Reduction of Risk Factors for ACL Re-injuries Using an Innovative Biofeedback Approach
Phase: NA
Conditions: Anterior Cruciate Ligament Injury
Sponsor: Virginia Polytechnic Institute and State University

 
Reduction of Risk Factors for ACL Re-injuries using an 
Innovative Biofeedback Approach  
“ACL Biofeedback Pilot” 
 
Protocol Number:  IRB# 17-007 
        NIAMS# R21AR069865-01A1  
 
National Clinical Trial (NCT) Identified Number:  NCT03273673 
 
Principal Investigator: Robin Queen, PhD, FACSM 
 
Sponsor: Virginia Tech: Biomedical Engineering and Mechanics 
 
 
 
Funded by: NIAMS  
Version Number:  v1.4 
27 October 2020 
 

NIH-FDA Clinical Trial Protocol   
ACL Biofeedback Pilot Protocol – v1.2 27 October 2020 ii 
 
Summary of Changes from Previous Version: 
Date & 
Version  
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
07/31/2017 
V1.1 
 
6.1 & 8.2 
Added description of the adjustable 
stool and the specific height for the stool 
so that it will be placed within 0.5 inches 
of the popliteal fold during both the 
assessment and the biofeedback 
session.  
This change was made in order to standardize 
the location of the adjustable stool during 
testing and training for those participants who 
are able to complete a squat with their heels on 
the ground and their thighs parallel to the floor.  
09/05/2017 
V1.2 
Title Page 
Added the clinical trial identification 
number 
Clinical trial approved through clinicaltrials.gov 
with the following identification number 
NCT03273673 
11/06/2017 
V1.3 
1.3 
Corrected the tracking time points for 
the biofeedback interventions 
Needed to update the schedule of events to 
include tracking of Adverse Events as well as the 
no shows for the biofeedback interventions to 
indicate that these would be completed at each 
of the visits, which will occur two times per week 
for the 6 weeks of the intervention period.  
01/02/2018 
V1.4 
1.3 
Updated Table 1.3 Schedule of Activities 
(SoA) 
This table was updated to clarify when various 
outcome measures were being collected for the 
various treatment groups.  
01/02/2018 
V1.4 
5.2 
Updated the exclusion criteria 
Updated the exclusion criteria to include 
exclusion from the study if a potential 
participant was still attending formal physical 
therapy more than two times per week at the 
time of study enrollment 
01/02/2018 
V1.4 
6.1.1 
Updated Biofeedback intervention 
information including information on 
the warm-up and the foot position 
during the squat assessments.  
To improve clarity and provide details regarding 
both foot position during the squat testing and 
training as well as providing details on 
standardization of pre-intervention warm-up this 
portion of 6.1.1 has been updated.   
01/02/2018 
8.2 
Additional information provided 
regarding the set-up of the bicycle for 
In order to standardize the assessments being 
completed as part of this study, additional 

NIH-FDA Clinical Trial Protocol   
ACL Biofeedback Pilot Protocol – v1.2 27 October 2020 iii 
V1.4 
warm-up as well as the plyobox used 
during testing.  
information was provided regarding the setting 
of seat height for the bicycle for warm-up as well 
as the height of the plyobox to be used during 
both the biomechanical assessments as well as 
the intervention sessions.  
 
 
 
 

  
ACL Biofeedback Pilot Protocol – v1.2 27 October 2020 ii 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 4 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 5 
2 
INTRODUCTION ............................................................................................................................................ 6 
2.1 
Study Rationale .................................................................................................................................... 6 
2.2 
Background........................................................................................................................................... 6 
2.3 
Risk/Benefit Assessment .................................................................................................................... 8 
2.3.1 
Known Potential Risks ..................................................................................................... 8 
2.3.2 
Known Potential Benefits ................................................................................................ 8 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 8 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 9 
4 
STUDY DESIGN ............................................................................................................................................. 9 
4.1 
Overall Design ...................................................................................................................................... 9 
4.2 
Scientific Rationale for Study Design.............................................................................................. 11 
4.3 
Justification for Dose ......................................................................................................................... 11 
4.4 
End of Study Definition ..................................................................................................................... 11 
5 
STUDY POPULATION ................................................................................................................................ 11 
5.1 
Inclusion Criteria ................................................................................................................................ 11 
5.2 
Exclusion Criteria ............................................................................................................................... 12 
5.3 
Lifestyle Considerations .................................................................................................................... 12 
5.4 
Screen Failures .................................................................................................................................. 12 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 13 
6 
STUDY INTERVENTION ............................................................................................................................ 14 
6.1 
Study Intervention(s) Administration ............................................................................................... 14 
6.1.1 
Study Intervention Description ..................................................................................... 14 
6.1.2 
Dosing and Administration ............................................................................................ 15 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 16 
6.2.1 
Acquisition and accountability ...................................................................................... 16 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 16 
6.2.3 
Product Storage and Stability ....................................................................................... 16 
6.2.4 
Preparation ...................................................................................................................... 16 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 16 
6.4 
Study Intervention Compliance ........................................................................................................ 17 
6.5 
Concomitant Therapy ........................................................................................................................ 18 
6.5.1 
Rescue Medicine ............................................................................................................ 18 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 18 
7.1 
Discontinuation of Study Intervention ............................................................................................. 18 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 18 
7.3 
Lost to Follow-Up ............................................................................................................................... 19 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 19 
8.1 
Efficacy Assessments ....................................................................................................................... 19 
8.2 
Safety and Other Assessments ....................................................................................................... 20 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 22 

  
ACL Biofeedback Pilot Protocol – v1.2 27 October 2020 iii 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 22 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 22 
8.3.3 
Classification of an Adverse Event .............................................................................. 22 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 23 
8.3.5 
Adverse Event Reporting .............................................................................................. 24 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 24 
8.3.7 
Reporting Events to Participants ................................................................................. 25 
8.3.8 
Events of Special Interest ............................................................................................. 25 
8.3.9 
Reporting of Pregnancy ................................................................................................ 25 
8.4 
Unanticipated Problems .................................................................................................................... 26 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 26 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 26 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 27 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 27 
9.1 
Statistical Hypotheses ....................................................................................................................... 27 
9.2 
Sample Size Determination .............................................................................................................. 27 
9.3 
Populations for Analyses .................................................................................................................. 28 
9.4 
Statistical Analyses............................................................................................................................ 28 
9.4.1 
General Approach .......................................................................................................... 28 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 28 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 29 
9.4.4 
Safety Analyses .............................................................................................................. 29 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 29 
9.4.6 
Planned Interim Analyses ............................................................................................. 29 
9.4.7 
Sub-Group Analyses ..................................................................................................... 30 
9.4.8 
Tabulation of Individual participant Data .................................................................... 30 
9.4.9 
Exploratory Analyses ..................................................................................................... 30 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 30 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 30 
10.1.1 
Informed Consent Process ........................................................................................... 30 
10.1.2 
Study Discontinuation and Closure ............................................................................. 31 
10.1.3 
Confidentiality and Privacy ........................................................................................... 32 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 32 
10.1.5 
Key Roles and Study Governance .............................................................................. 32 
10.1.6 
Safety Oversight ............................................................................................................. 33 
10.1.7 
Clinical Monitoring .......................................................................................................... 33 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 34 
10.1.9 
Data Handling and Record Keeping ............................................................................ 34 
10.1.10 
Protocol Deviations ........................................................................................................ 35 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 35 
10.1.12 
Conflict of Interest Policy .............................................................................................. 36 
10.2 
Additional Considerations ................................................................................................................. 36 
10.3 
Abbreviations ...................................................................................................................................... 37 
10.4 
Protocol Amendment History ........................................................................................................... 38 
11 
REFERENCES ............................................................................................................................................. 40 
 

ACL Biofeedback Pilot 
Version 1.0 
Protocol <IRB# 17-007> 
27 October 2020 
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
1 
STATEMENT OF COMPLIANCE 
 
This clinical trial, which will be referred to as ACL Biofeedback Pilot throughout the rest of the 
document, will be conducted in compliance with this protocol, the International Conference on 
Harmonisation Good Clinical Practice (ICH GCP) as well as applicable state, local and federal regulatory 
requirements. Each engaged institution will have a current Federal-Wide Assurance (FWA) issued by the 
Office for Human Research Protections (OHRP) and will provide this protocol and the associated 
informed consent documents and recruitment materials for review and approval by an appropriate 
Institutional Review Board (IRB) registered with OHRP. Any amendments to the protocol or consent 
materials will be approved by the appropriate IRB prior to implementation. Select one of the two 
statements below:  
 
(1) The ACL Biofeedback Pilot trial will be carried out in accordance with International Conference 
on Harmonisation Good Clinical Practice (ICH GCP) and 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, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent forms, recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made by the IRB of record regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
 
1.1 
SYNOPSIS  
Title: 
Reduction of Risk Factors for ACL Re-injuries using an Innovative 
Biofeedback Approach 
Study Description: 
ACL injuries are common among athletes and due to residual 
muscle weakness, limited knee motion and asymmetrical 
movement patterns after surgery many of these athletes will 
sustain secondary ACL injuries following return to sports. This 
project seeks to determine if a novel biofeedback-based 
rehabilitation approach can decrease a known risk factor for 
secondary injuries to the ACL. The project specifically focuses on 
correcting asymmetric movement patterns, a known risk factor for 
secondary injury that is not directly addressed by existing 
interventions through a 6 week therapy based biofeedback 
intervention. 

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Objectives: 
 
Primary Objective:  Determine the impact of a biofeedback training 
program on decreasing asymmetrical vertical ground reaction 
forces, frontal plane knee range of motion and the peak knee 
extension moment, known risk factors for secondary ACL injuries.   
 
