How do the Neck Muscles Influence Head Acceleration During Sport-associated Impact Events in High School Athletes?
Phase: NA
Conditions: Sport-related Concussion, Brain Concussion, Healthy
Sponsor: University of Michigan

 
 
HUM00152807 
NCT03883165 
 
How do the neck muscles influence head acceleration during sport-associated impact events in 
high school athletes? 
 
Principal Investigator: James T. Eckner, M.D., M.S. 
Date approved by IRB -  06/16/2023 
 

 
 
How do the neck muscles influence head acceleration 
during sport-associated impact events in high school 
athletes? 
Protocol Number: HUM00152807 
National Clinical Trial (NCT) Identified Number:   03883165  
Principal Investigator: James T. Eckner, M.D., M.S. 
Sponsor: N/A 
Funded by: NIH: Eunice Kennedy Shriver National Institute of Child Health and 
Human Development 
Version Number: v.2.3 
15 May 2023 
 
 
Summary of Changes from Previous Version: 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
1.2, 2.3.2, 4.1, 4.2, 4.3, 
6.1.1, 6.1.2, 6.2, 9.2, 
9.4.5 
Low-Volume exercise group removed from 
protocol. 
Reduce enrollment following COVID pandemic. 
1.3 
Clarification to criteria defining protocol deviation 
- updating number of days that create a 
deviation. 
Reducing documentation burden associated with 
schedule deviations 
2.3.1, 2.3.3, 5.2 
Removal or MRI contraindication as exclusion 
criteria. 
Low enrollment number.  MRI data is not used for 
primary outcome.  Removing this criterion may 
increase the number of eligible participants. 

  
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 3 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 4 
2 
INTRODUCTION ............................................................................................................................................ 4 
2.1 
Study Rationale .................................................................................................................................... 4 
2.2 
Background........................................................................................................................................... 5 
2.3 
Risk/Benefit Assessment .................................................................................................................... 8 
2.3.1 
Known Potential Risks ..................................................................................................... 8 
2.3.2 
Known Potential Benefits ................................................................................................ 9 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 10 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 11 
4 
STUDY DESIGN ........................................................................................................................................... 13 
4.1 
Overall Design .................................................................................................................................... 13 
4.2 
Scientific Rationale for Study Design.............................................................................................. 13 
4.3 
Justification for Dose ......................................................................................................................... 13 
4.4 
End of Study Definition ..................................................................................................................... 14 
5 
STUDY POPULATION ................................................................................................................................ 14 
5.1 
Inclusion Criteria ................................................................................................................................ 14 
5.2 
Exclusion Criteria ............................................................................................................................... 14 
5.3 
Lifestyle Considerations .................................................................................................................... 15 
5.4 
Screen Failures .................................................................................................................................. 15 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 16 
6 
STUDY INTERVENTION ............................................................................................................................ 17 
6.1 
Study Intervention(s) Administration ............................................................................................... 17 
6.1.1 
Study Intervention Description ..................................................................................... 17 
6.1.2 
INTERVENTION Administration .................................................................................. 17 
6.2 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 17 
6.3 
Study Intervention Compliance ........................................................................................................ 18 
6.4 
Concomitant Therapy ........................................................................................................................ 18 
6.4.1 
Rescue Medicine ............................................................................................................ 18 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 18 
7.1 
Discontinuation of Study Intervention ............................................................................................. 18 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 18 
7.3 
Lost to Follow-Up ............................................................................................................................... 19 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 19 
8.1 
Efficacy Assessments ....................................................................................................................... 19 
8.2 
Safety and Other Assessments ....................................................................................................... 22 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 22 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 22 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 22 
8.3.3 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 24 
8.3.4 
Adverse Event Reporting .............................................................................................. 25 
8.3.5 
Serious Adverse Event Reporting ............................................................................... 25 

  
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8.3.6 
Reporting Events to Participants ................................................................................. 25 
8.3.7 
Events of Special Interest ............................................................................................. 25 
8.3.8 
Reporting of Pregnancy ................................................................................................ 25 
8.4 
Unanticipated Problems .................................................................................................................... 26 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 26 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 26 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 26 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 27 
9.1 
Statistical Hypotheses ....................................................................................................................... 27 
9.2 
Sample Size Determination .............................................................................................................. 27 
9.3 
Populations for Analyses .................................................................................................................. 27 
9.4 
Statistical Analyses............................................................................................................................ 27 
9.4.1 
General Approach .......................................................................................................... 28 
9.4.2 
Analysis of the Primary Efficacy Endpoint .................................................................. 28 
9.4.3 
Analysis of the Secondary Endpoint(s) .......................... Error! Bookmark not defined. 
9.4.4 
Safety Analyses .............................................................................................................. 28 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 28 
9.4.6 
Planned Interim Analyses ............................................................................................. 28 
9.4.7 
Sub-Group Analyses ..................................................................................................... 29 
9.4.8 
Tabulation of Individual participant Data .................................................................... 29 
9.4.9 
Exploratory Analyses ..................................................................................................... 29 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 29 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 29 
10.1.1 
Informed Consent Process ........................................................................................... 30 
10.1.2 
Study Discontinuation and Closure ............................................................................. 30 
10.1.3 
Future Use of Stored Specimens and Data ............................................................... 31 
10.1.4 
Key Roles and Study Governance .............................................................................. 31 
10.1.5 
Safety Oversight ............................................................................................................. 31 
10.1.6 
Clinical Monitoring .......................................................................................................... 32 
10.1.7 
Quality Assurance and Quality Control ....................................................................... 32 
10.1.8 
Data Handling and Record Keeping ............................................................................ 33 
10.1.9 
Protocol Deviations ........................................................................................................ 33 
10.1.10 
Publication and Data Sharing Policy ........................................................................... 33 
10.1.11 
Conflict of Interest Policy .............................................................................................. 34 
10.2 
Additional Considerations ................................................................................................................. 34 
10.3 
Abbreviations ...................................................................................................................................... 34 
10.4 
Protocol Amendment History ........................................................................................................... 36 
11 
REFERENCES ............................................................................................................................................. 37 
 

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STATEMENT OF COMPLIANCE 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form will be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
Investigators and clinical trial site staff responsible for study conduct, management, or oversight will 
complete Human Subjects Protection training in best practices for research. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
How do the neck muscles influence head acceleration during sport-
associated impact events in high school athletes? 
Study Description: 
Sport-related concussion is a common injury associated with significant 
short- and long-term disability in high school athletes.  This project will 
study up to 72 healthy male and female soccer athletes to determine how 
neck strengthening exercise affects head acceleration during sport-
associated impacts (AIM 1) and define the mechanism relating neck 
strength and neck muscle volume to head acceleration under different 
impact conditions (AIM 2).  The long term goal of this project is to optimize 
neck strengthening exercise programs to decrease the risk of concussion in 
high school athletes. 
 
 
Objectives: 
Primary Objective (AIM 1):  To determine the effect of manual resistance 
neck strengthening exercise on net head acceleration during simulated 
sport-associated impacts to the head (direct loading condition).  
Secondary Objective (AIM 1):  To determine the effect of manual 
resistance neck strengthening exercise on net head acceleration during 
simulated sport-associated impacts to the body (indirect loading 
condition).   
Exploratory Objective (AIM 1):  To determine the effect of manual 
resistance neck strengthening exercise over time on neck strength, cervical 
muscle volume, neuromuscular recruitment, and net head acceleration 
under direct and indirect loading as well as during voluntary soccer 
heading. 
 
Exploratory Objective (AIM 2):  To determine the relative influences of 
baseline neck strength and cervical muscle volume on net head 
acceleration during simulated sport-associated impacts to the head and 
body with and without volitional, anticipatory cervical muscle pre-
contraction to brace for the impact.   
 
 

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Endpoints: 
Primary Endpoint:  Mean area under the net head acceleration vs. time 
curve during direct loading, with anticipatory bracing, at Assessment Time 
Point 4. 
Secondary Endpoint: Mean area under the net head acceleration vs. time 
curve during indirect loading, with anticipatory bracing, at Assessment 
Time Point 4. 
Study Population: 
Up to 72 male and female high school soccer athletes in and around Ann 
Arbor Michigan. 
Phase: 
N/A 
Description of 
Sites/Facilities Enrolling 
Participants: 
University of Michigan.  
Description of Study 
Intervention: 
Neck strengthening resistance exercise.   
Study Duration: 
Approximately 60 months. 
Participant Duration: 
Approximately 4 months. 
 
 

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1.2 
SCHEMA 
 
Refer to Section 1.3, Schedule of Activities, for additional detail. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior to 
Enrollment 
Total N=72:  screen potential participants by inclusion and exclusion 
criteria.  Obtain informed consent 
Assessment 1 
(Baseline) 
Perform baseline assessments: anthropometrics, neck strength, cervical 
muscle volume (inc. MRI) and activation, head acceleration.  
*Not all participants will undergo MRI 
Control (n=36) 
High Intensity (n=36) 
Assessment 2 
(4 weeks) 
Interim assessment:  anthropometrics, neck strength, cervical muscle 
volume and activation, head acceleration 
Exercise 
Exercise 
Assessment 3 
(8 weeks) 
Interim assessment:  anthropometrics, neck strength, cervical muscle 
volume and activation, head acceleration 
Exercise 
Assessment 4 
(12 weeks) 
Final assessment:  anthropometrics, neck strength, cervical muscle volume 
(inc. MRI) and activation, head acceleration 
*Not all participants will undergo MRI 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Initial Phone Screening 
Day -90 to -2 
In-person screening/Intake 
Day -30 to -1 
Baseline Assessment (#1)  
Day 1 
Baseline MRI 
Day 1 +/- 10 days 
Exercise (2x/week) 
Weeks 1-4 
Interim Assessment (#2) 
28 +/- 10 days from #1 
Exercise (2x/week) 
Weeks 5-8 
Interim Assessment (#3) 
28 +/- 10 days from #2 
Exercise (2x/week) 
Weeks 9-12 
Final Assessment (#4) 
28 +/- 10 days from #3 
Final MRI 
28 +/- 10 days from #3 
Eligibility review 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
X 
 
 
 
 
 
 
 
 
 
Medical and sport history 
X 
X 
 
 
 
 
 
 
 
 
 
Screening physical examination 
 
X 
 
 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
Anthropometric assessment 
 
 
X 
 
 
X 
 
X 
 
X 
 
Randomized group allocation 
 
 
X 
 
 
 
 
 
 
 
