Clinical trial NCT03922139
Conditions: Compartment Syndrome of Leg
Sponsor: University of Wisconsin, Madison
Start date: 2019-10-08; Completion date: 2021-12-15
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
After diagnosis of Chronic Exertional Compartment Syndrome (CECS), the participants will be referred to both physical therapy and Botox injection. In physical therapy, the therapist will perform strength measurements of the lower leg (ankle plantarflexion and dorsiflexion) which will be repeated 2 months following the injection. An ultrasound-guided injection of 50 units of Botox will be administered into the tibialis anterior. 25 units will be injected into two different spots in the muscle one being more proximal and the other distal. This will be a one-time injection and will be observed as to how it effects participant symptoms over the next 6 months at either a clinic visit (at 2 months) or telephone call (at 4 and 6 months after injection) via the University of Wisconsin Running Index. Two months following the injection, the participant will undergo repeat measurements of strength using the Kiio Force Sensor.

Should potential participants of childbearing potential wish to enroll in the study, a urine pregnancy test will be performed prior to enrollment; participants will not be enrolled if test is positive.

Detailed description:
Chronic exertional compartment syndrome (CECS) is an overuse injury first described by Mavor in 1956 that typically affects young endurance athletes, classically distance runners. CECS occurs primarily in the lower leg, predominantly in the anterior compartment, although it has been reported elsewhere in the body.

The pathophysiology of CECS is not completely understood. Similar to acute compartment syndrome, it is thought to result from increased pressure within the restrictions of the fascial planes of a muscle compartment. Exercise increases blood flow to active muscles causing them to expand. If constricted by surrounding noncompliant fascia, such swelling increases pressure within the muscle compartment. Ultimately, pressure within the compartment reduces blood flow leading to muscle ischemia and pain when metabolic demands cannot be met. Several studies have demonstrated decreased blood flow and oxygenation in the legs of symptomatic patients with CECS.

Cessation of inciting activities resolves symptoms in most cases of CECS. Without this cessation, the prognosis for CECS is poor if treated non-operatively. Should symptoms continue, patients are referred for possible muscle compartment release, currently the most widely accepted treatment approach despite a significant number of treatment failures. To date, no alternative non-operative approach has successfully treated refractory symptoms.

Recently, it has been hypothesized that botulinum toxin could reduce intramuscular pressure in CECS . Isner-Horoboti et al, performed abobotulinum toxin A injections into the anterior and anterior/lateral compartments in 16 individuals with a mean follow up of 4.4 months (range 3-6 months). Fifteen (95%) patients were asymptomatic after intervention with fourteen (88%) exhibiting normalized post-exercise compartment pressures. Using manual muscle testing, they determined that 11 patients displayed decreased strength though did not produce noticeable subjective weakness. A later case report by Baria and Sellon presented the first long-term follow up (14 months) of a CECS case treated with botulinum toxin injections (Botox) in which the patient reported continued pain relief and had resumed her active lifestyle without adverse effects.

The proposed investigation will aim to build upon the results of existing studies. The novelty of this approach involves a differing dosage of the toxin (Botox) into a more targeted muscle group, specifically the tibialis anterior, while also utilizing a smaller dosage than in previous studies. Further, while previous studies have used manual muscle testing to test strength, many studies have found this method unreliable. As such, a Kiio force sensor will be used at multiple time points to determine weakness quantitatively. Lastly, the reliable and validated University of Wisconsin Running Index will be used to evaluate return to sport.

After diagnosis of CECS, the participants will be referred to both physical therapy and Botox injection. In physical therapy, the therapist will perform strength measurements of the lower leg (ankle plantarflexion and dorsiflexion) which will be repeated 2 months following the injection. An ultrasound-guided injection of 50 units of Botox into the tibialis anterior will be performed. 25 units will be injected into two different spots in the muscle, one being more proximal and the other distal. This will be a one-time injection that will be monitored to see how it effects participant symptoms over the next 6 months at either a clinic visit (at 2 months) or telephone call (at 4 and 6 months after injection) via the University of Wisconsin Running Index. Two months following the injection, the participant will undergo repeat measurements of strength using the Kiio Force Sensor.

Should potential participants be of childbearing potential wish to enroll in the study, a urine pregnancy test will be performed prior to enrollment; participants will not be enrolled if test is positive.

Arms: arm 1: Ultrasound guided 1 mg/1 mL injection.

25 units of Botox will be injected 2 cm proximal and 2 cm distal to the midpoint of the tibialis anterior muscle.
Interventions: intervention 1: OnabotulinumtoxinA Injection
Intervention descriptions: intervention 1: Ultrasound guided 1 mg/1 mL injection.

25 units of Botox will be injected 2 cm proximal and 2 cm distal to the midpoint of the tibialis anterior muscle.

Protocol documents:
Prot_SAP_000.pdf: 
ONABOTULINUMTOXINA (BOTOX) EFFECT ON PAIN AND FUNCTION IN CHRONIC 
EXERTIONAL COMPARTMENT SYNDROME: A PILOT STUDY
NCT03922139
Principal Investigator: Michael Suer, MD
Version Date: June 15, 2020


Botox for CECS 
PI: Michael Suer, MD 
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Version #: 3 
MSUER@UWHEALTH.ORG 
ONABOTULINUMTOXINA (BOTOX) EFFECT ON PAIN AND FUNCTION 
IN CHRONIC EXERTIONAL COMPARTMENT SYNDROME: A PILOT 
STUDY 
NCT03922139
. 
Principal Investigator: Michael Suer, MD 
This document is confidential. 
No part of it may be transmitted, reproduced, published, or used by other persons without prior written 
authorization from the Sponsor or Principal Investigator. 
PROTOCOL VERSION and AMENDMENTS 
Protocol 
Version 
Date 
Change Initiated 
(Initials) 
Brief description of protocol modification/actions requested, if any 
Template 
V1 
5/4/2017 
MJS 
Original 
V2 
4/16/2019 
JTW 
Protocol updated to match changes mentioned in CP002 
V3 
6/15/2020 
JTW 
Protocol updated to change reimbursement to cash 


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STATEMENT OF COMPLIANCE 
 
(1) The research will be carried out in accordance with Good Clinical Practice (GCP) as required by the following: United 
States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR 
Part 56) ICH E6  
All key personnel (all individuals responsible for the design and conduct of this trial) have completed Human Subjects 
Protection Training. 
 
  
I agree to ensure that all staff members involved in the conduct of this study are informed about their obligations in meeting 
the above commitments.  
 
 
Principal Investigator: ____Michael Suer, MD______  
Print/Type Name  
 
 
 
Signed: _____________________________________  
  
 
 


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Funding Sponsor: 
University of Wisconsin Division of Rehabilitation Medicine 
Study Product: 
OnabotulinumtoxinA (Botox) 
 
 
 
  Participating sites: 
 
        University of Wisconsin Hospitals and Clinics 
 
 
 
 


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List of Abbreviations 
 
 
AE 
Adverse event 
CECS 
Chronic Exertional Compartment Syndrome 
IMP 
Intramuscular Pressure 
PT 
Physical Therapy 
SAE 
Serious Adverse Event 
TA 
Tibialis Anterior 
US 
Ultrasound 
UP 
Unanticipated Problem 
UWRI 
University of Wisconsin Running Index 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Summary 
ONABOTULINUMTOXINA (BOTOX) EFFECT ON PAIN AND FUNCTION 
IN CHRONIC EXERTIONAL COMPARTMENT SYNDROME: A PILOT 
STUDY 
 
 
Title 
OnabotulinumtoxinA (Botox) effect on pain and function in chronic exertional 
compartment syndrome: a pilot study 
Short Title and Precis 
Botox for the treatment of chronic exertional compartment syndrome 
Methodology 
Open label pilot study 
Study Duration 
1 year 
Study Center(s) 
University of Wisconsin Hospitals and Clinics 
Objectives 
Determine effect of Botox on pain and function using the University of 
Wisconsin Running Index 
Number of Subjects 
10 subjects consisting of 20 legs 
Diagnosis  
Chronic exertional compartment syndrome (CECS)  
Main Inclusion Criteria 
Patients between the ages of 18-40 with confirmed diagnosis of CECS with 
intramuscular pressure measurements 
Main Exclusion Criteria 
Previous surgery in the lower extremity including, but not excluded only to, 
fasciotomy, knee arthroscopy, knee arthroplasty, fixation of fracture, foot/ankle 
surgery 
Study Product, Dose, 
Route, Regimen 
Botox (reconstituted at100 units/mL) to be injected under ultrasound guidance 
as 25 units into each the proximal and distal anterior tibialis muscle for a total 
of 50 units injected into the anterior tibialis muscle 
FDA status of product 
FDA approved 
Duration of 
administration 
6 month follow up time after injection of medication. Typical duration of action 
of Botox is 10-12 weeks 
Reference therapy 
No direct comparison 
Statistical 
Methodology 
A very brief description of the main elements of the statistical methodology to 
be used in the study. (As few lines as possible). 
 
