Prevention of Skeletal Muscle Adaptations to Traumatic Knee Injury and Surgery
Phase: PHASE1
Conditions: Anterior Cruciate Ligament Reconstruction
Sponsor: University of Vermont

 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Protocol 
 
 
Project Title: 
Version Date: 
Prevention of skeletal muscle adaptations to traumatic knee 
injury and surgery 
7-2-19 
 
 
NCT number:
NCT02945553
Principal 
Investigator 
(contact):  
Michael J. Toth 
Principal 
Investigator:  
Bruce D. Beynnon 
Grant Sponsor:
NIAMS R21 AR069199
 
 

 
 
Summary 
Injury to the knee joint and its associated soft tissues, such as the anterior cruciate ligament (ACL) and 
menisci, is common and highly debilitating. Surgical treatment improves knee biomechanics and 
function, but muscle weakness often persists for years despite rehabilitation, hindering resumption of 
normal activities, increasing risk of further injury and, in a majority of patients, accelerating the 
development of post-traumatic knee osteoarthritis (PTOA). The time interval from injury through the 
early, post-surgical period is critical for the development of functional deficits, as trauma from the injury 
and surgery combine with muscle disuse to reduce skeletal muscle size and function. Rather than 
attempt to remediate these adaptations after they occur, which is marginally successful, a more 
proactive approach that prevents these adaptations from developing may yield better long-term 
functionality and, in turn, improve clinical and patient-reported outcomes. The post-injury and early, 
post-surgical periods, however, are not amenable to classic rehabilitation strategies, requiring 
development of new rehabilitative approaches. To address these gaps in clinical treatment options early 
following ACL injury and surgical repair, our goals in this project are to: 1) to evaluate the utility of 
neuromuscular electrical stimulation (NMES), begun early following knee injury and maintained through 
the early, post-surgical period, to prevent muscle atrophy and intrinsic contractile dysfunction. Our 
rationale for these studies is that prevention of skeletal muscle fiber atrophy and intrinsic contractile 
dysfunction will maintain whole muscle functionality in the injured leg, as these cellular indices are 
fundamental determinants of whole muscle function. Accordingly, the effect of NMES to maintain whole 
muscle function may reduce the risk for re-injury and PTOA progression, as well as improve patient-
reported outcomes. To accomplish our goals, patients with traumatic knee injury will be randomized to 
our current standard of care rehabilitation or rehabilitation plus early use of NMES or a sham NMES, 
with measurements of skeletal muscle structure and function at the whole body, tissue and cellular 
levels, as well as patient-reported outcomes. NMES will begin shortly following injury (within 3 wks) and 
run till 3 wks post-surgery, with volunteers being evaluated twice pre-surgery and then at 3 wks and 6 
mos  post-surgery for muscle size, function, clinical and patient-oriented outcomes and deterioration of 
knee joint cartilage. Primary outcomes of muscle fiber size and function will be measured from tissue 
acquired from skeletal muscle biopsies at 3 wks post-surgery from both the injured and non-injured 
legs. If successful, our results could shift conventional thinking/clinical practice in this field to emphasize 
the need for early rehabilitative interventions to prevent skeletal muscle atrophy and dysfunction. 
Moreover, our data will provide important preliminary data to set the stage for development of a 
randomized, controlled clinical trial to more adequately test the utility of NMES to prevent the 
progression of PTOA.
 
 
Purpose:  
Literature Cited 
1. 
Beynnon, B. D., Vacek, P. M., Newell, M. K., Tourville, T. W., Smith, H. C., Shultz, S. J., Slauterbeck, J. R., and 
Johnson, R. J. (2014) The effects of level of competition, sport, and sex on the incidence of first-time noncontact 
anterior cruciate ligament injury. Am J Sports Med 42, 1806-1812 
2. 
Griffin, L. Y., Albohm, M. J., Arendt, E. A., Bahr, R., Beynnon, B. D., DeMaio, M., Dick, R. W., Engebretsen, L., 
Garrett, W. E., Hannafin, J. A., Hewett, T. E., Huston, L. J., Ireland, M. L., Johnson, R. J., Lephart, S., Mandelbaum, B. 
R., Mann, B. J., Marks, P. H., Marshall, S. W., Myklebust, G., Noyes, F. R., Powers, C., Shields, C., Shultz, S. J., 
Silvers, H., Slauterbeck, J., Taylor, D. C., Teitz, C. C., Wojtys, E. M., and Yu, B. (2006) Understanding and preventing 
noncontact anterior cruciate ligament injuries: a review of the Hunt Valley II Meeting. Am J Sports Med 34, 1512-1532 
3. 
Palmieri-Smith, R. M., Thomas, A. C., and Wojtys, E. M. (2008) Maximizing quadriceps strength after ACL 
reconstruction. Clin Sport Med 27, 405-424 
4. 
Paterno, M. V., Rauh, M. J., Schmitt, L. C., Ford, K. R., and Hewett, T. E. (2014) Incidence of second ACL injuries 2 
years after primary ACL reconstruction and return to sport. Am J Sports Med 42, 1567-1573 
5. 
DiStasi, S., Myer, G. D., and Hewett, T. E. (2013) Neuromuscular training to target deficits associated with second 
anterior cruciate ligament injury. J Orthop Sports Phys Ther 43, 777-A711 
6. 
Lohmander, L. S., Englund, P. M., Dahl, L. L., and Roos, E. M. (2007) The long-term consequence of anterior cruciate 
ligament and meniscus injuries: osteoarthritis. Am J Sports Med 35, 1756-1769 
7. 
Ajuied, A., Wong, F., Smith, C., Norris, M., Earnshaw, P., Back, D., and Davies, A. (2014) Anterior cruciate ligament 
injury and radiologic progression of knee osteoarthritis: a systematic review and meta-analysis. Am J Sports Med 42, 
2242-2252 
8. 
Keays, S. L., Newcombe, P. A., Bullock-Saxton, J. E., Bullock, M. I., and Keays, A. C. (2010) Factors involved in the 
development of osteoarthritis after anterior cruciate ligament surgery. Am J Sports Med 38, 455-463 
9. 
Hart, J., Turman, K., Diduch, D., Hart, J., and Miller, M. (2011) Quadriceps muscle activation and radiographic 

