Clinical trial NCT03218384
Conditions: Iron-deficiency
Keywords: Injectafer ferric carboxymaltose Supplemental Iron
Sponsor: NYU Langone Health
Start date: 2017-09-07; Completion date: 2022-04-04
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to better understand how body levels of iron affect the ability to exercise in patients with heart failure (HF).

Heart failure is a condition in which abnormal pumping action of the heart reduces the flow of blood to the body. Patients with heart failure may feel shortness of breath or leg fatigue when they exercise. Iron is an essential nutrient in the diet. In heart failure patients, low body levels of iron might increase shortness of breath and fatigue.

Detailed description:
The purpose of this prospective, double blind parallel group randomized study is to compare the effects of ferric carboxymaltose vs. placebo on skeletal muscle mitochondrial oxidative capacity, submaximal exercise tolerance, and health-related quality of life in non-anemic Heart Failure (HF) patients with functional iron deficiency.

Arms: arm 1: HF patients with functional iron deficiency assigned to receive one-time dose of Ferric Carboxymaltose 750 mg. Participants will undergo serial assessment before and 4 weeks after study drug administration arm 2: HF patients with functional iron deficiency assigned to receive one-time dose of Placebo (saline injection). Participants will undergo serial assessment before and 4 weeks after study drug administration.
Interventions: intervention 1: Ferric Carboxymaltose intervention 2: Placebo intervention 3: 31P MRS/MRI
Intervention descriptions: intervention 1: Intravenous Ferric Carboxymaltose 750 mg mixed under sterile conditions in 100 ml of normal saline for final concentration of 7.5 mg/ml and administered via volumetric infusion pump over 15 minutes. intervention 2: 100 ml of normal saline solution, and administered via volumetric infusion pump over 15 minutes. intervention 3: Each participant will perform the same rhythmic plantar extension exercise protocol twice, for sequential acquisition of magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) measurements. For the exercise protocol, the participant will lay supine on the scanning table with the right leg inside the volume coil. The exercise consists of repeated plantar flexion movements using resistance bands at a frequency of one repetition per second for 1-2 minutes. Data are collected continuously for 2 minutes before the exercise (baseline), during exercise, and 5 minutes after the exercise for the MRS and MRI experiments.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
Ferric Carboxymaltose to Improve Skeletal Muscle Metabolism in Heart 
Failure Patients With Functional Iron Deficiency 
 
NCT Number: 
NCT03218384 
Study Number: 
17-00444 
 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
June 24, 2022 
 


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Study Title: Ferric Carboxymaltose To Improve Skeletal Muscle Metabolism in Heart Failure Patients 
with Functional Iron Deficiency 
 
 
 
 
Principal Investigator:  
Stuart Katz, MD 
 
 
 
 
Department of Medicine 
 
Research Team: 
 
Ravinder Regatte, Ph. D. (Department of Radiology) 
 
 
 
 
Rajiv Menon (Department of Radiology) 
 
 
 
 
 
 
 
 
 
 
 
 
Regulatory Sponsor: 
NYULMC 
Source of Funding: 
American Regent, Inc. 
One Luitpold Drive, P.O. Box 9001,Shirley, NY 11967  
631-924-4000 
Study Product: 
Ferric Carboxymaltose (Injectafer) marketed by American 
Regent Inc. (Shirley NY) 
Protocol Number: 
s17-00444 
IND Number: 
IND Exemption Letter Requested 
 
 


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Study Summary 
 
Title 
Ferric Carboxymaltose To Improve Skeletal Muscle Metabolism in 
Heart Failure Patients with Functional Iron Deficiency 
Short Title 
FCM To Improve Sk. Muscle Metabolism in HF Patients with Fe Def. 
Protocol Number 
NYULMC IRB number: s17-00444 
Phase 
Phase 2 study of FDA-approved drug 
Methodology 
Double-blind, placebo-controlled single center randomized clinical trial 
Study Duration 
2 years 
Study Center(s) 
Single Center (NYULMC) 
Objectives 
To compare the effects of ferric carboxymaltose vs. placebo on skeletal 
muscle mitochondrial oxidative capacity, submaximal exercise 
tolerance, and health-related quality of life in HF patients with functional 
iron deficiency. 
Number of 
Subjects 
50 subjects will enrolled to identify 32 subjects eligible for 
randomization 
Diagnosis and 
Main Inclusion 
Criteria 
Clinically stable ambulatory chronic heart failure patients with functional 
iron deficiency without contraindication to study procedures (MRI and 
intravenous infusion of ferric carboxymaltose) 
Study Product, 
Dose, Route, 
Regimen 
Ferric carboxymaltose (Injectafer®) 750 mg intravenously, or normal 
saline (placebo) 
Duration of 
administration 
A single dose of ferric carboxymaltose or placebo will be administered. 
Reference therapy 
Placebo 
Statistical 
Methodology 
The change in the primary and secondary endpoints from baseline to 
week 4 will be compared between the two treatment arms by two-sided 
two sample t-test or Wilcoxon rank sum test. Significance will be 
decided at alpha=0.05. 
 
 
 


