MiACLR: Michigan Initiative for Anterior Cruciate Ligament Rehabilitation
Phase: NA
Conditions: Anterior Cruciate Ligament Injury
Sponsor: University of Michigan

 
 
 
 
Official Title: MiACLR: Michigan Initiative for Anterior Cruciate Ligament Rehabilitation 
NCT Number:  NCT03626857 
Document Date: February 25, 2022 

 
 
i 
MiACLR:  Michigan Initiative for Anterior Cruciate Ligament Rehabilitation 
 
Protocol Number:  HUM00144992 
National Clinical Trial (NCT) Identified Number: NCT03626857 
Principal Investigator:  Riann Palmieri-Smith, PhD, ATC 
Funded by:  National Institute of Child Health and Human Development 
Version Number: 8.0 
February 25, 2022 
 
Summary of Changes from Previous Version:  
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
1.2, 1.3 
Study Schema 
Intervention visits split up to follow/ 
match the SOA. Testing visits 
corrected too  
1.4 
Schedule of Activities 
Adjusted study visits and windows 
from weeks to days. Added footnotes 
for clarification of interventional visits. 
Added the clinical x-ray record review 
(approved in previous amendment).  
4.1 
Overall Design 
Addition of sex as a stratification 
factor as requested by the DSMB.  
8.1 
Efficacy Assessments 
Added clinical x-ray record review 
and language for SOC group. Both 
were approved in the last IRB 
amendment, but the wrong version of 
the protocol was used for 
submission.  
8.3.3 
Events of Special Interest 
Addition of graft failure as an event of 
special interest as requested by the 
DSMB.  

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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 3 
1 
PROTOCOL SUMMARY ............................................................................................................................... 4 
1.1 
Synopsis ................................................................................................................................................ 4 
1.2 
Schema – Treatment groups ............................................................................................................. 6 
1.3 
Schema – SOC Control group ........................................................................................................... 7 
1.4 
Schedule of Activities (SoA) ............................................................................................................... 8 
2 
INTRODUCTION ............................................................................................................................................ 9 
2.1 
Study Rationale .................................................................................................................................... 9 
2.2 
Background........................................................................................................................................... 9 
2.3 
Risk/Benefit Assessment .................................................................................................................. 11 
 
Known Potential Risks ................................................................................................... 11 
 
Known Potential Benefits .............................................................................................. 12 
 
Assessment of Potential Risks and Benefits .............................................................. 12 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 15 
4 
STUDY DESIGN ........................................................................................................................................... 17 
4.1 
Overall Design .................................................................................................................................... 17 
4.2 
Scientific Rationale for Study Design.............................................................................................. 17 
4.3 
Justification for Dose ......................................................................................................................... 18 
4.4 
End of Study Definition ..................................................................................................................... 20 
5 
STUDY POPULATION ................................................................................................................................ 20 
5.1 
Inclusion Criteria ................................................................................................................................ 20 
5.2 
Exclusion Criteria ............................................................................................................................... 20 
5.3 
Lifestyle Considerations .................................................................................................................... 20 
5.4 
Screen Failures .................................................................................................................................. 21 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 21 
6 
STUDY INTERVENTION ............................................................................................................................ 22 
6.1 
Study Intervention(s) Administration ............................................................................................... 22 
 
Study Intervention Description ..................................................................................... 22 
 
Dosing and Administration ............................................................................................ 22 
6.2 
Measures to Minimize Bias:  Randomization and Blinding .......................................................... 23 
6.3 
Study Intervention Compliance ........................................................................................................ 24 
6.4 
Concomitant Therapy ........................................................................................................................ 24 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION / 
WITHDRAWAL .......................................................................................................................................................... 25 
7.1 
Discontinuation of Study Intervention ............................................................................................. 25 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 25 
7.3 
Lost to Follow-Up ............................................................................................................................... 27 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 27 
8.1 
Efficacy Assessments ....................................................................................................................... 27 
8.2 
Safety and Other Assessments ....................................................................................................... 32 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 34 
 
Definition of Adverse Events (AE) ............................................................................... 34 
 
Definition of Serious Adverse Events (SAE) .............................................................. 34 
 
Events of Special Interest ............................................................................................. 34 
 
Classification of an Adverse Event .............................................................................. 35 

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Time Period and Frequency for Event Assessment and Follow-Up ....................... 37 
8.3.6 
Adverse Event Reporting .............................................................................................. 37 
8.3.7 
Adverse Event of Special Interest Reporting ............................................................. 38 
8.3.8 
Serious Adverse Event Reporting ............................................................................... 38 
8.3.9 
Reporting Events to Participants ................................................................................. 39 
8.3.10 
Events of Special Interest ................................................ Error! Bookmark not defined. 
8.3.11 
Reporting of Pregnancy ................................................................................................ 40 
8.4 
Unanticipated Problems .................................................................................................................... 40 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 40 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 40 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 41 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 41 
9.1 
Statistical Hypotheses ....................................................................................................................... 41 
9.2 Sample Size Determination .......................................................................................................................... 41 
9.3 Populations for Analyses ............................................................................................................................... 42 
9.4 Statistical Analyses ........................................................................................................................................ 42 
9.4.1 General Approach 
42 
9.4.2 Analysis of the Primary Efficacy Endpoints ......................................................................................... 43 
9.4.3 Analysis of the Secondary Endpoint(s) ................................................................................................ 43 
9.4.4 Safety Analyses 
43 
9.4.5 Baseline Descriptive Statistics .............................................................................................................. 44 
9.4.6 Planned Interim Analyses ...................................................................................................................... 44 
9.4.7 Sub-Group Analyses 
44 
9.4.8 Tabulation of Individual participant Data ............................................................................................. 44 
9.4.9 Exploratory Analyses 44 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 45 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 45 
10.1.1 
Informed Consent Process ........................................................................................... 45 
 
Study Discontinuation and Closure ............................................................................. 46 
10.1.3 
Confidentiality and Privacy ........................................................................................... 46 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 47 
10.1.5 
Key Roles and Study Governance .............................................................................. 47 
10.1.6 
Safety Oversight ............................................................................................................. 47 
10.1.7 
Clinical Monitoring .......................................................................................................... 48 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 48 
10.1.9 
Data Handling and Record Keeping ............................................................................ 48 
10.1.10 
Protocol Deviations ........................................................................................................ 50 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 50 
10.1.12 
Conflict of Interest Policy .............................................................................................. 50 
10.2 
Additional Considerations ................................................................................................................. 51 
10.3 
Abbreviations ...................................................................................................................................... 51 
10.4 
Protocol Amendment History ........................................................................................................... 52 
11 
REFERENCES ............................................................................................................................................. 53 
 

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STATEMENT OF COMPLIANCE 
 
The 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 form(s), 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 
regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form. 

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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title:  
MiACLR: Michigan Initiative for Anterior Cruciate Ligament 
Rehabilitation  
Study Description:  
This study is a single-center, randomized, double-blind, placebo- 
controlled parallel-group clinical trial to examine the combined 
efficacy of neuromuscular electrical stimulation (NMES) and 
eccentric exercise (ECC) to promote the recovery of quadriceps 
strength, improve physical and biomechanical function, and reduce 
the risk of post-traumatic osteoarthritis (OA) after ACLR. Study 
interventions will begin immediately after ACLR at the first 
postoperative visit. The 2 arms of the trial include:   
• 
NMES + ECC: NMES for 8 weeks followed by ECC for 8 
weeks;  
• 
NMES placebo + ECC placebo:  NMES placebo for 8 weeks 
followed by ECC placebo for 8 weeks.  
 
An additional group of participants will be enrolled, but not 
randomized and will receive neither study intervention; rather, they 
will serve as a Standard of Care (SOC) control group. All three 
groups of participants will receive standard of care ACL rehabilitation 
 
Objectives:  
Primary Objective: To determine whether NMES+ECC will maximize 
quadriceps strength symmetry better than NMES placebo + ECC 
placebo at 9 months and 18 months post- anterior cruciate ligament 
reconstruction (ACLR).  
 
 
Secondary Objective 1:  To determine whether NMES+ECC will limit 
negative changes in cartilage health, defined as decreased 
proteoglycan cartilage density measured with T1rho or increased 
cartilage matrix degradation measured with T2 mapping in relation to 
the contralateral side, at 18 months following ACLR.  
 
Secondary Objective 2: To determine whether NMES+ECC will 
maximize biomechanical symmetry and physical function better than 
NMES placebo + ECC placebo at 9 months and 18 months post-
ACLR.  
 
Exploratory Objective: We will compare the SOC control group to the 
placebo group to assess the ability of reducing the intensity of 
NMES and ECC to achieve a “true” placebo.  
 
Endpoints:  
Primary Endpoints: change from baseline to 9 months and to 18 
months post-ACLR in isokinetic quadriceps strength symmetry index 
 
Secondary Endpoints:  1) T1 rho and T2 relaxation time symmetry 

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scores for knee joint cartilage in the deep and superficial layers, 2) 
knee flexion angle/moment symmetry, 3) score on the Knee Injury 
and Osteoarthritis Outcome Score, 4) hop distance symmetry at 18 
months 
 
Exploratory Endpoints:  Change from baseline to 9 months and to 18 
months post-ACLR in isokinetic quadriceps strength symmetry 
index.  
 
Study Population:  
150 patients who have sustained a unilateral ACL injury between the 
ages of 14-45 years will be consented. Of those, 122 participants will 
be randomized to one of the two treatment groups; 10 of those 
participants will be removed from analysis due to the COVID-19 
pandemic. 28 participants will be enrolled (not randomized) to the 
SOC Control group.  
 
 
Phase:  
III 
 
Description of 
Sites/Facilities 
Enrolling 
Participants:  
The University of Michigan  
 
Description of Study 
Interventions:  
This study combines the following interventions into two randomized 
treatment arms:  
NMES:  defined as delivery of high-intensity neuromuscular 
electrical stimulation (NMES) beginning in weeks 0-2 post-ACLR 
and continuing for 8 weeks.  
ECC:  defined as delivery of eccentric exercise (ECC)  at 70-90% of 
the 1 RM (repetition maximum) beginning  between the 6th-10th week 
post-operative until the 14-18th week post-operative.  
NMES placebo:  defined as delivery of low-intensity neuromuscular 
electrical stimulation (NMES) beginning in weeks 0-2 post-ACLR 
and continuing for 8 weeks.  
ECC placebo:  defined as delivery of eccentric exercise (ECC) at 
15% of the 1 RM (repetition maximum) beginning between the 6th-
10thth week post-operative until the 14-18th week post-operative.  
 
The treatment groups to which participants will be randomized are:  
(1) NMES + ECC 
(2) NMES placebo + ECC placebo 
 
There will also be a SOC Control group in which participants receive 
no study-related treatment or placebo outside of their standard of 
care physical therapy.  
Study Duration:  
5 years 
Participant Duration:  Approximately 20 months from the time the consent form is signed 
Estimated Time to 
Complete 
Enrollment:  
5 years 
 
 

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1.2 SCHEMA – TREATMENT GROUPS 
 
Prior to  
Enrollment 
 
 
 
Testing  
Visit 1 
(Repeat if needed) 
 
 
 
 
 
 
 
 
 
 
 
Intervention 
Visits 1-16 
 
 
Testing  
Visit 2 
 
 
 
Intervention 
Visits 17-32 
Testing 
Visit 3 
 
 
 
Testing 
Visit 4 
 
 
Testing 
Visit 5 
 
Total N = 122:  Obtain informed consent. Screen for inclusion and exclusion criteria;  
obtain history, document. 
Perform baseline (pre-ACL reconstruction) assessments. 
Bilateral Isokinetic/Isometric Thigh (Quadriceps/Hamstrings) Muscle Strength  
Questionnaires: KOOS, Tampa, Tegner, PROMIS, VR-12, Marx 
A/P Knee and SOC Clinical X-ray; Quadriceps Ultrasound; Quadriceps Activation; Biomechanics, Optional 
Muscle Biopsy 
9 month Follow-up assessments of study endpoints  
Bilateral Isokinetic/Isometric Thigh (Quadriceps/Hamstrings) Muscle Strength  
Questionnaires: KOOS, Tampa Scale, Tegner, PROMIS, Marx 
Quadriceps Ultrasound; Quadriceps Activation;  
Gait and Hopping Biomechanics 
Intervention Delivery. 
2x/week for approximately 8 weeks. 8 weeks of NMES (or placebo) begin 0-2 weeks post 
ACLR.  
Randomize 
ACL Reconstruction   
Final Follow-up assessments of study endpoints  
Bilateral Isokinetic/Isometric Thigh (Quadriceps/Hamstrings) Muscle Strength  
Questionnaires: KOOS, Tampa Scale, Tegner, PROMIS, Marx 
Quadriceps Ultrasound; Quadriceps Activation;  
Gait and Hopping Biomechanics 
A/P Knee X-ray; Knee MRI 
Optional Muscle Biopsy 
Post-NMES intervention Assessment 
Bilateral Isometric Thigh (Quadriceps) Muscle Strength  
Questionnaires: KOOS, Tampa Scale, Tegner, PROMIS, Marx 
Quadriceps Ultrasound;  
Post-ECC intervention Assessment 
Bilateral Isokinetic/Isometric Thigh (Quadriceps/Hamstrings) Muscle Strength  
Questionnaires: KOOS, Tampa Scale, Tegner, PROMIS, Marx 
Quadriceps Ultrasound; Quadriceps Activation;  Optional Muscle Biopsy 
Standard of Care Physical Therapy 
Arm 2 
N = 56 
Arm 1 
N = 56 
Intervention Delivery. 
2x/week for approximately 8 weeks. 8 weeks of ECC (or placebo) begin between weeks 
6-10 post ACLR (0-2 weeks after Visit 2) 

