Comprehensive Cardiovascular Diseases (CVD) Risk Reduction Trial in Persons With Serious Mental Illness
Phase: NA
Conditions: Cardiovascular Risk Factors, Serious Mental Illness
Sponsor: Johns Hopkins University

Protocol: Comprehensive Cardiovascular Disease Risk Reduction Trial in Persons with Serious Mental Illness (IDEAL) 
 
 
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Intervention Trial to Decrease Cardiovascular Risk in Persons With Serious Mental Illness 
 
 
September 3, 2018 
NCT02127671 
 

Protocol: Comprehensive Cardiovascular Disease Risk Reduction Trial in Persons with Serious Mental Illness (IDEAL) 
 
 
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STUDY PROTOCOL 
 
COMPREHENSIVE CARDIOVASCULAR DISEASE RISK REDUCTION TRIAL  
IN PERSONS WITH SERIOUS MENTAL ILLNESS  (IDEAL) 
 
September 3, 2018 
 
 
 

Protocol: Comprehensive Cardiovascular Disease Risk Reduction Trial in Persons with Serious Mental Illness (IDEAL) 
 
 
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                                                              Table of Contents 
1. ABSTRACT 
3 
2. SPECIFIC AIMS 
3 
3. BACKGROUND AND SIGNIFICANCE 
4 
4. DESIGN SUMMARY 
6 
5. STUDY POPULATION AND ELIGIBILITY 
7 
6. RECRUITMENT 
7 
7. DATA COLLECTION AND MEASUREMENTS 
8 
8. QUALITY ASSURANCE AND QUALITY CONTROL 
11 
9. RANDOMIZATION AND BLINDING 
11 
10. INTERVENTION 
11 
11. DATA MANAGEMENT 
17 
12. DATA ANALYSIS 
17 
13. DATA SECURITY 
21 
14. SAFETY  
21 
15. REFERENCES 
24 
 
 
 
 

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IDEAL Trial Protocol  
 
1. ABSTRACT     
 
Persons with serious mental illness (SMI), such as schizophrenia and bipolar disorder, die on average 25 
years earlier than persons without SMI.  Much premature death in SMI is attributable to CVD with CVD-related 
mortality rates twice those of the overall population.  Accordingly, this vulnerable group, comprising at least 15 
million Americans, has a high burden of modifiable CVD risk factors including smoking, obesity, hypertension, 
diabetes, and dyslipidemia.  The American Heart Association (AHA) recently set ambitious strategic Impact 
Goals to improve the cardiovascular health of all Americans and reduce deaths from CVD by 20 percent by 
2020.  Substantial efforts are underway to meet these goals in the general population.  Still, interventions need 
to be adapted for persons with SMI who often have substantial barriers related to cognitive impairment and 
psychiatric symptoms.  Hence, without special efforts to promote CV health and control risk factors in 
vulnerable populations like the SMI, it is unlikely that CV health will improve in SMI patients, and disparities in 
CV health will not only persist, but likely worsen.  In view of their extraordinary burden of CVD risk factors, the 
overarching objective of this protocol is to develop and test a scalable intervention that could be widely 
adopted to reduce risk in this vulnerable population.  Our multidisciplinary research team has expertise 
designing and rigorously testing interventions to decrease CVD risk in the general population and in persons 
with SMI.   
 
The IDEAL Trial is a community organization-based, two-arm clinical trial that will test the hypothesis that an 
18-month comprehensive, practical CVD risk reduction program will be superior to control in improving CV 
health in persons with SMI.  We will partner with Mosaic Community Services, Inc., a large mental health care 
organization, and enroll a target of 250 persons with SMI who attend 4 psychiatric rehabilitation day programs 
(PRPs) or adjoining mental health clinics.  Rehabilitation programs provide opportune settings to implement 
CVD risk reduction programs because patients attend several days a week and environmental components 
can take place on-site.  We will provide a common background of exercise classes and healthy changes to 
meals served.  Participants will then be randomized to receive this control condition or the 18-month active 
IDEAL intervention with a Heart Health Interventionist, who will provide on-site: 1) individual CVD risk reduction 
behavioral counseling (e.g., for smoking cessation, diet); 2) coordination with primary care providers to ensure 
appropriate management of risk factors (e.g., blood pressure control); and 3) collaboration with mental health 
staff and social supports to encourage and motivate participants to reach goals. The primary outcome will be 
the change in estimated CVD risk from the global Framingham Risk Score; secondary outcomes will include 
AHA metrics for CV health. Accomplishing meaningful reductions in CVD throughout the population will require 
targeted interventions focusing on vulnerable, high-risk groups such as those with SMI. If successful, this trial 
will provide persuasive evidence for use of a practical, comprehensive CVD risk reduction strategy in SMI to 
reduce health disparities. 
 
2. SPECIFIC AIMS 
     Accomplishing meaningful reductions in CVD throughout the US population will require implementation of 
targeted interventions that focus on vulnerable, high-risk groups such as those with serious mental illness. In 
this context, we propose the following Specific Aims: 
Primary Aim:  
1. Test the hypothesis that the active IDEAL intervention is more effective than the control condition in 
reducing CVD risk using the global Framingham Risk Score (FRS).  
Secondary Aims: 
2. Determine the effect of the active intervention compared to control on AHA metrics for ideal CV health 
risk behaviors and health risk factors: 
a. Weight and BMI; 
b. Physical fitness with 6-minute walk test; 
c. Healthy diet measured by self-report; 
d. Smoking cessation with biochemical validation; 
e. Fasting plasma glucose levels and diabetes mellitus treated to goal (HgBA1c); 

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f. Blood pressure levels and hypertension treated to goal; 
g. Lipid levels (total cholesterol, LDL-C, HDL-C, triglycerides) and dyslipidemia treated to goal; 
3.   Determine the effects of the active intervention on other outcomes: health status (SF-12); quality of 
life (Euroqol); medication use for CVD risk factors; and medication adherence. 
 4.   Assess costs per participant and perform a cost effectiveness analysis. 
        Exploratory Aims: 
        5.   Conduct analyses to identify potential mediator variables (e.g., intervention participation,  
         medication use for CVD risk factors and adherence); 
        6.   Assess organizational factors that could facilitate the most effective future dissemination. 
  
The primary outcome variable will be reduction in CVD risk with global FRS from randomization to 18 months. 
Six-month FRS and 6 and 18-month changes in health risks comprise secondary outcomes.  
 
 
3. BACKGROUND AND SIGNIFICANCE 
 
Public Health Burden of Cardiovascular Disease in Persons with Serious Mental Illness 
 Persons with SMI, over 5 percent of the population or 15 million Americans, comprise a high-risk group for 
CVD-related mortality with rates approximately twice those of the overall US.1-5  SMI frequently produces 
challenges in everyday functioning due to cognitive impairment and ongoing psychiatric symptoms;6 
accordingly, populations with SMI are often characterized by socioeconomic and environmental risk factors for 
CVD such as unemployment, low-income and social isolation.7  The AHA Strategic Plan (co-authored by Dr. 
Appel) defines 7 goals for ideal CV health for all Americans including ideal health behaviors (BMI <25 kg/m2, 
physical activity at goal levels, healthy diet, nonsmoking) and ideal health factors (fasting blood glucose 
<100mg/dl, untreated blood pressure <120/<80mmHg, untreated total cholesterol <200mg/dl).8  Persons with 
SMI experience increased prevalence of unhealthy levels of these CVD risk factors, summarized below. 
 
Overweight and obesity are at epidemic levels in SMI, particularly in women, where 60% are obese.9-12 
Physical inactivity and unhealthy diet contribute.  The vast majority of SMI require ≥1 long-term psychotropic 
medication, yet many psychotropic classes cause weight gain, in part from increased appetite.13-17 In particular, 
2nd generation antipsychotics lead to substantial weight increases; in the case of olanzapine, up to 0.9 kg/mo.18 
 
Physical inactivity is prevalent in SMI; Dr. Daumit reported persons with SMI report 50% higher leisure time 
inactivity than the general population.19  An accelerometry study showed only 4% of persons with SMI in a 
psychiatric rehabilitation program (PRP) met recommended moderate to vigorous physical activity in bouts of 
≥10 minutes.20  Lack of affordable, safe places to exercise, and negative affective states such as depression 
may be important barriers.   
 
Unhealthy diet is reported in persons with SMI with some studies reporting higher fat and lower fruit and 
vegetable intake and others show higher overall caloric intake.21-23 Persons with SMI are also likely to depend 
on others for meals; preliminary baseline data from Dr. Daumit’s study show 40% of participants relying on 
others to buy or prepare food when they eat at home. 
 
