Clinical trial NCT02752191
Conditions: Pediatric Congenital Heart Disease
Keywords: ferumoxytol
Sponsor: Paul Finn
Start date: 2016-04-01; Completion date: 2018-12-19
Enrollment: 17 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The standard clinical cardiovascular MRI practice for children with CHD frequently involves the use of gadolinium-based contrast agents (GBCA) to enhance tissue contrast. Most GBCAs are small molecules that quickly cross the capillary wall and access the interstitial space, a process which diminishes the signal contrast between blood vessels and surrounding tissue. Therefore, these types of GBCA are most useful for first-pass MR angiography, wherein the images are acquired quickly during the initial 15-30 seconds post-injection when the GBCA concentration is much higher in the arteries than in the interstitial space. For young children with complex CHD, the stringent requirements for high spatial resolution, and the need for cardiac gating and good blood-myocardium contrast in order to provide detailed evaluation of intracardiac structures are not compatible with conventional GBCA-based first-pass MR angiography. Even with Ablavar® (gadofosveset trisodium), an FDA approved GBCA with longer intravascular half-life than other GBCAs, cardiac-gated Ablavar®-enhanced MRI may be insufficient for young children with CHD based on our institutional experience and on data from the literature; there remains diminished blood-tissue contrast during the high-resolution cardiac-gated MRI. Furthermore, there have been safety concerns regarding gadolinium deposition in brain tissues after repeated GBCA exposure as well as concerns of nephrogenic systemic fibrosis (NSF) associated with GBCA injection in young children \< 2 years old who may have immature renal function. The long-term health consequences of these effects in the pediatric population are unclear. For the above reasons, we seek to study the diagnostic imaging effectiveness of Feraheme (Feraheme®), an FDA-approved drug for parenteral iron supplementation, as an MRI contrast agent in children with CHD. Although Feraheme® has been approved for the treatment of iron deficiency anemia secondary to renal disease, Feraheme® has been used as an off-label MRI contrast agent at select medical centers.

Detailed description:

Arms: arm 1: Ferumoxytol, 4mg/kg of body weight, one time infusion of several minutes arm 2: gadofosveset, 0.03mmol/kg, one time bolus injection
Interventions: intervention 1: ferumoxytol intervention 2: gadofosveset
Intervention descriptions: intervention 1: ferumoxytol as an MRI contrast agent infused over several minutes intervention 2: gadofosveset as an MRI contrast agent injected over several seconds

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Number: 0001 
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FERAHEME AS AN MRI CONTRAST AGENT FOR PEDIATRIC CONGENITAL 
HEART DISEASE 
 
Protocol Number: 
0001 
Version Date: 
01/13/2016 
Investigational Product: 
Feraheme (Feraheme®) 
IND Number: 
0000 
Development Phase: 
IV 
Funding Organization: 
National Institutes of Health (Sponsor) 
ClinicalTrials.gov ID 
NCT02752191 
Principal Investigator: 
Name: J. Paul Finn, M.D. 
 
Telephone: 
+1.310.825.0958 
Fax: 
 
+1.310.825.0880 
E-mail: 
pfinn@mednet.ucla.edu 
Medical Monitor: 
Name: J. Paul Finn, M.D. 
Telephone: 
+1.310.825.0958 
E-mail: 
pfinn@mednet.ucla.edu 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.   


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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties include 
ensuring the safety of the study subjects enrolled under my supervision and providing the National 
Institutes of Health with complete and timely information, as outlined in the protocol.  It is 
understood that all information pertaining to the study will be held strictly confidential and that 
this confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of the 
study staff and myself, I agree to maintain the procedures required to carry out the study in 
accordance with accepted GCP principles and to abide by the terms of this protocol. 
 
Protocol Number: 0001 
 
Protocol Title:  FERAHEME AS AN MRI CONTRAST AGENT FOR PEDIATRIC 
CONGENITAL HEART DISEASE 
 
Protocol Date:  1/13/2016 
 
 
 
 
Investigator Signature  
 
Date 
 
J. Paul Finn, M.D  
Chief, Diagnostic Cardiovascular Imaging and Director, Magnetic Resonance Research 
Print Name and Title 
Site # 
1 
 
Site Name 
UCLA 
Address 
Peter V. Ueberroth Building, Suite 3371 
 
10945 LeConte Ave 
 
Los Angeles, CA 90095-7206 
Phone Number 
+1.310.825.0958 
 
 


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TABLE OF CONTENTS 
LIST OF TABLES 
5 
1 
LIST OF ABBREVIATIONS 
6 
2 
PROTOCOL SYNOPSIS 
8 
3 
STUDY HYPOTHESES 
15 
4 
BACKGROUND 
15 
4.1 
Overview of Cardiovascular MRI ...................................................................................... 17 
4.2 
Challenges of Cardiovascular MRI in Children ................................................................. 17 
4.3 
MRI Clinical Standard of Care in Children with CHD ...................................................... 17 
4.4 
Safety Concerns with GBCAs ............................................................................................ 17 
4.5 
Feraheme as an Alternative MRI Contrast Agent .............................................................. 21 
4.6 
Overview of Non-Clinical Studies ..................................................................................... 22 
4.7 
Overview of Clinical Studies ............................................................................................. 22 
5 
STUDY RATIONALE 
28 
5.1 
Benefit to Risk Assessment ................................................................................................ 30 
5.2 
Monitoring of AEs after Feraheme Administration ........................................................... 30 
6 
STUDY OBJECTIVES 
31 
7 
STUDY DESIGN 
31 
7.1 
Study Overview .................................................................................................................. 31 
7.2 
Study Design Part I............................................................................................................. 32 
7.3 
Study Design Part II ........................................................................................................... 33 
8 
CRITERIA FOR EVALUATION 
34 
8.1 
Part I – Comparision between Faraheme and Ablavar ....................................................... 34 
8.2 
Part II – Comparision between ventilator-gated and self-gated MUSIC-MRI................... 34 
9 
SUBJECT SELECTION 
35 
9.1 
Study Population ................................................................................................................ 35 
9.2 
Inclusion Criteria ................................................................................................................ 35 
9.3 
Exclusion Criteria ............................................................................................................... 35 
10 CONCURRENT MEDICATIONS 
36 
10.1 Allowed Medications and Treatments ................................................................................ 36 
10.2 Prohibited Medications and Treatments ............................................................................. 36 
11 STUDY TREATMENTS 
36 
11.1 Method of Assigning Subjects to Treatment Groups ......................................................... 36 
11.2 Blinding .............................................................................................................................. 36 
11.3 Formulation of Test and Control Products ......................................................................... 37 
11.4 Supply of Study Drug at the Site ........................................................................................ 37 
11.5 Storage ................................................................................................................................ 38 
11.6 Study Drug Accountability ................................................................................................. 38 
12 STUDY PROCEDURES AND GUIDELINES 
38 
12.1 Clinical Assessments .......................................................................................................... 38 
12.2 MRI Procedures .................................................................................................................. 38 


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13 EVALUATIONS BY VISIT (ONLY 1 VISIT) 
41 
13.1 Visit 1 (Day/Week/Month #) .............................................................................................. 41 
14 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
42 
14.1 Adverse Events ................................................................................................................... 42 
14.2 Serious Adverse Experiences (SAE) .................................................................................. 43 
14.3 Medical Monitoring ............................................................................................................ 43 
15 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
44 
15.1 Early Discontinuation ......................................................................................................... 44 
15.2 Withdrawal of Subjects from the Study ............................................................................. 44 
15.3 Replacement of Subjects .................................................................................................... 44 
16 PROTOCOL VIOLATIONS 
44 
17 DATA SAFETY MONITORING 
45 
18 STATISTICAL METHODS AND CONSIDERATIONS 
45 
18.1 Data Sets Analyzed ............................................................................................................ 45 
18.2 Demographic and Baseline Characteristics ........................................................................ 45 
18.3 Definition of Numeric Efficacy Outcomes ........................................................................ 45 
18.4 Primary Efficacy Endpoints ............................................................................................. 46 
18.5 Secondary Efficacy Endpoints ......................................................................................... 48 
18.6 Safety Evaluations .............................................................................................................. 48 
18.7 Sample Size and Power Estimate for Primary Efficacy Endpoints .................................... 49 
19 DATA COLLECTION, RETENTION AND MONITORING 
49 
19.1 Data Collection Instruments ............................................................................................... 49 
19.2 Data Management Procedures ............................................................................................ 50 
19.3 Data Quality Control and Reporting .................................................................................. 50 
19.4 Archival of Data ................................................................................................................. 50 
19.5 Availability and Retention of Investigational Records ...................................................... 50 
19.6 Monitoring .......................................................................................................................... 51 
19.7 Subject Confidentiality ....................................................................................................... 51 
20 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
51 
20.1 Protocol Amendments ........................................................................................................ 51 
20.2 Institutional Review Boards and Independent Ethics Committees .................................... 52 
20.3 Informed Consent Form ..................................................................................................... 52 
20.4 Publications ........................................................................................................................ 53 
20.5 Investigator Responsibilities .............................................................................................. 53 
21 REFERENCES 
53 
 


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LIST OF TABLES 
Table 1: Literature summary of AE/SAE rate of Feraheme injection (therapeutic dose @ 
approximately 7 mg iron/kg injected at up to 30 mg /sec) in CKD/Iron Deficiency Anemia 
patients (both pre- and post-marketing studies) 
 
Table 2. Aggregate adverse events reported in post-marketing safety trials of Feraheme® 
 
Table 3: Literature summary of AE/SAE rate of Feraheme injection for MRI.  
 
Table 4: UCLA Patient Safety Data Summary after Feraheme Infusion as an MRI Contrast Agent 
in Pediatric CHD Patients. 
 
Table 5: A comparison of AE/SAE incidence rates for Feraheme vs. Ablavar based on FDA/EMA 
product labels. 
 
Table 6.  AE Severity Grading 
 
Table 7.  AE Relationship to Study Drug 
 
 


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1 
LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this study report. 
 
Abbreviation or special term 
Explanation 
% 
Percent 
3D 
Three Dimensional 
4D 
Four Dimensional  
AE 
Adverse event 
bSSFP 
Balanced steady state free precession 
CE-MRA 
Contrast-Enhanced Magnetic Resonance 
Angiography 
CFR 
Code of Federal Regulations 
CHD 
Congenital Heart Disease 
CKD 
Chronic Kidney Disease 
CNR 
Contrast to noise ratio 
CO2 
Carbon dioxide 
CRF 
Case report form 
CT 
Computed Tomography 
CVMRI 
Cardiovascular magnetic resonance imaging 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FOV 
Field of view 
GBCA 
Gadolinium Based Contrast Agents 
GCP 
Good Clinical Practice 
Gd 
Gadolinium 
GFR 
Glomerular filtration rate 
HIPAA 
Health Insurance Portability and Accountability Act 
of 1996 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 


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Abbreviation or special term 
Explanation 
ICU 
Intensive Care Unit 
IDA 
Iron deficiency anemia 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
kg 
Kilogram  
LV 
Left ventricular  
M.D. 
Medical doctor 
mg 
milligram 
min 
Minute 
MR 
Magnetic Resonance 
MRA 
Magnetic Resonance Angiography 
MRI 
Magnetic resonance imaging 
MUSIC-MRI 
Multiphase, Steady-State Imaging with Contrast 
Enhancement 
NICU 
Neonatal intensive care unit 
NSF 
Nephrogenic systemic fibrosis  
PA 
Pulmonary artery 
pCO2 
Partial pressure of carbon dioxide 
PDB 
Prospect of direct benefit 
PI 
Principal Investigator 
RF 
Radiofrequency 
ROI 
Region of interest 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
UCLA 
University of California at Los Angeles 
USPIO 
Ultra-Small, Super-Paramagnetic Iron Oxide 
 
 
 


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2 
PROTOCOL SYNOPSIS 
TITLE 
Feraheme as an MRI Contrast Agent in Pediatric Congenital 
Heart Disease 
Principal Investigator 
J. Paul Finn, M.D. 
FUNDING 
ORGANIZATION 
National Institutes of Health (Sponsor) 
NUMBER OF SITES 
1 
OBJECTIVES 
1. To compare the diagnostic effectiveness of Ablavar®-
based ventilator-gated MUSIC-MRI with Feraheme®-
based ventilator-gated MUSIC-MRI in pediatric patients 
with CHD. (Study Part I) 
2. To determine the diagnostic effectiveness of an accelerated 
self-gated MUSIC-MRI cardiovascular MRI technique 
(henceforth referred to as ‘self-gated MUSIC-MRI’) for 
pediatric patients with CHD, which ultimately may not 
require sedation or general anesthesia. (Study Part II) 
3. To summarize the safety of Feraheme® and Ablavar® as 
an MRI contrast agent in pediatric patients with CHD. 
MUSIC-MRI (MUltiphase Steady-state Imaging with Contrast 
enhancement is a high resolution 3D cardiac-gated 
cineangiographic imaging technique played out over multiple 
time phases of the cardiac cycle. The MUSIC-MRI sequence 
is described in Han et al. (1) 
BRIEF 
RATIONALE 
The standard clinical cardiovascular MRI practice for children 
with CHD frequently involves the use of gadolinium-based 
contrast agents (GBCA) to enhance tissue contrast. Most 
GBCAs are small molecules that quickly cross the capillary 
wall and access the interstitial space, a process which 
diminishes the signal contrast between blood vessels and 
surrounding tissue. Therefore, these types of GBCA are most 
useful for first-pass MR angiography, wherein the images are 
acquired quickly during the initial 15-30 seconds post-
injection when the GBCA concentration is much higher in the 
arteries than in the interstitial space. For young children with 
complex CHD, the stringent requirements for high spatial 
resolution, and the need for cardiac gating and good blood-
myocardium contrast in order to provide detailed evaluation of 
intracardiac structures are not compatible with conventional 
GBCA-based first-pass MR angiography. Even with Ablavar® 
(gadofosveset trisodium), an FDA approved GBCA with 
longer intravascular half-life than other GBCAs, cardiac-gated 
Ablavar®-enhanced MRI may be insufficient for young 


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children with CHD based on our institutional experience and 
on data from the literature; there remains diminished blood-
tissue contrast during the high-resolution cardiac-gated MRI. 
Furthermore, there have been safety concerns regarding 
gadolinium deposition in brain tissues after repeated GBCA 
exposure as well as concerns of nephrogenic systemic fibrosis 
(NSF) associated with GBCA injection in young children < 2 
years old who may have immature renal function. The long-
term health consequences of these effects in the pediatric 
population are unclear. For the above reasons, we seek to study 
the 
diagnostic 
imaging 
effectiveness 
of 
Feraheme 
(Feraheme®), an FDA-approved drug for parenteral iron 
supplementation, as an MRI contrast agent in children with 
CHD. Although Feraheme® has been approved for the 
treatment of iron deficiency anemia secondary to renal disease, 
Feraheme® has been used as an off-label MRI contrast agent 
at select medical centers, including a Stanford study of 
Feraheme®-enhanced pediatric tumor imaging under a 
separate IND.  
STUDY DESIGN 
The study has two parts:  
Part I: Open-label, exploratory, case-control, single-center 
diagnostic efficacy study in 80 children (age newborn-6 years 
old) to compare Feraheme®-enhanced and Ablavar®-
enhanced MRI 
Part II: Open-label, exploratory, single-center diagnostic 
efficacy study in 40 children (age newborn-6 years old) to 
validate advanced MRI techniques to enable respiratory-
motion self-gated image acquisitions. Such acquisition 
strategies may ultimately enable high-resolution 4D MRI of 
children with CHD who undergo MRI during free-breathing 
without sedation or anesthesia.   
NUMBER OF 
SUBJECTS 
Part I: 80 (40 control and 40 test group) 
Part II: 40  
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria:  
1. Male or female pediatric patients of all ethnicities (age 
newborn to 6 years) with known or suspected CHD with 
inconclusive echocardiographic exams and are referred 
for cardiovascular MRI for further evaluation of cardiac 
anatomy and function.  
2. Written informed consent obtained from subject’s legal 
representative/guardian(s) and ability for subject to 
comply with the requirements of the study. 


