Clinical trial NCT02458690
Conditions: Depression Major Depressive Disorder Dysthymic Disorder Depressive Symptoms Cardiovascular Diseases Heart Diseases Coronary Artery Disease Stroke
Keywords: Primary Care Older Adults Computerized and Telephonic Psychotherapy Cognitive-Behavioral Therapy Antidepressant Medications
Sponsor: Indiana University
Start date: 2015-07-01; Completion date: 2021-03-01
Enrollment: 216 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this randomized controlled trial is to evaluate whether the investigators modernized IMPACT intervention for depression (eIMPACT), delivered before the onset of cardiovascular disease (CVD), reduces the risk of future CVD. Participants will be primary care patients who are depressed but do not have a history of CVD. Half of the participants will receive standard depression treatment in primary care (usual care), and the other half will receive one year of eIMPACT, a collaborative stepped care program including antidepressants and computerized and telephonic cognitive-behavioral therapy. To evaluate change in CVD risk, the investigators will measure artery function using ultrasound before and after the 1-year treatment period. It is hypothesized that patients who receive the eIMPACT intervention will have greater improvements in artery function than patients who receive usual care.

Detailed description:
Cardiovascular disease (CVD) is the number one killer of American men and women, and its economic burden is substantial and on the rise. Adults with depression are at elevated risk of CVD events and poor CVD prognosis. Unfortunately, past trials of depression treatments have not observed the anticipated cardiovascular benefits. A novel explanation for these null results is that the interventions in these trials, which all involved patients with preexisting CVD, were delivered too late in the natural history of CVD. To begin to evaluate our hypothesis that treating depression before clinical CVD onset could reduce CVD risk, the investigators are conducting a phase II randomized controlled trial of 216 primary care patients aged ≥ 50 years with a depressive disorder and CVD risk factors but no clinical CVD. Patients will be randomized to one year of eIMPACT, our modernized IMPACT intervention, or usual primary care for depression. eIMPACT is a collaborative stepped care intervention involving a multidisciplinary team delivering evidenced-based depression treatments consistent with patient preference. The investigator shave modernized our intervention by incorporating computerized cognitive-behavioral therapy and delivering other treatment components via telephone. Our central hypothesis is that eIMPACT will improve endothelial dysfunction, which is considered a barometer of CVD risk, in depressed adults by decreasing depressive symptoms, autonomic dysfunction, systemic inflammation, and platelet activation. The investigators will test our central hypothesis by carrying out these specific aims: (1) to determine whether eIMPACT reduces the excess CVD risk of depressed patients (primary outcome: endothelial dysfunction; exploratory outcome: incident CVD events) and (2) to examine candidate mechanisms underlying the effect of eIMPACT on CVD risk (secondary outcomes: depressive symptoms, autonomic dysfunction, systemic inflammation, and platelet activation). A positive trial would generate the mechanistic rationale, efficacy evidence, and effect size estimates needed to justify and design a multisite, event-driven, phase III trial to confirm eIMPACT's efficacy in reducing CVD risk. Demonstrating that depression treatment reduces CVD risk, the primary expected outcome of this line of research, would have a substantial positive impact. It would identify a novel target (depression) for CVD prevention efforts, and it would equip providers with a new disseminable and scalable tool (eIMPACT) to simultaneously treat depression and manage the CVD risk of a large cohort of high-risk patients. Collectively, these changes to clinical practice should translate into reduced CVD morbidity, mortality, and costs.

Arms: arm 1: eIMPACT is a 12-month, modernized, collaborative, stepped care intervention consisting of (1) computerized and telephonic cognitive-behavioral therapy for depression and (2) select antidepressant medications included in an algorithm optimized for cardiovascular disease risk reduction. It is a collaborative care intervention in which a multidisciplinary team delivers established depression treatments consistent with patient preference. It uses a stepped, flexible, treat-to-target approach that modernizes the IMPACT intervention by harnessing technology to minimize staff and space requirements. Interventions are Beating the Blues, Problem Solving Treatment in Primary Care, and select FDA-approved antidepressants. The treatment team consists of a depression clinical specialist, a supervising MD with expertise in primary care and IMPACT, and the patients' primary care providers. arm 2: Patients and their primary care providers are informed of the depressive disorder diagnosis, and follow-up is encouraged. There are no restrictions on the care received. The Eskenazi Health primary care clinics utilize a team care approach, with PCPs supported by embedded behavioral health clinicians and affiliated psychiatrists.
Interventions: intervention 1: Beating the Blues (BtB) intervention 2: Problem Solving Treatment in Primary Care (PST-PC) intervention 3: Antidepressant Medications intervention 4: Usual Care
Intervention descriptions: intervention 1: BTB is a widely used, empirically supported, stand-alone CBT program for depression designed for primary care patients and appropriate for adults with little computer experience and a 5th-6th grade reading level. BtB utilizes an interactive, multimedia format to deliver eight 50-minute, weekly therapy sessions. Although sessions are tailored to each patient's problems, general topics include challenging dysfunctional thoughts, activity scheduling, problem solving, graded exposure, task breakdown, sleep management, and relapse prevention. Patients are also assigned tailored homeworks that are customized to their needs and reviewed at the start of each session. intervention 2: PST-PC is a manualized, empirically supported CBT developed for use by healthcare professionals in primary care. The focus of the 6-10 30-minute sessions is teaching patients approaches for solving current problems contributing to depression. We are delivering PST-PC via telephone. intervention 3: The IMPACT treatment manual provides guidelines for using antidepressants, such as selecting a medication, titrating, switching to another medication, managing side effects, and avoiding drug interactions. To optimize eIMPACT for CVD risk reduction, we have restricted the IMPACT list of antidepressants to SSRIs (sertraline, escitalopram, paroxetine, fluoxetine, citalopram), duloxetine, bupropion, and mirtazapine. These medications are FDA approved for the treatment of depression and are the safest from a cardiovascular perspective. intervention 4: Patients randomized to usual primary care for depression are informed of their depression diagnosis, encouraged to follow-up with their Eskenazi Health primary care provider, and provided a list of local mental health services. The patient's primary care provider will receive a letter indicating that their patient has a depressive disorder and was randomized to usual care. This letter also provides a list of local mental health services. Like those in the intervention group, usual care patients continue to have access to services that are part of usual care in the targeted systems. There are no restrictions on the care received. The Eskenazi Health primary care clinics utilize a team care approach, with PCPs supported by embedded behavioral health clinicians and affiliated psychiatrists.

Protocol documents:
Prot_SAP_000.pdf: 
Revision Date: July 13, 2018 
 
eIMPACT Trial: 
Modernized Collaborative Care to Reduce the Excess CVD Risk of Older Depressed Patients 
(ClinicalTrials.gov ID: NCT02458690) 
 
Trial Protocol 
7/13/2018 
 
Jesse C. Stewart, Ph.D. 
Principal Investigator 
Department of Psychology 
Indiana University-Purdue University Indianapolis 
402 N. Blackford Street, LD 100E 
Indianapolis, IN 46202 
 
Christopher M. Callahan, M.D. 
Co-Investigator 
Department of Medicine 
Indiana University School of Medicine 
HITS Suite 2000 
Indianapolis, IN 46202 
 
John I. Nurnberger, Jr., M.D., Ph.D. 
Co-Investigator 
Department of Psychiatry 
Indiana University School of Medicine 
791 Union Drive 
Indianapolis, IN 46202 
 
Samir K. Gupta, M.D., M.S. 
Co-Investigator 
Department of Medicine 
Indiana University School of Medicine 
Emerson Hall, Room 421 
545 N. Barnhill Dr.  
Indianapolis, IN 46202-5124 
 
Richard J. Kovacs, M.D. 
Co-Investigator 
Department of Medicine 
Indiana University School of Medicine 
Krannert Institute of Cardiology, Room E300 
1801 N. Senate Blvd., Suite E4000 
Indianapolis, IN 46202 
 
Robert V. Considine, Ph.D. 
Co-Investigator 
Department of Medicine 
Indiana University School of Medicine 
Gatch Clinical Building, Room 455 
1120 W. Michigan Street 
Indianapolis, IN 46202 
 
 
 


Revision Date: July 13, 2018 
Sujuan Gao, Ph.D. 
Co-Investigator 
Department of Biostatistics 
Indiana University School of Medicine 
410 West 10th Street, Suite 3000 
Indianapolis, IN 46202 
 
Bruce L. Rollman, M.D., M.P.H. 
Consultant 
Professor of Medicine, Psychiatry,  
Clinical and Translational Sciences, and Biomedical Informatics 
University of Pittsburgh School of Medicine 
230 McKee Place, Suite 600 
Pittsburgh, PA 15213 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Revision Date: July 13, 2018 
Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Inclusion/Exclusion Criteria 
4.0 
Enrollment/Randomization 
5.0 
Study Procedures 
6.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or Others 
7.0 
Study Withdrawal/Discontinuation 
8.0 
Statistical Considerations 
9.0 
Privacy/Confidentiality Issues 
10.0 
Follow-Up and Record Retention 
 
 


