Physical Therapy Versus Internet-Based Exercise Training for Patients With Knee Osteoarthritis
Phase: NA
Conditions: Knee Osteoarthritis
Sponsor: University of North Carolina, Chapel Hill

 
 
 
 
 
 
 
 
 
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Physical Therapy Versus Internet-Based Exercise Training for Patients With Knee 
Osteoarthritis (PATH-IN) 
 
 
NCT Number: NCT02312713 
 
 
Date of the protocol: May 1, 2017  
 
 

 
 
 
 
 
 
 
 
 
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RESEARCH STRATEGY 
 
A.  Demonstrate that the condition imposes a significant burden on the health of individuals and/or 
populations (Criterion 1)  
A.1.0 Knee Osteoarthritis (OA) is Highly Prevalent.  Knee OA is one of the most common chronic health 
conditions in the U.S., affecting about 9.3 million adults 1.  Recent data show that 45% of people will develop 
symptomatic OA in their lifetime 2.  Knee OA disproportionately affects racial and ethnic minorities (particularly 
African Americans), women and individuals with lower socioeconomic status 2,3.  Because of the forecasted 
growth in the U.S. older adult population, the prevalence of knee OA is expected to rise dramatically over the 
next several decades 4.  In addition, studies show knee OA is occurring earlier in the life course, affecting 
younger adults more often than in previous years 5,6.  This is likely due to the increased incidence of traumatic 
knee injuries and obesity, two main risk factors for knee OA.  The rising prevalence and earlier occurrence of 
knee OA highlight the need for effective disease management strategies.  
A.2.0  Knee OA Has A Significant Negative Impact on Many Patient-Centered Outcomes.  Pain is the 
leading concern for patients living with knee OA and the most common reason for seeking health care for this 
condition 7. However, pain is only one of many patient-centered outcomes negatively affected by knee OA.  
Disability and functional limitations are also very common.  In fact, OA is the most frequently reported cause of 
disability in the U.S. 8, commonly affecting walking, stair-climbing, and other daily tasks 9.  Among older adults, 
disability from knee OA is as great as that due to cardiovascular disease and greater than any other medical 
condition 9.  Data from the National Health Interview Survey show that people with arthritis-related disability 
(including knee OA) have more numerous, longer, and more bothersome disabilities than people with heart 
disease-related disability 10.  Many studies have also shown that OA negatively impacts a wide range of other 
outcomes including sleep difficulties 11,12, fatigue 13, depressive symptoms and other aspects of psychological 
health 14, work limitations 15, social participation 16, and overall quality of life 17,18.    
 
The following quotes from patients in our recent focus groups illustrate the impact of knee OA from the 
patient perspective:  “Getting up your normal daily movement is what you might say restricted…because it’s an 
enormous amount of pain.”  “I take a lot of (work) leave.  And it bothers me so bad that I have to take a lot of 
leave just to sit at home and lay at home.  I just can’t sand the pain.”  “When I go through it (OA pain), it’s like it 
turns my whole day around.  Because it’s like you’re thinking that ‘cause you’ve already promised people 
you’re going to be somewhere…so you really have to fight through that pain.” 
 
B.  Explain how the results of the study would likely improve health care and outcomes (Criterion 2) 
B.1.0  Overview of the Project’s Impact on Health Care and Outcomes. This project has great potential to 
impact health care performance and outcomes by evaluating strategies to improve pain, function, and other 
patient-centered outcomes among the large number of patients with knee OA.  As described below, physical 
activity is a key component of managing knee OA symptoms and minimizing functional limitations.  However, 
the majority of adults with knee OA are physically inactive, and additional evidence-based strategies are 
needed to help these patients to adopt and maintain regular activity 19-21.  Physical therapy (PT) is one 
resource for instructing patients with knee OA in an appropriate exercise program.  However, as described 
below, there are limitations to PT services that may particularly impact medically underserved patient groups.  
This study will compare the effectiveness of standard PT and a novel, tailored internet-based exercise training 
(IBET) program that could be disseminated widely and therefore improve physical activity levels and 
associated patient-centered outcomes among many patients with knee OA.   
B.2.0  Physical Activity is a Key Component of Managing Knee OA but Highly Underutilized.  Many 
studies have confirmed that both aerobic and strengthening exercises improve pain, function, and other key 
outcomes among patients with knee OA 22,23.  A meta-analysis of clinical trials of exercise for knee OA found 
that pooled effect sizes (e.g., magnitude of treatment response) for aerobic exercise were 0.52 and 0.46 for 
pain and disability, respectively; for strengthening exercises, pooled effect sizes were 0.39 and 0.32, 
respectively 24. These are medium-to-large effect sizes are comparable to those observed for pharmacological 
treatment of OA 25.  Based on this evidence, exercise is considered a cornerstone of managing knee OA 26,27. 

 
 
 
 
 
 
 
 
 
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However, despite the strong evidence for exercise in managing OA symptoms, the majority of adults with OA 
are physically inactive 28,29.  In a recent study of adults who had or were at risk for knee OA, only 2% of African 
Americans and 13% of whites were currently meeting guidelines for physical activity 29.  Recent data from the 
Centers for Disease Control and Prevention (CDC) show that among US adults with arthritis (primarily OA), 
over half report doing 0 minutes of walking per week, and 66% reported <90 minutes of walking per week 
(which is the minimum amount of weekly walking shown in a randomized clinical trial to lower pain and improve 
function) 30,31.   In addition, health care providers often do not incorporate recommendations to exercise for 
patients with OA and other musculoskeletal conditions 32,33.  Primary reasons for low rates of exercise 
recommendations include: limited contact time with patients, lack of knowledge of clinical guidelines and 
appropriate exercises, and lack of support materials 34,35.  These barriers can all be addressed by the proposed 
internet-based exercise training program.  
B.3.0  Physical Therapy is a Resource for Helping Patients with OA to Increase Exercise, but There are 
Access Limitations.  PT is a recommended component of treatment for patients with knee OA 26,27,36, typically 
focusing on evaluation of patients’ functional limitations and prescription of a home exercise program. Although 
PT is clearly an important resource for helping patients with knee OA to increase physical activity, there are 
limitations in multiple dimensions of access to PT for patients with knee OA.  First, there is a nationwide 
shortage of physical therapists to meet this demand.  A recent model projecting the supply and demand of 
physical therapists between 2010 and 2020 indicates a shortage between 9,000 and 41,000 therapists in the 
US 37. Second, in addition to a general shortage of physical therapists, there are medically underserved areas 
in which therapists are even rarer or lacking entirely.  This is particularly important because patients who are 
more likely to reside in medically underserved areas (e.g., racial and ethnic minorities, individuals with lower 
socioeconomic status) are also those who bear a greater burden of knee OA 3,38,39.  Third, patients without 
health insurance have little or no affordable access to PT services.  Even for insured patients, copayments 
often make this service cost-prohibitive, and this challenge is likely to continue for low income patients despite 
the implementation of the Affordable Care Act.  Fourth, even for patients with adequate health insurance, the 
number of covered PT visits for knee OA has been declining, and the number of allowed visits is not sufficient 
to provide patients with the instruction, and support needed to adopt and maintain an exercise program, 
particularly in the context of a chronic pain condition 40.  Fifth, some patients opt not to seek PT for knee OA 
because of time and schedule constraints, even when insurance and copayments are not a barrier.  All of 
these access-related issues highlight a need for novel, alternative methods to provide patients with knee OA 
with instruction and support physical activity.  In fact, there is widespread consensus that evidence-based 
interventions are needed to help adults with OA to adopt and maintain adequate levels of physical activity 19-21.  
In the 2010 National Public Health Agenda for Osteoarthritis, the second overall recommendation (out of 10) 
for reducing the burden of OA in the US is to “widely promote programs of low impact, moderate intensity 
aerobic activity and muscle strengthening exercise for adults with knee and hip OA.”  A specific priority is to 
“increase access and continue to identify additional effective packaged programs for physical activity that can 
be delivered safely in a variety of acceptable and accessible formats and settings.” These points have all been 
echoed by the patient stakeholders involved in this project, who voiced a need for instruction, support, and 
accountability to help them in being physically active.     
B.4.0  Internet-Based Physical Activity Programs Can be Widely Disseminated, but Evidence is Needed 
in Knee OA.  There has been increasing use of the internet to deliver physical activity and other behavioral 
programs 41.  While face-to-face PT visits and other physical activity programs clearly have value, there are 
several important opportunities associated with internet-based delivery.  First, internet-based programs can be 
delivered widely at relatively low cost.  Second, these programs remove transportation related barriers and 
offer flexibility in terms of the times in which patients can access the program.  Third, internet-based programs 
can allow tailoring of physical activities to individuals’ preferences and abilities; this is important because 
research has supported the utility of a tailored approach to physical activity 42.   
A number have studies support the effectiveness of internet-based physical activity programs 41.  However, 
the majority of studies have focused on young and middle-aged adults, with very little research targeting 
individuals ≥65 43.  This is an important limitation when considering patients with knee OA.  A recent study 
evaluated a 12-week internet-based physical activity program among sedentary older adults 43.  The program 
involved both video-based and text format guidance and offered an individually tailored approach to physical 

