Preventing Posttraumatic Osteoarthritis With Physical Activity Promotion
Phase: NA
Conditions: Anterior Cruciate Ligament Injuries, Exercise, Cartilage, Articular, Knee Injuries, Osteoarthritis, Osteoarthritis, Knee, Arthritis, Joint Diseases
Sponsor: University of North Carolina, Chapel Hill

Complete Title: Preventing Posttraumatic Osteoarthritis with Physical Activity Promotion 
 
 
 
Short Title: Tar Heel Walks 
Drug or Device Name(s): N/A 
FDA IND/IDE (if applicable): N/A 
Sponsor: North Carolina Translational and Clinical Sciences Institute 
Protocol Date: April 26, 2023 
NCT Number: NCT04906499 
 
 
 
 
 
 
 
 
 
 
Sponsor 
North Carolina Translational and Clinical Sciences Institute 
Brinkhous-Bullitt, 2nd floor 
Chapel Hill, NC, 27599 
United States 
Study Principal Investigator: Brian Pietrosimone 
209 South Road, CB# 8700 
Chapel Hill, NC, 27599 
Phone 919-962-3617 
email: pietrosi@email.unc.edu 
 
 
 
 
 

Page 2 of 32 
 
PROTOCOL TITLE:  
Preventing Posttraumatic Osteoarthritis with Physical Activity Promotion 
Short Title:  
Tar Heel Walks 
Lead Investigator: 
Brian Pietrosimone, PhD 
 University of North Carolina at Chapel Hill 
Protocol Version: 1 
Version Date: 4/26/2023 
 
I confirm that I have read this protocol and understand it.    
Principal Investigator Name:  
 
Brian Pietrosimone, PhD 
Principal Investigator Signature:  
 
Date:   
 
 
 
4/26/2023 
 
 
 

Page 3 of 32 
 
Table of Contents 
 
ABBREVIATIONS AND DEFINITIONS OF TERMS .......................................................................................................... 4 
PROTOCOL SYNOPSIS ....................................................................................................................................................................................... 5-7 
BACKGROUND AND RATIONALE .................................................................................................................................................................... 8-10 
1 
STUDY OBJECTIVES .......................................................................................................................................................................... 11 
2 
INVESTIGATIONAL PLAN ............................................................................................................................................................ 11-13 
3 
STUDY PROCEDURES .................................................................................................................................................................. 13-15 
4 
STUDY EVALUATIONS AND MEASUREMENTS ........................................................................................................................... 15-16 
5               STATISTICAL CONSIDERATIONS ................................................................................................................................................. 16-18 
6 
STUDY INTERVENTION (DEVICE, DRUG, OR OTHER INTERVENTION) ............................................................................................ 18 
7               STUDY INTERVENTION ADMINISTRATION (IF APPLICABLE) ........................................................................................................... 18 
8           SAFETY MANAGEMENT .............................................................................................................................................................. 18-20 
9           DATA COLLECTION AND MANAGEMENT ...................................................................................................................................... 220 
10           RECRUITMENT STRATEGY ........................................................................................................................................................... 22-23 
11           CONSENT PROCESS ..................................................................................................................................................................... 23-24 
12           PLANS FOR PUBLICATION ................................................................................................................................................................ 24 
13           REFERENCES ................................................................................................................................................................................ 24-27 
APPENDIX ............................................................................................................................................................... 28-32 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 4 of 32 
 
Abbreviations and Definitions of Terms 
 
 
 
 
Abbreviation 
Definition 
ACL 
Anterior Cruciate Ligament 
ACLR 
Anterior Cruciate Ligament Reconstruction 
AE 
Adverse Event 
API 
Application Programming Interface 
FDA 
Food and Drug Administration 
HIPPA 
Health Insurance Portability and Accountability Act   
IRB 
Institutional Review Board 
KOOS 
Knee Injury and Osteoarthritis Outcomes 
KOOS-QOL 
Knee Injury and Osteoarthritis Outcomes Score Quality of Life Subscale 
MOTION 
MusculOskeleTal Injury preventiON 
MRI 
Magnetic Resonance Imaging 
ms 
millisecond 
MSU 
Michigan State University 
OA 
Osteoarthritis 
PA 
Physical Activity 
PI 
Principal Investigator 
PID 
Participant Identifier 
PTOA 
Posttraumatic Osteoarthritis 
SAE 
Serious Adverse Event 
SMS 
Short Message Service 
SQL 
Structured Query Language 
UNC-CH 
University of North Carolina at Chapel Hill 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 5 of 32 
 
 
 
PROTOCOL SYNOPSIS 
  
Study Title 
Preventing Posttraumatic Osteoarthritis with Physical Activity 
Promotion 
Funder 
North Carolina Translational and Clinical Sciences Institute 
Clinical Phase 
Pilot Study 
Study Rationale 
Osteoarthritis (OA) is a leading cause of disability worldwide 
resulting in severe limitations in daily activities and chronic pain. It is 
estimated that 35% of posttraumatic OA (PTOA) cases occur after 
knee injuries and surgeries such as anterior cruciate ligament (ACL) 
injury and ACL reconstruction (ACLR). Optimal free-living 
mechanical loading, which refers to the forces acting on the knee 
caused by daily activities, plays an essential role in maintaining knee 
articular cartilage health. After ACLR, individuals take fewer steps 
per day as compared to uninjured controls. This results in 
insufficient free-living mechanical loading to joint tissues and is 
associated with early PTOA development. Adequate physical activity 
(PA) is recommended to help reduce risk of PTOA, but it is unclear 
how changes in PA acutely impact knee joint cartilage health. The 
overall objective of this pretest-posttest experimental pilot study is 
to determine how optimizing free-living mechanical loading through 
Daily step (i.e., PA) promotion intervention improves cartilage 
composition in individuals who demonstrate insufficient free-living 
mechanical loading after ACLR. A daily step promotion intervention 
will be delivered over 8 weeks using commercially available PA 
monitors and the patients’ own smartphone to provide daily 
personalized and achievable step goals to increase daily step counts 
to a level consistent with healthy PA participation. We hypothesize 
that Magnetic Resonance Imaging (MRI) markers of proteoglycan 
density associated with PTOA development will improve after 8-
weeks of daily step promotion intervention. We also hypothesize 
that greater changes in steps per day will be associated with 
improved proteoglycan density. The proposed work is innovative, in 
that this study will use a novel combination of outcomes that will 
lead to unprecedented insight into the influence of daily step 
promotion in mitigating early PTOA development. 
Study Objective(s) 
Primary  
• 
Determine the change in MRI markers of proteoglycan density 
(i.e., cartilage composition) after 8-weeks of the daily step 
promotion intervention. 

