Comparison of Non-Surgical Treatment Options for Chronic Exertional Compartment Syndrome (CECS)
Phase: PHASE2
Conditions: Chronic Exertional Compartment Syndrome
Sponsor: Walter Reed National Military Medical Center

COVER PAGE 
COMPARISON OF NON-SURGICAL TREATMENT OPTIONS FOR CHRONIC EXERTIONAL 
COMPARTMENT SYNDROME (CECS) 
NCT: 04409600 
STUDY PROTOCOL v1.13 
IRB APPROVED: 13 MAY 2024 
UPLOADED TO CLINICALTRIALS.GOV DATE: 06 DEC 2025 

EIRB Protocol Template (Version 1.13)
1.0
General Information
*Please enter the full title of your protocol:
Comparison of Non-Surgical Treatment Options for Chronic Exertional Compartment Syndrome 
(CECS)
 
 
*Please enter the Protocol Number you would like to use to reference the protocol:
MIRROR Project 5 - Comparison of Non-Surgical Treatment Options for CECS
* This field allows you to enter an abbreviated version of the Protocol Title to quickly identify 
this protocol.
 
 
Is this a multi-site protocol (i.e. Each site has their own Principal Investigator)?
Yes
 
 
Does this protocol involve the use of animals?
Yes
No
 
 
2.0
Add sites
2.1 List sites associated with this study:
Is 
Primary? Site Name
P and R - Walter Reed National Military Medical Center (WRNMMC)
 
3.0
Assign project personnel access to the project  
3.1 
 Please add a Principal Investigator for the study: 
*
Name
Role
Training Record
Leggit, Jeffrey 
Charles 2959460, 
Maryland
Principal 
Investigator
 View Training 
Record
Responsibility
Student
Site Chair
Resident
Fellow
3.2 If applicable, please select the Research Staff personnel: 
A) Additional Investigators 
N

Name
Role
Training Record
Velasco, Teonette O
Associate Investigator
 View Training Record
B) Research Support Staff 
Name
Role
Training Record
Lucio, Whitley B
Research Coordinator
 View Training Record
Ory, Rian Lyndzie, MS
Research Coordinator
 View Training Record
Seales, Paul Evan, BS, MS, MD 
LCDR
Monitor
 View Training Record
3.3 
Please add a Protocol Contact:
*
Name
Role
Training Record
Leggit, Jeffrey Charles 2959460, 
Maryland
Study Contact
 View Training Record
Lucio, Whitley B
Study Contact
 View Training Record
Ory, Rian Lyndzie, MS
Study Contact
 View Training Record
Velasco, Teonette O
Study Contact
 View Training Record
The Protocol Contact(s) will receive all important system notifications along with the Principal Investigator. (i.e. The 
protocol contact(s) are typically either the Protocol Coordinator or the Principal Investigator themselves). 
3.4
If applicable, please select the Designated Site Approval(s):
Name
Role
Training Record
Helgeson, Melvin Dennis
Department Chair
 View Training Record
Add the name of the individual authorized to approve and sign off on this protocol from your Site (e.g. the Site Chair).
4.0
 
Project Information
4.1  
What department(s) will be associated with this protocol?
* 
Physical Medicine & Rehab
4.2  
Is the IRB of record for this study an IRB/HRPP that does NOT use EIRB? If Yes, complete the 
* 
application according to the IRB/HRPP Determination.
If your Projects or Protocols are under the oversight of another IRB that does use EIRB, stop this 
submission and contact the core site and request an invitation as a performing site.

If your Project or Protocol is now being submitted for the first time to an IRB that does use EIRB, 
continue with this application and answer the questions to be reviewed by the IRB.
Answering yes means the board of record is an IRB that does NOT use EIRB.
  Yes  
  No
4.3  
Is this protocol research, expanded access, or humanitarian use device?
* 
 Yes  
 No
4.4  
 What type of protocol is this?
*
Behavioral Research
Biomedical Research
Clinical trial (FDA regulated)
Educational Research
Expanded Access
Humanitarian Use Device (HUD)
Psychosocial Research
Oral History
Other
4.5  Are you conducting this project in pursuit of a personal degree?
  Yes  
  No
4.7  
Is this human subjects research? (As defined by 32 CFR 219) 
* 
   Human subject means a living 
individual about whom an investigator (whether professional or student) conducting research: 
   (i) Obtains information or biospecimens through intervention or interaction with the individual, and 
uses, studies, or analyzes the information or biospecimens; or 
  (ii) Obtains, uses, studies, analyzes or generates identifiable private information or identifiable 
biospecimens.  
 Yes  
 No
4.8  
 Do you believe this human subjects research is exempt from IRB review?
*
  Yes  
  No
5.0
 
Personnel Details
5.1  Does the Principal Investigator have a Permanent Change of Station (PCS) Date or Estimated 
Institutional Departure Date (EIDD)?
  Yes  
  No
5.2  List any Research Team members without EIRB access that are not previously entered in the protocol:
No results found

5.3  Are any Contractors or Subcontractors involved in this study? If yes, please list them and describe their role.
 Yes  
 No
Name:
(Last, First, M.I.)
Velasco, Teonette 
O
Role on Protocol:
Associate 
Investigator
Phone Number:
703-634-9457
Email Address:
teonette.velasco.
ctr@usuhs.edu
Associated 
Institution:
The Geneva 
Foundation / 
WRNMMC
Name:
(Last, First, M.I.)
Ory, Rian L
Role on Protocol:
MIRROR 
Regulatory 
Affairs Manager
Phone Number:
909-904-5034
Email Address:
rian.ory.
ctr@usuhs.edu
Associated 
Institution:
The Geneva 
Foundation / 
USUHS
Name:
(Last, First, M.I.)
Lucio, Whitley B
Role on Protocol:
MIRROR Sr. 
Regulatory 
Affairs & Data 
Manager
Phone Number:
202-375-8831
Email Address:
whitley.lucio.
ctr@usuhs.edu
Associated 
Institution:
The Geneva 
Foundation / 
USUHS
5.4  
Will you have a Research Monitor for this study?
Yes 
No 
N/A 
Research Monitor Qualifications
Ensure the individual has expertise consistent with the nature of risk(s) identified within your 
study and is independent of the team conducting the research.
Research Monitor Role:
The Research Monitor is responsible for providing medical guidance and overseeing 
participant safety. They will review and keep abreast of Adverse Events and UPIRTSOs and 
determine their relatedness to the protocol. The Research Monitor will make recommendations 

on changes to the informed consent process and study procedures based on review of study 
events. They have the authority to stop the research study if they have concerns for the safety 
and/or well-being of the research participants. The Research Monitor may withdraw individual 
study participants and take any other actions necessary to protect the rights and safety of the 
human subjects. The Research Monitor may discuss the protocol with study investigators, 
interview human subjects, and consult with others outside the protocol about the research. The 
Research Monitor will co-sign all new reportable events and continuing review reports. The 
Research Monitor will promptly report any observation or findings to the Institutional Review 
Board (IRB), Human Protections Administrator (HPA), or Institutional Official.
If applicable, you may nominate an individual to serve as the Research Monitor:
Paul Evan Seales, BS, MS, MD LCDR
6.0
 
Data/Specimens
6.1  Does the study involve the use of existing data or specimens only (no interaction with human 
subjects)?
  Yes  
  No
7.0
 
Funding and Disclosures
7.1  Source of Funding:
Funding Source
Funding Type
Amount
:
Other
USU Award Number: 
HU00011920011
:
Research 
Development 
Testing and 
Evaluation 
(RDT&E) funds
Musculoskeletal Injury 
Rehabilitation Research 
for Operational Readiness
(MIRROR)
836683
Total amount of funding:
836683
7.2  Do you or any other Investigator(s) have a disclosure of a personal interest or financial nature 
significant with sponsor(s), product(s), instrument(s) and/or company(ies) involved in this study?
  Yes  
  No
All personnel engaged in research must complete and attach a Conflict of Interest (COI) form.
8.0
 
Study Locations
Selected Users

8.1  Is this a collaborative or multi-site study? (e.g., are there any other institutions involved?)
 Yes  
 No
8.2  Study Facilities and Locations:
Institution Site Name
Site Role
FWA or DoD 
Assurance 
Number
Assurance 
Expiration 
Date
Is there an 
agreement?
IRB Reviewing for 
Site
P&R
Uniformed 
Services 
University
Coordinating 
center
FWA00001628
05/04
/2026
:
IAIR
:
WRNMMC 
IRB
Army
Alexander 
T. 
Augusta 
Military 
Medical 
Center 
(ATAMMC)
Performance 
site
FWA00017754
11/20
/2028
:
IAIR
:
WRNMMC 
IRB
Army
Carl R. 
Darnall 
Army 
Medical 
Center 
(CRDAMC)
Performance 
site
FWA00026734
08/18
/2028
:
IAIR
:
WRNMMC 
IRB
Army
Womack 
Army 
Medical 
Center 
(WAMC)
Data analysis
FWA00012834
03/14
/2028
:
IAIR
:
WRNMMC 
IRB
Army
Madigan 
Army 
Medical 
Center 
(MAMC)
Performance 
site
FWA00003277
09/17
/2026
:
IAIR
:
WRNMMC 
IRB
P&R
Walter 
Reed 
National 
Military 
Medical 
Center 
(WRNMMC)
Lead site
FWA00017749
03/11
/2027
:
WRNMMC 
IRB
Other:
Other Institution 
Site
Site Role
FWA or DoD 
Assurance 
Number
FWA or DoD 
Expiration Date
Is there an 
agreement?
IRB Reviewing 
for Site
No results found
8.3  Are there international sites?

Attach international approval documents, if applicable, when prompted. Note: Ensure local research 
context has been considered
  Yes  
  No
8.4  Is this an OCONUS (Outside Continental United States) study?
  Yes  
  No
Select  the area of responsibility:
Have you obtained permission from that area of responsibility? (This is a requirement prior to study 
approval)
  Yes  
  No
9.0
 
Study Details
9.1  Key Words:
Provide up to 5 key words that identify the broad topic(s) of your study
Chronic Exertional Compartment Syndrome (CECS), Gait Re-Training, Gait Analysis, 
Botulinumtoxin A, Military
9.2  Background and Significance:
Include a literature review that describes in detail the rationale for conducting the study. Include 
descriptions of any preliminary studies and findings that led to the development of the 
protocol.  The background section should clearly support the choice of study variables and 
explain the basis for the research questions and/or study hypotheses.  This section establishes 
the relevance of the study and explains the applicability of its findings
Chronic exertional compartment syndrome (CECS) is a debilitating disorder affecting mostly an 
active population. The proposed pathophysiology is increased pressure in muscle compartments 
causing pain, paresthesia, and inability to tolerate exercise in the affected fascial compartment. 
CECS involves the lower extremities, primarily affects young active adults, and limits running and
/or endurance activities. While the incidence of CECS in the general population is unknown, the 
prevalence in the military population has been found to be 0.49 cases per 1000 patient-years.1,4,
5,7
 
The current standard for definitive treatment of CECS is surgical fasciotomy of the involved 
compartments.  According to a 2016 systematic review, surgical intervention for CECS is 
successful in only 66% of those affected, with 13% of patients reporting complications from 
surgery, and 6% needing a repeat procedure.  A 2013 retrospective analysis of military 
5
members showed fasciotomy for CECS was successful in only 55% of those affected. 
Additionally, 28% were unable to return to full activity, 16% suffered surgical complications, and 
6% underwent repeat fasciotomy. Of 661 participants, 106 were referred for medical discharge 
from the Armed Forces.
A 2014 military cohort found 22% of patients were medically 
6 
discharged or had surgical revision at short-term to mid-term follow-up. Additionally, 28% of 
service members were unable to return to full duty and 45% experienced incomplete relief of 
symptoms.  Besides risks and complications, surgery also required a mean of 13 weeks to return 
4
to full activity when effective.7,8,9
 
Formalized gait retraining is an attractive alternative to fasciotomy. It aims to influence the 
effect of foot contact and running kinematics to reduce leg compartment pressures which 
relieves pain. Diebal et al. published a case series of 10 military members with CECS who 
underwent a Supervised Gait Retraining (SGR) program that emphasized forefoot running. At six-
weeks and one-year post-intervention, running distance, pain, and performance all significantly 

improved. This case series also showed significant patient satisfaction with patients reporting 98 
or better on the single assessment numeric evaluation (SANE) and 92 or better on the lower leg 
outcome survey.  A 2015 prospective cohort study showed home-based gait retraining (HBGR) is 
3
an effective alternative to SGR while reducing time and invested resources.
 Despite high rates 
10
of success in limited case studies, real world application of gait retraining has limitations. Many 
patients struggle to make and/or sustain adaptations in their running style. Some patients have 
severe pain with exercise which limits efforts at effective gait re-training.
 
A newer proposed treatment for CECS is the intramuscular administration of botulinumtoxin A 
(BoNT-A) into the muscles of the involved compartment(s). BoNT-A is FDA approved for 
intramuscular, intradetrusor, or intradermal use for muscle spasticity, migraine headaches, 
detrusor instability and severe forehead lines, lateral canthal lines, and glabellar lines in 
adults.  A 2013 case series studying botulinum toxin injections for CECS demonstrated 
normalized intramuscular pressure up to nine months post-injection in 87.5% (14/16) of 
patients, and exertional pain was completely eliminated in 94% (15/16) of patients. Eleven 
patients experienced reduced muscle strength that was without functional consequences and 
transient resolving within 3 months. Only 1 of the 16 patients complained of new posterior leg 
pain that did not appear to be related to BoNT-A injections. There were no other adverse effects 
reported.
An additional 2016 case report showed effective pain and paresthesia relief from CECS 
1 
after 1 set of injections for a recreational female athlete. In this report, the patient’s symptoms 
resolved within 1 week. More importantly, she was able to return to full recreational activity 
within 4 weeks, with no return of symptoms throughout the 14 months of follow up without any 
weakness or adverse effect.2
 
Military sports medicine clinics at Fort Belvoir Community Hospital (FBCH) and the Uniformed 
Services University (USU) as well as the Department of Physical Medicine & Rehabilitation at 
Walter Reed National Military Medical Center WRNMMC) currently utilize BoNT-A (trade 
names BOTOX® or Xeomin®) injections for the non-surgical treatment of CECS. All of our 
performance sites currently offer BoNT-A (trade names BOTOX® or Xeomin®) injections as 
standard of care non-surgical treatment options for CECS.
 
An unpublished retrospective review of patients with CECS treated with BoNT-A at FBCH Sports 
Medicine Clinic from 2014 to 2017 provided data on twenty-nine patients who were treated with 
BoNT-A for CECS (Protocol title: "Intramuscular botulinum toxin A injections for chronic 
exertional compartment syndrome: A retrospective therapeutic case series" Reference#: 
905663). Prior to treatment, none of the 29 patients were able to perform their desired activity 
and 24% were unable to run one mile without severe leg pain. After botulinum injections, these 
numbers improved to 66% and 72% respectively. Sixty-nine percent of the patients reported 
that they were satisfied or somewhat satisfied with their treatment, twelve patients continued to 
have sustained relief by the time they were contacted, and seven patients experienced a 
recurrence of symptoms. In those with recurrence, the mean duration of improvement was 7.8 
months. Of note, 11 patients received both BoNT-A and fasciotomy during their treatment 
course. Only one patient reported a favorable response to fasciotomy and failure with BoNT-A, 
suggesting that BoNT-A injections might be predictive of success with fasciotomy.
 
