Multi-Center: Non-Anesthetized Plexus Technique for Infant (BPBP) MRI Evaluation
Conditions: Brachial Plexus Palsy Due to Birth Trauma, Injury, Newborn
Sponsor: Shriners Hospitals for Children

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TITLE: Multi-Center: Non-Anesthetized Plexus Technique for Infant (BPBP) MRI 
Evaluation (NAPTIME) 
 
 
Principal Investigator: 
Michelle James, MD 
Shriners Hospitals for Children- Northern California 
2425 Stockton Blvd. 
Sacramento, CA 95817 
916-453-2049 
MJames@shrinenet.org 
 
 
 
Research 
Site(s): 
 
Andrea Bauer, MD 
Boston Children’s Hospital 
300 Longwood Avenue 
Boston, MA 02115 
617-355-6021 
 
 
Ann Van Heest, MD 
Gillette Children’s Healthcare 
200 University Avenue East 
St. Paul, MN 55101 
651-325-2200 
 
 
Sponsor: 
Shriners Hospitals for Children 
International Headquarters 
2900 Rocky Point Drive 
Tampa, Florida 33607 
 
 
 
Initial Version: 3/8/2017 
Modification: 3/24/2017 
Modification: 5/31/2017 
Modification: 6/21/2017 
Modification: 9/1/2017 
Modification: 3/6/2018 
 
 

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History of Changes 
 
Version 
Description of Changes 
March 8, 2017 
Original Document 
March 24, 2017 
Added UC Davis as research site 
May 31, 2017 
Expanded enrollment criteria 
June 21, 2017 
Changes research coordinators (RC) to research staff (RS) 
September 1, 2017 
Added option for repeat MRI and data collection of MRI experience 
March 6, 2018 
Added information to email/handout provided to subject families prior to 
MRI 

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PROTOCOL SIGNATURE PAGE 
 
Protocol Title: Multi-Center: Non-Anesthetized Plexus Technique for Infant (BPBP) MRI 
Evaluation (NAPTIME) 
 
The signature below provides the necessary assurances that this trial will be conducted 
according to the stipulations of the protocol, including all statements regarding confidentiality.  
This is in compliance with the principles outlined in applicable US Federal regulations and Good 
Clinical Practice Guidelines (ICH E6 Section 4.5.1, 6.2.5, and 8.2.2) 
 
 
__________________________________ 
Site Investigator’s Name*: (please print) 
 
 
__________________________________  
___________________ 
Site Investigator Signature  
 
 
 
Date Signed 
 
* The protocol should be signed by the local investigator who is responsible for day to day study 
implementation at his/her specific site.

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List of Abbreviations 
 
Adverse Event 
 
 
 
 
 
 
 
 
AE 
Unanticipated problems involving risks to subjects or others  
 
 
UPIRTSO 
Food and Drug Administration 
 
 
 
 
 
 
FDA 
Health Insurance Portability and Accountability Act  
 
 
 
HIPAA 
Institutional Review Board 
 
 
 
 
 
 
 
IRB 
Private Health Information 
 
 
 
 
 
 
 
PHI 
Medical Record Number 
 
 
 
 
 
 
 
MRN 
Shriners Hospitals for Children – Northern California 
 
 
 
SHCNC 
Principal Investigator  
 
 
 
 
 
 
 
PI 
Occupational Therapist 
 
 
 
 
 
 
 
OT 
Research Staff 
 
 
 
 
 
 
 
 
RS 
Magnetic resonance imaging  
 
 
 
 
 
 
MRI 
Somatosensory evoked potentials 
 
 
 
 
 
 
SSEP

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Table of Contents 
Study Summary .............................................................................................................................. 6 
Study Schema ................................................................................................................................. 7 
1.0 
Introduction: ........................................................................................................................... 8 
1.1 
Background ................................................................................................................ 8 
1.2 
Risks, Benefits and Alternatives ................................................................................ 8 
2.0 
Objectives: ........................................................................................................................... 10 
2.1 
Objectives ................................................................................................................ 10 
3.0 
Subject Selection: ................................................................................................................ 10 
3.1 
Inclusion Criteria ...................................................................................................... 10 
3.2 
Exclusion Criteria ..................................................................................................... 10 
3.3 
Number of Subjects ................................................................................................. 11 
3.4 
Inclusion of Gender, Minorities, and Vulnerable Populations ................................. 11 
4.0 
Study Design/Procedures: ................................................................................................... 11 
4.1 
General Design ........................................................................................................ 11 
4.2 
Avoiding Bias ........................................................................................................... 12 
4.3 
Study Procedures .................................................................................................... 12 
4.4 
Subject Recruitment Plans and Consent Process .................................................. 14 
5.0 
Subject Safety ...................................................................................................................... 16 
5.1 
Safety Assessment .................................................................................................. 16 
5.2 
Serious Adverse Event Reporting ........................................................................... 16 
6.0 
Data Handling and Record Keeping .................................................................................... 17 
6.1 
Data .......................................................................................................................... 17 
6.2 
Data Storage ............................................................................................................ 17 
6.3 
Confidentiality and Security ..................................................................................... 17 
6.4 
Source Documentation ............................................................................................ 17 
6.5 
Record Retention ..................................................................................................... 18 
7.0 
Quality Control and Quality Assurance ............................................................................... 18 
7.1 
Subject Safety .......................................................................................................... 18 
7.2 
Quality Control ......................................................................................................... 18 
7.3 
Monitoring Plan ........................................................................................................ 18 
8.0 
Statistical Considerations .................................................................................................... 18 
8.1 
Primary Study Endpoints ......................................................................................... 18 
8.2 
Secondary Study Endpoints .................................................................................... 19 
8.3 
Sample Size Determination and Power/Accrual Rate............................................. 19 
8.4 
Statistical Methods ................................................................................................... 20 
9.0 
Finance ................................................................................................................................ 20 
9.1 
Funding .................................................................................................................... 20 
9.2 
Costs to Subject ....................................................................................................... 20 
10.0 Study Organization .............................................................................................................. 20 
10.1 
Multiple PI Plan ........................................................................................................ 20 
10.2 
Phone meetings ....................................................................................................... 20 
11.0 References ........................................................................................................................... 21 

