Evaluating the Efficacy of Blood Flow Restriction Therapy in a Randomized Clinical Trial for Postoperative Rehabilitation Following Ankle Ligament Reconstruction
Phase: NA
Conditions: Ankle Reconstruction, Blood Flow Restriction Therapy, Physical Therapy
Sponsor: Texas Tech University Health Sciences Center

Grimes – BFR for ankle reconstruction
IRB#: FY2024-335
Study protocol – version 3.1 
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PROTOCOL
Evaluating the Efficacy of Blood Flow Restriction Therapy in a Randomized Clinical Trial for 
Postoperative Rehabilitation Following Ankle Ligament Reconstruction
CONFIDENTIAL  
Protocol No.
FY2024-335
PI:                                                                                                              Orthopaedic Surgeon: Jerry Grimes, MD1,2
CO-I:  
Orthopaedic Surgeon: Kenneth Stephenson, MD3 
Advising PT: Dr. Jean-Michel Brismée, PT, ScD4
 
 
 
 
 
 
                   Practicing PT: Dr. Jordan Fultz PT, DPT, OCS5 
Version No. / Version Date:
3.1 |18 February 2026
NCT Registration Number: 
pending 
 
Affiliations: 
1 Department of Orthopaedic Surgery and Rehabilitation, Texas Tech University Health Sciences Center, Lubbock, 
TX, USA
2University Medical Center
3 The Center for Orthopedic Surgery, Lubbock, TX, USA
4 Physical Therapy Today, Lubbock, TX, USA
5Department of Rehabilitation Sciences, Center for Rehabilitation Research, Texas Tech University Health Sciences 
Center, Lubbock, TX, USA
Protocol Template v2.0 (03/28/2025):
Adapted and modified from the TTUHSC Clinical Research Institute (CRI) Protocol Development Template 
and ICH guidance document E6 (Good Clinical Practices) Appendix B

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Version No.
Effective Date
Description of Change
Originator
1.0
15 September 2025Initial Release – major revamp of prior submissions 
from back in 2024. Clarification of protocol, 
addressing IRB questions, etc.
David Lanford and Wilson McDowell
2.0
21 October 2025
Protocol Modification includes: 
x
SNOSE randomization and Blinding 
procedures; affects participant 
identification number
x
Clarification of study sites; personnel; 
roles/responsibilities (study PT vs. 
treatment PT)
x
Clarification of exclusion of participants 
who have workers compensation for 
insurance
x
Clarification of study Master List and 
“key” and storage mechanisms
x
Personnel changes (protocol only) – 
removal of Jenny Hudnall, Evan 
Hernandez, Wilson (Cade) McDowell, 
and David Lanford on the protocol only 
for ease of future modifications.
Cayuse modification: addition of UMC site 
approval, study flow diagram
Jenny Hudnall
3.0
22 January 2026
Protocol modifications:
x
Additional citations added
x
Clarification of which limb(s) will be used 
for measurement
x
Clarification of visit windows from date of 
surgery rather than weeks of PT
x
Collection of provider names to retain 
blinding in a treatment/blinding log and 
measurement consistency
x
Clarification of data storage locations
x
Clarification of SAE/AE reporting
x
Meeting minutes will be emailed to the 
IRB for reference after SMB meetings.
Study Data Sheet (CRF) modifications: 
x
Removal of group information from study 
Data Sheets
x
Clarification of which limb(s) will be used 
for measurements
Personnel modifications (Cayuse only)
Addition of Landon Thomas, PT; Taylor Woods, PT; 
Tina Herston, PT as study personnel 
ICF changes: 
x
Removal of UMC PT as a PT site
David Lanford and Wilson McDowell

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Study protocol – version 3.1 
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x
Removed reference to contralateral limb 
measurements at baseline
Other: updated study flow diagram pdf
3.1
18 February 2026
PROTOCOL FORMATTING ONLY: Modifications 
requested by NCT.gov to separate outcomes 
measures. “More than one outcome measure 
appears to be described. The Outcome Measure 
describes multiple assessments with potentially 
different Units of Measure. Assessments with 
different Units of Measure (e.g., weight and 
height) must be presented in separate Outcome 
Measures. Please revise to present these 
assessments in separate Outcome Measures (e.g., 
weight in kilograms, height in meters), as 
appropriate, or to clarify how multiple 
measurements will be aggregated to arrive at one 
reported value (e.g., weight and height will be 
combined to report BMI in kg/m^2).” 
Correction/updates to Surgical Site and Clinical 
site addresses on protocol and ICF. 
Addition of Northstar Surgery Center as site in 
Cayuse along with letter of support.
Please note, official NCT Number is pending. Once 
number is obtained, separate modification will be 
submitted to update the ICF to include NCT 
Number. 
J Hudnall

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Abstract: 
Blood flow restriction therapy (BFR) is a rehabilitation modality which started in Japan under the name Kaatsu in 
the 1960s, but it has just recently been adopted by physical therapists in the US (2016) (44). BFR works by limiting 
arterial blood flow to a limb and obstructing venous outflow while having subjects perform exercise using light 
weight (2,3,4,8,11,23,27,33,36,44). Limiting circulation both limits oxygen delivery, which induces anaerobic 
metabolism, and causes the pooling of metabolites, which are chemical messengers that drive changes to bones, 
muscles, and soft tissues (11,12,20,22,24,25,31,33,39,41,43,47. This increase in chemical messengers stimulates 
the production of hypoxia inducible factors, which have wide ranging effects. Increases in HGH, the MTOR 
pathway, and a decrease myostatin activation lead to increases in IGF1, testosterone and a variety of other 
mediators, all of which help muscle growth (12,20,24,25,31,39).  Our study will be a single blinded clinical trial to 
investigate BFR for rehabilitation of patients after ankle ligament reconstruction, which requires prolonged 
immobility, which leads to loss of muscle mass and strength.(4,14,16,18,19,28,29 After consenting, we will 
randomly assign subjects to the BFR (Treatment) or the control group, which will receive the current standard of 
care (SOC). Both will experience casting and immobility, as per surgeon instructions, to protect their surgically 
repaired ligaments before splitting into BFR or SOC. Patients will then undergo prescribed physical therapy by a 
certified physical therapist for a minimum of 6 weeks. Data will be collected at the start of PT, at the end of the 
standard 6-weeks of PT, and (if the patient continues after the standard 6-weeks) the conclusion of PT. Outcome 
measures of interest include: muscle atrophy; ankle function; fatigability/manual muscle testing; pain scores; and 
cardiovascular effects (heart rate, blood pressure). Outcome measures will be compared between the SOC and BFR 
groups at the end of the study intervention. 
Keywords: ankle reconstruction; physical therapy; blood flow restriction therapy

