Novel MRI Sequence MR Fingerprinting in Breast MRI Feasibility Study
Phase: NA
Conditions: Breast Screening
Sponsor: UNC Lineberger Comprehensive Cancer Center

LCCC1853:  Novel MRI sequence- MR Fingerprinting in Breast MRI- Feasibility study 
 
NCT number NCT03846947 
Document Date October 30, 2018 

LINEBERGER COMPREHENSIVE CANCER CENTER 
Imaging Protocol Template 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
 February 2017 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
LCCC1853:  Novel MRI sequence- MR Fingerprinting in Breast MRI- Feasibility 
study  
 
 
 
Principal Investigator 
Cherie Kuzmiak (MD) 
Cherie M. Kuzmiak, DO, FACR, FSBI 
Director, Breast Imaging Division 
Director, Breast Imaging Fellowship Program 
Associate Professor of Radiology 
UNC School of Medicine 
Department of Radiology, CB #7510 
Physicians' Office Building, Rm #118 
170 Manning Drive 
Chapel Hill, NC 27599 
Office: 984-974-8123 
cherie_kuzmiak@med.unc.edu 
 
Principal Co-Investigator  
Yong Chen, PhD 
WanChen Tsai, MD 
Weili Lin, Ph.D. 
 
Sheryl Jordan, MD 
Sheila Lee, MD 
Michelle Rivera, MD 
Jozef Brozyna, DO 
Jami Lyon, DO 
Prasad Patel, MD 
David Ollila, MD 
Kristalyn Gallagher, DO 
Stephanie Downs-Canner, MD 
 
Biostatistician  
TengFei Li, PhD 
 
 
Sponsor:  University of North Carolina 
 
Funding Source:  
None 
 
 
 
 
 

LCCC1853 
 
October 30, 2018 
PI: Kuzmiak 
 
LCCC1853:  Novel MRI sequence- MR Fingerprinting in Breast MRI-Feasibility 
study  
 
 
 
 
 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal regulations 
and ICH guidelines. 
 
Principal Investigator (PI) Name:_______________________ 
 
PI Signature: ___________________ 
 
Date:____________________ 
 
Date of Protocol: October 30, 2018 
 
 
 
 

 
1 
TABLE OF CONTENTS 
 
1. 
BACKGROUND AND RATIONALE ................................................................. 3 
1.1. Study Synopsis ..................................................................................................... 3 
1.2. Disease Background ............................................................................................. 3 
1.3.   Conventional Imaging Modality ........................................................................ 4 
1.4. Investigational Imaging Modality ........................................................................ 5 
1.5. Rationale............................................................................................................... 5 
2. 
STUDY OBJECTIVES .......................................................................................... 6 
2.1. Primary Objectives ............................................................................................... 6 
2.2. Primary Endpoint ................................................................................................. 6 
3. 
PATIENT ELIGIBILITY ..................................................................................... 6 
3.1. Inclusion Criteria .................................................................................................. 6 
3.2. Exclusion Criteria ................................................................................................. 6 
4. 
STUDY PLAN ........................................................................................................ 7 
4.1. STUDY SCHEMA ............................................................................................... 7 
4.2. Study Procedures .................................................................................................. 7 
4.3. Time and Events Table ......................................................................................... 8 
5. 
INVESTIGATIONAL DEVICE  .......................................................................... 8 
5.1. Investigational Device Description ...................................................................... 8 
5.2. Expected Risks ..................................................................................................... 9 
6. 
UNANTICIPATED CONCERNS ........................................................................ 9 
6.1. Data and Safety Monitoring Plan ....................................................................... 10 

