Weight Loss and Exercise for Communities With Arthritis in North Carolina
Phase: NA
Conditions: Osteoarthritis
Sponsor: Wake Forest University

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Study Protocol 
 
 
Weight loss and Exercise for Communities with Arthritis in North Carolina (WE-CAN) 
 
 
8/26/20 
Principal Investigator 
Stephen P. Messier, PhD 
 
Co- Principal Investigator 
Leigh Callahan, PhD 
 
Site Principal Investigators 
Dan Beavers, PhD, Leigh Callahan, PhD, Stephen P. Messier, PhD, Kate Queen, MD 
 
Co-investigators 
Richard Loeser Jr., MD, Mary Lyles, MD, Shannon Mihalko, PhD, Gary Miller, R.D. PhD, 
Joanne Jordan, MD, MPH, Jeffery Katz, MD, MSc, Elena Losina, PhD, MSc, Sara Quandt, PhD 
 
Consultants 
Paul DeVita, PhD, David Hunter, MD 
 
 
Project Description: 
The global prevalence of knee osteoarthritis (OA) is estimated at greater than 250 million 
persons or 3.6% of the world population, ranking 23rd on the list of the most common sequelae. 
Knee OA is the most prevalent cause of mobility dependency and disability, with the time spent 
living with symptoms averaging 26 years. More than two-thirds of Americans age ≥ 20 years are 
overweight or obese. Two in three people who are obese will develop symptomatic knee OA in 
their lifetime.  In addition to the strong relationship between obesity and knee OA, a recent 
systematic review found no healthy consequences of overweight/obesity, even in individuals 
who are metabolically healthy.  
 
In 2004 we reported that a 5% weight loss, when combined with exercise, resulted in a 30% 
decrease in pain and a 24% improvement in function. Our recently completed trial entitled 
Intensive Diet and Exercise for Arthritis (IDEA) sought to improve on our work with a more 
intensive weight loss intervention, 2 to 3 times the weight loss we had recently achieved.  IDEA 
compared intensive diet (D) and exercise (E) interventions, separately and in combination, across 
an 18-month intervention period in 454 overweight and obese older adults with radiographic 
knee OA. An intent-to-treat analysis revealed that after 18 months the D+E group reduced pain 
by 51% compared to 25% and 28% for the D only and E only groups, respectively. The D+E 
group was also superior to the E group on self-reported physical function, health related quality 
of life, and walking speed, and had significantly lower knee joint loading and serum levels of IL-
6, a pro-inflammatory cytokine.  On average, our D+E intervention was twice as effective at 

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relieving pain as previous long-term OA trials. We concluded that wider adoption of intensive 
weight loss with a goal of at least 10% of baseline body weight combined with exercise could 
reduce the burden of disability related to knee OA.   
 
IDEA was an efficacy study with impressive results, a trial designed to determine the effects of 
intensive diet and exercise under ideal circumstances.  However, a common concern from 
physicians who treat people with knee OA is lack of practical means to implement this treatment 
in the clinical environment.  Indeed, there is no evidence regarding how this efficacious 
intervention could be successfully adapted to be effective in real world clinical and community 
settings and also be cost effective.   
 
We plan to conduct the first long-term (18 months) pragmatic (i.e., effectiveness) trial of 
intensive diet and exercise in older adults with knee OA under more usual conditions in both 
rural and urban communities across North Carolina.  Participants (age ≥ 50 years; BMI ≥ 27 
kg/m2 ) will be randomized to one of 2 groups: diet-induced weight loss and exercise or an 
attention control group.  The sample will consist of 820 ambulatory, community-dwelling 
persons that meet the ACR clinical criteria for knee osteoarthritis. The primary aim is to compare 
the intervention effects on knee pain.  Secondary aims will compare the intervention effects on 
self-reported function, mobility, health related quality of life, and the cost effectiveness and 
budgetary impact of the intervention. 
 
This program will deliver state-of-the-art weight-management techniques using procedures that 
are new to this area of research in a community setting. Our proposed study is innovative in at 
least 6 important ways.  
 
1. The first long-term trial of diet-induced weight loss and exercise in adults with knee 
OA delivered in a practical, less rigorously monitored, community setting. We will 
design and implement this intervention to make it cost-effective and to serve as a 
blueprint for diverse communities nationwide. If successful, the results can inform 
healthcare payers about the first non-pharmacologic treatment of proven benefit for 
overweight and obese adults with knee OA that also promises to decrease medical care 
costs.  
2. The first pragmatic behavioral health trial targeting rural and urban sites. Few 
pragmatic trials have focused on rural populations (Fortney et al; Gooch et al; Schmidt et 
al), and none was designed to affect behavior change using community health 
interventionists. About 25% of the US population lives in diverse rural communities. 
Most have fewer services and resources than urban communities (US Dept. of Agr). They 
report poorer health-related quality of life (National Rural Health Assoc.), reflecting 
higher prevalence of many disorders, including OA. Tailoring a non-pharmacologic 
intervention for communities with limited healthcare access would be a breakthrough for 
public health (National Rural Health Assoc.). 
3. The first evidence that this non-pharmacologic intervention can be implemented cost-
effectively in US communities. Successful results will lead to step-by-step guidelines 
regarding the selection of community intervention sites, ways to engage the medical 
community, and how to deliver a weight-loss and exercise intervention. In addition to the 
well-established association between obesity and knee OA, strong relationships exist 

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between high BMI/obesity and coronary heart disease, type 2 diabetes, high blood 
pressure, stroke, dyslipidemia, and certain types of cancer (Bhaskaran et al; Campbell ). 
This trial will provide a model for community leaders to develop and execute an effective 
diet and exercise program at a reasonable cost that will engage local physicians and 
healthcare providers who treat knee OA, obesity, and related comorbidities. 
4.  A practical treatment option for physicians who treat the comorbidities associated with 
high BMI. Both the CDC and the American Cancer Society have strategic initiatives that 
encourage community-based interventions to effectively reduce overweight and obesity 
(Bauer et al; Campbell). 
5. Focus on implementation and scalability of treatment approaches. The innovative 
features of the proposed study will bridge short-term efficacy and long-term outcomes. 
Identifying and applying the factors critical for intervention sustainability ensure 
translation from research to practice. 
6. Formal assessment of cost-effectiveness and Budget Impact Analysis. Although rarely 
performed in pragmatic trials, we will formally assess the cost-effectiveness of the 
implemented strategies. Results will allow clinicians and policymakers to assess the 
feasibility of community-based implementation 
 
The proposed study is uniquely designed to identify a practical, effective, non-pharmacologic 
therapy capable of reducing knee pain and improving function and quality of life in rural and 
urban communities of older, overweight and obese adults with knee OA.  
 