 
 
 
 
 
 
 
 
 
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activity recommendations.  This program resulted in significant increases in all types of physical activity, as 
well as significant improvements in physical function and mental health. Another recent small study of an 
internet-based program was also effective in improving physical activity levels among sedentary older adults 44. 
To our knowledge, no large clinical trials evaluating internet-based physical activity programs for knee OA 
have been completed.  One ongoing Canadian study is evaluating a physical activity website specifically for 
patients with early knee OA 45.  Studies have also shown significant improvements in physical activity and 
function following internet-based physical activity programs for patients with rheumatoid arthritis and following 
knee replacement surgery 46,47. Collectively this early evidence supports the feasibility and potential for 
internet-based physical activity programs among patients with knee OA, but large randomized controlled trials 
are still needed to establish this evidence base, particularly across the spectrum of knee OA from early to late 
stages.  The CDC maintains a list of physical activity programs (accessible on their website) that have an 
established evidence base for individuals with arthritis.  This list includes no internet-based interventions.  
Although there are some commercially available internet-based physical activity resources, these are not 
geared toward patients with lower extremity OA and do not include patient-specific tailoring based on 
consideration of pain and functional limitations.   
One limitation to an internet-based intervention is that not all patients with knee OA have regular internet 
access.  We also recognize that this may be a particular barrier for patients who live more rurally or have lower 
socioeconomic status.  However, the proportion of adults who use the internet regularly has been steadily 
rising, with about 85% of US adults reporting they are internet users; this includes 70% of adults age 50 and 
older and 80% of those dwelling in rural geographic regions 48.  Therefore we believe an internet-based 
program will be valuable to a large number of patients.  In addition, the internet-based program we propose to 
examine in this study is currently being converted to a mobile health platform, which will further increase reach, 
as internet use via cell phone is growing rapidly 49.    
B.5.0  Preliminary Data Support the Efficacy of an Internet-Based Exercise Training Program for 
Patients with Knee OA.  Visual Health Information developed and pilot tested a tailored, internet-based 
exercise training program for knee OA, through a Small Business Innovations Research Grant from NIH 
(1R43HD065358). Here we describe the rigorous development process and initial testing that support the 
potential of this tool to improve health care and outcomes.  
IBET Development Process.   
This system was developed by a multidisciplinary team, including substantial input from patients, 
physicians, and physical therapist collaborators. Main steps in the development process included: 
1.  Development of a preliminary website that allowed patients with knee OA to view animated models 
executing prescribed exercises, followed by a small validation study.  
2. Focus groups with physicians who treat patients with knee OA to obtain input on the design and features of 
a comprehensive IBET website. 
3. Development of the IBET website, including the following activities:  
a. Creation of exercise routines at five levels across a continuum of patient functional abilities, based on 
clinical practice guidelines and peer-reviewed publications. A panel of orthopedic surgeons, physiatrists, 
rheumatologists and physical therapists contributed to selection of appropriate exercises and placed them 
into five levels of difficulty. There are 30 possible exercises within each of the five levels. Exercise routines, 
randomly generated within each level, always include strengthening exercises that target multiple muscle 
groups, with a focus on those that support the knee, as well as stretching exercises.   
b. Development of an algorithm for placing patients into the five exercise levels.  This is based on the 14-
item modified short form of the Western Ontario and McMaster Universities Osteoarthritis Index (mSF-
WOMAC) 50 and several additional items that assess current physical activity, exercise ability, and use of 
assistive devices.  The algorithm was compared to the exercise level recommended by practicing physical 
therapists, for eight test patients. The physical therapists were familiarized with the content of the five 
exercise levels, performed a live intake evaluation of the patients, and placed patients into one of the 
exercise levels.  Each patient was independently evaluated by two physical therapists.  The algorithm 
consistently assigned patients into slightly lower exercise levels than suggested by the physical therapists.  
This was considered appropriate and desirable from the standpoint of patient safety and initial adherence, 
particularly since patients can request a higher level of exercise at any point in the program.  

 
 
 
 
 
 
 
 
 
5
c. Creation of exercise animations. Under the supervision of a physical therapist, Dr. Heiderscheit 
(consultant on the proposed project), each exercise was motion captured in a biomechanics laboratory. Retro 
reflective markers were placed on specific anatomical landmarks of the model subject and were 
subsequently animated. All animated exercises were then reviewed by five physical therapists to assure they 
represented the correct technique for performing the exercise.  
IBET General Description and Features 
Initial Assignment and Display of Exercises. When patients first log into the IBET site, they complete a brief 
set of measures, described above, to determine their initial exercise level.  Next, patients may select the 
gender and ethnicity (Caucasian, African American, Asian or Hispanic) of the animated model that 
demonstrates the correct technique for performing each exercise.  Each time patients log in to the system, a 
static version of their strengthening and stretching exercises is displayed.  Patients can click on each exercise 
to view the animated version. These files use vector graphics and can be made extremely small, allowing for 
nearly instantaneous presentation of the animations even with slow Internet connections.  Patients are also 
prescribed aerobic exercises, corresponding in intensity to the five levels of strengthening / stretching 
exercises. After completing each exercise session, patients are asked to record their performance of the 
exercises in the website.   
Changing Exercise Levels. At the end of each session patients are also given the option to move to a 
harder or easier workout at the next session. When patients opt for exercise progression, they are prompted to 
complete another web-based version of the mSF-WOMAC. If patients’ mSF-WOMAC scores are higher 
(worse) than previously, they are not advanced to the next level yet but are instead given a new exercise 
routine at their current level  If patients’ mSF-WOMAC score is less than (better) or equal to their previous 
mSF-WOMAC score, they are allowed to progress within the exercise continuum.  As patients progress to 
more difficult levels, their exercise routine may contain more difficult exercises, previously assigned exercises 
with increased weight, more sets or repetitions, or an increase in the number of exercises. If patients request 
an easier exercise routine at any point, they are first advised that slight increases in pain or discomfort are 
common when beginning an exercise program, and they may want to try icing and rest and then resume their 
current exercise program but consider reducing the frequency initially.  However, participants may still choose 
to immediately receive a new exercise program at an easier level.  In addition, if patients have difficulty with 
any particular exercises (e.g., it is painful or they cannot get into the required position), the system also 
provides an option to exchange that exercise for another within the same level.  
Pain Monitoring. Patients are also asked to report any increased pain as a result of their exercises.  If 
patients record increased pain for three consecutive settings without requesting a lower exercise level, they are 
sent an email suggesting they consider trying an easier exercise level.  If patients do not record having 
increased pain for two weeks and have not requested an increase in exercise level in that interval, they are 
sent an email suggesting they consider trying a more difficult level.   
IBET Pilot Study Data 
Design.  This was single group, pre- and post-training study to assess the acceptability, feasibility, and 
preliminary efficacy of the virtual exercise training website.   
Participants and Procedures. Participants were 10 primary care physicians and 42 of their patients 
(approximately 4 per physician) who had been diagnosed with knee OA.  Patients were identified by the 
primary care providers.  Eligible patients were provided with an access code for the IBET site, along with 
written instructions for entry.  Patients completed all baseline assessments within the IBET site and were 
assigned an exercise routine as described above.  After eight weeks of access to the IBET site, patients were 
asked to complete an online post-intervention assessment.   
 Results.  Participants’ average age was 62 years (SD=9); half were female; 40% had less education than a 
4-year college degree.  Use of the website was high. On average participants logged into the website 5.87 
times per week and reported completing exercises 4.7 times per week.  Table 1 shows mean baseline and 
follow-up scores for key study measures. The mSF-WOMAC decreased by about 7 points, which is a  
Table 1.  Results of IBET for Knee OA Pilot Study  
 