Tobacco smoking is extremely prevalent in SMI, with 70 to 80% reporting lifetime and half to more than two-
thirds reporting current smoking.22,24-26 Smokers with SMI report using more and higher tar cigarettes and 
consuming more nicotine compared with other US smokers.27,28 Smoking may be reinforced in SMI by 
lessening extrapyramidal effects from decreased blood antipsychotic levels, enhanced cognitive functioning 
from nicotine, socioeconomic factors and relative lack of other pleasurable pursuits.26,29 
 
 
Diabetes mellitus is estimated ≥ 1.5-2 times higher in SMI than the overall population.30-35 Multiple factors 
converge to increase risk of diabetes, and related emerging risks of glucose intolerance/insulin resistance and 

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the metabolic syndrome in SMI including obesity and physical inactivity.  Several antipsychotic medications 
also are implicated generally in proportion to their impact on weight gain and adiposity.18,30,36-40   
 
Hypertension prevalence is 50% higher in persons with SMI than those without.24  Obesity, physical inactivity,  
and alcohol use are likely contributing factors to elevated blood pressure.34,41-44 
 
Dyslipidemias are also prevalent in SMI; in particular, certain antipsychotics lead to elevated triglycerides and  
low HDL.18,34,45-49  With glucose intolerance, hypertension, dyslipidemia and abdominal adiposity all increased  
in SMI, metabolic syndrome prevalence is correspondingly 1.5 to 2 times higher in SMI as well.34,50 
 
Interventions to Reduce CVD Risk in Persons with SMI 
 
In order to accomplish meaningful reductions in CVD risk, targeted interventions will be required for 
populations with SMI, who urgently need to adopt healthy behaviors and decrease health risk factors.51  
Lifestyle interventions require tailoring for many with SMI, where cognitive deficits as well as other competing 
demands (e.g., psychiatric symptoms, economic stresses) are highly prevalent.  Although few studies have 
been conducted in PRPs, these facilities are well suited for implementing comprehensive CVD risk reduction 
interventions as infrastructure facilitates collaboration with staff for patients with SMI. 
Interventions to Improve Health Risk Behaviors:  
Weight loss and physical activity lifestyle interventions including those addressing multiple health behaviors are 
effective in the general population, yet these trials systematically exclude persons with SMI who have pressing 
need. Several studies of behavioral weight loss interventions in SMI have shown success; most focus on diet 
changes alone and are short-term.52-58 The ACHIEVE trial was the first long-term trial of a tailored behavioral 
weight loss intervention resulting in clinically significant weight loss for persons with SMI.59  
 
Tobacco cessation interventions are underutilized for persons with SMI despite their modest success with this 
population. A recent literature review reported more than half of smokers with mental illness are contemplating 
quitting within 6 months or planning to quit in the next 30 days.60  The 2009 evidence-based PORT 
schizophrenia treatment recommendations, co-authored by Dr. Dickerson, recommend smoking cessation  
treatment, specifically a psychosocial intervention and bupropion +/- nicotine replacement therapy (NRT).61  
These treatments produce evidence of smoking reduction and up to 33% abstinence.62-70 Since the PORT, 
varenicline has been found effective for abstinence and well-tolerated in smokers with schizophrenia, bipolar 
disorder and depression.71-85 Attendance levels in smoking cessation programs are associated with abstinence 
outcomes.65 To-date, interventions addressing all major CVD behavioral risks comprehensively have not been 
tested in persons with SMI. 
 
Interventions to Improve Health Risk Factors:   
In the general population, there is substantial evidence that non-physician interventionists (e.g., care 
managers) facilitating treatment and coordination with PCPs can improve single and multiple CVD risk 
factors.86-92 These interventions are thought beneficial by addressing patient environment and psychosocial 
factors and decreasing barriers to medication adherence.91 Other evidence shows interventions focusing 
directly on medication adherence in primary care are also effective in improving risk factors.93,94  
 
Several studies concentrating on multiple CVD risks have targeted SMI. In SMI, a small literature describes 
interventions in mental health clinics to improve primary care delivery including co-locating primary care (e.g., 
with nurse practitioner) or a care management model facilitating preventive screening and referral to primary 
care.95-98 These programs generally focus on overall health status and have not been specifically designed or 
staffed (i.e., with skilled interventionist) to effect changes in multiple CVD risk behaviors and factors. More 
recent evaluations of the behavioral health home incorporating primary care coordination into the specialty 
mental health care setting and other integrated care programs have shown mixed results with no or minimal 
effects on CVD risk factors. 97,99-104 

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Summary of significance: Persons with SMI are at extremely high risk for CVD morbidity and mortality. Unless 
effective interventions are developed and tested, this population will continue to lag far behind the nation in 
CVD goals, and disparities will likely persist if not worsen.  If the CVD risk reduction goal that the trial aims to 
attain could be applied widely to the millions with SMI in the US, tens of thousand of lives could be saved each 
year.3,105-107  Psychiatric rehabilitation programs (PRPs) provide an available, yet untapped structure for 
multifactor CVD risk reduction interventions in SMI.  
 
4. DESIGN SUMMARY 
 
 
The IDEAL Trial is a community organization-based, two-arm clinical trial that will test the hypothesis 
that an 18-month comprehensive, practical CVD risk reduction program will be superior to control in improving 
CV health in persons with SMI.  We will enroll a target of 250 persons with SMI who attend 4 psychiatric 
rehabilitation day programs or adjoining mental health clinics.  We will promote a common background of 
exercise classes and healthy changes to meals served.  Participants will be randomized to receive this control 
condition or the 18-month active IDEAL intervention with a health coach and nurse, who will provide on-site: 1) 
tailored CVD risk reduction education and counseling (e.g., for smoking cessation, diet); 2) collaboration with 
physicians to advocate for appropriate management of risk factors (e.g., blood pressure control); and 3) 
coordination with mental health staff and social supports to encourage and motivate participants to reach 
individually tailored CV health goals.  
 
 
 

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5. STUDY POPULATION AND ELIGIBILITY 
The study population will consist of adults, ages 18 and older from 4 psychiatric rehabilitation programs 
and affiliated outpatient mental health clinics. Table 1 lists eligibility criteria. To enhance the generalizability of 
this trial, we have few exclusion criteria.  
 
 
 
Participant eligibility is determined by completion of several screening measures.  Screening visits will occur 
on-site at rehabilitation centers and outpatient clinics. Study instruments are administered in-person by data 
collectors.  
 
 
6. RECRUITMENT  
 
Recruitment and retention strategies are facilitated because patients come on-site to the psychiatric 
rehabilitation programs or nearby to affiliated mental health clinics.  
 
For participant recruitment for the trial at psychiatric rehabilitation programs, we will recruit in several ways 
including announcements to mental health consumers (i.e., patients); posters; brochures and working with 
rehabilitation staff. We will make announcements during regular consumer meetings at the sites. We will also 
post posters and have flyers and brochures available in the rehabilitation center. We will work with 
rehabilitation staff to identify potential participants by reviewing their list of program attendees with them. 
Rehabilitation counselors may mention the trial to their consumers. Interested individuals will be directed to 
contact the study staff by phone or in person at the rehabilitation program. Study staff will be at the 
rehabilitation sites to discuss the study with any interested consumers. The study will be a behavioral health 
Table 1: Eligibility Criteria 
Inclusion criteria 
▪ Age 18 and older  
▪ Body mass index at least 25 kg/m2 OR 
 one of the following CVD risk factors: 
     -Hypertension (SBP>= 140mmHg or DBP>= 90mmHg or on antihypertensive medications; 
     -Diabetes mellitus (fasting blood sugar> 125mg/dl or hemoglobin A1c>6.5 or on a hypoglycemic 
medication);  
     -Dyslipidemia (LDL >130 mg/dl , HDL<40 or total cholesterol >=200 or on a lipid lowering agent); 
     -Current tobacco smoker 
▪ Able and willing to give informed consent  
▪ Completion of baseline data collection 
▪ Willing to accept randomization 
▪ Willing to participate in the intervention 
 
Exclusion criteria 
▪ Cardiovascular event (unstable angina, myocardial infarction) within the past 6 months 
▪ Serious medical condition which either limits life expectancy or requires active management (e.g., 
certain cancers) 
▪ Condition which interferes with outcome measurement (e.g., dialysis) 
▪ Pregnant or planning a pregnancy during study period.  Nursing mothers would need approval from 
physician. 
▪ Alcohol or substance use disorder if not sober/abstinent for 30 days 
▪ Planning to leave rehabilitation center or clinic within 6 months or move out of geographic area within 
18 months  
▪ Investigator judgment (e.g., for concerns about participant or staff safety) 

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organization-wide program offered to all consumers who may be eligible. Recruitment activities will be parallel 
to/ similar at the outpatient clinics as in the psychiatric rehabilitation programs, except there are no mental 
health consumer meetings.  
 
Participant retention is a very high priority. We will use strategies successful in the teams’ prior studies. In 
addition to maintaining strong participant rapport, we collect and review contact information throughout and will 
ask for relatives /friends’ contacts who can facilitate communication if needed. We also will have access to 
information through the PRP and clinic. We will make home visits to collect data on those who move out of the 
area.  
 
 
7. DATA COLLECTION AND MEASUREMENTS 
 
We will collect follow-up measures at 6, 12, and 18 months after baseline with in-person contacts at the study 
sites. (Table 2). The 12-month visit primarily serves as a way to maintain contact with participants. 
 
Measurements will be conducted using standardized operating procedures and quality control methods.  
Specific study forms will be used to collect data.  Table 3 summarizes the data collection schedule.  
 