Primary Hypothesis and Aim 
 
Hypothesis 1. A pragmatic, community-based, diet-induced weight-loss and exercise 
intervention will significantly reduce knee pain among overweight and obese adults aged ≥ 50 
years with knee OA compared to an attention-control group. 
 
Aim 1. To determine whether a pragmatic, community-based, 18-month diet-induced weight-
loss and exercise intervention implemented in three North Carolina counties with diverse 
residential (from urban to rural) and socioeconomic composition significantly decreases knee 
pain [as measured by the Western Ontario McMasters Universities Osteoarthritis Index 
(WOMAC) pain subscale] in overweight and obese adults with knee OA compared to an 
attention-control group. 
 
Secondary Hypotheses and Aims 
 
Hypothesis 2. A pragmatic, community-based, diet-induced weight-loss and exercise 
intervention will significantly improve self-reported function, health-related quality of life, and 
mobility among overweight and obese adults aged ≥ 50 years with knee OA compared to an 
attention-control group. 
 
Aim 2.  To determine whether a pragmatic, community-based, 18-month, diet-induced weight-
loss and exercise intervention improves WOMAC self-reported function, health-related quality 
of life as measured by the physical subscale of the SF-36 questionnaire and 6-minute walk 

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distance (an accepted measure of mobility) in overweight and obese adults with knee OA 
compared to an attention control group. 
. 
Hypothesis 3.  A pragmatic, community-based, diet-induced weight-loss and exercise 
intervention will be a cost-effective addition to treatment modalities in overweight and obese 
persons with knee OA. 
 
Aim 3.  To establish the cost-effectiveness of this pragmatic, community-based, multimodal diet-
induced weight-loss and exercise program by conducting cost-effectiveness and budgetary 
impact analyses using data from the current trial in a validated computer-simulated model of 
knee OA. 
 
Study Design 
We will randomize 820 overweight and obese (BMI 27 ≥ kg/m2), adults age ≥50 yrs knee OA 
into one of 2 groups: an intensive dietary restriction-plus-exercise (D+E) group or an attention 
control (nutrition and health) group.  Persons who have begun screening once we hit our overall 
recruitment goal of 820 will be allowed to complete the screening process therefore up to 840 
persons may be enrolled into the study.  Forsyth, Johnston, and Haywood Counties’ recruitment 
goals are 420, 210, and 210, (total 840) respectively.  Our minimum weight-loss goal for the 
weight-loss group will be 10% of body weight.  The exercise intervention will meet 3 days/wk at 
the clinical site.  The intervention will be comprised of both aerobic and strength training 
exercises.  When participants are unable to come into the facility for intervention, sessions will 
be conducted via phone or through video conferencing. The nutrition and health group will meet 
5 times over an 18 month period and receive a combination of webinars, video messages, text 
messages, emails (via personal email or Facebook), phone calls, and mailings for the remaining 
months.  Participants will be allowed to choose their preferred method.       
 
Primary Endpoint 
Western Ontario McMasters Universities Osteoarthritis Index (WOMAC).  We will measure 
self-reported physical function and pain using the WOMAC (scores will be pulled from the 
KOOS Questionnaire in which the WOMAC is embedded).  The LK version asks participants 
to indicate on a scale from 0 (none) to 4 (extreme) the degree of difficulty experienced in the 
last week due to knee OA. Individual scores for the 17 items are totaled to generate a summary 
score that could range from 0-68, with higher scores indicating poorer function. The pain index 
assesses participants’ pain on the same scale, ranging from 0 (none) to 4 (extreme). The pain 
subscale consists of 5 items and total scores can range from 0-20, with larger scores indicating 
greater dysfunction. This instrument has been validated and recommended by the Osteoarthritis 
Research Society as the health status measure of choice in older adults with knee OA.  In order 
to measure the minimal clinically improvement difference (MCID) participants will be asked to 
compare their knee pain to how it was at the beginning of the study.   
 
Secondary Endpoint 
Mobility. Our primary mobility measure will be 6-minute walk distance. Participants are told to 
walk as far as possible in 6 minutes on an established course. No personal timing devices are 
permitted, and participants are not provided feedback during the test. Results are significantly 
correlated to treadmill time and symptom-limited maximal oxygen consumption (r = 0.52 and r 

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= 0.53, respectively) and have a 3-month test-retest reliability of 0.86 (Pennix et al).  The Short 
Physical Performance Battery (SPPB) will also be used to measure mobility (Guralnik et al).  
The SPPB is comprised of the following tests (balance, walking speed, and chair rise).   A test 
of ascending and descending stair activity measured by the time (in seconds) it takes to ascend 
and descend a flight of 8 steps with 20cm (8 inch) step height and handrail will also be 
performed. 
 
Cost Effectiveness Resource utilization will be collected by questionnaire, with domains 
including visits to clinicians (physicians, nurses, physical therapists, others), tests, medications, 
injections, surgery, alternative therapies. The Work Productivity and Activity Impairment index 
(WPAI) will be used to assess absenteeism and reduced productivity while at work 
(presenteeism). 
 
