A National Trial of the ELM Lifestyle Program and Remission of the Metabolic Syndrome
Phase: NA
Conditions: Metabolic Syndrome
Sponsor: Rush University Medical Center

 
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The Enhanced Lifestyles for Metabolic Syndrome 
(ELM)  
 
Trial Protocol 
April 20, 2021  
 
 
 
 
 
 

 
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Protocol History 
DATE  
DESCRIPTION 
REVISED SECTION(S) 
6/2/20 
 
Original protocol 
 
 
7/21/20 
Adverse events and unanticipated problems will be reported 
to the DSMB quarterly instead of monthly. This revision was 
recommended by the DSMB at the Annual DSMB meeting 
held on 6/30/20. 
Safety Monitoring: Adverse Events  
Figure 7  
 
 
The timing of in-person data collection visits are now aligned 
with the date of randomization. This differs from the previous 
alignment to dates associated with intervention delivery. The 
DSMB recommended this change at the Annual DSMB 
meeting held on 6/30/20 
 
Outcomes Assessments: In-Person 
Follow-Up Visits  
10/13/20 
The Outcomes & Publications Committee extended the in-
person follow-up study visit window from 6 weeks to 9 
weeks. This was reported at the Steering Committee meeting 
on 10/13/20. 
 
Outcomes Assessments: In-Person 
Follow-Up Visits  
1/19/21 
The Steering Committee approved the following exclusion 
criterion to be included in the ELM Trial protocol on 1/12/21: 
 
 
Participation in any clinical trial, until at least six months 
following the end of the intervention phase. Individuals in 
long-term follow-up (over 6 months post intervention) 
may be enrolled in ELM. Individuals in studies that are 
not clinical trials, such as observational studies or surveys 
may be enrolled in ELM. 
  
Eligibility  
1/26/21 
The timing of in-person data collection visits is now aligned 
with the date of the last intensive phase session in the Group-
Based arm. This differs from the previous alignment to dates 
of randomization. The DSMB endorsed this change at the 
DSMB meeting held on 1/25/20. 
 
Outcomes Assessments  
2/8/21 
The original trial timeline was replaced with an updated 
timeline starting in Year 3. 
Trial Design  
4/20/21 
The Executive Committee approved the exclusion criterion 
below at the 4/20/21 EC meeting. 
 
Concurrent or planned participation in any other lifestyle 
intervention or behavioral weight loss program. 
Eligibility 
 
 
 

 
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Table of Contents 
 
BACKGROUND ............................................................................................................................................................ 4 
SPECIFIC AIMS ............................................................................................................................................................ 5 
TRIAL DESIGN ............................................................................................................................................................. 6 
EQUIPOISE AND BLINDING ......................................................................................................................................... 7 
ELIGIBILITY .................................................................................................................................................................. 8 
RECRUITMENT AND RANDOMIZATION ...................................................................................................................... 9 
INTERVENTIONS ....................................................................................................................................................... 11 
OUTCOMES ASSESSMENT ........................................................................................................................................ 14 
RETENTION ............................................................................................................................................................... 16 
DATA FLOW .............................................................................................................................................................. 17 
SAMPLE SIZE ............................................................................................................................................................. 19 
ANALYSIS PLAN ........................................................................................................................................................ 19 
TRIAL ORGANIZATION .............................................................................................................................................. 21 
SAFETY MONITORING .............................................................................................................................................. 21 
REFERENCES ............................................................................................................................................................. 24 
 
 
 

 
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BACKGROUND 
 
The metabolic syndrome (MetS) is a preclinical warning sign for heart failure, diabetes, and cardiovascular 
disease. Together, these chronic conditions account for the majority of health care costs. The MetS is diagnosed 
by the co-occurrence of at least 3 out of 5 cardio-metabolic risk factors: abdominal obesity, hypertension, 
hyperglycemia, hypertriglyceridemia, and low high-density lipoprotein cholesterol [1]. It quintuples the risk of 
diabetes, doubles the risk of cardiovascular disease [2], and is considered a state of prediabetes [3] and Stage A 
of heart failure [4]. 
  
The MetS has increased in prevalence from one-quarter to one-third of Americans over the past 20 years [5]. Its 
fundamental cause is a lifestyle characterized by an imbalance of energy intake and output, exacerbated by 
chronic stress. The current health care system treats it with drugs, which are not taken in 50%of the patients 
and do not slow progression in 50%that do take them. If as few as 40% of the 86 million Americans with the 
MetS made a sustained change in their lifestyle, it would result in a 60% reduction in health care costs and a 
savings of approximately $85 billion annually [6].  
 
Prior lifestyle interventions that examined sustained, 2-year remission of the MetS have produced success in 
10%-48% of participating patients. The greatest successes occurred in small experimental studies in 
Mediterranean countries following high-intensity dietary interventions that cannot be easily implemented in 
clinical practice. In the United States, the Diabetes Prevention Program found a 2-year remission of 11.1% in the 
549 participants randomized to the lifestyle arm who had the MetS at baseline [7]. All of the existing lifestyle 
interventions for the MetS targeted diet or diet plus physical activity. Chronic stress promotes the MetS directly 
by triggering the release of glucocorticoids [8] and indirectly by interfering with efforts to adopt healthy 
behaviors [9]. A 3-component lifestyle intervention targeting diet, physical activity, and chronic stress has never 
been evaluated for its ability to promote a sustained remission of the MetS.   
 
With support from the William G. McGowan Charitable Fund, a multidisciplinary team of investigators from the 
Rush Department of Preventive Medicine developed the Eat Love Move (ELM) Lifestyle Program, a group-based 
lifestyle intervention for the MetS designed for implementation in the current health care system. Preliminary 
data suggested that it is plausible that the ELM program can achieve sustained 2-year remission of the MetS in 
over 50% of patients [10], can be implemented in a clinical setting, and can be delivered with high fidelity at a 
different national site.  
 
The next step in this progressive program of research is to conduct a multi-site efficacy trial to test whether, and 
under what conditions, the ELM program can produce a sustained remission of the MetS when delivered across 
diverse national sites, and whether or not it offers a cost-effective alternative to the best option for lifestyle 
change that exists in current medical practice and is augmented by widely-available wearable technology.  
 
This multi-site trial is called the Enhanced Lifestyles for the Metabolic Syndrome (ELM) trial. Once the ELM trial 
began, the ELM Lifestyle Program was renamed the Group-Based Program. It will be compared to enhanced 
usual care, named the Self-Directed Program. The neutral names for the trial arms preserve equipoise and 
minimize reactivity to any pre-existing preferences. 
 

