Advanced MRI Applications for Mild Traumatic Brain Injury-Phase 2
Phase: NA
Conditions: Concussion, Traumatic Brain Injury
Sponsor: GE Healthcare

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Study Title: Advanced MRI Applications for Mild Traumatic Brain 
Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Revision/Amendment: 4.0 
Version Date: 14/Nov/2016 
 
 
 
 
 
Confidentiality Statement 
This protocol is provided for conducting a research study. The information contained in this document is confidential 
and, except to the extent necessary to obtain informed consent or EC/IRB approval, cannot be disclosed unless 
required by governmental regulation. Persons to whom any portion of the contents of this document is disclosed must 
be informed that the information is confidential and may not further be disclosed by them. 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
GEHC Study Number: 114-2015-GES-0017 
Revision/Amendment: 4.0 
Version Date: 14/Nov/2016 
 
 
Investigator’s Signature Page 
I hereby agree to: 
(i)   Conduct the investigation in accordance with the agreement, the investigational plan, applicable FDA or 
applicable government regulations, and conditions of approval imposed by the reviewing Ethics 
Committee, IRB or governing regulatory body; 
(ii)  Supervise all testing of the device involving human subjects; and 
(iii) Ensure that the requirements for obtaining informed consent are met. 
 
 
  
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
Print Name 
 
 
 
Site Name 
 
Site Address 
 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Table of Contents 
This document contains the following sections: 
Topic 
Page 
Investigator’s Signature Page ................................................................................................................... 2 
Table of Contents ..................................................................................................................................... 3 
Document and Version Control ................................................................................................................ 5 
Study Synopsis ......................................................................................................................................... 6 
1. Preliminary Investigations and Justification ...................................................................................... 8 
1.1. 
Literature Review ....................................................................................................................... 8 
1.2. 
Background on Clinical Evaluations for mTBI ............................................................................ 9 
1.3. 
Pre-Clinical Trials and Previous Clinical (human) Experience .................................................... 9 
2. Research Device ...............................................................................................................................10 
2.1. 
Identification and Description of Devices ................................................................................ 10 
2.2. 
Regulatory Status ..................................................................................................................... 11 
2.3. 
Device Risk Analysis ................................................................................................................. 11 
2.4. 
Device Accountability .............................................................................................................. 12 
3. Objectives of Research Study ...........................................................................................................13 
3.1. 
Study Objectives ...................................................................................................................... 13 
3.2. 
Study Endpoints ....................................................................................................................... 13 
4. Design of Research Study .................................................................................................................13 
4.1. 
Research Study Design and Rationale...................................................................................... 13 
4.2. 
Type of Research Study ........................................................................................................... 14 
4.3. 
Controls and Minimization of Bias ........................................................................................... 14 
5. Study Subjects ..................................................................................................................................15 
5.1. 
Number of Subjects ................................................................................................................. 15 
5.2. 
Subject Population ................................................................................................................... 17 
5.3. 
Protection of Vulnerable Subjects ........................................................................................... 17 
5.4. 
Inclusion and Exclusion Criteria ............................................................................................... 18 
5.5. 
Concurrent Enrollment ............................................................................................................ 21 
5.6. 
Screening Subjects for Enrollment ........................................................................................... 21 
6. Procedures for Research Study ........................................................................................................21 
6.1. 
Quality Procedures .................................................................................................................. 21 
6.2. 
Volunteer (Segment 0) Procedures ......................................................................................... 22 
6.3. 
mTBI Subject and non-mTBI Control (Segment 1 and 2) Procedures ...................................... 23 
6.4. 
MR Data Post-Processing (Imaging Laboratory Procedure) ..................................................... 26 
6.5. 
Withdrawal and Discontinuation Criteria ................................................................................ 27 
7. Training Plan ....................................................................................................................................27 
7.1. 
Training Plan for Research Device ........................................................................................... 27 
7.2. 
Training Plan for Protocol ........................................................................................................ 28 
8. Data Analysis and Statistics ..............................................................................................................28 
8.1. 
Overview .................................................................................................................................. 28 
8.2. 
Statistical Analysis Methods .................................................................................................... 29 
9. Deviations ........................................................................................................................................29 
9.1. 
Management of Protocol Deviations ....................................................................................... 29 
10. Complaint Handling and Adverse Event Reporting ...........................................................................30 
10.1. 
Foreseeable Adverse Events and Device Effects...................................................................... 30 
10.2. 
Adverse Event Definitions ........................................................................................................ 31 
10.3. 
Management of Adverse Event Reporting .............................................................................. 32 
10.4. 
Management of Serious Adverse Event and Unanticipated Adverse Device Effect Reporting 32 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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10.5. 
Management of Device Deficiencies/Complaints .................................................................... 33 
11. Early Termination or Suspension ......................................................................................................33 
11.1. 
Criteria for Early Termination or Suspension ........................................................................... 33 
11.2. 
Withdrawal of EC/IRB Approval ............................................................................................... 33 
12. Ethics Committee (EC) and Regulatory Filings ..................................................................................34 
12.1. 
Ethics Committee Approval Requirements .............................................................................. 34 
12.2. 
Management of Protocol Revisions/Amendments.................................................................. 34 
12.3. 
Informed Consent and Privacy Requirements ......................................................................... 34 
13. Data and Quality Management ........................................................................................................34 
13.1. 
Management of Data ............................................................................................................... 34 
13.2. 
Subject De-identification ......................................................................................................... 35 
13.3. 
Completion of Case Report Forms (CRFs) ................................................................................ 35 
13.4. 
Record Retention at the Site.................................................................................................... 36 
14. Monitoring Plan ...............................................................................................................................36 
14.1. 
Interim Data Reviews ............................................................................................................... 36 
14.2. 
Brief Description ...................................................................................................................... 36 
14.3. 
Reference to Approved Monitoring Plan ................................................................................. 36 
15. Publication Policy .............................................................................................................................37 
16. Additional Study Materials/References ...........................................................................................38 
16.1. 
Abbreviations and Terminology ............................................................................................... 38 
References ............................................................................................................................................. 40 
Appendix 1 – Study Site and Investigator List .........................................................................................42 
Appendix A – Segment 0 Volunteer Scan Log ..........................................................................................44 
Appendix B – fMRI QA Completion log ....................................................................................................46 
Appendix C – Screening Axis I/II Disorders (Exclusion Criteria) ...............................................................47 
Appendix D – Detail of Post-processing assessment modules .................................................................48 
Appendix E – Data collection by study visit .............................................................................................50 
Appendix F – Amendment to Protocol Version 1.0 to 2.0 ........................................................................54 
Appendix G – Amendment to Protocol Version 2.0 to 3.0 .......................................................................60 
Appendix H – Amendment to Protocol Version 3.0 to 4.0 .......................................................................73 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Document and Version Control 
This section records all changes made to the protocol for a specific study. In the table below, record each 
and every relevant change by indicating what changes were made. 
Revision 
Date 
(DD/Mmm/YYYY) 
Revision Author 
Comments/Changes 
1.0 
01/Jul/2015 
Angela Johnson 
Clinical writer – Draft finalized based on 28-29/May GE-
NFL Medical Advisory Board (MAB) and GEHC internal 
reviewer comments. 
2.0 
28/Sep/2015 
Angela Johnson 
Clinical writer – Revised as per APPENDIX F – 
AMENDMENT TO PROTOCOL VERSION 1.0 TO 2.0. 
3.0 
26/May/2016 
Angela Johnson 
Clinical writer – Revised as per APPENDIX G – 
AMENDMENT TO PROTOCOL VERSION 2.0 TO 3.0. 
4.0 
14/Nov/2016 
Angela Johnson 
Clinical writer – Revised as per APPENDIX H – 
AMENDMENT TO PROTOCOL VERSION 3.0 TO 4.0. 
 
 
 
 
 
 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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STUDY SYNOPSIS 
Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Research Type:  Clinical (human)     
  parallel segments of mTBI patients and non-TBI volunteers aged 
≥15 and ≤50 years old at the time of enrollment 
Investigators/ Study Sites:1 Up to nine (9) sites may be included in this study, as listed in Appendix 1 – Study Site 
and Investigator List. 
Study Sponsor:  GE Healthcare (GEHC) 
Sponsor Contact: John Strohmeyer, Senior Clinical 
Affairs Project Manger 
Address:  
3000 N Grandview Blvd 
Waukesha, WI 53188  
Telephone:  +1-609-865-7423 
E-mail: 
John.Strohmeyer@ge.com  
Research Manager Name:  
Amy Gallenberg 
Clinical Study Program Manager, 
GE/NFL Head Health Initiative  
Address: 
3200 N Grandview Blvd 
Waukesha, WI 53188  
Telephone:  +1-262-409-0704 
E-mail:  
Amy.Gallenberg@med.ge.com  
Medical Monitor Name:  
Victor Miranda, MD 
Executive Medical Director 
Address: 
 3000 N Grandview Blvd 
 Waukesha, WI 53188 
Telephone:  +1-262-544-3633 
E-mail:  
Victor.Miranda@ge.com  
Brief Description of Study Purpose: This data-driven study is being conducted for hypothesis generation in 
population of mild traumatic brain injury (mTBI) patients using advanced applications for magnetic resonance 
imaging (MRI) developed by the Sponsor, GE Healthcare (GEHC), and corresponding clinical neuropsychological 
assessments. This data is intended for future use in development of specialized MR acquisition, reconstruction, 
and processing software intended to identify mTBI biomarkers. 
Summary of Study Procedures: 
Clinical Site Procedures: Two parallel subject segments will be enrolled, including (1) mTBI patients with recent 
injury in Segment 1 and (2) subjects without recent TBI injury of similar age and demographic characteristics 
(non-TBI controls in Segment 2). Baseline health information, demographics, and medical history (including prior 
TBI injury) will be collected for both segments. 
Subjects will attend up to four sequential visits relative to injury date (mTBI subjects) or first study scan date 
(controls): Visit 1 = ≤72 hr, Visit 2 = 7±2 days, Visit 3 = 14±2 days, and Visit 4 = 90±7 days. The mTBI subjects 
(Segment 1) may start at Visit 1 or Visit 2. Each visit will include a clinical neuropsychological assessment battery 
and MR scan with GE Research Pack II (including research sequences and clinically useful T1, T2, Flair, and 
reconstructed SWI and DTI) will be evaluated by the site. 
Laboratory Procedures: Clinically acquired MR data (DICOM, P-files, and auxiliary files) will be transferred to an 
imaging laboratory for GE Research Pack II reconstruction of clinically useful views using multiband technology 
and study post-processing. Post-processed data and evaluations (as indicated on a per-module basis by the 
Sponsor) will be collected.  
 
FOOTNOTES CORRESPONDING TO NUMERALS IN THE TEXT 
 
1 The University of Michigan Site (originally Site 007) is removed due to non-participation.  

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Number of Subjects: Data will be collected for two groups (segments) of subjects: (1) mTBI subjects in Segment 
1; and (2) non-mTBI controls in Segment 2. The target of the study is to collect at least 210 complete datasets 
from mTBI patients and at least 105 complete datasets from control subjects. Accounting for all possible reasons, 
attrition is estimated at 40%. Thus, a maximum of 350 mTBI subjects and 175 non-TBI controls may be enrolled 
across all sites. While it is expected that sites should enroll approximately equal numbers of subjects, if possible, 
all sites are encouraged to accrue eligible mTBI subjects as rapidly as possible on an ongoing basis until the 
maximum number of subjects across all sites is reached. Thus, it is prospectively expected that per-site accrual 
may vary based on actual enrollment rates. 
Additionally, up to 10 volunteers without mTBI injury and not requiring urgent medical care (Segment 0 volunteer 
subjects) may be enrolled per-site for training and retraining purposes on study devices. 
Each site should enroll approximately half as many control subjects as mTBI subjects that complete two 
consecutive visits and thus provide two consecutive data points (complete either Visits 1 and 2, or Visit 2 and 3), 
e.g., one control may be enrolled for every two mTBI subjects. A report of mTBI subject enrollment will be 
generated by the Sponsor or its delegated contract research organization (CRO) and provided to the site on a 
monthly basis (30±7 days). The report will categorically detail the number of mTBI subjects completing at least 2 
visits based on (in order of priority) gender, age, handedness, highest educational level, and MR system used (if 
more than one system used at the site) as detailed in Section 5.1.1. Enrollment of non-mTBI controls. 
Controls are required to attend Visits 1 and 4, but may also attend Visit 2 and 3 when available. Per site, controls 
should be enrolled in a manner that achieves the same overall ratio within each characteristic category as the 
mTBI population that has completed two visits to date (per site, all mTBI patients enrolled from study start to 
date of monthly summary analysis), with the priority detailed in Table 2 of this protocol.  
 
Device/Product GEHC Modality: Magnetic Resonance (MR) 
Device/Product Description: 
The device under study is the GE Research Pack II advanced MRI application suite developed by the Sponsor, GE 
Healthcare (GEHC), which consists of acquisition software executable on commercially available Discovery MR750 
3.0T/Discovery MR750w 3.0T MR scanners and software for multiband image reconstruction and post-processing 
features (volumetry, Kurtosis, RS fMRI, RSI, and, as applicable, further advanced modules) executable on 
commercially available image processing workstations. GE Research Pack II is optimized for use with the 
investigational 32-channel head coil for 3.0T GE scanners (Nova Medical). 
Site-owned Discovery MR750 3.0T and/or MR750w 3.0T scanners with research coils will be used for acquisition, 
and commercially available VolumeShare 5 Advantage Workstations (AW) will be used for reconstruction and 
post-processing. Conventional accessory/ancillary devices, such as alternative MR coils, padding, communication, 
and safety devices may be provided by the site for use in this study (or by the sponsor, if unavailable for use at 
any investigational site).  
Regulatory Status:  
Pre-Market 
   GE Research Pack II and the 32-channel head coil for 3.0T MR systems (Nova Medical) are 
investigational medical devices. When used in conjunction with GE Research Pack II, the 
Discovery MR750 3.0T/MR750w 3.0T MR scanners, conventional coils, VolumeShare 5 
Advantage Workstation (AW), and other accessory/ancillary devices used in the study are 
considered investigational devices. 
Post-Market 
  
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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1. PRELIMINARY INVESTIGATIONS AND JUSTIFICATION 
1.1. Literature Review 
Over 1.1 million traumatic brain injuries (TBI) occur in United States emergency departments 
annually, including 50,000 fatalities and 43.4% chronic disability. 1 Up to 31.6% of the global 
population will experience TBI during their lifetime. 1 , 2 In particular, mild TBI (mTBI) occurs in about 
100-300 of 100,000 hospital-treated TBI cases, though actual occurrence in the general population 
is expected to be above 600/100,000, though many may fail to seek treatment despite potential 
long-term effects. 3 Cases of mTBI are particularly common in the military, sports, and among 
motorcyclists and bicyclists, posing a major public health concern worldwide. 4 Thus improved 
diagnostic and prognostic methods are necessary.  
Historically, mTBI has been treated as an “event” perceived to have little or no lasting effect on 
central nervous and organ systems. 5 Growing awareness of potential long-term impact of mTBI has 
based on recent reports of unexpectedly prolonged injury and subsequent identification of cerebral 
biomarkers and anatomical abnormalities has fostered awareness of mTBI, particularly in 
professional sports and the military. 6, 7 Currently, TBI injuries are commonly categorized by severity 
as mild, moderate, or severe based on the length of loss of consciousness (LOC), alteration of 
consciousness (AOC), or post-traumatic amnesia (PTA). 7 However, optimal and practicable routes 
for describing the interrelated factors in mTBI that play a role in clinical diagnosis, management, 
and outcomes of mTBI among the general population remain unclear. 
While biomarkers of more severe forms of TBI are often readily apparent, mTBI is extremely 
heterogeneous and complex and often difficult to detect. 8 Many clinicians and researchers now 
recognize that minute abnormalities following mTBI can result in potentially serious and adverse 
chronic conditions, including sleeping abnormalities, cognitive impairments, post-traumatic stress 
syndrome, increased suicide risk, depression, anxiety, and other neuropsychological effects. 2 
Furthermore, patients recovering from mTBI have different cognitive symptoms and white matter 
injury at different time points relative to injury, potentially indicating compensatory mechanisms or 
plasticity in response to injury. 9, 10  
Comprehensive characterization of mTBI pathophysiology using modern technologies, such as 
contemporary advanced magnetic resonance imaging (MRI) systems can provide precise 
information on brain injury magnitude and location. Unlike computed tomography systems, which 
are less costly but have limited usefulness in mTBI due to relatively low sensitivity to diffuse brain 
damage, MRI can detect characteristics of regional brain abnormalities necessary for diagnostic and 
prognostic decision-making. 8 , 11, 12  Using advanced MRI pulse sequence and parameter settings, 
optimized gradient pulses have the potential to yield critical information about cerebral injury, 
ranging from volumetric and structural data to specific information on neural tract function and 
metabolite concentrations.  Significant scientific advancements, however, will be required before 
MRI can provide extensive and reliable data required to diagnose and predict progression of mTBI. 
This exploratory study is conducted to aid in identifying correlations between mTBI imaging and 
symptoms that can help to improve advanced MRI applications for brain injury developed by the 
Sponsor, GE Healthcare. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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1.2. Background on Clinical Evaluations for mTBI 
The challenge of drawing relationships between cerebral abnormalities observed using MRI and 
clinical symptoms remains one of the most pressing issues in modern mTBI research. This issue is 
complicated by the lack of standardization in clinical neuropsychological assessments tools for mTBI 
and the heterogeneity of injury. Notably, numerous different tools have been developed for 
assessing concussion immediately following military injury (“blast concussion assessments”) and 
immediately following injury in sports (“sideline concussion assessments”). Different organizations, 
however, have reached very different conclusions on which tool is optimal, and no universal 
consensus on the optimal tool has been reached. A comprehensive review by McLeod and Leach 13 
(2012) compared self-report concussion scales/checklists from 290 original articles published 
between 1995 and 2008 identified over 20 tools commonly cited in mTBI literature, and a number 
of additional commercial tools that are now available. Notably, McLeod and Leach 13 also report 
that very few of these tools were created in a systematic manner that follows scale development 
processes and published psychometric properties. 
Efforts to standardize tools for clinical diagnosis and management of mTBI include the Military 
Acute Concussion Evaluation (MACE) and US Department of Defense Instruction (DoDI) 6490.11 14  
and numerous commercially available questionnaires and tests. In research, one of the most widely 
used standardized tools for mTBI assessment is the National Institutes of Health (NIH) National 
Institutes of Neurological Disorders and Stroke (NINDS) Common Data Elements (CDE), a set of 
multiple domain assessments for collection of clinical and imaging information from diverse TBI 
patients. 15 The first set of CDEs was developed in 2010 and was well-suited for hospital-based 
studies of acute TBI in adults. To broaden the utility of the TBI CDEs, experts were asked to update 
the recommendations to make them relevant to all ages, injury severity, and phases of recovery. 
The second version of the TBI CDEs (v.2) were developed in 2012 and were organized based on four 
major study types of epidemiological research: acute injury, hospitalized patients, studies of the 
rehabilitation for moderate/severe TBI, and mild TBI/concussion research. Many of the CDEs will 
overlap across study types, which allows for comparisons and meta-analysis across studies. This 
consistency also allows for continuity across disease areas, enabling increased efficiency and 
effectiveness of clinical research studies and clinical treatment, increasing data quality, facilitating 
data sharing, and helping educate new clinical investigators. 15 
1.3. Pre-Clinical Trials and Previous Clinical (human) Experience 
This study design is informed by preliminary results of three prior GEHC sponsored clinical studies 
conducted under the GE-NFL Head Health Initiative in 2014-2015 (GEHC Sponsored study Nos. 114-
2013-GES-0017; 114-2014-GES-0001, and 114-2014-GES-0046; GEHC Internal MWS DOC1461400, 
DOC1499099, and DOC1564473). Prior trials suggest that MR information derived from diffusion 
(specifically kurtosis measures), fMRI, arterial spin labeling (ASL), volumetry, and other measures 
may correlate with cognitive assessments and biomarkers of mTBI severity and progression. In 
addition, outcomes of the TRACK-TBI Multicenter Initiative sponsored by the National Institute of 
Neurological Disorders and Stroke (NINDS No. RC2NS069409) and the NCAA-DoD Grand Alliance 
joint venture sponsored by the Department of Defense (DOD) and National Collegiate Athletic 
Association (NCAA) support the growing interest and body of knowledge regarding clinical use of 
mTBI MRI applications. 16, 17 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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2. RESEARCH DEVICE 
2.1. Identification and Description of Devices  
2.1.1. GE Research Pack II Advanced MRI Application Suite 
GE Research Pack II is an advanced MRI application suite developed by the Sponsor, GE Healthcare 
(GEHC), consisting of acquisition software executable on Discovery MR750 3.0T/Discovery MR750w 
3.0T MR scanners. The software enables routine reconstruction of images using multiband 
technology as well as study-specific post-processing of other types of information not typically 
found in clinical images.  GE Research Pack II will include a comprehensive set of post-processing 
modules (volumetry, Kurtosis, RS fMRI, RSI, and, as applicable, further advanced modules) 
executable on VolumeShare 5 Advantage Workstations (AW). Acquisition includes pulse sequences 
and corresponding interface software to define radio frequency (RF), gradient pulses, and 
associated parameters to optimally shape gradient waveforms when used in conjunction with head 
coils. Echo time as well as imaging parameters for contrast and other characteristics have been 
enhanced for optimal results in mTBI based on commercially available MR sequences, including a 
variety of advanced modules like functional MRI (fMRI), transit time mapping (TT mapping), 
enhanced arterial spin labeling (eASL), 3D-enhanced T2* weighted angiography (eSWAN), and fluid 
attenuated inversion recovery (FLAIR), as well as specialized T1 and T2 sequences. To maintain and 
calibrate systems and for training, routine MR accessories such as MR imaging phantoms, may be 
used in this study. 18, 19  
2.1.2. 32-channel Multiband MR Brain Coil 
The 32-channel multiband MR brain coils are designed to speed up scan time with parallel imaging. 
GE Research Pack II is optimized for the 32-channel MR brain coil for GE 3.0T (Nova Medical, 
Wilmington, Massachusetts, USA). 20 It has high-sensitivity and ASSET performance, minimal noise, 
fast acceleration rates, and similar construction as conventional coils. Other commercially available 
MR coils may be used during this study in cases where the participant cannot be scanned with the 
research coil, as described in the study procedure. 
2.1.3. Discovery MR750 3.0T/Discovery MR750w 3.0T MR scanners 
Discovery MR750 3.0T/Discovery MR750w 3.0T MR scanners are whole-body magnetic resonance 
scanners indicated for diagnostic imaging, spectroscopic imaging, parametric mapping, and/or 
spectra, dynamic imaging of body structures/functions, including head and neck. Per site practice, 
routine accessory/ancillary devices may be used, i.e. padding, hearing protection, communication, 
and safety devices. DV24 or current software will be used. 
2.1.4. VolumeShare 5 Advantage Workstation (AW) 
Post-processing is completed on a VolumeShare 5 Advantage Workstation (AW), which supports 
image display, manipulation, reconstruction, post-processing, and selective recording and is 
intended to be used to create and review diagnostic evidence related to radiology procedures by 
trained and licensed physicians and/or qualified clinical/medical personnel.   