Body weight, height, hip/waist circumference, BMI. Body weight and height will be obtained 
using standard techniques. Only persons with a BMI ≥ 27 kg/m2 will be eligible.  
Circumference measurements will be collected using standard techniques. 
 
Medical History, Medications, and Blood Pressure. Participants will be given forms to assess 
medical history and presence of comorbidities.  Participants will also be asked questions about 
their medical history during the phone screen so as to reduce participant burden by identifying 
potential exclusion criteria.  Participants will be administered a medication questionnaire 
adapted from the ARIC study and widely used in field research and in our prior studies at each 
testing visit (ARIC).  
 
It is designed to obtain information about all prescription and over-the-counter medicines and 
supplements used during the 2 weeks prior to the interview (home or clinic). The participants 
will be mailed the medication form to fill out at home and will return the form to the 
interviewer.  Participants may also be asked to provide the interviewer with all medicine 
containers so that the interviewer can transcribe the information.  In addition participants will 
be encouraged to notify the study staff of any medication changes during the course of the 
study. 
 
In addition to the medical history and medication questionnaires, participants will also be given a 
risk stratification questionnaire at the first screening visit.  The purpose of this questionnaire is to 
determine if participants will need medical clearance prior to enrolling into an exercise program.  
The determination is based on the presence/absence of cardiovascular/pulmonary/metabolic 
disease risk factors, sign and symptoms, and known medical history.  The following schematic 
demonstrates how medical clearance will be determined (Figure 1).  The American College of 
Sports Medicine recommends that all patients are first screened to determine if they are 
participate in regular exercise (defined as performing planned, structured physical activity at 
least 30 min at moderate intensity on at least 3 days per week for at least the last 3 months).  If 
the participant responds with no medical clearance will be not be needed for those who have not 
been diagnosed with any CV, Metabolic, or renal disease and are showing no signs/symptoms.  If 
the response is yes those who have not been diagnosed as well as those with a diagnosis and are 
asymptomatic will not need physician clearance (Riebe et al., 2015).  Like the previous 
recommendations this is only for moderate intensity exercise.  Our exercise protocol falls within 

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this moderate intensity range.  The original protocol called for participants to exercise in the 
range of 50-75% of their maximal heart rate reserve (i.e., moderate to high intensity).  The range 
was previously modified to 40-60% of maximal heart rate reserve (i.e., moderate intensity).  
Hence, participants that have no diagnosis of CV, Metabolic, or renal disease or those that have 
been diagnosed but are asymptomatic will be enrolled without the need for physician clearance.  
Those who have signs and symptoms or who have been diagnosed but do not meet the exercise 
criteria will require medical clearance from their physician.  Final approval and acceptance into 
the program for patients will be provided by our study physician.  It’s worth noting the risk of 
serious adverse events occurring during properly supervised exercise is extremely low (< 1 per 
100,000 hours of exercise) even in older adults, with cardiovascular disease.  Blood pressure will 
also be measured. 
 
 
Figure 1: Exercise preparticipation health screening logic model for aerobic exercise 
participation (Updating ACSM’s Recommendations for Exercise Preparticipation Health Screening, MSSE 2015) 
 
 
 
Measures of Quality of Life and Self-Efficacy. The SF-36 is the most widely used and carefully 
validated measure of health related quality of life and will be used to yield 2 broad summary 
scores: physical health and mental health (Ware and Sherbourne).  The Eurqol Quality of Life 
will also be used to measure quality of life and health state (Brooks; EuroQuol).  The walking 
efficacy for duration scale measures one’s ability to walk/jog at a moderately fast pace for 
various durations (McAuly and Mihalko).  The Positive and Negative Affect (PANAS) measures 

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both positive and negative affect, leading to more insightful outlooks regarding participants' 
feeling states. This scale consists of 20 items that reflect the intensity of how the participant 
"feels" right now (Watson et al).  The gait efficacy/environmental efficacy scale will ask the 
participants’ confidence in performing certain activities (McAuley et al.).  Among the various 
components of subjective well-being, the Satisfaction with life scale is focused to assess global 
life satisfaction (Diener et al).  The Weight Efficacy Lifestyle Questionnaire (WEL) is a 20-item 
measure employed to assess self-efficacy for weight management (Clark et al).  The Perceived 
Stress Scale (PSS) will measure the degree to which people perceive their lives as stressful 
(Cohen et al).  The adherence self-efficacy questionnaire is designed to assess beliefs in one’s 
ability (confidence) to continue exercising at various intensities and frequencies (McAuly and 
Mihalko). 
 
Pain Catastrophizing Scale (PCS).  The PCS questionnaire will be used to assess 
catastrophizing (rumination, magnification, and helplessness) (Sullivan et al). 
 
Knee injury and Osteoarthritis Outcome Score (KOOS).  The KOOS questionnaire will be used 
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) (Roos & Lohmander). 
 
Intermittent and Constant Osteoarthritis Pain (ICOAP).  The ICOAP assesses pain in 
individuals with knee osteoarthritis taking into account both constant and intermittent pain 
experiences (Hawker et al). 
 
Dietary Intake.  National Cancer Institute Modified Health Habits and History Questionnaire 
(HHHQ) provides nutrient assessment of dietary intake.   
 
Health Literacy.     Behavioral Risk Factor Surveillance System measures health literacy.    
 
Physical Activity.  The Physical Activity Scale for the Elderly (PASE) has proven reliable in 
many of our clinical trials, including a group of 254 men and women aged ≥65 yrs (Washburn 
et al).    
 
Cognitive Functioning/Depression.  The MOCA will be used to measure cognitive function 
(Nasreddine et al).  Depression will be measured using the Center for Epidemiologic Studies 
Depression Scale (Burnam et al).   
 