Baseline 
8-Week Follow-up 
Test Statistics 

 
 
 
 
 
 
 
 
 
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substantial 
improvement and a 
large effect size. 
The World Health 
Organization Quality 
of Life (WHOQOL)51 
physical subscale 
and Knee Self-Efficacy  Scale 52 also improved significantly.  The WHOQOL psychological subscale improved, 
though this did not reach statistical significance.  Over three-quarters of the participants indicated their knee 
symptoms improved “some” or “a lot” since the beginning of the study, and 43% reported a reduction in the use 
of pain medication. Patients also indicated a high degree of satisfaction with the program.  On a scale of 18 
items assessing satisfaction with covering a broad range of aspects of the program and website (range 0-4), 
the mean score was 3.0 (SD=0.5).  Also confirming patient satisfaction with the website, 78% indicated that 
they would like to use the site in the future.   
B.6.0  Other OA Studies at the Duke and the Durham VA Medical Center (VAMC). Dr. Allen and 
colleagues have conducted other studies among patients with OA at Duke and the Durham VAMC that are part 
of an ongoing program of research in this patient group.  One trial, Self-Management of Osteoarthritis in 
Veterans: A Telephone-Based Intervention (VA HSR&D IIR 04-016), showed that the intervention resulted in 
significant improvements in pain other patient-centered outcomes 53,54.  Dr. Allen is also currently Principal 
Investigator of two clinical trials at Duke and the Durham VAMC, Patient and Provider Interventions for 
Managing Osteoarthritis in Primary Care (VA HSR&D IIR 10-126; NIAMS R01 AR059673-010) 55. These 
studies are collectively enrolling n=860 patients with knee and hip OA and are examining combinations of 
patient (telephone-based) and provider interventions, with an emphasis on non-pharmacological treatments.   
 Another clinical trial led by Dr. Allen at the Durham VAMC is evaluating Group Physical Therapy for Veterans 
with Knee Osteoarthritis (VA HSR&D IIR 09-056) 56.  This study is comparing group-based vs. traditional 
individual-based PT for knee OA, hypothesizing that the group approach will result in superior outcomes (due 
to the overall increased number of contact hours per veteran and the group support), while requiring fewer 
resources to deliver.  The proposed study is substantially different from our other work, evaluating a different 
modality, internet-based physical activity programming, for improving outcomes among patients with knee OA.  
However, these studies demonstrate our research teams experience with conducting large randomized clinical 
trials of behavioral interventions for patients with knee OA at our two proposed enrollment sites.  
 
 C. Demonstrate the technical merit of the application (Criterion 3)    
C.1.0  Study Design. This will be a randomized controlled trial with participants assigned to three groups: 
Standard PT for knee OA, IBET for knee OA, and wait list (WL) control, with allocation of 2:2:1, respectively. 
Participants will be stratified by enrollment source (described below) to ensure groups are balanced in this 
respect. The three measurement time points will be at baseline, four months, and 12 months (Figure 1 below).  
The duration of physical activity and PT interventions for individuals with knee OA have varied widely.  
Although some positive effects were observed after eight weeks in the pilot study of the IBET program, we 
have chosen a four month duration for the initial intervention period in this larger trial because, based on prior 
research, this is an adequate time period to observe meaningful changes in pain and function 57.  The 12-
month assessment will evaluate whether there are sustained effects beyond the initial intervention period.  The 
IBET group will continue to have access to the website between the 4-month and 12-month assessment 
points. We have chosen to continue website access during this period to simulate the manner in which the 
IBET could feasibly be delivered in the healthcare and other settings. Specifically, organizations could continue 
access to this website for a more extended period of time at little or no additional resources expended per 
patient. Following completion of the 12-month assessments, participants assigned to the WL control group will 
receive two PT visits plus access to the IBET intervention.  (Participants in this group will have no other 
 
Mean 
SD 
Mean 
SD 
t-value 
p-value 
pr 
mSF-WOMAC 
18.07 
7.75 
11.14 
8.47 
6.19 
<.001 
.70 
WHOQOL-Physical 
65.55 
16.53 
70.52 
14.53 
-2.11 
.041 
.31 
WHOQOL-Psychological 
73.81 
13.98 
75.62 
13.91 
-1.09 
.280 
.17 
Knee Self-Efficacy 
16.10 
4.62 
18.67 
5.93 
-4.02 
<.001 
.53 
SD=standard deviation; pr = point-biserial partial regression coefficient as measure of effect 
size with .14 small, .36 medium, and .51 large effect (Rosnow & Rosenthal, 2008).  

 
 
 
 
 
 
 
 