Page 6 of 32 
 
• 
Determine the associations between change in free-living 
mechanical loading and change in MRI markers of proteoglycan 
density (i.e., cartilage composition) after 8-weeks of the daily 
step promotion intervention. 
Secondary 
• 
Determine the change in self-reported knee function after 8-
weeks of daily step promotion intervention. 
• 
Determine daily step promotion intervention retention and 
compliance. 
Test Article(s) 
(If Applicable) 
Daily Step Promotion Intervention 
Study Design 
 
Single Arm Pre-test Post-test Clinical Trial 
Subject Population 
key criteria for Inclusion 
and Exclusion: 
Inclusion Criteria: Completed all other formal physical therapy, 
between the ages of 18 and 35, underwent an ACLR no earlier than 
6 months and no later than 5 years prior to enrollment, 
demonstrate < 8,000 steps per day, demonstrate clinically relevant-
knee symptoms 
Exclusion Criteria: Underwent an ACLR revision surgery, multiple 
ligament surgery, lower extremity fracture diagnosed with 
osteoarthritis in either knee, cochlear implant, metal in body, 
claustrophobia, history of seizures 
Number Of Subjects  
 
We anticipate needing to consent up to 30 participants inorder to 
enroll 10 of those participants after the daily step screening phase 
(i.e., individuals taking less than 8000 steps). 
Study Duration 
Each participant who fully screens into the study will complete four 
visits that will last up to 12 weeks 
• Screening Visit = 45 minutes and 1 week of monitoring in 
free-living settings 
• Baseline Visit = 2 hours and 2 weeks of monitoring in free-
living settings 
• Intervention = 8 weeks 
• Follow Up Visit = 1.5 hours and 1 week of monitoring in free-
living settings 
The entire study is expected to last from May 2021 to April 2023. 
Study Phases 
Screening 
Study Treatment 
Follow-Up   
(1) Screening Visit: The initial visit will include initial screening (i.e. 
screening question and fill out Knee Injury and Osteoarthritis 
Outcomes Score quality of life (KOOS-QOL) subscale, 
enrollment, walking biomechanics assessment, and 
instructional use of actigraph PA monitor which will be worn for 
7 days during all waking hours. 

Page 7 of 32 
 
(2) Baseline: The second visit will include Fitbit and smartphone 
initialization, collection of patient reported outcomes and MRI 
scan of their knee. Participants will wear the fitbit monitor on 
their non-dominant wrist for 2 weeks during all waking hours in 
free-living settings in preparation for the intervention.  
(3) Intervention/Treatment: Between the second and third visit, 
participants will receive daily short message service (SMS) 
message with daily step count goals on their smart phone for 8 
weeks. The daily step goal is based on an adaptive step goal 
paradigm in which their daily goal is based on the top 60th 
percentile of steps over the last 10 days. 
(4) Follow up: The third visit will include the completion of surveys, 
returning the fitbit monitor, instructional use of the actigraph 
monitor for second wear period over 7 days, and MRI.  
Efficacy Evaluations 
Cartilage Composition: Cartilage composition (i.e. proteoglycan 
density) will be measured using T1ρ relaxation times (millisecond; 
[ms]) of medial and lateral tibiofemoral articular cartilage from MRI 
imaging. 
Daily Steps: Objective daily step counts measured via Triaxial 
accelerometer and averaged over 7 days or wear 
Self-Reported Knee Function: Knee-related quality of life assessed 
via the KOOS-QOL questionnaire. 
Feasibility Outcomes: intervention retention rates (%) and 
intervention compliance (%) 
Pharmacokinetic 
Evaluations 
N/A 
Safety Evaluations 
Medical Monitor & IRB, Routine Safety Reports, Expedited Safety 
Reports 
Statistical And Analytic 
Plan 
Estimation of effect sizes for pretest and posttest MRI measures of 
proteoglycan density (i.e., cartilage composition) changes will be 
analyzed with pooled Cohen’s d effect sizes and corresponding 95% 
confidence intervals to determine the magnitude of outcome 
differences between time points. The relationship between daily 
step changes and MRI measures of proteoglycan density (i.e., 
cartilage composition) changes will be analyzed using bivariate 
Pearson product moment correlation coefficients and 95% 
confidence intervals will be constructed using Fisher’s 
transformations to estimate the strength of the associations. 
DATA AND SAFETY 
MONITORING PLAN 
Data tracking, entry, editing, updating and reporting will be 
completed by study investigators.  
All data quality control will be performed by the Principal 
Investigator (PI). 
 

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1 
STUDY OBJECTIVES 
 
1.1 
Introduction 
OA is a leading cause of disability worldwide10 that affects millions of Americans each year.24 Patients 
with knee OA report many challenges to daily life including greater days in lost work,1 poor mental 
health,13 and persistent pain.3 Patients with PTOA, which occurs after knee injury, make up as many as 
35% of total knee OA cases.8 PTOA significantly impacts patients after ACL injury and ACLR surgery with 
approximately 50% of patients developing PTOA within 20 years of injury or surgery.30 Physical activity 
(i.e., daily step) promotion through is a focus of current clinical guidelines for prevention of OA 
progression following a musculoskeletal injury.34 
 
Approximately 57% of North Carolinians with a history of knee injury have a lifetime risk of 
symptomatic PTOA.33 Optimal free-living mechanical loading (i.e. steps per day) is critical for 
maintaining ideal knee joint health. After ACLR, altered mechanical loading is linked to PTOA 
development.4,35 Patients with ACLR take 25% less steps per day (~2000 steps) compared to uninjured 
controls as early as 6 months post-ACLR which results in insufficient free-living mechanical loading that 
can persist for years if not addressed.5 Our preliminary cross sectional data demonstrate that lesser 
steps per day is associated with MRI measures of poor proteoglycan density related to PTOA 
development after ACLR. Reestablishing optimal free-living mechanical loading through daily step 
promotion may prevent irreversible cartilage damage and address a critical gap in PTOA 
prevention.16,34 Pilot data linking sufficient free-living mechanical loading and healthy joint biology is 
needed to develop PTOA prevention interventions that is scalable to larger populations via existing 
technology. 
 
This novel pilot study will provide essential proof-of-concept data linking mechanical loading in real-
world settings with biology through cartilage proteoglycan density assessment. Previous research has 
incorporated MRI measures of proteoglycan density in observational studies. However, this is the first 
experimental study to our knowledge to incorporate cutting-edge in vivo MRI assessment of 
proteoglycan density to test a PTOA prevention strategy. Furthermore, physical activity promotion 
used in this study targets step counts which are easily interpretable and can be monitored by health 
care professionals or the general population. We have purposefully incorporated the use of 
commercially available, cost-effective activity monitors and smart phones to promote accessibility 
when developing future randomized control trials and translation for use by patients. This study 
provides the first step in translating small scale observational and feasibility studies into larger 
randomized control trials to develop interventions that mitigate the risk of PTOA in patients after ACLR. 
 
1.2 
Name and Description of Investigational Product or Intervention  
Daily Step Promotion Paradigm: All participants will be outfitted with a Fitbit Charge 2 activity monitor. 
The monitor will be worn during all waking hours, and compliance will be considered as a day with ≥ 
1,000 steps. Participants will complete a 14-day "run-in" observation period while wearing the Fitbit 
but no PA promotion will occur. Individuals who are noncompliant during the "run in" period (<10 days 
with <1,000 steps) will be removed. For the intervention, participants will receive a text message each 
morning with a personalized, daily step count goal and a link used to confirm receipt of the goal for 8 
weeks. The preceding 10 days of step data will be rank ordered and the 60th percentile step count will 
be set as the goal for the next day. 