 
 


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Schematic of Study Design 
 
 
Flow diagram or study calendar (e.g., randomized controlled trial)  
 
 
Prior to enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 1 (Time 0) 
 
 
 
 
 
 
 
 
 
Visit 2 (2 months) 
 
 
 
 
 
Visit 3 (4 months) 
 
 
 
 
 
Visit 4 (6 months) 
 
 
 
 
 
Establish diagnosis of CECS through measurement of IMP.  
Screen potential subjects by inclusion and exclusion criteria; obtain history 
12  subjects 
enrolled 
Perform baseline assessments. 
- Referral to PT for pre-intervention strength assessment 
- Referral to study team at Pain Clinic for administration of UWRI and US-guided 
Botox injection into TA 
Follow up with PT for post-intervention strength assessment 
Office follow up with study team for administration of UWRI and monitoring of 
side effects 
Telephone follow up for administration of UWRI and monitoring of side effects 
Telephone follow up for administration 
of UWRI and monitoring of side 
effects 


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Contents 
Study Summary ....................................................................................................................................................................... 5 
1. 
Key Roles ...................................................................................................................................................................... 10 
2. 
Background and Introduction..................................................................................................................................... 10 
2.1 
Background and Rationale .................................................................................................................................... 10 
2.2 
Hypothesis ............................................................................................................................................................. 10 
2.3 
Study Agent ........................................................................................................................................................... 11 
2.4 
Summary of Relevant Preclinical Data .................................................................................................................. 12 
2.5 
Summary of Clinical Data ...................................................................................................................................... 12 
2.6 
Dose Rationale (for drugs and biologics only, delete for device) .......................................................................... 12 
2.7 
Potential Risk and Benefits to Subjects ................................................................................................................ 12 
2.7.1 
Known Potential Risks ...................................................................................................................................... 12 
2.7.2 
Protection Against Risks ................................................................................................................................... 13 
2.7.3 
Potential Benefits to the Subjects ..................................................................................................................... 14 
3. 
Study Objectives and Purpose ................................................................................................................................... 14 
4. 
Study Design and Endpoints ...................................................................................................................................... 14 
4.1. 
General Design ..................................................................................................................................................... 14 
4.1.1 
Primary Study Endpoints ................................................................................................................................... 14 
4.1.2 
Secondary Study Endpoints .............................................................................................................................. 15 
4.1.3 
Primary Safety Endpoints .................................................................................................................................. 15 
5. 
Study Subjects – Enrollment and Withdrawal .......................................................................................................... 15 
5.1. 
Subject Population ................................................................................................................................................ 15 
5.2. 
Inclusion Criteria .................................................................................................................................................... 15 
5.3. 
Exclusion Criteria .................................................................................................................................................. 16 
5.4. 
Subject Screening for Recruitment ....................................................................................................................... 16 
5.4.1 
Subject Identification ......................................................................................................................................... 16 
    5.4.2 Recruitment and Retention Strategies .................................................................................................................. 16 
5.5 
Vulnerable Populations ......................................................................................................................................... 16 
    5.5.1  Subject Capacity ............................................................................................................................................... 16 
5.5.2  
Subject/Representative Comprehension....................................................................................................... 17 
5.6 
Informed Consent .................................................................................................................................................. 17 
5.6.1 
Consent Form (see templates for UW-Madison) .............................................................................................. 17 
5.6.2  
Process of Consent ......................................................................................... Error! Bookmark not defined. 
5.6.4 
Revoking Consent ............................................................................................................................................. 17 
5.6.5  
Costs to the Subject ...................................................................................................................................... 17 
5.6.6 
Payment for Participation .................................................................................................................................. 18 
5.7 
Early Withdrawal of Subjects ................................................................................................................................ 18 
5.7.1 
Premature termination of study ......................................................................................................................... 18 
5.7.2 
When and How to Withdraw Subjects ............................................................................................................... 18 


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5.7.3    Data Collection and Follow-up for Withdrawn Subjects ..................................................................................... 18 
6 
Study Agent .................................................................................................................................................................. 10 
6.1 
Description and Formulation ................................................................................................................................. 19 
6.2 
Packaging .............................................................................................................................................................. 19 
6.3 
Preparation, Administration and Storage of Study Drug ....................................................................................... 19 
6.4 
Route of Administration ......................................................................................................................................... 19 
6.5 
Starting Dose and Dose Escalation Schedule ...................................................................................................... 19 
6.6 
Dose Adjustments/Modifications/Delays ............................................................................................................... 20 
6.7 
Prior and Concomitant Therapy/ Standard of Care ............................................................................................... 20 
6.8 
Blinding of Study Drug .......................................................................................................................................... 20 
6.9 
Receiving, Storage, Dispensing and Return of Study Agent ................................................................................ 20 
       6.9.1 Receipt of Drug Supplies ...................................................................................................................................... 20 
6.9.2 
Storage .............................................................................................................................................................. 20 
6.9.3 
Dispensing ......................................................................................................................................................... 20 
6.9.4 
Return of Disposal ............................................................................................................................................. 21 
7 
Study Procedures ........................................................................................................................................................ 21 
7.1 
LABS ..................................................................................................................................................................... 21 
7.2 
Established Standard of Care: .............................................................................................................................. 21 
7.3 
Method for Assigning Subjects to Treatment Groups ............................................. Error! Bookmark not defined. 
Table 3.  Study Calendar ................................................................................................................................................... 21 
7.4 
Study Visits ............................................................................................................................................................ 21 
7.4.1 
Screening/Baseline: .......................................................................................................................................... 21 
7.4.2 
Follow up: .......................................................................................................................................................... 21 
7.4.3 
Unscheduled: .................................................................................................................................................... 22 
7.5 
Risk Minimization: ................................................................................................... Error! Bookmark not defined. 
8 
Study Analysis ............................................................................................................................................................. 22 
8.1 
Sample Size Determination ................................................................................................................................... 22 
8.2 
Statistical Methods ................................................................................................................................................ 22 
8.3 
Subject Population(s) for Analysis ........................................................................................................................ 23 
8.4 
Planned Interim Analysis: ...................................................................................................................................... 23 
9 
Data Collection, Handling and Record Keeping ....................................................................................................... 23 
9.1 
Data Confidentiality ............................................................................................................................................... 23 
9.1.1 
Confidentiality of Subject Records .................................................................................................................... 23 
9.2 
Data Capture ......................................................................................................................................................... 24 
9.2.1 
Source Documents ............................................................................................................................................ 24 
9.2.2 
Case Report Forms ........................................................................................................................................... 24 
9.2.3 
Data Collection Tools ........................................................................................................................................ 24 
9.3 
Data Management ................................................................................................................................................. 24 
9.4 
Data Monitoring ....................................................................................................... Error! Bookmark not defined. 


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9.5 
Records Retention ................................................................................................................................................. 24 
9.6 
Specimen Banking .................................................................................................. Error! Bookmark not defined. 
10 
Assessment of Safety ............................................................................................................................................. 24 
10.1 
Specifications of Safety Parameters ..................................................................................................................... 24 
10.1.1 
Definition of Adverse Events (AE) ................................................................................................................. 24 
    10.1.2 Definition of Serious Adverse Events (SAE) ..................................................................................................... 25 
    10.1.3 Definition of Unanticipated Problems (UP) ....................................................................................................... 25 
10.2 
Classification of an Adverse Event ........................................................................................................................ 25 
    10.2.1 Severity of Event ............................................................................................................................................... 25 
10.2.3    Expectedness ................................................................................................................................................... 26 
10.3 
Time period and frequency for event assessment and follow-up ......................................................................... 26 
10.4 
Reporting procedures ............................................................................................................................................ 26 
10.4.1 
Adverse Event Reporting .............................................................................................................................. 27 
10.4.2 
Serious adverse event reporting ................................................................................................................... 27 
10.4.3 
Unanticipated problem reporting ................................................................................................................... 27 
10.4.4 
Events of special interest .............................................................................. Error! Bookmark not defined.s 
10.4.5 
Reporting of pregnancy ................................................................................... Error! Bookmark not defined. 
10.5 
Study Halting Rules ............................................................................................................................................... 28 
10.6 
Safety Oversight .................................................................................................................................................... 28 
10.7 
Unblinding Procedure .............................................................................................. Error! Bookmark not defined. 
11 
Study Monitoring, Auditing, and Inspecting ........................................................................................................ 28 
11.1 
Medical Monitoring ................................................................................................................................................ 28 
11.1.1 
Study Monitoring Plan ................................................................................................................................... 28 
11.1.2 Address how problems/side effects will be identified and handled ...................... Error! Bookmark not defined. 
11.2 
Protocol Deviations ............................................................................................................................................... 28 
11.2.1 Internal Data and Safety Monitoring Board .......................................................... Error! Bookmark not defined. 
11.2.2 Independent Data and Safety Monitoring Board .................................................. Error! Bookmark not defined. 
11.3 Auditing and Inspecting ............................................................................................................................................. 29 
11.4 Subject Compliance Monitoring ................................................................................... Error! Bookmark not defined. 
12 Ethical Considerations .................................................................................................................................................. 29 
13 Study Finances ............................................................................................................................................................... 29 
13.1 Funding Source ......................................................................................................................................................... 29 
13.2 Conflict of Interest ...................................................................................................................................................... 29 
13.3 Subject Stipends or Payments .................................................................................................................................. 29 
14 Publication Plan ............................................................................................................................................................. 30 
15 References ...................................................................................................................................................................... 30 
Attachments (incomplete) ..................................................................................................................................................... 30 
 