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Exclusion Criteria: 
1. 
Standard clinical contraindications to MRI, including 
subjects with cochlear implants and implanted cardiac 
devices 
2. 
Subjects with past or current diagnosis of iron 
overload due to hereditary hemochromatosis or other 
causes (for subjects receiving Feraheme injection 
only). 
3. 
Subjects with known hypersensitivity or allergy to 
iron oxide particles. 
4. 
Subjects with renal insufficiency defined as estimated 
glomerular filtration rate (eGFR) < 40 mL/min/1.73m2 
(for subjects receiving Ablavar injection only). 
5. 
Subjects who are critically ill at the time of MRI and 
for whom the period of general anesthesia and 
separation from the critical care nursery or intensive 
care unit poses added risk as deemed by referring 
cardiologists, cardiac surgeons or the managing 
radiologist (for Part II only). 
6. 
Other medical conditions, in the judgment of the 
clinician investigator, that would increase the risks to 
the child related to participation in the study. 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Ferumoxytol (Feraheme®): Stock Feraheme® formulation 
will be diluted by a factor of ≤ 30 with normal saline and 
administered by slow intravenous infusion for a total dose of 4 
mg of iron per kg of body weight. The total infusion time will 
be 10 minutes.  
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Gadofosveset (Ablavar®): Manufacturer recommended 
dosing of 0.03mmol/kg (0.12mL/kg) will be diluted 4-8x 
(based on body size) with normal saline and administered 
intravenously over 15 seconds at a rate of 0.3-1 mL/sec, 
depending on patient size.  
STUDY DURATION 
Screening and imaging: 1 day 
Total duration of the study: 5 years.  
CONCOMMITANT 
MEDICATIONS 
Allowed: The subjects are allowed to take concomitant 
medications as necessary or directed by the patient’s 
physician.  
Prohibited: None. 
EFFICACY 
EVALUATIONS 
In Part I, the Feraheme®-enhanced ventilator-gated MUSIC-
MRI image quality will be scored and compared with 
Ablavar®-enhanced ventilator-gated MUSIC-MRI. In Part II, 
the ventilator-gated MUSIC-MRI image quality will be scored 


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and compared with respiratory motion self-gated MUSIC-MRI 
using the contrast agent determined in Part I. The image quality 
scoring for both Part I and Part II will be performed for 7 
anatomical structures that are important for pediatric CHD 
patients, (i.e. aortic root, main pulmonary artery, coronary 
arteries, ventricular out-flow tracts, valves, ventricular 
chambers, and atria) using a 1-4 point scale. Image sharpness 
across lumen-wall interfaces will be quantified using 
established methods at the interventricular septum and the 
ascending aorta. The blood-myocardium contrast-to-noise 
ratio will be quantified using established methods.  
PRIMARY EFFICACY 
ENDPOINT 
Composite image quality score among the 7 anatomical 
structures (aortic root, main pulmonary artery, coronary 
arteries, ventricular outflow tracts, valves, ventricular 
chambers, atria). 
SECONDARY 
EFFICACY 
ENDPOINT 
1. Image quality score at the aortic root. 
2. Image quality score at the main pulmonary artery. 
3. Image quality score at the coronary arteries. 
4. Image quality score at the out-flow tracts. 
5. Image quality score at the valves. 
6. Image quality score at the ventricular chambers. 
7. Image quality score at the atria. 
8. Sharpness value at the interventricular septum. 
9. Sharpness value at the ascending aorta. 
10. Blood-myocardium contrast-to-noise ratio (CNR). 
SAFETY 
EVALUATIONS 
Safety Evaluations: 
1.  Incidence of acute AE will be monitored. 
2.  Continuous patient monitoring and recording of vital signs 
(pre-, during, and at least 30 min-post contrast agent injection) 
will be provided by expert and specialized staff, including 
pediatric anesthesiologists and /or staff from the UCLA 
Neonatal or Pediatric Intensive Care Units.  
3. Incidence of other AE up to 60 days post-MRI via a medical 
record review.  
 
Procedures to Reduce Risks of Feraheme Infusion: 
1. All patients will be screened for contraindications to 
Feraheme® administration, including a history of allergy 
to intravenous iron products and iron overload. 
2. Performing MRI in newborns to 6 years of age under 
sedation and/or general anesthesia with airway protection 
is considered the standard of care at most institutions 
performing pediatric cardiac MRI for this age group. In the 
case of a clinically urgent or life-threatening AE during the 
procedure, there will already be in place full airway 
protection and support of respiration.  


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3. Patients will undergo continuous monitoring of heart rate, 
blood pressure, oxygen saturation and ECG tracing for the 
duration of the MRI procedure and, at a minimum, 30 min 
after the injection. In the case of a clinically important AE, 
changes in vital signs will be evident immediately and 
appropriate treatment initiated. Protocols are in place to 
deal with acute AEs related to hypersensitivity and/or 
anaphylaxis. 
4. The dose of Feraheme® will be up to 4 mg /kg 
(approximately half the single therapy dose), diluted with 
saline and infused slowly per FDA guidelines.  
PLANNED 
INTERIM 
ANALYSES  
Part I  
After 50% enrollment is achieved in both the test and control 
groups, the Investigators will convene the DMC and request an 
interim analysis. The Investigators will not be blinded to the 
treatment assignment or to the images, but only to the image 
quality scores, which will be provided by independent 
experienced readers. If statistical significance is achieved for 
the primary efficacy endpoint in the interim analyses, the 
Investigators will close enrollment for Part I and will begin 
enrollment for Part II. If statistical significance is not achieved 
during the interim analyses, we will continue recruiting 
patients into the two groups (Feraheme® and Ablavar®) and 
the final statistical analyses will require a 0.025 level of 
confidence to claim statistical significance.  
 
Part II 
There will be no interim analyses in Part II of our study.  
 
Safety Evaluations 
Adverse events (AEs) will reviewed and monitored by the 
DMC on a quarterly basis. SAEs will be reported within 48 
hours and the DMC will be convened within one week to 
evaluate the protocol. 
STATISTICS 
 
PRIMARY EFFICACY ENDPOINTS:   
 
Part I: Diagnostic efficacy study in 80 children (age 
newborn-6 years old) to compare Feraheme®-enhanced and 
Ablavar®-enhanced MRI 
 
Control Group= Ablavar® + MUSIC-MRI 
Test Group= Feraheme® + MUSIC-MRI 


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The primary efficacy endpoint is the sum of diagnostic image 
quality scores (i.e. the composite score) from the 7 pre-
identified anatomical structures. A parametric two-sided t-test 
will be used to compare the Feraheme® group and the 
Ablavar® group where both groups will use ventilator-gated 
MUSIC-MRI. This comparison will be a two-sided test at the 
0.05 level of significance. A formal interim analysis for the 
image quality will be performed when 20 CHD subjects in each 
group have completed the image acquisition. The interim 
analysis will be prepared by an independent statistician and 
presented only to the independent DMC who will make 
recommendations about the ongoing conduct of the study. Two 
hypotheses will be used to preserve the overall type 1 error rate 
of 0.05 between this single interim analysis and the final 
analysis of the mean differences in the composite image 
quality scores. A two-sample t-test will be used to compare the 
Feraheme®-enhanced and the Ablavar®-enhanced groups for 
the primary analysis at the 0.025 level of significance.  
 
Part II:  Diagnostic efficacy study to compare self-gated 
MUSIC-MRI with ventilator-gated MUSIC-MRI in 40 
children 
 
Control = Contrast agent from Part I + ventilator-gated 
MUSIC-MRI 
Test = Contrast agent from Part I + self-gated MUSIC-MRI 
 
Part II will start after results from Part I are available.  The 
superior contrast agent as determined by Part I of the study or 
in the case that statistical significance is not achieved in Part I, 
the appropriate contrast agent in consultation with the DMC 
will be used for Part II. The primary efficacy endpoint is the 
composite image quality score from the 7 pre-identified 
anatomical structures. A parametric two-sided paired t-test will 
be used to compare the ventilator-gated MUSIC-MRI and self-
gated MUSIC-MRI groups. The quality of the self-gated 
MUSIC-MRI images is expected to be not much worse than 
those from ventilator-gated MUSIC-MRI images. This 
comparison of non-inferiority will be a one-sided test at the 
0.025 level of significance with a -1.75 margin in the 
composite image quality score.  
 
SECONDARY EFFICACY ENDPOINTS: 
 


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Part I: 
The image quality score for each individual anatomical 
structure will be compared between the two contrast agents.  
1. Image quality score at the aortic root. 
2. Image quality score at the main pulmonary artery. 
3. Image quality score at the coronary arteries. 
4. Image quality score at the out-flow tracts. 
5. Image quality score at the valves. 
6. Image quality score at the ventricular chambers. 
7. Image quality score at the atria. 
8. Sharpness value at the interventricular septum. 
9. Sharpness value at the ascending aorta. 
A parametric two-sided t-test will be performed after an 
appropriate transformation of individual score if needed. 
Similarly, the sharpness values and the CNR will be compared 
between the two groups using a two-sided  t-test. 
 
Part II: 
The image quality score for each individual anatomical 
structure will be compared between the two techniques 
(ventilator-gated MUSIC-MRI vs. self-gated MUSIC-MRI). A 
paired t-test will be used to determine the difference in image 
quality scores using appropriate transformation if needed. 
Similarly, the sharpness values and the CNR will be compared 
between the two groups using a two-sided t-test. 
 
SAFETY EVALUATIONS: 
 
Safety will be assessed through summaries of adverse events, 
vital signs recordings, and any relevant clinical laboratory test 
data (including change from baseline). Safety analyses will 
include all patients who receive any amount of study drug 
(safety population). All adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). 
Descriptive statistics will be used rather than inferential 
statistics. 
 
An independent DMC will monitor the safety data on an 
ongoing basis in this trial and will review data from a pre-
specified interim analysis. 
ABBREVIATED 
STUDY FLOW 
Part I:  
1. Patient is referred for cardiovascular MRI after 
inconclusive echocardiography exam. 
2. The Investigators discuss with the patient’s legal 
guardian(s) the study design and risks/benefits for 
Feraheme and Ablavar administration. 


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3. The patient’s legal guardian(s) decide(s) to participate 
in one of the study groups.  
4. Patient 
undergoes 
general 
anesthesia 
per 
our 
institutional standard protocol or is transferred from the 
neonatal ICU already sedated and intubated. 
5. Patient undergoes cardiovascular MRI (ventilator-
gated MUSIC-MRI) using either Feraheme or Ablavar 
and with continuous monitoring of vital signs and any 
AEs. AE treatments are delivered as needed.  
6. Patient recovers from anesthesia or sedation. 
7. Patient is followed up at 60 days post-MRI via a 
medical record review to capture any additional AE.  
 
Part II:  
1. Patient is referred for cardiovascular MRI. 
2. The Investigators discuss with the patient’s legal 
guardian(s) the study design and risks/benefits for 
either Feraheme or Ablavar administration, depending 
on the outcome of Part I. 
3. The patient’s guardian(s) provide written informed 
consent form.  
4. Patient 
undergoes 
general 
anesthesia 
per 
our 
institutional standard protocol or is transferred from the 
neonatal ICU already sedated and intubated. 
5. Patient undergoes cardiovascular MRI (ventilator-
gated MUSIC-MRI and self-gated MUSIC-MRI) using 
the contrast agent determined in Part I and with 
continuous monitoring of vital signs. AEs are 
recognized immediately and treatment delivered as 
appropriate.  
6. Patient recovers from anesthesia or sedation. 
7. Patient is followed up at 60 days post-MRI via a 
medical record review to capture any additional AE. 
 
3 
STUDY HYPOTHESES 
1. Feraheme®-enhanced MUSIC-MRI, which incorporates cardiac and respiratory gating, 
provides superior dynamic evaluation of anatomical structures that are important for 
pediatric CHD patients compared to Ablavar®. 
2. The self-gated MUSIC-MRI is non-inferior to ventilator-gated MUSIC-MRI. 
 
4 
BACKGROUND 
Contrast agents are used in cardiovascular MRI to augment tissue contrast. These agents typically 
exert strong T1 effects, which enhance MRI signal and tissue contrast. The large majority of 


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compounds used clinically are gadolinium-based contrast agents (GBCA), which contain 
gadolinium (Gd), a paramagnetic rare earth metal not found naturally in biological systems. 
4.1 
Overview of Cardiovascular MRI 
Cardiovascular MRI (CVMRI) refers to a group of MRI techniques that address anatomical, 
structural and functional assessment of the cardiovascular system. CVMRI has a number of 
advantages compared to other non-invasive imaging modalities, including lack of ionizing 
radiation, inherent 3D capabilities, unrestricted field of view (FOV) and flexibility in combining 
spatial and temporal resolution.  Uniquely, MRI can generate a wide range of soft tissue contrast 
to image specific aspects of the magnetic state of the tissues. In order to make an MR image, 
radiowave pulses and magnetic field gradient pulses are applied in a specific and customized order, 
called a ‘pulse sequence’, to highlight the properties of tissue magnetization most relevant to the 
clinical question. The administration of pharmaceutical contrast agents, such as GBCA and 
ferumoxytol, result in dramatic changes in the sensitivity of MRI to these tissue properties and the 
biodistribution of the agent is reflected in the image. In many situations, both contrast-enhanced 
and non-contrast enhanced images are acquired and may provide complementary information. For 
vascular anatomical assessment, techniques such as contrast-enhanced MR angiography (CE-
MRA) and non-contrast balanced steady state free precession (bSSFP) are often used to define 
vascular and cardiac anatomy. For functional assessment, sequential 2-dimensional cardiac cine 
imaging is the most widely used MRI technique for quantifying functional parameters of the heart, 
such as ventricular volumes and ejection fraction.  
Most MRI techniques require several seconds to several minutes to acquire and if an imaged organ 
moves during this time, the image becomes degraded by artifact. In all cases, gross body movement 
must be avoided and this is achieved in cooperative patients by requesting that they make no 
voluntary movements during the scan. However, some physiological movements, such as cardiac, 
respiratory and bowel peristalsis are partially or wholly involuntary and, for these, specific 
corrective or preventative maneuvers must be implemented. Therefore, cardiovascular MRI 
generally requires physiological motion compensation techniques for both cardiac and respiratory 
motion. The ECG signal is commonly used as a cardiac gating signal, although its reliability at 
higher field strengths (>= 3 Tesla) is more limited due to artifact caused by blood flowing in a 
stronger magnetic field (magnetohydrodynamic effect) (2). Respiratory motion artifact can be 
mitigated by breath holding, as and when appropriate, or by pausing mechanical ventilation in 
children (3). However, the maximum duration of a breath hold (on the order of 30 seconds) sets 
an upper limit on the amount of spatial and temporal detail that can be acquired in that time with 
MRI. Whereas modern scanners can acquire sufficient detail in this time for a 3-dimensional image 
without cardiac gating (such as for the first pass of a GBCA bolus), cardiac gated, multi-phase 3-
dimensional imaging takes several minutes to acquire and is therefore incompatible with breath-
holding. Techniques exist to compensate for breathing motion artifact when image acquisition 
takes several minutes. The motion of the diaphragm can be monitored by a so called ‘navigator 
echo’, sampled regularly at the lung-liver interface such that the image acquisition can be restricted 
to a specific time window within the breathing cycle. Such a navigator-gating strategy reduces 
respiratory motion related image blurring; however, the navigator sampling process takes time and 
interrupts the continuous radiowave pulsing necessary, and is therefore not well suited to 
techniques that sample the full cardiac cycle in steady state and which may undergo retrospective 
data sorting, such as MUSIC-MRI in our protocol. The current study will utilize two alternative 
respiratory motion compensation strategies which do not interrupt the steady state: 1) ventilator 