 
2 
7. 
STATISTICAL CONSIDERATIONS ............................................................... 11 
7.1. Study Design/Study Endpoints .......................................................................... 11 
7.2. Sample Size and Accrual.................................................................................... 11 
7.3. Data Analysis Plans ............................................................................................ 12 
8. 
STUDY MANAGEMENT ................................................................................... 12 
8.1. Institutional Review Board (IRB) Approval and Consent ................................. 12 
8.2. Registration Procedures...................................................................................... 13 
8.3. Data Management and Monitoring/Auditing ..................................................... 13 
8.4. Adherence to the Protocol .................................................................................. 13 
8.5. Amendments to the Protocol .............................................................................. 14 
8.6. Record Retention ................................................................................................ 14 
8.7. Obligations of Investigators ............................................................................... 15 
9. 
REFERENCES ..................................................................................................... 15 
 
 
 

 
3 
1. 
BACKGROUND AND RATIONALE 
1.1. 
Study Synopsis 
The ultimate goal of this proposed study is to evaluate potential clinical 
efficacy of a novel magnetic resonance imaging (MRI) approach, MR 
fingerprinting, capable of providing quantitative measures of important tissue 
properties, which could provide important insights into normal breast tissue.  We 
will recruit a totally of 30 patients scheduled for screening breast MRI for high 
risk normal patients.  The novel sequence, namely MR fingerprinting, will be 
added prior to the injection of MR contrast, followed by the rest of the clinical 
imaging sequences.  Quantitative maps, including T1, T2map will be computed 
from MR fingerprinting.   
1.2. 
Disease Background 
    In clinical setting, breast DCE MRI was performed for breast cancer 
staging, high risk screening, and problem solving when mammography, 
ultrasound and clinical findings were questionable. The protocol for screening 
MRI and clinical breast DCE MRI were the same. Patients were put on prone 
position with bilateral breasts fit in the dedicated breast coil. The following 
sequences will be taken: whole breast axial T1 weighted 3D SPGR, axial T2 
weighted FSE with fat saturation, followed with axial 3D T1-weighted fat-
saturated DCE MRI with one pre-contrast and three post contrast enhanced phases 
at the temporal resolution of 100 seconds followed with a high spatial resolution 
interview scan (0.9 mm isotropic 3D T1-weighted fat-saturated scan).  DCE MRI 
has high sensitivity for breast cancer detection (95%) while lack of specificity 
(37-86%) between tumor types as overlap between findings of benign and 
malignant lesions and among different breast cancer subtypes [1].  Specifically, 
DCE MRI is also a powerful tool for neoangengenesis evaluation or treatment 
response monitoring for breast cancer [2], with physio- pathologic measurements 
of the volume transfer constant (Ktrans), fraction of extracellular extravascular 
space (ve), and vascular density (vp) [3].   To obtain these pharmacokinetic 
parameters, a relation between the signal enhancement and contrast agent 
concentrations is required. The native T1 (T10) is calculated and then used to 
convert the signal enhancement curve to concentration curve [3]. The most 
commonly used method to measure T1 is variable flip angle (VFA) imaging 
which uses several short-repetition-time radiofrequency spoiled gradient-echo 
acquisitions with varying FAs [4-7]. However, the T1 measurement using VFA 
has been notified to be marked deviated up to 50% by the nonuniformity of the 
transmit radiofrequency (B1) field even in 1.5 T [8]. It would be very important to 
obtain the most accurate T10 value of breast tumor before contrast medium 
injection to calculate the most accurate pharmacokinetic parameters across 
different platform, vendors and machines.  Nevertheless, it is a daunting task to 
obtain quantitative measures of T10 independent of these potential confounding 
factors.  The current paradigm of MRI is to use a set of scanner settings to 
generate an image ‘weighted’ a specific MR contrast mechanism (physical 