 
 
Secondary Objectives:   To demonstrate our ability to recruit, retain 
and determine patient compliance in completing a biofeedback 
retraining program. 
Endpoints: 
Primary Endpoint for Objective 1: 
Peak Knee Extension Moment Symmetry 
 
Secondary Endpoints for Objective 1:  
Peak Vertical Ground Reaction Force Symmetry 
Vertical Ground Reaction Force Impulse Symmetry 
Frontal Plane Knee Range of Motion 
Peak Knee Flexion Angle Symmetry 
Peak Knee Flexion Angle 
Peak Knee Valgus 
 
Primary Endpoints for Objective 2: 
Number of intervention sessions attended (compliance) 
Number of missed biomechanical assessment time points 
(retention)  
Study Population: 
The target sample for this study will include patients between the 
ages of 14 and 21, who had a primary ACL reconstruction by one 
of the referring physicians (Southwest Virginia) and plan to return 
to sport participation. We will be recruiting both men and women 
for this study with no specific gender breakdown.   
Phase: 
Pilot Study 
Description of 
Sites/Facilities 
Enrolling Participants: 
This is a single site study for the intervention and testing of 
enrolled subjects.  Four referring physicians will be referring 
potential participants from a 60-mile radius around Blacksburg, 
Virginia.   
Description of Study 
Intervention: 
This will be a randomized controlled Phase 1, pilot clinical trial.  
Patients will be assigned to one of two study arms:  1) Biofeedback 
Intervention, 2) Attention Control.  All participants in the study will 
continue with any other usual medical care they receive for their 
ACL reconstruction. 
 
BIOFEEDBACK INTERVENTION 
The 6-week biofeedback training program is focused on altering 
loading and movement asymmetry during biweekly sessions on 
non-consecutive days (12 sessions). The biofeedback training 
program will provide sensory (visual and tactile) feedback to the 
subject to heighten awareness of asymmetrical movement 
strategies (e.g. load shift, movement asymmetry) during a squat. 
The two exercises that will be completed during the biofeedback 
training program will be a visual feedback squat and a resisted 
squat (tactile feedback).  Each of these tasks will be completed 30 
(3 sets of 10 repetitions) times per session.  We will provide a 20 
second rest between trials, and a 10 minute break between the 

ACL Biofeedback Pilot 
Version 1.0 
Protocol <IRB# 17-007> 
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NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
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visual and tactile feedback exercises to decrease the effect of 
fatigue.  
 
ATTENTION CONTROL 
The 6-week attention control group program will focus on providing 
educational information to the participants related to the clinical 
and sports expectations as they are released to return to sport.  
These participants will be asked to meet 6 times during the 6-week 
intervention time period.  Three of these visits will be completed in 
person and three will be completed using an online educational 
module (6 sessions).  The online sessions will be completed in 
week 1, week 3, and week 5 while the in person sessions will be 
completed during week 2, week 4, and week 6.  The content of 
these sessions will focus on providing information on ACL 
reconstruction, athlete expectation as they return to sport, 
incidence and risk factors for secondary ACL injuries, as well as 
some suggestions on the gradual progression back into sport. 
Study Duration: 
The estimated study duration is 2 years from the enrollment of the 
first patient until the completion of data analysis.  
Participant Duration: 
All participant visits will be completed in approximately 3 months 
(12 weeks) from the date of enrollment until all study visits are 
completed.  
 

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1.2 
SCHEMA 
 
 

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1.3 
SCHEDULE OF ACTIVITIES (SoA) 
Description 
Baseline 
6 Week Study Intervention Period 
Follow-Up 
 
Initial 
Biomechanical 
Assessment 
Weeks 
Biomechanical 
Assessment 2 
Biomechanical 
Assessment 3 
 
 
W1 
W2 
W3 
W4 
W5 
W6 
W6 
W12 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Participant Demographics 
X 
 
 
 
 
 
 
 
 
Participant Surgical Characteristics 
X 
 
 
 
 
 
 
X 
X 
Primary Outcome: Peak Knee Extension 
Moment Asymmetry 
X 
 
 
 
 
 
 
X 
X 
Secondary Outcomes 
X 
 
 
 
 
 
 
X 
X 
Exploratory Outcome Measures  
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Control in-person Interventions (No Show) 
 
 
X 
 
X 
 
X 
 
 
Control Online Interventions (No Show) 
 
X 
 
X 
 
X 
 
 
 
Biofeedback Interventions (No Show) 
 
X X X X X X X X X X X X 
 
 
Activity Level 
(All Participants) (1 time/week) 
 
X 
X 
X 
X 
X 
X 
 
 
Control Online Interventions (VAS Pain) 
One time per week 
 
X 
X 
X 
X 
X 
X 
 
 
Biofeedback Interventions (VAS Pain) 
3 times per biofeedback session 
 
X X X X X X X X X X X X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X X X X X X X X X X X X 
X 
X 

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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Nearly 1 in 60 adolescent athletes will suffer an Anterior Cruciate Ligament (ACL) injury1,27, at 
an estimated annual cost of $3 billion, and most will undergo an ACL reconstruction. 23,27,33 
Following reconstruction and rehabilitation, adolescent athletes have a 15 fold increased risk 
of secondary ACL injuries when compared to an uninjured athlete. 31  The high risk of re-
injury demonstrates that in many cases current post-operative interventions fail to restore 
adequate knee motion and neuromuscular control that are needed to decrease injury risk. 
Indeed, many patients cleared to return to sport by their doctors following ACL reconstruction 
demonstrate residual muscle weakness and imbalances, as well as asymmetrical movement 
patterns. 25,31,32,38,39  Based on this knowledge, we contend that one problem with current 
interventions is their focus on improving strength and joint range of motion while excluding 
the assessment of lower extremity movement patterns. The current return to sport criteria 
have been ineffective at returning athletes to sport while decreasing re-tear rates. This is 
confirmed in the American Academy of Orthopaedic Surgeons’ ACL return to sport 
guidelines, which state a need for restoration of movement, but do not provide objective 
measures of assessment. 5,16,30 Our preliminary data indicate that following ACL 
reconstruction and clinical release to return to sports most patients have residual limb 
asymmetries during jumping and landing.12,14,25 An article by Paterno et al reports that the 
primary risk factors for secondary ACL injury risk include asymmetrical frontal plane knee 
range of motion, and knee extension moment assessed during bilateral landing.32 These 
movement deficits are the only factors that have been associated with an increase in 
secondary ACL injury risk following return to sport. Thus, to decrease the risk for secondary 
ACL injuries, there is a pressing need to evaluate novel interventions that improve lower 
extremity movement patterns and restore movement and loading symmetry prior to release to 
return to full sport participation. 
 
Our preliminary data indicate that through the use of a biofeedback intervention we can 1) 
reduce risk factors for secondary ACL injury (reduce asymmetrical ground reaction forces, 
joint angles, and joint moments) one week after the completion of the intervention and 2) 
subjects are willing to attend biofeedback training sessions. This intervention provides 
simultaneous visual and tactile biofeedback as patients complete a single body weight task 
(squat) to alter landing mechanics.  Retraining the single body-weight task allows for training 
in a less ballistic, more controlled environment to restore neuromuscular function. We will 
complete a randomized trial (control versus biofeedback) using adolescent ACL patients and 
three-dimensional motion capture (1) to determine the impact of a novel biofeedback training 
program on decreasing secondary ACL injury risk factors (movement and loading 
asymmetry32), and (2) to establish our ability to recruit and retain patients while assessing 
intervention compliance and the psychometric characteristics of the outcome measures. 
 
 
2.2 
BACKGROUND  
 
ACL Injury and Re-injury: As many as 200,000 anterior cruciate ligament (ACL) injuries are 
diagnosed annually in the United States1,27, and almost all affected patients (94%) seek to 
restore joint stability by undergoing ACL reconstruction surgery at an estimated annual cost 

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of $3 billion.21,22,24 Because most patients receiving ACL reconstruction are adolescents 
between the ages of 15 and 3033, many seek to return fully to sports after rehabilitation.  
Unfortunately, doctors’ return-to-play decisions do not usually rely on objective measures of 
function5,6; instead, the decision is most often based on time, typically six to twelve months 
after surgery4-6,16,30. We and others have shown that athletes who are returned to sport based 
on current guidelines have residual muscle imbalances, muscle weakness, and altered lower 
extremity mechanics, and these deficiencies can be detected up to two years post-
surgery14,16,30.  
 
Athletes returned to sport prior to appropriate restoration of function are at a greater risk for 
secondary ACL tears, defined as tears of the ACL graft or contralateral intact ACL. 
Secondary tears of the ACL are surprisingly common: despite the fact that not all patients 
return to pre-injury sport participation, up to 29% of all ACL reconstruction patients suffer a 
secondary tear. In slightly different terms, one study has shown a 15 times greater likelihood 
of ACL tear in an ACL reconstructed patient compared to a non-injured group.31 Major risk 
factors for secondary ACL injury include movement and loading asymmetry between the 
surgical and non-surgical limbs.31,32 We recently showed that asymmetrical loading and 
movement patterns remain after patients have been returned to full sport participation. Thus, 
secondary ACL injuries are a significant problem that is largely influenced by the failure of 
current approaches to restore movement and loading symmetry and use objective measures 
to assess readiness to resume participation in sports. 
 
The Biofeedback Approach to Recovery: Our proposed biofeedback approach has its 
foundation in retraining programs that were developed and implemented for primary ACL 
injury prevention. These retraining programs are designed to alter lower extremity mechanics 
through retraining landing mechanics, a very dynamic and complex task.28 Such programs 
have proven effective for primary ACL tears: they decrease the risk factors for injury,20,28,29,40 
however they have not decrease the incidence of ACL tears since implementation11,20,29,37,40  
Our novel biofeedback approach combines successful aspects of these existing programs 
with visual and tactile biofeedback. This strategy is further informed by recent work that 
examined the use of visual biofeedback to reduce loading asymmetry.26 This work 
demonstrated that loading asymmetry could be attenuated using squatting tasks and visual 
biofeedback.26 Current therapy interventions focus on muscle strength and range of motion 
and are ineffective in decreasing the incidence and risk factors for secondary ACL injuries. 
This proposal will be the first to implement a biofeedback training program in an ACL 
reconstruction population. If successful, this work will have a significant impact: it will provide 
the first retraining program that directly targets and effectively decreases known risk factors 
for secondary ACL injury risk factors.  
 