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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2.2. Regulatory Status 
Discovery MR750 3.0T and/or Discovery MR750w 3.0T scanners, VolumeShare 5 Advantage 
Workstation (AW), MR phantoms, and conventional MR accessory and ancillary devices used in this 
study, including conventional MR coils, are commercial devices cleared by the US Food and Drug 
Administration (FDA). These devices are not indicated specifically for mTBI use and may be used in 
combination with investigational devices and components as part of this study, and are thus 
treated as investigational devices for research purposes.  
GE Research Pack II, including its acquisition and software (multiband reconstruction and post-
processing components), and the 32-channel multi-band MR brain coil for GE 3.0T (Nova Medical) 
are investigational MRI system components that are not currently cleared by the US FDA.  
2.2.1. Device Classification and Rationale 
Discovery MR750 3.0T and/or Discovery MR750w 3.0T scanners are considered Class II magnetic 
resonance diagnostic device per 21 CFR §892.1000. MR Coils are considered to be Class II 
components of a magnetic resonance diagnostic device, per 21 CFR §892.1000. The VolumeShare 5 
workstation is considered to be a Class II Picture archiving and communications system per 21 CFR 
§892.2050. 
2.3. Device Risk Analysis 
Eligible subjects will be required to satisfy site MR safety screening requirements and will then 
undergo MR scanning with the GE Research Pack II executed on commercial MR systems using the 
research 32-channel MR brain coil (or alternative commercial coil, in the event that that head size, 
medical conditions, deformities, anxiety, or other medical issues prevent use of the research coil). 
The investigational software and MR coil are optimized for technical performance and have similar 
safety profiles to those found in routine MRI imaging use in clinical settings. All scanning will be 
conducted using static field strengths of 3.0T or less. To mitigate risk to levels as low as reasonably 
practicable (ALARP), the study will employ MR safety methods in accordance with the 2013 ACR 
Guidance Document on MR Safe Practices (J. Magn. Reson. Imaging 2013;37:501–530). 21 
Foreseeable adverse events and device effects are described in Section 10.1. - Foreseeable Adverse 
Events and Device Effects are not expected to exceed those posed by conventional clinical exams 
on 3.0T MR systems. 
2.3.1. Risk Category/Rationale 
The MRI systems with GE Research Pack II and research coil under study are considered to be non-
significant risk devices per the 21 CFR §812.3 definition, as it: 
1) is not intended as an implant;  
2) is not purported or represented to be for a use in supporting or sustaining human life;  
3) is not for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, 
or otherwise preventing impairment of human health; and 
4) does not otherwise present a potential for serious risk to the health, safety, or welfare of a 
subject.  

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
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Protocol: 4.0 
 
 
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Furthermore, according to the US FDA Criteria for Significant Risk Investigations of Magnetic 
Resonance Diagnostic Devices Guidance for Industry and FDA Staff, 22 use of MRI devices in this 
study does not meet the operating conditions of significant risk for MR studies.   
2.4. Device Accountability 
2.4.1. Issuance of Devices to Clinical Sites 
One or more Discovery MR750 3.0T/Discovery MR750w 3.0T series MR scanners will be provided 
by the investigational sites. Sites may also provide conventional and commercially available MR 
accessory/ancillary devices for study use (such as imaging workstations, padding, coils, 
communication devices, and protective equipment), in accordance with standard site practices. In 
the event that any site does not have conventional ancillary/accessory devices available as required 
to complete study procedures, these may be provided by the Sponsor. 
The Sponsor will provide, install, and configure GE Research Pack II acquisition software on site-
provided MR systems. The Sponsor may also provide necessary investigational MR coils, imaging 
phantoms, and accessory/ancillary devices for study use (such as imaging workstations, padding, 
coils, communication devices, and protective equipment), if not already available for use at the 
investigational site. The unique identification information for study devices will be recorded. 
2.4.2. Issuance of Devices to Imaging Laboratories 
If not already available at laboratories executing GE Research Pack II software, the Sponsor may 
provide VolumeShare 5 Advantage Workstation (AWs) for study use. The unique identification 
information for study devices will be recorded. 
The Sponsor will provide, install, and configure GE Research Pack II software on these workstations, 
and, as deemed necessary by the Sponsor, provide training for the use, quality check, and 
maintenance of these devices. 
2.4.3. Labeling of Research Devices 
Research devices will be clearly labeled as investigational devices limited to by Federal (or United 
States) law to investigational use in accordance with per 21 CFR §812. 
2.4.4. Device Disposition  
At the end of the study, all components of the GE Research Pack II and identifiable subject 
information will be removed and/or uninstalled from study devices through manual or self-expiry 
procedures, and Sponsor-provided research devices will be returned to the Sponsor or 
dispositioned in accordance with applicable laws and regulations. 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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3. OBJECTIVES OF RESEARCH STUDY 
3.1. Study Objectives 
3.1.1. Primary Objective 
This data-driven study is being conducted for hypothesis generation in population of mTBI patients 
using advanced applications for magnetic resonance imaging (MRI) being developed by the 
Sponsor, GE Healthcare (GEHC), and corresponding clinical neuropsychological assessments. 
Acquired data are intended for future use in development of specialized MR acquisition, 
reconstruction, and processing software intended to identify biomarkers of mild traumatic brain 
injury (mTBI). 
3.1.2. Safety Objective: 
Type, incidence, severity, and relatedness to device of adverse events (AEs) will be recorded during 
active study participation, from when subject enters the MR scanning area until leaving the 
scanning area at each visit (not followed between visits). 
3.2. Study Endpoints 
3.2.1. Primary Endpoint 
Per-subject, per-visit collection of data elements from clinical sites (as detailed in Appendix E –Data 
Collection by Study Visit), including: 
1) GE Research Pack II MR image data (DICOM, P-files, and auxiliary files) 
2) Clinical neuropsychological assessment battery results 
3.2.2. Safety Endpoint: 
Type, incidence, severity, and relatedness to device of adverse events (AEs) 
4. DESIGN OF RESEARCH STUDY 
4.1. Research Study Design and Rationale 
This is an open-label, non-randomized, prospective, multi-site, parallel group (segment), 
hypothesis-generating study designed to collect data that will aid in future scientific and 
engineering exploration of correlations between clinical neuropsychological assessments and GE 
Research Pack II advanced MR imaging in mTBI patients. The results are primarily intended for 
scientific inquiry and engineering development purposes, and may be used in future regulatory 
submissions.  
Hypothesis-generating studies are designed to provide preliminary data for discovering possible 
leads worthy of further research study. 23 While hypothesis-testing studies are the gold standard of 
clinical research, the quality of such studies depends crucially on using informed “building blocks” 
of hypothesis-generating studies that generate pilot and feasibility data. 24 Hypothesis-generating 
studies are essential precursors to the development of future hypothesis-testing studies. 24 A 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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hypothesis-generating study is a widely accepted type of research study commonly performed as 
the first clinical step in pharmaceutical and medical device programs. 23  
4.2. Type of Research Study 
Open-Label 
 
There is a single study procedure, and both subjects and operators are 
aware of the procedure (no blinding) 
Blinded  
 
 
Double-Blinded 
 
 
 
Single-site  
 
 
Multi-site 
 
This study plans to include up to nine (9) sites 
Randomization 
Procedure: 
 
 
Not randomized: 
 
Consecutive mTBI subjects will be enrolled  
Single arm 
 
 
Comparator 
 
 
 
Parallel 
 
There are two parallel segments (mTBI patients in Segment 1 and non-
TBI controls in Segment 2)  
Crossover 
 
 
Prospective 
 
Data is prospectively collected  
4.3. Controls and Minimization of Bias 
Consecutive eligible mTBI subjects will be enrolled until the target enrollment is reached in order to 
minimize selection bias. The control population will be enrolled with characteristics that closely 
resemble those of the mTBI population, as defined by an analysis of the mTBI population 
completing two or more visits to-date on a monthly basis. Because the population is intentionally 
broad in this hypothesis-generating study to encompass a wide cross-section of the general clinical 
mTBI population, there may be confounders for testing specific correlates, which should be 
considered in study results. 
 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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5. STUDY SUBJECTS 
5.1. Number of Subjects 
Data will be collected for two groups (segments) of subjects: (1) mTBI subjects in Segment 1 and (2) 
non-mTBI controls in Segment 2. The target of the study is to collect at least 210 complete datasets 
from mTBI patients and at least 105 complete datasets from control subjects. Accounting for all 
possible reasons, attrition is estimated at 40%. Thus, a maximum of 350 mTBI subjects and 175 
non-TBI controls may be enrolled. 
While it is expected that sites should enroll approximately equal numbers of subjects, if possible, all 
sites are encouraged to accrue eligible mTBI subjects as rapidly as possible on an ongoing basis until 
the maximum number of subjects across all sites is reached. Thus, it is prospectively expected that 
some sites may have differing final accrual.  
 
Table 1 – Enrollment for mTBI subjects and controls 
Segment 
Description 
Total enrollment 
(all sites, N) 
Segment 1 
mTBI Patients are adolescents and adults who recently 
sustained head injury 
350 total 
Segment 2 
non-mTBI Subjects are enrolled as a control population 
175 total 
Additionally, up to 10 volunteers without mTBI injury and not requiring urgent medical care 
(Segment 0 volunteer subjects) may be enrolled per-site for training and retraining purposes on the 
investigational devices.  
 
 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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5.1.1. Enrollment of non-mTBI controls 
Enrollment Rate: Each site should enroll approximately half as many control subjects as mTBI 
subjects, at a rate of approximately one control enrollment for each two mTBI subjects that 
complete at least two visits (1:2). Though it is prospectively expected that actual enrollment rates 
may vary, it is the investigator’s responsibility to maintain this approximate rate in order to 
minimize possible bias due to variance in scanner performance (“scanner drift”) and other possible 
confounders. 
 
Population Matching: The study aims to achieve overall matched mTBI and control populations 
across sites. The overall population will be matched for characteristics identified in order of priority 
in Table 2. To enable sites to select control subjects that match the overall population, a report of 
mTBI subject enrollment will be generated by the Sponsor or its delegated contract research 
organization (CRO) and provided to the site on a rolling monthly basis. The report will categorically 
detail the number of enrolled mTBI subjects with the following characteristics (Table 2). The clinical 
site, under the supervision of the Principal Investigator, will be ultimately responsible for ensuring 
that matched controls are selected according to these criteria. 
 
Case-Control Matching: When possible, investigators are also encouraged to enroll individually 
matched mTBI and control cases of potential medical interest. Priority should be given, however, to 
ensuring an appropriate overall population match. 
 
Overall Population Reports:  
Table 2 – Population characteristics for enrollment of non-TBI controls (Segment 2) based monthly mTBI accrual by order 
of priority for matching 
Priority 
Characteristic 
Description/Unit 
1 
Gender 
Male, or 
Female 
 
2 
Age (years) 
≥15 to ≤18, 
>18 to ≤22, 
>22 to ≤26, 
>26 to ≤30, 
 
>30 to ≤34, 
>34 to ≤38, 
>38 to ≤42,  
>42 to ≤46, or 
>46 to ≤50 
3 
Handedness 25 
Left-handed (habitual or more skillful use of the left hand for writing and for 
most manual functions), 
Right-handed (habitual or more skillful use of the right hand for writing and 
for most manual functions), or 
Ambidextrous (Having equal facility in the use of both hands) 
4 
Highest educational 
level  26 
1. Some high school (9th to <12th grade),  
2. High school graduate (12th diploma),  
3. Some college no degree (>12th, no 
diploma),  
4. Associate's degree,  
5. Occupational Associate's,  
6. Bachelor's degree,  
7. Master's degree,  
8. Professional degree, or  
9. Doctoral degree 
 
5 
MR System used 
Each unique system (if more than one system used at the site) 
 
 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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5.2. Subject Population 
The populations under study are mTBI patients (Segment 1) and non-TBI controls (Segment 2). The 
mTBI patients will be diagnosed mTBI based on site practice and the American Congress of 
Rehabilitation (ACRM) Definition of Mild Traumatic Brain Injury (1993), 27 and the certainty of 
diagnosis will be recorded. Volunteers for training purposes (Segment 0) and non-TBI controls 
(Segment 2) will also be enrolled. It is well accepted that while some training can be done using 
simulations (phantoms), the complexity of in vivo human cerebral tissues cannot be fully duplicated 
without the use of living volunteers. 28 Thus, volunteer subjects will be used for essential activities 
of training/retraining study staff on clinical functionality.  
5.3. Protection of Vulnerable Subjects 
Eligible study staff, site employees, students, or fellows may volunteer to participate, in accordance 
with local EC/IRB policies. Investigators and study staff should ensure that no volunteer is under 
undue influence or coercion to participate, and the decision to volunteer or not will not affect 
educational, employment, or staff assignment status. 
Adolescent subjects aged 15 but less than 18 may be asked to participate as mTBI patients or 
controls (Segments 1 and 2). Minor subject may not volunteer for training (Segment 0). This 
research does not involve greater than minimal risk to children as subjects (45 CFR §46.404 and 21 
CFR §50.51). Written parental consent and assent to participate is required for minors, in 
accordance with 45 CFR §46.408 and applicable IRB policy. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
 
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5.4. Inclusion and Exclusion Criteria 
5.4.1. Inclusion Criteria by Study Segment 
Segment 0 (volunteer) Inclusion 
Segment 1 (mTBI patients) Inclusion 
Segment 2 (non-mTBI subjects) Inclusion 
Subjects included as volunteers for training (Segment 
0) will:  
1. Be aged ≥18 at the time of enrollment; 
2. Be able and willing to provide written informed 
consent for participation. 
 
Subjects included as mTBI patients (Segment 1) will:  
1. Be aged ≥15 and ≤50 years old at the time of 
enrollment; 
2. Be diagnosed with mTBI according to the standard 
diagnostic procedures at the investigational site in 
a timeframe that meets enrollment criteria for 
enrollment within 72 hours (Visit 1) or 7±2 days 
(Visit 3) from injury. 
3. Be capable of sufficiently clear communication 
and language fluency to allow the subject to 
provide written informed consent, or assent with 
parental or guardian consent for minors, and to 
complete study assessments (as per Section 5.3 - 
Protection of Vulnerable Subjects) for 
participation in all parts of the study. 
Subjects included as non-mTBI controls (Segment 2) 
will:  
1. Be aged ≥15 and ≤50 years old at the time of 
enrollment; 
2. Are of similar characteristics as the mTBI 
population in terms of gender, age, handedness, 
educational level, and scanner criteria (as per 
Section 5.1.1 Enrollment of non-mTBI controls) 
3. Be capable of sufficiently clear communication 
and language fluency to allow the subject to 
provide written informed consent, or assent 
with parental or guardian consent for minors, 
and to complete study assessments (as per 
Section 5.3 - Protection of Vulnerable Subjects), 
for participation in all parts of the study. 
 
5.4.2. Exclusion Criteria by Study Segment 
Segment 0 (volunteer) Exclusion 
Segment 1 (mTBI patients) Exclusion 
Segment 2 (non-mTBI subjects) Exclusion 
Subjects will be excluded that: 
1. Are currently enrolled in Segment 1 scanning in 
this study; 
2. Unable (such as due to urgent medical care needs) 
or unwilling to complete study procedures 
accurately or have any conflict of interest that 
Subjects will be excluded that have: 
1. Loss of consciousness (LOC) ≥5 minutes; 
2. Posttraumatic amnesia lasting ≥24 hr following 
mTBI; 
3. Current or prior (within past 10 years) moderate 
to severe TBI (GCS <13);  
Subjects will be excluded that have: 
1. Diagnosis of mTBI within the past 6 months; 
2. Prior (within past 10 years) moderate to severe 
TBI (GCS <13);  
3. Epilepsy with recurring seizures in past 10 years; 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
 
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could affect study results, in the opinion of the 
investigator; 
3. Have contraindications to MRI scanning, including: 
a. Current or suspected pregnancy per site 
practice; 
b. Other conditions that may constitute a hazard 
to the subject during study participation, per 
investigator; 
c. 
Inability to comply with any part of the site’s 
MR safety policy. 
 