 
 


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1. Key Roles 
 
Following is a list of all personnel in key roles: 
 
 
Principal Investigator:  
Michael Suer, MD 
Asst Professor (CHS) (UWMF) 
6630 University Avenue, Madison, WI 53562 
(608)263-8642 
msuer@uwhealth.org 
 
Investigator: 
David Bernhardt, MD 
Professor (CHS) (UWMF) 
2880 University Avenue, Madison, WI 53705 
(608)263-6477 
dtbernhardt@pediatrics.wisc.edu 
 
Study Staff: 
Matthew Cowling, MD 
Honorary Associate/Fellow 
621 Science Drive, Madison, WI 53711 
mcowling@wisc.edu 
 
Statistician: 
Stephanie Kliethermes, PhD 
Asst Professor (CHS)(UWSMPH) 
1685 Highland Ave 6147 
UW Med Foundation 
Centennial Building 
Madison, WI 53705 
kliethermes@ortho.wisc.edu 
 
2. Background and Introduction 
 
This document is a protocol for a human research study. This study is to be conducted according to US and 
international standards of Good Clinical Practice, applicable government regulations, and Institutional research 
policies and procedures.  
 
2.1 Background and Rationale 
 
Chronic exertional compartment syndrome (CECS) is an overuse injury first described by Mavori in 1956 
that typically affects young endurance athletes, classically distance runners. CECS occurs primarily in the 
lower leg, predominantly in the anterior compartment, although it has been reported elsewhere in the 
bodyii,iii,iv,v,vi. 
 
The pathophysiology of CECS is not completely understoodvii,viii,ix. Similar to acute compartment syndrome, 
it is thought to result from increased pressure within the restrictions of the fascial planes of a muscle 
compartment. Exercise increases blood flow to active muscles causing them to expand. If constricted by 
surrounding noncompliant fascia, such swelling increases pressure within the muscle compartment. 
Ultimately, pressure within the compartment reduces blood flow leading to muscle ischemia and pain when 


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metabolic demands cannot be met. Several studiesx have demonstrated decreased blood flow and 
oxygenation in the legs of symptomatic patients with CECS.  
 
Cessation of inciting activities resolves symptoms in most cases of CECS. Without this cessation, the 
prognosis for CECS is poor if treated non-operatively. Should symptoms continue, patients are referred for 
possible muscle compartment release, currently the most widely accepted treatment approach despite a 
significant number of treatment failuresx,xi,xii. To date, no alternative non-operative approach has 
successfully treated refractory symptomsii,viii,xiiixiv. 
 
Recently, it has been hypothesized that botulinum toxin could reduce intramuscular pressure in CECSxv. 
Isner-Horoboti et alxv, performed abobotulinum toxin A injections into the anterior and anterior/lateral 
compartments in 16 individuals with a mean follow up of 4.4 months (range 3-6 months). Fifteen (95%) 
patients were asymptomatic after intervention with fourteen (88%) exhibiting normalized postexercise 
compartment pressures. Using manual muscle testing, they determined that 11 patients displayed 
decreased strength though did not produce noticeable subjective weakness. A later case report by Baria 
and Sellonxvi presented the first long-term follow up (14 months) of a CECS case treated with botulinum 
toxin injections (Botox) in which the patient reported continued pain relief and had resumed her active 
lifestyle without adverse effects.  
 
The proposed investigation will aim to build upon the results of existing studies. The novelty of our approach 
involves a differing dosage of the toxin (Botox) into a more targeted muscle group, specifically the tibialis 
anterior. Further, while previous studies have used manual muscle testing to test strength, many studies 
have found this method unreliable. As such, we will be using the Kiio force sensor at multiple time points to 
determine weakness quantitatively. Lastly, we will be utilizing the reliable and validated University of 
Wisconsin Running Index to evaluate return to sport.   
2.2 Hypothesis 
Hypothesis: Injection of 50 units Botox into the tibialis anterior will alleviate pain associated with CECS. 
2.3 Study Agent 
OnabotulinumtoxinA (Botox) does not have FDA approval for the proposed use. It does have FDA approval for 
spasticity in both upper and lower extremities, cervical dystonia, bladder dysfunction, chronic migraine, primary 
axillary hyperhidrosis, blepharospasm, and strabismus.  
 
Maximum dosage is not well defined; dosage is dependent upon treatment effect and indication. The maximum 
cumulative dose should generally not exceed 400 units in a 3-month interval when treating one or more indications. 
 
Description: 
Formerly 
known 
as 
botulinum 
toxin 
type 
A; 
IM 
toxin 
that 
reduces 
local 
muscle 
activity. 
Approved and off-label uses include cervical dystonia, blepharospasm, strabismus, upper limb spasticity, lower limb 
spasticity, facial wrinkles, migraine prophylaxis, cerebral palsy, low back pain, excessive sweating, overactive 
bladder, 
and 
urinary 
incontinence 
associated 
with 
neurologic 
conditions. 
Distant spread of botulinum toxic effects from the site of injection has resulted in symptoms suggestive of systemic 
botulism (including respiratory compromise and death) after the use of botulinum toxins types A and B. Botulinum 
toxins types differ and different types are not exchangeable or substitutable for one another. 
 
Mechanism of Action 
OnabotulinumtoxinA blocks neuromuscular conduction by binding to receptor sites on motor nerve terminals, 
entering nerve terminals, and inhibiting the release of acetylcholine. Inhibition occurs as the neurotoxin cleaves a 
protein (SNAP-25) integral to the successful docking and release of acetylcholine from vesicles situated within nerve 
endings. After intramuscular injection of a therapeutic dose, onabotulinumtoxinA produces partial chemical 
denervation of the muscle resulting in a localized reduction in muscle activity. Additionally, the muscle may atrophy, 
axonal sprouting may occur, and extrajunctional acetylcholine receptors may develop. Evidence exists that 
suggests that reinnervation of the muscle may occur thereby slowly reversing muscle denervation produced by the 
neurotoxin. 


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A reduction in sialorrhea may also occur by blocking the liberation of acetylcholine in autonomic nerve terminals in 
the parotid and submandibular glands. There is no evidence of axonal sprouting and consecutive innervation in 
autonomic 
nerve 
fibers 
in 
sialorrhea 
studies. 
  
For treatment of neurogenic bladder, after injection into the detrusor muscle the efferent pathways of detrusor 
activity are affected via inhibition of acetylcholine release; inhibition of afferent neurotransmitters and sensory 
pathways is also thought to occur. Therapy increases maximal bladder capacity, reduces maximum detrusor 
pressure, reduces incontinence episodes, and may reduce the need for anticholinergics in patients with neurogenic 
overactive bladder. 
2.4 Summary of Relevant Preclinical Data 
2.5 Summary of Clinical Data 
 
Recently, it has been hypothesized that botulinum toxin could reduce intramuscular pressure in CECSxvii. 
Isner-Horoboti et alxv, performed abobotulinum toxin A injections into the anterior and anterior/lateral 
compartments in 16 individuals with a mean follow up of 4.4 months (range 3-6 months). Fifteen (95%) 
patients were asymptomatic after intervention with fourteen (88%) exhibiting normalized postexercise 
compartment pressures. Using manual muscle testing, they determined that 11 patients displayed 
decreased strength though did not produce noticeable subjective weakness. A later case report by Baria 
and Sellonxviii presented the first long-term follow up (14 months) of a CECS case treated with botulinum 
toxin injections (Botox) in which the patient reported continued pain relief and had resumed her active 
lifestyle without adverse effects.  
 