 
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assessments after their exposure to these interventions.)  Participants in all study groups will continue with 
their usual medical care they receive for OA during the full study period.     
C.2.0  Enrollment Sites.  We will enroll patients from two geographic regions and settings, to enhance 
generalizability.  First, we will enroll patients who have sought care for knee osteoarthritis from the University of 
North Carolina at Chapel Hill (UNC), a large not-for-profit healthcare system that provides both primary and 
specialty care.  Over 800,000 people receive outpatient care at UNC clinics annually.  Second, we will enroll 
participants with symptomatic knee OA from the Johnston County Osteoarthritis Project (JoCo OA), an ongoing 
study in rural North Carolina 58.  African Americans and 
individuals age 60 years of age and older comprise about 20% 
and 17% of the county’s population, respectively.  Households 
with limited education and lower income are common; 35% of 
individuals over age 25 have less than a high school diploma 
and 30% of jobs involve manufacturing, service or farming. 
Therefore this county and the JoCo OA study have a high 
prevalence of sociodemographic groups at high risk for OA, 
greater OA severity, and limited healthcare access.     
 C.3.0  Participant Eligibility Criteria.  This study will involve 
n=350 patients with symptomatic knee OA who meet the 
following criteria for at least one knee:        
• 
Physician Diagnosis of Knee OA.  For participants enrolled 
from the UNC healthcare system, this will be identified from 
electronic medical records and based on prior radiographic or 
MRI findings. For participants enrolled from JoCo OA, this will 
be identified from previous study-based radiographs and report 
of knee symptoms. 
Current Joint Symptoms.  We will use the following validated 
item: Do you have pain, aching or stiffness in one or both of your knees on most days of the week?  Exclusion 
criteria will be assessed from electronic medical records (UNC participants), study records (JoCo OA 
participants) and telephone screening.  A detailed list of exclusion criteria is shown in the Human Subjects 
Protection section.  Briefly, main exclusion criteria include:  no regular internet access, currently meeting 
physical activity guidelines, currently receiving PT for knee OA, health conditions that may make participation 
in mild to moderate physical activity unsafe, and pain-related conditions that could confound study outcomes.   
Based on the patient populations in our enrollment sites and experience from our previous studies, there will 
be an ample number of patients eligible for the proposed study.  Our estimate of potentially eligible patients at 
UNC is based on the number of outpatients age 55, n=119,517, and the prevalence of symptomatic knee OA 
in this age group (about 12%) 59,60.    Based on these numbers, we estimate there will be a total of over 14,000 
patients with knee OA at UNC. Given this large number, we will be able to focus recruitment on patients who 
live within reasonable driving distance to study enrollment sites and physical therapy clinics (which still 
encompasses a range of geographic regions in terms of urban / rural status). In JoCo OA, there are 
approximately 330 participants with radiographic, symptomatic knee OA.  In our recent trial of telephone-based 
osteoarthritis self-management 54, which also enrolled patients with hip and / or knee OA, 29% of patients who 
met initial eligibility criteria were ultimately eligible and consented to participate. We acknowledge that the 
enrollment rate for this study may be lower because of the requirement of regular internet access.  However, 
even if the enrollment rate was as low as 15%, this would translate into 50 patients from JoCo OA and over 
2,000 from UNC.  This exceeds our sample size goal, and we will enroll as many patients as possible from 
JoCo, since this is the smaller of the two enrollment sites.  
C.4.0  Enrollment Procedures. We will include three methods of recruitment, which we have successfully 
utilized in prior studies at Duke and the Durham VAMC. First, we will use a variety of methods to advertise the 
study to potential participants.  These may include: posting flyers and brochures in UNC clinics and other 
locations in the community; advertisements on a UNC website, physical therapy clinic websites, and other 
websites appropriate for reaching our target patient group; advertisements in newsletters, magazines and other 
appropriate print media; email blasts to UNC employees; advertisement on the UNC closed circuit television.  

 
 
 
 
 
 
 
 
 
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Second, UNC providers will be given flyers and brochures that they may distribute to patients. These self-and 
provider-referral activities will be conducted in a variety of UNC clinics and community locations that serve 
diverse groups of patients, particularly with respect to insurance and socioeconomic status.  For example, we 
will include the UNC Ambulatory Care Center, a large “safety net” clinic. Third, we will use UNC medical 
records to identify patients with diagnoses of knee OA and no exclusionary diagnoses, based on ICD-9 codes. 
Similarly, we will use data from JoCo OA to identify participants with verified knee OA or chronic knee 
symptoms that may be a sign of knee OA and no known exclusionary diagnoses. We will mail and or e-mail 
introductory letters to these individuals on behalf of the study team. Inclusion of this “direct contact” recruitment 
method is important for reaching eligible, interested patients who are not reached by self- or provider-referral 
methods; this enhances both the “accessibility” of the study to patients and the generalizability of the 
participant sample.  For all potential participants we will conduct a brief telephone screening questionnaire to 
verify for eligibility.  This will include questions that pertain to the American College of Rheumatology clinical 
criteria for knee OA.  .  We will obtain participants’ permission to ask a limited number of questions. If patients 
meet telephone screening criteria and are interested in participating, they will be asked to meet a study team 
member to complete consent, HIPAA authorization, and baseline assessments.  Following baseline 
assessments, participants will be given their randomization assignment by the project coordinator via 
telephone (since the research assistant who conducts baseline and follow-up assessments will be blinded to 
participants’ group assignment).  Randomization will be based on a computer generated sequence maintained 
by the project statistician or programmer.   Participants assigned to the standard PT group will then be 
scheduled for their initial visit.  Participants assigned to the IBET group will be given instructions and an 
individual code to access the website, as well as ankle weights and resistance bands.  Participants randomized 
to the WL group will be informed they will be provided with two PT visits and access to the IBET website after 
their follow-up assessments are complete.   
C.5.0  Internet-Based Exercise Training Program. Participants randomized to the IBET group will be 
provided with access to the website described in detail above (Section B.5.). They will be encouraged to 
access the system starting as soon as they are enrolled in the study and through the 12-month follow-up 
assessment.  Participants will be able to access the website as often as they like and may log their exercise 
daily.  If participants do not interact with the website for seven days, they will receive an email encouraging 
them to access the website, and most importantly to remain physically active. In accordance with current 
Department of Health and Human Services and other guidelines for physical activity among older adults 61, we 
will encourage participants to complete strengthening and stretching exercises, guided by the IBET website, at 
least three times per week. Because the strengthening exercises are relatively low intensity and based on 
experience with the pilot study, we do not believe there are safety concerns if participants choose to perform 
strengthening exercises more than three times per week.  However, as described above, if participants do 
experience an increase in pain, they will be advised to rest and then reinitiate their exercise program, 
considering a reduced frequency initially.  Also in accordance with physical activity guidelines, participants will 
be told that it is safe and appropriate to perform aerobic exercises daily, or as often as possible, guided by the 
recommendations on the IBET website for their current exercise level.  An overall guiding principle is that 
participants will be encouraged to be as physically active as their abilities, health conditions, and pain allow.   
Some of the strengthening exercises included in the IBET program involve ankle weights and resistance 
bands.  Therefore we will provide participants with ankle weights that can be adjusted in 1-lb increments, up to 
5 pounds, as well as two resistance bands of different tension levels.  These materials were also provided to 
participants in the pilot testing of the IBET program.   
Participants will be given a telephone number to contact a study team member if they need technical 
support regarding the website.  These telephone contacts will not involve any advisement regarding the 
physical activity. Within the website, participants may contact the study team if they have questions about the 
program.  Technical questions will be handled by a study team member familiar with the website.  Any 
questions regarding the exercise program itself will be handled by study co-investigators who are trained as 
physical therapists and have expertise in this area.  We will document the frequency and nature of these 
contacts, which will be useful in the overall evaluation of this internet-based resource.   
 
Although the results of the IBET pilot testing were excellent, and patients were very satisfied with this 
program, we are planning several enhancements prior to beginning this study.  These are based on feedback 

 
 
 
 
 
 
 
 
 
9
from our patient advisors and other stakeholders.  These changes will include:  1.) modification of the 
instructions regarding the recommended frequency for performing strengthening and stretching exercises, to 
match the proposed intervention; 2.) addition of a personalized feedback section that charts the times 
participants have logged into the system and completed their exercises, as well as when they have increased 
exercise levels; 3.) addition of a feature that will allow participants to try an entirely new exercise routine at the 
same level, for variety and 4.) minor modifications related to reading level of the instructions. 
C.6.0  Standard PT Intervention.   
C.6.1  Overview of PT Intervention.  We have modeled the standard PT intervention after typical elements of 
care provided to patients with knee OA 62.  While there is some variability in the treatment components 
employed by individual therapists, common aspects of PT for knee OA include: instruction in an appropriate 
home exercise program (focusing on strengthening and stretching exercises), instruction in strategies for 
pacing daily activities and protecting joints, evaluation of specific areas of weakness or inflexibility (which can 
then be used to tailor an exercise program), evaluation of mobility, stability, function, knee alignment, and 
possible limb length inequalities, and evaluation of the need for mobility aids, knee braces, and heel lifts. We 
have chosen not to include physical agents and electrotherapeutic modalities (e.g., electrical stimulation, 
ultrasound, TENS, diathermy) in the PT intervention for this study because there is no clear evidence to date 
for their effectiveness in knee OA 63; although these modalities may be utilized in some instances by physical 
therapists in treating knee OA, it is not common.  In keeping with standard outpatient PT practices for knee OA, 
physical therapist assistants (PTAs) may be involved with delivering the intervention.  Based on standard 
practice and licensure rules, physical therapists must complete the initial evaluation and develop the treatment 
plan.  PTAs may help to follow upon the treatment plan delivery (e.g., observe and assist participants in 
completing assigned exercises during clinic visits), with the PT being available at all times.   
 