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BACKGROUND AND SIGNIFICANCE
Ankle sprains, more specifically lateral ankle sprains, are one of the more common sources of ER visits, accounting 
for approximately 4-7% of all consultations and resulting in significant costs to the healthcare system in the United 
States (18). Conservative estimates range from $2-4 billion annually, though this number is thought to be 
underestimated. Despite their seemingly simple nature, ankle sprains can be complex (18,34). 
While many lateral ankle sprains (LAS) can be treated conservatively with pain management, rest, ice, 
compression, and elevation, up to 40% of those affected will develop chronic ankle instability (CAI), potentially 
necessitating surgical intervention (18,19,21,28,32). The Brostrom procedure is the surgical gold standard for ankle 
ligament reconstruction, addressing acute laxity or chronic instability through surgical reduction, tightening, or 
reconstruction of the lateral ankle ligament complex (16, 19, 21). Despite the high incidence of LAS and the 
widespread use of the Brostrom procedure, there is significant variability in postoperative protocols, leading to a 
lack of rehabilitation standardization and diverse outcomes (14). The primary debate in rehabilitation protocols 
centers on the timing of initiation; delayed mobilization versus early mobilization (40). Delayed mobilization, 
involving initial casting followed by a walking boot for 4-6 weeks, aims to protect repaired structures but can lead 
to atrophy and prolonged rehabilitation (36,40). Early mobilization, starting therapy immediately post-surgery, 
reduces atrophy and strength loss but carries the risk of graft damage. A currently new modality of rehabilitation, 
is blood flow restriction therapy (BFR). Utilizing BFR may allow patients to perform functional strength training at 
lower intensities, which will reap the benefits of protecting the repaired tissues as in delayed mobilization 
protocols while reaping the added benefits of early mobilization protocols (11,23,24,33,40,42,44,46). 
Blood Flow Restriction therapy (BFR) is a relatively new modality in the United States, only having been recognized 
by the American Physical Therapy Association (APTA) since 2018. Originating in Japan in the 1960s as "Kaatsu" 
(exercise with pressure), BFR was developed by Dr. Yoshiaki Sato, who observed physiological responses similar to 
heavy weight lifting from restrictive clothing. Traditional strength training requires loads of 60-70% of an 
individual's 1 rep max (1RM) for muscle hypertrophy and strength gains (6,7,11,23,27,29,33,37,46). In contrast, 
BFR achieves similar results at 10-30% of 1RM, or even passively, by partially occluding blood flow to the limbs 
without requiring the subject to exercise. Despite variability in BFR protocols, a common structure involves 
performing 4 sets of exercises at 30% 1RM in sets of 30, 15, 15, and 15 repetitions at 40-60% of limb occlusion 
pressure (LOP) for upper limbs and 60-80% LOP for lower limbs (6,11,21,23,27,33,37,44). The primary mechanism 
involves intermittent hypoxia, inducing the release of hypoxia-inducible factors (HIF-1 and HIF-2) and subsequent 
production of chemical mediators like nitrous oxide (NO), vascular endothelial growth factor (VEGF), human 
growth hormone (HGH), insulin-like growth factor 1 (IGF-1), testosterone, and 
catecholamines(12,24,25,31,33,38,39,41,43,45,47. BFR increases type II muscle fiber recruitment earlier than 
traditional exercise and induces metabolite buildup, leading to cellular swelling and protein synthesis. While the 
exact mechanisms are debated, BFR is clinically effective with a lower risk profile than initially expected 
(2,10,35,37,44,46). 
BFR training has quickly gained popularity among professional athletes, including every NFL team, for enhancing 
strength and aerobic capacity without the risks of high-intensity training (HIT)(23,33). BFR also offers benefits for a 
broader population, including rehabilitation after ankle ligament reconstruction. BFR protocols use lower loads, 
facilitating early rehabilitation and enhancing soft tissue healing, bone mineralization, endothelial function, and 
pain modulation through upregulation of endogenous opioid and endocannabinoid systems 
(11,12,20,22,24,25,31,33,38,39,41,43,44,45,47). Despite initial safety concerns, BFR has shown a favorable risk 
profile. Some researchers assert that there are no absolute contraindications to BFR. Initial fears of thrombus 
formation have been debunked, with data suggesting BFR is venoprotective(44). BFR has been safely used in 
patients with systolic pressures over 190mmHg, reducing cardiac workload by decreasing venous return. Our initial 
investigation will focus on young, healthy individuals, but BFR holds potential for broader applications (2,10,37,44). 
We propose that incorporating BFR in the rehabilitation of patients post-ankle ligament reconstruction will enable 
faster return to activities of daily living, less pain, reduced atrophy, and improved muscle strength compared to 
current protocols. BFR facilitates early strength training at lower loads, enhances soft tissue healing, improves 