 
Neck strength  
 
 
X 
 
 
X 
 
X 
 
X 
 
Cervical Muscle ultrasound 
 
 
X 
 
 
X 
 
X 
 
X 
 
Neck MRI 
 
 
 
X 
 
 
 
 
 
 
X 
Cervical muscle activation 
 
 
X 
 
 
X 
 
X 
 
X 
 
Net head acceleration 
 
 
X 
 
 
X 
 
X 
 
X 
 
Exercise (2x/week) with strength 
coach 
 
 
 
 
X 
 
X 
 
X 
 
 
Adverse event monitoring 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Neck strengthening exercise represents a simple and practical intervention to reduce the risk of sport-
related concussion (SRC) in the millions of student-athletes who play a high school sport in the US each 
year.  Athletes whose necks are less able to attenuate forces acting on their heads during an impact will 
experience greater head acceleration and therefore be at higher risk for sustaining SRC.  In fact, the only 
study to directly assess the neck’s influence on concussion risk was a prospective epidemiological 
investigation demonstrating that for every one-pound increase in neck strength there was a 5% reduction 
in the odds of sustaining SRC.12  However, neck strengthening exercise remains under-utilized in the 
high school athlete population, and there is a gap in our understanding of how the neck influences an 
athlete’s head acceleration under different impact conditions, as well as how these relationships may 
be modified by exercise.  There is a critical need to define these relationships and to develop optimal 
neck strengthening exercise protocols for high school athletes to reduce their risk of SRC. 
This work is expected to have a positive translational impact in the field because evidence-based 
prescription of neck strengthening exercise represents a significant advancement over the existing status 
quo, which ranges from an uninformed “shooting in the dark” approach to neck strengthening exercise 
prescription to no neck strengthening exercise at all.  Based on our own pilot results and published 
epidemiological work, we estimate that neck strengthening exercise may have the potential to prevent as 
many as 47,000 cases of SRC in high school athletes annually.  While this work will focus on high school 
soccer athletes, it will have translational potential to inform SRC prevention efforts in broader athlete 
populations, including youth and collegiate athletes, as well as athletes who participate in sports other 
than soccer. 
 

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2.2 
BACKGROUND  
 
Clinical and Societal Significance 
Sport and recreation-related concussion (SRC) is a common injury estimated to affect as many as 3.8 
million Americans each year, and is now recognized as a major public health concern in the U.S.45, 50  In 
the short-term, SRC causes a constellation of physical, cognitive, affective, and sleep-related signs and 
symptoms limiting an athlete’s ability to participate in academic, vocational, and recreational pursuits for a 
period of days to months.  A history of SRC increases an athlete’s risk for sustaining subsequent 
concussions in the short term,88 as well as for developing depression,30 dementia,29 and 
neurodegenerative diseases including chronic traumatic encephalopathy later in life.52  Given the myriad 
of negative short- and long-term consequences of SRC, developing injury prevention strategies is 
critically important.   
 
The ~7.8 million student-athletes who participate in organized sports at the high school level each year 
represent the single largest population of athletes at risk for sustaining SRC.58  In fact, we recently 
reported in JAMA more than one out of every 5 U.S. high school students who participate in contact and 
semi-contact sports has sustained at least one prior concussion.82  Further, concussions represent 
approximately 13% of all athletic injuries in this population.48  High school-aged and younger athletes 
whose brains have yet to fully develop are also thought to have a greater physiological susceptibility to 
concussion than adults.38   
 
Overall Scientific Premise 
This proposal is built upon the overall scientific premise that concussion occurs as a result of rapid head 
acceleration following external force application. An early explanation of the positive association between 
head acceleration and the risk of brain injury was provided by the Wayne State Tolerance Curve (WSTC), 
which demonstrated that injury risk increased with greater magnitudes and durations of linear head 
acceleration.28  Weaknesses of the WSTC include its failure to account for angular acceleration and its 
focus on more severe brain injury rather than SRC.  More recently, our group and others have performed 
field-based concussion biomechanics research using a helmet-based head impact sensor [Head Impact 
Telemetry (HIT) System] further supporting the relationship between head acceleration and the 
associated risk of SRC.5, 7, 18, 23, 68  We have recently published two reviews summarizing that body of 
work,4, 6 which now includes over 40 peer-reviewed scientific publications.  The HIT System provides the 
best in vivo biomechanical head impact data available today,1, 15, 65 but is limited by measurement error 
associated with imperfect coupling of the in-helmet sensors to the head.40  Furthermore, most studies 
using the HIT System have given relatively little consideration to impact durations.  Field-based 
biomechanics research provides an unparalleled ability to collect head acceleration data in vivo, but has 
failed to demonstrate a simple linear or angular acceleration threshold able to reliably discriminate 
between concussive and non-concussive head impacts.31, 56  Nonetheless, it is clear the risk of 
concussion associated with a given impact increases with increasing linear and angular head acceleration 
magnitudes and durations.66 
 
Head acceleration causes concussion by inducing brain tissue deformation that leads to microstructural 
and physiological injury.53  Since greater head acceleration magnitudes and durations both increase brain 
tissue deformation, this provides a mechanistic explanation for the observed relationship between head 
acceleration and concussion.   
 
Scientific Premise for AIM 1: AIM 1 is based on the scientific premise that attributes of an 
athlete’s cervical muscles (i.e., neck strength, cervical muscle volume and neuromuscular recruitment 
patterns) influence their risk of SRC for a given impact by modifying the resultant acceleration of their 
head.  Therefore, neck strengthening exercise has the potential to mitigate head acceleration during 
sport-associated impacts to reduce an athlete’s SRC risk.  The strongest evidence that the neck can 
influence an athlete’s risk of SRC comes from a large epidemiological study involving 6,704 high school 
male and female soccer, basketball, and lacrosse athletes.12  In that study there was a 5% decrease in 

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odds of SRC for every one-pound increase in neck strength.  However, that study did not address the 
mechanism relating neck strength to concussion risk so it cannot directly inform the development of neck 
strengthening exercise programs.  In contrast with that epidemiological evidence, two in vivo studies 
using the HIT System to measure head acceleration magnitudes as a proxy measure for concussion risk 
failed to support the hypothesis that having a larger, stronger neck is associated with lower head 
accelerations in American football and ice hockey athletes in the field.55, 67  While these field-based 
studies share strong ecological validity, a major weakness of both studies was their lack of experimental 
control.  Because impact conditions were not monitored, factors known to influence head acceleration, 
such as impact anticipation and bracing,34, 54 may have confounded any underlying association between 
cervical muscle attributes and head acceleration.  
 
Taking advantage of the greater experimental control achieved in a laboratory environment, we 
have previously reported on the influence of neck strength and circumference on head accelerations in 
response to standardized test loads.22  In 46 male and female contact sport athletes exposed to 
standardized loads in each plane of motion, we found greater neck strength and circumference were both 
significantly associated (r= .42 to r= .76) with lower head acceleration, quantified in that study as the 
changes in linear and angular velocity (ΔV in m/s and Δω in °/s) to account for both acceleration 
magnitude and duration given their mathematical equivalence to the areas under the linear and angular 
acceleration curves.  Other groups have used similar laboratory-based methodologies to administer 
sagittal-plane standardized test loads to subjects’ heads in pursuit of complementary study aims with 
similar results.63, 70, 75  Such experimental designs allow researchers to safely and precisely apply 
standardized test loads directly to the head, while measuring resultant linear and angular head 
accelerations with a high degree of accuracy.  However, with this standardization, precision, and control 
comes the loss of ecological validity as such testing paradigms do not closely mimic the circumstances 
athletes experience during live sport participation.  One approach to improving ecological validity while 
maintaining a high degree of experimental control is to study simulated sport-specific events in a lab 
environment.  Several studies have adopted this approach to either directly or indirectly assess 
relationships between various cervical attributes and head acceleration during lab-based soccer heading 
tasks, typically reporting significant associations between greater neck strength and/or circumference and 
lower head acceleration.3, 9, 32, 74  However, no study has investigated the effect of a neck strengthening 
intervention on head acceleration using a soccer heading model.  
 
The strongest direct support for the premise that neck strengthening exercise will decrease head 
acceleration during sport-associated impacts comes from our own group’s pilot data collected in 17 male 
and female youth and high school athletes.19  In our pilot study, 13 participants assigned to a supervised 
8-week manual resistance neck strengthening exercise program had greater increases in neck strength 
than 4 participants assigned to a control resistance exercise program not specifically targeting the neck.  
Athletes in both groups experienced decreases in head acceleration, again quantified as ΔV and Δω.  
Multiple other researchers have also demonstrated increases in neck strength and circumference with 
resistance training,8, 13, 27, 71, 72 but only one other published study has reported the effect of neck 
strengthening exercise on head acceleration in response to standardized loading.47  In that study, Mansell 
et al. randomly assigned 36 male and female collegiate soccer athletes to an 8-week flexion/extension-
based isotonic neck strengthening exercise program or a control program not including cervical 
resistance exercises.  The neck strengthening exercise group demonstrated increases in neck strength 
and circumference, but without a corresponding decrease in peak angular head acceleration during 
standardized loading in flexion and extension.   
 
Unfortunately, there are limitations associated with both of those interventional studies.  A 
limitation of our own pilot neck strengthening study19 was its small, unbalanced sample size, which limits 
statistical power and the generalizability of our results.  Furthermore, because we did not measure the 
resistance applied by the strength coach during the manual resistance exercises, we were unable to 
assess for evidence of dose-response relationships.  The Mansell et al. study47 was likely limited by a 
ceiling effect due to its inclusion of only highly-trained Division I collegiate athletes.  A potential ceiling 
effect is supported by our own data demonstrating non-linearity in the relationship between neck strength 

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and head acceleration.22  Furthermore those results may not generalize to non-collegiate populations.  In 
addition, that exercise intervention addressed only the sagittal plane, and only sagittal-plane angular head 
acceleration magnitude was considered as a kinematic outcome.  Finally, neither study’s laboratory-
based standardized test loads were representative of head impact events encountered by athletes during 
sport participation in the field.  There remains a knowledge gap in how neck strengthening exercise 
influences an athlete’s head acceleration during sport-associated impacts.   
 
AIM 1 will directly address this knowledge gap by determining the effect of manual resistance 
neck strengthening exercise on net head acceleration during direct force application to the head, force 
application to the body with inertial force transmission to the head via a simulated checking/blocking task, 
and voluntary soccer heading.  In designing AIM 1, we have addressed each of the limitations in the 
previous studies described above.   
 