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INTRODUCTION 
Statement of Compliance: This trial will be conducted in accordance with the ICH E6, the Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46), and the NHLBI Terms of Award. The 
Principal Investigator will assure that no deviation from, or changes to the protocol will take place without 
documented approval from the Institutional Review Board, except where necessary to eliminate an immediate 
hazard(s) to the trial participants. All personnel involved in the conduct of this study will have completed Human 
Subjects Protection Training and provided all required Conflict of Interests documentation before participation in 
research. 
Background and Significance: Heart failure affects an estimated 6 million persons in the US, and is associated 
with high rates of hospitalization (1.1 million per year), high health care costs (>$30 billion Medicare costs on an 
annual basis), and high mortality risk (30-50% over 5 years).1 The pathophysiology of heart failure is 
fundamentally determined by the failure of the circulatory system to deliver oxygen/nutrients sufficient for 
metabolic needs, and is best explained by a complex interplay between intrinsic abnormalities of myocardial 
contractile function and extra-cardiac factors that regulate oxygen utilization in metabolically active tissues. In 
patients with heart failure, reduced cardiac output reserve, impaired regulation of skeletal muscle blood flow, and 
abnormalities in skeletal muscle mass and mitochondrial function (e.g. reduced oxidative phosphorylation) all 
appear to be important determinants of exercise intolerance and may offer novel targets for therapy.2  
Iron is an essential trace element for oxidative metabolism. Many of the proteins responsible for oxygen 
transport to skeletal muscle (hemoglobin, guanylyl cyclase), oxygen storage (myoglobin) and oxygen utilization 
in skeletal muscle (cytochromes and iron-sulfur enzymes involved in electron transport in mitochondria) require 
iron as an essential co-factor for normal enzyme activity.2 Iron 
homeostasis is regulated by hepcidin, a liver-derived peptide 
hormone that modulates macrophage transfer of iron from 
enterocyte to the reticuloendothelial system by interaction with 
the iron channel protein ferroportin.3 Hepcidin secretion is 
modulated by metabolic sensors of tissue oxygen tension, and 
by inflammatory mediators such as interleukin-6 (Figure 1, 
adapted from ref 3). In patients with heart failure, chronic 
inflammation and hepatic congestion are associated with 
abnormal iron homeostasis characterized by increased hepcidin 
secretion and consequent functional iron deficiency with or 
without anemia.2 Functional iron deficiency is present in 35-50% 
of heart failure subjects and is associated with exercise intolerance and greater mortality risk in patients with 
concomitant anemia (HR 1.71, 95% CI 1.24-2.36, p=0.001) or without concomitant anemia (HR 1.44, 95% CI 
1.11-1.87, p=0.006).4-6  
Two randomized clinical trials of the effects of intravenous iron on measures of functional capacity have been 
published. The Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure (FAIR-HF) study 
was a randomized, double-blind placebo-controlled trial that compared the effects of treatment with intravenous 
ferric carboxymaltose vs. placebo for 6 months on measures of functional capacity in 459 patients with 
symptomatic chronic heart failure, hemoglobin level 9.5-13.5 g/dl, and functional iron deficiency.7 Ferric 
carboxymaltose was administered weekly to achieve the replacement dose based on a clinically used formula, 
and then given every 4 weeks based on serial measurements of serum ferritin and transferrin saturation. When 
compared with placebo, subjects who received ferric carboxymaltose improve symptoms, improved 6-minute 
walk distance and improved quality of life after 6 months (all p<0.001). These benefits were consistent across 
pre-specified subgroups, including subjects without anemia, and subjects with higher than median serum ferritin 
at study entry. Intravenous iron therapy was well-tolerated, with no difference in study discontinuation or adverse 
events when compared with placebo. The CONFIRM-HF (FerricCarboxymaltOse evaluatioN on perFormance in 
patients with IRon deficiency in coMbination with chronic Heart Failure) study was another randomized, double-
blind, placebo controlled trial that compared the effects of treatment with intravenous ferric carboxymaltose vs. 
placebo for 12 months on 6-minute walking distance in 304 patients with symptomatic chronic heart failure.8 The 
entry criteria and treatment regimens were similar to the FAIR-HF study, except the intravenous iron was given 
in doses ranging 500-750 mg via intravenous bolus. When compared with placebo, subjects who received ferric 
carboxymaltose demonstrated improved 6-minute walk distance (p<0.001), improved symptoms (p<0.001), 


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improved quality of life (all p=0.01) and reduced hospitalization risk (p=0.009) at 52 weeks of follow-up. These 
benefits were consistent across subgroups including subjects without anemia, and subjects with higher than 
median serum ferritin at study entry. Intravenous iron therapy was well-tolerated, with no difference in study 
discontinuation or adverse events when compared with placebo. Taken together, these two studies provide 
concordant evidence of improved exercise capacity in response to intravenous iron therapy even in patients 
without evidence of anemia. 
PRELIMINARY DATA 
We measured post-exercise phosphocreatine recovery time 
as a validated index of skeletal muscle mitochondrial 
oxidative capacity with a novel spectrally selective three-
dimensional turbo spin echo (3D-TSE) 31P MRS/MRI 
protocol developed at NYU School of Medicine in eight non-
anemic HF patients and five non-heart failure control 
subjects. In three of the HF patients with functional iron 
deficiency, the 31P MRS/MRI protocol was repeated one 
week after a single dose of ferric carboxymaltose 500 mg. In 
agreement with previous studies using surface coils, we 
showed that the post-exercise phosphocreatine recovery time 
was prolonged in HF subjects when compared with control 
subjects (Figure 1), both for the whole muscle of the lower 
extremity (MRS Global and MRI Global) and also for 
individual muscle groups. In three HF subjects with functional 
iron deficiency, intravenous administration of ferric carboxymaltose 500 mg increased serum ferritin (mean 67 
to 783 ng/mL), increased 6-minute walk distance (mean 342 to 369 m), decreased post-exercise 
phosphocreatine recovery time (mean 51 to 39 seconds, Figure 3), but did not change hemoglobin level (mean 
14.6 to 14.0 g/dL). Intravenous iron was well-tolerated. There were no adverse events related to study drug or 
study procedures. These data were presented in abstract form at the 2015 International Society for Magnetic 
Resonance in Medicine meeting. 
Significance: Abnormal iron homeostasis due to chronic inflammation and/or nutritional deficiencies affects 
over 1 billion persons worldwide. Functional iron deficiency is present in 50% of heart failure patients and is 
associated with more severe symptoms and greater risk for adverse outcomes with or without anemia.2 
Although the effects of iron deficiency on erythropoiesis are well characterized, there are no existing human 
data on the impact of iron deficiency on skeletal muscle metabolism, and only limited data on the extra-
medullary biological effects of intravenous iron therapy.  
STUDY OBJECTIVES 
A single-center, prospective double-blind parallel group randomized study is proposed to compare the effects of 
ferric carboxymaltose vs. placebo on skeletal muscle mitochondrial oxidative capacity, submaximal exercise 
tolerance, and health-related quality of life in HF patients with functional iron deficiency. The goal of this study is 
to provide novel “proof-of-concept” data to demonstrate biological plausibility to support the use of ferric 
carboxymaltose in HF patients and other disease populations with functional iron deficiency. 
32 eligible subjects will be randomly assigned (1:1) to ferric carboxymaltose 750 mg or placebo (normal saline) 
and will undergo serial assessment before and 4 weeks after study drug administration to address the following 
study endpoints: 
Primary Endpoint: To compare the effects of ferric carboxymaltose 750 mg vs. placebo on change in skeletal 
muscle mitochondrial oxidative capacity from baseline to 4 weeks (post-exercise phosphocreatine recovery time 
measured non-invasively with 31P-magnetic resonance spectroscopy). 
 
 
 
Figure 1. Mean±SEM data for comparison of global (31P-
MRS) and regional (31P-MRI, gastrocnemius medial (GM), 
gastrocnemius lateral (GL), and soleus muscle (SOL)) post-
exercise PCr recovery time constant between 5 healthy 
control subjects (blue bars) and 8 HF subjects (red bars). 