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1.3 SCHEMA – SOC CONTROL GROUP 
 
Prior to  
Enrollment 
 
 
 
Testing  
Visit 1  
(Repeat if needed) 
 
 
 
 
 
 
 
Testing  
Visit 2 
 
 
 
 
Testing 
Visit 3 
 
 
Testing 
Visit 4 
 
 
 
Testing  
Visit 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total N = 28:  Obtain informed consent. Screen for inclusion and exclusion criteria; obtain 
history, document. 
Perform baseline (pre-ACL reconstruction) assessments. 
Bilateral Isokinetic/Isometric Thigh (Quadriceps/Hamstrings) Muscle Strength  
Questionnaires: KOOS, Tampa, Tegner, PROMIS, VR-12, Marx 
A/P Knee and SOC Clinical X-ray; Quadriceps Ultrasound; Quadriceps Activation; Biomechanics, Optional Muscle 
Biopsy 
9 month Follow-up assessments of study endpoints  
Bilateral Isokinetic/Isometric Thigh (Quadriceps/Hamstrings) Muscle Strength  
Questionnaires: KOOS, Tampa Scale, Tegner, PROMIS, Marx 
Quadriceps Ultrasound; Quadriceps Activation;  
Gait and Hopping Biomechanics 
Standard of Care Physical Therapy 
ACL Reconstruction   
Final Follow-up assessments of study endpoints  
Bilateral Isokinetic/Isometric Thigh (Quadriceps/Hamstrings) Muscle Strength  
Questionnaires: KOOS, Tampa Scale, Tegner, PROMIS, Marx 
Quadriceps Ultrasound; Quadriceps Activation;  
Gait and Hopping Biomechanics 
A/P Knee X-ray; Knee MRI 
Optional Muscle Biopsy 
 
Bilateral Isometric Thigh (Quadriceps) Muscle Strength  
Questionnaires: KOOS, Tampa Scale, Tegner, PROMIS, Marx 
Quadriceps Ultrasound;  
 
Bilateral Isokinetic/Isometric Thigh (Quadriceps/Hamstrings) Muscle Strength  
Questionnaires: KOOS, Tampa Scale, Tegner, PROMIS, Marx 
Quadriceps Ultrasound; Quadriceps Activation;  Optional Muscle Biopsy 

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1.4 SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Pre-Screening (Phone 
and Record Review) 
Testing Visit  1 
 Enrollment/Baseline 
Repeat Testing Visit 1d 
ACL Surgery 
Intervention or SOC PT 
Visits 1-16f 
Testing Visit 2 
Post-NMES 
Intervention 
Intervention or SOC PT 
Visits 17-32g   
Testing Visit 3 
Post-ECC Intervention 
Testing Visit 4 
9 months post-ACLRc 
12 months post-ACLR 
15 months post-ACLR  
Testing Visit 5 
18 months post-ACLRc 
Days on Study (relative to ACLR) 
 
-365 
-30 
-30 
0 
 1-70 
 N/ah 
 56-
126 
 N/ah 
270 
365 
455 
540 
Visit Window (days)- Treatment Group 
0 
0 
0 
0 
0 
+7 
0 
+7 
+ 
30 
±14 
±14 
±30 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
ACL Reconstruction Surgery 
 
 
 
X 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
X 
 
 
 
 
 
 
 
 
 
Clinical Knee X-ray Record Review 
 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test a 
 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization b 
 
 
 
 
X 
 
 
 
 
 
 
 
Concomitant medication review 
 
  X--------------------------------------------------------------------------------------------------X 
Administer NMES or placebo e 
 
 
 
 
X 
 
 
 
 
 
 
 
Administer ECC or placebo e 
 
 
 
 
 
 
X 
 
 
 
 
 
Standard of Care Rehabilitation monitoring  
 
 
 
 
   X-----------------------------------------X 
 
 
 
Height & Weight 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
Assessment of Adverse Events 
 
  X--------------------------------------------------------------------------------------------------X 
Knee X-ray 
 
X 
X 
 
 
 
 
 
 
 
 
X 
Knee MRI 
 
 
 
 
 
 
 
 
 
 
 
X 
Quadriceps/Knee Ultrasound 
 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
Thigh Muscle Strength Assessment  
 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
Quadriceps Activation Assessment  
 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
Physical Activity Monitoring 
 
 
 
 
 
 
 
 
 
X 
X 
 
Questionnaires 
 
X 
X 
 
 
X 
 
X 
X 
 
 
X 
Gait Biomechanics 
 
X 
X 
 
 
 
 
 
X 
 
 
X 
Clinical Hop Testing 
 
 
 
 
 
 
 
 
X 
 
 
X 
Hopping Biomechanics 
 
 
 
 
 
 
 
 
X 
 
 
X 
Optional Muscle Biopsy 
 
X 
X 
 
 
 
 
X 
 
 
 
X 
a  Urine pregnancy test for women of child bearing potential 
b  Randomization will occur after ACL reconstruction and implemented at first intervention visit. SOC control group will not 
be randomized.  
c  Testing procedures will be scheduled within a 30 day window before or after 9 and 18 month testing date 
d Completed if Testing Visit 1 falls out of window 
e Does not apply to SOC control group 
f Intervention or SOC PT visits 1-16 can take place beginning on post-op day 1 but may begin up to 2 weeks after surgery.  
g Intervention or SOC PT visits 17-32 can take place beginning on day of Testing Visit 2 but may begin up to 2 weeks following that visit. 
hTesting Visit 2 and 3 will take place within 7 days of the last intervention or SOC PT visit.  

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2 
 
INTRODUCTION 
 
2.1 STUDY RATIONALE  
 
Anterior cruciate ligament (ACL) injuries are both common and costly, with approximately 
300,000 tears occurring annually, at a lifetime cost approaching $8 billion dollars. While ACL 
reconstruction (ACLR) successfully restores knee laxity to within normal limits, current ACL 
rehabilitation is, in part, inadequate, as it fails to restore quadriceps strength. These clinically 
significant reductions in quadriceps strength limit the patients’ ability to engage in physical 
activity, lead to a decreased quality of life, and are an independent predictor of the 
development of post-traumatic osteoarthritis (OA) that plagues over 50% of limbs within 10-20 
years of ACLR.  
 
Current ACL rehabilitation paradigms are inadequate, as they do not effectively target the 
mechanisms, muscle inhibition and altered muscle morphology, that lead to muscle weakness 
after ACL injury and ACLR. ACL injury results in a reflexive, neurological shutdown of the 
quadriceps muscle (i.e. muscle inhibition), while simultaneously changes in protein and genetic 
expression lead to altered muscle morphology (i.e. atrophy). Further, as muscle inhibition 
prevents full voluntary quadriceps activation, it can perpetuate changes in muscle morphology. 
Failure to treat both causes of quadriceps weakness is a critical problem with ACL rehabilitation 
as doing so prevents full muscle strength from being restored.  
 
2.2 BACKGROUND  
 
Anterior cruciate ligament (ACL) injury is a significant US public health problem. ACL tears 
are common, particularly in younger, physically active individuals, with approximately 300,000 
tears occurring each year in the US1,2 at an annual lifetime cost of $7. 6 billion when treated 
surgically. While in the short-to-intermediate term, consequences range from reduced functional 
and academic performance due to time loss from school or work; the long-term consequences 
are much greater, with post-traumatic osteoarthritis (OA) affecting an estimated 50% of 
reconstructed limbs3 between 10-20 years after injury4. Given the peak incidence for an ACL 
rupture is 16 years of age5, a significant number of young to middle age adults will be effected by 
premature joint degeneration for which no cure exists. Innovative treatment options capable of 
reducing the incidence of post-traumatic OA following ACL injury and ACL reconstruction 
(ACLR) are desperately needed. If the risk for OA following ACLR could be halved, the cost to 
society could be reduced by $1. 1 billion dollars annually. 3 
 
Quadriceps weakness persists after ACL injury and reconstruction. Quadriceps 
weakness (e. g. , deficits or declines in peak torque during isokinetic testing) is a common 
consequence of ACL injury and ACLR. Despite restoration of anterior-posterior knee laxity 
through surgery and aggressive rehabilitation protocols designed to re-establish strength, 
quadriceps weakness remains. 6-8 Achieving quadriceps strength in the injured/reconstructed 
limb that is 90% of the uninjured side is considered important for realizing a successful 
outcome and reducing re-injury risk after ACLR9; however patients are often released from 
formal care and cleared to return to full activity at values much lower than this criterion. 12-14 
Our own work illustrates this point, with quadriceps strength in the ACLR knee only averaging 
71. 2% of the uninjured side at the time patients were cleared by their physician to return to full 

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activity. 10 Only 20% of our patients (13/66) were able to achieve the recommended 90% 
quadriceps strength symmetry criterion between limbs at time of clearance. While quadriceps 
strength does seem to improve over time after return to activity, deficits of 10-20% can persist 
at two years and beyond. 11 Furthermore, quadriceps strength early after ACLR (4 months 
post-surgery) is significantly associated with joint space width narrowing at 4 years after 
reconstruction, suggesting restoring early quadriceps strength deficits may be significant to 
combatting post-traumatic OA. 17 
 
Quadriceps weakness is a risk factor for post-traumatic OA after ACL reconstruction. 
Degeneration of articular cartilage along with a breakdown of subchondral bone, otherwise 
known as OA, is a common condition affecting more than 26 million Americans. 12 OA that 
results secondary to traumatic joint injury is referred to as post-traumatic OA and accounts for 
~5. 6 million cases of OA annually. 13 Quadriceps strength is a risk factor for idiopathic OA14 and 
more recently has been linked with post-traumatic OA. Work by Keays et al. 15 demonstrated 
that six years after ACLR weak quadriceps muscles and low quadriceps to hamstring strength 
ratios data were able to discriminate between participants without OA (Kellgren and Lawrence 
(K-L) grades 0 and 1) and those with OA (K-L grade ≥2). Oiested and colleagues16 have also 
found a relationship between quadriceps strength loss that occurred 2 to 15 years following 
ACLR and knee OA (K-L grade ≥2).  
 
Using a prospective study design, Tourville et al17 noted that quadriceps strength loss measured 
within a few months following ACL injury was associated with joint space width narrowing by 
four years after ACLR. Given that quadriceps strength is a modifiable risk factor, targeting it with 
evidence-based interventions is a critical next step in combatting the post-traumatic OA resulting 
secondary to ACL injury (Aim 1). Further, identifying the magnitude of quadriceps weakness that 
predicts OA onset is unknown and also warrants study (Aim 2).  
 