Significance of our Approach: With the large proportion and increased incidence of ACL tears 
in adolescent athletes, it is imperative that we develop interventions to decrease the risk of 
secondary injuries and improve outcomes. Therefore, the goals of the proposed study are 
to determine the immediate impact of a biofeedback training program on decreasing risk 
factors for secondary ACL tears and determine if the impact is retained 6 weeks post-
intervention. This study will also demonstrate our ability to recruit and retain post-operative 
ACL reconstruction patients until the completion of the novel biofeedback intervention and to 
assess their compliance with completing all of the exercises at each training session. In 
addition, we will determine the psychometric properties of the primary outcome measures, 
which have been previously identified as risk factors for a secondary ACL injury. This study 
will provide the foundation for the design and development of future studies that could shift 
the post-operative rehabilitation paradigm to include the assessment and normalization of 

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movement and loading asymmetries before patients are returned to sport participation. By 
changing the post-operative rehabilitation process to include biofeedback, this work will 
ultimately decrease both health care costs associated with ACL injuries and the number of 
patients suffering secondary ACL tears. 
 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
There is a potential risk that participants could injure his/her foot, ankle, or knee or feel off 
balance while completing these tasks; however, the study team will ensure that the testing area 
is clean and free of debris.  The risk again will be no greater than if the participant were 
performing these tasks on his/her own and are no more difficult than the sporting tasks that the 
participant’s physician has allowed you to start doing during sport participation or what the 
participant would be doing at this point during physical therapy.  There is a potential risk to the 
participant’s confidentiality.  Every effort will be made to maintain his/her confidentiality, 
however this cannot be guaranteed. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
There will not be any direct benefits to the participant if he/she decides to participate in this 
research project. The participant will receive additional one-on-one exercise training as well as 
an explanation of his/her movement mechanics at the completion of the last day of testing if the 
participant is interested. Research conducted on these data may help researchers to better 
understand how visual and tactile biofeedback change the way that ACL reconstruction patients 
move and if these exercises are able to decrease the risk factors for secondary ACL injuries 
after patients return to sport participation. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
The risks to the participants in this pilot clinical research project are minimal compared to the 
potential benefits to both these patients as well as future ACL reconstruction patients.  The risks 
of participating in this study are not any greater than the risks in participating in athletics.  In 
order to minimize these risks, we will not ask the participants to complete any activities that 
have not been approved by his/her treating orthopaedic surgeon and that are not appropriate for 
the participant’s current stage in rehabilitation. The results from this study could alter post-
operative rehabilitation following ACL reconstruction leading to a decrease in the number of 
secondary ACL injuries following return to sports.   
 

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3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Determine the impact of a 
biofeedback training program on 
decreasing asymmetrical peak knee 
extension moment.   
 
 
Peak Knee Extension Moment 
Symmetry 
 
  
 
Peak knees extension moment 
asymmetry between the operative and 
non-operative side is a known risk 
factors for secondary ACL injuries and 
is therefore being used as the primary 
outcome to determine the ability of the 
biofeedback intervention to decrease a 
risk factor for secondary ACL injury 
risk.    
Secondary 
 
 
To demonstrate our ability to recruit, 
retain and determine patient 
compliance in completing a 
biofeedback retraining program. 
 
• Number of intervention sessions 
attended (compliance) 
 
• Number of missed 
biomechanical assessment time 
points (retention) 
This is a pilot clinical trial in which we 
need to determine both compliance 
with the biofeedback intervention as 
well as subject retention through the 
end of the study in order to 
appropriately plan for a future multi-
center clinical trial. 
Tertiary/Exploratory  
 
 
Determine the impact of a 
biofeedback training program on 
decreasing asymmetrical vertical 
ground reaction forces, frontal plane 
knee range of motion and the 
association between each of these 
measures and the change in the 
peak knee extension moment 
symmetry.   
 
Exploratory Endpoints:  
• Peak Vertical Ground Reaction 
Force Symmetry 
• Vertical Ground Reaction Force 
Impulse Symmetry 
• Frontal Plane Knee Range of 
Motion 
• Peak Knee Flexion Angle 
Symmetry 
• Peak Knee Flexion Angle  
• Peak Knee Valgus 
The peak knee extension moment is a 
known risk factor for secondary ACL 
injury risk, however, it is challenging to 
collect this measure in a clinical setting 
as it requires the collection of 
synchronized three-dimensional 
kinematic and kinetic data.  Therefore, 
these exploratory endpoints will be 
assessed to determine their 
association with the change in 
symmetry in the peak knee extension 
moment.  Through this analysis we 
hope to be able to identify additional 
measures to use in assessing this 
biofeedback intervention that will be 
more easily implemented in the clinical 
setting.  
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
Aim 1: Determine the impact of a biofeedback training program on decreasing asymmetrical 
vertical ground reaction forces, frontal plane knee range of motion and the peak knee extension 
moment, known risk factors for secondary ACL injuries.   
We will test the hypothesis that our biofeedback program will decrease the risk of secondary 
ACL injury by improving loading and movement symmetry during the dynamic task of landing 
from a jump 6 weeks post intervention.  
 

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Aim 2: To demonstrate our ability to recruit, retain and determine patient compliance in 
completing a biofeedback retraining program. 
We will demonstrate our ability to recruit 40 ACL reconstructed patients and assess study 
retention and compliance.   
 
Overview: The goal of this single site, pilot randomized clinical trial is to determine the impact of 
an innovative biofeedback training program on decreasing surrogate measures of secondary 
ACL injury risk in adolescent athletes. Movement and loading symmetry will be assessed using 
the limb symmetry index (𝑳𝑳𝑳𝑳𝑳𝑳= (𝑨𝑨𝑨𝑨𝑨𝑨 [𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺 − 𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵])/𝟎𝟎. 𝟓𝟓(𝑨𝑨𝑨𝑨𝑨𝑨[𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺] +
𝑨𝑨𝑨𝑨𝑨𝑨[𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵]) ∗𝟏𝟏𝟏𝟏𝟏𝟏)2,3,7,34 prior to (baseline) and at two time points following 
(immediately following training (efficacy), and 6 weeks after (durability)) the biofeedback training 
program (Aim 1; Figure 1).  
 
40 adolescent ACL patients (20 control, 20 intervention) will be recruited. Subjects will be block 
randomized into either the control arm or the intervention arm at baseline.  All intervention 
subjects will complete an in-person (no home exercises) biofeedback retraining program for 6 
weeks (2 times per week) with a focus on improving both load and movement symmetry through 
the use of tactile and visual feedback (Figure 1), which has been reported to be an effective 
biofeedback intervention26. Finally, this study will demonstrate our ability to recruit subjects, 
engage them in the novel biofeedback program, and retain them until study completion.  The 
outcomes from Aim 2 will inform future study designs.  

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Reducing measurement bias: To reduce the possibility of bias, the biofeedback intervention will 
be completed by a single individual (clinician – Athletic trainer) and the biomechanical 
assessments will be completed by a second individual who will be blinded to the subject’s group 
assignment (research technician). The research technician will be trained by Dr. Queen to 
complete the biomechanical assessment using a standard set of directions, while Dr. Williams 
will train the clinician to complete the intervention using a standard set of instructions in order to 
decrease between subject variability and provide consistent feedback to the subjects. The 
intervention instructor will be directly trained by the clinical rehabilitation expert in proper 
technique and instruction. The clinical expert and the intervention instructor will have a phone 
call every 3 weeks and the clinical expert will visit the testing site once every 4 months to review 
procedures and ensure proper instruction throughout the course of the study. 
 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
The control group for this pilot clinical trial is an attention control group that will be completing 6 
educational training sessions of the 6 week intervention period.  This control group will consist 
of ACL reconstruction patients who are at the same stage as those that are randomized into the 
intervention arm, but will receive no additional biofeedback or exercise interventions.  The 
attention control group was selected in order to decrease the chances of finding a group 
difference based on the additional time that the subjects were in contact with the study team.   
  
 
4.3 
JUSTIFICATION FOR DOSE 
 
Based on previous physical therapy based interventions as well as current clinical practice we 
have designed this study to be a 6 week intervention in which subjects will attend a biofeedback 
training session 2 times per week throughout the intervention period.  Two times a week was 
selected so that participants could space out these visits during the week to ensure that they 
were not attending sessions on subsequent days in order to decrease the risk of muscle 
soreness during the biofeedback training.  
 
 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last visit shown in the Schedule of Activities (SoA), Section 1.3. 
 
 
5 
STUDY POPULATION 
  
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. 
Provision of signed and dated informed consent form 

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2. 
ACL Reconstruction:  primary, unilateral ACL reconstruction with no pain in the 
contralateral leg 
3. 
Rehabilitation:  need to have completed at least 4.5 months of post-operative physical 
therapy and be within approximately 6 weeks of being ready to be released by his/her 
treating orthopaedic surgeon to return to full sport participation 
4. 
Stated willingness to comply with all study procedures and availability for the duration of 
the study  
5. 
Male or female, aged 14-21 
6. 
Willing to adhere to the ACL Biofeedback intervention regimen 
 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
1. 
For females: currently pregnant or planning to become pregnant  
2. 
History of more than one ACL reconstruction 
3. 
Post-operative complications that required additional surgical intervention 
4. 
Hospitalization for any reason other than the ACL reconstruction in the last 3 months 
5. 
Plans for additional surgical procedures in the next 12 months 
6. 
Live greater than 60 miles from the research lab  
7. 
Have limitations that would prevent them from attending the biofeedback training 
sessions 
8. 
Motor neuron diseases, Parkinson’s disease, multiple sclerosis 
9. 
Severely impaired hearing or speech (patients must be able to respond to phone calls) 
10. No access to a telephone 
11. Participating in another ACL intervention outside of standard post-operative physical 
therapy 
12. Attending post-operative physical therapy more than 2 times per week at the time of 
study enrollment.  
13. Inability to understand or speak English (since this will be required for the patient-based 
intervention) 
14. Other self-reported medical problem that would prohibit participation in the study 
15. Other health condition or personal issue judged by a study team member or primary care 
physician to make the patient inappropriate for study participation 
16. Knee extension moment limb symmetry index (LSI) greater than or equal to 90% at the 
time of the initial study assessment 
 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Not applicable 
 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in the study. A minimal 

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set of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). 
 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Recruitment: 
The target sample for this study will include patients between the ages of 14 and 21, who had a 
primary ACL reconstruction by one of the referring physicians. Participants will be excluded if 
they have a history of more than one ACL reconstruction, post-operative complications that 
required additional surgical intervention, hospitalization for any reason other than the ACL 
reconstruction in the last 3 months, plans for additional surgical procedures in the next 12 
months, or any other health conditions determined by the study team to be contraindications to 
participating in the biofeedback program.  Patients will also be excluded if they live greater than 
60 miles from the research lab or have limitations that would prevent them from attending the 
biofeedback training sessions. In order to meet inclusion criteria and be enrolled in the study, 
participants need to have undergone a primary ACL reconstruction, completed post-operative 
physical therapy and be released by his/her treating orthopaedic surgeon to return to full sport 
participation.  
 