Page 9 of 32 
 
1.3 
Risk-Benefit Ratio 
- Potential Benefits: This novel pilot study will provide essential proof-of-concept data linking 
mechanical loading in real-world settings with knee joint biology. The daily step promotion 
intervention used in this study targets step counts which are easily interpretable and can be monitored 
by health care professionals or the general population. We have purposefully incorporated the use of 
commercially available, cost-effective activity monitors and smart phones to promote accessibility 
when developing future randomized control trials and translation for use by patients. This study 
provides the first step in translating small scale observational and feasibility studies into larger 
randomized control trials to develop interventions that mitigate the risk of PTOA in patients after ACLR.  
 
There is the possibility that the subject may receive no direct benefit from participation. Using a PA 
monitor, like a Fitbit, has the potential to enhance the amount or intensity of PA in which a person 
participates. While all participants may not experience an improvement in their activity participation, it 
is possible that participation in this study may benefit some participants individually. 
 
- Potential Risks:  
• Risk of pain or injury from MRI 
o How to Minimize Risk: Participants will be screened at time of consent and the day 
before each MRI as per the protocol of the Biomedical Imaging Research Center to 
exclude those with cochlear implant, metal in body (i.e., non-surgical), claustrophobia, 
history of seizures, pacemaker, liver disease, high blood pressure, or diabetes from 
receiving an MRI. Participants will also wear ear plugs and offered MRI-safe headphones 
to protect their ears from loud noises. Both scanners are Food and Drug Administration 
(FDA)-approved and all new sequences will contain the same safeguards as standard 
(FDA-approved) clinical sequences to prevent harm to participants. 
• Risk that someone outside of approved research personnel could know participant information 
(breach of confidentiality). 
o How to Minimize Risk: The following actions will be taken to protect a participant’s 
private information: 1) Study personnel will have access to private consenting and 
research collection areas or participant interactions. 2) Data will only be inputted and 
reviewed by Institutional Review Board (IRB)-approved study personnel. 3) Paper 
records will be stored in locked filing cabinets and electronic files will be stored on 
REDCap and password-restricted, secure cloud-based storage maintained by a dedicated 
IT staff member in the Department of Exercise and Sport Science that can only be 
accessed by IRB-approved study personnel. 
 
1.4 
Relevant Literature and Data 
Individuals With Traumatic Knee Injuries Are a Representative High-Risk Population to Examine 
Mechanical Mechanisms of OA. OA is a leading cause of disability worldwide10 that affects millions of 
Americans each year.24 Approximately, 50% of individuals with a traumatic knee injury and surgery will 
develop radiographic OA within 20 years.30 OA significantly impacts individuals with ACL injury and 
ACLR at younger ages14 and leads to greater years lived with disability. Individuals post-ACLR 
demonstrate worse knee cartilage health25,45,48,50 and take an average of 1600 fewer daily steps 
compared to uninjured individuals28, both of which, may persist for years if not addressed. Therefore, 
individuals post-ACLR are a representative population to determine the effects of increasing loading 

Page 10 of 32 
 
frequency through daily steps on cartilage health because they have an increased risk of OA 
development6,9,26,30 and persistently take fewer daily steps compared to uninjured individuals.5,28 
Addressing underloading mechanisms in individuals at high-risk for OA is a unique opportunity to use 
non-pharmacological interventions to reduce the risk of OA and long-term disability. 
Low Loading Frequency is an Understudied Component of Altered Mechanical Loading on Knee Joint 
Health in Individuals at Risk for OA. OA has been historically and inaccurately described as a chronic 
disease of “wear and tear” implicating only overloading as the primary mechanical mechanism. 
However, animal models12,15,31,47 demonstrate that insufficient loading results in poor knee joint health 
providing a scientific basis to assess links of underloading and cartilage health in human models. 
Current evidence only supports that biomechanical underloading (i.e., lesser ground reaction force and 
knee moments) during a single step is associated with systemic biomarkers of cartilage degradation, 
poor cartilage composition measured via MRI T1ρ relaxation times, and OA post-ACLR.17,21,29,36-38,49,56 In 
comparison, only a few cross-sectional or longitudinal studies have linked low loading frequency with 
poor cartilage composition in individuals at risk7 or living with idiopathic knee OA.27,55 No studies to our 
knowledge have assessed the effects of increasing daily steps to recondition cartilage.  
Scientific Rigor of Using 8000 Steps to Classify Low Daily Step Group and Implementing Adaptive Daily 
Step Goals to Increase Loading Frequency. Individuals who take at least 7000-8000 daily steps 
consistently meet national weekly aerobic physical activity guidelines52,53 which provides empirical 
evidence to support the lower limit classification of 8000 daily steps to determine whether individuals 
6-12 months post-ACLR engage in low daily steps for. Adaptive daily steps goals are a feasible 
framework to increase loading frequency by over 2,000 daily steps in individuals at high risk for OA in 
as few as 8 weeks following initiation of the intervention.2,19 Furthermore, a previous study reports 
excellent compliance (97%) with this adaptive daily step goals framework in ACLR individuals.22 
Approximately, 50% of individuals 6-12 months post-ACLR take fewer than 8000 daily steps 
demonstrating that a substantial proportion of ACLR individuals will benefit from a daily step 
promotion. Therefore, individuals post-ACLR who take <8000 daily steps will be the target population 
for this study. 
 
Tibiofemoral Cartilage is Deconditioned and Less Resilient Following Traumatic Knee Injury and Surgery 
but Not Addressed in Recovery. Tibiofemoral cartilage T1ρ relaxation times increase after knee 
surgery23,45 (i.e., decreased proteoglycan density) and are greater in ACLR limb compared to the 
contralateral limb and limb of healthy controls (i.e., lower proteoglycan density).25,45,48,50 These results 
indicate that cartilage composition is compromised 6-12 months post-ACLR. Depletion of proteoglycan 
density in the extracellular matrix dampens the articular cartilage’s ability to resist loading.11,18,46 If 
cartilage is deconditioned and less resilient, then the tibiofemoral joint cannot resist excessive forces 
and may result in cartilage degeneration and increased risk of OA over time. There is a critical need to 
recondition the affected cartilage by increasing proteoglycan density (i.e., decreasing T1ρ relaxation 
times) in ACLR individuals. 
The Proposed Study Will Address Current Gaps by Establishing Proof of Concept Data if Increasing Daily 
Steps Can Recondition Cartilage by Improving Knee Joint Health. Previous studies in sedentary, 
otherwise healthy individuals report that progressively increasing loading frequency over 10-16 weeks 
increases cartilage proteoglycan density41,54 which supports the scientific rationale for implementing 
daily step promotion paradigm in the proposed study.  

Page 11 of 32 
 
1 
STUDY OBJECTIVES 
 
The overall objective of this pretest-posttest experimental pilot study is to determine how optimizing 
free-living mechanical loading through daily step promotion improves cartilage composition in 
individuals who demonstrate insufficient free-living mechanical loading after ACLR. 
 
1.4 
Primary Objective 
 
Aim 1. Determine the change in magnetic resonance imaging (MRI) markers of proteoglycan density 
after 8-weeks of daily step promotion. Hypothesis: Exposure to individualized physical activity 
promotion will decrease T1rho relaxation times (i.e. improve in vivo estimates of proteoglycan density) 
from pretest to posttest. 
 