Revision Date: July 13, 2018 
1.0 Background 
 
Significance 
 
CVD and depression are top public health concerns; they are highly prevalent, deadly, and costly. 
CVD is highly prevalent and disproportionately affects older adults.1 A total of 15.4 and 6.8 million Americans 
suffer from coronary artery disease (CAD) and cerebrovascular disease (CBV).1 CVD is also deadly. CAD and 
CBV are the first and fourth leading causes of death in the U.S.2 Finally, the economic burden of CVD is 
substantial. For 2009, total cost in the U.S. was estimated to be $312.6 billion, which is greater than all 
cancers.1 Furthermore, due to the rapidly growing elderly population, the prevalence of CAD and CBV are 
projected to increase by 18-22% by 2030, and the total cost is expected more than double.1 
 
Depression is also a top concern. In the U.S., major depressive disorder (MDD) has a lifetime prevalence of 
16.2%,3 and the point prevalence of depressive disorders in primary care is 16-19%.4,5 Depression is the 
leading cause of disability,6 and the annual total cost of depression is over $83.1 billion.7 By 2020, CVD and 
depression are projected to be the #1 and #2 causes of disease burden worldwide.6 
 
Depression is an independent risk and prognostic factor for CVD. 
Thirty years of evidence indicates that depression is an independent risk and prognostic factor for CAD and 
CBV.8,9 Meta-analyses have shown that adults with a depressive disorder or symptoms have a 64% greater 
risk of CAD onset10,11 and that depressed CAD patients have a 59% greater likelihood of a future CVD event 
than their nondepressed counterparts.9 The depression-CVD relationship is comparable in strength to 
conventional CVD risk factors12 and has been detected in men and women and in various age and racial/ethnic 
groups.8,13-15 Although other emotional factors have been linked to CVD,16 the depression association is the 
most consistently observed16 and seems to be independent of anxiety and hostility/anger.17 CVD risk increases 
with depression severity,10 indicating a dose-response relationship. Finally, depression has been linked to 
several atherogenic factors, which supports the biological plausibility of these prospective associations. 
 
Because depression satisfies 8 of Hill’s 9 criteria for causation,18 it is reasonable to conclude that depression is 
an independent, and potentially causal, risk factor for CVD. Experimental animal research also supports a 
causal relationship between depression and atherogenesis.19 The lack of experimental evidence in humans, 
however, prevents one from drawing a causal inference, as the possibility that a third factor (e.g., genetic 
variants related to inflammation) explains the depression-CVD association has not been ruled out.20 
 
The Problem: Attempts to improve CVD outcomes of depressed patients have been unsuccessful. 
Despite this strong evidence base, the few trials that have evaluated whether depression interventions reduce 
the likelihood of CVD events generally have not observed the anticipated benefits. A key study was the 
Enhancing Recovery in Coronary Heart Disease (ENRICHD) Patients trial, in which 2,481 post-MI patients with 
depression and/or low social support were randomized to cognitive-behavioral therapy (CBT) or usual care. 
After 29 months, no difference in nonfatal MI or death was found.21 In the Sertraline Antidepressant Heart 
Attack Randomized Trial (SADHART), depressed CAD patients randomized to selective serotonin reuptake 
inhibitor (SSRI) treatment had a numerically lower rate of CVD events than patients randomized to placebo.22 
This suggestive trend was not confirmed in the Myocardial Infarction and Depression Intervention Trial (MIND-
IT), in which depressed post-MI patients were randomized to a staged pharmacologic intervention or usual 
care.23 Follow-up studies of ENRICHD, SADHART, and MIND-IT confirmed the absence of intervention effects 
on medical outcomes.24-26 Interestingly, some post hoc analyses of these trials revealed that patients whose 
depression improved had better long-term medical outcomes.24,25,27 However, other researchers have 
suggested that these relationships may be due to confounding, as early improvements in medical status after a 
CVD event may predict both later improvements in depressive symptoms and a reduced likelihood of recurrent 
CVD events.28,29 This would explain the null intervention effects in these trials. 
 
There are two intriguing exceptions to these negative trials; however, methodological factors cloud 
interpretation. The first is the TeamCare trial,30 in which depressed patients with diabetes or CAD were 
randomized to usual care or blended collaborative care for depression and diabetes/CAD risk factor control. At 
12 months, the intervention group exhibited greater improvements in glycated hemoglobin, cholesterol, and 
blood pressure but not hospitalization rates. Unfortunately, it is unclear whether the depression or diabetes/ 


Revision Date: July 13, 2018 
CAD components were responsible for these improvements. The second is the Coronary Psychosocial 
Evaluation Studies (COPES) trial,31 in which 6 months of the IMPACT intervention was delivered to persistently 
depressed CAD patients. At 6 months, intervention patients had fewer CVD events (3 vs. 10), although only 13 
total events occurred. Unfortunately, this interesting trend was not maintained in a recent follow-up of this 
trial.32 In sum, the critical problem is the absence of interventions to improve CVD outcomes of a large cohort 
of (depressed) patients at elevated risk of CVD onset, poor CVD prognosis, and high healthcare costs. 
 
A Viable Solution: Treating depression before clinical CVD may yield cardiovascular benefits. 
Shimbo et al.33 and others28,34 have summarized possible reasons for why past depression trials did not  detect 
cardiovascular benefits, including (a) depression differences between treatment and control arms may have 
been too small to improve CVD outcomes (perhaps due to weak intervention effects, high spontaneous 
remission rates, or high treatment rates in the control groups), (b) treatment was not initiated while the patient 
was hospitalized, and (c) the interventions may have been too short (≤6 months). A novel explanation, 
however, is that the late timing of depression treatment in the natural history of CVD may have played a role. 
Critically, the past trials all involved patients with preexisting CVD. For several reasons (see b1), we previously 
hypothesized that treating depression before, versus after, clinical CVD onset could reduce CVD risk.13  
 
As a first step, we conducted a follow-up study35 of Indiana sites of the IMPACT trial,36 in which older 
depressed patients were randomized to collaborative care or usual care. We found that IMPACT patients 
without baseline CVD had a 48% lower risk of a hard CVD event than usual care patients, whereas there was 
no treatment effect among patients with baseline CVD. Our findings (a) provide preliminary support for our 
hypothesis that initiating depression treatment before clinical CVD onset may reduce CVD risk and (b) suggest 
a complement or alternative to the current paradigm of initiating depression treatment after clinical CVD onset 
to improve CVD prognosis. These unique results strengthen the case that depression is a CVD risk factor and 
suggest that depression treatment may bring about a clinically relevant reduction in CVD risk. 
 
The IMPACT trial, however, was not designed to test our hypothesis. Consequently, our findings are post hoc 
and observational, CVD outcomes were not pre-specified endpoints, and virtually no mechanistic data were 
collected. To address these key limitations, there is a current need for a well-powered, prospective trial. 
 
Establishing that depression treatment reduces CVD risk would have a substantial positive impact.  
In the scientific domain, a positive trial would vertically advance the field of behavioral medicine in three ways. 
(1) It would expand the focus of this research area to include delivering depression treatment before, instead of 
only after, CVD onset. (2) It would remove a critical barrier to progress (past null intervention effects on CVD 
outcomes) and pave the way for the next step project: a multisite, event-driven Phase 3 trial to confirm 
eIMPACT’s efficacy in reducing CVD risk. Specifically, a positive Phase 2 trial would generate the mechanistic 
rationale (biological plausibility of intervention effects), efficacy evidence (first support of our central hypothesis 
from a well-powered, prospective trial), and effect size estimates (intervention effects on FMD, candidate 
mechanisms, and CVD events, which would be combined with estimates from other relevant studies) needed 
to justify and design a Phase 3 trial. Moreover, a positive Phase 2 trial would further establish the feasibility of 
our recruitment, intervention, and assessment approaches. (3) The proposed trial will address two long 
unanswered questions: (a) Is depression a causal risk factor for CVD? (b) What mechanisms underlie the 
depression-CVD relationship? The lack of experimental evidence, which this trial could generate, prevents 
depression from being labeled a causal CVD risk factor. In addition, although several plausible mechanisms 
have been proposed, little direct support has been generated. Elucidating the mechanisms underlying the 
cardioprotective effect of eIMPACT would allow us to optimize our intervention for CVD risk reduction by 
adding adjunctive treatments directly targeting the identified mechanisms (e.g., anti-inflammatory medication). 
In the clinical domain, demonstrating that depression treatment reduces CVD risk, the main expected outcome 
of this overall line of research, would have a positive impact for three reasons. (1) It would identify a novel 
target for CVD prevention, likely leading to the inclusion of depression in risk management guidelines. (2) It 
would equip primary care providers with a new tool (eIMPACT) to simultaneously treat depression and manage 
the CVD risk of a large cohort of high-risk patients. This tool would also be of use to specialists working with 
patient groups in which depression is prevalent and CVD risk is high, such as those with diabetes and HIV.37,38 
(3) Positive results, combined our practical intervention, should facilitate the dissemination of eIMPACT, 
possibly resulting in higher rates of quality depression care. Even though addressing depression in medical 
settings is a priority, it goes untreated in many patients. Data from a nationally representative sample suggests 


Revision Date: July 13, 2018 
that that only 22% of MDD cases receive adequate care.3 Demonstrating that a depression intervention 
reduces CVD risk should move depression treatment up the priority list of both the patient and provider and 
should encourage healthcare administrators to divert more resources to depression care. In addition, because 
using a computerized CBT reduces dependence on trained therapists, eIMPACT is more disseminable and 
scalable, easier to deliver with high fidelity, and likely more cost effective and sustainable than current 
collaborative care models. Furthermore, eIMPACT has the potential to reach patients with logistical barriers to 
treatment, such as those in rural areas. eIMPACT’s properties (disseminable, scalable, cost-effective, 
sustainable, and accessible) maximize the public health impact of this line of research. 
 