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aerobic capacity and fatigue resistance, and modulates pain (4,6,11,21,23,27,33,36,37,40,46). No clinical 
investigations have yet explored BFR for post-ankle reconstruction rehabilitation, and existing data on BFR's 
efficacy is limited. Our study aims to evaluate BFR's efficacy compared to current standards, addressing disuse 
atrophy and muscle weakness safely and effectively. Success in this study could pave the way for further research 
into BFR for various soft tissue injuries, bone healing, endocrinological treatments, and rehabilitation for exercise-
intolerant individuals.
STUDY OBJECTIVES, PURPOSE, AND HYPOTHESES
Study Aims: 
1.
To evaluate the efficacy of Blood Flow Restriction (BFR) therapy compared to the current standard of care 
(SOC) in improving muscle atrophy, strength recovery, ankle functionality, and pain management in 
patients undergoing rehabilitation after ankle ligament reconstruction.
Objectives: 
1.
Evaluate Muscle Atrophy: To compare the extent of muscle recovery in the quadriceps and gastrocnemius 
muscles between patients receiving BFR therapy and those receiving the current standard of care. This 
will be done by comparing muscle circumference (3,4,6,9,11,14,21,23,29,36,40,44,48). 
2.
Assess Fatigability Recovery: To determine whether BFR therapy accelerates the recovery of dynamic 
lower extremity fatigability more effectively than the current standard of care as measured by manual 
muscle testing (MMT)(1,3,4,6,9,11,21,23,29,30,32,36,37,40,44,46,48). 
3.
Measure Functional Outcomes: To use the Foot and Ankle Disability Index (FADI) to evaluate 
improvements in ankle functionality and activities of daily living between the two treatment groups. 
(1,4,6,14,18,19,21,23,29,30,36,48)
4.
Monitor Pain Levels: To compare perceived pain levels during treatment and daily activities in patients 
undergoing BFR therapy versus those receiving standard care using a visual analog scale (VAS) 
(2,4,6,10,11,12,14,19,21,24,40)
5.
Analyze Cardiovascular Impact: To investigate changes in resting heart rate and blood pressure to identify 
any cardiovascular benefits associated with BFR therapy compared to the current standard of care 
(3,5,9,11,12,20,23,24,25,33,38,39,43,47). 
Hypothesis:
Muscle atrophy
1.
It is expected that, following a 6-week period of BFR on the lower affected limb, that subjects will show 
diminished atrophy of the lower limb at the level of maximal gastrocnemius circumference when 
compared to subjects who undergo the current SOC (1,3,4,9,21,22,23,24,29,36). 
2.
It is expected that, following a 6-week period of BFR on the lower affected limb, that subjects will show 
diminished atrophy of the thigh at 10cm and 20cm superior to the superior most aspect of the patella 
over those who utilize the current SOC (1,3,4,9,21,22,23,24,29,36).
Fatiguability
3.
It is expected that, following a 6-week period of BFR on the lower affected limb, that subjects will show 
improved plantarflexion fatigability, as measured by manual muscle testing, over those who receive the 
current SOC (1,3,4,9,21,22,23,24,29,36).
Functionality
4.
It is expected that, following a 6-week period of BFR on the lower affected limb, that subjects will show 
improved foot and ankle disability index scores when compared to those who receive the current SOC 
(3,4,9,14,19,21,22,28,30,32,40,48). 
Pain

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5.
It is expected that, following a 6-week period of BFR on the lower affected limb, that subjects will show 
diminished perception of pain both during therapeutic intervention and during ADL when compared to 
those who receive the current SOC (12,14,19,.21,40)
Cardiovascular impact
6.
It is expected that, following a 6-week period of BFR on the lower affected limb, that subjects will show 
greater changes in resting HR, consistent with their levels of activity prior to surgery, than will those who 
receive the current SOC. Those who undergo ankle ligament repair or reconstruction secondary to CAI 
with a concomitant lack of activity will experience a greater reduction in heart rate than those who 
undergo ankle ligament repair or reconstruction secondary to a sports or activity related, acute, injury 
(11,12,20,23,24,25,33,38,39,43,47). 
7.
It is expected that, following a 6-week period of BFR, subjects will exhibit a decrease in systolic blood and 
diastolic pressure, consistent with their level of presurgical activity, to a greater extent than does the 
cohort which receives standard of care. This only applies to those who go into surgery with a lack of 
previous conditioning. It has been suggested that elite athletes may actually see a small, but statistically 
significant rise is systolic blood pressure of 2-4mmHg. However, it is expected that untrained individuals 
will show a greater reduction in systolic and diastolic blood pressure than similarly untrained individuals 
who receive the current SOC (11,12,20,23,24,25,33,38,39,43,47). 
STUDY DESIGN
Study type: 
Randomized Clinical Trial
Study overview:
This study is designed as a randomized clinical trial to evaluate the efficacy of Blood Flow Restriction (BFR) therapy 
in postoperative rehabilitation following ankle ligament reconstruction. The study will be conducted at a single 
physical therapy (PT) center in the United States, with a focus on comparing BFR therapy to the current standard of 
care (SOC).
Patients who have undergone ankle ligament reconstruction surgery performed by participating orthopedic 
surgeons (JG; KS) will be randomized to either the treatment group (BFR therapy) or standard of care (SOC) group. 
Patients will then receive physical therapy (PT) managed by treatment physical therapists (t-PT). These therapists 
will perform BFR during the weekly PT sessions and provide the same at home exercises for participants in both 
groups. These physical therapists will not be part of the study team and will not collect study related data. 
Patients in the treatment group will begin BFR therapy at least 28 days post-op (+7 days). The therapy will be 
performed on the affected limb, focusing on hip and knee strength, with ankle strengthening in plantarflexion and 
dorsiflexion in a seated position. Additional exercises include multi-joint hip and knee strengthening, such as 
straight leg raises, side-lying external rotation hip exercises (clam shells), short arc quads, long arc quads, 
hamstring curls, and hip bridges. Manual therapy including soft tissue mobilization and joint mobilization for ROM 
restoration will be provided as needed at the discretion of the t-PT . 
The SOC group will receive traditional physical therapy methods without BFR at least 28 days post-op (+ 7 days). 
The protocol will include similar exercises to those in the BFR group but without occlusion. Manual therapy 
including soft tissue mobilization and joint mobilization for ROM restoration will be provided as needed at the 
discretion of the t-PT. 
Follow-up assessments and outcomes of interest will be collected by the study physical therapists (s-PT) . s-PTs 
collecting study visit data will be blinded to the patient’s treatment group. These measures include: muscle 
circumference (quadriceps and gastrocnemius), manual muscle testing (MMT) for fatigability recovery, Foot and 
Ankle Disability Index (FADI) for functional outcomes, pain levels using a visual analog scale (VAS), and 
cardiovascular measures (resting heart rate and blood pressure). 