Detailed measures are described below.  
Demographics and Medical History: We will collect demographic and contact information, medical history with 
a short checklist of conditions, Rose Angina Questionnaire, and assess alcohol or substance use using the 
ASI-Lite.108,109 
Mental health diagnoses and medications will be abstracted from PRP (or mental health clinic) charts. 
Participants and providers will confirm medications.  
Physical measures. 
Blood pressure will be determined by the OMRON 907 XL, a validated device which records BP using an 
oscillometric technique.110  Blood pressure will be obtained by trained, certified data collectors.  At each data 
collection time point that blood pressure is obtained (3 baseline visits and 1 randomization visit for pre-
enrollment time point, 3 visits for follow-up at 6 and 18 months respectively), measurements for blood pressure 
occur 1week apart, and 3 measurements (each separated by 30 seconds) will be obtained on the right arm of 
participants after they rest quietly in the seated position for at least 5 minutes.111 
Weight will be measured to the nearest 0.1 lb by a high quality digital scale with participants wearing light 
indoor clothes without shoes.  Duplicate measurements will be made.  Weight will be measured in lbs. for ease 
of interpretation by participants and converted to kg for calculation of BMI, calculated as the Quetelet index 
(kg/m2).   
Height to the nearest 0.1 cm will be measured at entry using a wall-mounted stadiometer.  The participant 
stands shoeless on a firm, level surface, with head in the horizontal (Frankfort) plane.  
Waist circumference will be measured with an anthropometric tape, in a horizontal plane 1 cm above the navel. 
Physical fitness will be measured by the 6-minute walk test. This measure is a valid predictor of VO2 max and 
has been shown to be responsive to increases in regular moderate physical activity.112-114 
Fasting blood measures will be collected at Mosaic, centrifuged, aliquoted and sent for processing. Total and 
HDL cholesterol, triglycerides, glucose, Hemoglobin A1C will be measured directly, and LDL cholesterol will be 
estimated by Friedwald equation unless direct measurement is needed.115  Serum CRP and insulin, kidney 
function (creatinine)) will also be measured.116-118 We will measure antibodies to viruses and bacteria such as 
herpes simplex virus and toxoplasma as previous studies have found an association between antibodies to 
infectious agents and clinical outcomes in serious mental illness.  Blood from part of the collected specimens 
will be frozen at -70° at Johns Hopkins for future investigation of putative risk factors related to cardiovascular 
disease.  Candidate assays include inflammatory markers, leptin and adiponectin. We also will store samples 
of whole blood at baseline for DNA for later studies. As this study will collect detailed information on 
medication, blood pressure, BMI, tobacco smoking and traditional laboratory markers of cardiovascular risk 
pre/post intervention, future analyses of stored serum samples will be able to be interpreted in the valuable 
context of these other risk factors. Approximately seven teaspoons of blood total will be collected at each study 

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time point with one teaspoon stored for future investigation and ½ teaspoon stored for future DNA testing (DNA 
storage at baseline only). We plan to store blood samples indefinitely. 
   Potential participants have specific choices on the consent form to decline or agree to have their 
blood stored and to DNA testing.  The serum samples will be identified with a code that does not include any 
identifying participant information and will be stored in a secure Johns Hopkins facility. There are currently no 
plans to re-contact subjects regarding their individual stored serum samples, and we will not release the results 
of future tests from serum samples to individual subjects.  We believe these procedures described above 
constitute minimal risk for the participants. Study samples may be shared with other researchers partnering 
with the study team for future research. If we do share any study samples with outside investigators not directly 
addressing the research questions in this protocol, an amendment/change in research or a new protocol would 
be submitted to the IRB.  
 
Expired carbon monoxide from the Micro Pro Smokerlyzer (Covita) will be collected and will confirm smoking 
status (see below).119  Urinary cotinine will be substituted for CO if the validity of CO is expected to be low 
(e.g., COPD or difficulty forming an adequate seal on the smokerlyzer) and if the participant is not using 
nicotine replacement therapy.120,121 
 
Urine will also be collected for Na, K, creatinine and protein.  
 
Questionnaires will be used for a variety of purposes including baseline data to describe participants, 
outcomes to assess intervention effects, and mediating variables to assess potential causal pathways. The 
study team has experience with these and similar instruments for persons with SMI.70  Instruments are 
described here: 
Healthy diet. Block Fat, Fruit, Vegetable and Fiber and Sodium Screener Questionnaires provide self-report of 
daily fruit, vegetable intake, and percent energy from fat.122 We also will use a questionnaire on sugar 
sweetened beverages. 
Tobacco smoking will be assessed with questions current smoking, 7-day and longer-term abstinence, 
Fagerstrom Test of Nicotine Dependence (FTND), a 6-item measure of behaviors related to dependence on 
nicotine, and self-efficacy questions related to quitting.123,124 123,124 Self-report of no cigarettes smoked in the 
past 7 days confirmed by carbon monoxide <7 will be used to calculate 7-day point prevalence 
abstinence.120,125 
 
Health status will be measured by the Medical Outcomes Study SF-12.126 
Physical activity will be collected by self-report with the Godin Leisure Time Exercise Questionnaire.  
Quality of life will be measured with the Euroqol EQ-5D, a brief 6 item instrument that is valid in persons with 
schizophrenia and bipolar disorder, and can be used for cost-effectiveness analyses.127-129  
Medication adherence will be measured with an adapted questionnaire based on the Morisky Medication 
Adherence Scale for each class of medications for CVD risk factors (e.g., antihypertensives, lipid lowering 
medications).130   
Mental health symptoms will be assessed by The Center for Epidemiologic Studies Depression Scale (CES-D) 
to measure depressive symptoms131,132 and the Behavior and Symptom Identification Scale (BASIS-24), a brief 
comprehensive mental status measure for overall mental health status.133-135 
Social Support will be measured with the Medical Outcomes Study Social Support Questionnaire136,137 
Other health measures related to CVD risk relevant in SMI population. We will use the Neighborhood 
Questionnaire to assess participants’ home environments for safe places to exercise and places to purchase 
healthy food, a questionnaire on food and shopping habits, the Questionnaire for Eating and Weight Patterns-
Revised to measure Binge Eating, and the Pittsburgh Sleep Quality Index.138-140 We will assess health literacy 
with the Health Literacy Skills Instrument. 
 
 
Participant semi-structured interviews (approximately 15-20 minutes) will be conducted at the end of the 18-
month intervention to gain an understanding of participant perceptions of and satisfaction with the heart health 
program and exercise classes. Interviews will be conducted with a convenience sample of participants across 

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the study locations. Interviews will be audio-recorded and transcribed. Transcripts will not contain names and 
will be kept in a secure location. Audiotapes will be destroyed after transcription is completed. 
 
 
Table 2: Data Collection 
Schedule  
Baseline 
6 mo 
12 mo 
18 mo 
Informed consent 
X 
 
 
 
Contact information 
X 
X 
X 
X 
Demographics 
X 
X 
 
X 
Medical conditions, 
substance use  
X 
X 
 
X 
Mental heath diagnoses 
X 
 
 
 
Medications 
X 
X 
x 
X 
Physical measures 
 
 
 
 
   Blood pressure 
X 
X 
 
X 
   Weight 
X 
X 
x 
X 
   Height 
X 
 
 
 
   Waist circumference 
X 
X 
 
X 
    6 minute fitness walk 
X 
X 
 
X 
Fasting blood measures 
X 
X 
 
X 
Urine measures 
x 
x 
 
x 
Expired Carbon Monoxide 
X 
X 
 
X 
Accclerometery 
x 
x 
 
x 
Questionnaires 
 
 
 
 
  Healthy diet 
X 
X 
 
X 
  Tobacco measures 
X 
X 
x 
X 
  Physical activity 
X 
X 
 
X 
  Health status 
X 
X 
 
X 
  Quality of Life 
X 
X 
 
X 
  Medication Adherence 
X 
X 
 
X 
  Mental health symptoms 
X 
X 
 
X 
  Social Support 
X 
X 
 
X 
  Other-Neighborhood,  
  Binge Eating, Sleep,     
  Health literacy 
X 
X 
 
X 
Semi-structured interview 
 
 
 
x 
Event surveillance 
 
X 
X 
X 
 
Event surveillance. We will collect data related to health care utilization and medical records related to CVD 
outcomes of interest.  This will include consent documents and medical release forms with appropriate text and 
a surveillance process that is applied identically to each randomized group. 
Food environment: We will analyze a random sample of menus at baseline, 6 and 18 mos. and use ESHA 
software to assess changes in total calories/nutrients in site meals as a result of dietary consultation.141  
 
Staff semi-structured interviews for organizational factors: To better understand the intervention 
implementation process and perspectives of intervention staff, non-intervention staff and leadership at Mosaic 
concerning the sustainability and future acceptability for dissemination of IDEAL, we will conduct semi-
structured interviews.  We will ask about the intervention’s perceived effectiveness, ease of or barriers, fit 
within the organization and financial models for continued support. We will interview before the intervention for 
baseline information and then at end of the 18-month intervention to assess changes due to the intervention. 
We will gain an understanding of factors that impact the intervention being acceptable and workable, and 
prepare for dissemination to other organizations. We expect to conduct interviews with 75 people, or a total of 

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150 interviews. Questions will include topics of perceived effectiveness of the intervention, ease or barriers for 
the intervention, fit within the organization and suggestions for future dissemination. The interview will be 
approximately 30 minutes in length. 
Interviews will be audio-recorded and transcribed. Transcripts will not contain names and will be kept in a 
secure location by Dr. Daumit. Audiotapes will be destroyed after transcription is completed. Individuals will not 
be identified by name in any publication. Mosaic leadership agrees that staff participation in the interview and 
any information shared will not affect employment or evaluation at Mosaic. 
 