There is also some variability in the number of PT visits provided to patients with knee OA, based on health 
care setting resources, insurance reimbursement, and patient needs and availability.  However, the typical 
range is between 3 and 8 visits.  Therefore we will utilize this same range of visits for the standard PT arm in 
this study.  All visits must be completed within the initial 4-month study period.  We considered an approach 
where all participants would receive the same number of visits.  However, we believe that allowing some 
degree of variability visit number, based on physical therapist assessment of patient needs, more closely 
reflects real-world clinical practice and will therefore be a more valid comparison to the IBET program.  As part 
of the study we will document the number of visits for each patient in the standard PT arm.   
 
Physical therapy in clinics proximal to UNC and within Johnston County, who have experience in treating 
patients with knee OA, will deliver this arm of the study. These clinics include:  Comprehensive Physical 
Therapy Center (Chapel Hill, NC), Advanced Physical Therapy (Smithfield, NC), and UNC Physical Therapy 
(Hillsborough and Cary clinics). We will involve multiple therapists to enhance generalizability. Although 
physical therapists will be given flexibility in their treatment of these patients, there will also be some degree of 
standardization in the elements included (described below). This will allow comparison to a relatively standard 
intervention (which is important for study internal validity) while also reflecting a degree of variability that exists 
in actual practice.  All study physical therapists will be trained in the standard PT arm elements described 
below.  Adam Goode, DPT, PhD Yvonne M. Golightly, PT, MS, PhD, study  co-investigators with clinical PT 
expertise, as well as experience in training physical therapists, will provide this training and oversee a subset 
of visits to ensure fidelity.  Specifically, Drs. Goode and Golightly will observe approximately the first five study 
visits for each participating physical therapist and approximately 10% thereafter.    
We have confirmed with PT services across multiple health systems that our planned standard PT 
intervention for knee OA reflects usual clinical practice.  In addition we have consulted with Anita Bemis-
Doherty, PT, DPT, MAS, Director of the Department of Clinical Practice for the American Physical Therapy 
Association.  She has provided input regarding the standard PT arm of this study and supports the approach 
we propose.  She will continue to serve on the Stakeholder Panel for this study and provide ongoing 
consultation to the study team in this regard. 
C.6.2  Specific Activities in the Standard PT Intervention.  
Evaluation:  Physical therapists will gather a relevant medical history from each participant, including prior 
joint injuries, recent joint injections, pain level, specific functional and activity limitations, use of assistive 
devices, and other health problems that could affect home exercise.  Some relevant information on these 

 
 
 
 
 
 
 
 
 
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topics, collected as part of the baseline study assessments, will be provided to physical therapists, within the 
study database, for each participant.  Physical therapists will also perform standard assessments including 
edema, range of motion, knee alignment, limb length equality, balance, and gait.  The history and evaluation 
will be documented in the study database on a standard form, adapted from one we have successfully used in 
another study of PT for knee OA 56. Based on these evaluations, therapists will provide treatment according to 
standard practice for knee OA, including:  prescription of therapeutic exercise, balance / neuromuscular 
education, manual therapy, gait / stair training and advisement about shoes / wedges.  Physical therapists may 
provide low-cost heel lifts or exercise therapy bands for patients when indicated.  However, devices such as 
knee braces will not be provided.    This reflects standard clinical practice, where patients typically pay out-of-
pocket for devices such as knee braces and acquire them separately from the actual PT visit.   
Education:  Physical therapists may provide participants with basic education in activity pacing and joint 
protection strategies, as appropriate. Activity pacing involves recognizing typical pain patterns and activities 
that exacerbate pain, planning for activity during typical periods of low pain, planning for rest during typical 
periods of high pain, and taking rest periods when pain and soreness begin to occur.  Joint projection 
strategies include decreasing the load on the knee joints during common activities such as walking, stair 
ascent / descent, rising from a chair, and doing other household activities.  Participants may also be instructed 
in the use of heat, cold, elevation, and / or self-massage, particularly with reference to use in conjunction with 
home exercises.  
C.7.0  Patient-Centered Outcome Measures 
All study assessments will be conducted in person by a trained research assistant blinded to study group 
assignment.  Primary and secondary outcomes, as well as process measures, will be assessed at baseline, 4-
months, and 12-months.  Demographic and clinical characteristics will be assessed at baseline. Participants 
will be paid $30 for completion of assessments at each time point. We have selected our outcomes on the 
basis of the input from our Stakeholder Panel, as well as the Initiative on Methods, Measurement, and Pain 
Assessment in Clinical Trials (IMMPACT) 66, which recommends measurement of four pain outcome domains:  
pain intensity (WOMAC pain subscale), physical functioning (WOMAC function scale, Satisfaction with 
Physical Function Scale, and Short Physical Performance Test Protocol), emotional functioning (Patient Health 
Questionnaire-8), and participant global impression of change. We have also included secondary outcomes 
and process measures related to physical activity.  
C.7.1  Primary Outcomes: Western Ontario and McMasters Universities Osteoarthritis Index. The primary 
outcome measure for this study is the WOMAC, a measure of lower extremity pain (5 items), stiffness (2 
items), and function (17 items).  All items are rated on a Likert scale of 0 (no symptoms) to 4 (extreme 
symptoms). The reliability and validity of the WOMAC total score and subscales have been confirmed 67.  In 
patients with hip or knee OA, Bellamy et al. reported internal consistency coefficients (Cronbach’s alpha) 
between 0.86 and 0.95 on WOMAC pain, stiffness, and function subscales.  Construct validity has been 
confirmed by a significant association with the Lequesne Algofunctional Index for Knees 67. The WOMAC has 
been widely used in trials behavioral interventions for patients with knee OA, confirming its sensitivity to 
change in these interventions. 
C.7.2 Secondary Outcomes. 
Satisfaction with Physical Function Scale. This is a validated 5-item questionnaire that assesses patients’ 
satisfaction with their ability to complete basic functional tasks that are often affected by lower extremity OA, 
including stair-climbing, walking, doing housework (light and heavy, and lifting and carrying 68.  All items are 
rated on a 7 point scale ranging from Very Dissatisfied (-3) Very Satisfied (+3). 
Objective Physical Function.  We will objectively assess physical function using seven tests.  This group of 
tests is  relevant to the proposed study because they assess aspects of daily function that require lower 
extremity strength, and that are often impacted by knee or hip OA.  This battery examines balance (4 tests 
including a side by side stand, semi-tandem stand, tandem stand, and a unilateral stand), time to rise from a 
chair and return to the seated position for 30 seconds, timed up and go-rising from a seated position, walking a 
short distance and returning to seated position, and a 2 minute step test.  For each test, the possible range of 
scores is 0-4, for a total range of 0-20. 
Depressive Symptoms – Patient Health Questionnaire-8.  We have chosen to include depressive symptoms as 
a secondary outcome because of the close association of these symptoms with pain.  Depressive symptoms 

 
 
 
 
 
 
 
 