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Assessments will be conducted at multiple time points for both the treatment and SOC groups:
x
Baseline: At initiation of physical therapy (28 days post-op + 7 days)
x
Visit 2: 63-70 days post-op
x
Visit 3 (optional): At the end of the study (for patients continuing beyond the standard 6-weeks of physical 
therapy)  
STUDY POPULATION
Population
The study will include patients who have undergone ankle ligament reconstruction surgery performed by 
participating orthopedic surgeons who are in the age range of 18-65(2,10,44).
Study sites 
Clinical sites (consenting visits and follow-up surgical visits)
Site 1
Study personnel: Jerry Grimes, MD
Location: Texas Tech Physicians Orthopedic Surgery Medical Pavilion Clinic 
Address: 3601 4th Street, Medical Pavilion, 4th Floor, Lubbock, TX 79430 
Site 2: 
Study personnel: Kenneth Stephenson, MD
Location: The Center for Orthopedic Surgery 
Address: 301 Utica Ave, Lubbock, TX 79416
Surgical sites
Site 1: 
Study personnel: Jerry Grimes, MD
Location: University Medical Center
Address: 602 Indiana Ave, Lubbock, TX 79415
Site 2: 
Study personnel: Kenneth Stephenson, MD
Location: Northstar Surgery Center
Address: 4640 N Loop 289, Lubbock, TX 79416  
Physical therapy site
Study personnel: Jordan Fultz, PT
Location: Physical Therapy Today (PTT)  
Address: 4138 19th St, Lubbock, TX 79407
Inclusion Criteria
1.
Age 18-65 years (2,10,44).
2.
Post ankle ligament reconstruction surgery (medial or lateral, with or without ankle scope).
3.
Capability of paying for physical therapy or having insurance coverage for at least 6 weeks of therapy.
Exclusion Criteria (2,10,44).
1.
Major cardiac or connective tissue disorders (e.g., Ehlers-Danlos syndrome, Marfan syndrome).
2.
Autoimmune disorders.
3.
History of stroke or deep vein thrombosis (DVT).

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4.
Bleeding or coagulation disorders.
5.
Congenital or developmental musculoskeletal disorders (e.g., cerebral palsy, Parkinson's disease).
6.
Pregnancy (current or planning to become pregnant in the next 4 months)
7.
Malignancy (cancer). 
8.
Professional athletes. 
9.
Workers compensation insurance status as worker’s compensation often does not cover the necessary 
duration of physical therapy (minimum of 4 weeks). 
10. Be currently enrolled or have been enrolled in another interventional clinical research study within the 
past 30 days (at time of consent); or
11. Be deemed unsuitable for inclusion in the study at the discretion of the Investigators
12. Cognitively not able to consent or participate in research (dementia; severe developmental delay; 
language/communication limitations; brain injury; etc.)
STUDY PROCEDURES
Screening and Enrollment
Screening
Screening and eligibility determination will take place at the contributing Orthopedic Surgeons respective offices
using study inclusion and exclusion criteria. Patients will be informed at this time that the cost of physical therapy 
will not go up by joining this project. If interested in the study, they will then undergo the Consenting Visit 
procedures outlined below. 
Consenting visit
If a patient is interested in the study, the consenting visit will occur in a private location by a member of the IRB 
approved study team. During this time, patients will have the ability to review the consent form and ask any 
questions. If they then decide to enroll, a copy of the signed consent form will be given to them and a copy will be 
uploaded in the EMR (for TTUHSC/UMC patients). Patients will be reminded at this time that the cost of physical 
therapy will not go up by joining this study.
Randomization
Following enrollment, subjects will be randomly assigned to either the intervention group (BFR therapy) or the 
control group (SOC). Patients will be randomized using sequentially numbered opaque sealed envelopes (SNOSE) 
with their treatment group and study ID number pre-assigned. These envelopes will contain the information 
regarding their randomization and will not be opened until after the patient is consented for the study. 
The subject’s treatment group will be communicated to their t-PT, after they have conducted the first visits’ 
measurements. The t-PT will not perform any data collection for the subjects they treat and will and will perform 
physical therapy for those patients.
A treatment/blinding log will be kept along with the enrollment log. This is for tracking which t-PT gives PT to each 
patient as well as determine which s-PTs perform measurements on each patient. A t-PT who has treated a patient 
while enrolled in the study will not be allowed to perform measurements and collect data for this patient. The 
collection of provider names (surgeon, t-PT, or s-PT) is for internal patient tracking procedures and measurement 
consistency. Provider identifiers for patient tracking ensures blinding and that a t-PT is not performing the 
measurements. Measurement consistency analysis may be analyzed after completion of the study.
Study visits
Study data collection visits will occur just prior to regular PT visits to avoid appearance of any marks or redness 
from use of BFR to unblind the s-PT. PT will be carried out in an open room except for exercises involving either 
BFR/non-BFR specifically as outlined in a sample PT plan shown in Appendix 6.