osteoarthritis following ACL revision. Knee Surg Sports Traumatol Arthrosc 19, 634-640 
10. 
Tourville, T. W., Naud, S., Slauterbeck, J. S., Johnson, R. J., and Beynnon, B. D. (2014) Relationship between 
isokinetic strength and tibiofemoral joint space width changes following ACL reconstruction. Am J Sports Med 42, 302-
311 
11. 
Beynnon, B. D., Johnson, R. J., Abate, J. A., Fleming, B. C., and Nichols, C. E. (2005) Treatment of anterior cruciate 
ligament injuries, Part I. Am J Sports Med 33, 1579-1602 
12. 
Beynnon, B. D., Johnson, R. J., Abate, J. A., Fleming, B. C., and Nichols, C. E. (2005) Treatment of anterior cruciate 
ligament injuries, Part 2. Am J Sports Med 33, 1751-1767 
13. 
Beynnon, B. D., Johnson, R. J., Naud, S., Fleming, B. C., Abate, J. A., Brattbakk, B., and Nichols, C. E. (2011) 
Accelerated versus nonaccelerated rehabilitation after anterior cruciate ligament reconstruction: a prospective, 
randomized, double-blind investigation evaluating knee joint laxity using roentgen stereophotogrammetric analysis. 
Am J Sports Med 39, 2536-2548 
14. 
Ingelsrud, L. H., Granan, L.-P., Terwee, C. B., Engebretsen, L., and Roos, E. M. (2015) Proportion of patients 
reporting acceptable symptoms or treatment failure and their associated KOOS values at 6 to 24 months after anterior 
cruciate ligament reconstruction: a study from the Norwegian Knee Ligament Registry. Am J Sports Med 43, 1902-
1907 
15. 
Jarvela, T., Kannus, P., Latvala, K., and Jarvinen, M. (2002) Simple measurements in assessing muscle performance 
after an ACL reconstruction. Int J Sports Med 23, 196-201 
16. 
Lautamies, R., Harilainen, A., Kettunen, J., Sandelin, J., and Kujala, U. M. (2008) Isokinetic quadriceps and hamstring 
muscle strength and knee function 5 years after anterior cruciate liagment reconstruction: comparison between bone-
paterllar tendon-bone and hamstring autografts. Knee Surg Sports Traumatol Arthrosc 16, 1009-1016 
17. 
Palmieri-Smith, R. M., and Abbey, T. C. (2009) A neuromuscular mechanism of posttraumatic osteoarthritis associated 
with ACL injury. Exerc Sport Sci Rev 37, 147-153 
18. 
Hart, J. M., Bietrosimone, B., Hertel, J., and Ingersoll, C. D. (2010) Quadriceps activation following knee injuries: a 
systematic review. J Athl Train 45, 87-97 
19. 
Callahan, D. M., Miller, M. S., Sweeny, A. P., Tourville, T. W., Slauterbeck, J. R., Savage, P. D., Maughan, D. W., 
Ades, P. A., Beynnon, B. D., and Toth, M. J. (2014) Muscle disuse alters skeletal muscle contractile function at the 
molecular and cellular levels in older adult humans in a sex-specific manner. J Physiol 592, 4555-4573 
20. 
Callahan, D. M., Tourville, T. W., Miller, M. S., Hackett, S. B., Sharma, H., Cruickshank, N. C., Slauterbeck, J. R., 
Savage, P. D., Ades, P. A., Maughan, D. W., Beynnon, B. D., and Toth, M. J. (2015) Chronic disuse and skeletal 
muscle structure in older adults: sex differences and relationships to contractile function. Am J Physiol Cell Physiol 
308, C932-C943 
21. 
Suetta, C., Frandsen, U., Jensen, L., Jensen, M. M., Jespersen, J. G., Hvid, L. G., Bayer, M., Petersson, S. J., 
Schrøder, H. D., Andersen, J. L., Heinemeier, K. M., Aagaard, P., Schjerling, P., and Kjaer, M. (2012) Aging affects 
the transcriptional regulation of human skeletal muscle disuse atrophy. PLoS ONE 7, e51238 
22. 
Beynnon, B. D., Fleming, B. C., Johnson, R. J., Nichols, C. E., Renström, P. A., and Pope, M. H. (1995) Anterior 
cruciate ligament strain behavior during rehabilitation exercises in vivo. Am J Sports Med 23, 24-34 
23. 
Lieber, R. L., Silva, P. D., and Daniel, D. M. (1996) Equal effectiveness of electrical and volitional strength training for 
quadriceps femoris muscles after anterior cruciate ligament surgery. J Orthop Res 14, 131-138 
24. 
Laufer, Y., and Snyder-Mackler, L. (2010) Response of male and female subjects after total knee arthroplasty to 
repeated neuromuscular electrical stimulation of the quadriceps femoris muscle. Am J Phys Med Rehabil 89, 464-472 
25. 
Gibson, J. N. A., Smith, K., and Rennie, M. J. (1988) Prevention of disuse muscle atrophy by means of electrical 
stimulation: maintenance of protein synthesis. Lancet 332, 767-770 
26. 
Dirks, M. L., Wall, B. T., Snijders, T., Ottenbros, C. L. P., Verdijk, L. B., and van Loon, L. J. C. (2013) Neuromuscular 
electrical stimulation prevents muscle disuse atrophy during leg immobilization in humans. Acta Physiol 210, 628-641 
27. 
Maffiuletti, N. A., Zory, R., Miotti, D., Pellegrino, M. A., Jubeau, M., and Bottinelli, R. (2006) Neuromuscsular 
adaptations to electrostimulation resistance training. Arch Phys Med Rehabil 85, 167-175 
28. 
Petterson, S. C., Mizner, R. L., Stevens, J. E., Raisis, L., Bodenstab, A., Newcomb, W., and Snyder-Mackler, L. (2009) 
Improved function from progressive strengthening interventions after total knee arthroplasty: A randomized clinical trial 
with an imbedded prospective cohort. Arthritis Care  Res 61, 174-183 
29. 
Lepley, L. K., Wojtys, E. M., and Palmieri-Smith, R. M. (2015) Combination of eccentric exercise and neuromuscular 
electrical stimulation to improve quadriceps function post-ACL reconstruction. Knee 22, 270-277 
30. 
Imoto, A. M., Peccin, S., Almeida, G. J., Saconato, H., and Atallah, A. N. (2011) Effectiveness of electrical stimulation 
on rehabilitation after ligament and meniscal injuries: a systematic review. Sau Paulo Med J 129, 414-423 
31. 
Kim, K. M., Croy, T., Hertel, J., and Saliba, S. (2010) Effects of neuromuscular electrical stimulation after anterior 
cruciate ligament reconstruction on quadriceps strength, function, and patient-oriented outcomes : a systematic 
review. J Orthop Sports Phys Ther 40, 383-391 
32. 
Hasegawa, S., Kobayashi, M., Arai, R., Tamaki, A., Nakamura, T., and Moritani, T. (2011) Effect of early 
implementation of electrical muscle stimulation to prevent muscle atrophy and weakness in patients after anterior 
cruciate ligament reconstruction. J Electromyogr Kinesiol 21, 622-630 
33. 
Hortobagyi, T., and Maffiuletti, N. A. (2011) Neural adaptations to electrical stimulation strength training. Eur J Appl 
Physiol 111, 2439-2449 
34. 
Miyatani, M., Kanehisa, H., Ito, M., Kawakami, Y., and Fukunaga, T. (2004) The accuracy of volume estimates using 
ultrasound muscle thickness measurements in different muscle groups. Eur J Appl Physiol 91, 264-272 
35. 
Harridge, S. D. R., Bottinelli, R., Canepari, M., Pellegrino, M. A., Reggiani, C., Esbjornsson, M., and Saltin, B. (1996) 
Whole-muscle and single-fibre contractile properties and myosin heavy chain isoforms in humans. Pflugers Arch-Eur J 
Physiol 432, 913-920 
36. 
Korhonen, M. T., Cristea, A., Alén, M., Häkkinen, K., Sipilä, S., Mero, A., Viitasalo, J. T., Larsson, L., and Suominen, 
H. (2006) Aging, muscle fiber type, and contractile function in sprint-trained athletes. J Appl Physiol 101, 906-917 
37. 
Andernord, D., Karlsson, J., Musahl, V., Bhandari, M., Fu, F. H., and Samuelsson, K. (2013) Timing of surgery of the 