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gating and 2) respiratory motion self-gating. With both methods, the radiofrequency and gradient 
activity continues without interruption throughout the entire respiratory and cardiac cycles. The 
ventilator gating strategy uses the air pressure signal from the endotracheal tube in patients 
undergoing positive pressure ventilation and directly reflects the ventilator driving pressure. 
Hence, this technique is not applicable to patients breathing spontaneously. For these cases, a 
promising alternative strategy is respiratory motion self-gating (4), whereby respiratory motion is 
detected by its periodic effect on the amplitude of the continuously acquired MRI signal, without 
the need for a navigator preparation. Respiratory self-gated cardiovascular MRI has the following 
benefits compared to navigators: 1) it does not disrupt the steady state MRI signal and allows us 
to capture the entire cardiac cycle during our MUSIC-MRI cardiac-phase resolved scans; 2) it 
provides a direct account of the effect of respiratory motion on the organ of interest. 
4.2 
Challenge of Cardiovascular MRI in Children 
The clinical value of MR is well established for a variety of cardiovascular disorders (5–9). 
Children with congenital heart disease (CHD) typically have both intra-cardiac and extra-cardiac 
vascular anomalies. Therefore, the ability to visualize both types of morphologic abnormalities is 
crucial. Although echocardiography is readily available, it may leave several morphologic and 
hemodynamic questions unresolved due to issues such as inadequate acoustic window. Cardiac 
CT with either single or dual source technology can yield high spatial resolution images with 
increasingly small radiation doses. However, sub-milliSievert doses are achievable only in the 
most ideal situations (low body mass index, sinus rhythm with excellent beta blockade).  Exposure 
to radiation, however low the dose, should be considered only when alternative methods are not 
available.  Furthermore, neonates and infants may have heart rates that challenge the temporal 
resolution of even dual source CT scanners.  With MRI, the temporal resolution of cine imaging 
can be adjusted to cope with even the fastest heart rates (10). MRI has been shown to be a versatile, 
non-invasive, and non-radiating technique for the evaluation of neonates, infants, and children, 
including those who are critically ill (9,11,12).  
 
In young children, the small caliber of the heart and blood vessels requires higher spatial resolution 
than in adults (5,7) for comparable detail. For adults and larger children, spatial resolution as 
previously reported (13–15) may be entirely adequate; for small children with diminutive central 
vessels, the requirements for high spatial resolution are much more stringent.  Further, children 
(particularly newborns to age 6) also often require the MRI exam to be done under general 
anesthesia (9) as they are unable to obey commands and may be critically-ill. 
4.3 
MRI clinical standard of care in children with CHD 
In children with CHD, echocardiography is universally regarded as the primary diagnostic imaging 
modality. When echocardiography is inconclusive, MRI is the preferred second line imaging 
modality due to the absence of ionizing radiation and the ability to incorporate functional as well 
as anatomic information. MRI for pediatric CHD routinely involves the use of GBCAs to evaluate 
extra-cardiac vascular anatomy, which may be complex and anomalous, but knowledge of which 
is essential to inform patient management. Gd is a rare earth metal not found naturally in biological 
systems, but with paramagnetic properties that greatly enhance the MRI signal. Because free Gd 
ions are toxic, GBCAs are stable chelates wherein the Gd ions are tightly bound with very high 
association constants.  The chelating molecule in turn modulates the biological distribution, 


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potency and pharmacokinetics of the contrast agent. Most GBCAs are small diffusible molecules 
that, following bolus intravenous injection, sustain a short intravascular peak and quickly access 
the interstitial space. Therefore, these extracellular GBCA are useful mainly for first-pass MR 
angiography, wherein the images are acquired during the initial 15-30 seconds post-injection 
before the GBCA leaks from the intravascular space. In children with CHD, this limited time 
window will generally preclude simultaneous high-resolution cardiac and vascular image 
acquisition, due to the requirement for gating to freeze cardiac motion. However, high resolution 
imaging of the intracardiac structures, including the great arteries, the cardiac chambers, the 
valves, and the coronary arteries and the outflow tracts, is essential for planning surgery or other 
interventions for these patients. 
 
Ablavar (Ablavar®, Lantheus Medical) is a GBCA, which binds reversibly to plasma proteins and 
therefore has a longer intravascular residence time and higher potency (r1 relaxivity) than the 
purely extracellular gadolinium agents.  At any time, 70% - 80% of the Ablavar in the blood is 
reversibly bound to serum albumin and the remainder is distributed in the extracellular space.  The 
binding to plasma proteins slows the initial distribution of Ablavar from the blood pool to the 
extracellular fluid space such that, whereas for the purely extracellular GBCAs the distribution 
half life is < 5 minutes, for Ablavar the distribution half life is on the order of 25 minutes. Because 
of its longer intravascular residence time, Ablavar extends the useful time window for vascular 
imaging to 20-30 minutes beyond the first pass. Once the distribution phase is complete, Ablavar 
and the other GBCAs are diluted by the extracellular fluid space (~15 liters in an average adult or 
~30% of body weight in a child under 6 years) and their effectiveness in enhancing the vascular 
signal is correspondingly diminished. Therefore, from the perspective of vascular MRI, the 
duration of the initial distribution phase is the most relevant because the strength of the vascular 
signal is determined by the concentration of the agent in the blood when the scan is being 
performed. Once distributed, the elimination half-life (due to renal excretion) of Ablavar is on the 
order of 19 hours.  
 
Ablavar is approved as a contrast agent for MR angiography in adult patients with peripheral 
vascular disease and has become the agent of choice at many institutions for pediatric CHD.  
Compared to the purely extracellular GBCAs, Ablavar has higher potency per unit dose of Gd (r1 
relaxivity), provides a longer time window for vascular imaging and leaks into the interstitial fluid 
space more slowly. However, like the extracellular GBCAs, its primary mode of elimination is by 
renal filtration of the unbound plasma fraction. Although this is an improvement over the purely 
extracellular agents, an even longer vascular residence time would be desirable in children for 
several reasons. Firstly, for combined and simultaneous high-resolution cardiac and vascular 
imaging in CHD patients, the concentration of contrast agent in the blood should remain constant 
over the several minutes of the imaging scan.  Secondly, in patients under anesthesia or sedation 
it is sometimes necessary to interrupt or repeat a scan if the anesthesiologist needs to adjust the 
depth or type of sedation on a patient specific basis.  Inadequate sedation may result in patient 
motion artifact which can render the study non-diagnostic. Time spent adjusting the sedation 
parameters and confirming physiologic stability may push the image acquisition window beyond 
the optimum time window for Ablavar, resulting in diminished image quality even if motion 
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Therefore, the overall effect of Ablavar® is qualitatively similar to the GBCAs with similar 
limitations, but on an expanded time scale which may be adequate if the study goes smoothly but 
which may result in compromised image quality if scans need to be paused or repeated. The 
hypothesized advantages of Feraheme over Ablavar are the purer and much longer intravascular 
residence time (intravascular half life of 15 hours vs 0.5 hours), such that high-resolution steady-
state cardiac and vascular imaging can be completed successfully, whether or not scans need to be 
paused or repeated.  
4.4 
Safety Concerns with GBCAs 
GBCAs have been used for over a quarter of a century and have a highly favorable safety profile, 
which is predominantly based on their stability in vivo. GBCAs are chelates designed to tightly 
bind gadolinium ions because free gadolinium ions are toxic (16). In recent years, some safety 
concerns have been raised relating to the association of nephrogenic systemic fibrosis (NSF) with 
GBCA exposure for patients with renal impairment, and observation of gadolinium deposition in 
brain tissue, even in patients with normal renal function (17–22). The gadolinium deposition in 
tissue may be particularly worrying in children because of their projected life-expectancy and in 
whom Gd may potentially persist indefinitely. Furthermore, there are concerns of hypersensitivity 
to GBCA injections (23,24) and association of Ablavar with prolongation of the QT interval on 
the ECG, which may pose more concern for cardiac arrhythmias in children with CHD than those 
with normal hearts.  
 
[Nephrogenic systemic fibrosis (NSF)] In 2006, associations between NSF and GBCA exposure 
(25,26) led to a boxed warning alert by the US FDA (27) and the EMA (28) to restrict the use of 
GBCAs in patients with renal insufficiency. Autopsy studies have reported the presence of 
gadolinium in skin, heart, blood vessels, lungs, lymph nodes, spleen, liver, kidney, and dura of 
patients with NSF (16). Almost a decade later however, the pathophysiology of NSF remains 
unclear.  Nevertheless, a consistent body of literature does suggest that slow clearance of GBCAs 
in patients with impaired renal function predisposes to transmetalation with release of free 
gadolinium ions, which have fibrogenic effects (29). The diagnosis of NSF is complex (30) and 
should only be made when clinical and histopathological criteria set forth by the Yale NSF 
Registry are met (31). NSF is described as skin discoloration and swelling progressing to 
erythematous papules, brawny lesions, and subcutaneous sclerosis (32,33) and occurs within 2-3 
months of exposure to GBCAs, but late onset cases have been reported (34). Recently, a new 
entity, termed gadolinium-associated plaques, was reported in two patients by Gathings et al. (35), 
whereby neither patient had NSF while only one patient had renal failure. Both patients, however, 
had erythematous plaques associated with sclerotic bodies thought to be pathognomonic for NSF. 
This occurrence was related to gadodiamide. 
 
The risk of GBCA-associated NSF is highest in those with an estimated glomerular filtration rate 
(eGFR) < 30mL/min/1.73m2 (1-7%) and those with acute renal failure (12-20%). The risk is lower 
for those with moderately decreased renal function (30-59mL/min/1.73m2) and even less for those 
with mild renal impairment (60-89mL/min/1.73m2). While there are a multitude of publications 
on GBCA-associated NSF, the most interesting reports are cases in which NSF did not develop in 
those with severe chronic kidney disease (CKD) (15-29 mL/min/1.73m2 eGFR), who were 
exposed to high doses of GBCAs (36,37). It is thought that other confounding risk factors beyond 


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impaired renal function such as concomitant acidosis, infection, acute pro-inflammatory events, 
immunosuppression, high-dose erythropoietin therapy, elevated iron /calcium /phosphate levels, 
and vasculopathy may play a role in the initiation of the NSF disease cascade. 
 
Zou et al. (33) in their review of 370 biopsy confirmed cases of NSF, suggest that eliminating risk 
factors may substantially reduce the risk of NSF without having to shift to other imaging 
modalities, which may incur risk of radiation and iodinated contrast-induced nephropathy. These 
preventable risk factors include using the lowest dose possible for diagnostic result (limiting 
GBCA dosage to <0.1mmol/kg), avoiding non-ionic linear GBCAs in those on dialysis or having 
eGFR < 30mL/min/1.73m2, dialyzing dialysis-dependent patients promptly after exposure, and 
delaying GBCA administration in the setting of acute renal failure particularly when 
proinflammatory conditions may exacerbate oxidative stress. The Contrast Media Safety 
Committee of the ESUR (29) also recently published recommendations for NSF-risk mitigation 
where they outlined the level of evidence and identified classes of recommendations for clinical 
practice. For the pediatric population, no specific evidence based-guidelines exist.  Guidelines for 
adults are typically used.  There have been 10 biopsy-proven pediatric cases of NSF, but since the 
implementation of guidelines, no new cases in children have been reported (38). To date, no cases 
of NSF have been reported in very young children (38). However, it is known that children younger 
than 2 years have immature renal function (39). The glomerular filtration rate (GFR) of pre-term 
and term newborns can be as low as 40 ml/min/1.73m2, and it gradually increases to 66 
ml/min/1.73m2 at 2 weeks after birth (39). Due to concerns about nephrogenic systemic fibrosis 
(NSF), The European Society of Urogenital Radiology warns against the use of GBCA, including 
gadofosveset, in children less than 1 year old (40). Therefore, a significant portion of the 
children in our study will have immature renal function with an unknown, but likely very 
low risk of developing NSF.  
 
[Possible retention in brain and other tissues] In July 2015, the US FDA issued a safety 
announcement regarding deposits of GBCAs in the globus pallidus and dentate nuclei of patients 
who have undergone multiple GBCA-enhanced MRI (41). The announcement was in response to 
reports of residual gadolinium deposits on non-contrast MRI of patients who had undergone 
multiple GBCA-enhanced MRI exams (42) -- some of whom had normal renal function (19,20), 
and in those exposed to ionic linear GBCA (gadopentetate dimeglumine) rather than macrocyclic 
GBCA (gadoteridol) (21). In a pictorial essay, Caruso et al. (17) first alluded to this phenomenon 
in 2001, but it was not until recently that the findings were publicized by Kanda et al. (18,20,21),  
confirmed by Errante et al. (19), and expanded by McDonald et al. (22). Their work is limited to 
patients with intracranial T1 shortening whereas work by others (43–45) suggests that insoluble 
gadolinium (in the form of gadolinium phosphate in bone tissue) may make up another portion of 
residual gadolinium deposit in the body. However, it remains unknown whether these deposits 
have any adverse clinical implications.  Their findings need confirmatory work, particularly to 
better understand whether certain types of GBCAs are more prone to residual deposition. If future 
research points to significant toxicity of these gadolinium deposits, young children exposed 
to GBCA, including the pediatric CHD population in the Ablavar group of our study, may 
be subject to higher risk due to their longer life expectancy compared to adults.  
 
