 
Ferumoxytol injection is an aqueous colloidal product that is formulated with mannitol. It is a black to reddish brown liquid, and is provided in single 
use vials containing 510 mg of elemental iron. Each mL of the sterile colloidal solution of ferumoxytol injection contains 30 mg of elemental iron 
and 44 mg of mannitol, and has low bleomycin-detectable iron. The formulation is isotonic with an osmolality of 270-330 mOsm/kg. The product 
contains no preservatives, and has a pH of 6 to 8. 
 


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Ferumoxytol injection consists of a superparamagnetic iron oxide that is coated with a carbohydrate shell, which helps to isolate the bioactive iron 
from plasma components until the iron-carbohydrate complex enters the reticuloendothelial system macrophages of the liver, spleen and bone 
marrow. The iron is released from the iron-carbohydrate complex within vesicles in the macrophages. Iron then either enters the intracellular 
storage iron pool (e.g., ferritin) or is transferred to plasma transferrin for transport to erythroid precursor cells for incorporation into hemoglobin. 
 
Ferumoxytol injection  Injection is available in single use vials. Each vial contains 510 mg of elemental iron in 17 mL (30 mg per mL).  
 
Use of ferumoxytol injection in this study meets criteria for IND exemption, since all of the following conditions apply: 
 
(i) the investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used 
to support any other significant change in the labeling for the drug; 
(ii) Ferumoxytol injection is lawfully marketed as a prescription drug product; the investigation is not intended to support a significant change in the 
advertising for the product; 
(iii) the investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly 
increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product; 
(iv) the investigation is conducted in compliance with the requirements for review by an IRB (21CFR56) and the requirements for informed consent 
(21CFR 50); and 
(v) the investigation is conducted in compliance with the requirements of 21CFR312.7 (Promotion and sale of investigational drugs). 
 
6.1.1 Acquisition 
Investigational product will be obtained from the US manufacturer of ferumoxytol injection  (AMAG pharmaceuticals). 
 
6.1.2 Formulation, Appearance, Packaging, and Labeling 
Ferumoxytol injection is available in single use vials in the following package sizes:  
 
 


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6.1.3 Product Storage and Stability 
Investigational product will be stored according to FDA-approved prescribing information (Store at 20o to 25oC (68o to 77oF). Excursions permitted 
to 15o – 30oC (59o – 86oF)). 
 
6.1.4 Preparation 
In accord with FDA-approved prescribing information, ferumoxytol injection will be administered as an intravenous infusion in 50-200 mL 0.9% 
Sodium Chloride Injection, USP or 5% Dextrose Injection, USP over at least 15 minutes.  
6.1.5 Dosing and Administration 
In accord with FDA-approved prescribing information, ferumoxytol injection will be administered as an initial 510 mg dose followed by a second 510 
mg dose 3 to 8 days later. Once added to intravenous infusion bags containing either 0.9% Sodium Chloride Injection, USP (normal saline), or 5% 
Dextrose Injection, USP, at concentrations of 2-8 mg elemental iron per mL, the investigational product will be used immediately but may be stored 
at controlled room temperature (25°C ± 2°C) for up to 4 hours. 
 
6.1.6 Route of Administration 
The investigational product will be administered by intravenous infusion. 
 
6.1.7 Dose Adjustments/Modifications/Delays 
Dosing may be discontinued due to intolerance, patient request, or protocol non-adherence. Modifications/Delay of dose outside of the FDA-
approved prescribing information is not permitted. 
 
6.1.8 Duration of Therapy 
Participants will receive the FDA-approved regimen of two doses of ferumoxytol injection (an initial 510 mg dose followed by a second 510 mg 
dose 3 to 8 days later).  
 
6.1.9 Tracking of Dose 
Study drug will be administered under supervision of research personnel at the NYU CTSI. The investigational product will be ordered in the EPIC 
medical record by the principal investigator and will be dispensed according to the protocol by the NYU Research Pharmacy.  
 