While alternative strategies like gait retraining and BoNT-A injections have emerged, the amount 
of data that is currently available to guide treatment is significantly limited. Studies assessing 
gait retraining in the treatment of CECS are few in number and small in power, with the largest 
published US case series involving 10 or fewer patients. Likewise, studies assessing the 
effectiveness of BoNT-A injections have thus far only included small, non-controlled, non-blinded 
case series. Perhaps the reason for paucity of data is a relative rarity of cases of CECS occurring 
at any single location. Military databases have thus far provided some of the best evidence for 
evaluating the effectiveness of fasciotomy for CECS, in large part because of the increased 
incidence of CECS among military members. By performing an intervention study at multiple 
military treatment facilities, we have the ability to evaluate non-surgical options for CECS with 
high quality, high-powered, blinded protocols.
 
This study will be the first of its kind to utilize blinding and a control while analyzing BoNT-A 
injections for CECS in the military health system. It will also be the first to judge whether formal 
gait retraining is required for the successful non-operative treatment of CECS or if BoNT-A 
injections is sufficient as a stand-alone treatment. The information gained from this study has 
the potential to revolutionize the treatment of CECS and provide guidance to physicians caring 
for these patients all over the world.
9.3  
Objectives/Specific Aims/Research Questions:

Describe the purpose and objective(s) of the study, specific aims, and/or research questions
/hypotheses
The long-term objective of this project is to simultaneously assess the effectiveness of non-
surgical treatments, botulinumtoxin A (BoNT-A) injections and supervised gait retraining (SGR), 
in terms of pain control and ability to return to full duty among adult active duty service 
members suffering from lower extremity Chronic Exertional Compartment Syndrome (CECS), 
specifically of the anterior and/or lateral comparments.1,2,3
 
This study will determine if successful supervised gait retraining is required for the successful 
non-operative treatment of anterior and/or lateral CECS or if BoNT-A injections is sufficient as a 
standalone treatment. Furthermore, this study will determine if BoNT-A injections plus 
supervised gait retraining is better.
 
Study Treatment Groups:
Group 1 - Home Based Gait Retraining (HBGR) and Normal Saline (placebo)
Group 2 - Supervised Gait Retraining (SGR) and Normal Saline (placebo)
Group 3 - BoNT-A + HBGR
Group 4 - BoNT-A + SGR 
Objective 1: Assess and compare the treatment efficacy of the below study treatment groups.
Hypothesis 1:BoNT-A injections will prove effective as a non-surgical treatment option for 
CECS.
Process for Hypothesis 1:  Evaluate functional improvements in Group 3 as compared to 
Group 1 via the subjective and objective data variables described in protocol sections 10.1 & 
10.2.
Hypothesis 2: Supervised Gait Retraining will prove effective as a non-surgical treatment 
option for CECS.
Process for Hypothesis 2:  Evaluate functional improvements in Group 2 as compared to 
Group 1 via the subjective and objective data variables described in protocol sections 10.1 & 
10.2.
Hypothesis 3: The use of both BoNT-A injections and supervised gait retraining will be more 
effective than either treatment alone. In adult active duty service members with CECS, the 
use of both BoNT-A injections and supervised gait retraining returns service members to full 
duty, including being able to complete their service-specific military physical tests, sooner 
and for sustained longer periods that SGR or BoNT-A injections alone.
Process for Hypothesis 3:  Evaluate functional improvements in Group 4 as compared to 
Groups 2 & 3 via the subjective and objective data variables described in protocol sections 
10.1 & 10.2. Assess the ability of all study groups to complete a 2-mile run and to compete 
their required service-specific physical fitness testing within the established standards at 8 
weeks, 3 months, 6 months, and 12 months post-study injection.
9.4  Study Design:
Describe study design in one to two sentences (e.g., prospective, use of existing records/data
/specimens, observational, cross-sectional, interventional, randomized, placebo-controlled, 
cohort, etc.). Specify the phase – Phase I, II, III, or IV – for FDA-regulated investigational drug 
research
Multi-site, single-blinded randomized placebo-controlled study
9.5  Target Population:
Describe the population to whom the study findings will be generalized
Adult military beneficiaries diagnosed with Chronic Exertional Compartment Syndrome (CECS)
9.6  Benefit to the DoD:

1.  
State how this study will impact or be of benefit to the Department of Defense
Chronic exertional compartment syndrome (CECS) may occur in the four compartments of the 
lower leg: anterior, lateral, superficial posterior, and deep posterior. CECS typically occurs in the 
anterior and/or lateral compartments and is commonly seen within the military and has been 
shown to result in both significant warfighter disability and degradation of the unit mission. 
Active duty military members represent a population with a significantly higher risk of CECS. 
Military members also face requirements for exercise training and fitness that are jeopardized by 
a condition that limits aerobic exercise and physical activity. Fasciotomy, the current standard 
definitive treatment, has significant limitations in terms of effectiveness and direct and indirect 
costs. Pooled data shows that 28-59% of military members with CECS who underwent 
fasciotomy were unable to return to full duty and approximately 20% ultimately required medical 
separation from the military.  Not included in these statistics was the loss of member 
1
productivity during appointments, procedures, and recovery time.
 
Given the significant impact of CECS on the military mission, there is strong interest and 
motivation to investigate less invasive and less costly alternatives to fasciotomy. Within the 
National Capital Region, military sports medicine physicians have been utilizing both Supervised 
Gait Retraining (SGR) and botulinumtoxin A (BoNT-A) injections for years. While results have 
been promising for both options, there is insufficient high-quality data to create treatment 
guidelines and protocols for other providers in the military who treat these patients.
 
Based on a retrospective review of 29 patients from Fort Belvoir Community Hospital who 
received BoNT-A injections for CECS, approximately two-thirds of these patients were able to 
return to their desired activity level. In addition, among 11 patients who eventually underwent 
both BoNT-A injections and fasciotomy, only 2 patients would recommend fasciotomy as the first 
intervention over BoNT-A. Additionally, 69% of the patients in this review expressed satisfaction 
with BoNT-A injections. Aside from self-limited weakness with ankle dorsiflexion, there were no 
significant adverse effects.  The next logical step is to study the effect of BoNT-A injections in a 
2
randomized, prospective, single-blinded, placebo- controlled fashion.
 
In our present era of constrained troop numbers and enhanced emphasis on deployment 
readiness for every military member, this study offers a unique opportunity to evaluate novel 
treatment options for a significant source of lost readiness and disease burden in the DoD. 
Additionally, the data from this study will be readily translatable to allied military and civilian 
athlete populations. Given the epidemiology of CECS, this study is likely only feasible in a tri-
service, multi-centered military environment. Results have the promise to greatly influence 
treatment decisions and help physicians and warfighters maintain the readiness and physical 
prowess of the fighting force.
10.0
 
Study Procedures, Data Management, and Privacy
10.1  Study Procedures:
Describe step-by-step how the study will be conducted from beginning to end
This study has two screening phases: 1) pre-screening based on initial inclusion/exclusion 
criteria (before informed consent) and 2) a formal screening phase to determine eligibility for 
randomization to intervention arm (after informed consent).
 
 
Recruitment, Pre-Screening (before consent), Study Introduction & Consent:
Potential participants will be identified via three methods: 
Under the HIPAA Preparatory to Research Provision, local study clinicians will review 
medical records of patients coming in to the Physical Medicine & Rehabilitation 
(PM&R), Orthopaedics, Physical Therapy (PT), and Sports Medicine clinics for 
suspected Chronic Exertional Compartment Syndrome (CECS) to identify prospective 
research participants for the purposes of seeking their authorization to participate/use 
their protected health information for this research study, 

2.  
3.  
If a local healthcare provider identifies a potential participant seen in the PM&R, 
Orthopaedics, PT or Sports Medicine clinic for suspected CECS as part of regular 
clinical care, they may refer them to a member of the local research team (who will be 
located within the clinic or available via phone) for further discussion, and 
Study flyers will be posted within the departments of PM&R, Orthopaedics, PT, and 
Sports Medicine.
If a potential participant expresses interest in learning more about the research study, a 
member of the research staff will briefly introduce the study, express the voluntary nature of 
participation, assess interest in participating, and screen the potential participant for initial 
eligibility in close collaboration with the patient’s attending provider. Initial eligibility (see 
Section 12.5 Inclusion Criteria #1-5 & Section 12.6 Exclusion Criteria #1-8) will be confirmed 
using an Inclusion/Exclusion CRF (Appendix A). This Inclusion/Exclusion CRF does not record 
any PII/PHI.
 
If the potential participant meets initial eligibility criteria as determined by the Inclusion
/Exclusion CRF and expresses interest in participating, an authorized study team member will 
initiate the formal consent discussion and, if applicable, obtain informed consent.
 
If a potential participant would like additional time to review the consent form, study 
procedures, risks and benefits, etc. they will be provided with a consent form and study 
brochure to take home and, if applicable, they may return to clinic at a later date to have any 
and all remaining questions answered and to finish the consent process.
 
Following completion of informed consent, the results of the Inclusion/Exclusion CRF will be 
entered into REDCap, an encrypted, access controlled, password protected electronic data 
capture and management system housed on a DoD server and maintained by the Uniformed 
Services University Information Technology (USU IT), by an authorized local study team 
member and a unique study ID will be automatically generated. This coded study ID will be 
used on all research data collection forms in place of the participant’s name, social security 
number, Department of Defense (DoD) ID, or other protected identifier. No PII will be entered 
into REDCap. Please see Appendix J for additional information on REDCap.
 
In order to document screen failures and refusals, the results of the Inclusion/Exclusion CRF 
will be entered into REDCap even if a patient doesn’t consent to participate in the study. The 
Inclusion/Exclusion CRF does not record any PHI/PII.
 
In order to adhere to WRNMMC’s recruitment policy, research activities (e.g., study 
introduction, consent conversations, etc.) will take place after the clinic visit has ended. 
Recruitment and consent conversations will take place in a private setting (e.g., closed clinic 
room, investigator’s office, etc.) to minimize the potential opportunity to be overheard or 
inadvertently witnessed.
 
 
Contact Information Data Collection (post-consent):
Immediately following consent, the participant will complete an Intake CRF (Appendix B). The 
Intake CRF will collect participant contact information (full name, last four digits of their social 
security number, preferred phone number, email address, etc.).
 
With the exception of the Consent Form and HIPAA Authorization, the Intake CRF is the only 
paper research form that will contain participant identifying information. It will be stored with 
the signed consent forms (in a locked cabinet inside of a locked room) and separately from all 
other paper research forms. All remaining paper research forms will be identified using a 
unique study ID and not by participant name, social security number, DoD ID, or other similar 
identifier. The Intake CRF will not be entered into REDCap.
 
 
Formal Screening (post-consent), Demographics & Baseline Data Collection:
 
Formal Screening:
As part of standard of care, other concomitant causes of leg pain will be ruled out with a 
physical examination, relevant medical history review and lower leg magnetic resonance 
imaging (MRI). 
 
As part of the formal screening procedures, the participant’s CECS diagnosis will be confirmed 
via an intramuscular compartment pressure test. To do this, the participant will have an 
intramuscular compartment pressure (IMCP) test done in one area at each of their anterior 
and lateral leg compartments at rest and post exerting on a treadmill, stairs, marching, or 
any type of exertional activity that increases the participant's leg pain and/or symptoms. 
Once they have their leg pain or symptoms reproduced while running or completing the 

offending exertional activity, they will then have repeat IMCP test done at 1 minute post 
exertion. The IMCP test is currently the diagnostic standard for CECS. The use of ultrasound 
imaging will be used to identify and mark the region of interest of the anterior and lateral leg compartments that will 
 If a participant has had any of these procedures performed within the 6 months prior 
be tested.
to study enrollment, the research team will review those results and not repeat procedures if 
the testing was adequate and acceptable for clinical standards.
 
Also as part of the formal screening procedures, participants will have their ankle brachial 
index (ABI) blood pressure taken on each side at their ankle, foot, and arm separately using a 
blood pressure cuff and Doppler instrument. Blood pressures will be taken at rest, then 1 
minute within completing approximately 50 repetitions of bilateral heel raises. At rest, an ABI 
measurement of less than or equal to 0.90 or greater than or equal to 1.4 on either side will 
be excluded from the study and resume normal care with their referring provider. If their ABI 
post exertion decreases in value greater than 0.2 compared to baseline, limb pressures are 
decreased greater than 30 mmHg compared to baseline, or they meet the previous exclusion 
baseline criteria for their ABI, then the participant will be excluded from the study and 
resume normal care with their referring provider. 
 
Any female participant will also be required to have a urine hCG test performed prior to study 
injection. If the urine hCG indicates the participant is pregnant, per stated inclusion/exclusion 
criteria, they will be formally withdrawn from the study and will resume normal care with their 
referring provider.
 
All of the formal screening procedures must be completed within 60 days post-study consent.
 
Demographics & Baseline Data Collection:
Prior to being randomized to a study arm beginning their assigned study treatment (saline or 
BoNT-A injection, SGR or HBGR), participants will complete a Demographics CRF (Appendix 
C) and a Baseline Data Collection CRF (Appendix D) which ask relevant medical and service 
history and demographic questions including: age, gender, body mass index (BMI), symptom 
duration and characteristics, treatment history, work status, military rank, branch of service, 
length of service, limited duty/profile status, occupational specialty, concomitant medical 
conditions, activities provoking symptoms, footwear characteristics and orthosis use, etc.  The 
Baseline Data Collection CRF also includes the following measures and clinical tests: Balance 
Error Scoring System (BESS), Numeric Pain Rating Scale (NPRS), University of Wisconsin 
Running Injury and Recovery Index (UWRI), Single Assessment Numerical Evaluation (SANE), 
Patient Specific Functional Scale (PSFS), gait analysis using advanced wearable technology as 
part of a self-paced treadmill test until cessation or the successful completion of a two-mile 
run (whichever occurs first), and objective leg length discrepancy measurement, foot 
parameters, lower extremity strength, range of motion (ROM), and palpation testing. A gait 
analysis Data Collection CRF (Appendix R) will be used to collect some of the gait analysis 
from the advanced wearable technology and will be completed after the participant's visit.
 
Many of the baseline questionnaires and clinical tests utilized in this study are already 
performed as standard of care. Please see attached Data Collection Schedule (Appendix H) for 
additional details.
 
Overall, the total time to complete all screening and baseline activities will be a maximum of 
5.5 hours.
 
 
Randomization:
Participants who meet final eligibility criteria (no other concomitant causes of leg pain, 
confirmed CECS diagnosis of the anterior and/or lateral compartments via intramuscular 
compartment pressure test and lower limb MRI, ABI between 0.90 and 1.40, and if applicable, 
negative pregnancy test) will be randomized to a study arm and their intervention dates (i.e. 
injection and/or supervised gait retraining) will be scheduled. Study injections (both placebo 
and BoNT-A) must occur within 60 days of randomization and ≥ 2 weeks post-intramuscular 
compartment pressure test. A computer-generated randomization program prepared by the 
study biostatistician will be used to assign participants uniformly across all four study arms.
 