2.6 Dose Rationale  
 
Dosing considerations were made in looking at previous studiesxv,xviii as well as medical expertise of the investigators 
in consultation with Dr Kristin Caldera, a neurorehabilitation physician extensive knowledge in use of the medication. 
A previous studyxviii have injected 40 units (20 proximal and 20 distal) into the each the TA, extensor digitorum 
longus, and extensor hallucis longus. Our protocol changes this dosing to 50 units total (25 proximal and 25 distal) 
into the TA as this is the main muscle involved in ankle dorsiflexion. Sparing the other muscles in the anterior 
compartment would provide some ankle dorsiflexion should the TA be weakened too much by the injection and 
allow for a lower overall dosage of the medication.  
 
Further, we chose a dosage on the low end recommended by the previous studies for hypertonicity in the TA. To 
ensure placement of the medication into the proper muscle, we will be using ultrasound guidance. A single injection 
will be performed in this study as previous studies have shown prolonged pain relief despite a known duration of 
action of the medication to be 2-6 months to help determine the duration of relief in this diagnosis. Given this 
duration of action, most side effects associated with muscle weakness are temporary and resolve over time.  
 
2.7 Potential Risk and Benefits to Subjects 
2.7.1 Known Potential Risks 
 
Immediate risks 
- 
Pain during injection 
- 
Infection of injection site 
- 
Bleeding following injection 
- 
Swelling at injection site 
 
Long-range risks 


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- 
TA weakness resulting in foot drop 
- 
Distant spread resulting in botulism-like symptoms including muscle weakness all over body, vision problems, 
difficulty speaking or swallowing, trouble breathing, loss of bladder control 
 
Reproductive 
- 
Injections will not be performed in individuals who are or who have a reasonable possibility of being pregnant.  
- 
Should potential subjects be of unknown pregnancy status and wish to enroll in the study, a urine pregnancy test 
can be performed prior to enrollment.  
 
Rationale 
- 
Despite the above risks, Botox has established as a safe procedure with minimal likelihood of serious side effects 
when done under sterile technique. The immediate risks are temporary and/or easily treated ameliorated with 
prompt treatment. 
- 
While using ultrasound guidance slightly increases risk for infection, the risk remains low and it will provide 
accurate placement of the medication to help avoid adverse effects and to establish treatment protocol. 
 
Value 
- 
CECS remains a difficult-to-treat entity as established treatments are limited and outcomes are less than ideal 
 
 
Please see package insert in appendix 
2.7.2 Protection Against Risks 
 
Immediate risks 
- 
Pain during injection 
o 
Barring other risks, this will be temporary and will be involved in the pre-injection consent. The needle 
to perform the injection will be of the smallest gage that can be reasonably considered to successfully 
perform the injection including visualization under US. The discomfort that can be experienced with 
some injections of Botox cannot be mitigated.  
- 
Infection of injection site 
o 
Sterile technique will be maintained with an assistant in the room to both assist with the injection and 
to monitor for sterile technique. Injection will be performed at a clinic that regularly performs injections 
under US guidance and has extensive experience in maintaining sterile technique.  
- 
Bleeding following injection 
o 
Subject on blood-thinning medication will not be included in the study. The gage of the needle will be 
relatively small and poses a minimal risk for prolonged bleeding. Should this occur, proper protocol of 
manual pressure and possible pressure bandage will be applied and the patient monitored for 
cessation of bleeding prior to departure from the clinic 
- 
Swelling at injection site 
o 
Subject will be counseled on proper wound care and have investigating physician contact information 
and rehabilitation on call physician information prior to injection should further guidance be warranted 
after the injection. 
 
Long-range risks 
- 
TA weakness resulting in foot drop 
o 
In not injecting the extensor digitorum longus and extensor hallucis longus, should this weakness 
occur, the subject will have some functional dorsiflexion from these spared muscles. If this effect does 
occur, the injection physician will follow up with the subject sooner than the planned 2 month follow 
up and can consider further treatment such as ankle foot orthosis to aid in safe ambulation at the cost 
of the research funding source. 
- 
Distant spread resulting in botulism-like symptoms including muscle weakness all over body, vision problems, 
difficulty speaking or swallowing, trouble breathing, loss of bladder control 


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o 
Subject will have proper physician contact information to monitor for side effects. The risk will be 
explicitly discussed during written consent prior to the injection as it is a black box warning mandated 
by the FDA for the treating medication.  
o 
Should these effects occur, subject with speak with either the investigating physician or rehabilitation 
physician on call. Effects will be triaged and appropriate referrals made up to and including evaluation 
in the emergency department.  
 
Withdrawal 
- 
Patients who wish to withdrawal from the study may do so by verbal or written request to the investigator. Or 
they may indicate withdrawal by failure to follow up with study protocol.  
 
2.7.3 Potential Benefits to the Subjects 
 
Benefits include pain reduction and potential return to sport 
2.7.4 Risk Minimization: 
 
To avoid risks associated with injection, sterile technique will be maintained by the treating physician and assistant 
during the injection. The assistant will also aid the treating physician in monitoring the sterile field for violations of 
sterile technique. Subjects will also be given follow-up instructions and instructions for contacting appropriate 
physician (investigating or on call rehabilitation physician) should adverse effects occur.  
3 Study Objectives and Purpose 
 
• Primary Objective: To assess the efficacy of OnabotulinumtoxinA (Botox) on decreasing pain associated with 
CECS. 
• Secondary Objective: To assess the safety and tolerability of 50 unit injections of Botox into the TA in subjects 
with CECS 
• Secondary Objective: To assess the ability to return to sport following injection of Botox in subjects with CECS 
 
4 Study Design and Endpoints 
4.1 General Design  
• Design: Feasibility study without randomization or blinding 
• Please see page 6 for schematic design of trial including duration of subject participation 
• Summary: Subjects will be enrolled in study at initial clinic visit by study staff at which time diagnosis of CECS 
will be established based on clinical criteria and measurement of IMP. Referrals will be made to study staff. Initial 
clinic visit with study staff will consist of baseline measurements of ankle plantarflexion and dorsiflexion strength 
using Kiio Force Sensor. The clinic visit with study staff will establish time point 0 and will consist of written 
consent for participation, US-guided Botox injection, and baseline UWRI. Two months following this visit, the 
patient will have follow up with study staff. Study staff will again measure ankle plantarflexion and dorsiflexion 
using the Kiio Force Sensor utilizing the same strength assessment protocol. Study staff will monitor for side 
effects and administer the UWRI. Telephone follow up assessment of the UWRI will be made by study staff at 4 
and 6 months. For patient incentive, cash will be distributed in person consisting of: $100 at time of injection, 
$50 at 2 month follow up, and $50 following the 6 month follow up. The final cash will be mailed to the subject to 
an address they provide at the time of follow up.  
4.1.1 Primary Study Endpoints 
 
1. Decrease in pain by 30% 


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4.1.2 Secondary Study Endpoints 
 
1. Change in ankle dorsiflexion strength 
2. Change in ankle plantarflexion strength 
3. Change in ability to perform activities of daily living  
4. Subject frustration with injury 
5. Subject perception of recovery from injury 
6. Pain in the 24 hours following running 
7. Change in running duration including weekly and longest run 
8. Change in running speed 
9. Subject confidence in increasing the duration and intensity of running 
4.1.3 Primary Safety Endpoints 
 
1. Lower extremity weakness with focus on ankle dorsiflexion weakness (i.e. foot drop) 
2. Bruising, bleeding, pain, redness, or swelling where the injection was given 
5 Study Subjects – Enrollment and Withdrawal 
 
• Accrual Goal: Goal of 12 patients within 1 year. Goal is based upon study being a feasibility study. Previous 
studies1 have performed 18 legs (9 patients) and did serve as a baseline for our study. 
• Screening will be performed at initial diagnosis prior to enrollment and prior to first injection. At the time of 
injection, investigator will review contraindications with participant including local infection, known 
hypersensitivity to botulinum toxin, neuromuscular disorder, dysphagia, breathing difficulties, and pregnancy.  
 
5.1 Subject Population  
 
Subjects will be greater than or equal to 18 years of age at the time of enrollment with no upper limit of age provided 
the subject meets inclusion criteria. There will be no limitations on enrollment based on race or ethnicity of the 
subject. Female subjects of childbearing potential will be screened for pregnancy prior to enrollment with urine 
pregnancy test. 
 