4. Diagnosis of mTBI within the past 6 months; 
5. Epilepsy with recurring seizures in past 10 years; 
6. Drug abuse (except marijuana) in past 10 years (if 
suspected or self-reported confirm by DAST-10 
screening); 
7. Alcohol abuse (if suspected or self-reported 
confirm by AUDIT-C screening); 
8. Current primary Axis I or II psychiatric disorders, 
except for disorders classified as minor and not 
expected to impact study conduct or integrity (as 
detailed in Appendix C – Screening Axis I/II 
Disorders): 
9. History of brain mass, neurosurgery, stroke, white 
matter disease, and/or dementia; 
10. Known cognitive dysfunction or structural brain 
disease/malformation; 
11. Structural brain injury on prior neuroimaging 
findings; 
12. Been prescribed antipsychotic/antiepileptic 
medications (including for current or past head 
injury); 
13. Unable (such as due to urgent medical care needs) 
or unwilling to complete study procedures 
accurately or have any conflict of interest that 
could affect study results, in the opinion of the 
investigator; 
14. Contraindications to MRI scanning, including: 
a. Current or suspected pregnancy, per site 
practice; 
b. Other conditions that may constitute a 
hazard to the subject during study 
participation, per investigator; 
4. Drug abuse (except marijuana) in past 10 years 
(if suspected or self-reported confirm by DAST-
10 screening); 
5. Alcohol abuse (if suspected or self-reported 
confirm by AUDIT-C screening); 
6. Current primary Axis I or II psychiatric disorders, 
except for disorders classified as minor and not 
expected to impact study conduct or integrity 
(as detailed in Appendix C – Screening Axis I/II 
Disorders): 
7. History of brain mass, neurosurgery, stroke, 
white matter disease, and/or dementia; 
8. Known cognitive dysfunction or structural brain 
disease/malformation; 
9. Structural brain injury on prior neuroimaging 
findings; 
10. Been prescribed antipsychotic/antiepileptic 
medications (including for past head injury); 
11. Unable (such as due to urgent medical care 
needs) or unwilling to complete study 
procedures accurately or have any conflict of 
interest that could affect study results, in the 
opinion of the investigator; 
12. Have contraindications to MRI scanning, 
including:  
• 
Current or suspected pregnancy per 
site practice; 
• 
Other conditions that may constitute a 
hazard to the subject during study 
participation, per investigator; 
• 
Inability to comply with any part of the 
site’s MR safety policy. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
 
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c. 
Inability to comply with any part of the site’s 
MR safety policy. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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5.5. Concurrent Enrollment 
5.5.1. Concurrent Research Activities 
Because this study does not involve a therapeutic intervention, subjects in all segments may 
concurrently participate in other research activities outside of this study that do not involve 
therapeutic interventions for mTBI or other conditions that could confound study results. If a 
patient decides to concurrently participate in other research studies with disqualifying 
interventions, in the opinion of the principal investigator, the subject should be withdrawn. 
5.5.2. Concurrent Segment Participation 
The mTBI patients in Segment 1 may not concurrently participate in other segments of the 
study. In the event that any subject initially without mTBI (Segments 0 and 2) experiences an 
mTBI injury during the course of the study, he/she may be discontinued from the current 
segment and enrolled into the mTBI segment (Segment 1), provided the subject is otherwise 
eligible for enrollment in Segment 1 and agrees to participate (including signing the Segment 1 
informed consent form). 
5.6. Screening Subjects for Enrollment 
All subjects will be screened according to the standard screening and recruitment procedures of 
the investigational site and will complete standard of care MR Safety Screening. The site may 
employ IRB-approved communications to recruit subjects, so long as such materials have been 
approved in accordance with applicable laws and regulations as well as local IRB policy. All 
eligible subjects will provide written informed consent, or assent with parental consent for 
eligible minors, prior to participation in study procedures. 
6.  PROCEDURES FOR RESEARCH STUDY 
6.1. Quality Procedures 
6.1.1. Rationale and Background for Quality Procedures 
Minute variations or changes in scanner performance can influence the ability of MRI to 
produce distinguishable characteristics in the brains of mTBI patients. Contemporary studies 
indicate that use of multiple MRI scanning devices of similar static field strength are acceptable 
for pooling and have low variance, supporting the feasibility of pooling multi-site MRI data 
effectively. 29, 30, 31 It is, however, necessary to collect quantitative performance data from MRI 
scanners to verify the reproducibility and variance between scanners critical to future analysis of 
the mTBI data collected in this study. The Sponsor will provide training on proper execution of 
quality procedures. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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6.2. Volunteer (Segment 0) Procedures 
6.2.1. Scan Procedures 
Volunteer MR scan sessions are expected to last approximately 90 min (no more than 120 
minutes) with an optional break after 60 minutes of scanning. Study staff should ensure that 
volunteers continue to meet the criteria for MR safety at the site immediately prior to MRI 
scanning. Volunteers will be provided with clothing safe for MRI (such as hospital gowns), 
hearing protection, and protective devices, per the site’s standard of care for MRI scanning. 
Subjects will be told how to communicate with the operator during scanning, and scanning may 
be stopped at any time if the subject reports discomfort. Volunteer scans may use any 
combination of study hardware and software necessary for training/retraining purposes, 
including GE Research Pack II acquisition software and conventional MR sequences on the 
device, research and conventional MR coils, and/or other MR accessory/ancillary devices. 
6.2.2. Participation in Multiple Scan Sessions 
Subjects enrolled in Segment 0 may participate in one or more MR scan session during the study 
if the following criteria are met: 
1. Volunteer subjects may be scanned once per 24 hour period 
2. Volunteer subjects may be scanned no more than 3 time per calendar week  
3. Volunteer subjects must have provided written informed consent using the most 
current IRB-approved ICF. The subject may be given the opportunity to provide consent 
using the most recent version prior to participation if a more recent IRB-approved ICF is 
available at the site. 
6.2.3. Scan Data 
There is no prospective plan to store MR image data from volunteer scans or to conduct post-
processing using this data; however, in the event of technical or safety issues data may be 
shared with the Sponsor for evaluation as part of this research data. The site will maintain a log 
of volunteer scans (Appendix A – Segment 0 Volunteer Scan Log). Logs may be disclosed and 
evaluated by the Sponsor to verify acceptability and training completion, and to determine if the 
site requires additional training. 
 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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6.3. mTBI Subject and non-mTBI Control (Segment 1 and 2) Procedures 
6.3.1. Visit Schedule 
Each mTBI patient (Segment 1) and non-mTBI control (Segment 2) will attend a series of up to 4 
visits (Table 3). Subjects in the mTBI group may enroll and start the study at either Visit 1 or Visit 
2 based on date of injury, and non-mTBI control subjects will attend visits on a similar schedule 
based on date of first study scan. Subjects should attend all study visits, when possible. Controls 
will be enrolled continuously, as described in Section 5.1.1. Enrollment of non-mTBI controls. 
When possible, if the site is using more than one MR scanner for study purposes, the same 
scanner should be used for all visits for a single subject. 
Table 3 - Visit schedule for mTBI and non-mTBI control segments 
Segment 
Description 
Visit Schedule 
 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Segment 1 
mTBI Subjects 
 
(may be enrolled at either 
Visit 1 or Visit 2, where 
first visit is considered 
baseline) 
≤72 hr* 
from injury 
(Baseline) 
Day 7±2* 
from injury 
Day 14±2 
from injury 
Day 90±7 
from injury 
NA 
Day 7±2* 
from injury 
(Baseline) 
Day 14±2 
from injury 
Day 90±7 
from injury 
Segment 2 
non-mTBI Controls 
Baseline # 
Day 7±2 
from baseline 
(optional) 
Day 14±2 
from baseline 
(optional) 
Day 90±7 # 
from baseline 
Segment 0 
volunteer subjects 
(training) 
Volunteers may participate one or more scans, if they remain eligible 
and satisfy Section 6.2.2. Participation in Multiple Scan Sessions  
Note: Day 0 is based on date of injury for mTBI patients (Segment 1) or the day of first study scan (baseline) for 
patients without mTBI (Segments 0 and 2). The date of first study scan is considered baseline for all subjects. 
* mTBI subjects may be enrolled at either Visit 1 or Visit 2.  
# Non-mTBI subjects should attend visits 1 and 4, and all 4 visits when possible. 
6.3.2. Handling Visit Completion, Missed Visits, and Loss to Follow-up 
First Visit (Baseline): All Segment 1 (mTBI subjects) and Segment 2 (non-mTBI controls) are 
required to complete their initial MRI scan and clinical neurological assessment within 24 hours 
(in either order), and are required to satisfy complete all parts of the visit within the visit 
window as defined in Table 2 (with the exception of requests for medical history and other 
historical information, which may be requested and added to the subject record at any time 
during the study, as data becomes available to the investigators). Any subject that is not able to 
complete all parts of the first visit within the visit window should be withdrawn from study once 
this becomes known. No additional information will be collected after the time of withdrawal, 
but information collected up until this point may be used and disclosed. Withdrawal due to 
inability to complete a visit is not considered a deviation if the subject is immediately removed 
from study (withdrawn) and no additional information is collected. 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Subsequent Visits – Missed or Incomplete Visits: For all subsequent visits, subjects may remain 
on study if a visit is missed or incomplete for any reason, at the investigator’s discretion (else 
the subject may be withdrawn). The site will note the reason for any missed or incomplete visits 
for subjects that remain on study, and these incomplete data sets will not considered a 
deviation. It is ultimately the responsibility of the investigator to ensure that data is maximally 
complete, as incomplete case data may impair scientific integrity of the study.  
 
Subsequent Visits – Missed Visit Window (Table 2): If a subject failed to complete a visit within 
the visit window, he/she may still be eligible to complete future visits as scheduled (Table 2). 
Except in exceptional circumstances, study procedures should not be conducted outside of the 
visit windows (Table 2). Any part of a study visit conducted outside of the protocol visit windows 
should be reported as a deviation. 
 
Lost to Follow-Up: If a subject is not able to be contacted for scheduled visits (Table 2), the 
subject will be withdrawn from study and considered lost to follow-up. The site should make 
reasonable attempts to contact all subjects and document these activities as part of the study 
source documentation stored in the study file. Subjects lost to follow-up are not considered in 
deviation of the protocol if documentation of reasonable attempt to contact is maintained by 
the site and the subject is withdrawal is documented in the study record. 
 
Withdrawal: Withdrawals should be documented as per Section 6.5. -Withdrawal and 
Discontinuation Criteria. Once a subject is withdrawn, he/she is no longer eligible to participate 
in any future study visits or procedures, but the data collected up until the time of withdrawal 
may still be used and disclosed as part of this research. 
6.3.3. Baseline Data Collection 
After the subject is determined eligible according to the inclusion/exclusion and has provided 
informed consent (and assent for minors), the following will be recorded for each subject: 
• 
General Medical History and Demographic Information 
• 
Prior mTBI Information: Current (for mTBI subjects) or prior TBI information (for all control 
and mTBI subjects), if available for the subject (it is prospectively expected that not all data 
may be available for each subject): 
o prior medical records 
o relevant laboratory reports 
o neuroimaging (including CT, MRI, or other scans) 
o baseline neuropsychological or cognitive assessments done for sports or 
occupational purposes (such as SCAT2/3 for sports players), which may be 
requested from prior care providers and collected as part of study data. 
• 
Baseline Clinical Information about the injury (must be collected within visit window): 
o injury presentation information 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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o health assessments (such as vital signs) collected during the visit 
o Certainty of Diagnosis for mTBI patients in Segment 1 (assessed on a 3-point ordinal 
scale). Eligible subjects are required to meet diagnostic criteria for mTBI at the site. 
In addition, a qualified physician or clinical psychologist on the study staff will assess 
certainty of diagnosis based on: 
1  =   Certain mTBI Diagnosis: Presents with a combination of physical, 
behavioral/emotional, and/or cognitive symptoms (not pre-existing) where 
recent head injury is strongly expected to play the central causal role. 
2  =   Probable mTBI Diagnosis: Presents with at least one physical, 
behavioral/emotional, and/or cognitive symptoms (not pre-existing) where 
recent head injury can be reasonably expected to play a causal role. 
3  =   Possible mTBI Diagnosis: Presents with at least one physical, 
behavioral/emotional, and/or cognitive symptoms (not pre-existing) where it 
is uncertain whether or not recent head injury plays a causal role (as in the 
case where symptoms assessment is complicated by other conditions or 
diagnoses pre-existing mTBI, such as mood disorders, physical disability, or 
other chronic conditions or medication use). 
Baseline will be considered the day of the first study scan for all subjects, and Baseline Data will 
be inclusive of information collected or requested based on the first visit (General Medical and 
demographic information, and prior mTBI information) and information collected at the first visit 
(Baseline Clinical Information). Only Baseline Clinical Information is required to be collected and 
reported within the visit window. Other information, such as medical history and prior records, 
may be updated in the subject record as it becomes available to the site. 
6.3.4. Visit Procedures (Clinical Neuropsychological Assessment and MR Scan) 
Each visit will consist of a Clinical Neuropsychological Assessment of symptoms self-report, 
cognitive behavioral scales, and physical testing (lasting approximately 60 minutes) and an MR 
scan session using GE Research Pack II acquisition software (lasting approximately 60 minutes). 
The MR scan should be completed within the interval 24 hours before or after the Clinical 
Neuropsychological Assessment (within 4 hours, when possible). The example listing of data 
collection to be performed at each visit is shown in Appendix E – Data Collection by Study Visit. 
For MR scanning, study staff should ensure that the subject meets the criteria for MR safety at 
the site immediately prior to MRI scanning. Subjects will be provided with clothing safe for MRI 
(such as hospital gowns), hearing protection, and protective devices, per the site’s standard of 
care for MRI scanning. Subjects will be told how to communicate with the operator during 
scanning, and scanning may be stopped at any time if the subject reports discomfort.  
All scans will be completed using 32-channel multiband research coil, except in in cases where 
the 32-channel multiband research coil cannot be used due to: (1) head size, (2) medical 
conditions, (3) deformities, (4) anxiety, or (5) other medical issues. Alternatively, any 
commercially available 32-channel MR coil available at the site may be used, and its applicable 
identifiers (i.e. make, model, etc.) will be recorded. 

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6.3.5. MR Acquisition Data (Clinical Site Procedure) 
For each scan session, the scan operator or designee will record parameters as described in the 
MR Data (Appendix E – Data Collection by Study Visit) to a Sponsor provided case report form 
(CRF). DICOM, P-files, and auxiliary files (collected according to the instructions provided by the 
Sponsor) will be recorded for each visit. This data will be transferred to the Sponsor or its 
identified contract research organization (CRO) for execution of the GE Research Pack II 
software. 
6.3.6. MR Acquisition Image Reads/Evaluations (Clinical Site Procedure) 
One or more site radiologist will read the clinically useful sequences acquired from GE Research 
Pack II. For reading, the clinically useful image set includes both the images produced routinely 
from the clinical interface (T1, T2, and Flair) and images that require reconstruction by the 
software due to use of multiband technology.  
Readers will assess the entire clinically useful image set (T1, T2, and Flair and reconstructed SWI 
and DTI) according to the NINDS CDE Tool: Imaging with additional Sponsor-provided elements 
(if necessary) added for research purposes. The reader will determine whether each case is 
normal or abnormal and complete the Sponsor-provided case report form (CRF) for each case. 
Readers are not required to be blinded to clinical care. Readers will have access to 
reconstructions necessary to review the full clinically useful image set (including conventional 
reconstructions available from the clinical interface and reconstructions of SWI and DTI 
produced by the GE Research Pack II software, which are not able to be produced on the clinical 
interface due to use of the investigational multiband technology). Readers will be blinded to 
other results of post-processing with GE Research Pack II. 
6.4. MR Data Post-Processing (Imaging Laboratory Procedure) 
Data from Segments 1 and 2 will be transferred to an imaging laboratory (Sponsor or contracted 
CRO) independent of the clinical care facility for GE Research Pack II data post-processing. GE 
Research Pack II acquisition data collected at clinical sites will be screened for quality and loaded 
onto a workstation for execution of the GE Research Pack II post-processing modules. 
Authorized study staff (such as technician, imaging scientist, and/or radiologist) will record post-
processing outcomes as detailed in Appendix D – Detail of Post-Processing Assessment Modules. 
During the course of the study, the Sponsor may provide technical optimizations to post-
processing modules, which will be recorded in the device accountability log. The principal 
investigator and imaging laboratory will be notified of any optimizations in post-processing 
technology using the form shown in Appendix D. Clinical sites may be asked to resolve issues of 
data quality or missing data identified by the processing facility or Sponsor. 
6.4.1. Incidental Findings  
MR imaging in this study is conducted using investigational MR sequences for research 
purposes. The investigational research sequences are not intended to provide diagnostic 
information; however, GE Research Pack II also contains components that may be useful as 
reference for the patient’s clinical care (including clinically useful T1, T2, Flair, and reconstructed 

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SWI and DTI MR data). Patient management should not be based solely on data acquired from 
research sequences. The other research MR images and related data generated as part of study 
procedures are not intended for use in patient management decisions or to be stored in patient 
medical records. In the event that a member of the study staff identifies something possibly 
abnormal in a research MR image that may be of medical significance, they shall notify the 
principal investigator. The principal investigator will be responsible for evaluating any such 
incidental findings and, if necessary according to his/her medical judgment, communicating 
findings to the patient and/or his or her regular physician, in accordance with IRB policy.   
6.5. Withdrawal and Discontinuation Criteria 
A subject may withdraw from study at any time, for any reason without consequence. The 
Investigator may withdraw a subject at any time for any reason, including some clinical 
conditions concurrent enrollment in another interventional research study that could confound 
results or pose risks to the patient, or use any medication, stimulant, or illicit substance that 
could interfere with safe study conduct or integrity of research data, in the opinion of the 
Principal Investigator. In the event that a subject experiences an additional TBI injury during the 
study period or sustains other significant injury that could interfere with study participation or 
outcomes, the subject should be withdrawn when the investigator becomes aware of the 
change in the subject’s medical status. In cases where the investigator is unsure if an injury 
would disqualify the subject, the case should be confirmed with the Sponsor’s medical monitor. 
The reasons for withdrawal and discontinuation for any subject shall be recorded, when known. 
These will be reported to the Sponsor. The EC/IRB should be notified per their notification of 
subject withdrawal policy. All data collected up until the time of subject withdrawal or 
discontinuation may be used in study analyses, may be used in any and all subsequent 
subanalyses determined necessary by the Sponsor, and will be stored by the Sponsor or its 
authorized representative. 
Note: For each subject’s first visit, the subject must complete their MR scan and neurological 
assessment per-protocol (baseline and prior medical history data may be collected at any time 
after enrollment). Thereafter, subjects that miss a visit or attend a visit outside of the scheduled 
window should not be withdrawn, and may continue in the study. Missing a visit or visit window, 
however, will be considered a protocol deviation and reported in accordance with Section 9.1. - 
Management of Protocol Deviations. 
7. 
TRAINING PLAN 
Training plan documents and logs of training attendance will be stored in the Sponsor’s clinical 
history file (CHF). 
7.1. Training Plan for Research Device 
The Sponsor will provide training on the research device and any device optimizations or 
versions released during the study. The Investigator may request that additional training be 
provided to staff by the Sponsor or previously trained study staff during the study. MR imaging 
phantoms may be used in training and retraining during this study, and phantom training data 
may be collected and disclosed to the Sponsor as part of this study. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
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7.1.1. Clinical Site Training on the Research Device 
The Sponsor will provide necessary training to study staff operating the GE Research Pack II 
acquisition on site MR scanners, and on the use of research coils. Volunteer subjects (Segment 
0) may be scanned during device training at the clinical site under the supervision of a Sponsor 
representative or for training/retraining by site personnel (with or without a Sponsor 
representative present). 
7.1.2. Imaging Laboratory Training on the Research Device 
The Sponsor will provide training necessary for the staff of the imaging laboratory providing 
quality control, conducting post-processing, and evaluating post-processing results. Training will 
be provided to the imaging laboratory on how to report technical or quality issues in post-
processing. 
7.2. Training Plan for Protocol 
Protocol training is intended for necessary study staff, which includes any individual that will 
operate the devices involved with the study, collect clinical data that is part of this study, 
analyze any data associated with the study, or is in any other way involved with this study.  
7.2.1. Clinical Site Training 
The Sponsor will provide training on the protocol to the clinical site personnel at the study 
initiation visit. The Sponsor will also provide training on any subsequent study amendments. The 
scope of training will include, but not be limited to, the research study protocol, study 
procedures, monitoring plan, completion and collection of Case Report Forms and other data 
through site visits and electronic transfers, and communications and/or other media such as 
web meetings. 
7.2.2. Imaging Laboratory Training  
The Sponsor will provide training to imaging laboratory prior to the start of post-processing 
procedures at the facility. Staff at the imaging laboratory conducting post-processing may 
receive separate training sessions necessary for quality control and execution of post-processing 
procedures. In the event that any changes to the quality control plan or post-processing 
technology are made, the Sponsor will also provide training, as necessary to ensure post-
processing data integrity and completion. 
8. DATA ANALYSIS AND STATISTICS 
8.1. Overview 
This exploratory hypothesis-generating study is primarily conducted to collect data for 
subsequent engineering and scientific analyses outside of this study. The report will summarize 
the subjects enrolled and type of datasets collected. Exploratory data analyses will not be part 
of the report unless deemed necessary. General statistical methods described in this section 
and/or other parametric or non-parametric methods, as appropriate for data analysis depending 

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Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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on the distribution of collected data, will be applied in exploratory analysis. Based on actual data 
distribution from this exploratory study, data transformation may be performed for data 
analysis. 
Clinical Neuropsychological Assessment will not be part of this study report either, but will be 
included in the exploratory analysis. Before statistical analysis, outcomes from a particular 
Clinical Neuropsychological Assessment may be summarized in a clinically meaningful way, such 
as totaling the score of all or some items in the assessment, determining an overall score or 
severity, or other methods. 
8.2. Statistical Analysis Methods 
8.2.1. General Statistical Method 
As necessary to support exploratory analyses for scientific and engineering purposes and/or 
regulatory submission, continuous variables will be summarized with standard descriptive 
statistics including counts, means, standard deviations, medians, and minimum, maximum. 
Categorical variables will be summarized with frequencies and percentages. 
8.2.2. Interim Analysis 
No interim analysis is planned.  
8.2.3. Handling of Missing Data  
No missing data imputation is planned. For subjects with missing data, outcomes may be 
interpolated or last observation carry forward methods may be applied in the exploratory 
analysis.  
8.2.4. Pass/Fail Criteria of the Study 
There are no statistical pass/fail criteria in this hypothesis-generating study. The study will be 
considered successful if data collection is sufficient to meet the Sponsor’s engineering and 
scientific goals. 
9. DEVIATIONS 
9.1. Management of Protocol Deviations 
Deviations to the protocol may occur when necessary to protect the life or physical well-being of 
a subject. Except in an emergency, prior approval by the Sponsor is required for changes in, or 
planned deviations from this protocol. If these changes affect the scientific soundness or the 
safety and welfare of the subject, prior EC/IRB approval is also required. Planned Protocol 
Deviation documentation must be filed in the Site Study Regulatory Binder. 
There are two types of unplanned protocol deviations, critical deviations and non-critical 
deviations. All deviations must be documented and reported, the criticality of the deviation will 
determine the reporting path. 