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During study visits the measurements will be taken as outlined below; s-PTs performing data collection will be 
blinded to the patient treatment group. A summary table (Table 1) displays specific data points that occur at each 
visit. Further details regarding measures of interest are outlined in the following section. 
Note: A patient is deemed ready to ‘graduate’ from physical therapy by the meeting all of the following indicators: 
x
90% of contralateral leg endurance as measured by standard MMT with a lowest acceptable score of 3 on 
the MMT scale
x
90% ROM of Contralateral leg 
x
Gastroc, Quadriceps 90% of size of contralateral limb 
x
A FADI score within 10% of the contralateral limb.
x
Upon Completion take a HR and Blood pressure and record with the previously taken measurements for 
the graduating standard.
Visit 1 (baseline)
Will occur on day one of PT (28 days + 7 days post-op) before PT commences. Limb measurements and strength 
testing will occur on the both limbs. Measurements include muscle circumference and atrophy, heart rate and 
blood pressure (BP), Foot and Ankle Disability Index (FADI), and Fatigability recovery/Manual Muscle Testing 
(MMT) at the discretion of the physical therapist. The patient will also be given an at home exercise program. 
In addition, activity level prior to surgery will be determined via the Global Physical Activity Questionnaire (GPAC) 
at the first study visit if not completed prior to initiation of PT
Visit 2: 
Visit 2 will occur either prior to exercises being carried out at either: 
x
graduation from physical therapy  
or 
x
63-70 days post-op prior to exercise being carried out
The measurements will be taken on whichever of the above dates occurs first. Measurements include muscle 
circumference and atrophy, heart rate and blood pressure (BP), Foot and Ankle Disability Index (FADI), and 
Fatigability recovery/Manual Muscle Testing (MMT) at the discretion of the s-PT. 
Visit 3: 
Visit 3 will occur only if: 
x
a patient has not graduated by 6th week of PT and insurance continues to fund or the patient desires to 
self-fund. 
or
the patient would like to receive additional PT after 6th week of PT and insurance continues to fund or the 
patient desires to self-fund
The measurements will be taken on the last day of the patients PT sessions. Measurements include muscle 
circumference and atrophy, heart rate and blood pressure (BP), Foot and Ankle Disability Index (FADI), and 
Fatigability recovery/Manual Muscle Testing (MMT) at the discretion of the s-PT. 
Visit 1 (baseline)(28 
+ 7 days post-op)
Visit 2
(63-70 days post-
op)
Visit 3
(last day of PT, if 
applicable)
Muscle atrophy
x (both limbs)
x
x
HR + BP
x
x
x
FADI
x
x
x

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Fatigability 
recovery/MMT
x (both limbs at 
discretion of PT)
x (at discretion of 
PT)
x  (at discretion of 
PT)
Early study withdrawal (if applicable)
In certain cases, a PI, Co-I, t-PT, or s-PT may terminate the participation of subjects in this study. If at any time, the 
PI, Co-I, t-PT, or s-PT believes that the study is no longer in the best interest of the subject, they may be removed. 
Severe adverse events, a change in the ability to perform therapy or a change in the ability of a subject to attend 
therapy as required within the visit window tolerance of the study may result in study termination.
Retention
Study retention will be aided by the frequency of follow up. Subjects will return to the PT centers multiple times 
weekly and will be seen by their surgeon multiple times throughout the process. No additional study specific 
subject retention practices will occur. Communication with patients regarding their involvement will include 
standard phone calls, HIPPA Approved texting methods as per the PT clinic’s standard operating procedures, and 
the subsequent visits. There will be no payment or reimbursement associated with study participation.
MEASURES OF INTEREST
Demographic information
The following demographic information will be collected for patients upon study enrollment
x
Age (years) 
x
Race (categorical) 
o
White
o
Black or African American
o
American Indian/Alaskan Native
o
Asian
o
Native Hawaiian or Other Pacific Islander
o
Two or more races
o
Decline to specify
x
Ethnicity
o
not of Hispanic, Latino/a, or Spanish origin
o
Mexican, Mexican American, Chicano/a, Puerto Rican, Cuban, Other Hispanic, Latino/a, Spanish 
Origin
o
Decline to specify
x
Sex (categorical)
o
Male
o
Female
x
BMI (kg/m^2) – BMI will be extracted directly from the EMR. Patient’s height and weight will not be 
collected and recorded. 
x
Insurance status (categorical)
o
none
o
private insurance
o
public insurance
PT duration measures of interest
x
Number of weeks of therapy prescribed at baseline by t-PT
x
Number of weeks of PT attended by patient
x
Reason for discrepancy (graduated early; additional sessions needed; lost to follow-up; etc.)
Intervention measures of interest