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Study Summary 
 
Title 
Multi-Center: Non-Anesthetized Plexus Technique for Infant (BPBP) 
MRI Evaluation (NAPTIME) 
Short Title 
NAPTIME 
Population: 
Infants with unilateral brachial plexus birth palsy 
Number of Subjects 
100 
Study Duration 
5 years 
Study site(s) 
Shriners Hospitals for Children - Northern California 
UC Davis Medical Center 
Boston Children’s Hospital 
Gillette Children’s Specialty Healthcare 
Objectives 
Primary Objective: Verify whether non-sedated 3D volumetric 
structural magnetic resonance imaging (MRI) obtained in the first 4- 12 
weeks of life can reliably discriminate between brachial plexus birth 
palsy (BPBP) injury patients who require surgical reconstruction versus 
those who will recover spontaneously. 
Secondary Objective 1: To assess whether MRI findings for pre-
operative planning in infants with BPBP, specifically the level(s) and 
extent of injury of each nerve root and the location of root injury (pre- 
vs. post-ganglionic), correlate with intraoperative findings identified 
during brachial plexus reconstructive microsurgery. 
Secondary Objective 2: Two standard BPBP clinical measures – the 
Active Movement Scale (AMS) and Toronto scores will be used to 
confirm clinical outcomes of our decision-making both for and against 
surgery. 
Statistical 
Methodology 
The primary analysis for this will be assessing the discriminant ability of 
the SRS system to distinguish patients who do versus do not go on to 
surgery, by estimating the area under the receiver operating 
characteristic (ROC) curve with a 95% confidence interval. 

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Study Schema 
 
 
Eligibility/ 
Screening 
 
 
 
MRI Scan 
 
 
 
 
 
 
 
 
 
 
Follow-up  
Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Potential participant identified in clinic 
MRI scan performed at ≥28 days and ≤4 months of age 
Off Study 
Unable to scan subject or MRI 
image is unreadable 
Scan read by neuroradiologist – 
SRS score not placed in chart 
Patient continues to visit clinic 
for normal follow-up, with or 
without surgical intervention 
 
 

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1.0 
Introduction: 
1.1 
Background 
Brachial plexus birth palsy (BPBP) affects approximately 1 in 1,000 children at birth, 
and though the majority of infants regain full function of the affected arm, many of 
these injuries result in lifelong disability.  Varying degrees of BPBP, from mild 
(neuropraxia) to severe (post-ganglionic root rupture or pre-ganglionic root 
avulsion), are indistinguishable on the initial clinical exam.  Serial clinical 
examination is the current gold standard for separating infants who will recover 
spontaneously from those who will need reconstructive surgery.  Unfortunately, this 
“wait and see” period may last for up to 6 months, and the effectiveness of surgery 
can decrease during this time.  The surgeon must balance the fact that 60-80% of 
infants with BPBP will recover spontaneously without surgery with the knowledge 
that earlier nerve repair improves outcomes for infants with more severe injuries.  A 
non-invasive diagnostic test which differentiates these two groups of infants with 
BPBP within weeks of birth may help improve surgeons’ prognostic accuracy and 
therefore the treatment of this disorder.  In addition, currently surgeons rely on 
operative exploration, visual inspection and somewhat non-specific somatosensory 
evoked potentials (SSEPs) to differentiate pre-ganglionic and post-ganglionic 
injuries, which have completely different surgical treatments.  A pre-operative test 
that provided accurate and specific diagnosis of each root injury would improve pre-
operative planning and accuracy of treatment. 
We have developed a rapid (<10 minute imaging acquisition) volumetric magnetic 
resonance imaging (MRI) sequence with high spatial resolution and soft tissue 
contrast that does not require sedation or administration of a contrast agent and 
provides an accurate assessment of the level and severity of both pre- and post-
ganglionic BPBP injuries [1].  The pilot data we acquired on 9 infants demonstrates 
the ability of this imaging protocol to distinguish those infants who went on to 
surgery at 6 months of age from those who made a spontaneous recovery.  
Additional study enrollment would validate the ability of imaging protocol to 
differentiate between operative and non-operative injuries, which would benefit both 
groups: first, those with injuries who do require surgery could potentially be 
reconstructed earlier and more accurately, and second, families of the majority of 
infants who will recover spontaneously could be spared months of worry.  Our 
research goal is to recruit a total of 100 patients over a 5-year period yielding at 
least 70 evaluable patients at three institutions (Shriners Northern California, Boston 
Children’s Hospital, and Gillette Children’s Specialty Hospital) utilizing the same 
imaging, serial clinical exams, and surgical protocols as our pilot study. 
1.2 
Risks, Benefits and Alternatives 
1.2.1 Risk Category 
This study is no greater than minimal risk.  Subjects will not encounter risks 
greater than those they would encounter in daily life. 
1.2.2 Potential Risks 
1.2.2.1 
There is a small risk of loss of confidentiality. 