anterior cruciate ligament. Arthroscopy 29, 1863-1871 
38. 
Shaarani, S. R., O’Hare, C., Quinn, A., Moyna, N., Moran, R., and O’Byrne, J. M. (2013) Effect of prehabilitation on the 
outcome of anterior cruciate ligament reconstruction. Am J Sports Med 41, 2117-2127 
39. 
Eitzen, I., Moksnes, H., Snyder-Mackler, L., and Risberg, M. A. (2010) A progressive 5-week exercise therapy 
program leads to significant improvement in knee function early after anterior cruciate ligament injury. J Orthop Sports 
Phys Ther 40, 705-721 
40. 
Grindem, H., Granan, L. P., Risberg, M. A., Engebretsen, L., Snyder-Mackler, L., and Eitzen, I. (2015) How does a 
combined preoperative and postoperative rehabilitation programme influence the outcome of ACL reconstruction 2 
years after surgery? A comparison between patients in the Delaware-Oslo ACL Cohort and the Norwegian National 
Knee Ligament Registry. Br J Sports Med 49, 385-389 
 
 
Objectives:   
Our primary goal is to evaluate the utility of NMES, begun early following knee injury and maintained 
through the early, post-surgical period, to prevent muscle atrophy and intrinsic contractile dysfunction. 
Prevention of skeletal muscle fiber atrophy and intrinsic contractile dysfunction will maintain whole 
muscle functionality in the injured leg (secondary goal), as these cellular indices are fundamental 
determinants of whole muscle function. Our rationale is that effects of NMES to maintain whole muscle 
function will reduce the risk for re-injury and PTOA progression, as well as improve patient-reported 
outcomes. Two aims are proposed: 
 
 
Primary Aim: To define the effect of early use of NMES during the post-injury and early, post-
surgery periods on adaptations in skeletal muscle fiber size and function in patients with 
traumatic knee injury. 
Hypothesis:  Early implementation of NMES will prevent or diminish skeletal muscle fiber 
atrophy and intrinsic contractile dysfunction. 
 
Secondary Aim: To examine whether early NMES improves whole muscle function at short-
term follow-up.  
Hypothesis: Early NMES will improve whole skeletal muscle isokinetic contractile function. 
 
 
Study Design:
Patients with recent, unilateral ACL rupture or combined ACL rupture/meniscus injury, who are 
undergoing surgical reconstruction, will be recruited and randomized to active NMES or control 
(placebo) interventions, with stratification for age, sex and graft type (knee extensor autograft, knee 
flexor autograft or allograft). All personnel performing assessments on patients/tissue will be blinded to 
group assignment. A within-subject design will be used, where the injured, surgically-treated leg will be 
compared to the contralateral, uninjured leg. NMES or control interventions will begin shortly following 
injury (within 3 wks) and run till 3 wks post-surgery. Patients will be evaluated twice pre-surgery and 
then at 3 wks and 6 mos post-surgery. There is the possibility for an additional visit prior to Pre-Surgery 
Testing #1 to assure that we consent volunteers and start the NMES/control intervention prior to 3 week 
post-injury. We will make every attempt to limit this  
Pre-surgery testing #1 (within 3 wks of injury) will consist of clinical/patient-oriented assessments 
(IKDC, KOOS) and functional testing (uninjured leg only).  
Consent/Device Training Visit will occur within 3 wks of injury to begin the NMES/control intervention if 
the Pre-surgery testing #1 visit cannot be scheduled within this time constraint. Volunteers will be 
consented and will undergo training in the use of the NMES or control intervention (detailed below). 
NMES/Control intervention will begin within 3 wks of injury following pre-surgery testing, with patients 
randomized (1:1). Active NMES intervention will consist of active NMES 5 d per week, with each session 
lasting 60 min. For the control intervention, volunteers will receive a sham NMES device to maintain 
blinding and will be told that they will receive imperceptible, microcurrent stimulation for pain mitigation. 
In the sham device, electrical leads are disconnected so that no current can leave the NMES device. 
Pre-surgery testing #2 (~1 wk pre-surgery) will be identical to Pre-surgery #1 testing, but will include 
strength testing of the injured leg.  