 
4 
parameter), where it is hoped that variations in the parameters will be accentuated. 
However, without quantitative knowledge of the parameters, the final image 
contrast may depend on many factors, which may complicate image interpretation 
and diagnostic performance [9]. Quantitative measurement can provide a great 
deal of information about tissue properties and pathological conditions, since 
these parameters ultimately determine the contrast that is observed in 
conventional images [10]. The investigational imaging sequence, MR 
fingerprinting, could be performed in a much shorter scanning time and provide 
more accurate quantitative tissue characteristics (T1 and T2 value). 
Despite the irreplaceable roles of breast DCE MRI in clinical practice (most 
sensitive and accurate in breast cancer detection and staging, and even provide 
more insight on the perfusion and functional change in treatment response 
monitoring before the tumor size change in patient undergoing chemotherapy or 
target therapy), MRI has been pushed to its limit today. One of the principle 
limitations is that lack of quantitative information for tissue/structure 
characterization.  
MR fingerprinting could be performed in a short time to obtain more 
accurate quantitative tissue characteristics (T1 and T2 value) simultaneously 
which would largely decrease examination time (which means reduce patient 
scanning time in the MR scanner, that is decreased patient suffering time on 
examination table and decrease examination expanse of hospital). 
1.3. 
  Conventional Imaging Modality 
The clinical DCE MRI of breast have been widely used for breast cancer screening, 
detection, staging and treatment response monitoring for decades. This image modality 
outperforms mammography and ultrasound of breast in breast cancer detection and extent 
evaluation [11]. There is no radiation risk for this imaging examination. The only two 
drawbacks of this study are longer examination time and gadolinium based contrast 
medium usage. The patients need to be rested on the examination table in a fixed prone 
position (not very comfortable) with bilateral breasts been fitted in the breast coiled for at 
least 30 to 40 minutes.  
As part of the MRI procedure subjects may receive a contrast agent called gadolinium. 
Gadolinium makes it easier to see details on the MRI pictures. An extremely rare disease 
called Nephrogenic Systemic Fibrosis (NSF) is associated with the use of gadolinium 
contrast agents in patients with chronic severe renal insufficiency or renal dysfunction 
due to hepato-renal syndrome or in the peri-operative liver transplantation 
period.  Exclusion criteria for this study are in compliance with the Food and Drug 
Administration’s advisory statements.  If subjects have any problems with their kidneys, 
they may be at risk for a condition called Nephrogenic Systemic Fibrosis (NSF) or 
Nephrogenic Fibrosing Dermopathy. NSF has been reported to occur between 2 days and 
18 months following injection of gadolinium. There is no known treatment for NSF. Some 
people have even died from this. Signs and symptoms of NSF may include: burning, 
swelling, hardening or tightening of the skin, blood vessels and internal organs (heart, 
lungs, liver; yellow spots on the white part of the eyes; joint swelling and stiffness; pain 
in the hip bones or ribs; muscle weakness. 

 
5 
Subjects’ study doctor will check how well their kidneys work before they are given 
gadolinium. Depending on how well their kidneys work, they may be given a reduced 
dose or they may not be able to take gadolinium at all. NSF has not been reported in 
people with normal kidneys. 
1.4. 
Investigational Imaging Modality 
The purpose of this study is to evaluate the novel quantitative MRI techniques, 
namely MR Fingerprinting (MRF), in clinical studies to determine whether they 
can provide better, faster, and more useful tissue information for clinical 
diagnosis. The MRF does NOT require gadolinium contrast medium injection, 
and will be acquired in about 6 minutes scanning time before the clinical contrast 
enhancement examinations and 6 minutes at the end of study. This work has been 
published in Nature for its accurate quantification of proton density, T1, T2 
relaxation times in the rapid multi-parametric MR technique[12]. Pilot studies 
with scans from hundreds of patients have demonstrated that the novel method 
can provide valuable information for various diseases in brain, liver, and prostate 
[13-16]. While it has shown great promise in these previous studies, clinical 
evaluation of this technique has been limited to a few medical centers worldwide 
due to complexity in installation, implementation and post-processing of the 
technique. Dr. Yong Chen, a newly recruited faculty at Department of Radiology, 
is a key developer of the MR Fingerprinting technique[16]. In this study, we 
propose to apply this novel technique at UNC and evaluate its performance for 
different conditions of breasts. We hypothesis that the quantitative MR imaging 
technique will lead to improved tissue characterization, diagnosis and 
quantification.   
1.5. 
Rationale 
This is a feasibility study of the use of the additional MRF scanning sequence 
with a total of 12 minutes scanning time to our clinical screening breast DCE MRI 
examination before contrast medium injection and at the end of scan.  This 
additional scanning sequence may provide faster and better quantitative tissue 
characterization comparing to conventional MR sequences. There is no 
investigational contrast agent in this study. We propose that the additional MRF 
sequence may provide faster and more accurate tissue characteristics imaging for 
clinical evaluation of breast tissue. Patients will be enrolled in with scheduled 
high risk screening DCE MRI (n=30). The MR imaging will be performed in the 
clinical 1.5T MR scanners in UNC as normally done for the patients MRI 
schedule. We only add an additional MRF sequence within the MRI exam just 
prior to the contrast enhancement scan.  
    Quantitative measurement of the breast tissue will be performed after the MR 
exam. The ROI of normal breast parenchyma was recorded. The ROI will be 
saved and encoded to the T1 map, T2 map in MRF, T1 weighted imaging, T2 
weighted imaging. A large variety of imaging ROI-based quantitative 
measures will be calculated among normal glands in bilateral breasts to 
evaluate different ROI characteristics among different patients and between 
bilateral breasts in each patient.  