 
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SPECIFIC AIMS 
 
The ELM trial aims to compare a Group-Based program to an enhanced usual care comparator 
called the Self-Directed program when implemented at the national level.  A total of 600 participants are 
recruited from 5 geographic regions (Rochester NY, Wilkes-Barre PA, Chicago IL, Kansas City MO, and Denver 
CO) and randomized into 1 of the 2 arms in a ratio of 1:1. The primary evaluation will occur after 2 years and will 
focus on sustained remission of the metabolic syndrome (MetS), sustained change in health behaviors, medical 
status, quality of life, and the cost-effectiveness of each arm. These aims are operationalized as the following 
Specific Aims. 
 
PRIMARY AIM 1 
Compare the Group-Based and Self-Directed arms on remission of the metabolic syndrome at the 2-year follow-
up. The hypothesis is that 2-year remission of the MetS will occur in > 40% in the Group-Based arm and in < 20% 
in the Self-Directed arm. 
 
SECONDARY AIMS 
AIM 2.   
Compare the Group-Based and Self-Directed arms on the behavioral risk factor targets of the treatment, and 
other secondary outcomes, at 6, 15, and 24 months. 
 
Aim 2a: Compare the Group-Based and Self-Directed arms on the proportion of participants achieving 
clinically significant improvement in behavioral risk factor targets of treatment:  (1) 2 cups of 
vegetables/day; (2) at least 150 minutes of  moderate intensity physical activity/week; (3) either the 
maximum score, or an increase of > 1 standard deviation of baseline distribution, on the 3-facet 
Mindfulness Questionnaire; and (4) a score of > 4 on each of the four domains of the Self-Reported Habit Index 
(diet, physical activity, emotion control, and sensory awareness).  
 
Aim 2b:  Compare the Group-Based and Self-Directed arms on the secondary outcomes of:  (1) > 5% loss 
of baseline weight; (2) kg of weight lost; (3) frequency of sugary beverage intake; (4) energy/vitality; (5) 
depressive symptoms; (6) social support for diet and exercise; (7) frequency of contacts with the health 
network; (8) perceived stress; (9) eating competence; (10) MetS components; (11) MetS severity; (12) 
Hemoglobin A1C; and (13) body mass index. 
 
AIM 3.  
Conduct a comprehensive health economic evaluation of the Group-Based and Self-Directed programs. 
 
Aim 3a:  Calculate the cost-effectiveness of the Group-Based relative to the Self-Directed programs.  
Cost-effectiveness is quantified using the Incremental Cost-Effectiveness Ratio and will reflect the 
cost of the programs in the two arms relative to their efficacy at promoting a sustained remission 
of the MetS. 
 
Aim 3b:  Model the projected clinical benefits and health care savings associated with dissemination 
of the Group-Based and Self-Directed programs. 
 
Aim 3c:  Compare the Group-Based and the Self-Directed programs on the number and dose of 

 
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medications, and health care utilization (primary care visits, specialty care visits, emergency room visits, hospital 
admissions) at 2 years. 
 
EXPLORATORY AIMS 
AIM 4.  
Evaluate the consistency of impact and delivery across national sites. 
 
Aim 4a:  Explore the efficacy of the Group-Based and Self-Directed programs in subgroups defined 
by:  geographic site, type of recruitment, age, gender, race/ethnicity, education, income, and number 
of MetS components. 
 
Aim 4b:  Explore the fidelity of delivery of the Group-Based and Self-Directed programs by 
geographic site. 
 
 
TRIAL DESIGN   
 
This is a 6-year, 5-site, randomized behavioral efficacy trial of 600 participants with the MetS. Trial coordination 
is conducted by a research coordinating unit (RCU) and an intervention coordinating unit (ICU), located within 
the Department of Preventive Medicine at Rush University Medical Center in Chicago. Patients with MetS who 
are motivated to manage it by changing their lifestyle, and do not have any medical contraindications or 
logistical barriers, are recruited serially from each of the 5 participating clinical centers over 4 waves of 6-month 
recruitment periods. Each site is expected to recruit 30 participants/wave, and 120 participants over all 4 waves, 
to achieve a total of 600 participants in the trial. Recruitment proceeds in 3 steps to confirm medical, behavioral, 
and logistical eligibility. Once a site has recruited 30 participants, they are randomized in a ratio of 1:1 to the 
Group-based or Self-Directed arm. Randomization is stratified by site in permuted blocks. Outcome evaluation is 
conducted at baseline, at the end of the intensive phase of the intervention at approximately 6 months, halfway 
through the maintenance period at approximately 15 months, and at the end of follow-up at approximately 24 
months. Figure 1 presents the trial design. Figure 2 presents the timeline for the 6-year trial including the set-up, 
serial recruitment in 4 waves, intervention, and maintenance. This revised trial timeline reflect s a 4-5 month 
suspension of in-person visits due to the Covid-19 pandemic. 
 
 
Figure 1. Trial design  
 
 
 

 
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Figure 2. Trial timeline  
 
 
EQUIPOISE AND BLINDING 
 
Investigator preference for, and confidence in, a specific trial result can be an independent source of post-
randomization bias triggering unintended interventions, treatment crossovers, co-intervention bias, and 
ascertainment bias. The potential for this bias in the ELM trial is minimized by targeting the mindset of the 
investigators. Their mindset has been shaped by presentations and discussions about objectivity as a hallmark of 
a scientific mindset, the need for discipline to keep preferences private, and the fallacy of expecting, in advance 
of a trial result, that one arm will be superior to the other. Trial arms have been renamed with neutral names: 
Group-Based (the treated group, previously the Eat Love Move (ELM) program); and Self-Directed (the enhanced 
care comparator). The blind is extended in trial operations to include: blinding to trial hypotheses but not to trial 
aims among all except the Principal Investigators; blinding to individual level treatment assignment among all 
but the interventionists; blinding of all but the senior biostatistician to the primary outcome of MetS; and 
blinding of interventionists to aggregated outcome data completion. Detection of risk of bias resulting from an 
absence of equipoise will be evaluated on an ongoing basis by assessing crossovers and co-interventions every 3 
months, and assessing differential attrition monthly.  

 
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ELIGIBILITY  
 
To be eligible for participation, 600 individuals must meet the inclusion criteria and not meet any of the 
exclusion criteria. 
 