Mechanisms for quadriceps weakness after ACL injury and ACLR. Muscle inhibition and 
muscle atrophy are considered to be the primary mechanisms leading to quadriceps 
weakness. Together, inhibition and atrophy are able to account for > 60% of the variance in 
quadriceps strength loss associated with ACL injury. 18 Muscle inhibition is a reflexive 
shutdown of the quadriceps muscles that results from altered neural signaling19,20, leads to a 
diminished ability to voluntarily contract the muscle, and overtime can result in muscle atrophy. 
Early after ACLR, the magnitude of inhibition is large (~25%) and can prevent effective 
strengthening, thus hindering rehabilitation. 21 In 
fact, despite resistance training in patients with 
knee injuries, quadriceps strength can remain 
unchanged or decline, an effect attributed to 
muscle inhibition. 21 Evidence also suggests that 
substantial inhibition (15%) can persist for 2 years 
after ACLR. 22 
 
Muscle atrophy, or the loss of quadriceps muscle 
mass, is the other leading mechanism proposed 
to contribute to quadriceps weakness. Muscle 
atrophy is a predictor of the strength deficits. 23 It 
is thought that adaptations in protein and genetic 
expression after ACLR can have a significant 
impact on muscle size and function. Evidence in 
support of this idea comes from studies 
Figure 1. Research studies showing 
NMES+exercise is superior to exercise 
alone at improving quadriceps strength in 
patients with ligament/ACL injuries 

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measuring molecular effects of muscle 
hypertrophic/atrophic pathways. These studies have 
found that hypertrophic pathways are depressed 
(insulin-like growth factor 1) and circulating 
biomarkers of muscle atrophy (myostatin and 
transforming growth factor-β) are significantly 
elevated after ACLR. 24 Work from our labs25 and 
others26 also indicates that quadriceps cross 
sectional area (CSA) is significantly reduced in the 
ACLR limb compared to the contralateral limb, and 
quadriceps muscle atrophy is a predictor of the 
strength deficits. Further, data from the NIH-funded 
Osteoarthritis Initiative has found that high 
quadriceps CSA is associated with greater 
quadriceps strength and less degenerative changes 
at the knee after ACLR. 27 
 
Neuromuscular electrical stimulation (NMES) and 
Eccentric Exercise (ECC) can restore quadriceps 
strength. NMES, when applied appropriately, can 
directly depolarize motor axons in the treated muscle 
leading to involuntary muscle contraction. 28 
Therefore, use of NMES is an attractive therapy to 
override muscle inhibition as it can activate the 
quadriceps exogenously. Previous work has shown 
that NMES is superior to exercise alone at improving 
muscle strength (Figure 1). 29-31 
 
To target muscle atrophy, emerging evidence suggests that the higher mechanical stress 
achieved via ECC is critical to initiate strain-sensing molecules that mediate tissue growth. 8 
Specifically, when a sarcomere is elongated by mechanical force, titin, the giant elastic protein 
that spans the entire length of a sarcomere, unfolds at the M- band, and removes its auto-
inhibition. 8,32 This positive strain of the sarcomere allows phosphorylation of titin-kinase that 
begins a cascade of signaling events that ultimately promote muscle growth. 8,32,33 Given the 
unique capability of ECC to mechanically promote protein synthesis, the incorporation of ECC 
into ACLR rehabilitation after muscle inhibition is minimized via NMES is likely an effective 
therapeutic prescription to promote the optimal recovery of quadriceps strength. Indeed, ECC 
has been shown to improve muscle strength34,35 and reduce atrophy34,36 following ACLR in small 
research studies (Fig. 2). Hence, it is our contention that applying these therapies in succession 
will maximize muscle strength gains after ACLR.  
 
2.3 RISK/BENEFIT ASSESSMENT   
 
 KNOWN POTENTIAL RISKS  
 
The majority of risks associated with this study are the same as those for medical treatment of 
ACL injury, surgical reconstruction of the ACL, physical therapy associated with ACL injury/ACL 
reconstruction, and the activities that the typical ACL patient took part in prior to their injury. 
Risks for this study are minimal, and major issues would be uncommon. For this study, the risks 
Figure 2. Data illustrating that 
eccentric exercise is superior to 
concentric exercise at improving 
quadriceps strength following ACLR. 
Data from Gerber et al (2007). 

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are as follows:  
 
1. Any risk specific to physical therapy or the eccentric exercise intervention (these risks would 
be similar) including knee effusion/hemarthrosis, muscle pain, rupture of graft tissue, or 
injured muscle, ligament or tendons.  
2. Any risk specific to the neuromuscular electrical stimulation (NMES) intervention, including 
muscle pain, rupture of graft tissue, fracture, or injury to muscle, ligaments or tendons. 
Discomfort during application of the electrical stimuli is common and to be expected during 
the NMES intervention.  
3. Any risk specific to the biomechanical testing that requires the subjects to hop/land including 
knee effusion/hemarthrosis, muscle pain, rupture of graft tissue, or injured muscle, ligament, 
or tendons.  
4. Any risk specific to musculoskeletal imagining (i.e., X-ray and MRI) including discomfort 
while lying in the scanner (MRI), exposure to radiation (X-ray), and exposure to loud noises 
(MRI). All appropriate precautions that occur with standard clinical imaging will take place, 
(i.e. use of lead vests for X-ray, ear plugs or equivalent for MRI) and, thus, the risk is 
mitigated.  
5. Any risk related to topical application of tape or electrical stimulation pads, which could 
occur secondary to all study procedures, such rash or itching.  
6. Any risk specific to the ACL reconstruction, including infection, cyclops lesion, deep vein 
thrombosis, damage to nerves/vessels, cellulitis, hemarthrosis requiring arthrocentesis, 
septic arthritis, pain not controlled with analgesics, as well as risks associated with 
anesthesia (e. g. , nausea and vomiting).  
7. Any risk related to the muscle biopsy including discomfort, infection, bruising, and/or blood 
clot.  
8. Any risk specific to loss of confidentiality.  
 
 KNOWN POTENTIAL BENEFITS  
 
The study participants and those affected by ACL injuries at large could benefit significantly 
from this study. This study will help to identify interventions that will improve/maximize 
quadriceps strength after ACLR. Research has shown that patients with stronger quadriceps 
muscles have improved functional performance, biomechanical symmetry and are less likely to 
re-injure their knees. Further, quadriceps weakness has been linked to the post-traumatic OA 
that affects upwards of 50% limbs after ACLR. Therefore, improving muscle strength has the 
potential to lessen the risk of OA, a hypothesis the proposed study will directly evaluate. Based 
on our pilot data, we would expect participants randomized to receive NMES+ECC would see 
greater improvements in quadriceps strength than patients in NMES placebo + ECC placebo 
and thus may directly benefit from participation.  
 
 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Risk 1:  Any risk specific to physical therapy or the eccentric exercise intervention (these risks 
would be similar) including knee effusion/hemarthrosis, muscle pain, rupture of graft tissue, or 
injured muscle, ligament, or tendons.  
Protection/Mitigation Risk 1:  We will only initiate the eccentric exercise intervention once 
participants have good quadriceps control. Further, no participant will begin eccentric exercise 
until their physician has cleared them to start the intervention. The BLAST leg press device (the 
device used to complete eccentric exercise) has multiple safeguards built in that allow the 
participants or investigator to stop the activity at any time. Participants will be instructed to tell 

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study staff if the feel pain in their knee joint and if this were to occur, the intervention would be 
stopped. If an injury were to occur, the research laboratory is approximately 100ft from the 
MedSport clinic where athletic trainers, doctors, nurses, and physical therapists are present.  
 
Risk 2:  Any risk specific to the neuromuscular electrical stimulation (NMES) intervention, 
including muscle pain, rupture of graft tissue, fracture, or injury to muscle, ligaments, or 
tendons. Discomfort during application of the electrical stimuli is common and to be expected 
during the NMES intervention.  
Protection/Mitigation of Risk 2:  Injury to any musculoskeletal tissue would be rare, however 
all participants will be instructed to alert study staff if they feel pain in their knee joint. If joint pain 
were felt, the intervention would be stopped. There is no way to prevent the discomfort in the 
muscle on the skin when the NMES intervention is applied. Large electrodes will be used to 
deliver the stimuli which disperse the current and minimize discomfort.  
 
Risk 3:  Any risk specific to the biomechanical testing that requires the subjects to hop/land 
including knee effusion/hemarthrosis, muscle pain, rupture of graft tissue, or injured muscle, 
ligament or tendons.  
Protection/Mitigation of Risk 3:  In order to minimize this risk, no ACLR participant will be 
allowed to undergo biomechanical testing unless cleared by their physician to do so. If injury 
were to occur during test, the study team would manage the injury and will then refer the 
participant to Drs. Wojtys or Bedi for follow-up. It is important to note that volunteers will not be 
performing the landing procedures until 9 months after ACL reconstruction (i. e., when the 
volunteer would typically be released to return to sport or activity).  
 
Risk 4:  Any risk specific to musculoskeletal imagining (i.e. , X-ray and MRI) including 
discomfort while lying in the scanner (MRI), exposure to radiation (X-ray), and exposure to loud 
noises (MRI).  
Protection/Mitigation of Risk 4: All appropriate precautions that occur with standard clinical 
imaging will take place (e. g. , use of lead vests for X-ray, ear plugs or equivalent for MRI).  
 
Risk 5:  Any risk related to topical application of tape or electrical stimulation pads, which could 
occur secondary to all study procedures, such rash or itching.  
Protection/Mitigation of Risk 5:  If irritation secondary to application of tape or electrical 
stimulation electrodes would occur, we would treat with topical hydrocortisone. If rash/irritation 
did not improve (or appeared to be something more severe), we would refer to Drs. Wojtys or 
Bedi for evaluation and treatment.  
 
Risk 6:  Any risk specific to the ACL reconstruction, including infection, cyclops lesion, deep 
vein thrombosis, damage to nerves/vessels, cellulitis, hemarthrosis requiring arthrocentesis, 
septic arthritis, pain not controlled with analgesics, as well as risks associated with anesthesia 
(e. g. , nausea and vomiting).  
Protection/Mitigation of Risk 6: This risk/event will be captured as the ACLR will occur after 
participants 
have signed informed consent/assent. If any of these were to occur or we noticed signs or 
symptoms of any of these conditions, we would refer to Drs. Wojtys or Bedi for immediate 
follow-up.  
 
Risk 7: Any risk related to the muscle biopsy including discomfort, infection, bruising, and/or 
blood clot.  
Protection/Mitigation of Risk 7: A sterile environment will be used to collect biopsy samples in 

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order to mitigate risk of infection. Participants will be sent home with instructions to care for their 
incision/wound after the biopsy. A study team member will follow-up with each participant opting 
to participate in the biopsy the day after the procedure.  
 
Risk 8:  Any risk specific to loss of confidentiality.  
Protection/Mitigation of Risk 7: To ensure confidentiality of subject data, only members of the 
study team will have access to the link between personal identifiers and a study ID number. 
Information about study participation may also be noted in the medical record to ensure 
continuity of care and proper billing. This information is protected by HIPAA and only accessible 
to authorized faculty and staff of the University of Michigan.  
 
Questionnaires and data files will be labeled with subject ID numbers. An encrypted file 
containing personnel identifiers will be stored on a secure server, and will only be accessible to 
the members of the study team. All electronic files will be stored on secure, encrypted servers 
within the University of Michigan system. Informed consents/assents, completed questionnaires, 
and other paper study source documents will be kept in locked files and stored in a room where 
key access is required.  

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3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
HYPOTHESES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
 
To determine if NMES+ECC 
will maximize quadriceps 
strength symmetry better than 
the NMES placebo + ECC 
placebo at 9 months and 18 
months post-ACL 
reconstruction (ACLR).  
 
Participants receiving 
NMES+ECC will have greater 
quadriceps strength symmetry 
at 9 and 18 months post-ACLR 
when compared with the other 
2 study arms.  
Co-primary endpoints:    
• 
Change from baseline to 9 
months post-ACLR in 
isokinetic quadriceps 
strength symmetry index. 
Change from baseline to 
18 months post-ACLR in 
isokinetic quadriceps 
strength symmetry index.  
This trial is designed to 
evaluate whether NMES and 
ECC can improve quadriceps 
strength. Thus, quadriceps 
strength at 9 months (when 
participants return to activity) 
and 18 months (longer-term 
assessment) are the primary 
endpoints for the trial.  
Secondary 
 
 
 
Secondary Objective 1:  To 
determine if NMES+ECC will 
limit negative changes in 
cartilage health, defined as 
decreased proteoglycan 
cartilage density measured 
with T1rho or increased 
cartilage matrix degradation 
measured with T2 mapping in 
relation to the contralateral 
side, at 18 months following 
ACLR.  
Participants in the 
NMES+ECC group will have 
significantly lower T1rho and 
T2 values in the injured knee 
compared to the uninjured 
knee, indicating greater 
proteoglycan density and less 
cartilage matrix degradation. 
Further, we would expect 
larger (injured/uninjured) 
ratios for both T2 and T1rho 
in the NMES placebo + ECC 
placebo group when 
compared to the NMES + 
ECC group. Ratios greater 
than 1. 0 would indicate less 
proteoglycan density (T1rho) 
and greater matrix 
degradation (T2).  
• 
T1 relaxation ratio at 18 
months post-ACL 
• 
T2 relaxation ratio at 18 
months post-ACL 
T1 and T2 relaxation times 
have been able to show early 
change in cartilage after ACLR 
and are sensitive to change in 
cartilage when the gold 
standard X-ray does not yet 
reveal change.  