 
6 
    
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
The purpose of this study is to evaluate the novel quantitative MRI techniques, 
namely MR Fingerprinting (MRF), in clinical studies to establish the T1 and T2 
value baselines of normal glandular tissue.  
2.2. 
Primary Endpoint 
The normal breast tissue T1, T2 value will be used to compare between sides in 
same patient and among the different patients and between two MRF sequences in 
pre-contrast phase and post contrast enhancement phase and also the differences 
between pre and post contrast enhancement phases. 
  
3. 
PATIENT ELIGIBILITY 
3.1. 
Inclusion Criteria 
3.1.1. English-speaking patients 
3.1.2. Ages 18 to 99 years old 
3.1.3. Scheduled to undergo a screening breast MRI study  
3.1.4. Capable and willing to provide signed informed consent 
3.2. 
Exclusion Criteria 
3.2.1. Claustrophobia  
3.2.2. Presence of pacemaker, intracranial aneurysm clip, bladder stimulator, cochlear 
implant or metal near eyes or near pelvis that would create excessive imaging 
artifact 
3.2.3. Known hypersensitivity to [contrast agent] or to any component of [contrast 
agent] refractory to standard medications (antihistamines, steroids) 
3.2.4. Impaired kidney function (serum creatinine level > 1.8 mg/dl or a glomerular 
filtration rate < 60 as approximated using serum creatinine levels) unless anuric 
and on dialysis. 
3.2.5. Inability to tolerate MRI (e.g., inability to lie flat for >1 hour) 
3.2.6. Pregnancy or lactating female 
  3.2.7   Previous history of mastectomy. 

 
7 
4. 
STUDY PLAN 
4.1. 
STUDY SCHEMA 
 
4.2. 
Study Procedures 
The patients will have a set of additional research scan of no more than 12 
minutes scan time (MRF) within their primary screening breast MRI study. 
Patient will receive their standard clinical care as usual. No follow up needed for 
this observational study. 
4.2.1. Enrollment/Recruitment 
A total of 30 women will be enrolled to this study. The 30 study subjects will be 
consecutively recruited from women who are scheduled to undergo a screening 
MRI.  Eligible patients will be identified by research staff review in coordination 
with the UNC Breast Clinic.   
 
Once a patient has been referred, the patient will be approached by a coordinator 
from Radiology to assess interest in participation.  
 
All eligible women who agree to participate in the study will be asked to come to 
their MRI appointment thirty minutes early to complete the informed consent 
process.   
 