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Secondary Endpoints. To compare the effects of ferric carboxymaltose 750 mg vs. placebo on: 
• 
Change in 6-minute walk test distance from baseline to 4 weeks 
• 
Change in Kansas City Cardiomyopathy Questionnaire score from baseline to 4 weeks 
• 
Change in laboratory markers of iron stores and complete blood count from baseline to 4 weeks 
STUDY DESIGN 
The proposed study design is a prospective, single-center, 
randomized, 
double-blind, 
parallel 
group 
placebo-
controlled study (Figure 2). Primary and secondary 
endpoints will be assessed before and 4 weeks after 
administration of ferric carboxymaltose or placebo. It is 
anticipated that the study will require 2 years to complete 
enrollment. 
Study population: Up to 50 subjects will be recruited from 
the clinical practice of the NYU Advanced Cardiac 
Therapeutics group at NYU Langone Medical Center. 36 
eligible subjects will be randomized. Study entry criteria are 
listed in the Human Subjects section below. 
Study visits: The study will require 3 visits over 
approximately 8-10 weeks for each subject: Visit 1: 
Screening; Visit 2: Baseline primary and secondary 
endpoint measurements, randomization, and study drug administration; Visit 3: final assessment of primary and 
secondary endpoint measurements. Additional details of the procedures at each study visit are described below. 
Study agent and control description: Ferric Carboxymaltose (Injectafer®, 750 mg iron/15 ml sterile single use 
vial) will be provided by the American Regent pharmaceuticals (Shirley, NY) to the NYU Investigational 
Pharmacy and stored in the NYU Investigational pharmacy at 20°C to 25°C according to manufacturer 
instructions. An IND exemption will be requested from the FDA. Ferric carboxymaltose is nonionic polynuclear 
iron (III) hydroxide carbohydrate complex that binds iron tightly and requires macrophage processing for release 
of iron into body stores.9, 10 Ferric carboxymaltose 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. The 
most common adverse reactions recorded in clinical trials (>2%) are nausea, hypertension, flushing, 
hypophosphatemia, and dizziness. The dosing and route of administration used in this study protocol are 
consistent with the FDA-approved prescribing information for this drug (see appendix for FDA-approved package 
insert) and prior studies of this agent in heart failure populations.  
Study drug administration: Intravenous ferric carboxymaltose 750 mg will be mixed under sterile conditions in 
100 ml of normal saline for final concentration of 7.5 mg/ml and administered via volumetric infusion pump over 
15 minutes. Placebo will consist of 100 ml of normal saline solution, and administered via volumetric infusion 
pump over 15 minutes. The research pharmacy will dispense study agent based on the randomized treatment 
allocation sequence. 
Study Agent blinding procedure. Since ferric carboxymaltose is a dark brown solution, the study agent will be 
administered by un-blinded research nursing personnel of the NYU Clinical Translational Science Institute who 
are not otherwise involved in the research study procedures. A licensed physician safety monitor not otherwise 
involved in study procedures will be available to monitor the infusion procedure. Blinded research personnel will 
not be present during the study agent infusion. Opaque covers over the study agent infusion equipment and 
curtains will be used to maintain blinding for the study participants. 
Study Drug Randomization Procedure: A variable size blocked randomization allocation scheme will be 
generated by an independent biostatistician and held by the NYU research pharmacy. When an eligible subject 
arrives at the research site for participation in study visit 2, a study drug order will be placed in the electronic 
medical record, and a randomization form will be hand-delivered to the NYU Investigational Pharmacy. The 
Investigational Pharmacist will confirm subject eligibility and assign the treatment allocation based on the 
sequence of the randomization code. The Investigational Pharmacist will process the study agent order in the 
electronic medical record, dispense assigned study drug to the un-blinded CTSI research nurse. Case report 
forms to track the treatment allocation for each participant (ID number and randomization code number) will be 
 
Figure 2. Study design overview. FCM=ferric carboxymaltose 
 


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completed by the NYU investigational pharmacist, and verified by the unblinded CTSI research nurse assigned 
to administer study drug. Blinded research personnel will not have access to the randomization case report form. 
Except in case of emergency, treatment allocation will not be revealed to the investigation team until the last 
enrolled subject has completed all of the study procedures and the database is locked. 
Study Assessments 
Schedule of Assessments. The Schedule of 
Assessments (Table 1) provides a list of the study 
procedures for each study visit. Each study visit will 
be conducted within a time window of ±10 days. 
Details of the study assessments are as follows: 
Screening 
procedures. 
Screening 
procedures 
include 
obtaining 
of 
written 
informed consent, vital signs, medical history, 
heart failure symptoms, medications history, 
cardiovascular examination, ankle brachial 
index, 6-minute walk test, and screening blood 
collection (comprehensive metabolic panel, 
serum phosphate, complete blood count, serum iron, total iron binding capacity, transferrin saturation, 
serum ferritin, and serum beta-HCG for women of childbearing potential) 
Vital Signs: Height (cm) will be measured at the screening visit. Weight (kg), seated systolic and diastolic 
blood pressure in the right arm (mmHg), seated heart rate (beats per minute), and resting oxygen saturation 
on room air (%) will be measured at each study visit. 
Medical History: The following information will be obtained from review of the medical record and/or 
patient interview at Visit 1: 1) Left ventricular ejection fraction (date and imaging mode); 2) Etiology of heart 
failure (ischemic or non-ischemic); 3) Duration of heart failure (years); 4) NYHA Class (I-IV); 5) Co-morbid 
diseases (hypertension, hyperlipidemia, coronary artery disease, chronic kidney disease, chronic lung 
disease, atrial fibrillation); 6) Medications by pharmacological class: angiotensin converting enzyme 
inhibitors, angiotensin receptor blockers, beta-adrenergic receptor blockers, digitalis glycosides, loop 
diuretics, mineralocorticoid receptor antagonists, statins, aspirin, thienopyridines, warfarin, and novel oral 
anticoagulant agents; 7) Demographic information including age, sex, ethnicity; 8) Contact information 
including home, work and mobile phones, street address, email address (to be purged after completion of 
study visits). 
Heart Failure Symptoms: The following information will be obtained from review of medical record and/or 
patient interview: 1) Functional capacity; 2) Orthopnea, paroxysmal nocturnal dyspnea, edema; 3) Medical 
resource use (doctor visit, emergency department visit, hospitalization); 4) Medication change; and 5) Use 
of appropriate measures to protect against pregnancy in women of childbearing potential. 
Cardiovascular examination: Limited physical examination to assess evidence of congestion including 
assessment of jugular venous pressure, lung exam, cardiac exam, abdominal exam for hepatomegaly, and 
extremity exam for edema and perfusion. 
Safety Blood Monitoring: Venous blood will be collected from a forearm vein with standard sterile 
venipuncture technique for analysis of biomarkers of iron stores (serum iron, total iron binding capacity, 
serum ferritin), complete blood count, comprehensive metabolic panel, serum phosphate, and beta-HCG 
(for women of childbearing potential) according to the schedule of assessments (Table 1). All laboratory 
analyses will be performed by the New York State licensed CLIA-compliant NYU Langone Medical Center 
Tisch Hospital Clinical Laboratory.  
Kansas City Cardiomyopathy Questionnaire. The KCCQ is a self-administered disease-specific health 
status instrument composed of 23 items that quantify the domains of physical limitation, symptoms, self-
efficacy, social limitation, and quality of life limitation from heart failure.11 Participants will complete the 
questionnaire form under the supervision of the research staff. The questionnaires will be scored by an 
automated system provided by the distributor of the questionnaire. 
Six-minute walk test: The 6-minute walk test is a validated quantitative measure of functional capacity in 
patients with heart and lung diseases. This submaximal self-paced test will be conducted according to 
Table 1. Schedule of assessments 