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6.2 Study Agent Accountability Procedures 
The investigational product will be sent by AMAG pharmaceuticals to the NYU Research Pharmacy and stored according to instructions in the 
FDA-approved prescribing information. Drug accountability logs will be maintained by the NYU Research Pharmacy. Unused investigational 
product will be returned to AMAG pharmaceuticals or disposed according to NYU Research Pharmacy protocol. 
 
7 Study Procedures and Schedule 
7.1 Study Procedures/Evaluations 
7.1.1 Study Specific Procedures 
Study visits (See Attached Study Schematic Figure and Schedule of Assessments Table): The study will require 3 visits over approximately 2 
weeks for each subject.  
 
• 
Visit 1: Informed consent and screening*  
• 
Visit 2: First dose of ferumoxytol injection Study Drug*  
• 
Visit 3: Second dose of ferumoxytol injection Study Drug  
 
*Visits 1 and 2 may occur on the same day. 
 
Screening procedures. After the informed consent form is signed, chart review and patient interview will be performed to determine eligibility. 
Screening will include subject interview and chart review to determine eligibility. Clinical information on co-morbid conditions, VAD settings, and 
concomitant medications will be collected. Vital signs in the seated position and a brief cardiovascular exam will be recorded. Women of 
childbearing potential will undergo urine or blood pregnancy testing. 
 
Study Drug Administration: Ferumoxytol injection will be administered to eligible subjects according to FDA-approved prescribing information. Prior 
to administration, interim history, concomitant medications, VAD settings, vital signs and a cardiovascular exam will be recorded. Two doses of 
ferumoxytol injection will be administered: an initial 510 mg dose followed by a second 510 mg dose 3 to 8 days later, each dose given as an 
intravenous infusion in 50-200 mL 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP while the subject is in a reclined or semi-
reclined position. Subjects will be observed for signs or symptoms of hypersensitivity reactions (including monitoring of blood pressure and pulse 
rate) during and for at least 30 minutes after ferumoxytol injection administration. The dose, date and time of infusion, duration of infusion, and 
treatment-related adverse effects (diarrhea, nausea, dizziness, hypotension, hypersensitivity) will be recorded. 
 
Clinical Data Collection for Research 
 
Laboratory data. Clinical blood test results (serum ferritin, transferrin saturation, and hemoglobin) before administration of ferumoxytol injection 
and from 2-24 weeks after administration of ferumoxytol injection will be recorded by medical chart review.  
 
Bleeding/Transfusion data. Information on bleeding events (source of bleeding, need for hospitalization, intervention(s)) and number of blood 
transfusion for 2-24 weeks after treatment will be collected from medical chart review. 


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Six-minute walk test. The six-minute walk test is routinely performed in VAD patients for clinical assessment of functional capacity. Results will be 
obtained by medical chart review. 
7.1.2 Standard of Care Study Procedures 
The only research procedure that differs from standard of care procedures is the administration of ferumoxytol injection, since this intravenous iron 
preparation is not available on the NYULH formulary. Iron-deficient VAD patients not participating in this study would be referred to outpatient 
infusion centers to receive other formulations of intravenous iron that require a greater number of visits for iron repletion. The risks associated with 
ferumoxytol injection are comparable to the known risks of other FDA-approved intravenous iron preparations on the formulary at NYULH. 
 
VAD patients routinely undergo laboratory testing for iron-deficiency anemia and serial assessment of submaximal exercise capacity with 6-minute 
walk testing as part of standard of care. 
 
7.2 Laboratory Procedures/Evaluations 
There are no research laboratory procedures or evaluations. 
7.3 Study Schedule 
 
Study visits will occur within a time window ±7 days of the times listed in this section.  
7.3.1 Screening  
 
Screening Visit (Visit 1, Day -14 to 0)  
• 
Obtain informed consent of potential participant verified by signature on written informed consent for screening form. 
• 
Review medical history to determine eligibility based on inclusion/exclusion criteria. 
• 
Record concomitant medications 
• 
Record VAD settings, seated vital signs (mean blood pressure, heart rate, oxygen saturation) and cardiovascular examination. 
• 
Schedule study visits for participants who are eligible and available for the duration of the study. If the participant is eligible to receive 
Ferumoxytol injection , the first administration of study drug may be completed on the same day as the screening visit. 
• 
Obtain urine or blood pregnancy test in women of child-bearing potential. 
• 
Provide participants with instructions for the return for the infusion of Ferumoxytol injection . 
 