Aim 2. Determine the associations between change in free-living mechanical loading and change in MRI 
markers of proteoglycan density after 8-weeks of daily step promotion. Hypothesis: Greater increases 
in steps per day will be associated with greater decreases in T1rho relaxation times (i.e. improve in vivo 
estimates of proteoglycan density) from pretest to posttest. 
 
1.5 
Secondary Objective 
 
Aim 3. Determine the change in self-reported knee function after 8-weeks of daily step promotion. 
Hypothesis: Self-reported knee function measured via the Knee Injury and Osteoarthritis Outcome 
Score Quality of Life Subscale will increase from pretest to posttest indicating improved knee related 
quality of life 
Aim 4: Determine intervention retention and compliance. Hypothesis: Participants will demonstrate 
≥90% retention and ≥95% compliance with monitor wear. 
2 
INVESTIGATIONAL PLAN (brief overview) 
 
2.1 
Study Design 
Type of design: Single-arm pre-test post-test clinical trial 
- 
Screening Visit: The initial visit will include initial screening (i.e. screening question and fill out 
KOOS-QOL subscale), enrollment, walking biomechanics assessment, and instructional use of 
actigraph physical activity monitor which will be worn for 7 days during all waking hours. 
 
- 
Baseline: The second visit will include Fitbit and smartphone initialization with MSU Researcher, 
collection of patient reported outcomes and MRI scan of their knee. Participants will wear the fitbit 
monitor on their non-dominant wrist for 2 weeks during all waking hours in free-living settings in 
preparation for the intervention.  
 
- 
Intervention/Treatment: Between the second and third visit, participants will receive daily SMS 
message with daily step count goals on their smart phone for 8 weeks. The daily step goal is based 

Page 12 of 32 
 
on an adaptive step goal paradigm in which their daily goal is based on the top 60th percentile of 
steps over the last 10 days. 
 
- 
Follow up: The third visit will include the completion of surveys, returning the fitbit monitor, 
instructional use of the actigraph monitor for second wear period over 7 days, and MRI. 
 
2.2 
Allocation to Treatment Groups and Blinding (if applicable) 
This study is a single arm study. All participants received the treatment so neither the participants nor 
the researchers were blinded to treatment allocation. 
 
2.3 
Study Duration, Enrollment and Number of Subjects 
 
Study Duration: The duration of an individual’s participation will last up to 12 weeks (3 months). The 
screening visit will last 45 minutes in-person and participants will wear the Actigraph physical activity 
monitor for 1 week in free-living settings. If participants screen into the study, then they will complete 
an in-person baseline visit which will last 2 hours and wear a fitbit on their wrist in free-living settings 
for 2 weeks. The intervention will last 8 weeks. The follow-up visit will last 1.5 hours in person and 
participants will wear the Actigraph physical activity monitor for 1 week in free-living settings. 
 
Enrollment: Once a potential participant has been identified and has indicated that he/she is interested 
in participating in the study, a study team member will then administer a screening questionnaire via 
telephone or in person at the orthopaedic clinic or laboratory to further assess eligibility. We will 
obtain participants’ verbal consent to ask a limited number of questions that include 
inclusion/exclusion criteria.  
 
Participants will be asked screening questions to determine if they are eligible for the study.  
 
If the individual meets self-reported screening criteria, score less than 87.5 on the KOOS-QOL, and are 
interested in participating, participants will provide written informed consent and sign a HIPPA form at 
the clinic. They will be outfitted with a research-grade actigraph accelerometer to monitor daily during 
free-living settings for 7 days and fill out the demographic form, knee injury history form. The actigraph 
will be secured on a belt and placed on the right hip. Participants will be instructed to wear the device 
for 7 days (removed for water activity and sleep). After 7 days, participants will return to the 
laboratory. If participants average <8000 steps per day over the wear period then they will continue 
with the baseline visit. 
Number of Subjects: We anticipate needing to consent up to 30 participants in order to enroll 10 
participants after the daily step screening phase (i.e., individuals taking less than 8000 steps) for the 
project because preliminary data suggested that 2/3rd of patients up to 5 years post-ACLR take less 
than 8000 daily steps.  
2.4 
Study Population 
We will include individuals who: 

Page 13 of 32 
 
• Provide informed consent and sign a HIPPA form prior to any study procedures are performed. 
• Have completed all other formal physical therapy and therapeutic exercise regimens, and will 
not be engaging in any other formal therapy for their ACLR during the study 
• Are between the ages of 18 and 35. 
• Underwent an ACLR no earlier than 6 months and no later than 5 years prior to enrollment. 
• Demonstrate < 8,000 steps per day during the screening phase of the study as assessed using 
the Actigraph GT9X Link monitor51 
• Demonstrate clinically relevant-knee symptoms, defined as a KOOS-QOL subscale score < 72.2.20 
This criteria was updated and approved by the IRB on 5/5/2022 to expand criteria to include 
individuals reporting KOOS QOL score <87.52.20 
 
Participants will be excluded if: 
• The participant underwent an ACLR revision surgery due to a previous ACL graft injury 
• Multiple ligament surgery was indicated at the time of ACLR surgery. 
• A lower extremity fracture was suffered during the ACL injury. 
• The participant has been diagnosed with osteoarthritis in either knee. 
 
Due to the MRI outcomes participants will be excluded if they have: 
• Cochlear implant 
• Metal in body 
• Claustrophobia 
• History of seizures 
 
3 
STUDY PROCEDURES 
 
3.1 
Screening Procedures 
 
Once a potential participant has been identified and has indicated that he/she is interested in 
participating in the study, a study team member will then administer a screening questionnaire via 
telephone or in person at the orthopaedic clinic or the laboratory to further assess eligibility. We will 
obtain participants’ verbal consent to ask a limited number of questions that include 
inclusion/exclusion criteria. If the individual meets self-reported screening criteria, score less than 87.5 
on the KOOS quality of life subscale, and are interested in participating, participants will provide 
written informed consent and sign a HIPPA form at the clinic. They will be outfitted with a research-
grade actigraph accelerometer to monitor daily during free-living settings for 7 days and fill out the 
demographic form, knee injury history form. The actigraph will be secured on a belt and placed on the 
right hip. Participants will be instructed to wear the device for 7 days (removed for water activity and 
sleep). After 7 days, participants will return to the laboratory. If participants average <8000 steps per 
day over the wear period then they will continue with the baseline visit. 
 
3.2 
Baseline Visit Procedures 
If participants average <8000 steps per day over the wear period then they will undergo an MRI at the 
Biomedical Imaging Research Center, complete surveys (KOOS) and be outfitted with a Fitbit Charge 2 
monitor on their wrist by a researcher. 

Page 14 of 32 
 
 
After this process is complete, participants will be connected to a member of the Michigan State 
University study team using a HIPAA compliant video conferencing platform. The investigator from 
MSU will guide the participant through monitor initialization and sync the monitor with the 
participant’s personal mobile device. The Fitbit Versa 2 is well suited for our study design based on its 
ability to display SMS messages on a digital interface, ease of charging, ability to wirelessly sync data 
using a smartphone, and ability to continuously capture daily steps using the Fitbit Application 
Programming Interface (API). Monitor will be worn during all waking hours, and compliance will be 
considered as a day with = 1,000 steps recorded. At this visit participants will be provided a handout 
that describes the physical activity promotion exposure, dates of the physical activity promotion (8 
weeks), and a reminder card indicating the date of their follow-up visit. 
 
