Neuromuscular Intervention Targeted to Mechanisms of ACL Load in Female Athletes
Phase: NA
Conditions: Rehabilitation, ACL Reconstruction
Sponsor: Mayo Clinic

 
 
 
 
 
 
 
Neuromuscular Intervention Targeted to Mechanisms of 
ACL Load in Athletes 
 
NCT03190889 
 
October 28, 2024 

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IRB Minimal Risk Protocol Template  
 
General Study Information 
 
Principal Investigator:       Nathaniel Bates, PhD 
 
 
 
 
 
 
 
 
Study Title:    Neuromuscular Intervention Targeted to Mechanisms of ACL Load in Athletes 
 
Protocol version number and date:     version 4.5, 08/27/2020 
 
Research Question and Aims 
 
Specific Aims and Hypotheses 
Aim 1.  Determine if prospective measures can identify patient risk profiles for second ACL injury by 
separation of patient groups using biomechanical and clinical risk factors.  
Hypothesis 1A: Landing biomechanics (vGRF, frontal and transverse plane hip moments, frontal plane knee 
and hip motion, and asymmetrical sagittal plane knee moments), quadriceps and hamstrings strength and single 
leg postural stability will effectively identify discrete patient risk profiles for second injury based on knee 
abduction (KAA) and hip adduction angles (HAA), surrogates for ACL injury. 
Aim 2.  Determine the effects of differential rehabilitation, including the impact on biomechanical measures of 
ACL injury risk and return to sport readiness after ACLR. 
Hypothesis 2A: Changes in hip and knee kinematics and kinetics (frontal and transverse plane hip moment, 
frontal plane knee motion, and sagittal plane knee motion) will vary by treatment group, with the greatest 
changes occurring in the Targeted neuromuscular training (TNMT) > Standard of care (STAN) > HOME 
groups. Hypothesis 2B: Changes in clinical performance measures (hop symmetry; quadriceps and hip abductor 
Note: If this study establishes a human specimen repository (biobank) for research 
purposes, do not use this template. Use the Mayo Clinic Human Specimen Repository 
Protocol Template found on the IRB home page under Forms and Procedures at 
http://intranet.mayo.edu/charlie/irb/ 
 
First-time Use: Use this template to describe your study for a new IRB submission. 
1. Complete the questions that apply to your study. 
2. Save an electronic copy of this protocol for future revisions.    
3. When completing your IRBe application, you will be asked to upload this document to the protocol 
section. 
Modification:  To modify this document after your study has been approved: 
1. Open your study in IRBe. Click on the study ‘Documents’ tab and select the most recent version of the 
protocol. Save it to your files. 
2. Open the saved document and activate “Track Changes”.  
3. Revise the protocol template to reflect the modification points , save the template to your files 
4. Create an IRBe Modification for the study and upload the revised protocol template. 

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and extensor strength; single limb balance and self-reported function) will vary by treatment group, with the 
greatest changes in the TNMT > STAN > HOME groups.  
Exploratory Aim.  Develop a clinical algorithm that classifies patient risk for second ACL injury. 
Hypothesis EA:  Clinical tests of strength (quadriceps and hamstrings), balance, 2D jump landing mechanics 
(frontal and sagittal plane knee angle), and knee laxity) will effectively identify patient risk for second ACL 
injury. 
Background  
Importance of the problem. Second ACL injury, whether it is an insult to the ipsilateral graft or the contralateral 
ligament, is a growing problem after reconstruction. Besides missing an additional year of athletic participation, 
increasing health care costs, and increased psychological distress, re-injury and subsequent revision surgery 
have significantly worse outcomes compared with those after initial reconstruction.8-10 Second injuries have 
been reported to occur at a rate of 1 in 17 (6%) within the first two years of surgery.26 However, a second tear 
prevalence of 29% has been reported.5-7, 27 This is substantially higher than initial ACL injuries, reported to 
occur at a rate of 1 in 60 to 100.28, 29 Risk factors for second injury include younger athletes 6 who return to 
high-level sporting activities early. 27, 30 Both sexes are at risk for second ACL injury, with females reported as 
having higher risk of contralateral injury,15, 26 and males having an increased risk of ipsilateral injury.8, 31, 32 
Thus, it is critical to include both sexes in second ACL injury prevention programs. 
Improvement in scientific knowledge and clinical practice: Patients have differential responses after 
ACL injury, including their functional abilities, movement biomechanics, neuromuscular performance, and 
quadriceps strength.18, 19, 33-39 Building from our prior funded work, we propose to prospectively evaluate these 
varying patient characteristics in an attempt to identify distinct groups with differing levels of risk for second 
injury (Aim 1). Our previous work revealed that there were three risk groups among uninjured female athletes. 
The significance of identification of patient groups with distinct needs is profound. Prospective identification of 
at-risk patients who are the most appropriate recipients of enhanced treatment will likely reduce second ACL 
risk, and yield a more efficacious delivery of health care resources after ACLR. The Cincinnati group18 
described this differentiation in ACL deficient patients as the ‘rule of thirds,’ with one third of patients able to 
function without limitations and not needing to undergo surgical stabilization, one third adapting their activity 
level without surgery, and one third requiring surgery to perform daily activities without knee instability. A 
classification scheme described by the University of Delaware also differentiates ACL deficient patients into 
groups of thirds including copers (no limit in abilities), non-copers (unable to function without knee instability) 
or potential copers (individuals who have the potential to function without ACLR).19 There is evidence these 
differences in functional abilities and movement characteristics persist after ACLR. A randomized clinical trial 
concluded individuals who exhibit poor knee stability and function after injury may require additional time to 
return to pre-injury functional levels.40 In addition, some may be unable to develop appropriate quadriceps 
strength symmetry to support a return to high-level sports.40 These data indicate not all patients experience the 
same magnitude or duration of impairments and symptoms after ACLR. Consequently, multiple post-operative 
rehabilitation strategies may be necessary to facilitate optimum patient care and outcomes.  
Working from the rule of one-thirds, identification of distinct patient groups with unique needs after 
surgery is a novel approach for integration of optimum second injury prevention strategies. Primary-injury risk 
factors provide an important window into the underlying biomechanical and neuromuscular deficits that may 
persist after ACL injury and reconstruction.25 Using a statistical analysis clustering technique, distinct groups 
with relative risk for first-time ACL injury have been identified, including low, moderate and high risk groups. 
Single limb postural stability combined with biomechanical variables including vertical ground reaction force 
(vGRF), frontal plane hip adduction moment minimum, and pelvis angle during drop jump landings were 

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identified as significant contributors to frontal plane knee loading, a surrogate for ACL injury risk. This work 
has demonstrated the existence of discernable groups of athletes that are more appropriate for targeted 
neuromuscular training (TNMT) intervention to prevent first-time ACL injury. 
 