Scientific Premise for AIM 2: AIM 2 is based on the scientific premise that anticipatory pre-
contraction of the cervical muscles to brace for an impact influences head acceleration.  Furthermore, 
cervical muscle attributes (i.e., neck strength and cervical muscle volume) influence head acceleration 
differently with vs. without cervical muscle pre-contraction.  This premise is supported by our own work 
demonstrating that head acceleration, again reported as ΔV and Δω, decreased by 12.3% and 9.7%, 
respectively, during anticipatory cervical muscle pre-contraction as compared to relaxed, upright sitting.22  
Recent finite element modeling work, as well as numerous other studies in the concussion and whiplash 
literature, have also reported decreased head acceleration in response to various forms of loading during 
trials with vs. without anticipation and/or cervical muscle pre-contraction.34, 41, 44, 57, 63, 70, 75  However, the 
design of those studies limits the insight they can provide into which cervical muscle attribute is most 
responsible for controlling head acceleration with vs. without anticipatory pre-contraction.  While not the 
primary objective, our previous work demonstrated greater neck strength and circumference were each 
significantly associated with lower ΔV and Δω across all directions of head motion under both anticipation 
conditions (r= .42 to r= .60 for neck strength; r= .60 to r= .76 for neck circumference).22  In that study, 
more of the variability in head acceleration was explained by neck strength for 6 of the 7 models under 
the anticipated condition, but by neck circumference for 6 of the 7 models without anticipation.  That 
finding suggests neck strength and cervical muscle volume may influence head acceleration differently 
depending on cervical muscle pre-contraction status.  We are unaware of other reports to directly quantify 
the relationships between individual cervical muscle attributes and head acceleration with vs. without 
anticipatory cervical muscle pre-contraction.   
 
The premise that neck strength and cervical muscle volume may exert differential influences on 
head acceleration during anticipated vs. unanticipated impacts is further supported when considering 
each potential cervical contributor to head acceleration.  Previous work concluded that since the 
mechanical properties of the neck’s non-contractile tissues (e.g., bone, ligament) are not affected by 
muscle activation, and because peak head acceleration is reached before either a reflexive or voluntary 
muscular response has had time to occur, head acceleration is primarily influenced by the mechanical 
properties of the cervical muscles.70  Passive muscle stiffness is strongly influenced by the amount of 
muscle tissue being acted upon.26, 85  In contrast, the stiffness of actively contracting muscle increases 
proportionally with muscle activation and torque.2, 37, 84  Therefore for any volume of cervical muscle, 
greater neck strength (i.e., torque generation) associated with improved neuromuscular recruitment is 
expected to confer greater muscle stiffness during maximal anticipatory cervical muscle pre-contraction to 
brace for the impact. While muscle strength and volume co-vary, these characteristics are known to 
change independently from one another with aging,42, 86 disuse,11, 81 and of greater direct applicability to 
this proposal, following resistance training.25  There remains a knowledge gap in how individual cervical 
muscle attributes affect head acceleration during sport-associated impacts with vs. without anticipatory 
cervical muscle pre-contraction to brace for the impact.  
 
AIM 2 will directly address this knowledge gap by comparing the relative weights of neck strength 
and cervical muscle volume in predicting net head acceleration during anticipated and unanticipated 
impacts to the head and body.   

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2.3 
RISK/BENEFIT ASSESSMENT   
2.3.1 KNOWN POTENTIAL RISKS  
 
Potential risks associated with each component of the study include: 
 
Collection of demographic and historical information:  Loss of privacy and/or 
confidentiality is the main potential risk associated with this component of the study.  
This risk is considered non-serious.  Likelihood:  rare (< 1%).   
 
Collection of anthropometric data:  Subjects may feel embarrassed if they consider their 
height or weight to be outside of their self-perceived desirable range.  There is also 
potential loss of privacy and/or confidentiality associated with anthropometric data 
collection.  These risk are collectively considered non-serious.  Likelihood:  infrequent (1-
10%).   
 
Cervical muscle volume (MRI) and cross sectional area (ultrasound) assessments:  
There is no radiation exposure associated with either MRI or ultrasonography and there 
are no known adverse long term effects associated with either imaging modality.  It is 
possible that subjects may feel uneasy while confined to the small space inside the MRI 
scanner.  It is also possible that during sonographic assessment of the neck muscles the 
carotid baroreceptors could be stimulated by the transducer head resulting in a syncopal 
or near syncopal episode (fainting/near-fainting).  These risks are considered non-
serious.  Likelihood:  rare (< 1%).  Not all subjects will undergo an MRI scan.  
 
Neck strength assessment:  Subjects may feel muscular discomfort associated with 
maximal isometric contraction of their cervical muscles.  This risk is considered non-
serious.  Likelihood: infrequent (1-10%).   
 
Assessment of the head’s dynamic response to direct force application:  Subjects may 
initially be concerned about how the direct force application loads will feel.  This risk is 
considered non-serious.  Likelihood:  likely (10-25%).  Subjects could potentially 
experience neck pain or a headache associated with this loading condition.  The most 
likely etiology for neck pain is anticipated to be mild cervical muscle strain and the most 
likely etiology for headache is anticipated to be cervicogenic headache.  The risk of 
developing neck pain or headache is considered non-serious.  Likelihood:  rare (< 1%).  
It is not expected that any more serious neck or neurological injury (concussion, 
radiculopathy, spinal cord injury, or vascular injury) will result from this procedure.     
 
Assessment of the head’s dynamic response during the standardized checking/blocking 
and voluntary soccer heading tasks: Subjects could again potentially experience neck 
pain or a headache associated with these loading conditions.  Again, these risks are 
considered non-serious.  Likelihood: rare (< 1%).  Specific to the simulated 
checking/blocking task, subjects could also potentially experience musculoskeletal back, 
chest, or shoulder pain or “have the wind knocked out of them” due to the impacts 
delivered to their torsos by the punching bag.  The risk of developing musculoskeletal 
pain or “having the wind knocked out of them” is also considered non-serious.  
Likelihood:  rare (< 1%).  It is not expected that any more serious injuries such as 
fracture or joint dislocation will result from these procedures.  Both tasks were designed 
to simulate the low-end of forces experienced by an athlete while performing a soccer 

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header or being checked/blocked during live soccer play and are therefore felt to be less 
risky than their routine participation in sport and no more risk than they experience in 
normal, everyday recreational activities. In addition, the controlled laboratory conditions 
under which the headers will be performed will allow ample time to properly align the 
head with the ball to ensure correct heading technique. The proposed soccer heading 
task, which involves less than 10 headers performed with an incoming ball velocity of 
less than 10 m/s, represents fewer headers at a lower velocity, and with a less-inflated 
ball than would be expected to occur during a high school soccer practice or a physical 
education class activity focusing on heading skills. Furthermore, this protocol represents 
an overall smaller combination of repetitions and ball velocities than has been used in 
existing research studies involving standardized soccer headers. Similar studies in the 
past have included as many as 20 headers and ball velocities up to 25 m/s. The soccer 
heading and checking/blocking tasks were developed with input from our expert soccer 
advisor, Mr. Greg Ryan, the former University of Michigan Women's Varsity Soccer 
coach, who has extensive soccer coaching experience at the high school level is also of 
the opinion these controlled tasks will not pose any safety risk to high school soccer 
athletes, and will be no greater risk than youth members of the general population are 
exposed to during normal recreational activities. 
 
Kinematic measurements: Light emitting diodes used with a high speed kinematic 
camera system may become hot to the touch when left to record continuously.  Subjects 
could experience a minor superficial skin burn if a light emitting diode became too hot 
and was left in place, although this would be unlikely as the diodes are not affixed 
directly to the skin, but rather to a plastic plate surface affixed to the skin.  The risk 
associated with this is considered non-serious.  Likelihood:  rare (< 1%).   
 
Skin preparation/application of skin adhesives:  Subjects may experience minor skin cuts 
or irritation associated with skin shaving or the adhesive backing on the surface EMG 
electrodes or other superficially adherent sensors.  The risk associated with this is 
considered non-serious.  Likelihood:  infrequent (1-10%). 
 
Fitting of boil-and-bite mouth guards:  Subjects could receive minor burn to their hands 
or mouths while using boiling water to fit mouth guards to their mouth if direct contact 
with the boiling water occurred.  The risk of burn is considered non-serious.  Likelihood:  
rare (< 1%). 
 
Supervised exercise sessions:  Subjects are anticipated to experience delayed-onset 
muscle soreness following resistance training, which is a normal training-related 
phenomenon.  The risk associated with this is considered non-serious.  Likelihood: 
frequent (>25%).  It is not expected that any serious training-related injuries will result 
from participation in study exercise sessions.        
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Subjects allocated to both study groups may potentially benefit from the resistance training 
exercise program administered by the Certified Strength and Conditioning Specialist during the 
study.  Resistance training is anticipated to improve muscle strength and endurance and has 
the potential to enhance subjects’ athletic performance as well as to reduce their risk of 
sustaining sport-related injury.  In addition, subjects will receive a 4-month gym membership, 

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permitting them unrestricted access to the gym’s exercise facilities for the duration of their 
membership.   
 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
All study activities will be approved and monitored by the UM IRB-MED.   
 
The PI, who is a licensed and board certified Physical Medicine and Rehabilitation physician will 
complete a final in-person eligibility determination for each subject.  If the PI is unavailable to 
perform the in-person eligibility determination, then a qualified designated Co-I will complete the 
final in-person eligibility determination in the PI’s absence.  Potential subjects with any historical 
or physical examination findings felt by the PI, or his designee, to place them at potentially 
elevated risk for injury will be excluded.   
 
Subject privacy will be protected during laboratory assessments by testing in a private 
environment closed to the outside in the presence of study personnel only.  To ensure the 
confidentiality of data and personal information, all electronic data will be coded.  Only the PI 
and appropriate study personnel will have access to the key, which will be stored on a 
password-protected secure computer maintained by the University of Michigan.   
 
Prior to each laboratory testing and exercise session, subjects will complete a brief warm-up 
routine including static and dynamic neck stretches.  All exercise sessions will be administered 
by a Certified Strength and Conditioning Specialist (CSCS) so the risk of sustaining any 
exercise-related injury is felt to be lower than that typically present during unsupervised or 
indirectly supervised resistance training exercise.   
 
Additionally, the following test-specific safety measures will be employed to minimize risk to 
subjects during laboratory testing: 
 
 
Neck MRI and cervical muscle cross sectional area measurements with ultrasound:  
Subjects will undergo ultrasound testing while seated in a chair with bilateral armrests.  
The tester will be seated immediately adjacent to the subject during the assessment.  In 
the unlikely event of a syncopal episode, the subject will be prevented from falling to 
minimize potential risk of injury.     
 