 
8. QUALITY ASSURANCE AND QUALITY CONTROL 
 
Quality Assurance pertains to activities that promote collection of high quality data, and Quality Control 
refers to activities that detect emerging data issues with sufficient time to implement appropriate corrective 
actions.  Our approach to Quality Assurance includes: 1) preparing a manual of operations; 2) implementing a 
master trainer model to train and certify other staff; 3) train and certify all data collectors; 4) recertify data 
collectors at least annually; 5) routinely calibrate equipment; 6) maintain logs of certified staff and calibrated 
equipment.  Our approach to Quality Control includes: 1) monitoring counts of completed data collection items; 
2) monitoring distribution of trial outcomes, overall, by data collector and site; 3) record lag time in data entry; 
4) issue queries on missing data, out of range values or illogical data relations; 4) review types and distribution 
of data entry errors; and 5) prepare reports for staff, investigators and DSMB on Quality Control.  Investigators 
will review CVD risk factor data to determine study endpoints and adjudicate as needed in a masked fashion.  
 
 
9. RANDOMIZATION AND BLINDING 
 
     Randomization to the IDEAL intervention or control will be stratified by gender and site. Within each 
stratum, blocked randomization assignments are computer generated by the trial statistician in equal allocation 
within each block, where the block size is randomly generated to be either a size of 2 or 4. A data table 
containing these generated assignments is loaded into the trial’s REDCap database for web-based delivery to 
randomize eligible participants after confirmation of eligibility and informed consent. This REDCap 
randomization assignment table is accessible only to the statistician and the data manager. Prior to obtaining 
the assignment, the study coordinator will confirm the participant meets all eligibility criteria and all required 
baseline data have been collected. Then the coordinator logs into REDCap to receive the group assignment for 
the specific participant and communicates the treatment assignment to the participant. Due to the nature of the 
intervention, participants and interventionists will be aware of group assignment, however, data collection staff 
will be kept blinded Due to the nature of the intervention, both participants and interventionists will be aware of 
the assignment.  Until the trial end, investigators, other staff and participants are masked to outcome data, with 
the exception of trial statistician, study coordinator, data manager and data analyst.  We will take considerable 
efforts to ensure data collection staff will be kept blinded to assignment (e.g., exclude them from all parts of 
intervention delivery, remind participants not to share group assignment, designate/track unmasked staff).  
 
10. INTERVENTION 
 
 
Intervention: 
Common Background: To establish environments conducive to healthy behaviors and standardized across 
sites, the study will provide training for group physical activity classes open to all participants, and a dietician to 
consult to improve the health of meals served.  We train PRP staff to deliver group exercise classes using a 
DVD we provide, and recommend classes are held three times per week. Classes focus on aerobic condition 
and follow a progression appropriate for sedentary adults, gradually building to 40 minutes of moderate 
intensity physical activity, and be designed to build exercise confidence.142  We have used this successfully in 
SMI.70,143,144  In order to support active intervention participants’ ability to select healthy foods, a study dietician 
will work with PRP staff to identify healthier menu choices, so that food served is more consistent with AHA 

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Healthy Steps. The dietician will be sensitive to budgetary issues and federal food guidelines. This common 
background will make available a needed foundation for physical activity and healthy diet choices to occur. 
However, these offerings are very unlikely to be sufficient alone for significant behavior change.  
Randomized groups: 
   Control condition: The control group will receive this common background. 
   Active intervention: The active group will receive this common background and the IDEAL intervention. 
    Figure 1 displays our active IDEAL intervention framework. PRP staff, social supports, mental health 
providers (e.g., psychiatrists) and PCPs already have relationships with individual patients.  For a participant 
randomized to the IDEAL intervention, the intervention staff (health coach and nurse) work directly with the 
participant on health risk behaviors and catalyze support from others, serving as a bridge between these 
individuals and the participant in moving toward ideal health risk behaviors and factors, resulting in improved 
CV health and quality of life. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IDEAL Intervention goals include heart healthy behaviors (weight loss, physical activity, diet, smoking 
cessation) and heart healthy factors (blood sugar, BP, cholesterol) (Table 3).  We use AHA goals and modify 
some (e.g.,10 lb. weight loss instead of BMI<25) to provide intermediate targets achievable with the study 
sample over 18-months.8  Strategies combine individual counseling and goal-setting, consulting with the 
physician to optimize CV risk factor treatment, and working with PRP staff, social supports and mental health 
providers. 
Health coaches coordinate resources and work with participants to develop tailored strategies to achieve the 
heart healthy goals.  Coaches will be physically located on-site at Mosaic. Embedding health coaches at 
community sites will enable optimal coordination of heart healthy planning with other PRP staff and allow 
coaches the opportunity, in addition to scheduled sessions, to take advantage of everyday occurrences to 
reinforce healthy choices and behavior change (e.g., encouraging participant to go to exercise class, checking 
in and giving positive reinforcement for reporting decreased cigarette use, healthy vending machine choice or 
improved medication adherence, rewarding a participant for self-monitoring at a weigh-in). Coaches will be 
skilled facilitators with training in health behavior change and individual-level counseling, with a skill level 
typical for a community health educator, and will not require a Master’s degree.145 Health coaches will receive 
training,146,147 content supervision and will have ongoing, regular interaction with the Intervention Director and 
the nurse. The health coach is modeled after a position that would be feasible and sustainable in a community 
mental health setting, with back-up nurse support. 
Individual 
Health Coach 
& Nurse 
Improved CV Health 
Risks 
 
Risk Behaviors 
Weight 
Physical activity 
Diet 
Smoking 
 
Risk Factors 
Diabetes mellitus 
Cholesterol 
Blood pressure 
 
Improved 
CV Health 
Improved 
Quality of 
Life 
 
Primary care 
provider 
(PCP) 
Rehabilitation 
program staff 
+ social 
supports 
 
Mental 
health 
providers 
Figure 1. IDEAL Intervention Framework for Moving 
Towards CV Health in Persons with SMI 
-Dashed lines designate 
new relationships  

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A study nurse will be a Registered Nurse or equivalent with responsibility to support health coaches by serving 
as an ongoing clinical resource. The nurse regularly will review participants’ progress on heart health factors 
with the coach. He/she will collaborate with PCPs in advocating for participants’ CV health. The nurse will be 
trained in smoking cessation pharmacotherapy principles and will provide NRT and education and monitoring 
to interested and eligible participants using established guidelines (Treating Tobacco Use and Dependence: 
2008).  
The coach and nurse report to an intervention director with motivational interviewing and health behavior 
change expertise. The intervention director implements quality assurance, and may also provide direct 
services to participants.  
Individual Coaching Sessions (20-30 mins.) will be held at least weekly for up to 6 months, then at least bi-
weekly for 12-15 months with the health coach, based on participant need.  The initial sessions will focus on 
building rapport and using motivational interviewing to review current heart healthy risk behaviors and factors, 
medication adherence, and to identify individual goals.  Guided by the FRS score, the participant’s abilities, 
interests and readiness to address each risk factor, risks and targeted behaviors will be addressed either 
simultaneously or sequentially.148 (See Table 1). Participants will work with their health coach to identify 
behavioral changes topics from a list of recommended sessions (e.g., healthy weight management, becoming 
smoke free, staying physically active). The coach will use solution-focused therapy to encourage attainment of 
individual goals and provide reinforcements. The nurse provides educational and counseling sessions related 
to specific CVD risk factors tailored to participant needs.  
Primary Care Provider (PCP) and Psychiatrist Coordination: The nurse will review the participant’s baseline 
labs, physical measurements and medications and then initiate contact with the PCP to share data on baseline 
CVD risk factors and on any uncontrolled CV health risks and medication adherence. The nurse will 
accompany the participant on selected visits to the PCP in the community in order to facilitate a collaborative 
relationship and assist the participant in reaching CV health goals. The nurse identifies modifiable components 
of the FRS taking into consideration participants’ preferences for change and individual abilities. The nurse or 
coach will follow up with the PCP and psychiatrist as needed to facilitate coordination of behavioral strategies 
and any pharmacologic treatment and coordinate additional visits as needed. Guidelines for DM, HTN, lipid 
control and smoking cessation consistent with AHA, JNCVII, ATP-III and ADA and other prevailing guidelines 
and evidenced-based approaches including those emerging during the conduct of the trial are made available 
to physicians.30,41,71,84,85,149-158 Intervention staff communicate with participants and providers about tailoring 
goals as needed (e.g., higher HgbA1c target). SMI patients often have communication barriers, may have 
medication adherence issues due in part to lack of medication reconciliation across service settings, and often 
require advocates to make appointments and follow-up on tests. The coach and nurse will facilitate this 
coordination for improved CV health.  For participants who smoke and are interested in pharmacotherapy, the 
nurse will communicate with PCPs or psychiatrists to advocate for prescription of varenicline or bupropion 
and/or nicotine replacement therapy (NRT), and may provide NRT.. 
Staff and Social Supports Coordination: The health coach serves as a change agent, leveraging PRP staff and 
social supports around the participant’s CV health goals. (Figure 1) Coaches when possible attend regular 
PRP staff case management meetings, which include residential staff for participants in supported housing.  
Here the coach updates staff on participants’ progress with reaching CV health goals.  Having the coach on-
site enables two-way communication about participant CV health: 1) The coach encourages staff to promote 
adherence to heart health recommendations (e.g., attending exercise class) and individually identified plans 
(e.g., setting quit date); 2) PRP staff inform coaches about ongoing issues that could interfere with participant 
progress towards CV health goals (e.g., change in living situation).The coaches also will encourage social 
support and may include family members or peers in intervention sessions to support the participant for better 
control of risk factors (e.g., tobacco smoking). Through all of these pathways, the health coach and nurse 
coordinate a team-based approach to improve participants’ CV health. 
Mental Health Provider Coordination:  Participants have therapists and psychiatrists they see for mental care 
and psychotropic medication treatment; for the most part they will be in the adjoining mental health clinics. For 
uncontrolled risk factors, the health coach or nurse may work with mental health providers to strategize on how 
to improve CV health (e.g., adherence to diet and medication for diabetes). Psychotropic prescribing practices 
are not specific intervention targets, however, the psychiatrist may decide to modify medications based on the 

