Conditions: Serious Mental Illness Schizophrenia Schizoaffective Disorder Bipolar Disorder Cardiovascular Disease Major Depressive Disorder Psychosis NOS
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 227
Healthy volunteers: no

Brief summary:
Patients with severe mental illness (SMI) die younger than persons in the general population. Much of the excess mortality for SMI patients is attributable to cardiovascular disease, and is exacerbated by treatment with second-generation antipsychotics (2GAs). Although the cardiovascular risks are well-known, and safe, efficacious therapy exists, few SMI patients receive cardiovascular prevention drugs. Care delivery fragmentation and poor patient adherence are central problems to reducing cardiovascular risks for patients with SMI. To address these problems, we propose to conduct a multi-site, open-label, randomized controlled trial comparing an initial treatment strategy of free, fixed-doses of two generic, cardiovascular prevention drugs (statins and angiotensin drugs) delivered within mental health clinics versus usual treatment. The study will include adult patients (18+ years old) with schizophrenia, schizoaffective disorder, bipolar disorder, major depressive disorder, or psychosis not otherwise specified (NOS) who have received 2GAs treatment within the past six months from within four mental health clinics in the Boston area. We have three aims: 1) to compare the proportions of subjects in each arm who are receiving cardiovascular drug treatment and are adherent to therapy during 12-months of follow-up; 2) to compare changes in composite (e.g., Framingham scores) and individual (e.g., lipid levels) cardiovascular risk factor levels using an intent-to-treat (ITT) approach; and 3) to compare risk factor levels, accounting for variation in adherence over time, using causal inference techniques to estimate the per-protocol effect of the intervention. Our three aims examine whether this low cost, streamlined treatment strategy increases the numbers of subjects receiving cardiovascular prevention therapy and improves cardiovascular risk levels. We will follow subjects for 12 months, and collect interview and biometric data at baseline and over the following 12 months. Subjects will have the option to continue for another 12 months, during which we will continue to collect interview and biometric data, but will not prescribe cardiovascular medications. This population-based initial treatment strategy could be an effective and efficient approach for overcoming traditional barriers to cardiovascular disease prevention within the SMI population. Findings from this study will inform efforts to improve care and outcomes, and to enhance survival for patients with severe mental illness.

Detailed description:
By design, all subjects in the Intervention arm will start by being under treatment. During the course of follow-up, we expect that some will stay consistently on treatment, some will discontinue treatment (become non-adherent), while others will make transitions on and off treatment in various patterns. In contrast, by design, subjects in the Usual Treatment (control) arm do not start on treatment; however, some will initiate treatment as a result of usual clinical care, e.g., primary care physician initiation. At any point we will be comparing two binary outcomes (on or off treatment) and will use standard methods for comparing two proportions to test statistical significance and get confidence intervals for the difference in the percent on treatment in the two arms. Participants who are ineligible for randomization will be followed similarly to participants in the Usual Treatment Arm, in a third, non-randomized group, which will be excluded from the primary analysis.

Arms:
arm 1: Simvastatin 20mg PO daily and/or Losartan 25mg PO daily arm 2: We will compare the initial treatment intervention with usual treatment (control arm), with both arms superimposed on a system of regular monitoring base. The investigators will make no effort to alter or influence treatment or use of that treatment for subjects in the control arm. Note that our goal in the Control arm is to characterize "usual treatment". We will not intervene in this care except in emergencies. Some patients who need care for metabolic syndrome may not be receiving it - just as they would if not in our trial.

Interventions: intervention 1: Simvastatin intervention 2: Losartan
Intervention descriptions: intervention 1: 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitors intervention 2: Angiotensin II receptor antagonist

Protocol document:
Prot_002.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCT02188121 
 
Protocol Title: Clinical trial to reduce cardiovascular health risks in patients with serious 
mental illness 
 
Protocol Version date: 02/21/18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version date: 10/02/2017  Page:  1 
Principal Investigator: Dost Öngür, M.D., Ph.D, McLean Hospital 
 
Site Principal Investigators: Sally Reyering, M.D., BayCove. Mark Viron, M.D., Mass 
Mental Health Center, Louisa Sylvia, Ph.D, Massachusetts General Hospital, Elaine 
Farash, MSW., Edinburg Center  
 
 
Department: Schizophrenia and Bipolar Disorder Program, McLean Hospital, 115 Mill 
Street, Belmont, MA 02478 
 
Protocol Title: Clinical trial to reduce cardiovascular health risks in patients with serious 
mental illness 
 
Protocol Version date: 2/21/2018 
Sponsor / Funding Source: NIMH; 1R01MH104560-01   
 
 
 
 
 
 
 
I. 
Background and Significance 
 
Individuals with serious mental illness (SMI) experience pre-mature mortality compared 
with the general population, with cardiovascular disease being a major cause.[1-6] 
Patients with SMI have elevated risk for both metabolic and cardiovascular 
complications,[7-10] and treatment with second-generation antipsychotics (2GAs) 
contributes to these risks. National guidelines recommend regular monitoring for 
patients receiving 2GAs, however, evidence suggests that screening and treatment for 
cardiovascular risks by psychiatrists and primary care physicians (PCPs) remains 
infrequent.[11-13] Focus on primary prevention is also warranted and holds promise given 
the population’s elevated risk levels.[14, 15] 
 
Several safe and efficacious prescription drugs exist to prevent cardiovascular 
complications.[16-21] In particular, there is substantial evidence supporting primary 
prevention efficacy (e.g., in improving survival) and safety of statins and angiotensin 
receptor blockers (ARBs), including in patients with moderate lipid and blood pressure 
levels.[22-25] Moreover, many of these drugs now are available as low cost generics, 
which improves their cost-effectiveness.[26, 27] These treatments, however, are largely 
untested among SMI patients.[28] 
 
Much of the care delivery in the U.S. is fragmented, which has hindered the ability to 
provide optimal care for many patients. The fragmentation has been associated with 
poor quality and poor coordination across conditions or sites.[29] Fragmentation is 
particularly problematic for mental health care due to common health care financing and 
delivery system characteristics, such as mental health carve-outs, as well as the stigma 
associated with mental illness. These issues likely contribute to failures in monitoring, 
treatment and adherence.[30-32] National estimates suggest that as few as 10% of SMI 
patients receive appropriate care for cardiovascular prevention.[11]Care coordination is a 
persistent challenge, especially with the SMI patient population. Numerous experiments 
such as the primary care medical home (PCMH) and accountable care organizations 


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(ACO) are ongoing, but to date have largely focused on primary care.[33-36] SMI patients, 
however, may view the psychiatrist’s office (or mental health clinic) as their clinical 
home.[37, 38] They may be poorly adherent with recommendations to seek primary 
care.[39, 40] There also is evidence to suggest PCPs are less ready to care for SMI 
patients.[41, 42] Thus, a more patient centered approach for those with SMI would be to 
build the home in the mental health clinic.  
 
Patient adherence to chronic drug therapy often is poor.[43-46] Non-adherence is 
exacerbated by complex regimens and polypharmacy, both of which are common for 
SMI patients.[47-51] Poor adherence affects not only the effectiveness of treatment but 
also presents challenges in analyzing intervention effects in RCTs, e.g., ITT estimates 
could be biased estimates of the per-protocol effect.[52-56] For example, post-
randomization confounding will arise if sicker patients are less able to tolerate treatment 
or more likely to be non-adherent. Examples of potential confounders include the insight 
and cognitive ability. 
 