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Critical Deviations: Deviations that significantly affect the safety, efficacy, integrity or conduct of 
the study. These deviations must be reported to the Sponsor no later than 5 working days from 
awareness of occurrence and reported to the EC/IRB per the deviation reporting policy.  
If an Investigator uses a device without obtaining informed consent, the Investigator shall 
consider this a critical deviation and report the event to the Sponsor and the EC/IRB within 5 
working days of the occurrence. 
Sponsor contact for Critical Protocol Deviations: 
John Strohmeyer, Senior Clinical Affairs Project Manager 
Phone: +1-609-865-7423 
john.strohmeyer@ge.com 
Non-Critical Deviations: Protocol deviations that DO NOT significantly affect the safety, efficacy, 
integrity or conduct of the trial. These deviations must be documented on the Case Report Form 
Protocol Deviation page and will be reviewed by the study monitor. 
10. COMPLAINT HANDLING AND ADVERSE EVENT REPORTING 
10.1. Foreseeable Adverse Events and Device Effects 
MRI does not use ionizing radiation (high-energy radiation that can potentially cause damage to 
DNA, such as those found in X-rays and CT scans). MRI of 8.0T or less is widely considered non-
significant risk for adults and adolescents, in accordance with the limits defined in the US FDA 
document Criteria for Significant Risk Investigations of Magnetic Resonance Diagnostic Devices 
(June 20, 2014). The safety profile of 3.0T MR scanning is well characterized, and adverse events 
are expected to occur at frequencies equivalent or less than conventional MRI using 
commercially-released scanners (adverse events are expected to occur in less than 1 in 100,000 
patients; P < 10-5). 21 Foreseeable adverse events of 3.0T MRI scanning of the head in this study 
may include the following: 
• 
During any MRI scan, the use of strong magnets may cause pacemakers, artificial limbs, 
and other implanted medical devices that contain metal to malfunction or heat up 
during the exam. Subjects are screened against site MR safety standards to mitigate 
these risks. 
• 
During any MRI scan, any loose metal objects may cause damage or injury if it gets 
pulled toward the magnet. Subjects are screened for ferrous metallic objects before 
entering the scan area to minimize these risks. 
• 
Dyes from tattoos or tattooed eyeliner can cause skin or eye irritation, and subjects may 
be asked to remove make-up for this reason. 
• 
Medication patches can cause a skin burn, and subjects may be asked to remove these 
or other attached medical devices before scanning for this reason. 
• 
The wire leads used to monitor an electrocardiogram (ECG) trace or respiration during a 
scan must be placed carefully to avoid causing a skin burn, and subjects may be asked to 
remove these or other attached medical devices before because of this. 

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• 
Prolonged exposure to radio waves during the scan could lead to slight warming of the 
body. Patients will be monitored for signs of discomfort throughout scanning to mitigate 
these risks. 
• 
Rapidly changing magnetic fields can, under certain conditions, cause nerves close to 
the skin to become stimulated.  This is known as Peripheral Nerve Stimulation (PNS). 
Patients will be monitored for signs of discomfort throughout scanning to mitigate these 
risks. 
• 
Transient hearing loss or tinnitus can be caused by acoustic noise levels in excess of 99 
dB during MRI scanning. Mandatory hearing protection will be used during scanning to 
minimize acoustic noise levels. 
• 
Feelings of anxiety triggered by the partially enclosed space within the scanner or noise 
generated during the exam. Patients will be monitored for signs of discomfort 
throughout scanning to mitigate these risks. 
The occurrence of these risks it mitigated to levels as low as reasonably practicable (ALARP) in 
accordance with the 2013 ACR Guidance Document on MR Safe Practices (J. Magn. Reson. 
Imaging 2013;37:501–530), 21 within includes MR safety screening and hearing protection 
guidelines to minimize acoustic noise levels during scanning. 
Because subjects are having a neurological assessment that includes physical and cognitive 
tests, there are some risks to subjects completing these assessments. These include physical or 
mental stress, fatigue, minor to moderate injury risk associated with physical tests (such falls or 
abrasions during balance tests, in rare cases), and confidentiality risks due to disclosure of 
personal information (e.g. sociodemographics, health, and occupational status information). The 
risks associated with these tests are not expected to exceed those encountered during routine 
examinations of head injury. 
10.2. Adverse Event Definitions 
Adverse Event (AE): As defined by EN ISO 14155-2011: any untoward medical occurrence, 
unintended disease or injury, or untoward clinical signs (including abnormal laboratory findings) 
in subjects, users or other persons, whether or not related to the investigational medical device. 
Serious Adverse Event (SAE): As defined by EN ISO 14155 – 2011: an adverse event that  
(a) led to death; 
(b) led to a serious deterioration in the health of the subject, that either resulted in: 
(1) a life-threatening illness or injury, or 
(2) a permanent impairment of a body structure or a body function, or 
(3) in-subject or prolonged hospitalization, or 
(4) medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to body structure or a body function; 
(c) led to fetal distress, fetal death or a congenital abnormality or birth defect. 
Anticipated: Any adverse event and/or reaction, the specificity or severity of which is consistent 
with the IRB approved informed consent, protocol, investigator brochure, or product labeling. 
Unanticipated adverse device effect (UADE): As defined by 21 CFR §812.3: means any serious 
adverse effect on health or safety or any life-threatening problem or death caused by, or 

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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. 
10.3. Management of Adverse Event Reporting 
Any adverse events will be recorded in the subjects study record and the Adverse Event Case 
Report Form. Subjects will be followed for adverse events and device effects from the time they 
arrive for each study visit (immediately after providing informed consent for the first visit, and 
upon arriving to the study area for each subsequent visit, until the subject leaves the study area 
after each visit). The following information should be obtained: 
▪ 
Description of Event 
▪ 
Date of onset and resolution  
▪ 
Intensity (mild, moderate, severe) 
- Mild: Symptom(s) barely noticeable to the subject or does not make the subject 
uncomfortable. The AE does not influence performance or functioning. Prescription 
drugs are not ordinarily needed for relief of symptom(s). 
- Moderate: Symptom(s) of a sufficient severity to make the subject uncomfortable. 
Performance of daily activities is influenced. Treatment of symptom(s) may be needed. 
- Severe: Symptom(s) of a sufficient severity to cause the subject severe discomfort. 
Treatment for symptom(s) may be given. 
▪ 
Serious (yes/no)  
▪ 
Relationship to device (unrelated, possibly related, probably related) 
- Unrelated: The adverse event is reasonably expected to be related to (or caused by) a 
concurrent illness, effect of another device/drug or other cause, and is unlikely related 
to the investigational product 
- Possibly related: The adverse event is reasonably expected to be related to the 
investigational product, and an alternative etiology is equally or less likely compared to 
the potential relationship to investigational product 
- Probably related: There is a strong relationship to investigational product, or recurs on 
re-challenge, and another etiology is unlikely, or there is no other reasonable medical 
explanation for the event. 
▪ 
Treatment given and/or action taken (procedure stopped, withdrawn from study, no action) 
▪ 
Anticipated (yes/no) 
Adverse events will be reported to the local EC/IRB per their policy. 
10.4. Management of Serious Adverse Event and Unanticipated Adverse Device 
Effect Reporting 
All SAEs and or UADEs will be documented as above and reported both electronically and in 
writing to the Sponsor within 72 hours of knowledge of the event.  The Investigator shall submit 
the Adverse Event Case Report Form and GEHC_GQP_10.07.005_F002 Site Notification and 
Assessment of Serious and Unexpected Adverse Events (GEHC internal document DOC0910335) 
with redacted supporting documentation to SAE mailbox. If the event resulted in the death of a 

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subject, the event shall also be reported via telephone to the Sponsor within 24 hours of 
knowledge of the event. SAEs will be reported to the local EC/IRB per their policy.  
Sponsor contact for SAEs and/or UADEs: 
Victor Miranda, MD, Executive, Medical Director 
Phone: +1-262-544-3633 
Fax: +1 800-888-3983 
E-mail: SAE@ge.com  
If additional information (i.e. outcome of event, date event resolved, additional treatments) is 
required to submit a follow-up report, the Investigator shall update the AE CRF and resubmit to 
the Sponsor. The Investigator shall submit the follow-up SAE and/or UADE report to the local 
EC/IRB per their policy.  
10.5. Management of Device Deficiencies/Complaints 
Any deficiencies regarding the operation of the device or software or any malfunctions are to be 
reported to the Sponsor’s Clinical Affairs Project Manager. In the event that these deficiencies 
constitute a device complaint on a post-market system per the US FDA 21 CFR §820.198 
definition, the Sponsor’s complain handling procedures will be followed. 
Sponsor contact for device complaints: 
John Strohmeyer, Senior Clinical Affairs Project Manager 
Phone: +1-609-865-7423 
E-mail: john.strohmeyer@ge.com  
11. EARLY TERMINATION OR SUSPENSION 
11.1. Criteria for Early Termination or Suspension 
The study may be terminated early if the Sponsor determines that unanticipated adverse 
event(s) presents an unreasonable risk to subjects or for any other reason as Sponsor 
determines to be appropriate. Termination shall occur no later than 5 working days after the 
sponsor makes the determination and no later than 15 working days after Sponsor first received 
notice of the effect. The Sponsor will promptly notify the Investigators of any determination to 
terminate the study outside of the protocol timeframe. The Sponsor will provide each 
Investigator with written guidelines/instructions on termination processes and timelines. The 
Investigator is responsible for reporting the early termination to their local EC/IRB.  
11.2. Withdrawal of EC/IRB Approval 
The Investigator is to notify the Sponsor of any withdrawal of EC/IRB approval within 5 working 
days of such occurrence. If the EC/IRB terminates or suspends its approval of the Study, the 
Investigator will promptly notify Sponsor and provide a detailed written explanation of the 
termination or suspension. Upon receipt, the sponsor will provide written 
guidelines/instructions on subject withdrawal/termination processes and timelines. 

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12. ETHICS COMMITTEE (EC) AND REGULATORY FILINGS 
12.1. Ethics Committee Approval Requirements 
This study is to be submitted to the ethic committee (EC) or institutional review board (IRB) at 
the investigational site for review and approval prior to enrolling subjects. The Investigator is 
responsible for keeping approval current and maintaining appropriate correspondence and 
reports. Copies of all EC/IRB applications, approval letters, Informed Consent Forms (ICF), and 
other correspondence are to be sent to the Sponsor, with originals kept in the Site Study 
Regulatory Binder. 
12.2. Management of Protocol Revisions/Amendments  
Protocol revisions and/or amendments shall be approved by the Sponsor, the investigational 
site, and the Principal Investigator. The investigator will assume responsibility for attaining 
necessary institutional and EC/IRB approvals for necessary amendments or revisions. 
12.3. Informed Consent and Privacy Requirements 
Informed consent will be obtained from all subjects prior to participation in the study, per the 
determination of the EC/IRB. 
Informed consent will be documented in the source record of each subject. The Investigator or 
designee will consent the subject per regulatory guidelines which include the subject has ample 
time to review the ICF and have all questions answered to their satisfaction; the subject may 
take the ICF home to review with family members or others prior to agreeing to participate in 
the study; upon agreeing to participate in the study, the subject will sign and date the 
document, and the person who consented the subject will also sign and date the document.   
Minor patients enrolled in Segment 1 and Segment 2 (no minor volunteers may be enrolled in 
Segment 0) will also be required to provide assent to participate. Segment 1 and Segment 2 
subjects will provide informed consent for main study. 
For adult volunteers in Segment 0, the subject will provide informed consent to cover all scan 
sessions conducted after the day the ICF is signed (in accordance with the scan session 
requirements set forth in Section  6.2 - Volunteer (Segment 0) Procedure. If a new version of the 
ICF is approved by the IRB during the time that the subject is participating, the subject must be 
re-consented using the latest version of the ICF prior to any subsequent visits. The subject will 
be given a copy of the signed ICF and the original will be retained with subject files.  
13. DATA AND QUALITY MANAGEMENT 
13.1. Management of Data 
No clinical data or images are expected to be collected for post-processing or data analysis from 
subjects that participate in Segment 0 scanning, unless unexpected technical or safety issues are 
observed (in which case data may be shared with the Sponsor for evaluation as part of this 
research study). MR image data (DICOM) and P-files may be collected to investigate abnormal 
device functionality issues or complaints reported during Segment 0, in which case these de-

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identified images and associated de-identified image or system data may be stored or provided 
to the Sponsor for engineering purposes. 
Data will be submitted from the investigator to the Sponsor or its authorized representative as 
described in the Data Management Plan (DMP). The Principal Investigator at each participating 
site is ultimately responsible for submitting data to the Sponsor and ensuring that all data 
arrives in a timely manner.  
MR images and data as well as clinical assessments will be collected from subjects enrolled in 
this study. All MR images and image data will be labeled with a subject identification designation 
(SID) that will not contain any identifiable personal information. 
The Sponsor (GE Healthcare) may use de-identified image data, Clinical Neuropsychological 
Assessment data, and other data collected as part of this study (such as prior baseline TBI data, 
previous TBI data, and prior neuroimaging results related to TBI injury) and other de-identified 
clinical data for future technology development, marketing purposes, regulatory submissions, 
publications, published registries or database of mTBI research, or any other possible use, 
including public collaborative projects with industry leaders and independent research groups. 
The approved Data Management Plan (DMP) will be located in the study’s Clinical History File 
(CHF) maintained by the Sponsor. 
13.2. Subject De-identification 
Each enrolled subject will be assigned a unique Subject Identification number which is used to 
de-identify subject data. The Investigator or designee will record subject information and assign 
a unique subject identification number to each subject. These numbers will be assigned in the 
order of enrollment, in the numbering sequence provided by the Sponsor.   
13.3. Completion of Case Report Forms (CRFs) 
Data may be collected using paper CRFs, electronic CRFs, and/or data file transfers. Data from 
Segment 0 volunteers, Segment 1 mTBI patients, Segment 2 non-TBI controls may be recorded, 
stored, and housed by different means in accordance with the current Data Management Plan 
(DMP). 
To ensure the quality and integrity of the data, it is the responsibility of the Principal 
Investigator or designee in a timely manner to complete a data collection via paper CRF and/or 
electronic means for each subject who is enrolled in this study. GEHC will provide paper CRFs 
and/or instructions for setup and completion of electronic forms. Paper CRF and electronic data 
will be completed as information becomes available. 
If errors or omissions are found in the course of monitoring, a query will be raised and the site 
shall make the correction per Good Documentation Practices on the CRFs and/or electronic 
systems. In the event of an audit or data review once the CRFs or electronic data records have 
been pulled from the site, a Data Clarification Form (DCF) will be generated and the error, 
omissions or clarifications will be corrected on these forms. 
The Principal Investigator or medically qualified designee will sign and date the indicated places 
on the CRF or provide appropriate confirmation, such as electronic signatures and/or written 

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signature confirmation for electronic records. This signature will indicate that a thorough 
inspection of the data has been made and will thereby certify the contents of paper and/or 
electronic forms. 
13.4. Record Retention at the Site 
All records pertaining to the conduct of the study, including Case Report Forms and/or 
electronic records, Informed Consent Forms, Ethics Committee correspondence, and other study 
documentation must be retained at the Site for inspection at any time by the GEHC Study 
Monitor or designee to ensure that study procedures are followed. Elements should include the 
following: 
▪ 
Subject Files – containing the completed subject CRFs, (signed/dated) Informed Consent 
Form(s) 
▪ 
Regulatory Binder – containing the protocol and amendments, EC/IRB submissions and 
approvals, (blank) Informed Consent Form(s), Site study logs and sub-contracted site 
qualifications and contracts. 
▪ 
Reference Manuals – containing the resource list, responsibilities of the Investigator, 
Sponsor, adverse event and informed consent guidelines, study aids (training material, 
device screen shots), and other instructions, if applicable 
No physical or electronic records will be destroyed without notification and approval by GE 
Healthcare. 
14. MONITORING PLAN 
14.1. Interim Data Reviews 
The Sponsor may access data throughout the study for purposes of tracking study progress and 
conducting pilot data evaluations. Pilot evaluations at each site will be conducted after 
approximately the first 5 mTBI subject (Segment 1) study scans are completed. These are not 
required to be unique subjects. Thereafter, the Sponsor may access data at any time during the 
study. 
14.2. Brief Description 
In collaboration with the site, the Sponsor will ensure proper monitoring of the study to confirm 
that all the clinical requirements are met. Monitoring visits will ensure adherence to the 
protocol, completion of informed consents, IRB review of the study, maintenance of records, 
primary outcomes review and review of the CRFs and source documentation for accuracy and 
completeness.   
14.3. Reference to Approved Monitoring Plan 
The approved monitoring plan will be located in the study’s Clinical History File (CHF) 
maintained by the Sponsor. 