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1.2.2.2 
While there is no known direct effect of high static magnetic field 
strength, there are secondary safety considerations of the static 
magnet field to consider, namely the possibility that medical 
equipment (for example, pacemakers) will malfunction in the 
magnetic field, or that the magnetic force exerted by the static 
field will cause motion of ferromagnetic materials (either 
implanted or external to the body).  These are standard issues 
involved in MR imaging, and we already have procedures in 
place to address them for imaging.  MRI safety is documented by 
screening the patient prior to scan and by completing a 
questionnaire prior to scan.  The risks are reasonable in that the 
anticipated benefits and/or knowledge gained from the results of 
this study could determine other medical treatments that provide 
a better clinical outcome. 
1.2.3 Protection Against Risk 
1.2.3.1 
Data collected will be recorded in such a manner (coded) that 
subjects will not be identified.  The key code and all study 
documents with coded data (such as case report forms) will be 
stored in a locked cabinet file and/or password-protected 
computer file in an access controlled office only accessible to 
research personnel.  Information about study subjects will be 
kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 
(HIPAA). 
1.2.3.2 
MRI safety is well documented in neonates.  Additional risks are 
further reduced by preformatting the MRI with swaddling and MRI 
safety questionnaire and screening prior to the scan.  To 
eliminate the risk of injury from external objects, there will be a 
“zero-tolerance” policy for ferromagnetic materials in the scan 
room during patient scans.  Subject’s parent/guardian will 
remove all ferromagnetic items (jewelry, pocket contents, belt 
buckles, footwear with steel nails or toe covers, etc.) before 
entering the magnet room, and only non-magnetic equipment will 
be allowed within the scan room.  All subjects are subjected to a 
metal detector screening (similar to that performed at airport 
security booths) before being permitted to enter the scanning 
suite. 
1.2.4 Potential Benefits to the Subject 
The results from this study could benefit future patients by providing an 
earlier stratification of injury severity and the opportunity for earlier surgery 
for those who may need it. 
1.2.5 Alternatives to Participation 
The patient can choose to not participate in the study and they will continue 
to receive standard care at the research site. 

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2.0 
Objectives: 
2.1 
Objectives 
2.1.1 Primary Objective 
Verify whether non-sedated 3D volumetric structural magnetic resonance 
imaging (MRI) obtained ≥28 days and ≤4 months old can reliably 
discriminate between brachial plexus birth palsy (BPBP) injury patients who 
require surgical reconstruction versus those who will recover spontaneously. 
2.1.1.1 
Hypothesis: 
The SRS will effectively be able to discriminate between infants 
who require surgical reconstruction versus those who will 
recover spontaneously. 
2.1.2 Secondary Objective 1: 
Assess whether MRI findings for pre-operative planning in infants with 
BPBP, specifically the level(s) and extent of injury of each nerve root and the 
location of root injury (pre- vs. post-ganglionic), correlate with intraoperative 
findings identified during brachial plexus reconstructive microsurgery. 
2.1.2.1 
Hypothesis: 
MRI findings for pre-operative infants will exhibit characteristics 
similar to those found intraoperatively. 
2.1.3 Secondary Objective 2: 
Two standard BPBP clinical measures – the Active Movement Scale (AMS) 
and Toronto scores will be used to confirm clinical outcomes of our decision-
making both for and against surgery. 
2.1.3.1 
Hypothesis: 
AMS and Toronto scores will improve to functional levels at final 
follow-up for those subjects who were determined not to need 
surgery.  AMS and Toronto scores will improve following surgical 
intervention for those subjects who undergo surgery. 
3.0 
Subject Selection: 
3.1 
Inclusion Criteria 
3.1.1 Diagnosis of brachial plexus birth palsy. 
3.1.2 Age at consent ≤4 months 
3.2 
Exclusion Criteria 
3.2.1 Bilateral brachial plexus birth palsy. 
3.2.2 Age at MRI <28 days or >4 months old (patients can be enrolled prior to 28 
days of age, but the imaging must occur in the 28 days to 4 months’ time 
period).  The lead PI will need to approve the enrollment of a subject who 
will have the MRI after 90 days of age. 
3.2.3 Concomitant medical conditions that would preclude performance of or 
confound interpretation of MRI or any clinical assessment. 

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3.3 
Number of Subjects 
Up to 100 subjects will be enrolled from the three research sites. 
3.4 
Inclusion of Gender, Minorities, and Vulnerable Populations  
3.4.1 Entry into this study is open to patients of both genders. 
3.4.2 Entry into this study is open to patients of all ethnic backgrounds. 
4.0 
Study Design/Procedures: 
4.1 
General Design 
4.1.1 This will be a multicenter prospective cohort study of patients with BPBP.  
The study will take place at Shriners Hospitals for Children – Northern 
California, Boston Children’s Hospital, and Gillette Children’s Specialty 
Healthcare.  MRIs for subjects at SHCNC will be performed at UC Davis 
Medical Center. 
4.1.2 All infants with BPBP between 0 and 12 weeks of age who present for 
treatment to a participating site will be offered participation in this study.  
Those infants with concomitant birth injuries that would make positioning in 
the MRI scanner difficult or painful (such as a birth humerus or clavicle 
fracture) will have their enrollment deferred.  If the injury heals and the MRI 
can be performed within the required age range, they may be included in the 
study.  If not, they will be excluded.  Those infants who attempt to complete 
or actually complete the MRI scan but end up with unusable images will 
continue to be followed clinically, but will be removed from participation in 
this study.  Table 1 below shows the visit schedule for study participants and 
what forms/activities need to be completed at each visit. 
Table 1. Schedule of visits. 
 
Enroll-
ment 
Follow-up 
Forms/ 
Activity 
Baseline 
Study 
visits 
until 
surgery 
decision 
Surgery 
(if 
needed) 
Study 
visits 
until 
Month 12 
Month 
12 
 
Month 
18 
(±3 mo) 
Month 
30 
(±3 mo) 
Enrollment 
x 
 
 
 
 
 
 
Patient 
Assessment 
x 
x 
 
x 
x 
x 
x 
Procedures  
 
 
x 
 
 
 
 
MRI 
Assessment  
x 
 
 
 
 
 
 
Study 
Closeout 
x* 
x* 
x* 
x* 
x* 
x* 
x 
* If MRI cannot be completed, if patient withdraws, or is lost to follow-up. 