Post-surgery testing #1 (3 wks) will consist of bilateral muscle biopsies for cellular structure and 
function measures and bilateral thigh muscle size assessments.  
Standardized rehabilitation will begin 3 wks post-surgery, with both groups undergoing the same 
accelerated rehabilitation program that is standard of care within our practice.  
Post-surgery testing #2 (6 mos post-surgery) will include bilateral thigh muscle size and strength, 
single leg hop test, clinical/patient-related outcomes and magnetic resonance imaging-based 
assessments of cartilage volume/composition. Physical activity will be measured by accelerometry (5 d 
each) throughout the study to be used as a possible covariate in our statistical model. 
Procedures:  
All of the procedures and interventions on volunteers recruited for these studies are carried out solely for 
research purposes, as none are part of standard therapy in ACL rupture patients that are candidates for 
surgical repair. We will describe procedures that will be performed for the Primary and Secondary Aims. 
Primary Aim 
Primary outcomes include: skeletal muscle fiber cross-sectional area (CSA) and contractile function. 
Percutaneous skeletal muscle biopsy of the vastus lateralis (VL) will be performed on both the 
injured and non-injured leg 3 wks following surgery. Tissue will be proportioned for mechanical 
(single fiber function) and immunohistochemical (IHC) measurements. The VL was chosen because 
of its importance in attenuating shock to articular cartilage during normal ambulation. Thus, 
deterioration of function in the quadriceps muscle group may have implications for longer-term 
development of knee osteoarthritis in ACL injured/reconstructed patients. The following measures 
will be assessed from muscle tissue. 
Single fiber function will be assessed on segments of chemically-skinned muscle fibers, as used 
routinely by our lab. Cellular function will be measured on chemically-skinned, fiber segments, 
including force, velocity and power, as described by us (1). These measures will be available on the 
most abundant fiber types: MHC I, IIA and IIAX (>90% of fibers in cancer patients (2)).  
Single fiber cross-sectional area (CSA) will be measured by IHC, as described (1), with the 
addition of MHC IIA and IIX antibodies to delineate MHC II sub-types, as described (3), as these 
comprise the majority of fibers (MHC I, IIA, IIAX; >90%) in cancer patients (4).  
Secondary outcome is accelerometry measures of weight-bearing activity. Procedures that will be 
performed on volunteers to obtain these primary and secondary outcome measures are described 
below. 
Accelerometry will be performed (5 d each): at baseline and ~weekly throughout the 5 week 
intervention, as described (5).  
Secondary Aim 
Primary outcome is knee extensor torque. 
Thigh muscle function will be assessed by isokinetic/isometric dynamometry (70° isometric and 60 
and 180 °/sec isokinetic), as described (5), to determine whether use of NMES improves retention 
of knee extension torque by comparing between injured and non-injured legs. 
Secondary outcomes include: clinical and patient-oriented outcomes, functional testing (single leg hop) 
and quadriceps muscle cross-sectional area. These outcomes are assessed with the goal of providing 
preliminary data to the expected randomized clinical trial if our hypotheses are proved correct.  
Clinical/Patient-oriented outcomes including IKDC score, MOS-SF36 and KOOS scales. 
Whole leg functional testing will be assessed using the single leg hop test, as described by us (6).  
Quadriceps muscle cross-sectional area will be measured to examine whether protection of NMES 
against atrophy apparent at the single fiber level (primary outcome) is evident from whole muscle 
imaging measures. This would allow for easier tracking of the efficacy of NMES using whole muscle 
imaging in future trials. 
Cartilage volume and composition will be measured in patients at 6 months post-surgery. This 

measurement is included to evaluate whether NMES helps to mitigate the progression of PTOA, as 
measured by decline in cartilage volume, and is included to inform future trials. The MRI 
measurement will be conducted at UVMMC and post-processing of de-identified MRI scans will be 
accomplished by our collaborator, Dr. Brian Petrisimone, at the University of North Carolina. 
 
Interventions 
 
NMES will be conducted on the quadriceps of the injured/operative leg using a portable device (Empi 
Continuum; DJO Global), starting within 3 wks post-injury and continuing till 3 wks post-surgery, with 
NMES re-started 72 hrs post-surgery. The injured leg will be immobilized at 40º, with electrodes affixed 
to the anterior surface of the thigh, as we have shown that even maximal contraction at this angle 
produces minimal strain on the healing ACL graft (7). Symmetrical, biphasic pulses (400 µs duration at 
50 Hz) will be used, with a duty cycle of 50% (10 s on, 30 s off) and maximal-tolerated, contractions 
below pain threshold using patient-selected intensity. NMES sessions will occur 5 d/week, once daily for 
60 min per occasion (5 min warm-up, 50 min stimulation, 5 min cool down). Volunteers will self-report 
device use and stimulation intensity (see Appendix 1), both of which will be reviewed during weekly 
phone contacts, with self-reported adherence confirmed using the compliance monitoring feature built-in 
to the NMES device software.  
An issue with the built-in compliance monitoring feature is that the research team only learns of 
volunteer non-compliance after s/he returns that device. That is, if the volunteer is not truthfully 
completing the self-reported compliance log and reporting non-compliance during weekly phone 
contacts, s/he could be skipping NMES sessions without the research team’s knowledge. To overcome 
this problem and to improve compliance with the NMES intervention, we have designed a modified 
NMES device and smartphone/tablet app that allows for real-time monitoring of compliance with the 
NMES prescription. In collaboration with Dr. Chris Skalka, an assistant professor in the Dept. of 
Computer Science, as well as a senior engineering capstone design group, we have designed a cyber-
physical system that provides real-time compliance tracking of NMES use. This is detailed in the 
attached proposal, which was funded by a LCOM/CEMS Biomedical Engineering Pilot Grant. Briefly, 
this system encompasses three components: an instrumented NMES device, a smartphone app and a 
back-end server program with automated compliance analysis capabilities. The instrumented NMES 
contains a low-cost, low-powered, embedded device that detects, quantifies and stores NMES device 
use data and can transmit these data via Bluetooth (detailed in attached Appendix to Amendment 11). 
The smartphone app is able to acquire data (data pull) from the instrumented NMES device and 
communicate the data to a back-end server via the Internet, where data will be stored, analyzed, and 
made available to care providers. Finally, there is software on a HIPAA compliant portion of the LCOM 
server that will store these data and analyze them to calculate compliance with the NMES regimen. We 
will ask volunteers to use this device to test the utility of this cyber-physical system to track compliance 
with the NMES prescription. The device itself does not work any differently than a standard NMES 
device, with the exception of the requirement to turn on an additional power switch. The 
smartphone/tablet app is simple to use and the volunteers will be instructed on its use. Finally, the 
server-based software is also designed to automatically send ‘push’ notifications to the volunteer’s 
phone/tablet to provide positive reinforcement when s/he completes assigned NMES sessions and to 
inquire if there are any problems or if the volunteer would like to contact the research team if there is 
non-compliance. In addition to these contacts, the research coordinator will be in contact with the 
volunteer on the usual schedule of interactions (once per week) to inquire about compliance and any 
issues the volunteer might be having with the NMES device. Finally, the app is written for the iOS 
operating system. If the volunteer does not have a compatible device, we will loan them a device for the 
duration of the study. 
Control intervention Volunteers randomized to control will receive a sham NMES device to maintain 
blinding and will be told that they will receive imperceptible, microcurrent stimulation for pain mitigation 
(8). In the sham device, leads are disconnected inside the device so that no electrical current is emitted. 
Patients in the NMES group will, in turn, be told that their intervention will both induce muscle 
contraction and provide pain mitigation, so that any placebo effect for pain mitigation will be evenly 
distributed between groups. Controls will undergo the same frequency of interaction with study 
personnel as the NMES group 
Literature cited 