A fixed-dose combination of pills could serve as a useful tool for minimizing non-
adherence to treatment.[57-61] Use of moderate doses also yields clinical benefits with 
fewer side effects and complications.[62-64] Multiple trials have demonstrated that 
simplifying the regimen could facilitate effectiveness by improving treatment 
adherence.[65-70] A simplified, initial treatment strategy also could be more feasible for 
busy mental health clinics to implement. We propose that augmenting cardiovascular 
care within the mental health clinic could be a better structural integration strategy 
versus locating these efforts in primary care.[38, 71-73] This behavioral health home model 
arguably is the most patient centered design for the subset of patients with these 
established relationships and illnesses that require specialized care.[74-77] The 
intervention also could serve as a prevention strategy for behavioral health homes, i.e., 
“software” that supports the “hardware” of structural reforms.[78-81]  
 
II. 
Specific Aims: 
 
Our model posits that two major barriers to recommended cardiovascular treatment of 
patients with SMI are the fragmentation of medical care and poor treatment adherence. 
SMI patients typically receive care from psychiatrists located in mental health clinics; 
psychiatrists not surprisingly tend to focus on psychiatric illness, and are less 
comfortable prescribing non-psychiatric treatments given the range of initiation points, 
drug choices, starting doses, and treatment targets.[28, 83, 84] Moreover, mental health 
care in the US has significant resource constraints including on the number of clinicians, 
who in turn have limited time to address all patient needs.[85, 86] Thus, physical health 
concerns often are left to the primary care physician (PCP), who monitors potential 
metabolic or cardiovascular complications and initiates medical treatments; however, 
PCPs practice in different locations. Communication between psychiatrists and PCPs 
about individual patients can be difficult, especially in the absence of electronic health 
records and information exchanges, and a priori agreements about treatment goals and 
individual clinician roles and responsibilities.[87-92] Moreover, patients need to visit the 
PCP, with whom they may not have the same levels of access, relationship, or contact, 


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as they do with their psychiatrist;[93, 94] in addition to this PCP-visit adherence, patients 
also would need to adhere to the monitoring/treatment recommendations, which given 
the multiple drugs with potentially different administration schedules and symptoms of 
their mental illness could be challenging. Our intervention addresses both fragmentation 
and adherence by embedding treatment within the mental health clinic and simplifying 
the prescribing process by reducing the treatment options to a single one.  
 
Our specific aims are as follows: 
1) To compare the proportions of subjects in each arm who are on a cardiovascular 
treatment regimen and adherent to therapy during follow-up 
2) To compare changes in composite and individual risk factor levels by arm  
3) To compare composite and individual risk factor levels by arm, accounting for 
adherence variation over time via causal inference techniques. 
 
Our hypotheses are that subjects in the intervention arm will have higher adherence and 
greater cardiovascular risk reduction compared with subjects in the control arm. We 
also hypothesize that the improvement in cardiovascular risk reduction will be mitigated 
after we account for adherence variation over time. 
 
Trial Study Design Overview: This is an open-label, multi-site, randomized controlled 
trial aimed at assessing a simplified initial treatment approach (fixed-, moderate-dose 
combination) of statin and/or ARB, in this case simvastatin 20 mg once per day, and/or 
losartan 25mg once per day; for reducing cardiovascular risks among SMI patients who 
have received standing 2GA therapy anytime within 6 months prior to study enrollment. 
These patients are at elevated cardiovascular risk but frequently do not receive 
recommended monitoring or treatment. We hypothesize that this monitoring/treatment 
failure reflects both the fragmentation of care delivery for these patients and low patient 
adherence; accordingly, our trial assesses a simplified treatment initiation strategy that 
uses a moderate-dose, fixed drug regimen, which has been tested successfully in other 
patient populations and in other parts of the world. We have two study arms: 1) 
Intervention consisting of treatment initiation with a fixed-dose regimen of a statin and/or 
an ARB; and 2) Usual treatment;  We will also follow non-Randomized subjects who 
signed consent, but were not eligible to continue on to randomization into the 
Intervention or Usual Treatment arms. Table 1 displays the six assessment steps. 
Assessment steps will be the same for each study site. 
 
The efficacy of statins to reduce cholesterol levels and for ARBs to reduce blood 
pressure is not in doubt.  In this study, we are assessing whether our study design 
enables a high degree of adherence with these medications.  As described below, we 
will prescribe a statin and/or an ARB to eligible patients, including subjects in the study 
who are already on one of the two study medications and prescribe the one they are not 
on.  In the latter case, we will use adherence with the new medication as the outcome. 
 
Although we have designed this study to ensure the lowest possible adverse event 
profile by providing a fixed low dose of each medication, some patients nonetheless 
complain of side effects and some randomized to the intervention arm have decided to 


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discontinue the study medications as a result.  Our goal in this study is to implement a 
strategy of cardiovascular risk reduction with maximal adherence; therefore we are not 
testing solely the effects of the specific study medications simvastatin and losartan. 
Given this logic, we would like to add a set of “second-line” medications to offer patients 
who would like to stop the simvastatin and/or losartan.  Based on considerations of 
tolerability and cost, we have selected atorvastatin 10mg/d and valsartan 40mg/d as the 
second line medications. Valsartan and atorvastatin will be referred to as the “second 
line study drugs” in the remainder of this consent form. At the low dose of 10 mg/day for 
atorvastatin, adverse effects are less likely.  The ASCOT trial found tolerability and 
safety of 10 mg atorvastatin daily to be comparable to that of placebo during a median 
of 3.3 years of follow-up; the CARDS trial found no significant difference in overall 
frequency of adverse or serious reactions between subjects treated with atorvastatin 10 
mg daily or placebo during a median follow-up of 3.9 years.  Likewise, valsartan at 40 
mg/daily is well-tolerated and has evidence of clinical benefit in cardiovascular disease.  
 
When a patient complains of subjective side effects (i.e. side effects that are not 
attributable to medical complications or reactions, such as elevated CK or 
rhabodomylosis), we will make the best estimate of which of the two study medications 
(statin or ARB) may be causing the side effect.  This is aided by the fact the two 
medications often have divergent side effects (in particular myopathy vs. cough 
respectively).  We will offer the patient the second-line medication to replace only the 
first-line medication that we believe is the culprit.  If we cannot distinguish which 
medication may be causing the side effect, we will offer the option of switching both 
medications.  If the patient tries the switch and ultimately would like to go back on the 
first-line medication, we will allow that.  The rationale is that our goal is to keep patients 
on fixed low-dose cardioprotective medications, regardless of the specific medication.   
 
Because each subject’s medication regimen will be different and the reported side 
effects can vary greatly, we cannot provide an algorithm about which medication will be 
switched for which second-line medication.  However, our procedure will be as follows: 
when a participant reports any side effect or adverse event (SE or AE) to study staff, the 
staff will notify the PI of the report in the same day.  The PI will consult with study staff 
to determine whether it is possible the SE/AE is related to study medications (e.g. 
whether the subject is in the intervention or control arm, whether they have another 
condition that accounts for the report, whether they have been in an accident etc).  And 
if so, the team will also assess whether the SE/AE can be attributed to one of the two 
study medications (e.g. myalgias for statin, or cough for ARB) for patients who are 
taking both study medications.  Note that some patients in the intervention arm are 
taking only one of the two study medications and in these cases the attribution is more 
straightforward.  If this attribution cannot be made with confidence, the team will consult 
with other study staff (Dr. John Hsu – coPI for the study from MGH Internal Medicine, 
Dr. Daniel Singer from MGH Cardiology, Dr. Eldrin Forster from BWH Cardiology) for 
further discussion of the case and additional recommended laboratory or other 
assessments. 
 
If the AE/SE is possibly related to study medications:  


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1) the PI and study staff will consider whether there are potential means for 
mitigating the complaint (e.g. take with food, change the time of day of 
medication administration etc) and offer these to the participant.   
2) If these are unacceptable to the participant or they are tried and found to be not 
effective, the participant will be offered the option of stopping the study 
medication they are on and starting the second-line study medication as outlined 
in this amendment.  The risks and benefits of the second-line medication will be 
discussed with the participant as was done for first-line medication.  For 
participants who agree to try the second-line medication the team will order and 
provide the medication as outlined. 
3) The staff will remind the participant both at Step (1) and Step (2) that they are 
free to stop the study medication at any point if they so choose. 
 
Note that when a participant stops a first-line medication and starts a second-line 
medication, this will likely be out of cycle for our 90-day medication dispensation 
schedule.  To maintain maximum flexibility of scheduling in those cases and to avoid 
waste, we will have the ability to dispense 45 tablets of the second-line medication 
instead of 90 so the participant can return for their next scheduled visit and 
subsequently go on the 90-day schedule. 
 
As always, if a patient chooses to stop the study medication or becomes non-adherent 
with it despite our offer of second-line medications, we will note this information. 
Patients will not be offered second line medications in the event of a medically 
significant adverse reaction such as elevated CK or rhabdomylosis. Participants will 
only be offered second line medications when complaining of subjective side effects 
with no medical complications (e.g. headache or abdominal pain with no relevant 
changes in blood samples).  Participants who start second line medications will be 
asked to return in 2-4 weeks for a safety check similar to when participants started the 
first line treatments.  
 