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4.2 
Avoiding Bias 
4.2.1 Patient enrollment 
All infants with BPBP between 0 and 12 weeks of age who present for 
treatment to a participating site will be offered participation in this study. 
4.2.2 Surgeon blinded to SRS score 
Surgeons will be blinded to neuroradiologist-derived SRS score.  SRS score 
will not be put into the medical record so that the surgeons are blinded to the 
SRS score. 
4.2.3 Standardization of indications for surgery 
Surgeons will adhere to standard indications for microsurgery in infants with 
BPBP. These are: 1) flail arm and Horner’s syndrome 2) Toronto score less 
than 3.5, 3) failure to recover antigravity elbow flexion and/or antigravity 
shoulder abduction (AMS score for elbow flexion and/or abduction less than 
5), 4) failure to bring the hand to the mouth (cookie test), or other clinical 
indication of lack of appropriate nerve recovery. 
4.3 
Study Procedures 
4.3.1 Study Visits 
At the baseline visit, we will collect patient demographics, prenatal and 
perinatal history, as well as information on any concomitant birth injuries.  A 
standardized physical examination will be conducted at the enrollment visit 
and all subsequent study visits, consisting of the Toronto Score and AMS 
score.  The Narakas score and the MRI will take place at or around the time 
of enrollment into the study.  At the time of the MRI scan, the 
neuroradiologist will document the status of each nerve root as normal, post-
ganglionic rupture, or pre-ganglionic avulsion, in addition to calculating the 
numerical SRS.  For those infants who undergo microsurgery, we will 
document the indications for surgery, operative findings at each nerve root, 
and procedure performed at each nerve root. 
4.3.2 MRI Scan and Shriners Radiological Score 
An MRI will be performed according to the protocol specified in Appendix A.  
Families will be given instructions prior to their MRI appointment to keep 
their child awake prior to the exam and to feed them within 30 minutes of the 
exam to increase the chance of the baby being sleepy during the exam time. 
Tips for a successful MRI and website links to the MRI sounds and a MRI 
cartoon may also be provided. Each infant will be positioned in an MRI 
scanner either using a swaddle blanket or using a vacuum suction controlled 
infant positioner, the MedVac Immobilizer (CFI Medical, Fenton, MI) [26].  
The MRI scanning protocol is composed of a localizer sequence followed by 
traditional sagittal T2 sequence and 3D proton density CUBE (General 
Electric trade name, Milwaukee, WI) or SPACE (Siemens Medical USA, 
Malvern, PA) coronal sequence oriented in the plane of the cervical spine 
and extended anteriorly to include the involved brachial plexus.  The total 
scanning will be approximately 8 minutes excluding initial positioning time, of 
which the localizer, traditional sagittal T2 and coronal 3D proton density 
CUBE/SPACE sequences are 1 minute, 3.4 minutes and 3.5 minutes 
respectively.  Subjects’ experience with the MRI scanning process will be 

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recorded, e.g. the number of times the subject wakes up during the scan or 
the total time needed to obtain the scan. 
Each subject’s MRI scan will be reviewed independently by neuroradiologist 
investigators.  The neuroradiologists will interpret the MRI scan and report 
their findings in the medical record as per standard clinical protocols.  
Surgeons and families will be aware of these findings and will be able to 
view the images.  However, the SRS calculation will be performed outside 
the medical record and will not be available to surgeons until after data 
collection is completed in order to minimize bias.  Our pilot data 
demonstrated inter-rater reliability (Krippendorff's alpha) of 0.78 for 
calculation of the SRS.  The neuroradiologist investigators at the other study 
centers will read and calculate SRS scores for the pilot study subjects with 
the goal of exceeding an inter-rater reliability of 0.75 with the other 
neuroradiologists prior to testing study subjects.  In addition, during the study 
period, a subset of MRI scans will be de-identified and shared between 
institutions for the purposes of inter-observer and intra-observer analysis.  
Figure 1 illustrates the calculation of the SRS score from the MRI findings.  
Each injured level is first assigned 1 point, with additional points assigned for 
pre-ganglionic injuries: 2 points for each absent nerve rootlet, 2 points for 
each pseduomeningocele, 0.5 points for each abnormal nerve rootlet; and 
for post-ganglionic injuries: 1.5 points for each neuroma and 0.5 points for 
each abnormal nerve.  If the zone of injury includes both the pre- and post-
ganglionic regions, only the pre-ganglionic injury is scored.  The total 
radiologic score ranges from 0 points (no evidence of nerve root injury on 
MRI) to 25 points (all 5 levels with pre-ganglionic pseudomeningoceles and 
absent nerve rootlets).  In addition, the neuroradiologist will score each 
nerve root level as intact, post-ganglionic rupture, or pre-ganglionic avulsion. 
 This information will then be compared with the findings at surgery as 
described above for those infants who undergo surgery. 
 
Figure 1. Calculation of the Shriners Radiological Score (SRS) 
 