Based on our prior and ongoing studies, we are confident that 40 participants can be enrolled 
within the 24 month recruitment period. We will use the electronic medical record to identify all 
patients who had an ACL reconstruction within the last 4 months or who are scheduled to have 
an ACL reconstruction with any of the referring orthopaedic surgeons. The medical records will 
be used to determine eligibility based on study inclusion and exclusion criteria. The parents, if 
the patient is a minor, of all potentially eligible patients will be approached by the treating 
orthopaedic surgeon or member of the surgeon’s clinical staff. If the patient is over the age of 
18, he/she will be approached directly by the treating orthopaedic surgeon. The three referring 
physicians have been working with the research study team on the recruitment and enrollment 
of ACL reconstruction patients for the last 4 months on an industry sponsored knee brace study.  
During this time the study team has been able to implement a successful recruitment procedure 
in which the patients are identified by the physician extenders in each clinic.  These individuals 
then discuss the research study with the potential subject to determine the subject’s interest in 
participation. 
 
Retention:  
All participants will be treated with respect, and we will be considerate of the time and energy 
that is involved with participation in this study.  Participant retention will begin with the 
recruitment process.  Based on medical records and release of information consent forms from 
the treating physician, only those patients who do not actively opt out will be contacted by phone 
to receive follow-up information about the study and assess their interest in participating.  Once 
enrolled in the study, all participants will have contact with the study team at each measurement 
time point (baseline, 6 weeks and 12 weeks). In addition, based on group randomization the 
participants will also have contact with the study team either two times a week for six weeks or 
once a week for six weeks. Based on our prior experience, this level of contact helps to keep 
participants engaged.  Calls to participants will also be scheduled at times that are preferred 
and convenient for each participant.  We will also use telephone calls to remind participants 
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asked to complete 3 in-person educational sessions as well as three online training modules 
over the 6 week intervention period.  This will encourage continued participation form patients 
assigned to this arm.  Also, the importance of compliance will be emphasized throughout the 
study.  Participants who do decide to withdraw from study participation however, will be 
encouraged to complete the study assessments.  The reason for any missed intervention 
sessions as well as assessment sessions will be recorded for future analysis in order to improve 
planning for subsequent clinical trials.  
 
All successful and unsuccessful attempts to contact participants will be documented within the 
subjects study record.  Additionally, alternate contact numbers will be requested from 
participants to aide in locating the subject.  
 
Participant recruitment and retention statistics will be collected and monitored on a regular basis 
such that any problems or negative trends can be identified early and appropriate measures 
taken and/or procedures modified. 
 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
This will be a randomized controlled Phase 1, pilot clinical trial.  Patients will be assigned to one 
of two study arms:  1) Biofeedback Intervention, 2) Attention Control.  All participants in the 
study will continue with any other usual medical care they receive for their ACL reconstruction. 
 
BIOFEEDBACK INTERVENTION 
The 6-week biofeedback training program is focused on altering loading and movement 
asymmetry during biweekly sessions on non-consecutive days (12 sessions). The biofeedback 
training program will provide sensory (visual and tactile) feedback to the subject to heighten 
awareness of asymmetrical movement strategies (e.g. load shift, movement asymmetry) during 
a squat. The two exercises that will be completed during the biofeedback training program will 
be a visual feedback squat and a resisted squat (tactile feedback).  Each of these tasks will be 
completed 30 (3 sets of 10 repetitions) times per session.  We will provide a 20 second rest 
between trials, and a 10 minute break between the visual and tactile feedback exercises to 
decrease the effect of fatigue. Prior to the biofeedback intervention session, each participant will 
complete a 5-minute warmup on a stationary bike as was described during the biomechanical 
assessments.  
 
Visual feedback: The simplest way to provide biofeedback during a squat is through visual 
feedback of load. Under this approach, subjects are asked to stand on force plates, which 
measure the ground reaction forces (load) beneath each foot. Shoulder width for each 
participant will be measured as the distance between acromioclavicular joints.  This distance will 
then be measured on the force plates and 2 pieces of tape will be placed this distance apart 
(one on each force plate) and participants will be asked to stand with one heel on each piece of 
take.  Stance width will be recorded on the data collection sheet and then entered into REDCap 
so that this distance can be used during each subsequent training and testing session and foot 
position can be measured and marked prior to participant arrival. Participants face a projection 
screen that displays two bar graphs of the vertical ground reaction force, depicting each foot’s 

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load. Subjects will be asked to stand with their feet shoulder width apart (one foot on each force 
plate) with their hands in front on them with the shoulder flexed to 90 degrees for counter 
weight. The foot width will be standardized to ensure that foot placement is consistent for both 
the squatting trials as well as during the biofeedback training. The subject will be asked to squat 
down until their thighs are parallel with the ground or until their heels begin to come off from the 
ground, whichever occurs first. A stool will be placed behind the subject and will be set to the 
height where the subject’s thigh will be parallel to the ground if they sat down (stool will be 
placed at the height of the popliteal fold), so that the subject will know the deepest position they 
have to achieve. If the subject is able to achieve a squat position where the thigh is parallel to 
the floor they will be instructed to squat until they barely touch down on the bench and then 
slowly stand back up without transferring any weight to the bench. Subjects are asked to squat 
down and watch the change in load beneath each foot. After completing the first squat, subjects 
will be asked to complete all subsequent squats with the goal of keeping the bars level on the 
graph or maintaining equal within a LSI ≥ 90% (symmetric) load on both feet. This process will 
be completed a total of 30 times (3 sets of 10 repetitions each) during each of the training 
sessions with the same goal each time of maintaining the bars at an equal level. This is a simple 
measure that subject can easily understand and that can be altered through biofeedback.24  
 
Tactile feedback: The second set of exercises at each biofeedback session will be resisted 
squats. A subject will be asked to squat while an external force is applied to the side of the knee 
(Figure 3) requiring the subject to work against this resistance to maintain balance and complete 
the squat. The band will be placed on the surgical limb of each patient and will be pulled at 
approximately a 45 degree angle toward the contralateral side. Pulling the subject toward the 
non-operative limb (one that is typically displaying higher loads) will require the subject to pull 
toward the surgical limb and maintain good frontal plane position by resisting frontal plane 
valgus. This is a typical exercise utilized in the clinic to aid in equal weight bearing and active 
hip abduction. The squat position that will be used during these exercises will be the same as 
the squat position used in both the visual biofeedback task as well as during the biomechanical 
testing. The subjects will be asked to stand with their feet at the standardized width and again 
squat until they make contact with the stool that will be positioned behind them during the 
biofeedback session. Subjects will be asked to complete 30 tactile feedback squats (3 sets of 10 
squats) during each of the biofeedback sessions. 
 
ATTENTION CONTROL 
The 6-week attention control group program will focus on providing educational information to 
the participants related to the clinical and sports expectations as they are released to return to 
sport.  These participants will be asked to meet 6 times during the 6-week intervention time 
period.  Three of these visits will be completed in person and three will be completed using an 
online educational module (6 sessions).  The online sessions will be completed in week 1, week 
3, and week 5 while the in person sessions will be completed during week 2, week 4, and week 
6.  The content of these sessions will focus on providing information on ACL reconstruction, 
athlete expectation as they return to sport, incidence and risk factors for secondary ACL injuries, 
as well as some suggestions on the gradual progression back into sport.   
6.1.2 DOSING AND ADMINISTRATION 
 
The dose for each participant will be dependent on the group to which he/she is randomized.  
However, the dose will be the same for all participants in the Biofeedback Intervention as well 
as being the same between all participants in the Attention Control arm of the study.  
 

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BIOFEEDBACK INTERVENTION 
The 6-week biofeedback training program is focused on altering loading and movement 
asymmetry during biweekly sessions on non-consecutive days (12 sessions). The biofeedback 
training program will provide sensory (visual and tactile) feedback to the subject to heighten 
awareness of asymmetrical movement strategies (e.g. load shift, movement asymmetry) during 
a squat. The two exercises that will be completed during the biofeedback training program will 
be a visual feedback squat and a resisted squat (tactile feedback).  Each of these tasks will be 
completed 30 (3 sets of 10 repetitions) times per session.  We will provide a 20 second rest 
between trials, and a 10 minute break between the visual and tactile feedback exercises to 
decrease the effect of fatigue.  
 
ATTENTION CONTROL 
The 6-week attention control group program will focus on providing educational information to 
the participants related to the clinical and sports expectations as they are released to return to 
sport.  These participants will be asked to meet 6 times during the 6-week intervention time 
period.  Three of these visits will be completed in person and three will be completed using an 
online educational module (6 sessions).  The online sessions will be completed in week 1, week 
3, and week 5 while the in person sessions will be completed during week 2, week 4, and week 
6.  The content of these sessions will focus on providing information on ACL reconstruction, 
athlete expectation as they return to sport, incidence and risk factors for secondary ACL injuries, 
as well as some suggestions on the gradual progression back into sport. 
 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
Not applicable 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Not applicable 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Not applicable 
 
6.2.4 PREPARATION 
 
Not applicable 
 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
This will be a randomized controlled trial (see figure below).   
 
Participating patients will be randomized using a 1:1 between the Intervention vs. Control arms.  
 

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Participants will be equally allocated between the two groups, with randomization stratified 
according to gender, age and activity level to ensure that the groups are balanced in these 
respects.  All participants in the study will continue with any other usual medical care they 
receive for their ACL reconstruction.   
 
Eligible participants will be randomized following the first biomechanical assessment (during 
which informed consent is obtained).  After this baseline biomechanical assessment, 
participants will be scheduled for his/her first study visit (biofeedback intervention or control in-
person education session) at this time each participant will be informed about the research arm 
to which they have been assigned. The Research Assistant will call participants within 24-48 
hours of each appointment to remind them of their appointment day and time as well as answer 
any questions.   
 