Assessment of the head’s dynamic response to direct force application:  During our 
experience using this technique, concerned subjects have been uniformly relieved after 
experiencing the first load applied to their head.  The testing apparatus is designed to 
limit forced displacement of the head and the drop height of the weight is set so that no 
more energy is delivered to the subject’s head than is necessary to generate a reliable, 
measurable dynamic response.  In our experience using the direct force application 
model, measured head accelerations are approximately 10-fold less than the minimum 
values typically reported in the literature to cause concussion in athletes in the field.    
 
Assessment of the head’s dynamic response during the simulated checking/blocking and 
voluntary soccer heading tasks:  Subjects will wear a mouth guard during these tasks for 
dental protection.  Both tasks were designed to simulate the low-end of forces 
experienced by an athlete while performing a soccer header or being checked/blocked 
during live soccer play and are therefore felt to be no more risk than their routine 

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participation in everyday recreational activities.  In addition, the controlled laboratory 
conditions under which the tasks will be performed will allow ample time to properly align 
the head/body with the ball/punching bag to ensure correct heading/blocking technique.  
The proposed soccer heading task represents fewer headers of lower magnitude than 
would be expected to occur during a high school soccer practice or a physical education 
class activity focusing on heading skills.  Furthermore, this protocol utilizes an overall 
smaller combination of repetitions and ball velocities than has been used in previous 
research studies involving standardized soccer headers.3, 14, 15, 23, 30, 31, 47, 55, 62  We are not 
aware of any existing research using a similar checking/blocking task that can be 
compared to our proposed protocol, but the subjective experience of the volunteers who 
were involved during protocol development was that no discomfort occurred.  During the 
simulated checking/blocking task, the distance the boxer’s punching bag swings before 
contacting the subject’s body is set sufficiently low so as not to displace the subject’s 
feet upon contact with the minimum amount of energy delivered as necessary to 
generate a reliable, measurable dynamic head response.  The soccer heading and 
checking/blocking tasks were both developed with safety input from a collegiate soccer 
coach with extensive experience working with high school soccer athletes. 
 
Kinematic measurements:  Kinematic recording will be paused between trials to 
minimize the chances of light emitting diode heating. 
 
Fitting procedures for boil-and-bite mouth guards:  While fitting the boil-and-bite mouth 
guards, after removing the unit from the boiling water subjects will fully submerge it in 
cold water before placing it in their mouths.  
 
The risk level for all study activities is no more than minimal because subjects will not be 
performing any activities riskier than those they routinely experience in their day-to-day lives.  
All eligible subjects are high school athletes who are expected to routinely experience minor, 
and in some cases major, trauma to the head, neck, and body during sport participation, such 
as regular voluntary heading of a soccer ball.  Routine sport participation is felt to be associated 
with a much greater potential for injury than the controlled experimental procedures associated 
with this study.  In addition, participation in a resistance training exercise program under the 
direct supervision of a Certified Strength and Conditioning Specialist is felt to be safer than 
participation in an unsupervised or indirectly supervised resistance training program, as is 
typical for high school athletes.  As such, we feel the potential benefits to subjects, as well as 
the potential future benefits of this work to athletes like those participating in this study, 
outweigh the minimal risks to subjects. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
 
 
Primary Objective (AIM 1):  
To determine the effect of 
manual resistance neck 
strengthening exercise on net 
head acceleration during 
simulated sport-associated 
Primary Endpoint:  Mean area 
under the net head acceleration 
vs. time curve during direct 
loading, with anticipatory 
bracing, at Assessment Time 
Point 4. 
 
Head acceleration is used as the 
study’s lab-based proxy 
measure for concussion risk 
(greater head acceleration is 
associated with greater risk).  
Concussion is most commonly 
caused by direct force 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
impacts to the head (direct 
loading condition).   
 
 
application to the head.  This 
study seeks to determine how 
manual resistance neck 
strengthening exercise 
influences an athlete’s head 
acceleration under direct 
loading. 
Secondary 
 
 
Secondary Objective (AIM 1):  
To determine the effect of 
manual resistance neck 
strengthening exercise on net 
head acceleration during 
simulated sport-associated 
impacts to the body (indirect 
loading condition).   
 
 
Secondary Endpoint:  Mean 
area under the net head 
acceleration vs. time curve 
during indirect loading, with 
anticipatory bracing, at 
Assessment Time Point 4. 
 
While a less common 
mechanism than direct loading 
to the head, concussion can also 
be caused by indirect 
transmission of forces to the 
head from the body.  This study 
therefore seeks to also 
determine how manual 
resistance neck strengthening 
exercise influences an athlete’s 
head acceleration under 
indirect loading. 
Tertiary/Exploratory  
 
 
Exploratory Objective 1 (AIM 1): 
To determine the effect of 
manual resistance neck 
strengthening exercise over 
time on neck strength, cervical 
muscle volume, neuromuscular 
recruitment, and net head 
acceleration under direct and 
indirect loading as well as during 
voluntary soccer heading.  
Exploratory Objective 2 (AIM 2): 
To determine the effect of 
manual resistance neck 
strengthening exercise on the 
relative influence of neck 
strength vs. cervical muscle 
volume on net head 
acceleration during direct and 
indirect loading with and 
without volitional, anticipatory 
cervical muscle pre-contraction 
to brace for the impact.  
Exploratory AIM 1 Endpoints:  
Neck strength (peak 
force/moment and rate of 
force/torque development); 
total cervical muscle volume 
(estimated based on sex, neck 
circumference, cervical 
ultrasound and MRI 
measurements); cervical muscle 
activation (agonist muscle 
activation, antagonist muscle 
inhibition based on surface 
EMG); mean area under the net 
head acceleration vs. time curve 
during direct and indirect 
loading, with anticipatory 
bracing, at Assessment Time 
Points 1, 2, 3; mean area under 
the net head acceleration vs. 
time curve during voluntary 
soccer heading at Assessment 
Time Points 1, 2, 3, 4.  
Exploratory AIM 2 Endpoints:  
Mean area under the net head 
acceleration vs. time curve 
Resistance training is known to 
increase muscle strength 
through more efficient 
neuromuscular recruitment 
(i.e., muscle activation patterns) 
before muscle hypertrophy (i.e., 
increase in muscle size) occurs.  
This study seeks to understand 
the effect of resistance exercise 
on neck strength, as well as 
cervical muscle volume and 
activation patterns.  This study 
also seeks to determine the 
relative influence of neck 
strength vs. cervical muscle 
volume on head acceleration 
during impacts to the head and 
body that are anticipated (i.e., 
with bracing) vs. unanticipated 
(i.e., without bracing), and will 
explore whether the relative 
influence of neck strength vs. 
cervical muscle volume on head 
acceleration is influenced by 
manual resistance neck 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
during direct and indirect 
loading, without anticipatory 
bracing, at Assessment Time 
Points 1, 2, 3, 4.  
 
strengthening exercise.  In 
addition to the direct and 
indirect loading conditions, 
which are both passive (i.e., 
force application is not initiated 
by the subject), voluntary 
soccer heading is also included 
as an exploratory loading 
condition representing a more 
active sport-associated impact 
scenario.   
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
In this single-site randomized clinical trial, 72 high school soccer athletes will complete a series of 4 
laboratory assessment sessions before, during, and after a 12-week resistance training program 
including either high intensity neck strengthening exercises or control exercises not targeting the neck.  
During each laboratory assessment, measurements will be performed to assess key cervical muscle 
attributes, as well as the head’s net acceleration under multiple loading conditions designed to reflect 
the range of impact scenarios encountered by athletes during sport participation.  The primary loading 
conditions will be direct force application to the head using the customized loading apparatus designed 
by our group for our previous research19, 22 and a standardized checking/blocking task involving impacts 
to the body with inertial force transmission to the head.  In addition, a voluntary soccer heading task will 
be used as an exploratory loading condition.   
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The control exercise group will perform only “shoulders-down” resistance exercises not directly 
targeting the neck so that the effects of the high intensity neck exercise program can be distinguished 
from changes associated with normal age-related growth and development or generalized effects of 
resistance training not specifically targeting the neck.   
 
4.3 
JUSTIFICATION FOR DOSE 
 
All subjects will exercise 2 days per week under the direct supervision of a study-assigned strength coach 
(National Strength and Conditioning Association Certified Strength and Conditioning Specialist, CSCS, 
certification), with a minimum of 1 day of rest between exercise sessions.  Subjects will be assigned 
either to a high intensity neck strengthening exercise group or to a control exercise group performing 
only “shoulders-down” resistance exercises not directly targeting the neck.  All exercises will be 
performed in accordance with National Strength and Conditioning Association standards.76  The neck 
strengthening program will include manual resistance exercises in sagittal-plane flexion and extension, 
coronal-plane lateral flexion to the left and right, and axial-plane rotation to the left and right, as well as 
dumbbell shoulder shrugs as previously described by our group.19  For each group, the exercise program 

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will progress in volume and intensity over the duration of the study, to accommodate muscular fitness 
adaptation.  Such progression is considered vital to the long-term efficacy of resistance exercise 
programming. 
 