These three practice changes (identifying a novel treatment target, equipping providers with a new tool, and 
facilitating intervention dissemination) should reduce CVD morbidity, mortality, and costs, as our preliminary 
results suggest that treating 1,000 depressed patients may prevent 164 hard CVD events over 5 years.35 
Recently, the American Heart Association set its 2020 Impact Goal, which is “to improve the cardiovascular 
health of all Americans by 20%, while reducing deaths from CVDs and stroke by 20%.” In addition, NHLBI 
expressed a commitment to reducing socioeconomic status (SES) disparities in CVD in its strategic plan.39 
Given that depression is highly prevalent, especially in low SES groups,40 depression treatment could play a 
key role in achieving AHA’s goal and in reducing health disparities. Although our preliminary results suggest 
that a negative trial is unlikely, its importance should not be overlooked. Such an outcome would indicate a 
need to shift our focus to designing and evaluating alternative approaches to reducing the excess CVD risk of 
depressed patients (e.g., intervening directly on the underlying mechanisms). 
 
Innovation 
 
Depression treatment will be delivered before clinical CVD onset, a promising complement or 
alternative to current paradigm of treating depression in CVD patients to improve CVD outcomes.  
We propose and report preliminary evidence that treating depression before, versus after, the onset of clinical 
CVD could yield more pronounced cardiovascular benefits, an idea that is plausible for several reasons. 
 
One, earlier treatment of another CVD risk factor, hypercholesterolemia, produces larger benefits,41-43 perhaps 
by slowing atherosclerotic progression.44 Combining data from trials and prospective studies, Law et al.42 
estimated that the risk reduction in CAD events of a 1.8 mmol/l decrease in LDL cholesterol (achievable with 
statins) was greater among patients in their 50s (77%) than those in their 60s (61%) and 70s (49%). Other 
evidence suggests that earlier treatment may slow atherosclerotic progression, as younger age at initiation of 
statin treatment predicted smaller increases in carotid intima-media thickness over time in children with familial 
hypercholesterolemia.44 A recent meta-analysis of genetic studies also bolsters the earlier treatment rationale; 
it was found that lower LDL cholesterol beginning early in life (due to a mutation) confers a 3 times greater 
reduction in CAD risk than the same lowering of cholesterol later in life (due to statin treatment).41 Altogether, 
these findings raise the possibility that earlier treatment of other modifiable CVD risk factors, including 
depression, may also slow atherosclerotic progression and prevent CVD events to a greater degree. We are 
not the first to argue for earlier treatment of CVD risk factors;45-50 we are just the first to apply this rationale to 
depression. Steinberg et al. stated that “much of the same reasoning [for hypercholesterolemia] applies to 
obesity, cigarette smoking, hypertension, diabetes mellitus, and other reversible risk factors” (p. 627).48 
 
Two, our past work15,17 and other studies indicate that depression exerts a cardiotoxic influence early in CVD 
pathogenesis. Depression is reliably associated with endothelial dysfunction51 and predicts progression of 
subclinical atherosclerosis in humans15,17,52,53 and early atherogenesis in primates.19 Intervening earlier, when 
depression is exerting a deleterious effect, would minimize exposure to this CVD risk factor.  
 
Three, depression treatments may have greater antidepressive efficacy before clinical CVD onset. Most trials 
of depressed CVD patients have reported relatively small effect sizes for depression outcomes (0.20-0.38).54 
Similarly, the depressive symptoms effect size observed in our IMPACT follow-up study was 0.06 among 
depressed patients with baseline CVD; however, it was much larger (0.69) among patients without baseline 
CVD (see c2.2). A possible explanation is that subgroups of depressed CVD patients in the past trials were 
experiencing vascular depression55 (which responds poorly to treatment56,57) or an adjustment reaction related 
to CVD diagnosis and treatment (which is more likely to spontaneously remit58,59). Consistent with the latter 
idea, two trials have reported medium effect sizes in CVD patients with persistently elevated depressive 


Revision Date: July 13, 2018 
symptoms.31,60 Because we will enroll depressed patients without clinical CVD, our sample should have few 
patients from the subgroups thought to be contributing to the smaller effect sizes of past trials.  
 
Four, conventional prognostic factors, such as CVD event severity or cardiovascular interventions (e.g., 
revascularization procedures), may override the effect of depression during the later stages.16,61 
 
We will examine multiple candidate mechanisms of eIMPACT's hypothesized effect on CVD risk. 
As we have done previously,15 we will conduct formal statistical mediation tests to examine the leading 
candidate mechanisms through which depression treatment may reduce CVD risk – i.e., decreases in 
depressive symptoms, autonomic dysfunction, systemic inflammation, and platelet activation. We will also 
explore atherogenic behavioral factors, conventional CVD risk factors, and depression care variables as 
potential mechanisms (see c3.5). Although many plausible mechanisms have been proposed previously, 
testing for mediation is rare in this field,62 particularly in the favorable context of a RCT, which allows for 
stronger inferences. The proposed study would be the first prospective trial to examine candidate mechanisms 
underlying the hypothesized cardioprotective effect of depression treatment initiated before CVD onset. 
 
eIMPACT is a novel intervention and an appropriate selection for the proposed trial. 
Although collaborative depression care has been examined in CVD patients,31,60,63 no trials in this area have 
incorporated computerized psychotherapy into this framework. The original IMPACT intervention is an 
established, collaborative, stepped care program involving a multidisciplinary team delivering evidenced-based 
treatments (antidepressants and psychotherapy) consistent with patient preference.36,64,65 We will modernize 
the IMPACT intervention (a) by adding a computerized CBT, Beating the Blues (BtB), as the first-line 
psychotherapy and (b) by delivering other components, including Problem Solving Treatment in Primary Care 
(PST-PC), via telephone. BtB is a stand-alone CBT program for depression designed for primary care patients 
and appropriate for adults with lower reading levels and computer experience.66 BtB uses an interactive, 
multimedia format to deliver 8 weekly sessions, the structure and content of which mirror face-to-face CBT. We 
will also deliver PST-PC via telephone, which Davidson et al.60 recently found to be feasible and efficacious.  
 
In addition to being novel, there are two reasons why eIMPACT is an appropriate selection. First, the eIMPACT 
components are efficacious and acceptable. In the IMPACT trial,36 45% of intervention patients versus 19% of 
usual care patients had >50% reduction in depressive symptoms, and satisfaction was high. In our IMPACT 
follow-up study,35 we observed a moderate to large effect size for depressive symptoms (see c2.1). BtB has 
more empirical support than any other computerized psychotherapy, including a positive RCT of 274 primary 
care patients.67,68 BtB has been found to be a potent intervention,67-75 with effect sizes comparable to face-to-
face CBT.76 In our pilot trial, we observed a large BtB effect size for depressive symptoms (see c2.2). BtB has 
been shown to be acceptable to patients66,74,75 and was recently found to be effective, acceptable, and 
preferred to usual care among older adults.77 In 2006, NICE recommended BtB for managing depression in the 
English National Health Service.78 Early studies in the U.S. are promising,79 and large trials are underway 
(including Dr. Rollman's trial; NCT01482806). Because we are retaining the key elements of the IMPACT 
model and our pilot data support the efficacy of BtB in the target population, we expect eIMPACT to achieve an 
effect size as large as the original IMPACT intervention with fewer human resources. 
 
Second, eIMPACT fits very well with our long-term goal of developing, optimizing, and disseminating 
treatments to improve the CVD outcomes of a large cohort of patients at elevated risk of CVD onset, poor CVD 
prognosis, and high healthcare costs. To achieve this goal, large-scale dissemination and adoption must be 
possible. Because eIMPACT uses a stand-alone computerized CBT, it is more disseminable and scalable, 
easier to deliver with high fidelity, and likely more cost effective80 and sustainable than current collaborative 
care models. Given that components of eIMPACT are computer and telephone delivered, it also has the 
potential to reach patients with logistical barriers. Finally, implementation tools for the IMPACT intervention are 
available (see impact-uw.org) and could be leveraged to facilitate dissemination and adoption of eIMPACT. 
  
Our trial design is not ideal for determining the differential efficacy of the eIMPACT components. If that was our 
goal, we would have chosen a 2 Antidepressants (yes, no) x 2 CBT (yes, no) design. While such a study would 
be valuable, our trial is the preferable next step in our view. First, we selected a flexible and efficacious 
treatment model to achieve our broader objective of determining whether successfully treating depression 
earlier in the natural history of CVD reduces CVD risk. Second, dismantling eIMPACT could neutralize some 


Revision Date: July 13, 2018 
key strengths (i.e., stepped care, patient choice, and treat to target), potentially compromising its efficacy. 
Third, justifying the higher cost of a dismantling study is difficult when the intact treatment has not been shown 
to reduce CVD risk in a prospective trial. Based on our IMPACT follow-up study,35 we expect eIMPACT 
patients to receive both antidepressants and CBT (50%), antidepressants only (26%), CBT only (12%), or 
neither component (12%). To generate hypotheses, we propose supplemental analyses to explore which 
components are most strongly related to the outcomes (see c3.5). 
 