Factors that contribute to primary ACL injury risk provide an important window into the underlying 
deficits that may persist after ACL injury and reconstruction. Age and activity level are significant factors, as 
young active individuals are the most likely cohort to sustain a second ACL rupture. 6, 27, 30, 41 Surgical factors 
include decreased graft size,42, 43 use of allograft tissue,44 vertical graft position,45-47 and a lax graft.45, 48 
Anatomical risk factors may also contribute to ACL injury risk and include an increase in the posterior-inferior 
lateral tibial plateau slope and decreased notch width.49 Genetic factors also likely play a role. While it is 
encouraging that so many potential factors have been identified which may contribute to second ACL injury 
risk, none of these factors can be modified through non-surgical intervention. Modifiable biomechanical and 
neuromuscular measures associated with second ACL injury have been identified. Previous work by our 
laboratory included a prospective clinical trial, 56 athletes who had undergone ACLR underwent testing before a 
return to pivoting and cutting sports. Thirteen athletes sustained a subsequent injury.15 Specific injury predictive 
parameters identified during testing included a net internal rotation moment of the uninvolved hip, an increase 
in total frontal plane knee movement, greater asymmetry in internal knee extensor moment at initial contact, and 
deficits in single-leg postural stability of the involved limb.15 These parameters predicted second injury in this 
population with excellent sensitivity (0.92) and specificity (0.88).  
Differences in functional abilities after ACLR may be differentiated by more than biomechanical and 
neuromuscular characteristics. Clinically measured muscle weakness may persist for years after ACLR. 
Quadriceps strength is strongly related to measurements of knee function in athletes who have undergone 
ACLR.20-24 While hamstrings strength alone may not show a significant effect on knee function following ACL 
injury and reconstruction,22, 50 hamstrings activation may be an important component in neuromuscular control 
of the reconstructed knee, especially in females, who tend to be ‘quadriceps dominant’. 50, 51 In addition, deficits 
in the hamstrings-quadriceps torque production ratio also appear to be a key variable in the primary ACL injury 
risk model.52, 53 The relationship between muscle weakness and differential risk for second injury has not been 
established. An understanding of the interplay may, however, be critical to the development of effective, group-
specific intervention programs and reduction of second-injury risk.25  
It is currently unknown if biomechanical and clinical measures may effectively discern groups of patients who 
are at greatest risk for second ACL injury. Evaluation of movement mechanics and clinical characteristics, 
including strength, limb stability and self-reported function, at the time a patient initiates sports-specific training 
may yield insight to differential responses after ACLR. If distinct patient groups are identified, this information 
may be used to provide differentiated interventions based on risk for second injury.  In Aim 2 of this proposal, 
we will evaluate the effects of differential rehabilitation interventions.  Our Exploratory Aim will be the initial 
step in translating the biomechanics-based, group algorithm into a clinical application for individualized 
categorization of risk.  The results of this work may instigate a paradigm shift in treatment, and promote a more 
efficacious utilization of healthcare resources by providing enhanced care to those patients who are at greatest 
risk for secondary injury. 
Impact on patient care. One of the factors that contributes to second ACL injury is incomplete or 
ineffective rehabilitation.54 Aberrant neuromuscular and biomechanical patterns are commonly seen up to 2 
years after ACLR and may help explain the high rate of second ACL injury.11-16 Deficits in the neuromuscular 
control of both lower extremities following ACLR have been directly implicated in the risk for second ACL 
injury15 and may not only be a result of the initial knee injury and subsequent surgery, but may also characterize 
the athlete’s pre-injury movement patterns. Therefore, identification and subsequent targeted treatment of 

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aberrant post-ACLR movement patterns for both limbs are critical not only to maximize functional recovery but 
also to reduce the risk for second ACL injury. Though neuromuscular training programs result in a 73.4% 
decreased risk of a non-contact primary-ACL injury compared to those who do not participate in neuromuscular 
training55, the efficacy of similar programs for reduction of second-ACL injury risk has not been examined.  
An evidence-based targeted neuromuscular training (TNMT) program has been designed to reduce the 
incidence of second ACL injury. This training program was developed with consideration to modifiable factors 
related to second-injury risk, the principles of motor learning, and careful selection of the exercises that may 
most effectively modify aberrant neuromuscular programs. In Aims 2 and 3 of this competing renewal proposal 
we will evaluate the effects of differential treatment interventions. Notably, we will assess the effectiveness of 
TNMT, including the utilization of visual and verbal biofeedback.  Validation of this evidence-based, late-phase 
TNMT program may significantly impact clinical practice patterns through its integration in rehabilitation 
settings, and serve as a critical factor in reduction of second injury risk. Ultimately, determining if less intensive 
HOME and STAN training programs are effective interventions for patients who are at reduced risk for second 
ACL injury may prove to be a tremendous time and cost savings for patients and the health-care system. 
 
 
Study Design and Methods 
 
Methods 
Overall Strategy. This is a prospective, randomized, repeated measures single- blind clinical trial. The purposes 
of this study are to 1) stratify patient risk for second ACL injury, and 2) determine the effects of differential 
treatment intervention, including targeted neuromuscular training (TNMT), home program only (HOME) and 
standard clinical (STAN) training, on clinical, biomechanical, and neuromuscular performance measures 
associated with an increased secondary ACL injury risk. At this time there is no evidence to support one 
intervention as either superior or inferior to the other interventions proposed in this study.  After the initial ACL 
injury and study enrollment, all patients will participate in standardized pre-operative rehabilitation. They will 
then undergo surgery by a fellowship-trained sports medicine surgeon at Mayo Clinic, Rochester, MN. Data for 
Aim 1 will be obtained from biomechanical, neuromuscular and clinical testing performed during Pre-Testing. 
Data for Aim 2 and the Exploratory Aim will be obtained from biomechanical and clinical test results obtained 
from Pre- and Post-Testing time points.  
 