7.3.2 Enrollment/Baseline 
 
Enrollment/Baseline Visit (Visit 2, Day 0) 
• 
Verify informed consent documentation. 
• 
Verify inclusion/exclusion criteria. 


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• 
Assess for interim changes in clinical status or concomitant medications. 
• 
Record VAD settings, seated vital signs (mean blood pressure, heart rate, oxygen saturation) and cardiovascular examination. 
• 
Obtain urine or blood pregnancy test in women of childbearing potential (if visit is occurring >1 day after screening visit). 
• 
Record vital signs and assess clinical stability of subject. 
• 
Administer the study treatment as described with monitoring for hypersensitivity. 
• 
Provide participants with instructions for the return for the infusion of Ferumoxytol injection . 
 
 
7.3.3 Final Study Visit 
 
Enrollment/Baseline Visit (Visit 3, Day 3-8) 
• 
Verify informed consent documentation. 
• 
Verify inclusion/exclusion criteria. 
• 
Assess for interim changes in clinical status or concomitant medications. 
• 
Record VAD settings, seated vital signs (mean blood pressure, heart rate, oxygen saturation) and cardiovascular examination. 
• 
Obtain urine or blood pregnancy test in women of childbearing potential. 
• 
Record vital signs and assess clinical stability of subject. 
• 
Administer the study treatment as described with monitoring for hypersensitivity reactions. 
• 
Report status of iron repletion to clinical care team. 
 
7.3.4 Withdrawal/Early Termination Visit 
There will be no visit required for early termination. Participants will be asked to provide permission for continued access to their medical record for 
6 months. 
7.4 Concomitant Medications, Treatments, and Procedures 
 
All concomitant prescription medications taken during study participation will be recorded on the case report forms (CRFs). For this protocol, a 
prescription medication is defined as a medication that can be prescribed only by a properly authorized/licensed clinician. Medications to be 
reported in the CRF are concomitant prescription medications, over-the-counter medications and non-prescription medications. 
 
8 Assessment of Safety 
8.1 Specification of Safety Parameters  
Ferumoxytol injection is lawfully marketed in the US and is being administered according to FDA-approved prescribing information. The PI will 
serve as the medical monitor for the study. Subjects will be observed for known treatment-related adverse events as described in the prescribing 
information including evidence of hypersensitivity for 30 minutes after infusion of ferumoxytol injection. 


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8.1.1 Definition of Adverse Events (AE) 
 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity during the course of the study.  
Intercurrent illnesses or injuries should be regarded as adverse events.  Abnormal results of diagnostic procedures are considered to be adverse 
events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
 
8.1.2 Definition of Serious Adverse Events (SAE) 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major clinical significance. They may jeopardize 
the subject, and may require intervention to prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would typically be 
considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious adverse events.  
 
8.1.3 Definition of Unanticipated Problems (UP) 
 
 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  


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• Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such as the IRB-approved protocol or consent 
form, the investigators brochure, etc) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a reasonable possibility that the incident 
experience, or outcome may have been caused by the procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, psychological, economic, or social harm). 
 
8.2 Classification of an Adverse Event 
8.2.1 Severity of Event 
 
For AEs not included in the protocol defined grading system, the following guidelines will be used to describe severity. 
 
• Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities. 
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. Moderate events may cause some 
interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or other treatment. Severe events are 
usually potentially life-threatening or incapacitating. 
 
8.2.2 Relationship to Study Agent 
 
The clinician’s assessment of an AE's relationship to study agent (drug, biologic, device) is part of the documentation process, but it is not a factor 
in determining what is or is not reported in the study. If there is any doubt as to whether a clinical observation is an AE, the event will be reported.  
 