Participants will be assigned to one of four treatment groups:
Group 1 - Home Based Gait Retraining (HBGR) and Normal Saline (placebo)
Group 2 - Supervised Gait Retraining (SGR) and Normal Saline (placebo)
Group 3 - BoNT-A + HBGR
Group 4 - BoNT-A + SGR
 
Study Intervention:

 
BoNT-A Injections:
Those randomized into a BoNT-A injections group (i.e., Group 3 or 4) will receive up to 2 
injections per affected anterior and/or lateral compartment. Per standard clinical procedure, a 
solution of 25 units of Botulinum toxin, per 1 mL of normal saline will be used for each 
injection. Standard aseptic technique will be followed. Insertion into the correct compartment 
will be accomplished using ultrasound guidance. The anterior and/or lateral compartments will 
each be separated into thirds measuring from the tibial plateau to the head of the calcaneus. 
Injections will be given at approximately 1/3 the distance from the tibial plateau for the 
proximal injection and 2/3 the distance from the tibial plateau for the distal injection. 
Injections will only be given in the compartments that have elevated compartment pressure 
using the standard Pedowitz criteria: 1) a pre-exercise pressure greater than or equal to 15 
mmHg, 2) a 1 minute post-exercise pressure of greater than or equal to 30 mmHg, or 3) a 5 
minute post-exercise pressure greater than or equal to 20 mmHg.
 If the lateral 
12 
compartment is affected, a total of 50 units of botulinum toxin will be given. The proximal 
aspect of the peroneus longus and brevis is approximately 1/3 the distance from the tibial 
plateau and it will receive 25 units of botulinum toxin A. The distal aspect of the peroneus 
longus and brevis is approximately 2/3 the distance from the tibial plateau and this area will 
also receive 25 units of botulinum toxin A. If the anterior compartment is affected, a total of 
50 units of botulinum toxin will be given; 25 units to the proximal anterior compartment and 
25 units to the distal anterior compartment.1,2
 
Of note, CECS mainly affects the anterior and lateral compartments and is rarely seen in the 
superficial posterior or deep posterior areas; thus, the anterior and lateral compartments will 
be the focus of this study and patients with concomitant or isolated posterior compartment 
symptoms will not be included in this study. Participants who receive BoNT-A injections will be 
provided with a Post-Injection After Care Handout (Appendix O). The information provided to 
the participant after the injection are observed signs and/or symptoms that could occur with 
receiving either a BoNT-A or saline injection. This handout is not likely to expose the blinding 
of the injection that the participant receives as part of the study.
 
Saline Injections:
Those randomized into the normal saline groups will receive injections in the identical manner 
above, using the appropriate amount of solution (0.5 mL to 1 mL). The syringes will be 
prepared by the clinical research staff using standard sterile techniques, out of view of the 
participant to ensure appropriate blinding.
 
Study Injection Documentation (both groups):
All injections will be done under ultrasound guidance. The provider will use the ultrasound 
machine to identify bony landmarks of the tibial plateau and will then move the probe 
laterally towards the fibular head to identify the anterior and lateral compartments of the 
lower leg. Distally, the provider will identify the midway area between the fibular head and 
the tip of the lateral malleolus.
 
Study injection administration to the participant will be documented using a 
Treatment Documentation CRF (Appendix N). This Treatment Documentation CRF will be 
entered into REDCap. Study injection administration will also be documented in the 
participant's electronic medical record following standard procedures.
 
Supervised Gait Retraining (SGR):
The SGR course will focus on mid-forefoot strike, increasing their cadence while shortening 
their stride, and decreasing their peak ground reaction force. This program has been 
developed by physical therapists at West Point and the Army DPT program in Fort Sam 
Houston. This program uses group physical therapy sessions, lower extremity exercises, 
home exercise training drills, and advanced wearable technology to effectively change key 
gait parameters.
 
Supervised physical therapy sessions will be documented using a SGR Physical Therapy 
Documentation CRF (Appendix M). This SGR Physical Therapy Documentation CRF will be 
entered into REDCap. Study supervised physical therapy sessions will also be documented in 
the participant's electronic medical record following standard procedures. Participants in the 
SGR group(s) will also be sent home with a handout (Appendix L) explaining exercises that 
can/should be done from home to supplement their supervised physical therapy sessions.
 
Home Based Gait Retraining:
The HBGR will focus on increasing cadence, running softer and increasing endurance strength 
with exercises for the lower extremity. A handout (Appendix L) explaining desired exercises 
and gait retraining will be given to each participant with daily exercise instructions. 
Participants will be contacted weekly as a reminder to complete their home program.

 
For participants assigned to the HBGR group, their first (and only) study-related in-person 
physical therapy session and follow up communications will be documented using an HBGR 
Physical Therapy Documentation CRF (Appendix Q). This HBGR Physical Therapy 
Documentation CRF will be entered into REDCap. Their first (and only) study-related in-
person physical therapy visit will also be documented in the participant's electronic medical 
record following standard procedures.
 
Both the SGR & HBGR Groups:
Initiation of physical therapy visits for both SGR and HBGR groups can be greater than or 
equal to 2 weeks post-injection. All participants (regardless of study arm) will be instructed to 
avoid other physical therapy and invasive treatments (including acupuncture) while 
participating in this study. Concomitant medications and therapies will be recorded at each 
follow up visit (Appendix M & Appendix Q). Participants will be free to participate in optional 
complimentary activities available to them as standard of care such as aquatics and yoga. 
 
 
Follow Up Data Collection:
For all study groups, participants will complete a Follow Up Data Collection CRF (Appendix E) 
at 8 weeks (+/- 1 week), 3 months (+/- 2 weeks), 6 months (+/- 2 weeks) and 12 months 
(+/- 2 weeks) post-study injection and a Long Term Follow Up Data Collection CRF (Appendix 
F) at 24 months (+/- 4 weeks) post injection. The Follow Up Data Collection CRF and Long 
Term Follow Up Data Collection CRF both include the following measures: Numeric Pain Rating 
Scale (NPRS), University of Wisconsin Running Injury and Recovery Index (UWRI), Single 
Assessment Numerical Evaluation (SANE), Patient Specific Functional Scale (PSFS), and the 
Global Rate of Change (GROC). Additionally, patients will be asked about their ability to 
complete their service-specific military physical training requirements, running and activity 
leg symptoms, footwear characteristics and orthosis use, pertinent medical history, and 
treatment satisfaction at each follow-up time point.
 
At 8 weeks (+/- 1 week), 3 months (+/- 2 weeks), 6 months (+/- 2 weeks), and 12 months 
(+/- 2 weeks) post-injection, participants will undergo Balance Error Scoring System (BESS) 
testing, objective foot parameters, ankle strength, range of motion (ROM), ankle brachial 
index (ABI) blood pressure, and palpation tests, and a gait and run analysis using advanced 
wearable technology as part of a self-paced treadmill test until cessation or the successful 
completion of a two-mile run (whichever occurs first). A gait analysis Data Collection CRF 
(Appendix R) will be used to collect some of the gait analysis from the advanced wearable 
technology and will be completed after the participant's visit. 
 
Participants will also be asked about involvement in non-study related activities and 
treatments including acupuncture/acupressure, aquatics, anti-inflammatory/pain medication, 
athletic taping, change in running shoes, chiropractor, dry needling, electrical stimulation, 
foot orthotics, gait retraining, ice pack/massage, massage, physical therapy, strengthening, 
stretching, yoga, and other treatments.
 
Intramuscular compartment testing of participant’s anterior and lateral compartments will be 
re-tested at 6 months (+/- 2 weeks) post-injection. The same compartments tested at 
baseline or at a previous test 6 months prior to consent of the study, will be recollected at the 
6 month time point. 
 
Results of the in-person clinical assessments and the intramuscular compartment testing will 
be recorded in the Follow Up Data Collection CRF. 
Overall, the 8 week, 3 month, 6 month, and 12 month follow up activities will take 
approximately 2.5 hours each and the 24 month follow up activities will take approximately 
30 minutes each.
 
If the participant has a change of duty station (permanent or temporary) and/or cannot make 
an in-person visit, the following will be collected using Appendix E, Follow Up Data Collection 
Sheet: relevant medical and service history and demographic questions including age, 
gender, body mass index, symptoms duration, location, and characteristics, treatment 
history, work status, military rank, branch of service, length of service, limited duty/profile 
days, occupational specialty, concomitant medical conditions, activities provoking symptoms, 
location of symptoms, footwear characteristics and orthosis use, etc., numeric pain rating 
scale (NPRS), University of Wisconsin Running Injury and Recovery Index (UWRI), Single 
Assessment Numerical Evaluation (SANE), Patient Specific Functional Scale (PSFS) will also be 
assessed. This may be collected with electronic mail, postal mail, and/or telephone 
communication with the participant.

Many of the activities in this study are performed regularly as part of standard of care for 
patients being seen for lower extremity CECS. Please see Appendix H: Data Collection 
Schedule for details on which activities are standard of care.
 
Study Completion:
Participants' study completion or withdrawal will be documented on the Study Completion CRF 
(see Appendix S).
 
Additional Considerations - COVID-19:
For as long as deemed clinically appropriate, there will be additional precautions in place to 
ensure the health and safety of research staff and research participants and to combat the 
spread of COVID-19.  Research staff will closely follow all current local clinical guidelines 
regarding the use of PPE, hand washing, disinfecting of equipment, proper distancing, etc. 
Additionally, the study team will reduce the need for in-person research-specific visits when 
possible. For participants assigned to one of Standardized Gait Retraining (SGR) groups, 
some of their clinical follow ups during the physical therapy period may be conducted and 
documented as a video/telehealth encounter. For participants assigned in all groups, the 24-
month follow up visit which requires no physical examination can be conducted remotely, 
meaning the participants can complete the questionnaires electronically, over the phone, or 
hard copy via mail all while remaining at home.
 
 
Study Blinding:
Participants will be blinded to assigned treatment arm (i.e., saline vs. BoNT-A injection) until 
3 months post-injection.
 
Blinding will be revealed to the participants after all the components of the 3 month follow-up 
visit have been completed. Participants who are not satisfied with their treatment results and
/or who are unable to complete a 2-mile run without producing pain and/or symptoms will be 
offered the option to receive BoNT-A injections and/or Supervised Gait Retraining if they had 
not received those active treatments.
 
At the 6 month follow-up visit, participants who are still not satisfied with their treatment 
results and/or still unable to complete a 2-mile run will be offered any remaining treatment 
option, including surgical fasciotomy which is offered as standard of care. Participants who 
express interest in surgical fasciotomy will be referred to an orthopaedic surgeon who will 
dictate and guide this treatment option. Further details and scheduling will be per the 
orthopaedic surgeon’s recommendations. Patients who cross over to alternative treatment 
options (including surgical fasciotomy) will remain in the study and will continue to follow up 
with the research team at the intervals listed above.
 
 
Data Entry:
With the exception of the Intake CRF which collects participant contact information, all coded 
research data will be entered into REDCap, an encrypted, access controlled, password 
protected electronic data capture and management system housed on a DoD server and 
maintained by the Uniformed Services University (USU). No PII will be entered into REDCap. 
See Appendix J for additional information on REDCap. See Appendix I for a PDF copy of the 
REDCap forms for this study.
 
 
Additional Info - MIRROR/USU:
This research study is being conducted as part of Musculoskeletal Injury Rehabilitation 
Research for Operational Readiness, formerly known as the Collaboratory for Musculoskeletal 
Injury Rehabilitation Research (CMIRR), which is based out of the Department of Physical 
Medicine & Rehabilitation (PM&R) at the Uniformed Services University (USU). MIRROR is 
focused on advancing musculoskeletal injury (MSI) rehabilitative care within the military 
healthcare system in order to reduce the burden MSIs have on military readiness and to 
ultimately enhance the operational capabilities of the armed forces. MSIs affect approximately 
800,000 service members annually and result in 25 million days of limited duty. These 
conditions are the primary reasons for medical discharge/downgrade and result in 34% of 
medical evacuations from theatre. MIRROR was developed as a means to study risk factors of 
common MSIs, generate prevention strategies, optimize treatments, and establish return-to-
duty criteria that is based on scientific evidence rather than case-specific clinical judgment 
alone.
 

MIRROR involves interdisciplinary and inter-service partnerships, the Department of Defense 
(DoD), and several major academic medical centers. To ensure military mission focus and 
scientific relevance, MIRROR is guided by a steering committee composed of members from 
the Joint Program Committees (JPCs) at the U.S. Army Medical Research and Materiel 
Command (USAMRMC), military operational leaders, and experts in musculoskeletal medicine 
from the military and civilian communities. MIRROR aims to be the world’s leader in military 
relevant musculoskeletal injury care research.
 
Currently, research projects are being deployed at more than 17 military and civilian 
treatment facilities nationwide.
 
MIRROR/USU is serving as a Coordinating Center for this study and will also be providing 
remote regulatory support. Staff from MIRROR/USU will not interact with human subjects and 
will not have access to the paper research records or any identifiable research data to include 
the Master List, the Informed Consent Documents/HIPAA Authorizations, or any other form of 
participant PHI/PII. De-identified research data will shared MIRROR/USU and maintained 
indefinitely for possible use in future research.
 
There will be appropriate data sharing agreements in place between the data owner(s) (e.g., 
DHA for AHLTA) and the Walter Reed National Military Medical Center (WRNMMC), as well as 
the Uniformed Services University (USU) and all appropriate parties involved in the handling 
of data (e.g., The Geneva Foundation).
10.2  Data Collection:
Describe all the data variables, information to be collected, the source of the data, and how the 
data will be operationally measured.
Please see attached Data Collection Schedule (Appendix H).
 
The local study team will collect study data directly from the study participant, from their 
attending provider or, where applicable, from the participant’s medical record (i.e., relevant 
medical and treatment history and relevant clinical notes) and record it on paper CRFs (see 
Appendixes A-F). Study completion will be documented (see Appendix S). The completed 
paper CRFs will serve as source documents for this study. Participants may also enter study 
data directly into REDCap using a coded survey link. In these cases, the completed eCRFs will 
be printed and stored in the participant's research files and serve as source documents. Other 
source documents include relevant laboratory results (i.e., hCG urine test) and relevant 
clinical notes which will be printed, redacted, and stored in the participant’s research file.
 
With the exception of the Informed Consent Form, HIPAA Authorization, and Intake CRF 
(Appendix B) which collects contact information, all paper CRFs will be identified using a 
unique study ID only, and not by the participant’s name, social security number, DoD ID, or 
other protected identifier.
 
The primary outcome will be functional improvement via statistical changes in the Balance 
Error Scoring System (BESS), University of Wisconsin Running Injury and Recovery Index 
(UWRI), Single Assessment Numerical Evaluation (SANE), Patient Specific Functional Scale 
(PSFS), Global Rate of Change (GROC), objective data from the gait and run analyses (e.g., 
average vertical load rate, cadence, foot pattern strike, etc.), ability to return to full active 
duty, and ability to complete a 2-mile run. Full active duty is defined as meeting all service 
specific requirements of physical training and ability to complete work duties with either no 
pain or pain that is tolerable as determined by the patient.
 
Secondary outcomes will include pain reduction according to the Numeric Pain Rating Scale 
(NPRS), ability to complete service specific military physical training requirements, and 
patient satisfaction. To assess patient satisfaction, patients will be asked if they were or were 
not satisfied with intervention at each follow up time point.
 