[Hypersensitivity]  Although the rate of reported cases of NSF has declined, issues relating to 


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hypersensitivity remain. The overall rate of AEs for all GBCAs given at clinical doses (0.1-
0.2mmol/kg) is estimated to be between 0.07 to 2.4% (46). As a comparison, the rate of AEs for 
low-osmolality iodinated contrast agents is 0.15% (47) to 0.2% (46). While hypersensitivity-like 
reactions associated with GBCAs vary from 0.004% to 0.7%, the frequency of serious life-
threatening anaphylactic reactions associated with these agents is exceedingly uncommon (0.001 
to 0.01% (46) vs. 0.04% for nonionic low-osmolality iodinated contrast (46)). According to 
analysis of data reported in FDA MedWatch by Prince et al. (24), the risk of death associated with 
GBCA administration is less than 1 in a million (‘equivalent to the risk of dying from a chest X-
ray, consuming 0.5L of wine, smoking 1.4 cigarettes, or traveling 86 miles by car’).  In contrast, 
the fatality rate for iodinated contrast is 0.9 per 100,000 injections or 2.1 fatalities per one million 
studies using low-osmolality contrast agents based on FDA data from 1990-1994 (46). The death 
rate for ionic linear GBCAs is seven times higher than from nonionic linear agents (24) whereas 
the frequency of acute adverse reactions to GBCAs is eight times higher in those with prior 
reactions to GBCAs. For those with prior reactions to GBCAs, the administration of gadobenate 
dimeglumine is contraindicated (46). Other risk factors for acute hypersensitivity reactions include 
a history of asthma and multiple drug or food allergies. Although there is no cross-reactivity 
between GBCA and iodinated contrast agents, the frequency of GBCA-related adverse event is 
2.3-3.7 times higher in those with prior reaction to iodinated contrast (48).  
4.5 
What is Feraheme and what is its potential as an alternative MRI contrast agent? 
Feraheme® (AMAG Pharmaceuticals, MA) is a proprietary formulation of the iron supplement 
ferumoxytol. Initially designed as an intravascular MRI contrast agent, Feraheme® was approved 
as a bolus intravenous (IV) iron supplement by the FDA in 2009, specifically for the treatment of 
iron deficiency anemia (IDA) secondary to chronic kidney disease (CKD). Each manufacturer-
provided 17-mL vial contains 510mg elemental iron (30 mg Fe /mL) and was administered as an 
IV bolus in as little as 17 seconds (1 mL/sec), a practice recently revised in favor of slow infusion 
over 15 minutes (49). The therapeutic dose for the treatment of IDA calls for two 510-mg injections 
given 3-8 days apart. Compared to other IV iron supplements, Feraheme was developed to have 
lower free iron release (50), decreased immunologic allergic reaction, and improved safety profile 
(50–52). As an ultra-small superparamagnetic iron oxide (USPIO) nanoparticle, Feraheme has a 
long intravascular half-life of 14 hours, high r1 relaxivity, and is incorporated into the 
hematopoietic pathway as supplemental iron once the outer carbohydrate shell is degraded (53). 
These properties along with its approved therapeutic use in patients with kidney dysfunction and 
lack of gadolinium make Feraheme an attractive alternative to GBCAs for first-pass and steady 
state MRI (53,54).  To date, imagers have explored Feraheme for cardiovascular applications (55–
57), renal transplant imaging (58), inflammation imaging (59–61), and cancer imaging (62–65).   
 
By exploiting the imaging properties of Feraheme® appropriately in small children, it is possible 
to acquire images with unprecedented detail, without the need for breath holding. Our group 
recently developed a technique termed 4-dimensional MUSIC-MRI, which produces 4 
dimensional contrast-enhanced images of the beating heart in children, without breath holding (1). 
Additionally, Feraheme® can overcome issues related to both short-term and long-term 
gadolinium deposition in soft tissues. In our practice at UCLA, Feraheme®-enhanced MRI has 
informed clinical decision-making in children with complex and life threatening diseases in ways 
that would otherwise not have been possible. For this reason, we feel that we have sufficient 


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preliminary data to support the prospect of direct benefit (PDB) to patients who undergo MRI with 
Feraheme® in our investigator-initiated, single center, exploratory, open label clinical trial.   
4.6 
Overview of Non-Clinical Studies 
A review of non-clinical studies is not relevant because Feraheme® is a medication approved by 
the FDA for IV treatment of iron deficiency anemia in adults with chronic renal disease. 
4.7 
Overview of Clinical Studies 
Feraheme® has been FDA approved since 2009 for the treatment of iron deficiency anemia in 
adults with chronic kidney disease (CKD).  Based on the manufacturer’s estimate, there have been 
more than 1.2 million administrations since FDA approval in 2009 (Personal Communication, 
AMAG). The following sections summarize the safety profile of Feraheme® as well as Ablavar®, 
the control agent in this study, for adult/pediatric patients and for therapeutic/diagnostic use.  
4.7.1 Feraheme as a Therapeutic Agent 
The safety and efficacy of Feraheme® as an I.V. iron replacement therapy agent has been widely 
studied in adult chronic kidney disease (CKD) patients with iron deficiency anemia. Table 1 
summarizes findings with regard to safety profile of Feraheme from major pre- and post-marketing 
studies (>100 patients) in the literature, which point to an anaphylaxis rate ranging from 0 to 0.2% 
at the approved therapeutic dose.  
 
Table 1: Literature summary of AE/SAE rate of Feraheme injection (therapeutic dose @ 
approximately 7 mg iron/kg injected at up to 30 mg /sec) in CKD/Iron Deficiency Anemia patients 
(both pre- and post-marketing studies) 
Author/Year 
Patient Population 
# of 
Patients 
AE Rate 
SAE Rate 
Anaphylaxis 
Rate 
Spinowitz 2008 
(66) 
CKD 
304 
10.6% 
None 
None 
Singh 2008 (51) 
CKD stages 1-5 
750 
5.2% 
1/750 
(0.1%) 
1/750 
(0.1%) 
Provenzano 
2009 (52) 
CKD stage 5D on 
hemodialysis 
110 
8.2% 
1/110 
(0.9%) 
None 
Vadhan-Raj 
2014 (67) 
Iron Deficiency 
Anemia 
609 
14.6% 
4/609 
(0.7%) 
1/609 
(0.2%) 
Schiller 2014 
(68) 
Dialysis-dependent 
CKD 
8666 
1.25% 
18/8666 
(0.2%) 
2/8666 
(0.02%) 
Hetzel 2014 (69) 
Iron Deficiency 
Anemia 
406 
14.3% 
2/406 
(0.5%) 
1/406 
(0.2%) 
AE: Adverse Event; SAE: serious AE 


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SAE includes hypotension, hypersensitivity/anaphylactoid reactions, syncope, dyspnea, loss of 
consciousness  
 
Since the approval of Feraheme in 2009, there have been a number of large patient cohort studies 
(at least 10425 patients in total) (67–72). The patient cohorts included CKD patients and iron 
deficiency anemia patients without CKD but with a prior history of unsatisfactory oral iron 
therapy. The AE data reported in these post-marketing studies are summarized in Table 2. It should 
be noted that the anaphylaxis rate of post-marketing data so far is 0.03% based on pooled data.   
 
Table 2. Aggregate adverse events reported in post-marketing safety trials of Feraheme® 
Event type 
n 
(total n=10425) 
Total 
Percent 
Percent  
Range 
Gastrointestinal 
174 
1.74% 
0.6% - 12.5% 
Headache 
57 
4.21% 
1.8% - 13.3% 
Muscle spasm /arthralgias 
40 
2.96% 
1.5% - 23.3% 
Cough /sneezing 
21 
0.22% 
0.1% - 5% 
Pruritus /rash /flushing 
68 
0.68% 
0.4% - 10% 
Dizziness 
56 
0.56% 
0.2% - 5% 
Dyspnea /chest pain 
48 
0.48% 
0.2% - 5% 
Hypersensitivity 
12 
0.14% 
0.1% - 0.1% 
Hypotension 
51 
0.55% 
0.4% - 2.5% 
Peripheral edema 
25 
3.36% 
2.5% - 3.5% 
Anaphylaxis 
3 
0.03% 
0% - 1.3% 
CCAEE 
9 
0.89% 
0.8% - 1% 
Urinary tract infections, nasopharyngitis 
39 
5.67% 
5.4% - 7.5% 
*Hetzel et al (n=406), Vadhan-Raj et al (n=608), MacDougall et al (n=80), Schiller et al (n=8666), Auerbach et al 
(n=60), Lu et al (n=605);  **CCAEE=Composite Cardiovascular Adverse Event Endpoint  
 
4.7.2 Feraheme as a Diagnostic MRI Contrast Agent 
Data in Literature: There is less published safety information related to use of Feraheme as a 
diagnostic agent. Table 3 summarizes the AE and SAE rates associated with diagnostic Feraheme 
administration in adults and children based on our literature search. To the knowledge of the 
Investigators, no clinically significant hypotension, hypersensitivity/anaphylactoid reactions, 
syncopy, dyspnea, loss of consciousness or fatalities have been reported so far that is associated 
with Feraheme administration as an MRI contrast agent. 
Table 3: Literature summary of AE/SAE rate of Feraheme injection for MRI.  
Author/Year 
Patient Age 
Group 
# of 
Patients 
AE Rate 
SAE Rate Anaphylaxis 
Rate 


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Ning 2015 (73) 
Children & 
Young Adults 
86 
Not 
reported 
None 
None 
Walker 2015 (74) 
Adult 
10 
None 
None 
None 
Nayak 2015 (58) 
Children 
10 
None 
None 
None 
Muehe et al. 2015 
(75)   
Children & 
Adult 
49 
Children & 
19 Adults 
4/85 (5%) 
None 
None 
Ruangwattanapaisarn 
et al. 2015 (76) 
Children 
23 
None 
None 
None 
Klenk et al. 2014 
(77) 
Children & 
Young Adults 
22 
None 
None 
None 
Bashir et al., 2013 
(78) 
Adult 
16 
None 
None 
None 
D’Arceui et al. 2013 
(79) 
Adult 
8 
None 
None 
None 
Alam et al. 2012 (80) 
Adult 
16 
None 
None 
None 
Thompson et al. 
2012 (81) 
Children 
7 
None 
None 
None 
Hassan et al., 2011 
(82) 
Children 
6 
1/6 (16%) 
None 
None 
Li et al. 2005 (83) 
Adult 
12 
1/12 (8%) 
None 
None 
AE: Adverse Event; SAE: serious AE 
 
The Feraheme® doses used in the literature as a diagnostic contrast agent ranged from 3 mg /kg 
to 7 mg/kg (58,73–83). For imaging purposes at our institution, we have used 4 mg/kg in 208 
patient studies, which is in line with the dose used in the majority of Feraheme®-enhanced MRI 
publications shown in Table 3. Therefore, we will continue using 4mg/kg in the current study, for 
both Part I and Part II studies, when applicable.  
 
UCLA Institutional Experience in Children: Based on data in the literature and communications 
with other centers in the U.S. and Europe, including UCLA, there have been approximately 2,000 
studies (both clinical and research) using Feraheme as a contrast agent. To our best knowledge, so 
far there have been no reports of serious or life threatening AEs associated with using Feraheme® 
as an imaging agent in children. In the therapeutic use of Feraheme, the two life-threatening safety 
concerns with Feraheme® in the overall experience with the product have been hypotension and 
hypersensitivity reactions. To date, 79 unique children with CKD or CHD have undergone 
Feraheme® enhanced MRI under anesthesia at UCLA, all without any AEs. We also 
retrospectively identified 34 pediatric patients who underwent clinically-indicated Ablavar®-
enhanced MRI under general anesthesia and compared the hemodynamic parameters (heart rate, 


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systolic and diastolic blood pressure), oxygenation (pulse oximetry) and ventilation (end-tidal 
CO2) between a subset of the Feraheme group (50 consecutive children with complete anesthesia 
records) and the Ablavar group (34 children with complete anesthesia records), as well as between 
different time points (pre-injection, immediately post-injection, 30 min post-injection and >1 hr 
post-injection) within each group. No statistically significant change in intra-group temporal 
variations of mean heart rate, blood pressure, oxygenation, or ventilation was observed 
immediately pre-injection, immediately post-, 30 minutes post, and >1 hour post-injection for both 
the Feraheme® group and the Ablavar® group (Figures 1&2, one-way ANOVA, p>0.05). There 
was no statistical difference in these parameters between the two groups using t-test, Wilcoxon, or 
ANOVA methods.  
 
 
 
Figure 1.  Comparative measurements of hemodynamic variability in children who underwent 
Ablavar vs Feraheme-enhanced MRI exams under general anesthesia. The intra-group 
hemodynamic variations seen in mean heart rate (A), systolic blood pressure (B), diastolic blood 
pressure (C), immediately pre-injection, immediately post-injection, 30 minutes post-injection, 
and >1 hour post-injection were not statistically significant for both Feraheme and Ablavar 
groups (p>0.05). One-way ANOVA was used to test for statistical significance between 
measurements at different time points within each group.  n=34 (age range 2 days to 12.5 years) 
for Ablavar enhanced MRI; n=50 (age 3 days to 19 years) for Feraheme-enhanced MRI.  bpm: 
beats per minute 
 
 


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Figure 2.  Comparative measurements of oxygenation and ventilation in children who underwent 
Ablavar vs Feraheme-enhanced MRI exams under general anesthesia. With the exception of mean 
pulse oximetry at 30 minutes post-Ablavar injection (p=0.05), the intra-group mean pulse oximetry 
(A), and mean end-tidal CO2 (B) measurements immediately pre-injection, immediately post-
injection, 30 minutes post-injection, and >1 hour post-injection were not statistically significant 
for both Ablavar and Feraheme groups (p>0.05). One-way ANOVA was used to test for statistical 
significance between measurements at different time points within each group. n=34 (age range 2 
days to 12.5 years) Ablavar enhanced MRI; n=50 (age 3 days to 19 years) for Feraheme-enhanced 
MRI. 
Table 4 summarizes our safety data of Feraheme® in pediatric CHD patients at UCLA. 
Continuous monitoring of vital signs and symptoms of adverse reaction was performed up to 1 
hour post-Feraheme® injection. Thus far, in 35 pediatric patients with CHD, we have not identified 
any adverse reactions in these patients.  
 
Table 4: UCLA Patient Safety Data Summary after Feraheme Infusion as an MRI Contrast 
Agent in Pediatric CHD Patients 
 
CHD 
Total number 
35 
Dose (mg/kg) 
3.9 ± 0.7 
Infusion time () 
15s to 5min* 
SAE 
0 
Hypotension (>10mmHg BP drop) 
0 
Edema 
0 
Cough 
0 
Muscle spasms 
0 
Rash 
0 
Dyspnea 
0 
Pyrexia 
0 


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Vomiting 
0 
CHD: congenital heart disease; s: seconds; min: minute; AE: adverse event; SAE: Severe AE, including 
acute anaphylaxis and hypersensitivity reactions and clinically significant hypotension  
*: After the recent FDA Boxed Warning (March 2015), the Investigators modified our administration 
protocol to infuse the dilute Feraheme over 5-10 minutes in the pediatric CHD patients.  
4.7.3 Comparison of Feraheme® vs. Ablavar® Safety 
According to the Feraheme® package label from the FDA, its anaphylactic/hypersensitivity rate 
is approximately 0.2% (3 out of 1726 administrations of the therapy dose in pre-marketing clinical 
trials) and hypotension was reported in 33 out of 1726 subjects, including 3 severe hypotensive 
reactions. According to the ferumoxytol (Rienso®) package from the European Medicines Agency 
(EMA), the rate of serious hypersensitivity and hypotension reactions combined is 0.2% (3 out of 
1562 subjects), and out of the 3 serious reactions, 1 (<0.1%) was characterized as an anaphylactoid 
reaction. In a more recent study of 8666 CKD patients who underwent Feraheme® administration, 
two patients (0.02%) experienced anaphylactoid reactions (68). The aggregate rate of anaphylaxis 
in post-marketing trials is 0.03% (See Table 2), lower than that reported on package inserts, which 
was based on pre-marketing clinical trials. As a comparison, Ablavar (Ablavar®), which is a 
widely used gadolinium based MRI contrast agent, has an anaphylactoid/anaphylactic reaction rate 
of 0.1% (2 out of 1676 subjects according to its label from the FDA). However, Ablavar®, because 
it is a gadolinium based contrast agent, is included in the group of agents listed by the FDA as 
having a possible association with NSF in patients with insufficient renal function. Also, Ablavar 
is associated with cardiac electrical conduction effects, most specifically prolongation of the QT 
interval. This has caused some institutions to shy away from including it in their drug formulary. 
Furthermore, gadolinium is a foreign element and is not a natural constituent of biological systems. 
This concern is underscored by the recent discovery of gadolinium deposits in patients’ brains after 
repeated exposure to GBCA (17–22), even those with normal renal function. Iron, on the other 
hand, is an essential element for life and iron deficiency is associated with a plethora of potentially 
serious health consequences. Despite these objective facts, Feraheme®, perhaps by inferential 
association with larger iron particles such as ferumoxides (Feridex®) which have been commonly 
associated with hypersensitivity and back pain, may be perceived as higher risk by the general 
community than gadolinium-based agents, which are generally deemed to have a very good safety 
profile. Table 5 summarizes the adverse reaction rates of Feraheme® (full therapeutic dose) and 
Ablavar® (0.03 mmol/kg) from their respective most recent FDA/EMA product labeling. 
 