 
Table 1: Assessments 
Step 1: Recruitment 
Clinicians review their list of scheduled patients to identify potential subjects and ask 
these patients if they are interested in a research study. If patients agree, the 
research team approaches them to describe the study, obtain consent, sign DMH 
authorization form (if applicable), sign the APCD access release (optional), and 
schedule initial visit.   


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Step 2: Eligibility Screening 
RAs conduct initial interview  
Study nurses collect (screening) blood samples and vital signs, e.g., weight and 
height, and blood pressure 
RAs collect urine pregnancy tests for all women of childbearing potential. 
After the screening laboratory tests are available, study nurses will assess the 
eligibility for each potential subject and conduct the initial safety check. For example, 
if there are any subjects who appear to have signs of active cardiovascular disease 
or diabetes, we will intervene immediately via referral to PCP office or ED visit as 
appropriate. 
Step 3: Baseline and Medication Visit (eligible subjects asked back for a 
medication visit ) 
Random assignment of eligible subjects into one of two study arms: Intervention vs. 
Usual Treatment 
Subjects who are ineligible will have the option of participating as a Non-Randomized 
subject where study data will be collected. 
Study nurse prescribes fixed dose statin and/or ARB drugs (Intervention arm only). 
If subjects are randomized into the treatment arm and are already taking either a 
statin or any anti-hypertensive medication, they will be prescribed only the drug they 
are not already taking (e.g. participants on a statin will be prescribed only losartan). 
If subjects are already taking either a statin or anti-hypertensive medication, we will 
not alter the dosage of the previously prescribed medication. 
We will send letters about the trial to the subject’s PCP, regardless of subject’s 
randomization.  
Intervention arm subjects will get an additional blood draw in-between the medication 
visit and first follow-up visit to ensure it is safe for them to continue taking the study 
medications. 
Step 4: Follow-up Visits (every 3 months for 12 months) 
RAs conduct follow-up interviews, perform pill counts, and collect urine pregnancy 
tests (all arms) 
Study nurses collect blood samples and vital signs; conduct safety checks; track 
visits (dates, clinician type), diagnoses, prescription drugs (names, doses, pill counts 
of cardiovascular drugs), and medical events (all arms) 
Study nurses will record and reconcile medication lists at every visit, and note 
changes in medications. 
Study nurse prescribes additional fixed dose statin and/or ARB drugs (Intervention 
arm only). 
Participants who have baseline CK values within 2*ULN will be enrolled in the study. 
If these participants are randomized into the treatment arm, and will be receiving 
treatment with a statin, they will be asked to come for additional safety blood draws 
once per month in addition to one draw one week following the first dose of study 
drugs. This draws will be done to ensure participant safety while taking the study 
medications. If a trend of increasing CK is observed, the study medications will be 
discontinued (Intervention arm only). 


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Participants prescribed the ARB who exhibit symptoms of hypotension (e.g., 
syncope, dizziness) and/or have an SBP measurement of <100 mmHg at the follow-
up visit will additionally be evaluated for orthostatic hypotension and tachycardia. 
Study PIs will be notified, and will make a decision based on these criteria to either 
continue or discontinue the ARB at this time. These participants will be asked to 
come back within one week of their follow-up visit for an additional blood pressure 
check. (Intervention arm only). 
Step 5: Final Assessment 
All items from step 2 (Eligibility Screening), plus below items: 
RAs conduct final exit interview 
Study nurses conduct study exit plans / transfer of care 
Step 6: Post-Study Follow-up Visits (every 6 months for 12 months after Final 
Assessment - Participants in all study arms) 
RAs conduct follow-up interviews and perform pill counts. 
Study nurses collect blood samples and vital signs; track visits (dates, clinician type), 
diagnoses, prescription drugs (names, doses, pill counts of cardiovascular drugs), 
and medical events 
Study nurses record and reconcile medication lists at every visit, and note changes in 
medications.  
The 12-month post follow-up visit will follow the same protocol as Step 5. 
 
III. 
Subject Selection 
 
Eligibility: Eligible subjects will have incident or prevalent (i.e., first episode or chronic) 
cases of SMI. In this study we have defined SMI as schizophrenia, schizoaffective 
disorder, or bipolar disorder. The study’s definition of SMI also includes subjects with 
major depressive disorder, or psychosis NOS with some evidence of functional 
impairment (an inability to work or live independently and/or being on disability income). 
Note that the bipolar patients, and some unipolar depression patients, at our study site 
generally have severe disease and many are on chronic 2GA regimens. Also, many 
subjects with MDD at our study sites have psychotic features and require chronic 2GA 
treatment as well. Subjects must have received standing treatment with a 2GA anytime 
in the past 6 months, and receive their mental health care at one of 4 study sites: 
McLean Hospital, BayCove Gill Clinic, Mass Mental Health Center, Edinburg Center or 
Massachusetts General Hospital Outpatient Bipolar Clinic. We will not carry out 
diagnostic interviews and instead will include all patients with an eligible chart diagnosis, 
as indicated by subject’s psychiatrist, in order to maximize the representative nature of 
the sample and to more closely approximate how this intervention could be 
operationalized in real-world practices.  
 
Eligible subjects also must be stable with respect to their psychiatric conditions, e.g., 
prevalent cases have no psychiatric hospitalizations in the past 4 weeks. Because we 
are interested in a viable, real-world intervention, we will include subjects with existing 
relationships with other non-psychiatric clinicians and collect information on physicians 
seen before and after randomization; we will also include subjects who are already 


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receiving treatment for increased cardiovascular risk (i.e. subjects who are already 
prescribed either a statin or ARB drug). In this case, subjects will be given the remaining 
non-prescribed medication (e.g. subjects already receiving treatment with a statin will be 
prescribed losartan, and subjects receiving any anti-hypertensive treatment will be 
prescribed simvastatin). We will not alter the dosing of any previously prescribed 
medication, including any statin or anti-hypertensive medications. Subjects who are 
already receiving both medications, will be included in the non-randomized group.  We 
will include patients with state appointed legal guardians or health proxies with durable 
power of attorney who have the specific authority to make mental health care decisions 
or to consent to participate in research. Guardians or proxies will use substituted 
judgment when deciding to enroll the patient in this research study. State sponsored 
legal guardians are the preferred surrogate, however, we will accept health care proxies 
with durable power of attorney; no other form of surrogate will be accepted, participants 
with other forms of surrogates that are unable to provide consent on their own will be 
excluded. The relationship between the participant and surrogate will be recorded on 
the informed consent form that all parties have signed. We will include patients who 
cannot speak English. We will follow the PHRC policy on Obtaining and Documenting 
Informed Consent of Subjects who do not Speak English as found on the PHRC website 
at http://navigator.partners.org/ClinicalResearch/Non-English_Speaking_Subjects.pdf.  
An attempt to administer all aspects of the proposed research will be made through the 
use of an official translating service (i.e. electronic, phone, or in person translator). The 
consenting process for non-English speakers will always be done in the presence of an 
official hospital translator when using the short from consent procedure. Any measures 
that are invalidated by translation will be discarded during analysis. Since our primary 
measures are adherence, evidence through pill counts and improvement in metabolic 
risk factors, there is still value to the study and the subject to participation of non-
English speakers.  
 
Other inclusion criteria include the following: 
• Incident or prevalent cases of SMI: including schizophrenia, schizoaffective 
disorder, bipolar disorder, major depressive disorder, and psychosis NOS with 
some evidence of functional impairment.  
• Age 18 years and older. 
• Recent treatment with a 2GA, e.g., having received treatment with a standing 
2GA anytime in the past 6 months. Concomitant psychotropic medications will be 
allowed as there are no contraindications with this regimen. Ongoing treatment of 
their mental illnesses  at one of three mental health clinics: McLean Hospital 
(McLean outpatient clinicians), BayCove, Edinburg Center, and Mass Mental 
Health Center, defined as entering one of the treatment programs as a de novo 
patient (new disease) or having been diagnosed >2 years ago and had at least 
six visits in the past 12 months (prevalent disease). 
 