Brachial flow-mediated dilation (FMD) is an innovative and appropriate primary outcome. 
The proposed trial would be the first to examine the effect of depression treatment, delivered before clinical 
CVD onset, on endothelial dysfunction. Endothelial dysfunction, the impaired ability of the vascular lining to 
maintain normal homeostasis,81 is an early precursor to and plays a central role in atherosclerosis.82 FMD is a 
noninvasive technique that uses high-resolution ultrasound to measure changes in brachial diameter in 
response to stimuli,83 with results correlating closely with coronary endothelial function.84,85 Measurements are 
made before and after endothelium-dependent and endothelium-independent stimuli.86 The endothelium-
dependent stimulus is hyperemic blood flow triggered after the release of an inflated blood pressure cuff 
around the forearm. The shear stress from the increased blood flow causes endogenous vasodilators (e.g., 
nitric oxide) to be released from the endothelium, which relaxes the vascular smooth muscle. This dilation of 
the brachial artery is thus a measure of the endothelium’s ability to respond normally to hyperemic shear 
stress. Nitroglycerin, the endothelium-independent stimulus that directly relaxes smooth muscle, is then 
applied to assess the smooth muscle’s functional capacity. If FMD is low and nitroglycerin-mediated dilation is 
normal, the endothelium (and not the smooth muscle) can be safely assumed to be dysfunctional.  
 
FMD is the best choice for the primary outcome of the proposed trial for several reasons. One, endothelial 
dysfunction is considered a barometer of total CVD risk and the final common pathway through which CVD risk 
factors promote atherosclerosis.87-89 Endothelial dysfunction (a) has been observed in adults with CVD risk 
factors but no detectable disease,83,90-97 (b) is related to other vascular disease measures,98-100 and (c) is an 
independent predictor of CVD events among initially healthy persons, at-risk individuals, and CVD patients.101-
112 Two, intervention-related improvements in FMD predict a reduced incidence of CVD events,113-115 indicating 
that FMD is a predictor of clinical benefit. In contrast to anatomic measures such as coronary calcification and 
carotid thickness, FMD also responds within weeks of pharmacologic and behavioral interventions,87 making it 
well suited to evaluate if a new treatment approach holds promise. Three, FMD is a continuous measure of 
CVD risk that provides greater statistical power than dichotomous outcomes. Thus, trials with FMD as the 
primary outcome require much smaller samples and shorter follow-ups than CVD event-driven trials. Four, a 
recent meta-analysis51 and our pilot findings (see c2.3) demonstrate that depressed adults exhibit evidence of 
endothelial dysfunction as measured by FMD relative to their nondepressed counterparts. 
Although results of some surrogate endpoint trials have not been confirmed in subsequent event-driven 
trials,116 this risk is minimized here. First, we have already detected a beneficial effect of a similar intervention 
on CVD events in our post hoc analysis of the IMPACT trial,35 increasing the likelihood that we will see a 
comparable effect in a prospective, event-driven Phase 3 trial. Second, in the proposed Phase 2 trial, we will 
collect event data and explore whether eIMPACT patients show a clinically relevant reduction in events.  
 
Using a statewide information exchange to identify CVD events is unique and has advantages. 
We will leverage this unique resource to identify CVD events. The Indiana Network for Patient Care 
(INPC),117,118 the nation’s largest clinical data repository (see Facilities and Other Resources), was an NIH-
funded expansion of the Regenstrief Medical Record System,119 which has been used extensively for clinical 
research. The INPC contains 4.7 billion bits of standardized clinical data for 14.7 million patients from 19,000 
physicians, 90 hospitals, and 110 clinics and other sites. The participating systems deliver registration records; 
coded diagnoses and procedures; laboratory, pathology, and vital signs data; emergency department, 
inpatient, and outpatient encounter data; and pharmacy data. INPC also gathers data from Indiana Medicaid 
and other commercial payers, as well as death data from the Indiana State Department of Health. 
 
Advantages of our approach include minimal attrition and an observation period that can be easily extended. 
As in our IMPACT follow-up study,35 we anticipate having event data for nearly all randomized patients, given 
that (a) we will identify most CVD events through INPC searches (no patient participation required) and (b) we 
have developed procedures (e.g., follow-up calls) to identify the few events that may occur outside of the INPC 


Revision Date: July 13, 2018 
catchment area. Extending the observation period to capture more CVD events would also require few 
resources, as it would involve the data manager re-running INPC search programs. 
 
Proposed Research and Conceptual Framework 
We will conduct a Phase 2 randomized controlled trial of 220 primary care patients aged 50+ years with a 
depressive disorder and CVD risk factors but no clinical CVD. Patients will be randomized to 12 months of 
eIMPACT or usual care and will be followed for a mean of 4 years. The conceptual framework guiding our trial 
is shown in Figure 1. Our central hypothesis is that eIMPACT will improve endothelial dysfunction by 
decreasing depressive symptoms, autonomic dysfunction, systemic inflammation, and platelet activation. 
 
The atherogenic physiologic and behavioral factors in Figure 1 are the leading candidate mechanisms through 
which depression treatment may reduce CVD risk. Substantial literatures indicate that depression is reliably 
associated with each factor,120-126 as well as endothelial dysfunction.51 Although far fewer in number, some 
studies have reported more direct evidence. We and others have observed that the strength of the depression-
CVD association is attenuated after adjusting for autonomic function indices,127,128 inflammatory markers,128-130 
physical activity,130-133 and smoking.15,130,131,133 Finally, evidence suggests that CBT and SSRIs decrease 
autonomic dysfunction,134-137 inflammation,138-143 platelet activation,144-147 and smoking.148,149 While we propose 
that treatment-related reductions in depressive symptoms (paths a and b) will result in decreases in the 
atherogenic factors (paths d and e), we also hypothesize that SSRIs and SNRIs will reduce CVD risk via their 
direct effects on inflammation and 
platelet activation (path c).33,147,150 
We chose the physiologic factors 
as secondary outcomes, given that 
they represent likely pathways 
through which behavioral factors 
increase CVD risk (path f). This 
conceptualization is in line with 
current models of the depression-
CVD relationship151 and empirical 
findings.152-155 We will examine 
behavioral factors as mechanisms 
in exploratory analyses. 
2.0 Rationale and Specific Aims 
 
Cardiovascular disease (CVD) is a top public health concern in the U.S. CVD is highly prevalent and is the 
number one killer of Americans. Moreover, its economic burden is substantial and on the rise.1,2 Thirty years of 
evidence indicates that adults with depression are at increased risk of CVD events and poor CVD prognosis;8,9 
however, attempts to improve the CVD outcomes of depressed patients have been unsuccessful. The few 
trials21-23,30-32 that have evaluated whether depression interventions reduce the likelihood of CVD events 
generally have not observed the anticipated benefits. The reasons for these null results have been the subject 
of debate.34 We recently proposed a novel explanation: the depression interventions in these trials, all of which 
involved patients with preexisting CVD, may have been delivered too late in the natural history of CVD.13 We 
hypothesized that treating depression before, versus after, the onset of clinical CVD could reduce CVD risk 
because: (1) earlier treatment of another CVD risk factor, hypercholesterolemia, yields more pronounced 
benefits,41-44 (2) depression exerts a cardiotoxic influence early in CVD pathogenesis,17,19,51,53 (3) depression 
treatments appear to have greater antidepressive efficacy prior to clinical CVD onset,36,54 and (4) conventional 
prognostic factors may override depression's harmful effect during the later stages of CVD.16,61 
 
As a first step, we conducted an 8-year follow-up study35 of Indiana sites of the Improving Mood-Promoting 
Access to Collaborative Treatment (IMPACT) trial,36 in which older depressed patients were randomized to a 
collaborative care intervention or usual care. Results supported our hypothesis. Intervention patients without 
baseline CVD had a 48% lower risk of myocardial infarction (MI) or stroke than usual care patients. There was 
no treatment effect among patients with baseline CVD. Although these results are unique and potentially 
significant, the IMPACT trial was not designed to test our hypothesis. Thus, our findings are post hoc and 
observational, CVD outcomes were not pre-specified endpoints, and virtually no mechanistic data were 
collected. To address these key limitations, there is a current need for a well-powered, prospective trial. 
 Positive relationship 
 Negative relationship 
Psychotherapy 
(computerized & 
face-to-face) 
Depressive 
Symptoms 
Endothelial 
Dysfunction 
&  
CVD Events 
b 
a 
c 
d 
e 
f 
eIMPACT
Figure 1. Conceptual Framework of the Proposed Clinical Trial 
Antidepressants 
(SSRIs & SNRIs) 
Physiologic Factors 
 
Autonomic Dysfunction 
Systemic Inflammation 
Platelet Activation 
Behavioral Factors 
 