Table 5: A comparison of AE/SAE incidence rates for Feraheme vs. Ablavar based on FDA/EMA 
product labels. 
AE Type 
Feraheme 
Ablavar 
Hypersensitivity/anaphylactic 
0.1%-0.2%  
0.1%-0.2% 
Risks of NSF for patients with renal 
impairment? 
No 
Yes 
Risks of arrhythmia due to 
prolongation of ECG QT interval 
No 
Yes 


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Pruritus 
1.2% 
4% 
Hypertension 
1.0% 
1% 
Dizziness 
2.6% 
1% 
Headache 
1.8% 
4% 
Nausea 
3.1% 
4% 
Hypotension 
2.5% 
(<1% and not shown on 
the Prescribing 
Information 
 
 
Edema 
1.5% 
Vomiting 
1.5% 
Abdominal pain 
1.3% 
Chest pain 
1.3% 
Cough 
1.3% 
Pyrexia 
1.0% 
Back pain 
1.0% 
Muscle spasms 
1.0% 
Dyspnea 
1.0% 
Rash 
1.0% 
Vasodilatation 
(<1% and not shown on 
the Prescribing 
Information) 
3% 
Paresthesia 
3% 
Injection site bruising 
2% 
Dysgeusia 
2% 
Burning sensation 
2% 
Venipuncture site bruise 
2% 
Feeling cold 
1% 
 
5 
STUDY RATIONALE 
In children with congenital heart disease (CHD), echocardiography is universally regarded as the 
primary diagnostic imaging modality. When echocardiography is inconclusive, MRI is the 
preferred second line imaging modality due to the absence of ionizing radiation and the ability to 
incorporate functional as well as anatomic information. The current MRI contrast agents are based 
on chelates of the rare earth element, gadolinium (Gd). Feraheme® (AMAG Pharmaceuticals) is 
a proprietary formulation of Feraheme, an ultra-small, super-paramagnetic iron oxide (USPIO) 
nanoparticle, approved by the FDA as an intravenous iron therapy for anemia in adult chronic 
kidney disease. Compared to GBCAs, Feraheme exhibits a unique combination of high signal 
potency (r1 relaxivity) and a long intravascular residence time, which make it very powerful for 


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MR imaging of pediatric CHD.  By exploiting these unique imaging properties of Feraheme 
appropriately, it is possible to acquire images with unprecedented detail, without the need for 
breath holding, both of which are crucial in tiny babies.  Our group recently developed a technique 
termed 4-dimensional MUSIC-MRI (MUltiphase Steady state Imaging with Contrast) (1), which 
leverages the specific imaging properties of Feraheme to produce 4 dimensional images of the 
beating heart in children, during uninterrupted ventilation. By lifting the requirement for breath 
holding, it becomes possible to prolong the image acquisition time sufficient to capture multiple 
phases of the cardiac cycle with very high spatial resolution and with high contrast to noise ratio 
(CNR). By capturing a true, isotropic 3-dimensional set of images over multiple phases of the 
cardiac cycle, it becomes trivial to reconstruct 2-dimensional slices of the beating heart in any 
arbitrary plane. Effectively, this is equivalent to acquiring an infinite set of individual slices in 
multiple orientations, analogous to 2-dimensional cine MRI slices or 2-dimensional planes on 
echocardiography. However, in the case of 2-dimensional cardiac cine and echocardiography, the 
individual planes must be specified at the time of the study. This would be prohibitively time 
consuming, if not geometrically impossible and if not acquired during the original scan, such slices 
cannot be reconstructed after the fact even if they would help guide surgical decision-making. 
With MUSIC-MRI, any arbitrary slice can be interrogated after the fact and forever, providing a 
permanent repository for interrogation of any cardiac structure should this become clinically 
relevant in a way that was not originally anticipated. Already in our practice at UCLA, Feraheme 
MRI has informed clinical decision-making in complex diseases and critically ill children in ways 
that would not otherwise have been possible, even invasively. For example, decisions about 
whether to perform bi-ventricular vs. single ventricle repair in complex CHD and about the extent 
and nature of thrombosis and infection have been based soundly on information provided by the 
unique combination of Feraheme® and techniques developed at UCLA to exploit its properties. 
Feraheme® has already proved to be invaluable in these patients at our institution. We have 
accumulated sufficient preliminary evidence in our daily clinical practice (see Appendix) to 
support the prospect of direct benefit (PDB) in children undergoing Feraheme®-enhanced MRI.  
 
Our current MUSIC-MRI technique uses the ventilator circuit air-pressure signal for respiratory 
motion gating (i.e. ventilator-gated MUSIC-MRI). Therefore, the technique is currently only 
applicable to patients who are under anesthesia/sedation with endotracheal intubation. Our long-
term goal is to enable free-breathing MUSIC-MRI scans in children who may not require 
anesthesia or sedation for MRI. In these cases, an alternative respiratory motion gating strategy 
will need to be developed and validated, and the image acquisition time will need to be further 
shortened to ensure high quality studies in these patients. Therefore, in Part II of our study, we will 
develop such an MRI pulse sequence using a respiratory motion self-gating technique and 
compressed sensing image reconstruction (self-gated MUSIC-MRI) and we will test the hypothesis 
that the self-gated MUSIC-MRI pulse sequence is non-inferior to the ventilator-gated MUSIC-
MRI in a cohort of children with CHD.  
5.1 
Benefit to Risk Assessment 
Feraheme infusion is associated with risks, which include acute anaphylactoid reactions and 
hypotension, as well as other types of less severe adverse events such as rash, nausea and vomiting. 
The investigators are fully aware of the potential risks of Feraheme infusion and the following is 
our plan to mitigate these risks. As summarized in our Overview of Clinical Studies in Section 4.5, 
Feraheme® and the control contrast agent, Ablavar®, have a similar and small risk of 


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hypersensitivity/anaphylactoid reactions in pre-marketing clinical trials and the post-marketing 
data of Feraheme® safety point to a lower reported incidence of anaphylaxis than pre-marketing 
data. Furthermore, the elemental iron in its core is indispensible for normal biosynthesis and 
energy metabolism. Iron deficiency is the most widespread disorder in the world and its prevalence 
in children is 3-7% in the U.S. (84). It has been shown that the majority of pediatric CHD patients 
do not meet the recommendations for iron uptake (85). In normal neonates, body iron stores reach 
a nadir at about six months of age and in order to meet the demands of rapid growth must be 
appropriately supplemented by a diet rich in iron, such as formula. In sick neonates, body iron 
stores are frequently low from birth and these patients often require iron supplements (85). In these 
patients, it seems likely that Feraheme® may offer a nutritional iron boost, over and above its 
imaging applications. Therefore, for the pediatric CHD patient population in this study, who will 
need a high quality cardiovascular MRI exam in order to inform surgical decision-making, the 
Investigators feel the potential benefit for these children greatly outweighs the potential 
incremental risks associated with participating in this study, especially given the recent reports of 
gadolinium deposits in the brain tissue after repeated GBCA exposure (17–22).  
 
5.2 
Monitoring of Adverse Events after Feraheme® Administration 
A careful interview with the patient’s legal guardians will be conducted before each study. The 
pediatric CHD patients will undergo clinical screening procedures for exclusion criteria. In 
children examined under anesthesia or sedation for MRI at UCLA, the full spectrum of anesthetic 
and sedative agents is routinely available, as is the full spectrum of pharmacological agents 
required to treat anaphylactic or other adverse drug reactions. Due to the specific concerns about 
acute AEs, including hypersensitivity and anaphylactic reactions, awareness of the possibility of 
such occurrence will be appropriately emphasized among the anesthesiology and NICU staff. The 
following safety strategies are in place at UCLA to mitigate any risks associated with infusion of 
Feraheme in our pediatric patients with CHD: 
1) All patients will be screened for contraindications to Feraheme administration, including a 
history of allergy to intravenous iron products and iron overload. 
2) Prior to Feraheme infusion, all patients will be sedated (or anesthetized), intubated and 
ventilated such that, in the case of a serious AE, there will already be in place full airway 
protection and support of respiration. Anesthesia is routinely employed in most centers for 
infants and young children undergoing cardiac MRI who cannot reliably follow verbal 
instructions during imaging.  
3) Continuous patient monitoring and recording of vital signs (heart rate, blood pressure, 
oxygen saturation and ECG) before, during and for at least 30 minutes following Feraheme 
infusion will be provided by expert and specialized staff, including pediatric 
anesthesiologists and /or staff from the UCLA Neonatal or Pediatric Intensive Care Units.  
These vital signs data will be uploaded to the UCLA electronic medical record system. In 
the case of a clinically urgent or life-threatening AE, changes in vital signs will be 
recognized immediately and appropriate treatment initiated.  
4) The dose of Feraheme will be up to 4 mg /kg (approximately half the single therapy dose), 
diluted with saline and infused slowly (approximately over 10 minutes). Our infusion rate 
will be consistent with latest FDA guidelines on a mg/kg/sec basis.  
 


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Consistent with institutional clinical practice at UCLA and other Centers of Excellence in pediatric 
cardiovascular MRI, anesthesia in the pediatric CHD patients will be performed by specialized 
pediatric anesthesiologists regardless of contrast agent used (Feraheme® vs. Ablavar®) with 
continuous monitoring of heart rate, blood pressure, pulse oximetry, end tidal CO2, and, where 
appropriate, anesthetic gas levels (such as sevofluorane). All of the children in our study will have 
protected airways and mechanical ventilatory support from the start of the procedure to the end.  
Clinically urgent and life-threatening adverse reactions to any agent may include laryngeal edema 
and bronchospasm, where prior endotracheal intubation may be lifesaving.  Should other events 
occur involving changes in heart rate, heart rhythm and /or blood pressure, the anesthesiologist 
can focus his / her attention on the appropriate use of chronotropic or inotropic agents, intravenous 
fluids and /or vasoactive drugs, without having to secure the airway.  All patient physiological 
monitoring data are, and will continue to be, digitized and transferred in real time to the electronic 
patient medical record, where they are stored permanently and retrievably. Relevant abstractions 
from these and other patient safety data (protected health information removed) will be included 
in our DMC, IRB and IND adverse event reports.  
6 
STUDY OBJECTIVES 
1. To compare the diagnostic efficacy of Ablavar®-based MUSIC-MRI with Feraheme®-based 
MUSIC-MRI in pediatric patients with CHD. (Study Part I) 
2. To determine the diagnostic efficacy of an accelerated self-gated MUSIC-MRI cardiovascular 
MRI technique for pediatric patients with CHD, which ultimately may not require sedation or 
general anesthesia. (Study Part II) 
3. To summarize the safety of Feraheme® and Ablavar® as an MRI contrast agent in pediatric 
patients with CHD. 
7 
STUDY DESIGN 
7.1 
Study Overview 
This is an exploratory, investigator-initiated, prospective, open label, case-control, single center, 
phase IV study that will examine the diagnostic effectiveness of Feraheme® as an MRI contrast 
agent in pediatric patients with CHD. A total of 120 patients with suspected or known CHD (age 
newborn to 6 years) of all ethnicities, females and males, will be enrolled. Total duration of subject 
participation in the imaging study will be approximately 1.5 hours.  In general, we expect the 
pediatric MRI scans to take no more than about 60 minutes once the scan begins. We will also 
follow up the children for up to 60 days. Total duration of the study is expected to be 5 years. Our 
study has two parts: 
1) Part I is a comparison study between Feraheme®-enhanced MRI and Ablavar®-enhanced 
MRI. The goal of Part I is to compare the diagnostic efficacy of these two contrast agents for 
pediatric CHD using our validated technique MUSIC-MRI (1). We hypothesize that Feraheme® 
provides superior diagnostic effectiveness than Ablavar® for these patients. The duration of Part 
I is expected to be 3 years. 
2) Part II is expected to commence after the statistical significance of the primary endpoint of 
Part I is confirmed and the goal is to determine the diagnostic efficacy of an MRI pulse sequence 
(self-gated MUSIC-MRI), which will leverage advanced image reconstruction techniques and 


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respiratory motion compensation strategies. Self-gated MUSIC-MRI may ultimately enable high-
quality free-breathing cardiovascular MRI for pediatric CHD patients who are able to undergo 
imaging without sedation or general anesthesia (i.e. children >6 years old who can consistently 
follow verbal instructions during scanning). The duration of Part II is expected to be 2 years. 
7.2 
Study Design Part I: diagnostic efficacy of Feraheme vs. Ablavar  
For Part I of our study, the legal guardian(s) of all consecutive pediatric patients with suspected or 
known CHD referred for cardiovascular MRI will be given the option of having their child 
undergoing an Ablavar®-enhanced MRI or a Feraheme®-enhanced MRI, after the potential 
benefits and risks of both agents are clearly explained and their questions addressed. The risks and 
benefits of using each of these agents will be verbally discussed with the patients’ legal guardians 
and referring cardiologists or cardiac surgeons. A copy of the written IRB-approved informed 
consent will be provided. Because Feraheme®-based imaging is in use at several pediatric 
specialty centers, including UCLA whereby Feraheme is used more frequently than GBCA-based 
imaging for children in our study age-group, in the current state of professional equipoise, we 
judge it appropriate to allow parents to participate in the choice of agent (see Section 11.1.1 for 
detailed justification). Those choosing to undergo an Ablavar®-enhanced MRI will be considered 
the “control” group while those choosing to undergo a Feraheme®-enhanced MRI will be 
considered enrolled in the “test” group. We plan to recruit 40 patients for test group and 40 patients 
for the control group with consideration of approximately 10% missing or unusable image quality. 
To avoid performing a study with larger-than-necessary enrollment, the Investigators will request 
an interim analysis at 50% enrollment for both groups. If statistical analyses, either as part of 
interim analyses requested by the Investigators, or after full enrollment, shows statistically 
significant primary endpoint comparison, we will close Part I enrollment and begin Part II 
enrollment using the superior agent identified in Part I. If statistical significance is not reached for 
the primary endpoint during interim analyses, the patient enrollment for both test and control 
groups will continue until full enrollment, at which time another final statistical analyses will be 
performed with p<0.025 considered statistically significant. If statistical significance is not 
reached at full enrollment, we will seek advice from the DMC regarding Part II of the study, 
including contrast agent to be used.  
 
See Section 11.1.1 for justification for involving the patient’s parents in patient group assignment.  
 