Randomization will be based on a computer generated sequence maintained by the project 
statistician.  The Research Assistant or Principle Investigator will obtain the randomization 
status from the statistician. 
 
Participant randomization assignments will be entered and stored in a password protected, 
study specific database maintained by the research assistant and verified by the study 
statistician. 
 
As this is an open trial, therefore, participant unblinding procedures are not necessary. 
 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
All members of the study staff will endeavor to maximize adherence to the study’s protocol and 
minimize non-compliance.  However, it is the responsibility of the Principal Investigator to report 
all protocol deviations/violations to the Virginia Tech IRB within 10 business days of the time the 
PI becomes aware to the event.  In addition, the PI will include a summary of any protocol 
deviations/violations in the biannual report to the study’s Safety Officer.  Protocol deviations will 
be collected, analyzed, and monitored in the study’s protocol deviation log, which is kept in the 
Investigator’s regulatory files within a locked file cabinet.  A sample protocol deviation form can 
be found in the MOOP (Appendix J). 
 
Protocol deviations include, but are not limited to, the following examples: 
o 
Enrollment or randomization of an ineligible participant 
o 
Follow-up visit at a time point different from that specified in the protocol 
o 
Failure to obtain Informed Consent 
o 
Entering a participant into another clinical study  
Randomization
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o 
Failure to keep IRB approval up-to-date 
o 
Wrong treatment administered to participant 
 
 
6.5 
CONCOMITANT THERAPY 
 
Not applicable 
 
6.5.1 RESCUE MEDICINE 
 
Not applicable 
 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Discontinuation from the ACL Biofeedback intervention does not mean discontinuation from the ACL 
Biofeedback Pilot study, and remaining study procedures should be completed as indicated by the study 
protocol.  If a clinically significant finding is identified (including, but not limited to changes from 
baseline) after enrollment, the investigator or qualified designee will determine if any change in 
participant management is needed. Any new clinically relevant finding will be reported as an adverse 
event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
At the time of discontinuation an AE or SAE report will be completed and submitted to the IRB 
as well as to KAI per the information included in the MOOP (Section 10.0 Safety Reporting).  
 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), or other medical condition or situation occurs such 
that continued participation in the study would not be in the best interest of the 
participant 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Study participant sustains an ACL tear of either limb 
• 
Participant unable to attend the ACL Biofeedback intervention session for 2 days/weeks 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Case Report Form (CRF) (MOOP Appendix K). Subjects who sign the informed consent form 

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and are randomized but do not receive the study intervention may be replaced.  Subjects who 
sign the informed consent form, and are randomized and receive the study intervention, and 
subsequently withdraw, or are withdrawn or discontinued from the study, will be replaced. 
 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for 3 consecutive 
scheduled visits and is unable to be contacted by the study staff.  
 
The following actions must be taken if a participant fails to return to the lab for a required study 
visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 1 
week of the missed visit and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain if the participant wishes to and/or should continue 
in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls will 
be made to the participant). These contact attempts will be maintained in the study 
database.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
All patients will be cleared by their treating orthopaedic surgeon to complete the tasks in this 
study prior to enrollment.  The orthopaedic surgeon will provide the study team with signed 
confirmation that the patient has been released to complete the study activates based on their 
current post-operative recovery (physician release letter) as well as providing the patient's 
confirmation that they approval the release of their information (patient release of information) 
so that they are able to be contacted by the study team to determine the patient’s interest in 
participating in the study. 
 
Based on our prior and ongoing studies, we are confident that 40 participants can be enrolled 
within the 24 month recruitment period. Patients will be identified by his/her treating orthopaedic 
surgeon as being appropriate for study enrollment at approximately 4.5 months post-ACL 
reconstruction and safe to complete the study tasks.  Once the surgeon and patient have 
agreed to an interest in study participation and the patient has provided signed consent for 
release of information, the medical records will be reviewed by a member of the study team to 
determine enrollment eligibility based on study inclusion and exclusion criteria. All potentially 
eligible patients (parents if the patient is a minor) will be approached by the treating orthopaedic 
surgeon or member of the surgeon’s clinical staff. If the patient is over the age of 18, he/she will 
be approached directly by the treating orthopaedic surgeon. During this discussion, the treating 
surgeon will explain the activities to be completed during the study and will provide the patient 
with documentation that the surgeon believes the patient is medically appropriate for study 
enrollment. The referring physicians have been working with the research study team on the 
recruitment and enrollment of ACL reconstruction patients for the last year on an industry 

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sponsored knee brace study. During this time the study team has been able to implement a 
successful recruitment procedure in which the patients are identified by the physician extenders 
or the surgeon and the above described procedure has been completed in each clinic. If a 
patient is interested in participating, the signed consent to release information is sent to the 
research study team and the secondary medical record screening is completed. Informed 
consent and assent will be approved by the institutional review board. 
 
Prior to the start of the study, all participants (and parents will complete parental permission and 
patient will complete ascent if participant is <18 years old) will complete informed consent in 
person in the lab. The consent form will be sent to the potential participant by email or mail 
based on the patient's preference prior to study enrollment. Potential participants (parents if the 
potential participant is a minor) will be allowed to review the consent form prior to his/her first 
visit to the lab. Each participant will be allowed ample time to review the consent form and 
determine if he/she is interested in participating in the study. All questions will be answered prior 
to the consent form being signed and the study being initiated. If a consented subject becomes 
18 during the course of the study he/she will be consented as an adult at the next study visit.  
 
Following administration of the consent and HIPAA authorization, we will measure height and 
weight and determine BMI. If female participants become pregnant, their active involvement in 
the study will end because later stage pregnancy will alter movement mechanics due to 
increased joint laxity.  In addition, weight gain would also likely confound study results.  As part 
of the telephone screening process, women will be excluded if they self-report being pregnant or 
planning to become pregnant.  
 
We will aim to ensure that subject selection is equitable and all relevant demographic groups 
have access to study participation by contacting all patients who meet inclusion / exclusion 
criteria, regardless of demographic characteristics.  We have also aimed to produce recruitment 
and intervention materials that are appropriate for individuals with low literacy or education 
levels.  We will continue to recruit patients until we reach our sample size goal of n=40. 
 
Screening questionnaire data will be entered directly into the study database.  We will have 
paper copies of screening questionnaires that may be used in cases of computer network 
failure.  We anticipate this will be rare.  However, if paper forms are needed, data will then be 
entered as soon as possible.  Any paper copies that are used will be stored in the subject’s 
individual study folders which are kept in a locked file cabinet in a locked office of a study team 
member. 
 
Subject data for all subjects enrolled in the study will be entered into a secure computerized 
enrollment log.  This data will be accessible only to study personnel needing access to fulfill 
their study related duties. 
 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Following recruitment and the completion of informed consent, each subject will be asked to 
complete an initial biomechanical assessment in the Kevin P. Granata Biomechanics Lab at 
Virginia Tech. All subjects will be asked to wear form fitting shorts and a shirt, plus a pair of 
athletic shoes (Nike Pegasus, Nike Inc, Beaverton, CO) all of which will be provided for them to 
use during testing (Figure 2). Previous literature has shown that differences in footwear can 
alter the ground reaction forces.35,38 Therefore in a between-subject design comparing two 

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groups (Aim 1) it is important to alleviate any potential differences due to footwear. Patients will 
warm up by cycling on a stationary bike at a comfortable pace for 5 minutes. The seat height for 
the bike will be standardized for all subjects so that when the leg is fully extended at the bottom 
of the pedal stroke there will be between 5 and 10 degrees of knee flexion.  The seat settings 
will then be recorded on the data collection sheet and entered into REDCap in order to ensure 
that the same seat settings are used at each visit. After the warm-up, patients will have retro-
reflective markers attached at specific locations on both lower extremities to track segmental 
motion during both squatting and landing. Three-dimensional coordinate data will be collected 
using a 10-camera motion capture system at a sampling rate of 120 Hz (Qualysis, Sweden). 
Ground reaction forces will be collected using 2 embedded force plates at a sampling rate of 
2400 Hz (AMTI, Watertown, Massachusetts). Each subject will be asked to complete a standing 
trial followed by a series of squatting and landing trials as described below: 
 
Squatting trial: Subjects will be asked to complete 15 bilateral squats.  Subjects will be asked to 
stand with their feet shoulder width apart (one foot on each force plate) with their hands in front 
on them with the shoulder flexed to 90 degrees for counter weight.  The foot width will be 
standardized to ensure that foot placement is consistent for both the squatting trials as well as 
during the biofeedback training.   The subject will be asked to squat down until their thighs are 
parallel with the ground or until their heels begin to come off of the ground. A stool will be placed 
behind the subject and will be set to the height where the subject’s thigh will be parallel to the 
ground if they sat down (the stool will be placed at the height of the popliteal fold), so that the 
subject will know the deepest position they have to achieve. The stool will be placed within 0.5 
inches of the desired location using a height adjustable plyobox and dense foam padding. The 
height setting of the plyobox will be recorded for each subject on the data collection form and 
will subsequently be entered into REDCap to ensure that the same plyobox position is used 
during each assessment and each biofeedback session. If the subject is able to achieve a squat 
position where the thigh is parallel to the floor they will be instructed to squat until they barely 
touch down on the bench and then slowly stand back up without transferring any weight to the 
bench. The squat assessment will be completed so that the exact same setup and protocol will 
be used for the biofeedback training program and obtain a baseline measure of skill during a 
squat.  Upon completion of the squatting trials, subjects will be asked to complete 10 vertical 
stop-jump tasks. The stop-jump task was selected based on its game-like nature. The stop-jump 
task is a good simulation of a basketball jump-shot or heading a soccer ball and therefore could 
produce loads and movements that are closely related to those seen during game play.       
 