3.3 
Intervention/Treatment procedures 
 
Detailed procedures can be found in “Appendix A. Extended Intervention Document.”  Following 
monitor initialization and registration, participants will complete a 14-day “run-in” period during which 
they will wear the Fitbit (=10 days of compliance) but no physical activity promotion will occur. This 
establishes participant compliance, understanding of the Fitbit, and baseline daily step data to 
generate the first individualized step goals for the physical activity promotion period. Individuals who 
do not meet compliance requirements needed to set the daily goals (>10 days with at least 1,000 
steps). Participants who are compliant will be exposed to physical activity promotion for 8 weeks. 
During this period of time, participants will receive an SMS message (or email if they don't have a 
smart phone) each morning containing a personalized step count goal for the day and a link which they 
will click to confirm receipt of the goal. To set the daily goal, the preceding 10 days of step data will be 
rank ordered and 60th percentile step count will be set as the goal for the following day. Calculation of 
daily goals will be automated, and will occur prior to our standard goal communication time (8 AM). 
 
3.4 
Follow-up procedures 
 
After the intervention, participants will be outfitted at the laboratory with the research-grade 
actigraph accelerometer to monitor daily during free-living settings for 7 days and fill out the surveys 
(KOOS). The actigraph will be secured on a belt and placed on the right hip. Participants will be 
instructed to wear the device for 7 days (removed for water activity and sleep). Participants will also 
undergo another MRI of the surgical limb at the Biomedical Imaging Research Center. 
 
3.5 
Unscheduled visits – N/A 
 
3.6 
Concomitant Medication documentation – N/A 
 
3.7 
Rescue medication administration (if applicable) – N/A 
 
3.8 
Subject Completion/ Withdrawal procedures 
 

Page 15 of 32 
 
A participant may be withdrawn from the study at any time if the participant or the investigator feels 
that it is not in the subject’s best interest to continue.  All participants are free to withdraw from 
participation at any time, for any reason, specified or unspecified, and without prejudice. A participant 
will be withdrawn from the study for non-compliance of the protocol or lost to follow-up. Reasonable 
attempts will be made by the investigator to provide a reason for subject withdrawals.  
 
3.9 
Screen failure procedures: 
 
A participant will screen out from the study if: 
 
1) They don't meet screening criteria (<8000 steps per day over 7 days during the initial actigraph 
physical activity monitoring period) 
2) They are non-compliant with the Fitbit monitoring "run in" observation period over 14 days. A 
participant will be determined non-compliant if they fail to accumulate 1,000 daily steps for more 
than 5 days during this period of time. 
Participants will be notified that they failed the screening to qualify for the intervention, return the 
actigraph or fitbit monitor, and not continue with the baseline visit, intervention, or follow-up visit. 
 
4 
STUDY EVALUATIONS AND MEASUREMENTS  
 
4.1 
Efficacy Evaluation (if applicable) 
 
Cartilage Composition: Cartilage composition will be measured using T1ρ relaxation times (ms) of 
medial and lateral tibiofemoral articular cartilage from MRI imaging. The measurement demonstrates 
excellent test-retest and inter-rater reliability.39 T1ρ relaxation times are inversely related to cartilage 
proteoglycan density. Lower T1ρ relaxation times or decreases in T1ρ relaxation times indicate greater 
proteoglycan density or increase proteoglycan density respectively. 
 
Daily Steps: Objective daily step counts measured via Triaxial accelerometer and averaged over 7 days 
or wear (i.e., Actigraph Link or Fitbit Charge 2)5,22,32 
Self-Reported Knee Function: The Knee Injury and Osteoarthritis Outcomes Score (KOOS) 
Questionnaire assesses the participant’s opinion about their pain, other symptoms, function in 
activities of daily living, function in sport and recreation and knee related quality of life. We will focus 
the primary analysis on the KOOS-QOL subscale, as it represents the most responsive KOOS 
subscale.42 The KOOS is a valid42 and reliable44 self-reported questionnaire of outcomes following knee 
specific injury and has been used previously by the PI.39,40 All other KOOS subscales will be collected 
and analyzed alternative analyses.43 KOOS QOL is measured on a scale of 0-100 with a greater score 
indicating better self-reported knee function. 
Feasibility Outcomes: intervention retention rates (%) and intervention compliance (%) 
 
4.2 
Pharmacokinetic Evaluation (if applicable)  - N/A 

Page 16 of 32 
 
4.3 
Safety Evaluations 
Medical Monitor: 
All adverse events will be reported to Dr. Troy Blackburn from the MOTION Science Institute at the 
University of North Carolina at Chapel Hill (UNC-CH). Dr. Troy Blackburn, Co-Director of the 
(MusculOskeleTal Injury preventiON) MOTION Science Institute, will be responsible for the 
independent safety monitoring since he is not a co-investigator or collaborator on this project. Dr. Troy 
Blackburn has previous experience as a PI in clinical trials for patients with knee injuries 
(NCT02605876) and therefore has the experience and knowledge regarding the scientific area of study 
and study design, which will be important in understanding the analysis and interpretation of the data 
to ensure participant safety as well as ethical, scientifically rigorous study conduct. 
 
Institutional Review Board 
The research described in this proposal meets the definition of human subject’s research of a 
biomedical or behavioral nature. As such, we have approval from human subjects research from the 
IRB for Biomedical Research at UNC-CH. This approval has been obtained prior to the recruitment or 
enrollment of study participants and the collection of any study-related data. The Michigan State 
University (MSU) study team and IRB for Biomedical Research will rely on the UNC-CH IRB for 
Biomedical Research as the single IRB for the duration of the proposed study. 
 
Routine Safety Reports and Expedited Safety Reports 
Dr. Lisee or Dr. Pietrosimone will report all adverse events (both serious and non-serious), 
unanticipated problems, study progress, and protocol deviations to the safety officer, Dr. Troy 
Blackburn (who is not affiliated with the study), on a biannual basis (every 6 months) or as requested in 
a detail and summary format. All adverse events (both non-serious and serious) will be collected, 
analyzed, and monitored in the study’s adverse event log, which is kept in Dr. Lisee and Dr. 
Pietrosimone’s regulatory files on a secured server. Dr. Troy Blackburn will also ensure the enrollment 
rate is consistent with the project timeline, verify that the participants meet enrollment criteria, and 
that each subject has been consented. Please see Section 7: Safety Management for more details. 
 