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American Thoracic Society guidelines at Visits 1 and 2. Subjects will be asked to walk along a 30 meter 
marked path in a corridor at a self-selected pace. Subjects will receive standardized instruction before and 
during the walking test. The distance walked after 6 minutes (meters) will be recorded. 
31P-MRS and MRI protocol: We will use a spectrally selective three-dimensional turbo spin echo (3D-
TSE) protocol for measurement of phosphocreatine recovery kinetics on a 3T Siemens MRI scanner as 
previously described (Siemens Medical Solutions, Erlangen, Germany).6 Each subject will perform the 
same rhythmic plantar extension exercise protocol twice, for sequential acquisition of MRS and MRI 
measurements respectively. For the exercise protocol, the subject will lay supine on the scanning table 
with the right leg inside the volume coil. The exercise consists of repeated plantar flexion movements using 
resistance bands at a frequency of one repetition per second for 1-2 minutes. Data are collected 
continuously for 2 minutes before the exercise (baseline), during exercise, and 5 minutes after the exercise 
for the MRS and MRI experiments. The phosphocreatine recovery kinetics will be calculated as previously 
described.12 
Ankle brachial index. Systolic blood pressure in the brachial artery and in the posterior tibialis artery or 
dorsalis pedis artery will be determined with a Doppler ultrasound flow probe. The ankle brachial index is 
calculated as the ratio of the ankle:arm pressures. 
Adverse Event Monitoring: The Principal Investigator is responsible for monitoring and reporting adverse 
events to the ethical review board. The definitions and procedures for classification and reporting of 
adverse events (AEs) are described in the Human Subjects section below. Subjects will be prompted to 
report any new problems or events since the start of the study at each visit. 
Early Withdrawal Criteria: Subjects may be removed from participation based on the following criteria: subject 
request, intolerance of study drug or study procedures, intercurrent illness that alters risk of participation or 
interferes with study procedures, acquisition of new information that affects subject eligibility (e.g. pregnancy or 
prohibited concomitant medication), or other situations that would put the subject at increased risk, compromise 
adherence to study procedures, or confound interpretation of the study findings. Women of childbearing potential 
will be instructed to use accepted methods of contraception to avoid pregnancy during the study, and will have 
a blood pregnancy test at screening, and before all study visits with efficacy endpoint assessments. 
Early study termination criteria: The study may be prematurely terminated or suspended by the Principal 
Investigator due to issues related to participant safety, study futility, failure to meet accrual, site performance, or 
data quality and completeness milestones, failure to adhere to ethical standards in the conduct of human subjects 
research, or other study protocol deviations.  
 
DATA ANALYSIS 
 
Data management and analysis: All data will be recorded on paper case report forms as primary source 
documentation and will be transferred to a secure REDCap electronic database protected by the NYU firewall. 
Case report forms and electronic data will use a randomly assigned Study ID number and will not include any 
identifiers. A separate study folder with study subject contact information will be kept in a locked cabinet in a 
locked room. PHI for each subject will be securely destroyed after completion of the study visits. 
Hypothesis to be tested: The null hypothesis to be tested is that there is no difference between ferric 
carboxymaltose and placebo for the change in the primary and secondary study endpoints over 4 weeks. 
 
Description of analysis sets: 
Efficacy analysis dataset.   Intention to treat (ITT) will be defined as all patients who have been randomized to 
study treatment and completed at least one follow-up visit with primary endpoint data collection. The ITT data 
set will be used for the primary and secondary efficacy endpoints and ancillary study endpoints. 
   
Safety analysis dataset.   All patients who received study drug, and for whom post-dose data are available, will 
be included in the safety analysis set. 


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Analysis plan for primary and secondary endpoints: 
The objective is to compare the change in the primary and secondary endpoints over time between the two 
treatment groups. 
 
Descriptive analysis techniques will be used to characterize study participants. 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.  
 
The primary endpoint is change in the phosphocreatine recovery time (s). Secondary endpoints are 1) change 
in six-minute walk distance (m), change in quality of life score (points), and change in hemoglobin (g/dL), serum 
ferritin (ng/ml), and transferrin saturation (%). The change in the primary and secondary endpoints from 
baseline to week 4 will be compared between the two treatment arms by two-sided two sample t-test or 
Wilcoxon rank sum test. Significance will be decided at alpha=0.05. 
 
We will also construct multivariable regression models with treatment assignment as the main predictor and the 
change in the primary or secondary endpoint as the outcome variable while adjusting for patients’ 
characteristics such as baseline value of the endpoint, age, sex, ethnicity, hemoglobin level, and measures of 
disease severity and their interactions with the treatment assignment if necessary. Pre-specified subgroup 
analyses are based on median age, sex, heart failure etiology (ischemic vs. non-ischemic), NYHA functional 
Class, median serum ferritin level, and sex-stratified median hemoglobin level. 
 
Missing Data Consideration: We anticipate a low percentage of missing data due to the short duration of the 
study and relatively small data set. The missing data will be handled by intent-to-treat analysis in principle, with 
last value carried forward. We will compare baseline data in subjects with and without missing data to identify 
factors contributing to missingness. As sensitivity analyses, a “per protocol” analysis, and analysis with multiple 
imputation will be undertaken with five imputed datasets using the NORM software. Parameter estimates and 
their standard errors will be derived by averaging across the five imputations and by adjusting for their variance. 
 