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Assessments will be conducted at multiple time points for both the treatment and SOC groups at Visit 1 (baseline), 
Visit 2, and Visit 3 (if applicable). This information will be collected by the s-PTs who are blinded to the patient 
treatment group. Information will be collected on the Study Data Sheets and then transcribed into the Master BFR 
Data Sheet for analysis. 
1.
Muscle atrophy measurement – gastrocnemius (1,3-6,9,11-13,20-25,27,29,30,33,36,37,39,40,43-47)
Measurement location: maximal circumference of the gastrocnemius muscle
Unit: cm
Range: varies by participant
Corresponding study data sheet: Appendix 1
Time frame: baseline/Visit 1 (28 days + 7 days post-op), Visit 2 (63-70 days post op), Visit 3 (optional – 
upon completion of PT)
2.
Muscle atrophy measurement – quadriceps (1,3-6,9,11-13,20-25,27,29,30,33,36,37,39,40,43-47)
Measurement location: 10 cm and 20 cm above the superior aspect of the patella
Unit: cm
Range: varies by participant
Corresponding study data sheet: Appendix 1
Time frame: baseline/Visit 1 (28 days + 7 days post-op), Visit 2 (63-70 days post op), Visit 3 (optional – 
upon completion of PT)
3.
Fatigability recovery using manual muscle testing (MMT) (1,3,4,6,8,9,11,12,20,22-
24,29,30,33,36,37,39,40,43-46,48)
Measurement description: Manual muscle testing (MMT) will be used to evaluate plantar flexion 
fatigability with the ankle in a neutral position, unweighted. This will help determine the effectiveness of 
BFR therapy in restoring muscle fatigability compared to the standard of care.
Score range: 5 – 10+ (higher score indicates better fatigability recovery)
Corresponding study data sheet: Appendix 2 
Time frame: baseline/Visit 1 (28 days + 7 days post-op), Visit 2 (63-70 days post op), Visit 3 (optional – 
upon completion of PT)
4.
Foot and Ankle Disability Index (FADI) (1,3-6,9,11,14,19,20-22,25,29,30,32,36,37,39,40,43,44,48)
Measurement description: The Foot and Ankle Disability Index (FADI) will be used to measure the 
functional ability of the ankle and foot, assessing improvements in daily living activities and overall 
functionality. 
Score range: 0 – 100 (lower scores indicate more foot/ankle disability)
Corresponding study data sheet: Appendix 3 
Time frame: baseline/Visit 1 (28 days + 7 days post-op), Visit 2 (63-70 days post op), Visit 3 (optional – 
upon completion of PT)
5.
Pain Management – Visual analog scale (3,4,6,11,12,20-22,24,25,31,36,37,39,40,42- 44)
Measurement description: Pain will be assessed using a visual analog scale (VAS), rated from 0-10, and 
recorded during the study visits to help evaluate the effectiveness of BFR therapy in reducing pain during 
rehabilitation. They will also be verbally asked during each therapy session to ensure subject comfort.  
Score range: 0 – 10 (higher score indicates higher levels of pain)
Corresponding study data sheet: Appendix 4
Time frame: baseline/Visit 1 (28 days + 7 days post-op), Visit 2 (63-70 days post op), Visit 3 (optional – 
upon completion of PT)
  
6.
Cardiovascular impact – heart rate (11,12,20,22,23,24,25,33,38,39,43,45,47)
Measurement description: Resting heart rate will be measured u to determine if BFR therapy provides any 
incidental cardiovascular benefits.

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Measurement tool: automatic cuff (Omron Bronze, OMRON HEALTHCARE CO Kyoto, Japan)
Range: varies by participant
Units: beats per minute (bpm)
Corresponding study data sheet: Appendix 5
Time frame: baseline/Visit 1 (28 days + 7 days post-op), Visit 2 (63-70 days post op), Visit 3 (optional – 
upon completion of PT)
7.
Cardiovascular impact – blood pressure (11,12,20,22,23,24,25,33,38,39,43,45,47)
Measurement description: Resting blood pressure will be measured u to determine if BFR therapy 
provides any incidental cardiovascular benefits.
Measurement tool: automatic cuff (Omron Bronze, OMRON HEALTHCARE CO Kyoto, Japan)
Range: varies by participant
Units: systolic/diastolic in mmHg
Corresponding study data sheet: Appendix 5
Time frame: baseline/Visit 1 (28 days + 7 days post-op), Visit 2 (63-70 days post op), Visit 3 (optional – 
upon completion of PT)
STUDY TREATMENT
Note that the PT program that all patients will receive is a complete PT protocol. It is independent of insurance 
authorization and a sample program is included for reference in Appendix 6. 
Control group
The control group will receive standard of care PT.  
Intervention group
The intervention group will receive the standard of care PT performed with BFR on affected limb. 
The intervention group will be treated with a BFR Smarttools SmartCuffs versions 3.0 or higher. During the baseline 
visit, the device will be placed over the affected limb’s greater trochanter and inflated to 60% of their limb 
occlusion pressure. This will be titrated up to 80% over the first week to ensure subject comfort. During the 
remaining physical therapy sessions, patients will perform exercises prescribed by a licensed t-PT to perform under 
occlusion with a load of 30% of the subjects estimated 1-rep max. 
RISKS, BENEFITS, AND CONFIDENTIALITY
Risks
As BFR is still in its nascent stages, there have been concerns concerning the safety of the modality which have 
been determined to have been unfounded. The theoretical concerns surrounded the changing of the caliber of 
blood vessel lumens and the potential for thrombosis both in the dorm of DVT and PE, but no evidence has been 
uncovered to support such concerns (2,10,37,44). In fact, BFR has been shown to upregulate thrombolytic 
pathways, most notably hypoxia induced tPA release and no elevation in thrombotic markers like D-dimer have 
been observed. In fact, in a countrywide study undertaken in Japan, the incidence of deep vein thrombosis and 
pulmonary emboli were lower in the BFR groups than in the general population (44). As postsurgical patients are at 
an increased risk for DVT and PE at baseline, investigation of BFR as a means to mitigate risk through the 
mechanisms listed above would be a valuable contribution, but are outside of the scope of this study. 
The main risk to subjects will be the development of bruising where the occlusive cuffs are placed. This can be 
mitigated by proper placement by a licensed physical therapist who ensures there is a layer of clothing between 
the skin and the occlusive cuff so that no “pinching” can occur when the desired limb goes through the full range 
of motion. We are unaware of reports of bruising in subjects who perform BFR on the lower extremity due to the 
proximal location, at the greater trochanter, and the propensity of subjects to wear clothing which covers the area 