 
 
5.2  Inclusion Criteria  
 
Inclusion Criteria  
1 
Willing to provide written informed consent  
2 
Willing to comply with all study procedures and be available for the duration of the study  
3 
Male or female, at least 18 years of age 
4 
Documented diagnosis of CECS 
5 
Females of childbearing potential must have a negative urine pregnancy test prior to enrollment and agree 
to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to 
randomization, for the duration of study participation, and for 7 days following completion of therapy.   
• 
A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a 
tubal ligation, or remaining celibate by choice) who meets the following criteria: 
o 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
• 
Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at 
any time in the preceding 12 consecutive months). 
 


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5.3 Exclusion Criteria 
 
Exclusion Criteria 
1. History of hypersensitivity or allergy to any of the study drugs or drugs of similar chemical classes 
2. Known neuromuscular disease  
3. Known pulmonary disease including but not limited to asthma, pneumonia, or upper respiratory tract 
infection 
4. Dysphagia  
5. Known cardiac disease including but not limited to congestive heart failure, arrhythmia, or history of 
myocardial infarction 
6. History of lower extremity fasciotomy 
7. Enrolled in another clinical trial or has used of any investigational drugs, biologics, or devices within 30 
days prior to randomization  
8. Currently or have taken in the past medications that affect neuromuscular function, aminoglycosides, 
muscle relaxants, or other botulinum neurotoxin agents 
9. Women who are pregnant or breast-feeding 
10. Vulnerable populations 
11. Not suitable for study participation due to other reasons at the discretion of the investigator  
 
5.4 Subject Screening for Recruitment  
5.4.1 Subject Identification 
Potential subjects will be identified at the time of diagnosis by the investigators. Using their clinical discretion, 
discussion of the study will be offered alongside current standard treatments. Should the participating be interested 
in participation, the written consent form will be provided and clinic appointments scheduled with study staff for 
enrollment. Participant name and contact information will be provided to study staff by the diagnosing investigator 
for further contact with the study team.  
Prior to enrollment, primary investigator will discuss via telephone call the timeline, interventions, goals, potential 
side effects, and incentive of the study. If more discussion is desired by potential subjects, co-investigators can 
contact potential subjects by telephone prior to scheduled enrollment. Eventual enrollment in the study will be 
elective provided the subject meets inclusion criteria. 
5.4.2 Recruitment and Retention Strategies 
Investigators have practice specialties of sports medicine, pain medicine, and peripheral vascular that lend 
themselves to identifying potential subjects in clinic. As this is a feasibility study, there will be no differentiation 
amongst sexes, races, or ethnicities and simply the first ten individuals enrolled and undergoing treatment will be 
the group studied.  
 
Retention strategies include incentives provided at the time of injection, 2-month follow up, and 6-month follow up. 
Incentive will consist of $100 cash at the time of injection, and $50 at each the 2-month and 6-month follow up for 
a total of $200. Second retention measure is telephone follow up for the 4 and 6-month follow ups in lieu of clinic 
visit 
 
5.5  Vulnerable Populations 
Vulnerable populations will not be included in this study. 
5.5.1  Subject Capacity 
 
Subjects must have the capacity to provide informed consent as determined by the PI and study team.  


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5.5.2  Subject/Representative Comprehension 
 
Prior to providing written consent, investigator will ask that subjects recall and restate what they have been told 
during the informed consent process to ensure comprehension.  Further, teams will follow state laws and 
institutional policies to determine who will serve as legal authorized representative (LAR) and that research teams 
will include these LARs to the extent possible in the consent process. 
5.6 
Informed Consent 
 
Study staff will be responsible for ensuring that valid written consent is obtained and documented for all subjects. 
 
5.6.1 Process of Consent 
 
• 
Written informed consent will be obtained by the physician performing the Botox injection prior to injection is 
performed.  
• 
Consent to perform the injection will be performed on the standard UW Health Botulinum Toxin Injection 
Consent Form (301647-DT) available on UConnect and in Appendix 1. Consent for participation in the study 
will also be signed prior to enrollment via the consent in Appendix 2. 
• 
Informed consent will be obtained in person by competent individuals making witness signature unnecessary. 
• 
Investigator will review the consent form with the subject and obtain written consent prior to performing Botox 
injection at the time of the first clinic visit (time 0). For individuals that are non-English speakers, a translator 
will be present to review consent in the same manner as with subjects who speak English.  
5.6.2 Consent Form (see templates for UW-Madison) 
Please see supporting documents (Appendix 1 and 2)  
 
5.6.3 HIPAA 
Information about study subjects will be kept confidential and managed according to the requirements of the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). HIPAA documentation will be integrated into the 
consent form (Appendix 2). Attached as part of our application is a signed subject authorization form that includes:  
 
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI.  
5.6.4 Revoking Consent 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the 
ability to use all information collected prior to the revocation of subject authorization.  For subjects that have revoked 
authorization to collect or use PHI, attempts should be made to obtain permission to collect at least vital status (i.e. 
that the subject is alive) at the end of their scheduled study period. 
5.6.5  Costs to the Subject 
There will be no cost to subjects for the clinic visits or procedures that are done for research purposes only and 
are not part of subject’s regular care. These services will be paid for via Division of PM&R research grant. 
 
Subjects will have to pay for basic expenses like any childcare, food, parking, or transportation related to study 
activities.  
 


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If treatment for side effects is needed while in the study, the subject or subject’s insurance will be financially 
responsible for this treatment.  
 
5.6.6 Payment for Participation 
 
For completion of all the study visits, subjects will receive a total of $200 in cash for completing in this study.   
 
• 
We will give $100 cash for receiving the Botox injection, obtaining baseline measurements with the 
physical therapist, and filling out the UWRI questionnaire.  
 
• 
We will then provide $50 cash after having strength measurements repeated at 2 months and following 
up with physician for monitoring of side effects and completion of UWRI.  
 
• 
Final $50 cash will be mailed to the participant after the 6 month telephone call for completing the study.  
 
• 
If subject chooses to leave or we take subject off the study for any reason, they will be allowed to keep 
the money already given them. 
 
Enrollment of individuals with a potential status relationship, including family members of the research team, will be 
declared in an application to the IRB (Initial Review Application, Change of Protocol) and justification for the 
inclusion of these subjects provided. The IRB will then assess on a case-by-case basis whether the inclusion is 
warranted by the protocol, the recruitment and consent process are free from undue influence, and the 
confidentiality of these subjects will be protected adequately.  
 
5.7 Early Withdrawal of Subjects 
5.7.1 Premature termination of study 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written 
notification, documenting the reason for study suspension or termination, will be provided by the suspending or 
terminating party to the Division of PM&R and regulatory authorities. If the study is prematurely terminated or 
suspended, the PI will promptly inform the IRB and will provide the reason(s) for the termination or suspension.  
 
Circumstances that may warrant termination or suspension include, but are not limited to:  
• 
Determination of unexpected, significant, or unacceptable risk to participants  
• 
Demonstration of efficacy that would warrant stopping  
• 
Insufficient compliance to protocol requirements  
• 
Data that are not sufficiently complete and/or evaluable  
• 
Determination of futility  
 
Study may resume once concerns about safety, protocol compliance, data quality are addressed and satisfy the 
sponsor, IRB and/or FDA. 
5.7.2 When and How to Withdraw Subjects 
 
As the study involves a one-time injection, subjects will be withdrawn of their own volition or by failure to adhere to 
protocol requirements.  
5.7.3    Data Collection and Follow-up for Withdrawn Subjects 
 


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Intervention is a one-time injection. Therefore, patients who opt out of the study will not be able to opt out of 
treatment once injection is performed.  
6 Study Agent 
6.1 Description and Formulation 
 
Botox will be prepared by the central pharmacy per standardized protocol as directed by Allergan: 
Prior to injection, reconstitute each vacuum-dried vial of BOTOX with only sterile, preservative-free 0.9% 
Sodium Chloride Injection USP. Draw up the proper amount of diluent (1 mL) in the appropriate size 
syringe, and slowly inject the diluent into the vial. Discard the vial if a vacuum does not pull the diluent 
into the vial. Gently mix BOTOX with the saline by rotating the vial. Record the date and time of 
reconstitution on the space on the label. BOTOX should be administered within 24 hours after 
reconstitution. During this time period, reconstituted BOTOX should be stored in a refrigerator (2° to 8°C).  
 