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15
participant’s CVD risks.  The health coach and nurse will facilitate communication between the psychiatrist and 
PCP as needed.  
Program materials: Individual visit manuals are developed to guide coaches in conducting sessions. Options 
tools, cards with pictures of modifiable behaviors based on the participant’s risk factors, are used to identify 
conversation topics. These tools give the participant the autonomy to choose specific behaviors to discuss, 
while also allowing the coach to provide direction for the session.  
Self-monitoring: Participants will be encouraged to self-monitor eating, exercise and smoking behaviors 
as appropriate to their individually tailored behavioral goals and cognitive abilities. Simple paper trackers are 
made available for this purpose.. 
Reinforcements: We plan a points system to reinforce behavior change. Points are awarded for 
recommended behaviors (e.g., decreased cigarette smoking, group exercise) and can be traded for cheaper 
items (e.g., pen, key chain) or saved for larger rewards (e.g., CD player).  Rewards are used to reinforce 
healthy habits that forgo immediate gratification (e.g., eating candy now) for larger, delayed gratification 
(e.g.,weight maintenance).  
Quality assurance: We will ensure high-quality intervention delivery through training, case management 
meetings and fidelity measurement. Coaches receive initial training on CVD risk behaviors and risk factors, 
and all intervention staff are trained in behavior change theories, working with persons with SMI, motivational 
interviewing and implementing the intervention according to the manual of procedures. Follow-up training 
occurs quarterly. Case management intervention meetings with the study team are used to review each 
participant’s CVD risk factors and current treatment plan and help facilitate behavior change and/or appropriate 
monitoring or treatment. The meetings ensure that all participants are reviewed regularly, and those with 
uncontrolled risk factors are prioritized. The intervention director facilitates meetings for the intervention team, 
and as needed, investigators with expertise in CVD risk reduction strategies participate. To ensure high fidelity, 
health coach and nurse sessions are either observed in person or audio recorded and reviewed by the 
intervention director for adherence to the protocol. Fidelity reviews occur at least quarterly. 
Process measures: For active intervention participants, we will track intervention session completion, exercise 
class participation, and interim progress towards goals (e.g., weight, pedometer counts, expired CO) for 
participant feedback, case management and analysis of potential mediators. 
 
NRT: Nicotine patches and nicotine lozenges are FDA approved and available as over the counter 
pharmacotherapy for tobacco cessation. For interested participants in the active intervention arm who are 
smokers and would like to quit or reduce their smoking, we will provide and supervise the use of nicotine 
patches and nicotine lozenges as nicotine replacement therapy for them. Nicotine patches are dosed every 24 
hours; nicotine lozenges (2 and 4mg doses) are used as needed initially every 1-2 hours and then tapering 
down to every 4-8 hours over several weeks.  Nicotine patch initial dosing is based on the level of smoking at 
baseline, with 21mg generally used for those smoking 1 pack of cigarettes per day; 44mg may be used for 
those smoking 2 packs per day. Patches and lozenges may be used in combination. 
 
 
 
 
 
 

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Table 3. Features of IDEAL Active Intervention  
CVD Risk 
Targets 
AHA Strategic Goals 
 
IDEAL Trial Goals 
Traditional Behavioral 
Modification Approach 
IDEAL Intervention Approach  
Healthy Weight 
Weight: BMI<25 
kg/m2* 
 
 
Encourage 10 lb. weight loss. 
Normal weight participants 
encouraged to maintain 
weight. 
-Lifestyle behavioral 
counseling 
-Health education 
-Self-monitor calories, 
weight 
-Participant identifies focus 
of change  
-Self-reward  
-Patient-centered weight loss counseling   
-Simplified Healthy Eating tracker  
-Health coach weighs participant and 
monitors weight progress 
-Coach guides participant towards directs 
high impact behavioral goals 
-Coach rewards attendance behaviors 
 Encourage and incentivize exercise class , 
participation and home exercise  
Physical 
Activity 
Physical Activity: 150+ 
min/wk moderate 
Physical Activity: 150+ min/wk 
moderate 
-Health education 
-Role of social support  
-Provide PRP with exercise resources 
-Encourage class attendance, incentivize 
participation,  
-Provide pedometer and instructions, 
provide exercise DVD, reinforce use 
Diet 
Healthy Diet: 4-5 AHA 
components 
 
Customized to clinical 
condition 
Healthy diet approach similar 
to DASH emphasizing 
avoidance of sugar 
beverages, salty/greasy and 
processed food, sugar drinks 
and sweets. Eat smart 
portions and more 
fruits/vegetables. 
-DASH Diet education 
-Participant identifies focus 
of dietary change 
-Role of social support 
 
-Simplified diet education messages 
-Wallet size card with dietary messages  
-Coach recommends specific dietary 
targets 
-Coach communicates with residential 
staff/social supports 
-Pre-printed shopping lists 
-“Field Trips” to model decision making 
-Consult with PRP staff to provide healthier 
meals on-site 
Smoking 
Stop smoking 
 
Stop smoking 
 
Increased readiness to quit 
smoking 
 
-Provide general 
information about risks of 
smoking and benefits of 
quitting  
-5As: Ask, Advise, Assess, 
Assist, Arrange 
-4D’s (Delay, Deep 
Breathe, Drink water, Do 
something to take your 
mind of smoking) 
-Provide information on 
nicotine replacement 
therapy and other 
pharmacotherapy 
-Counseling tailored to readiness to quit 
-Motivational interviewing and 4D’s 
-Coach communicates with PRP staff, 
residential program counselor and/or home 
social support about goals and strategies 
for smoking cessation 
-Facilitate access/provide nicotine 
replacement therapy (NRT) and work with 
physician and individual to incorporate 
reducing/quitting into treatment plan, --
Communicate with PCP and psychiatrist to 
advocate for pharmacotherapy for smoking 
cessation including varenicline, bupropion 
and NRT 
-Contingency management with CO testing    
Control Blood 
Sugar 
Fasting glucose: <100  
 
HbA1c<7% for diabetes 
-Heath education 
-Self monitoring: 
carbohydrate intake and 
blood sugar 
-Problem solving to 
increase medication and 
diet adherence 
-Teach/reinforce self-management skills 
-Assist with glucose monitoring 
-Simplified dietary messages: (e.g., “No 
sugar drinks”) 
-Solution-focused therapy for medication 
adherence. 
- Coordinate with PCP regarding HbA1c 
targets and any suggested medication 
changes -Communicate with PRP staff, 
residential counselor and/or home social 
support about diet and medication 
-Encourage and incentivize exercise class 
participation and home exercize  
Control BP 
Blood Pressure 
<120/80 or treated to 
goal 
Control blood pressure, SBP 
<140 mmHg, DBP<90mmHg 
-Heath education 
-Self monitoring: sodium 
intake and blood pressure 
-Problem solving to 
increase medication and 
diet adherence 
-Simplified messages (“Avoid 
packaged/canned foods”) 
-Solution-focused therapy for medication 
adherence -Coordinate with PCP about BP 
therapeutic goals and any medication 
adjustments 
-Coach communicates with PRP staff, 
residential counselor and/or home social 
support about diet and medication 
-Encourage and incentivize exercise class 
participation and home exercise 

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Lower 
Cholesterol 
Total Cholesterol 
<200 or treated to 
goal 
 
Lower cholesterol, total 
cholesterol <200mg/dl, 
LDL<130 mg/dl* 
-Heath education 
-Self monitoring: calorie and 
fat intake  
-Problem solving to 
increase medication and 
diet adherence 
-Simplified dietary messages (e.g., “Avoid 
junk food”) 
-Solution-focused therapy for medication 
adherence  
-Coordinate with PCP regarding cholesterol 
therapeutic goals and medication  
-Coach communicates with PRP staff, 
residential counselor and/or home social 
support about diet and medication 
-Encourage and incentivize exercise class 
participation and home exercise  
 
 

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11. DATA MANAGEMENT 
 We will store data in REDCap.159 Built-in range and logic checks will prompt data checks and confirmation 
in real-time during data collection. The analyst will routinely conduct thorough checking and cleaning, 
examining distributions and data patterns and evaluation to detect inconsistencies. Outliers (e.g., extreme 
weight changes) will be identified using Rosner’s extreme Studentized deviate (ESD).160 Every effort will be 
made to determine correctness of outliers in a timely manner. Confirmed outliers will be flagged and set aside 
in the principal secondary analyses. Those removed will be treated as all other missing data; sensitivity 
analyses will be conducted to assess influence of outliers on results. The data manager will create detailed 
variable documentation and the data analyst will conduct analysis per protocol under direction of the study 
statistician.   
 