 
11
and severity will be assessed using the PHQ-8, a reliable and valid measure of depression71.  The PHQ-8 is an 
eight-item survey derived from the Primary Care Evaluation of Mental Disorders (PRIME-MD) diagnostic tool, 
and consists of items corresponding to the depression criteria listed in the Diagnostic and Statistics Manual 
Fourth Edition (DSM-IV).  Each of the eight questions is scored as 0 (not at all) to 3 (nearly every day), so that 
total scores range from 0 to 24.   
The Knee injury and Osteoarthritis Outcome Score (KOOS). The KOOS is a patient-reported outcome 
measurement instrument, developed to assess the patient’s opinion about their knee and associated problems. 
The KOOS evaluates both short-term and long-term consequences of knee injury and also consequences of 
primary osteoarthritis (OA) }. It holds 42 items in five separately scored subscales: KOOS Pain, KOOS 
Symptoms, Function in daily living (KOOS ADL), Function in Sport and Recreation (KOOS Sport/Rec), and 
knee-related Quality of Life (KOOS QOL). Some of these items overlap with those with the WOMAC, and in 
those instances questions will only be asked once.  
The PROMIS Sleep-related Impairment Instrument. The PROMIS adult sleep related impairment item bank 
focuses on self-reported perceptions of alertness, sleepiness, and tiredness during usual waking hours, and 
the perceived functional impairments during wakefulness associated with sleep problems or impaired 
alertness. It assesses sleep-related impairment over the past seven days. This scale includes 8 items, each 
measured on a 5-point Likert scale. 
The PROMIS Fatigue Instrument. The PROMIS Fatigue instruments evaluate a range of self-reported 
symptoms, from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of 
exhaustion that likely decreases one’s ability to execute daily activities and function normally in family or social 
roles. Fatigue is divided into the experience of fatigue (frequency, duration, and intensity) and the impact of 
fatigue on physical, mental, and social activities. It assesses fatigue over the past seven days,  This scale 
includes 8 items, each measured on a 5-point Likert scale. 
Patient Global Assessment of Change. We will use the Patient Global Impression of Change scale to evaluate 
participants’ perspectives on overall changes in their joint pain during the study period.  This single-item 
measure asks participants to describe their change in pain on a 7-point rating scale with the following options: 
“very much improved,” “much improved,” “minimally improved,” “no change,” “minimally worse,” “much worse,” 
and “very much worse.”  This scale has been widely used in clinical trials of chronic pain treatments and is 
specifically recommended by IMMPACT 66. 
The Brief Fear of Movement Scale. The Brief Fear of Movement Scale is a six item scale for assessing fear of 
movement in OA.  The scale specifically assesses activity avoidance due to pain-related fear of movement. All 
items are measured on a 4-point scale from “strongly agree” to “strongly disagree.” 
Physical Activity Measures 
Physical Activity Scale for the Elderly.  The Physical Activity Scale for the Elderly (PASE) is a self-
report, 12-item scale that measures level occupational, household, and leisure activity during a one-week 
period. 73  This scale was particularly developed for use among older adults; although all participants in the 
proposed study will not be age 65 or over, patients with knee OA typically have more limited physical activity 
than the general population.  Therefore we believe this scale will be more applicable to our participant group 
than scales that were developed for younger adults.   
Additional Self-Report Physical Activity Items.  In addition to the assessment of overall physical activity 
that will be provided by the PASE, we are particularly interested in purposeful exercise behaviors that 
correspond to the IBET intervention and those typically prescribed in the context of standard PT for knee OA. 
We will ask participants, at each assessment point, to report the number of times and minutes per week, on 
average, they are completing strengthening, stretching, and aerobic exercises 
Use of IBET Website / Number of PT Visits Attended.  As described above, participants’ use of the 
IBET website will be logged within the site.  Therefore we will be able to compare use (e.g., number of log-ins 
and records of completion of exercise weekly) throughout the 12-month time period for participants in that 
study arm.  Similarly, for patients in the Standard PT group, we will document the number of visits and the 
proportion of scheduled visits attended. 
C.7.3  Process Measures.  We will include two key process measures that have been associated with change 
in physical activity behavior. These will help us to understand potential mechanisms underlying any observed 
improvement in the IBET and / or standard PT interventions.  

 
 
 
 
 
 
 
 
 
12
Self-Efficacy for Exercise Scale.  The Self-Efficacy for Exercise scale assesses individuals’ confidence in  
engaging in exercise in nine different situations that could present barriers (including having pain when 
exercising) 75.  For each situation, individuals are asked to rate their confidence in being able to exercise three 
times a week for 20 minutes each time, on a scale of 0 (not confident) to 10 (very confident).  Validity of this 
measure was confirmed by expected associations with actual exercise, as well as physical and mental health. 
Social Support for Exercise Scale. 76  This scale includes 13 items that assess the frequency with which friends 
and family members (separately) engage in behaviors that may either support exercise (e.g., “Gave me 
encouragement to stick with my exercise program”) or discourage exercise (e.g., “Complained about the time I 
spend exercising”).  All items are measured on a scale of 1 (none) to 5 (very often).  The scale has shown 
acceptable test-retest reliability and internal consistency reliability. In addition, the scale was correlated with 
exercise habits, providing evidence of concurrent criterion-related validity 76.   
C.7.4  Demographic and Clinical Characteristics. For Specific Aim#3, we will focus on evaluating potential 
differential effects of the IBET and / or standard PT interventions, with particular interest in differences 
according to participant age and baseline physical function.  We are interested in potential age-related 
differences for two reasons.  First, we are interested in understanding whether older individuals respond 
differentially to an internet-based exercise program, since they may be less comfortable with this technology 
compared to younger adults.  Second, older individuals typically have more comorbid health problems and 
activity limitations, and we are interested in understanding whether this results in any differential effectiveness 
of the two types of interventions.  We are similarly interested in potential differences according to patients’ 
baseline functional status, so that we can understand whether patients with more severe disease may respond 
differentially two the two types of interventions. 
We may also explore differential effects according to some of the following additional participant 
characteristics, which are also important for describing the study sample: race / ethnicity, gender, household 
financial state, education level, work status, marital status, and internet use / comfort, health literacy, body 
mass index (BMI), joint involvement (i.e., report of all joints affected by arthritis), duration of OA symptoms, 
general self-rated health, and comorbid illnesses (Self-Administered Comorbidity Questionnaire 78).  
C.7.5. OA Treatment Use.  We will also assess participants’ OA treatment use at each time point, via self-
report, to evaluate whether there are any changes during the study period.  For example, we are interested in 
understanding whether patients in the intervention groups may reduce pain medications if their symptoms 
improve.  In addition, these data will provide information about whether other new treatment occurred (e.g., 
joint injection) that may have an impact on outcomes during the study period.  Specific treatment aspects will 
include: pain medications for OA (prescription and non-prescription), knee braces, walking aids, physical 
therapy and joint injections. At the two follow-up time points we will also ask participants to indicate whether 
they think they currently use more, less, or about the same amount of pain medication to control their OA 
symptoms since starting the study. 
C.7.6  Participant Feedback on IBET and Standard PT Arms.   We will ask participants in the IBET group to 
complete the same Program Satisfaction questions described in the pilot study, at the 4-month assessment 
point.  We will develop similar questions that pertain to the standard PT arm.  In addition, we will ask 
participants to answer open-ended questions regarding both interventions.  For example, we will ask 
participants which aspects of the interventions were most and least helpful, usability of the IBET website, 
content of the PT sessions, and ways we may be able to further improve the interventions.    
C.8.0  Data Analyses 
C.8.1 General Overview.  Our statistical approach is guided by the PCORI Methods Report. For the superiority 
hypotheses (H1, H3), analyses will be conducted on an intent-to-treat (ITT) basis; patients will be analyzed in 
the arm to which they were randomized, regardless of adherence, using all data up to the 12-month follow-up 
or last available measurement prior to exclusion or dropout 79.   Additional exploratory analyses focusing on 
alternative, more restrictive analytic cohorts (e.g., as treated) may be considered for the superiority 
hypotheses, to provide additional information about the impact of magnitude of exposure to the interventions.  
For non-inferiority hypotheses (H2, H4), the ITT analysis would not be the conservative approach; therefore, it 
is recommended to perform analysis on both an intent-to-treat and per-protocol basis 80,81.  
C.8.2 Descriptive statistics. Descriptive statistics, including graphical displays, will be used to summarize all 
study variables overall and by randomization arm.  We will construct individual and mean trajectory plots of the 