This will be an intention to treat study and additional data that will be collected via the 
Demographics CRF (Appendix C) and Baseline Data Collection CRF (Appendix D) includes:
Standard Demographics (e.g., Age, Sex, military occupational specialty, height, weight, 
BMI, MOS)
Length of military service
Symptom duration (including length of limited duty, military profile)
Previous Treatments
Time to diagnosis

Concomitant medical conditions
Footwear characteristics and orthosis use
Activities provoking symptoms, and perceived exertion (Borg) tolerance
Duration of symptoms when present
Performance on military fitness tests
Ability to perform occupational related tasks
Objective lower extremity strength, range of motion (ROM), ankle brachial index (ABI) 
blood pressure, palpation, leg length, foot parameters tests
10.3  At any point in the study, will you request, use, or access health information in any form, including 
verbal, hard copy and electronic?
 Yes  
 No
10.4  Review the definitions below and respond to the following two questions.  If you are not sure of the 
answers, email 
 for assistance.
DHA.PrivacyBoard@mail.mil
   The 
 is 
Military Health System (MHS)
defined as all DoD health plans and DoD health care providers that are organized under the 
management authority of, or in the case of covered individual providers, assigned to or employed by, 
  
the Defense Health Agency (DHA), the Army, the Navy, or the Air Force  
 
MHS workforce members
are employees, volunteers, trainees, and other persons whose conduct, in the performance of work 
  
for the MHS, is under the direct control of the MHS, whether or not they are paid by the MHS.  MHS 
 are persons or entities that provide a service to the MHS and require protected 
business associates
health information (PHI) to provide the service.
Are you an MHS workforce member?
Yes, I am an MHS workforce member 
No, I am not an MHS workforce member 
10.5  Have you consulted with an MHS data expert to determine the data elements required for your study?
Consulting with a data expert often saves time later in the compliance process because the data 
expert can advise on the data available in the numerous MHS information systems, the quality of 
that data and the methods for encrypting and collapsing data.  To schedule a consult with an 
MHS data expert, send an email to: (
)
DHA.PrivacyBoard@mail.mil
Yes, then complete the questions below according to the data consult 
No, then complete the questions below according to the best of your knowledge 
10.6  Indicate how you will request data from the MHS.  Select all that apply.
Talking with MHS health care providers or MHS health plans about specific research 
participants
Obtaining MHS hard copy records specific to research participants
Obtaining data from an MHS information system(s)
10.7  If you are obtaining data from an MHS information system(s), indicate whether you plan to receive a 
data extract or whether you plan to access an MHS information system directly to create a data set.
A data extract is when the MHS or a contractor provides the data set directly to the 
researcher.  When receiving a data set through data extract, the researcher may indicate 
whether the data elements should be provided as is, encrypted or collapsed.  In contrast to a 
data extract, access to an information system means that the researcher may directly access an 
MHS information system and create a data set for the research study
Data Extract
Access

10.8  Do you intend to request de-identified data from the MHS in your research study? 
There are different two methods for de-identifying data pursuant to HIPAA:
1) Safe Harbor Method: Removing all of the identifiers listed in Table 1 below, provided that the 
researcher does not have actual knowledge that the remaining data can be used alone or in 
combination with other information to identify the individual who is the subject of the information
2) Statistical Method: An expert, with appropriate knowledge of and experience with generally 
accepted statistical and scientific principles and methods for rendering information not 
individually identifiable, determines that the data is not individually identifiable
  Yes  
  No
10.9  Indicate the MHS information system(s) from which you will seek to obtain data
If you do not know which system(s) contains the data elements you need, refer to the Guide for 
DoD Researchers on Using MHS Data or request guidance from an MHS data expert at: DHA.
.
PrivacyBoard@mail.mil
 
Below is a list of commonly used MHS systems. If the system from which you seek to obtain 
data is not listed below, list the name of the system in the “Other MHS Systems” category below
PHI Systems:
MHS Information System
Requesting Data
:
AHLTA
:
Yes
:
CHCS
:
Yes
:
ESSENTRIS
:
Yes
PII-Only Systems:
MHS Information System
Requesting Data
No results found
De-Identified Data & Other Systems:
Information System
Requesting Data
Other MHS System (May include PII and
/or PHI)
List other system here:
MHS Genesis
:
Yes
10.10  Do you intend to merge or otherwise associate the requested data with data from any sources 
outside of the MHS, including other DoD systems that are not part of the MHS?
Yes, will merge data 
No, will not merge data 
10.11  Indicate the data elements about research participants or relatives, employers, or household 
members of the research participants that you will request from MHS hard copies or from MHS 
information systems. 
If you will merge data, also indicate non-MHS data elements about research participants or 

relatives, employers, or household members of the research participants that you will have access 
to in any form or medium.
Direct and 
Indirect 
Identifiable Data 
Elements
DHA Hard 
Copies
DHA Data 
Elements 
to be 
Accessed
DHA Data 
Elements 
Verbal
Extracted 
DHA 
Digital 
Data
Downloaded 
DHA Digital 
Data
Non-DHA 
Hard 
Copies or 
Digital
1.  Names 
2.  Postal 
address with 
only town, 
city, state, 
and zip code 
3.  Postal 
address with 
all geographic 
subdivisions 
smaller than 
state, 
including 
street 
address, city, 
county, 
precinct, zip 
code and their 
equivalent 
geocodes, 
except for the 
initial three 
digits of a zip 
code if, 
according to 
the current 
publicly 
available data 
from the 
Bureau of 
Census: 1) 
the 
geographic 
unit formed by 
combining all 
zip codes with 
the same 
three initial 
digits contains 
more than 
20,000 
people; and 2) 
the initial 
three digits of 
a zip code 
from all such 
geographic 
units 
containing 
20,000 or 
fewer people 
is changed to 
000

4.  Dates 
including all 
elements 
(except year) 
directly 
related to an 
individual, 
including 
birthdate, 
admission 
date, 
discharge 
date, and date 
of death 
5.  Ages over 
89 and all 
elements of 
dates 
(including 
year) 
indicative of 
such age, 
unless you will 
only request a 
single 
category of 
“age 90 or 
older” 
6. Telephone 
Numbers
7.  Fax 
Numbers 
8.  Email 
Addresses
9.    Social 
Security 
Numbers
10.   Medical 
Record 
Numbers 
(MRN) 
(including 
record ID)
11.   Health 
Plan 
Beneficiary 
Numbers  
(including 
DEERS ID, 
Electronic 

Data 
Interchange 
Personal 
Identifier 
(EDIPI) or 
Number 
(EDIPN))
12.   Account 
Numbers 
13.   Certificate
/License 
Numbers 
14.   Vehicle 
identifiers and 
serial 
numbers, 
including 
license plate 
numbers 
15.   Device 
identifiers and 
serial numbers 
16.   Web 
Universal 
Resource 
Locators 
(URLs) 
17.   Internet 
Protocol (IP) 
address 
numbers 
18.   Biometric 
identifiers, 
including 
finger and 
voice prints 
19.   Full-face 
photographic 
images and 
any 
comparable 
images
20.   Any 
other unique 
identifying 

number, 
characteristic, 
or code 
(including non-
military 
provider IDs)
21.   Free Text 
Fields
If you are obtaining SSNs, provide a justification as to why and explain why a substitute cannot 
be used.
Due to guidelines stated within DoDI 1000.30, Reduction of SSN Use within DoD, the reduction 
or elimination of SSN usage must occur wherever possible. If SSNs are required to complete the 
project, the PI must provide a justification and explanation as to why a substitution cannot be 
used.
For example:
• If alternatives to SSN (e.g., EDIPNs or pseudo person IDs) are sufficient in other instances, 
will those alternatives to SSN usage be sufficient to respond to Congressional inquiries and
/or Senior DoD stakeholders inquiries?
• Are alternatives to SSN used first?
• Are those alternatives to SSN insufficient to combine data from multiple data sources? Is 
the issue that some individuals do not possess alternatives ID numbers and SSN is the only 
way to identify them?
DoD ID numbers and SSNs are used to identify and locate patients in MTFs. For this study, the 
local study team will use both DoD IDs and the last 4 digits of SSNs to identify and track 
participants and their medical records within the individual enrolling hospital only. The full DoD 
ID and the last 4 digits of the participant’s SSN will be recorded on the paper Intake CRF 
(Appendix B) alongside other contact information. The paper Intake CRF will be stored separately 
from all other paper research data alongside the signed Informed Consent Documents and HIPAA 
Authorizations in a locked cabinet inside of a locked room, only accessible by local personnel 
authorized by the PI. With the exception of the paper Intake CRF and the electronic Master List, 
the participant’s SSN will not be recorded on any other paper CRFs, will not be entered into the 
electronic database, and will not be shared with other participating institutions.
a. Will you receive or obtain health information?
Note: If you indicate you are not receiving health information, the answer 
must be consistent with the DHA data source. For a non-health 
information data request, if you are a non-MHS employee or non-MHS 
business associate, you may not access an information system that has 
PHI or LDS. For both MHS and Non-MHS employees and MHS business 
associates, you may 
 include data elements in the above table on: 
NOT
1)  lines 10 or 11, 2) line 21 if the free text field comes from a PHI or LDS 
system, and 3) lines 12, 13, or 18 if the account numbers, certificate and 
license numbers, biometric data, or any other data elements are health 
information created or received by an MHS health care provider, health 
plan, or business associate in relation to the physical or mental health or 
condition of an individual or payment for health care.
Yes, I will receive or obtain health information 
No, I will not receive or obtain health information 
b. If no data elements were checked in the above table, is it possible that the requested DHA 
data is or will be identifiable because of any unique data elements, triangulation, or small cell 
size?  
Data elements were checked in the above table, STOP HERE.

NOTE: A unique data element includes any unique features that alone are not identifiable but 
that could be used to identify an individual within the context of other information, such as any 
type of code (such as diagnosis or procedural), rank of general or admiral, gender, or race. 
Triangulation means using different data elements that when combined can be used to identify 
an individual, such as including the above lists of unique data elements in a data set. 
Determining whether an individual is identifiable through triangulation requires consideration of 
all data elements in combination. Within the military, the use of rank and/or diagnosis code, 
procedural codes, or any other code that changes on a predictable basis, increases the possibility 
of identification. Small cell size means that there is only a small number of eligible individuals 
that satisfy the category description. Department of Defense Manual 6025.13, Medical Quality 
Assurance and Clinical Quality Management in the Military Health System MHS, provides that the 
threshold for de-identifying data within the MHS requires a cell size of three, but also states that 
the de-identification standards must meet the DoD implementation of the HIPAA Privacy Rule. 
Centers for Medicare and Medicaid also gives guidance on small cell size stating that no data cell 
less than 11 may be published or displayed. However, the Office for Civil Rights’ OCR, which is 
the official regulatory office for the HIPAA Privacy Rule, provides that OCR does not designate a 
universal value for small cell size in accordance with the de-identification standard; instead, the 
cell size should be set at a level that is appropriate to mitigate risk of identification by the 
anticipated recipient of the data set. This means that a cell size of 3 or 11 may not meet the 
HIPAA Privacy Rule requirements if the cell size level does not appropriately mitigate risk of 
identification by the anticipated recipient of the data set.
Note: If dates are altered as a means of de-identifying the data, diagnosis and 
procedural codes need to be rolled-up or collapsed. If dates are provided “as time 
between events,” the roll-up is not necessary.   
Yes, the DHA data will become identifiable
No, the DHA data will not become identifiable
10.12  Do you believe it is possible for the MHS data to become identifiable because of triangulation, a 
small cell size, or any unique data element(s)?
Triangulation means using different data elements that are not themselves identifiable but that 
when combined can be used to identify an individual. For example, triangulation would use rank 
and race together to determine the identity of an individual with a particular health condition.
 
Small cell size means that there is only a small number of eligible individuals that satisfy the 
category description. Guidance for acceptable cell size is available from the Centers for Medicare 
and Medicaid Services. For example, the rank category of four star generals with a particular 
diagnosis may be less than 30, so the rank category may need to be expanded to include lower 
ranks.
 
A unique data element includes any unique features that are not explicitly enumerated in the 
categories of data in rows 1 – 20 of the table above (in Section 10.10), but that could be used to 
identify an individual. Unique data elements include characteristics that are not themselves 
identifying, such as the rank of general or admiral, or a race or gender, but within the context of 
other information could be identifiable.
Yes, I believe there is a reasonable possibility the MHS data will become identifiable 
No, I believe there is no reasonable possibility the MHS data will become identifiable 
10.13  Have you completed and uploaded an appropriate HIPAA document ( i.e. HIPAA Authorization will 
be obtained or Waiver/alteration of HIPAA Authorization is being requested)?
Yes 
No 
N/A 
If yes, please check which one.
HIPAA Authorization
HIPAA Waiver (Full or Partial)
Other (please provide copies when uploading Other Study Documents)

10.14  Managing Data (Data Management and/or Sharing Plan) and/or Human Biological Specimens for 
this Study:
Include in this section the plan for acquiring data (both electronic and hard copy), access during 
the study, data/specimen storage and length of time stored, shipment/transmission, and the 
plan for storage and final disposition at the conclusion of the study. Describe any data 
agreements in place for accessing data within and/or outside of your institution (e.g., Data 
Sharing Agreement, Data Use Agreement, Business Agreements, etc.)
Data Capture Methods:
The local study team will collect study data directly from the study participant, from their 
attending provider or, where applicable, from the participant’s medical record (i.e., relevant 
medical and treatment history (retrospective collection) and relevant clinical notes throughout 
duration of study participation (prospective collection) and record it on paper CRFs (see 
Appendixes A-F).
 
If for any reason a research participant is unable to physically come in for an in-person follow up 
visit, we will obtain as much data remotely (electronically, via phone, via mail or via medical 
record review) as possible.
 
The completed paper CRFs will serve as source documents for this study. Participants may also 
enter study data directly into REDCap using a coded survey link. In these cases, the completed 
eCRFs will be printed and stored in the participant's research files and serve as source 
documents. Other source documents include relevant laboratory results (i.e., hCG urine test) and 
relevant clinical notes which will be printed, redacted, and stored in the participant’s research file.
 
 
Electronic Data Entry:
Following each research visit, a local study team member will review the paper CRFs for accuracy 
and completeness and then enter the collected non-personally identifiable data from the paper 
CRFs into REDCap, an encrypted, access controlled, password protected electronic data capture 
and management system housed on a Department of Defense (DoD) server and maintained by 
the Uniformed Services University Information Technology (USU IT). No PII will be entered into 
REDCap. The information collected on the Intake CRF will not be entered into REDCap.
 
Please see Appendix J for additional information on REDCap.
 
 
Data Storage & Access:
With the exception of the Informed Consent Form, HIPAA Authorization, Intake CRF (Appendix B) 
and electronic Master List, all research data (both paper and electronic) will be identified using a 
unique study ID only, and not by the participant’s name, date of birth, social security number, 
DoD ID, or other protected identifier.
 
Paper research forms and source documents will be stored in a locked cabinet inside of a locked 
room, accessible only by local research staff designated and authorized by the Principal 
Investigator. The paper Intake CRF which records participant contact information will be stored 
separately from the coded paper research forms alongside the Informed Consent Forms and 
HIPAA Authorizations in a locked cabinet inside of a locked room, accessible only by authorized 
local research staff.
 