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4.3.2.1 
Subjects who do not complete the scan or end up with unusable 
images can repeat the MRI up to two additional times as long as 
they are within the eligibility window. 
4.3.3 Surgery 
The decision to proceed to surgery will be made by the operating surgeon 
using the accepted standard clinical indications.  These are: 1) flail arm and 
Horner’s syndrome 2) Toronto score less than 3.5, 3) failure to recover 
antigravity elbow flexion and/or antigravity shoulder abduction (AMS score 
for elbow flexion and/or abduction less than 5), 4) failure to bring the hand to 
the mouth (cookie test), or other clinical indication of lack of appropriate 
nerve recovery.  For those infants in the study who undergo microsurgical 
plexus exploration, the status of each nerve root will be recorded by the 
operating surgeon as intact, postganglionic rupture, or pre-ganglionic 
avulsion.  This status will be determined based on the intraoperative 
appearance of the nerve root as well as intraoperative SSEP testing as 
follows: avulsed (no repeatable response with maximal stimulation), ruptured 
(repeatable response to SSEPs but without distal motor function), or intact 
(repeatable response to SSEPs with distal motor function). 
4.3.4 Follow-up 
AMS and Toronto score data will be collected prospectively at subsequent 
routine clinic visits.  Infants will be examined until 6 months of age or until a 
decision for surgery is made, then until 1 year of age depending on the 
infant’s recovery.  After 1 year of age the progression of clinic visits varies 
based on the severity of the child’s injury, with planned study visits at 18 and 
30 months of age (2.5 years of age/±3 mo), regardless of surgery decision 
(i.e., both cohorts will be followed). 
4.3.5 Removal from study 
Subjects will be dropped from the study if a readable MRI is not produced, 
even after multiple attempts. 
4.3.6 Description of study treatments or exposures/predictors 
The primary predictor is the MRI-based Shriners Radiological Score (SRS.) 
Each patient’s MRI will be read by the local study neuroradiologist and given 
a score between 0 and 25.  The secondary predictors are the specific 
neuroradiologist interpretations of the MRI at each level (for later comparison 
with intraoperative findings). 
4.4 
Subject Recruitment Plans and Consent Process 
4.4.1 Waiver of HIPAA Authorization for Recruitment of Prospective Subjects 
4.4.1.1 
HIPAA authorization will be obtained at the time of informed 
consent.  We are requesting a waiver of HIPAA authorization for 
recruitment of prospective subjects.  The use of health 
information for screening purposes does not represent more than 
a minimal risk to privacy. 

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4.4.1.2 
It would not be possible to conduct this study without access to 
PHI, because the research staff will need to identify appropriate 
candidates prior to contacting their respective families. 
4.4.1.3 
Data will be coded and stored in a secured locked office.  PHI 
will not be reused or disclosed to any other person or entity, 
except as required by law or for authorized oversight of the 
research project.  Any disseminated data will be aggregated and 
coded.  PHI will be destroyed at the earliest opportunity but no 
sooner than 2 years from the completion of this study. 
4.4.1.4 
Only IRB approved research staff for this study and those 
authorized for oversight of the research project will have access 
to PHI. 
4.4.1.5 
We will screen the electronic medical record for appropriate 
candidates for this study.  PHI that will be accessed are name, 
MRN, DOB, dates of clinic visits, and medical notes. 
4.4.2 Recruitment 
4.4.2.1 
Patient recruitment will take place during regular clinic 
appointments at each center.  Research staff (RS) at each site 
will screen clinic schedules for appropriate candidates and alert 
the surgeon prior to a candidate’s visit.  On the day of the clinic 
visit, the surgeon will introduce the study to the parents/legal 
guardian, including risks and benefits of study participation, and 
answer any questions.  If the parents/legal guardians express 
interest in participating, the RS will provide additional information, 
answer any questions, and then go through the formal consent 
process and obtain signature(s).  Child assent will not be 
required due to the age of the subjects.  The family will be given 
a copy of the signed consent form for their records. 
4.4.2.2 
If patients will be seen for this first time between 28 days and 4 
months of age, the RS will secure a time slot for the MRI scanner 
ahead of time so that the MRI can be performed on the same 
day as the clinic visit.  In this way, the MRI scan will occur as 
soon as possible after enrollment into the study.  Patients whose 
first visit occurs prior to the age of 28 days will complete the 
research MRI at their next regularly scheduled clinic visit or at 
another time of their choosing.  A handout or email given to 
families will contain information and tips about the MRI so that 
families can plan for the extra time needed to complete the MRI. 
4.4.2.3 
To minimize patient/family burden, ensure a high rate of 
retention, and maximize the likelihood that complete data are 
collected for each patient, the study visit schedule will mimic a 
regular clinic visit schedule.  The only deviation necessary would 
be to complete the research MRI. 
4.4.3 Informed consent process 

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4.4.3.1 
Informed Consent will be obtained from their legally authorized 
representative or guardian by study staff authorized to consent 
for this study. 
4.4.3.2 
The consent process will include a thorough discussion of all the 
elements outlined in the informed consent document, including 
but not limited to what is expected to happen during the study, 
risks and benefits of the planned assessments, and any possible 
alternatives. 
4.4.3.3 
Subjects and their guardians will be presented with a verbal 
introduction to the study.  They will then review the consent 
document section by section with the research personnel.  The 
research staff will state that participation in the study is voluntary 
and that their care will not be affected should they choose to not 
participate.  They will also be told that they can withdraw from the 
study at any time. 
4.4.3.4 
Consent will be obtained in a private location. 
4.4.3.5 
The subject/parent or guardian will be provided with an ample 
amount of time to ask questions before making their decision 
through extensive discussion between the parent or guardian 
and the research staff.  This discussion includes the subject or 
guardian summarizing study procedures in their own words to 
ensure their comprehension level is adequate. 
4.4.3.6 
Potential subjects may take as much time as they would like to 
consider their participation in the study. 
4.4.3.7 
Consent of subjects enrolled at SHCNC will be documented in 
OnCore.  The original consent form at all sites will be stored in 
locked filing cabinets at each site that only the research staff has 
access to. 
4.4.3.8 
The subject/family will be given a copy of the signed consent 
form. 
5.0 
Subject Safety 
5.1 
Safety Assessment 
This study does not include experimental procedures. 
5.1.1 No toxicities, injuries, complications or significant risks are expected with 
activities other than nerve exploration.  These activities, performed as part of 
standard clinical care, will not require reporting as a study AE.  At SHCNC, 
all standard SHC policies will be followed to insure subject safety while 
participating in all study-related procedures. 
5.2 
Serious Adverse Event Reporting 
5.2.1 Any Serious and Unexpected adverse event, and Grade III or above with a 
reported causality of “possible,” “probably,” or “likely” must be reported to the 
Study PI in an expedited method. 