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OBJECTIVES 
HYPOTHESES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Secondary Objective 2: To 
determine if NMES+ECC will 
maximize biomechanical 
symmetry and physical 
function better than the 
placebos at 9 months and 18 
months post-ACL 
reconstruction (ACLR).  
Participants receiving NMES + 
ECC will have greater knee 
flexion angle and moment 
symmetry, higher scores on 
the KOOS, and larger 
distances hopped on the 
crossover hop and single-
legged hop at 9 and 18 months 
when compared with other 3 
study arms.  
• 
Knee joint flexion angle 
and moment at 9 months 
post ACLR  
• 
Knee joint flexion angle 
and moment at 18 months 
post ACLR  
• 
Score on KOOS at 9 
months post-ACLR 
• 
Score on KOOS at 18 
months post-ACLR 
• 
Distance hopped during 
cross-over hop and single-
legged hop for distance at 
9 months post-ACLR 
• 
Distance hopped during 
cross-over hop and single-
legged hop for distance at 
18 months post-ACLR 
Knee flexion angle and 
moment are sensitive to 
changes in quadriceps 
strength. KOOS is a validated 
and reliable scale to assess 
patient-perceived function after 
ACLR. Distance hopped during 
the cross-over and single-
legged hop for distance are 
standard clinical hop tests 
used after ACLR.  
Exploratory Objective:  To 
assess the ability of reducing 
the intensity of NMES and 
ECC to achieve a “true” 
placebo by comparing the 
NMES placebo + ECC placebo 
to the SOC Control group.  
Participants receiving NMES 
placebo + ECC placebo will 
have similar change to those in 
the SOC control group from 
baseline to 9 months and to 18 
months post-ACLR in isokinetic 
quadriceps strength symmetry 
index.  
• 
Change in isokinetic 
quadriceps strength 
symmetry index from 
baseline to 9 months post-
ACLR 
• 
Change in isokinetic 
quadriceps strength 
symmetry index from 
baseline to 18 months post 
ACLR 
 
This trial is designed to 
evaluate whether NMES and 
ECC can improve quadriceps 
strength. Thus, quadriceps 
strength at 9 months (when 
participants return to activity) 
and 18 months (longer-term 
assessment).  

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4 
STUDY DESIGN  
 
4.1 OVERALL DESIGN 
 
In order to determine whether high intensity NMES +ECC can improve quadriceps strength 
better than the current standard of care (NMES placebo + ECC placebo) (primary objective), we 
propose a comparative effectiveness, single-center, randomized, double-blind, parallel group, 
placebo-controlled trial of NMES and ECC in patients with ACLR. One-hundred twelve 
participants scheduled to undergo an ACLR will be randomized into one of two study arms:  1) 
NMES + ECC ; or 2) NMES placebo + ECC placebo. All participants regardless of assignment 
will undergo standard of care ACL rehabilitation that focuses on minimizing effusion, restoring 
range of motion, and improving muscle strength (standard concentric exercises). The study 
intervention duration is 14-18 weeks, with NMES and NMES placebo beginning within 2 weeks 
of the ACLR and is provided twice/week for 8 weeks and ECC and ECC placebo beginning 6-10 
weeks post-ACL surgery and is provided twice/week for 8 weeks.  
Additionally, 28 patients will be enrolled into a control group where no study interventions are 
provided and participants will be followed and tested as they undergo physical therapy as 
prescribed by their treating physician. These patients are eligible for the study but refuse to 
participate in the randomized controlled trial however, they are willing to participate in the study 
procedures to provide efficacy measures.  
We will randomize participants to treatment groups using minimization, a method of unbiased 
allocation ensuring balance across stratification factors: meniscal injury and treatment, articular 
cartilage injury (described below), sex and graft type. (See section 6. 3 for details on the 
randomization method using the minimization method. ) 
Our primary outcomes will be examined at three study time points:  1) pre-ACLR (within 2 
weeks prior), 2) 9 months post-ACLR (±2 weeks), and 3) 18 months post-ACLR (±2 weeks). 
MRI and X-ray measures will be collected at 18 months post-ACLR, biomechanical measures at 
9 and 18 months post-ACLR, hop testing at 9 and 18 months post-ACLR and questionnaires at 
all 3 time points. Additionally, we will examine change in quadriceps muscle strength and 
muscle volume from baseline to post-NMES intervention (testing visit 2) and post-ECC 
intervention (testing visit 3) in an attempt to understand the effects of the individual components 
of the combined NMES+ECC intervention.  
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
A double-blind, parallel group, placebo-controlled randomized clinical trial assessing the 
superiority of NMES and ECC will be utilized. This design was chosen to assess whether our 
multimodal intervention (NMES + ECC) is superior to the placebo arm. An independent group of 
participants will receive only the standard of care rehabilitation therapy to assess the ability of 
reducing the intensity of NMES and ECC to achieve a “true” placebo. This additional non-
randomized group strengthens the study by confirming the sham NMES & ECC procedures can 
serve as “true” placebos.  
 
 

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4.3 JUSTIFICATION FOR DOSE 
 
Neuromuscular Electrical Stimulation: Patients randomized into the NMES + ECC arm will 
receive NMES 2x/week for 8 weeks following ACLR, beginning 0-2 weeks post-operative. For 
the first two weeks, NMES will be delivered in the clinic by the patients’ physical therapist. The 
treatment intensity for the first two weeks will be set to the maximum tolerated by the patient, 
but all other stimulation parameters will remain the same as outlined for the remaining 6 weeks 
of NMES intervention. For the last 7 weeks of NMES treatment, patients will be positioned in a 
dynamometer with their hips flexed to 90° and ACL knee flexed to 60°. Stimulating electrodes 
will be placed over the vastus lateralis proximally and the vastus medialis distally. An electrical 
stimulator (Vectra Neo, DJO Global, Vista, CA) will be set to deliver a 2500 Hz alternating 
current, modulated at 75 bursts/s, with a ramp-up time of 2-seconds, followed by a 50-second 
rest period. Fifteen isometric actions lasting 10 seconds each will be elicited during each 
session. The treatment intensity will be set at a minimum intensity (higher if tolerated) to achieve 
a maximum voluntary isometric quadriceps contraction (MVIC) in the injured limb that is 
equivalent to an MVIC of 40% of the contralateral side. Justification for Dose: Dose response 
curves from previous work show that in order to recover ~70% of isometric quadriceps strength, 
NMES needs to be delivered at an intensity that will elicit 40% of the contralateral MVIC.  
 
NMES placebo. Participants randomized to the NMES placebo + ECC placebo arm will receive 
an NMES placebo intervention 2x/week for 8 weeks following ACLR, beginning 0-2 weeks post-
operative (to mimic the timing associated with the NMES intervention). The NMES placebo will 
utilize the same equipment and follow the same protocol as in the actual NMES intervention, 
with the exception that the intensity of the current will be set lower in the last 6 weeks of NMES 
intervention. The treatment intensity will be set at an intensity to achieve a MVIC of 15% of the 
injured side. In the first 2 weeks of NMES treatment will be delivered at max tolerated by the 
patient as is done for the NMES active arm. Justification for Dose: In our pilot work, electrical 
stimulation of this intensity does not result in improvements in muscle strength; as such it is a 
fitting placebo for the current trial.  
 
High-Intensity Eccentric Exercise (ECC): Participants randomized into the NMES + ECC arm 
will receive ECC 2x/week for 8 weeks, beginning between 6 - 10 weeks post-ACLR when 
adequate quadriceps control is achieved, determined by the participant's physician. To perform 
the ECC, patients will be positioned in a BLAST!™Leg Press (BioLogic Engineering Inc. ) with 
their ACLR knee range of motion limited to 20 to 60° of knee flexion. Patients will perform warm-
up trials consisting of 10 concentric and eccentric quadriceps actions with the ACLR limb. 
Following the warm-up trial, each participant will perform 10 isokinetic eccentric quadriceps 
actions with the ACLR limb. In total for each session, patients will complete 4 sets of 10 leg 
press actions with 2-minute rests between each set. During the eccentric actions, patients will 
train at an eccentric intensity equal to 70-90% of their one-repetition maximum (this will be 
recorded at the beginning of each week), and a concentric intensity equal to 40% of their one 
repetition maximum. Justification for Dose:  In our pilot work35,37, using an eccentric intensity 
identical to that described above, patients, on average, realized a 90% improvement in 
quadriceps strength over 6 weeks (which is shorter than the 8 weeks implemented in this study).  
 
ECC placebo:  Participants randomized to the NMES placebo + ECC placebo arm will receive 
an ECC placebo intervention 2x/week for 8 weeks, beginning at 6 - 10 weeks following ACLR. 
ECC placebo will utilize the same equipment and follow the same protocol as in the actual 
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is lower. Rather than training at 70-90% of their MVIC, patients will train at 40%. This intensity is 
too low to generate increases in muscle strength. Justification for Dose: In our pilot work, 
eccentric exercise of this intensity does not result in improvements in muscle strength; as such, 
it is a fitting placebo for the current trial.  
 
Standard of Care:  All participants, both those receiving study intervention (i.e. NMES + ECC 
or NMES placebo + ECC placebo) or in the SOC control group, will receive standard of care 
physical therapy post-ACLR. The SOC control group will provide confidence that the intensity of 
NMES and ECC in the placebo group is sufficiently low.  
 
 

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4.4 END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit (month 18) shown in the Schedule of Activities (SoA), Section 1. 
4.  
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in 
the last study participant.  
 
5 
STUDY POPULATION 
 
5.1 INCLUSION CRITERIA 
 
In order to be eligible to participate in this trial, an individual must meet all of the following 
criteria:  
1. Provision of signed and dated informed consent/assent form 
2. Stated willingness to comply with all study procedures and availability for the duration of 
the study  
3. Male or female, aged 14-45 years 
4. Have an ACL tear diagnosed by a physician  
5. Scheduled to undergo ACL reconstruction with any type of autograft (i.e. , a graft of 
tissue from one point to another of the same individual's body) 
6. Patient receiving physical therapy at a MedSport facility 
 
5.2 EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria below will be excluded from participation in 
this study.  
 
Exclusion Criteria at time of screening:  
1. Previous major surgery to either knee 
2. Patients who experience a knee dislocation (prior to or in conjunction with the ACL tear) 
3. Female volunteers who are pregnant or planning to become pregnant during the study 
period 
4. Patients who cannot undergo an MRI (e. g. metal in body)  
 
Exclusion Criteria at time of randomization:  
1. Bony fracture accompanying the ACL injury 
2. Multi-ligament reconstruction at the time of the ACLR 
 
5.3 LIFESTYLE CONSIDERATIONS 
Not applicable 
 
 

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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 
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 
 
• 
Patients: Approximately 150 patients (10 of which will be removed from analysis due to 
the COVID-19 pandemic) will be recruited without regard to gender, race or ethnicity. 
Potential participants must be between 14-45 years of age.  
• 
Anticipated accrual rate: 30 patients per year 
• 
Anticipated number of sites: 1 
• 
Source of participants: Our primary source of participants will come from Michigan 
Medicine (in particular MedSport).  
• 
Recruitment venues: Michigan Medicine, Local Physical Therapy Clinics 
• 
How potential participants will be identified and approached: To identify potential 
participants, we will examine electronic medical records from MedSport, which is part of 
Michigan Medicine, for patients who have been diagnosed with an ACL tear. Our study 
coordinator will examine the record for any exclusion criteria that may also be listed. 
Once a potential participant is identified, we will approach the patient at a scheduled 
appointment with their orthopedic surgeon. At this appointment, the coordinator will 
provide information about the study, gauge patient interest in participating, and confirm 
eligibility. If the potential participant expresses interest in participating we will follow-up 
with a phone call or email within 3 days to schedule a pre-operative/baseline testing 
session.  
• 
Recruitment strategies:  Direct recruitment through Michigan Medicine, Flyers in local 
physical therapy clinics in Ann Arbor, Flyers around University of Michigan campus, 
clinicaltrials.gov  
• 
Subject retention: In regard to subject retention, every effort will be made by the study 
team to achieve optimal retention of participants. We deliver study interventions at a time 
that corresponds with participants’ regularly scheduled physical therapy visits (i.e., they 
are already in our clinic for treatment and we simply schedule their intervention to 
coincide with their existing appointment). This has led to 100% subject retention in our 
pilot work. Retaining subjects at the 9-month data collection time point should not be 
problematic as patients are still reporting to the clinic at that time (or have just completed 
therapy and thus are easily accessible to study staff). We will schedule the 9-month 
appointment time at the time of their last intervention session and follow-up with an email 
and postcard reminder 2 weeks prior to that appointment. Additionally, we will follow-up 
with an email 2 days prior to the scheduled appointment to confirm attendance. Similar 
procedures led to 100% retention in our pilot trial. For the 18-month time point, phone 
and email contact will be made with subjects or their parents or guardians (if applicable) 
one month prior to our goal date for testing. When participants are reached, we will 
schedule a time for an MRI and a separate time to come to MedSport for X-rays, as well 
as strength/biomechanical testing. Reminders will be emailed and mailed to participants 

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10 days prior to their scheduled test dates and emailed again at 2 days prior to the test 
date. In our prior trial, we approached select patients in a similar manner at one-year 
post-ACLR and 95% agreed to return for follow-up.  
• 
Subject Incentives: Participants will receive $25/week for undergoing study 
interventions (16 weeks x $25 = $400) (groups randomized to receive interventions 
only). All Participants (randomized and SOC control) will receive $10/hour for each hour 
of study testing in which they participate. If the participant is a minor, the minor will 
receive the incentive.   
 