The volume load of neck strengthening exercise will be calculated using a modified protocol previously 
employed by our group for the elbow flexors.61  For shoulder shrugs the volume load for each exercise 
session will be defined as the product of the dumbbell weight x the force of gravity (g= 9.8 m/s2) x the 
number of repetitions performed during the exercise session, to yield a volume load for the exercise 
session in N.  During manual resistance exercise, the strength coach will hold a hand-held dynamometer 
against the subject’s head to measure and record the force applied during manual resistance.  For both 
dumbbell shrugs and manual resistance exercises, the total cumulative exercise volume load will be 
defined as the sum of the individual session volume loads over all exercise sessions completed by the 
subject.  Since subjects assigned to the control group will not perform neck strengthening exercise, their 
exercise volume load will remain zero throughout the study. 
 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the final lab assessment (#4) and final MRI, as shown in the Schedule of Activities (SoA), 
Section 1.3. 
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
globally. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form, or assent form with parental consent for 
minors 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
3. Male or female, aged 13-19 
4. Participated in a soccer team, club, or other soccer program/organization within the preceding 2 
years 
5. Be willing to adhere to the assigned exercise regimen 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria on self/parental-report or screening examination, 
as appropriate, will be excluded from participation in this study: 
 
1. Prior history of trauma-induced neck injury of sufficient severity to require treatment by a medical 
provider within 30 days of injury or to limit sport participation for > 1 day (note: having received 

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routine chiropractic treatment in the absence of a recent traumatic injury to the neck will not be 
considered to meet this criterion) 
2. Any prior history of whiplash injury, stinger/burner, or cervical radiculopathy diagnosed by a 
medical provider 
3. Any prior history of bone, disk, neural, or ligamentous abnormality identified on cervical spine 
medical imaging performed for any reason that is felt by the PI (or designee) to present a risk to 
study participation 
4. Any prior history of surgery involving the cervical spine (note: having undergone non-spine 
surgery to the soft tissue structures in the neck will not necessarily exclude participation, but will 
be considered on a case-by-case basis by the PI, or his designee, with consultation from the 
performing surgeon when deemed appropriate) 
5. Self-report of moderate or severe neck pain (rated as 5 or greater on a 10-point pain scale) 
lasting > 1 day in the previous 6 months that required treatment by a medical provider or that 
limited sport participation for > 1 day (note: having received routine chiropractic treatment in the 
absence of moderate-severe neck pain will not be considered to meet this criterion)  
6. Self-report of low back pain (any severity) associated with morning stiffness occurring 30 days or 
more in the previous 3 months 
7. Prior episode(s) of unexplained upper extremity numbness, tingling, or weakness suspicious to 
the PI, or designee, for a stinger/burner or cervical radiculopathy 
8. Prior history of concussion in the previous 6 months diagnosed by a medical provider or 
suspected by the subject, or the parent/guardian of a minor (if no medical evaluation was sought) 
9. Personal history of migraine headaches within the previous 3 years diagnosed by a medical 
provider 
10. Personal history of anxiety disorder diagnosed by a medical provider 
11. Parental/guardian history of anxiety disorder diagnosed by a medical provider 
12. Prior personal or parental history of the following medical conditions known to be associated with 
atlanto-axial instability diagnosed by a medical provider:  rheumatoid arthritis or other systemic 
inflammatory disease with joint involvement, Down Syndrome, mucopolysaccharoidosis, Ehlers-
Danlos Syndrome, Marfan Syndrome 
13. Known exposure to or infection with head lice in the previous 30 days 
14. Serious allergic reaction to nickel/metal jewelry 
15. Known or suspected pregnancy (for females) 
 
16. Presence of significant abnormality on a standardized screening neurological and 
musculoskeletal physical examination performed by the PI, or designee, including: pain with 
palpation or active range of motion of the cervical spine, abnormal active range of motion of the 
cervical spine, positive Spurling test, upper motor neuron signs (spasticity, hyper-reflexia (grade 
4+), Hoffman sign, >2 beats of ankle clonus, Babinski sign/up-going toes), upper extremity reflex 
asymmetry, marfanoid body habitus (all of the following: arm span to height ratio > 1.05, hand 
length to height ratio > 0.11, foot length to height ratio > 0.15, upper body segment to lower body 
segment ratio < 0.89), or hypermobile joints (Beighton score > 4) or abnormal Schober test (< 
5cm difference between standing and full forward flexion). 
17. Prior participation in a resistance exercise training program including exercises specifically 
intended to target the neck muscles within 3 months of enrollment, or intention to begin 
participating in such an exercise program outside of the study protocol during the upcoming 12-
week study period 
18. Unable to speak and understand English. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
N/A 
 
5.4 
SCREEN FAILURES 
 

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Screen failures are defined as participants who do not meet the study inclusion/exclusion criteria as 
determined during the initial phone screening assessment or initial in-person screening evaluation. A 
minimal set of screen failure information will be retained to ensure transparent reporting of screen 
failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, and eligibility criteria. 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a time 
sensitive factor (e.g., diagnosed concussion within the past 6 months) may be rescreened. Rescreened 
participants will be assigned the same participant number as for the initial screening. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
High school-aged soccer athletes will be recruited primarily through the athletics programs at local high 
schools, following local approval at each individual institution.  Coaches, managers, athletic trainers, or 
other team/athletics personnel will be asked to post and/or distribute paper and/or electronic 
recruitment materials to those athletes who are members of the school’s soccer teams.  In addition, we 
will also recruit through other non-school-based local soccer clubs, camps, and programs in a similar 
manner, including recruitment through local soccer and/or fitness facilities.  Lastly, we will advertise on 
the Michigan Institute of Clinical Health Research (MICHR) UM Health Research website 
(https://umhealthresearch.org), in UMHS clinics, and through public advertisements and outreach as 
necessary.  UM Health Research is a secure registry database that matches people to clinical research 
studies, and is supported by the Michigan Institute for Clinical and Health Research.   
 
Interested individuals (and/or their parents/guardians if minors) will complete an initial self-reported 
screening evaluation (either electronically with phone review or during a single phone session, per 
individual preference and availability) with a member of the study to assess study inclusion and 
exclusion criteria and to describe the details of the study.  Those who pass the initial screening 
assessment and are interested in participating after hearing full study details will be scheduled for a final 
in-person eligibility assessment by the PI, or his designee, which will include a targeted screening 
physical examination.   
 
Potential subjects passing both components of the screening assessment will then be invited to enroll in 
the study and those wishing to do so will complete the informed consent process (assent for minors 
with accompanying parent/guardian consent).  All subjects will provide written informed consent using 
UM IRB-MED approved informed consent documents with a qualified member of the study team.  Minor 
children under the age of 18 will provide written assent and a parent/guardian will provide written 
consent.  During the in-person consent process the consenting study team member will review the 
entire informed consent document with the subject (and parent/guardian when applicable), including all 
potential risks associated with the study and will provide an opportunity to ask any questions they may 
have. 
   
To promote study recruitment and retention, subjects will be compensated for their participation in this 
study.  Compensation will be incrementally disbursed upon successful completion of each of the four 
laboratory testing sessions, with greater amounts provided for each successive testing session to 
incentivize full study completion.  Subjects will also receive a 4-month membership at a local fitness 
facility as well as paid parking during study-associated appointments through the study.   

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6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
The study intervention is participation in a supervised exercise program.  Participants will perform two 
exercise sessions per week, with at least one day between sessions.   All participants will perform a 
standardized set of general resistance exercises targeting the chest, shoulders, back, upper and lower 
extremities, and core.  In addition, those participants allocated to the high intensity neck strengthening 
group will also perform manual resistance exercises in sagittal plane flexion and extension, coronal 
plane lateral flexion in both directions, and axial plane rotation in both directions, as well as dumbbell 
shoulder shrugs. 
 
6.1.2 INTERVENTION ADMINISTRATION 
 
The supervised exercise program will be administered by a Certified Strength and Conditioning 
Specialist.  Manual resistance exercises will be performed lying horizontally on a standard weight lifting 
bench using a similar protocol as previously described by our group.19  For each repetition, the CSCS will 
apply steady manual resistance through the both the concentric and eccentric phases of cervical range 
of motion.  Shoulder shrugs will be performed at a tempo allowing for steady controlled movement to 
be maintained throughout the concentric and eccentric phases with a brief pause at the top of the shrug 
motion using the maximum load comfortably completed by each participant for the target number of 
repetitions while maintaining correct form.  The high intensity neck strengthening exercise program will 
increase in volume and intensity over the study duration to accommodate muscular fitness adaptation.  
All exercises were performed in accordance with National Strength and Conditioning Association 
standards.76 
 
6.2 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Subjects will be randomized using a centralized electronic randomization tool with equal allocation to 
the control and high-intensity neck strengthening groups.  Balanced block randomization will be used to 
ensure equal sex and age category balance between the groups.  Age category will correspond to high 
school under-class (i.e., age 13.0 - 16.49 years at the time of randomization) vs. upper-class (i.e., age 
16.50 – 19.99 years) status given the typical maturation occurring in adolescents through the high 
school years. Subjects will be considered enrolled in the trial upon randomization and available data will 
be included in the intention to treat analysis.  The Study Statistician, Strength Coach, Study Coordinator, 
and PI (or his Co-I designee when necessary to make a determination of AE relatedness to the study) will 
not be blinded to subject group allocation.   Other members of the study team, including those 
responsible for performing the laboratory- and radiology-based assessment will be blinded to group 
allocation status.  Subjects will not be informed of their group allocation status, although they will be 
aware of whether or not they are performing neck strengthening exercises during their exercise 
sessions.  Subjects will be instructed not to discuss whether they are performing neck strengthening 
exercises with study team members during either laboratory- or radiology-based assessment sessions.   
 

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6.3 
STUDY INTERVENTION COMPLIANCE 
 
Subjects will be given the opportunity to make-up any missed exercise sessions within 7 days of the 
originally scheduled date, so long as at least one day of rest is scheduled between successive exercise 
sessions.  Subjects will be considered to have successfully completed the exercise protocol if at least 20 
of the 24 exercise sessions are attended, with no more than 2 missed sessions during any 4-week block. 
 
6.4 
CONCOMITANT THERAPY 
 
Participation in a resistance training exercise program including exercises specifically intended to target 
the neck muscles either in the 3 months prior to study enrollment or a plan to begin participating in such 
an exercise program outside of the study protocol at any point during the 12-week study period are 
criteria for exclusion.   
 
6.4.1 RESCUE MEDICINE 
 
N/A 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Discontinuation from the exercise intervention does not necessarily mandate immediate discontinuation 
from the study.  If a subject is unable to continue participating in their assigned exercise intervention 
due to injury, illness, or other reason, they will still be eligible to complete all or part of the next 
scheduled study assessment(s) so long as they are able to do so within 7 days of discontinuation of the 
intervention, they have completed at least 4 exercise sessions since their last assessment was 
performed, and they remain able to participate in the upcoming lab-based (and MRI, as applicable) 
assessment.  If a clinically significant finding is identified (including, but not limited to changes from 
baseline) after enrollment, the PI or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Date and reason for study intervention discontinuation 
• 
Eligibility for and ability to perform upcoming study assessments 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
• 
Pregnancy, unless written clearance to continue study participation is provided by the treating 
obstetrician or other physician managing the pregnancy 
• 
Significant study intervention non-compliance  

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• 
If any clinical adverse event (AE) or other medical condition or situation occurs that precludes 
the subject’s ability to participate in the study or such that continued participation in the study 
would not be in the best interest of the participant 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to participate in study exercise program for 14 or more consecutive days. 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who are randomized and drop out subsequently will not be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for 4 scheduled visits or more 
than 14 days and is unable to be contacted by the study team.  
 