7.3 
Study Design Part II: diagnostic efficacy of ventilator-gated MUSIC-MRI vs. self-
gated MUSIC-MRI 
The Part II study will commence after statistical significance of the primary endpoint of Part I is 
confirmed. The overall goal of Part II is to develop and validate a more advanced MUSIC-MRI 
pulse sequence that incorporates image acceleration and compressed sensing reconstruction 
techniques as well as respiratory motion self-gating methods. Our current MUSIC-MRI pulse 
sequence is designed for young patients (newborn to 6 years old) who undergo cardiovascular MRI 
under general anesthesia or sedation per our institutional standard practice. The ventilator air 
pressure signal is currently used as a respiratory motion gating signal in our ventilator-gated 
MUSIC-MRI pulse sequence. For older children with CHD who can reliably follow verbal 
instructions during the MRI examination, undergoing sedation or anesthesia for the purpose of 
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that is capable of acquiring high-quality images of the heart and blood vessels of these patients 
without anesthesia/sedation or the need for a ventilator gating signal would be highly desirable. 
To achieve this goal, the investigators plan to first validate such a self-gated MUSIC-MRI 
technique against the existing ventilator-gated MUSIC-MRI technique in patients undergoing MRI 
under anesthesia or sedation, a similar setup as Part I. The reasons for testing the new pulse 
sequence in younger patients under anesthesia/sedation rather than in older patients without 
anesthesia are two fold: 1) This strategy provides a means for the investigators to verify the 
diagnostic effectiveness of the self-gated MUSIC-MRI sequence against the “gold-standard’ 
ventilator-gated MUSIC-MRI sequence, which would not be possible in spontaneously breathing 
patients. 2) Even in patients under anesthesia with mechanical ventilation, potential benefits of 
self-gated MUSIC-MRI include shorter acquisition time (8-10 min for current MUSIC-MRI vs. 
approximately 4-5 min for the accelerated self-gated MUSIC-MRI) and improved respiratory 
motion gating, as the self-gating signal is a more direct measurement of diaphragmatic motion than 
the ventilator circuit air-pressure signal. Therefore, in the Part II study, we will recruit 40 patients 
who provide informed consent into the contrast agent group (either Feraheme® or Ablavar®) 
identified in Part I of the study. In each patient, the current ventilator-gated MUSIC-MRI pulse 
sequence and the to-be-developed self-gated MUSIC-MRI pulse sequence will be performed 
sequentially in a randomized order by flipping a coin. Other than the added self-gated MUSIC-
MRI pulse sequence and target enrollment differences, all other aspects of study design for Part II, 
including patient safety monitoring and safety data recording, will be the same as Part I. The 
additional self-gated MUSIC-MRI pulse sequence will require approximately 5 minutes to 
perform. At the end of Part II study, we will perform statistical analyses specified in Section 18 to 
confirm the diagnostic efficacy of the self-gated MUSIC-MRI pulse sequence.  
If no statistical significant difference for the primary endpoint was found in Part I, we will seek 
advice from the DMC regarding whether or not to start Part II of the study. If the DMC decides in 
favor of pursuing Part II of the study, they will also comment on which contrast agent to be used. 
In offering advice for the choice of agent in Part II, the Investigators will ask the DMC to take the 
following factors into consideration:  
1. Numerical superiority of one agent in Part I, even if statistical significance cannot be 
reached.  
2. Superiority of one agent for the secondary endpoints in Part I.  
3. Differences in safety information observed during Part I, if any, and differences in safety 
based on the current literature at the end of Part I study, including risks of life-threatening 
reactions, risks to immature kidneys in the participants, potential long-term risks of 
gadolinium deposit in neurological tissues.    
 
8 
CRITERIA FOR EVALUATION 
8.1 
Part I – Comparison between Feraheme® and Ablavar® 
8.1.1 
Primary Endpoint 
A statistically significant difference in composite image quality score for 7 important anatomical 
structures between Feraheme®-enhanced vs. Ablavar®-enhanced ventilator-gated MUSIC-MRI.  


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8.1.2 
Secondary Endpoints 
A statistically significant difference in image quality scores in each of the 7 important anatomical 
structures between Feraheme®-enhanced vs. Ablavar®-enhanced ventilator-gated MUSIC-MRI. 
A statistically significant difference in sharpness measurements at the ascending aorta and the 
interventricular septum.  
A statistically significant difference in blood-myocardium CNR measurements. 
8.1.3 
Safety Endpoints 
• 
Incidence of AE for both the test group and the control group. 
• 
Changes in vital signs recordings (hemodynamic parameters, oxygenation, and ventilator 
parameters) associated with Feraheme® administration 
• 
Changes in vital signs recordings (hemodynamic parameters, oxygenation, and ventilator 
parameters) associated with Ablavar® administration 
8.2 
Part II – Comparison between Ventilator-Gated MUSIC-MRI and Self-Gated 
MUSIC-MRI 
8.2.1 
Primary Endpoint 
Statistically non-inferior composite image quality score of self-gated MUSIC-MRI for 7 important 
anatomical structures compared to the ventilator-gated MUSIC-MRI.  
8.2.2 
Secondary Endpoints 
1. Statistically non-inferior image quality scores for the self-gated MUSIC-MRI in each of 
the 7 important anatomical structures compared with the ventilator-gated MUSIC-MRI.  
2. Statistically non-inferior sharpness measurements at the ascending aorta and the 
interventricular septum using the self-gated MUSIC-MRI compared with the ventilator-
gated MUSIC-MRI. 
3. A statistically non-inferior blood-myocardium CNR measurements.  
8.2.3 
Safety Endpoints 
• 
Incidence of AE during and after Feraheme administration. 
• 
Changes in vital signs recordings (hemodynamic parameters, oxygenation, and ventilator 
parameters) associated with contrast agent administration (Feraheme or Ablavar). 
9 
SUBJECT SELECTION 
9.1 
Study Population 
Pediatric patients of all ethnicities, age newborn to 6 years, of either gender with known or 
suspected CHD will be recruited. This specific age population has been chosen because our 
preliminary experiences suggest that the PDB is greatest in the smallest and sickest children. 
Furthermore, all patients of ages < 6 years undergoing cardiac MR imaging are routinely examined 
under anesthesia with controlled ventilation independently of our study and under the direct and 


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continuous observation of a pediatric anesthesiologist or neonatologist. These elements minimize 
the relative risk of Feraheme® administration by enabling airway protection and the ability to 
perform non-breath-held diagnostic studies in potentially fragile patients. Our study population 
will include patients with any types of CHD who are clinically referred to cardiovascular MRI; 
however, we expect our patient recruitment to be concentrated in more complex forms of CHD, 
such as Tetralogy of Fallot, because these are the patients that typically have inadequate 
echocardiographic exams and are referred for MRI. We do not expect our study population to have 
eGFR<40 mL/min/1.73m2, although renal insufficiency is an exclusion criteria for the Ablavar® 
group of Part I study.  
9.2 
Inclusion Criteria 
1. Male or female pediatric patients (age newborn to 6 years) of all ethnicities with known or 
suspected CHD with insufficient echocardiographic exams and are referred for cardiovascular 
MRI for further evaluation of cardiac anatomy and function.  
2. Written informed consent obtained from subject’s legal representative/guardian(s) and ability 
for subject to comply with the requirements of the study. 
9.3 
Exclusion Criteria  
1. 
Standard clinical contraindication to MRI, including subjects with cochlear implants and 
implanted cardiac devices 
2. 
Subjects with past or current diagnosis of iron overload due to hereditary 
hemochromatosis or other causes (for subjects receiving Feraheme® injection only). 
3. 
Subjects with known hypersensitivity or allergy to iron oxide particles. 
4. 
Subjects with renal insufficiency defined as estimated glomerular filtration rate (eGFR) < 
40 mL/min/1.73m2  (for subjects receiving Ablavar® injection only). 
5. 
Subjects who are critically ill at the time of MRI and for whom the period of general 
anesthesia and separation from the critical care nursery or intensive care unit poses added 
risk as deemed by referring cardiologists, cardiac surgeons or the managing radiologist 
(for Part II only). 
6. 
Other medical conditions, in the judgment of the clinician investigator, that would increase 
the risks to the child related to participation in the study.  
10 CONCURRENT MEDICATIONS 
Concurrent medication is allowed as clinically necessary for the subject.  
10.1 Allowed Medications and Treatments 
Concurrent medication is allowed as clinically necessary for the subject.  
10.2 Prohibited Medications and Treatments 
None 


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11 STUDY TREATMENTS 
11.1 Method of Assigning Subjects to Treatment Groups 
Refer to Section 7.2 for patient group assignment in Part I of the study.  For Part II of the study, 
all subjects will undergo the ventilator-gated MUSIC-MRI and self-gated MUSIC-MRI in one 
imaging session in a randomized order by flipping a coin.  
 
11.1.1  Justification for Parents Participation in Patient Group Assignment 
We plan to allow parents to participate in the decision about treatment assignment in Part I of this 
open-label, evaluator-blinded study. Feraheme-based imaging is in use at several pediatric 
specialty centers, including UCLA whereby Feraheme is used more frequently than GBCA-based 
imaging for children in our study age-group. In the current state of professional equipoise, we 
judge it appropriate to allow parents to participate in the choice of agent. There is no a priori 
reason to expect MRI image quality, ventricular or aortic wall definition, or the risks of 
anaphylaxis or other important AEs to be influenced by parental preferences; thus the 
generalizability of our scientific conclusions will not be diminished by allowing parents to 
influence the treatment assignment for their children. Recruitment of children in clinical studies is 
a challenging process. Based on our clinical investigative experience in the particular patient 
population at UCLA, many parents and/or legal guardians are more willing to participate in a study 
without randomization of treatment than one that required randomization of the child’s treatment. 
We expect this route of recruitment will facilitate recruitment and successful completion of the 
study.  In scenarios where the patient’s legal guardians defer and ask the managing clinician to 
make ‘the best choice’, the decision will be based on the apparent needs of the trial at the time and 
the patient will be assigned the group that is under-enrolled with reference to the target enrollment. 
If our patient group assignment method results in a severely distorted imbalance (e.g. nearly all 
parents elect either Feraheme or Ablavar), the DMC will be convened and asked to advise on a 
corrective measure, which may include changing the patient group allocation method.  
 
11.2 Blinding 
For Part I of the trial, the image readers will be blinded to the patient’s information and the contrast 
agent used.  For Part II of the trial, the image reviewers will be blinded to the techniques used. In 
both cases (Part I and Part II), scores for image quality, sharpness and CNR measurements will 
remain blinded to the managing clinician and the Investigators and only the study statistician will 
be able to pair the contrast agent assignment /score (for Part I) and technique assignment /score 
(for Part II).  
11.3 Formulation of Test and Control Products 
Formulation of Test Product 
Feraheme (Feraheme®) is an FDA approved drug manufactured by AMAG Pharmaceuticals for 
I.V. administration as an iron supplement for iron deficiency anemia in chronic kidney disease. It 
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 
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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.   
Formulation of Control Product 
Ablavar® is an FDA approved MRI contrast agent for evaluation of aortoiliac occlusive disease 
in adults with known or suspected peripheral vascular disease. Ablavar is a sterile, nonpyrogenic, 
formulation of stable gadolinium diethylenetriaminepentaacetic acid (GdDTPA) chelate derivative 
with a diphenylcyclohexylphosphate group. Each mL of Ablavar contains 244 mg of gadofosveset 
trisodium (0.25 mmol), 0.268 mg of fosveset, and water for injection. It contains no preservative 
and the solution pH ranges between 6.5 and 8.0. Gadofosveset trisodium is chemically trisodium-
{(2-(R)-[(4,4-diphenylcyclohexyl) 
phosphonooxymethyl]-
diethylenetriaminepentaacetato)(aquo) gadolinium(III), with a molecular weight of 975.88 
g/mol, and an empirical formula of C33H40GdN3Na3O15P.  
Packaging and Labeling 
Feraheme® and Ablavar used in this study will be commercial product and will be in the 
commercial primary container/closure system.  Investigational labels, with the required caution 
statement, “Caution-new drug limited by Federal Law to Investigational Use” will be used to over-
label individual vials of commercial product by the UCLA pharmacy before supplying to the 
investigator for the clinical study.  
Dosage/Dosage Regimen 
Feraheme will be infused intravenously at a dose level of 4 mg of iron per kg of body weight.  
Ablavar is administered by an intravenous bolus at a dose of 0.03 mmol/kg body weight over a 
period of time up to 30 seconds followed by a normal saline flush.  
Administration Instructions  
The drug will be administered by a nurse or MRI technologist who is trained on the clinical 
protocol and will be administered under the direction of the Principal Investigator.  
11.4 Supply of Study Drug at the Site 
The investigators will obtain Feraheme® and Ablavar® from the UCLA Hospital pharmacy with 
the investigational labels and the IND caution statement.  
11.5 Storage 
Feraheme will be stored at 20° to 25°C (68° to 77°F). Excursions permitted to 15° – 30°C (59° – 
86°F) and ABLAVAR will be stored up to 25°C (77°F); excursions permitted to 15-30°C.  
11.6 Study Drug Accountability 
Both Feraheme and Ablavar used in our study will be marketed product and they will be obtained 
from the UCLA Medical Center pharmacy in pre-packaged sterile vials. Any unused contrast 
agents will be disposed of according to Standard Procedures at the imaging site. 


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12 STUDY PROCEDURES AND GUIDELINES 
Prior to conducting any study-related activities, written informed consent and the Health Insurance 
Portability and Accountability Act (HIPAA) authorization must be signed and dated by the subject 
or subject’s legal representative/guardian(s).   
12.1 Clinical Assessments 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at the date of study MRI. 
Dose, route, unit frequency of administration, and indication for administration and dates of 
medication will be captured. 
Demographics  
Demographic information (date of birth, gender, race) will be recorded at Screening. 
Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory history, 
and information regarding underlying diseases will be recorded at Screening. 
Physical Examination 
N/A 
Vital Signs / Oximetry / Ventilatory Parameters 
Continuous heart rate, blood pressure, ECG, pulse oximetry, and end tidal CO2 will be monitored 
for the duration of the MRI study and until the subject is recovered or returned to the Intensive 
Care facility, or for 30 minutes after the infusion, whichever is longer.  
Adverse Events 
Information regarding occurrence of acute adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation to study 
drug will be recorded on the case report form (CRF). Each patient will be followed up via a review 
of medical record at 60 days after MRI study to capture any additional AEs.  
12.2 MRI Procedures   
12.2.1 Patient Preparation and Setup 
All patients will undergo MRI on an FDA approved, clinical 18-channel Siemens 3.0T Magnetom 
TIM Trio scanner, and running version B17 software.  The appropriate RF receiver coil 
configuration will be chosen depending on patient size; for example neonates may be studied using 
a 16 element adult knee coil, infants using an adult head-neck coil combination and older children 
using surface flex coils or a body array coil. Fixed (spine) coil elements in the patient table may 
be used in combination with any of the other coils (except the knee coil).   
 