6 
STUDY INTERVENTION 
 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
 
 STUDY INTERVENTION DESCRIPTION 
 
The following study interventions will be administered in addition to standard of care ACL 
rehabilitation as prescribed by the operating physician. Note that the SOC control group will not 
receive study interventions; they will only receive standard of care ACL rehabilitation.  
 
Neuromuscular electrical stimulation (NMES): This study intervention will be delivered using the 
Vectra Neo (DJO Global, Vista, CA) 
 
Eccentric Exercise:  Eccentric exercise will be delivered using a BLAST!™ Leg Press System 
(BioLogic Engineering).  
 DOSING AND ADMINISTRATION 
 
Neuromuscular Electrical Stimulation: Participants randomized into the NMES + ECC will 
receive NMES 2x/week for 8 weeks following ACLR, beginning 0-2 weeks post-operative. For 
the first two weeks, NMES will be delivered in the clinic by the participants’ physical therapist. 
The treatment intensity for the first two weeks will be set to the maximum tolerated by the 
participant, but all other stimulation parameters will remain as outlined below for the remaining 6 
weeks. For the last 6 weeks of NMES treatment, participants will be positioned in a 
dynamometer with their hips flexed to 90° and ACL knee flexed to 60°. Stimulating electrodes 
will be placed over the vastus lateralis proximally and the vastus medialis distally. A 
Chattanooga stimulator (Vectra Neo) will be set to deliver a 2500 Hz alternating current, 
modulated at 75 bursts/s, with a ramp-up time of 2-seconds, followed by a 50-second rest 
period. Fifteen isometric actions lasting 10 seconds each will be elicited during each session. 
The treatment intensity will be set at a minimum intensity (higher if tolerated) to achieve a 
maximum voluntary isometric quadriceps contraction (MVIC) in the injured limb that is 
equivalent to an MVIC of 40% of the contralateral side. Dose Changes:  During the last 6 
weeks of NMES treatment intensity will be set at the beginning of each week to ensure strength 
gains are considered throughout the study. The study team will consider a dose change if the 
participant cannot tolerate the electrical stimulation. If this were to occur, the physical therapist 
in charge of the intervention would determine the maximum amount of electrical stimulation 
tolerable by the participant and determine the percentage of the MVIC from the contralateral, 
uninjured limb this stimulation would produce.  
 

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NMES placebo. Participants randomized to NMES placebo + ECC placebo will receive an 
NMES placebo intervention 2x/week for 8 weeks following ACLR, beginning 0-2 weeks post-
operative (to mimic the timing associated with the NMES intervention). Similar to the NMES 
intervention group, for the first two weeks NMES will be delivered in the clinic by the 
participants’ physical therapist. The treatment intensity for the first two weeks will be set to the 
maximum tolerated by the participant, but all other stimulation parameters will remain as 
outlined below for the last 6 weeks. The NMES placebo will utilize the same equipment and 
follow the same protocol as in the actual NMES intervention, with the exception that the intensity 
of the current will be set lower. The treatment intensity will be set at an intensity to achieve a 
MVIC of 15% of the injured side.  
 
High-Intensity Eccentric Exercise (ECC):  Participants randomized into the NMES + ECC 
group will receive ECC 2x/week for 8 weeks, beginning between 6 - 10 weeks post-ACLR when 
adequate quadriceps control is achieved. To perform the ECC, participants will be positioned in 
a BLAST!™Leg Press (BioLogic Engineering Inc. ) with their ACLR knee range of motion limited 
to 20 to 60° of knee flexion. Participants will perform warm-up trials consisting of 10 concentric 
and eccentric quadriceps actions with the ACLR limb. Following the warm-up trial, each 
participant will perform 10 isokinetic eccentric/concentric quadriceps actions with the ACLR 
limb. In total for each session, patients will complete 4 sets of 10 eccentric/concentric actions 
with 2-minute rests between each set. During the eccentric actions, participants will train at an 
intensity equal to or greater than 70-90% of their concentric one-repetition maximum (this will be 
recorded at the beginning of each week). Concentric intensity will be set at 40% of the one-
repetition maximum. Dose Changes: Treatment intensity will be set at the beginning of each 
week to ensure strength gains achieved during the study period are reflected in the dose 
delivered. The timing of initiation eccentric exercise will be evaluated on a patient-by-patient 
basis. It will begin when the patient has adequate quadriceps control to handle this type of 
training and will be determined by the physical therapist working with the participant and their 
physician.  
 
ECC placebo:  Participants randomized to NMES placebo + ECC placebo will receive an ECC 
placebo intervention 2x/week for 8 weeks, beginning at 6 - 10 weeks following ACLR. ECC 
placebo will utilize the same equipment and follow the same protocol as in the actual eccentric 
intervention, with the exception that participants will train eccentrically at 10% of their MVIC.  
 
 
6.2 MEASURES TO MINIMIZE BIAS:  RANDOMIZATION AND BLINDING 
 
Procedures for assignment to a study group:  Participants in the treatment groups will be 
allocated to one of the two study arms using minimization38,39, a method of unbiased allocation 
ensuring balance across confounding factors. This approach is selected over the more common 
random permuted blocks within stratum design because of the importance of controlling for two 
known confounders (1) meniscal injury and treatment and (2) articular cartilage injury – that 
have 4 x 3 = 12 combinations. Some of these combinations are relatively rare (e. g. meniscal 
tear left intact) which would result in potential imbalance (and subsequent loss of power) among 
the study arms. We will also include graft type (bone-patellar tendon-bone or quadriceps 
tendon, hamstring,) and sex as  minimization factors. A secure web-based application 
developed by the Data Coordinating Center will be used by the research coordinator to enter 
participant information (e. g. , participant ID, minimization factors) and to obtain the assigned 
study arm.  
 

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The following definitions of meniscal tears/treatment will be used for minimization:  1) 
normal/intact; 2) torn/excision (partial or complete); 3) torn/repaired; 4) torn/left intact. Articular 
cartilage injury will be defined using the Modified Outerbridge Scale and used in minimization as 
follows:  1) grade 1 (normal or soft); 2) grade 2 (partial thickness lesions; and 3) grade 3 and 4 
(full-thickness lesions).  
 
Blinding. Considerable care will be taken to ensure fidelity of blinding. Study staff will have 
standardized scripts to describe treatment arms to participants in order to prevent different 
treatment expectations. Study staff collecting outcome measures will not be aware of treatment 
assignment. Physical therapists, delivering the interventions, will be provided with treatment 
allocation from the DCC. Blinded data reviews will be done and the statistical analysis plan will 
be written prior to database lock and unblinding of statisticians.  
 
6.3 STUDY INTERVENTION COMPLIANCE 
 
Treatments will be delivered in person, so we will be able to directly monitor adherence. 
Adherence will be quantified as a count variable defined as the total number of sessions 
completed relative to the number of session prescribed (32 sessions total: 16 of both NMES and 
ECC or corresponding placebos). We will also use CRFs to record the percentage of MVIC that 
the NMES treatment produced in each session, as well as the intensity of the eccentric 
contractions during ECC sessions. We will then determine the number of session participants 
trained at the recommended dosage relative to the number of sessions recommended (32 total) 
to have an assessment of dosage adherence.  
 
6.4 CONCOMITANT THERAPY 
 
All participants in this trial will be undergoing standard anterior cruciate ligament rehabilitation 
as prescribed by their physician and delivered by their physical therapist. Physical therapists will 
record the components of the standard rehabilitation delivered at each visit for entry in the study 
database. Eccentric exercise will not be a part of standard of care rehabilitation. While low-
intensity NMES is generally considered to be part of ACLR standard of care rehabilitation, all 
study participants will receive NMES regardless of group assignment and thus any additional 
treatment with NMES is not warranted. The experimental NMES intervention will be of high 
intensity, while the placebo NMES will be of low intensity. The low-intensity NMES used for our 
placebo is generally what is used in standard of care ACL rehabilitation.  
 
 

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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION / WITHDRAWAL 
 
It is critical to the integrity of this study that participants adhere to the visit schedule outlined in 
the protocol. As such, every reasonable effort should be made to convey the importance of 
remaining on the study to the participants.  
 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
 
Study interventions may be discontinued for any of the following reasons:  
• Unacceptable toxicity (this may include serious adverse events [SAEs] related to study 
treatment) 
• Participant request or withdrawal of consent 
• Pregnancy 
• Investigator discretion 
 
In instances where participants elect to discontinue NMES treatment per protocol, the following 
procedure will be followed:  
1) Participant will be asked if they would be willing to continue with NMES at a maximum 
tolerated dosage.  If yes, patient will continue trial with NMES at this revised dosage.  If 
no, go to #2. 
2) Participant will be asked if they would be willing to continue with the ECC treatment only 
(i.e.,  discontinue NMES, but remain in the study and only receive ECC per protocol).  If 
yes, participant will continue in trial only completing ECC.  If not, go to #3 
3) Participant will be asked if they would be willing to continue being followed to gather 
study-related measurements, but receive no study-related interventions.  If yes, 
participant will continue in trial only being measured as outlined in the study protocol.  If 
no, participant will be withdrawn from the study as requested.  
 
Consistent with the intention-to-treat principle, randomized participants who permanently 
discontinue study interventions will continue in the study, and remaining study procedures may 
be completed as indicated by the study protocol. The data to be collected at the time of study 
intervention discontinuation will include the following:  
• 
In any participant who does not complete study interventions, we will attempt to gather 
MRI, strength, and biomechanical data at the 18 month study time-point. Of note, these 
participants will not be considered SOC control group participants for future study 
conduct or analyses.  
 
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  

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• 
If any 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 
• 
Participant is unable to tolerate study intervention dosage 
• 
Due to COVID-19, or any other pandemic crisis 
The reason for participant discontinuation of study intervention will be recorded on the 
Treatment Status Case Report Form (CRF). Withdrawal from the study will be recorded on the 
Final Status CRF. Participants who were discontinued from treatment due to COVID-19 or other 
pandemic crisis may be replaced.   
 
 

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7.3 LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for four scheduled 
visits and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:  
• 
The site will attempt to contact the participant within one day of the missed visit and 
attempt to reschedule the visit. Study staff will 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 and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts will be documented in the participant’s 
study file.  
• 
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  
 
Enrollment/Baseline/Testing Visit 1/Repeat Testing Visit 1 
The following study procedures and evaluations will be performed at Testing Visit 1 (-30 days)) 
and may be repeated if the surgery is rescheduled making the visit fall outside of the 30 day 
window:  
 
• 
Informed consent or assent (for participants under the age of 18 years of age) 
• 
Urine pregnancy test for women of child bearing potential. Child bearing potential is 
defined as a premenopausal female capable of becoming pregnant.  
• 
Concomitant medication review 
• 
Height (cm) and weight (kg) 
• 
Adverse event review and evaluation 
• 
Anterior/Posterior (A/P)A knee X-ray. Briefly, participants will be positioned for the X-
rays using a Synaflexer (BioClinica, Inc. ) to ensure similar positioning across study 
time points. The X-ray tech at MedSport will be responsible for obtaining images.  
• 
Clinical Knee X-ray - The knee x-rays that are gathered as part of standard clinical 
care for an ACL injury will be pulled from MiChart an used to determine patellar 
alignment.  Specifically, from the lateral and patella “sunrise” views, we will use 
custom written MATLAB, semi-automatic software to determine measures of patellar 
alignment. From the sunrise view, edge detection will be used semi-automatically to 
identify the anterior margins of the femur and posterior margins of the patella. 
Anatomical landmarks required for the following measurements will be determined 
automatically and include the most anterior point of the medial and lateral femoral 
condyles, the deepest point of the intercondylar sulcus, apex of the patella, and the 
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dysplasia will include sulcus angle and sulcus depth as described by Merchant et 
al.1 Measures reflecting trochlear sulcus and patellar tilt will include the lateral 
patellofemoral angle and congruency angle. Patellofemoral index, ratio of medial and 
lateral patellofemoral joint space, will also be determined. From the lateral view, 
patellar height will be measured manually which reflects the ratio of the length of the 
patellar articular surface to the length of the patella tendon measured from the lower 
pole of the patella to the insertion into the tibia tubercle 
 