The exclusion criteria are as follows: 
• Unstable/active disease or potential contraindications, e.g., diabetes, unstable 
angina or recent acute coronary syndrome, pregnancy, very high risk factors on 
the screening labs (e.g., CPK>2*ULN, liver disease (AST> 2*ULN   ALT> 2*ULN) 


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; A1c>7%;), renal failure (creatinine ≥1.3mg/dL or GFR<60 mL/min/1.73m2), liver 
failure, or both statin and angiotension drug contraindications (when possible we 
will provide the study medication that does not interact with previously prescribed 
medications, i.e. subjects taking lithium  will only be prescribed simvastatin since 
anti-hypertensives are contraindicated with lithium). Participants whose screening 
labs indicate high cholesterol (LDL > 200 mg/dL), hypertension (SPB > 160 
mmHg), or hypotension (SBP< 120 mmHg)  will be included; however we will not 
prescribe both study medications; we will only provide the study medication that 
can be taken safely. For example, a participant with high cholesterol will be 
referred to their PCP for care and administration of a statin, but could still receive 
losartan in the treatment arm.  
• Unable to provide informed consent, e.g., has dementia, developmental 
disability, other cognitive disorder, or fails screening mini-mental status exam. 
• Women who are pregnant or breastfeeding  
 
Subjects that sign consent and but are excluded during the eligibility screening may 
continue in the study in the Non-Randomized Arm if they choose. The above criteria 
indicate exclusion from the randomized arms of the study. Participants who meet 
exclusionary criteria (i.e. receiving medications from both of the study medications 
classes, incidence cases of diabetes, or elevated lab values) will be included in the non-
randomized arm and followed in a similar fashion to the Usual Treatment Group. 
Participants who would like to participate in this group and have already signed consent 
will be asked to sign the new consent form that reflects these procedures. 
 
IV. 
Subject Enrollment 
 
Recruitment: On recruitment days, the study nurse and research assistants (RA) will 
work with clinicians to identify potential study subjects among the patients scheduled for 
the day. Clinicians will identify people potentially eligible for participation. Once 
someone has consented to participate in the study and signed a DMH authorization 
form, if applicable, and potentially signed the APCD authorization, the study RA and NP 
may access medical records to verify study eligibility. Study staff will regularly check 
medical records for the duration of the study period (approximately once every 3-
months). Consent will always be obtained, and the consent form signed, by a licensed 
physician investigator or by an APRN/NP listed on the protocol. In the event that the 
APRN/NP is not present when a potential participant wants to sign the consent form, the 
NP will be telephoned so that any questions can be answered prior to the subject 
signing the consent. The participant will sign the consent form, the RA will initial next to 
the signature, and then the APRN/NP will then sign the consent form at the first study 
visit in the presence of the subject. This will provide an additional opportunity for the 
subject to speak with one of the prescribing clinicians before both parties have signed 
the form ad study procedures begin. We will also recruit patients through the Partners 
Online Research Portal (clinicaltrials.partners.org). These advertisements will be 
approved by the Partners IRB. In addition, we will use the Research Patient Data 
Registry (RPDR) to screen and recruit potential study participants receiving care at our 
Partners study sites, McLean Hospital and the Massachusetts General Hospital 


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Outpatient Bipolar Clinic. After running data queries using the study’s inclusion and 
exclusion criteria, we will request detailed data through RPDR in order to directly 
contact those patients who are eligible for the study and who have consented to be 
contacted in future for research purposes. Detailed data requests, including identifying 
information such as medical information and contact information, will be approved by 
the Partners IRB.  
 
Random (1:1) allocation: We will assess eligibility, NP’s will conduct the informed 
consent process, then randomize eligible subjects to one of two arms: 1) fixed-dose 
statin and/or ARB; or 2) usual treatment with greater monitoring. In both arms, the 
patient’s clinical care remains within the original mental health clinics. We will use a 
computerized random number generator. Participants unable to be randomized due to 
eligibility issues discovered at the first study visit will still be followed as not-randomized 
subjects. 
 
Randomization scheme: We will start with a concealed, simple subject-level 
randomization scheme, e.g., web or telephone delivered random sequence.[104-106] We 
also will consider concealed, block randomization schemes, e.g., accounting for clinic 
and time with randomly varied block sizes. An investigator not involved in the arm 
assignment or clinical care of subjects will perform the generation and allocation 
concealment. 
 
Intervention: The multi-component intervention exploits a number of strategies from 
incentive theory and behavioral economics, including: a) a simplified drug regimen; b) 
free treatments; c); framing of goals and goal setting; and d) focus on immediate 
cardiovascular risks within a larger plan for risk reduction.[107-114] 
 
Control: We will compare the initial treatment intervention with usual treatment (control 
arm), with both arms superimposed on a system of regular monitoring base. The 
RA/APRN pair will make no effort to alter or influence treatment or use of that treatment 
for subjects in the control arm. Note that our goal in the Control arm is to characterize 
“usual treatment”. We will not intervene in this care except in emergencies requiring us 
to notify the patient’s treatment team. Some patients who need care for metabolic 
syndrome may not be receiving it – just as they would if not in our trial. 
 
Follow-up: Up to 24 months. We will censor subjects (from the intervention) who receive 
a diagnosis of diabetes, when they develop a cardiovascular or cerebrovascular event, 
who die, or who leave the study health care systems. During each follow-up visit, the 
study nurse will review all prescription drugs and the RA will perform pill counts of 
cardiovascular drugs (we will ask subjects to bring all of their drugs in to each study 
visit). The study nurse will perform safety checks comparable to that during baseline 
evaluation. For subjects in either arm identified during our safety checks or who have 
events, we will recommend that they receive more intensive care from primary care 
physicians, cardiologists, or endocrinologists, and will message their clinicians. We will 
continue to monitor these subjects throughout the follow-up period albeit now on a more 
intensive treatment regimen. 


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At the end of the study, we will characterize the clinical care for subjects in both 
study arms, thus providing a detailed description of “usual treatment,” and information 
about care received from other clinicians for subjects in the intervention arm. We will 
report on all clinicians seen (specialty, location, visit frequency and timing), conditions 
diagnosed and treated (psychiatric and medical), and cardiovascular conditions 
diagnosed and treated (major events such as ED visits or hospitalizations, diagnoses, 
drugs, doses). We will compile adverse events using the CATIE adverse event reporting 
tool as a base.[115] 
Subjects will have the option to continue coming to follow-up visits after the 12-
month endpoint every 6 months for another 12 months. We will not continue to 
prescribe medicine to subjects in the intervention arm, rather we would continue to 
collect data so we can get a longer-term picture of “usual treatment” for those in each 
study arm (including non-randomized). RAs will perform pill counts at these additional 
follow-up visits, to get information about medication adherence for an additional year. 
NPs will continue to draw blood and ask subjects about their medications and medical 
history. Participants who have already signed consent and would like to participate in 
the post-study year of follow-up visits, will be asked to the new consent form prior to 
starting study procedures. 
 
Endpoints: The two main study endpoints at 12 months correspond to the study aims: 
A) cardiovascular prevention treatment including patient adherence to treatment; and B) 
individual and composite cardiovascular risk factors, e.g., modified Framingham risk 
scores that includes lipid profiles and blood pressures.  
If subjects continue to be followed for an additional year, we will address the same 
study aims after the randomization portion of the study is over. This will be useful to 
understand what happens to participants after being a part of the study in terms of their 
treatment and medication adherence.  
 
Compensation: Subjects will be compensated by check in 2-3 weeks from their study 
visit. They will receive $20 per study visit for Visits 3-5, and $50 each for the first, 
second, and both post-study follow-up visits. Participants will receive $100 for the final 
study visit at 12-months from study enrolment. Subjects randomized into the 
intervention arm will receive an additional $10 for the safety check blood draw. All 
additional safety check blood draws will also be compensated at $10 per additional 
draw. The total expected compensation amount for the first 12-months is $270 
(intervention group). Subjects that participate in the post-study follow-up visits will 
receive $50 for each 6-month follow-up visit for an addition $100. The total expected 
compensation for a subject who completes the study and post-study follow-ups is $370. 
Compensation will come in the form of a check, which takes two weeks to process and 
will then be mailed to participants, or brought to the next study visit.  
 