The coded electronic research data for this study will be stored in REDCap, an encrypted, access 
controlled, password protected electronic data capture and management system housed on a 
Department of Defense (DoD) server and maintained by the Uniformed Services University 
Information Technology (USU IT). No PII will be entered into REDCap.
 
This coded electronic research data will only be accessible by local research staff designated and 
authorized by the Principal Investigator and authorized staff from Musculoskeletal Injury 
Rehabilitation Research for Operational Readiness (MIRROR), formerly known as the 
Collaboratory for Musculoskeletal Injury Rehabilitation Research (CMIRR), which is based out of 
the Department of Physical Medicine & Rehabilitation at the Uniformed Services University (USU) 
and is serving as the data coordinating center for this research study. Staff from MIRROR/USU 
will not have access to the paper research records or any identifiable research data to include the 
Master List, the informed consent forms/HIPAA authorizations, or any other form of participant 
PHI/PII. Access to the electronic coded research data will be governed strictly on an individual-
by-individual basis within REDCap. Individual data access as well as privileges will be clearly 
delegated, audited, and monitored by MIRROR/USU.
 

There will be appropriate data sharing agreements in place between the data owner(s) (e.g., 
DHA for AHLTA) and the Walter Reed National Military Medical Center (WRNMMC), as well as the 
Uniformed Services University (USU) and all appropriate parties involved in the handling of data 
(e.g., The Geneva Foundation).
No recruitment will occur at Womack Army Medical Center (WAMC). The WAMC team will only 
conduct coded data analysis. Authorized WAMC study team members will analyze the coded gait 
data points obtained from each of the recruiting sites at the baseline, 8-week, 3-, 6-, and 12-
month follow up time points. This coded gait data will be stored in a USU-hosted password 
protected cloud based storage service accessible only by authorized study team members. The 
WAMC team will analyze the gait data using MATLAB and the results will be stored in the same 
USU-hosted password protected cloud based storage service. No identifiable information will be 
used or transferred during this process. The WAMC team will not have access to the coded 
master lists from the participating sites at any time.
 
Authorized members of the local study team will create and maintain a separate electronic 
master list which matches unique study IDs with participant names. The electronic master list 
will be stored separately from the coded electronic research data in a secure, password protected 
Excel spreadsheet on a computer and network that requires CAC access and will only be 
accessible by local research staff.
 
All research data and forms (both paper and electronic) will only be accessible by authorized 
study staff, the local IRB, and applicable governmental agencies as part of their duties and in 
accordance with federal law. These duties include making sure that research participants are 
protected.
 
Informed Consent Forms and HIPAA Authorizations will be maintained for a period of 6 years 
following study closure and then securely shredded. Paper research forms will be maintained for 
a period of 5 years following study closure and then securely shredded. The master list 
connecting unique study ID to participant identifiers will be destroyed within one year of study 
closure. Once the master list is permanently destroyed, the collected study data will be 
considered de-identified. The electronic de-identified research data will be maintained indefinitely 
as described in protocol section 10.15.
Is this a data repository?
  Yes  
  No
10.15  Managing Data (Data Management and/or Sharing Plan) and/or Human Biological Specimens for 
Future Research:
If the study involves collecting, storing, or banking human specimens, data, or documents 
(either by the Investigator or through an established repository) for FUTURE research, address. 
How the specimens/data will be used, where and how data/specimens will be stored (including 
shipping procedures, storage plan, etc.), whether and how consent will be obtained, procedures 
that will fulfill subjects’ request as stated in the consent, whether subjects may withdraw their 
data/specimens from storage, whether and how subjects may be recontacted for future research 
and given the option to decline, whether there will be genetic testing on the specimens, who will 
have access to the data/specimens, and the linkage, the length of time that data/specimens will 
be stored and conditions under which data/specimens will be destroyed.
Long Term Data Storage & Access:
The de-identified electronic dataset will be maintained by MIRROR/USU indefinitely or as long it 
is practicable to maintain.
                         
De-identified electronic research data will be securely transmitted from local study teams to the 
MIRROR/USU via REDCap or the DoD SAFE application (or other comparable safe data sharing 
system implemented by the local site and/or the US Army/DHA). REDCap utilizes Secure Sockets 
Layer (SSL) in addition to other safeguards on its web server to maintain secure communication 
with end-users (see Appendix J). DoD SAFE uses a TLS (Transport Layer Security) protocol when 
files are uploaded and downloaded.
 
Once received, the electronic de-identified research data will be stored within an encrypted, 
access controlled, password protected electronic data capture and management system housed 
on a Department of Defense (DoD)-compliant server.
 

Access to the de-identified research data will be governed strictly on an individual-by-individual 
basis within the secure electronic data capture and management system. Individual data access 
as well as privileges will be clearly delegated, audited, and monitored by MIRROR/USU.
 
There will be appropriate data sharing agreements in place between the data owner(s) (e.g., 
DHA for AHLTA) and the Walter Reed National Military Medical Center (WRNMMC), as well as the 
Uniformed Services University (USU) and all appropriate parties involved in the handling of data 
(e.g., The Geneva Foundation).
 
 
Consent for Future Use:
The Informed Consent Form for this research study states that de-identified research data will be 
shared with the MIRROR/USU and maintained indefinitely for possible use in future research. By 
consenting for this research study, participants agree to allow us to maintain their de-
identified research data indefinitely for possible use in future research.
 
 
Data Withdrawal:
Because there will be no way to link an individual's identity to their specific research data, 
participants will not be able to withdraw their de-identified research data from storage.
Is this a data repository?
 Yes  
 No
If Yes, provide the name of the Repository
USU OCIO REDCap
Who will have access to the Repository?
MIRROR core team, investigators, study team members, as applicable.
Access to the de-identified research data will be governed strictly on an individual-by-individual
basis within the secure electronic data capture and management system. Individual data access 
as well as privileges will be clearly delegated, audited, and monitored by MIRROR/USU.
What data type will be stored in the Repository?
Protected Health Information
Limited Data Set
De-identified Data
11.0
 
Statistical/Data Analysis Plan
11.1  Data Analysis Plan and Statistical Considerations:
List the statistical methods to be used to address the primary and secondary objectives, specific 
aims, and/or research hypotheses. Explain how missing data and outliers will be handled in the 
analysis. The analysis plan should be consistent with the study objectives. Include any subgroup 
analyses (e.g., gender or age group). Specify statistical methods and variables for each analysis. 
Describe how confounding variables will be controlled in the data analysis.
To maximize efficiency of the factorial study design, the clinical effectiveness of each treatment 
will be measured simultaneously using logistic regression analysis. Specifically, the regression 
model will include three binary independent variables, one for each treatment group, with group 
1 (HBGR + NS) as the reference treatment. In this way, the group 3 coefficient (BoNT-A + 
HBGR) will correspond to the effect estimate of group 3 vs 1 (specific aim 1), the group 2 
coefficient (SGR + NS) will correspond to the effect estimate of group 2 vs 1 (specific aim 2), 
and the group 4 coefficient (BoNT-A + SGR) will correspond to the effect estimate of group 4 vs 
either 2 or 3 (specific aim 3).
 
Missing Data and Outliers:

In keeping with statistical analysis standards in randomized controlled trials, data will be 
analyzed using complete-case, intention-to-treat (ITT) analysis—that is, we will analyze all study 
subjects who received treatment assignment and for whom we obtained sufficient outcome data.
 
Confounding Variables:
Clinical effectiveness will be studied using a factorial randomized design. Such designs are widely 
recognized to yield unbiased estimates by removing confounding between treatment and 
outcome when sufficiently powered.
 
11.2  Sample Size:
We are requesting to enroll up to 620 participants (155 per treatment group) across all 
performance sites in order to evaluate a final sample of 480 subjects (120 per treatment group) 
across all performance sites. Up to 125 of these participants will be enrolled at WRNMMC. Up to 
125 of these participants will be enrolled at each of the other performance sites.
11.3  Total number of subjects requested (including records and specimens):
620
11.4  If you are recruiting by study arm, please identify the arms of the study and how many subjects will 
be enrolled in each arm
Across all performance sites, up to 620 participants will be uniformly randomized across the four 
treatment groups: Up to 155 participants in Group 1 - Home Based Gait Retraining (HBGR) and 
Normal Saline (placebo), up to 155 participants in Group 2 - Supervised Gait Retraining (SGR) 
and Normal Saline (placebo), up to 155 participants in Group 3 - BoNT-A + HBGR, and up to 155 
participants in Group 4 - BoNT-A + SGR.
11.5  Please provide a justification for your sample size
Using a 2x2 factorial design and assuming success rates for passing the US Army 2-mile run test 
among control (saline/home based gait retraining), botulinumtoxin A (BoNT-A) injection, 
supervised gait retraining (SGR), and combined therapy (BoNT-A + SGR), respectively, are 15%, 
80%, 50%, and 85%, we estimate that enrolling a grand total of at least 60 patients would yield 
80% power to detect the effect of BoNT-A, enrolling a grand total of at least 120 patients would 
yield 80% power to detect the effect of SGR, and enrolling a grand total of at least 380 patients 
would yield 80% power to demonstrate the benefit of combined therapy (BoNT-A + SGR) vs. 
either therapy in isolation. If we can obtain complete data on more than 380 participants, then it 
will strengthen our power. We hope to have a final sample of 480 participants. Assuming roughly 
20% attrition and accounting for screen failures, we are requesting to enroll up to 620 
participants across all performance sites.
 
Power was estimated using Monte Carlo simulations assuming uniform randomization among four 
groups in the 2x2 factorial design, while testing for statistical significance simultaneously among 
the four groups of control, BoNT-A, SGR, and combined therapy using a generalized linear 
model. Statistical significance was indicated if the corresponding p< 0.05 per generalized linear 
model.
12.0
 
Participant Information
12.1  Subject Population:
Active duty service members aged 18-60 (inclusive) diagnosed with Chronic Exertional 
Compartment Syndrome (CECS) of their anterior and/or lateral compartments in their lower leg.
12.2  Age Range:

Check all the boxes that apply. if the age range of potential subjects (specimens, records) does 
not match the range(s) selected, please specify in the text box.
0-17
18-24
25-34
35-44
45-54
55-64
65-74
75+
18-60 (inclusive)
12.3  Gender:
Male
Female
Other
12.4  Special categories, check all that apply
Minors /Children
Students
Employees - Civilian
Employees - Contractor
Resident/trainee
Cadets /Midshipmen
Active Duty Military Personnel
Wounded Warriors
Economically Disadvantaged Persons
Educationally Disadvantaged Persons
Physically Challenged (Physical challenges include visual and/or auditory impairment)
Persons with Impaired Decisional Capacity
Prisoners
Pregnant Women, Fetuses, and Neonates
Non-English Speakers
International Research involving Foreign Nationals - Headquarters Review is necessary
You must also consider the requirements of DoDI 3216.02, Enclosure 3, paragraph 7.e.
12.5  Inclusion Criteria:
Order 
Number
Criteria
1 
Active duty service member age 18-60 (inclusive).
 
2 
Fluent in speaking and reading English
 
3 
Unable to run 2 miles without producing pain and/or symptoms, including aching, 
burning, numbness, tingling, and/or weakness in the affected limb.
 
4 
Has difficulty completing the running portion of their service specific physical 
training due to pain and/or symptoms in the affected limb.

1.  
2.  
3.  
 
5 
Meets clinical diagnostic criteria for CECS of the anterior and/or lateral 
compartment(s) in the lower leg, per clinical exams (e.g., physical examination, 
intramuscular compartment pressure test (IMCP test needle testing), lower leg 
MRI, etc.).
 
12.6  Exclusion Criteria:
Order 
Number
Criteria
1 
Prior Botulinum toxin injection(s) in the lower leg compartments of the affected 
limb.
 
2 
Prior compartment release of the affected limb.
 
3 
Recent (within the last 6 months) lower limb injury that needed medical 
intervention
 
4 
Undergone formal gait retraining within the last 6 months.
 
5 
Allergic to BoNT-A  (trade names BOTOX® or Xeomin®)
 
6 
Pregnant or breastfeeding.
 
7 
Medical history and/or clinical exams (e.g., physical examination, intramuscular 
compartment pressure test, lower limb MRI, amyotrophic lateral sclerosis (ALS), 
myasthenia gravis, Lambert-Eaton Syndrome, or any neuromuscular junction 
disorders) indicate other more likely causes of leg pain and/or symptoms.
 
8 
Ankle Brachial Index (ABI) blood pressure ≤ 0.90 or or >/= to 1.4 within the last 
6 months. Post Exertion ABI is >0.2 or limb pressure decreases > 30 mmHg.
 
13.0
 
Recruitment and Consent
13.1  Please describe the recruitment process, including how subjects will be identified and selected for 
the study.
Potential participants will be identified via three methods: 
Under the HIPAA Preparatory to Research Provision, local study clinicians will review 
medical records of patients coming in to the Physical Medicine & Rehabilitation (PM&R), 
Orthopaedics, Physical Therapy (PT), and Sports Medicine clinics for suspected Chronic 
Exertional Compartment Syndrome (CECS) to identify prospective research participants 
for the purposes of seeking their authorization to participate/use their protected health 
information for this research study, 
If a local healthcare provider identifies a potential participant seen in the PM&R, 
Orthopaedics, PT or Sports Medicine clinic for suspected CECS as part of regular clinical 
care, they may refer them to a member of the local research team (who will be located 
within the clinic or available via phone) for further discussion, and 
Study flyers will be posted within the departments of PM&R, Orthopaedics, PT, and Sports 
Medicine.
If a potential participant expresses interest in learning more about the research study, a member 
of the research staff will briefly introduce the study, express the voluntary nature of 
participation, assess interest in participating, and screen the potential participant for initial 
eligibility in close collaboration with the patient’s attending provider. Initial eligibility (see Section 

1.  
2.  
3.  
12.5 Inclusion Criteria #1-5 & Section 12.6 Exclusion Criteria #1-8) will be confirmed using an 
Inclusion/Exclusion CRF (Appendix A). This Inclusion/Exclusion CRF does not record any PII/PHI.
 
If the potential participant meets initial eligibility criteria as determined by the Inclusion
/Exclusion CRF and expresses interest in participating, an authorized study team member will 
initiate the formal consent discussion and, if applicable, obtain informed consent.
 
If a potential participant would like additional time to review the consent form, study procedures, 
risks and benefits, etc. they will be provided with a consent form and study brochure to take 
home and, if applicable, they may return to clinic at a later date to have any and all remaining 
questions answered and to finish the consent process.
 
Following completion of informed consent, the results of the Inclusion/Exclusion CRF will be 
entered into REDCap, an encrypted, access controlled, password protected electronic data 
capture and management system housed on a DoD server and maintained by the Uniformed 
Services University Information Technology (USU IT), by an authorized local study team member 
and a unique study ID will be automatically generated. This coded study ID will be used on all 
research data collection forms in place of the participant’s name, social security number, 
Department of Defense (DoD) ID, or other protected identifier. No PII will be entered into 
REDCap. Please see Appendix J for additional information on REDCap.
 
In order to document screen failures and refusals, the results of the Inclusion/Exclusion CRF will 
be entered into REDCap even if a patient doesn’t consent to participate in the study. The 
Inclusion/Exclusion CRF does not record any PHI/PII.
 