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over which the occlusive cuffs are placed unprompted. Bruising is more common in the upper extremity, which is 
outside of the scope of this study, but included for completeness. 
The main risk with which we will be dealing is subjects experiencing delayed onset muscle soreness (DOMS) which 
are common and at their peak after the first session (2,6,10,23,27,37,44). DOMS is diminished after the second 
session and can be absent after the third and any subsequent sessions. The most concerning adverse event in the 
literature is the onset of rhabdomyolysis, but it is important to note that the case reports in which it is outlined 
concern individuals who deviated drastically from accepted protocols and performed the exercises without 
appropriate medical supervision (35). To our knowledge, there have been no cases of rhabdomyolysis in subjects 
or patients who have been under the supervision of healthcare professionals, and a plausible mechanism by which 
it could occur in individuals who adhere to accepted protocols, like the 30,15,15,15 at 30% of an individual’s 1-rep 
max, which we will be utilizing, is lacking. The modality, when appropriately implemented, has been determined to 
be safe even in high-risk populations, with Anderson et al. proclaiming, “there are no absolute contraindications 
for BFR” (2). 
Loss of confidentiality will be protected against by only utilizing password protected computers and encrypted 
software with a blinded model where no identifiable data will be kept in the same location. For a loss of 
confidentiality to be realized, a third party would be required to access separate computers in separate locations 
and break encryption to match patient names with data.
Benefits
Subjects randomized into the BFR protocol (intervention group) may experience faster and more complete 
recovery post ankle ligament reconstruction. 
(3,4,6,7,9,11,12,20,21,22,23,24,25,27,33,36,37,38,39,40,43,44,45,47,48)
Results of this study may help standardize use of BFR in the future and improve outcomes for other patients.   
Confidentiality
Each patient will be assigned a number based on their order of enrollment and to ensure study blinding as per 
SNOSE randomization procedure outlined above. This study number will be recorded in a Master List (Excel file) 
along with the patient's name and medical record number (MRN). The Master List acts as a key to link patient 
identities to their study data.
The original copies of the physical consent forms and Study Data Sheets will be retained in locked filing cabinets at 
the surgeon’s offices/PT offices until they are transferred via secured lockbox to the TTUHSC Orthopaedic Surgery 
Research Office. The Study Data Sheets will not contain any patient specific information; all patient data on the 
data sheet will be de-identified. No dates are collected on the patient data sheets. 
Regarding provider PHI on the Study Data Sheets: the Study Data Sheets will contain a location for identification of 
the s-PT. This is to ensure blinding and perform measurement comparisons as outlined in the Study Procedures – 
Screening and Enrollment – Randomization section above (page 9). 
Both the consent forms and individual Study Data Sheets will be scanned into the study regulatory binder which is 
housed on the TTUSHC Box server which may only be accessed by IRB approved personnel. The patient data sheet 
information will then be entered into the Master BFR Study Data Sheet (excel file) for statistical analysis. The 
Master BFR Study Data Sheet does not contain any PHI (patient or provider) and will be used for statistical analysis. 
For TTUHSC/UMC patients, electronic scans of the consent documents and Study Data Sheetwill be uploaded to 
the password protected uploaded into their EMR.
All data will be stored in a HIPAA-compliant, password-protected TTUHSC Box or computer and will be retained for 
3 years after study closure and then destroyed, in accordance with TTUHSC and federal policy.

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Only individuals who are IRB approved will have access to the Master List (Enrollment Log), Master BFR Study Data 
Sheet (Excel, for statistical analysis), Consent forms, and individual Study Data Sheets. 
PATIENT SAFETY AND EVENT REPORTING
Continual routine interaction between the study physicians and physical therapists will allow for increased 
monitoring of adverse events. Both groups of individuals will follow the patients as per normal standard of care
after surgery. 
During scheduled PT visits, the trained therapist will engage in visual examination of each patient to determine if 
any study related adverse events occur. If a study related adverse event occurs, the physicians and physical 
therapists will determine if it is in the patient’s best interest to continue in the study. 
In addition, this will result in the study team reviewing the study inclusion/exclusion criteria and adjust as needed 
to reduce the risk to other patients.  Currently enrolled patients will be reexamined to determine if they are at risk 
for a similar adverse event.
Adverse events (AEs), serious adverse events (SAEs), and unanticipated adverse device effects (UADEs) will be 
closely monitored throughout the study. These events may be associated with unplanned revision procedures prior 
to the planned ankle ligament reconstruction or may occur at any point throughout the study period. All events 
will be documented and submitted to the IRB and assessed for severity, causality, and relationship to the study 
procedures.
As this study is a collaboration between several institutions (UMC/TTUHSC, Center for Orthopaedic Surgery, 
Physical Therapy Today) a comprehensive review of all patient’s medical records from all institutions is not 
possible. Instead of reviewing medical records, patients will be asked if any AEs/SAEs have occurred since their last 
study visit. Events reported to the study team will then be reported to the IRB as outlined below. 
Adverse events:
Adverse Events (AEs) may occur at any point throughout the study period including but not limited to:
භ
Transitory Local Irritation: Temporary local irritation at the site of intervention, which may include 
redness, swelling, or discomfort. (2,10,44)
භ
Infection: Any signs of infection at the surgical site or related to the use of BFR equipment, such as fever, 
redness, swelling, or discharge.
භ
Allergy: Allergic reactions to materials used in the study, such as adhesives, bandages, or the BFR device.
භ
Delayed Wound Healing: Prolonged healing time of the surgical or intervention site, beyond the 
expected duration.
භ
Protrusion: Protrusion or displacement of any surgical implant or device used during the study
Adverse events will not be reported to the IRB unless they escalate to SAEs. They will however be included for 
review in safety monitoring board meetings. 
Serious adverse events (2,10,44)
Serious Adverse Events (SAEs) are defined as events that result in significant medical consequences, including but 
not limited to:
භ
Hospitalization or prolonged hospitalization.
භ
Significant disability or incapacity.
භ
Life-threatening conditions.
භ
Death.