Inclusion Criteria 
 
1. Men and women with MetS, defined by the Joint Interim Statement of the IDF, NHLBI, AHA,WHF, IAS, 
IASO [1]. To meet these MetS criteria the participant has ≥ 3  of the following 5 components:  
a. Waist circumference of ≥ 102 cm for men and ≥ 88 cm for women; 
b. Triglycerides ≥150 mg/dL or treatment for elevated triglycerides; 
c. HDL cholesterol <40 mg/dL in men and <50 mg/dL in women, or treatment for low HDL; 
d. Systolic blood pressure ≥ 130 mmHg; diastolic blood pressure ≥ 85 mm Hg; or treatment for 
                               hypertension; 
e. Fasting plasma glucose 100-125 mg/dL (range inclusive) or on metformin 
2. Age 18 years or older. 
 
Exclusion Criteria 
 
Safety: 
3. 
Unable to walk 2 consecutive blocks without assistance; pain, tightness, or pressure in the chest during 
physical activity; dizziness or lightheadedness without clearance from their physician.  
4. 
History of an eating disorder in the past 5 years.   
5. 
History of major cardiovascular illness: stroke; myocardial infarction; congestive heart failure > NYHA 
Class I; uncontrolled hypertension (SBP>180 or DBP > 110); unstable angina or an active prescription for 
sublingual nitroglycerin; or other cardiovascular illness deemed to limit safe participation.  
6. 
Individuals with moderate hypertension (SBP ≥160 and ≤180; DBP ≥100 and ≤110) without written 
consent from their physician.   
7. 
Severe food allergies or intolerances/preferences.  
 
Logistics: 
8. 
Unable to consistently attend group classes at a scheduled time due to lack of reliable transportation, 
schedule conflicts, travel, plans to relocate, upcoming surgery, etc. 
9. 
No reliable access to the internet via a computer or mobile device.  
10. Participant does not have a primary care physician and does not want one at the time of enrollment.  
 
Motivation: 
11. Unwilling, unable, or not ready to make lifestyle changes.  
12. Unable or unwilling to complete the run-in protocol. 
 
Risk of Attrition: 
13. Unwilling to consent to randomization.  
 

 
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Special Population Needs: 
14. 
Not fluent in English.  
15. 
Visual or hearing impairment.  
 
Confounding with Medical Treatment: 
16. 
Current diagnosis of type 1 or type 2 diabetes, on any diabetes medications except metformin, or a 
screening A1c ≥7.0. Individuals with fasting blood glucose ≥ 126 or Hemoglobin A1c ≥6.5 and < 7.0 
without confirmation from their physician that they do not have diabetes.  
17. 
Inpatient treatment for a psychiatric condition within the past 6 months, or currently receiving 
treatment for schizophrenia or other serious psychiatric illness.  
18. 
≥ 30 days of oral corticosteroid use within the last year, history of solid organ transplant, or history of 
stem cell transplant.  
19. 
Use of weight loss medications in the last 3 months, or unwilling to abstain from weight loss 
medications or supplements during the trial.  
20. 
Pregnant women, planning a pregnancy in the next 24 months, given birth in the last 6 months, or 
currently breastfeeding. 
21. 
History of bowel resection or bariatric surgery.  
22. 
Any medical condition known to influence the etiology of MetS (e.g., uncontrolled hypothyroidism, 
endocrine hypertension, etc.). 
23. 
Currently taking antiretroviral therapy. 
24. 
Receiving dialysis 
25. 
Cancer treatment within the last 6 months, excluding chemoprophylaxis or treatment for non-
melanoma skin cancer 
26. 
Participation in any clinical trial, until at least six months following the end of the intervention phase. 
Individuals in long-term follow-up (over 6 months post intervention) may be enrolled in ELM. 
Individuals in studies that are not clinical trials, such as observational studies or surveys may be 
enrolled in ELM. 
27. Concurrent or planned participation in any other lifestyle intervention or behavioral weight loss program. 
28. 
 
Not Suitable for Group Treatment 
29. 
Probable major depression, defined as a PHQ-8 score ≥ 10. 
30. 
Problematic use of alcohol and/or recreational drugs, defined as ASSIST screening score of ≥27.  
31. 
Cognitive impairment, defined by a Montreal Cognitive Assessment (MoCA) score of ≤25. 
 
Carry-Over Effects 
32. 
Previous participation in an ELM program or currently living with ELM participant.  
 
 
RECRUITMENT AND RANDOMIZATION 
 
Identification of Potential Participants 
 
There are 3 key strategies used to identify potential participants. 
1. Electronic Medical Records. The RCU has developed an algorithm for interrogating medical records. This 
algorithm identifies patients with probable MetS, without a diagnosis of diabetes,  > 18 years of age, and 

 
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English speaking. All patients identified are sent an introductory letter with the option of opting out of 
receiving a subsequent recruiting phone call within 2 weeks of receipt of the letter. 
 
2. Referral by Medical Provider. Referrals are accomplished in medical clinics by embedding research 
assistants within the clinic, posting recruitment materials in the exam rooms, and/or clinic-specific 
activities developed by a provider who serves as a local champion. 
 
 
3. Self-Referral. Internet-based recruitment, advertisements, Facebook, and mass media visibility make it 
possible for interested potential participants to contact trial staff directly. 
 
Sites have the flexibility to tailor their recruitment approaches to those that are likely to have the most success 
within their community.  
 
 
Screening  
 
Screening takes place in 3 steps.  
 
Step 1:  Initial Telephone Screening 
Telephone screening provides a first pass at determining medical, behavioral, and logistical eligibility. 
Prospective participants are first asked about their interest in the trial. Then they self-report their status on 
MetS components and respond to a series of questions about medical, logistical, and safety eligibility. They are 
asked 2 specific questions about behavioral eligibility based upon willingness and ability to make changes in 
their lifestyle. Conditional upon eligibility after the screener is complete, prospective participants are asked 
about their continued interest in the trial and their willingness to attend an Information Session to get more 
information. 
 
Step 2:  Information Session 
The Information Session aims to provide potential participants with a better understanding of what lifestyle 
change entails and what is required for participation in a randomized clinical trial. The approach is not a “hard 
sell” to enhance participation, but rather an effort to obtain true informed consent by giving the prospective 
participant the opportunity to engage in a thoughtful consideration of the pros and cons of participation, 
following the procedures developed by Goldberg and Kiernan [11]. This group-based session features a 
PowerPoint presentation that includes information on the Group-Based and Self-Directed lifestyle programs, the 
research process, and the meaning of informed consent. It provides potential participants with an opportunity 
to discuss the pros and cons of participation with each other and decide whether or not the trial is right for 
them. These discussions include such considerations as current life priorities, time needed for lifestyle change, 
confidence in making changes at the current time, and expected barriers. They are then asked to consider 
participation over the upcoming week, and then to call the site research staff if they continue to be interested in  
participating.   
 