• 
Study specific testing. Specialized measurements will be recorded by study staff 
(post-doctoral fellow, graduate students). Thigh muscle strength and quadriceps 
activation will require the use of a Cybex dynamometer equipped with both an anti-
shear and a knee attachment. Biomechanics will be recorded with standard 
procedures using a Vicon Nexus motion capture system. Quadriceps/Knee Cartilage 
ultrasonograpy will be used to gather measurements of quadriceps atrophy and 
femoral cartilage thickness. An optional muscle biopsy may be gathered to assess 
markers of inflammation, muscle damage, and hypertrophy/atrophy. Biopsy may also 
be used for muscle phenotyping.  
• 
Questionnaires  
o PROMIS Physical Function computer adaptive test (PF CAT): The National 
Institutes of Health (NIH) Patient-Reported Outcomes Measurement 
Information System (PROMIS®) Roadmap initiative (www. nihpromise. org) is 
a cooperative research program designed to develop, evaluate, and 
standardize item banks to measure patient-reported outcomes (PROs) across 
different medical conditions as well as the US population. The PF CAT is a 
broad instrument evaluating physical function in both upper and lower 
extremities; by responding to the test taker’s selections in real time, it is able 
to reduce the number of questions needed to accurately ascertain a patient’s 
functional status. A patient typically answers between 4-12 questions from a 
bank of 121 possible questions, and, usually, the test is completed in less 
than 1 minute. This test has demonstrated good-to-excellent construct validity 
in patients who have undergone ACL reconstruction. 41 
o The Knee injury and Osteoarthritis Outcome Score (KOOS) is a knee-specific 
measure intended to examine patient reported outcomes after injuries that 
may lead to post-traumatic osteoarthritis, like an ACL injury. KOOS consists 
of 5 subscales:  1) Pain, 2) Other Symptoms, 3) Function in daily living (ADL), 
4) Function in sport and recreation (Sport/Rec) and 5) knee related Quality of 
life (QOL). The previous week is the time period considered when answering 
the questions. Standardized answer options are given (5-point Likertscale) 
and each question is assigned a score from 0 to 4. A normalized score (100 
indicating no symptoms and 0 indicating extreme symptoms) is calculated for 
each subscale.  
o The Tegner Activity Scale is a numerical scale with each value (0–10) 
representing specific activities. An individual who participates in competitive 
sports including soccer, football, and rugby at the elite level is considered to 
have an activity level of 10. An individual participating in the above listed 
sports but at the recreational level is considered to have an activity level of 6. 
An individual on sick leave or disability pension due to knee problems is 
considered to have an activity level of 0. The Tegner scale has proven valid, 
reliable, and responsive to change. 42   

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o The Marx scale is utilized to assess a person’s level of physical activity. It 
focuses on four activities:  running, deceleration, cutting, and pivoting. 
Participants are asked to indicate approximately how many times in the past 
12 months they performed each of these activities while at their healthiest 
and most active state. The four knee functions are rated on a 5-point scale of 
frequency and scores are added up to a maximum of 16 points with a higher 
score indicating more frequent participation. This scale has been shown to be 
both valid and reliable. 43   
o The Tampa Scale of Kinesiophobia (TSK-11) is a patient reported outcome 
developed to assess ‘fear of movement-related pain’ in patients with 
musculoskeletal pain. Each item is scored on a 4-point Likert scale, ranging 
from 1 ‘strongly disagree’ to 4 ‘strongly agree’; total scores vary between 11 
and 44, with higher scores indicating higher levels of fear of movement-
related pain. Validity, Reliability, sensitivity, and specificity have all been 
established and fall in an acceptable to excellent range. 44  
 
 
 

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Intervention Visits 1-16 (For Randomized Participants Only) 
The following study procedures and evaluations will be performed at Visit 1-16 (twice per week 
during Weeks 1-8):  
 
• 
Randomization. At Intervention Visit 1, subjects will be randomized prior to the 
administration of the study intervention.  
• 
Study Intervention. At Visits 1-16, NMES or placebo will be administered twice per week. 
Study intervention parameters will be recorded by the physical therapist.  
• 
Concomitant medication review 
• 
Adverse event review and evaluation 
• 
Standard of Care Rehabilitation Assessment (to be collected until discharged from 
formal physical therapy) 
 
Intervention Visits 17-32 (For Randomized Participants Only) 
The following study procedures and evaluations will be performed at Visit 17-32 (twice per week 
during Weeks 9-16):  
 
• 
Study Intervention. At Visits 17-32, ECC or placebo will be administered twice per week. 
Study intervention parameters will be recorded by the physical therapist.  
• 
Concomitant medication review 
• 
Adverse event review and evaluation 
• 
Standard of Care Rehabilitation Assessment (to be collected until discharged from 
formal physical therapy) 
 
Testing Visit 2 
The following study procedures and evaluations will be performed at testing visit 2 (post-NMES 
intervention visit):  
 
• 
Height (cm) and weight (kg) 
• 
Adverse event review and evaluation 
• 
Study-specific testing. Specialized measurements will be recorded by study staff 
(post-doctoral fellow, graduate students). Thigh muscle strength and quadriceps 
activation will require the use of a Cybex dynamometer equipped with both an anti-
shear and a knee attachment. Quadriceps/Knee Cartilage ultrasonograpy will be 
used to gather measurements of quadriceps atrophy and femoral cartilage thickness.  
• 
Questionnaires. The PROMIS questionnaire will be administered in order to assess 
participant perceived function. Knee injury and Osteoarthritis Outcome Score is a 
knee-specific measure intended to examine patient reported outcomes after injuries 
that may lead to post-traumatic osteoarthritis, like an ACL injury. Tegner and Marx 
scores will be assessed in order to examine participant’s activity levels. The Tampa 
Scale of Kinesiophobia will be delivered to determine participant’s fear of re-injury.  
• 
For those in the standard of care group – patients will reach the testing visit 2-time point 
when they have completed 16 PT treatments – approximately 2x a week for 8 weeks. 
• 
Special considerations will be made for those with insurance visit limitations such as 
patients will reach testing visit 2 when they have completed 8 PT treatments – 
approximately 1x a week for 8 weeks.  
• 
 
 
Testing Visit 3 

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The following study procedures and evaluations will be performed at testing visit 3  (post-ECC 
intervention visit):  
 
• 
Height (cm) and weight (kg) 
• 
Adverse event review and evaluation 
• 
Study specific testing. Specialized measurements will be recorded by study staff 
(post-doctoral fellow, graduate students). Thigh muscle strength and quadriceps 
activation will require the use of a Cybex dynamometer equipped with both an anti-
shear and a knee attachment. Quadriceps/Knee Cartilage ultrasonograpy will be 
used to gather measurements of quadriceps atrophy and femoral cartilage thickness. 
A muscle biopsy may be gathered to look at markers of inflammation, muscle 
damage, and hypertrophy/ atrophy. Biopsy may also be used for muscle 
phenotyping.  
• 
Questionnaires. The PROMIS questionnaire will be administered in order to assess 
participant perceived function. Knee injury and Osteoarthritis Outcome Score is a 
knee-specific measure intended to examine patient reported outcomes after injuries 
that may lead to post-traumatic osteoarthritis, like an ACL injury. Tegner and Marx 
scores will be assessed in order to examine participant’s activity levels. The Tampa 
Scale of Kinesiophobia will be delivered to determine participant’s fear of re-injury.  
• 
For those in the standard of care group – patients will reach the testing visit 3-time point 
when they have completed 32 total PT treatments – approximately 2x a week for 16 weeks. 
• 
Special considerations will be made for those with insurance visit limitations such as 
patients will reach testing visit 3 when they have completed 16 total PT treatments – 
approximately 1x a week for 16 weeks.  
 
 
Testing Visit 4 
The following study procedures and evaluations will be performed at Testing Visit 4 (Week 36 [9 
months post-ACLR]):  
 
• 
Concomitant medication review 
• 
Height (cm) and weight (kg) 
• 
Adverse event review and evaluation 
• 
Study specific testing. Specialized measurements will be recorded by study staff 
(post-doctoral fellow, graduate students). Thigh muscle strength and quadriceps 
activation will require the use of a Cybex dynamometer equipped with both an anti-
shear and a knee attachment. Biomechanics will be recorded with standard 
procedures using a Vicon motion capture system. Clinical hop tests only require the 
use of a tape measure that will be attached to ground. Quadriceps/Knee Cartilage 
ultrasonograpy will be used to gather measurements of quadriceps atrophy and 
femoral cartilage thickness.  
• 
Questionnaires. The PROMIS questionnaire will be administered in order to assess 
participant perceived function. Knee injury and Osteoarthritis Outcome Score is a 
knee-specific measure intended to examine patient reported outcomes after injuries 
that may lead to post-traumatic osteoarthritis, like an ACL injury. Tegner and Marx 
scores will be assessed in order to examine participant’s activity levels. The Tampa 
Scale of Kinesiophobia will be delivered to determine participant’s fear of re-injury.  
 
Testing Visit 5 

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The following study procedures and evaluations will be performed at Testing Visit 5 (Week 72 
[18 months post-ACLR]):  
 
• 
Concomitant medication review 
• 
Height (cm) and weight (kg) 
• 
Adverse event review and evaluation 
• 
A/P knee X-ray   
• 
Magnetic Resonance Images. MRI images of the involved and uninvolved knees will 
be recorded to assess knee joint cartilage. Scans will be approximately 1 hour in 
length and will take place at University Hospital on the 3T Phillips Research Scanner. 
Positioning and sequences will be described in the MOP.  
• 
Study specific testing. Specialized measurements will be recorded by study staff 
(post-doctoral fellow, graduate students). Thigh muscle strength and quadriceps 
activation will require the use of a Cybex dynamometer equipped with both an anti-
shear and a knee attachment. Biomechanics will be recorded with standard 
procedures using a Vicon MX motion capture system. Clinical hop tests only require 
the use of a tape measure that will be attached to ground. Quadriceps/Knee 
Cartilage ultrasonograpy will be used to gather measurements of quadriceps atrophy 
and femoral cartilage thickness. An optional muscle biopsy may be gathered to look 
at markers of inflammation, muscle damage, and hypertrophy/ atrophy. Biopsy may 
also be used for muscle phenotyping.  
• 
Questionnaires. The PROMIS questionnaire will be administered in order to assess 
participant perceived function. Knee injury and Osteoarthritis Outcome Score is a 
knee-specific measure intended to examine patient reported outcomes after injuries 
that may lead to post-traumatic osteoarthritis, like an ACL injury. Tegner and Marx 
scores will be assessed in order to examine participant’s activity levels. The Tampa 
Scale of Kinesiophobia will be delivered to determine participant’s fear of re-injury.  
 
12 and 15 Month Physical Activity Assessments  
In order to account for physical activity occurring between the 9 and 18 month testing visits, 
study staff will email participants a physical activity assessment questionnaire at 12 and 15 
months post-ACLR. The assessment will include a modified Marx Questionnaire. The Marx 
Questionnaire will be modified to reflect a 3-month period rather than a 12-month period. This 
assessment will also inquire about specific sports/activities that study enrollees are participating 
in.  
 
8.2 SAFETY AND OTHER ASSESSMENTS 
 
Subject Screening: The lead study coordinator, graduate student, or post-doctoral fellow will 
examine medical records prior to approaching patients in clinic regarding enrollment. If the study 
staff finds that a patient meets any of the study exclusion criteria, that patient will not be 
approached for enrollment into the study. If after examining medical records the patient appears 
to be eligible for study enrollment, study staff will approach in clinic, describe the study, and 
determine interest for potential enrollment. If a patient expresses interest in enrollment, they will 
be sent home with the study consent form and study staff will make follow-up contact within 3 
days. During this contact, the staff member will screen subjects using the subject 
inclusion/exclusion criteria case report form to confirm eligibility. If eligibility is confirmed, study 
staff will schedule the first testing visit. The following information will be collected during 
screening:  

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• 
Date of birth  
• 
Injury history 
• 
Type of ACL reconstruction patient will undergo     
• 
Date of scheduled reconstruction surgery.  
 
 

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8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312. 32 (a)).  
 
 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
Serious adverse events (SAE) are defined as any event temporally associated with the subject’s 
participation in research that meets any of the following criteria:  
• 
Results in death; 
• 
Is life-threatening (places the subject at immediate risk of death from the event as it 
occurred); 
• 
Results in inpatient hospitalization or prolongation of existing hospitalization; 
• 
Results in a persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions; 
• 
Results in a congenital anomaly/birth defect; 
• 
Any other adverse event deemed to jeopardize the subject’s health and results in either a 
medical or surgical intervention so as to prevent one of the outcomes listed above.  
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. [Consistent with 21 CFR 312. 32 (a)] 
 
Exclusions to the SAE definition for purposes of this study will include:  
 
• 
Planned admissions to the hospital or elective procedures for pre-existing conditions, which 
occur during the course of study participation, will not be considered as SAEs.  
 
• 
Adverse events which result in admission or observation at a hospital for 23 hours or less, 
will not be considered serious unless they also meet one of the other SAE definition criteria 
(e. g. deemed to jeopardize the subject’s health and results in either a medical or surgical 
intervention.  
 