NOTE: State is the study agent is IND/IDE exempt. If not, state reference number and identify the holder. 
6.2 Packaging 
• 
Study drug will be supplied by the central pharmacy within 24 hours of scheduled injection per their usual protocol.  
• 
Drug will be packaged in a clear plastic bag with the patient’s identifying information clearly visible on the outside 
and placed in the refrigerator set between 2o and 8o C. 
• 
Individual syringes will also be labeled with subject’s identifying information 
6.3 Preparation, Administration and Storage of Study Drug 
Botox will be prepared by and delivered by the UW Pharmaceutical Research Center (PRC) per standardized 
protocol as directed by Allergan: 
Prior to injection, reconstitute each vacuum-dried vial of BOTOX with only sterile, preservative-free 0.9% 
Sodium Chloride Injection USP. Draw up the proper amount of diluent (1 mL) in the appropriate size 
syringe, and slowly inject the diluent into the vial. Discard the vial if a vacuum does not pull the diluent 
into the vial. Gently mix BOTOX with the saline by rotating the vial. Record the date and time of 
reconstitution on the space on the label. BOTOX should be administered within 24 hours after 
reconstitution. During this time period, reconstituted BOTOX should be stored in a refrigerator (2° to 8°C).  
 
Contact agent at the UW Pharmaceutical Research Center is Susan Johnston, who can be reached at (608) 263-
8863.  
6.4 Route of Administration 
• 
Dose: 50 units will be injected into the TA (25 proximal, 25 distal) under US-guidance. 
• 
Treatment duration: Established duration of action on muscular weakness of other uses of Botox is between 2 
and 4 months. Given this novel treatment, duration of action in our study is unknown. 
• 
Expected side effects include: 
• 
Weakness in the muscle injected 
• 
Injection site pain 
• 
Injection site bleeding 
 
6.5 Starting Dose and Dose Escalation Schedule 
None 


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6.6 Dose Adjustments/Modifications/Delays 
Following injection, dosage cannot be changed and study will maintain the aforementioned dose for the duration of 
this study. Based on studies for other indications, Botox has been shown to take effect in approximately 2 weeks 
and last between 2 and 4 months. 
6.7 Prior and Concomitant Therapy/ Standard of Care 
Patient will not undergo concomitant medical therapy including, but not limited to physical therapy or surgical 
fasciotomy. If the patient has undergone previous physical therapy for the same diagnosis, this data will be collected 
but will not alter ability to participate in the study. Previous fasciotomy will cause exclusion of the participant from 
enrolling in the study. Allowed in the study are over-the-counter pain medications including NSAIDs and Tylenol as 
needed.  
6.8 Randomization and Blinding of Study Drug 
The subjects and drug will not be blinded in this study and subjects will not be randomized into differing treatment 
arms.  
 
6.9 Receiving, Storage, Dispensing and Return or Disposal of Study Agent  
 
Table 2: Study Agent information at a glance: 
 
Name 
Source 
Storage  
Dispensing 
Disposal 
Botox 
UW Pharmacy 
Stored 
in 
Pain 
Clinic refrigerator 
until 
time 
of 
injection 
One-time 
injection will be 
performed 
by 
treating physician 
Excess 
medication will be 
disposed 
of 
in 
appropriate 
medical 
waste 
containers 
 
6.9.1 Receipt of Drug Supplies 
After reconstitution, the UW Pharmaceutical Research Center will deliver the medication to the UW Pain Clinic 
(1102 S Park St, 3rd floor, Madison, WI). At delivery, an inventory will be performed and a drug receipt log filled out 
and signed by the person accepting the shipment.  The designated study staff will count and verify that the shipment 
contains all the items noted in the shipment inventory.  Any damaged or unusable study drug in a given shipment 
(active drug or comparator) will be documented in the study files. 
6.9.2 Storage 
Drug will be stored at the UW Pain Clinic refrigerator set between 2o and 8o C until the time of injection. 
 
6.9.3 Dispensing 
Drug will be ordered by the lead investigator prior to the scheduled clinic visit one. The drug will be prepared, 
assigned to the appropriate patient, and delivered to the UW Pain Clinic by the UW Pharmacy within 24 hours of 
the appointment. Regular study drug reconciliation will be performed to document drug assigned, drug consumed, 
and drug remaining.  This reconciliation will be logged on the drug reconciliation form, and signed and dated by the 
study team. 
 
 


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6.9.4 Return or Disposal 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and drug 
remaining.  This reconciliation will be logged on the drug reconciliation form, signed and dated.  Any discrepancies 
noted will be investigated, resolved, and documented prior to destruction of unused study drug.  Drug destroyed on 
site will be documented in the study files. 
 
7 Study Procedures 
 
Procedure: US-guided Botox injection 
Under ultrasound guidance, the TA will be identified in both a longitudinal and transverse fashion to isolate the 
muscle from the surrounding tissues and identify any potential vascular or nervous structures. After cleansing the 
skin with chlorhexidine solution and utilizing sterile technique, the muscle will be viewed in longitudinally. Using an 
in-plane approach, the muscle will be injected proximally and distally with 25 units of Botox mixed to 1 unit: 1 mL. 
Following injection, the sites will be monitored for cessation of bleeding and any immediate side effects prior to 
discharge from the clinic.  
7.1 LABS 
 
There are no labs that are anticipated to be drawn in this study.  
7.2 Established Standard of Care:  
Table 3.  Study Calendar 
 
Process 
Screening 
Baseline 
(initial clinic 
visit; time 0) 
Follow-up 1  
(2 months, in 
clinic) 
Follow-up 2  
(4 months, telephone) 
Final Visit  
(6 months, 
telephone) 
IMP 
Measurement 
SOC 
X 
 
 
 
UWRI 
 
X 
X 
X 
X 
Kiio Force 
Measurement 
X 
 
X 
 
 
Botox 
injection into 
TA 
 
X 
 
 
 
 
Indicate if study or standard of care by using “X” for study and “SOC” for standard of care. 
7.3 Study Visits 
7.4.1 Screening/Baseline:  
Screening and consent will be discussed with PI at clinic visit in which IMP measurement (CECS diagnosis) is taken 
prior to enrollment in the study. Once consent is obtained, baseline force measurements (with PT) and UWRI (at 
study clinic visit 1) will both be scheduled within 1 month of IMP measurement.  
7.4.2 Follow up:  
 
Table 4. Acceptable Window for Study Visits (including weekends) 
 
Visit 
Window 
Activities 


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PT visit 1 
Within 1 month of IMP 
measurement 
Kiio Force 
measurement of ankle 
plantarflexion and 
dorsiflexion 
Study visit 1 
(establishes time 0 of 
study) 
Within 1 months of IMP 
measurement 
Written consent 
reviewed and collected 
UWRI baseline 
US-guided Botox 
injection into TA 
PT visit 2 
2 months +/- 5 days 
Kiio Force 
measurement of ankle 
plantarflexion and 
dorsiflexion 
Follow-up 1 
(Clinic) 
2 months +/- 5 days 
UWRI 
Evaluation for side 
effects 
Follow-up 2 
(Telephone) 
4 months +/- 1 week 
UWRI 
Evaluation for side 
effects 
Follow-up 3 
(Telephone) 
6 months +/- 1 week 
UWRI 
Evaluation for side 
effects 
 
7.4.3 Unscheduled: 
 
Possible AEs: Following investigators learning of potential AEs, subject will be contacted over telephone to discuss 
case. If deemed warranted by the investigator’s clinical impression, subject will be scheduled for evaluation in clinic 
at earliest available appointment. Subject will be evaluated by investigator and symptoms addressed as clinically 
appropriate. If symptoms deemed a side effect of the medication, these will be documented in the patient’s chart 
for inclusion in the medication effects. 
 
7.4.4 Final Study Visit 
 
Study will conclude for each subject after the 6-month telephone follow-up encounter as each subject will only 
undergo a single injection for the study and will not be evaluated again under this protocol. Given the medication 
duration of action, adverse effects should not occur following this encounter. However, participants will be 
permitted to contact the study investigators should possible AEs occur, at which point the protocol mentioned 
above in 7.4.3 will be followed.  
 