Tobacco Use 
Physical Inactivity 
CVD Med Nonadherence 


Revision Date: July 13, 2018 
 
Our long-term goal is to develop, optimize, and disseminate treatments to improve CVD outcomes of a large 
cohort of patients at elevated risk of CVD onset, poor CVD prognosis, and high healthcare costs. This project’s 
objective is to test whether our modernized IMPACT intervention (eIMPACT), delivered before CVD onset, 
reduces CVD risk. We propose a Phase 2 randomized controlled trial of 220 primary care patients (≥50 years, 
40% African American) with a depressive disorder and CVD risk factors but no clinical CVD. Patients will be 
randomized to 12 months of eIMPACT (a collaborative stepped care program including antidepressants and 
computerized and telephonic cognitive-behavioral therapy) or usual care (usual primary care for depression). 
Patients will be followed for a mean of 4 years. The primary outcome is endothelial dysfunction assessed by 
brachial flow-mediated dilation (FMD),81 which is considered a barometer of CVD risk.88 Critically, intervention-
related improvements in FMD predict a reduced incidence of CVD events.113-115 Our central hypothesis is that 
eIMPACT will improve endothelial dysfunction in depressed patients by decreasing depressive symptoms, 
autonomic dysfunction, systemic inflammation, and platelet activation, which are leading candidate 
mechanisms. We will test our central hypothesis by carrying out these specific aims: 
 
Aim 1: Determine whether eIMPACT reduces the excess CVD risk of depressed patients. Depressed 
patients randomized to eIMPACT, versus usual care, will exhibit a clinically and statistically significant 
improvement in the primary outcome of endothelial dysfunction at the 12-month post-treatment visit 
(Hypothesis 1). We will also explore whether eIMPACT patients, versus usual care patients, show a clinically 
relevant reduction (25% lower relative risk156,157) in CVD events (exploratory outcome) over a mean 
observation period of 4 years (1-year intervention period plus 3-year follow-up period). 
 
Aim 2: Examine candidate mechanisms underlying the effect of eIMPACT on CVD risk. Depressed 
patients randomized to eIMPACT, versus usual care, will exhibit greater decreases in the secondary outcomes 
of depressive symptoms (Hypothesis 2), autonomic dysfunction (Hypothesis 3), systemic inflammation 
(Hypothesis 4), and platelet activation (Hypothesis 5) at the 12-month post-treatment visit. We will also explore 
whether decreases in these four candidate mechanisms (a) are associated with improvements in endothelial 
dysfunction and (b) are partial mediators of eIMPACT’s hypothesized cardioprotective effect. 
A positive trial would generate the mechanistic rationale, efficacy evidence, and effect size estimates needed 
to justify and design a multisite, event-driven Phase 3 trial to confirm eIMPACT’s efficacy in reducing CVD risk. 
Conversely, a negative trial would indicate a need to evaluate alternative approaches to reducing the excess 
CVD risk of depressed patients. Demonstrating that depression treatment reduces CVD risk, the main 
expected outcome of this line of research, would have a substantial positive impact. It would identify a novel 
target (depression) for CVD prevention efforts, and it would equip providers with a new disseminable and 
scalable tool (eIMPACT) to treat depression and manage the CVD risk of a large cohort of high-risk patients. 
These clinical practice changes should translate into reduced CVD morbidity, mortality, and costs, as our 
preliminary results suggest that treating 1,000 depressed adults may prevent 164 CVD events over 5 years.35 
 
3.0 Inclusion/Exclusion Criteria 
 
Inclusion criteria 
 
• 
Primary care patients 
• 
Age ≥ 50 years 
• 
Current depressive disorder 
• 
Elevated CVD risk 
 
To identify patients with a current depressive disorder, ResNet assistants will administer the PHQ-9,158 a 
validated diagnostic measure designed for primary care patients.159-162 We will consider patients to have a 
depressive disorder if (a) they have a PHQ-9 ≥10158 and (b) they meet criteria for a PHQ-9 depressive disorder 
diagnosis (2 or more of the 9 depressive symptoms, including depressed mood or anhedonia, present in the 
past two weeks).160 The cut point of ≥10 has 88% sensitivity and 88% specificity for MDD diagnosed by a 
clinical interview.158 The combination of a PHQ-9 ≥10 and a PHQ-9 depressive disorder diagnosis helps to 
ensure that false positives will not be enrolled. In addition to its diagnostic validity, we chose a PHQ-9 case 
finding approach because: (a) it is feasible in primary care and is how depressed patients will likely be 


Revision Date: July 13, 2018 
identified in clinical practice, (b) recent successful trials have used similar approaches,31,60,163 and (c) we 
observed evidence of a signal of depression treatment on endothelial function and inflammation in our pilot 
trial, in which we used the PHQ-9. 
 
Elevated CVD risk will be defined as ≥1 (if 60+ years) or ≥2 (if 50-59 years) of the following risk factors in the 
medical record in the past 5 years but no clinical CVD: hypertension, hypercholesterolemia, diabetes, or 
current smoking. According to the Framingham risk calculator for primary care patients,164 the odds of a CVD 
event of a 50-year-old man/woman with 2 risk factors is about equivalent to that of a 60-year-old man/woman 
with 1 risk factor. 
 
Exclusion Criteria 
 
• 
History of clinical cardiovascular disease 
• 
Presence of the following chronic disorders: HIV/AIDS, chronic kidney disease, or active cancer/current 
cancer treatment 
• 
History of bipolar disorder or psychosis 
• 
Continuous (e.g., daily) treatment for a systemic inflammatory condition (e.g., rheumatoid arthritis, 
lupus, Crohn's disease, and ulcerative colitis) in the past 3 months. Nonsteroidal anti-inflammatory drug 
(NSAID) use is allowed, given its high prevalence in the target population. 
• 
Current use of anticoagulants (Aspirin and cholesterol and blood pressure medications are allowed.) 
• 
Acute risk of suicide 
• 
Severe cognitive impairment (≥3 errors on 6-item cognitive screen165) 
• 
Current pregnancy 
• 
Ongoing depression treatment with a psychiatrist outside of the Eskenazi Health/Midtown system 
(ongoing depression treatment with a Eskenazi Health/Midtown psychiatrist is allowed, as we will be 
able to collaborate and coordinate depression care) 
 
A history of clinical CVD will be defined as any of the following in the medical record before enrollment: CAD 
(ICD-9 410-414, 429.2) or CBV (ICD-9 430-434) diagnosis, acute MI (CK-MB >3.0 ng/ml or troponin >0.3 
μg/L), percutaneous coronary intervention (ICD-9 00.66, 36.03, 36.06, 36.07, 36.09; CPT 92980-92984, 
92995, 92996), or coronary artery bypass graft (ICD-9 36.10-36.19; CPT 33510-33536). 
 
4.0 Enrollment/Randomization 
 
We will use the 3-stage process of our past trials to recruit patients. First, the Regenstrief Medical Records 
System,166 one of most comprehensive electronic medical records, will be searched in accordance with HIPAA 
to generate lists of eligible patients. Next, ResNet assistants will obtain permission to approach from each 
patient's provider. ResNet, Indiana University’s primary care practice-based research network, is the sole 
mechanism through which patients in the targeted clinics can be contacted for research. ResNet also 
maintains a patient registry, which will also be used by ResNet to identify potentially eligible patients. Finally, 
ResNet assistants will conduct high-intensity in-clinic and telephone screening and will enroll eligible patients 
(see Appendix 1 for Screening Interview). ResNet assistants will use a paper copy or a REDCap version of the 
Screening Interview. Through administering the eligibility interview refined in our pilots, ResNet assistants will 
assess cognitive function, medical/psychiatric status, and depression status; will obtain consent and 
authorization; and will implement the suicidal ideation protection protocol. 
 
We estimate that ≈4,320 patients (45/week) will need to be approached, consistent with the IMPACT trial.36 We 
will be able to start recruitment immediately, as the infrastructure, personnel, and protocols are in place from 
the PI’s recent trials. At the Indiana sites of the IMPACT trial, 6.4% of approached patients were randomized. 
We conservatively estimate that 5% of approached patients will be randomized (9/month) in the proposed trial. 
Patients who meet inclusion/exclusion criteria and consent will be scheduled for the pre-treatment visit. 
Because only patients who attend this visit will be randomized, it will serve as a prerandomization compliance 
screening.167 
 


Revision Date: July 13, 2018 
In the unanticipated event of slower-than-projected recruitment, we will first request direct referrals from 
providers in the targeted clinics. Next, we will pursue expanding recruitment to another healthcare system in 
Indianapolis, such as the VAMC or Community Health Network. Finally, we will extend the recruitment window 
up to a year if the benefits to the primary outcome of endothelial dysfunction (ample power due to a larger 
sample) outweigh the costs to the exploratory outcome of CVD events (shorter observation period).  
 
At the end of the pre-treatment visit described below, the randomization procedure will be initiated. To balance 
the groups on two strong FMD correlates,91 randomization will be stratified by sex and age (50-59 and 60+ 
years) using random number sequences.168 Sequentially numbered sealed envelopes containing group 
assignment will be prepared by the study statistician (Dr. Gao). 
 
5.0 Study Procedures 
 
Overview, Visits, and Setting 
 
We will conduct a Phase 2 randomized controlled trial of 220 primary care patients aged 50+ years with a 
depressive disorder and CVD risk factors but no clinical CVD. Patients will be randomized to 12 months of 
eIMPACT, our modernized IMPACT intervention, or usual care and will be followed for a mean of 4 years. 
 