Review of the consent will take place in the privacy of an exam room, or when 
possible, a sample consent form will be sent to the patient via email prior to the 
patient’s visit to allow for ample review.   
4.2.2. Research Imaging 
4.2.2.1.Imaging Procedures 
The investigational MR protocol will be implemented on the existing MR 
scanners without any modifications to the existing, FDA approved machine, 
Patient 
Scheduled for 
screening MRI 
enrolled 
before the 
scheduled time 
Screening MRI scan 
with Investigational 
sequences before 
Contrast medium 
injection and at the end 
of scan. 
Image Review  
The image were stored 
and analyzed for ROI of 
different tissue at both 
sides of breast 
Screening MRI report 
extraction two weeks 
after  
Screening MRI report 
extraction two weeks 
after  

 
8 
equipment, or safety standards. Patients will receive their standard of care 
imaging. During the screening scan, they will receive the research sequence. The 
additional sequences will be performed at no cost to the patient other than a small 
increase in the amount of time spent inside the MR scanner. The additional 
sequences are 12 minutes in total and do not place individuals at any increased 
risk. 
4.2.3. Standard of Care Biopsy 
           Almost all of the patients undergoing screening MRI do not have breast cancer.   
No further intervention with biopsy in this screening population. There is no change of 
standard of care for the screening population. 
4.2.4. Medical Record Abstraction  
The breast MRI report will be extracted one week after completion of the MRI 
exam for confirmation of normal status. 
 
 
4.3. 
Time and Events Table 
 
 
 
Pre-study 
30 
minutes 
before 
MRI 
Time Point 
1 
At MRI 
exam 
Time Point 
2 
1 week 
After MRI 
exam 
Time Point 
3 
After 30 
cases 
completed 
MRI 
Informed Consent 
X 
 
 
 
Breast MRI with 
research MRF 
 
X 
 
 
Medical 
Record 
Abstraction  
 
 
X 
X 
Imaging analysis 
 
 
 
X 
 
*Include any necessary notes detailing specifics of procedures outlined in table. 
5. 
INVESTIGATIONAL DEVICE  
5.1. 
Investigational Device Description 
Investigational sequences will be developed at UNC. The proposed study will 
be performed on the 1.5T MR scanners: (1) Main campus Siemens Avanto, 
Invivo 7-channel; (2) Out-patient Imaging center: Siemens Magnetom Aera, 
Sentinelle Coil. The scanners are FDA approved and all new sequenced 

 
9 
possess the same safeguards as standard (FDA approved) clinical sequences to 
prevent harm to subjects. The study does not need any contrast administration 
unless it is required for standard clinical examination. For each consented 
subject, the additional scans will add no more than 12 minutes to the total 
scanning time. That is 6 minutes with two MRF sequences (3 minutes on each 
MRF sequence) pre-contrast enhancement phase and 6 minutes with two MRF 
sequences at the end of post contrast enhancement phase. 
 
The investigational MR protocol will be implemented on the existing MR 
scanners without any modifications to the existing, FDA approved machine, 
equipment, or safety standards. Patients will receive their standard of care 
imaging. In addition, they will receive the research sequence. The additional 
sequences will be performed at no cost to the patient other than a small 
increase in the amount of time spent inside the MR scanner. The additional 
sequences are no more than 12 minutes and do not place individuals at any 
increased risk. 
 
The research images will not be interpreted or analyzed for clinical decisions 
related to the patient.  As such, this study will request that the IRB make a 
determination that this study is no greater than minimal risk. This study meets 
all the requirements for an NSR determination including: 
• 
The device will not be implanted. 
• 
The device is not intended to support or sustain human life. 
• 
The device is not being used of substantial importance in diagnosing, 
curing, mitigating, or treating disease. 
• 
The device does not present a potential for serious risk to health, safety, or 
welfare of a subject. 
5.2. 
Expected Risks 
The additional sequences are no more than 12 minutes and do not place 
individuals at any increased risk. 
6. 
UNANTICIPATED CONCERNS 
6.1.1. Unanticipated Adverse Device Effect (UADE) 
The investigational device exemption (IDE) regulations define an unanticipated 
adverse device effect (UADE) as “any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects” 
(21 CFR 812.3(s)). 