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5.2.2 The PI will ensure that SHC Headquarters and all applicable regulatory 
organizations are notified per regulatory guidelines. 
5.2.2.1 
Shriners Hospitals for Children must be notified of any Serious 
and Unexpected adverse event, via the OnCore reporting 
mechanism, within 10 days of occurrence. 
5.2.3 Notifying participating investigators 
5.2.3.1 
The study PI will notify all participating investigators of any 
reported SAE adverse event associated with the study. 
6.0 
Data Handling and Record Keeping 
6.1 
Data 
Data collected will include demographic information, physical examinations, Toronto 
scores and AMS, MRI readings, and surgery information. 
6.2 
Data Storage 
6.2.1 The data collected for this study will stored (during and after the study) in 
OnCORE® Enterprise Research System, SHC’s clinical research data 
management system housed on SHC servers.  Members of the research 
team will enter data into the SHC system with unique user IDs and 
passwords.  During the analysis phase, all secure web-based information 
transmissions will be encrypted. 
6.2.2 Source documents will be stored in locked filling cabinets that only 
authorized personnel will be able to access. 
6.3 
Confidentiality and Security 
6.3.1 All study data will be stored on SHC authorized servers outlined in this 
protocol.  All computer systems will require a password to gain access.  Data 
will be coded which will not allow for identification of any individuals from the 
code.  The code sheet will be stored separately from the data. 
6.3.2 Investigators, approved study staff, and appropriate organizations such the 
sponsor, collaborators, government agencies, and IRB may review records 
for research, quality assurance, and data analysis. 
6.3.2.1 
A limited data set from each site will be sent to Boston Children’s 
Hospital for statistical analysis. 
6.3.3 In the event that a subject revokes authorization to collect or use PHI, the 
investigator, by regulation, retains the ability to use all information collected 
prior to the revocation of subject authorization.  For subjects that have 
revoked authorization to collect or use PHI, attempts should be made to 
obtain permission to collect at least vital statistics (i.e. that the subject is 
alive) at the end of their scheduled study period. 
6.4 
Source Documentation 
6.4.1 Data from each measure will be recorded onto paper data collection sheets 
before electronic entry.  During the study, these source documents will be 

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stored in locked filing cabinets that only the study team has access to and on 
encrypted, password protected computers.  After the study, source 
document and study files will be archived in a locked secure environment. 
6.5 
Record Retention 
6.5.1 Clinical research records at SHCNC will be retained per SHC Standard 
Operating procedure on Clinical Research Records Retention.  Record 
retention at participating sites will follow their respective institutional 
guidelines. 
6.5.2 Any finding that materially affect the safety and medical care of past subjects 
from this study will be reported to the IRB for 2 years after closure. 
7.0 
Quality Control and Quality Assurance 
7.1 
Subject Safety 
Because there are no study initiated interventions, the risk to subjects’ safety is 
minimal.  No additional measures will be taken in regards to patient safety. 
7.2 
Quality Control 
7.2.1 MRI 
All participating neuroradiologists will evaluate and score the MRI for the 
patients who participated in the pilot study, to establish inter- and intra-rater 
reliability prior to reading MRIs for the study.  The first two MRIs completed 
at each site will be de-identified to patient and site and will be distributed to 
and read by all 3 neuroradiologists. 
7.2.2 Physical Exam Assessments 
In order to standardize the AMS scoring, the lead occupational therapist will 
meet with the therapists at the other sites to ensure consistency of scoring.  
This meeting/training will ensure that all sites will be scoring in the same 
manner going forward. 
7.3 
Monitoring Plan 
7.3.1 The individuals responsible for data safety and monitoring will be the PIs and 
Co-Investigators.  There are no conflicts of interest to declare, as the 
investigators have no personal or financial interest in this study. 
7.3.2 The PIs will assure that informed consent is obtained prior to performing any 
research procedures, that all subjects meet eligibility criteria, and that the 
study is conducted according to the IRB-approved research plan. 
7.3.3 The PIs will complete yearly reports detailing the study progress and subject 
status, any adverse events and any protocol deviations.  These items will be 
discussed at the investigator meetings.  Data will be presented in a blinded 
manner for confidentiality.  Protocol adherence will be monitored by the PIs 
and the Co-Investigators.  Protocol deviations are reported to the IRB at the 
time of continuing review. 
8.0 
Statistical Considerations 
8.1 
Primary Study Endpoints 