4.14: Sample size calculation:  
Our pilot data demonstrated that 
the post-exercise phosphocreatine 
recovery time constant decreased 
by >10 seconds in all 3 non-
anemic HF subjects with functional 
iron deficiency who received ferric 
carboxymaltose with mean±SD 
decrease 11.4±3.4 seconds. Table 
2 presents the minimal detectable 
difference between treatment 
groups over time based on 
estimates of a range of standard 
deviations of the between-group 
difference and assuming 0-20% dropout, power=0.90, two-tailed alpha=0.05. Table 2 indicates that the 
proposed sample size provides adequate power to detect moderate to large changes in the post-exercise 
phosphocreatinine recovery time, even when accounting for 20% drop-out. A 10-second change in 
phosphocreatine recovery time is likely meaningful, since our pilot data suggest that a 10-second decrease 
would place many HF subjects back to the normal or near normal range. The sample size of 16 subjects per 
treatment arm will provide >80% power to detect a 35 m difference in six minute walk distance (consistent with 
a moderate improvement in submaximal exercise capacity, based on data from FAIR-HF and other 
assumptions as above) and a 20-point difference in the KCCQ score (consistent with a large improvement in 
health status, based on previous data from FAIR-HF and other assumptions as above).11 
 
Table 2. Estimates of minimal detectable between-group difference for post-exercise phosphocreatine 
recovery time based on power 0.9 with 2-tailed alpha=0.05. 


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HUMAN SUBJECTS 
 
1. Risks to Human Subjects 
a) Human Subjects Involvement, Characteristics, and Design  
This is a prospective single center double-blind placebo-controlled randomized clinical trial in human subjects 
with chronic heart failure. Since iron metabolism varies greatly among different mammalian species, it is 
necessary to study human subjects in order to obtain relevant information that might eventually favorably 
impact human health. 
The study entry criteria are as follows: 
Inclusion Criteria:  
• 
Age 21-75 years 
• 
Symptomatic NYHA Class II-III heart failure >3 months 
• 
Guideline-recommended heart failure treatment for > 3 months 
• 
Hemoglobin >10 g/dl for men and >9 g/dl for women 
• 
Functional iron deficiency (defined as serum ferritin level <100 ng/ml or between 100 and 299 ng/ml with 
transferrin saturation <20%) 
• 
Left ventricular ejection fraction <40%, or left ventricular ejection fraction ≥40% with left atrial enlargement 
(left atrial volume index >28 ml/m2) and/or left ventricular hypertrophy (left ventricular mass index >95 
g/m2 (women) or >115 g/m2 (men) determined by echocardiogram within last 24 months. 
• 
Able and willing to provide written informed consent 
Exclusion Criteria:  
• 
Presence of implantable defibrillator, permanent pacemaker, other metal implant not compatible with 
3TMRS/MRI, or other contraindication to 3T MRS/MRI procedures 
• 
Heart failure due to infiltrative cardiomyopathy, restrictive cardiomyopathy, or hypertrophic 
cardiomyopathy 
• 
Weight <50 kg or >120 kg 
• 
Height < 5 feet 4 inches (1.63 m) 
• 
Coronary or cerebral atherothrombotic events in the past 6 months 
• 
Hospitalization of emergency room visit for heart failure within past 3 months 
• 
ICD shock in last 3 months 
• 
Known peripheral artery disease or ankle-brachial index <0.9 at screening visit 
• 
Exercise primarily limited by angina, lung disease or neuromuscular disease 
• 
Systolic blood pressure <100 or >160 mmHg 
• 
Heart rate <50 or >110 min-1 
• 
Estimated glomerular filtration rate <30 ml/min 
• 
Liver function tests >3 times upper limit of normal 
• 
Serum phosphate below normal limit 
• 
Pregnant or breast-feeding women 
• 
Women of child-bearing potential unwilling to use recommended contraception methods during the 
study 
• 
Treatment with intravenous iron in past year 
• 
Treatment with erythropoiesis stimulating agents in the past year 
• 
Known intolerance of intravenous iron 
• 
History of anaphylaxis 
• 
Participation in another clinical trial within last 30 days. 
 
Recruitment strategy. We will use admission and emergency department logs, clinic appointment logs, and 
other existing electronic hospital information systems to identify potentially eligible subjects from within our 
clinical practice. Clinical personnel in the NYU Heart Failure program meet on a weekly basis to identify 
potential study subjects. An experienced research coordinator will initiate contact with the attending physician 


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to obtain additional information on potential eligibility and permission to approach the subject. Based on 
historical data from the NYU Heart Failure Quality Improvement Program case identifications over the past 
year, there are approximately 1200 annual discharges with primary HF diagnosis from NYU Langone Medical 
Center (Tisch, Bellevue, and Manhattan VA hospitals). If we conservatively estimate that 50% of those 
admissions are re-admissions, then approximately 1800 unique heart failure cases will be identified over the 
proposed 18-month period of enrollment (100 unique cases/month). For the pilot study presented above, this 
recruitment strategy allowed us to enroll eight subjects over 3 months. Accordingly, we believe that this clinical 
volume is sufficient to support our proposed enrollment target of 1-2 randomized subjects per month. 
We will also recruit patients at NYU Langone Health with use of the MyChart patient portal of the EPIC 
electronic health record. A DATACORE query of the EPIC database will be conducted to identify potentially 
eligible subjects (based on inclusion criteria of age 21-75 years, ICD9 and ICD10 codes for acute, chronic, and 
acute on chronic systolic heart failure, and acute, chronic, and acute on chronic diastolic heart failure, and 
exclusion criteria of ICD codes for permanent pacemaker or implantable defibrillators). After approval from 
DATACORE, an invitation letter will be placed in MyChart (text of invitation letter is attached in Research 
Navigator). 
We will also recruit patients using printed advertisements in the free morning newspaper, AM New York, and 
electronic advertisement on Facebook pages with content relevant to heart failure patient. The advertisement 
text is attached in Research Navigator.  
A telephone script for respondents to MyChart invitation letters, and print and electronic advertisements is 
attached in Research Navigator. Personal identifiers will only be recorded for respondents who meet eligibility 
for a screening visit and express willingness to be scheduled for a screening visit. 
There are no vulnerable populations enrolled in this study. 
There are no collaborating sites for this study. All research data will be created and analyzed at NYULMC. 
b) Sources of Materials  
The research material generated in this protocol will consist of clinical assessments, laboratory measurements 
and physiological measurements obtained from the human subject participants. 
Historical information related to demographics and the cause, severity, and treatment of heart failure will be 
recorded from the medical record or obtained by subject interview. Other research data will be obtained as a 
result of completion of the research procedures described above. These data include blood test results, 6-
minute walking test results, and the results of the 31P-MRS and MRI analysis of skeletal muscle bioenergetics 
in response to plantar flexion exercise. There will be no data collection related to prospective clinical testing or 
clinical care. The research database will not retain any identifiers after completion of study procedures. 
The Principal Investigator and other trained study personnel will have access to private health information only 
during active participation in the study. This information will be used only for scheduling participant visits, for 
confirmation of correct identity at study visits, and for review of medical records as described in study 
procedures. All identifying information will be kept separate from the other research records in a locked cabinet 
in a locked room or on a secure electronic database. All identifiers (except signed consent forms) will be 
destroyed after the subject has completed the last visit. No identifiers will be retained in the research database 
after completion of study procedures. 
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. Primary source documents with identifiers 
including signed consent forms and contact information will be kept separately in a locked cabinet in a locked 
room. All primary source documents with identifiers (except signed consent forms) will be destroyed after the 
subject has completed the last visit. Other primary source documents including case report forms, laboratory 
reports, and results of the 6-minute walking test, and the 31P-MRS and MRI analysis of skeletal muscle 
bioenergetics in response to plantar flexion exercise will be kept in a project notebook in a locked cabinet in a 
locked office. Research data without identifiers will be recorded on the NYULMC 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.  