Inclusion/Exclusion Criteria   
Inclusion Criteria: 
(1) Age ≥ 50 years 
 
(2) Knee Pain plus ACR Criteria for Knee Osteoarthritis  
 
(3) BMI = 27 ≥ kg/m2 
 

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Exclusion Criteria: 
1. Significant co-morbid disease that would threaten safety or impair ability to participate in 
interventions or testing (Method: Medical history; medications; physical exam; telephone 
pre-screen; risk stratification) 
a. Blindness 
b. Type 1 diabetes 
c. History or symptoms of coronary artery disease or pulmonary disease with no 
medical clearance (symptoms include angina, unreasonable breathlessness, 
dizziness/fainting/blackouts) 
d. Unable to walk without a device 
e. Lower extremity fracture (within previous 3 months) 
f. Joint Replacement (excluded if double KR or within previous 6 months) 
g. Knee injection or surgery (within previous 3 months) 
h. Lower extremity injury that affects activities of daily living 
i. Bariatric Surgery 
2. Not sufficiently overweight or obese, BMI < 27 kg/m2  (Method: Ht/Wt)  
3. Not having knee pain: (Method:  < 1 on the pain scale, WOMAC and Telephone Screen) 
4. Inability to finish 18-month study or unlikely to be compliant (Method: Telephone 
Screen, Screening Interviews) 
a. Planning to leave area > 2 month during the next 18 months 
b. Unwilling to change eating or physical activity habits 
c. Unwilling to attend exercise/diet sessions 
d. Participating in another intervention study (only if the other study has requested 
they not be enrolled) 
e. Living > 30 minutes from the intervention site 
5. Age, age < 50 (Method: Telephone Screen & Demographics Forms) 
6. Other conditions that may prohibit the effective delivery of the intervention (Method: 
Telephone Screen) 
a. Unable to provide own transportation to exercise center 
b. Unable to read or write, cannot speak or read English 
Randomization Procedures 
We propose a stratified block randomization with block size unknown to investigators and staff 
will ensure equal accrual to each study arm. Prestratification will balance pretrial BMI values 
(27.0-34.9 kg/m2, 35.0-44.9 kg/m2, ≥45 kg/m2) and gender, which could predict intervention 
effect and associations between secondary outcome variables. We will also use county as a fixed 
effect for randomization. A computer program will randomize participants into the 2 groups, 
verify eligibility, and provide identification number and intervention assignment. This system 
worked very successfully in the IDEA study. 
 

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Interventions 
Diet-induced weight loss plus exercise 
Months 0 -6  
There will be two individual sessions per month and 2 group sessions per month for the 
first 6 months. The behavioral sessions will focus on awareness of changing eating 
habits to lower caloric intake. Educational content information regarding what food 
changes to make, how to make them, and why they are important will be clearly 
explained and discussed with participants and significant others. Each group session 
will include problem solving, review of a specific food topic, and tasting of several 
well-balanced, low-fat, nutritious foods prepared with widely available ingredients. 
During the individual sessions, the counselor will review individual progress, solve 
problems, answer questions, and set goals.  During the initial individual session, the 
nutrition counselor will give the participant a weight history background questionnaire.  
The major emphasis for Period 1 is to enhance participant awareness of the importance 
and the need to change eating habits, i.e. lower caloric intake for weight loss.  Each 
participant should be given the opportunity to practice skills using goal setting in a 
stepwise approach.  Participants will follow a weekly menu plan which will incorporate 
meal replacements into their diet plan.  Lean Shakes, a General Nutrition Center (GNC), 
product will be the meal replacement used.  Participants may replace the Lean Shakes 
with a healthy, low-calorie meal of their choice, such as Lean Cuisine.  Motivation and 
encouragement through the combined efforts of the nutrition counselor, the participant, 
significant others and the nutrition staff will enhance adherence.   
Months 7-12   
In period 2 participants will focus on continued weight loss to reach the study weight 
loss goal of 10% of baseline weight.  Participants will attend one group and one 
individual session per month. Once the weight loss goal is achieved an individual may 
either begin weight maintenance, or they may continue to lose additional weight using 
safe and healthy nutrition practices.  Participants will follow a weekly menu plan with 
recipes using traditional foods and the option to incorporate meal replacements. The 
traditional meals will contain 400-600 kcals, be low in fat and added sugars, and high in 
vegetables, fruits, and whole grains. Snacks may be a bar, fruit, or vegetable providing 
~100-120 kcals. Daily caloric intake for each participant will be adjusted to his or her 
rate of weight change. Each group will be encouraged to take a daily 
multivitamin/mineral supplement containing no more than 100% of the Dietary 
Reference Intake for any particular nutrient. As fewer meal replacements are consumed, 
intervention staff will assist in developing meal plans to provide the prescribed 
macronutrient-balanced energy intake.   
Months 13-18   
Period 3 will emphasize weight management over time, with 1 monthly individual 
contact.  Weight loss can continue throughout the intervention, provided the participant 
wants to and has not reached a level associated with health hazards; i.e. a 20% body 
weight loss at 6 months or >30% at 12 months.  Participants will continue to follow a 

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weekly menu plan with recipes using traditional foods and the option to incorporate meal 
replacements.  
 
The exercise intervention will cover an 18-month period.  The exercise program will 
consist of a 15-minute aerobic phase, a 20-minute strength-training phase, a second 15-
minute aerobic phase, and a 10-minute cool-down phase.  These sixty-minute exercise 
sessions will be conducted three days per week (two days/week will be center based).  
Each participant will be prescribed an individual walking prescription by the exercise 
leader, which will be adjusted accordingly, as each participant progresses throughout the 
18 months.  The exercise will be of moderate intensity.  Alternate forms of aerobic 
exercise, such as but not limited to stationary bike, elliptical trainer, or treadmill walking, 
can be used in place of over-ground walking. This choice could be based on participant 
preference, the limitations of the exercise facility, or the participant’s pain level.  To 
motivate participants to be physically active intervention staff will plan an optional fun 
walk.  The walk will take place at Wake Forest University. Participants do not have to 
participate in the walk in order to be in the study.  If a participant chooses to participate 
in the walk they will be asked to sign a waiver.  
 