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15. PUBLICATION POLICY 
All publications that use data fully or partially acquired in this study are subject to the terms of 
the contractual agreement between the Sponsor and Site relevant to this research. The Sponsor 
retains the rights to use and publish this study data in full or in part and any publications 
thereof, in accordance with intellectual property laws and applicable regulations. 
 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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        Version Date: 14/Nov/2016 
16. ADDITIONAL STUDY MATERIALS/REFERENCES 
16.1. Abbreviations and Terminology 
ACRM 
American Congress of Rehabilitation 
ADC 
 
 
Apparent diffusion coefficient 
ADHD 
Attention Deficit Hyperactivity Disorder 
ALARP  
 
As low as reasonably practicable 
AOC 
 
 
Alteration of consciousness 
AUDIT-C  
 
The Alcohol Use Disorders Identification Test 
AW 
 
 
Advantage workstation (VolumeShare 5) 
BESS 
 
 
Balance Error Scoring System 
COWAT 
Controlled Oral Word Association Test (subtest of the Multilingual Aphasia 
Examination) 
CPS 
 
 
Commercial Pulse Sequence 
CRO 
 
 
Contract research organization 
DAST-10 
Drug Abuse Screening Test (10 items) 
dB 
 
 
Decibels 
DICOM 
Digital Imaging and Communications in Medicine (imaging file standard) 
D-KEFS  
 
Delis-Kaplan Executive Function System 
DOD 
 
 
US Department of Defense 
DoDI 
 
 
US Department of Defense Instruction 
eASL 
 
 
Enhanced arterial spin labeling 
eSWAN  
 
3D-enhanced T2* weighted angiography 
FFOV 
 
 
Frequency field of View 
FFOV 
 
 
Frequency Field of View 
FLAIR 
 
 
Fluid attenuated inversion recovery 
fMRI 
 
 
functional MRI 
FOV 
 
 
Field of View 
GCS 
 
 
Glasgow Coma Scale 
GCS-E 
 
 
Glasgow Coma Scale - extended 
GE Research Pack II 
Name of the advance MRI application software suite consisting of acquisition 
(pulse sequences and related interface) and post-processing components 
designed for use with the research coil  
GOS-E 
 
 
Extended Glasgow Outcomes Scale 
GSC 
 
 
Graded symptoms checklist 
HSS 
 
 
Hospital for Special Surgery 
HVLT-R 
Hopkins Verbal Learning Test – Revised 
ICA 
Independent Component Analysis 
LOC 
 
 
Loss of consciousness 
MACE 
Military Acute Concussion Evaluation 
MR mTBI Biomarkers  
Biomarkers of mTBI clinical neurological symptom and MR image, data, and 
clinical finding clinical evolution 
mTBI 
 
 
Mild traumatic brain injury 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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        Version Date: 14/Nov/2016 
NCAA 
 
 
National Collegiate Athletic Association  
NIH 
 
 
National Institutes of Health 
NINDS  
 
National Institute of Neurological Disorders and Stroke 
PD 
 
 
Proton Density 
PFOV 
 
 
Phase field of view 
PFOV 
 
 
Phase Field of View 
PSI 
 
 
WAIS-IV/WISC-IV Processing Speed Index 
PTA 
 
 
Post-traumatic amnesia 
PVP 
 
 
Polyvinylpyrrolidone 
RF 
 
 
Radiofrequency 
RS 
 
 
Resting state 
SAR 
 
 
Specific Absorption Rate 
SCAT 
 
 
Sports Concussion Assessment Tool 
SCAT 
 
 
Standardized Concussion Assessment Tool 
SCOAT  
 
Sports Concussion Office Assessment Tool 
TBI 
 
 
Traumatic brain injury 
TE 
 
 
Echo time 
TR 
 
 
Relaxation time 
TT Mapping 
 
Transient Time Mapping 
UADE 
 
 
Unanticipated adverse device effect 
WAIS 
 
 
Wechsler Adult Intelligence Scale 
WISC-IV  
 
Wechsler Intelligence Scale for Children–Fourth Edition, fourth edition 
WMI 
 
 
WAIS-IV/WISC-IV Working Memory Index 
 
 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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        Version Date: 14/Nov/2016 
References 
1. Corrigan J, Selassie A, Orman J. The epidemiology of traumatic brain injury. J Head Trauma Rehabil. 
2010;25(2):72-80. 
2. Peskind E, Brody D, Cernak I, McKee A, Ruff R. Military- and sports-related mild traumatic brain 
injury: clinical presentation, management, and long-term consequences. J Clin Psychiatry. 
2013;74(2):180-8. 
3. WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med. 2004;43 
Suppl:28-60. 
4. Peskind E, Brody D, Cernak I, McKee A, Ruff R. Military- and sports-related mild traumatic brain 
injury: clinical presentation, management, and long-term consequences. J Clin Psychiatry. 
2013;74(2):180-8. 
5. Masel B, DeWitt D. Traumatic brain injury: a disease process, not an event. J Neurotrauma. 
2010;27(8):1529-40. 
6. Casson I, Viano D, Powell J, Pellman E. Twelve Years of National Football League Concussion Data. 
Sports Health. 2010;2(6):471-483. 
7. O'Neil M, Carlso K, Storzbach D. Complications of Mild Traumatic Brain Injury in Veterans and 
Military Personnel: A Systematic Review. Evidence-based Synthesis Program. Washington (DC): 
Department of Veterans Affairs (US); 2013. 
8. Kou Z, Wu Z, Tong K, et al. The role of advanced MR imaging findings as biomarkers of traumatic 
brain injury. J Head Trauma Rehabil. 2010;25(4):267-82. 
9. Lipton M, Kim N, Hulkower M, et al. Robust detection of traumatic axonal injury in individual mild 
traumatic brain injury patients: intersubject variation, change over time and bidirectional changes 
in anisotropy. Brain Imaging Behav. 2012;6(2):329-42. 
10. Demographics and Clinical Assessment Working Group of the International and Interagency 
Initiative toward Common Data Elements for Research on Traumatic Brain Injury and Psychological 
Health. Position statement: definition of traumatic brain injury. Arch Phys Med Rehabil. 
2010;91(11):1637-40. 
11. Mondello S, Muller U, Jeromin A, Streeter J, Hayes R, Kevin K. Blood-based diagnostics of traumatic 
brain injuries. Expert Rev Mol Diagn. 2011;11(1):65-78. 
12. Lee B, Newberg A. Neuroimaging in Traumatic Brain Imaging. NeuroRx. 2005 April; 2(2):. 
2005;2(2):372–383. 
13. McLeod T, Leach C. Psychometric properties of self-report concussion scales and checklists. J Athl 
Train. 2012;47(2):221-3. 
14. Coldren R, Kelly M, Parish R, Dretsch M, Russell M. Evaluation of the Military Acute Concussion 
Evaluation for use in combat operations more than 12 hours after injury. Mil Med. 
2010;175(7):477-81. 
15. NINDS Common Data Elements. Traumatic Brain Injury. NINDS Common Data Elements. Mar 26, 
2014. Available at: 
http://www.commondataelements.ninds.nih.gov/tbi.aspx#tab=Data_Standards. Accessed 
Apr 04, 2014. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
Page 41 of 74 
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        Version Date: 14/Nov/2016 
16. Brain and Spinal Injury Center UCSF. TRACK-TBI Multicenter Initiative. Brain and Spinal Injury Center 
UCSF. 2015. Available at: http://www.brainandspinalinjury.org/research.php?id=189. 
Accessed Apr 14, 2015. 
17. Abdullah S. DOD and the NCAA join forces in a grand alliance to understand traumatic brain injury. 
us.army.mil. 2014. Available at: 
http://www.army.mil/article/132656/DOD_and_the_NCAA_join_forces_in_a_grand_allian
ce_to_understand_traumatic_brain_injury/. Accessed Apr 15, 2015. 
18. Quantitative MRI Diffusion Phantom. High Precision Diagnostics, Inc. 2015. Available at: 
http://www.hpd-online.com/diffusion-phantom.php. Accessed May Jun, 2015. 
19. Quantitative MRI System Phantom. High Precision Diagnostics, Inc. 2015. Available at: 
http://www.hpd-online.com/system-phantom.php. Accessed Jun 05, 2015. 
20. Nova Medical, Inc. Thirty-two channel whole-brain array for General Electric 3T MRI scanners 2013. 
Model NMSC075-3GE. 
21. Expert Panel on MRI Safety. ACR Guidance Document on MR Safe Practices: 2013. Journal of 
Magnetic Resonance Imaging. 2013;37:501–530. 
22. US FDA. Criteria for Significant Risk Investigations of Magnetic Resonance Diagnostic Devices Jul 14 
2003. 
23. Occupational Health Services: A Practical Approach: Chapter 29 - Research. University of Alberta. 
2012. Available at: http://www.ualberta.ca/~gjhangri/ohp/CH-29.htm. Accessed Oct 29, 2013. 
24. Kraemer. The Role of Hypothesis-Generating and Pilot Studies as Precursors to Hypothesis-Testing 
in Clinical Research. JSM. 2012;49. 
25. Farlex. Medical Dictionary for the Health Professions and Nursing. 7th ed. Johnsburg, IL: Stedman's; 
2011. 
26. Educational Attainment. U.S. Census Bureau - Census.gov. 2014. 
http://www.census.gov/hhes/socdemo/education/. Accessed Jun 22, 2015. 
27. Mild Traumatic Brain Injury Committee of the Head Injury Interdisciplinary Special Interest Group of 
the American Congress of Rehabilitation Medicine. Definition of mild traumatic brain injury. J Head 
Trauma Rehabil. 1993;8(3):86-87. 
28. Lee B, Newberg A. Neuroimaging in Traumatic Brain Imaging. NeuroRx. 2005;2(2):372–383. 
29. Stonnington C, Tan G, Klöppel S. Interpreting scan data acquired from multiple scanners: A study 
with Alzheimer's disease. Neuroimage. 2008;39(3):1180-1185. 
30. Jovicich J, Marizzoni M, Sala-Llonch R, Bosch B, Bartrés-Faz D. Brain morphometry reproducibility in 
multi-center 3T MRI studies: a comparison of cross-sectional and longitudinal segmentations. 
Neuroimage. 2013;83:472-84. 
31. Costafreda S, Brammer M, Vêncio R, et al. Multisite fMRI reproducibility of a motor task using 
identical MR systems. J Magn Reson Imaging. 2007;26(4):1122-6. 
 
 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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APPENDIX 1 – STUDY SITE AND INVESTIGATOR LIST  
The following investigators at each study site will be responsible for the conduct of this study:  
Investigator(s):* 
 
Site 001 
Teena Shetty, MD  
(Principal Investigator)  
Tel:  
1 (212) 774-2138 
e-mail:  shettyt@hss.edu 
Hospital for Special Surgery (HSS) 
525 East 71st Street, Belaire 5th floor 
New York, NY 10021 US 
Site 002 
Pratik Mukherjee, MD, PhD  
(Principal Investigator) 
Tel:  
1 (415) 750-2146 
e-mail:  pratik.mukherjee@ucsf.edu 
University of California at San 
Francisco (UCSF) 
185 Berry Street, Lobby 6 
San Francisco, CA 94121 US 
Site 003 
Joseph C Masdeu, MD, PhD  
(Principal Investigator) 
Tel:  
1 (713) 441-1150 
e-mail: jcmasdeu@houstonmethodist.org 
Houston Methodist Neurological 
Institute 
6560 Fannin Street, Scurlock 802 
Houston, Texas 77030 US 
Site 004 
Michael Collins, PhD  
(Co- Principal Investigator) 
Tel:  
1 (412) 432-3668 
e-mail:  collinsmw@upmc.edu   
Anthony P. Kontos, Ph.D.  
(Co-Principal Investigator)  
Tel:  1 (412) 432-3725  
Email:   akontos@pitt.edu        
 
University of Pittsburgh Medical 
College 
3200 South Water St. 
Pittsburgh, PA 15203 
 
UPMC Sports Medicine Concussion 
Program 
Department of Orthopedic Surgery 
University of Pittsburgh 
200 Lothrop St Pittsburgh,  
PA 15213-2582 
Site 005 
Gillian A. Hotz, PhD  
(Principal Investigator) 
Tel:  
1 (305) 243-4004 
e-mail:  ghotz@med.miami.edu  
University of Miami Hospital 
Lois Pope Life Center 
1095 NW 14th Terrace 
Miami, FL 33136        
Site 006 
Michael McCrea, PhD, ABPP-CN 
(Principal Investigator) 
Tel:  
1 (414) 955-7302 
e-mail:  mmccrea@mcw.edu  
Medical College of Wisconsin  
Department of Neurosurgery 
9200 West Wisconsin Avenue,  
Milwaukee, Wisconsin 53226 
Site 008 
Roland Lee, MD  
(Principal Investigator) 
Tel:  
1 (619) 543-6766 
e-mail:  
rrlee@ucsd.edu 
University of California, San Diego 
Radiology/RIL, 9500 
Gilman Drive, MC 0852,  
La Jolla, CA  92093-0852     
Site 009 
Thomas M. Talavage, PhD  
(Principal Investigator) 
Tel:  
1 (765) 494-5475 
e-mail:  
tmt@purdue.edu  
Purdue University 
School of Electrical & Computer 
Engineering 
465 Northwestern Ave 
West Lafayette, IN  47907-2035 
Site 010 
Jeffery J. Bazarian, MD, MPH 
(Principal Investigator) 
Tel:  
1 (585) 275-2909 
e-mail: Jeff_Bazarian@URMC.Rochester.edu  
University of Rochester Medical Center  
Department of Emergency Medicine, 
265 Crittenden Blvd, Box 655C, 
Rochester, NY 14642 
* The identifier Site 007 was reserved for a site no longer participating in the study. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Sample Document – Not for Study Use 
(Please use most current Sponsor-provided 
document version) 
APPENDIX A – SEGMENT 0 VOLUNTEER SCAN LOG 
Segment 0 volunteers may be enrolled for training/retraining purposes only. 
Date 
Site 
ID 
Volunteer 
No. 
 
Scanner ID 
(if multiple 
scanners 
used for 
study at site) 
Volunteer is 
Eligible (per 
Segment 0 inclusion/ 
Exclusion and criteria 
for repeat scanning) 
Sponsor 
representative 
present during 
scanning 
(Yes/No) 
Scan 
completed 
(Yes/No) 
If no, reason not 
completed 
Coil Used 
(if used, specify 
make/ 
manufacturer) 
Scan Operators 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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APPENDIX B – FMRI QA COMPLETION LOG 
This appendix is removed as per Amendment to protocol version 1.0 to 2.0 amendment ID Nos. #7 and #9. This log is no longer used as part of this 
study. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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APPENDIX C – SCREENING AXIS I/II DISORDERS (EXCLUSION CRITERIA) 
Table C-1:  Screening Criteria for Exclusion of Subjects with DSM-IV Axis I and II Disorders  
Inclusion/Exclusion 
clarification 
Additional Screening Requirements 
(if requirements cannot be met, the subject should be excluded) 
Axis 
Disorder 
May be Included* 
Clinical diagnosis of Major Depressive Disorder (MDD) should be 
excluded. 
 
If a subject self-reports depression without MDD diagnosis, subject 
should be included if screening Hamilton Score 
(http://dcf.psychiatry.ufl.edu/files/2011/05/HAMILTON-
DEPRESSION.pdf; Hamilton M. A rating scale for depression. J Neurol 
Neurosurg Psychiatry 1960; 
23:56–62) is within normal ranges (0-19).   
 
Scores of ≥20 are excluded (indicating moderate, severe, or very severe 
depression) 
Axis I 
Depression 
May be Included* 
If a subject self-reports anxiety, screening should include a Zung Self-
Rating Anxiety Scale, a rapid and validated assessment developed by 
Duke and including 20 questions (Zung WWK. A rating instrument for 
anxiety disorders. Psychosomatics. 1971; 12(6): 371-379). 
Axis I 
anxiety disorders 
Excluded 
N/A 
Axis I 
bipolar disorder 
May be Included* 
Subjects should be excluded if currently receiving prescription 
medication for the disorder (may be included if not currently be treated) 
AND the response to “Does the disorder limit your functioning in routine 
daily occupational or personal activities?” is YES based on self-response. 
(Note: Both criteria should be met for exclusion) 
Axis I 
ADHD, autism spectrum 
disorders 
Excluded 
N/A 
Axis I 
 autism 
Excluded 
N/A 
Axis I 
anorexia nervosa 
Excluded 
N/A 
Axis I 
bulimia nervosa 
Excluded 
N/A 
Axis I 
schizophrenia 
Excluded 
N/A 
Axis I 
Other condition 
May be Included* 
Subjects should be excluded if currently receiving prescription 
medication for the disorder (may be included if not currently be treated) 
AND the response to “Does the disorder limit your functioning in routine 
daily occupational or personal activities?” is YES based on self-response. 
(Note: Both criteria should be met for exclusion) 
Axis II 
narcissistic personality 
disorder, 
histrionic personality 
disorder, 
avoidant personality 
disorder, 
dependent personality 
disorder, 
obsessive-compulsive, 
personality disorder 
intellectual disabilities 
Excluded 
N/A 
Axis II 
paranoid personality 
disorder 
Excluded 
N/A 
Axis II 
schizoid personality disorder 
Excluded 
N/A 
Axis II 
schizotypal personality 
disorder 
Excluded 
N/A 
Axis II 
borderline personality 
disorder 
Excluded 
N/A 
Axis II 
antisocial personality 
disorder 
Excluded 
N/A 
Axis II 
other disorders 
 
 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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        Version Date: 14/Nov/2016 
APPENDIX D – DETAIL OF POST-PROCESSING ASSESSMENT MODULES 
Post-Processing Assessment Document Version: 1.0 [Protocol Amendment 4.0]  
Sponsor Release Date: 14/Nov/2016 
Date Received by PI:   _________ 
 
 
_______________________________ 
Printed Name of Principal Investigator 
 
 
___________________________________________ 
Signature of Principal Investigator 
 
_______________________________ 
Printed Name of Sponsor Representative 
 
 
___________________________________________ 
Signature of Sponsor Representative 
 
  
Module 
Number 
Module Title 
Assessments 
Assessor 
Output type 
Assessment Instructions 
Type of Stored 
Files 
1 
Volumetry 
Post-
Processing 
Module 
1. Whole brain 
2. Parenchyma 
3. Supratentorial 
region 
4. Cortical gray 
matter 
5. Hippocampus 
6. Thalamus 
7. Caudate 
nucleus 
(labeled as 
‘Caudate’ on 
device the 
report) 
8. Putamen 
9. Globus 
pallidus 
(labeled as 
‘Pallidum’ on 
device report) 
10. Amygdala 
technician (non-
radiologist) 
Numerical 
Record the numerical 
output for each 
anatomical region as 
cubic centimeters (cm3)  
1. DICOM 
2. P-files 
3. Auxiliary 
data (if 
applicable) 
2 
Kurtosis Post-
Processing 
Module  
1. ADC 
2. eADC 
3. FA 
4. OrthoK 
5. ParK 
6. MuMinK 
7. MuMaxK 
8. AKC min 
9. AKC max 
10. Mean K 
11. FA-K 
12. Color FA 
 
 
N/A 
Twelve (12) 
electronic 
quantitative 
image maps 
and one (1) 
corrected 
diffusion 
weighted 
image set 
No assessments 
conducted 
1. DICOM 
2. P-files 
3. Auxiliary 
data (if 
applicable) 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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3 
RS fMRI Post-
Processing 
Module 
1. Default Mode 
Network 
2. Primary Visual 
Network 
3. Secondary 
visual 
4. Left motor 
(hand) 
5. Right motor 
(hand) 
6. Left motor 
(face) 
7. Right motor 
(face) 
8. Dorsal 
attention 
system  
9. Executive 
control 
network (left) 
10. Executive 
control 
network (right) 
11. Salience 
network 
N/A 
Thirteen 
(13) seed-
based and 
thirty (30) 
ICA-based 
network 
images 
No assessments 
conducted 
1. DICOM 
2. P-files 
3. Auxiliary data 
(if applicable) 
4 
RSI Post-
Processing 
Module 
1. free water 
2. neurite density 
N/A 
two (2) 
electronic 
quantitative 
image maps 
of the brain 
No assessments 
conducted 
1. DICOM 
2. P-files 
3. Auxiliary data 
(if applicable) 
 
5 
QSM Post-
Processing 
Module 
susceptibility 
N/A 
One 
electronic 
quantitative 
image map 
No assessments 
conducted 
DICOM 
6 
SWI 
combined 
echo 
susceptibility 
Radiologist 
Images 
Check for microbleeds 
(instructions on the 
reader report form) 
 
1. DICOM 
2. P-files 
3. Auxiliary 
data (if 
applicable) 
 
7 
MR 
Spectroscopy 
Metabolite ratios 
Technician 
N/A 
(numerical 
values 
already 
produced by 
scanner-
based 
processes) 
From the DICOM viewed 
on AW, record each 
bilateral value  
(na, cr, ch, mi, h2o)  
 
DICOM 
Text file 
 
 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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        Version Date: 14/Nov/2016 
APPENDIX E – DATA COLLECTION BY STUDY VISIT 
Detail of Data Collection by Study Visit Version: 4.0  
Sponsor Release Date: 14/Nov/2016 
Date Received by PI:   _________ 
 
 
_______________________________ 
Printed Name of Principal Investigator 
 
 
___________________________________________ 
Signature of Principal Investigator 
 
_______________________________ 
Printed Name of Sponsor Representative 
 
 
___________________________________________ 
Signature of Sponsor Representative 
 
Key:  Applicable data points are marked by segment, where 1 = Segment 1 mTBI patients, 2 = Segment 2 non-
mTBI controls, 0 = volunteers for training. 
Note: The intervals of each visit are defined in Protocol Table 2. Screening for enrollment eligibility should 
occur before Visit 1 begins, and may be conducted in advance or immediately prior to the start of Visit 1 
in accordance with site recruitment practices. Screening and Visit 1 may occur on the same day id the 
protocol requirements are met. 
 