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The primary endpoint is the surgeon’s decision for or against surgery, typically made 
by 6 months of age.  Surgeons will make their decision based on all available clinical 
data, including the MRI, but will be blinded to the neuroradiologist’s scoring of the 
SRS and its components. 
8.2 
Secondary Study Endpoints 
The secondary outcome will be the surgeon’s intraoperative findings during brachial 
plexus reconstructive microsurgery.  Specifically, agreement between MRI and 
intraoperative findings, with respect to the level(s) and extent of injury of each nerve 
root and the location of root injury (pre- vs. post-ganglionic) will be determined. 
AMS and Toronto scores will be evaluated at 12, 18 and 30 months of age, which 
will correlate roughly with 6, 12, and 24 months post-operatively for those infants 
who undergo surgery. 
8.3 
Sample Size Determination and Power/Accrual Rate 
The sample size was calculated based on the primary aim which is to determine the 
discriminant ability of the SRS system to discern infants requiring surgical 
intervention and those who will recover spontaneously, based on the area under the 
receiver operating characteristic (ROC) curve.  To prove that the SRS has the 
discriminant ability to effectively identify surgical patients, we would like to 
demonstrate an area under the curve (AUC) of at least 0.90.  Assuming an expected 
surgical rate of 30% and a null AUC of 0.75, 70 subjects would be required to 
achieve 80% power with a type I error of 5%.  Table 2 indicates the variations in 
sample size calculation if the true surgical rate is higher or lower than 30%.  This 
demonstrates that there is little variation in the number of necessary surgical 
subjects given various surgical rate scenarios.  Obtaining at least 21 surgical 
subjects would provide greater than 80% power to test for an AUC of at least 0.90.  
Thus, the assumption of a 30% rate with an enrollment of 70 evaluable patients 
should be sufficient to meet the goals of the study. 
During the 1-year time frame of our pilot study, we identified 16 subjects that met 
eligibility criteria.  Of these, 3 families declined participation, and 4 infants were not 
able to complete the MRI scan.  As our technique of positioning the infant improved 
over the pilot study, we believe a higher percentage of infants will be able to 
complete the MRI scan successfully going forward.  There is a similar volume of 
BPBP patients at our two institutions, such that we expect approximately 15 subjects 
per year will be eligible to participate at each site, with 10 per year at each site likely 
to consent and complete the MRI scan successfully.  Thus, we will plan to enroll 
patients for the first 3.5 years of the study and expect to yield 105 eligible 
participants.  Assuming that 85% of eligible infant’s consent and at least 75% have 
adequate MRI scans, it will be possible to obtain the required sample size.  A third 
site has been included to help guard against poorer than expected accrual and to 
provide for more generalizable results. 
Table 2. Sample size required to detect an AUC of 0.90 with 80% power. 
Surgical 
rate 
Number of 
surgical subjects 
Number of non-
surgical subjects 
Total number 
of subjects 
25% 
21 
66 
82 
30% 
21 
51 
70 
35% 
22 
41 
63 
40% 
23 
34 
57 

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8.4 Statistical Methods 
The primary analysis for this will be assessing the discriminant ability of the SRS 
system to distinguish patients who do versus do not go on to surgery, by estimating 
the area under the receiver operating characteristic (ROC) curve with a 95% 
confidence interval.  In addition, an optimal cutoff value for the SRS will be identified 
using Youden’s Index which maximizes the sum of sensitivity and specificity.  
Sensitivity and specificity will be estimated to help quantify the utility of the SRS 
system to discern between surgical patient groups.  The area under the ROC curve 
(AUC) for the SRS system may be compared to the AUC for the AMS, currently part of 
clinical surgical decision making, to assess whether the MRI score offers a 
comparable, earlier detection method for the need for surgical intervention.  
Secondary analysis will include comparing MRI nerve root findings at each nerve root 
level (C5, C6, C7, C8, and T1) with intraoperative root findings in surgical patients.  
Weighted kappa coefficients along with 95% confidence intervals will be estimated to 
assess the concordance in detecting intact, ruptured, or avulsed roots between MRI 
and intraoperative inspection.  In addition, inter- and intra-rater reliability of the SRS 
will be assessed by estimating Krippendorff’s alpha along with a 95% confidence 
interval.  The AMS and Toronto evaluations at 18 and 30 months of age in the non-
operative group will be used to confirm that these patients do achieve spontaneous 
recovery, and will be compared with the scores for the surgery group at the same time 
points. 
9.0 
Finance 
9.1 
Funding 
This study is being funded by a grant from Shriners Hospitals for Children.  
Budgeted funds will be administered by the SHCNC RC and payments to BCH and 
Gillette Children’s Hospital will be approved by Dr. James. 
9.2 
Costs to Subject 
The subject is not anticipated to incur any additional costs at the study center for 
participation in the study.  Costs for the MRI will be covered by grant funds. 
10.0 Study Organization 
10.1 
Multiple PI Plan 
The multiple PI plan was chosen because this study includes 3 institutions (Shriners 
Hospital – Northern California, Boston Children’s Hospital, and Gillette Children’s 
Specialty Healthcare), and at each institution, 2 different disciplines (pediatric hand 
surgeons and pediatric neuroradiologists).  The leadership team has worked closely 
together on the pilot for this study, and 2 of the PIs (James & Bauer) have 
successfully collaborated on several research projects.  Oversight of the study, 
along with scientific responsibility, will be provided by Dr. James and Dr. Bauer.  The 
neuroradiologists at each institution will be responsible for the MRI studies.  Dr. 
James, Dr. Bauer, and Dr. Van Heest will be responsible for examining the patients 
and collecting the outcomes data. 
10.2 
Phone meetings 
The PIs will hold conference calls at least quarterly, and the RC at SHCNC will 
maintain an agenda and minutes for each call.  Decisions on scientific direction 
will be made by the team, after receiving input from all members (representing 
both specialties and all institutions as appropriate); Dr. James will make the final 
decision if any conflicts arise. 