Intervention Locations: Forsyth County: The diet and exercise classes will be offered at a 
number of sites within Winston-Salem.  Participants will be allowed to pick the location 
that is most convenient for them to attend.  Classes will take place at the Clinical 
Research Center on the Wake Forest University Campus, at St. Peter’s World Outreach 
Center, and at Smiley’s Fitness.  Haywood County: The diet and exercise classes will be 
held at the Haywood Regional Health & Fitness Center in Waynesville, NC.  Johnston 
County: The diet and exercise classes will be held at the Clayton Community Center and 
the Johnston Medical Mall.  Participants will also be allowed to exercise outdoors at the 
intervention sites when the weather permits.  Staff will schedule set times when outdoor 
walking will be allowed. 
 
The following measures will be taken in the event participants are unable to come into 
the facility: 
1. Virtual Sessions - Participants will be given the option to attend virtual 
exercise and diet classes.  Intervention classes will be taught via Zoom. 
Participants will be provided with the class login information. The group and 
diet exercise sessions will be recorded and posted to our study Facebook page 
as well as sent to participants who are unable to attend the live sessions. 
Recordings will be edited so that only the class exercise and diet instruction 
can be viewed (beginning and end of the session as participants log in and out 
will be cut out of the video).  As a security measure the virtual classes will be 
locked after 10 minutes so that no others can join the class. Additionally 
participants will not be given access to record the session.  Individual sessions 
will also be conducted via Zoom. 
2. Phone Sessions – Staff will call participants to deliver the diet group and 
individual session content.  All participants have previously been provided 
with at home exercise manuals.  Staff will also use this time to review our 
non-facility-based exercise plans.   

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3. Email Sessions – Participants may also choose to receive the diet group and 
individual session content via email.  All participants have previously been 
provided with at home exercise manuals.  Staff will also use this time to 
review our non-facility-based exercise plans.   
 
 
All intervention staff in the WE-CAN study will be CPR certified.  The exercise 
coordinator, who is part of the coordinating center and is responsible for maintaining 
exercise protocol congruity between the intervention sites, will train and supervise the 
intervention staff.  Intervention staff will meet monthly with the exercise coordinator to 
discuss any potential problems, risks, and concerns that have risen.  AEDs will be 
available at each location.  Emergency drills will be performed monthly in addition the 
AED will be checked monthly.  The clinical research center (Forsyth), Johnston Medical 
Mall (Johnston), and the Haywood Regional Health and Fitness Center (Haywood) also 
house cardiac rehabilitation programs and will also have crash carts available.       
 
Nutrition & Health Intervention 
The nutrition and health (attention control) intervention will cover an 18-month period.  There 
will be five total face to face group meetings over the 18 months, with one meeting each at 
months 1, 3, 6, 9, and 15; and during the other months (months 2, 4-5, 7-8, 10-14, 16-18) 
participants will receive a combination of informational packets, webinars, text messages, and 
emails.  Participants will be able to select their preferred method.  Each group meeting will last 
approximately one hour and will be held at St. Peter’s World Outreach Center and at Senior 
Services in Winston-Salem, NC.   The sessions will be interactive and will provide useful 
information on such topics as proper foot care, general nutrition, health behaviors, management 
of medications, and sleep practices. The Community Advisory Board will give input on the class 
sessions.   
 
Experts across a broad range of relevant topics that are of interest to older adults will provide 
information via information packets, webinars, text messages or emails. These monthly contacts 
and email blasts will keep the participants in the nutrition and health group engaged in the WE-
CAN study and will increase adherence to the group sessions and the testing visits.    
 
Participants in both interventions will be provided with items with the study logo such as t-shirts 
and tote bags to promote group bonding and study adherence.  Additionally, giftcards will be 
raffled at various class sessions.  In order to better balance the amount of money spent on the two 
groups participants in the Nutrition & Health group will receive a $100 (gift cards) for 
completing the testing appointments.  They will be given $25 at 6 months and $75 at 18 months.   
At the 12-month testing appointments the participants will receive an incentive with the study 
logo.  Participants in the Diet & Exercise group will be receiving meal replacements for the first 
year of the study.   
 
 

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Procedures-Screening and Follow-up Visits.  
           
Procedures-Screening and Follow-up Visits.   
Prescreening visit (PSV). Individuals who contact our recruitment office in response to 
advertising will be asked a series of brief questions that focus on major eligibility criteria.  A 
screening visit appointment will be made for participants who meet major eligibility criteria.  A 
medical history form and a medication form will be mailed to the participants for them to 
complete.  If participants are unable to come in for testing appointments research staff will call 
participants via Webex to collect study data (participants can choose whether to attend virtually 
or only via phone).  Staff will use a HIPPA compliant version of Webex (set up by Wake 
Measurements 
PSV 
SV1 
FU6 
FU12 
FU18 
Explanation 
Questionnaires 
Informed Consent 
 
x 
 
 
 
 
Eligibility Questionnaire 
x 
 
 
 
 
To determine  eligibility 
Medical History/Med History 
FU 
xc 
x 
x 
x 
x 
For  eligibility and to document changes in health 
Risk Stratification 
xc 
x 
 
 
 
Used to screen cardiovascular risk 
Comorbidities Questionnaire 
 
x 
 
x 
x 
 
Randomization 
 
x 
 
 
 