Visit 
Payment 
Baseline Visit 
$50.00 
Medication Visit 
$50.00 
Safety Check (Intervention Group) 
$10.00 


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Follow-Up #1 
$20.00 
Follow-Up #2 
$20.00 
Follow-Up #3 
$20.00 
Final Visit  
$100.00 
Post-Study Follow-Up 
$50.00 
Post-Study Final Visit 
$50.00 
Any additional visit safety-check  
$10.00 
 
There is also a bonus system for follow-up visits that may earn participants up to $420 (Usual 
Treatment Group) or $430 (Intervention Group). 
 
In order to receive a bonus, Follow-Up #2 and Follow-Up #3 need to be scheduled and attended 
within one month after the end of the scheduling window in order to receive the bonus. If the 
participant completes the visit outside of the scheduling window, they will still get paid the 
baseline payment of $20.00. The scheduling window refers to the two-week window within 
which a visit is due, which is 83 days from the prior visit. A member of the study team will 
contact participants to let them know when visits are due.  
 
• If a participant completes Follow-Up #1, then staff will compensate $40.00 for Follow-
Up #2. 
• If a participant completes Follow-Up #1 and Follow-Up #2, then staff will compensate 
$60.00 for Follow-Up #3. 
• If a participant completes Follow-Up #1 or Follow-Up #2 (but not both visits), then 
compensation for Follow-Up #3 will be $40.00 
 
V. 
Study Procedures 
 
Study Site: The study will take place at four sites: McLean Hospital, BayCove Gill Clinic, 
Mass Mental Health Center, Edinburg Center, and Massachusetts General Hospital 
Outpatient Bipolar Clinic. Study procedures will be the same at each site. Study staff will 
bring all study equipment, including study drugs, with them to the separate sites and 
carry out all study procedures, leaving no burden on staff from these sites. 
Contacting patient’s current treater: The only information to be shared with the PCP is 
the “PCP letter” (included in the IRB application). This letter will be sent out between the 
inclusion/exclusion visit, only for patients eligible to be randomized, and the 
randomization visit, when we find out what arm of the study the patient is going into. 
Since this letter is sent prior to randomization, the letter does not include information on 
what study arm the patient is assigned to. The letter states that the participant will be 
explicitly removed from the study if requested by the PCP for medical purposes. The 
logic of this design is as follows: ours is a randomized open-label study.  The treatment 
as usual arm is intended to capture naturalistic primary care of our patients while the 
intervention arm tests the impact of a cardiovascular preventive regimen.  In these trials, 
"contamination" across study arms is a major concern.  This refers to a process 


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whereby the usual clinical care is enhanced due to awareness of the study 
aims.  Clinicians who are aware that their patients' care is being evaluated on certain 
criteria may consciously or unconsciously pay more attention to these criteria.  This 
effect typically makes the treatment as usual arm appear more robust and reduces the 
odds of detecting an intervention effect. Our goal is to avoid this contamination effect 
while also ensuring that PCPs are adequately informed and have an opportunity to 
intervene if they deem it necessary. As per our study design, there is no ongoing 
communication with the PCP. By sending them a letter before study arm assignment, 
we ensure that the PCP can request the patient be excluded. As the individual 
responsible for the overall medical care of the participant, the PCP has the power to 
veto patient participation in this study. The PI’s name and contact information on this 
study will be included in the PCP letter so that the PCP may contact the PI with study 
design questions. If the PCP desires to know whether the patient is going on the 
medication arm they then have to go through routine channels (e.g. ask the patient) to 
obtain this information.  If the PCP contacts the research team asking for this 
information, we will provide it.  But this approach minimizes "contamination" from the 
study team, and approximates routine clinical care if the patient were placed on a 
medication by another clinician. To further minimize contamination we will not 
communicate routine lab results to the PCP. However if in the course of the study, 
should lab results require immediate attention, study nurses will triage and contact 
subject PCP accordingly.  
 
We will send another letter at study completion informing the participant’s PCP of the 
treatment the participant received as a part of their study.  
 
Anytime staff attempts to contact a participant’s PCP or any other provider, staff will 
confirm the contact information with the participant prior to attempting communication. 
This will be done to ensure that the participant still receives care from the indicated 
provider, as participants occasionally change clinics over the course of the study period.  
Data Collection: During Recruitment (Step 1 in T1), all participants, or their legal 
surrogates, will complete a Consent Survey that asks 11 simple questions about the 
study such as “What is being studied in this study?” and “Will you lose any of your 
services or benefits if you refuse to participate?” For participants, or 
guardians/healthcare proxies who do not answer correctly, the study nurse or RA will 
repeat the information and re-administer the survey. Participants who still cannot 
complete the survey correctly will be excluded. Participants, or their guardians/proxies, 
do not need to answer each question exactly as indicated, but rather demonstrate 
understanding of the correct answer (e.g. participant does not need to provide the 
names of every illness studied in the research project, but can simply name one or say 
“psychotic disorders”). The participant’s legal surrogate or proxy will make decisions 
using “substituted judgment,” meaning that the surrogate must consider the subject’s 
own views when consenting to this study. The relationship between the guardian or 
proxy and participant will be recorded on the informed consent form.  Participants with 
legal guardians must still assent to the study verbally and through signing the consent 
form. Participant assent will be gauged at every study visit, informed consent being 


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acquired if and when a participant regains legal power of consent. The study visits will 
consist of 30-minute interviews with the study nurse, followed by 30-60 minute 
interviews with the RA. The study nurse will collect vital signs, blood samples, and 
prescribe the fixed-dose study medications for the intervention group. The nurse will 
also collect information on side effects/adverse events on medication, medication 
changes, information on ED visits/hospitalizations/PCP or other clinician visits/any other 
service utilization for medical/psychiatric purposes. The medication adherence 
assessment will include: self-report, RA pill counts, review of medical records, and 
independently collected pharmacy data (e.g., APCD) to examine drug dispensing. We 
will calculate chlorpromazine (CPZ) equivalents for standardized 2GA dose estimates.  
In the RA portion of the visit, we will collect ancillary clinical data using standardized 
forms. Examples of potential items include age, gender, living condition, employment 
status, internet access, cancer screening history, socioeconomic status (using the 
Hollingshead scale), social support (using the Duke social support and stress scale), 
food and diet questionnaires, non-cardiovascular medical conditions, cardiovascular 
disease risk (using the Global CVD risk assessment), estimated IQ (using the North 
American Adult Reading Test), smoking status (using the Elyse Tobacco Questionnaire 
and the Fagerstrom Test for Nicotine Dependence), and clinical insight (using the Scale 
for Unawareness of Mental Disorder, SUMD). RAs will assess cognition using the BACS 
(Brief assessment of cognition in schizophrenia). In addition, the RA will complete the 
WHODAS 2.0 (WHO Disability Assessment Schedule) which assesses cognition, 
mobility, self-care, social interactions, and life activities (work, school etc.).[116-119] 
Subjects will also be assessed on their medication attitude and adherence (using the 
Drug Attitude Inventory, the Voils medication adherence scale, and the Physician Trust 
Scale). We will refine the standardized data collection; assess feasibility, interpretability, 
and respondent burden; insure that the final instruments are feasible within the 30-
minute interview; and insure that our instruments are consistent with current literature 
and latest expert opinion.  
At baseline and all subsequent visits, the RAs will quantify psychiatric symptoms; we 
will train and periodically test RAs ability to do this. Since the SMI participants will be 
mixed diagnostically, the RA will complete symptom assessments; examples include the 
Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Positive 
Symptoms (SAPS), and Scale for Assessment of Negative Symptoms (SANS) for 
psychosis but also the Montgomery-Asberg Depression Rating Scale (MADRS)[120] 
Young Mania Rating Scale (YMRS),[121]  Multnomah Community Assessment Scale 
(MCAS), Fagerstrom Test for Nicotine Dependence, International Physical Activity 
Questionnaire (IPAQ), and finally a Clinical Global Impression (CGI) scale.[122, 123] All 
instruments and questionnaires will be administered via Partners RedCap. 
After each visit, the RA will also extract data from the patient’s mental health clinic chart 
for information related to diagnostic changes, clinical developments, medication 
prescription, and any healthcare utilization. 
 