For all collected AEs, the clinician who examines and evaluates the participant will determine the AE’s causality based on temporal relationship 
and his/her clinical judgment. The degree of certainty about causality will be graded using the categories below. 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other possible contributing factors can be ruled out. The 
clinical event, including an abnormal laboratory test result, occurs in a plausible time relationship to drug administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be clinically 
plausible. The event must be pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge procedure if 
necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence of other factors is unlikely. The clinical event, 
including an abnormal laboratory test result, occurs within a reasonable time after administration of the drug, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge 
information is not required to fulfill this definition. 
• Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event occurred within a reasonable time after 
administration of the trial medication). However, other factors may have contributed to the event (e.g., the participant’s clinical condition, 


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other concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related,” as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal relationship to drug administration 
makes a causal relationship improbable (e.g., the event did not occur within a reasonable time after administration of the trial medication) 
and in which other drugs or chemicals or underlying disease provides plausible explanations (e.g., the participant’s clinical condition, other 
concomitant treatments). 
• Not Related – The AE is completely independent of study drug administration, and/or evidence exists that the event is definitely related to 
another etiology. There must be an alternative, definitive etiology documented by the clinician. 
 
8.2.3 Expectedness 
The principal investigator or an appropriately licensed Co-investigator will be responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk information 
previously described for the study agent. 
 
8.3 Time Period and Frequency for Event Assessment and Follow-Up 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by a study monitor. All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate RF. Information to be collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study product (assessed only by those with the training and authority to make a diagnosis), and time of resolution/stabilization of the 
event. All AEs occurring while on study must be documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as baseline and not reported as an AE. 
However, if the study participant’s condition deteriorates at any time during the study, it will be recorded as an AE. UPs will be recorded in the data 
collection system throughout the study. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at each level of severity to be performed. 
AEs characterized as intermittent require documentation of onset and duration of each episode. 
 
The PI will record all reportable events with start dates occurring any time after informed consent is obtained until 7 (for non-serious AEs) or 30 
days (for SAEs) after the last day of study participation. At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit. Events will be followed for outcome information until resolution or stabilization.  
 
All unresolved adverse events should be followed by the investigator until the events are resolved, the subject is lost to follow-up, or the adverse 
event is otherwise explained.  At the last scheduled visit, the investigator should instruct each subject to report any subsequent event(s) that the 
subject, or the subject’s personal physician, believes might reasonably be related to participation in this study.  The investigator should notify the 
study sponsor of any death or adverse event occurring at any time after a subject has discontinued or terminated study participation that may 


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reasonably be related to this study.  The sponsor should also be notified if the investigator should become aware of the development of cancer or 
of a congenital anomaly in a subsequently conceived offspring of a subject that has participated in this study.  
 
8.4 Reporting Procedures – Notifying the IRB  
8.4.1 Adverse Event Reporting 
Adverse events that do not meet criteria as Serious Adverse Events or Unanticipated Problems will be reported to the IRB at the time of annual 
continuation review. 
 
8.4.2 Serious Adverse Event Reporting 
Serious adverse events will be reported to the IRB within 72 hours. 
 
8.4.3 Unanticipated Problem Reporting 
 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an UP report form. It is the site investigator’s 
responsibility to report UPs to their IRB and to the study sponsor. The UP report will include the following information: 
 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• A detailed description of the event, incident, experience, or outcome; 
• An explanation of the basis for determining that the event, incident, experience, or outcome represents an UP; 
• A description of any changes to the protocol or other corrective actions that have been taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 
• UPs that are SAEs will be reported to the IRB and to the study sponsor within 72 hours of the investigator becoming aware of the event. 
• Any other UP will be reported to the IRB and to the study sponsor within 7 business days of the investigator becoming aware of the 
problem. 
• All UPs should be reported to appropriate institutional officials (as required by an institution’s written reporting procedures), the supporting 
agency head (or designee), and OHRP within<insert timeline in accordance with policy> of the IR’s receipt of the report of the problem from 
the investigator. 
 
8.4.4 Reporting of Pregnancy 
Pregnancy will be reported to the IRB within 72 hours. If pregnancy is discovered before administration of the two doses of ferumoxytol injection, 
participation in the study will be terminated. If pregnancy is determined during the 6-month follow-up period, the subject will be requested to allow 
continued follow-up to determine the pregnancy outcome. 