The following actions must be taken if a participant fails to return for a required study visit: 
• 
The study team will attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, multiple telephone calls, emails, 
and/or text messages, and, a certified letter or equivalent may be sent to the participant’s last 
known mailing address or local equivalent methods). These contact attempts will be 
documented in the participant’s study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
Methodology for measuring kinematic outcome: Net head acceleration will be measured under direct 
force application, as well as standardized checking/blocking and voluntary soccer heading tasks at 4 time 
points (see Section 1.3).  Our rationale for including loading conditions involving direct force application 
to the head as well as force application to the body with resultant transmission of inertial forces to the 
head (the simulated checking/ blocking task) is that concussions can, by definition, occur as a result of 
both of these mechanisms.51   Voluntary soccer heading is being used as a second, more ecologically-
valid direct loading condition.  The order of testing will be randomized across subjects and practice trials 
will be performed for each task prior to data collection to familiarize subjects with each procedure.  
 
Loading conditions:  
Standardized direct force application to the head in forced flexion, extension, lateral flexion, and 
axial rotation.    We will use a customized laboratory testing apparatus to deliver controlled forces to 
the head via headgear connected to cable with in-line weight-drop, similar to as previously described 
by our group.19, 22  The results of three trials will be averaged, in each direction during active 
isometric neck muscle pre-contraction (as if bracing in anticipation of being struck in the head during 
live play) as well as during relaxed upright sitting (to simulate an unanticipated blind-side impact) 

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conditions.19, 22  An effort will be made to prevent subjects’ knowledge of the precise timing of force 
application during the unanticipated condition using strategies such as wearing blinders and being 
exposed to ambient white noise. sEMG will be used as biofeedback to ensure appropriate neck 
muscle activation under both conditions, in a similar manner as in our previous pilot study.19 
 
Standardized impacts to the body will be applied in the coronal plane by swinging a boxer’s heavy 
punching bag suspended from the ceiling like a pendulum into the subject’s lateral shoulder to 
simulate a sport checking or blocking event.  Subjects will stand on a force plate in an athletic ready 
position so that the punching bag surface lightly touches the lateral aspect of their shoulder while 
hanging at rest.  The punching bag will be drawn back in a standardized manner and released to elicit 
lateral flexion of the head and neck in the coronal plane upon impact to the shoulder (monitoring to 
ensure they are not displaced from the force plate).  The results of three trials will be averaged 
during active pre-contraction of the neck and torso muscles (as if bracing in anticipation of being 
checked or blocked by an opponent during live play) as well as a relaxed upright standing (to simulate 
an unanticipated blind-side collision) conditions.  An effort will again be made to prevent subjects’ 
knowledge of the precise timing of force application during the unanticipated condition using 
strategies such as wearing blinders and being exposed to ambient white noise. sEMG will again be 
used to ensure appropriate neck muscle activation under both conditions, as above. 
 
Standardized voluntary soccer headers will also be performed in the sagittal plane.  One heading task 
will involve an active heading strategy with the goal of returning a soccer ball directly back in the 
direction from which it was pitched with as much velocity as possible, as if performing an 
attacking/offensive soccer header.  A second heading task will be similar, except with a goal of gently 
directing the soccer ball to the ground in the direction from which it was pitched as if performing a 
glancing header to pass the ball to the foot of a teammate.  For both tasks, a standard soccer ball 
inflated at the low end of the recommended inflation range) will be pitched to the subject from a 
soccer machine using similar methodology as has been applied in previous soccer heading studies.33, 
35, 60, 74  The results of three trials will be averaged under both heading strategies. 
 
Net head acceleration measurement: 
For each loading condition, net head acceleration will be measured using a kinematic camera system 
in a similar manner as previously described by our group.19, 22  Subjects will wear optoelectronic 
markers (infrared emitting diodes) to allow tracking of head position in space and relative to the 
torso.  Signal processing will be performed in a similar manner as previously described by our group 
to calculate head accelerations.19, 22  For the checking/blocking and soccer heading tasks, subjects will 
wear a thin force sensor on their shoulder (for checking/blocking) or forehead (for soccer heading) to 
identify the time of impact between their shoulder/forehead and the punching bag/soccer ball, 
respectively.  In the unlikely event that head kinematics patterns are not sufficiently stereotyped 
under a given loading condition for between-subject comparisons of AUC for the net head 
acceleration vector, which does not directly account for directionality, then we would decompose 
the net acceleration vector into its individual linear and angular components.  Participants will also 
wear a second inertial measurement unit (body-worn sensor) on their heads to provide redundant 
head acceleration data as a back-up in the unlikely event that the kinematic camera data cannot be 
adequately resolved.  Additionally, if the force sensing resistor used to identify the onset of head 
acceleration during the checking/blocking and soccer heading tasks unexpectedly fails for a given 
trial, we would alternatively use a similar technique to the one we have previously employed to 
identify the onset of head acceleration from the kinematic dataset via a trailing window.20, 46   
 
Methodology for measuring cervical muscle attributes: Given that muscular adaptation to resistance 
exercise results in strength gains attributable to both improved neuromuscular recruitment and muscle 
hypertrophy, we will assess neck strength as well as cervical muscle volume and neuromuscular 
activation.   
 
Neck strength  

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Neck strength will be measured both in terms of the peak force/moment and rate of force/torque 
development in cervical flexion, extension, axial rotation, and lateral flexion using a customized 
laboratory testing apparatus similar to that previously described by Dr. Vasavada.80  Measured force 
values will be converted to moments, in N·m, by multiplying each force value by the neck’s estimated 
moment arm.   
 
Cervical muscle volume  
The total cervical muscle volume will be measured using magnetic resonance imaging (MRI) without 
contrast in a similar manner as previously described by Dr. Vasavada.89 The volume of individual 
cervical muscles will be calculated by integrating the cross sectional areas (CSA’s) across slices 
multiplied by slice center-to-center spacing and total cervical muscle volume will be calculated as the 
sum of volumes of the individual muscles.    
 
Estimated cervical muscle volume will also be calculated at each assessment using a predictive 
regression equation developed by Dr. Vasavada’s lab, which has been shown to accurately account 
for 87% of the variance in MRI-based total cervical muscle volume based on overall neck 
circumference and sex.89  We will further refine this regression-based estimate by incorporating the 
sonographic anatomical cross-sectional areas (CSA’s) of key cervical muscles measured at each 
assessment time point, with validation of the expanded model using our MRI-based cervical muscle 
volume measurements.  We will assess the sternocleidomastoid (SCM), upper trapezius (TRAP), 
splenius capitis (SPL), and semispinalis capitis (SEMI) muscles, which we have previously studied with 
acceptable test-retest reliability (intra-class correlation coefficients, ICC= .91 to ICC= .99) and validity 
as compared to criterion-standard MRI CSA measurements (R= .76 to R= .97).21   In the unlikely event 
that we are unable to adequately predict total cervical muscle volumes using Dr. Vasavada’s 
regression equation,89 we would alternatively assess cervical muscle hypertrophy using total neck 
circumference and the sonographic anatomical CSA measurements of the SCM, TRAP, SPL, and SEMI 
muscles.  
 
Cervical muscle activation  
We will quantify neuromuscular recruitment of the cervical muscles in terms of agonist muscle 
activation and antagonist muscle inhibition, using a similar surface electromyography (sEMG) 
protocol as during our pilot neck strengthening study.19  Briefly, after standard skin preparation 
sEMG electrodes placed over the SCM, TRAP, SPL, and SEMI muscles will measure muscle activation 
during maximum voluntary contraction and under each loading condition.  Raw sEMG data will be 
normalized with respect to each muscle’s maximum amplitude, with agonist muscle activation and 
antagonist muscle inhibition calculated as the mean normalized sEMG amplitude (percentage of 
maximum) of the agonist and antagonist muscles during maximum voluntary contraction in each 
plane of motion.  The mean activation level of each cervical muscle will also be measured during the 
loading tasks, allowing assessment of agonist activation and antagonist inhibition, as well as agonist-
antagonist co-contraction and muscle activation onset latencies during loading.   
 
Estimated cervical muscle stiffness 
We will estimate cervical muscle stiffness by imposing cervical muscle volume, head kinematics, and 
sEMG data onto Dr. Vasavada’s multi-body dynamic neck model78 in a similar manner as previously 
used to accurately estimate joint stiffness in an elbow model.36   
 
All results will be collected by the study team through the conduct of this research study and are for 
research purposes only.  As such, no medical record review will be performed and no study results will 
routinely be reported to participants.  Individual participant or parent/guardian requests for study 
results will be considered by the PI on a case-by-case basis and requested information will be provided 
at the discretion of the PI when feasible for the study team to do so.   
 

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8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Potential participants meeting any exclusion criteria (See Section 5.2), either during the initial phone 
screen or the final in-person screening assessment which includes a brief screening physical 
examination, may potentially be at slightly increased risk for injury as a result of study participation and 
so out of caution will be excluded from study participation. 
 
Potential participants with disqualifying findings on the screening physical examination (and their 
parent/guardian if they are a minor) will be notified verbally at the time of the screening examination, 
and will subsequently be notified in writing, of the specific disqualifying physical exam finding.  They will 
be advised to follow up with their primary care physician. 
 
Participants will be asked at the beginning of each study-associated exercise and testing session whether 
they have experienced any AE’s as described below in Section 8.3.4.  Participants will also be observed 
by the study team during each study visit for AE’s.   
 
Any moderate or severe AE’s will be reported to the PI, or his designee, for determination of the need 
for medical follow up.  If immediate emergent medical care is deemed necessary 9-1-1 will be called.  If 
urgent, non-immediate, medical care is deemed necessary the participant will be referred to a local 
Emergency Department or Urgent Care Center via their own private transportation.  If non-urgent 
medical care is deemed necessary, the participant will be referred to their own physician’s office.  If no 
medical care is deemed necessary, the participant will be advised to monitor their condition and contact 
their own physician if their condition worsens prior to their next study visit.  
 
All study MRI’s will be reviewed by the Study Radiologist for quality control purposes, as well as to 
screen for incidental findings of clinical significance.  If incidental clinically significant findings are 
identified, the Study Radiologist will note them in the research MRI report and will alert the PI (or his 
designee if he is unavailable) to their presence.  The PI (or his designee) will subsequently contact the 
subject (and their parent/guardian if they are a minor) by phone to notify them of the incidental finding 
and advise them to follow up with their primary care physician.  In addition, a written notification of the 
incidental finding, including a copy of the research MRI report, will be sent to the subject, as well as to 
their primary care physician, or an alternative physician providing them medical care if this is their 
preference.  
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)).   
 