In order to adhere to WRNMMC’s recruitment policy, research activities (e.g., study introduction, 
consent conversations, etc.) will take place after the clinic visit has ended. Recruitment and 
consent conversations will take place in a private setting (e.g., closed clinic room, investigator’s 
office, etc.) to minimize the potential opportunity to be overheard or inadvertently witnessed.
13.2  Compensation for Participation:
Participants will not be financially compensated for their participation in this research study.
13.3  Please describe the pre-screening process. If no pre-screening, enter Not Applicable in the text editor
This study has two screening phases: 1) pre-screening based on initial inclusion/exclusion 
criteria (before informed consent) and 2) a formal screening phase to determine eligibility for 
randomization to intervention arm (after informed consent).
 
 
Pre-Screening (before consent):
Potential participants will be identified via three methods: 
Under the HIPAA Preparatory to Research Provision, local study clinicians will review 
medical records of patients coming in to the Physical Medicine & Rehabilitation (PM&R), 
Orthopaedics, Physical Therapy (PT), and Sports Medicine clinics for suspected Chronic 
Exertional Compartment Syndrome (CECS) to identify prospective research participants 
for the purposes of seeking their authorization to participate/use their protected health 
information for this research study, 
If a local healthcare provider identifies a potential participant seen in the PM&R, 
Orthopaedics, PT or Sports Medicine clinic for suspected CECS as part of regular clinical 
care, they may refer them to a member of the local research team (who will be located 
within the clinic or available via phone) for further discussion, and 
Study flyers will be posted within the departments of PM&R, Orthopaedics, PT, and Sports 
Medicine.
If the potential participant meets initial eligibility criteria as determined by the Inclusion
/Exclusion CRF and expresses interest in participating, an authorized study team member will 
initiate the formal consent discussion and, if applicable, obtain informed consent. In order to 
adhere to WRNMMC’s recruitment policy, research activities (e.g., study introduction, consent 
conversations, etc.) will take place after the clinic visit has ended.
 
 
Formal Screening (post-consent):
As part of standard of care, other concomitant causes of leg pain will be ruled out with a physical 
examination, relevant medical history review and lower leg magnetic resonance imaging (MRI). 

1.  
2.  
 
As part of the formal screening procedures, the participant’s CECS diagnosis will be confirmed via 
an intramuscular compartment pressure test. To do this, the participant will have an 
intramuscular compartment pressure (IMCP) test done in one area at each of their anterior and 
lateral leg compartments at rest and post exerting on a treadmill, stairs, marching, or any type 
of exertional activity that increases the participant's leg pain and/or symptoms. Once they have 
their leg pain or symptoms reproduced while running or completing the offending exertional 
activity, they will then have repeat IMCP test done at 1 minute post exertion. The IMCP test is 
currently the diagnostic standard for CECS. The use of ultrasound imaging will be used to identify and mark the 
 If a participant has had any of 
region of interest of the anterior and lateral leg compartments that will be tested.
these procedures performed within the 6 months prior to study enrollment, the research team 
will review those results and not repeat procedures if the testing was adequate and acceptable 
for clinical standards.
 
Also as part of the formal screening procedures, participants will have their ankle brachial index 
(ABI) blood pressure taken on each side at their ankle, foot, and arm separately using a blood 
pressure cuff and Doppler instrument. Blood pressures will be taken at rest, then 1 minute within 
completing approximately 50 repetitions of bilateral heel raises. At rest, an ABI measurement of 
less than or equal to 0.90 or greater than or equal to 1.4 on either side will be excluded from the 
study and resume normal care with their referring provider. If their ABI post exertion decreases 
in value greater than 0.2 compared to baseline, limb pressures are decreased greater than 30 
mmHg compared to baseline, or they meet the previous exclusion baseline criteria for their ABI, 
then the participant will be excluded from the study and resume normal care with their referring 
provider. 
 
Any female participant will also be required to have a urine hCG test performed prior to study 
injection. If the urine hCG indicates the participant is pregnant, per stated inclusion/exclusion 
criteria, they will be formally withdrawn from the study and will resume normal care with their 
referring provider.
 
Participants will be assigned to one of four treatment groups:
Group 1 - Home Based Gait Retraining (HBGR) and Normal Saline (placebo)
Group 2 - Supervised Gait Retraining (SGR) and Normal Saline (placebo)
Group 3 - BoNT-A + HBGR
Group 4 - BoNT-A + SGR
13.4  Consent Process:   Revised Common Rule, Section 219.116:  General requirements for informed 
consent, whether written or oral, are set forth in this paragraph and apply to consent obtained in 
accordance with the requirements set forth in paragraphs (b) through (d) of this section. Broad 
consent may be obtained in lieu of informed consent obtained in accordance with paragraphs (b) and 
(c) of this section only with respect to the storage, maintenance, and secondary research uses of 
identifiable private information and identifiable biospecimens.
Are you requesting a waiver or alteration of informed consent?
  Yes  
  No
Please explain the consent process:
Consent will be obtained in accordance with principles of Belmont Report and Common Rule 
guidelines. The consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation. A copy of the signed consent form will be 
given to the participant and the original will be stored in a locked cabinet inside of a locked office 
locally at each performance site. Documentation of consent will be recorded in the participant’s 
medical record. No Legally Authorized Representatives will be utilized.
 
Potential participants will be identified via three methods: 
Under the HIPAA Preparatory to Research Provision, local study clinicians will review 
medical records of patients coming in to the Physical Medicine & Rehabilitation (PM&R), 
Orthopaedics, Physical Therapy (PT), and Sports Medicine clinics for suspected Chronic 
Exertional Compartment Syndrome (CECS) to identify prospective research participants 
for the purposes of seeking their authorization to participate/use their protected health 
information for this research study, 
If a local healthcare provider identifies a potential participant seen in the PM&R, 
Orthopaedics, PT or Sports Medicine clinic for suspected CECS as part of regular clinical 

3.  
care, they may refer them to a member of the local research team (who will be located 
within the clinic or available via phone) for further discussion, and 
Study flyers will be posted within the departments of PM&R, Orthopaedics, PT, and Sports 
Medicine.
If a potential participant expresses interest in learning more about the research study, a member 
of the research staff will briefly introduce the study, express the voluntary nature of 
participation, assess interest in participating, and screen the potential participant for initial 
eligibility in close collaboration with the patient’s attending provider. Initial eligibility (see Section 
12.5 Inclusion Criteria #1-5 & Section 12.6 Exclusion Criteria #1-8) will be confirmed using an 
Inclusion/Exclusion CRF (Appendix A). This Inclusion/Exclusion CRF does not record any PII/PHI.
 
If the potential participant meets initial eligibility criteria as determined by the Inclusion
/Exclusion CRF and expresses interest in participating, an authorized study team member will 
initiate the formal consent discussion and, if applicable, obtain informed consent.
 
Formal consent, as represented by the act of signing a dated, IRB approved consent statement 
for the study will only occur after confirming initial eligibility using the Inclusion/Exclusion CRF, a 
thorough review of what is involved in the study, and after all questions have been answered. 
Potential participants will be provided information regarding Botulinum toxin injections, gait 
retraining and surgical fasciotomy. If desired, potential participants will be allowed to discuss the 
option of fasciotomy with a surgeon prior to deciding to participate in the study. Potential 
participants will also be reminded of the expectations placed on them if they enroll, including the 
blinded randomization and formal screening processes and the study follow up schedule.
 
The potential participant will be given a copy of the informed consent to read before, during, and
/or after discussion of the informed consent with the Research Coordinator, Principal 
Investigator, Associate Investigator, or other authorized study team member. Sufficient time will 
be given to the potential participant to understand the study purpose, study procedures and time 
commitments, potential risks and benefits, and the types of health information that will be 
accessed, collected, and used by the research team if they agree to participate in the study. 
Questions can be raised by the potential participant at any time during the consent discussion 
and also at any time during the conduct of the study. The potential participant will be instructed 
that their participation is completely voluntary and that they may withdraw from the study at 
any time without penalty. Their decision to participate or to not participate, or to withdraw from 
the study after consent, will not affect their access to health care that they are otherwise entitled 
to and it will not affect their military position.
 
Potential participants will also be given a Participation Timeline Handout (Appendix P) on the 
time commitments for each of the study arms that the participant could be randomized into. This 
handout will be explained to the participant to aid them in understanding their time commitment 
to the study. Once the participant has all of their questions about the time commitments 
satisfied, they will initial a line on the informed consent form confirming that they received this 
information.
 
The authorized study team member present during the consent conversation will confirm that the 
potential participant has no additional questions before deciding to provide consent. If a potential 
participant would like additional time to review the consent form, study procedures, risks and 
benefits, etc. they will be provided with a copy of a blank consent form and study brochure to 
take home and, if applicable, they may return to clinic at a later date to have any and all 
remaining questions answered and to finish the consent process.
 
In order to adhere to WRNMMC’s recruitment policy, research activities (e.g., study introduction, 
consent conversations, etc.) will take place after the clinic visit has ended. Recruitment and 
consent conversations will take place in a private setting (e.g., closed clinic room, investigator’s 
office, etc.) to minimize the potential opportunity to be overheard or inadvertently witnessed.
 
Every effort will be made to eliminate the perception of authority, which is a particularly 
important consideration when recruiting Active Duty study participants. When applicable, the 
study investigators will be in scrubs or civilian clothes instead of uniform and will introduce 
themselves as doctor rather than their military rank. Some potential participants may be patients 
of the study PI or AI. In these cases, the consent conversation will be initiated by non-physician 
study staff to prevent any misconception of coercion or undue influence.
In the event a reconsent is required, participants will be reconsented the next time they report to 
clinic for a research visit. For participants who have had a change of duty station and will not be 
returning to clinic in person, a letter may be sent to the participant through postal mail and/or 
electronic mail.  

13.5  DoDI 3216.02 requires an ombudsman to be present during recruitment briefings when research 
involves greater than minimal risk and recruitment of Service members occurs in a group setting. If 
applicable, you may nominate an individual to serve as the ombudsman.
N/A 
Propose ombudsman 
13.6  Withdrawal from Study Participation:
Explain the process for withdrawal and specify whether or not the subjects will be given the 
opportunity to withdraw their data their data/specimens in the event they wish to withdraw from 
the study
Participant Withdrawal:
Participants may withdraw from the study at any time without penalty. Participants will be 
informed that withdrawal will not affect their access to health care that they are otherwise 
entitled to and it will not affect their military position.
 
If a participant withdraws from the study, we may retain and analyze all coded data collected up 
to the time of withdrawal if the data is necessary to maintain the integrity of the 
study.  However, no further data will be collected after the date of withdrawal.
 
Participants may contact the study research coordinator or Principal Investigator to initiate the 
formal withdrawal process. Participants will be advised to follow-up with their personal provider if 
they chose to withdraw.
 
 
Withdrawal Without Participant Consent:
Participants will be removed from the study if they fail to meet the formal screening criteria 
outlined in protocol section 13.3.
 
Additionally, a participant may be withdrawn from the study without their consent if remaining in 
the study might be dangerous or harmful to them. Participation may also be stopped if the 
military mission requires it, if they lose their right to receive medical care at a military hospital, if 
the study is canceled, if they fail to adhere to the protocol and/or therapy plan, or if they display 
inappropriate behavior towards study personnel.
 
 
The reason for any withdrawal/removal will be documented (see Appendix S).
14.0
 
Risks and Benefits
14.1  
Risks of Harm:
Identify all research-related risks of harm to which the subject will be exposed for each research 
procedure or intervention as a result of participation in this study.  Consider the risks of breach 
of confidentiality, psychological, legal, social, and economic risks as well as physical risks.  Do 
not describe risks from standard care procedures; only describe risks from procedures done for 
research purposes
With the exception of the injection itself, all of the study activities are regularly performed in a 
standard clinical environment as procedures and treatment for CECS of the anterior and/or 
lateral compartments in the lower leg, therefore the potential risks directly associated with study-
specific activities and procedures are minimal. However, there are standard risks common with 
some of these procedures.
 

The potential side effects of Botulinum toxin A injections include: rare minor side effects of 
bleeding, pain, soreness, infection, transient general muscle weakness and muscular atrophy, flu-
like symptoms, and even rarer transient breathing and swallowing difficulties which has the 
potential to cause death if not appropriately treated.
 
The potential side effects of saline injections include: pain, soreness, bleeding, and infection 
which are all very rare.
 
The potential side effects of IMCP needle insertion for intramuscular compartment pressure 
testing include: pain which is minimized with local anesthesia, soreness, minor local bleeding, 
and the rare incidence of infection.
 
The potential risks for balance screening, physical objective measurements, physical 
performance based testing, gait retraining, standard gait analysis, self-paced treadmill test, and 
lower strengthening and stretching exercises include: physical discomfort (increased pain and 
reduced activity level), soreness, possible chronic or acute musculoskeletal injury, overuse or a 
fall.
 
Any time information is collected for a study, there is a small risk of breach of confidentiality.
14.2  
Measures to Minimize Risks of Harm (Precautions, safeguards):
For each research procedure or intervention, describe all measures to minimize and/or eliminate 
risk of harms to subjects and study personnel
All available precautions will be taken to minimize the above-mentioned risks. Standard clinic 
protocols will be followed to reduce the risks of infections and related complications.
 
To minimize the risk to participants, once they receive their injection, a waiting period of at least 
15 minutes will occur at the clinic. This waiting period is to observe for any side effects that may 
occur due to the injection. The participant will also be given an after care injection handout. In 
order to safeguard participants, providers will use ultrasound guidance to identify the locations of 
the anterior and lateral compartments of the lower leg. Expected soreness may occur from the 
study injection procedures which may impact the start of physical therapy visits to 2 weeks post 
injection. Providers will be trained on all study procedures. All of this will provide consistent 
delivery of treatment to the targeted areas and minimize risk to the participant. 
 
In order to protect participant confidentiality, research data will be identified using a unique 
study ID only, and not by participant name, date of birth, social security number, DoD ID, or 
other similar identifier. All available measures allowed by law will be taken by research staff to 
protect participant confidentiality. See protocol section 14.3 for additional information.
 
All participants will be evaluated for adverse events at each follow-up visit and concomitant 
medications and treatments will be documented. All adverse events, regardless of severity, will 
be reported to the Principal Investigator and Research Medical Monitor. The Research Medical 
Monitor will review all adverse events. Adverse events will also be reported according to the 
guidelines stated in Protocol Section 16.
14.3  
Confidentiality Protections (for research records, data and/or specimens):
Describe in detail the plan to maintain confidentiality of the research data, specimens, and 
records throughout the study and at its conclusion (e.g., destruction, long term storage, or 
banking). Explain the plan for securing the data (e.g., use of passwords, encryption, secure 
servers, firewalls, and other appropriate methods). If data will be shared electronically with 
other team members/collaborators outside the institution, describe the method of transmission 
and safeguards to maintain confidentiality. Explain whether this study may collect information 
that State or Federal law requires to be reported to other officials or ethically requires action, e.
g., child or spouse abuse

Upon consenting for the study, participants will be assigned a unique study ID. With the 
exception of the Informed Consent Form, HIPAA Authorization, Intake CRF (Appendix B) and 
electronic Master List, all research data (both paper and electronic) will be identified using this 
unique study ID only, and not by the participant’s name, date of birth, social security number, 
DoD ID, or other protected identifier.
 