 
STATISTICAL CONSIDERATIONS 
 
 
4.4 
Primary Endpoint 
 
1.) T1rho relaxation times in the medial femoral condyle at pre-intervention: MRI marker of T1rho 
relaxation times of medial femoral articular cartilage (i.e proteoglycan density) at pre-intervention  
2.) T1rho relaxation times in the medial femoral condyle at post-intervention: MRI marker of T1rho 
relaxation times of medial femoral articular cartilage (i.e proteoglycan density) at post-intervention 
3.) T1rho relaxation times in the lateral femoral condyle at pre-intervention: MRI marker of T1rho 
relaxation times of lateral femoral articular cartilage (i.e proteoglycan density) at pre-intervention 
4.) T1rho relaxation times in the lateral femoral condyle at post-intervention: MRI marker of T1rho 
relaxation times of lateral femoral articular cartilage (i.e proteoglycan density) at post-intervention 

Page 17 of 32 
 
5.) T1rho relaxation times in the medial tibial condyle at pre-intervention: MRI marker of T1rho 
relaxation times of medial tibial articular cartilage (i.e proteoglycan density) at pre-intervention 
6.) T1rho relaxation times in the medial tibial condyle at post-intervention: MRI marker of T1rho 
relaxation times of medial tibial articular cartilage (i.e proteoglycan density) at post-intervention 
7.) T1rho relaxation times in the lateral tibial condyle at pre-intervention: MRI marker of T1rho 
relaxation times of lateral tibial articular cartilage (i.e proteoglycan density) at pre-intervention 
8.) T1rho relaxation times in the lateral tibial at post-intervention: MRI marker of T1rho relaxation times 
of lateral tibial articular cartilage (i.e proteoglycan density) at post-intervention 
9.) Change in daily steps: change in average steps per day over 7 day physical activity monitor wear pre-
intervention (baseline) to approximately 8-weeks (post-intervention) after physical activity 
promotion intervention 
10.) Change in T1rho relaxation times in the medial femoral condyle: change in MRI marker of T1rho 
relaxation times of medial femoral articular cartilage (i.e proteoglycan density) from pre-
intervention (baseline) to approximately 8-weeks (post-intervention) after physical activity 
promotion intervention 
11.) Change in T1rho relaxation times in the medial tibial condyle: change in MRI marker of T1rho 
relaxation times of medial tibial articular cartilage (i.e proteoglycan density) from pre-intervention 
(baseline) to approximately 8-weeks (post-intervention) after physical activity promotion 
intervention 
12.) Change in T1rho relaxation times in the lateral femoral condyle: change in MRI marker of T1rho 
relaxation times of lateral femoral articular cartilage (i.e proteoglycan density) from pre-intervention 
(baseline) to approximately 8-weeks (post-intervention) after physical activity promotion 
intervention 
13.) Change in T1rho relaxation times in the lateral tibial condyle: change in MRI marker of T1rho 
relaxation times of lateral tibial articular cartilage (i.e proteoglycan density) from pre-intervention 
(baseline) to approximately 8-weeks (post-intervention) after physical activity promotion 
intervention 
 
4.5 
Secondary Endpoint 
 
1.) KOOS-QOL subscale at pre-intervention 
2.) KOOS-QOL subscale at post-intervention 
3.) Daily step promotion intervention retention: percentage of patients retained at post-intervention 
visit 
4.) Daily step promotion intervention compliance: percentage of days participant is compliant with 
fitbit monitor wear (>1,000 steps per day) 
 
4.6 
Statistical Methods 
 
Owing to the preliminary nature and small sample size, we will emphasize estimation of effect sizes 
rather than formal inferential statistical hypothesis testing for future grant proposals. Pretest and 
posttest outcomes will be analyzed with pooled Cohen’s d effect sizes and corresponding 95% 
confidence intervals to determine the magnitude of outcome differences between time points. The 
relationship between outcome changes will be analyzed using bivariate Pearson product moment 

Page 18 of 32 
 
correlation coefficients and 95% confidence intervals will be constructed using Fisher’s transformations 
to estimate the strength of the associations.  
 
4.7 
Sample Size and Power 
We will enroll 10 individuals allowing for 18% attrition (n=2 individuals not completing the study) for a 
total of 8 participants. With 8 ACLR individuals at each time point, we will be powered (80% power, 
two-tailed alpha level of 0.05) to detect a strong time effect in proteoglycan density (d=1.2) and strong 
correlation (r=0.77) between change in steps and change in proteoglycan density. 
 
4.8 
Interim Analysis 
We are only collecting 8-10 participants as a proof-of-concept study for pilot data to support grant 
applications for larger clinical trials. Therefore, an interim analysis is not necessary. 
 
5 
STUDY INTERVENTION (DEVICE, DRUG, OR OTHER INTERVENTION) 
 
Detailed procedures can be found in “Appendix A. Extended Intervention Document.”  Following 
monitor initialization and registration, participants will complete a 14-day “run-in” period during which 
they will wear the Fitbit (=10 days of compliance) but no physical activity promotion will occur. This 
establishes participant compliance, understanding of the Fitbit, and baseline daily step data to 
generate the first individualized step goals for the physical activity promotion period. Individuals who 
do not meet compliance requirements needed to set the daily goals (>10 days with at least 1,000 
steps). Participants who are compliant will be exposed to physical activity promotion for 8 weeks. 
During this period of time, participants will receive an SMS message (or email if they don't have a 
smart phone) each morning containing a personalized step count goal for the day and a link which they 
will click to confirm receipt of the goal. To set the daily goal, the preceding 10 days of step data will be 
rank ordered and 60th percentile step count will be set as the goal for the following day. Calculation of 
daily goals will be automated, and will occur prior to our standard goal communication time (8 am). 
 
6        STUDY INTERVENTION ADMINISTRATION (IF APPLICABLE)  
N/A 
7. 
SAFETY MANAGEMENT  
 
Definitions: 
• Adverse Event (AE) - An adverse event is any unfavorable and unintended diagnosis, sign 
(including an abnormal laboratory finding), symptom, or disease temporarily associated with 
the study intervention, which may or may not be related to the intervention. AEs include any 
new events not present during the pre-intervention period or events that were present during 
the pre-intervention period, which increased in severity. 
• Serious Adverse Event (SAE) – A serious adverse event is any untoward medical occurrence that 
results in death, is life-threatening, requires or prolongs hospitalization, causes persistent or 
significant disability/incapacity, results in congenital anomalies/birth defects, or, in the opinion 
of the investigators, represents other significant hazards or potentially serious harm to research 

Page 19 of 32 
 
participants or others. 
• Unanticipated Problems – Unanticipated problems are not included in the 45 CFR part 46, but 
are defined by the OHRP as any incident, experience or outcome that meets all of the following 
requirements: 1) unexpected events that are 2) related or possibly related to participation in 
the research that 3) place subjects or others at greater risk of harm than was previously known 
or recognized. All three criteria above must be met to qualify the event as an unanticipated 
problem. 
 
Monitoring Roles: 
• Medical Monitor - A physician or other designated medical practitioner who is responsible for 
the day-to-day safety aspects of the study and can be consulted regarding individual 
participants. 
• IRB - A committee established the grantee/sponsoring Institution to review and approve 
research involving human subjects. The IRB ensures human subject research is conducted in 
accordance with all federal, institutional, and ethical guidelines. 
 