 
 
12.  DATA ANALYSIS 
Our target is to enroll two-hundred and fifty participants recruited from 4 sites in 1 health organization, 
randomized in equal allocation to active intervention (Group A) and control (Group B), stratified by site.  Formal 
assessments are at baseline, 6, and 18 months. Primary analyses will be conducted under the intention to treat 
principle.161   
Core analytical model: Let Yijk denote the log-transformed FRS for the ith participant at the jth visit (j = 0, 1, 
or 2), corresponding to the baseline, 6, and 18-month visits), in the kth treatment group (k = 0 or 1 
corresponding to intervention groups A and B). Xik is a vector of pre-randomization covariates (which will 
include study site indicators). The longitudinal regression model for the primary analysis is:E[Yijk ] = Xik +  + 
j + k + jk + eijk with the constraints that each of (j , k ,jk ) equals 0 when an index is as its lowest value.  
The eijk are independent unless the (i, k) subscripts are the same.  For participant (i,k) the eijk have an 
unstructured 33 covariance matrix.  The  measure the influence of baseline covariates, the j give visit 
effects within Group A, k baseline treatment effects (which under effective randomization should be close to 0) 
and the jk are the treatment by visit interactions, “the treatment effects.” The primary testing contrast is to 
compare baseline to 18-month changes in FRS (the primary outcome) between intervention groups, i.e. testing 
the hypothesis that 21 = 0. Data at 6 months, though not the primary outcome, will help determine whether the 
changes over 18 months are linear. The primary analysis will follow the intention to treat principle and will not 
adjust for post randomization variables. This core model is also applicable to other secondary continuous 
outcomes such as weight, blood pressure and lipids, and other CVD risk scores, in their original scale or log-
transformed as appropriate.  Modeling will be implemented via SAS PROC Mixed (or the Stata or R-
equivalents). Site effects will be included to account for possible within-site clustering.  
Missing and incomplete data: Prevention is far superior to statistical treatments; every effort will be made to 
collect outcome data on all randomized.  The underlying missing data process determines the biasing effects 
of missing data and structures valid analytic strategies.162 The primary analysis above treats all missing 
primary outcomes as resulting from a MAR process, through which the probability of missing can depend on all 
observed information (Observed FRS, covariates) but does not depend on any FRS scores that are not 
recorded. If the probability of a potential observation being missing depends on what has, but not on what 
hasn’t been observed, termed missing at random (MAR), then estimates based on an appropriate analytic 
model (both the mean and error structure) for the observed data will not be biased. A valid model for the 
observed data allows the missing data process to be ignored. If the missing is informative, meaning that the 
probability of an observation being missing depends on the value of that observation, then bias cannot be 
avoided by modeling the observed data alone, and the impact of such bias would be evaluated using sensitivity 
analysis. Data set aside (censored) due to protocol defined high-leverage events such as pregnancy or a 
serious medical event (e.g., liver failure) that may strongly influence components of the FRS will be treated as 
missing at random. 
 
Secondary Analyses 
Analysis of secondary outcomes:  We will replicate the foregoing analyses for measured outcomes (BP [raw 
scale], lipid levels and HgbA1c levels [log scale].  For dichotomous outcomes (e.g., HTN control, lipid control, 
diabetes control, smoking cessation) GEE based logistic regression modeling will be conducted using SAS 

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Proc Genmod (or the Stata or R-equivalents) with a logistic link and a within-individual, unstructured correlation 
structure. We will use data for all participants to compare changes in outcomes over time between intervention 
arms. For certain dichotomous outcomes we will include only “at risk” participants (e.g., smoking cessation in 
smokers). Medication use for CVD risk factors and psychotropics will be assessed and compared between 
arms and adherence examined using conventional methods.163-165  
Sensitivity Analyses: We will conduct sensitivity analyses with multiple imputation with respect to departures 
from the MAR assumption. The model will be derived from our primary analytical model under MAR, 
maintaining the covariance structure and modifying the imputation mean according to informative missing data 
scenarios. Second, to evaluate potential impact of out of window FRS scores on the robustness of findings 
from the primary analysis, we will set aside all the out of window measurements and repeat the analyses 
following the core analytic modeling approach described previously. When the number of out of window FRS 
scores is high, we will modify the core analytic model with more flexible mean (e.g. use the actual follow-up 
time as a continuous variable rather than a categorical variable with prespecified follow-up time window) and 
covariance (e.g., heterogeneous TOEP or heterogeneous AR) structure to accommodate the more variable 
intervals for follow-up times between 2 outcome assessments. We will produce model-based estimate on 
mean outcome changes at 6 and 18 months between groups and utilize robust inferences. Third, we will 
conduct analyses restricting the study sample to those in age range to 30-79, which corresponds to the 
suggested age range of the FRS. 
 
Exploratory Analyses: We will perform several types of exploratory analyses related to other outcomes of 
interest, and potential moderators or mediators. We will explore the effects of the IDEAL intervention using 
other potential outcomes of interest. For example, we will investigate the AHA/ACC ASCVD risk score which 
became available during the trial. We will systematically evaluate the efficacy of the IDEAL intervention in 
study subgroups defined by baseline (pre-randomization) variables. We are especially interested in baseline 
variables related to psychiatric conditions (psychiatric diagnosis, symptoms, substance use and psychotropic 
medications). We will also explore the efficacy of the intervention in subgroups by baseline cvd risk, 
race,gender and medications for CVD risk factors. These analyses will be performed by including the 
interaction (product) terms in the analysis models for study outcomes. The trial is not powered for these 
exploratory analyses, and we will be careful in interpreting any findings.  
 
 In addition to these and for analyses that preserve the intention to treat principle, we will also perform 
informative exploratory analyses based on subgroups defined post-randomization to characterize aspects of 
the intervention that may be related to improved outcomes in the active group. Such analyses will use post-
randomization variables that are potential mediators - interventionist visit and exercise class participation, 
medication modifications, medication adherence and self-monitoring activities.166  For example, for patients 
with BP controlled at baseline with medications, medications may be lowered if lifestyle changes occur. As a 
result, gauging intervention effects based on measured BP or HTN control alone may underestimate such 
effects as effects could partially be reflected though reduced use of medications. These analyses are more 
prone to biases so that protection from confounding afforded by randomization is not likely applicable. 
Propensity score stratifications will be used to manage potential confounding in these analyses. Nevertheless, 
these findings will be interpreted with caution and will be considered exploratory. 
 
Cost Analysis. The primary analysis will be conducted from the perspective of an adopting organization or 
payer (e.g., Medicaid). The main goal is to estimate the incremental implementation costs of the active 
intervention relative to the control. Resource measurement will focus on sampling and tracking intervention 
staff time.  We will sample at specified intervals throughout the intervention at each site for one week at a time. 
Tracking specific tasks will allow us to eliminate time spent strictly on research and perform sensitivity analyses 
with different potential levels of efficiency (e.g., amount of active client involvement versus administrative time).  
We will also have data on self-reported utilization of office visits and hospitalizations and medication data that 
can be used to calculate cost per participant and total costs. With estimates of total costs for the active group 
and control, we will be able to estimate incremental costs for the active intervention and the incremental costs 
per incremental improvement in 1°and 2°outcomes.  To extend the time horizon forward, we will use the global 
FRS to project the proportion in each group expected to have a CV event within 10 years and the present 

Protocol: Comprehensive Cardiovascular Disease Risk Reduction Trial in Persons with Serious Mental Illness (IDEAL) 
 
 
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value of costs and QALYs associated with events.  This will allow us to perform a societal perspective cost-
utility analysis.167  For all analyses, we will conduct univariate sensitivity analyses by varying assumptions and 
assess the uncertainty of our estimates by bootstrapping for 10000 replications, drawing 
samples with replacement where samples have the same number of observations as the main study.168   
 