 
 
 
 
 
 
 
 
 
13
longitudinal outcome variables to understand their general trends over the study period.  In addition, we will 
explore the variability and correlation structure of the longitudinal outcome variables.  All statistical analyses 
will be performed using the SAS (Cary, NC) software package / R (www.r-project.org). 
C.8.3 Missing Data.  Because the main predictors of interest, intervention arm and patient characteristics, are 
collected at baseline, we do not anticipate much missing data in these variables.  There may be missing values 
in the outcome measures due to dropout, death, a missed interim assessment, or item non-response. Given a 
thorough understanding of the missing data mechanism, it is possible to use all of the available information in 
analysis, rather than using only subjects with completely observed information.  Our main analysis technique 
for the primary outcomes, general linear mixed models via maximum likelihood estimation, implicitly 
accommodates missingness when it is due either to treatment, to prior outcome, or to other baseline covariates 
included in the model, defined as missing at random 82. Therefore, inferences will be valid even if we have 
differential dropout by intervention arm.  If the missing values are related to other measured patient factors, 
such as age or comorbidity, then multiple imputation (MI) provides a framework for incorporating information 
from these variables, while still preserving a parsimonious main treatment effect model 83, and is described as 
a significant advantage in recommendations from Panel on Handling Missing Data in Clinical Trials 84. 
Depending on the type and scope of missing data, MI will be conducted via the SAS procedure PROC MI or 
the SAS macro IVEware (http://www.isr.umich.edu/src/smp/ive/).  If the probability of dropout is related to the 
actual missing response (which is unobserved because it is missing) or to other unobserved quantities, the 
missing data due to dropout is considered missing not at random (MNAR) or nonignorable 85. There is a 
possibility that data may be MNAR, and we propose as additional sensitivity analyses to explore MNAR 
methods, including selection and pattern-mixture models 85. 
C.8.4.  Specific Aim #1. H1 (Superiority):  Patients who receive either IBET or standard PT will have clinically 
relevant improvements in pain, stiffness, and function, measured by the WOMAC at 4-month follow up, 
compared with patients in the WL control group; H2 (Non-Inferiority): The IBET intervention will be non-inferior 
to the standard PT intervention at 4-month follow-up, indicated by  a mean WOMAC score less than 5 points 
higher than standard PT.  For Specific Aim #1, we will use a linear mixed model (LMM) that accounts for the 
correlation between a participant’s repeated measurements over time. Because of the small number of time 
points, we will apply an unstructured covariance matrix to take into account the within-patient correlation 
between repeated measures. The fixed-effect portion of the model will have the form: Yit = β0 + β14month+ 
β2IBET*4month+ β3PT*4month, where Yit is the WOMAC score for subject i at t=0 and 4 months. We will 
estimate the parameters in the model and set up contrasts for tests of hypotheses using the SAS procedure 
MIXED (Cary, NC). Specifically, for H1, we will test for a difference in mean WOMAC scores between the IBET 
and/or PT group and the WL group at the primary time point of 4 months by testing that β2=0 and/or β3=0.  For 
H2, we chose a non-inferiority limit of 5 points for mean WOMAC scores because it is reasonable and on the 
border of what would be considered a clinically important effect  86 . The null hypothesis in the non-inferiority 
framework is that IBET is inferior to standard PT in management of OA symptoms. We will test the non-
inferiority hypothesis by examining the estimate of the contrast β2-β3. Specifically, we will examine the 95% CI 
of the estimated contrast β2-β3, and if the upper limit of the interval is less than the threshold value of 5 points, 
we will conclude non-inferiority of IBET to PT 81.  If we conclude non-inferiority, we test will for superiority of 
IBET to PT at 4 months by examining the 95% CI of the estimate of β2-β3 for inclusion of 0 and the p-value for 
the test of the contrast β2-β3 =0. Time is coded in this model to fit a constrained longitudinal data model 
(cLDA), in which baseline WOMAC score is modeled as a dependent variable in conjunction with the constraint 
of a common baseline mean across the treatment arms 87. In this way, the cLDA model is comparable to an 
ANCOVA model; the two models are equivalent when there is no missing data. However, unlike an ANCOVA, 
participants who are missing follow-up measurements are included in the cLDA model because baseline is part 
of the response vector. For improvement in precision, the model will also be adjusted for enrollment site 
(stratification variable) 88. Similar procedures will be used to assess all continuous secondary outcomes.   
C.8.5. Specific Aim #2: H1 (Superiority):  Patients who receive either IBET or standard PT will have clinically 
relevant improvements in pain, stiffness, and function, measured by the Western Ontario and McMasters 
Universities Osteoarthritis Index (WOMAC) at 12-month follow up, compared with patients in the WL control 
group; H2 (Non-Inferiority): The IBET intervention will be non-inferior to the standard PT intervention at 12-
month follow-up, indicated by  a mean WOMAC score less than 5 points higher than standard PT . As 

 
 
 
 
 
 
 
 