Step 3:  Baseline Exam  
The baseline exam has three components. If a prospective participant fails to attend a session or complete a 
required component, he/she is given one opportunity to reschedule or retry, except in special circumstances, as 
judged by the site Principal Investigator.  
 
 
Component 1 (Visit A). The first in-person visit includes obtaining informed consent, demographic 
information, and assessment of eligibility criteria by questionnaire, medication questionnaire, and instructions 
for the Run-In period. 

 
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Component 2 (Run-In Period). A Run-In period was developed to identify those who are willing and able 
to engage in a selected set of activities required by the Group-Based program. This Run-In includes successful 
completion of the accelerometer protocol (wear accelerometer for 7 consecutive days, 10 hours/day), food and 
beverage logs (record all food and beverage intake over an entire day for a minimum of 3 weekdays and 1 
weekend day), and completion of a worksheet that outlines a logistical plan for how to access vegetables and a 
location for physical activity (completed at home or during Visit B).   
 
 
Component 3 (Visit B). The second in-person visit includes a 12-hour fasting blood draw, physical 
measures, confirmation that the Run-In protocol was completed successfully, and completion of baseline 
questionnaires. Visit B occurs within 1 month of randomization. At the conclusion of Visit B, prospective 
participants are asked about continued interest, informed of expected wait time until the start of the program, 
and entered into the recruitment waiting protocol where they are kept informed of likely dates of starting 
treatment in ongoing contacts every 2 weeks. If a prospective participant is ineligible based on metabolic 
syndrome criteria or needs medical clearance for trial participation, the research assistant will follow-up with a 
phone call. 
 
Randomization 
 
Randomization is conducted by the RCU in permuted blocks and stratified by site. Since 1 of the arms in the trial 
is a  group-based treatment of 15 participants/group, randomization will occur when 30 prospective participants 
are confirmed to be eligible and interested. Treatment should begin immediately after randomization. Upon 
randomization, participants are informed of the arm to which they were randomized by a mailed letter, an 
email, and a follow-up phone call from the respective site interventionist.  
 
As randomization progresses, key population descriptors are compared in the trial arms to ensure that 
randomization is successfully balancing arms on key baseline characteristics. If any key covariate, such as age, 
race, gender, employment status, weight, or MetS component, differs by treatment arm, additional stratification 
in the randomization scheme is considered.  
 
 
INTERVENTIONS 
 
Highly motivated participants are recruited to help determine the better and more cost-effective way to 
encourage sustained lifestyle change to reverse the MetS. 
 
 
The two arms are similar in the evidence-based content they provide, access to the website, and the use of a 
Fitbit to self-monitor physical activity. In both arms, lab results are sent to the participant and, with participant 
permission, to the primary care provider with encouragement to discuss the results. The arms differ in mode of 
delivery and intensity of contact. The Group-Based arm features face-to-face group contacts and a common 
protocol for accomplishing sustained behavior change. The Self-Directed arm features individual initiative and an 
individually-determined implementation schedule for achieving sustained behavior change. Within a context of 
highly-motivated patients, it is currently unclear which of these treatment approaches is better. 
 
The Group-Based Arm 
 
The Group-Based lifestyle program is the former Eat Love Move (ELM) lifestyle program, renamed in keeping 
with equipoise. It aims to achieve sustained change in lifestyle through the development of 4 habits that 

 
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become automatic in daily life. The hypothesized pathway guiding this program is shown in Figure 3 below.  This 
is a 3-component treatment, targeting simultaneously diet, physical activity, and mindful awareness. Each 
component is translated into an ELM Leaf which is an easy-to-remember phrase representing each of the 4 
habits. Each habit has a quantified implementation (enactment) target (in yellow), which is monitored by 
interventionists on a weekly basis. Success in achieving automaticity in each of these 4 habits is the behavioral 
mediator. The hypothesis is that if these 4 habits become automatic parts of daily life, they will translate into a 
clinically significant improvement in the behavioral risk factor targets of vegetable intake, physical activity, and 
mindful awareness. If clinically significant improvement in these health behaviors is achieved, the hypothesis is 
that this will translate into clinically significant weight loss (the biological mediator) and sustained remission of 
the MetS (the primary outcome). 
 
 
Figure 3. The hypothesized pathway for the Group-Based program. 
 
The intervention team at each site consists of a health psychologist, a registered dietitian, and health coach (e.g. 
lay person who has achieved success with lifestyle modification). Together they co-facilitate group meetings of 
approximately 15 participants. There is an intensive phase where meetings are held weekly for 3 months and bi-
weekly for 3 months. The first 3 months is aimed at initiating change, focusing primarily on food intake, eating 
behavior, and weight. The last 3 months is aimed at maintenance, focusing on physical activity and a variety of 
other strategies that enhance maintenance. A maintenance phase follows the intensive phase where 
participants meet on a monthly basis to check in, report on challenges and successes, and learn about a new 
topic of their choice.    
 
The format for all of the sessions in the intensive phase is an ecologically valid set of activities within which old 
habits emerge and new habits can be explored. Participants work out together, prepare a vegetable dish 

 
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together, and eat while participating in an experiential exercise. The duration of each session is 90 minutes: 
physical activity (20 min), cooking demonstration (20 min), and discussion (50 min).   
 
The maintenance phase (months 7 to 24 after randomization) consists of participant-led monthly meetings. 
Participants are encouraged to broaden their health network by opening maintenance sessions to members of 
other ELM groups at the site and participating in national ELM activities through the website. Meetings are 
available at least twice a month for the duration of the intervention to minimize non-attendance due to 
competing activities. The health psychologist and dietitian alternate in supporting the participant-led meetings. 
 
The Self-Directed Arm 
 
The Self-Directed lifestyle program is intended to represent an enhanced version of what is currently available in 
clinical practice for patients who express an interest in using lifestyle change to manage their MetS. The current 
state-of-the-art in primary care for lifestyle management is the provision of evidence-based health education, 
featuring clear guidelines and behavioral targets, endorsed by the American Heart Association, American 
Diabetes Association, United States Department of Agriculture, and the Academy of Nutrition and Dietetics. 
Educational tip sheets are sent to participants on a monthly basis by their preferred method. Further 
enhancement is provided by giving all participants a Fitbit, one of the most popular wearable activity trackers 
available in technology today, and instructing them in how to use it to self-monitor their physical activity. An 
additional enhancement is provided by giving participants access to the ELM website that contains educational 
materials and other trial-related information. 
 