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SAEs will be reported to the IRB within 3 days of study personnel discovery. 
Unanticipated adverse device effects
Unanticipated Adverse Device Effects (UADEs) are adverse effects that are unexpected in terms of nature, severity, 
or frequency and are associated with the use of the BFR device or any other medical devices used in the study.
භ
Hospitalization or prolonged hospitalization.
භ
Significant disability or incapacity.
භ
Life-threatening conditions.
භ
Death.
Adverse Event Monitoring:
Prior to enrollment of the first study participant, a safety monitoring board will be established, have an 
introductory meeting, and will subsequently be set to meet at least twice a year to review all adverse events. 
During the first meeting the board will review the definition of all adverse events and serious adverse events. A 
summary of all AEs/SAEs will be provided to the SMB at their semi-annual meetings or more frequently if they 
occur. In the event of any SAE, the case will be reviewed to determine the root cause and if any changes to the 
protocol might be required. Additionally, if there are multiple AEs, the safety monitoring board may meet to 
determine if any changes to the protocol are necessary. 
After each meeting, the SMB will determine if any adjustments need to be made to the protocol and study 
inclusion/exclusion criteria based on patient safety. These updates will then be provided to the IRB in a study 
modification. Meeting minutes will be emailed to the IRB for reference after SMB meetings. 
HIPPA
This study involves a limited data set with the following identifiable data point(s) being collected: 
x
Provider name
This is captured as a data point of interest for internal patient tracking (blinding) and may be used for 
measurement validity/consistency measurements as described above (Study Procedures - Screening and 
Enrollment – Randomization on page 9). 
PHI will be de-identified in methods described previously. No PHI will be included in any final publications resulting 
from the study.
DATA STORAGE
The original copies of the physical consent forms and individual Study Data Sheets will be retained in locked filing 
cabinets at the surgeon’s offices/PT offices until they are transferred via secured lockbox to the TTUHSC 
Orthopaedic Surgery Research Office. The Study Data Sheets will not contain any patient specific information; all 
patient data on the data sheet will be de-identified. No dates are collected on the patient data sheets. 
Regarding provider PHI on the Study Data Sheets: the Study Data Sheets will contain a location for identification of 
the s-PT. This is to ensure blinding and perform measurement comparisons as outlined in the Study Procedures – 
Screening and Enrollment – Randomization section above (page 9). 
Both the consent forms and individual Study Data Sheets will be scanned into the study regulatory binder which is 
housed on the TTUSHC Box server which may only be accessed by IRB approved personnel. The patient individual 
Study Data Sheet information will then be entered into the Master BFR Study Data Sheet (excel file) for statistical 
analysis. The Master BFR Study Data Sheet does not contain any PHI and will be used for statistical analysis. 
For TTUHSC/UMC patients, electronic scans of the consent documents and patient data sheets will be uploaded to 
the password protected uploaded into their EMR.

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Page 17 of 21
All data will be stored in a HIPAA-compliant, password-protected TTUHSC Box or computer and will be retained for 
3 years after study closure and then destroyed, in accordance with TTUHSC and federal policy.
Only individuals who are IRB approved will have access to the Master List (Enrollment Log), Master BFR Data Sheet 
(Excel, for statistical analysis), Consent forms, and individual Study Data Sheets. 
ANALYSIS
Descriptive statistics such as mean, median, mode, standard deviation, and minimum/maximum values will be 
obtained for thigh and lower limb circumference as is described in the protocol, blood pressure, heart rate, FADI, 
and plantarflexion fatigability via MMT for subjects in both the experimental and control groups. Data will be 
subjected to a chi-squared test to determine variance and distribution to inform which test, parametric or 
nonparametric, will be used to evaluate each data set. If the data meets parametric criteria, Paired t tests will be 
performed by comparing the pretest and posttest data for weeks 1vs5, weeks 1vs10 and weeks 5vs10 for each 
data set to determine significance of outcomes. If the data obtained is nonparametric, a Wilcoxon Signed-rank test 
will be performed. Alpha will be set to .05 for significance, with Bonferroni corrections, and the target sample size 
of 84 has been chosen to ensure a power of .9 with ample room to address the fact that this investigation is the 
first of its kind and assumptions based on existing data collected on anterior cruciate ligament reconstruction or 
Achilles tendon reconstruction may not serve as perfect proxies. Existing studies have been able to achieve 
significant, appropriately powered data with much smaller sample sizes, almost all of which are fewer than 50 
participants, and we believe significant data will be achieved prior to enrollment of subject 84, but the current lack 
of data requires we begin with a higher assumed sample size to avoid an underpowered result.
Justification of sample size
This study will enroll a total of 105 subjects to allow for a 20% attrition rate such that the study will have at least 
84 evaluable subjects available for statistical analysis.
At minimum, the following previously published studies will serve as the historical control references:
x
Li X, Li J, Qing L, Wang H, Ma H, Huang P. Effect of quadriceps training at different levels of blood 
flow restriction on quadriceps strength and thickness in the mid-term postoperative period after 
anterior cruciate ligament reconstruction: a randomized controlled external pilot study. BMC 
Musculoskelet Disord. 2023 May 8;24(1):360. doi: 10.1186/s12891-023-06483-x. PMID: 
37158913; PMCID: PMC10165811.
x
Jack RA 2nd, Lambert BS, Hedt CA, Delgado D, Goble H, McCulloch PC. Blood Flow Restriction 
Therapy Preserves Lower Extremity Bone and Muscle Mass After ACL Reconstruction. Sports 
Health. 2023 May;15(3):361-371. doi: 10.1177/19417381221101006. Epub 2022 Jun 27. PMID: 
35762124; PMCID: PMC10170230.
x
Ohta H, Kurosawa H, Ikeda H, Iwase Y, Satou N, Nakamura S. Low-load resistance muscular 
training with moderate restriction of blood flow after anterior cruciate ligament reconstruction. 
Acta Orthop Scand. 2003;74(1):62-68. doi:10.1080/00016470310013680
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