 
WOMAC 
 
x 
x 
x 
x 
Pain is primary and function secondary outcomes.  
Will be taken from the KOOS 
Knee Injury and Osteoarthritis 
Outcome Score (KOOS) 
 
x 
x 
x 
x 
Assesses patient’s opinion about their knee and 
associated problems 
PASE scale 
 
x 
x 
x 
x 
Physical Activity Scale for the Elderly 
MOCA 
 
x 
 
 
x 
Montreal Cognitive Assessment 
EuroQol Quality of Life(EQ5D) 
 
x 
x 
x 
x 
Quality of life measure 
Resource Utilization  
 
x 
x 
x 
x 
Visits to clinicians, tests, medications, injections, 
surgery, alternative therapies 
Work Productivity and Activity 
Impairment Index 
 
x 
x 
x 
x 
assesses absenteeism and presenteeism 
DHQ II 
 
x 
x 
x 
x 
NIH Diet History Questionnaire 
SF-36 
 
x 
x 
x 
x 
Health related quality of life (physical, mental) 
Health Literacy 
 
x 
x 
x 
x 
 
Adherence Self Efficacy 
 
x 
x 
x 
x 
Confidence in exercising at various intensities and 
frequencies 
Adherence for Duration 
 
x 
x 
x 
x 
Confidence in walking for different durations 
Gait Efficacy 
 
x 
x 
x 
x 
Confidence in completing tasks 
Demographics 
 
x 
 
 
 
 
Medication form 
 
x 
x 
x 
x 
Atherosclerosis Risk in Communities form 
Weight Efficacy Questionnaire 
 
x 
x 
x 
x 
Self-Efficacy for Weight Management 
PANAS 
 
x 
x 
x 
x 
Positive and Negative Affect Scale 
SWL 
 
x 
x 
x 
x 
Satisfaction with Life 
Perceived Stress 
 
x 
x 
x 
x 
Stress 
Pain Catastrophizing Scale 
 
x 
x 
x 
x 
Catastrophizing 
Intermittent and Constant 
Osteoarthritis Pain (ICOAP) 
 
x 
x 
x 
X 
Intermittent and Constant Pain 
CES-D 
 
x 
x 
x 
X 
Depression 
Transition Questionnaire 
 
 
x 
x 
X 
Knee pain 
Adverse Events  
 
 
x 
x 
X 
Also collected as they occur 
Physical Performance Tests/Knee Exam 
height 
xc 
x 
 
 
 
To determine BMI 
weight 
xc 
x 
x 
x 
X 
To determine BMI 
Knee exam 
 
x 
 
 
 
To determine  eligibility 
6 minute walk 
 
x 
x 
 
X 
Measure of mobility 
Expanded Short Physical 
Performance Battery (SPPB) 
 
x 
x 
x 
X 
Gait speed, sit to stand, balance tests; predicts 
disability 
GaitRite 
 
x 
x 
x 
X 
mobility measures  
Stair Climb 
 
x 
x 
x 
X 
mobility measure 
xc = brief screen by self-report, PSV = Prescreening Visit. SV = screening visit. FU = follow-up. 

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Forest University).  To reduce participant burden only the following questionnaires will be 
collected: cost effectiveness questionnaires, WOMAC, KOOS, Physical Activity Scale for the 
Elderly (PASE), Health-Related Quality of Life (HRQL), and efficacy measures.  In the event 
participants do not wish to conduct a phone or virtual session a questionnaire packet will be 
mailed to participants to complete and return.  The webex testing session will last 
approximately 1 hour. 
 
Screening Visit One (SV1) Individuals will come to Worrell Professional Building on the 
campus at Wake Forest University.  SV1 includes an explanation of the study and obtaining 
informed consent.  Other assessments include medical history and medication use (previously 
mailed), cardiovascular risk, height and weight (to calculate BMI), hip/waist circumference 
measurements, blood pressure, and a knee exam.  The MOCA & CES-D will be administered.  
The following questionnaires will be given:  demographics, cost effectiveness questionnaires, 
WOMAC, KOOS, Physical Activity Scale for the Elderly (PASE), Health-Related Quality of 
Life (HRQL), dietary intake questionnaires, health literacy, perceived stress, pain 
catastrophizing, and efficacy measures.  Physical performance measures include the SPPB, 6 
minute walk, GaitRite, and stair climb.  This screening visit will last approximately 3 - 4 hours.  
 
Randomization Visit (RV) Individuals will come to Worrell Professional Building on the 
campus at Wake Forest University.  At the RV an orientation to the group will be done. 
 
6-month Follow-up Data Collection Visit (FU6): Participants will return to Worrell 
Professional Building to repeat all measures collected at baseline (minus the MOCA, knee 
exam, and demographics).  The testing session will last approximately 2.5 – 3.5 hours.   
 
12-month Follow-up Data Collection Visit (FU12): Participants will return to Worrell 
Professional Building to repeat all measures collected at baseline (minus the knee exam and 
demographics).  The testing session will last approximately 2.5 – 3.5 hours.   
 
18-month Follow-up Data Collection Visit (FU18): Participants will return to Worrell 
Professional Building to repeat all measures collected at baseline (minus the knee exam and 
demographics).  The testing session will last approximately 2.5 – 3.5 hours.  At the end of 18 
months the participants will have a mini session on what the other group received.    
 
Usage of Facebook 
The research study would like to incorporate the usage of Facebook in the study.  We plan on 
using Facebook in the following ways.  
 
1) Recruitment  
a. The study has created digital ads (submitted with this amendment) that will be 
used in Facebook ads.  Ads posted will be pop up ads. 
 
2)     Study Notifications & Contact Method 
a. The study will set up a Facebook page in which participants will be given the link 
(usage will not be required but will be an additional method that participants can 

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use to contact study staff or find out study information).  A description of this 
usage is listed below. 
i. Study info such as press releases, news articles, manuscripts will be posted 
to the study Facebook page.  This information will also be provided in 
study newsletters (for those not on Facebook). 
ii. Information regarding site closings (such as in the event of inclement 
weather or holidays) or intervention materials (group intervention classes) 
will be posted on the Facebook page.  Please note all participants will be 
given information regarding holiday closings and weather policies in their 
intervention classes.  A study phone number will be given to each 
participant which will be updated in the event of a closing.  It will not be 
necessary to check Facebook to learn of a study closing. 
iii. Participants in the study will also be able to use Facebook as a means of 
contacting the staff by sending a private message (email) to the staff.  This 
method may be useful to the nutrition and health group in which 
participants will be given a choice to their preferred method of contact 
(email, phone, Facebook private message).   
 