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c. Potential Risks  
The risks of the research procedures in this protocol are generally similar to the risks of the same procedures 
performed in the course of clinical care. The potential risks to study participants are as follows; 
Risk of ferric carboxymaltose (Injectafer®): Ferric Carboxymaltose (Injectafer®, 750 mg iron/15 ml single use 
vial) 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. The most common adverse reactions recorded in 
clinical trials (>2%) are nausea, hypertension, flushing, hypophosphatemia, and dizziness. Rare occurrences 
of anaphylactic or anaphylactoid reactions have also been reported. The dosing and route of administration 
used in this study are consistent with the FDA-approved prescribing information for this drug. In the FAIR-HF 
study, ferric carboxymaltose was administered repeatedly over 6 months to 304 subjects with chronic heart 
failure. Reported adverse events did not differ from placebo. There were no anaphylaxis events or other 
allergic reaction events reported. In the CONFIRM-HF study, 150 heart failure subjects received intravenous 
ferric carboxymaltose for 1 year. Overall adverse events did not differ from placebo. There were no 
anaphylaxis events, but there was one episode of rash, one episode of urticaria, and one episode of flushing 
reported in the ferric carboxymaltose group. Taken together, this reported experience of repeated dosing of 
ferric carboxymaltose over 6-12 months in a combined group of 454 patients with heart failure does not 
suggest a signal of increased risk of adverse effects in heart failure when compared to clinical trial population 
data included in the package label.  
Risks of MRI:  
Magnetic Field Risks: MRI uses a strong magnetic field to create images of the body.  Because of the strong 
magnetic field, the metal objects within the body or within the MRI room could cause injury. Subjects with metal 
implants will be excluded from the study. Standard operating procedures in MRI rooms check for any possible 
external metal objects before the scan. 
Risk of Anxiety/Claustrophobia: The MRI scans are obtained is a small space that may be stressful for some 
subjects with claustrophobia. We will exclude subjects with known claustrophobia and terminate the MRI 
scan upon subject request. 
Risk of High Noise Levels: The MRI scanner produces loud noises that may increase anxiety in some subjects. 
Disposable earplugs to reduce the noise levels but will still allow voice communication with the scanner operator 
will be provided to all subjects. 
Risk of MRI Systems Failure (Quench): This is a rare event caused by loss of the magnetic field. Subjects will 
be immediately brought out of the magnet room if system failure is detected. 
Risk of Neurostimulation: Some subjects may experience muscle twitches or tingling sensations and a slight 
increase in body temperature during some types of scan activity.  These are very unlikely under current MRI 
guidelines. 
Risks in Pregnant Women: Although there are no known risks of MRI on pregnant women or a fetus, there is a 
possibility of yet undiscovered pregnancy related risks.  Since there is no direct benefit from participating in this 
protocol for a pregnant woman, we will exclude pregnant women. If a woman becomes pregnant during the 
study, we will request to follow the health of the mother and fetus during pregnancy, and the health of the mother 
and child for 30 days after delivery. 
Incidental MRI findings; The MRI scan is for research purposes only and is not directed toward or designed for 
clinical diagnosis. Per Department of Radiology procedures, all MRI scans will be reviewed by a clinical 
radiologist, and any abnormal findings will be reported to the subject, and the subject’s physician. 
Risk of phlebotomy: Phlebotomy is commonly associated with transient pain and minor bleeding at the needle 
site, and rarely major bleeding, infection or vasovagal reaction with transient hypotension. The risks of 
phlebotomy in this study do not differ from risks of phlebotomy for clinical blood tests. 
Risk of intravenous line: Placement of an intravenous catheter is commonly associated with transient pain and 
minor bleeding at the needle site, and rarely major bleeding, infection or vasovagal reaction with transient 
hypotension. The risks of placement of an intravenous catheter in this study do not differ from risks of 
phlebotomy. 


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Other Study Risks: 
Risk of exercise: The 6-minute walk test is a self-limited submaximal exercise test in which the study subject 
selects the walking pace and has the option to stop and rest as needed. Since the purpose of this test is to 
simulate daily walking activity, the small risks associated with submaximal exercise do not substantially differ 
from risk associated with exercise in daily activities. A study with over 2000 elderly subjects demonstrated no 
serious adverse events associated with the 6-minute walk test. The plantar flexion exercise during the 31P-
MRS and MRI procedure consists of rhythmic plantar flexion against low resistance and is akin to stepping on 
a brake or gas pedal in a car. Accordingly, the small risk associated with this submaximal exercise does not 
substantially differ from risk associated with exercise in daily activities. 
Risk of breach of confidentiality: There is a small risk of breach of confidentiality of protected health information 
related to participation in this protocol. 
2. Adequacy of Protection Against Risks 
a. Recruitment and Informed Consent 
Recruitment will be conducted in accordance of the policies of the New York University IRB and FDA 
regulation 21CFR, Part 50. Potential subjects will be identified by the primary cardiologist supervising patient 
care during periods of clinical stability in an ambulatory care setting. The primary cardiologist will determine 
whether the potential participant is willing to consider discussion of the study with research staff. If the primary 
cardiologist determines that the potential participant is willing to discuss the study, research staff will provide 
the potential participant with additional information about the study and offer the opportunity to read the IRB-
approved consent form. The rationale, procedures and potential risks of the procedures in the study will be 
explained to each participant by the Principal Investigator or his appointed designee. Each subject will be told 
that participation in the studies described in this proposal is strictly voluntary, that refusal to participate will not 
alter the patient's relationship with her physician, that the studies constitute research and that the information 
obtained may increase understanding of the role of body iron and exercise in general but will not be specifically 
helpful to the individual patient's care. The subject’s comprehension of the major aspects of the study 
procedures, study risks, and study benefits will be determined by asking the subject to respond to questions 
about the study. A signed, IRB-approved informed consent form will be obtained from each subject by the 
Principal Investigator or his designee on the day of the enrollment. A copy of the most current version of the 
IRB-approved Patient Informed Consent Form, along with a copy of each subject’s signed and dated consent 
form will be kept in a designated research administrative file in a locked cabinet in a locked room. A signed 
copy of the consent form will be given to each subject. Due to the complexity of the study procedures, only 
subjects able to speak either English or Spanish will be enrolled. For Spanish speaking subjects, the entire 
consent process will be conducted in Spanish by a fluent native Spanish-speaking member of the research 
staff. A Spanish consent form will be created and submitted to the IRB after final IRB-approval of the English 
language consent form. 
b. Protections Against Risk  
The study is deemed to be greater than minimal risk, primarily due to the potential side effects of ferric 
carboxymaltose. To minimize risk, all procedures will be performed in clinically stable subjects who meet 
eligibility criteria under the direct supervision of the principal investigator, and/or other trained study personnel. 
All study procedures are performed within the CTSI Clinical Research Center or MRI Center with nearby 
access to emergency procedures in the event of unanticipated 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 the study agent, ferric carboxymaltose, according to the FDA-approved prescribing 
information 
• 
Active surveillance for potential study drug 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 
• 
Use of the MRI imaging center standard clinical protocol to prevent transport of ferromagnetic materials 
into the imaging environment  
• 
Safety monitoring by the Principal Investigator 
 