Qualitative Analysis:  Interviews will be transcribed and coded. NVivo will be used to enter and  
group discrete passages from data into themes. We will use the constant comparative method169 to categorize 
transcript statements that demonstrate common attributes, then combine categories into broader, recurrent 
themes using a hybrid approach where we will start with larger categories and then add nodes and subnodes 
as new concepts emerge until saturation of ideas is reached. Findings will be compiled to inform ongoing 
implementation and future sustainability and dissemination. 
Power analyses:  The trial has sufficient resources to enroll a target of 250 participants.  With this sample 
size, our objective was to determine the minimum detectable difference (MDD) in relative risk reduction in the 
global Framingham Risk Score (FRS). Our assumptions are as follows:  
  Two-sided type I  error=0.05; type II  error=0.20; 90% follow-up. 
  Baseline absolute CVD risk with global FRS =11% from ACHIEVE Trial (n=291, Table 1);  
  Standard deviation of change in global FRS=3% from ongoing ACHIEVE Trial (from Dr. Daumit’s 
pilot  weight loss intervention in SMI, similar SD of 2.9%); 
 Global FRS change in controls=5% relative risk reduction. Controls could experience some 
reduction in  CVD risk because of secular trends and offerings of physical activity classes on-site.  
However, aging increases CVD risk and might counterbalance these effects.  We conservatively 
assume a 5% relative reduction in the control group, even though their risk might not change or 
might increase over time. 
With these assumptions, our MDD is a 10.7% reduction in relative risk in global FRS. 
 Table 4 demonstrates the relation between baseline and 18-month follow-up and absolute and relative 
changes in global FRS with the example of a percent risk reduction in the control group of 5% and an MDD of 
10.7%.  The reduction in relative risk ratio of 10.7% (MDD= 1 – RRR) is very similar in magnitude to the direct 
difference in relative risks [95% - 84.8% = 10.2%] at 18 months. If risk is unchanged or rises in the controls, 
our MDD will be lower.   
Table 5. Minimal Detectable Differences for Relative 
Framingham Risk Score Reduction by follow-up rates and % 
risk reduction in controls 
 
MDD, assuming a Relative Reduction  
in Control Group of: 
Follow-up rate 
0% 
2.5% 
5% 
100% 
9.7% 
10.0% 
10.1% 
95% 
9.9% 
10.2% 
10.4% 
90% 
10.3% 
10.5% 
10.7% 
85% 
10.5% 
10.8% 
11.1% 
80% 
10.9% 
11.1% 
11.4% 
 
 
 
Table 4: Calculation of Relative Risk Reduction to 10 year Framingham Risk Score from Baseline to Follow-up  
 
Baseline 
FRS Risk 
Follow-up 
FRS Risk 
Relative Reduction, 
within-group 
Relative Reduction, 
between-group 
Minimum Detectable 
Difference (MDD) 
 
10yr Probability of 
CVD Event 
Relative Risk 
Percent 
 Risk Reduction 
Relative Risk Ratio 
(RRR) 
MDD=1-RRR 
Active  
11% 
9.33% 
9.33%/11%=0.848 
1 - 0.848 = 0.152 
(15.2%) 
0.848/0.95=0.893 
1 - 0.893 = 0.107 (10.7%) 
Control 
11% 
10.45% 
10.45%/11%=0.95 
1 - 0.95 =0.05 (5%) 

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Table 5 displays MDD for ranges of follow-up rates and relative risk reduction in the control group. The MDD of 
10.7% is very achievable.  IDEAL will combine lifestyle/behavioral modification with improved clinical 
management of CVD risk factors. In studies of lifestyle interventions, reported relative reductions in CV risk 
scores range from 9-16%,172,178,179  and for care management interventions, 91,174 from 12%-23%.  Table 6 
displays ranges of changes in individual CV risk factors and corresponding estimated changes in global FRS 
from interventions in the literature with components similar to IDEAL. Even with the understanding that 
intervention components will not likely be fully additive, and that except for smoking cessation, these estimates 
are from studies in the general population and not SMI, Table 6 provides support for many scenarios where the 
MDD in FRS of 10.7% would be attainable. We have precision for estimating clinically significant intervention 
effects in secondary outcomes.  The 95%confidence interval (CI) for an effect estimate is +/-1.96* sqrt(2/n)*, 
where n is the sample size per group and the common SD for change in the measured outcome of interest for 
both groups. Assuming 90% follow-up, the 95% CI for the intervention effect of difference in change between 
groups would be: glucose 7.9 mg/dl; SBP 3.5mmHg, weight 4.0 lbs; total cholesterol 9.0 mg/dl; HDL 2.9mg/dl; 
SF-12 Physical Functioning 7.9. The SDs for change are derived from the ACHIEVE Trial. For smoking 
cessation, we assume 75 smokers per group with 1.3% quit rate in the controls (i.e., 1 of 75). We will have 
80% power to detect a quit rate of 14% or higher in the active group using a 2-sided alpha of 0.05.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 6. Reported CVD risk factor changes and estimated relative reduction in global FRS 
Risk Factor 
Reported range of change in risk factor 
Corresponding Δ in  
Global FRS♯ 
SBP 
Lifestyle interventions: 3.7-8mmHg 170-172  
5-15% 
Care management: 6-11mmHg 93, 173, 174 
6-19% 
Total cholesterol 
Lifestyle intervention: 19mg/dl 172   
10% 
Care management: 12.9-15.5 mg/dl 91, 175 
7-7.5% 
HDL 
Lifestyle interventions: 2-2.4mg/dl171, 172  
4-5% 
Smoking cessation 
Psychosocial /buproprion +/-NRT* 12-33%62-68 
1 -3.3%± 
Fasting 
glucose/HgbA1C 
Lifestyle interventions: HgbA1c 0.5-0.99171, 176 
Care management: fasting glucose, 7.7-20mg/dl, HbgA1c 1.191, 174, 177 
*in SMI. ±After weighting by the anticipated prevalence of smoking.  ♯ To estimate global 
FRS Δ, we used median risk factor levels in ACHIEVE. Then, for each risk factor separately, 
we applied literature-reported changes in that risk factor to the global FRS equation. 

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13. DATA SECURITY 
Each participant will be assigned a study ID number that will be used, instead of name or other identifying 
information, on all study data collection materials. The link between identifying information and the study ID will 
be kept in a separate database with password access available only to the data analyst and principal 
investigators. Paper records will be kept in locked file cabinets. Data will be published only in aggregate, with 
no identifying characteristics of individuals published or presented. All study staff annually sign a confidentiality 
statement attesting to their understanding of, and willingness to abide by, written policies on research ethics 
and confidentiality. For data entry and management, we will use REDCap, a web-based application for building 
and managing data entry and databases. 159  REDCap data is housed on secure servers at the Johns Hopkins 
Biostatistics Center under firewall protection with offsite access through VPN. The database will contain 
embedded checks for internal consistency and data completeness. Missing and questionable data will be 
queried in source documents and corrected, and double data entry will be performed for primary outcome data. 
Database access is password protected and restricted to authorized personnel only (e.g., data collectors 
cannot see intervention data), and REDCap provides audit trails for tracking data manipulation and user 
activity. Data will be exported from REDCap to SAS for analysis. Analytic files will be stored on secure Johns 
Hopkins network servers and accessed on encrypted and password-protected computers.  
 
 
14. SAFETY 
 
Safety Monitoring 
      
Participant safety will be closely monitored. Protection of research participants begins with the eligibility criteria, 
which are designed to exclude individuals with a serious medical condition that would preclude their ability to 
participate in a cardiovascular risk reduction program.  During the study, clinical care will be provided by the 
participants’ usual specialty mental health providers and the primary care physician, not by the study.  
 
 If a participant develops a medical or psychiatric issue, the safety of continuing or resuming the intervention 
will be ascertained by the study clinician in collaboration with the participant’s regular providers. Surveillance 
for serious adverse events and other relevant clinical events will occur by questionnaire at regularly scheduled 
intervals. We may be come aware of medical problems including abnormal blood pressure or laboratory tests. 
Results of routine clinical labs and physical measures obtained as a part of data collection will be provided to 
participants and physicians at baseline and after study completion. Measures meeting criteria for alert values 
will be communicated more quickly.  
 
 
 
 
Potential Risks 
 
The study should not involve any major risk to screenees and trial participants.  Recommended treatments, 
both lifestyle and pharmacologic, are based on prevailing national guidelines.  However, there are some risks.  
Sources of risk include medication-related adverse events, such as hypoglycemic events, side effects from 
medications for CVD risk factors prescribed by the patient’s primary care physician and side effects from 
nicotine withdrawal or over-the-counter nicotine replacement therapy. For example, improved health behaviors 
from the intervention (e.g., physical activity, weight loss) may lead to hypoglycemia or hypotension in those 
already taking medications and necessitate adjusting diabetes or blood pressure medications.  In addition, 
physical activity is associated with a small risk of cardiovascular complications (less than 1 per 187,500 
person-hours of exercise).180  Physical activity can also increase the risk of musculoskeletal discomfort or 
injury.  Blood drawing may cause some discomfort and/or bruising at the site of the venipuncture. The methods 
that participants may use to restrict calories (e.g. extreme calorie restriction or unbalanced dietary pattern) may 
lead to inadequate energy intake or lower than recommended intake of essential nutrients. In addition, 

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23
participants run the risk of a breach in confidentiality. These risks should be rare. Plans to minimize these risks 
are described below. 
 