3) Participant Posting 
a. The study will set up its account as a page therefore it will not be a private group.  
Therefore the study will only post study information (press releases, articles, etc.) 
and site information.  We will not post pictures or study participant information.  
However participants whom are on Facebook will be allowed to post to the study 
page.  All posts will be reviewed by the study staff to ensure no other participants 
are identified as being a part of the study.   
 
Informed Consent 
 
Signed informed consent will be obtained from each subject.  Consent will be obtained by study 
coordinator, interventionists, and testing staff.  Participants will be consented at screening visit 
one (SV1).  Upon arrival each potential subject will meet with a staff member to review the 
study consent form. No study specific procedures will be done prior to the signing of the consent 
form. Staff members administering the informed consent must use the following steps in order to 
orient the potential subject to the purpose of the research.   
• 
The staff member will verbally explain the study to the potential subject, providing all 
pertinent information (purpose, procedures, risks, etc.), and will allow the potential 
subject ample opportunity to ask questions.   
• 
Following this verbal explanation, the potential subject will be provided with the consent 
form and schedule to review. The potential subject will be given as much time as they 
need to consider whether or not to participate in the research.   
• 
After allowing time for the potential subject to read the consent form, the staff member, 
will meet with the potential subject to answer any additional questions he/she may have. 

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• 
Once the potential subject has all of their questions answered and has agreed to 
participate, they will be asked to sign and date the consent form. The staff member will 
also sign and date the consent. 
• 
A copy of the informed consent will be made and given to the subject.  
In the event a person wishes to discuss the study with a family member or would like additional 
time to think about participating in the study, the staff member will make a note of this in the 
subject file and the staff will follow-up with the potential subject.  
Once a person has completed the screening appointment and the data has been entered into study 
website the project manager will randomize the subject by selecting the randomization program 
in the WE-CAN website.  Participants will be placed into either the diet & exercise group or the 
attention control (nutrition & health) group. 
Safety Monitoring Plan 
An internal safety committee has been established to monitor participant safety and to evaluate 
the progress of the study.  In addition NIAMS has selected a DSMB to monitor study safety and 
progress.   
Adverse Event and Serious Adverse Event Collection and Reporting 
Adverse Event (AE) - An AE 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,  including excessive delayed 
onset muscle soreness (DOMS) as some minimal muscle soreness will be expected after the 
training session. AEs include any new events not present during the pre-intervention period or 
events that were present during the pre-intervention period which has increased in severity.  
Participants will be asked if any events have occurred on a monthly basis prior to their 
intervention class and at each testing session.  Participants will be encouraged to report AEs as 
they occur. 
Study staff will report non-serious adverse events (related and unrelated to the study) to site project 
manager and principal investigator within 7 days of notification of the event and will be reported to the 
coordinating center quarterly. Testing staff will inquire about adverse events prior to testing to ensure 
there are no unreported events.  The site physician/PA will review non serious adverse events (AE) on a 
weekly basis.  Non serious adverse events will be included in the NIAMS safety report and submitted bi-
annually.    
Serious Adverse Event (SAE) - An SAE 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 
participants or others. 
Staff will report serious adverse events (related and unrelated to the intervention) to the site 
project manager, principal investigator, and study physician.  The clinical site will reports SAEs 

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to the coordinating center within 24 hrs of notification.  SAEs will be reported to NIAMS within 
24 hours of being reported to the PI (within 48 hours of initial report).  The WFU IRB does not 
require the reporting of adverse events unless it is serious, unexpected and related to the study. 
Follow-up information will be provided to the PI, DSMB/Safety Officer, and IRB, as 
appropriate.   
 
NIAMS has assigned a Data Safety Monitoring Board (DSMB) or safety monitor to monitor all 
aspects of the study.  
 
 
The DSMB/Safety Monitor will have the following charges:  
• To review the entire study protocol, the operations manual, and the informed consent and 
assent forms for recruitment, randomization, intervention, participant safety, data management, 
auditing plans for participant records, and quality control and analysis plans, and to identify 
needed modifications.  
• To review data related to efficacy, recruitment, randomization, compliance, retention, protocol 
adherence, trial operating procedures, forms completion, intervention effects, gender and 
minority inclusion, and participant safety over the course of the trial.  
• To identify problems related to safety over the course of the study and to report them in writing 
to the PIs, who will ensure that the appropriate individuals receive the report.  
• To identify a need for additional data relevant to safety and to request them from investigators.  
• To propose appropriate analyses and periodically review developing data on safety and 
endpoints.  
• To make recommendations regarding recruitment, intervention effects, retention, compliance, 
safety, and continuation of the study.  
• To send the Program Administrator and PIs written reports following each DSMB meeting, 
addressing all issues raised, and subsequently sent to the IRB.  
• At any time, the DSMB may recommend discontinuation of any component/intervention of the 
study for any of the following reasons:  
1) Compelling evidence from this or any other study of an adverse effect sufficient to override 
any potential benefit of the interventions to the target population.  
2) Compelling evidence from this or any other study of a significant beneficial effect whose 
continued denial to other study group(s) would be unethical.  
3) A very low probability of addressing the study hypothesis within a feasible time frame.  
 
Statistical Considerations 
Data Management 
The Data Management Group, part of the Coordinating Center, has primary responsibility for 
randomization and analyzing data generated by the clinical centers. Data will be collected on 
hard-copy forms at each site and transformed to an electronic database. Our web-based 
management system will assure integrity and validity. Dynamic reports and periodic statistical 
analyses will monitor quality. A participant-based inventory system will track recruitment, 
retention, adherence, and missing data from entry through exit, close-out, and lock-down of final 
datasets. Our team developed a similar database for the IDEA and START studies.   