 
1. 
Callahan, D. M., Miller, M. S., Sweeny, A. P., Tourville, T. W., Slauterbeck, J. R., Savage, P. D., Maughan, D. W., 
Ades, P. A., Beynnon, B. D., and Toth, M. J. (2014) Muscle disuse alters skeletal muscle contractile function at the 
molecular and cellular levels in older adult humans in a sex-specific manner. J Physiol 592, 4555-4573 
2. 
Toth, M. J., Miller, M. S., Callahan, D. M., Sweeny, A. P., Nunez, I., Grunberg, S. M., Der-Torossian, H., Couch, M. E., 
and Dittus, K. (2013) Molecular mechanisms underlying skeletal muscle weakness in human cancer: reduced myosin-
actin cross-bridge formation and kinetics. J Appl Physiol 114, 858-868 
3. 
Fry, C. S., Noehren, B., Mula, J., Ubele, M. F., Westgate, P. M., Kern, P. A., and Peterson, C. A. (2014) Fibre type-
specific satellite cell response to aerobic training in sedentary adults. J Physiol 592, 2625-2635 
4. 
Callahan, D. M., Tourville, T. W., Miller, M. S., Hackett, S. B., Sharma, H., Cruickshank, N. C., Slauterbeck, J. R., 
Savage, P. D., Ades, P. A., Maughan, D. W., Beynnon, B. D., and Toth, M. J. (2015) Chronic disuse and skeletal 
muscle structure in older adults: sex-specific differences and relationships to contractile function. Am J Physiol Cell 
Physiol 308, C932-C943 
5. 
Toth, M. J., Shaw, A. O., Miller, M. S., VanBuren, P., LeWinter, M. M., Maughan, D., and Ades, P. A. (2010) Reduced 
knee extensor function in heart failure is not explained by inactivity. Int J Cardiol 143, 276-282 
6. 
Tourville, T. W., Naud, S., Slauterbeck, J. S., Johnson, R. J., and Beynnon, B. D. (2014) Relationship between 
isokinetic strength and tibiofemoral joint space width changes following ACL reconstruction. Am J Sports Med 42, 302-
311 
7. 
Beynnon, B. D., Fleming, B. C., Johnson, R. J., Nichols, C. E., Renström, P. A., and Pope, M. H. (1995) Anterior 
cruciate ligament strain behavior during rehabilitation exercises in vivo. Am J Sports Med 23, 24-34 
8. 
Lambert, M. I., Marcus, P., Burgess, T., and Noakes, T. D. (2002) Electro-membrane microcurrent therapy reduces 
signs and symptoms of muscle damage. Med Sci Sports Exerc 34, 602-607 
Questionnaires:
We will assess patient symptoms and functionality using the IKDC score, the MOS-SF36 and the KOOS 
knee score. 
Risks/Benefits:   
Potential risks: Below we have highlighted those procedures/measurements that have anything greater 
than negligible risk to the volunteers’ health for each phase of the study.  
Muscle biopsies: Risks associated with the muscle biopsy procedure include excessive bleeding, 
persistent numbness or infection. In general, all of these risks are well below 1% (1). Regarding 
bleeding risk, any volunteer with known coagulopathies will be excluded from participation. Any 
volunteer that is taking medications that may impact coagulation (eg, NSAIDS) will be instructed to 
discontinue this medication prior to the biopsy, as approved by their physician/surgeon. Our laboratory 
has never had an adverse event related to the muscle biopsy procedure. The muscle biopsy will be 
performed by trained, qualified clinicians in a closely-controlled, medical environment.  
Muscle strength testing: There is risk for muscle soreness or injury resulting from whole muscle 
functional testing. Appropriate warm up exercises will be performed to prevent muscle soreness/injury.  
Whole leg functional testing (single leg hop): The single leg hop tests carries a small risk that the 
healing ACL graft could be damaged. To minimize this possibility, we will not perform this assessment 
until the surgeon has cleared the volunteer for this test. Our laboratories (Beynnon) have extensive 
experience with performing this test on volunteers with ACL reconstruction at 6 months post-surgery 
without any adverse events. 
Quadriceps muscle cross-sectional area: Each CT scan of the mid-thigh (2 per volunteer) exposes 
volunteers to the equivalent of 110 d of normal background radiation. The exposure from the CT is 
focused on a single slice at mid-thigh. 
NMES intervention: NMES is a generally safe procedure, delivered in the proposed study by an FDA 
approved device. Although evidence is limited, some have suggested that NMES could increase the risk 
of DVT, which may have serious health consequences. However, the risk of DVT in this population is 
quite low and we will exclude any individual with a known coagulopathy. Moreover, because of the 
location of the stimulating electrodes (upper leg), the risk of NMES dislodging a DVT is likely minimal. 
Patients may experience some painful muscle contractions as they first adjust the stimulus to a tolerable 
level, this will be quickly mitigated by reducing the stimulation intensity. After treatment, muscle 
soreness may occur. The level of fatigue and/or soreness, however, will be similar to that which occurs 
following a standard exercise training session and should dissipate over time as the voluneer’s muscles 
become accustomed to the electrically-stimulated contractions (ie, they become trained). The modified 
NMES device functions are identical to an unmodified device (certified by UVMMC TSP; see attached 