The Self-Directed arm has been designed to serve as a clinically relevant comparator. It is intended to be the  
optimum status quo in medicine and technology, to which the efficacy and the cost-effectiveness of the Group-
Based intervention can be compared. It has not been designed to control for attention, content, format, or other 
potential treatment mechanisms.  
 
Each site has a Self-Directed Coordinator who meets with each participant post-randomization to introduce 
them to the components of the Self-Directed program, and train them on use of their Fitbit and the ELM 
website. The Self-Directed Coordinator is available, via telephone, to answer participant questions about the 
trial. The Coordinator calls the participants every 3 months to answer questions about the trial and to enhance 
protocol adherence. The Coordinator does not answer medical or behavioral questions about lifestyle change. 
Instead, the participant is referred back to the relevant educational sheet or the primary care physician to get 
such questions answered. The essential role of the Coordinator is to facilitate participant ability to adhere to the 
protocol and to prevent risk of drop-out. 
 
Fidelity Monitoring 
 
Group-Based Program Fidelity 
Interventionists attend 3 days of training held by the Intervention Coordinating Unit at Rush University Medical 
Center in Chicago. Treatment fidelity, guided by the recommendations of the NIH Behavior Change Consortium 
[12], assesses 3 dimensions of fidelity: delivery, receipt, and enactment, all of which are tracked by the Research 
Coordinating Unit and overseen by the Intervention Coordinating Unit supervisors in weekly meetings. Delivery 
of the treatment is enhanced by the availability of video recordings of each group session illustrating key points. 
Selected video recordings are reviewed by Intervention Coordinating Unit supervisors, written and verbal 
feedback is provided, and additional training is conducted, as needed. Receipt of the treatment is assessed by 
participant attendance records and brief comprehension forms completed by participants after each session. 

 
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Enactment of the treatment is monitored by reviewing physical activity data from the Fitbit and weekly 
participant self-reported engagement in the 4 ELM habits (e.g. filling ½ plate of vegetables on most days, taking 
10,000 steps on most days, pausing before responding, and noticing thoughts, bodily sensations, smells, colors, 
and tastes).  
 
Self-Directed Program Fidelity 
The Self-Directed Coordinators at each site participate in a 4-hour WebEx training led by the Intervention 
Coordinating Unit and the Self-Directed Program Supervisors. During this training, the Self-Directed Program 
Manual is presented. The coordinators engage in role plays to learn how to best navigate participant questions. 
All contacts between the Self-Directed Coordinators and participants are tracked by the Research Coordinating 
Unit. The Intervention Coordinating Unit reviews monthly reports to ensure all one-on-one orientation sessions 
are completed within 3 weeks of randomization, mailings are sent in a timely manner, and quarterly phone calls 
are completed. The frequency of connecting to the ELM website is tracked. The site Self-Directed Coordinators 
meet monthly with the Self-Directed Program Supervisors to address any problems, concerns, and possible drift 
from the protocol.  
 
OUTCOMES ASSESSMENT 
 
Participant Contacts 
 
In-Person Follow-Up Visits 
These visits are intended to document the impact of the treatments over time. Thus it is important that the 
timing of the assessments align with pivotal dates associated with intervention delivery (e.g., completion of the 
6-month intensive phase, half-way through the 18-month maintenance phase, at the end of the trial at 24 
months).  
 
 The timing of in-person follow-up visits is presented in the table below. This timing applies to all participants, 
regardless of the treatment arm to which they 
were assigned. The target date of first follow-
up visit is one day after the date of the last 
meeting in the intensive phase of the Group-
Based arm. The second and third follow-up 
visits are 9 and 18 months post-intensive 
phase, respectively. All follow-up visits have a 
9-week window for completion that opens on 
the target date.  
 
The essential goals of these visits are to collect follow-up data, update/confirm contact information, monitor 
adverse events, and promote retention. These contacts also provide the opportunity to sustain a professional 
and caring relationship with the participant throughout the 2-year trial. All visits are conducted by the same staff 
member, whenever possible, to cultivate a relationship that can aid in retention. 
 
Telephone Contacts 
The main purpose of the telephone contacts is to ascertain vital status, obtain information on health care 
utilization and co-interventions, and update contact information. These contacts occur at 3 months from 
randomization (for the first telephone contact) and then every 3 months after the date of the last group session. 
There is a total of 5 telephone contacts. This schedule is the same for all participants randomized at the same 
time, regardless of the arm to which they were assigned. The window for completion of telephone contacts is 2 
weeks before and after the target date.  
Table 1. Timing of In-Person Follow-Up Visits 
Visit # 
Schedule 
First (Post-Intensive Intervention – PII) 
Date of last group session of 
intensive phase (session 19) 
Second (Mid-Maintenance – MM) 
~9 months after intensive phase 
 
Third (End of Treatment – EoT) 
~18 months after intensive phase 
 

 
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Assessments 
Table 2 presents the assessments completed at each trial visit.  
Table 2.  Assessments by trial visit and assessor 
Assessment 
Frequency of Assessment  
B=Baseline, PII = Post-Intensive 
Intervention, MM = Mid-
Maintenance, EoT = End-of-
Treatment  
           Assessor 
RA =   Research Assistant  
PPT = Participant 
Accelerometry 
B, PII, MM, EoT 
RA 
Vital Status, Adverse Events, Co-
Interventions 
3, PII, 9, 12, MM, 18, 21, EoT  
RA 
Contact Info 
B,3, PII, 9, 12, MM, 18, 21, EoT 
RA 
Five-Facet Mindfulness Questionnaire 
B, PII, MM, EoT 
RA  
Eating Competence  Questionnaire 
B, PII, MM, EoT 
RA  
Demographics 
B, PII, MM, EoT 
RA 
Labs (Lipid Panel, Glucose and A1c) 
B, PII, MM, EoT 
RA 
Medical History 
B, PII, MM, EoT 
RA 
NCI’s Fruit and Vegetable Screener 
B, PII, MM, EoT 
RA 
Food Log and Logistic Plan 
B 
RA 
Perceived Stress Scale 
B, PII, MM, EoT 
RA 
Depression: Patient Health Questionnaire 
(PHQ-8) 
B, PII, MM, EoT 
RA 
Physical Measures (BP, HR, Waist, Weight, 
Height) 
B, PII, MM, EoT 
RA 
Automatic Habits: Self-Report Habit Index 
B, PII, MM, EoT 
RA 
Social Support for Diet and Exercise 
B, PII, MM, EoT 
RA 
Sugar-Sweetened Beverage Intake 
B, PII, MM, EoT 
RA 
Visit log 
B, PII, MM, EoT 
RA 
Quality of Life: Short Form Health Survey 
(SF-36)  
B, PII, MM, EoT 
RA 
Contacts with Health Network 
B, PII, MM, EoT 
RA 
Prescription Medications 
B, PII, MM, EoT 
RA 
MacArthur Ladder of Subjective Social 
Standing 
B 
PPT 
USDA Food Security 
B 
RA 
Treatment Credibility Questionnaire 
B 
PPT 
Patient Preference for Each Treatment 
B 
RA 
Program Satisfaction 
EoT 
PPT 
Substance Use/Abuse - WHO ASSIST 
B 
RA 