8 Study Analysis 
8.1 Sample Size Determination 
Using a one-way ANOVA and assuming independence of leg scores for each patient, we will have 80% power to 
detect an overall significant F-test (assuming a  2 (SD=1) point decrease in pain score from baseline to 6 months) 
with n=6 patients (e.g. 12 legs).  Accounting for potential drop-out (15%) and, additionally, adjusting for non-


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parametric analyses, n=10 patients will be sufficient to provide preliminary effect sizes at each time point which will 
help inform power analyses for studies planned beyond this pilot study.     
8.2 Statistical Methods 
Basic descriptive statistics, means (SD) and medians (IQR) for continuous variables and frequencies (percentages) 
for categorical variables will be used to summarize patient outcomes.  For the primary outcome, change in pain 
(from baseline) will be assessed at each time point (2,4,6 months) using Friedman’s ANOVA.  Friedman’s ANOVA 
is the non-parametric analog to one-way repeated measures ANOVA and is often used for ordinal outcomes.  If 
necessary and feasible, GEE models will be constructed to further assess changes in pain while accounting for 
intra-subject correlation.  Secondary endpoints utilizing the UWRI will also be assessed in this manner.  Change in 
strength outcomes at baseline and 2 months will be assessed using Wilcoxon signed rank tests or, if necessary, 
linear mixed effects models for repeated measures, to account for intra-subject correlation (left and right legs).   
8.3 Subject Population(s) for Analysis 
The subject population for analyses will include all patients who receive the botox injection.  We intend to minimize 
loss to follow-up; however, if patients drop out of the study, we will attempt to use statistical methods that allow for 
missing outcomes (e.g. GEE/Linear models for repeated data) so that all available data can be used for analysis.   
8.4 Planned Interim Analysis:  
No interim analyses are planned for this study.  
9 Data Collection, Handling and Record Keeping 
9.1 Data Confidentiality  
• 
Subject encounters include questionnaires will be submitted to the electronic record on RedCap according to the 
subject’s respective medical record number. Following conclusion of the study, the investigators will utilize the 
database to review the medication effect and perform data analysis.  
• 
Except for publication, data will not be shared with other researchers and identifiable information will not be 
released to third parties. 
 
 
9.1.1 Confidentiality of Subject Records 
By signing the protocol, the Investigator agrees that IRB representative may consult and/or copy study documents 
in order to verify CRF data. By signing the consent form, the subject agrees to this process. If study documents will 
be photocopied during the process of verifying CRF information, the subject will be identified by unique code only 
and full names and similar identifying information (such as medical record number or social security number) will 
be masked. 
 
The Clinical Site Investigators will ensure that the identity of subjects will be protected. All study records will be 
maintained in a secure fashion with access limited to essential study personnel only. All study documents submitted 
to the Coordinating Center will have identifiers removed other than dates of birth and service and subjects will be 
identified with a study-specific identification number only. The Clinical Site Investigators will maintain, in a secure 
location, an enrollment log that includes subject identifying information and links subjects to their study-specific 
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9.2 Data Capture  
9.2.1 Source Documents 
 
1. Physical therapy clinic notes 
2. Procedure note and respective US images 
3. Copies of transcription certified after verification as being accurate and complete from clinic visits with 
investigators 
4. Completed UWRI questionnaires from both clinic and telephone encounters that had been entered into 
RedCap 
 
9.2.2 Case Report Forms 
 
See Appendix 4: Sample tracking 
See Appendix 5: AEs 
See Appendix 6: Telephone contact  
 
9.2.3 Data Collection Tools 
Study will utilize RedCap for data collection and management. 
9.3 
Data Management 
 
Investigator, Michael Suer, will serve as the DCC for the study. The DCC agrees to be responsible for implementing 
and maintaining quality control and quality assurance systems with written standard operation procedures (SOPs) to 
ensure that trial is conducted and data are generated, documented, and reported in compliance with the protocol, 
accepted standards of Good Clinical Practice (International Conference on Harmonization E6), and all applicable 
federal, state, provincial, and local laws, rules, and regulations relating to the conduct of the clinical trial in an ongoing 
and auditable manner.”  
9.4 
Records Retention 
Data will be retained for 4 years following the conclusion of the study. 
 
 
10   Assessment of Safety 
10.1 
Specifications of Safety Parameters 
 
Lower extremity weakness with focus on ankle dorsiflexion weakness (i.e. foot drop), will be both quantitative and 
qualitative data. 
Bruising, bleeding, pain, redness, or swelling where the injection was given will be qualitative data 
 
10.1.1 Definition of Adverse Events (AE)  
Adverse event means any untoward medical occurrence associated with the use of an intervention in humans, 
whether or not considered intervention-related (21 CFR 312.32 (a)). 
 


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10.1.2 Definition of Serious Adverse Events (SAE)  
Serious adverse event or serious suspected adverse reaction. An AE or suspected adverse reaction is considered 
"serious" if, in the view of either the investigator or sponsor, it results in any of the following outcomes: death, a 
life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. 
 
10.1.3 Definition of Unanticipated Problems (UP)  
OHRP considers unanticipated problems involving risks to participants or others to include, in general, any incident, 
experience, or outcome that meets all of the following criteria:  
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described in the 
protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) 
the characteristics of the participant population being studied;  
• 
Related or possibly related to participation in the research (“possibly related” means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in the 
research); and  
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.  
 
This study will use the OHRP definition of UP. 
10.2 
Classification of an Adverse Event 
10.2.1 Severity of Event 
All AEs will be assessed by the clinician using a protocol defined grading system. For AEs not included in the 
protocol defined grading system, the following guidelines will be used to describe severity.  
 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities.  
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. Moderate 
events may cause some interference with functioning.  
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or other 
treatment. Severe events are usually potentially life-threatening or incapacitating. 
 
10.2.2 Relationship to Study Agent 
 
In a clinical trial, the study product must always be suspect. To help assess, the following guidelines are used.  
 
For all collected AEs, the clinician who examines and evaluates the participant will determine the AE’s causality 
based on temporal relationship and his/her clinical judgment. The degree of certainty about causality will be graded 
using the categories below.  
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, occurs 
in a plausible time relationship to drug administration and cannot be explained by concurrent disease or 
other drugs or chemicals. The response to withdrawal of the drug (de-challenge) should be clinically 
plausible. The event must be pharmacologically or phenomenologically definitive, with use of a satisfactory 
re-challenge procedure if necessary.  


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Probably Related – There is evidence to suggest a causal relationship, and the influence of other factors 
is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable time 
after administration of the drug, is unlikely to be attributed to concurrent disease or other drugs or chemicals, 
and follows a clinically reasonable response on withdrawal (de-challenge). Re-challenge information is not 
required to fulfill this definition.  
• 
Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the trial medication). However, other factors may have 
contributed to the event (e.g., the participant’s clinical condition, other concomitant events). Although an 
AE may rate only as “possibly related” soon after discovery, it can be flagged as requiring more information 
and later be upgraded to “probably related” or “definitely related,” as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the event did not occur 
within a reasonable time after administration of the trial medication) and in which other drugs or chemicals 
or underlying disease provides plausible explanations (e.g., the participant’s clinical condition, other 
concomitant treatments). 
• 
Not Related – The AE is completely independent of study drug administration, and/or evidence exists that 
the event is definitely related to another etiology. There must be an alternative, definitive etiology 
documented by the clinician. 
10.2.3 Expectedness 
 
Principle investigator will be responsible for determining whether an AE is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk information 
previously described for the study agent. 
 
10.3 
Time period and frequency for event assessment and follow-up 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and interviews of 
a study participant presenting for medical care, or upon review by a study monitor. All AEs including local and 
systemic reactions not meeting the criteria for SAEs will be captured on the appropriate RF. Information to be 
collected includes event description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of resolution/stabilization of 
the event. All AEs occurring while on study must be documented appropriately regardless of relationship. All AEs 
will be followed to adequate resolution.  
 
Any medical condition that is present at the time that the participant is screened will be considered as baseline and 
not reported as an AE. However, if the study participant’s condition deteriorates at any time during the study, it will 
be recorded as an AE. UPs will be recorded in the data collection system throughout the study.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at each 
level of severity to be performed. AEs characterized as intermittent require documentation of onset and duration of 
each episode.  
 
The PI will record all reportable events with start dates occurring any time after informed consent is obtained until 
7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At each study visit, the 
investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for outcome 
information until resolution or stabilization. 
10.4 
Reporting procedures 
Reporting will be performed by Michael Suer according to HSIRB standard protocols: 
Immediate Report to the IRB  
An AE/SAE meeting the above definition of an unanticipated problem must be reported to the IRB immediately 
if both of the following conditions are met:  


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o 
The event occurred at a site under the purview of the UW Health Sciences (HS) IRB or Minimal Risk 
(MR) IRB  
o 
The event is immediately life threatening or severely debilitating to other current subjects 
The IRBs expect that these reports will be rare. SAEs that meet these conditions must be reported to the IRB 
Chair or IRB Director via telephone (preferred) or email as soon as possible, but no later than 1 business day after 
the research team becomes aware of the event. The research team will then discuss with the IRB Chair or IRB 
Director what action needs to be taken related to the occurrence (e.g., suspension of study enrollment, change in 
treatment regimen) to prevent further harm from occurring. This initial report to the IRB Chair or IRB Director must 
be followed with the submission of a reportable event in ARROW within 2 business days after the local research 
team becomes aware of the event.  
 