Landing trial: Subjects will be asked to complete 10 trials of a vertical stop-jump task. During the 
vertical stop-jump task, subjects will run straight forward for up to 5 steps taking off on 1 foot, 
landing on 2 feet (one foot on each force plate), and taking off again on 2 feet.16,18,20,21 Prior to 
testing maximum jump height will be determine using a vertec. During testing, a ball will be hung 
above the force plates at 75% of the subject’s maxmum jump height to provide a target during 
jumping. Subjects will be instructed to jump up and grab the ball and then come down bilaterally 
on the two force plates.   No instructions will be provided on how to land or what to do with their 
arms to initiate the jump. The stop-jump task will be used to determine if the biofeedback 
intervention is effective at decreasing secondary ACL risk factors as these risk factors were 
determined during landing. Subjects will be allowed to practice the task between 3 and 5 times 
until they are comfortable with the movement. A minimum of 5 minutes’ rest will be given 
between conditions to minimize the effects of fatigue.  If the results of the baseline jumping 
assessment indicates that the subject has a limb symmetry index (LSI) of greater than or equal 
to 90%, which is indicative of limb symmetry during hopping in healthy subjects, he/she will be 
excluded from the intervention.  
   

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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse Event (AE) – Any untoward or unfavorable medical occurrence in a clinical research 
study participant, including any abnormal sign (e.g. abnormal physical exam or laboratory 
finding), symptom, or disease, temporally associated with the participants’ involvement in the 
research, whether or not considered related to participation in the research. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (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:  
• 
Results in death  
• 
Is life threatening, or places the participant at immediate risk of death from the event as 
it occurred  
• 
Requires or prolongs hospitalization  
• 
Causes persistent or significant disability or incapacity  
• 
Results in congenital anomalies or birth defects  
• 
Is another condition which investigators judge to represent significant hazards 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following 
guidelines will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and his/her 

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clinical judgment. The degree of certainty about causality will be graded using the categories 
below. In a clinical trial, the study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable 
possibility that the study intervention caused the AE, or there is a temporal relationship 
between the study intervention and event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study intervention and the AE. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event occurs within a reasonable time 
after administration of the study intervention, is unlikely to be attributed to concurrent 
diagnosis. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
 
 
8.3.3.3 EXPECTEDNESS  
 
The study clinician and the principle investigator in consultation will be responsible for 
determining whether an adverse event (AE) is expected or unexpected.  An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with 
the risk information previously described for the study intervention. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits 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 case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed by the study 
clinician), 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.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
The study principle investigator and either of the research assistants will record all reportable 
events with start dates occurring any time after informed consent is obtained until 7 (for non-
serious AEs) or 30 days (for SAEs) after the last day of study participation.  At each study visit, 
the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events will be 
followed for outcome information until resolution or stabilization. 
 

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8.3.5 ADVERSE EVENT REPORTING  
 
All AEs are collected, analyzed, and monitored by using an Adverse Event Form (MOOP 
Appendix G). AEs and/or laboratory abnormalities identified in the protocol as critical to 
participant safety will be reported to the NIAMS and the safety officer. All AEs experienced by a 
participant during the time frame specified in the protocol (from the initial day of testing as well 
as the initiation of the biofeedback program through the end of the study) will be reported, as 
outlined in the protocol (Section 1a of the MOOP). 
 
The procedure for collecting and reporting AEs will be detailed in the following sections.  This 
information will include the role of the Principal Investigator and the Medical Monitor (Dr. 
Thomas K. Miller) in assigning severity and defining the relationship between the AE and the 
study intervention.  A sample AE form can be found in Appendix G.  Requirements for reporting 
AEs to the NIAMS and the study’s independent Safety Officer (SO)) is described below. 
 
The Principal Investigator (PI) and study staff members will be responsible for the safety of 
study participants.  It is not anticipated that there will be any significant physical or psychological 
risks associated with this study.  However, federal regulations require prompt reporting to the 
Virginia Tech Institutional Review Board (IRB), all injuries, adverse events, or other 
unanticipated problems involving risks to subjects or others that occur in the course of a 
subject’s participation in this research study. 
 
Study team members who become aware of any adverse event related to the study will notify 
the principal investigator, Dr. Queen, immediately.  Study team members will have contact 
information for Dr. Queen for daytime, evening and weekend hours. If Dr. Queen is not available 
for contact when a study team member becomes aware of a study-related adverse event, Dr. 
Savla or Dr. Ollendick, co-investigators on the study, will be contacted.  Once Dr. Queen (or a 
co-investigator) is contacted about the adverse event, she / he will make a determination about 
the reporting requirements in accordance with the Virginia Tech IRB guidelines.  This will 
include notification of the Virginia Tech IRB within 24-hours if a study-related death, within 5 
business days if another serious adverse event, and within 10 business days if a protocol 
deviation/violation, or other unanticipated problem.     
 
The Principal Investigator will report all adverse events and protocol deviations to the study’s 
NAIMS safety officer on a biannual basis, or as requested. The PI or co-investigator will report 
all serious adverse events to the study’s safety officer within 48 hours of the event being made 
known to the investigator.  This immediate report will be followed by a detailed written report as 
soon as possible.   
 
All adverse events will be collected, analyzed, and monitored in the study’s adverse event log, 
which is kept in the Investigator’s regulatory files within a locked file cabinet. 
 
The following definitions from the US Office of Human Research Protections will be used: 
 
Adverse Event (AE):  Any untoward or unfavorable medical occurrence in a subject, including 
any abnormal sign, symptom, or disease, temporally associated with the subject’s participation 
in the research, whether or not considered related to the subject’s participation in the research.  
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 

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The study clinician will immediately report to the sponsor any serious adverse event, whether or 
not considered study intervention related, including those listed in the protocol and must include 
an assessment of whether there is a reasonable possibility that the study intervention caused 
the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal 
relationship between the study intervention and the event. In that case, the investigator must 
immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. The study sponsor will be 
responsible for notifying the Food and Drug Administration (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.   
 
All serious adverse events (SAEs), unless otherwise specified in the protocol and approved by 
the IRB and the NIAMS, require expedited reporting by the Principal Investigator to the study's 
Safety Officer. SAEs will be reported to the Safety Officer and the NIAMS, through the NIAMS 
contractor within 48 hours of being reported to the Investigator.  The immediate reports will be 
followed by detailed, written reports as soon as possible as follow up information may be 
required before a written report can be provided.  The Principal Investigator will report all 
serious adverse events to the study’s NAIMS safety officer on a biannual basis.  
 
Study team members who become aware of any serious adverse event related to the study will 
notify the principal investigator, Dr. Queen, immediately.  Study team members will have contact 
information for Dr. Queen for daytime, evening and weekend hours. If Dr. Queen is not available 
for contact when a study team member becomes aware of a study-related adverse event, Dr. 
Savla or Dr. Ollendick, co-investigators on the study, will be contacted.  Once Dr. Queen (or a 
co-investigator) is contacted about the serious adverse event, she / he will make a 
determination about the reporting requirements in accordance with the Virginia Tech IRB 
guidelines.  This will include notification of the Virginia Tech IRB within 24-hours if a study-
related death, within 5 business days if another serious adverse event.     
 
All serious adverse events will be collected, analyzed, and monitored in the study’s serious 
adverse event log (MOOP Appendix H), which is kept in the Investigator’s regulatory files within 
a locked file cabinet. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
The Principal Investigator and study staff will send an IRB approved letter to each study 
participant in the event of an AE or SAE that is determined by the IRB to change the study risks 
to the participant. In addition, at the completion of the study an IRB approved letter will be sent 
to each participant to inform them that the study is completed and provide them with information 
related to the study outcomes and provide a link to any research articles that are published 
related to this study. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
Not applicable 
 
8.3.9 REPORTING OF PREGNANCY  

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Not applicable 
 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to participants or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review 
Board (IRB). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB, the Safety 
Officer and the NIAMS, through the NIAMS contractor within 48 hours of being reported 
to the Investigator.  The immediate reports will be followed by detailed, written reports as 
soon as possible as follow up information may be required before a written report can be 
provided.  The Principal Investigator will report all serious adverse events to the study’s 
NAIMS safety officer on a biannual basis.  
• 
Any other UP will be reported to the IRB and the Safety Officer and the NIAMS, through 
the NIAMS contractor within 10 business days if a protocol deviation/violation, or other 
unanticipated problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
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NIAMS contractor, and the Office for Human Research Protections (OHRP) within 10 
business days of the IRB’s receipt of the report of the problem from the investigator.] 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Not applicable 
 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
All statistical analysis will be completed under the direction of Dr. Salva. Depending on the 
outcome, change (completion-baseline), or the value at completion will be assessed, and the 
statistical significance of the group differences can be assessed by a t-test or the non-
parametric equivalent (2-sample Wilcoxon).  Standardized differences will be calculated for the 
purposes of powering the subsequent clinical trial.    
  
• 
Primary Efficacy Endpoint(s):  
We will test the hypothesis that our biofeedback program will decrease the risk of 
secondary ACL injury by improving loading and movement symmetry (knee extension 
moment asymmetry) during the dynamic task of landing from a jump 6 weeks post 
intervention.  
 
Movement and loading symmetry will be assessed using the limb symmetry index (𝑳𝑳𝑳𝑳𝑳𝑳=
(𝑨𝑨𝑨𝑨𝑨𝑨 [𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺 − 𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵])/𝟎𝟎. 𝟓𝟓(𝑨𝑨𝑨𝑨𝑨𝑨[𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺𝑺] + 𝑨𝑨𝑨𝑨𝑨𝑨[𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵𝑵]) ∗
𝟏𝟏𝟏𝟏𝟏𝟏)2,3,7,34 prior to (baseline) and at two time points following (immediately following 
training (efficacy), and 6 weeks after (durability)) the biofeedback training program. 
 
• 
Secondary Efficacy Endpoint(s): 
No hypothesis testing will be completed for the secondary endpoint as this is a pilot 
clinical trial and will be used to determine the best procedures to following when 
planning a subsequent multi-center clinical trial.  Therefore, we will demonstrate our 
ability to recruit 40 ACL reconstructed patients and assess study retention and 
compliance. 
 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
This is a pilot study, with the purpose of discerning parameter estimates for use in powering a 
subsequent multi-center clinical trial. To estimate statistical power for this pilot design, we 
consider a comparison of outcomes by group across time. Previous studies have not examined 
the knee extension moment limb symmetry index, therefore the difference in knee joint position 
and the knee extension moment will be employed as proxy variables in order to estimate 
statistical power for this pilot design. We considered a comparison of outcomes between pre- 
and post-intervention17,18 and side-to-side differences in ACL-R patients. (Table 4).15   
 

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Using 2-sided testing between groups based on previous results, we will need 14 patients 
overall randomized at 1:1 
ratio assuming 80% power 
to detect a significant 
difference in the knee 
extension moment 
between the groups with 
α=0.05.13 Therefore, with 
recruitment of 40 subjects 
(goal of retaining 30 
subjects through study completion), we are adequately powered to declare significance. Thus, 
while not the primary purpose of this experiment, we are adequately powered to declare 
significance between groups.  
 