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8.5 Reporting Procedures – Notifying the Study Sponsor 
 
The study clinician will complete a SAE Form within the following timelines: 
 
• All deaths and immediately life-threatening events, whether related or unrelated, will be recorded on the SAE Form and submitted to the 
study sponsor within 72 hours of site awareness. See Section 1, Key Roles for contact information. 
• Other SAEs regardless of relationship will be submitted to the study sponsor within 72 hours of site awareness. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be chronic or the adherence to be stable. 
Other supporting documentation of the event may be requested by the DCC/study sponsor and should be provided as soon as possible.  
 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator shall provide further information, as 
applicable, on the unanticipated event or the unanticipated problem in the form of a written narrative.  This should include a copy of the completed 
Unanticipated Problem form, and any other diagnostic information that will assist the understanding of the event.  Significant new information on 
ongoing unanticipated adverse effects shall be provided promptly to the study sponsor. 
8.6 Study Halting Rules 
 
Administration of study agent will be halted when three grade 3 AEs determined to be “probably related” are observed.  
 
It is the responsibility of the Principal Investigator to oversee the safety of the study.  This safety monitoring will include careful assessment and 
appropriate reporting of adverse events as noted above, as well as the construction and implementation of a site data and safety-monitoring plan.  
The data and safety monitoring plan will include systematic review of accrual, protocol deviations, data integrity and adverse event monitoring by 
the PI on an ongoing basis. The PI will report a summary of the data and safety monitoring record to the IRB at the time of annual continuation 
application, or earlier in accord with IRB regulation in the event of Reportable New Information. 
 
9 Statistical Considerations 
9.1 Statistical and Analytical Plans (SAP) 
The statistical analysis plan is summarized in the following sections. 
 
9.2 Statistical Hypotheses 
Primary Feasibility Objective: The null hypothesis for the primary feasibility objective is that 75% of the subjects will successfully complete 
ferumoxytol injection treatment as per study protocol.  
 


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There are no hypotheses to be tested for the primary safety objective and exploratory secondary objectives. Descriptive statistics will be used to 
analyze these data. The purpose of the analyses is to obtain estimates of the study treatment risk in the study population, and the magnitude and 
variance of change in the exploratory endpoints in the study population. These pilot data will be useful for planning of future clinical trials. 
9.3 Analysis Datasets 
Feasibility analysis dataset.  Intention to treat (ITT) will be defined as all patients who provide consent and are eligible to receive study treatment. 
The ITT data set will be used for the primary feasibility endpoint. 
  
Safety objective and exploratory objectives analysis dataset.  All eligible subjects who received any study drug, and for whom post-dose data are 
available, will be included in the safety and exploratory objectives analysis set. 
9.4 Description of Statistical Methods 
9.4.1 General Approach 
This is a single-arm open label study with a primary feasibility outcome. Descriptive statistics will be used to summarize pertinent characteristics of 
the study population. 
 
Study Endpoints: 
Primary Feasibility Endpoint: The proportion of eligible subjects who complete ferumoxytol injection therapy per study protocol. 
 
Primary Safety Endpoint: The incidence of treatment-related adverse events 
 
Other Exploratory Endpoints:  
• 
Change from pre-treatment baseline in serum ferritin 2-24 weeks after ferumoxytol injection therapy 
• 
Change from pre-treatment baseline in transferrin saturation 2-24 weeks after ferumoxytol injection therapy 
• 
Change from pre-treatment baseline in hemoglobin level 2-24 weeks after ferumoxytol injection therapy 
• 
Change from pre-treatment baseline in 6-minute walk distance 2-24 weeks after ferumoxytol injection therapy 
 
9.4.2 Analysis of the Primary Efficacy Endpoint(s) 
Chi-Square analysis will be used to compare the observed proportion of successful completion of ferumoxytol injection treatment with the null 
hypothesis of 0.75. Statistical significance will be inferred for one-tailed p-value <0.05. 
 