Adequacy of Protection Against Risks 
 
Informed consent.  Procedures for recruitment, consent, intervention, data collection and analysis will be 
reviewed and approved by the Johns Hopkins Institutional Review Boards and the DSMB.  
We will use a two-stage consent procedure: one consent form will be signed upon entry that covers 
screening and baseline data collection for the study. Another will be signed at the time of randomization. The 
consent forms will detail the purpose of the study, the requirements for participation, and the potential benefits 
and risks. In consenting individuals to participate in the study, the following procedures will be used: 1) 
Procedures involved in the study will be fully explained to participants by study staff trained in informed 
consent procedures for persons with serious mental illness. 2) Participants will complete a brief test of 
comprehension of study procedures to demonstrate that they understand the risks and benefits of study 
participation and clearly consent, before consent is accepted.  Any wrong answers are corrected and additional 
information given to clarify, until a person can easily answer all items successfully or they indicate they do not 
wish to continue.  3) Those agreeing to participate will sign the consent form. 
 
Protection against risk: General 
The safety approach will be implemented similar to the investigators’ other trials (e.g., POWER Trial). We 
will have a medical safety officer who will be in charge of developing the safety protocol for the trial, and he will 
promote and monitor safety throughout the study. As in our previous studies, the safety officer does not 
provide direct medical care and is not involved in the intervention. We will use standardized materials including 
a manual of procedures and forms. NHLBI has considered materials that we developed in the POWER Trial as 
models which are now used in other NHLBI-supported lifestyle intervention trials.  
 
Hypoglycemia, hypotension or other potential consequences of improved health behaviors or changes in 
medication: These will be minimized by having the intervention team communicate closely with the primary 
care physician and rehabilitation program staff about medication changes, exercise participation and 
coordinate assistance for participants in blood sugar monitoring. For example, if an active intervention group 
participant is taking a sulfonylurea and has significantly increased exercise frequency, the intervention team 
will communicate with the PCP and raise the suggestion of a glucose-lowering agent that would have lower 
risk of hypoglycemia, such as metformin. The interventionist will also ensure appropriate follow-up with the 
PCP after any medication changes.  
Physical activity: The small risk of physical activity will be minimized by emphasizing moderate (as opposed to 
vigorous) activity, and by following American College of Sports Medicine guidelines regarding need for medical 
examination prior to beginning an exercise program. Participants who wish to progress to vigorous activity will 
be advised to obtain approval from their primary care physician. Risk of injury is further minimized by 
instruction on proper exercise technique, the importance of warm-up and cool-down exercises, and proper 
stretching techniques.  
Blood drawing: All phlebotomy is performed by an experienced phlebotomist. Participants will be given 
information on how to contact Dr. Daumit if complications occur. 
Extreme weight loss methods. The interventionist and mental health program staff will be aware of the 
possibility that intervention subjects could use extreme methods to lose weight. Participants will be reminded 
regularly of the importance of safe weight loss. Those who have a sudden, marked weight reduction will be 
interviewed to determine if extreme measures have been taken. The intervention staff will be trained to detect 
evidence of extreme measures and will be given strategies for responding. 
Nicotine replacement therapy and smoking cessation. We will educate participants about symptoms of nicotine 
withdrawal and teach coping strategies. NRT including in combination (patches and lozenges) is considered 
safe and risks are far less than those associated with tobacco use, even in smokers with known cardiovascular 
disease and in those who continue smoking while using NRT.181-188 Certain plasma levels of medications 
including olanzapine, clozapine and fluvoxamine may be higher after smoking cessation.  We will discuss use 
of NRT with participants’ primary care physicians and psychiatrists and monitor symptoms carefully at each 

Protocol: Comprehensive Cardiovascular Disease Risk Reduction Trial in Persons with Serious Mental Illness (IDEAL) 
 
 
24
weekly to bi-weekly intervention visit so that risks are minimized. We will communicate with providers regarding 
smoking cessation so that psychotropic medication dosage adjustment may be made if needed. 
 
Breach of confidentiality: All participant information will be considered confidential. This confidentiality will be 
assured through several mechanisms.  For the study, each participant will be assigned an anonymous study 
ID, which will be used on all study forms. In addition, all study forms and paper records that contain participant 
information will be kept in secured, locked areas when not in use.  Such materials, when in use, will be kept 
away from public scrutiny.  Forms that need to be discarded will be destroyed.  Moreover, access to all 
participant data and information will be restricted to authorized personnel. In the case of computerized study 
data, access will be password protected.  When the study database is ready for analysis, it will not contain 
actual identities of participants.  During active data collection, hard copies of data collection forms will be 
stored in locked areas with access only by authorized personnel.  Finally, neither the mental health programs 
nor participants will be identified by name in any publications.  Data will not be presented in such a way that 
the identity of individual participants can be inferred. 
 
Similarly, for staff semi-structured interviews, all information will be considered confidential. This confidentiality 
will be assured through several mechanisms. Transcripts will not contain names and will be kept in a secure 
location by Dr. Daumit. Audiotapes will be destroyed after transcription is completed. Individuals will not be 
identified by name in any publication. Mosaic leadership agrees that staff participation in the interview and any 
information shared will not affect staff employment or evaluation.  
 
Participant reimbursement: At baseline and 6 months, for completing data collection activities, participants will 
receive 15 dollars. At 18 months, for completing data collection activities, participants will receive 25 dollars. 
This increase in payment as participants’ time in the study progresses is to recognize their commitment to the 
study. Staff will receive a 25 dollar gift card for completing a semi-structured interview. 
 
 
Importance of knowledge to be gained: Persons with serious mental illness have high burdens of each major 
cardiovascular risk behavior, yet persons with SMI have been systematically excluded from interventions to 
decrease cardiovascular risk. If successful, this proposed cardiovascular risk reduction intervention could be 
disseminated widely. The minimal health risks to participants are offset by the potential benefits to participants 
and to the greater population with chronic mental illness. 
 
Potential benefits to the study participants who receive the active intervention include improved health 
behaviors and improved cardiovascular risk factor profiles. The physical activity classes are available for active 
and control participants. Potential benefits to others include the possibility that the research will lead to the 
dissemination of effective interventions to decrease CVD risk in persons with serious mental illness.  
There is no specific benefit to staff for participating in interviews. Information learned from their perspectives 
potentially will help disseminate health interventions in mental health organizations in the future.  
Data and safety monitoring plan:  Protection of research participants begins with the eligibility criteria, which 
are designed to exclude individuals with a serious medical condition that would preclude their ability to 
participate in a cardiovascular risk reduction program.  During the study, clinical care will be provided by the 
participants’ usual specialty mental health providers and the primary care physician, not by the study.  
Participants will be made aware of this delineation of responsibility.  However, recognizing the opportunity for 
early detection of clinical problems and the small risk of study-related morbidity, we will perform periodic safety 
assessments.  We will inquire about cardiovascular and musculoskeletal symptoms at 6-month intervals.  
Safety monitoring will consist of a symptom questionnaire and the Rose Angina questionnaire.  Any positive 
responses to these questions will be reviewed by the safety officer; clinically significant results will lead to 
referral to the primary care physician.  Information that comes to the attention of study personnel informally 
(e.g., through data collection or intervention activities at the center) may also lead to referral. Symptoms that 
will lead to referral include (but are not limited to) those that suggest cardiovascular disease (e.g., exertional 
chest pain, dyspnea, presyncope or syncope), uncontrolled hypertension, uncontrolled diabetes or 

Protocol: Comprehensive Cardiovascular Disease Risk Reduction Trial in Persons with Serious Mental Illness (IDEAL) 
 
 
25
complications of physical activity.  Participants are also queried at these same timepoints about possible 
adverse events (defined below).  Positive responses trigger an adverse event (AE) record, which is reviewed 
and classified as either gastrointestinal, cardiovascular, musculoskeletal, or other in nature.  This information is 
then reported to the DSMB.  Similar information reported by participants at other times (e.g., during 
intervention classes) is duly noted and followed up with as needed to assure participant safety. The following 
constitute adverse events (AEs): heart attack, stroke, transient ischemic attack, heart failure, coronary 
angioplasty or bypass surgery, angina pectoris, broken bone, torn ligament, and any other serious injury to the 
bone or muscle.  Evidence of the occurrence of these events is based on participant self-report that a health 
care professional has diagnosed the condition.  We will attempt to verify the diagnosis through contact with the 
primary care physician.  Though not considered AEs for this study, we also track and report the incidence of 
hyperlipidemia, gallbladder disease, diabetes, cancer and hospitalization.  All other outcomes that may be 
construed as being an adverse consequence of study participation, such as an injury while performing a study 
measurement, are documented, reviewed, and followed up on as needed by a study clinician. 
 
A Data and Safety Monitoring Board will be established and will meet at least annually during the study. 
The DSMB members will be research scientists not otherwise connected to the study whose expertise includes 
the disciplines and skills needed to initially review the protocol and then monitor intervention progress, quality 
of the data and safety of the participants.  Members will include experts in CVD prevention, mental health and 
clinical trials. Prevailing NIH and IRB policies will dictate the specific roles of this committee, which will review 
the protocol before the start of fieldwork. Adverse events will be reviewed initially by the safety officer and Dr. 
Daumit and then reported locally to the IRB, the DSMB and the NIH project office according to prevailing 
policies of these review bodies. This plan should ensure participant safety. 
 
 
 

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