 
9.3 
POPULATIONS FOR ANALYSES 
 
The following populations will be included in the statistical analysis: 
 
• 
Modified Intention-to-Treat Analysis Dataset (participants who completed at least 50% of 
the intervention visits in the Biofeedback Arm of the study and who attended at least one 
of the post-intervention assessment visits) 
• 
Safety Analysis Dataset: defines the subset of participants for whom safety analyses will 
be conducted (participants who completed at least intervention visit) 
• 
Per-Protocol Analysis Dataset: defines a subset of the participants in the full analysis 
(ITT) set who complied with the protocol sufficiently to ensure that these data would be 
likely to represent the effects of study intervention according to the underlying scientific 
model (participants who completed at least 80% of the study intervention visits) 
• 
Other Datasets that may be used for sensitivity analyses 
 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
• 
For descriptive statistics the results will be reported as percentages as well as means 
and standard deviations as appropriate for the measure.  Categorical data will be 
reported as percentages while continuous data will be reported as means with standard 
deviations as well as data ranges.  
• 
For inferential tests, indicate the p-value and confidence intervals for statistical 
significance (Type I error) and whether one or two-tailed. 
• 
Checks for the assumption of normality will be performed prior to additional statistical 
procedures.  If this assumption is not met then corrective procedures will be applied 
such as transformation or nonparametric tests as appropriate. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The goal of the proposed study is to determine the impact of an innovative biofeedback training 
program on decreasing risk factors for secondary ACL injuries in adolescent athletes. Based on 
Table 4: Sample Size Calculations (N=sample size per group) 
 
Pre-
intervention 
Post-
intervention 
Sample 
Size 
Peak Knee Extension Moment10 
3.7 ± 0.9 
2.4 ± 0.5 
N=7 
Peak Knee Flexion18 
88.8 ± 8.0 
105.0 ±5.6 
N=5 
 
Control 
Intervention 
Sample 
Knee Flexion Angle 18 
83.5 ± 20.5 
103.8 ± 16.3 
N=15 
Vertical ground reaction force18 
2.0 ± 0.4 
1.6 ± 0.3 
N=14 

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previous work, the primary variable of interest and a surrogate for secondary ACL injury risk will 
be the knee extension moment limb symmetry index (LSI).  The previously established 
movement asymmetry risk factors32 and therefore the primary measures of interest are the knee 
extension moment, vertical ground reaction force, and frontal plane knee range of motion. 
Symmetry between the operative and non-operative limbs in this study will be determined by 
calculating the limb symmetry index (LSI). Asymmetry in the peak knee extension moment has 
been identified as significant predictors of secondary ACL injuries (therefore reduction in this 
asymmetry will decrease the risk for secondary ACL injuries).32   
 
For Aim 1 of this pilot study a within subject repeated measures assessment (ANOVA), as 
implemented under mixed models, will be used to determine if a clinical (LSI>90%) and/or 
statistical difference exists between the pre- and the two post-intervention time points (efficacy 
and durability) for the primary outcome of interest (knee extension moment asymmetry). Post-
hoc testing will be completed for any variable that is determined to be statistically different.   
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
For Aim 2, we will calculate rates of recruitment, retention and compliance.  No hypothesis tests 
will be performed.  However, correlates to these metrics will be assessed.   For each of the 
outcome measures the between session analysis will allow us to calculate test-retest reliability.  
The use of correlations will allow us to compute criterion and predictive validity. 
 
Study retention will be defined as a subject who attends each of the biomechanical testing 
session (baseline, immediately following intervention (intervention)/6 weeks after baseline 
(control), and then 6 weeks after training (intervention) or 12 week after the baseline (control). 
Proportion retention will be computed by dividing the number of retained subjects at the end of 
the intervention by the total number of patients randomized into the study.  Compliance with the 
intervention will be defined as a subject who attends at least 80% of the biofeedback training 
sessions during the six weeks of the intervention.  Proportion adherence will be computed by 
dividing the number of sessions attended by the total number training sessions (number of 
training sessions n=12). 
 
9.4.4 SAFETY ANALYSES 
 
Monthly reports will describe target and actual enrollment by site and in aggregate, individuals 
screened with reasons for screen failure, and enrollment status (enrolled, active, completed, 
discontinued treatment, and lost to follow-up). Monthly reports will also list or summarize AEs 
and SAEs. Administrative reports will list the forms completed, entered, and missing, and/or 
erroneous data and forms. The NIAMS has requested a monthly study update to be provided on 
the fifth of every month by the study PI. Reports to the Safety Officer (SO) will be completed 
biannually throughout the study and will be submitted by the study PI to KAI based on a 
schedule that will be on when the first subject is enrolled into the study. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Not applicable – study will be block randomized in order to decrease the potential for differences 
in baseline characteristics between the two study groups (Intervention and Control). 
 
9.4.6 PLANNED INTERIM ANALYSES  
 

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Not applicable 
 
9.4.7 SUB-GROUP ANALYSES 
 
Due to the pilot nature of this clinical trial we will not be performing any subgroup analyses.  
However, in order to better understand the outcomes and in an attempt to plan for a future multi-
center trial, we will explore possible confounders such as age, time from surgery, time in 
rehabilitation, concomitant meniscal pathology, sex, and the initial injury mechanism.  This 
information could allow for program modifications and/or determine if certain baseline 
characteristics need to be achieved prior to starting the biofeedback program. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Individual participant data will be recorded in the study database, however, study results that will 
be reported will be based on the group aggregate data for each of the study groups.  
 
9.4.9 EXPLORATORY ANALYSES 
 
Over the course of the study secondary outcomes will be examined to determine any mediating 
effects these variables may have, which could explain differences across time (Table 3). 
Secondary outcomes will be evaluated using exploratory analyses in order to generate 
hypotheses for future studies. These exploratory 
analyses will be conducted using linear mixed 
models.23,35,36 We will test both primary and 
secondary outcomes at an alpha level of 0.05 and 
will not control for potential Type-I errors due to 
multiple testing, using Bonferroni or Hochberg 
criteria,8,9,19 due to the pilot nature of this study. If 
an effect is declared ‘significant’ we will provide a 
cautionary note in resulting publication, as to the 
exploratory nature of the findings.   
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
All patients will be approached by their treating orthopaedic surgeon to inquire about their 
interest in hearing more about this clinical trial.  At that time the clinician will provide the 
potential participant with a release letter (MOOP Appendix C) that indicates that the patient is 
clinically ready to participant in this clinical trial.  At that time, the potential participant will also be 
asked to sign the release of information consent (MOOP Appendix B).  This signed form will be 
sent to the study team to indicate the potential participant’s interest in learning more about the 
research project.  
Table 3: Outcome Measurements 
 
Primary Outcomes 
Peak Knee Extension Moment Symmetry 
Secondary Outcomes 
Peak Vertical Ground Reaction Force Symmetry 
Vertical Ground Reaction Force Impulse Symmetry 
Frontal Plane Knee Range of Motion  
Peak Knee Flexion Angle Symmetry 
Peak Knee Flexion Angle 
Peak Knee Valgus 

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Consent forms describing in detail the study intervention, study procedures, and risks are given 
to the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted 
with this protocol; (1) adult informed consent, (2) Minor ascent, and (3) parental permission.  
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB)-approved and the participant will be asked to read and review 
the document. The investigator will explain the research study to the participant and answer any 
questions that may arise. A verbal explanation will be provided in terms suited to the 
participant’s comprehension of the purposes, procedures, and potential risks of the study and of 
their rights as research participants.  Participants will have the opportunity to carefully review 
the written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their family or surrogates or think about it prior to agreeing 
to participate. The participant will sign the informed consent document prior to any procedures 
being done specifically for the study. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy of 
the informed consent document will be given to the participants for their records. The informed 
consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The 
rights and welfare of the participants will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
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 principle investigator 
(PI will then contact all study participants to provide information on the status of the study), the 
NIAMS, as well as regulatory authorities.  If the study is prematurely terminated or suspended, 
the Principal Investigator (PI) will promptly inform study participants, the Institutional Review 
Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension.  
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule. 
  
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 that the primary endpoint has been met 
• 
Determination of futility 
 
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the NIAMS, IRB and/or Food and Drug Administration (FDA). 
 

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10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
the clinical information relating to participants. Therefore, the study protocol, documentation, 
data, and all other information generated will be held in strict confidence. No information 
concerning the study or the data will be released to any unauthorized third party without prior 
written approval of the NIAMS.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the NIAMS, representatives of the 
Institutional Review Board (IRB), or regulatory agencies may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) for the participants in this study. The clinical study site will permit 
access to such records. 
 
The study participant’s contact information will be securely stored for internal use during the 
study. At the end of the study, all records will continue to be kept in a secure location for as long 
a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at Virginia Tech. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by Virginia Tech research staff will be secured and password 
protected. At the end of the study, all study databases will be de-identified and archived at 
Virginia Tech. 
 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued 
by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality 
and privacy to participants. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at Virginia Tech. After the study is 
completed, the de-identified, archived data will be stored at in the ACL Biofeedback REDCap 
database that was designed for this clinical trial.  The use of this data by other researchers 
including those outside of the study will be approved by the Institutional Review Board as a 
retrospective review of existing data with the permission of the study principle investigator.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 

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Principal Investigator 
Medical Monitor 
Robin Queen, PhD, FACSM 
Associate Professor  
Biomedical Engineering and Mechanics 
Orthopaedic Surgery 
Thomas Miller, MD 
Chief of Sports Medicine Carilion Clinic 
Associate Professor 
Orthopaedic Surgery 
Virginia Tech 
Virginia Tech Carilion School of Medicine 
Carilion Clinic 
Virginia Tech Carilion School of Medicine 
445 Old Turner Street 
230 Norris Hall – Virginia Tech 
Blacksburg, VA 
Institute – Orthopaedics & Neurosciences 
2331 Franklin Rd. 
Roanoke, VA 
(540) 231-3134  
(540) 776-0221 
rmqueen@vt.edu 
tkmiller@carilionclinic.org 
 
 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a Safety Officer (SO) who has expertise as an 
orthopaedic surgeon and is familiar with the ACL reconstruction and rehabilitation. The SO was 
appointed by the NIAMS and is independent from the study conduct and free of conflict of 
interest, or measures should be in place to minimize perceived conflict of interest.  The SO will 
operate under the rules stated by the NIAMS and this information was reviewed at the study’s 
organizational meeting. At this time, each data element that the SO needs to assess will be 
clearly defined. The SO will provide input to the NIAMS through the NIAMS contractor. 
 