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11.0 References 
1. 
Shen, P.Y., et al., Non-Sedated Rapid Volumetric Proton Density MRI Predicts 
Neonatal Brachial Plexus Birth Palsy Functional Outcome. J Neuroimaging, 2016. 
2. 
Foad, S.L., C.T. Mehlman, and J. Ying, The epidemiology of neonatal brachial 
plexus palsy in the United States. J Bone Joint Surg Am, 2008. 90(6): p. 1258-64. 
3. 
Greenwald, A.G., P.C. Schute, and J.L. Shiveley, Brachial plexus birth palsy: a 10-
year report on the incidence and prognosis. J Pediatr Orthop, 1984. 4(6): p. 689-92. 
4. 
Waters, P.M., Comparison of the natural history, the outcome of microsurgical 
repair, and the outcome of operative reconstruction in brachial plexus birth palsy. J Bone 
Joint Surg Am, 1999. 81(5): p. 649-59. 
5. 
Pondaag, W., et al., Natural history of obstetric brachial plexus palsy: a systematic 
review. Dev Med Child Neurol, 2004. 46(2): p. 138-44. 
6. 
Gilbert, A. and J.L. Tassin, [Surgical repair of the brachial plexus in obstetric 
paralysis]. Chirurgie, 1984. 110(1): p. 70-5. 
7. 
Blair, D.N., et al., Normal brachial plexus: MR imaging. Radiology, 1987. 165(3): p. 
763-7. 
8. 
Doi, K., et al., Cervical nerve root avulsion in brachial plexus injuries: magnetic 
resonance imaging classification and comparison with myelography and computerized 
tomography myelography. J Neurosurg, 2002. 96(3 Suppl): p. 277-84. 
9. 
Landi, A., et al., The role of somatosensory evoked potentials and nerve conduction 
studies in the surgical management of brachial plexus injuries. J Bone Joint Surg Br, 
1980. 62-B(4): p. 492-6. 
10. Caporrino, F.A., et al., Brachial plexus injuries: diagnosis performance and reliability 
of everyday tools. Hand Surg, 2014. 19(1): p. 7-11. 
11. Nagano, A., et al., Usefulness of myelography in brachial plexus injuries. J Hand 
Surg Br, 1989. 14(1): p. 59-64. 
12. Vredeveld, J.W., et al., The findings in paediatric obstetric brachial palsy differ from 
those in older patients: a suggested explanation. Dev Med Child Neurol, 2000. 42(3): p. 
158-61. 
13. Slooff, A.C., Obstetric brachial plexus lesions and their neurosurgical treatment. 
Microsurgery, 1995. 16(1): p. 30-4. 
14. van Dijk, J.G., W. Pondaag, and M.J. Malessy, Obstetric lesions of the brachial 
plexus. Muscle Nerve, 2001. 24(11): p. 1451-61. 
15. Ijkema-Paassen, J. and A. Gramsbergen, Polyneural innervation in the psoas 
muscle of the developing rat. Muscle Nerve, 1998. 21(8): p. 1058-63. 

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16. Chow, B.C., S. Blaser, and H.M. Clarke, Predictive value of computed tomographic 
myelography in obstetrical brachial plexus palsy. Plast Reconstr Surg, 2000. 106(5): p. 
971-7; discussion 978-9. 
17. Radiation Risks and Pediatric Computed Tomography (CT): A Guide for Health 
Care Providers. . 2012  [cited 2016; Available from: http://www.cancer.gov/about-
cancer/causes-prevention/risk/radiation/pediatric-ct-scans. 
18. Tse, R., et al., The diagnostic value of CT myelography, MR myelography, and both 
in neonatal brachial plexus palsy. AJNR Am J Neuroradiol, 2014. 35(7): p. 1425-32. 
19. Rappaport, B.A., et al., Anesthetic neurotoxicity--clinical implications of animal 
models. N Engl J Med, 2015. 372(9): p. 796-7. 
20. Michelow, B.J., et al., The natural history of obstetrical brachial plexus palsy. Plast 
Reconstr Surg, 1994. 93(4): p. 675-80; discussion 681. 
21. Curtis, C., et al., The active movement scale: an evaluative tool for infants with 
obstetrical brachial plexus palsy. J Hand Surg Am, 2002. 27(3): p. 470-8. 
22. Bain, J.R., et al., Navigating the gray zone: a guideline for surgical decision making 
in obstetrical brachial plexus injuries. J Neurosurg Pediatr, 2009. 3(3): p. 173-80. 
23. Malessy, M.J. and W. Pondaag, Neonatal brachial plexus palsy with neurotmesis of 
C5 and avulsion of C6: supraclavicular reconstruction strategies and outcome. J Bone 
Joint Surg Am, 2014. 96(20): p. e174. 
24. Tse, R., et al., International Federation of Societies for Surgery of the Hand 
Committee report: the role of nerve transfers in the treatment of neonatal brachial plexus 
palsy. J Hand Surg Am, 2015. 40(6): p. 1246-59. 
25. Little, K.J., et al., Early functional recovery of elbow flexion and supination following 
median and/or ulnar nerve fascicle transfer in upper neonatal brachial plexus palsy. J 
Bone Joint Surg Am, 2014. 96(3): p. 215-21. 
26. Stecker, M.M., A review of intraoperative monitoring for spinal surgery. Surg Neurol 
Int, 2012. 3(Suppl 3): p. S174-87. 
27. Leshikar, H.B., et al., Clavicle Fracture Is Not Predictive of the Need for 
Microsurgery in Brachial Plexus Birth Palsy. J Pediatr Orthop, 2016.

Appendix A: MRI Protocol 
Page | 23  
MRI scanning protocols for brachial plexus consists of the following pulse sequences:  
 
Each infant will be positioned in an MRI scanner either using a swaddle blanket or vacuum 
suction controlled infant positioner, the MedVac Immobilizer 
 
Required sequences: 
o Localizer sequence 
o Sagittal T2 sequence through cervical spine 
o Coronal 3D proton density CUBE (General Electric trade name, Milwaukee, WI) or 
SPACE (Siemens Medical USA, Malvern, PA) sequence oriented in the plane of the 
cervical spine and extended anteriorly to include the involved brachial plexus. 
o The total scanning time will be approximately 10-15 minutes excluding initial 
preparation time.  Total study time will be 30 minutes. 
 
Optional sequences only when time allows and required sequences are diagnostic quality: 
o Coronal T2 fast spine echo 
o Coronal T2 fat saturation CUBE (General Electric trade name, Milwaukee, WI) or 
SPACE (Siemens Medical USA, Malvern, PA) sequence oriented in the plane of the 
cervical spine and extended anteriorly to include the involved brachial plexus. 
o Coronal STIR (Short TI Inversion Recovery) CUBE (General Electric trade name, 
Milwaukee, WI) or SPACE (Siemens Medical USA, Malvern, PA) sequence oriented 
in the plane of the cervical spine and extended anteriorly to include the involved 
brachial plexus.