email from Wallace Elliott). Thus, the risks of using the modified device are the same as above. 
Control intervention: The modified NMES device will not emit any current. Thus, there is no risk 
associated with this intervention. 
Magnetic resonance imaging (MRI): MRI is a generally safe procedure. The effects of magnetic fields 
in an MRI scanner have been extensively studied, and there are no known significant risks with an MRI 
exam. The subject may, however, be bothered by feelings of confinement (claustrophobia), and by the 
noise made by the magnet during the procedure. There is a small risk of decreased hearing immediately 
after an MRI scan.  To help lessen this risk, subjects will be asked to wear earplugs or earphones while 
in the magnet. Some degree of fatigue or anxiety could occur while undergoing testing.  Should this 
occur, efforts will be made to minimize discomfort. 
Benefits: NMES may improve skeletal muscle structure or function and, in turn, preserve muscle 
strength, as it has been found in other orthopedic surgical conditions (2). If NMES is shown to have 
beneficial effects on skeletal muscle, further research and application of the technique to ACL injured 
patients may assist in the development of more effective post-injury/surgery care to mitigate long-term 
functional morbidity and the development of PTOA. 
Literature cited 
1. 
Tarnopolsky, M. A., Pearce, E., Smith, K., and Lach, B. (2011) Suction-modified Bergström muscle biopsy technique: 
Experience with 13,500 procedures. Muscle Nerve 43, 716-725 
2. 
Stevens-Lapsley, J. E., Balter, J. E., Wolfe, P., Eckhoff, D. G., and Kohrt, W. M. (2012) Early neuromuscular electrical 
stimulation to improve quadriceps muscle strength after total knee arthroplasty: a randomized controlled trial. Phys 
Ther 92, 210-226 
Therapeutic Alternatives:   
There are no therapeutic alternatives to NMES following injury and no standard of care rehabilitation 
interventions at this time. Following ACL reconstruction surgery, all patients will receive physical 
rehabilitation in accordance with current standard of care practices. 
Data Safety and Monitoring:  
Considering the size and scope of the study, which, because of the limited follow-up with the R21 
mechanism, does not include assessment of final clinical outcomes (eg, progression of PTOA), as well 
as the low risk to participants, and pursuant to NIH guidelines, we will establish a formal Data Safety 
Monitoring Plan, which will provide oversight to protect against risk to safety and confidentiality. 
 The PIs (Toth and Beynnon) and Drs. Slauterbeck will monitor the safety of the research 
procedures for this study on a daily basis. If an event occurs that affects participant safety, the PIs 
and/or Dr. Slauterbeck will alert the Safety Officer (Clinical Orthopedist: Adam Shafritz), who will 
adjudicate the event with respect to its severity, expectedness and relatedness to participation in the 
study according to the aforementioned criteria. If any problems arise with the NMES intervention, the 
research coordinator, who will not be blinded to treatment status, will address this problem with the 
Safety Officer to determine the course of action that is in the best interest of the patient’s safety and 
long-term health. Because numerous clinical trials in our laboratory have demonstrated the safety of the 
proposed regimen of testing in patients from a broad range of clinical backgrounds (eg, young knee 
trauma patients, heart failure patients, cancer patients, healthy elderly), we expect minimal problems 
related to testing. Thus, we do not feel that it is reasonable to incorporate "stoppage criteria" for the 
overall study. Instead, the Safety Officer will decide whether an individual participant should continue 
with the study following occurrence of any adverse events or unanticipated problems taking into 
consideration what is in the best interest of that individual. 
On an annual basis, Drs. Toth, Beynnon and Slauterbeck will assess data being gathered and safety 
of volunteers to assess the pattern or frequency of events to identify occurrence of any event or problem 
that significantly alters the safety profile of the procedures being performed, unless occurrence of a 
serious adverse event or unanticipated problem necessitates re-evaluation of the expected risk of the 
study procedures at an earlier time point. Additionally, they will evaluate data collection and storage to 
ensure the confidentiality of data and quality. Each of these evaluations will be followed by reports of 
study progress and patient safety to the University of Vermont Committee on Human Research in the 
Medical Sciences via yearly progress reports and to the appropriate NIH program officer. The report will 
include information regarding study status, participant information and safety information. This report will 

also be forwarded to the Safety Officer for his/her independent review. Following his/her review, an 
additional meeting between the Safety Officer and the PIs will be held to finalize that year’s safety 
report. 
 
Adverse Event and Unanticipated Problem Reporting:  
Adverse events will be reported by one of 3 mechanisms. First, the joint University of 
Vermont/University of Vermont Medical Center (UVMC) Committee for Human Subject Research 
Adverse Event Reporting Document. These reports will be forwarded to the office of the Committee for 
Human Research in the Medical Science (CHRMS) within 5 days of the event. Reporting any adverse 
events will be the responsibility of the PI. The CHRMS will make a determination as to whether 
additional reporting requirements are indicated. Second, the UVMC Patient Safety Reporting system 
(SAFE), which may be initiated by health care center staff or study personnel. These forms will be 
forwarded within 3 days to the PI, UVMC Risk Management Office, CHRMS and other appropriate 
agencies, as indicated by the nature of the report. Finally, the UVMC Medication/IV Event Report Form, 
with distribution and timing as noted above. This latter mechanism might be used with events related to 
blood sampling. Reviews of protocol specific adverse events will be performed no less than annually. 
Additionally, any adverse event that occurs will be forwarded to the PI for reporting to the Human 
Subject Research Protection Office within 1 week of occurrence. Of note, these protections against risk 
include both physical risks to the volunteers, as well as risks associated with any breach in 
confidentiality. 
On an annual basis, Drs. Toth, Beynnon, Slauterbeck and the Safety Officer will assess data being 
gathered and safety of volunteers to assess the pattern or frequency of events to identify occurrence of 
any event or problem that significantly alters the safety profile of the procedures being performed, 
unless occurrence of a serious adverse event or unanticipated problem necessitates re-evaluation of the 
expected risk of the study procedures at an earlier time point. Additionally, they will evaluate data 
collection and storage to ensure the confidentiality of data and quality. Each of these evaluations will be 
followed by reports of study progress and patient safety to the University of Vermont CHRMS via yearly 
progress reports and to the appropriate NIH program officer. The report will include information 
regarding study status and safety of volunteers (occurrence of AEs/SAEs. This report will also be 
forwarded to the NIH Program Officer for his review. 
Withdrawal Procedures:  
Volunteers will be withdrawn if the research team, clinician and/or safety officer feels that further 
participation in the study or performance of any procedure associated with this study would, in any way, 
put the volunteer at undue risk or not be in their best interest. Moreover, volunteers may be withdrawn if 
s/he fails to attend scheduled visits or do not comply with instructions from research staff. 
Sources of Materials:  
An individual research record will be kept on each volunteer in compliance with HIPAA standards. This 
record will contain identifying data, demographic information and results from all clinical research 
measurements and evaluations. The results of all testing will be kept confidential. In addition, skeletal 
muscle tissue samples will be taken and will be used for measurement of muscle size, structure and 
function. All materials gathered in conjunction with the proposed studies will be used for research 
purposes only and will be available only to research personnel working on these studies, who have 
obtained proper training in human subjects research and privacy protection.  
 
DRUG AND DEVICE INFORMATION
Drug (s) 
X 
Not applicable 
 
Device (s) 
 
Not applicable 
 
The interventional device used in this study: EMPI Continuum complete electrotherapy system has 
received FDA approval (501K: K093324) for retarding disuse-related atrophy, which we believe is one of 
the primary mechanisms whereby muscle adaptations evolve in patients in the early, post-surgical 
period. That is, muscle disuse secondary to pain, limited range of motion and muscle weakness (the 
latter being due to neural inhibition caused by joint pain/swelling) causes skeletal muscle fiber atrophy 
and weakness. 