10.1.7 CLINICAL MONITORING 
 
With this study being a single site study there will not be site visits.  However, these assurances 
will be made by the study PI at the site as well as being verified by the clinical health 
psychologist who is a member of the study team, but not involved in the day to day testing of 
these participants.   
 
The purpose of these reviews is to: 
• 
Ensure the rights and safety of participants 
• 
Confirm that the study’s conduct follows GCP guidelines 
 
• 
Ensure maintenance of required documents 
• 
Verify adherence to the protocol 
• 
Monitor the quality of data collected 
• 
Ensure accurate reporting and documentation of all AEs 
 
During monitoring visits, the data recorded on CRFs are reviewed and verified against source 
documents to ensure: 
• 
Informed consent has been obtained and documented in accordance with IRB/ FDA 
regulations 
• 
The information recorded on the forms is complete and accurate 
• 
There are no omissions in the reports of specific data elements 
• 
Missing examinations are indicated on the forms 
• 
Participant disposition when exiting the study is accurately recorded 
 

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The Study PI will ensure that the clinical monitor has access to all study documents, including 
informed consent forms, drug accountability records, and source documents, including pertinent 
hospital or medical records. 
 
Once the review is complete, a monitoring report is drafted to provide feed-back regarding the 
activities that were accomplished and any problems or issues that may have been uncovered 
during the visit. The report should be straightforward, stating any problems uncovered and 
describing recommendations to address them.  A timeline should be agreed upon and included 
in the report to ensure that follow-up of any issues is completed and implemented into the 
study’s procedures.  The review as described above will be completed once every quarter 
throughout the study by the clinical health psychologist along with the study PI.   
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Audits of source-to-database documents will occur regularly, with complete audits of critical 
variables, and random sample audits of non-critical variables. In addition, there will be complete 
audits of selected subjects. The data management binder, developed and maintained by RMT, 
will be regularly updated to reflect the current status of the study, and the databases will be 
subject to planned quality control audits. In addition, data management will produce regular 
quarterly reports of data quality, recruitment metrics, and outstanding queries. 
 
While this is a pilot study and data will be easily tracked, we intend to set up systems that will 
mimic the larger proposed trial. A critical component is the development of a data management 
plan that documents key processes and procedures. The plan will be incorporated into a project 
specific data management binder that includes the protocol, scope of work, annotated data 
forms, database structure, query rules, data flow scheme, specific work instructions for all data 
management processes, copies of supporting forms and data clarification forms, and audit 
plans. Upon screening and enrollment, research data entry will occur in the web-based REDCap 
software program which will have undergone extensive validation and testing to meet HIPAA 
compliance rules. New data will be inspected for completeness, and queried for programmed 
logic checks and out-of-range values. Only consented subjects will have their data stored and 
entered in REDCap. The person responsible for data will work with the project manager to set 
up tracking participant enrollment, CRF completion and prompts for email and telephone 
reminders and appointment scheduling. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the principle investigator. The investigator is responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  Most of the source data for this clinical trial will be collected directly in an 
electronic REDCap database to avoid issues with data entry and improve speed of data 
collection for the participants.  
 
Hardcopies of the study visit worksheets will be provided for use as source document 
worksheets for recording data for each participant enrolled in the study if the participant is 
unable to complete the outcome forms within the electronic system.  Data recorded in the 

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electronic case report form (eCRF) derived from source documents should be consistent with 
the data recorded on the source documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) will be entered into REDCap, a 21 CFR Part 11-compliant data capture system 
provided by Virginia Tech. The data system includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, 
or inaccurate. Clinical data will be entered directly from the source documents. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an International Conference on Harminosation (ICH) region and until 
there are no pending or contemplated marketing applications in an ICH region or until at least 2 
years have elapsed since the formal discontinuation of clinical development of the study 
intervention. These documents should be retained for a longer period, however, if required by 
local regulations. No records will be destroyed without the written consent of the NIAMS, if 
applicable. It is the responsibility of the NIAMS to inform the investigator when these documents 
no longer need to be retained. 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), or Manual of Operations and 
Procedures (MOOP) 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 GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the principle investigator to use continuous vigilance to identify and 
report deviations within 10 working days of identification of the protocol deviation, or within 30 
working days of the scheduled protocol-required activity.  All deviations must be addressed in 
study source documents, reported to the NIAMS Program Official and the Safety Officer.  
Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) per their 
policies. The site investigator is responsible for knowing and adhering to the reviewing IRB 
requirements. Further details about the handling of protocol deviations will be included in the 
MOOP.  
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
The study team will seek to publish study findings as soon as they are available.  We will aim to 
write papers describing the study design, baseline sample characteristics, and other analyses of 
interest regarding baseline measures, as these become available.  We will perform regular data 
cleaning throughout the study so that analyses of main study outcomes may begin very shortly 
after these assessments are completed.  The study team will follow guidelines for authorship as 
recommended by the International Committee of Medical Journal Editors (ICMJE).  We expect 

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that manuscripts describing main study outcomes will involve authorship of all study co-
investigators (as long as ICMJE criteria are met).  Other manuscripts must be reviewed and 
approved by the Principal Investigator and Senior Statistician on the project, at minimum, before 
submission. 
 
In compliance with the current NIH policy to ensure public access to NIH funded research all 
publications will be submitted in an electronic format upon acceptance for any publications that 
result from research supported, in whole or in part by the funding for this project. The final 
manuscript is defined as the final version accepted for journal publication, and includes all 
modifications from the publishing peer review process.  
 
In compliance with the NIH policy, electronic submission will be made directly to the NIH 
National Library of Medicine's (NLM) PubMed Central (PMC): 
http://www.pubmedcentral.nih.gov. PMC is the NIH digital repository of full-text, peer-reviewed 
biomedical, behavioral, and clinical research journals. It is a publicly-accessible, stable, 
permanent, and searchable electronic archive.  
At the time of submission, the author will specify the timing of the posting of her final manuscript 
for public accessibility through PMC. Posting for public accessibility through PMC is requested 
and strongly encouraged as soon as possible (and within twelve months of the publisher's 
official date of final publication).  
 
The publisher may choose to furnish PMC with the publisher's final version, which will 
supersede the author's final version. Also, if the publisher agrees, public access to the 
publisher's final version in PMC can occur sooner than the timing originally specified by the 
author for the author's final version.  
 
Additional details for submitting authors pertaining to the implementation of the NIH policy can 
be found at the following website: http://www.nih.gov/about/publicaccess/index.htm. 
 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with the NIAMS has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
Not Applicable 
 
 
 

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10.3 ABBREVIATIONS 
 
ABS 
Absolute Value 
ACL 
Anterior Cruciate Ligament 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
CFR 
Code of Federal Regulations 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FWA 
Federal-Wide Assurance  
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act  
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
LSI 
Limb Symmetry Index 
MOOP 
Manual of Operations and Procedures 
NCT 
National Clinical Trial 
NIAMS 
National Institute of Arthritis and Musculoskeletal and Skin Diseases 
NIH  
National Institutes of Health 
NLM 
National Library of Medicine 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
PMC 
PubMed Central 
SAE 
Serious Adverse Event 
SO 
Safety Officer 
SoA 
Schedule of Activities 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
V1.1 
 
07/31/2017 
 
Section 6.1 & 8.2 
Added description of the adjustable 
stool and the specific height for the 
stool so that it will be placed within 0.5 
inches of the popliteal fold during both 
the assessment and the biofeedback 
session.  
This change was made in order to 
standardize the location of the 
adjustable stool during testing 
and training for those 
participants who are able to 
complete a squat with their heels 
on the ground and their thighs 
parallel to the floor.  
V1.2 
09/05/2017 
 
Title Page 
Added the clinical trial identification 
number 
Clinical trial approved through 
clinicaltrials.gov with the 
following identification number 
NCT03273673 
V1.3 
11/06/2017 
 
Section 1.3 
Corrected the tracking time points for 
the biofeedback interventions 
Needed to update the schedule of 
events to include tracking of 
Adverse Events as well as the no 
shows for the biofeedback 
interventions to indicate that 
these would be completed at each 
of the visits, which will occur two 
times per week for the 6 weeks of 
the intervention period.  
V1.4 
01/02/2018 
 
Section 1.3 
Updated Table 1.3 Schedule of 
Activities (SoA) 
This table was updated to clarify 
when various outcome measures 
were being collected for the 
various treatment groups.  
V1.4 
01/02/2018 
 
Section 5.2 
Updated the exclusion criteria 
Updated the exclusion criteria to 
include exclusion from the study 
if a potential participant was still 
attending formal physical 
therapy more than two times per 
week at the time of study 
enrollment 
V1.4 
01/02/2018 
 
Section 6.1.1 
Updated Biofeedback intervention 
information including information on 
the warm-up and the foot position 
during the squat assessments.  
In order to improve clarity and 
provide details regarding both 
foot position during the squat 
testing and training as well as 
providing details on 
standardization of pre-
intervention warm-up this 
portion of 6.1.1 has been 
updated.   
V1.4 
01/02/2018 
 
Section 8.2 
Additional information provided 
regarding the set-up of the bicycle for 
warm-up as well as the plyobox used 
during testing.  
In order to standardize the 
assessments being completed as 
part of this study, additional 
information was provided 
regarding the setting of seat 
height for the bicycle for warm-
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plyobox to be used during both 
the biomechanical assessments as 
well as the intervention sessions.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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