. 
9.4.3 Analysis of the Secondary Endpoint(s) 
Descriptive analysis techniques will be used to characterize clinical characteristics of the study participants, and incidence of adverse events and 
change in secondary exploratory outcomes. Center and variability of continuous variables will be presented as means (SD) when they follow a 
normal distribution and as medians and interquartile range otherwise. Log transformation will be applied on variables with skewed distribution 


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9.4.4 Safety Analyses 
Descriptive analysis techniques will be used to characterize clinical characteristics of the study participants, and incidence of adverse events and 
change in secondary exploratory outcomes. Center and variability of continuous variables will be presented as means (SD) when they follow a 
normal distribution and as medians and interquartile range otherwise. Log transformation will be applied on variables with skewed distribution 
 
9.5 Sample Size 
The null hypothesis for the primary feasibility objective is that 75% of the subjects will successfully complete ferumoxytol injection treatment as per 
study protocol. 20 subjects will provide >80% power (one-tailed alpha=0.05) to detect <40% successful completion of ferumoxytol injection 
treatment. 
10 Source Documents and Access to Source Data/Documents 
 
Source data are all information, original records of clinical findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study findings.  Source data are contained in source documents.  Examples of these original documents, and 
data records include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and 
at medico-technical departments involved in the clinical trial. It is acceptable to use CRFs as source documents. If this is the case, it should be 
stated in this section what data will be collected on CRFs and what data will be collected from other sources. 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All data requested on the CRF will be recorded.  All 
missing data will be explained.  If a space on the CRF is left blank because the procedure was not done or the question was not asked, “N/D” will 
be recorded.  If the item is not applicable to the individual case, “N/A” will be recorded.  All entries will be printed legibly in black ink.  If any entry 
error has been made, a single straight line will be drawn through the incorrect entry and enter the correct data above it.  All such changes will be 
initialed and dated.  For clarification of illegible or uncertain entries, the clarification will be printed above the item, then initialed and dated. 
 
Access to study records will be limited to IRB-approved members of the study team. The investigator will permit study-related monitoring, audits, 
and inspections by the IRB/EC, the sponsor, government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.).  The investigator will ensure the 
capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government regulatory authorities and applicable 
University compliance and quality assurance offices. 
 


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11 Quality Assurance and Quality Control 
 
QC procedures will be implemented beginning with the data entry system and data QC checks that will be run on the database will be generated. 
Any missing data or data anomalies will be communicated to the site(s) for clarification/resolution. 
 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data are generated, documented (recorded), and reported in 
compliance with the protocol, GCP, and the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing 
Practices (GMP)). 
 
12 Ethics/Protection of Human Subjects 
12.1 Ethical Standard 
 
The investigator will ensure that this study is conducted in full conformity with Regulations for the Protection of Human Subjects of Research 
codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and/or the ICH E6. 
 
12.2 Institutional Review Board 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to the IRB for review and approval. 
Approval of both the protocol and the consent form must be obtained before any participant is enrolled. Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study. All changes to the consent form will be IRB approved; a 
determination will be made regarding whether previously consented participants need to be re-consented. 
 
12.3 Informed Consent Process 
 
The investigators will comply with applicable regulatory requirements and should adhere to 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 
and/or ICH GCP. Prior to the beginning of the trial, the investigator will have the IRB’s written approval for the protocol and the written informed 
consent form(s) and any other written information to be provided to the participants. 
12.3.1 Consent and Other Informational Documents Provided to Participants 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the participant and written documentation of informed 
consent is required prior to starting intervention/administering study product. 


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12.3.2 Consent Procedures and Documentation 
 
The consent process will be conducted by trained IRB-appproved personnel during a time of clinical stability in a quiet private room located in the 
NYULH Clinical Research Center. Extensive discussion of risks and possible benefits of participation will be provided to the participants and their 
families. Consent forms will be IRB-approved and the participant will be asked to read and review the document. The investigator will explain the 
research study to the participant and answer any questions that may arise. All participants will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as research participants. Participants will have the 
opportunity to carefully review the written consent form and ask questions prior to signing. The participants should have the opportunity to discuss 
the study with their surrogates or think about it prior to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. The participants may withdraw consent at any time throughout the course of the trial. A copy of 
the signed informed consent document will be given to the participants for their records. The rights and welfare of the participants will be protected 
by emphasizing to them that the quality of their medical care will not be adversely affected if they decline to participate in this study. 
 