The research described in this proposal meets the definition of human subject’s research of a biomedical 
or behavioral nature. As such, we have approval from human subjects research from the IRB for 
Biomedical Research at UNC-CH. This approval has been obtained prior to the recruitment or enrollment 
of study participants and the collection of any study-related data. The MSU study team and IRB for 
Biomedical Research will rely on the UNC-CH IRB for Biomedical Research as the single IRB for the 
duration of the proposed study. The proposal is considered a low-risk study and an early phase clinical 
trial. As such, a formal Data Safety Monitoring Board may not be required. However, the final 
determination of the need for a Data Safety Monitoring Board will be made in collaboration with NC 
TraCS. 
Dr. Lisee and Dr. Pietrosimone will oversee data collection monitoring and all issues related to participant 
safety, data collection protocols, and participant confidentiality. Dr. Lisee and Dr. Pietrosimone will 
collect all adverse events for any study-related issues pertaining to safety and all adverse events will be 
reported to Dr. Troy Blackburn from the MOTION Science Institute at the UNC-CH. Dr. Troy Blackburn, 
Co-Director of the MOTION Science Institute, will be responsible for the independent safety monitoring 
since he is not a co-investigator or collaborator on this project. Dr. Troy Blackburn has previous 
experience as a PI in clinical trials for patients with knee injuries (NCT02605876) and therefore has the 
experience and knowledge regarding the scientific area of study and study design, which will be 
important in understanding the analysis and interpretation of the data to ensure participant safety as 
well as ethical, scientifically rigorous study conduct. 
It is not anticipated that there will be any significant physical or psychological risks associated with this 
study. However, federal regulations require prompt reporting to the IRB at UNC-CH, all injuries, adverse 
events, or other unanticipated problems involving risks to patients or others that occur during a patient’s 
participation in this research study. Study team members who become aware of any adverse event or 
unanticipated problems related to the study will notify Dr. Lisee or Dr. Pietrosimone, immediately. Study 
team members will have contact information for both PIs for daytime, evening, and weekend hours. If 
both Dr. Lisee and Dr. Pietrosimone are not available for contact when a study team member becomes 

Page 20 of 32 
 
aware of a study-related adverse event, Dr. Spang, the Medical Monitor on the study, will be contacted. 
Once Dr. Pietrosimone or the PI at MSU are contacted about the event, Dr. Pietrosimone will make 
appropriate reports in accordance with the UNC-CH IRB guidelines. This will include notification of the 
UNC-CH IRB and the Safety Officer.  
Dr. Lisee or Dr. Pietrosimone will report all adverse events (both serious and non-serious), unanticipated 
problems, study progress, and protocol deviations to the safety officer, Dr. Troy Blackburn (who is not 
affiliated with the study), on a biannual basis (every 6 months) or as requested in a detail and summary 
format. All adverse events (both non-serious and serious) will be collected, analyzed, and monitored in 
the study’s adverse event log, which is kept in Dr. Lisee and Dr. Pietrosimone’s regulatory files on a 
secured server. Dr. Troy Blackburn will also ensure the enrollment rate is consistent with the project 
timeline, verify that the participants meet enrollment criteria, and that each subject has been consented. 
8.  
DATA COLLECTION AND MANAGEMENT 
  
All data storing and sharing methods will be approved by the UNC-CH’s Institutional Review Board. 
 
In Person Study Data Protections: Prior to performing any study related activities, potential adult 
participants will provide written informed consent. All consent procedures will be completed by 
qualified and trained members of the study team. This includes informing each potential participant of 
the purpose of the project, possible risks, their personal rights, and potential benefits of the study. All 
possible exclusion criteria will be verified following informed consent. Extreme care will be taken to 
ensure that there will be no breach of participant confidentiality. 
 
Outcomes Data: All outcomes data will be managed using REDCap, which is a secure online platform for 
building and managing online databases provided at no cost to investigators at UNC-CH. The study team 
has been using REDCap for the past 5 years and is versed in building, acquiring and securing data using 
this database. REDCap also provides automated export to statistical packages (e.g. R, SPSS, and SAS) 
that will be used to analyze data from this study. UNC-CH also offers REDCap training twice a month as 
well as onsite support for assistance in building or managing REDCap databases. All pre-processed and 
post-processed Actigraph physical activity data, magnetic resonance imaging data, patient-reported 
outcome data will be stored electronically on a secure password-protected server maintained by UNC-
CH. Only investigators with IRB and PI clearance will be given access to the password-protected folders 
on the secure server. All individuals must have current UNC-CH online access credentials to access the 
server and personal access will be reviewed annually to purge or renew personnel access. The PI can 
remove access to the server for individuals if necessary. 
 
• Data Entry: data will be entered into REDCap from electronic files by investigators (i.e. processed 
magnetic resonance imaging data and joint tissue metabolism) or directly by study participants 
(i.e. demographics, patient-reported outcomes). Outcome measures will be cut and pasted from 
electronic files or collection software into REDCap to minimize data entry error. All outcome 
measure data will be entered by two individual investigators. 
• Data Editing: means and standard deviations for datasets will be calculated each month and 
crossed referenced between databases for each investigator. If means are different investigators 
will look to determine which outcomes differ. In the case that investigators cannot come to a 
consensus on the correct outcome measure, the PI will act as an arbiter. 

Page 21 of 32 
 
• Updating: data may need to be updated due to an error in data entry. After the incorrect data 
point has been determined the PI should be notified and the Signature Log should be signed 
indicating who changed data in the spread sheet, what data was changed, for what reason was it 
changed as well as the time and date it was changed. A new database with the current date 
should be created. The previous database with the error will not be deleted. 
• Statistical Analyses: data will be reported directly from REDCap to statistical analysis software 
for statistical analysis. 
 
Fitbit Data: Each participant will be assigned a unique participant identifier (PID) code generated and 
stored in the Microsoft Structured Query Language (SQL) database following the informed consent 
process. This PID code will be used to label participant data so that the data remain de-identified. Only 
investigators with IRB and PI clearance will be given access to the password-protected folders on the 
secure server which will be administered by a Co-Investigator. 
 
Fitbit Data Protections: We will be storing participant demographics, mobile device information, and 
Fitbit Versa 2 PA monitor-related data using Microsoft SQL Server database software. Data for each 
participant will be de-identified and stored with a unique study identifier to maintain confidentiality. 
We will utilize a normalized schema design which will facilitate indexing (for performance), strong data 
types (for stability and data integrity), and User-Level security to allow us to maintain access control lists 
for accessing data, reading data, writing data. Data backups will be done utilizing the software’s built-in 
backup scheduling mechanism. This will create daily, full, backup files that will reside in a designated 
storage location and access will be governed by an access control list which will allow us to maintain a 
need-to-know policy within the study team. This approach, using Microsoft SQL Server, will also allow us 
to take advantage of industry best-practice and facilitate the scaling of these practices in the future 
development of larger-scale clinical trials. For redundancy, we will backup files to separate external 
solid-state password protected hard drives on a weekly basis at both research sites. 
 
Methods and Systems to Ensure Data Confidentiality and Subject Privacy 
The privacy and confidentiality of research participants are to be respected and protected at all times. 
The proposed research study will comply with the HIPAA Privacy Rule as well as all other state, federal, 
and institutional regulations intended to protect the rights, safety, and welfare of human participants 
involved in research studies. We will attempt to minimize the collection, storage, and transmission of 
information containing patients’ personal identifiers, and, whenever identifiers are necessary, protect 
against unauthorized access or disclosure. In addition, we will employ several rigorous procedures for 
protecting against risks to participant privacy and confidentiality of data. We will only collect and store 
information about study participants that is relevant to the research as outlined in the protocol. All 
electronic data will be collected and stored on secure password-protected computers. Some paper 
documents, such as the consent form, will be required, and these will be stored in a locked file cabinet 
in a locked office of a study team member. We will establish a shared folder on a secure UNC-CH server 
to house all study data. This folder, as well as all study databases, will be password-protected, and only 
study team members who need access to these data will have permissions. Individual patient data will 
not be shared with individuals outside the study team, except as required by law and/or for regulatory 
purposes. All individuals on the study team must regularly fulfill certification requirements in Human 
Subjects Protection training. Study personnel are also regularly trained in stringent computer and 
information security procedures. All electronic study data will be securely backed up on a nightly, 
monthly, and biannual schedule. Monthly and biannual backups will be kept on static media throughout 
the duration of the study and for at least 5 years after study completion. Research study records will be 

Page 22 of 32 
 
maintained for no less than 7 years following the completion of the study, after which time personal 
identifying information will be removed. Research information in a participant’s medical record will be 
kept indefinitely. 
 