 EVENTS OF SPECIAL INTEREST 
A graft failure will be considered an Adverse Event of Special Interest (AESI) in the MiACLR trial. Graft failures will 
be diagnosed by the patient’s physician using a combination of objective laxity (e.g. positive pivot shift) and/or MR 
imaging.  Any such diagnosis, whether treated with an ACL reconstruction revision or not, will be characterized as 
an AESI.  A graft failure is being considered as an AESI as the ACL graft could potentially be impacted by the 
interventions of interest in the study.  As such, a higher than suspected number of ACL graft failures in either group 
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unsafe.  It is expected that ~10% of ACL grafts will fail with autograft ACL reconstruction and standard ACL 
rehabilitation. 
 CLASSIFICATION OF AN ADVERSE EVENT  
8.3.4.1 SEVERITY OF EVENT 
 
The intensity of all AEs will be graded using a five-point grading scale in which the following 
descriptions of severity will apply. Note that for some AEs, Grades 4 and/or 5 may not be 
applicable. In those cases only 3 different grades (Grade 1-3) are to be considered:  
 
• 
Mild (Grade 1) – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities.  
• 
Moderate (Grade 2) – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning.  
• 
Severe (Grade 3) – Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. They are medically significant but not 
immediately life-threatening. Of note, the term “severe” does not necessarily equate to 
“serious”.  
• 
Life-threatening (Grade 4) – Events result in life-threatening consequences; urgent 
intervention indicated.  
• 
Fatal (Grade 5) – Events result in death.  
 
8.3.4.2 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 
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.  
 
• 
Definitely Related: The AE is known to occur with the study interventions/procedures, 
follows an obvious sequence of time from the study intervention or procedure, the event 
ceases on discontinuation of the study intervention or procedure (and reoccurs on 
restarting), and/or the event includes data that was only collected for this study 
• 
Probably Related: The AE is lesser known or suspected to occur with the study 
interventions/procedures, follows a reasonable sequence of time from the study 
intervention or procedure, and the event ceases or diminishes with discontinuation of the 
study intervention or procedure.  
• 
Possibly Related: The AE is lesser known or a possible effect of the study 
interventions/procedures, occurs in sequence of time from the study intervention or 
procedure, for which the event may be attributed to the study intervention or procedure, 
and/or the event could be explained by the characteristics of the population of study (i.e. 
young or middle-aged adults, person who have suffered an ACL injury and underwent a 
subsequent ACL reconstruction) 
• 
Unlikely Related: The AE is not a previously known or a suspected effect of the study 
intervention or procedure, does NOT follow a sequence of time from the study 
intervention or procedure, for which the event could be attributed to the administration of 
the study intervention or completion of any study procedure, and/or the event can be 
readily explained by the characteristics of the population under study.  

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• 
Unrelated: The AE is not known to be an effect of the study intervention or procedure, 
does NOT follow a sequence of time from the study intervention or procedure, for which 
the event could be attributed to the administration of the study intervention or completion 
of any study procedure, and/or the event can be readily and easily explained by the 
characteristics of the population under study. An event would also be considered 
unrelated, if a subject never received study drug, study device, or underwent research 
study procedure.  
 
 

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• 
 
 
8.3.4.3 EXPECTEDNESS  
 
The Principal Investigator or designee will be responsible for determining whether an AE is 
expected or unexpected. An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the 
study intervention in the protocol or informed consent.  
 
 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
A consistent methodology for eliciting AEs will be used at all subject evaluation time points that 
includes open-ended questions such as:   
• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new or changed health problems since you were last here?”  
 
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. AEs may also be identified through medical 
record review or through physician evaluation.  
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution.  
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
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.  
 
All reportable events with start dates occurring any time after informed consent is obtained until 
the last study visit (i.e. 18 month study visit). 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 until last study visit. In the event that an AE or SAE occurred at 
the last study visit it would be followed for 7 days (non-serious AEs) or 30 days (serious AEs) 
after said study visit.  
 
8.3.6 ADVERSE EVENT REPORTING  
 
All adverse events (AEs), whether observed by the investigator or reported by the participant, 
are recorded in the study database by study coordinators. For each AE, the date of onset, 
severity, and duration is recorded on the electronic case report form (eCRF). In addition, the 

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investigator or designee will assess whether the AE is serious or not, relationship to study 
intervention, and whether it is expected or not. All AEs will be monitored and followed until they 
are adequately resolved or until the end of the study (i.e. 18 month study visit). All AEs must be 
submitted to the database via the AE eCRF within 72 hours of first knowledge of the event. 
There will be a special form that is completed for serious adverse events; see Section 8. 3. 6 
below.  
 
8.3.7 ADVERSE EVENT OF SPECIAL INTEREST REPORTING 
If a graft failure, the only AESI for the current study, is identified by the study team through patient reporting or 
review of medical records it will be monitored and reported using the guidelines discussed in section 8.3.5.  If the 
graft failure, however, results in an ACL revision reconstruction this would result in an SAE which would be 
monitored and reported as discussed in section 8.3.7.  Whether designated as an AE or an SAE the AESI will be 
flagged and specifically reported to the DSMB providing details regarding the number for each study group, and a 
breakdown of how the AESIs were thought to occur (traumatic or atraumatic).  The AESIs will be followed for 
outcome information until resolution (e.g. date of revision surgery), stabilization (e.g. end of care for the AESI), or 
study completion, with stop dates recorded for resolution. 
8.3.8 SERIOUS ADVERSE EVENT REPORTING  
 
All SAEs will be mapped to system organ classes (SOC) using preferred MedDRA SOC terms, 
graded for severity and relationship to study drugs as detailed above, and recorded with start 
dates occurring any time after informed consent is obtained until 30 days after the last day of 
study participation. At each study visit, the investigator or designee will inquire about the 
occurrence of SAEs since the last visit and study participants, and their significant others will be 
asked in advance to notify the study investigators immediately regarding any hospitalization, 
serious change in their health or in the event of a death. Events will be followed for outcome 
information until resolution or stabilization, with stop dates recorded for resolution.  
 
Regardless of whether the SAE is deemed related to use of the study interventions, the data for 
the SAE must be reported with the appropriate information by the study investigators or their 
designee to the Data Coordinating Center within 24 hours of learning of the event. In addition, 
new follow-up data must be reported within 24 hours of receipt. The designated study medical 
monitor, Tariq Awan, DO, or designee may be contacted at any time for immediate discussion 
regarding such an event.  
 
Hospitalizations for the following reason, which are not related to an AE, do not require 
reporting:  
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
preexisting conditions.  
When recording a death, the event, or condition that caused or contributed to the fatal outcome 
should be reported as the single medical concept. If the cause of death is unknown and cannot 
be ascertained at the time of reporting, the report will be identified as an “Unexplained Death”.  
Investigators must report all SAEs to their governing IRB/IEC, as required by local regulations 
and guidelines.  

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A record of all SAEs, by study subject and preferred SOC terms will be recorded centrally by the 
DCC.  
 
8.3.9 REPORTING EVENTS TO PARTICIPANTS  
 
We will notify participants of any safety information that modifies the risk profile and may change 
their willingness to continue in the study. Changes in risk profile or study design affecting 
participant  safety will be address via protocol amendment. This information would be reviewed 
with active subjects who would be asked to sign the amended consent to continue study 
participation.  
 
 
 

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8.3.10 REPORTING OF PREGNANCY  
 
If a participant were to report a pregnancy during the study period the interventions would be 
stopped and follow-up would be discontinued.  
 
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.  
 
This definition could include an unanticipated adverse device effect, any serious adverse effect 
on health or safety or any life-threatening problem or death caused by, or associated with, a 
device, if that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of subjects (21 CFR 812. 3(s)).  
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review 
Board (IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP 
report will include the following information:  
 
• 
Protocol identifying information:  protocol title and number, PI’s name, and the IRB 
project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP.  
 
 
 

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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 and to the 
DCC/study sponsor within 24 hours of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 7 days of 
the investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures).  
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
If an unanticipated problem occurs that places a participant at greater risk than originally 
anticipated, participants will be notified. Changes in risk profile or study design affecting 
participant safety will be address via protocol amendment. This information would be reviewed 
with active subjects who would be asked to sign the amended consent to continue study 
participation.  
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 STATISTICAL HYPOTHESES 
The primary hypothesis is that quadriceps strength symmetry will be greater with the 
combination of NMES and ECC relative to the placebos at both 9 months and 18 months post-
ACLR. Statistically, the following null and alternative hypotheses will test the superiority of the 
combination of NMES + ECC versus placebo arm in the change from baseline to 9 months and 
18 months post-ACLR in isokinetic quadriceps strength symmetry index separate analyses:  
 
H01: Δ9mo NMES + ECC ≤ Δ9mo NMES placebo + ECC placebo 
HA1: Δ9mo NMES + ECC > Δ9mo NMES placebo + ECC placebo 
H06: Δ18mo NMES + ECC ≤ Δ18mo NMES placebo + ECC placebo 
HA6: Δ18mo NMES + ECC > Δ18mo NMES placebo + ECC placebo 
 
where Δ reflects the adjusted mean change from baseline at 9 or 18 months post-ACLR in 
isokinetic quadriceps strength symmetry index.  
 
9.2 SAMPLE SIZE DETERMINATION 
 
For the main study objectives, the sample size of 112 participants (56 per each of the 2 
treatment groups ) allows sufficient power to test the primary hypotheses regarding two 
separate comparisons (each co-primary endpoint) of the combination NMES + ECC vs NMES 
placebo + ECC placebo. Each test will be conducted using a two-sided 0. 025 Type I error level 
(=0. 05/2, the Bonferroni adjustment for two comparisons). We hypothesize that the effect size 
(treatment difference / standard deviation) will be at least 0. 7 for the tests of NMES + ECC vs 
NMES placebo + ECC placebo. Assuming 20% drop-out (resulting in an effective sample size of 
45 per group), we have at least 80% power to detect this effect size. Preliminary data from the 

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same site with a comparable patient population and primary endpoint demonstrated a 1. 14 
effect size. Because of the small sample size and variability in measurements in this preliminary 
study, we conservatively reduced the effect size for this study. 35  
An additional cohort of 28 participants will be studied – the SOC control group. The sample size 
of 28 participants for this group is based on feasibility considerations.  
Thus, the total sample size for the trial is 140 participants.  
 
9.3 POPULATIONS FOR ANALYSES 
 
Several analysis sets will be used in analyses:  
• 
The main population for efficacy will be the modified intention-to-treat population (mITT), 
defined as all participants randomized and receiving at least one study intervention. 
Subjects will be analyzed by assigned treatment.  
• 
A second analysis set will be used to assess the robustness of the primary conclusions in 
the subset of participants in the mITT analysis set. This set contains participants who 
complied with the protocol sufficiently to ensure that these data would be likely to represent 
the effect of treatment according to the underlying scientific model. The Per Protocol (PP) 
analysis set will consist of all subjects in the mITT population who do not have a major 
protocol violation, inclusive of violation of entry criteria.  
The Safety Population is defined as all participants who are randomized and receive at least 
study intervention. The Safety Population will be used for all safety analyses. Subjects will 
be analyzed by assigned treatment.  
• 
All participants in the SOC control group will be included in the exploratory analyses.  
 
9.4 STATISTICAL ANALYSES 
 
A statistical analysis plan (SAP) will be written for the study that contains detailed descriptions 
of the analyses to be performed. The SAP will be finalized prior to the database lock and 
unblinding of the data. The approach to analyses affected by the COVID-19 or other pandemic 
crisis will be described in the SAP along with the analyses for the exploratory objective.  
 
9.4.1 GENERAL APPROACH 
 
The design of this randomized controlled study is a placebo-controlled investigation of the 
combination of NMES and ECC vs NMES placebo + ECC placebo. Continuous variables will be 
summarized using descriptive statistics including n, mean, median, standard deviation, range (e. 
g. , minimum and maximum). Qualitative variables will be summarized using counts and 
percentages. Summaries will be provided by treatment group and overall. Unless otherwise 
specified, statistical analyses will be performed using SAS Version 9 or higher. For the co-
primary endpoints, the nominal significance level is 0. 025 (two-sided test with a Bonferroni 
adjustment for two comparisons); for all other statistical tests, the nominal significance level is 0. 
05 (two-sided). p-values and confidence intervals will be reported.  
 
Linear models will be used for most analyses (primary and key secondary endpoints that are 

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continuous), with terms for treatment group, type of graft, surgeon, age, gender and baseline in 
all models.  
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINTS  
 
The primary hypotheses will be tested at the two-sided 0. 025 level, adjusting for the multiple 
comparisons of 2 co-primary endpoints. Separate linear models will be fit for each of the two co-
primary endpoints, one for the 9-month and one for the 18-month changes from baseline in 
isokinetic quadriceps muscle strength. As described above, the model will include treatment 
group, type of graft, surgeon, age, gender, and baseline isokinetic quadriceps strength 
symmetry index. Least-squares (LS) mean change from baseline, along with associated 
standard errors, will be presented for each intervention group. For the comparisons of 
combination NMES + ECC to the placebo group, group LS mean differences in the change from 
baseline will be presented, along with associated 97. 5% upper confidence bounds and p-
values. The primary analysis of the primary endpoints will use the mITT analysis set. A 
secondary analysis of the primary endpoints will use the PP analysis set. Appropriate non-linear 
parametric or non-parametric tests may be applied if the assumptions of the model are not 
satisfied. Details will be presented in the SAP.  
 