The study nurse also will collect basic vital signs, e.g., EKG, weights, height (BMI, waist 
circumference), blood pressures and heart rate, and collect blood samples for 
laboratory tests, e.g., lipid panels, HbA1cs. As part of the baseline safety evaluation, we 
will collect additional laboratory test values, e.g., liver function tests. The study nurse 


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will receive laboratory values and provide appropriate follow up, which includes 
reporting any critical values to patient and care providers, referring for further treatment 
as indicated and documenting exclusion based on criteria listed in the protocol. The 
supervising physician of record for APRNs will be Dr. Dost Ongur. 
 
Obtaining Study Drugs: Study nurse practitioners will prescribe study medication for 
subjects as follows: simvastatin 20 mg once per day, and/or losartan 25mg once per 
day or atorvastatin 10mg once per day and/or valsartan 40 mg once per day. The grant 
will pay for study medications at no cost to participants. The McLean Hospital Research 
pharmacy will procure the study medication for all study sites and dispense 
prescriptions in 3 month supplies.  The study staff will pick up prescriptions from the 
pharmacy and provide to the subject during the study visit. Since the medications will be 
provided the same day, investigators will not store medications in any way, other than to 
transport the mediations to the various study sites. Study staff will follow the same 
procedures for procuring and dispensing medications at all external sites. That is, study 
staff will procure medications from The McLean Hospital Research pharmacy the 
morning of external site visits and transport the medications to dispense at each site.   
 
Additional Data Sources: There are other noteworthy data sources for this trial: 1) clinic 
records; 2) electronic health records for two clinics; 3) APCD. RAs will systematically 
review the visit schedules and local medical records from each clinic for each subject. 
Additionally, McLean is scheduled to roll out its electronic health record (Epic Systems) 
during the course of this study, which we have extensive experience using in other 
settings.[131-134] These data sources will provide complementary data sources for cross-
validation (e.g., pharmacy fills, see quality checks below) as well as longitudinal 
information on psychiatric visit adherence, primary care visit frequency, and major 
unfavorable clinical events, e.g., ED visits and hospitalizations for psychiatric or 
cardiovascular events.  
The study staff will request that participants agree to have All Payers Claim Database 
(APCD) queried by study staff such that they may access all insurance claims made on 
behalf of the participant. The APCD is an excellent source of ancillary information to 
reconcile all patient report and medical record information. Participants will not be 
required to agree to have the APCD accessed in order to participate. There is a detailed 
data management plan that details how all data will be kept and how participant 
information with remain private. For secure data transmissions, we use a secure FTP, 
which is available through Partners Research Computing (RC). We then keep the data 
on our dedicated servers managed by RC, which are behind the Partners firewall. We 
limit data access such that only the programmer/analysts working on the project can 
access the data; the data remain on the servers at all time; and at no time, do any of the 
data leave the servers (e.g., no data on laptops, desktops, or other devices). 
Blood Pressure Checks: Participants prescribed the ARB who exhibit symptoms of 
hypotension (e.g., syncope, dizziness) and/or have an SBP measurement of <100 
mmHg at the follow-up visit will additionally be evaluated for orthostatic hypotension and 


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tachycardia. These participants will be asked to come back within one week for an 
additional blood pressure check and study PIs will be notified.  
Subjects who exhibit a combination of any 2 of the 3 criteria (self-reported/observed 
symptoms, SBP <100 mmHg, or abnormal orthostatic measures) or all 3 criteria will be 
discontinued from the ARB for at least one week before coming back in for the 
additional safety follow-up. Study nurses will assess whether the signs/symptoms are 
still present, or have been alleviated after discontinuing the study drug. Study PIs will be 
contacted to make the decision to continue/discontinue the study drug.  
If a participant exhibits only one of the three criteria at a routine follow-up visit (i.e. just 
self-report symptoms), we will not discontinue the ARB before the safety follow-up. If the 
subject continues to meet one of the three criteria at the safety follow-up, subjects will 
be asked to stop the ARB for at least one week, then come back in for reassessment.  
Depending on the nature of the symptoms, vitals, and blood pressure levels at this 
safety follow-up, study nurses will decide whether these symptoms are related to the 
ARB versus dehydration, other drug use, or other unrelated factors. Study PIs will be 
contacted and ultimately make the decision to either continue or discontinue the ARB. If 
the subject self-reports the above symptoms at the visit and they appear to be unrelated 
to any other physical signs at the safety visit, then study PIs/physicians will consider 
continuing the study drug and reassessing in a week versus stopping for one week and 
reassessing.  
Once study PIs have come to a decision about continuing/discontinuing the ARB, all 
subjects will be asked to come back for an additional safety assessment one week after 
the decision to confirm that they are safe to continue the course of action recommended 
by our team.    
 
Training/Skills Assessments: We have systematic RA and APRN research training 
programs in place: 
Training: Dr. Öngür’s division has an extensive RA training program directed by Ann 
Shinn, MD, which has sessions on participant recruitment, informed consent, chart 
review and discussion of symptom scales. Dr. Shinn first conducts live patient 
interviews watched by RAs, and then the RAs conduct interviews observed by Dr. 
Shinn. In all cases, trainees complete symptom scale forms; we have excellent inter-
rater reliability for symptom scales (0.8-0.9). At the end of training Dr. Shinn certifies 
RAs as competent to carry out these assessments. RAs also will receive similar training 
to perform their chart reviews. The APRNs will be certified by the Hospital as able to 
carry out safety checks, vital signs, and blood draws, as well as prescribe medications 
in the state of Massachusetts as part their job duties. The APRNs will join the RA 
training described above for the participant recruitment and informed consent portion. 
Whenever possible we will use standardized processes and forms, e.g., standardized 
study laboratory order forms. 
 
Data Entry: We will use several strategies to augment and evaluate the quality of data 
entry: 1) standardized forms, e.g., for laboratory test orders, subject interviews, and 


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medical record data abstraction; 2) structured data entry through a secure, server-
based database system, e.g., MS Access; 3) double entry of standardized forms with 
routine error checks, e.g., every third subject; and 4) automated checks for value 
changes across observation points, e.g., sudden increase or decrease in symptom 
levels – flag values for additional review. 
 
Additional Quality Checks: We also will perform complementary quality checks: 1) 
routine checks for missing values; 2) cross-validation of data (e.g., psychiatric symptom 
levels) by comparing study data vs. medical record information for a random sample of 
subjects; 3) cross-validation of adherence data: (a) self-report vs. (b) RA pill counts vs. 
(c) medical record (plus EHR/LMR for the two Partners clinics) vs. (d) APCD pharmacy 
records (both study arms – includes capture of any drugs prescribed by non-
psychiatrists and/or dispensed by pharmacies);[135-137] and 4) periodic trend checks to 
identify and confirm large changes in any outcome or covariate values. During follow-
up, we will ask any subjects who forget to bring their drugs to a visit for the pill count to 
bring their drugs in to their next clinical appointment for a “catch up” pill count. We will 
use a standardized process for addressing imputation of missing values or reconciliation 
of different values. 
 
VI. 
Biostatistical Analysis 
 
Analysis of Aim 1: Treatment: By design, all subjects in the Intervention arm will start by 
being under treatment. During the course of follow-up (FU), we expect that some will 
stay consistently on treatment, some will discontinue treatment (become non-adherent), 
while others will make transitions on and off treatment in various patterns (e.g., 
subsequent modifications made by any PCP and/or changes in adherence over time). In 
contrast, by design, subjects in the Usual Treatment (control) arm do not start on 
treatment; however, some will initiate treatment as a result of usual clinical care, e.g., 
PCP initiation. For this aim, in which we study treatment use at various time points, only 
an intent-to-treat (ITT) approach is relevant since whether or not subjects are on 
treatment is the outcome itself. 
Characterization of Usual Treatment: We also will carefully describe care under Usual 
Treatment, including the timing of initiation, treatment choice, adherence, prescribing 
clinicians, and visit patterns for subjects in the control arm. We will characterize the 
involvement of other clinicians for subjects in both arms, and clinic traits.  
Treatment Operational Definition: To start, we will use the same treatment definition for 
both study arms, i.e., current use of a statin and angiotensin drug. Because there are 
multiple potential drugs for cardiovascular prevention, we will alter this definition in a 
series of sensitivity analyses. For example, we will examine a minimal cardiovascular 
treatment variable in which we define treatment as current use of any cardiovascular 
drug, independent of the therapeutic class or mechanism of action. We also will 
examine a partial treatment variable in which we count the number of distinct 
cardiovascular prevention drugs.  
Analysis approach 1: We will plot the percent on “adequate” CVD prevention care, at 
baseline and the four quarterly follow up times to monitor how treatment activity unfolds 
over time in the two arms of the trial. At any given follow-up point we will be comparing 