A copy of the signed informed consent document will be stored in the subject’s research record. The consent process, including the name of the 
individual obtaining consent, will be thoroughly documented in the subject’s research record. Any alteration to the standard consent process (e.g. 
use of a translator, consent from a legally authorized representative, consent document presented orally, etc.) and the justification for such 
alteration will likewise be documented.  
 
12.4 Participant and Data Confidentiality 
All patient data will be kept strictly confidential, except when published for purposes of reporting data. In that case, the patients are never 
identified. All electronic data will be de-identified and transmitted and stored with secure systems that meet or exceed Federal guidelines 
(REDCap). The Principal Investigator will maintain files with identifying information in a locked cabinet in a locked room or in password-protected 
files on a password-protected computer. No vulnerable subject populations will be enrolled in this study. 
 
Information about study subjects will be kept confidential and managed according to the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the ability to use all information 
collected prior to the revocation of subject authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should be 
made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the sponsor(s) and their agents. No information 
concerning the study or the data will be released to any unauthorized third party without prior written approval of the sponsor. 
 


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The representatives of the IRB or other governmental regulatory office may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use during the study. At the end of the study, all 
records will continue to be kept in a secure location for as long a period as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be transmitted to and stored at NYU 
Langone Medical Center. This will not include the participant’s contact or identifying information. Rather, individual participants and their research 
data will be identified by a unique study identification number. The study data entry and study management systems used by clinical sites and by 
NYU Langone Medical Center research staff will be secured and password protected. At the end of the study, all study databases will be de-
identified and archived at the NYU Langone Medical Center. 
 
 
13 Data Handling and Record Keeping 
13.1 Data Collection and Management Responsibilities 
Information about study subjects will be kept confidential and managed according to the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA). A random Study ID code will be assigned to each participant. This code will be used on all written and 
electronic research records. The Principal Investigator and study coordinator will be able to link the Study ID code back to the personal information 
during the interval of active participation in the study, but this link will be destroyed after the subject has completed the study procedures. Consent 
forms, links between Study ID and personal information, paper case report forms, laboratory reports, and other study data will be kept in a project 
notebook in a locked cabinet in a locked office. Research data without identifiers will be maintained on the NYU School of Medicine REDCap 
system. The REDCap system provides secure password protected storage of research information behind the NYU firewall and provides quality 
control and audit trail functions to validate the integrity and quality of the research data. Study data records will be maintained for a minimum of 3 
years, or longer if requested by Sponsor. 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. The investigator is responsible for 
ensuring the accuracy, completeness, legibility, and timeliness of the data reported. 
 
All source documents will be completed in a neat, legible manner to ensure accurate interpretation of data. Black ink is required to ensure clarity of 
reproduced copies. When making changes or corrections, the original entry will be crossed out with a single line, and initialed and dated. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for recording data for each participant enrolled 
in the study. Data reported in the eCRF derived from source documents should be consistent with the source documents or the discrepancies 
should be explained and captured in a progress note and maintained in the participant’s official electronic study record. 
 


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13.2 Study Records Retention 
 
Study documents will be retained for the longer of 3 years after close-out, 5 years after final reporting/publication, or 2 years after the last approval 
of a marketing application is approved for the drug for the indication for which it is being investigated or 2 years after the investigation is 
discontinued and FDA is notified if no application is to be filed or if the application has not been approved for such indication. No records will be 
destroyed without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained. 
 
13.3 Protocol Deviations 
 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of Procedures (MOP) requirements. The noncompliance 
may be either on the part of the participant, the investigator, or the study site staff. As a result of deviations, corrective actions are to be developed 
by the site and implemented promptly. 
 
These practices are consistent with ICH E6: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, section 5.1.1 
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site PI/study staff to use continuous vigilance to identify and report deviations that change subject risk within 3 working 
days of identification of the protocol deviation. 
 
All protocol deviations must be addressed in study source documents, reported to IRB on an annual basis at time of continuing review. 
 
Protocol deviations must be reported to the local IRB per their guidelines. The site PI/study staff is responsible for knowing and adhering to their 
IRB requirements. Further details about the handling of protocol deviations will be included in the MOP. 
 