Prior to Feraheme or Ablavar infusion, all patients will be asleep, intubated and ventilated such 
that, in the case of a clinically urgent or life-threatening AE, there will already be in place full 


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airway protection, physiological monitoring and support of respiration. Consistent with 
institutional clinical practice at UCLA, anesthesia in the pediatric CHD patients will be performed 
by specialized pediatric anesthesiologists regardless of contrast agent used (Feraheme vs. Ablavar) 
with continuous monitoring of heart rate, blood pressure, pulse oximetry, end tidal CO2, and, where 
appropriate, anesthetic gas levels (such as sevofluorane). In the case of a SAE, changes in vital 
signs will be recognized immediately and appropriate treatment initiated. All of the children in our 
study will have protected airways and mechanical ventilatory support from the start of the 
procedure to the end.  Serious adverse reactions to any agent may include laryngeal edema and 
bronchospasm, where prior endotracheal intubation may be lifesaving. Should other events occur 
involving changes in heart rate, heart rhythm and /or blood pressure, the anesthesiologist can focus 
his / her attention on the appropriate use of chronotropic or inotropic agents, intravenous fluids 
and /or vasoactive drugs, without having to secure the airway.  All patient physiological 
monitoring data are, and will continue to be, digitized and transferred in real time to the electronic 
patient medical record, where they are stored permanently and retrievably. Relevant abstractions 
from these and other patient safety data (protected health information removed) will be included 
in our DMC, IRB and IND adverse event reports.  
 
Once asleep and intubated, patients will be positioned in the appropriate receiver coils and 
monitored with ECG and with MRI compatible pulse oximetry and non-invasive blood pressure 
measurement (InVivo Medical Solutions, Inc.). The vital signs monitoring equipment will all be 
FDA approved devices. The end-tidal CO2 line will be interfaced via a three way plastic stop-cock 
to the respiratory port of the MRI physiological monitoring unit. In this way, the respiratory signal 
is split so as to provide both uninterrupted end-tidal CO2 monitoring and airway pressure signal.  
The airway pressure trace is available for use as a respiratory gating signal to compensate for 
respiratory motion artifact without interrupting patient ventilation (1).  
 
12.2.2 Contrast Agent Dose and Injection Rate  
12.2.2.1 Feraheme® Dose and Injection Rate 
Once patients are positioned and outfitted with receiver coils, venous access lines and 
physiological monitoring sensors, dilute Feraheme® will be administered by slow intravenous 
infusion to a total dose of 4 mg /kg (1,83). According to the recent FDA warning issued in March 
2015, the entire therapeutic dose (510mg of Fe) of Feraheme should be injected as a slow infusion 
over 15 min or longer. For an average adult of 75kg body weight, 510 mg corresponds to 7 mg /kg 
and a 15 min infusion time corresponds to an infusion rate of 0.45 mg /kg.min. We will infuse 4 
mg/kg of Feraheme which, at the rate suggested by the FDA, would require 8 min 30 sec to infuse. 
We will round this time up to 10 minutes for practicality and to ensure we do not exceed the 
recommended rate. The Feraheme will be diluted before injection for safety as well as practical 
reasons. The FDA warning dated March 2015 requires that Feraheme not to be injected without 
dilution to minimize risks of acute adverse reactions. The weight of patients in our study may range 
from 1kg (neonate) to 20 kg (6 year old).  For neonates or small infants, the absolute volume of 
Feraheme to be used may be < 0.5 ml, and without significant dilution, controlling infusion of this 
volume over 10 minutes would be technically impractical. The factor by which the Feraheme can 
be safely diluted will also be influenced by the patient’s physiological status. Patients with cardiac 
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For precise calibration of dose and delivery rate in the study group, the following considerations 
apply: 
 
The stock formulation of Feraheme® is an isosmolar solution containing 30 mg elemental iron 
equivalent per ml. Therefore, 4 mg of iron is contained in 0.13 ml of undiluted Feraheme®.  Total 
administered volume of undiluted Feraheme® is therefore 0.1333 ml /kg * weight in kg.  Due to 
the requirement to infuse over several minutes, the stock formulation will be diluted by a factor of 
6-30 with normal saline and infused over 10 minutes (600 secs).  This rate corresponds to an 18 
minute infusion period for a 500 mg dose of iron in a 70 kg adult and is therefore within the 15 
minute infusion guideline set forth by the FDA in March, 2015.  
 
12.2.2.2 Ablavar Dose and Injection Rate 
Each patient in the Ablavar group of our study will receive 0.03 mmol/kg of Ablavar, the FDA 
approved dose for MR angiography. The Ablavar will be diluted up to 8 fold and injected over 
15-20 seconds (86). These dose and injection rates are consistent with our current institutional 
standard practice. 
12.2.3 MRI Scanning Procedures 
As for all patients, the MRI system will perform automatic adjustment procedures to optimize the 
homogeneity of the magnetic field, customized to the individual patient.  It will also perform 
standard RF frequency adjustment of the transmitter RF field and calibration of the receiver coil 
elements.  All parameters for RF dose (SAR or specific absorption rate) and gradient switching 
rates will be within FDA approved limits and monitored continuously by permanent and 
immutable software and hardware watchdogs (Siemens product specifications on file at FDA).  
 
With the patient being ventilated continuously, the following MRI pulse sequences will be 
performed: 
 
For Study Part I, each patient (regardless of test or control group assignment) will undergo MRI 
using the following MRI pulse sequences: 1) Conventional 2D cine imaging for cardiac function 
assessment and phase-contrast MRI for flow quantification in imaging planes specified by a 
radiologist or cardiologist at the point of delivery, per our institutional standard practice regardless 
of our research protocol. These image acquisitions are necessary to ensure that each patient will 
get a diagnostic MRI study regardless the outcome of our research and will only be performed 
when the patient is considered by the supervising anesthesiologist to be stable for ventilator-
controlled breath-hold maneuvers; 2) The 3D cine ventilator-gated MUSIC-MRI MRI, based on 
which the Feraheme vs. Ablavar comparison will be performed.  
 
For Study Part II, each patient will undergo the same MRI pulse sequence as Part I of our study. 
In addition, each patient will undergo the to-be-developed self-gated MUSIC-MRI MRI and the 
order of the ventilator-gated MUSIC-MRI and the self-gated MUSIC-MRI will be randomized. 
The self-gated MUSIC-MRI pulse sequence will require an additional 5 min of scan time and 
anesthesia time without breath holding, which the investigators feel does not add significant 
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13 EVALUATIONS BY VISIT (ONLY 1 VISIT) 
13.1 Visit 1 (Day/Week/Month #) 
1. 
Clinical indication for contrast enhanced cardiovascular MRI established by discussion 
involving the referring clinician and the Investigators or designee. 
2. 
Clinical rationale for Feraheme vs. Ablavar is discussed with the patient’s legal guardian(s) 
by the Investigators or designee in Part I of the study and the patient’s legal guardian(s) are 
given the choice to choose Feraheme vs. Ablavar as the contrast agent. In Part II of the study, 
the superior contrast agent as determined in Part I of the study will be used and the benefits 
and risks of undergoing a combination of ventilator-gated MUSIC-MRI and self-gated 
MUSIC-MRI will be discussed with the patient’s legal guardian(s) 
3. 
Obtain written informed consent and HIPAA authorization and assent, if appropriate by the 
Investigators or designee. 
4. 
Assign the subject a unique screening number. 
5. 
Record demographics data. 
6. 
Record medical history, including a history of hypersensitivity reactions to iron products and 
iron overload. Screen for inclusion and exclusion criteria. 
7. 
Procedure for sedation and cardio-respiratory support discussed with the anesthesiologist or 
NICU staff by the Investigator or designee. 
8. 
Patient undergoes general anesthesia with endotracheal intubation or is transported sedated 
and intubated from the NICU. 
9. 
Record concomitant medications. 
10. 
Perform and record vital signs. 
11. 
Perform and record oximetry. 
12. 
Perform and record results of blood pressure testing. 
13. 
Contrast infusion. 
14. 
Continue monitoring and recording vital signs and oximetry up to 30 min after infusion 
15. 
MRI exam (ventilator-gated MUSIC-MRI for Part I of the study, and both ventilator-gated 
and self-gated MUSIC-MRI for Part II of the study). 
16. 
Patient recovers from anesthesia/sedation. 
It is noted that one or more of Items 1-through-7 may occur on a day different from (prior to) the 
day of the MRI study. All of these procedures will be included in ‘Visit 1’ with relevant dates as 
appropriate.   
 
14 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
14.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with the treatment.  An AE is therefore any unfavorable and unintended sign (including an 


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abnormal laboratory finding), symptom or disease temporally associated with the administration 
of an investigational product, whether or not related to that investigational product.   
The Investigator will probe, via discussion with the subject, for the occurrence of AEs during each 
subject visit and record the information in the site’s source documents.  Adverse events will be 
recorded in the patient CRF.  Adverse events will be described by duration (start and stop dates 
and times), severity, outcome, treatment and relation to study drug, or if unrelated, the cause. 
14.1.1 AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0 should be used to assess and grade AE severity, including laboratory abnormalities 
judged to be clinically significant. If the experience is not covered in the criteria, the guidelines 
shown in Table 6 below should be used to grade severity. It should be pointed out that the term 
“severe” is a measure of intensity and that a severe AE is not necessarily serious. 
Table 6.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no 
medical intervention or therapy required. The subject may be 
aware of the sign or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required, hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as 
it occurred. This does not refer to an experience that 
hypothetically might have caused death if it were more severe. 
 
14.1.2 AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the guidelines 
in Table 7. 
Table 7.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or 
expected response pattern to the suspected drug; that is confirmed by 
stopping or reducing the dosage of the drug; and that is not explained by any 
other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to the suspected 
drug; that is confirmed by stopping or reducing the dosage of the drug; and 
that is unlikely to be explained by the known characteristics of the subject’s 
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Possibly 
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to that suspected 
drug; but that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the 
study drug. 
14.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed.  
Serious Adverse Experience Reporting 
The investigators will document all SAEs that occur (whether or not related to study drug). The 
collection period for all SAEs will begin after informed consent is obtained and end after 
procedures for the study visit have been completed. In accordance with the standard operating 
procedures and policies of the local Institutional Review Board (IRB), the site investigator will 
report SAEs to the IRB.   
14.3 Medical Monitoring 
J. Paul Finn, M.D. should be contacted directly at these numbers to report medical concerns or 
questions regarding safety. 
Phone: (310) 825-0958 
 
15 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
15.1 Early Discontinuation 
A subject may be discontinued from study treatment at any time if the subject’s legal guardians or 
the Investigators feel that it is not in the subject’s best interest to continue.  The following is a list 
of possible reasons for study treatment discontinuation:  
• 
Subject withdrawal of consent  
• 
Subject is not compliant with study procedures 
• 
Adverse event that in the opinion of the investigator would be in the best interest of the subject 
to discontinue study treatment 
• 
Protocol violation requiring discontinuation of study treatment 


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• 
Lost to follow-up 
• 
Sponsor request for early termination of study 
If a subject is withdrawn from treatment due to an AE, the subject will be followed and treated by 
the Investigator until the abnormal parameter or symptom has resolved or stabilized.   
15.2 Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or the 
Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals. 
The reason for the subject’s withdrawal from the study will be specified in the subject’s source 
documents.   
15.3 Replacement of Subjects 
Subjects who withdraw from the study prior to the recording of the MRI images required for 
statistical analyses will be replaced. 
16 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigator, or Sponsor fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary endpoint 
criteria.  Protocol violations for this study include, but are not limited to, the following: 
• 
Failure to meet inclusion/exclusion criteria 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The Sponsor will determine if a protocol violation will result in withdrawal of a subject. 
17 DATA SAFETY MONITORING  
A Data Monitoring Committee (DMC) will review data relating to safety and efficacy, will conduct 
and review interim analyses, and will ensure the continued scientific validity and merit of the 
study, according to the UCLA Data Safety Monitoring Board Operations Manual. There will be at 
least 3 members, who will have no other role in the trial, including at least one expert with 
statistical expertise, one member with clinical specialty of pediatric cardiology, and one member 
with experience serving on independent data review boards. At the first meeting, held before the 
trial either face-to-face or via tele-conference, the committee will approve or revise the charter. 
The chair of the DMC will be appointed by the PI of the study.  
18 STATISTICAL METHODS AND CONSIDERATIONS 
The primary efficacy analysis of visual imaging quality will be conducted using all usable scans 
from the patients. All safety analyses will be conducted using a population defined as all patients 
undergoing study contrast-agent (Safety Population).   


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18.1 Data Sets Analyzed 
All eligible patients who receive Feraheme or Ablavar infusion as part of our study will be included 
in the data analysis. The results will be reported separately for the two contrast agents.  
18.2 Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized by treatment group and 
study part. While the study is too small to expect statistical significance in sub-groups, the efficacy 
and safety results will be examined by standard age categories (neonates (0-to-1 month of age), 
infants and toddlers (1 month to 2 years of age) and children (>2 years of age)) and any clinically 
important differences reported. 
18.3 Definition of Numeric Efficacy Outcomes 
Subjective Image Quality Scores: The image quality will be independently scored by 2 board 
certified blinded readers with >5 years of cardiovascular MRI reading experience using a 1-4 point 
scale (1). The composite image quality score for each subject will be a number between 7 (all 
subjective image quality scores are 1=non-diagnostic) to 28 (all subjective image quality scores 
are 4=clear visualization). The scores will be assessed separately for each of the following seven 
anatomical structures that are important for imaging pediatric CHD patients: the aortic root, the 
pulmonary artery (PA), the coronary arteries, the out-flow tracts, the valves, the ventricles, and the 
atria. If the difference in the composite score is greater than or equal to 4 between two image 
readers, the readers will read the image together in a consensus reading session and arrive at a 
consensus for each of the 7 structures. The criteria for assigning scores will be as follows: 1) For 
aortic root and PA, 1=nondiagnostic (vessels not visualized or diagnostically not assessable due 
to small size and /or motion artifact and /or poor contrast enhancement), 2=vessels visualized but 
with poor contrast enhancement and /or motion artifact so as to limit confident assessment and 
measurement of dimensions, 3=vessels visualized with good contrast so as to enable confident 
assessment of patency but with poor edge definition due to motion artifact so as to limit confident 
measurement of dimensions, 4=vessels visualized with good contrast and good edge definition 
such that patency and dimensions are confidently assessable; 2) For coronary arteries: 
1=nondiagnostic (vessels not visualized or diagnostically not assessable due to small size and /or 
motion artifact and /or poor contrast enhancement), 2=only origins of main coronary arteries 
confidently identifiable, 3=origins and proximal course of RCA and left anterior descending 
(LAD) confidently evaluable, 4=origin, proximal and mid courses of RCA and LAD and proximal 
takeoff of left circumflex confidently evaluable; 3) For out-flow tracts and valves: 
1=nondiagnostic (structures not visualized or diagnostically not assessable due to small size and 
/or motion artifact and /or poor contrast enhancement, 2=annulus and sinotubular junction 
visualized but borders not sufficiently well defined for confident measurement, 3=annulus and 
sinotubular junction visualized with well defined borders sufficient for confident measurement, 
4=annulus and sinotubular junction clearly visualized with well defined borders sufficient for 
confident measurement and valve leaflets clearly seen; 4) For the ventricles and atria: 
1=nondiagnostic (chambers not visualized or diagnostically not assessable due to small size and 
/or motion artifact and /or poor contrast enhancement, 2=chambers distinguishable but walls 
poorly defined and only gross features evaluable, 3=chambers clearly distinguishable with well 
defined septum and free walls confidently evaluable but with poor definition of the papillary 


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muscles and trabeculae, 4=chambers clearly distinguishable with excellent wall definition and with 
clear definition of the papillary muscles and trabeculae. 
 
Image Sharpness Values: Objective image sharpness will be measured through the interventricular 
septum and ascending aorta using a previously described method (1). The image sharpness scores 
will be measured by drawing a linear signal profile and calculating the slope of the signal intensity 
curve. The slope is defined as the image intensity difference divided by the distance between the 
two points at 20% and 80% of the dynamic range, respectively.  
 