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two binary outcomes (on or off treatment) and will use standard methods for comparing 
two proportions to test statistical significance and get confidence intervals for the 
difference in the percent on treatment in the two arms. We will use a Bonferroni 
correction so the four separate tests or CIs will have an overall level of 0.05 or 95% CI, 
respectively.     
Analysis approach 2: We will use all available follow-up data to construct a summary 
measure of the mean percentage of follow-up time during which each group was on 
treatment. Since we expect the distribution of outcomes to be non-normally distributed, 
we will get a test of significance for no difference between the mean outcomes in the 
two arms using a randomization test.  A 95% confidence interval for the difference of 
percentage of time on Tx will be obtained using bootstrap methods. We will use STATA 
13.0 for all analyses.  
Analysis of Aim 2: ITT Effect on Cardiovascular Risk Factors: For aim 2, our primary 
outcome is the difference in summary risk level changes (e.g., modified Framingham 
score) between our two study groups, i.e., do intervention subjects experience 
differential changes in cardiovascular risk levels compared to control subjects. This 
outcome will be continuously measured (but not necessarily normally distributed).[138-140] 
We will also examine individual risk factor levels, including LDL, SBP, and HbA1c. By 
virtue of randomization and given the size of our study, the mean baseline values will be 
very close to equal, with the profile of the mean levels of the outcomes diverging over 
time. Our main analytic strategy is to use an ITT analysis, such that subjects provide 
data for the group to which they were randomized regardless of protocol adherence.  
Initially, we will get descriptive plots showing the profile of mean outcome over time in 
each group. This plot will be suspect if missing data (e.g., loss to follow-up) do not occur 
completely at random (MCAR). For more definitive analysis, we will use methods for 
analysis of repeated measures data that provide valid estimates of the profiles of mean 
outcomes over time under the weaker, missing at random (MAR) assumption that 
allows the probability of missing data to depend on measured characteristics. We also 
expect that the outcomes will be non-normally distributed based on our past experience 
in studying adherence. This likely bimodal adherence distribution could induce a 
corresponding bimodal distribution in the changes in outcome levels. All of the 
outcomes are likely to show this sort of non-normality. The HbA1c data also could be 
skewed. In general, we will therefore use analysis methods that are robust to non-
normality.   
For analysis of the repeated outcomes data, we will use econometric-style OLS linear 
model analysis of the repeated mean levels of the outcome over the five observation 
times (baseline + four follow-up times). This approach is robust to non-normal 
distributions. For constructing standard errors we will use cluster and heterogeneity 
robust estimation methods. Among estimation methods for this model, we will 
emphasize the use of the “fixed effects” (FE) option, which can be implemented in 
STATA using the xtreg command with the FE option. This essentially amounts to 
change score analysis that is generalized for use in situations with more than two 
repeated measures. This will provide estimates of the profiles of mean change from 
baseline in each of the treatment arms along with significance tests for contrasts 
between the two profiles. For plotting, the profiles of change will be anchored at the 
observed mean values in each arm at baseline. Inverse Probability (IP) weighting 


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methods will be used to account for possible endogenous loss to follow up in connection 
with the proposed analysis. Weighting will be based on baseline characteristics and for 
any given subject; the same weights will be applied to each repeated measure. We will 
finalize our analytic protocol before examining the outcome data, i.e., a priori delineation 
of the analytic protocol as is becoming the standard of analysis. We will use only 
marginal distributions to guide the appropriateness of the final choice of methods. Thus, 
we mitigate the potential for bias resulting from post-hoc choice of analysis or 
significance testing.  
 
Analysis of Aim 3: Per-Protocol Effect on Cardiovascular Risk Factors: For Aim 3, we 
will study the same composite and individual risk factor outcomes as for Aim 2, but will 
estimate the per-protocol effect rather than the ITT effect. ITT is the effect of 
assignment to the strategies of interest; the per-protocol effect is the effect of following 
the strategies as indicated in the protocol and is the implicit target of inference. To 
estimate the per-protocol effect, however, one needs to make assumptions similar to 
those commonly made in the analysis of observational studies. Specifically, when 
adjusting for measured covariates, the valid estimation of the per-protocol effect 
requires that all fixed and time-varying factors that jointly predict the outcome and 
adherence to the assigned intervention are measured without error. We will adopt two 
analytic approaches, both involving adjustment via inverse probability (IP) weighting.  
Analysis approach 1: We will artificially censor participants when they stop adhering to 
the assigned strategy. We will censor subjects in the active treatment arm if/when their 
adherence drops below 80% of the intended dose, based on estimates of the proportion 
of days covered (PDC).[141-144] In sensitivity analyses, other adherence cutoff points will 
be used, as in our other past studies.[145] For subjects in the control arm, we will follow 
two censoring strategies: (i) subjects will be censored if/when they start taking one of 
the drugs assigned to the active treatment arm, (ii) subjects will never be censored, 
which is equivalent to interpreting any treatment they receive as standard of care. We 
will conduct separate analyses under each of these two censoring strategies. We will 
compare the average outcome between arms at pre-specified time points during the 
follow-up. The outcome models will be similar to those described for Aim 2, but they will 
be fit to those remaining uncensored at the corresponding time. This approach requires 
no assumptions about the dose-response curve for adherence because only adherent 
subjects contribute to the fit of the outcome model. 
Analysis approach 2: We will estimate the parameters of structural models that specify 
the dose-response curve for adherence in the treatment arm. We will use a flexible 
dose-response function that incorporates information on both cumulative dose and 
recency, and builds on previous trial data. This analytic approach is more statistically 
efficient because it does not involve artificial censoring, but will require extensive 
sensitivity analyses to ensure that the estimates are not sensitive to the choice of dose-
response function.  
 
Power Calculations: We anticipate having adequate power for this trial. To illustrate, we 
will focus on comparison of treatment use at one time point. By design, all subjects in 
the intervention arm will receive cardiovascular prevention treatment, while none in the 
control arm (usual treatment) will have started treatment. At each follow-up time point, 


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some intervention subjects could be non-adherent (no use), and some control subjects 
could have started treatment (use). We will test the significance of (with confidence 
intervals) the difference in the percent on treatment between the two study arms at each 
time point separately, using Bonferroni multiple comparison methods (exam-specific 
alpha=0.05/4 to get an overall test with alpha=0.05). Based on the literature, <15% of 
control subjects might initiate treatment. With one-sided alpha =0.0125 and 150 
subjects in each comparison group (classifying subjects lost to follow-up as not on care 
so that sample size is constant), we estimate having 80% power to detect a 26% 
difference in use, and 90% power to detect a 20% in cardiovascular treatment use. We 
also have adequate power (90%) to detect clinically sensible cardiovascular risk 
changes (e.g., one standard deviation change in LDL levels in the absence of 
treatment), using modified two-sample normal theory and comparable assumptions 
(details available on request). 
 
VII. 
Risks and Discomforts 
 
The core of the intervention involves the administration of new medications, albeit 
medications that are already recommended by the guidelines, i.e. the trial will assess a 
population-based approach to provide patients with recommended guidelines, 
compared with usual practice.  We have selected the population-based approach of 
using the same fixed moderate dose intervention for all eligible subjects randomized to 
the intervention arm.  This ensures that any complications and adverse events are 
minimized.  Nonetheless, any treatment intervention is associated with certain potential 
adverse events.  In this study, we consider 2 categories of concerns: inadvertent 
disclosure of confidential information, and medication associated side effects. 
 
Disclosure of confidential information: 
One potential risk is a breach of the subjects’ confidentiality.  This could lead to their 
employer, insurance company, or others finding out that the subject participated in a 
research study. We minimize this risk by assigning each participant with a subject code 
to ensure that any protected health information is stored separately from clinical and 
diagnostic information. Study data to be analyzed will be stored on password-protected 
computers or else in locked filing cabinets in locked offices. Participants are informed of 
these potential risks in the consent form. Names of subjects will not be used in any 
publication of research results.  Thus the identities of individual participants will be 
known only to the research team.  
 