10.4.1 Adverse Event Reporting  
Any other AE/SAEs that meet the definition of an unanticipated problem as described above must be reported to 
the HS or MR IRB within 14 business days. 
10.4.2 Serious adverse event reporting  
 
The study clinician will complete a SAE Form within the following timelines:  
All deaths and immediately life-threatening events, whether related or unrelated, will be recorded on the SAE Form 
and submitted to the DCC/study sponsor within 24 hours of site awareness. See Section 1, Key Roles for contact 
information. Other SAEs regardless of relationship, will be submitted to the DCC/study sponsor within 72 hours of 
site awareness.  
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be chronic or 
the adherence to be stable. Other supporting documentation of the event may be requested by the DCC/study 
sponsor and should be provided as soon as possible. The study sponsor will be responsible for notifying FDA of 
any unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later than 7 
calendar days after the sponsor's initial receipt of the information. 
 
10.4.3 Unanticipated problem reporting  
 
The site investigator will be responsible for creating and completing a UP report form. Incidents that meet the OHRP 
criteria for UPs will be reported promptly on the following timeline:  
• 
UPs that are SAEs will be reported to the IRB and to the DCC/study sponsor within 24 hours of the investigator 
becoming aware of the event. 
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 14 business days of the investigator 
becoming aware of the problem. 
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s written reporting 
procedures), the supporting agency head (or designee), and OHRP within 14 business days of the IR ’s receipt 
of the report of the problemfrom the investigator. 
 
The UP report will include the following information:  
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the event, incident, experience, or outcome represents an UP; 
• 
A description of any changes to the protocol or other corrective actions that have been taken or are proposed in 
response to the UP. 
 


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10.5 
Study Halting Rules 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written 
notification, documenting the reason for study suspension or termination, will be provided by the suspending or 
terminating party to the Division of PM&R and regulatory authorities. If the study is prematurely terminated or 
suspended, the PI will promptly inform the IRB and will provide the reason(s) for the termination or suspension.  
 
Circumstances that may warrant termination or suspension include, but are not limited to:  
• 
Determination of unexpected, significant, or unacceptable risk to participants  
• 
Demonstration of efficacy that would warrant stopping  
• 
Insufficient compliance to protocol requirements  
• 
Data that are not sufficiently complete and/or evaluable  
• 
Determination of futility  
 
Study may resume once concerns about safety, protocol compliance, data quality are addressed and satisfy the 
sponsor, IRB and/or FDA. 
 
10.6 
Safety Oversight 
The Principal Investigator will serve as the DMC. REDCap will provide the DMC and the study biostatistician the 
ability to efficiently collect the needed data and provide safety oversight of the protocol. 
11 Study Monitoring, Auditing, and Inspecting 
11.1 
Medical Monitoring 
The Principal Investigator will serve as the medical monitor for the study. In the design of the study, the investigators 
will have regular follow up with the research participants to allow close monitoring for AE/SAEs. Should AE/SAEs 
occur outside of clinical hours, participants will be provided at time of consent with appropriate instructions for 
contacting clinician for triage.  
11.1.1 Study Monitoring Plan 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are protected, that 
the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with 
the currently approved protocol/amendment(s), with GCP, and with applicable regulatory requirement(s).  
• 
Monitoring for this study will be performed by the principal investigator  
• 
Monitoring will be provided during all clinic visits by qualified study staff including initial assessment and 2-
month follow up. He will also be responsible for monitoring participants immediately following intervention prior 
to a safe discharge from the clinic. The remainder of monitoring will be targeted data verification of endpoint 
and safety.    
• 
PI will be provided copies of monitoring reports within 7 days of visit.  
• 
Independent audits will not be conducted  
• 
Investigators will perform internal quality management of study conduct, data collection, documentation and 
completion.  
 
11.2 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or MOP requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a result of 
deviations, corrective actions are to be developed by the site and implemented promptly.  
These practices are consistent with ICH E6:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  


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• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
The site PI/staff will be responsible for continuous vigilance to identify and report deviations to the protocol. 
These will be reported within 7 working days of identification of the protocol deviation, or within 7 working days 
of the scheduled protocol-required activity. All deviations must be addressed in study source documents, 
reported to Program Official and DCC. Protocol deviations will be sent to the local IRB per their guidelines. The 
site PI/study staff is responsible for knowing and adhering to their IRB requirements. Further details about the 
handling of protocol deviations will be included in the MOP.  
 
11.3 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB (or their 
representatives), the sponsor, government regulatory bodies, of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).  The investigator will ensure the 
capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
12 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA Title 21 
part 312 and International Conference on Harmonization guidelines), applicable government regulations, applicable 
local and state laws, and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics Committee (EC) 
or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study 
conduct.  The decision of the EC/IRB concerning the conduct of the study will be made in writing to the investigator 
and a copy of this decision will be provided to the sponsor before commencement of this study.  The investigator 
should provide a list of EC/IRB members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient information 
for subjects to make an informed decision about their participation in this study.  See Attachment ___ for a copy of 
the Subject Informed Consent Form.  This consent form will be submitted with the protocol for review and approval 
by the EC/IRB for the study.  The formal consent of a subject, using the EC/IRB-approved consent form, must be 
obtained before that subject undergoes any study procedure.  The consent form must be signed by the subject or 
legally acceptable surrogate, and the investigator-designated research professional obtaining the consent.  
13 Study Finances 
13.1 Funding Source 
Funding will be provided by an internal Department of Orthopedics and Rehabilitation Research Fund. 
13.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain greater 
than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly constituted 
Conflict of Interest Committee with a Committee-sanctioned conflict management plan that has been reviewed and 
approved by the study sponsor prior to participation in this study.  All UW investigators will follow the UW conflict of 
interest policy. 
13.3 Subject Stipends or Payments 
Subjects will be paid with cash. For patient incentive, cash will be distributed in person consisting of: $100 at time 
of injection, $50 at 2 month follow up, and $50 following the 6 month follow up. The final cash amount will be mailed 
to the subject to an address they provide at the time of follow up.  


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14 Publication Plan 
 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the information 
provided by the sponsor for the purposes of performing the study, will be published or passed on to any third party 
without the consent of the study sponsor.  Any investigator involved with this study is obligated to provide the 
sponsor with complete test results and all data derived from the study. 
Attachments (incomplete) 
Appendix 1: Botulinum Toxin Injection Consent (301647-DT) 
Appendix 2: Study Consent Form 
Appendix 3: Botox package insert 
15 References 
 
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ix Wilder RP, Magrum E. Exertional compartment syndrome. Clin Sports Med 2010; 29:429. 
xTurnipseed WD, Hurschler C, Vanderby R Jr. The effects of elevated compartment pressure on tibial 
arteriovenous flow and relationship of mechanical and biochemical characteristics of fascia to genesis of 
chronic anterior compartment syndrome. J Vasc Surg 1995; 21:810. 
xi Rorabeck CH, Bourne RB, Fowler PJ. The surgical treatment of exertional compartment syndrome in athletes. J 
Bone Joint Surg Am. 1983;65:1245–1251. 
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leg. Long-term followup. Am J Sports Med. 1993;21:811–817. 
xiii Fronek J, Mubarak SJ, Hargens AR, et al. Management of chronic exertional anterior compartment syndrome 
of the lower extremity. Clin Orthop Relat Res 1987; :217. 
xiv Micheli LJ, Solomon R, Solomon J, et al. Surgical treatment for chronic lower-leg compartment syndrome in 
young female athletes. Am J Sports Med 1999; 27:197. 
xv Isner-Horobeti ME, Dufour SP, Blaes C, et al. Intramusular pressure before ad after botulinum toxin in chronic 
exertional compartment syndrome of the leg: a preliminary study. Am J Sports Med. 2013;41:2558-66. 
xvi Baria MR, Sellon JL. Botulium toxin for chronic exertional compartment syndrome: a case report with 14 
month follow-up. Clin J Sport Med. 2016;26:111-13.  
 


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xvii Isner-Horobeti ME, Dufour SP, Blaes C, et al. Intramusular pressure before ad after botulinum toxin in chronic 
exertional compartment syndrome of the leg: a preliminary study. Am J Sports Med. 2013;41:2558-66. 
xviii Baria MR, Sellon JL. Botulium toxin for chronic exertional compartment syndrome: a case report with 14 
month follow-up. Clin J Sport Med. 2016;26:111-13.