 
Common Rehabilitation. All study participants will follow the same rehabilitation guidelines before and 
immediately after surgery, until they are cleared by their attending surgeon to return to full participation in 
sports. After clearance, they will be randomized into the differential treatment groups. Entry into this phase is 
criteria-based, and represents the standards identified in the literature for entry into the final phase of 
rehabilitation.  These criteria include: symmetrical knee range of motion; minimal or no pain and knee effusion; 
quadriceps strength ≥ 80% compared to contralateral limb (180°/sec and 300°/sec); self-report of function ≥ 
80%; limb symmetry index during single leg hop for distance ≥ 80%. Both pre- and postoperative rehabilitation 
protocols are a composite of previously published, evidence-based protocols from expert researchers and 
clinicians.65-67  
 
Differential Rehabilitation.  Once study participants are cleared for full participation in sports, they will be 
randomized into one of three groups for differential treatment. This will include HOME, STAN and TNMT 

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groups. If patient lives at a distance from Mayo Clinic and cannot participate in the weekly training but is able 
to come to both testing session they will be randomized into the HOME and STAN programs.  
 
 
HOME Program is distinguished by patients participating in a home only intervention that consists of 
running exercises performed twice a week for six to eight weeks. No plyometric or agility drills are performed 
in this study arm. This represents the minimal intervention to prepare for a return to sports. No neuromuscular 
training or movement training beyond the sagittal plane will be performed.  
           Patients in the STAN group will be used as the control group. They will receive no training. They will 
participate in the two testing sessions and the weekly survey updates.  
  
Patients who are enrolled in the TNMT group will participate in 12 sessions of supervised outpatient 
physical therapy over a six to eight week period. The TNMT protocol is distinguished by performance of 
exercises designed to enhance core and hip strength, performance of neuromuscular training exercise that are 
designed to correct movement flaws associated with second ACL injury25, providing verbal and visual feedback 
and performance of single leg drills on both legs.  
Augmented feedback is a key treatment feature for the TNMT group. Feedback will be provided for 
appropriate exercises, including dynamic jumping, stepping and lunging activities. Structured feedback has 
been shown to promote positive changes in jump landing biomechanics.57-61 Specific feedback will be provided 
regarding toe to heel landing, landing on both feet at the same time, landing with feet hip width apart, knees 
over the midfoot, landing with knee flexion > 30°, trunk in front of hips, and no lateral trunk flexion.57  Real 
time and delayed movement feedback will be provided using a commercially available system (Dartfish, 
Alpharetta, GA) to capture two-dimensional kinematics, and a force plate (Bertec Corp., Columbus, OH) to 
capture vertical ground reaction forces. The use of expert video feedback utilizing a standardized movement 
checklist has been shown to improve lower extremity dynamics during jump landing activities including a 
reduction in vertical ground reaction forces and increases in sagittal plane angular knee displacement.92  
Evidence based techniques will be utilized to aid patients in the TNMT group to master optimal dynamic 
movement strategies,17, 18 which will include the use of a standardized movement evaluation performed by the 
subject’s physical therapist.63 Therapists will instruct patients in the desired movement quality, review presence 
of high risk movement patterns, and cue the patient for correct movement performance. The therapist will 
determine if an anterior or lateral video view is appropriate for providing the visual necessary feedback. For 
each of the TNMT exercises there will be four phases. The three treatment sessions in each phase will match the 
three phases of motor learning (cognitive, associative and autonomous). 
aNMT (augmented NeuroMuscular Training) training. A 12-session, return to sport training program 
were modified from prior investigations to include real-time aNMT biofeedback. aNMT biofeedback training 
will consist of 2 sets of 10 repetitions per session with a progression in volume as exercise intensity increases 
(Squat: 40 repetitions during weeks 1-2; Pistol Squat, 40 repetitions during week 3-4, Overhead Squat, 80 
repetitions during weeks 5-6) over the 6-week training period. aNMT biofeedback maps the values of key 
biomechanical variables, computed continuously in real-time, to a geometric shape that athletes view via a 
heads-up display consisting of a high-resolution screen fixed in a constant position in the eye’s field of view. 
The biomechanical variables—selected based on our prior NIH-funded research that identified them as 
contributing injury risk factors—include: 1) Lateral trunk flexion (optimal = 0°), 2) Knee to hip sagittal plane 
moment ratio (<1), 3) Knee abduction moment (≤0 Nm), 4) Foot placement (1:1 ratio to hip width) 5) VGRF 
ratio (1:1 ratio between limbs) and 6) Landing position.  
The desired outcome for athletes to achieve while performing each intervention exercise is to move so as 
to produce a rectangular shape and make the shape as large as possible. This is achieved when each targeted 

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biomechanical variable is at the desired value. Deviations of the variables from desired values result in specific 
and systematic changes to the feedback shape: 1) Lateral trunk flexion causes the object to lean to the respective 
side, 2) Inverse dynamics will determine the hip to knee sagittal plane moment ratio; reduced relative hip 
moment contributions shrink the shape and larger ratios make it bigger, 3) Knee abduction moment changes 
cause the stimulus to pinch (excessive valgus) or expand (excessive varus) at the middle, 4) Foot position 
changes the width of the stimulus base; feet too close together causes the base to be narrower than the top and 
too far apart causes it to be wider than the top, 5) VGRF asymmetry causes the corner of increased load to drop, 
and 6) The stimulus translates left or right if landing position deviates laterally from a target on the floor. After 
receiving basic instruction about how to accomplish the exercises, athletes must discover the movement pattern 
that produces a stimulus shape as close to the desired rectangle as possible and maintain the stimulus in a large 
rectangular shape as best as she can on each repetition. No explicit directions will be provided to athletes on 
their movement other than to achieve the goal shape. Based on our preliminary studies, we expect that the 
aNMT protocol will be especially beneficial to an athlete who can respond to self-guided, implicit learning 
strategies to correct multiple deficits that are likely cumulative in the exacerbation of injury risk. Given the 
automated, objectively prescribed mapping between the athlete and the stimulus, there is no interaction between 
the technician and the stimulus during aNMT delivery. This ensures blinding of the technician. 
 