 
10 
6.1.2. Unanticipated Problems (UP) 
As defined by UNC’s IRB, unanticipated problems involving risks to study 
subjects refers to any incident, experience, or outcome that: 
• Is unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document; and (b) the characteristics of the subject population being 
studied; 
• Is related or possibly related to a subject’s participation in the research; 
and  
• Suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) related 
to the research than was previously known or recognized. 
6.1.3. Reporting 
6.1.4. UADEs 
UADEs must be reported by the clinical investigator to the sponsor and the 
reviewing IRB, as described below:  
 
For this device study, investigators are required to submit a report of a UADE to 
the FDA, the manufacturer of the device and the UNC IRB as soon as possible, 
but in no event later than 10 working days after the investigator first learns of the 
event (§ 812.150(a)(1)), using the MedWatch Form 3500A.   Sponsors  must 
immediately conduct an evaluation of a UADE and must report the results of the 
evaluation to FDA, the UNC IRB, and participating investigators within 10 
working days after the sponsor first receives notice of the effect (§§ 812.46(b), 
812.150(b)(1)).  
 
For this device study, we will submit a report of a UADE to the manufacturer and 
the IRB as soon as possible, but no later than 10 working days after the 
investigators first learn of the event. 
6.1.5. UP 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB must be reported by the Study Coordinator using the IRB’s web-
based reporting system.   
 
Any unanticipated problem that occurs during the conduct of this study and that 
meets at least the first two criteria listed in section 8.2 must be reported to the 
UNC IRB using the IRB’s web-based reporting system.   
6.2. 
Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of patient safety in 
this trial with periodic reporting to the Data and Safety Monitoring Committee 
(DSMC).  

 
11 
 
Meetings/teleconferences will be held at a frequency dependent on study accrual, 
and in consultation with the study Biostatistician.  These meetings will include the 
investigators as well as protocol nurses, clinical research associates, regulatory 
associates, data managers, biostatisticians, and any other relevant personnel the 
principal investigators may deem appropriate.  At these meetings, the research 
team will discuss all issues relevant to study progress, including enrollment, 
safety, regulatory, data collection, etc. 
 
The team will produce summaries or minutes of these meetings. These summaries 
will be available for inspection when requested by any of the regulatory bodies 
charged with the safety of human subjects and the integrity of data including, but 
not limited to, the oversight (Office of Human Research Ethics (OHRE) 
Biomedical IRB, the Oncology Protocol Review Committee (PRC) or the North 
Carolina TraCS Institute Data and Safety Monitoring Board (DSMB).   
 
The UNC LCCC Data and Safety Monitoring Committee (DSMC) will review the 
study on a regular (quarterly to annually) basis, with the frequency of review 
based on risk and complexity as determined by the UNC Protocol Review 
Committee.  The UNC PI will be responsible for submitting the following 
information for review: 1) safety and accrual data including the number of study 
participants treated; 2) significant developments reported in the literature that may 
affect the safety of participants or the ethics of the study; 3) preliminary response 
data; and 4) summaries of team meetings that have occurred since the last report.  
Findings of the DSMC review will be disseminated by memo to the UNC PI, 
PRC, and the UNC IRB and DSMB.   
7. 
STATISTICAL CONSIDERATIONS 
7.1. 
Study Design/Study Endpoints 
This prospective single instituted study will enroll about 30 patients that are 
scheduled to have screening breast MRI study to have the investigational MR 
sequences in the same study schedule adding no more than 12 minutes scanning 
time. The study ends when enough number of patients collected and analyzed. 
7.2. 
Sample Size and Accrual 
Our objective is to approximate the reliability for the 3D MR Fingerprinting 
method, which can be quantified by the Intraclass Correlation Coefficients (ICC). 
Given the previous preliminary experience of Dr. Yong Chen using 3T MRI in 
Case Western Hospital, the ICC for T1 and T2  MRF are 0.82 and 0.875, 
respectively, with 12 healthy pre-menopausal volunteers scanned twice within 7-
15 days. Suppose we choose 30 normal subjects and select 2 breast tissue 
locations for both left and right breasts for each subject to obtain 120 breast tissue 
images. For each breast tissue image we have two measurements using the MRF. 
For T1, our hypothesis test is H0: ICC= 0.82 vs. H1: ICC<0.82, and the power 
will be 0.858 with significance level α =0.05 according to [17, 18], if the true 