 
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Montreal Cognitive Assessment 
B 
RA (if needed) 
 
 
Change of Status 
 
The trial status of a participant refers to their level of participation in the trial. A  Participant Status Form is 
completed whenever a status change occurs. All efforts are made to collect data on the primary outcome (MetS 
at 2 years), at the very least. 
 
Lost-to-Follow-Up. A participant is considered “lost-to-follow-up” after missing two consecutive trial 
contacts without responding to messages, texts, or other forms of communication. Staff exhausts all 
avenues to locate the participant, including telephoning at least 10 times on different days, at 
varying times of day, contacting secondary contacts and the last medical provider on record, and 
checking online to identify new contact information. Failure of these attempts triggers a registered 
letter sent to the participant’s most recent address, to which non-response confirms the status as 
“lost-to-follow-up.” 
  
 
Withdrawal from the Intervention. This status applies to a participant who no longer wants to 
participate in any intervention activities, but is willing to continue completing follow-up visits.  
 
Withdrawal from the Trial. This status applies to a participant who is no longer willing to participate 
in any part of the ELM trial, including group meetings, phone calls, or follow-up visits. However, the 
participant may allow the trial to use lab and medical data routinely collected by his/her provider. 
 
Withdrawal of Consent. This status applies to a participant who no longer wishes to participate in 
the trial and declines use of data collected during routine visits with the provider. The status must 
be requested in writing by the participant and reported to the IRB. 
 
Administrative Withdrawal. This status applies to a participant for whom it is no longer safe for the 
participant or for the trial staff to continue involvement in the trial. The ELM Safety Committee 
makes this determination in collaboration with the local site PI. This status terminates all further 
contact with the participant.  
 
Deceased. This status is assigned once confirmed by the safety committee after review of the 
adverse event.   
 
RETENTION 
 
Retention has been excellent (90-100%) in the past clinical trials administered by the coordinating center at 
Rush.  However, to assume a conservative approach, the sample size is calculated assuming a 20% loss to follow-
up at 24 months. Key strategies to enhance retention include: (1) patient-centered recruitment emphasizing 
consideration of both the pros and cons of participation, from the participant’s perspective; (2) maintaining 2-3 
alternative contacts for each participant at enrollment; (3) same staff member assesses outcomes and maintains 
regular contact with participant over time; (4) minimization of transportation burden by providing free parking 
and transportation vouchers; (5) reimbursement for assessment time; (6) reminders about appointments for 
scheduled intervention and follow-up visits; (7) birthday and holiday cards; (8) collaborative partnerships with 
providers in participating clinics to enhance their support for their patient’s participation; and (9) negotiating 
with potential drop-outs to encourage partial withdrawal rather than withdrawal of consent. To reduce 

 
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differential drop out, all staff are trained and re-trained to insure equipoise, enthusiasm for a conclusive answer 
to the question rather than a specific result, and timely response to participant inquiries.  
 
Participants at retention risk, based upon non-attendance at group meetings or inability to contact during 3-
month phone calls, triggers a retention protocol. Depending upon the unique situation, the appropriate person 
(Group-Based interventionist, Self-Directed Coordinator, Outcomes Assessor) makes every effort to contact the 
participant for the purpose of understanding their perspective and any life situation that may have triggered the 
retention risk.  For participants who are firm about decisions to terminate contact with the trial, every effort is 
made to keep the door open for a change in this decision at a later time. This is done by requesting the 
participant’s permission to call at a later time to check it, the timing of such a call to be mutually agreed upon. 
  
DATA FLOW 
 
The trial has two main data flows. One is for recruitment and outcome assessment and the other is for 
intervention support. Data are collected using a variety of electronic systems including: 
 
 
Snap Surveys.  Advanced software that allows for the customization of online data capture forms. 
 
SharePoint.  A secure platform that houses the ELM website. SharePoint allows for sharing of data, 
documents, and publically accessible information. 
 
CentrePoint. A secure platform that transfers accelerometry to the Research Coordinating Unit (RCU). 
 
Quanum Portal. A secure platform that transfers participant lab results directly to the RCU. 
 
Reports provided to investigators feature site-specific aggregated data on recruitment, outcomes, and 
intervention quality. Research Assistants and interventionists have access to the ELM website, but are limited to 
viewing only data pertinent to their site and job responsibilities.  
 
Recruitment and Outcome Assessments 
 
Outcomes collection begins at recruitment and continues in 3-month intervals over the 2-year follow-up period. 
The specific outcome variables collected can be found in the Outcomes Assessment section. The RCU provides 
recruitment reports and data tracking tables, via the ELM website, to help Research Assistants monitor 
recruitment and submission of outcome measures. Figure 4 presents the flow of outcomes data. 

 
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Figure 4. Elm Trial Outcomes Data Flow 
 
Intervention Assessments 
 
The RCU provides delivery support for specific intervention components and reports on the quality of 
intervention delivery.  
 
In the Group-Based arm, the RCU supports the intervention by delivering automatic text messages that are 
tailored to content presented in the prior week and sent on a pre-existing schedule. At selected group meetings, 
the RCU prepares personalized feedback reports for each participant. The RCU creates reports on intervention 
progress assessed as class attendance, weight loss compared to the goal of  > 5% loss of baseline body weight, 
and step count compared to the goal of 10,000 steps on most days. The RCU also creates reports on 3 treatment 
fidelity measures: 
 
Delivery.  Documentation of delivery of specific intervention components;  
 
Receipt.  Participant self-reports of acquisition and understanding of specific group content; 
 
Enactment. Participant self-reports of daily vegetable intake, mindfulness habits, and old habit 
recognition.  
These reports are uploaded weekly by the RCU to relevant receivers via the ELM website, including 
interventionists, participants, investigators, and Intervention Coordinating Unit supervisors.  
 