Biomechanical Testing Protocol Testing will be conducted at Mayo Clinic, prior to clinical testing. This portion 
of the data collection session will last approximately one hour. Testing will include collection of three-
dimensional kinematic data with a high-speed, 10-camera motion capture system collected at 240 Hz (Motion 
Analysis, Santa Clara CA). Kinetic data will be collected at 1200 Hz from two force plates (Bertec, Columbus, 
OH) embedded into the floor and synchronized with motion data. We have demonstrated excellent reliability in 
our sagittal- and frontal-plane hip and knee mechanics both within and between testing sessions. We have 
excellent intraclass correlations in knee flexion angles and moments (0.933; 0.926 respectively), knee abduction 
angles and moments (0.993; 0.931 respectively), knee internal rotation (0.971; 0.666 respectively).3  Reflective 
markers will be placed on the anatomical landmarks of the lower limbs, pelvis, trunk, neck, arms, and hands. 
The digital cameras will record the 3D coordinates of each marker first during a static pose (standing 
calibration) to define neutral alignment. Subjects will complete a trial to identify the functional hip joint center73 
on both limbs for post-processing of joint center calculations. Subsequent kinematic measures will be 
referenced in relation to this position.  
Dynamic task descriptions 
 
 Drop vertical jump (DVJ): Subjects will begin the protocol by standing on top of a box (height of 31cm) with 
their feet 35 cm apart. Subjects will then drop off the box (without jumping) and land with their feet on the floor 
below, followed immediately by a maximum vertical jump with an overhead target. Both of the subject’s feet 
must land separately on the two adjacent platforms, and a staggered foot fall to initiate the drop jump must be 
avoided. Five acceptable trials will be collected and post-processed. 
Single cross-over drop (COD): To test the right lower extremity, subjects will stand on the right side of the top 
of box (height of 31cm) with their left foot. Subjects will be asked ‘hop’ off the box, crossing the midline of 
their body and landing with their right foot on the force plate to their left, holding the position for 3 seconds. A 
double hop on the landing (where the foot loses contact with the force plate) or the lack of a 3-second hold 
following the jump will not be utilized in the analysis. Five acceptable trials will be collected. 
Single leg drop (SLD): Subjects will stand on a box (height of 31cm) on one foot. Subjects will be asked to drop 
off the box (without jumping), landing with their foot on the force plate below, and hold the position for 3 

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seconds. A double hop on the landing (where the foot loses contact with the force plate) or the lack of a 3-
second hold following the jump will not be utilized in the analysis. Five acceptable trials will be collected. 
Countermovement jump (CMJ): Subjects will stand on the floor with feet shoulder width apart. Subjects will be 
asked to squat down and execute a maximal vertical jump in one fluid movement. Five acceptable trials will be 
collected. 
Single leg postural balance will be assessed using force plates. Two force plates (Bertec, Columbus, OH) will 
be used to measure static and dynamic bilateral and unilateral postural stability under eyes open and eyes closed 
conditions. During testing subjects will stand on one foot on the force plate sensor for 30 seconds with opposite 
knee flexed to 90° and the hands positioned on the hips. During the trial, COP path length, COP path velocity, 
and mean COP sway (limit of stability) will be recorded. Each task will be performed three times and the 
average of the three scores will be utilized for statistical analysis.  
 
These movements are common sport activities and ones that can be completed safely in a controlled laboratory 
environment, posing no more risk than would be assumed during normal sports participation. 
 
Data Analysis: Standard International Society of Biomechanics (ISB) conventions for calculating Euler angles 
will be used to describe lower extremity motions (Figure 2B).74 From the standing trial, a kinematic model 
comprised of twelve skeletal segments and 36 degrees of freedom will be defined using commercial software 
(Visual 3D, C-Motion, Inc. Germantown, MD). The tracked 3D marker coordinate data recorded for the 
movement trials will be processed with custom software (MATLAB, MathWorks, Inc. Natick, MA) 
environment through the Visual3D pipeline to solve the generalized coordinates for each frame. These data will 
be low-pass filtered with a cubic smoothing spline at a 12 Hz cut-off frequency. The ground reaction force 
(GRF) data recorded for each limb will be used to normalize the kinematic data to 100% of stance at 1% 
increments (N=101), with initial contact defined as the instant when vertical GRF first exceeds 10N. From the 
3D kinematic and force plate data, 3D moments at hip and knee will be computed using inverse dynamic 
analysis within Visual3D. The 3D moment vector in each joint will be decomposed in three components, each 
oriented along one of the axes of a standard joint coordinate system. The resulting variables represent the total 
moment due to muscle, ligament, and contact forces with respect to each axis.  The moment arm and the 
horizontal distance from the resultant GRF to the knee joint center and COM will be calculated using Visual3D 
and MATLAB. These variables will be collected simultaneously and imported into the database with the 
kinematic and kinetic measures. Center of pressure (COP) and the anterior/ posterior, medial/lateral and vertical 
components of the force platform will be used to estimate the lateral distance between the resultant GRF vector 
and virtual knee joint center. Visual3D utilizes the geometrical approach to the inertial properties in order that 
segments are more generalizable to multiple models. The mass proportions of the segments were derived by 
Dempster75 and the inertial properties were derived by Hanavan.76 
 
The force platform data will be synchronized with the motion data to ensure accuracy of the 
representative model. The marker set and the segment coordinate systems are already constructed and have been 
found to be reliable.3 In the frontal plane if the GRF, reacting to the COM, passes lateral to the center of the 
head of the femur, that results in an external hip abduction moment, which is counter balanced by an internal 
hip adductor torque.77, 78 These concepts assume static equilibrium and neglect the inertia of the body segments 
between hip and ground. The inverse dynamic analysis performed will include all inertial effects.  
 