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No vulnerable subject populations will be enrolled in this study. 
All research subject data will be kept strictly confidential, except when published for purposes of reporting data. 
In that case, the subjects are never identified. All electronic data will be de-identified and transmitted and 
stored with secure systems that meet or exceed Federal guidelines (REDCap database behind NYU firewall). 
The Principal Investigator will maintain files with identifying information in a locked cabinet in a locked room. 
c. Potential Benefits of the Proposed Research to Human Subjects and Others 
There is no expected benefit for participant in this study. The feasibility data acquired in this study may 
eventually help future heart failure patients, or patients with other diseases associated with functional iron 
deficiency. 
d. Importance of the Knowledge to be Gained  
Anemia of chronic disease associated with inflammation and functional iron deficiency is the second most 
common cause of anemia worldwide. Functional iron deficiency is common in patients with heart failure and 
may be associated with impaired functional capacity and increased risk for hospitalization and death. 
Intravenous iron therapy has been shown to improve various measures of functional capacity, but the 
mechanism of action and target population with greatest likelihood has not been identified. This study is 
designed to provide proof-of-concept data to support future investigations of the role of iron in the 
pathogenesis of exercise intolerance. This line of investigation may eventually have impact on therapeutic 
strategies for maintenance of iron homeostasis in healthy populations, and heart failure and other chronic 
inflammatory disease populations. 
e. Data and Safety Monitoring Plan 
The research procedures described in this protocol are deemed to be greater than minimal risk.  
The Principal Investigator will serve as the medical monitor for the study and will be responsible for monitoring 
and reporting of adverse events to the NYU IRB  according to the following definitions and procedures: 
Adverse Event Definitions  
An Adverse Event (AE) is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and does not necessarily require a causal relationship with the study treatment. An AE 
can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporarily associated with the use of a medicinal product, whether or not related to the study 
procedures.  Diseases, signs, symptoms, or laboratory abnormalities already existing at the time of enrollment 
are not considered AEs unless they worsen (i.e., increase in intensity or frequency).  Surgical procedures 
themselves are not adverse events; they are therapeutic measures for conditions that require surgery.  The 
condition for which the surgery is required may be an AE.  Surgical procedures planned prior to randomization 
and the conditions leading to these measures are not AEs unless the event exacerbates or worsens after 
randomization.  
A Serious Adverse Event (SAE) is any untoward event that:  
1. Is fatal  
2. Is life-threatening  
3. Results in persistent or significant disability or incapacity  
4. Is a congenital abnormality or birth defect  
5. Requires inpatient hospitalization or prolongation of existing hospitalization with the following exceptions:  
• 
Preplanned (prior to the study) hospital admissions unless the hospitalization is prolonged.  
• 
Planned admissions (as part of a study—e.g., routine biopsies)  
• 
23 hour hospitalization or re-hospitalizations  
• 
Hospitalization for elective procedure (e.g. generator change for ICD or pacemaker) 
• 
Emergency department visits  
 


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Important medical events that may not result in death, be life-threatening, or require inpatient hospitalization 
may be considered an SAE when, based on appropriate medical judgment, they may jeopardize the patient 
and may require medical or surgical intervention to prevent one of the outcomes listed above.  
Life-threatening indicates that the patient was, in the view of the investigator, at immediate risk of death from 
the adverse event as it occurred.  It does not include an adverse event that, had it occurred in a more severe 
form, might have caused death.  
Persistent or significant disability/incapacity indicates that the event resulted in permanent or significant and 
substantial disruption of the patients’ ability to carry out normal life functions. 
Classification of Adverse Events 
The Principal Investigator will assess all AEs to determine the severity of the event, the possible causal 
relationship with study drug or study procedures, and whether the event is anticipated or unanticipated 
according to the following definitions: 
1) Severity. The severity (intensity) of each AE will be determined by the Principle Investigator according to the 
following definitions:  
Mild: Symptom(s) or sign(s) barely noticeable to the subject or does not make the subject uncomfortable. The 
AE does not influence performance or functioning. Treatments are not ordinarily needed for relief of 
symptom(s).  
Moderate: Symptom(s) or sign(s) that cause the subject to be uncomfortable or may require downtitration of 
study drug. Treatment of symptom(s) may be needed.  
Severe: Symptom(s) or sign(s) that cause the subject severe discomfort or may cause cessation of treatment 
with study drug. Treatment for symptom(s) are often needed.  
Life-threatening: Symptom(s) or sign(s) of a sufficient severity/intensity to cause the subject to be at 
immediate risk of death. These cases will be classified as a Serious Adverse Event. 
2) Relationship to study procedures. The temporal/causal relationship between the study procedures and the 
AE will be determined by the Principle Investigator according to the following definitions:  
Definite: Clearly related to the study procedures.  
Probable: Likely (high suspicion) related to the study procedures.  
Possible: Possibly but not likely (low suspicion) related to the study procedures.  
Unrelated: Clearly not related to the study procedures.  
3) Anticipated or unanticipated. The relationship of the AE to the known side effect profile of the study drug and 
the known clinical manifestations of heart failure and other pre-existing co-morbid conditions will be determined 
by the Principal Investigator according to the following definitions: 
Anticipated: Consistent with the known side effect profile of study drug or other study procedures and/or 
known clinical manifestations of heart failure or other pre-existing co-morbid conditions. 
Unanticipated: Not known to be associated with study drug, other study procedures, heart failure, or other 
pre-existing co-morbid conditions. 
 