  
For the control intervention, an EMPI 300PV that is modified to have its leads disconnected within the 
device will be used. For both leads on the device (1 and 2), the ferrites directly proximal to the leads are 
removed and a dummy load resistor (1 Megohm) is used to bridge the output to simulate the resistance 
of human skin (see Appendix 3). This bridging is necessary, as the device will not function if no load is 
detected. This yields a device that cannot deliver any electrical stimulus to the patient throughout the 
stimulus intensity range of the device.
FDA approval:
The EMPI Continuum is approved to mitigate muscle atrophy/dysfunction associated with muscle disuse 
(501K: K093324). 
Risk assessment:  
The device (and similar devices) has been used extensively in the orthopedic and neural rehabilitation 
settings by physical and occupational therapists and in numerous disease states (heart failure, chronic 
obstructive pulmonary disease, knee replacement) to improve muscle size and function in clinical trial 
settings. Thus, NMES is generally a safe modality, with a long safety record. Although evidence is 
limited, some have suggested that NMES could increase the risk of dislodging a deep vein thrombosis 
(DVT) because of the rhythmic muscle contractions induced by the electrical stimulation. However, 
several published reports show that NMES significantly reduces the risk of developing DVTs. In fact, the 
device we are using is FDA-approved for prevention of DVT of the calf muscles immediately following 
surgery, as it would function similar to intermittent pneumatic compression. Moreover, the population we 
are studying is generally at low risk for DVT and we will actively exclude any individual with a known 
coagulopathy or DVT. Because of the location of the stimulating electrodes (upper leg), the risk of 
NMES dislodging a DVT is likely minimal. Finally, during the first couple of NMES sessions, muscle 
soreness may occur, but this is comparable to what might occur with classical exercise training and 
dissipates over time.  
 
 
SUBJECT CHARACTERISTICS, IDENTIFICATION AND RECRUITMENT 
Subject Selection:   
A single cohort of patients will provide data to address both aims. Patients with recent, unilateral ACL 
rupture or combined ACL rupture/meniscus injury, who are undergoing surgical reconstruction, will be 
recruited and randomized to NMES or control, with stratification for age, sex and graft type (knee 
extensor autograft, knee flexor autograft and allograft). A within-subject design will be used (Fig 3), 
where the injured, surgically-treated leg will be compared to the contralateral, uninjured leg. 
We chose to study patients with ACL rupture, with or without meniscus injury, as this trauma is 
immediately disabling, dramatically reduces muscle strength and increases the risk of further injury and 
developing PTOA (1-4). Although neuromuscular adaptations differ slightly between ACL and combined 
ACL/meniscus injury post-surgery, injury types will be distributed equally by randomization. Inclusion of 
both injury types provides broader generalizability of our results. We will also stratify randomization by 
graft type (knee extensor autograft, hamstring autograft and allograft groups) using an adaptive 
randomization approach to assure that groups are frequency matched for the different graft types. 
Use of the uninjured leg as a within-subject control is common in this field and justified by results from 
our labs (4) and others (5) showing that its size and function are maintained throughout the proposed 
study period (4, 5). While whole muscle strength in the uninjured leg is reduced slightly compared to 
uninjured control volunteers due to cross-over neural inhibition (6), there is no evidence that this would 
affect the intrinsic structure or function of its single muscle fibers differently in NMES and control groups. 
Nonetheless, we will assess strength in the uninjured leg repeatedly throughout the study to verify its 
constancy and, in turn, its suitability as a within-subject control, particularly for the secondary aim. 
Within 3 wks of injury is the closest time point for initiation of NMES in our experience (7-12), with the 
rationale that starting closer to the index injury would best preserve muscle size and function. Practically 
speaking, individuals who tear their ACL and require surgical reconstruction typically do not get a final 
diagnosis of the ACL rupture and the requirement of surgical repair for 1-3 wks post-injury. Thus, the 
timeframe that we have chosen for starting the NMES or control intervention is in keeping with the 
typical timeframe that NMES could be used clinically. We will continue NMES till 3 wks post-surgery 

because this is when patients typically begin more aggressive strengthening/anabolic exercises and 
increased weight-bearing activity that would substitute for the NMES stimulus. Building on this last point, 
we chose to assess our primary outcomes for the primary aim at 3 wks post-surgery, as this is likely 
their functional nadir based on post-surgical deficits in other orthopedic populations (13), which allows 
for resolution of the effects of NMES to mitigate atrophy and contractile dysfunction. Finally, we chose 6 
mos for primary outcomes for the secondary aim (knee extensor strength) because this represents the 
time patients are typically tested for return to pre-injury activities, but when there are still marked 
functional deficits (12) that could adversely affect joint health. 
 
Literature cited: 
1. 
Keays, S. L., Newcombe, P. A., Bullock-Saxton, J. E., Bullock, M. I., and Keays, A. C. (2010) Factors involved in the 
development of osteoarthritis after anterior cruciate ligament surgery. Am J Sports Med 38, 455-463 
2. 
Ajuied, A., Wong, F., Smith, C., Norris, M., Earnshaw, P., Back, D., and Davies, A. (2014) Anterior cruciate ligament 
injury and radiologic progression of knee osteoarthritis: a systematic review and meta-analysis. Am J Sports Med 42, 
2242-2252 
3. 
Hart, J., Turman, K., Diduch, D., Hart, J., and Miller, M. (2011) Quadriceps muscle activation and radiographic 
osteoarthritis following ACL revision. Knee Surg Sports Traumatol Arthrosc 19, 634-640 
4. 
Tourville, T. W., Naud, S., Slauterbeck, J. S., Johnson, R. J., and Beynnon, B. D. (2014) Relationship between 
isokinetic strength and tibiofemoral joint space width changes following ACL reconstruction. Am J Sports Med 42, 302-
311 
5. 
Shaarani, S. R., O’Hare, C., Quinn, A., Moyna, N., Moran, R., and O’Byrne, J. M. (2013) Effect of prehabilitation on the 
outcome of anterior cruciate ligament reconstruction. Am J Sports Med 41, 2117-2127 
6. 
Hart, J. M., Bietrosimone, B., Hertel, J., and Ingersoll, C. D. (2010) Quadriceps activation following knee injuries: a 
systematic review. J Athl Train 45, 87-97 
7. 
Tourville, T. W., Johnson, R. J., Slauterbeck, J. R., Naud, S., and Beynnon, B. D. (2013) Assessment of early 
tibiofemoral joint space width changes after anterior cruciate ligament injury and reconstruction: a matched case-
control study. Am J Sports Med 41, 769-778 
8. 
Beynnon, B. D., Johnson, R. J., Fleming, B. C., Kannus, P., Kaplan, M., Samani, J., and Renström, P. (2002) Anterior 
cruciate ligament replacement: comparison of bone-patellar tendon-bone grafts with two-strand hamstring grafts. J 
Bone Joint Surg 84, 1503-1513 
9. 
Beynnon, B. D., Uh, B. S., Johnson, R. J., Fleming, B. C., Renström, P. A., and Nichols, C. E. (2001) The elongation 
behavior of the anterior cruciate ligament graft in vivo: a long-term follow-up study. Am J Sports Med 29, 161-166 
10. 
Tourville, T. W., Johnson, R. J., Slauterbeck, J. R., Naud, S., and Beynnon, B. D. (2013) Relationship between 
markers of type II collagen metabolism and tibiofemoral joint space width changes after ACL injury and reconstruction. 
Am J Sports Med 41, 779-787 
11. 
Beynnon, B. D., Vacek, P. M., Sturnick, D. R., Holterman, L. A., Gardner-Morse, M., Tourville, T. W., Smith, H. C., 
Slauterbeck, J. S., Johnson, R. J., and Shultz, S. J. (2014) Geometric profile of the tibial plateau cartilage surface is 
associated with the risk of non-contact anterior cruciate ligament injury. J Ortho Res i32, 61-68 
12. 
Beynnon, B. D., Johnson, R. J., Naud, S., Fleming, B. C., Abate, J. A., Brattbakk, B., and Nichols, C. E. (2011) 
Accelerated versus nonaccelerated rehabilitation after anterior cruciate ligament reconstruction: a prospective, 
randomized, double-blind investigation evaluating knee joint laxity using roentgen stereophotogrammetric analysis. 
Am J Sports Med 39, 2536-2548 
13. 
Dreyer, H. C., Strycker, L. A., Senesac, H. A., Hocker, A. D., Smolkowski, K., Shah, S. N., and Jewett, B. A. (2013) 
Essential amino acid supplementation in patients following total knee arthroplasty. J Clin Invest 123, 4654-4666 
 