 
14
described above, will use a linear mixed model (LMM), adding in the 3 parameters for the 12-month period 
(12month, IBET*12month, PT*12month).  We will follow the same testing procedures for the 12-month 
parameters as described for the 4-month. Similar procedures will be used to assess longer term effects of all 
continuous secondary outcomes at 12-months.   
C.8.6. Specific Aim #3: Examine whether individual patient characteristics (particularly age and baseline  
functional status) are associated with differential improvement in the IBET and / or standard PT interventions.  
Patients may vary in their response to the intervention programs; this variation is known as heterogeneity of 
treatment effects (HTE). We will be conducting a descriptive HTE analyses 89. We have two a priori defined 
patient characteristics (noted above) and will conduct a separate descriptive HTE for each characteristic for 
primary and secondary outcomes, as defined in the PCORI Methods Report.  We will initially treat age as a 
continuous variable and evaluate whether treatment response varies with increasing age; we will also evaluate 
treatment response within discrete age categories (e.g., by decade).  With respect to functional status, we will 
evaluate potential differential response on the basis of participants’ baseline scores on the SPPT (objective 
physical function test), since this is a separate measure from our primary outcome (WOMAC).  We will initially 
treat baseline SPPT composite scores as a continuous variable (0-12).  We will also evaluate treatment 
response within discrete baseline SPPT score categories of <5, 5-8, and >8, which have been shown to predict 
adverse outcomes.  We will construct individual and mean trajectory plots of the longitudinal outcome variables 
by patient characteristics and treatment arm to understand their general trends over the study period.  Our 
general steps in this secondary analysis will be to add the patient characteristics main effect, as well as the 
interaction variables, to the linear mixed model defined above.  We will examine the parameter and 95% CI of 
the parameter estimates for the 3-way interactions treatment*time*patient characteristic (e.g. 
IBET*4month*age) to determine whether there is evidence of HTE for that characteristic. New state-of-the art 
modeling methods have taken the exploration of HTE to the next level, making it possible to explore and 
identify multidimensional subgroups exhibiting heterogeneous treatment effects. We will explore whether the a 
priori defined patient characteristics define multidimensional subgroups that exhibit HTE. We will utilize two 
different analytic strategies for doing so: multivariable logistic regression90,91  and recursive partitioning 92,93.  
Each has unique strengths as well as limitations, and each approaches the problem of identifying the 
multidimensional subgroups differently.  Our general steps in this secondary analysis will be: construction of 
outcome variables; identification of multidimensional subgroups via logistic regression and recursive partioning; 
and, finally, examination of treatment effects within the multidimensional subgroups.  
C.8.7. Additional Exploratory Analyses. We may also conduct exploratory analyses of associations among 
other measures collected as part of this study. This may include associations among variables at baseline, 
potential roles of baseline variables as moderators or mediators of treatment effects, or association of baseline 
variables with intervention uptake and outcomes. 
C.8.8  Sample size. The sample size estimate of n=350 patients, 140 per each of the IBET and standard PT 
arms and 70 in the WL arm, is based on H2, the non-inferiority hypothesis, as this is the most conservative 
80,94,95, and on a randomization of 2:2:1 96. In our proposed analysis, this involves testing the IBET*4month and  
PT*4month interactions in our model. Sample size calculations are based on this comparison and use methods 
appropriate for ANCOVA analyses, which are equivalent in terms of efficiency to our linear model as noted 
above, in randomized trials 87. For the non-inferiority test the method is based on performing a one-sided two-
sample t-test sample size calculation at the alpha=0.025 level for the between group difference at the 4 month 
time point, multiplied by a factor 1-(rho)^2, where rho represents the Pearson correlation between baseline and 
follow-up time point outcome measures 97.This sample size is then adjusted to compensate for potential 
missing observations due to attrition. Based on data from our other OA studies, we assume a correlation of 0.6 
between WOMAC scores at baseline and at 4 months and an SD for WOMAC scores of 17.5. With 80% 
power, alpha=0.025, SD=17.5, rho=0.60, and a 10% attrition rate by 4 months, 140 patients in each of the 
IBET and standard PT groups, need to be enrolled at baseline to identify less than a 5 point difference in mean 
WOMAC scores between the two treatment groups. We selected the 10% attrition rate based our prior 
research of behavioral interventions for OA of similar duration 54. For H1, with alpha=0.05, SD= 17.5, rho=.6, 
and approximately 10% attrition rate by 4 months, we have 80% power to detect moderate effect size of 0.35, 
corresponding to a 6.1 point difference (approximately 13% improvement, which corresponds to a clinically 
relevant difference) in mean total WOMAC scores at 4 months for either of the 2 intervention compared to WL 

 
 
 
 
 
 
 
 
 
15
control.  For the remaining secondary outcomes we will also be powered to detect a moderate 0.35 effect size 
difference for either of the two intervention compared to the WL control group. We did not conduct a power 
analysis for the HTE analysis for Aim #3 because we are proposing a descriptive HTE 89 and have followed the 
PCORI Methods Report on this issue. However, our analyses for Aim #3 will provide meaningful and practical 
data to Stakeholders and organizations with potential to incorporate the IBET program – for example, whether 
patients with different characteristics differentially benefit from IBET vs. standard PT for knee OA.   
C.9.0  Data Management and Quality Control.  Study tracking data will be entered into a database created 
by expert programmers at the UNC Sheps Center for Health Services Research, which has been developed 
and refined over many years in the context of other clinical trials. This database includes safeguards for 
ensuring tracking data are collected reliably for all participants (e.g., required fields, limited sets of appropriate 
responses) and will be thoroughly tested by the study team prior to beginning the clinical trial.  This database 
can be easily customized for the proposed project.  We are also able to randomize participants within this 
database.  Customized reports allow the research assistant and project coordinator to identify daily tasks in 
need of completion, as well as generate flow charts to monitor overall study progress.  Screening and outcome 
measures will be recorded in this same database. As with the tracking database, screening and outcome 
measures will be programmed to ensure reliable data (e.g., required fields, set ranges of responses) and will 
be thoroughly tested by the study team before beginning the study.  The study team will conduct regular 
checks and cleaning of screening and outcomes data, throughout the study period, to monitor data quality.  
The database will also house information on study PT visits, including the initial evaluation form and progress 
notes for all visits.  
C.10.0  Project Timeline and Management Plan. We are proposing a 3-year study.  The first 4 months will 
be devoted to start-up activities, including additional stakeholder input on the IBET program and incorporation 
of modifications accordingly.  This phase will also involve training of personnel and finalization of study 
databases.  Enrollment will take place over the next 16 months (through year 2, month 8), with 4-month follow-
up completed by year 3 month 1 and 12-month follow-up completed by year 3, month 9.  The final 3 months of 
the project will be devoted to final analyses and dissemination and implementation related activities. This 
timeline will require us to enroll 21-22 participants per month, and this is very reasonable based on our 
experience with prior clinical trials and the resources requested for this project (particularly research assistant 
effort).   
C.11.0.  Participant Retention.  
 
We will utilize strategies to promote participant retention that have been successful in our prior and 
ongoing clinical trials of patients with symptomatic OA (which include diverse groups of patients in terms of 
gender, health status, education level, and race / ethnicity)54-56.  First, we have chosen a wait list control group, 
versus a usual care control group that receives no treatment.  We have found that this helps with fostering 
retention in any study group that is “inactive” at the beginning of the trial period.  Second, we are providing 
compensation that will be adequate to support participants’ time and travel for study assessments.  Third, we 
will be working with at least three different PT clinics to deliver that intervention arm; this will minimize driving 
distances for participants.  Fourth, we will make any reasonable accommodation possible for participants to 
complete their baseline and follow-up assessments.  We are selecting assessment sites with convenient 
parking and at central locations, and we will conduct assessments outside of normal business hours when 
needed.  Although we plan for study assessments to occur in-person, if participants are unable to come to a 
study location for a follow-up assessment point (but are otherwise eligible to continue the study), we will allow 
telephone-based assessment in order to minimize loss-to-follow-up.  Our main outcome measures (WOMAC) 
has been validated for telephone administration.     
 
D.  Demonstrate the patient-centeredness of the application (Criterion 4) 
The proposed project is highly relevant to patients because knee OA is a leading cause of pain and 
disability 98,99, outcomes of great importance to patients 100-102. OA-related pain also has a detrimental impact 
on other important patient-centered outcomes such as depression, anxiety, employment, relationships, sleep, 
fatigue, employment, and quality of life 12,18,103,104.  In addition, arthritis (including knee OA) is a key barrier to 
engaging in other healthy behaviors, such as physical activity, and it is strongly associated with obesity 105-107. 
Therefore interventions that help patients manage knee OA-related pain also have tremendous potential for 

 
 
 
 
 
 
 
 
 
16
affecting other health outcomes of importance to patients. This project addresses two key PCOR questions: 
1. “What can I do to improve the outcomes that are most important to me?”  Specifically, information 
generated from this project will enable patients with knee OA to know whether participating in an internet-
based exercise program may be as effective of an option as standard PT for improving physical activity and 
associated patient-centered outcomes. Since some patients experience barriers to access to PT for knee OA 
(e.g., insurance or related, availability of physical therapists, schedule constraints), it is important for patients to 
know whether there are alternative resources that will help them to improve outcomes like pain and function via 
support of an appropriate physical activity program. 
2. “Given my personal characteristics, conditions and preferences, what should I expect will happen to me?”  
Results of this project (Specific Aim #3) will help patients and providers understand whether patient 
characteristics (particularly age and baseline physical function) are associated with differential effectiveness of 
IBET vs. standard PT among patients with knee OA.   
 
 
 

 
 
 
 
 
 
 
 
 
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