 
Visits (Clinical Site) 
Screening 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Eligibility 
Eligibility per the inclusion 
criteria/ Exclusion criteria 
0,1,2 
 
 
 
 
MR Safety Screening 
 
0 (all visits),1,2 
1,2 
1,2 
1,2 
Screening completion for 
eligibility (if applicable) 
1,2 
 
 
 
 
Hamilton Score 
1,2 
 
 
 
 
Zung Score 
1,2 
 
 
 
 
DAST-10 
1,2 
 
 
 
 
AUDIT C 2 
1,2 
 
 
 
 
Written informed Consent 
0,1,2 
 
 
 
 
Baseline medical and demographic data 
Baseline characteristics (i.e. 
vital signs) 
 
1,2 
1,2 
1,2 
1,2 
History of prior concussion 
 
1,2 
 
 
 
If applicable, relevant prior 
TBI-related medical records 
may be collected and 
provided to the Sponsor. For 
each prior TBI the following 
should be collected: 
 
1,2 
 
 
 
Clinical notes describing 
the case by the site PI or 
 
1,2 
 
 
 
 
FOOTNOTES CORRESPONDING TO NUMERALS IN THE TEXT 
 
2 In the event that all points come from AUDIT C question #1, the investigator will determine eligibility based on his or her medical 
judgment. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
Page 51 of 74 
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        Version Date: 14/Nov/2016 
 
 
Visits (Clinical Site) 
Screening 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
clinical neurologist 
(mandatory if a prior TBI 
event is reported) 
Neuroimaging (when 
available) 
 
1,2 
 
 
 
 
Baseline cognitive 
assessments like SCAT2/3 
or other 
neuropsychological (when 
available) 
 
1,2 
 
 
 
Prior TBI-related medical 
records and/or laboratory 
reports (when available) 
 
1,2 
 
 
 
Certainty of mTBI diagnosis 
on a 3 point ordinal scale, 
where 1 = certain mTBI 
diagnosis, 2 = probable mTBI 
diagnosis, 3 = possibly mTBI 
diagnosis) (as defined in 
Section 6.3.3. Baseline Data 
Collection: Certainty of 
Diagnosis) 
1 
 
 
 
 
How much sleep did you 
have last night (hr) 
 
1,2 
1,2 
1,2 
1,2 
History of exposure to 
contact sports 
 
1,2 
1,2 
1,2 
1,2 
NINDS CDE Tools3 
(versions used may be updated if new versions are released during the study or for other research purposes)  
TBI Type, Place, Cause 
(TBI CDE Version 4.0) 
1 
 
 
 
 
Injury Presentation (TBI 
CDEs Version 4.0) 
1 
 
 
 
 
Post-injury status (TBI 
CDEs Version 5.0) 
1 
 
 
 
 
Medical history (to 
include prior TBI history) 
 
1,2  
1,2 (changes 
since last 
visit/recent 
use) 
1,2 (changes 
since last 
visit/recent 
use) 
1,2 (changes 
since last 
visit/recent 
use) 
General Core version 
1.0 
1,2 
 
 
 
 
Language spoken 
1,2 
 
 
 
 
Socioeconomics (TBI 
CDE Version 5.0) 
1,2 
 
 
 
 
 
FOOTNOTES CORRESPONDING TO NUMERALS IN THE TEXT 
 
3 The National Institute of Neurological Disorders and Stroke (NINDS) and several Co-sponsoring Federal agencies have the 
common mission of developing data standards for clinical research, resulting in production of the NINDS Common Data 
Elements (CDE) worksheets for assessment of Traumatic Brain Injury (TBI) by the CDE Working Groups for all ages and severities 
(August 2013 Version; http://www.commondataelements.ninds.nih.gov). Some assessments may be used in a modified form 
for research purposes or may be updated if new versions become available during the study. Consult the Sponsor-provided CRF 
for specific line items of the GE adaptations to these forms. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
Page 52 of 74 
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        Version Date: 14/Nov/2016 
 
 
Visits (Clinical Site) 
Screening 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Medication, stimulant, 
or illicit substance 
 
1,2 
1,2 
(changes 
since last 
visit) 
1,2 
(changes since 
last visit) 
1,2 
(changes since 
last visit) 
Additional elements 
 
 
 
 
 
How much sleep did 
you have last night? 
 
1,2 
1,2 
1,2 
1,2 
History of exposure to 
contact sports (sports 
played, position, dates) 
 
1,2 
1,2 
1,2 
1,2 
Clinical Assessments 
Symptoms self-report 
 
 
 
 
 
Rivermead Post-
Concussion Symptoms 
(PCS) Questionnaire 
 
1,2 
1,2 
1,2 
1,2 
Cognitive Behavioral  
 
 
 
 
 
GOS-E 4 
 
1,2 
1,2 
1,2 
1,2 
BSI-18 
 
1,2 
1,2 
1,2 
1,2 
GCS-E 5 
 
1,2 
1,2 
1,2 
1,2 
Trail Making Test (TMT) 
Parts A & B 
 
1,2 
1,2 
1,2 
1,2 
WISC-IV or WAIS-IV (based 
on age of subject) WMI 
and PSI composite scores, 
requiring subtests: 
 
 
 
 
 
Digit span (WMI 
component) 
 
1,2 
1,2 
1,2 
1,2 
Letter-numbering 
sequence (WMI 
component) 
 
1,2 
1,2 
1,2 
1,2 
Coding (PSI component) 
 
1,2 
1,2 
1,2 
1,2 
 
FOOTNOTES CORRESPONDING TO NUMERALS IN THE TEXT 
 
4 Glasgow Outcome Scale Extended (GOS-E). The Glasgow Outcome Scale (GOS) is a global scale for functional outcome that rates 
patient status into one of five categories: Dead, Vegetative State, Severe Disability, Moderate Disability or Good Recovery. The 
Extended GOS (GOSE) provides more detailed categorization into eight categories by subdividing the categories of severe 
disability, moderate disability and good recovery into a lower and upper category. Extended Glasgow Outcome Scale (GOS-E) 
ratings are shown below. Use of the structured interview is recommended to facilitate consistency in ratings. 
1. 
Death 
2. 
Vegetative state 
3. 
Lower severe disability 
4. 
Upper severe disability 
5. 
Lower moderate disability 
6. 
Upper moderate disability 
7. 
Lower good recovery 
8. 
Upper good recovery 
 
Accessed online at www.tbi-impact.org/cde/mod_templates/12_F_01_GOSE.pdf 08/Sep/2015 
5 Nell et al. An extended Glasgow Coma Scale (GCS-E) with enhanced sensitivity to mild brain injury. Arch Phys Med Rehabil. 2000 
May;81(5):614-7. 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Visits (Clinical Site) 
Screening 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Symbol Search (PSI 
component) 
 
1,2 
1,2 
1,2 
1,2 
HVLT-R 
 
1,2 
1,2 
1,2 
1,2 
Physical Tests 
 
 
 
 
 
BESS 6 
 
1,2 
1,2 
1,2 
1,2 
MR Data (Clinical Site) 
MR Scanner Information 
 
 
 
 
 
System ID 
 
1,2 
1,2 
1,2 
1,2 
Model of MR Scanner 
 
1,2 
1,2 
1,2 
1,2 
MR in/out time (exposure 
time on 24 hr clock) 
 
1,2 
1,2 
1,2 
1,2 
GE Research Pack II Scan 
 
MR Data 
 
 
 
 
 
DICOM 
 
1,2 
1,2 
1,2 
1,2 
P-files 
 
1,2 
1,2 
1,2 
1,2 
Auxiliary files 
 
 
 
 
 
MR Scan information 
 
 
 
 
 
MR in/out time (exposure 
time on 24 hr clock) 7 
 
1,2 
1,2 
1,2 
1,2 
Make/model of any MR 
accessories used 
 
1,2 
1,2 
1,2 
1,2 
MR Coils used 
 
 
 
 
 
32-channel (Nova 
Medical) coil 
use/identity 
 
1,2 
1,2 
1,2 
1,2 
Conventional coil 
make/model 
 
1,2 
1,2 
1,2 
1,2 
Errors (Y/N) and 
comments 
 
 
 
 
 
Site Radiologist Reads of T1, 
T2, Flair, and reconstructed 
SWI and DTI Acquisitions  
(NINDS TBI CDE Version 4.0) 
 
1,2 
1,2 
1,2 
1,2 
MR Post-processing (processed at Imaging Laboratory for data from indicated visits) 
Post-processing assessment 
modules and evaluations 
(Appendix D) 
 
1,2 
1,2 
1,2 
1,2 
Note: In the event that updates to assessments are elements are required during the course of the study, the 
Sponsor may provide an updated listing to the sites for use in this study. 
 
 
 
FOOTNOTES CORRESPONDING TO NUMERALS IN THE TEXT 
 
6 The BESS should be performed on a firm surface. Foam pads should not be used for BESS testing in this study. 
7 Exposure time (Te) is estimated by subtracting the MR scanning time in from MR scanning time out (Ti and To, respectively), as 
given by Te = To – Ti 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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APPENDIX F – AMENDMENT TO PROTOCOL VERSION 1.0 TO 2.0 
Purpose: This amendment document describes the changes from protocol version 1.0 to 2.0, as follows: 
1. To remove a non-participating site (University of Michigan). 
2. To remove the MR phantom daily and monthly sub-studies. Notably, MR phantoms may still be used in 
routine training and calibration for the study, as originally described in the protocol version 1.0, to ensure 
quality; however, no systematic data collection will be performed for this data. 
3. To clarify language in Appendix E regarding description and identify of cognitive and symptoms 
assessments. 
The following amendments were made to version 1.0 to produce version 2.0. Point-by-point revisions are shown as 
additions in double-underline (double-underline) and deletions in strikethrough (strikethrough) for each change 
made in this amendment for the previous version. 
Item 
Section 
Revision or Clarification 
Justification 
1 
Study Synopsis 
Site 
007 
Jeffrey S. Kutcher, 
MD (Principal 
Investigator) 
Tel: 734-936-9055 
e-mail: 
jkutcher@med.umic
h.edu  
University of 
Michigan 
2301 
Commonwealth 
Blvd. 
An Arbor, MI   
48105 
[Footnote added] 1. The University of Michigan Site (originally Site 
007) is removed due to non-participation. 
 
Study Sponsor:  GE 
Healthcare (GEHC) 
Sponsor Contact: John 
Strohmeyer,  Senior Clinical 
Affairs Project Manger 
Address:  
3200 3000 N 
Grandview Blvd 
Waukesha, WI 
53188 
 
Telephone: 
 +1-609-865-7423 
E-mail: John.Strohmeyer@ge.com  
Research Manager Name:  
Amy Gallenberg 
Clinical Study Program 
Manager, 
GE/NFL Head Health 
Initiative  
Address: 
3200 N Grandview 
Blvd 
Waukesha, WI 
53188 
 
Telephone: 
 +1-262-409-0704 
E-mail: 
Amy.Gallenberg@med.ge.com  
Medical Monitor Name:  
Victor Miranda, MD 
Executive Medical Director 
Address: 
 3200 3000 N 
Grandview Blvd 
 Waukesha, WI 
5318
8 
Telephone: 
 +1-262-544-3633 
E-mail: Victor.Miranda@ge.com  
Removed a non-
participating site 
(University of 
Michigan) from the 
synopsis site lists.  
 
Updated street 
address of Sponsor 
contact. 
2 
Study Synopsis - 
Summary of Study 
Procedures: 
Daily fMRI QA (performed before the start of human scanning on 
each scan day) and monthly system phantom and, if determined 
necessary by the Sponsor, monthly diffusion phantom scanning will 
be performed to verify MR system stability and characteristics 
throughout the study.  
Removed reference to 
the MR phantom daily 
and monthly sub-
studies. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Item 
Section 
Revision or Clarification 
Justification 
3 
Study Synopsis - 
Device/Product 
Description: 
Site-owned Discovery MR750 3.0T and/or MR750w 3.0T scanners 
with research coils will be used for acquisition, and commercially 
available VolumeShare 5 Advantage Workstations (AW) will be used 
for post-processing. Conventional accessory/ancillary devices, such 
as alternative MR coils, padding, communication, and safety devices 
may be provided by the site for use in this study (or by the sponsor, if 
unavailable for use at any investigational site). The Sponsor will 
provide MR imaging phantoms necessary for study quality assurance 
procedures. 
Removed reference to 
devices the MR 
phantom daily and 
monthly sub-studies 
for quality assurance. 
4 
Section 2.1.1. GE 
Research Pack II 
Advanced MRI 
Application Suite 
GE Research Pack II is an advanced MRI application suite developed 
by the Sponsor, GE Healthcare (GEHC), consisting of acquisition 
software executable on Discovery MR750 3.0T/Discovery MR750w 
3.0T MR scanners and a comprehensive set of post-processing 
modules (volumetry, Kurtosis, RS fMRI, RSI, and, as applicable, 
further advanced modules) executable on VolumeShare 5 Advantage 
Workstations (AW). Acquisition includes pulse sequences and 
corresponding interface software to define radio frequency (RF), 
gradient pulses, and associated parameters to optimally shape 
gradient waveforms when used in conjunction with head coils. Echo 
time as well as imaging parameters for contrast and other 
characteristics have been enhanced for optimal results in mTBI based 
on commercially available MR sequences, including a variety of 
advanced modules like functional MRI (fMRI), transit time mapping 
(TT mapping), enhanced arterial spin labeling (eASL), 3D-enhanced 
T2* weighted angiography (eSWAN), and fluid attenuated inversion 
recovery (FLAIR), as well as specialized T1 and T2 sequences. To 
maintain and calibrate systems and for training, routine MR 
accessories such as MR imaging phantoms, may be used in this study. 
18, 19  
Clarified that MR 
phantoms may still be 
used in routine 
training and 
calibration for the 
study, as originally 
described in the 
protocol version 1.0, 
to ensure quality; 
however, no 
systematic data 
collection will be 
performed for this 
data. 
 
5 
Section 2.1.3 MR Imaging 
Phantoms 
2.1.3 MR Imaging Phantoms 
MR Quality Imaging Phantom Models (Quantitative Diffusion 
Phantom 19 and Quantitative System Phantom 20; High Precision 
Device, Inc., Boulder, CO, USA) are modeled after the human head 
imaging characteristics. The Quantitative Diffusion Phantom consists 
of a sphere containing small areas of varied contrast agents designed 
for quantitative standardization, including recording of the apparent 
diffusion coefficient (ADC). The Quantitative System Phantom is a 
plastic sphere containing vials of varied polymer polyvinylpyrrolidone 
(PVP) aqueous solutions for standardization of isotropic diffusion in 
H2O, designed for measuring B1 uniformity, B0 uniformity, geometric 
linearity, gradient amplitude, slice profile, slice positioning accuracy, 
landmark accuracy, system center frequency drift (short time 
duration), resolution, signal-to-noise ratio (SNR), and 
accuracy/precision of T1 and T2 measurements.  
 
Removed reference to 
devices the MR 
phantom daily and 
monthly sub-studies 
for quality assurance. 
6 
Section 4.2. Type of 
Research Study 
This study plans to include up to seven (7) sites 
Revised to match 
synopsis language. 
There are currently 6 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Item 
Section 
Revision or Clarification 
Justification 
active sites, but up to 
7 may participate. 
7 
Section 6.1.2. MR 
Imaging Phantoms 
(monthly procedure)/ 
Section 6.1.2 fMRI 
Quality Assurance (QA) 
Tool (daily procedure) 
6.1.1 MR Imaging Phantoms (monthly procedure) 
To enable future evaluation of performance between scanners and 
reproducibility of findings, each site will perform MR Imaging 
Phantom Model scans (Quantitative System Phantom and, if 
determined necessary by the Sponsor, Quantitative Diffusion 
Phantom, as described in Section 3.1.3 MR Imaging Phantoms) at 
least once per month (at intervals of 30±5 days). Monthly phantom 
scans will be completed in accordance with the manufacturer’s 
instructions and, if necessary, additional scanning instructions 
provided by the Sponsor.  
For each phantom scan performed as part of the quality procedure, 
study staff will record the DICOM output and provide results to the 
Sponsor for regular technical processing and review. Additional MR 
imaging phantom scanning may be conducted at any time during the 
study (except during a clinical scan of a human subject), at the 
discretion of the investigator. If the investigator observes any issues 
that he or she suspects could interfere with the intended function or 
performance of the device, the Sponsor should be informed. 
6.1.2 fMRI Quality Assurance (QA) Tool (daily procedure) 
fMRI is inherently sensitive to minor and expected variations in local 
systems that do not typically impact clinical scanning. In order to 
ensure the integrity of fMRI data, at the start of each day of study 
scanning, prior to the first scan of a human subject the fMRI Quality 
Assurance (QA) tool should be executed on each scanner used in the 
study. This procedure is conducted with no human in the bore. 
Completion of the fMRI QA procedure should be logged in the fMRI 
QA Completion Log, as shown in Appendix B – fMRI QA Completion 
Log. 
Removed the 
procedures for MR 
phantom daily and 
monthly sub-studies. 
8 
Section 7.0 Training Plan Training plan documents and logs of training attendance will be 
stored in the Sponsor’s clinical history file (CHF). 
 
Clarified that there is a 
separate training plan, 
to be stored in the 
HAT file. 
9 
Section 7.1. Training Plan 
for Research Device 
The Sponsor will provide training on the research device and any 
device optimizations or versions released during the study. The 
Investigator may request that additional training be provided to staff 
by the Sponsor or previously trained study staff during the study. MR 
imaging phantoms may be used in training and retraining during this 
study, and phantom training data may be collected and disclosed to 
the Sponsor as part of this study. 
 
Clarified that MR 
phantoms may still be 
used as part of training 
and, though not 
systematically 
collected, any such 
data may be disclosed 
to the Sponsor as part 
of research. 
10 
Section 13.4. Record 
Retention at the Site 
▪ 
Subject Files – containing the completed subject CRFs,    
(signed/dated) Informed Consent Form(s) 
Corrected 
typographical error. 
This should read that 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Section 
Revision or Clarification 
Justification 
▪ 
Regulatory Binder – containing the protocol and amendments, 
EC/IRB submissions and approvals, (blank and signed/dated) 
Informed Consent Form(s), Site study logs and sub-contracted 
site qualifications and contracts. 
 
signed ICFs are stored 
in subject files (not the 
regulatory binder). The 
regulatory binder will 
contain copies of blank 
ICF versions. 
11 
Section 16.1. 
Abbreviations and 
Terminology 
UADE 
 
Unanticipated adverse device effect 
Added abbreviation. 
12 
Appendix A – Segment 0 
Volunteer Scan Log 
Segment 1 0 volunteers may be enrolled for training/retraining 
purposes only. 
 
Corrected 
typographical error in 
the instruction, 
referencing Segment 0 
(volunteers). 
13 
Appendix B – fMRI QA 
Completion Log 
 
Appendix B – fMRI QA Completion log 
This appendix is removed as per Amendment to protocol version 1.0 
to 2.0 amendment ID Nos. #7 and #9. This log is no longer used as 
part of this study. 
[content tables of log removed] 
Removed the log 
corresponding to MR 
Phantom procedures, 
which are removed 
per amendment #7. 
 
The Appendix B 
header is maintained 
to keep the 
alphanumeric order of 
appendices consistent. 
 
14 
APPENDIX E – DATA 
COLLECTION BY STUDY 
VISIT 
 
 
 
Visits (Clinical Site) 
Scree
ning 
Visit 1 
Visit 
2 
Visit 3 
Visit 4 
Eligibility 
… 
 
 
 
 
 
AUDIT C 2 
1,2 
 
 
 
 
… 
 
 
 
 
 
Baseline medical and demographic data 
Certainty of 
mTBI 
diagnosis 
on a 3 point 
ordinal 
scale, where 
1 = certain 
mTBI 
diagnosis, 2 
= probable 
mTBI 
diagnosis, 3 
= possibly 
1 
1 
 
 
 
Clarifies the 
procedures to be 
completed, including 
footnotes as reference 
to scales. Removed the 
SCAT GSC and added 
GOS-E. 
 