The timing of activities is shown in the table below. We will strive to schedule patients within two weeks of 
enrollment, although some visits will fall outside of that window due to conflicts in the patients’ schedules and 
no-showed or rescheduled appointments. Patients will attend a 3-hour pre-treatment visit at the Indiana CTSI 
Clinical Research Center. To minimize the effect of extraneous factors on FMD,169,170 patients will be told to 
fast and to avoid tobacco and exercise for ≥8 hours before their visit. The exam room will be kept at 68-71°F, 
and premenopausal women will be scheduled within 2 weeks of menstruation onset. Patients will have their 
height, weight, and BP measured; will complete self-report scales on a secure SurveyMonkey website 
designed for this study visit; and will undergo FMD and heart rate variability assessments and a blood draw 
(standard venipuncture). To end this visit, the randomization procedure will be initiated, the patient and the 
treatment team will be notified of the assignment, and the mid-treatment call and post-treatment visit will be 
scheduled. If the patient is randomized to the eIMPACT intervention, the depression clinical specialist will 
conduct a brief session over FaceTime to orient the patient to intervention materials and to schedule the initial 
assessment. The FaceTime session will not be recorded. Within 2 weeks, the depression clinical specialist will 
call eIMPACT patients to initiate treatment, and a research assistant will send a letter to the primary care 
providers of usual care patients to notify them that their patient has a depressive disorder and to encourage 
follow-up. Approximately six months after randomization, research assistants will contact all patients to 
complete the 45-min mid-treatment call. First, a brief questionnaire used in our pilot trials will be administered 
to assess for the occurrence of CVD events since enrollment. As we have also done in our pilot projects, the 
self-reported scales completed at pre-treatment will then be readministered. Approximately twelve months after 
randomization, patients will return to the Clinical Research Center for the post-treatment visit, during which all 
factors measured at pre-treatment will be reassessed. Finally, research assistant will contact patients annually 
after their post-treatment visit to complete the follow-up calls, with the last call coming within 2 weeks of the 
study end date. These calls will follow the same procedures as the mid-treatment call.  
 
The schedule of participant reimbursement is as follows: $100 for the pre-treatment visit, $25 for the mid-
treatment call, $100 for the post-treatment visit, $20 for each of the annual follow-up calls, and up to $10 per 
visit to cover parking or transportation costs. 
 
 
 
 
 
 
 
The setting, which is identical to the IMPACT trial, is the primary care clinics of two healthcare systems 
affiliated with Indiana University: Eskenazi Health and Indiana University Health. Eskenazi Health, a safety net 
 
Year 01 
Year 02 
Year 03 
Year 04 
Year 05 
Recruitment & Pre-Treatment Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mid-Treatment Calls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Treatment Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Annual Follow-Up Calls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Analysis & Manuscript Submission 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Revision Date: July 13, 2018 
healthcare system, provides care for ≈20% of the population of Indianapolis. The Eskenazi Health Center for 
Senior Health, where elderly patients receive primary care, is included in the targeted clinics. About 90% of 
Eskenazi patients are underinsured or uninsured, and 50% are African American. Therefore, these patients 
provide special opportunities to research diseases that disproportionately affect lower SES and minority 
populations, such as CVD.1,171 Indiana University Health, a large academic medical center, is Indiana's most 
comprehensive healthcare system. 
 
Treatment Groups 
 
eIMPACT 
eIMPACT is a collaborative stepped care intervention involving a multidisciplinary team delivering evidenced-
based treatments consistent with patient preference. We will modernize the IMPACT intervention (a) by adding 
a computerized CBT as the first-line psychotherapy and (b) by delivering some of the other components via 
telephone or FaceTime (see below). None of the computerized, telephonic, or FaceTime sessions will be 
recorded. Other than restricting the list of antidepressant medications to maximize CVD risk reduction, the 
remaining IMPACT components will not be altered. 
 
Beating the Blues (BtB; Ultrasis PLC) is a widely used, empirically supported, stand-alone CBT program for 
depression designed for primary care patients and appropriate for adults with little computer experience and a 
5th-6th grade reading level.66 In prior trials, we have used the UK and US versions; we will use the US version in 
the proposed trial (see www.beatingthebluesus.com for a brief video tutorial). BtB utilizes an interactive, 
multimedia format to deliver eight 50-minute, weekly sessions, the structure and content of which mirror face-
to-face CBT. Although sessions are tailored to each patient’s problems, general topics include challenging 
dysfunctional thoughts, activity scheduling, problem solving, graded exposure, task breakdown, sleep 
management, and relapse prevention. Patients are also assigned tailored homeworks.  
 
To minimize treatment barriers (e.g., transportation issues) and attrition, to reduce subject burden, and to 
ultimately facilitate implementation of eIMPACT, BtB sessions will occur in a private room at the Clinical 
Research Center, at Dr. Stewart’s laboratory, at the patient’s primary care clinic, or in a location selected by 
the patient where s/he can access a computer with internet, such as the patient’s home, the patient’s work, a 
family member’s/friend’s home, or a public library. Patient preference will drive the location decision. Patients 
will be offered with ear bud headphones if they plan to use them at remote locations and do not already own a 
pair that they would rather use. All patients completing BtB will be provided with a BtB binder that contains 
printouts of all BtB worksheets. 
 
To begin each in-person BtB session, an assistant will collect the homework. The patient will then work alone 
through the BtB session at his/her own pace, with the assistant providing help only with technical issues. To 
end the session, the assistant will give the patient the printed homework. 
 
Remote BtB sessions will scheduled, just like in-person sessions. To begin each remote BtB session, an 
assistant call the patient to instruct the patient to put last week’s homework in the BtB binder, to address any 
technical issues, and to ensure that the patient has launched the correct BtB session for that day. The patient 
will then work alone through the BtB session at his/her own pace, with the assistant monitoring progress 
remotely on the secure BtB website set up for this trial. To end the session, the assistant will call the patient 
back to address any questions and ensure that the patient has identified the correct printed homework in the 
BtB binder. 
 
Problem Solving Treatment in Primary Care (PST-PC) is a manualized, empirically supported CBT developed 
for use by healthcare professionals in primary care.172-177 The focus of the 6-10 30-minute sessions is teaching 
patients approaches for solving current problems contributing to depression. PST-PC was the first-line therapy 
in the IMPACT trial; however, it is our second-line therapy. We will deliver PST-PC primarily via telephone or 
FaceTime (although in-person sessions are also allowed), which Davidson et al.60 found to be feasible and 
efficacious in the recent CODIACS Vanguard trial. Our consultant (Dr. Rollman) also completed the Bypassing 
the Blues trial in which his team delivered collaborative depression care to cardiac patients via telephone and 
observed positive results.63 
 


Revision Date: July 13, 2018 
The IMPACT treatment manual provides guidelines for using antidepressants, such as selecting a medication, 
titrating, switching to another medication, managing side effects, and avoiding drug interactions.65 To optimize 
eIMPACT for CVD risk reduction, we have restricted the IMPACT list of antidepressants to SSRIs, duloxetine, 
bupropion, and mirtazapine. These medications are FDA approved for the treatment of depression and are the 
safest from a cardiovascular perspective.178,179 We are prohibiting the use of most serotonin-norepinephrine 
reuptake inhibitors (SNRIs) and all tricyclics due to their potential adverse effects on cardiovascular 
parameters.178,179 We do not expect this change to have a negative effect on depression outcomes, as 
antidepressants not on our list of allowed medications are typically used only as second- or third-line 
treatments and also have contraindications.65 
 
At the first session, the depression clinical specialist (DCS), a Master’s-level licensed mental health counselor 
(LMHC), will review depression materials and discuss treatment options. The DCS will then work with the 
patient’s primary care provider to develop a plan that follows the IMPACT algorithm65 with modifications noted 
above. Our modernized algorithm recommends a Step 1 treatment of 8-12 weeks of BtB or an antidepressant 
depending on the patient preference. Providers will manage prescriptions. In addition to delivering PST-PC, the 
DCS will help the patient adhere to antidepressant therapy and schedule pleasurable activities. If the patient is 
taking an antidepressant at baseline, the dose will be increased, BtB will be added, or the antidepressant will 
be discontinued and another one will be prescribed or BtB will be delivered. If the patient wants psychotherapy 
but has a strong preference for traditional treatment, PST-PC will be offered at Step 1. The DCS will have 
weekly team meetings with the supervising psychiatrist (Dr. Nurnberger) and primary care expert (Dr. 
Callahan), during which new cases and those requiring plan changes will be discussed. Fidelity to the 
eIMPACT algorithm will be continually assessed and recorded by the supervisors at these team meetings, and 
adjustments needed to ensure high fidelity will be made. 
 
The DCS will follow patients for 12 months, while monitoring response.158 At the start, the DCS will attempt to 
have telephone sessions or contacts at least every 2 weeks. For patients who achieve remission (≥50% PHQ-9 
reduction and <3 MDD symptoms36), the DCS will develop a relapse prevention plan and follow up monthly. 
Step 2 treatment – which involves either augmenting Step 1 treatment with an antidepressant or 
psychotherapy or switching to another antidepressant or psychotherapy – will be delivered to patients who do 
not achieve remission. If a patient does not respond after 6-10 more weeks, Step 3 treatment will be initiated, 
which consists of additional medications and psychotherapy, hospitalization, or other services. In the IMPACT 
trial,36 intervention patients had 9.2 ± 6.2 in-clinic sessions and 6.1 ± 5.1 telephone contacts with a DCS during 
the 12 months of treatment. At the end of the 12 month treatment phase, the participant will receive a 
certificate indicating completion of eIMPACT treatment. We expect similar numbers in our trial, although most 
sessions/contacts will be via telephone. Based on our experiences, one DCS can manage 80-100 patients. 
The maximum number of patients in treatment at any given time in this trial will not exceed 80.  
 