In the Self-Directed arm, data collected by the Self-Directed Coordinator includes completed telephone calls and 
frequency of participant-initiated contacts. These data are sent to the RCU and displayed quarterly in aggregate 
form on the ELM website for review by the Self-Directed Coordinator, investigators, and the ICU supervisors. 
 
Participants in both arms are able to view their own data and track their progress in step counts and weight 
change. The RCU also tracks frequency of daily log-ons to the ELM website by participants in both arms. Figure 5 
presents the flow of intervention data. 

 
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Figure 5. Intervention Data Flow 
 
SAMPLE SIZE 
 
The primary outcome of the trial is remission of MetS at 24 months. MetS remission (meeting criteria for <3 
MetS components) is clinically relevant and the most common endpoint in MetS trials. Sample size was based 
upon the assumptions that the chi-square test will be used to compare proportions of participants who remit 
MetS at 24 months by trial arm, with an overall significance level of 0.05, and power of 85%. This requires a 
sample size of 117 participants per group, or a total sample size of 234. 
 
Consideration must be given to the fact that the proposed trial employs a “partially clustered” design where 
clustering is present in only 1 of the 2 arms. The Group-Based Program is delivered to participants in groups, or 
clusters, of approximately 15 participants. Connection and interactivity within each of these “experimentally-
induced” clusters is a key component. The intraclass correlation coefficient (ICC) measures the extent to which 
participant responses are influenced by the cluster to which they belong. Since this clustering feature is present 
in only one of the two arms, its effect is muted. Results from our previous studies are consistent with those of 
others [13-14] indicating that the ICC could reasonably range from 0.01 to 0.20. We conservatively assume an 
ICC of 0.15 and adjust the total sample size required to achieve 85% power to 286 per arm or a total sample size 
of 572. We adjust upward to 300 participants/arm, a total sample size of 600 participants, 120 participants at 
each of 5 clinical sites, and 8 intervention clusters per site. 
 
ANALYSIS PLAN 
 
Analyses will be performed using an intent-to-treat approach that includes all patients as randomized, 
regardless of treatment dose. All analyses will use two-sided tests conducted at α=0.05. Basic summary statistics 
will be based upon cluster-adjusted chi-square tests and t-tests. If a distribution is non-normal, cluster-adjusted 

 
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Wilcoxon rank sum tests will be used. Supplemental analyses will include mixed effects regression models to 
account for cluster effects and control for important covariates. The impact of missing data will be evaluated 
using sensitivity analyses. If data are missing at random, multiple imputation will be employed. If data are not 
missing at random, an appropriate statistical model will be employed (e.g. a pattern mixture model with 
sensitivity analyses).  
 
The primary hypothesis is achievement of a clinically significant MetS remission at 24 months in > 40% of the 
participants in the Group-Based program and < 20% of the participants in the Self-Directed program. Achieved 
rates will be observed, relative to these benchmarks, without statistical support. The primary statistical analysis 
will compare MetS remission at 24 months between the trial arms using a cluster-adjusted chi-square test. A 
secondary analysis will compare these rates using a mixed effects logistic regression model examining treatment 
over time (i.e., baseline through 24 months), a treatment*time interaction, and adjustments for age, gender, 
race/ethnicity, socioeconomic status, geographic site, BMI, number of co-morbidities, and number of MetS 
components. Random effects (e.g. random intercept, time, intervention cluster) will be included in the model 
only if they significantly improve model fit as determined by the likelihood ratio test.  
 
Behavioral treatment targets will be compared by arm, without statistical support, as the proportion of 
participants achieving clinically significant goals (as presented in the hypothesized pathway in Figure 3), based 
upon the pre-determined benchmarks. Statistical support will be provided by a cluster-adjusted chi-square test. 
All other secondary and exploratory outcomes will be compared using the relevant cluster-adjusted t-test or chi 
square test. These comparisons will be conducted using data from post-intensive intervention, mid-
maintenance, and end-of-treatment visits and trends over time will be examined. Supplementary analyses will 
use generalized linear mixed effects modeling, with a behavioral treatment target or weight as the outcome, 
treatment group as the primary predictor, random effects to account for time, site, and cluster, and selected 
covariates.  
 
The health economic evaluation  features the incremental cost effectiveness ratio (ICER) for the 2 trial arms, 
where the ICER = (C1 – C0)/(E1 – E0), and C is intervention cost, E is effectiveness at remission of MetS, subscript 1 
denotes the Group-Based arm, and subscript 0 denotes Self-Directed arm. The ratio yields the cost differential 
for MetS remission in the 2 trial arms. In addition, the ICER will be calculated for each Quality-Adjusted Life Year 
(QALY) gained. The analysis will be conducted from the commercial payer, public payer, and societal 
perspectives. Sensitivity analyses will be conducted to account for the potential influence of plausible changes in 
cost assumptions. 
 
The projected benefits of disseminating the Group-Based Program will be modeled by combining the observed 
rate of MetS remission in the trial with published national estimates of cardiometabolic disease risk and added 
health care costs associated with MetS. Projections will focus on the number of potential cases of type 2 
diabetes, coronary heart disease, and stroke averted, and potential healthcare savings, in the overall adult 
population, Medicare population (65+), adults on Medicaid, and privately insured adults.  
 
Exploratory analyses examine the efficacy to treatments within important population subgroups. These 
comparisons will be presented by forest plots. Intervention fidelity within each treatment arm is monitored on 
an ongoing basis by the Intervention Coordinating Unit, with remediation delivered promptly when problems 
are identified. Observed fidelity data will be compared to the clinically significant goal of at least 80% adherence 
to key components for the overall trial, and stratified by geographic site. 
 

 
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TRIAL ORGANIZATION 
 
Figure 6 presents the structure of this multi-site trial. Leadership is provided by an eight-member Steering 
Committee comprised of the Principal Investigators of all 5 sites, the Trial Chair, the Research Coordinating Unit 
Director, and the Intervention Coordinating Unit Director. Decision-making uses consensus as a primary strategy. 
Votes on key questions are carried by a majority. Intervention training and fidelity is overseen by the 
Intervention Coordinating Unit. Quality of Data transmittal is overseen by the Research Coordinating Unit. 
Scientific Committees guide all scientific aspects of the trial. An independent Data and Safety Monitoring Board 
approves the trial protocol, monitors data quality and safety, and monitors outcomes by trial arm. It makes 
recommendations to the investigators and the funder by providing independent reports simultaneously. 
 