Process for Locking Final Data 
Following completion of the study, the PI will conduct a final evaluation to ensure all data has been 
inputted into the REDCap database. The PI, with assistance from MSU study team members will conduct 
a final evaluation to ensure all Fitbit data has been inputted into and stored in the SQL database. Then, 
the PI will notify the University REDCap Administrator to lock the REDCap study database and co-
investigator to lock the SQL study database. 
 
Planned Procedures for Data Access and Sharing 
At the conclusion of the study, datasets will be locked for the required amount of time as outlined by 
the University’s Institutional Review Board. At the conclusion of this period, data will be destroyed in 
accordance to the University’s Institutional Review Board. The UNC-CH has offices responsible for 
ensuring privacy and confidentiality standards and safeguarding data security at the recipient site to 
avoid manipulation of data with the intent of identifying participants. The UNC-CH is HIPAA compliant; 
therefore, any datasets generated from human participants will be free of any identifiers that would 
allow linkages to individual participants and variables that could lead to deductive disclosure of 
individual participants. The final dataset will include a comprehensive group of outcome measures 
(demographics, injury and surgical data, physical activity data, patient-reported outcomes, and 
magnetic resonance imaging of knee tissues). The entire dataset will link the outcomes and 
demographics but will be devoid of patient identifying information. We will make our data available to 
other investigators that contact the PI and provide written commitment to: 1) only use the data for 
purposes currently unplanned by the investigators, 2) only use the data for research purposes and not 
to contact patients or potential future research participants, as well as 3) destroy or return raw data 
following completion of data analysis. 
 
Data Request Process: Prior to authorizing data transfer the requesting PI must provide written specific 
aims for the study and regulatory approval from their institution for study of de-identified data. The PI 
of this study will decide on approving data transfer for the specific aims requested. The requestor must 
additionally request data use if new specific aims arise. The request process is meant to limit duplication 
of analyses. 
 
Data Sharing Process: Data will be stored on a secure server at MSU. Cleaned processed and 
unprocessed data will be stored in its original form and using the SQL database infrastructure. We will 
transfer de-identified data using a secure electronic server. This process will take place in 2 weeks of the 
initial request unless additional data cleaning is required. 
 
Privacy: De-identified data will always be transferred. 
 
 
9.        RECRUITMENT STRATEGY 
 
We will complete the following recruitment strategies for the proposed study: 
 

Page 23 of 32 
 
• Potential participants will be recruited verbally from classes following approval by individual 
course instructors. At this time, potential participants will be read a standard recruitment script 
detailing the inclusion criteria, procedures, duration, benefits, and potential risks associated 
with participation, and will be allowed to ask any questions pertaining to the investigation. All 
recruitment procedures will be conducted by members of the research team at the end of the 
specified class meetings. This will allow nonparticipating students the option of leaving the 
classroom, thereby alleviating pressure to participate. Individuals who are interested in 
participating and who meet the inclusion criteria will be provided with the PI’s contact 
information and asked to contact the PI to address any additional questions regarding the study 
and to schedule data collection. 
• Participants will be recruited via informational, IRB-approved flyers posted on the UNC-CH 
campus and in local rehabilitation clinics. 
• Participants will be recruited via an informational email posted on the UNC-CH server. In the 
event UNC students are recruited and enrolled in the study, they will be made aware their 
participation is completely voluntary, and their decision to enroll in the study, or to withdraw 
from the study at any time will not affect their grades or status as a student. Additionally, if a 
UNC employee is recruited and enrolled they will be made aware their participation in the 
study is completely voluntary and their decision to enroll or withdraw at any time will not affect 
their status as an employee. 
• Participants will be recruited using EPIC and physician referral from UNC Orthopedics or 
Campus Health (Co-investigators, Jeff Spang, Ganesh Kamath, and Robert Creighton). All 
subjects must receive physician approval to return to regular, unrestricted physical activity to 
be eligible for participation. Drs. Spang, Kamath and Creighton will provide subjects with 
information regarding participation in the study following the subject’s clinical visit at which 
this approval is obtained. 
• Participants will be recruited usingthe Carolina Data Warehouse. We will receive a list of 
patients with ACL reconstruction within the past 5 years from the Carolina Data Warehouse. 
This patient list will include names and multiple forms of contact information that will be used 
to contact potential subjects via telephone, letter/US Mail, or email depending on the available 
contact information to determine the individual’s interest in participating in the study. 
 
10. 
CONSENT PROCESS  
 
The screening and consenting process will be done in a private room. The study coordinator or 
research assistant will ask the potential participant screening questions based on the 
inclusion/exclusion criteria for the study. Participants will be included if they answer yes to the 
following questions: 
• Have completed all other formal physical therapy and therapeutic exercise regimens, and will 
not be engaging in any other formal therapy for their ACLR during the study 
• Are between the ages of 18 and 35. 
• Underwent an ACLR no earlier than 6 months and no later than 5 years prior to enrollment 
 
Participants will be excluded if they answer yes to the following questions: 
• The participant underwent an ACLR revision surgery due to a previous ACL graft injury. 
• Multiple ligament surgery was indicated at the time of ACLR surgery. 
• A lower extremity fracture was suffered during the ACL injury. 

Page 24 of 32 
 
• The participant has been diagnosed with osteoarthritis in either knee. 
 
The study coordinator or research assistants will verbally discuss the general protocol with the patient 
using the consent form as a guide. They will also briefly review the purpose of the project and any 
potential risks of the study. The consent form will be given to the patient to read. The participant will 
be reminded that engagement in research in voluntary and they can stop the study at any time. All 
major points about the study purpose, the study protocol including the daily step promotion 
intervention and data collection procedures, and risks to participating in the study will be reviewed 
verbally between the patient and the study coordinator or research assistants. The subject will be 
given time to consider the study and to discuss further with the study coordinator or research assistant 
if desired. After all questions have been answered and the subject shows verbal understanding of the 
study, signatures will be obtained and the subject will be given a copy to keep. The study member will 
also sign the consent form as the person obtaining consent. 
 
The PI or the Study Coordinator will be obtaining consent from subjects. The surgeons will not consent 
any of their own patients during the study. 
 
11.       PLANS FOR PUBLICATION  
 
The investigators of this study plan to publish the results of the study as a technical note or short 
report in the one of the following journals: Arthritis Care and Research, Journal of Athletic Training, or 
the Journal of Sports Rehabilitation. 
 
12.      REFERENCES  
 
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Knee Function, Symptoms, and Radiographic Osteoarthritis in Military Officers [abstract]. Arthritis 
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APPENDIX 
Appendix A. Extended Intervention Document
 

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