13.4 Publication and Data Sharing Policy 
 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical trials registration policy as a condition 
for publication. The ICMJE defines a clinical trial as any research project that prospectively assigns human subjects to intervention or concurrent 
comparison or control groups to study the cause-and-effect relationship between a medical intervention and a health outcome. Medical 
interventions include drugs, surgical procedures, devices, behavioral treatments, process-of-care changes, and the like. Health outcomes include 
any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events. The 
ICMJE policy, and the Section 801 of the Food and Drug Administration Amendments Act of 2007, requires that all clinical trials be registered in a 
public trials registry such as ClinicalTrials.gov, which is sponsored by the National Library of Medicine. Other biomedical journals are considering 
adopting similar policies. For interventional clinical trials performed under NIH IC grants and cooperative agreements, it is the grantee’s 


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responsibility to register the trial in an acceptable registry, so the research results may be considered for publication in ICMJE member journals. 
The ICMJE does not review specific studies to determine whether registration is necessary; instead, the committee recommends that researchers 
who have questions about the need to register err on the side of registration or consult the editorial office of the journal in which they wish to 
publish. 
 
14 Study Finances 
14.1 Funding Source 
This study is funded by an unrestricted grant from AMAG pharmaceuticals. The study design was determined by the Principal Investigator. 
 
14.2 Costs to the Participant 
There will be no costs to the participant for research procedures (infusions of ferumoxytol injection). Standard of care procedures will continue to 
be billed to the patient and their insurer. 
 
14.3 Participant Reimbursements or Payments 
Subjects will receive $50 via check for each completed study visit, even if the visits occur on the same day. The total for completion of the study is 
$150. 
15 Conflict of Interest Policy 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical. Therefore any actual 
conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts managed in a way that is 
appropriate to their participation in the trial.  
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain greater than the minimum allowable by 
their institution, etc.) must have the conflict reviewed by the NYU Langone Conflict of Interest Management Unit (CIMU) with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study sponsor prior to participation in this study. All NYULMC 
investigators will follow the applicable conflict of interest policies. 
 
 
 


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16 References 
 
1. 
Becnel M, Ventura HO and Krim SR. Changing our Approach to Stage D Heart Failure. Prog Cardiovasc Dis. 2017. 
2. 
Kirklin JK, Naftel DC, Pagani FD, Kormos RL, Stevenson LW, Blume ED, Myers SL, Miller MA, Baldwin JT and Young JB. 
Seventh INTERMACS annual report: 15,000 patients and counting. J Heart Lung Transplant. 2015;34:1495-504. 
3. 
Amione-Guerra J, Cruz-Solbes AS, Bhimaraj A, Trachtenberg BH, Pingali SR, Estep JD, Park MH and Guha A. Anemia after 
continuous-flow left ventricular assist device implantation: characteristics and implications. Int J Artif Organs. 2017:0. 
4. 
Saraon T and Katz SD. Targeting Iron Deficiency Anemia in Heart Failure. Prog Cardiovasc Dis. 2016;58:407-15. 
5. 
Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, Maggioni AP, McMurray JJ, O'Connor C, Pfeffer MA, 
Solomon SD, Sun Y, Tendera M, van Veldhuisen DJ, Committees R-H and Investigators R-H. Treatment of anemia with darbepoetin 
alfa in systolic heart failure. N Engl J Med. 2013;368:1210-9. 
6. 
Lewis GD, Malhotra R, Hernandez AF, McNulty SE, Smith A, Felker GM, Tang WHW, LaRue SJ, Redfield MM, Semigran MJ, 
Givertz MM, Van Buren P, Whellan D, Anstrom KJ, Shah MR, Desvigne-Nickens P, Butler J, Braunwald E and Network NHFCR. 
Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: 
The IRONOUT HF Randomized Clinical Trial. JAMA. 2017;317:1958-1966. 
7. 
Lu M, Cohen MH, Rieves D and Pazdur R. FDA report: Ferumoxytol for intravenous iron therapy in adult patients with chronic 
kidney disease. Am J Hematol. 2010;85:315-9.