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Statistical Analyses  
Statistical analyses will be conducted according to intention-to-treat principles using SAS. 
Primary Aim.  
The primary hypothesis of long-term reduced WOMAC pain at 18 months will be tested based 
on a two-tailed significance level of 0.05 using contrast statements from a repeated measures 
mixed linear model with time (6, 18 mos), randomization arm (D+E vs control), and the 
interaction, which adjusts the means at each time point for potential missing data bias (Laird and 
Ware). Intervention-effect estimates will be further adjusted for baseline pain values, BMI, 
county, and gender; analysis will match design, so the variance estimate will not be biased. 
Participant ID number will be included as a random effect to control for within-subject 
variability, and the longitudinal model will use an unstructured covariance matrix. In the unlikely 
event the model does not converge, a first-order autoregressive (AR[1]) covariance structure will 
be fit instead. Maximum-likelihood techniques will estimate parameters, as in the IDEA trial 
(Messier et al). Preliminary analyses will be conducted to check the shape of the distributions 
and variances between groups and as a function of the covariates. Regression diagnostics and 
residual plots will help to find appropriate transformations, if necessary. We will include 
exploratory analyses of subgroups, defined by gender, age (<70 vs ≥70 years), baseline BMI 
(27.0-34.9, 35-44.9, ≥45 kg/m2), county, and race to determine any differential pain responses. 
Secondary Aims 
Repeated measures mixed linear models similar to Aim 1 will be used to analyze WOMAC 
function, 6-minute walk, and SF-36 physical subscale. Each outcome will be modeled separately, 
and 18-month effectiveness will be tested based on a two-tailed significance level of 0.05. The 
model will include the fixed effects study arm, time, time-group interaction, county, gender, 
baseline BMI, and baseline values of the outcome; participant ID number will be included as a 
random effect, and an unstructured covariance will be used assuming model convergence is not a 
problem (AR[1] otherwise). Preliminary analyses will be conducted to check the shape of the 
distributions and variances between groups and as a function of the covariates. Regression 
diagnostics and residual plots will help to find appropriate transformations, if necessary. 
Missing Data 
If missing data are related to outcomes, our results could be biased. Our models will include 
variables from previous visits determined to predict loss to satisfy Little and Rubin’s conditions 
for data considered missing at random (MAR). If “informative censoring” occurs, we will 
compare analyses using subjects with complete data, multiple imputations, or explicit modeling 
of the censoring mechanism (Conaway, 1993, Wu and Bailey, 1989). 
Primary Outcomes 
Aim 1. A total sample of 820 (410/group) will provide 94% statistical power to detect differences 
≥15% in pain at the 2-sided 0.05 significance level with 80% retention (2-sample t-test, Nquery 
Advisor). Based on ADAPT (Messier et al).  The D+E group in IDEA reduced pain by an 
average of 51%. This approach utilizes the conditional variance approach of Borm et al. for the 
estimation of power for ANCOVA models using group standard deviation 𝜎𝜎= 3.50, Pearson 
correlation between baseline and 18-month pain score of 𝜌𝜌= 0.4 for a conditional standard 
deviation 𝜎𝜎𝑐𝑐= 3.21 (𝜎𝜎𝑐𝑐= ඥ1 −𝜌𝜌2 × 𝜎𝜎), and 18-month treatment WOMAC pain means ~D+E 

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= 5.03 vs E-only control = 5.92 (Δ = -0.887). Variations of anticipated power due to 
modifications in 
retention and 
treatment effect are 
presented in Table 
1. Correlation 
between baseline 
and 18 month pain 
values are 
estimated from the IDEA trial, while anticipated treatment effects and standard deviation for pain 
were obtained using weighted averages of D+E and non-D+E treatments from the ADAPT and 
IDEA studies, with some attenuation of the anticipated treatment effect due to the pragmatic 
nature of WE-CAN (Table 1). 
 
 
Secondary Outcomes 
Aim 2. Our sample size provides a moderate effect size of 0.234 at 85% power with relevant 
detectable differences. However, all estimates from IDEA and ADAPT were collected under 
rigorously controlled conditions; therefore the estimates for the pragmatic trial are conservative. 
We assume in Table 8 a total baseline sample size of N=820, 80% retention at 18 months, and a 
0.05 level of significance for all tests. The detectable and % differences from control aim to 
achieve 85% power. The mean differences in WOMAC function for D+E compared to D only 
and E only in IDEA were -3.3 and -4.3, respectively. Likewise, the differences in 6-minute walk 
distance for the D+E group versus D only in IDEA and ADAPT (41.5 and 42.1, respectively) 
indicate that the mean difference to achieve 85% power (15.2 m) is modest. IDEA indicated that 
SF-36 physical subscale was significantly improved in the D+E arm, with an observed difference 
of 2.8 compared to E alone (Table 2). 
 
 
 
 
 
 
 
Table 1:    Power estimates for WOMAC pain, assuming baseline N=820, correlation between BL and 18 months=0.4, 
and common group SD = 3.50. 
18 month Control 
Mean WOMAC 
Pain 
18 Month D+E WOMAC 
Pain (% difference from 
Control) 
 
18-Month Retention 
70% 
75% 
80% 
85% 
Power 
5.92 
 
5.15 (13%) 
81% 
84% 
86% 
88% 
5.03 (15%) 
91% 
92% 
94% 
95% 
4.91 (17%) 
96% 
97% 
97% 
98% 
Table 2: Detectable absolute and relative (%) differences for secondary outcomes, n = 
410/group, 80% retention, 85% statistical power, α = 0.05. Correlation between baseline and 
18M values is ρ. 
Variable 
Anticipated 18m 
Control mean* 
Standard 
Deviation 
𝜌𝜌 
D+E Mean (% change 
from C) 
WOMAC Function 
17.5 
11.5 
0.6 
15.3 (-12.3%) 
Mobility: 6-Minute Walk (m) 
509 
90.7 
0.7 
524 (3.0%) 
SF-36 Physical Score (0-100) 
42.0 
10.1 
0.5 
44.1 (4.9%) 

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