 
12 
ICC=0.72; the power will be 0.935 with significance level α =0.05, if the true 
ICC=0.70. For T2 image, if we test H0: ICC= 0.875 vs. H1: ICC<0.875, the 
power will be 0.969 with significance level α =0.05, if the true ICC=0.775; the 
power will be 0.873 with significance level α =0.05, if the true ICC=0.80; the 
power will be 0.749 with significance level α =0.05, if the true ICC=0.815. 
Therefore, we propose 30 normal control subjects with measurements twice, to 
measure the reliability of the 3D MRF technology. The measurement will be 
evaluated for both before and after contrast enhancement. 
7.3. 
Data Analysis Plans 
 We will calculate the inter-subject and intra-subject variability and estimate the ICC and 
its confidence interval for both the T1 and T2 values of normal breast tissue between the 
two MRF sequences at pre-contrast phase, and the post contrast delayed phase, 
respectively, to establish the parameter stability between scan times. We will also 
estimate the T1, T2 value change from pre to post contrast enhancement phases to 
establish the baseline value of normal breast parenchyma at pre and post contrast 
enhancement phases. We will compare the results with previous literature [19] and 
use independent two sample t-test to check if significant difference between MRF and 
with results in previous literature does not exist. 
 
 
8. 
STUDY MANAGEMENT 
8.1. 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an 
IRBapproved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 

 
13 
8.2. 
Registration Procedures 
Study participants will be registered into OnCore®, a web based clinical research 
platform by one of the Study Coordinators. 
8.3. 
Data Management and Monitoring/Auditing 
Image datasets will be stored on a secure server in the Biomedical Research Imaging 
Center with patient identifiers removed.  De-identified copies of these may be stored 
temporarily on password-protected computers or portable hard drives for use in data 
analysis.  Quantitative data extracted from the images and results of data analysis will be 
maintained on a secure server.  All data will be archived on a password-protected 
computer in the office of the PI and backed up with a RAID system.  Datasets will be 
maintained for at least five years from the close of the study. 
8.4. 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall 
be conducted exactly as described in the approved protocol.   
8.4.1. Emergency Modifications 
UNC investigators may implement a deviation from, or a change of, the protocol 
to eliminate an immediate hazard(s) to trial subjects without prior UNC’s 
IRB/IEC approval/favorable opinion.   
 
For any such emergency modification implemented, an IRB modification form 
must be completed by UNC Research Personnel within five (5) business days of 
making the change.   
8.4.2. Single Subject Exceptions 
8.4.3. Eligibility single subject exceptions are not permitted for Lineberger 
Comprehensive Cancer Center Investigator Initiated Trials under any 
circumstances. Other types of single subject exceptions may be allowed if 
proper regulatory review has been completed in accordance with 
Lineberger Comprehensive Cancer Center’s Single Subject Exceptions 
Policy. Other Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance meets 
any of the following criteria:  

 
14 
• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs please follow the guidelines below: 
 
Protocol Deviations: UNC personnel will record the deviation in OnCore®, and 
report to any sponsor or data and safety monitoring committee in accordance with 
their policies.  Deviations should be summarized and reported to the IRB at the 
time of continuing review. 
 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB 
online mechanism used to report Unanticipated Problems.   
 
Unanticipated Problems: 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB must be reported by the study team using the IRB’s web-based 
reporting system.   
8.5. 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be 
originated and documented by the Principal Investigator at UNC.  It should also 
be noted that when an amendment to the protocol substantially alters the study 
design or the potential risk to the patient, a revised consent form might be 
required.   
 
The written amendment, and if required the amended consent form, must be sent 
to UNC’s IRB for approval prior to implementation.  
8.6. 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial must be retained by the 

 
15 
study investigator.  In the case of a study with a drug seeking regulatory approval 
and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on 
Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this 
investigational study. 
8.7. 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study participants.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study 
staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion. 
9. 
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