Two-dimensional video collection of jump landing mechanics will be collected concurrent to three-
dimensional drop jump (DVJ, SLD, COD, CMJ) testing.   Continuous two-dimensional data will be collected 
with two digital video cameras (Bosch LLC, Farmington Hills, MI) at 60 Hz.  Cameras will be positioned 

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anteriorly and laterally to the subject at 90 degree angles, and placed on tripods at a height of 0.3 m.  Data 
analysis will be performed using commercially available software (Dartfish, Alpharetta, GA).  Motions to be 
evaluated include frontal plane knee and hip angles at initial contact and at peak knee flexion, and knee flexion 
angle at initial contact.                 
Clinical Testing Protocol. This portion of the data collection session will last approximately two hours.  
A. Subjects will be required to complete self-report questionnaires specific to their current knee function. The 
data will be collected using OBERD (Outcome Based Electronic Research Database), a software system 
integrated into the Mayo Clinic infrastructure to facilitate collection and consolidation of data.  Questionnaires 
include the Marx Activity Scale (ICC of 0.97 for test-retest reliability)79, Tegner scale (ICC of 0.82 for test-
retest reliability)80, International Knee Documentation Committee (IKDC) Subjective Knee Evaluation (ICC 
test-retest reliability of 0.95)81, Knee Osteoarthritis Outcome Score (KOOS) (ICC test-retest reliability of 0.61-
0.95)82, Knee Outcome Survey-Activities of Daily Living (KOS-ADLS) and Sports (KOS-ADL Sports) (ICC 
test-retest reliability of 0.94) 83 Global Rating score (GRS) (ICC test-retest reliability of 0.88) 84 and the Anterior 
Cruciate Ligament Return to Sport after Injury (ACL-RSI) (Cronbach’s Alpha= 0.92)91. 
B. Strength will be measured on both limbs using a clinical dynamometer (either Humac, CSMi, Stoughton, 
MA, or Biodex System, Biodex, Shirley, NY).  
1. Isokinetic quadriceps and hamstrings strength: Subjects will be seated on the dynamometer with the hip and 
knee flexed to 90°. Prior to testing, they will undergo a short warm-up. A test session will consist of 10 
repetitions at slow (180°/sec) and fast (300°/sec) speeds through a knee range of motion of 0-100°. Peak flexion 
and extension torques will be recorded.  
2. Isokinetic hip abduction strength: Subjects will stand in front of the rotating arm of the dynamometer. A test 
session will consist of two test sets of 5 repetitions at 120°/second moving into abduction. Peak abduction 
torque will be recorded.  
3. Isometric hip abduction strength: Isometric abduction strength will be collected using a custom force sensing 
strap. Subjects will stand with their feet placed shoulder-width apart, their knees aligned directly above each 
foot, and hips and knees slightly flexed. A non-stretchable athletic wrap will be secured around the subject’s 
thighs, superior to the femoral condyles and patella, and secured with tape or Velcro. Three practice repetitions 
will be conducted in which the subjects will maximally abduct their thighs and push out against the wrap. 5 
maximum efforts will be conducted and recorded. A strain gauge will measure induced voltage and display 
force output on a monitor. Maximum abduction force in all 5 trials will be recorded.  
C. Patient functional performance will be evaluated with a battery of hop tests. Reliability of the unilateral hop 
tests is good, with ICC coefficients ranging from .92-.96.85, 86 
1. Single leg hop for distance tests: The limb symmetry indexes (LSIs) for the single hop, cross-over hop, and 
triple hop tests are all based on the maximum distance jumped with a controlled landing, and performance will 
be calculated by dividing the distance hopped on the involved leg by the distance hopped on the uninvolved leg. 
Hop distance will be measured to the nearest centimeter on a standard measuring taped secured to the floor. The 
maximum hop distance of two trials will be used for analysis.  
2. Single leg timed hop: The 6-meter timed hop is a measure of how fast it takes the athlete to hop 6-meters on 
one leg. A handheld or digital timing system will be used by a trained tester. The 6-meter timed hop LSI will be 
calculated by dividing the time recorded for the uninvolved (or dominant leg) divided by the time recorded for 
the involved leg.  
D.  Skeletal maturity will be evaluated with a modified Pubertal Maturation Observational Scale (PMOS).  
Maturational categories will include prepubertal (equivalent to Tanner87, 88 Stage 1), early pubertal (equivalent 
to Tanner Stages 2 and 3) or late or postpubertal (equivalent to Tanner Stages 4 and 5).  The categories are 

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based on several indicators of pubertal maturation (growth spurt, menarchal status, body hair, sweating, and 
muscular definition).89  The scale reliably classifies subjects into developmental stages and is based on 
parental/participant report, and investigator observations.90  The reliability of the scale has been demonstrated to 
be high.89 
F.  Passive anterior knee laxity will be captured with a GNRB arthrometer (Genourob, Laval, France) or a Blue 
Bay arthrometer (Blue Bay Research Inc, Navarre, FL, USA) using an automated 134 N anterior push on the 
posterior aspect of the tibia or a Blue Bay arthrometer (Blue Bay Research Inc, Navarre, FL, USA) using a 134 
N anterior pull on the tibia. 
 
Tracking 
During the six weeks of training, patients will be contacted weekly via email or text message. The surveys will 
include questions of compliance and involvement of sport activities. If the patient prefers, the surveys can be 
conducted over the phone rather than on the computer. The coordinator will call the patient/guardian if the 
survey has not been filled out after two notices.  Post training, the patient will receive monthly surveys of injury 
surveillance for two years. Then yearly follow up for 4 years. Patients will be followed a total of 6 years.    
 
Check all that apply. If none apply, leave blank: 
 
  This is a multisite study involving Mayo Clinic and non-Mayo Clinic sites.  
When checked, describe the research procedures/activities being conducted only at Mayo Clinic: 
 
  Mayo Clinic staff will be engaged in research activity at a non-Mayo Clinic site.  When checked, provide 
the location and a detailed description of the Mayo Clinic research staff involvement. 
 
 
  This study is to establish and/or maintain an ongoing database or registry for research purposes only. 
 
  The research involves contact or interaction with subjects, for example, surveys, questionnaires, 
observation, blood draw. 
 
  The study involves photographing, audiotaping or videotaping subjects (and guests).  
 
CITED REFERENCES 
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Krosshaug T, Steffen K, Kristianslund E, Nilstad A, Mok KM, Myklebust G, et al. The Vertical Drop 
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Surg Am. 2014;96(9):705-11. PMCID: 4001460. 