Usual Care  
This arm was modeled after the IMPACT trial control group.36 At the pre-treatment visit, patients will be 
informed of their depression diagnosis and group assignment, will be provided with a list of local mental health 
services (with contact information) available to Eskenazi patients, and will be encouraged to follow-up with their 
primary care provider regarding their depression. These patients will also be reminded (from the informed 
consent statement) that, although we will pass along information to their primary care provider, participants in 
this group do not receive any depression treatment from the study team; instead,  all depression treatments 
that participants in this group receive during the study are delivered by their usual providers. The patient’s PCP 
will also receive a letter indicating that their patient has a depressive disorder and was randomized to usual 
care. This letter will encourage the PCP to follow-up with their patient to address their depression, will note that 
there are no restrictions on the care that these patients can receive, and will provide the same list of Eskenazi 
mental health services given to patients. Although this feedback could result in treatment that would not have 
occurred naturally in primary care, informational support alone is unlikely to improve depression outcomes.180 
Moreover, our pilot trial indicates that depression outcomes achieved with usual care in targeted clinics remain 
suboptimal (see c2.2). Patients in both arms will continue to have access to services that are part of usual care 
in the targeted systems. There will be no restrictions on the care received, although new depression treatments 
received outside of the trial are discouraged in the eIMPACT group. 
 
Assessments 


Revision Date: July 13, 2018 
 
 
 
Pre-Treatment*  
(0 months) 
Mid-Treatment†  
(6 months) 
Post-Treatment*  
(12 months) 
Annual Calls†     
(2-4 calls) 
Endothelial Dysfunction (Primary Outcome) 
X 
 
X 
 
Atherogenic Physiologic Factors (Secondary Outcomes) 
X 
 
X 
 
Depressive Symptoms (Secondary Outcome) 
X 
X 
X 
X 
CVD Events (Exploratory Outcome) 
 
X 
X 
X 
Atherogenic Behavioral Factors 
X 
X 
X 
X 
Conventional CVD Risk Factors 
X 
 
X 
 
Miscellaneous Factors 
X 
X 
X 
X 
*Clinical Research Center Visit. †Telephone Call. 
 
Endothelial Dysfunction (Primary Outcome) 
Patients will undergo FMD assessments at Dr. Gupta’s laboratory in accordance with consensus guidelines.81 
Dr. Gupta as well as Ms. Grounds and Ms. Scott (our vascular ultrasonographers) have undergone certified 
training through the University of Wisconsin Brachial Artery Reactivity Testing Symposium. Our group has 
performed 700+ FMD assessments in the past 10 years. We utilize a GE Logiq E ultrasound system with 
AccessPoint 2011 software. To illustrate the reproducibility of our results, we performed paired FMDs over 1-4 
weeks in 11 healthy volunteers in 2013. Intraclass correlations for baseline diameter, reactive hyperemia, and 
FMD were 0.98, 0.98, and 0.70, which compare favorably to other laboratories.181-183  
 
After a 10-minute supine rest, high-resolution baseline images of the brachial artery will be obtained from 3 
consecutive cardiac cycles. Next, the forearm cuff will be inflated to 250 mmHg for 5 minutes and then rapidly 
deflated. At 60 and 90 seconds post deflation, images from 3 consecutive cardiac cycles will be acquired. 
Brachial diameters will be measured at peak R wave. FMD values will be computed as % increase in diameter 
at 60 or 90 seconds post deflation196,197 (the larger of the two values). Percent change in reactive hyperemic 
flow velocities will also be computed to ensure that sufficient shear stress triggers were induced. 
 
Atherogenic Physiologic Factors (Secondary Outcomes) 
To quantify autonomic function, we will assess high-frequency heart rate variability, a parasympathetic index, 
following established guidelines.184,185 See our paper186 for complete details. Briefly, using an electrode 
arrangement recommended by Qu et al.,187 a HIC-2000 impedance cardiograph, and MindWare software, 
estimates of high-frequency heart rate variability (ln of ms2/Hz) will be derived by spectral analysis (bandwidth: 
0.15-0.40 Hz) from 1-minute epochs of ECG data obtained during the last 5 minutes of a 10-minute rest period. 
To control for the influence of respiration rate on high-frequency heart rate variability, participants will complete 
a paced-breathing computer task set to a normal resting rate of 12 breaths/minute during ECG data collection.  
Values will be corrected for respiration.188,189 Blood samples obtained by research nurses from the median 
cubital vein will be centrifuged within 20 minutes. Plasma aliquots will be frozen at -80°C until the time of assay 
at the Indiana CTSI Clinical Research Assay Laboratory directed by Dr. Considine. To quantify systemic 
inflammation, we will measure IL-6 and CRP levels using R&D Systems ELISA kits. To quantify platelet 
activation, we will measure levels of platelet-specific release products, β-thromboglobulin (BTG) and platelet 
factor 4 (PF4),190 using R&D Systems ELISA kits. The remaining plasma aliquots will saved for possible future 
assays. Assistants scoring the autonomic data and performing the assays will be blind to assignment. 
 
Depressive Symptoms (Secondary Outcome)  
Like the IMPACT trial,36 we will assess depressive symptoms with 20 depression items of the Symptom 
Checklist-90 (SCL-20), a reliable and valid measure.191-194 We will examine total score and % remitted. We also 
added an item (”Sleeping too much") to the SCL-20 to measure this symptom of atypical depression that was 
not including in the original questionnaire. We will also administer the PHQ-9 to assess depressive symptoms.  
 
CVD Events (Exploratory Outcome) 
Our exploratory outcome, modeled after the JUPITER trial,195 is time to first major CVD event, defined as: CVD 
death (ICD-10 I20-I25 or I60-I69 the first-listed cause of death); nonfatal MI (CK-MB >3.0 ng/ml, troponin >0.3 
μg/L, or ICD-9 410); nonfatal stroke (ICD-9 430-432, 433.01, 433.11, 433.21, 433.31, 433.91, 434.01, 434.11, 
434.91); unstable angina requiring hospitalization (inpatient admission ICD-9 411.1); and revascularization – 
i.e., percutaneous coronary intervention (ICD-9 00.66, 36.03, 36.06, 36.07, 36.09; CPT 92980-92984, 92995, 
92996) or coronary artery bypass graft (ICD-9 36.10-36.19; CPT 33510-33536). Because recruitment will occur 
during Years 01-02, the mean observation period will be 4 years (1-year intervention period plus 3-year follow-


Revision Date: July 13, 2018 
up period), with a range of 3-5 years. The Regenstrief programmer who worked on our IMPACT study35 will 
identify candidate CVD events by searching the INPC every 6 months (blind to assignment), with the last 
search performed on the end date. To capture the small number of events that may occur outside of the INPC 
catchment area, patients will complete a CVD questionnaire at mid- and post-treatment and during the follow-
up calls. If a reported event is not in the INPC, we will request medical records from the patient to confirm the 
event. Our cardiologist (Dr. Kovacs), also blinded, will use standardized criteria to adjudicate all CVD events 
for this exploratory outcome. Dr. Kovacs has served on endpoint committees for past trials. When needed, Dr. 
Kovacs will consult with the cardiologist on the DSMB (also blinded). Given that we are coding “harder” events 
and that many events will be positive for multiple markers, it is unlikely that coded events will be misclassified. 
We may fail to detect (and thus initially misclassify) a few events through INPC, which is why we are obtaining 
patient reports and medical records. 
 
Atherogenic Behavioral Factors 
The BRFSS Tobacco Use Questionnaire, International Physical Activity Questionnaire, and the Morisky 
Questionnaire (MMAS-8) will assess tobacco use, physical activity, and adherence to cholesterol and blood 
pressure medications, respectively. Each scale possesses strong psychometric properties.196-198  
 
Conventional CVD Risk Factors 
SBP and DBP will be the mean of the last 2 of 3 readings.199 Fasting cholesterol, glucose, insulin, and HbA1c 
will be quantified using standard methods. BMI will be computed from measured height and weight.  
 
Miscellaneous Factors 
Standard questions from our pilot studies will be used to assess demographics, medical history/update, 
psychiatric history/update, and current medications. Depression care variables (e.g., dose and duration of 
antidepressants, # and type of psychotherapy sessions) will be extracted from the treatment notes for 
eIMPACT patients. To obtain additional depression care data, all patients will complete a brief interview at the 
mid- and post-treatment visits and during the follow-up calls. Consistent with approved Authorization Form for 
this study, we will also periodically extract relevant depression treatment data (e.g., dose and duration of 
antidepressants) from the electronic medical record for all patients. We will also assess anxiety symptoms 
using the Generalized Anxiety Disorder-7 (GAD-7),200 hostility/anger using the Buss-Perry Aggression 
Questionnaire,201 trait positive affect using the Positive Affect subscale of the Positive and Negative Affect 
Schedule (PANAS),202,203 and sleep quality using the Pittsburgh Sleep Quality Index,203 all of which are widely 
used and validated instruments. We will also assess depression treatment satisfaction using an item employed 
in other recent depression trials conducted on the IUPUI campus and for the occurrence of any potential 
adverse events using a brief questionnaire. Finally, the Regenstrief programmer will identify potential adverse 
events by searching the INPC every 6 months (before DSMB meetings) for emergency department visits, 
hospitalizations, and deaths. 
 