 
Figure 6. ELM trial organization 
 
SAFETY MONITORING 
 
This trial presents low risk to participants given the nature of the lifestyle interventions and the trial 
measurements collected. Participants are thoroughly screened prior to enrollment to ensure their ability to 
participate in lifestyle interventions. Nonetheless, several types of unanticipated problems and adverse events 
may occur and will be monitored. All potential events reported by a participant or staff member are 
documented using the Adverse Events Form. This form is submitted to the Research Coordinating Unit (RCU), 
which will then submit it to the Site Physician within a predetermined timeline. The Site Physician adjudicates 
the event following guidelines and reports back to the RCU. The RCU sends the completed adjudication form to 
the Chair of the Safety and Ethics Committee and Trial Chair, as described below. Summary reports are provided 
to the Rush IRB and the Data and Safety Monitoring Board. The Chair of the Safety and Ethics Committee can 
alert the Data Safety and Monitoring Board at any other time at his/her discretion.  

 
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Adverse Events 
 
The following procedures occur dependent upon determination of the event. 
 
 
Adverse Events and Serious Adverse Events that are not Unanticipated Problems are submitted to the 
central IRB in the annual Continuing Review application. These events are officially reported to the 
Steering Committee at its monthly meeting and semi-annually to the DSMB. 
 
 
Unanticipated Problems are submitted to the central IRB within 1 week of the Safety & Ethics 
Committee’s review. The Steering Committee is to be notified promptly, and in no case longer than one 
month from the Committee’s review. The DSMB is to be notified quarterly. 
A summary of this reporting process is presented in Figure 7. 
 
Critical Alert Values 
Immediate risk is posed, and actions are needed, for the following problems. 
 
 
Blood Pressure Above 160/100.  Should this event occur, the research assistant contacts the 
participant’s provider or designee to obtain a recommendation for patient care, prior to the participant leaving.  
If the participant does not want their primary care physician to be contacted, then the research assistant 
contacts the Site Physician. If a provider cannot be reached within one hour or before the participant plans to 
leave, the safety protocol is as follows:  
 
 
Blood Pressure between 160/100 and 180/110 and NO symptoms. Participant is told that their blood 
pressure is elevated and they need to see their doctor as soon as possible for repeat testing and evaluation.  
 
 
Blood Pressure between 160/100 and 180/110 WITH symptoms, such as (but not limited to) chest 
pain, shortness of breath, blurred vision or headache. Participant is urged to go to the nearest Emergency 
Department.    
 
 
Blood Pressure higher than 180/110. Participant is urged to go to the nearest Emergency Department.    
 
 
Glucose < 40 or ≥500; Triglyceride > 1,000  All lab results are reviewed by the Site Physician prior to 
being sent to a participant. If the glucose alert occurs, the Site Physician contacts the participant or his/her 
provider within 24 hours. If the triglyceride alert occurs, the Site Physician notifies the participant by phone and 
advises him/her to contact his/her primary care provider.   
 
 
 

 
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Figure 7: Process of Unanticipated Problems and Adverse Event Reporting  

 
Trial Protocol, Version 3.3: April, 2021 
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REFERENCES 
 
1. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith 
SCJ, International Diabetes Federation Task Force on Epidemiology and Prevention, National Heart, Lung, 
and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis 
Society, the International Association for the Study of Obesity (2009) Harmonizing the metabolic syndrome: 
a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and 
Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; 
International Atherosclerosis Society; the International Association for the Study of Obesity. Circ 120:1640-
1645. 
2. Go AS, Mozaffarian D, Roger VL (2014) Heart disease and stroke statistics - 2014 update: a report from the 
American Heart Association. Circ 129:e28-e292. 
3. Grundy SM (2012) Pre-diabetes, metabolic syndrome, and cardiovascular risk. J Am Coll Cardiol 59:635–643 
4. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, 
Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW (2009) 2009 focused update incorporated 
into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of 
the American College of Cardiology Foundation/American Heart Association Task Force on Practice 
Guidelines:  developed in collaboration with the International Society for Heart and Lung Transplantation. 
Circ 119:e391-e4791.  
5. Moore JX, Chaudhury N, Akinyemiju T (2017) Metabolic syndrome by race/ethnicity and sex in the United 
States, National Health and Nutrition Examination Survey, 1988-2012. Prev Chronic Dis 
14:160287.DOI:http://dx.doi.org/160210.165888/pcd160214.160287 
6. Boudreau DM, Malone DC, Raebel MA, Fishman PA, Nichols GA, Feldstein AC, Boscoe AN, Ben-Joseph RH, 
Magid DJ, and Okamoto LJ (2009) Health care utilization and costs by metabolic syndrome risk factors.  
Metab Syndr Relat Disord 7:305-314. 
7. Orchard TJ, Temprosa M, Goldberg R, Haffner S, Ratner R, Marcovina S, Fowler S, the Diabetes Prevention 
Program Research Group (2005) The effect of metformin and intensive lifestyle intervention on the 
metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med 142:611-619. 
8. Rosmond R (2005) Role of stress in the pathogenesis of the metabolic syndrome. Psychoneuroendocrinology 
30:1-10. 
9. Bergmann N, Gyntelberg F, Faber J (2014) The appraisal of chronic stress and the development of the 
metabolic syndrome: a systematic review of prospective cohort studies. Endocr Connections 3:R55-R80. 
10. Powell LH, Appelhans BM, Ventrelle J, Karavolos K, March ML, Ong JC, Fitzpatrick SL, Normand P, Dawar R, 
Kazlauskaite R (2018) Development of a lifestyle intervention for the metabolic syndrome: discovery through 
proof-of-concept. Health Psych 37:929-939. 
11. Goldberg JH, Kiernan M (2005) Innovative techniques to address retention in a behavioral weight-loss trial.  
Health Educ Res 20:493-447. 
12. Bellg AJ, Borrelli B, Resnick B, Hecht J, Minicucci DS, Ory M, Ogedegbe G, Orwig D, Ernst D, Czajkowski S, 
Treatment Fidelity Workgroup of the NIH Behavior Change Consortium (2004) Enhancing treatment fidelity 
in health behavior change studies: best practices and recommendations from the NIH Behavior Change 
Consortium. Health Psych 23:443-451. 
13. Campbell MK Fayers PM, Grimshaw JM (2005) Determinants of the intracluster correlation coefficient in 
cluster randomized trials: the case of implementation research. Clinical Trials 2:99–107. 
14. Dziak JJ, Nahum-Shani I, Collins LM (2012) Multilevel factorial experiments for developing behavioral 
interventions: power, sample size, and resource considerations. Psychol Methods 17:153-175. 
15. Hedges LV (2009) Adjusting a significance test for clustering in designs with two levels of nesting. J Educ 
Behav Stat 34:464–490.