Moved certainty of 
diagnosis to screening 
visit, per logistical 
recommendation by 
CRO. 
 
Added that recent 
substance/alcohol use 
would be recorded, in 
addition to changes in 
status. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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        Version Date: 14/Nov/2016 
mTBI 
diagnosis) 
… 
 
 
 
 
 
Clinical Assessments 
… 
 
 
 
 
 
SCAT2 
Graded 
Symptoms 
ChecklistG
OS-E 4 
 
1,2 
1,2 
1,2 
1,2 
BSI-18 
 
1,2 
1,2 
1,2 
1,2 
GCS-E 5 
 
1,2 
1,2 
1,2 
1,2 
… 
 
 
 
 
 
Medical 
history 
(to 
include 
prior TBI 
history) 
 
1,2  
1,2 
(chan
ges 
since 
last 
visit/r
ecent 
use) 
1,2 
(chang
es 
since 
last 
visit/r
ecent 
use) 
1,2 
(chang
es 
since 
last 
visit/r
ecent 
use) 
… 
 
 
 
 
 
MR Data (Clinical Site) 
… 
 
 
 
 
 
Per-sequence 
information 
 
 
 
 
 
Frequency 
Field of 
View 
(FFOV) 
 
1,2 
1,2 
1,2 
1,2 
Phase Field 
of View 
(PFOV) 
 
1,2 
1,2 
1,2 
1,2 
Ease of use 
(1-5 Likert)6 
 
 
 
 
 
… 
 
 
 
 
 
[added footnote] 2. In the event that all points come from AUDIT C 
question #1, the investigator will determine eligibility based on his or 
her medical judgment. 
 
[added footnote] 4. Glasgow Outcome Scale Extended (GOS-E). The 
Glasgow Outcome Scale (GOS) is a global scale for functional outcome 
that rates patient status into one of five categories: Dead, Vegetative 
State, Severe Disability, Moderate Disability or Good Recovery. The 
Extended GOS (GOSE) provides more detailed categorization into 
eight categories by subdividing the categories of severe disability, 
moderate disability and good recovery into a lower and upper 
category. Extended Glasgow Outcome Scale (GOS-E) ratings are shown 
below. Use of the structured interview is recommended to facilitate 
consistency in ratings. 
1. 
Death 
2. 
Vegetative state 
3. 
Lower severe disability 
4. 
Upper severe disability 
 
 
Removed per-
sequence information 
duplicated in DICOM 
and ease of use 
assessment, which 
does not directly 
support study aims. 
 
Note that coil 
information should be 
recorded per case, but 
should be 32-ch nova 
coil for most patients 
(unless unable to use 
for medical reasons). 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Justification 
5. 
Lower moderate disability 
6. 
Upper moderate disability 
7. 
Lower good recovery 
8. 
Upper good recovery 
 
Accessed online at www.tbi-
impact.org/cde/mod_templates/12_F_01_GOSE.pdf 08/Sep/2015 
 
[added footnote] 5. Nell et al. An extended Glasgow Coma Scale 
(GCS-E) with enhanced sensitivity to mild brain injury. Arch Phys Med 
Rehabil. 2000 May;81(5):614-7. 
 
[removed footnote 6 corresponding to removed assessment]  Five 
point Likert scale (1-5) scale for “How easy is the pulse sequence to 
use?”, rated as follows: 
1 -  Very easy to use 
2 – Easy to use 
3 – Neutral 
4 – Difficult to use 
5 – Very difficult to use 
 
 
 
 
 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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APPENDIX G – AMENDMENT TO PROTOCOL VERSION 2.0 TO 3.0 
Purpose: This amendment document describes the changes from protocol version 2.0 to 3.0, as follows: 
1. To clarify language surrounding study enrolment, data collection, and withdrawal. These are clarifications 
to the original procedure designed to improve consistency of execution across sites and do not alter the 
scientific intent of the original procedures. 
2. To add specific definition around for scoring on the existent 3-point diagnostic certainty scale and 
baseline data collection. 
3. To clarify terminology related to devices and software, including which will clinically useful sequences can 
be read by study readers.  
4. Clarifies that patients that experience a second TBI or other severe injury that could interfere with the 
study during their enrolment should be withdrawn. 
5. Updates Appendix D with most current post-processing details. 
The following amendments were made to version 2.0 to produce version 3.0. Point-by-point revisions are shown as 
additions in double-underline (double-underline) and deletions in strikethrough (strikethrough) for each change 
made in this amendment for the previous version. 
Item 
Section 
Revision or Clarification 
Justification 
15 
Study Synopsis: Summary 
of Study Procedures 
Summary of Study Procedures: 
Clinical Site Procedures: Two parallel subject segments will be 
enrolled, including (1) mTBI patients with recent injury in Segment 1 
and (2) subjects without recent TBI injury of similar age and 
demographic characteristics (non-TBI controls in Segment 2). 
Baseline health information, demographics, and medical history 
(including prior TBI injury) will be collected for both segments. 
Subjects will attend up to four sequential visits relative to injury date 
(mTBI subjects) or first study scan date (controls): Visit 1 = ≤72 hr, 
Visit 2 = 7±2 days, Visit 3 = 14±2 days, and Visit 4 = 90±7 days. The 
mTBI subjects (Segment 1) may start at Visit 1 or Visit 2. Each visit 
will include a clinical neuropsychological assessment battery and MR 
scan with GE Research Pack II (including research sequences and 
clinically useful T1, T2, Flair, and reconstructed SWI and DTISWAN) 
will be evaluated by the site. 
Laboratory Procedures: Clinically acquired MR data (DICOM, P-files, 
and auxiliary files) will be transferred to an imaging laboratory for GE 
Research Pack II reconstruction of clinically useful views using 
multiband technology and study post-processing. Post-processed 
data and evaluations (as indicated on a per-module basis by the 
Sponsor) will be collected. 
Clarifies multiband and 
processing views from 
the study may be 
clinically useful. 
16 
Study Synopsis: 
Device/Product 
Description 
Device/Product Description: 
The device under study is the GE Research Pack II advanced MRI 
application suite developed by the Sponsor, GE Healthcare (GEHC), 
which consists of acquisition software executable on commercially 
available Discovery MR750 3.0T/Discovery MR750w 3.0T MR 
scanners and software for multiband image reconstruction and  and 
post-processing features modules (volumetry, Kurtosis, RS fMRI, RSI, 
Clarified language 
describing study 
software modules for 
consistency of 
terminology. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Justification 
and, as applicable, further advanced modules) executable on 
commercially available image processing workstations. GE Research 
Pack II is optimized for use with the investigational 32-channel head 
coil for 3.0T GE scanners (Nova Medical). 
Site-owned Discovery MR750 3.0T and/or MR750w 3.0T scanners 
with research coils will be used for acquisition, and commercially 
available VolumeShare 5 Advantage Workstations (AW) will be used 
for reconstruction and post-processing. Conventional 
accessory/ancillary devices, such as alternative MR coils, padding, 
communication, and safety devices may be provided by the site for 
use in this study (or by the sponsor, if unavailable for use at any 
investigational site). 
17 
Section 2.1.1. GE 
Research Pack II 
Advanced MRI 
Application Suite 
GE Research Pack II is an advanced MRI application suite developed 
by the Sponsor, GE Healthcare (GEHC), consisting of acquisition 
software executable on Discovery MR750 3.0T/Discovery MR750w 
3.0T MR scanners. The software enables routine reconstruction of 
images using multiband technology as well as study-specific post-
processing of other types of information not typically found in clinical 
images.  and aGE Research Pack II will include a comprehensive set of 
post-processing modules (volumetry, Kurtosis, RS fMRI, RSI, and, as 
applicable, further advanced modules) executable on VolumeShare 5 
Advantage Workstations (AW). 
Clarifies which views 
from the study are 
clinically useful for 
evaluable by the site. 
18 
Section 2.1.2. 32-channel 
Multiband MR Brain Coil 
2.1.2 32-channel Multiband MR Brain Coil 
The 32-channel multiband MR brain coils are designed to speed up 
scan time with parallel imaging. GE Research Pack II is optimized for 
the 32-channel MR brain coil for GE 3.0T (Nova Medical, Wilmington, 
Massachusetts, USA). 20 
Clarified terminology, 
for consistency. 
19 
Section 2.1.4. 
VolumeShare 5 
Advantage Workstation 
(AW) 
Post-processing is completed on a VolumeShare 5 Advantage 
Workstation (AW), which supports image display, manipulation, 
reconstruction, post-processing, and selective recording and is 
intended to be used to create and review diagnostic evidence related 
to radiology procedures by trained and licensed physicians and/or 
qualified clinical/medical personnel.   
 
Clarified terminology, 
for consistency. 
20 
Section 2.2. Regulatory 
Status 
GE Research Pack II, including its acquisition and software (multiband 
reconstruction and post-processing components), and the 32-
channel multi-band MR brain coil for GE 3.0T (Nova Medical) are 
investigational MRI system components that are not currently 
cleared by the US FDA.  
 
Clarified terminology, 
for consistency. 
21 
Section 2.4.2. Issuance of 
Devices to Imaging 
Laboratories 
If not already available at laboratories conducting executing GE 
Research Pack II post-processing software,, the Sponsor may provide 
VolumeShare 5 Advantage Workstation (AWs) for study use. The 
unique identification information for study devices will be recorded. 
The Sponsor will provide, install, and configure GE Research Pack II 
post-processing software on these workstations, and, as deemed 
necessary by the Sponsor, provide training for the use, quality check, 
and maintenance of these devices. 
Clarified terminology, 
for consistency. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Justification 
 
22 
Section 5.1.1. Enrollment 
of non-mTBI controls 
Enrollment Rate: Each site should enroll approximately half as many 
control subjects as mTBI subjects, at a rate of approximately one 
control enrollment for each two mTBI subjects that complete at least 
two visits (1:2). Though it is prospectively expected that actual 
enrollment rates may vary, it is the investigator’s responsibility to 
maintain this approximate rate in order to minimize possible bias 
due to variance in scanner performance (“scanner drift”) and other 
possible confounders. 
 that complete two consecutive visits and thus provide two 
consecutive data points (complete either Visits 1 and 2, or Visit 3 and 
4), e.g., one control may be enrolled for every two mTBI subjects.  
Population Matching: The study aims to achieve overall matched 
mTBI and control populations across sites. The overall population will 
be matched for characteristics identified in order of priority in Table 
2. To enable sites to select control subjects that match the overall 
population, a report of mTBI subject enrollment will be generated by 
the Sponsor or its delegated contract research organization (CRO) 
and provided to the site on a rolling monthly basis. The report will 
categorically detail the number of enrolled mTBI subjects with the 
following characteristics (Table 2). The clinical site, under the 
supervision of the Principal Investigator, will be ultimately 
responsible for ensuring that matched controls are selected 
according to these criteria. 
 
Case-Control Matching: When possible, investigators are also 
encouraged to enroll individually matched mTBI and control cases of 
potential medical interest. Priority should be given, however, to 
ensuring an appropriate overall population match. 
 
Overall Population Reports: A report of mTBI subject enrollment will 
be generated by the Sponsor or its delegated contract research 
organization (CRO) and provided to the site on a monthly basis (30±7 
days). The report will categorically detail the number of mTBI 
subjects with the following characteristic characteristics (Table 2). 
The clinical site, under the supervision of the Principal Investigator, 
will be ultimately responsible for ensuring that matched controls are 
selected according to these criteria.  
Table 2 – Population characteristics for enrollment of non-TBI 
controls (Segment 2) based monthly mTBI accrual by order of priority 
for matching 
Controls are required to attend Visits 1 and 4, but may also attend 
Visit 2 and 3 when available. Per site, controls should be enrolled in a 
manner that achieves the same overall ratio within each 
characteristic category as the mTBI population that has completed 
two visits to date (per site, all mTBI patients enrolled from study start 
to date of monthly summary analysis), with the priority indicated 
above (i.e. highest priority should be given that the control 
population’s overall characteristics resemble those of the mTBI 
subject population’s characteristics for #1, then #2, etc.). 
Standardized and 
clarified enrolment of 
controls procedure. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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23 
Section 5.4.2. Exclusion 
Criteria by Study 
Segment 
6. Drug abuse (except marijuana) in past 10 years (if suspected or 
self-reported confirm by DAST-10 screening); 
Drug abuse (except marijuana) in past 10 years based on DAST-10 
screening; 
 
7. Alcohol abuse (if suspected or self-reported confirm by AUDIT-C 
screening); 
Alcohol abuse based on AUDIT-C screening; 
… 
12. Been prescribed antipsychotic/antiepileptic medications 
(including for current or past head injury); 
 
Clarified wording 
around screening 
requirements for mTBI 
subjects in the 
exclusion criteria. No 
change in scientific 
intent. 
24 
Section 5.4.2. Exclusion 
Criteria by Study 
Segment 
4. Drug abuse (except marijuana) in past 10 years (if suspected or 
self-reported confirm by DAST-10 screening); 
Drug abuse (except marijuana) in past 10 years based on DAST-10 
screening; 
 
5. Alcohol abuse (if suspected or self-reported confirm by AUDIT-C 
screening); 
Alcohol abuse based on AUDIT-C screening; 
… 
10. Been prescribed antipsychotic/antiepileptic medications 
(including for past head injury); 
 
Clarified wording 
around screening 
requirements for 
control subject in the 
exclusion criteria. No 
change in scientific 
intent. 
25 
Section 6.3.1. Visit 
Schedule 
Each mTBI patient (Segment 1) and non-mTBI control (Segment 2) 
will attend a series of up to 4 visits (Table 3). Subjects in the mTBI 
group may enroll and start the study at either Visit 1 or Visit 2 based 
on date of injury, and non-mTBI control subjects will attend visits on 
a similar schedule based on date of first study scan. If a subject 
attends a visit outside of this visit window, this will be considered a 
protocol deviation and reported in accordance with Section 9.1. - 
Management of Protocol Deviations. Subjects should attend all study 
visits, when possible. Controls will be enrolled continuously, as 
described in Section 5.1.1. Enrollment of non-mTBI controls. When 
possible, if the site is using more than one MR scanner for study 
purposes, the same scanner should be used for all visits for a single 
subject. 
Table 3 - Visit schedule for mTBI and non-mTBI control segments 
Segment 
Description 
Visit Schedule 
 
 
Visit 
1 
Visit 
2 
Visit 
3 
Visit 
4 
Segment 
1 
mTBI 
Subjects 
 
(may be 
enrolled at 
≤72 
hr* 
from 
injur
y 
Day 
7±2* 
from 
injury 
Day 
14±2 
from 
injury 
Day 
90±7 
from 
injur
y 
Clarified language 
surrounding protocol 
visits and removed 
redundant language 
references deviation 
definition. This does 
not change the 
scientific intent of the 
study, but it rather 
intended to clarify the 
procedure for 
consistent execution 
across sites. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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either Visit 1 
or Visit 2, 
where first 
visit is 
considered 
baseline) 
(Bas
eline
) 
NA 
Day 
7±2* 
from 
injury 
(Baseli
ne) 
Day 
14±2 
from 
injury 
Day 
90±7 
from 
injur
y 
Segment 
2 
non-mTBI 
Controls# 
Basel
ine # 
Day 
7±2 
from 
baselin
e 
(option
al) 
Day 
14±2 
from 
baseline 
(optional
) 
Day 
90±7 
# 
from 
basel
ine 
Segment 
0 
volunteer 
subjects 
(training) 
Volunteers may participate one or 
more scans, if they remain eligible 
and satisfy Section 6.2.2. 
Participation in Multiple Scan 
Sessions  
Note: Day 0 is based on date of injury for mTBI patients (Segment 1) 
or the day of first study scan (baseline) for patients without mTBI 
(Segments 0 and 2). The date of first study scan is considered 
baseline for all subjects. 
* mTBI subjects may be enrolled at either Visit 1 or Visit 2.  
# Non-mTBI subjects are required toshould attend visits 1 and 4, but 
should attendand all 4 visits, when possible.. 
26 
Section 6.3.2. Handling 
Visit Completion, Missed 
Visits, and Loss to Follow-
up 
First Visit (Baseline): All Segment 1 (mTBI subjects) and Segment 2 
(non-mTBI controls) are required to complete their initial MRI scan 
and clinical neurological assessment within 24 hours (in either order), 
and are required to satisfy complete all parts of the visit within the 
visit window as defined in Table 2 (with the exception of requests for 
medical history and other historical information, which may be 
requested and added to the subject record at any time during the 
study, as data becomes available to the investigators). Any subject 
that is not able to complete all parts of the first visit within the visit 
window should be withdrawn from study once this becomes known. 
No additional information will be collected after the time of 
withdrawal, but information collected up until this point may be used 
and disclosed. Withdrawal due to inability to complete a visit is not 
considered a deviation if the subject is immediately removed from 
study (withdrawn) and no additional information is collected. 
 
Subsequent Visits – Missed or Incomplete Visits: For all subsequent 
visits, subjects may remain on study if a visit is missed or incomplete 
for any reason, at the investigator’s discretion (else the subject may 
be withdrawn). The site will note the reason for any missed or 
incomplete visits for subjects that remain on study, and these 
incomplete data sets will not considered a deviation. It is ultimately 
Added clarifying 
language to ensure 
consistent execution 
of missed visit 
procedures across 
sites. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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the responsibility of the investigator to ensure that data is maximally 
complete, as incomplete case data may impair scientific integrity of 
the study.  
 
Subsequent Visits – Missed Visit Window (Table 2): If a subject 
failed to complete a visit within the visit window, he/she may still be 
eligible to complete future visits as scheduled (Table 2). Except in 
exceptional circumstances, study procedures should not be 
conducted outside of the visit windows (Table 2). Any part of a study 
visit conducted outside of the protocol visit windows should be 
reported as a deviation. 
 
Lost to Follow-Up: If a subject is not able to be contacted for 
scheduled visits (Table 2), the subject will be withdrawn from study 
and considered lost to follow-up. The site should make reasonable 
attempts to contact all subjects and document these activities as part 
of the study source documentation stored in the study file. Subjects 
lost to follow-up are not considered in deviation of the protocol if 
documentation of reasonable attempt to contact is maintained by 
the site and the subject is withdrawal is documented in the study 
record. 
 
Withdrawal: Withdrawals should be documented as per Section 6.5. 
-Withdrawal and Discontinuation Criteria. Once a subject is 
withdrawn, he/she is no longer eligible to participate in any future 
study visits or procedures, but the data collected up until the time of 
withdrawal may still be used and disclosed as part of this research. 
 