Minimal Risk Protocol Template [IRB 10429.009] 
 
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5. 
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39. 
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R01AR055563/MayoWork/Protocol_17.00602500_08_27_2020.doc  
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Effective: 10/10/2016 
 
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Resources:   
Space.  The research methodology described in this application will primarily be conducted in the Biodynamics 
Laboratory.  Patient care and rehabilitation will be provided in Mayo Clinic Sports Medicine Centers (SMCs).   
 
Mayo Clinic has recently built two state of the art outpatient Sports Medicine Centers (SMCs) in Rochester and 
Minneapolis, MN.  The offices and facilities of the SMCs are dedicated to creating an atmosphere of clinical, 
research and academic excellence.  All facilities and resources are readily available to Dr. Bates, and include 
everything necessary for the successful completion of this proposal. The availability of two sports medicine 
rehabilitation centers within the Mayo Clinic system that provide standardized care enhances the ability to 
provide patient services to a large geographic region.  Both clinics occupy more than 20,000 square feet.  
Eleven physical therapists, seven athletic trainers, and three performance coaches provide rehabilitation 
services.  Physician treatment rooms are housed on the same floor at each site.  Five sports medicine, 
fellowship-trained physicians comprise the surgical team, including Dr. Aaron Krych (PI).  All of the surgery 
providers are participating in the investigation. 
 
This project will utilize the dual clinical spaces available at Mayo Clinic Sports Medicine housed within the 
Dan Abraham Healthy Living Center (DAHLC) in Rochester, MN, as well as Mayo Clinic Square in downtown 
Minneapolis, MN. The DAHLC houses approximately 25,000 square feet of clinical sports medicine treatment 
space, which includes exam rooms, radiology suite with access to MRI, strength and mobility training 
equipment, an enclosed turf field, reception area, open office space for staff that is in close proximity to the 
clinical treatment space. In addition, there is another approximately 13,000 feet of clinical sports medicine 
space housed in the Charlton Building for a total of approximately 38,000 feet of clinical treatment space in 
Rochester, MN. Mayo Clinic Square is comprised of approximately 25,000 square feet of clinical sports 
medicine treatment space, which includes exam rooms, radiology suite with access to MRI, strength and 
mobility training equipment, isokinetic/isometric dynamometers, an enclosed turf field, reception area, open 
office space for staff that is in close proximity to the clinical treatment space. These state of the art facilities will 
be the site of patient care and rehabilitation following ACL reconstruction surgery. 
 
The Biodynamics Laboratory is located within the SMC in Minneapolis, MN.  It contains approximately 1,800 
square feet dedicated to the latest state-of-the art, cutting edge technology motion capture and neuromuscular 
control assessment currently available.   
 
Equipment.   
1. 
14 Camera Motion Analysis System (Raptor Cameras, Motion Analysis Corp., Santa Rosa, CA) with 
assorted height mounting rails and 14 mounting brackets for flexible camera placement (Figure FE1). 
2. 
Cortex software (v3, Motion Analysis Corp., Santa Rosa, CA) including Skelton Builder, Calcium, 
BioFeedTrak, and Kintools RT.  
3. 
Four (4) 60 x 90 centimeter, 6-component force plates (Bertec, Columbus, OH) 
4. 
Motion analysis data acquisition computer workstation: Dell Precision T7500, 6-core Xeon X5690 3.47 
GHz CPU, 12 GB ECC RAM, 3 Hitachi 15k SAS hard drives (250GB boot drive and 2x 500GB drives in a 
RAID 0 array), dual Nvidia Quadro 2000 video cards, and 3 30” Dell monitors, Windows 7. UPS battery 
backup on all motion capture equipment. 
 

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5. 
Three (3) Microsoft Lifecam Studio HD webcams (Higher quality cameras are needed for this study, 
please see the budget justification for the proposed make and model of purchase) 
6. 
One (1) static digitizing probe for creating calibration marker locations on hard-to-reach anatomical 
landmarks. 
7. 
Two (2) Visual 3D motion analysis software licenses (C-motion inc., Germantown, MD) 
8. 
Two (2) Microsoft Kinect 3D cameras (Microsoft Corp., Redmond, WA) 
9. 
Two (2) Wii Balance boards (Nintendo of America, Inc., Redmond, WA)  
10. 
Two HumacNORM isokinetic and isometric dynamometers with accompanying software (Figure FE2, 
CSMi, Stoughton, MA). 
11. 
Two Humac balance devices with accompanying software (CSMi, Stoughton, MA. 
12. 
One GNRB arthrometer (Genourob, Laval, France)  
13. 
Two (2) complete Simi Aktisys marker-based and marker-less motion analysis systems with associated 
cameras, hardware, and software (Simi Reality Motion Systems GmbH, Unterschleissheim, Germany). 
14. 
Thirteen (13) Dartfish Motion Pro Premium licenses with fourteen (14) associated cameras and 
necessary hardware split between Mayo Clinic Rochester and Mayo Clinic Square facilities (Dartfish USA, 
Inc., Alpharetta, GA). 
 
Computer/Office 
Adequate dedicated office space and computing capabilities already exists within the laboratories and clinical 
facilities to meet the needs of all personnel included in this project. Each listed clinical and laboratory space 
also has designated multimedia conference room space with teleconferencing capabilities. All key personnel 
have office space in both Minneapolis and Rochester SMCs. 
 
 
  (1a)  This is a multisite study involving Mayo Clinic and non Mayo Clinic sites. When checked, describe in 
detail the research procedures or activities that will be conducted by Mayo Clinic study staff. 
 
  (1b)  Mayo Clinic study staff will be engaged in research activity at a non Mayo Clinic site.  When checked, 
provide a detailed description of the activity that will be conducted by Mayo Clinic study staff. 
 
 
Subject Information 
 
Target accrual:  This study will enroll 150 subjects.  Anticipating a 30% dropout rate, this will yield a final 
accrual of 120 subjects. 
 