Medication associated side effects: 
 
Common side effects for simvastatin include headache, abdominal pain, constipation, 
nausea, and upper respiratory infection. There is an increased risk of skeletal muscle 
effects (e.g. myopathy and rhabdomyolysis) with doses 80mg or higher.  
 
Common side effects for losartan are diarrhea, muscle cramps, insomnia, nasal 
congestion, dizziness, low blood pressure, and syncope (fainting). 
 


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Common side effects for atorvastatin include diarrhea, insomnia, nausea, and upper 
respiratory infection (common cold). There is an increased risk of skeletal muscle 
effects (myopathy and rhabdomyolysis) with higher doses. Patients might experience 
pains or stiffness in the arms and legs if that happens. In addition, there is also an 
increased risk of stroke or transient ischemic attack at doses of 80mg.   
 
Common side effects for valsartan are diarrhea, joint or back pain, insomnia, fatigue, 
dizziness, low blood pressure, and syncope (fainting). 
 
Since we are using low to moderate doses of these generic medications and they have 
had few complications with large amounts of trial and post-marketing data, we expect 
any adverse effect to be rare and low intensity.  Nonetheless, we will handle adverse 
events as follows: 
Any adverse events due to any cause that occurs during the course of this trial, whether 
or not related to the study medication, will be reported to the Partners IRB, the NIMH, 
and the FDA in a written report including demographic information and a narrative 
explanation of the event. The study nurses will inform the study PIs, who will then 
determine whether to discontinue the medications; this determination could involve 
members of the DSMB.  For example, if a subject reports mild self-resolving fatigue that 
does not appear to be temporally associated with the study medications, we would 
record the event for the appropriate reports but could determine that the event was 
unlikely to a) be related to the medication; b) pose a clinically meaningful risk to the 
subject.  In contract, should a subject report difficulty breathing and the nurse reports 
signs of edema, we would immediately stop the medication and make sure the subject 
receives immediate, appropriate treatment. 
 
Several alternative medication treatments exist for reducing cardiovascular risks. 
Participants will be made aware of these alternative treatment options as well as the 
potential side effects of the study medications in the informed consent document to 
allow them to make an informed decision about whether to enroll in this study. 
 
Psychiatric Evaluation: 
Some participants might feel uncomfortable answering questions during the psychiatric 
evaluation. They will not be forced to answer if they do not wish to answer any particular 
question. 
 
Blood Draws: 
Blood draw may lead to a small arm bruise and, in rare cases, clot or infection at the 
site the blood was drawn. Some people become light-headed during or immediately 
after a blood draw.  These are rare occurrences and in our experience the vast majority 
of participants tolerate blood draws well.  Participants will be monitored for 15 minutes 
following the blood draws to ensure they are doing well. 
 
VIII. 
Potential Benefits 
 


Version date: 10/02/2017  Page:  22 
It is hoped that results from this study can be used to implement cardiovascular care 
within mental health clinics.  Since cardiovascular disorders are a main source of 
morbidity and mortality for SMI patients, such an intervention may constitute a major 
improvement in the health of this population.  A fixed-dose combination of pills could 
serve as a useful tool for minimizing non-adherence to treatment.[57-61] Use of moderate 
doses also yields clinical benefits with fewer side effects and complications.[62-64] The 
intervention also could serve as a prevention strategy in behavioral health homes, an 
emerging new approach to unified care for patients with SMI.  
 
IX. 
Monitoring and QA 
 
We will capture all psychiatric and medical diagnoses and prescription drugs. We will 
identify and intervene on any subject who demonstrates unstable psychiatric or medical 
disease. Potential intervention triggers include finger stick glucose (FSG) levels > 200, 
QTc>500ms on ECG, or signs of diabetes, renal, or liver failure based on laboratory 
results. Note that the intervention focuses on cardiovascular prevention, and does not 
attempt to treat diabetes (though cardiovascular complications are a paramount clinical 
concern for diabetics); we do not believe that a fixed-dose approach is clinically 
appropriate for diabetes treatment. Other triggers include symptoms consistent with 
unstable angina, suicidal/homicidal ideation, or other unstable clinical situation in the 
judgment of the study staff. In these cases the PI will be notified by pager, and will 
authorize contact with the patient’s psychiatrist and PCP; and in extreme cases, the PI 
may refer the patient to the emergency department (ED) for immediate evaluation. For 
subjects without a PCP, but not requiring emergency attention, we will refer the subject 
to a medical clinic suggested by the mental health staff at the study site. For these 
events occurring during screening, we will exclude subjects from the trial; for events 
occurring during the trial, we will report the event to the DSMB. 
 
We will constitute an independent DSMB with a statistician, psychiatrist, cardiologist, 
and endocrinologist. The board will meet every six months and/or after enrollment of 
every 50 subjects, will be available for more frequent consultation as needed, and will 
review the preliminary data on efficacy and safety issues such as major clinical events, 
unstable disease, and drop-outs, as well as assess trial data quality. Prior to trial start, 
the DSMB will develop a review protocol and outcomes/thresholds for stopping the trial. 
We also will register the trial on clinicaltrials.gov and apply for the Investigational New 
Drug (IND) application 
 
 
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SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
NCT02188121 
Protocol Title: Clinical trial to reduce cardiovascular health risks in 
patients with serious mental illness 
Statistical Analysis Plan Date: 02/10/2018 
 


Background: This trial focuses on SMI patients who are potentially eligible for cardiovascular prevention 
therapy (through statin and angiotensin medications such as angiotensin receptor blockers or ARBs) but 
who have not yet received it. The trial compares a prevention strategy intervention with usual care with 
respect to use of therapy. The trial includes those on partial therapy and excludes those with detected 
cardiovascular disease or diabetes, and assesses whether the intervention increases cardiovascular 
prevention use relative to usual care. 
  
Eligibility summary: Eligibility criteria include a diagnosis of schizophrenia, schizoaffective disorder, or 
bipolar disorder; second generation antipsychotic (2GA) therapy within the past six months before trial 
entry; and mental health care at one of the study sites at the time of trial entry. We exclude subjects who 
already have a diagnosis of diabetes or cardiovascular disease; who already are receiving therapy with 
both statins and angiotensin medications (i.e., the same therapeutic drug classes as used in the 
intervention); or who have contraindications to both drug classes.  
 
Primary study outcome: The main outcome is use of the cardiovascular prevention medications over the 
12-months after study initiation. For each individual, we define the primary outcome as the proportion of 
the 12 follow-up months during which she/he either received any of the prescribed medication or the 
medication became clinically contraindicated after trial entry (as decided by the treating physician).  We 
will assess the outcome using medication counts at each study visit (i.e., at the 3-, 6-, 9-, and 12-month 
study visit), supplemented by subject self-reports and the clinic chart review. For subjects who are 
eligible to receive both statins and ARB medications at baseline, we will calculate the number of days 
that they receive both medications during the 12 months of follow-up. For subjects who are eligible to 
receive only one of the two medications at baseline (i.e., because of pre-existing therapy with or because 
of contraindications to the other prevention medication before trial entry), we will calculate the number 
of days that they receive the medication during the 12 months of follow-up, with the same approach for 
addressing changes in subsequent eligibility.  
 
Analysis of the primary study outcome: The primary analysis will follow the intention-to-treat (ITT) 
principle. We will use regression analysis to estimate the mean average of the primary outcome in each 
group and the difference between the mean outcomes, along with its 95% confidence interval and using 
the p-value for a null hypothesis. If clinically meaningful imbalances are detected in baseline covariates 
despite randomization, we will adjust for those covariates. If necessary, we will adjust for selection bias 
due to loss to follow-up via inverse-probability weighting. In supplemental analyses to the main ITT 
approach, we also will conduct appropriately adjusted per-protocol analyses. We will use STATA 13.0 for 
all analyses. We also will examine a number of pre-specified subgroup analyses, in which we examine 
whether the intervention might be more effective among those SMI patients who are more likely to 
receive fragmented care or less likely to be adherent to complex treatment regimens, e.g., SMI patients 
with Medicaid versus those with commercial health insurance.