At WRNMMC, paper research forms and source documents will be stored in a locked cabinet 
inside of a locked room within the Department of Physical Medicine & Rehabilitation (America 
Bldg. 1st Floor), accessible only by local research staff designated and authorized by the Principal 
Investigator. The paper Intake CRF which records participant contact information will be stored 
separately from the coded paper research forms alongside the Informed Consent Forms and 
HIPAA Authorizations in a locked cabinet inside of a locked room, accessible only by authorized 
local research staff.
 
The coded electronic research data for this study will be stored in REDCap, an encrypted, access 
controlled, password protected electronic data capture and management system housed on a 
Department of Defense (DoD) server and maintained by the Uniformed Services University 
Information Technology (USU IT). No PII will be entered into REDCap. The Intake CRF will not be 
entered into REDCap.
 
Authorized members of the local study team will create and maintain a separate electronic 
Master List which matches the unique study IDs with participant names. The electronic Master 
List will be stored separately from the coded electronic research data in a secure, password-
protected Excel spreadsheet on a computer and network that requires CAC access.
 
The electronic Master List, the Intake CRF, and all research data and forms (both paper and 
electronic) will only be accessible by authorized local study staff, the local DoD research office, 
the WRNMMC Department of Research Programs (DRP), and applicable governmental agencies 
as part of their duties and in accordance with federal law (except as stated in the next 
paragraph). These duties include making sure that research participants are protected.
 
Musculoskeletal Injury Rehabilitation Research for Operational Readiness (MIRROR) which is 
based out of the Department of Physical Medicine & Rehabilitation at the Uniformed Services 
University (USU) is serving as the data coordinating center for this research study. As such, 
authorized staff from MIRROR/USU will have access to the coded research data that is entered 
into REDCap. Staff from MIRROR/USU will not have access to the paper research records or any 
identifiable research data including the electronic Master List, the informed consent forms/HIPAA 
authorizations, information recorded on the Intake CRF, or any other participant PHI/PII. There 
will be appropriate data sharing agreements in place between the data owner(s) (e.g., DHA for 
AHLTA) and Walter Reed National Military Medical Center as well as the Uniformed Services 
University (USU) and all appropriate parties involved in the handling of data (e.g., The Geneva 
Foundation).
 
Any research data shared with an approved agency for review will be linked only to the 
participant’s unique study ID and not with the personal identity of the participant (i.e., name, 
DOB, DoD ID, social security number, address, phone number, etc.). If the research data is used 
in scholarly presentations or journal articles, the investigators will protect the anonymity of 
individual participants and report only aggregate date (e.g., group means) where appropriate. 
Participants will not individually identified in any publication or presentation of research results.
14.4  
Potential Benefits:
Describe any real and potential benefits of the research to the subject and any potential benefits 
to a specific community or society
If the individuals in the research are considered experimental subjects (per 10 USC 980), and 
they cannot provide their own consent, the protocol must describe the intent to directly benefit 
all subjects
We cannot guarantee that a participant will benefit from participation in this study because as 
with any treatment intervention, there is a potential for no relief of CECS symptoms in their 
anterior and/or lateral compartment(s). However, potential benefits include a relief of symptoms, 
avoidance of surgical fasciotomy, and return to full active duty status.
 

Study results may help to improve future rehabilitative care for musculoskeletal injuries in the 
military population and have a positive impact on force readiness.
14.5  
Privacy for Subjects:
Describe the measures to protect subject’s privacy during recruitment, the consent process, and 
all research activities, etc.
Recruitment, consent conversations, and follow up research activities will take place in a private 
setting (e.g., closed clinic room, investigator’s office, etc.) to minimize the potential opportunity 
to be overheard or inadvertently witnessed. Information being collected will be limited to only 
the minimum amount of data necessary to accomplish the proposed research.
14.6  
Incidental or Unexpected Findings:
Describe the plan to address incidental findings and unexpected findings about individuals from 
screening to the end of the subject’s participation in the research. In cases where the subject 
could possibly benefit medically or otherwise from the information, state whether or not the 
results of screening, research participation, research tests, etc., will be shared with subjects or 
their primary care provider. State whether the researcher is obligated or mandated to report 
results to appropriate military or civilian authorities and explain the potential impact on the 
subject
There is the possibility incidental findings could reveal information the participant would not 
otherwise be aware of. In cases where the participant could possibly benefit medically or 
otherwise, the participant will be notified and, when appropriate, so will their primary care 
provider. Research representatives will not share incidental and unexpected findings with anyone 
else unless required by law.
 
Because our participants are active duty military personnel, information regarding the 
participant's health may be required to be reported to appropriate medical or command 
authorities to ensure the proper execution of the military mission, including evaluation of fitness 
for duty.
 
Although unlikely, incidental findings could impact a participant’s future ability to receive health 
or life insurance, as is the case with all medical care. Incidental findings may also make the 
participant feel anxious.
15.0
 
Study Monitoring
15.1  Your study requires either Data and Safety Monitoring Plan (DSMP) or a Data and Safety Monitoring 
Board (DSMB).
DSMP 
DSMB 
Both 
Not Applicable 
A DSMP should describe the plan to monitor the data to verify that the data are collected and 
analyzed as specified in the protocol. Include who will conduct the monitoring, what will be 
monitored, and the frequency of monitoring. It should also include the plan to ensure the safety 
of subjects
Participant Safety Monitoring Plan:

1.  
2.  
3.  
4.  
5.  
To ensure the safety of participants the PI and Research Medical Monitor will:
Monitor the conduct of the protocol per the approved study plan and ensure protection of 
human participants. This may involve periodic review of medical records and/or research 
files of enrolled participants.
Review and keep abreast of adverse events and protocol deviations that occur during the 
research.
The PI and Research Medical Monitor will review and sign adverse event logs/reports, 
protocol deviation logs/reports, and continuing reviews/annual progress reports.
If there is concern about the welfare of enrolled participants, the PI and/or Research 
Medical Monitor will stop the research study in progress, remove individual participants 
from a study, and take whatever steps necessary to protect the safety and well-being of 
research participants until the IRB can assess the situation.
Ensure that all study team members keep current required human subjects research 
trainings which require renewal every 3 years.
If an adverse event or protocol deviation occurs, it will be evaluated by the Principal Investigator 
and Research Medical Monitor (if applicable) and appropriate actions will be taken as outlined in 
Section 16.0 Reportable Events. In the case of an emergency, first responders will be called. In 
order to address the challenge of early identification of an increased risk of a known adverse 
event, all adverse event data will be tracked and evaluated.
 
On-site providers will monitor the progress and health of the participants alongside our Research 
Monitor. Participants can elect to withdraw from the study at any time. Participants may also be 
taken out of the study at any point if a research provider (or one of their treating providers) 
determines that it is no longer safe for them to continue with the study. If a participant elects to 
drop out of the study or is withdrawn for safety reasons, they will resume standard of care 
treatment with their assigned health provider(s).
 
 
Data Monitoring Plan:
Data will be collected and stored in both paper CRF and electronic format as described previously 
in protocol section 10.14 Data Management. In addition to data quality and data validation 
checks done continually by REDCap for electronic format data, authorized MIRROR staff will 
perform routine checks of the coded electronic data entered into REDCap to ensure that data has 
been properly input and that data entry is consistent with expected values. The local PI will 
ensure that paper research forms and the electronic Master List are completed and securely 
stored in accordance with stated protocol procedures.
 
Please see protocol Section. 14.3 Confidentiality Protections and 14.5 Privacy for Subjects for 
additional information regarding how we will protect participant privacy and confidentiality 
throughout this study.
16.0
 
Reportable Events
16.1  Reportable Events: Consult with the research office at your institution to ensure requirements are 
met. Describe plans for reporting unexpected adverse events and unanticipated problems. Address 
how unexpected adverse events will be identified, who will report, how often adverse events and 
unanticipated problems will be reviewed to determine if any changes to the protocol or consent form 
are needed and the scale that will be used to grade the severity of the adverse event. 
Consult with the research office at your institution to ensure requirements are met
 
• Describe plans for reporting expected adverse events. Identify what the expected adverse 
events will be for this study, describe the likelihood (frequency, severity, reversibility, short-
term management and any long-term implications of each expected event)
 
• Describe plans for reporting unexpected adverse events and unanticipated problems. Address 
how unexpected adverse events will be identified, who will report, how often adverse events and 
unanticipated problems will be reviewed to determine if any changes to the research protocol or 
consent form are needed and the scale that will be used to grade the severity of the adverse 
event
AEs/SAEs/UPIRTSOs:

All adverse events (AEs), regardless of severity, will be reported to the Principal Investigator and 
Research Medical Monitor. The Research Medical Monitor will review all adverse events.
 
All Serious Adverse Events (SAEs) that are unexpected and related, or possibly related, to study 
participation will be reported to the IRB and the Research Monitor via telephone or email within 
24 hours of discovery and a complete written report via eIRB will follow within 5 business days.
 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOs) will be reported to the 
IRB and the Research Monitor via telephone or email within 24 hours of discovery and a 
complete written report via eIRB will follow within 5 business days.
 
Unexpected (but not serious) adverse events occurring in subjects enrolled at WRNMMC which, in 
the opinion of the PI, are related or possibly related to study participation AND places subjects or 
others at a greater risk of harm that was previously known or recognized in the protocol will be 
reported to the IRB and Research monitor via telephone or email within 24 hours 24 hours of 
discovery and a complete written report via eIRB will follow within 5 business days.
 
Expected adverse events and AEs/SAEs that are not related or not possibly related to study 
participation will be tracked by the local study team using an Adverse Event Tracking Log and 
reported to the IRB at the time of continuing review or, if applicable, at study closure. Continuing 
Review (CR) Progress Reports are generally performed on a 12-month cycle. More frequent 
Progress Reports may be required at the discretion of the IRB.
 
Because this is a multi-center study, a summary of adverse events study-wide will be included 
with the CR.
 
 
Protocol Deviations:
All protocol deviations, both major and minor, will be reported to the Principal Investigator. The 
Principal Investigator will review all protocol deviations.
 
Major protocol deviations will be promptly reported to the local IRB via telephone or email within 
24 hours of discovery and a complete written report will follow within 5 working days. The 
investigator is required to make the determination whether the deviation meets the criteria for 
an unanticipated problem involving risks to subjects or others. The IRB Chair or IRB staff 
member shall also make the determination if the protocol deviation meets the definition of an 
unanticipated problem involving risks to participants or others. If the IRB Chair or IRB Staff 
member determines and documents that the deviation is an unanticipated problem involving 
risks to subjects or others or the deviation resulted from serious or continuing noncompliance, 
the IRB staff member shall place the deviation on the agenda of the next available IRB meeting 
for review. If the IRB Chair or IRB Staff member determines and documents that the deviation is 
not an unanticipated problem involving risks to subjects or others, the IRB Chair or staff member 
shall acknowledge the submission and complete the review through an administrative review 
procedure.
 
Minor protocol deviations will be tracked by the local study team using a Protocol Deviation Log 
and reported to the IRB at the time of continuing review or, if applicable, at study closure. Follow 
up visits that occur outside of the windows stated in protocol Section 10.1 will be considered 
minor protocol deviations.
17.0
 
Equipment/non-FDA Regulated Devices
17.1  Does the study involve the use of any unique non-medical devices/equipment?
  Yes  
  No
18.0
 
FDA-Regulated Products
18.1  Will any drugs, dietary supplements, biologics, or devices be utilized in this study?

Drugs
Dietary Supplements
Biologics
Devices
N/A
18.2  Drugs, Dietary Supplements and Biologics/Vaccines details:
Are drug(s) in this research being used in accordance to the approved labeling?
Are drug(s) in this research being used in a manner other than its approved labeling?
Enter Dietary Supplements and Biologics/Vaccines in the Drug Information table. Complete all 
relevant fields in the table (“Protocol Drug Details” screen). If the question is not relevant, leave 
the question blank and/or do not change the default selection.
View 
Details
Drug Name
FDA Approved
A new drug or a 
new use of an 
already 
approved drug:
IND Number
Trade Drug 
Name: Botox
Generic Drug 
Name:
Investigational 
Drug Name:
Yes 
Yes 
 
Trade Drug Name:
Botox 
Generic Drug Name:
 
Investigational Drug Name:
 
Identify the name of the 
manufacturer or source of 
investigational drug/biologic:
Allergan  
Is the drug supplied at no cost?
Yes  
Is the Drug FDA Approved:
Yes  
Is this a new drug or a new 
use of an already approved 
drug
Yes  
Is an IND necessary
No  
IND Number
 
Who holds the IND:
N/A  
IND details:
N/A - please see section below for exemption rationale.  
If FDA Approved and an IND is 
not required, Please provide a 
rationale for exemption:
BotulinumtoxinA injections are already currently used in the 
sports medicine clinics at Fort Belvoir Community Hospital 
(FBCH) and the Uniformed Services University (USU) as 
well as in the Dept. of Physical Medicine & Rehabilitation 
(PM&R) at Walter Reed National Military Medical Center 
(WRNMMC) for the non-surgical treatment of CECS.    
Additionally, our use of BoNT-A in this study does not  
require an IND because it meets all of the required 
exemption  criteria outlined by the FDA:    1) The drug we 
propose to use is currently lawfully marketed in the United 
States.  2) This study/investigation is not intended to be 
reported to the FDA as a well-controlled study. This study is 
also not intended to support neither a new indication of this 
drug nor a change to the current labeling of this drug.  3) 
This study does not intend to support a significant change 
in  advertising for the drug.  4) Although this drug is not 
currently explicitly approved for the treatment of CECS, it is 

currently FDA approved for injection into extremity 
musculature for other medical conditions. We will be using 
this drug following a similar dosing guideline, using a 
similar route of administration, and in a population that it is 
already FDA approved for. Our intended procedures do not 
significantly increase the risks associated with the use of 
this drug.  5) This study will be conducted in compliance 
with the requirements for review by our IRB board.  6) This 
study is not intended to promote or commercialize this drug 
product.  
Are you currently using this 
IND in another research 
project?
No  
If yes, list the IRB Number(s):
N/A  
Dose Range:
50-100 units per limb  
Frequency:
one time  
Route of administration:
injection  
Will the investigational 
pharmacy be dispensing?
No  
If the source is not a FDA 
licensed facility, provide details 
regarding the purity, quality, 
stability and sterility of the 
investigational drug/biologic:
N/A - the source is an FDA licensed facility  
Identify who will be preparing 
the investigational drug
/biologic for administration and 
describe in detail how it will be 
prepared:
The BoNT-A will be prepared by a trained physician or 
nurse. Four syringes using 25 units of BoNT-A and 1 mL of 
normal saline will be prepared per limb.  
Indication(s) under 
Investigation:
BoNT-A (trade name BOTOX, generic name 
onabotulinumtoxinA) is currently FDA approved for injection 
into extremity musculature for other medical conditions (i.
e. muscular hypertrophy/spasticity). We are  investigating 
its usage for chronic exertional compartment syndrome.  
Where will the drug be stored
Within a locked cabinet in a Dept. of Physical Medicine & 
Rehabilitation procedure room  
Drug Storage Restrictions 
(including temperature, etc.):
Unopened vials of BoNT-A (trade name BOTOX, generic 
name (onabotulinumtoxinA) will be stored in a refrigerator 
set for 2°C to 8°C or 36°F to 46°F.  
Administration Instructions:
Standard aseptic technique will be followed. Insertion of the 
correct compartment will be accomplished using ultrasound 
guidance. The anterior and lateral compartment will be 
separated into thirds measuring from the tibial plateau to 
the head of the calcaneus. Injections will be given at 
approximately 1/3 the distance from the tibial plateau for 
the proximal injection and 2/3 the distance from the tibial 
plateau for the distal injection. Injections will only be given 
to compartments that have elevated pressures. If the 
lateral compartment is affected, the peroneus longus and 
brevis muscles will receive 25 units proximally and 25 units 
distally, for a total of 50 units, of BoNT-A. If the anterior 
compartment is affected, a total of 50 units of BoNT-A will 
be given: 25 units at the proximal region and 25 units at 
the distal region.  
Possible Untoward Effects, 
Their Symptoms & Treatment:
The potential side effects for BoNT-A (trade name BOTOX, 
generic name onobotulinumtoxinA) include: rare minor side 
effects of bleeding, pain, infection, transient general muscle 
weakness and muscular atrophy, flu-like symptoms, and 
even rarer transient breathing and swallowing difficulties 
which has the potential to cause death if not appropriately 
treated.  