Subject population (children, adults, groups):  All subjects will be patients who undergo primary ACL 
reconstruction, and will be recruited from the practices of the sports medicine surgical team at Mayo Clinic, 
Rochester, MN, as well as the practices of the surgeon affiliates of the sports medicine team at Cincinnati 
Children’s Hospital Medical Center, Cincinnati, OH.  Recruitment will also include primary ACL 
reconstruction patients from the sports medicine surgical team at the University of Minnesota, Minneapolis, 
MN, and primary ACL reconstruction patients from the sports medicine surgical team at Mayo Clinic Health 
System, La Crosse, WI. This will include male and female patients between the ages of 13 and 30 years in age 

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at the time of injury. The University of Minnesota and Mayo Health System locations will serve only as referral 
sites as no research activity will occur there. 
 
Inclusion Criteria:  
1. Age, 13 ≥ 30 years, 2. Acute, first-time, isolated ACL injury, 3. No history of previous knee surgery 
to either extremity, 4. No low back or lower extremity injury in the year prior to ACL injury 
necessitating medical care, 5. Pre-injury participation in cutting, jumping or pivoting sports for ≥ 50 
hours/year, 6. Plan to return to full participation in sports following ACL reconstruction.  
 7. Mechanism of injury did not involve a direct blow to the knee  
 
Patients who sustain a medial collateral ligament (MCL) injury are eligible for study participation if 
medial knee instability is resolved prior to surgery.  
 
This age range is selected secondary to the majority of ACL injuries occurring in young, active 
individuals who participate in jumping, cutting and pivoting sports on a regular basis. 
 
Patients with simple meniscus tears (i.e., 2 cm vertical longitudinal tear) that do not necessitate 
alterations in rehabilitation will be eligible for study participation. 
 
Exclusion Criteria:   
Patients with complex, repairable meniscus tears (i.e., radial or root repair), multi-ligment repair, and 
patients with full thickness articular cartilage lesions will not be eligible for participation.  
 
 
Research Activity 
 
Check all that apply and complete the appropriate sections as instructed.  
  
1. 
  Drug & Device:  Drugs for which an investigational new drug application is not required. Device for 
which (i) an investigational device exemption application is not required; or the medical device is 
cleared/approved for marketing and being used in accordance with its cleared/approved labeling. (Specify in 
the Methods section) 
 
2. 
  Blood:  Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture.  
 
3. 
  Biological specimens other than blood:  Prospective collection of human biological specimens by 
noninvasive means that may include: urine, sweat, saliva, buccal scraping, oral/anal/vaginal swab, sputum, 
hair and nail clippings, etc. 
 
4. 
  Tests & Procedures:  Collection of data through noninvasive tests and procedures routinely employed 
in clinical practice that may include: MRI, surface EEG, echo, ultrasound, moderate exercise, muscular 
strength & flexibility testing, biometrics, cognition testing, eye exam, etc.  (Specify in the Methods section) 
 

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5. 
  Data (medical record, images, or specimens):  Research involving use of existing and/or prospectively 
collected data. 
 
6. 
  Digital Record:  Collection of electronic data from voice, video, digital, or image recording. (Specify in 
the Methods section) 
 
7. 
  Survey, Interview, Focus Group:  Research on individual or group characteristics or behavior, survey, 
interview, oral history, focus group, program evaluation, etc.  (Specify in the Methods section) 
 
 
 NIH has issued a Certificate of Confidentiality (COC).  When checked, provide the institution and 
investigator named on the COC and explain why one was requested. ________________________ 
 
 
Biospecimens – Categories 2 and 3 
 
(2)  Collection of blood samples. When multiple groups are involved copy and paste the appropriate section 
below for example repeat section b when drawing blood from children and adults with cancer.  
 
a. From healthy, non-pregnant, adult subjects who weigh at least 110 pounds. For a minimal risk 
application, the amount of blood drawn from these subjects may not exceed 550ml in an 8 week period 
and collection may not occur more frequently than 2 times per week. 
Volume per blood draw: _____ml   
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.) ___________ 
 
b. From other adults and children considering age, weight, and health of subject. For a minimal risk 
application, the amount of blood drawn from these subjects may not exceed the lesser of 50 ml or 3 ml 
per kg in an 8 week period, and collection may not occur more frequently than 2 times per week.   
Volume per blood draw: _____ml 
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.) ___________  
 
(3)  Prospective collection of biological specimens other than blood: ______________________________ 
 
 
Review of medical records, images, specimens – Category 5 
 
For review of existing data: provide a date range or an end date for when the data was generated. The end date 
can be the date this application was submitted to the IRB.  Example: 01/01/1999 to 12/31/2015 or all records 
through mm/dd/yyyy.  
Date Range: 
 

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Check all that apply (data includes medical records, images, specimens).  
 
  (5a)  Only data that exists before the IRB submission date will be collected.   
 
 
  (5b)  The study involves data that exist at the time of IRB submission and data that will be generated after 
IRB submission. Include this activity in the Methods section.  
Examples 
• The study plans to conduct a retrospective chart review and ask subjects to complete a questionnaire.  
• The study plans to include subjects previously diagnosed with a specific disease and add newly 
diagnosed subjects in the future.  
 
  (5c)  The study will use data that have been collected under another IRB protocol. Include in the Methods 
section and enter the IRB number from which the research material will be obtained. When appropriate, note 
when subjects have provided consent for future use of their data and/or specimens as described in this protocol.  
 
Enter one IRB number per line, add more lines as needed 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 
  (5d)  This study will obtain data generated from other sources. Examples may include receiving data from 
participating sites or an external collaborator, accessing an external database or registry, etc.  Explain the source 
and how the data will be used in the Methods section.  
 
  (6)  Video audio recording: Describe the plan to maintain subject privacy and data confidentiality, 
transcription, store or destroy, etc.  
Files will be stored on a secured server to which only authorized study personnel may access.  Files will be 
names according to the subject’s research study ID.  Files will be used for research analysis only and not 
distributed.   
 
HIPAA Identifiers and Protected Health Information (PHI) 
 
Protected health information is medical data that can be linked to the subject directly or through a combination 
of indirect identifiers.  
 
Recording identifiers (including a code) during the conduct of the study allows you to return to the medical 
record or data source to delete duplicate subjects, check a missing or questionable entry, add new data points, 
etc. De-identified data is medical information that has been stripped of all HIPAA identifiers so that it cannot be 
linked back to the subject. De-identified data is rarely used in the conduct of a research study involving a chart 
review.   