Number of Subjects:  
We intend to enroll a total of 24 volunteers. This will allow for n=20 to complete the study, conservatively 
assuming 20% total attrition rate. 
Inclusion/Exclusion Criteria:  
Patients (50:50 men-women) will be included if they are/have: 1) 18-50 yrs; 2) BMI <35 kg/m2 ; 3) 
acute, first-time, ACL rupture with or without meniscus injury and 4) scheduled to undergo 
reconstruction with any type of autograft or allograft. Patients will be excluded if they are/have: 1) history 
of prior knee/lower extremity surgery or non-surgical intervention (eg, intra-articular injection) on either 
leg; 2) abnormal laxity of any lower extremity ligament other than the injured ACL; 3) signs or symptoms 
of arthritis, autoimmune or inflammatory disease or diabetes; 4) grade IIIb or greater articular cartilage 
lesions (ICRS criteria) and/or 5) women who are/plan on becoming pregnant.  
Inclusion of Minorities and Women:  
Inclusion of Women 
     This study will include equal numbers of men and women. 
Inclusion of Minorities 
     Every effort will be made to recruit minorities for the proposed studies. The contribution of minorities 

to the total population of Vermont is 3.2%, with a similar minority profile in Chittenden County (3.6%), 
where the University of Vermont (UVM) is located.  
Inclusion of Children:
The proposed studies will not include children. The rationale for this decision is based on the fact that 
children are a vulnerable population and it could be argued that performance of the invasive procedures 
proposed in these studies, such as muscle biopsies, would not be justified without proven efficacy of the 
NMES intervention. Based upon the Belmont Report (Part C, §3), there is an order of preference for 
performing research on volunteers, which stipulates that in research that does not have a known 
therapeutic value, or by extrapolation to the proposed studies, where the utility of the therapeutic 
intervention is in question, that those less burdened populations should be called upon first to accept the 
risks of research. In the context of this criterion, this would mean that adults be studied before children. 
Traumatic knee injury is indeed relevant to children, as a fraction of patients experience this injury in 
their late teenage years. However, we believe that it is prudent to first investigate the utility of NMES in 
the adult population before it is evaluated in children. If our studies are successful, we would anticipate 
that future randomized, controlled trials evaluating the efficacy of NMES to improve current rehabilitation 
strategies for recovery from traumatic knee injury and surgical repair would include children. 
Recruitment:  
Patients will be recruited from the Sports Medicine service of the UVMMC Department of Orthopedics 
and Rehabilitation. Additionally, because we have to identify volunteers within 3 week of injury, we will 
also receive referrals to our research group from other local clinical practices, local universities and 
University student health offices who have a suspected ACL rupture. These clinical practices will 
document patient’s interest in the study and consent to have their contact information sent to our 
research team. 
Consent Procedures:  
Someone with a treatment relationship will introduce the study to potential volunteers (UVMMC 
Department of Orthopedics and Rehabilitation, EMRAP, athletic trainers at local universities). If the 
patient expresses interest in the study and would like more information about the study, the research 
coordinator or PI will contact the volunteer, explain the study and will provide a copy of the informed 
consent. The PI and/or the research coordinator will answer any questions by phone or in person. 
Moreover, the PI or the research coordinator will discuss the protocol with the volunteer at length and 
answer any remaining questions.  
Information Withheld From Subjects:     
Volunteers randomized to the sham, microcurrent stimulation group will not be told that the device that 
they receive was modified to emit no electrical current. This deception is necessary so that we can 
achieve a proper sham intervention, which was requested by the NIH review group. The review group 
was concerned that the volunteer’s knowledge of no intervention (if we had a standard of care control 
with no sham device being used) would affect their efforts on volitional tests, such as strength testing 
(secondary aim) and functional testing, or their report of quality of life and knee pain/function on 
questionnaires. The latter measurements were of particular concern, as the committee considers these 
metrics essential for future randomized controlled trials to test the efficacy of NMES in this patient 
population. Thus, they felt that a sham device was needed to eliminate bias. We will debrief volunteers at 
the completion of the study regarding this deception. 
For debriefing of volunteers randomized to the sham control group, we will contact volunteers by phone 
to schedule a time to provide them with the Debriefing Form and explain the deception and sign the 
Debriefing Form. There is also a place on the form for volunteers to check “Yes” or “No” as to whether 
we may use their data. Many of the volunteers were students. Some of them have moved out of the area 
since their participation in the study. In these volunteers, we will try to contact them via phone, text or 
email to debrief them verbally. In this event, study personnel will use a script that mirrors the points noted 
in the debriefing memo. This Script will also be used to document the volunteers assent/decline to 
assent, as well as the date of the contact and, for those patients who we cannot contact, these dates of 
attempts to contact. We will provide the volunteers with a copy of the Debriefing Form and obtain their 
signature after the phone conversation. For those volunteers who we cannot contact, we will attempt to 
contact them two (2) times. Any volunteer who cannot be contacted for debriefing will be noted in the 
Continuing Review.