Potential or Actual Antidotes 
for Excessive or Adverse Drug 
Effect:
Potential excessive BoNT-A (trade name BOTOX, generic 
name onobotulinumtoxinA) drug effect may produce 
neuromuscular weakness with a range of symptoms and 
should be medically treated immediately and may require 
hospitalization. In the event of an overdose, an antitoxin is 
available through contact with the local and state health 
departments to the CDC. The antitoxin will not reverse any 
effects that have occurred prior to the antitoxin 
administration.  
Contraindications and 
Interactions, If Known:
Individuals who have known hypersensitivity to BoNT-A 
(trade name BOTOX, generic name onobotulinumtoxinA) or 
its ingredients/components and individuals that have a 
presence of infection at the site of injection.  
Investigators Authorized to 
Prescribe:
Dr. Jeffrey Leggit  
Trade Drug 
Name: Xeomin
Generic Drug 
Name:
Investigational 
Drug Name:
Yes 
Yes 
 
Trade Drug Name:
Xeomin 
Generic Drug Name:
 
Investigational Drug Name:
 
Identify the name of the 
manufacturer or source of 
investigational drug/biologic:
Merz Pharmaceuticals  
Is the drug supplied at no cost?
Yes  
Is the Drug FDA Approved:
Yes  
Is this a new drug or a new 
use of an already approved 
drug
Yes  
Is an IND necessary
No  
IND Number
 
Who holds the IND:
N/A  
IND details:
N/A - please see section below for exemption rationale.  
If FDA Approved and an IND is 
not required, Please provide a 
rationale for exemption:
botulinumtoxinA injections are already currently used in the 
sports medicine clinics at Fort Belvoir Community Hospital 
(FBCH) and the Uniformed Services University (USU) as 
well as in the Dept. of Physical Medicine & Rehabilitation 
(PM&R) at Walter Reed National Military Medical Center 
(WRNMMC) for the non-surgical treatment of CECS.    
Additionally, our use of BoNT-A in this study does not  
require an IND because it meets all of the required 
exemption  criteria outlined by the FDA:    1) The drug we 
propose to use is currently lawfully marketed in the United 
States.  2) This study/investigation is not intended to be 
reported to the FDA as a well-controlled study. This study is 
also not intended to support neither a new indication of this 
drug nor a change to the current labeling of this drug.  3) 
This study does not intend to support a significant change 
in  advertising for the drug.  4) Although this drug is not 
currently explicitly approved for the treatment of CECS, it is 
currently FDA approved for injection into extremity 
musculature for other medical conditions. We will be using 
this drug following a similar dosing guideline, using a 
similar route of administration, and in a population that it is 
already FDA approved for. Our intended procedures do not 
significantly increase the risks associated with the use of 

this drug.  5) This study will be conducted in compliance 
with the requirements for review by our IRB board.  6) This 
study is not intended to promote or commercialize this drug 
product.  
Are you currently using this 
IND in another research 
project?
No  
If yes, list the IRB Number(s):
N/A  
Dose Range:
50-100 units per limb  
Frequency:
One time  
Route of administration:
Injection  
Will the investigational 
pharmacy be dispensing?
No  
If the source is not a FDA 
licensed facility, provide details 
regarding the purity, quality, 
stability and sterility of the 
investigational drug/biologic:
N/A - the source is an FDA licensed facility  
Identify who will be preparing 
the investigational drug
/biologic for administration and 
describe in detail how it will be 
prepared:
The BoNT-A will be prepared by a trained physician or 
nurse. Four syringes using 25 units of BoNT-A and 1 mL of 
normal saline will be prepared per limb.  
Indication(s) under 
Investigation:
BoNT-A (trade name Xeomin, generic name 
incobotulinumtoxinA) is currently FDA approved for 
injection into extremity musculature for other medical 
conditions (i.e. muscular hypertrophy/spasticity). We are  
investigating its usage for chronic exertional compartment 
syndrome.  
Where will the drug be stored
Within a locked cabinet in a Dept. of Physical Medicine & 
Rehabilitation procedure room  
Drug Storage Restrictions 
(including temperature, etc.):
Unopened vials of BoNT-A (trade name Xeomin, generic 
name incobotulinumtoxinA) will be stored at room 
temperature 20°C to 25°C (68°F to 77°F).  
Administration Instructions:
Standard aseptic technique will be followed. Insertion of the 
correct compartment will be accomplished using ultrasound 
guidance. The anterior and lateral compartment will be 
separated into thirds measuring from the tibial plateau to 
the head of the calcaneus. Injections will be given at 
approximately 1/3 the distance from the tibial plateau for 
the proximal injection and 2/3 the distance from the tibial 
plateau for the distal injection. Injections will only be given 
to compartments that have elevated pressures. If the 
lateral compartment is affected, the peroneus longus and 
brevis muscles will receive 25 units proximally and 25 units 
distally, for a total of 50 units, of BoNT-A. If the anterior 
compartment is affected, a total of 50 units of BoNT-A will 
be given: 25 units at the proximal region and 25 units at 
the distal region.  
Possible Untoward Effects, 
Their Symptoms & Treatment:
The potential side effects for BoNT-A (trade name Xeomin, 
generic name incobotulinumtoxinA) include: rare minor side 
effects of bleeding, pain, infection, transient general muscle 
weakness and muscular atrophy, flu-like symptoms, and 
even rarer transient breathing and swallowing difficulties 
which has the potential to cause death if not appropriately 
treated.  
Potential or Actual Antidotes 
for Excessive or Adverse Drug 
Potential excessive BoNT-A (trade name Xeomin, generic 
name incobotulinumtoxinA) drug effect may produce 
neuromuscular weakness with a range of symptoms and 
should be medically treated immediately and may require 
hospitalization. In the event of an overdose, an antitoxin is 

1.  
2.  
3.  
4.  
5.  
6.  
Effect:
available through contact with the local and state health 
departments to the CDC. The antitoxin will not reverse any 
effects that have occurred prior to the antitoxin 
administration.  
Contraindications and 
Interactions, If Known:
Individuals who have known hypersensitivity to BoNT-A 
(trade name Xeomin, generic name incobotulinumtoxinA) or 
its ingredients/components and individuals that have a 
presence of infection at the site of injection.  
Investigators Authorized to 
Prescribe:
Dr. Jeffrey Leggit  
18.4  Reporting Requirements for FDA-regulated research under IND and IDE:
Describe the process for complying with FDA regulatory requirements for adverse event 
reporting and adverse device effects reporting to the sponsor
N/A
 
BotulinumtoxinA injections are already currently used in the sports medicine clinics at Fort 
Belvoir Community Hospital (FBCH) and the Uniformed Services University (USU) as well as in 
the Dept. of Physical Medicine & Rehabilitation (PM&R) at Walter Reed National Military Medical 
Center (WRNMMC) for the non-surgical treatment of CECS.
Additionally, our use of BoNT-A in this study does not require an IND because it meets all of the 
required exemption criteria outlined by the FDA:
The drug we propose to use is currently lawfully marketed in the United States.
This study/investigation is not intended to be reported to the FDA as a well-controlled 
study. This study is also not intended to support neither a new indication of this drug nor 
a change to the current labeling of this drug. 
This study does not intend to support a significant change in advertising for the drug.
Although this drug is not currently explicitly approved for the treatment of CECS, it is 
currently FDA approved for injection into extremity musculature for other medical 
conditions. We will be using this drug following a similar dosing guideline, using a similar 
route of administration, and in a population that it is already FDA approved for. Our 
intended procedures do not significantly increase the risks associated with the use of this 
drug.
This study will be conducted in compliance with the requirements for review by our IRB 
board.
This study is not intended to promote or commercialize this drug product.
18.5  Sponsor (organization/institution/company):
N/A
If applicable, provide sponsor contact information:
Jeffrey C. Leggit, MD, CAQSM
Walter Reed National Military Medical Center
Uniformed Services University
(301) 295-9460
jeff.leggit@usuhs.edu
19.0
 
Research Registration Requirements
19.1  ClinicalTrials.gov Registration:
Registration is not required 
Registration pending 

1.  
2.  
3.  
4.  
5.  
6.  
7.  
8.  
9.  
10.  
11.  
12.  
Registration complete 
“NCT” number:
NCT04409600
19.2  Defense Technical Information Center Registration (Optional):
Registration is not required 
Registration pending 
Registration complete 
20.0
 
References and Glossary
20.1  References:
Isner-Horobeti, M.-E., S. P. Dufour, C. Blaes, and J. Lecocq. "Intramuscular Pressure 
Before and After Botulinum Toxin in Chronic Exertional Compartment Syndrome of the 
Leg: A Preliminary Study." 
 41.11 (2013): 2558-
The American Journal of Sports Medicine
566.
Baria, M. R., and J. L. Sellon. "Botulinum Toxin for Chronic Exertional Compartment 
Syndrome." 
 (2016): 1.
Clinical Journal of Sport Medicine
Diebal AR, Gregory R, Alitz C, Gerber JP. Forefoot Running Improves Pain and Disability 
Associated with Chronic Exertional Compartment Syndrome. The American Journal of 
40.5 (2012):1060-1067.
Sports Medicine 
Dunn, J. C., and B. R. Waterman. "Chronic Exertional Compartment Syndrome of the Leg 
in the Military." 
 33.4 (2014): 693-705.
Clinics in Sports Medicine
Campano, D., J. A. Robaina, N. Kusnezov, J. C. Dunn, and B. R. Waterman. "Surgical 
Management for Chronic Exertional Compartment Syndrome of the Leg: A Systematic 
Review of the Literature." 
 
Arthroscopy: The Journal of Arthroscopic & Related Surgery
32.7 (2016): 1478-486.
Waterman, B., et al. “Surgical Treatment of Chronic Exertional Compartment Syndrome of 
the Leg.” 
, 95.7 (2013): 592-596.
The Journal of Bone and Joint Surgery
Schepsis, A. A., D. Martini, and M. Corbett. "Surgical Management of Exertional 
Compartment Syndrome of the Lower Leg: Long-term Followup." The American Journal of 
 21.6 (1993): 811-17.
Sports Medicine
Slimmon, D., K. Bennell, P. Brukner, K. Crossley, and S. N. Bell. "Long-Term Outcome of 
Fasciotomy with Partial Fasciectomy for Chronic Exertional Compartment Syndrome of the 
Lower Leg." 
 30.4 (2002): 581-88.
American Journal of Sports Medicine
Willits, K., N. Pasic, and D. Bryant. "Assessing Long-Term Outcomes in Individuals 
Undergoing Fasciotomy for Chronic Exertional Compartment Syndrome of the Lower Leg 
(SS-44)." 
 29.6 (2013): n. 
Arthroscopy: The Journal of Arthroscopic & Related Surgery
pag.
Helmhout, P, Diebal, AR, van der Kaaden, L, Harts C, Beutler A and Zimmermann W. The 
Effectiveness of a 6-Week Intervention Program Aimed at Modifying Running Style in 
Patients With Chronic Exertional Compartment Syndrome. The Orthopaedic Journal of 
 3.3 (2015): 1-10
Sports Medicine
Aweid, O., A. Del Buono, P. Malliaras, H. Iqbal, D. Morrissey, N. Maffulli, and N. Padhiar. 
"Systematic Review and Recommendations for Intracompartmental Pressure Monitoring in 
Diagnosing Chronic Exertional Compartment Syndrome of the Leg." Clinical Journal of 
 22.4 (2012): 356-70.
Sport Medicine
Pedowitz, R. A., A. R. Hargens, S. J. Mubarak, and D. H. Gershuni. "Modified Criteria for 
the Objective Diagnosis of Chronic Compartment Syndrome of the Leg." The American 
 
 18.1 (1990): 35-40.
Journal of Sports Medicine
20.2  Abbreviations and Acronyms:
ABI - Ankle brachial index 
AE - Adverse Events
AHLTA - Armed Forces Health Longitudinal Technology Application 

ALS - Amyotrophic lateral sclerosis 
ATAMMC - Alexander T. Augusta Military Medical Center
BESS - Balance Error Scoring System
BMI - Body Mass Index
BoNT-A - botulinumtoxin A
Borg - Perceived exertion tolerance
CECS - Chronic Exertional Compartment Syndrome
CMIRR - Collaboratory for Musculoskeletal Injury Rehabilitation Research
CRDAMC - Carl R. Darnall Army Medical Center 
CRF - Case Report Form
DEERS - Defense Enrollment Eligibility Reporting System
DHA - Defense Health Agency 
DoD - Department of Defense
DPT - Department of Physical Therapy
FBCH - Fort Belvoir Community Hospital
FDA - Food and Drug Administration
GROC - Global Rate of Change 
HBGR - Home Based Gait Retraining
hCG - Human chorionic gonadotropin
HIPAA - Health Insurance Portability and Accountability Act 
HPA - Human Protections Administrator
IMCP - Intramuscular Compartment Pressure
IRB - Institutional Review Board 
ITT - Intention-to-treat
JPC - Joint Program Committees
MAMC - Madigan Army Medical Center
MHS - Military Health System
MIRROR - Musculoskeletal Injury Rehabilitation Research for Operational Readiness
MOS - Military Occupational Specialty
MRI - Magnetic Resonance Imaging
MSI - Musculoskeletal injury 
MTF - Military Treatment Facility
OCIO - Office of the Chief Information Officer
PHI - Protected health information
PII - Personally identifiable information
PM&R - Physical Medicine & Rehabilitation
PPE - Personal protective equipment 
PSFS - Patient Specific Functional Scale
PT - Physical Therapy
REDCap - Research Electronic Data Capture
ROM - Range of motion
SAE - Serious Adverse Events
SAFE - Secure access file exchange
SANE - Single Assessment Numerical Evaluation
SGR - Supervised Gait Retraining
SSL - Secure Sockets Layer 
TLS- Transport Layer Security 
UPIRTSO - Unanticipated Problems Involving Risks to Subjects or Others
USU - Uniformed Services University
USUHS - Uniformed Services University of the Health Sciences
USU IT - Uniformed Services University Information Technology
UWRI - University of Wisconsin Running Injury and Recovery Index
WAMC - Womack Army Medical Center 
WRNMMC - Walter Reed National Military Medical Center