27 
Section 6.3.3 Baseline 
Data Collection 
After the subject is determined eligible according to the 
inclusion/exclusion and has provided informed consent (and assent 
for minors), he/she will undergo an initial assessmentthe following 
will be recorded for each subject at the first visit: 
• 
, wherein gGeneral medical Medical Hhistory and 
Dedemographic informationInformation,  
• 
Prior mTBI Information: Current (for mTBI subjects) or prior TBI 
history information (if applicablefor all control and mTBI 
subjects), if available for the subject (it is prospectively expected 
that not all data may be available for each subject):,  
o 
prior medical records 
o 
relevant laboratory reports 
o 
neuroimaging (including CT, MRI, or other scans) 
o 
baseline neuropsychological or cognitive assessments 
done for sports or occupational purposes (such as 
SCAT2/3 for sports players), which may be requested 
from prior care providers and collected as part of 
study data. 
Clarifies language 
around collection of 
baseline data to match 
the actual electronic 
data capture (EDC) 
implementation. Adds 
definition around the 
3-point scoring for 
diagnostic certainty to 
ensure consistent 
execution across sites. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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• 
Baseline Clinical Information about the injury (must be 
collected within visit window): 
o 
injury presentation information 
o 
, baseline health information assessments (such as 
vital signs) collected during the visit, and  
o 
diagnostic certainty Certainty of Diagnosis (for mTBI 
patients in Segment 1) (assessed on a 3-point ordinal 
scale). Eligible subjects are required to meet 
diagnostic criteria for mTBI at the site. In addition, a 
qualified physician or clinical psychologist on the study 
staff will assess certainty of diagnosis based on: 
4  =   
Certain mTBI Diagnosis: Presents with a 
combination of physical, behavioral/emotional, 
and/or cognitive symptoms (not pre-existing) 
where recent head injury is strongly expected 
to play the central causal role. 
5  =   
Probable mTBI Diagnosis: Presents with at 
least one physical, behavioral/emotional, 
and/or cognitive symptoms (not pre-existing) 
where recent head injury can be reasonably 
expected to play a causal role. 
6  =   
Possible mTBI Diagnosis: Presents with at least 
one physical, behavioral/emotional, and/or 
cognitive symptoms (not pre-existing) where it 
is uncertain whether or not recent head injury 
plays a causal role (as in the case where 
symptoms assessment is complicated by other 
conditions or diagnoses pre-existing mTBI, 
such as mood disorders, physical disability, or 
other chronic conditions or medication use). 
information will be recorded 
. For subjects with current mTBI or prior TBI injury, prior medical 
records, neuroimaging (including CT, MRI, or other scans), and 
available baseline neuropsychological or cognitive assessments done 
for sports or occupations purposes (such as SCAT2/3 for sports 
players) may be requested from prior care providers and collected as 
part of study data.  
Baseline will be considered the day of the first study scan for all 
subjects., and Baseline Data will be inclusive of information collected 
or requested based on the first visit (General Medical and 
demographic information, and prior mTBI information) and 
information collected at the first visit (Baseline Clinical Information). 
Only Baseline Clinical Information is required to be collected and 
reported within the visit window. Other information, such as medical 
history and prior records, may be updated in the subject record as it 
becomes available to the site. 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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28 
Section 6.3.4. Visit 
Procedures (Clinical 
Neuropsychological 
Assessment and MR 
Scan) 
Each visit will consist of a Clinical Neuropsychological Assessment of 
symptoms self-report, cognitive behavioral scales, and physical 
testing (lasting approximately 60 minutes) and an MR scan session 
using GE Research Pack II acquisition software (lasting approximately 
60 minutes). The MR scan should be completed within the interval 24 
hours of before or after the Clinical Neuropsychological Assessment 
(within 4 hours, when possible). The example listing of data 
collection to be performed at each visit is shown in Appendix E – 
Data Collection by Study Visit. 
For MR scanning, study staff should ensure that the subject meets 
the criteria for MR safety at the site immediately prior to MRI 
scanning. Subjects will be provided with clothing safe for MRI (such 
as hospital gowns), hearing protection, and protective devices, per 
the site’s standard of care for MRI scanning. Subjects will be told how 
to communicate with the operator during scanning, and scanning 
may be stopped at any time if the subject reports discomfort.  
All scans will be completed using 32-channel multiband research coil, 
except in in cases where the 32-channel multiband research coil 
cannot be used due to: (1) head size, (2) medical conditions, (3) 
deformities, (4) anxiety, or (5) other medical issues. Alternatively, 
any commercially available 32-channel MR coil available at the site 
may be used, and its applicable identifiers (i.e. make, model, etc.) will 
be recorded. 
 
Terminology updates, 
for consistency with 
prior sections. 
29 
Section 6.3.5. MR 
Acquisition Data (Clinical 
Site Procedure) 
For each scan session, the scan operator or designee will record 
parameters as described in the MR Data (Appendix E – Data 
Collection by Study Visit) to a Sponsor provided case report form 
(CRF). DICOM, P-files, and auxiliary files (collected according to the 
instructions provided by the Sponsor) will be recorded for each visit. 
This data will be transferred to the Sponsor or its identified contract 
research organization (CRO) for execution of the GE Research Pack II 
software (including multiband reconstruction for SWI and DTI and 
study post-processing). 
 
While SWI and DTI are 
clinically useful, this is 
removed to correct 
misinterpretation that 
these are linked with 
multiband technology. 
30 
Section 6.3.6. MR 
Acquisition Image 
Reads/Evaluations 
(Clinical Site Procedure) 
One or more site radiologist will read the clinically useful sequences 
from acquired from GE Research Pack II. For reading, the clinically 
useful image set includes both the images produced routinely from 
the clinical interface ( (T1, T2, and Flair, ) SWANand images that 
require reconstruction by the software due to use of multiband 
technology (SWI and DTI).  
Readers will assess the entire clinically useful image set (T1, T2, and 
Flair and reconstructed SWI and DTI) MR acquisitions according to 
the NINDS CDE Tool: Imaging with additional Sponsor-provided 
elements (if necessary) added for research purposes, . The reader 
will determine whether each case is normal or abnormal and 
complete the Sponsor-provided case report form (CRF) for each case. 
Clarifies which 
software used in the 
study produce images 
of possible clinical 
usefulness to the site, 
as assessable by site 
readers. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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and the result will be recorded. Readers are not required to be 
blinded to clinical care. Readers will have access to reconstructions 
necessary to, but will be review the full clinically useful image set 
(including conventional reconstructions available from the clinical 
interface and reconstructions of SWI and DTI produced by the GE 
Research Pack II software, which are not able to be produced on the 
clinical interface due to use of the investigational multiband 
technology). Readers will be  blinded to other results of post-
processed processing with GE Research Pack II.. 
 
31 
Section 6.4.1. Incidental 
Findings 
MR imaging in this study is conducted using investigational MR 
sequences for research purposes. The investigational research 
sequences are not intended to provide diagnostic information; 
however, GE Research Pack II also contains components that may be 
useful as reference for the patient’s clinical care (including clinically 
useful T1, T2, Flair, and reconstructed SWI and DTI SWAN MR data 
conducted during research scan sessions). Patient management 
should not be based solely on data acquired from research 
sequences. The other research MR images and related data 
generated as part of study procedures are not intended for use in 
patient management decisions or to be stored in patient medical 
records. In the event that a member of the study staff identifies 
something possibly abnormal in a research MR image that may be of 
medical significance, they shall notify the principal investigator. The 
principal investigator will be responsible for evaluating any such 
incidental findings and, if necessary according to his/her medical 
judgment, communicating findings to the patient and/or his or her 
regular physician, in accordance with IRB policy.   
 
Terminology updates, 
for consistency with 
prior sections. 
32 
Section 6.5. Withdrawal 
and Discontinuation 
Criteria 
A subject may withdraw from study at any time, for any reason 
without consequence. The Investigator may withdraw a subject at 
any time for any reason, including some clinical conditions 
concurrent enrollment in another interventional research study that 
could confound results or pose risks to the patient, or use any 
medication, stimulant, or illicit substance that could interfere with 
safe study conduct or integrity of research data, in the opinion of the 
Principal Investigator. In the event that a subject experiences an 
additional TBI injury during the study period or sustains other 
significant injury that could interfere with study participation or 
outcomes, the subject should be withdrawn when the investigator 
becomes aware of the change in the subject’s medical status. In 
cases where the investigator is unsure if an injury would disqualify 
the subject, the case should be confirmed with the Sponsor’s medical 
monitor. 
Note: For each subject’s first visit, the subject must complete their 
MR scan and neurological assessment per-protocol (baseline and 
prior medical history data may be collected at any time after 
enrollment). Thereafter, sSubjects that miss a visit or attend a visit 
outside of the scheduled window should not be withdrawn, and may 
continue in the study. Missing a visit or visit window, however, will 
Clarifies that patients 
that experience a 
second TBI or other 
severe injury that 
could interfere with 
the study during their 
enrolment should be 
withdrawn. Also, 
clarifies that data 
associated with 
baseline exams can be 
collected throughout 
the study, but is 
requested/identified 
at the baseline visit 
window. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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be considered a protocol deviation and reported in accordance with 
Section 9.1. - Management of Protocol Deviations. 
 
33 
Section 7.1. Training Plan 
for Research Device 
7.2.1 Clinical Site Training on the Research Device 
… 
7.2.2 Imaging Laboratory Training on the Research Device 
 
Removed redundant 
headers to clarify text. 
There is no change to 
the intent of these 
sections. 
34 
Section 10.1. 
Foreseeable Adverse 
Events and Device Effects 
Because subjects are having a neurological assessment that includes 
physical and cognitive tests, there are some risks to subjects 
completing these assessments. These include physical or mental 
stress, fatigue, minor to moderate injury risk associated with physical 
tests (such falls or abrasions during balance tests, in rare cases), and 
confidentiality risks due to disclosure of personal information (e.g. 
sociodemographics, health, and occupational status information). 
The risks associated with these tests are not expected to exceed 
those encountered during routine examinations of head injury. 
 
Clarifies risks 
associated with 
physical and cognitive 
tests. 
35 
Section 10.3. 
Management of Adverse 
Event Reporting 
Any adverse events will be recorded in the subjects study record and 
the Adverse Event Case Report Form. Subjects will be followed for 
adverse events and device effects from the time they arrive for each 
study visit (immediately after providing informed consent for the first 
visit, and upon arriving to the study area for each subsequent visit, 
until the subject leaves the study area after each visit). The following 
information should be obtained: 
 
Clarifies the window 
for AE reporting in the 
study. 
36 
Section 10.4. 
Management of Serious 
Adverse Event and 
Unanticipated Adverse 
Device Effect Reporting 
All SAEs and or UADEs will be documented as above and reported 
both electronically and in writing to the Sponsor within 72 hours of 
knowledge of the event.   The Investigator shall submit the Adverse 
Event Case Report Form and GEHC_GQP_10.07.005_F002 Site 
Notification and Assessment of Serious and Unexpected Adverse 
Events (GEHC internal document DOC0910335) with redacted 
supporting documentation to SAE mailbox. If the event resulted in 
the death of a subject, the event shall also be reported via telephone 
to the Sponsor within 24 hours of knowledge of the event. SAEs will 
be reported to the local EC/IRB per their policy.  
 
Clarified reporting 
media for SAEs, in 
include electronic 
report. 
37 
Section APPENDIX E – 
DATA COLLECTION BY 
STUDY VISIT 
Note: The intervals of each visit are defined in Protocol Table 2. 
Screening for enrollment eligibility should occur before Visit 1 begins, 
and may be conducted in advance or immediately prior to the start 
of Visit 1 in accordance with site recruitment practices. Screening 
and Visit 1 may occur on the same day id the protocol requirements 
are met. 
 
 
Visits (Clinical Site)… 
Screening 
… 
Eligibility 
Added note to clarify 
screening/recruiting is 
per local site 
recruitment 
procedures. Clarified 
wording to match 
revisions in the 
protocol body. 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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Written informed Consent 
0,1,2 
… 
Eligibility per the inclusion 
criteria/ Exclusion criteria 
0,1,2 
… 
MR Safety Screening 
 
… 
Screening completion for 
eligibility (if applicable) 
1,2 
… 
Hamilton Score 
1,2 
… 
Zung Score 
1,2 
… 
DAST-10 
1,2 
… 
AUDIT C 2 
1,2 
… 
Written informed Consent 
0,1,2 
… 
Baseline medical and demographic data 
… 
 
… 
Certainty of mTBI diagnosis 
on a 3 point ordinal scale, 
where 1 = certain mTBI 
diagnosis, 2 = probable 
mTBI diagnosis, 3 = possibly 
mTBI diagnosis) (as defined 
in Section 6.3.3. Baseline 
Data Collection: Certainty 
of Diagnosis) 
1 
… 
… 
 
… 
Site Radiologist Reads of 
T1, T2, Flair , and/or 
SWANand reconstructed 
SWI and DTI Acquisitions  
(NINDS TBI CDE Version 
4.0) 
 
… 
MR Post-processing (processed at Imaging Laboratory for 
data from indicated visits) 
Post-processing assessment 
modules and evaluations 
(Appendix D) 
 
… 
Added reference to 
the additional 
definition of diagnostic 
certainty provided in 
the body of the 
protocol. 
38 
APPENDIX D – DETAIL OF 
POST-PROCESSING 
ASSESSMENT MODULES 
Post-Processing Assessment Document Version: 1.0 
[Protocol Amendment 4.0]  
 
Modu
le 
Numb
er 
Modul
e Title 
Assessme
nts 
Assessor 
Outpu
t type 
Reader 
Assessment 
Instructions 
Type of 
Stored 
Files 
1 
Volum
etry 
Post-
Proces
sing 
Modul
e 
1. Whole 
brain 
2. 
Parenchy
ma 
3. 
Supratent
orial 
region 
4. Cortical 
gray 
matter 
5. 
Hippocam
pus 
6. 
Thalamus 
technician 
(non-
radiologist) 
Numer
ical 
Record the 
numerical 
output for 
each 
anatomical 
region as 
cubic 
centimeters 
(cm3)  
4. DIC
OM 
5. P-
files 
6. Auxi
liary 
dat
a (if 
appl
icab
le) 
Added protocol 
version number to 
header. Clarifies that 
the version found in 
the protocol is 
considered the current 
version until/unless an 
additional iteration of 
this page is generated 
by the Sponsor and 
signed by the sites. 
 
Removed “Reader” 
from header to avoid 
possible 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
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7. Caudate 
nucleus 
(labeled as 
‘Caudate’ 
on device 
the 
report) 
8. 
Putamen 
9. Globus 
pallidus 
(labeled as 
‘Pallidum’ 
on device 
report) 
10. 
Amygdala 
2 
Kurtos
is 
Post-
Proces
sing 
Modul
e  
1. ADC 
2. eADC 
3. FA 
4. ParK 
5. 
MuMinK 
6. 
MuMaxK 
7. AKC 
min 
8. AKC 
max 
9. Mean K 
10. FA-K 
11. Color 
FA 
 
 
N/A 
Twelve 
(12) 
electro
nic 
quanti
tative 
image 
maps 
and 
one (1) 
correct
ed 
diffusi
on 
weight
ed 
image 
set 
No 
assessments 
conducted 
4. DIC
OM 
5. P-
files 
6. Auxi
liary 
dat
a (if 
appl
icab
le) 
 
3 
RS 
fMRI 
Post-
Proces
sing 
Modul
e 
1. Default 
ModePrim
ary Visual 
Network 
2.Seconda
ry visual 
3.Left 
motor 
(hand) 
4.Right 
motor 
(hand) 
5.Left 
motor 
(face) 
6.Right 
motor 
(face) 
7.Dorsal 
attention 
system  
8.Executiv
e control 
network 
(left) 
9.Executiv
e control 
network 
(right) 
10.Salienc
e network
 
N/A 
 
Thirte
en (13) 
seed-
based 
and 
thirty 
(30) 
ICA-
based 
netwo
rk 
images 
No 
assessments 
conducted 
4. DIC
OM 
5. P-
files 
6. Auxil
iary 
data 
(if 
appli
cabl
e) 
4 
RSI 
Post-
Proces
sing 
Modul
e 
1. free 
water 
2. neurite 
density 
N/A 
two (2) 
electro
nic 
quanti
tative 
image 
maps 
of the 
brain 
No 
assessments 
conducted 
4. DIC
OM 
5. P-
files 
6. Auxil
iary 
data 
(if 
appli
cabl
e) 
misinterpretation (as 
some sites may 
interpret reader to 
inherently mean 
radiologist).  
 
Added SWI 
combination echo 
post-processing and 
updated data 
standards forMR Spect 
and QSM. 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
Page 72 of 74 
DOC1689463 (Rev. 4.0) 
 
        Version Date: 14/Nov/2016 
Item 
Section 
Revision or Clarification 
Justification 
 
5 
QSM 
Post-
Proces
sing 
Modul
e 
susceptibil
ity 
Radiologist 
or 
qN/Aualifie
d imaging 
scientist 
One 
electro
nic 
quanti
tative 
image 
map 
Check for 
microbleeds 
(Microbleeds 
present Y/N) 
No 
assessments 
conducted 
Overall IQ 
(rated as 1 = 
poor, 2 = 
some aspects 
are poor, 3 = 
acceptable, 4 
= good, 5 = 
excellent)  
DICOM 
6 
SWI 
combi
ned 
echo 
susceptibil
ity 
Radiologist 
Images 
Check for 
microbleeds 
(instructions 
on the reader 
report form) 
 
4. DIC
OM 
5. P-
files 
6. Auxi
liary 
data 
(if 
appl
icab
le) 
 
76 
MR 
Spectr
oscop
y 
Metabolit
e ratios 
Technician 
N/A 
(nume
rical 
values 
alread
y 
produc
ed by 
scanne
r-
based 
proces
ses) 
From the 
DICOM 
viewed on 
AW, record 
each bilateral 
value the 
ratios: NA/Cr, 
Ch/Cr, mI/Cr 
and H2O/Cr. 
From the text 
file   
<pfile>_combi
ne_pro.shf, 
record the 
five values(na, 
cr, ch, mi, 
h2o)  
: ratio_val_na, 
ratio_val_cr, 
ratio_val_ch, 
ratio_val_mi, 
ratio_val_h2o  
DICOM 
Text file 
 
 
 
 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
Page 73 of 74 
DOC1689463 (Rev. 4.0) 
 
        Version Date: 14/Nov/2016 
APPENDIX H – AMENDMENT TO PROTOCOL VERSION 3.0 TO 4.0 
Purpose: This amendment document describes the changes from protocol version 3.0 to 4.0, as follows: 
1. To add information for additional study sites and investigators. The listing of sites and investigators is 
moved to Appendix 1 to conform with current Sponsor requirements. 
2. To remove neurological assessments (Stroop Color and Word Test and D-KEFS) to reduce the overall 
duration (time) of assessments. 
3. To add a note that the BESS may be performed in modified form (on a firm surface). 
The following amendments were made to version 3.0 to produce version 4.0. Point-by-point revisions are shown as 
additions in double-underline (double-underline) and deletions in strikethrough (strikethrough) for each change 
made in this amendment for the previous version. 
Item 
Section 
Revision or Clarification 
Justification 
39 
Study Synopsis / 
Appendix 1 
[Study site and investigator details are move to Appendix 1] 
Site 
008 
Roland Lee, MD  
(Principal Investigator) 
Tel:  
1 (619) 543-6766 
e-mail:  
rrlee@ucsd.edu 
University of California, 
San Diego 
Radiology/RIL, 9500 
Gilman Drive, MC 0852,  
La Jolla, CA  92093-0852    
Site 
009 
Thomas M. Talavage, PhD  
(Principal Investigator) 
Tel:  
1 (765) 494-5475 
e-mail:  
tmt@purdue.edu  
Purdue University 
School of Electrical & 
Computer Engineering 
465 Northwestern Ave 
West Lafayette, IN  
47907-2035 
Site 
010 
Jeffery J. Bazarian, MD, MPH 
(Principal Investigator) 
Tel:  
1 (585) 275-2909 
e-mail: 
Jeff_Bazarian@URMC.Rochest
er.edu  
University of Rochester 
Medical Center  
Department of 
Emergency Medicine, 
265 Crittenden Blvd, 
Box 655C, Rochester, 
NY 14642 
[Table Note] * The identifier Site 007 was reserved for a site no 
longer participating in the study. 
As per current 
standard 
documentation 
requirements of the 
Sponsor, sites and 
investigators are 
placed in an Appendix 
to the protocol. 
 
Added site and 
investigator 
information for 
additional 
participating sites (Site 
007-009). 
 
 
40 
Appendix E – Data 
Collection by Study Visit 
 
Stroop 
Color and 
Word 
Test 
 
1,2 
1,2 
1,2 
1,2 
 
 
Removed neurological 
assessments (Stroop 
Color and Word Test) 
to reduce the overall 
duration (time) of 
assessments. 
 
 

Study Title: Advanced MRI Applications for Mild Traumatic Brain Injury - Phase 2 
Study Number: 114-2015-GES-0017 
Protocol: 4.0 
 
 
Page 74 of 74 
DOC1689463 (Rev. 4.0) 
 
        Version Date: 14/Nov/2016 
41 
 
 
 
D-KEFS 
Verbal 
Fluency 
Test 
(includes 
Letter 
Fluency/CO
WAT test 
and other 
primary 
and 
secondary 
measures) 
 
1,2 
1,2 
1,2 
1,2 
 
 
Removed neurological 
assessments (all parts 
of the D-KEFS) to 
reduce the overall 
duration (time) of 
assessments. 
42 
 
 
BESS 6 
 
1,2 
1,2 
1,2 
1,2 
[Footnote] 6 The BESS should be performed on a firm surface. Foam 
pads should not be used for BESS testing in this study. 
 
 
Added a note that the 
BESS may be 
performed in modified 
form (on a firm 
surface). 
 
End of Document