Note:  delayed onset muscle soreness is a normal, anticipated occurrence following resistance exercise 
training and is therefore not considered an AE for the purposes of this study. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 

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An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of the 
investigator or his designee, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
8.3.2.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.2.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) will have their relationship to study intervention assessed by the PI, or his 
designee, based on temporal relationship and his/her clinical judgment. The degree of certainty about 
causality will be graded using the categories below. The study-assigned exercise program will always be 
considered suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event occurs in a plausible time relationship to 
study intervention administration and cannot be explained by concurrent disease or other 
exposure/event (e.gs., drug, chemical, toxin, pathogen, activity, environmental factor, traumatic 
event). The response to withdrawal of the study intervention (dechallenge) should be clinically 
plausible. If medically appropriate, a rechallenge procedure may be employed, with a positive 
response to rechallenge considered as confirmation of definite relatedness. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event occurs within a reasonable time after administration of the 
study intervention, is unlikely to be attributed to concurrent disease or other or other 
exposure/event, and follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 

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can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event whose temporal relationship to study intervention 
administration makes a causal relationship improbable (e.g., the event did not occur within a 
reasonable time after administration of the study intervention) and in which other disease or 
exposure/event provides plausible explanations (e.g., the participant’s clinical condition, other 
concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
8.3.2.3 EXPECTEDNESS  
 
The PI, or his designee, will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described in Section 2.3.1, or if it is not known to be 
associated with any non-disqualifying underlying disease, disorder, or condition affecting the 
participant. 
8.3.3 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits or if communicated to the study team between visits.  The study 
team will not prompt participants for any specific solicited AE’s, but will ask about unsolicited AE’s at 
each study visit using the following general question: “Have you noticed any new illness, injury, or other 
health-related concerns since your last study visit?”  
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study intervention (assessed by the PI or his 
designee with the training and authority to make a diagnosis), and date of resolution/stabilization of the 
event. All AEs occurring while on study must be documented appropriately regardless of relationship. All 
AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The study coordinator or project manager will record all reportable events with start dates occurring any 
time after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last 
day of study participation.  At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the last visit.  Events will be followed for outcome information until resolution or 
stabilization. 

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8.3.4 ADVERSE EVENT REPORTING  
 
AE and SAE reporting to IRBMED will occur per IRBMED standard reporting guidelines.  Reporting to the 
DSMB will occur in conjunction with annual DSMB meetings as scheduled per the DSMB Charter.  
Additionally, any serious adverse event deemed possibly, probably, or definitely related to 
study procedures, or were IRBMED standard reporting guidelines otherwise necessitate more 
immediate reporting, will be reported to the DSMB on the same schedule as reports to IRBMED or 
within 14 calendar days of identification, whichever occurs first. 
 
Note that if a series of related, expected AE’s of moderate severity appear to be occurring at a 
frequency greater than previously known or expected, the study team will report this to IRBMED and 
the DSMB within 14 calendar days of identifying the trend. 
 
Unrelated, non-serious AE’s (expected or unexpected) will not be reported to IRBMED or the DSMB 
unless there appears to be a trend of events occurring at a frequency greater than previously known or 
expected, in which case the study team will also report this trend to IRB-MED as well as the DSMB within 
14 calendar days of identifying the trend. 
 
8.3.5 SERIOUS ADVERSE EVENT REPORTING  
 
Related, unexpected SAE’s resulting in death or any life-threatening outcome will be reported to 
IRBMED and the DSMB within 7 calendar days of becoming aware of the event.  Other related, 
unexpected SAE’s will be reported to IRB-MED and the DSMB within 14 days of becoming aware of the 
event. 
 
Unrelated, unexpected SAE’s will be reported per standard IRBMED guidelines and in conjunction with 
regularly scheduled DSMB meetings. 
 
Note, there are no related, expected SAE’s associated with this study.  
 
8.3.6 REPORTING EVENTS TO PARTICIPANTS  
 
If the study team becomes aware of new knowledge regarding related, unexpected AE’s/SAE’s that may 
affect other current or future study participants, the study team will seek input from the DSMB as to 
whether/how to communicate this information to other current participants and/or whether/how to 
amend the IRB-MED approved informed consent documents for future participants.  Re-consenting will 
be performed for subjects actively involved in the study if deemed necessary by the PI, IRMBED, or 
DSMB. 
 
8.3.7 EVENTS OF SPECIAL INTEREST  
 
N/A 
 
 
8.3.8 REPORTING OF PREGNANCY  
 

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If a study participant becomes pregnant during the study period, or becomes aware of a previously 
unidentified pre-existing pregnancy during the study period, they will be permitted to continue study 
participation at the discretion of their treating obstetrician (or other physician responsible for managing 
their pregnancy, e.g., family medicine physician) and a letter of clearance for ongoing study participation 
will be requested to document this clearance. 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The study team will report unanticipated problems (UPs) to IRBMED. The UP report will include the 
following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are actual AEs or SAEs will be reported to IRB-MED as described above in Section 8.3.5-
8.3.6.  
• 
Any other UPs representing newly identified possibility of previously unsuspected harm will be 
reported to IRB-MED within 14 days of the study team becoming aware of the problem.  
• 
If IRB-MED concurs that a UP exists, the UP will be reported to appropriate institutional and 
external officials as required under IRB-MED’s reporting policies and procedures.  
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  

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If UPs are identified that may affect current or future study participants, the study team will seek input 
from the DSMB as to whether/how to communicate this information to current participants and/or 
whether/how to amend the IRBMED approved informed consent documents for future participants. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
Primary Efficacy Endpoint:  
 
There will be evidence of a dose-response effect for neck strengthening exercise on net head 
acceleration under direct load application proportional to the volume load of exercise.   
 
Secondary Efficacy Endpoint: 
 
There will be evidence of a dose-response effect for neck strengthening exercise on net head 
acceleration under indirect load application proportional to the volume load of exercise.   
 
9.2 
SAMPLE SIZE DETERMINATION 
 
Our power calculation is based on AIM 1.  Assuming net head acceleration (on the logarithmic scale) 
will follow linear trends over time, then our power calculation is based on comparison of the slope of 
this change, which has 9/14 of the variance, i.e., 36% less variance, than the underlying log(net head 
acceleration) measurements.  As a result, the standardized effect size (Cohen’s d value) of the slope is 
approximately 1.25 times greater than that of the underlying log(net head acceleration) 
measurements.  Based on our own pilot data,19 we expect observed standardized effect sizes to be 
between .6 and 1.0 for log(net head acceleration), depending on the variability of the individual 
measurements across the 4 directions of motion.  These values correspond with a 20% overall 
reduction in un-transformed net head acceleration.  A total of 30 subjects in each exercise group 
(control and high intensity), will provide power of between .83 [for standardized effect size for log (net 
head acceleration) of .6 and 1.0 [for standardized effect size for log(net head acceleration) of 1.0] 
depending on the actual observed standardized effect size in the population.  To account for the 
possibility of a drop-out rate of up to 20%, we will plan to enroll up to a total of 72 subjects.   
 
9.3 
POPULATIONS FOR ANALYSES 
 
All participants will be included in the analysis, including participants contributing only a partial data set.  
The only exception would be in cases where the PI, study statistician, and Exercise 
Physiology/Engineering/Radiology study CoI-lead (for volume-load vs. lab-based vs. imaging-based data) 
agree there is legitimate threat to the validity of data collected in any individual participant due to 
technical error not identified at the time of assessment that cannot be resolved through post-processing 
(e.g., incorrect gain settings leading to signal saturation or failure of MRI field of view not covering the 
full extent of cervical musculature to be measured).   
 
9.4 
STATISTICAL ANALYSES 

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9.4.1 GENERAL APPROACH 
 
Prior to the analysis, all data will be examined and transformed as necessary to achieve approximate 
normality.  Descriptive statistics will be used to characterize the distribution, central tendency (mean, 
median), and variability (standard deviation, range, interquartile range) of each continuous variable.  All 
subjects will be included in the analysis and an alpha of .05 will be considered significant for statistical 
testing. 
 
9.4.2 ANALYSIS OF THE PRIMARY AND SECONDARY EFFICACY ENDPOINTS 
 
We expect a percentage reduction in net head acceleration as the volume load of exercise performed 
increases over the 12 week exercise program, so we will assess net head acceleration on a logarithmic 
scale to allow us to model and detect a constant change.  For example, a 20% reduction in net head 
acceleration corresponds to a difference of log(.8) on the log-scale, regardless of the initial value of net 
head acceleration. We will use linear mixed models to describe the longitudinal changes in log(net head 
acceleration) over the volume loads of exercise performed at each of the four study time points, and to 
test the significance of this change across the three exercise groups.   
 
9.4.3 SAFETY ANALYSES 
 
AEs and SAEs will be summarized by severity, relatedness, and expectedness using counts, with each AE 
counting only one time for a given participant, and will be presented in a table format.    
 
9.4.4 BASELINE DESCRIPTIVE STATISTICS 
 
Intervention groups will be compared on baseline characteristics (including demographics, cervical 
muscle attributes, and net head accelerations under each loading condition) to assess for the presence 
of any baseline differences between the groups before participation in the study-assigned exercise 
intervention.  Categorical and continuous variables will be assessed using chi-square tables and ANOVA, 
respectively. 
 
9.4.5 PLANNED INTERIM ANALYSES  
 
Consistent with the original proposal submitted to and funded by NIH, a blinded interim analyses will be 
performed by the study statistician in Study Year 3, or upon protocol completion by 15 participants in 
the treatment group, whichever marker of the study mid-point comes first.  The results of the interim 
analysis will be reviewed by the PI and shared with the study team for dissemination as preliminary 
study results, but will not be used to halt ongoing study activities. 
 
In addition, the strength of the estimated total cervical muscle volume prediction algorithm with respect 
to MRI-based measured total cervical muscle volume will be reassessed by the study statistician on an 
ongoing basis throughout the study period.  Pending determination of the strength of the estimated 
total cervical muscle prediction algorithm, the MRI portion of the study protocol will be amended to 
minimize the time and expense associated with MRI acquisition and analysis for the remainder of the 
study.   
 

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In the event that an immediate DSMB review is required in response to any AE(s), SAE(s), or UP(s) (see 
Sections 8.3.5-8.3.6 and 8.4.2), new study enrollment will temporarily be suspended until the DSMB has 
met and assessed the need for ongoing modification to study enrollment and/or study intervention 
activities.  Ongoing study activities will continue without interruption unless an unexpected, study-
related SAE occurs, in which case ongoing study activities associated with the portion of the study 
protocol deemed to have caused the SAE will be temporarily suspended pending DSMB review and 
recommendations.  
 