Blood-Myocardium CNR: The blood-myocardium CNR will be measured by drawing three regions 
of interest (ROI), one at the center of left ventricular (LV) cavity, one at the interventricular septum 
and one in the background air region. The CNR will be calculated as the difference in mean signal 
intensity between the LV cavity ROI and the septum ROI divided by the standard deviation of the 
background air ROI signal.  
 
18.4 Primary Efficacy Endpoints 
18.4.1 Part I – Difference in the composite image quality score between Feraheme and Ablavar 
The primary efficacy endpoint for Part I is the composite image quality score, which is defined as 
the sum of the subject image quality scores assigned to seven important anatomical structures for 
pediatric CHD patients: the aortic root, the PA, the coronary arteries, the outflow tracts, the valves, 
the ventricles, and the atria. The score will be the average scores from all the image readers. The 
consensus reading will occur if the difference in the composite score from the same image is 4 or 
greater. The composite image quality score will be tested for normality using the Shapiro-Wilk 
and Shapiro-Francia tests. For normally distributed data, comparison will be made between the 
composite image quality scores for Feraheme and Ablavar using a parametric two-sided t-test with 
an appropriate transformation if needed. If statistical transformation of the image quality score is 
not possible, a non-parametric Wilcoxon-rank-sum test can be considered. The null hypothesis is 
that there is no difference in the composite subjective image quality scores between Feraheme and 
Ablavar. This comparison will be a two-sided test at the overall 0.05 level of significance. 
Summary statistics of mean, standard deviation and their 95% confidence intervals of each contrast 
agent and the difference will be used for statistical description. There will be a formal interim 
analysis and a primary analysis for image quality score. The primary analysis of image quality 
scores will be performed when 80 CHD subjects are enrolled and the images are scored by the 
image readers. Scores for subjective image quality, sharpness and CNR measurements will remain 
blinded from the Investigators and only the study statistician will be able to pair the contrast 
assignment and the score. 
 
[Interim Analyses]: To avoid performing a study with larger-than-necessary enrollment for Part 
I of our study, a formal interim analysis for the composite imaging score will be performed at 
approximately 20 CHD subjects for each of the contrast group (50% of the target number for the 
primary analysis). Alpha-spending for the interim analyses and the primary analysis will be 0.025 
and 0.025 (both two-sided), respectively. The overall alpha for the composite image quality score 
will be preserved at the two-sided 0.05 significance level. The interim analysis of the composite 
image quality score will be conducted by an independent statistician under the charter of the DMC. 


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The interim effect of Feraheme compared to the Ablavar of ventilator-gated MUSIC-MRI based 
on the average composite score from two image readers will be tested with a two group t-test with 
an appropriate transformation if needed. Non-parametric Wilcoxon rank sum test will be 
considered if the data are not normally distributed based on the Shapiro-Wilk and Shapiro-Francia 
tests and transformation is not feasible.  
18.4.2 Part II – Difference in the composite image quality score between ventilator-gated and self-
gated MUSIC-MRI 
The primary efficacy endpoint for Part II is the composite image quality score defined in 18.4.1. 
Data will be tested for normality using the Shapiro-Wilk and Shapiro-Francia tests.  The composite 
subjective image quality score will be compared between ventilator-gated MUSIC-MRI and the 
self-gated MUSIC-MRI using a paired t-test with appropriate transformation if needed. If the data 
are not normally distributed and transformation is not possible, a Wilcoxon-sign-rank test will be 
considered. The null hypothesis is that the mean difference in the image quality scores of the self-
gated images is smaller than or equal to the mean from ventilator-gated images with the non-
inferiority margin of – 1.75 (self−ventilator ≤ -1.75). The alternative hypothesis is that the mean 
difference in image quality score of self-gated images from the ventilator-gated images is greater 
than the non-inferiority margin of -1.75 (self−ventilator > -1.75) (see the detail of choosing the 
margin in section 18.7.2.).  
Rejection of the null hypothesis will occur if the p-value is ≤0.025. Scores for subjective image 
quality will remain blinded from the Investigators and only the study statistician will be able to 
pair the MRI pulse sequence and the score. No interim analyses will be performed in Part II of the 
study.  
18.5 Secondary Efficacy Endpoints 
18.5.1 Part I – Differences in individual image quality score (per segment or structure), image 
sharpness values, and CNR measurements for Feraheme vs Ablavar 
The secondary efficacy endpoints for Part I are the individual image quality score for each of the 
seven anatomical structures as defined in 18.3, the image sharpness values for the ascending aorta 
and the interventricular septum, and the CNR measurements for each contrast agent. Data will be 
tested for normality using the Shapiro-Wilk and Shapiro-Francia tests.  The average image quality 
scores of each anatomic structure between two readers, the image sharpness values, and the CNR 
measurements will be compared using a parametric two group t-test with an appropriate 
transformation if needed. If the data are not normally distributed and transformation is not possible, 
a non-parametric Wilcoxon-rank-sum test will be considered. Kappa statistics will be reported 
between two independent scores in each secondary endpoint. 
18.5.2 Part II – Differences in individual image quality score (per segment or structure), image 
sharpness values, and CNR measurements for ventilator-gated vs self-gated MUSIC-MRI 
The secondary efficacy points for Part II are the individual subjective image quality score for each 
of the seven anatomical structures as defined in 18.3, the image sharpness values for the ascending 
aorta and the interventricular septum, and the CNR measurements for the two MRI techniques. 
Data will be tested for normality using the Shapiro-Wilk and Shapiro-Francia tests.  The average 
image quality scores of each anatomic structure between two readers, the image sharpness values, 
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inferiority of 0.75 for the image quality scores. If the data are not normally distributed and 
transformation is not possible, a non-parametric Wilcoxon-rank-sum test will be considered. 
Kappa statistics will be reported between two independent scores in each secondary endpoint. 
18.6 Safety Evaluations 
AEs, SAEs, AEs resulting in premature withdrawal from the study, AEs of special interest 
(hypersensitivity reactions and blood pressure changes requiring intervention), and study related 
adverse events will be listed and summarized by contrast agent group. For the purpose of safety 
evaluation, the patients in both Part I and Part II who received the same contrast agent will be 
included in a single safety report. Due to the limited study cohort size and the small anticipated 
AE rates, no formal inferential statistical analyses will be performed for AEs. However, while the 
study is too small to expect statistical significance in sub-groups, the efficacy and safety results 
will be examined by standard age categories (neonates (0-to-1 month of age), infants and toddlers 
(1 month to 2 years of age) and children (>2 years of age)) and any clinically important differences 
reported. 
18.7 Sample Size and Power Estimate for the Primary Efficacy Endpoints 
18.7.1 Part I – Difference in the composite image quality score between Feraheme and Ablavar 
Sample size and power estimates are based on data from an internal pilot analysis.  Based on the 
average composite image quality scores of two independent readers, the mean image quality score 
was 25.62 with a standard deviation of 1.82 for the Feraheme-enhanced, ventilator-gated MUSIC-
MRI group. The difference in the image quality scores between two readers was a mean of -1.96 
with a standard deviation of 2.72. We expect the agreement between two independent readings 
will improve with consensus reading in cases with largely different image quality scores (4 or more 
absolute difference in the score).  
          
Based on the above preliminary analyses, for the interim analysis, a sample size of 20 in each 
contrast agent group will achieve a power of 62% to detect a difference of 1.75 (7% reduction) in 
the composite image quality scores between the Ablavar group and the Feraheme group with an 
estimated standard deviation of 2.10 in each group and a significance level of 2.5%. 
In the primary analysis, a sample size of 36 subjects will achieve a power of 90% to detect a 
difference of 1.75 (7% reduction) in composite image quality scores between the Ablavar group 
and the Feraheme group with an estimated standard deviation of 2.10 in each arm and a 
significance level of 2.5%. Taking into consideration missing data due to unusable image quality 
or incomplete studies, we plan to enroll 40 CHD subjects in each group (N=80).  
18.7.2 Part II – Difference in the composite image quality score between ventilator-gated and self-
gated MUSIC-MRI 
The quality of self-gated images are expected to be of at least equal quality to ventilator-gated 
images with a larger standard deviation due to variation in the methods of respiratory motion 
gating. We choose the non-inferior margin (87) to ensure that the upper bound of the 95% confidence 
interval (CI) for the difference between ventilator-gated and self-gated (ventilator − self-gated) is 
less than 1.75. We expect the mean of the composite image quality score for ventilator-gated 
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score.  The margin of 1.75 was derived using an expected mean of 24.75 for the self-gated image 
(~4% reduction in image quality score compared to that achieved with the ventilator-gated 
method). The non-inferiority comparison will be a one-sided test at a 0.025 level of statistical 
significance and a -1.75 margin. A sample size of 36 will achieve a statistical power of greater 
than 90% to detect non-inferiority between ventilator-gated and self-gated MUSIC-MRI using a 
one-sided t-test with a non-inferiority margin of -1.75 and a true difference of zero with a standard 
deviation of 3.0 and a significance level of 2.5%. Taking into account missing data due to unusable 
image quality or incomplete studies, we plan to enroll 40 CHD subjects. 
19 DATA COLLECTION, RETENTION AND MONITORING 
19.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject treated with the study drug.   
Study personnel will enter data from source documents corresponding to a subject’s visit into the 
protocol-specific electronic Case Report Form (eCRF) when the information corresponding to that 
visit is available. Subjects will not be identified by name in the study database or on any study 
documents to be collected by the Sponsor (or designee), but will be identified by a subject number 
and initials. 
If a correction is required for an eCRF, the time and date stamps track the person entering or 
updating eCRF data and create an electronic audit trail.   
The Investigators are responsible for all information collected on subjects enrolled in this study.  
All data collected during the course of this study must be reviewed and verified for completeness 
and accuracy by the Investigators.  A copy of the eCRF will remain at the Investigators’ site at the 
completion of the study. 
19.2 Data Management Procedures 
The data will be entered into a validated database. The Data Management group will be responsible 
for data processing, in accordance with procedural documentation. Database lock will occur once 
quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 
19.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. All changes to the study 
database will be documented. 
19.4 Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate 
backup 
copies 
of 
the 
database 
and 
related 
software 
files 
will 
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At critical junctures of the protocol (e.g., production of interim reports and final reports), data for 
analysis is locked and cleaned per established procedures. 
19.5 Availability and Retention of Investigational Records 
The Investigators will make study data accessible to the monitor, other authorized representatives 
of the Sponsor (or designee), IRB, and Regulatory Agency (e.g., FDA) inspectors upon request.  
A file for each subject will be maintained that includes the signed Informed Consent, HIPAA 
Authorization and copies of all source documentation related to that subject.  The Investigators 
will ensure the reliability and availability of source documents from which the information on the 
CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study File 
Notebook, etc.) will be kept secured for two years after the center has been notified that the IND 
has been discontinued.  There may be other circumstances for which the Sponsor is required to 
maintain study records and, therefore, the Sponsor will be contacted prior to removing study 
records for any reason. 
19.6 Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor according to the U.S. CFR 
Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).   By signing this protocol, the 
Investigator grants permission to the Sponsor (or designee), and appropriate regulatory authorities 
to conduct on-site monitoring and/or auditing of all appropriate study documentation. 
19.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a subject number and subject initials will identify 
all study subjects on CRFs and other documentation submitted to the Sponsor.  Additional subject 
confidentiality issues (if applicable) are covered in the Clinical Study Agreement. 
20 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312). 
 
Any serious, unexpected suspected adverse reactions, findings from other clinical, animal, or in-
vitro studies that suggest significant human risk, and any clinically important increases in the rate 
of a serious suspected adverse reaction will be sent to the FDA, Division of Medical Imaging 
Products, and to all investigators no later than 15 calendar days after determining that the 
information qualifies for reporting [21 CFR 312.32(c)(1)].  Additionally, any unexpected fatal or 
life-threatening suspected adverse reaction will be reported to the FDA Division of Medical 
Imaging Products no later than 7 calendar days after initial receipt of the information [21 CFR 
312.32(c)(2)].  Each submission will be addressed to the Regulatory Project Manager and/or the 
Chief, Project Management Staff for the Division. 
To maintain confidentiality, all reports, evaluation forms, and other records will be identified by a 
coded number and initials only. All study records will be kept in a locked file cabinet and code 
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another locked file cabinet.  Clinical information will not be released without written permission 
of the subject, except as necessary for monitoring by the FDA.  The Investigator must also comply 
with all applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act 
of 1996, EU Data Protection Directive 95/46/EC). 
20.1 Protocol Amendments 
Any amendment to the protocol will be written by the Investigators. Protocol amendments cannot 
be implemented without prior written IRB approval except as necessary to eliminate immediate 
safety hazards to patients. A protocol amendment intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately, provided the IRBs are notified within five 
working days. 
20.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB of the participating 
center prior to study initiation. Serious adverse experiences regardless of causality will be reported 
to the IRB in accordance with the standard operating procedures and policies of the IRB, and the 
Investigator will keep the IRB informed as to the progress of the study.  The Investigator will 
obtain assurance of IRB compliance with regulations. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning patient recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to the IRB.  
The IRBs written unconditional approval of the study protocol and the informed consent form will 
be in the possession of the Investigator before the study is initiated. This approval must refer to 
the study by exact protocol title and number and should identify the documents reviewed and the 
date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB approval except when necessary to eliminate immediate hazards to the patients or 
when the change(s) involves only logistical or administrative aspects of the study.  Such 
modifications will be submitted to the IRB and written verification that the modification was 
submitted and subsequently approved should be obtained.   
The IRB must be informed of revisions to other documents originally submitted for review; serious 
and/or unexpected adverse experiences occurring during the study in accordance with the standard 
operating procedures and policies of the IRB; new information that may affect adversely the safety 
of the patients of the conduct of the study; an annual update and/or request for re-approval; and 
when the study has been completed. 
20.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US 
Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, 
and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if 
applicable), and local regulations. 
 
The Investigator will prepare the informed consent form, HIPAA authorization prior to submission 
to the IRB.  The consent form generated by the Investigator must be acceptable to the Sponsor and 
be approved by the IRB.  The written consent document will embody the elements of informed 
consent as described in the International Conference on Harmonisation and will also comply with 


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local regulations. The Investigators will send an IRB-approved copy of the Informed Consent 
Form to the Sponsor (or designee) for the study file. 
 
A properly executed, written, informed consent will be obtained from each subject prior to entering 
the subject into the trial.  Information should be given in both oral and written form and subjects 
(or their legal representatives or legal guardians) must be given ample opportunity to inquire about 
details of the study.  If appropriate and required by the local IRB, assent from the subject will also 
be obtained.  If a subject is unable to sign the informed consent form (ICF) and the HIPAA 
authorization, a legal representative may sign for the subject.  A copy of the signed consent form 
(and assent) will be given to the subject or legal representative or legal guardian(s) of the subject 
and the original will be maintained with the subject’s records. 
20.4 Publications  
The preparation and submittal for publication of manuscripts containing the study results shall be 
in accordance with a process determined by mutual written agreement among the study Sponsor 
and participating institutions.  The publication or presentation of any study results shall comply 
with all applicable privacy laws, including, but not limited to, the Health Insurance Portability and 
Accountability Act of 1996.  
20.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when to protect the safety, rights or welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in accordance 
with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make 
those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be responsible 
for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity 
and all unanticipated problems involving risks to subjects or others (to include amendments 
and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except when necessary 
to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 
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