Assessment of the extent of missing data and its mechanism will be explored for the primary 
endpoints using the mITT analysis set. Graphical and numerical descriptive methods will be 
used to summarize and the primary outcome over time by intervention group and overall. We 
will begin by assuming missing at random, and employ multiple imputation methods45,46 to 
handle missing data. Other more complicated methods may be employed if there are concerns 
about differential follow-up and nonignorable missing (where the stochastic process that 
generates missingness is explicitly modeled such as a pattern mixture model47) as a sensitivity 
analysis. The model will include the same covariates that are included in the primary analysis.  
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
All tests of secondary endpoints (e. g. , T1 relaxation ratio at 18 months post-ACL, score on 
KOOS at 9 months post-ACLR) will be conducted at the two-sided 0. 05 level, without 
adjustment for multiplicity, using comparable models as for the primary endpoints. The mITT 
analysis set will be used. Appropriate non-linear parametric or non-parametric tests may be 
applied if the assumptions of the model are not satisfied. Details will be presented in the SAP.  
 
In addition, for endpoints used to assess secondary objective 1 (i. e,. T1 relaxation ratio at 18 
months post-ACL and T2 relaxation ratio at 18 months post-ACL), we will include articular 
cartilage injury and meniscus injury and treatment as covariates in the linear model.  
 
9.4.4 SAFETY ANALYSES 
 
Safety analyses will be performed on the safety analysis set. Safety data, including frequency of 
events and proportion of participants experiencing events (e. g. , serious adverse events, 
adverse events leading to early discontinuation of study intervention), will be summarized 
descriptively overall and by treatment group. For categorical safety outcomes, numbers and 
percentages will be used. For continuous safety outcomes, number, mean, standard deviation, 
median, interquartile range, minimum and maximum will be used to summarize changes from 
baseline to each study visit in vital signs.  

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9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
The treatment groups will be compared descriptively with respect to demographic and baseline 
variables (e. g. , age, race, quadriceps strength symmetry index). No statistical tests will be 
used to compare the treatment groups. In addition, graphical and numerical descriptive methods 
will be used to summarize demographic and baseline characteristics by intervention group and 
overall.  
 
9.4.6 PLANNED INTERIM ANALYSES  
 
Not applicable. There will be one final analysis that will occur after the last participant’s last visit 
and the database is locked and unblinded.  
 
9.4.7 SUB-GROUP ANALYSES 
 
Age at time of ACLR and BMI are other biological factors that can influence ACLR outcomes 
and thus will be considered as covariates and adjusted for in our analyses, as described above. 
Evaluation of model diagnostics will be included to avoid over-fitting because of the number of 
parameters that are being assessed.  
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Key efficacy and safety data will be listed by individual participant. Details will be in the SAP.  
 
9.4.9 EXPLORATORY ANALYSES 
  
Several planned exploratory analyses will be conducted:  
• 
For the primary endpoints, we will incorporate articular cartilage injury and meniscus 
injury and treatment as covariates in the linear model, with attention to fit statistics to 
avoid over-fitting.  
• 
For endpoints used to assess the secondary objective 1 (i.e. , T1 relaxation ratio at 18 
months post-ACL and T2 relaxation ratio at 18 months post-ACL), we will also explore 
activity during the return to activity period, activity level prior to injury, BMI and other 
interaction effects to assess effect modification, with caution to avoid over-fitting 
• 
We will also examine the ability of quadriceps strength at 9 months post-ACLR to predict 
changes in cartilage health at 18 months post-ACLR. To do this we will employ linear 
models with several parameterizations of strength (e. g. , continuous, quartiles, binary 
threshold), assessing the discrimination and calibration for the prognostic models (will 
include other potential factors in addition to 9-month post-ACLR strength). Additional 
relationships among variables, such as the correlation of T2 and T1rho MRI measures of 
OA to X-ray measure of OA, will be explored graphically, summarized descriptively, and 
modeled using multivariable linear or logistic models.  
• 
We will examine change in quadriceps muscle strength and muscle volume from 
baseline to post-NMES intervention (testing visit 2) and post-ECC intervention (testing 
visit 3) in an attempt to understand the effects of the individual components of the 
combined NMES+ECC intervention.  
 
Several exploratory analyses will be performed to assess the ability to reduce the NMES and 

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ECC intensity in the placebo treatment group so that it reflects a “true” placebo condition. The 
SOC control group is a group of participants who were eligible for the randomized controlled trial 
but refused and were willing to consent to an observational arm.  
Specifically, 
• 
The demographic and baseline variables will be summarized in the SOC control group 
(no NMES or ECC treatment) using equivalent tabular and graphical methods to those 
described in Section  9. 4. 5.  
• 
The co-primary and key secondary endpoints will be summarized in the SOC control 
group for all observed cases.  
 
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 
 
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 consent materials are submitted with this 
protocol. There is a separate consent document for those who wish to be randomized, and 
those that do not (SOC Control Consent).  
 
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 or designee 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.  
 
 
Participants that are under the age of 18 will be asked to sign an assent form (in this study the 
consent form is the same form as the assent form) following the same procedures listed above. 

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In addition to the minor signing the consent form, one parent/legal guardian of the minor will be 
required to consent to participation.  
  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 study participants, 
investigator, and funding agency. If the study is prematurely terminated or suspended, the 
Principal Investigator (PI) or designee 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 
 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). ] 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigator, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover all 
types of tests (e. g. , MRI, X-rays) in addition to 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 
third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible.  
 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying 
study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records 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 at each clinical site 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, whichever is longer.  
 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the University of Michigan. This will not include the 

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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 the University of Michigan research staff will be secured and 
password protected. At the end of the study, all study databases will be de-identified and 
archived at the University of Michigan.  
 
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 the University of Michigan. No 
biological specimens will be collected for this study.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE  
 
The Principal Investigator, Dr. Riann Palmieri-Smith, is responsible for the overall management 
and day-to-day operational oversight for the MiACLR study. She will be supported by the 
University of Michigan Statistical Analysis of Biomedical and Educational Research (SABER) 
Data Coordinating Center, under the direction of Dr. Cathie Spino, which is responsible for data 
collection, monitoring, and statistical activities. Dr. Palmieri-Smith and the SABER group will 
meet routinely throughout the study to administratively direct and monitor the progress of the 
clinical trial and to respond to any design, implementation or administrative issues that arise 
during the study 
 
 
10.1.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) 
composed of individuals with the appropriate expertise, including orthopaedics, physical 
therapy, and statistical/data analysis. Members of the DSMB should be independent from the 
study conduct and free of conflict of interest, or measures should be in place to minimize 
perceived conflict of interest. The DSMB will meet at least semiannually to assess safety and 
efficacy data on each arm of the study. The DMSB will operate under the rules of an approved 
charter that will be written and reviewed at the organizational meeting of the DSMB. At this time, 
each data element that the DSMB needs to assess will be clearly defined. The DSMB will 
provide its input to the National Institute of Child Health and Human Development.  
 
 

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10.1.7 CLINICAL MONITORING 
 
Throughout the course of the study, data will be monitored for accuracy and completeness and 
study procedures will be monitored for adherence to the protocol and Good Clinical Practices 
(GCP). In addition to frequent contacts through e-mail and telephone, on-site monitoring visits 
will be coordinated by the Statistical Analysis of Biomedical and Educational Research (SABER) 
unit at the University of Michigan. SABER (the Data Coordinating Center for this study) will be 
responsible for operational aspects and monitoring of the trial, including at least annual 
monitoring visits and/or remote source data verification.  
The clinical monitor will ensure that:  
• 
Data collected and entered into the database are verifiable against source documents 
for the participants. The clinical monitor will need access to subject medical records and 
other study-related records needed to verify the entries on the electronic case report 
forms.  
• 
Appropriate consent is obtained for each participant prior to study procedures.  
• 
The rights and well-being of participants are being protected.  
• 
The study is conducted in accordance with the currently approved protocol (including 
study treatment being used in accordance with the protocol), with any other study 
agreements, with GCP and with applicable regulatory requirements.  
• 
Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). 
The CMP describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and the 
distribution of monitoring reports.  
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
DCC staff will prepare a data management plan. The data management plan will describe the 
front-and back-end edit checks, as well as forms tracking procedures, that will be implemented 
to ensure timely and high-quality data collection. It will also define the periodic reports that will 
be shared with site coordinators and PIs that summarize site performance. The data 
management procedures will be consistent with the International Conference on Harmonisation 
(ICH E6) standards for Good Clinical Practice (GCPs).  
Monitoring of site performance will be carried out under the direction of the DCC. The Executive 
Committee will meet approximately monthly to review enrollment and retention reports, interval 
AEs and SAEs, compliance with the interventions, protocol compliance including interval study 
withdrawals, and delinquency reports as available.  
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
Comprehensive data coordinating center (DCC) functions for this clinical trial, including 
database development, web-based data entry and management, as well as the creation and 
export of study reports for the DSMB will be provided by the University of Michigan Statistical 

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Analysis of Biomedical and Education Research (SABER) group. Housed in the top nationally 
ranked Department of Biostatistics, SABER, in its 17-year existence, has served as the DCC for 
over 50 studies, including multiple NIH-sponsored networks.  
The DCC will use OpenClinica® (OpenClinica Clinical Trial Software; OpenClinica, LLC, 
Waltham, MA), a clinical trial software platform for electronic remote (i.e., site-based entry) data 
capture and clinical data management, as the basis for our custom-designed data entry and 
management system. The majority of data will be collected via electronic Case Report Forms 
(CRFs); however, other data sources, such as laboratory data from the central laboratory, may 
be used. In these circumstances, the DCC will also utilize electronic data transfer. Protocols for 
the transfer of data, with careful attention to data integrity, will be written by experienced 
programmers and stored in the OpenClinica database or data mart.  
The DCC has established a set of standard operating procedures (SOPs) governing the 
processes used to ensure patient privacy and data confidentiality, including the use of 
anonymous participant IDs on CRFs and in reports. OpenClinica® enables compliance with 
Good Clinical Practice (GCP) and regulatory requirements by providing differentiated user roles 
and privileges, password and user authentication security, electronic signatures, SSL 
encryption, and comprehensive auditing to record and monitor access and data changes.  
 
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 site PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. In addition to the protocol, Dr. Palmieri-Smith will prepare a 
Manual of Operations will provides additional detail on data collection procedures, including 
source documentation, eCRF completion guidelines, data handling procedures and procedures 
for data monitoring and quality control that ensure these data are accurate, consistent, complete 
and reliable and in accordance with ICH 36.  
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  
 
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. Data recorded in the 
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) and clinical laboratory data will be entered into OpenClinica a 21 CFR Part 11-
compliant data capture system provided by the Data coordinating Center 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 Harmonisation (ICH) region and until 

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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 sponsor, if 
applicable. It is the responsibility of the sponsor 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, GCP, or MOP 
requirements. The noncompliance may be either on the part of the participant, the investigator, 
or the study site staff. It is the responsibility of the site to use continuous vigilance to identify and 
report deviations within 5 working days of identification of the protocol deviation or scheduled 
protocol-required activity. The DCC will summarize protocol deviations in site performance. As a 
result of deviations, corrective actions are to be developed by the site and implemented 
promptly.  
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations:  
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication.  
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results 
information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be 
made to publish results in peer-reviewed journals. Data from this study may be requested from 
other researchers 2 years after the completion of the primary endpoint by contacting Riann 
Palmieri-Smith, PhD, ATC.  
 
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 NICHD 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.  
 

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10.2 ADDITIONAL CONSIDERATIONS 
 
There are no additional considerations identified at this time.  
 
 
10.3 ABBREVIATIONS 
 
The list below includes abbreviations utilized in this template. However, this list should be 
customized for each protocol (i.e. , abbreviations not used should be removed and new 
abbreviations used should be added to this list).  
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ACL 
Anterior Cruciate Ligament 
ACLR 
Anterior Cruciate Ligament Reconstruction 
A/P 
Anterior/Posterior 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
ECC 
Eccentric Exercise 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
KOOS 
Knee Injury and Osteoarthritis Outcome Score 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 

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MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
MVIC 
Maximum Voluntary Isometric Contraction 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
NMES 
Neuromuscular electrical stimulation 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TSK-11 
Tampa Scale of Kinesiophobia  
UP 
Unanticipated Problem 
US 
United States 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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