9.4.6 SUB-GROUP ANALYSES 
 
We will include sex as a covariate in the statistical models, as well as explore possible interactions 
between sex and other independent variables, to identify any sex-based differences in the relationship 
between exercise volume load and the net head acceleration outcome. 
 
9.4.7 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
N/A 
 
9.4.8 EXPLORATORY ANALYSES 
 
We will construct linear models with net head acceleration as the outcome and combinations of neck 
strength and/or cervical muscle volume as the predictor(s) for direct and indirect force application 
under both the anticipated and unanticipated conditions.  Rather than comparing the B coefficients of 
the neck strength and cervical muscle volume terms, which are scale-dependent, we will instead 
quantify the impact of each cervical covariate on net head acceleration by calculating the differences in 
R2 values of statistical models with vs. without each cervical variable.  These differential R2 values 
indicate the importance of each cervical variable in the model, accounting for the other. There is no 
known analytic solution in the statistical literature to confirm statistically whether one differential R2 
value is higher than the other unless the null hypothesis is zero differential R2,14 which is not the case 
here.  Instead, we will use the bootstrap as a nonparametric tool to assess the variability in the 
differential R2 values.24  By bootstrapping the subjects a sufficient number of times, we can obtain a set 
of differential R2 values and use them to construct 95% confidence intervals around the differential R2 
values of both cervical variables during the anticipated and unanticipated conditions. If the confidence 
intervals are non-overlapping, we will conclude that the cervical variable associated with a greater 
decline in R2 value upon its removal from the full model is significantly more impactful on the net head 
acceleration for the given anticipation condition.   
 
We will compare the magnitudes of the Β coefficients associated with each cervical independent 
variable at each time point in the linear mixed model analyses predicting log(net head acceleration).  
The effect of neck strengthening exercise on the exploratory net head acceleration during soccer 
heading outcomes will be analyzed using a similar statistical analysis plan as described above in Section 
9.4.2.   
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 

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10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
IRB-MED-approved informed consent forms describing in detail the study intervention, study 
procedures, and risks will be given to each participant and written documentation of informed consent 
(or assent with parent/guardian consent) will be obtained prior to starting intervention/administering 
study intervention.   
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
A waiver of informed consent for screening purposes will be obtained from IRB-MED to allow potential 
participants to be screened for study eligibility prior to undergoing the informed consent process in an 
effort to save ineligible individuals from the inconvenience of unnecessary study-related procedures if 
they are not eligible to participate in the study.  Those individuals who are eligible and interested in 
participating in the study will complete the informed consent (or assent with parent/guardian consent 
for minors) process in person with the PI, or a designated member of the study team. 
 
Informed consent (or assent with parent/guardian consent for minors) is a process that is initiated prior 
to the individual’s agreeing to participate in the study and continues throughout the individual’s study 
participation. Consent/Assent forms will be UM Institutional Review Board (IRBMED)-approved and the 
participant (and parent/guardian for minors) will be asked to read and review the document. A member 
of the study team will explain the research study to the participant (and parent/guardian for minors) 
and answer any questions that may arise. A verbal explanation will be provided in terms suited to the 
participant’s (and parent’s/guardian’s for minors) comprehension of the purposes, procedures, and 
potential risks of the study and of their rights as research participants.  Participants (and 
parent/guardian for minors) will have the opportunity to carefully review the written consent form and 
discuss/ask questions prior to signing. All participants, regardless of age, will have the opportunity to 
discuss the study with their family or surrogates or think about it prior to agreeing to participate. The 
participant will sign the informed consent document (or assent document with the parent/guardian 
signing the consent document) prior to any procedures being done specifically for the study. Participants 
(and their parent/guardian for minors) will be informed that participation is voluntary and that they may 
withdraw from the study at any time, without prejudice. A copy of the informed consent/assent 
document will be given to the participants for their records. The informed consent/assent process will 
be conducted and documented in the source document (including the date), and the form signed, 
before the participant undergoes any study-specific procedures. The rights and welfare of the 
participants (and their parent/guardian for minors) will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this study.  
Any children who become adults during the course of the study will not be re-consented after their 18th 
birthday. 
 
 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 

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Participant confidentiality and privacy are strictly held in trust by the study team. This confidentiality is 
extended to cover biological imaging results in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information generated 
will be held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of IRB-MED.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the UM Institutional Review Board (IRB-MED), 
members of the DSMB, or other regulatory agencies may inspect all documents and records required to 
be maintained by the investigator for the participants in this study. The study site will permit access to 
such records. 
 
The study participant’s contact information and research data, which is for purposes of statistical 
analysis and scientific reporting, will be securely stored at the University of Michigan for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by IRB-MED and Institutional policies.  At the end of the study, the study 
database will be de-identified and stored at the University of Michigan. 
 
The study team will not apply for a Certificate of Confidentiality for this study. 
 
10.1.3 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at the University of Michigan. After the study is 
completed, the data will be de-identified and archived for potential use in the future by the study team. 
Permission to store de-identified data will be included in the informed consent.  A copy of MRI data will 
also be maintained in the research section of participants’ electronic medical records at the University of 
Michigan/Michigan Medicine.  
 
When the study is completed, the study team will maintain access to de-identified study data. 
 
10.1.4 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
DSMB Safety Officer 
James T. Eckner, M.D., M.S. 
Associate Professor 
Hugh J.L. Garton, M.D., M.H.Sc. 
Professor 
University of Michigan 
Dept. of PM&R  
University of Michigan 
Dept. of Neurosurgery  
325 E. Eisenhower Pkwy 
Ann Arbor MI 48108 
1500 E. Medical Center Drive 
SPC 5338 
Ann Arbor, MI 48109 
734-936-7200 
734-936-7010 
jeckner@med.umich.edu 
hgarton@med.umich.edu 
 
10.1.5 SAFETY OVERSIGHT 
 

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Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
3 individuals with the appropriate expertise, including biostatistics, pediatric neurosurgery, and pediatric 
sports medicine. Members of the DSMB will be independent from the study conduct and free of conflict 
of interest.  The DSMB will meet annually to assess safety and efficacy data on each arm of the study. 
The DMSB will operate under the rules of an approved charter that will be written and reviewed at the 
organizational meeting of the DSMB. At this time, each data element that the DSMB needs to assess will 
be clearly defined. The DSMB will provide its input to the PI and the National Institutes of Health 
Program Officer assigned to this project. 
 
10.1.6 CLINICAL MONITORING 
 
Clinical study monitoring will be conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct 
of the trial is in compliance with the currently approved protocol/amendment(s), with good clinical 
practice, and with applicable regulatory requirement(s).  
 
Monitoring for this study will be performed by the Michigan Institute of Clinical and Health Research.  
Clinical monitor responsibilities will include:  
• 
Review of study documents, creation of the Clinical Monitoring Plan (CMP), and on-site study 
initiation visit prior to the start of enrollment 
o The CMP will describe in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and the 
distribution of monitoring reports. 
• 
On-site and/or virtual interim data and regulatory monitoring visits approximately every 6 
months throughout the trial with review of approximately 50% of enrolled participants’ charts. 
• 
On-site study close-out visit upon completion of the trial. 
• 
Provision of copies of monitoring reports to the PI and study coordinator/program manager 
within 14 days of visit. 
• 
Planned independent audits will not be conducted outside of the CMP, although it is possible 
that a random audit could be scheduled by the University of Michigan Office of Research 
Compliance Review (OCRC). 
 
10.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
reviewed for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological imaging is collected, documented (recorded), and 
reported in compliance with the protocol, IRB guidelines, and the Human Research Protection Program 
(HRPP) Operations Manual.  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 

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10.1.8 DATA HANDLING AND RECORD KEEPING  
 
10.1.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the study team at the University of Michigan under the 
supervision of the PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. 
 
All source documents will be completed in a neat, legible manner to ensure accurate interpretation of 
data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents will be consistent with the data recorded on the source 
documents.  
 
Clinical data (including adverse events (AEs) and expected adverse reactions data) will be entered into 
REDCap, a secure, HIPAA compliant data capture system provided by MICHR. The data system includes 
password protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source 
documents. 
 
10.1.8.2 STUDY RECORDS RETENTION  
 
Study documents will be retained for a minimum of 3 years from the date of final ClinicalTrials.gov 
reporting. These documents will be retained for a longer period, however, if required by local 
regulations.  
 
10.1.9 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol document or Manual of 
Procedures (MOP) requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions will be developed by the 
site and implemented promptly.  
 
It is the responsibility of the PI to use continuous vigilance to identify and report deviations not affecting 
participant safety as ORIOs in compliance with the current standard ORIO reporting guidance issued by 
IRBMED.   
 
10.1.10 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 

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manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers 5 years after the 
completion of the primary endpoint by contacting the PI.  
 
10.1.11 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with IRB-MED has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.3 ABBREVIATIONS 

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The list below includes abbreviations utilized in this template.  However, this list should be customized for 
each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). 
 
AE 
Adverse Event 
AUC 
Area Under the Curve 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CSA 
Cross-Sectional Area 
CSCS 
Certified Strength and Conditioning Specialist 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
EMG 
Electromyography 
FFR 
Federal Financial Report 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIT 
Head Impact Telemetry 
HRPP 
Human Research Protection Program 
ICC 
Intra-Class Correlation Coefficients 
IRB 
Institutional Review Board 
MOP 
Manual of Procedures 
MRI 
Magnetic Resonance Imaging 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SCM 
Sternocleidomastoid 
sEMG 
Surface electromyography 
SEMI 
Semispinalis Capitis 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
SPL 
Splenius Capitis 
SRC 
Sport and Recreation Related Concussion 
TRAP 
Upper Trapezius 
UM 
University of Michigan 
UP 
Unanticipated Problem 
US 
United States 
WSTC 
Wayne State Tolerance Curve 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
 
 
 
 
 
 
 
Version 
Date 
Description of Change  
Brief Rationale 
1.0 
5/22/2019 
Additional discussion of risk 
Per IRB Request 
1.1 
5/22/2019 
Expansion of exclusion criteria for 
screening exam 
Per PM&R Spine Physician recommendation 
        1.2 
 10/19/22 
 Permission for virtual IMV’s 
 Per MICHR Monitor request 
2.2 
12/20/22  
Removed low-volume exercise group 
from protocol 
Reduced enrollment following COVID 
pandemic 
2.2 
 12/20/22 
Clarifications to criteria defining 
protocol deviation- updating number 
of days that create a deviation.  
Reducing documentation burden associated 
with schedule deviations 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

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