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Review the list of subject identifiers below and, if applicable, check the box next to each HIPAA identifier 
being recorded at the time of data collection or abstraction.  Identifiers apply to any subject enrolled in the 
study including Mayo Clinic staff, patients and their relatives and household members.  
 
Internal refers to the subject’s identifier that will be recorded at Mayo Clinic by the study staff. 
External refers to the subject’s identifier that will be shared outside of Mayo Clinic. 
 
Check all that apply: 
INTERNAL 
EXTERNAL 
Name 
 
 
Mayo Clinic medical record or patient registration number, lab accession, 
specimen or radiologic image number  
X 
 
Subject ID, subject code or any other person-specific unique identifying 
number, characteristic or code that can link the subject to their medical data   
X 
 
Dates: All elements of dates [month, day, and year] directly related to an 
individual, their birth date, date of death, date of diagnosis, etc.   
Note: Recording a year only is not a unique identifier.  
X 
 
Social Security number 
 
 
Medical device identifiers and serial numbers 
 
 
Biometric identifiers, including finger and voice prints, full face photographic 
images and any comparable images 
X 
 
Web Universal Resource Locators (URLs), Internet Protocol (IP) address 
numbers, email address 
X 
 
Street address, city, county, precinct, zip code, and their equivalent geocodes 
X 
 
Phone or fax numbers 
X 
 
Account, member, certificate or professional license numbers, health 
beneficiary numbers 
 
 
Vehicle identifiers and serial numbers, including license plate numbers 
 
 
Check ‘None’ when none of the identifiers listed above will be recorded, 
maintained, or shared during the conduct of this study.  (exempt category 4) 
 None 
 None 
 
 
 
 
Data Analysis 
 
Power analyses and study endpoints are not required for minimal risk research, pilot or feasibility studies.  
 
  No statistical information. If checked, please explain: 
 
 
Power Statement:   

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We expect that the minimal clinically significant effect size of TNMT on knee biomechanics is 0.17 or above. 
Using an a priori power analysis based on repeated measures ANOVA, we expect that to achieve 80% power 
with α = 0.05, this study will require a final accrual of 87 subjects. This assumes a correlation coefficient of 0.3 
among the repeated measures, which is likely conservative. Thus, an accrual of 116 (with an estimated 30% 
dropout rate) subjects will be sufficient to determine if a clinically significant reduction in uninvolved limb 
transverse plane hip net moment impulse, frontal plane knee joint ROM, initial contact sagittal plane knee 
moment asymmetry, and deficits of involved limb postural stability has occurred as a result of TNMT. This 
sample size provides adequate power for all variables of interest for Aims 1 and 2.  Mayo Clinic averages more 
than 120 ACLR per year in the Minneapolis/Rochester region on individuals under age 25. Thus, the available 
patient pool is more than adequate to meet study requirements. 
 
Data Analysis Plan:  
Aim 1:  We will utilize normal mixture based clustering analysis70 to identify groups with distinguished risks 
based on a priori covariates (i.e., demographics and biomechanical variables). Our previous work used a similar 
approach to effectively cluster subjects into three distinct risk groups. We intend to confirm disparate risk for 
injury by assessment of the magnitude of differences across groups using knee and hip abduction angles, 
surrogates for ACL injury.   
 
The normal mixture model approach works by assuming the density of the covariates for a subject x, can be 
described as: 
 
 
where (i) K is the number of mixture components (groups), (ii) 
 is the unconditional probability that a subject 
fall into the kth group, and (iii) 
 is the multivariate normal density with mean  and covariance . 
Estimates of the parameters, 
are typically obtained using maximum likelihood. The number of 
groups is most commonly chosen to optimize the Bayesian Information Criterion (BIC). Often assumptions 
such as a common covariance matrix for all k, or common shape (i.e., correlation) matrix, are made to make 
estimation feasible, depending on the size of data, and these decisions are also commonly made on the basis of 
BIC. In this work we intend to assume a common , and assess the validity of this assumption via model 
diagnostics. Once parameter estimates are obtained, clustering is performed by calculating the probability of 
group membership m for a given subject, conditional on his/her covariate values, i.e., 
 
 
The subject will then be assigned to the group k that results in the largest conditional group membership 
probability 
. This approach has been shown to perform very well in the presence of a large 
number of variables with the inclusion of a variable selection mechanism.71, 72  We will leverage such an 
approach in our analysis to identify a reduced set of biomechanical variables that most informatively 
differentiate the subjects. 
 
Aim 2:   

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Aim 2 will utilize a prospective, single blind, randomized clinical trial design. Subjects from Aim 1 will 
comprise the study sample. Subjects will undergo testing twice.  
We will use a repeated-measures ANOVA model with between-subjects factors that include 
interactions, to determine the effect of TNMT compared to HOME or STAN treatment on clinical performance 
after ACLR. Specifically, for a response of interest y, e.g., hip abductor strength, for the ith subject in the kth 
treatment group, with l = 0 indicating before intervention and l = 1 indicating after,  
 
 
 
 
  
 
 
 
with (i) intercept , (ii) subject random effect 
, (iii) pure error (or noise) 
, (iv)  
is the main effect due to intervention, and (vi) 
 is the interaction effect allowing intervention efficacy to 
vary with intervention type. The fixed effects are constrained such that 
. In this model, the 
baseline (i.e., pre-treatment) response for an individual is: 
 
 
 
Thus, the pre- intervention response for a given subject is the same regardless of which intervention group  
they were assigned to, since nothing would have happened yet within their intervention group to distinguish 
them from other groups. Under the formulation in (1), the difference between observations before and after 
intervention is: 
 
 
 
where 
, 
, and 
. The primary inference of interest is with 
respect to the relative efficacy of rehabilitation type 
 and the effect of risk group on intervention efficacy, 
along with their interaction 
. Thus, this inference could equivalently be conducted using the pairwise 
differences in a straightforward one-way ANOVA model. We will assess model assumptions (e.g., normality 
and constant variance) via residual diagnostics and apply transformations if needed. Where appropriate, we will 
also utilize Tukey HSD post hoc analysis to further determine significance between groups on intervention 
effect. 
Endpoints 
There will be no known direct medical benefits to subjects from participating in this study. 
 
Primary: Completion of all study activities 
Secondary: Second injury