IRB Reporting 
Federal regulations require timely reporting by investigators to their local IRB of unanticipated problems posing 
risks to subjects or others.  The following describes the NYULMC IRB reporting requirements, though 
Investigators at participating sites are responsible for meeting the specific requirements of their IRB of record.  
 
Report Promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later than 5 working days 
from the time the investigator becomes aware of the event: 
• 
Unanticipated problems including adverse events that are unexpected and related 


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– Unexpected: An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed consent document and 
other relevant sources of information, such as product labeling and package inserts.  
– Related to the research procedures: An event is related to the research procedures if in the 
opinion of the principal investigator, the event was more likely than not to be caused by the 
research procedures.  
– Harmful: either caused harm to subjects or others, or placed them at increased risk 
 
Other Reportable events: 
The following events also require prompt reporting to the IRB, though no later than 5 working days: 
• Complaint of a research subject when the complaint indicates unexpected risks or the complaint cannot 
be resolved by the research team. 
• Protocol deviations or violations (includes intentional and accidental/unintentional deviations from the 
IRB approved protocol) for any of the following situations:  
– one or more participants were placed at increased risk of harm  
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 
• Breach of confidentiality 
• Incarceration of a participant when the research was not previously approved under Subpart C and the 
investigator believes it is in the best interest of the subject to remain on the study. 
• New Information indicating a change to the risks or potential benefits of the research, in terms of 
severity or frequency. (e.g. analysis indicates lower-than-expected response rate or a more severe or 
frequent side effect; Other research finds arm of study has no therapeutic value; FDA labeling change or 
withdrawal from market) 
 
Other Reportable events: 
• 
Deviations from the study protocol 
Deviations from the protocol must receive IRB approval before they are initiated. Any protocol deviations 
initiated without IRB approval that may affect the scientific soundness of the study, or affect the rights, safety, 
or welfare of study subjects, must be reported to the IRB as soon as a possible, but no later than 5 working 
days of the protocol deviation. 
• 
Withdrawal of IRB approval 
An investigator shall report to the American Regent Inc. (funding entity) a withdrawal of approval by the 
investigator’s reviewing IRB as soon as a possible, but no later than 5 working days of the IRB notification of 
withdrawal of approval. 
 
 
Data Handling and Record Keeping 
 
Confidentiality: 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, case report forms, laboratory reports, and results of the 6 minute walking test, and the 
31P-MRS and MRI analysis of skeletal muscle bioenergetics in response to plantar flexion exercise will be kept 
in a project notebook in a locked cabinet in a locked office. Research data without identifiers will be maintained 


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on the NYULMC 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.  
Confidentiality and HIPAA: 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. 
Source Documents: Source data for the current proposal will include nursing records from the CTSI, case 
report forms, laboratory reports, and MRI reports. These data will be kept in a project notebook in a locked 
cabinet in a locked room. 
Case Report Forms: The study case report form (CRF) is the primary data collection instrument for the study.  
All data requested on the CRF must be recorded. The data on paper CRF will be transferred to the electronic 
database and then will be destroyed. The electronic database has quality features to ensure that all fields have 
entered values, and that entered values are of the correct data entry type, and that numbers fall within pre-
specified ranges.  
Records Retention: Source documents will be retained for at least 2 years after completion of the study. 
Electronic data will be retained for at least 5 years. 
 
Study Monitoring, Auditing, and Inspecting 
 
Study Monitoring Plan. This study will be monitored according to the monitoring plan as stated in the 
protocol.  The investigator will allocate adequate time for such monitoring activities.  The Investigator will also 
ensure that the monitor or other compliance or quality assurance reviewer is given access to all the above 
noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has 
adequate space to conduct the monitoring visit. 
Auditing and Inspecting. The investigator will permit study-related monitoring, audits, and inspections by the 
IRB/EC, 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. 
 
Ethical Considerations 
This study is to be conducted accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted Institutional Review Board (IRB) 
or independent Ethics Committee (EC) in agreement with local legal prescriptions, for formal approval of the 
study conduct.  
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study. This consent form 
will be submitted with the protocol for review and approval by the IRB/EC for the study.  The formal consent of 


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a subject, using the IRB/EC-approved consent form, must be obtained before that subject undergoes any study 
procedure.  The consent form must be signed by the subject, and the investigator-designated research 
professional obtaining the consent.  
 
Study Financial Information 
Source of funding: This is an investigator-initiated proposal funded by American Regent, Inc. American 
Regent Inc. will provide study drug and funds to support study personnel and study procedures. 
Conflict of Interests: All faculty investigators have completed their annual conflict of interest submission. 
Individual investigator conflict of interest forms are submitted with this application. 
Human subject costs/payments: There are no costs to the subjects enrolled in this proposal. All procedures 
are done strictly for research purposes and there will be no billing to subject or their insurance. Subjects will 
receive a stipend in the form of a check as compensation for time, travel, and inconvenience as follows: Visit 1 
(1 hour): $75; Visit 2 (3 hours with study drug infusion) $200; and Visit 3 (2 hours) $100. Total payment for 
subjects who complete all three visits is $375. 
 
 


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Meynard D, Babitt JL and Lin HY. The liver: conductor of systemic iron balance. Blood. 2014;123:168-
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Anker SD, Comin Colet J, Filippatos G, Willenheimer R, Dickstein K, Drexler H, Luscher TF, Bart B, 
Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, 
Ponikowski P and Investigators F-HT. Ferric carboxymaltose in patients with heart failure and iron deficiency. 
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Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, McDonagh T, 
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Investigators C-H. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in 
patients with symptomatic heart failure and iron deficiency. European heart journal. 2015;36:657-68. 
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randomized controlled trials across different indications. Arzneimittel-Forschung. 2010;60:386-98. 
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Koch TA, Myers J and Goodnough LT. Intravenous Iron Therapy in Patients with Iron Deficiency 
Anemia: Dosing Considerations. Anemia. 2015;2015:763576. 
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Spertus J, Peterson E, Conard MW, Heidenreich PA, Krumholz HM, Jones P, McCullough PA, Pina I, 
Tooley J, Weintraub WS, Rumsfeld JS and Cardiovascular Outcomes Research C. Monitoring clinical changes 
in patients with heart failure: a comparison of methods. American heart journal. 2005;150:707-15. 
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Parasoglou P, Xia D, Chang G and Regatte RR. Dynamic three-dimensional imaging of 
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