All items of the questionnaires to be administered at the pre-treatment visit (see Appendix 2), mid-treatment 
visit (see Appendix 3), post-treatment visit (see Appendix 4), and annual follow-up calls (see Appendix 5) can 
be found in the appendices. 
 
Suicidal Ideation Protection Protocol 
 
For the entire protocol, see Appendix 6. 
 
6.0 Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or Others 
 
We have developed a Data and Safety Monitoring Plan and Board to ensure the safety of participants and to 
monitor data quality and participant recruitment, accrual, and retention. 
 
Data and Safety Monitoring Plan: 
• 
If an adverse event occurs, its severity will be promptly graded using the following scale: 
1. Mild: Awareness of sign or symptom but easily tolerated 
2. Moderate: Interference with normal daily activities 
3. Severe: Inability to perform normal daily activities  


Revision Date: July 13, 2018 
4. Life Threatening: Immediate risk of death from the reaction as it occurred 
• 
After grading severity, the attribution of the adverse event will be graded using the following scale: 
1. Definite: Adverse event clearly related to study involvement 
2. Probable: Adverse event likely related to study involvement 
3. Possible: Adverse event may be related to study involvement 
4. Unlikely: Adverse event doubtfully related to study involvement 
5. Unrelated: Adverse event clearly not related to study involvement 
• 
All adverse events that meet the IUPUI IRB prompt reporting requirements (i.e., unexpected, related or 
possibly related to participation in the research, and suggest that the research places subjects or others 
at a greater risk of harm than was previously known or recognized) will be reported the IUPUI IRB, 
CRC Research Subject Advocate, and NIH immediately. All other adverse events will be reported to 
these entities at the time of continuing review. 
• 
A summary of adverse event data (frequency, types, and corrective actions) will be provided to the 
IUPUI IRB, CRC Research Subject Advocate, and NIH at the time of continuing review. 
 
Data and Safety Monitoring Board: 
• 
A 4-member, independent Data and Safety Monitoring Board (DSMB) will be formed to provide 
independent oversight. The DSMB will consist of a psychiatrist (from the Indiana University Department 
of Psychiatry), a cardiologist (from the Indiana University Krannert Institute of Cardiology), a clinical 
trialist (from the Indiana University Department of Biostatistics), and a medical ethicist (from the Indiana 
University Center for Aging Research), all of whom will not be part of the study team. 
• 
Adverse events that are severe, life-threatening, or unanticipated will be immediately reviewed by the 
DSMB. At 6-month intervals, the DSMB will prepare a formal report of participant recruitment, accrual, 
retention, data quality, and adverse events. At that time, the DSMB will also determine whether the 
study should continue unchanged, be modified, or be stopped. The IUPUI IRB, CRC Research Subject 
Advocate, and NIH will receive copies of all DSMB reports at the time of continuing review. 
 
7.0 Study Withdrawal/Discontinuation 
 
All participants will be considered enrolled at the end of the ResNet interview. The informed consent statement 
describes the possibility of and the procedures for withdrawing from the study. A participant may notify either 
the principal investigator or any member of the research team at any time via email, phone, or in-person that 
s/he wants to withdraw from the study for any reason. The schedule of participant reimbursement is as follows: 
$100 for the pre-treatment visit, $25 for the mid-treatment call, $100 for the post-treatment visit, $20 for each of 
the annual follow-up calls, and up to $10 per visit to cover parking or transportation costs. If a participant 
withdraws before the pre-treatment assessment visit, no payment will be provided.  
 
Other reasons for study withdrawal/discontinuation are (a) the participant’s primary care provider or another 
provider seeing the participant (e.g., a psychiatrist outside of the study team) no longer believes that his/her 
patient is appropriate for this trial after a triggering of the Suicidal Ideation Protection Protocol or any other 
reason, (b) the participant develops acute or serious illness that precludes completion of the main study visits 
within the allowed timeframes, and (c) the participant, in the assessment of the eIMPACT psychiatrist, exhibits 
evidence of a psychotic disorder or bipolar disorder (both of which are exclusionary conditions and could 
interfere with treatment delivery/effectiveness) during the 1-year treatment phase of the trial. In the case of 
situation (b), the patient will not complete any future study visits or calls. However, if the patient provides 
permission, electronic medical record data (e.g., incident CVD events) will still be obtained going forward, 
consistent with our Authorization Form. In the case of situation (c), patients with a psychotic disorder or bipolar 
disorder would likely benefit from psychotropic medications, such as antipsychotic medications or mood 
stabilizer, that are beyond what are provided in this trial. 
 
For Usual Care patients who score in the “severe depression” range (20-27) on the PHQ-9 at the mid-
treatment (6 months), the DCS (a) will contact the patient's primary care provider in person, by phone, or 
through the electronic medical record to notify the provider of the patient's high depressive symptoms and to 
urge the provider to follow-up and (b) will provide a list of local mental health services, including referral to a 
psychiatrist outside of the study team. In addition, participants in both treatment groups who continue to exhibit 


Revision Date: July 13, 2018 
elevated depressive symptoms (PHQ-9 ≥10) at post-treatment will be will urged to follow-up with their primary 
care providers regarding their depression. Their providers will also receive a letter from the study team 
indicating that their patient has completed participation in the treatment phase of the trial and continues to have 
elevated depressive symptoms. This letter will also urge physicians to follow-up with their patients and will 
provide a list of local mental health services. Finally, for participants in both treatment groups who score in the 
“severe depression” range (20-27) on the PHQ-9 during an annual follow-up call, the DCS (a) will contact the 
patient's primary care provider in person, by phone, or through the electronic medical record to notify the 
provider of the patient's high depressive symptoms and to urge the provider to follow-up and (b) will provide a 
list of local mental health services, including referral to a psychiatrist outside of the study team. 
 
8.0 Statistical Considerations 
 
Sample Size and Power Considerations  
 
Endothelial Dysfunction  
Using the effect size of depression treatment on FMD from our pilot trial, we need 88 patients (44 per arm) to 
detect a group difference in FMD of 1.7% (d = 0.61) at 12 months, assuming a power level of 0.80 and a Type I 
error of 0.05. This would be a clinically relevant difference. Assuming a conservative attrition rate of 20%,204 we 
will have 172 completers (220 x .80) for FMD, yielding power levels of 0.98 for d = 0.61 and 0.80 for d = 0.43.  
 
Candidate Mechanisms  
We expect at a power level ≥0.80 for the candidate mechanisms (Hypotheses 2-5), as we will be able to detect 
effect sizes as small as d = 0.43 with 172 completers. In our IMPACT study35 and pilot trial, effect sizes for 
depressive symptoms (d = 0.69 and 1.33), IL-6 (d = 0.43), and CRP (d = 0.78) were in the medium-to-large 
range. In other studies, effect sizes of 0.52 were found for psychological interventions on heart rate 
variability,205-207 1.00 for SSRIs on IL-6,143 0.74 for SSRIs143 and 0.85 for CBT138 on CRP, 0.91146 and 0.46144 
for SSRIs on BTG, and 0.87 for SSRIs on PF4.144  
 
CVD Events  
Over the mean observation period of 4 years, we anticipate a cumulative CVD event rate of 20% (39 events) 
and a 25% lower relative risk (HR ≤ 0.75) in eIMPACT versus usual care. These estimates are reasonable, as 
we observed a CVD event rate of 24% and a 46% lower relative risk (event rate: 18% vs. 31%) in our IMPACT 
secondary analysis that had a 4-year observation period. Our high-risk sample will differ from the typical 
sample of a risk reduction trial in that (a) all patients will have depression and ≥1 CVD risk factor and (b) many 
will be of low SES and/or African American, two groups at elevated risk for CVD event.1,171 Although we expect 
to have CVD event data for nearly all patients, we assume a conservative attrition rate of 10%, leaving 194 
completers. As is typical of Phase 2 trials, our trial is not designed to detect a statistically significant difference 
in clinical events; however, a 25% relative risk reduction would be a clinically relevant signal (statin therapy 
reduces risk by ≈30%156) and has been used to power recent event-driven Phase 3 cardiology trials.157  
 
Statistical Analyses 
 
We will use the intent-to-treat approach.208 All tests will be two-tailed with p <.05 considered significant. 
Supplemental analyses of completers will be performed. We will assess for differences in all baseline factors. 
Due to randomization, we do not expect baseline group differences. Even so, any differences will be taken into 
account when interpreting results, and any baseline factors that differ between the groups will be included as 
covariates in sensitivity analyses. Aim 1: We will test our hypothesis that eIMPACT patients will exhibit greater 
improvement in endothelial dysfunction (Hypothesis 1) by performing a two-sample t-test with FMD at 12 
months as the dependent variable. If there is a group difference in baseline FMD, analyses of covariance 
(ANCOVAs) adjusting for baseline level will also be performed. We will also explore whether eIMPACT patients 
show a clinically relevant reduction (25% lower relative risk) in CVD events by running a Cox proportional 
hazards model with treatment group predicting time to first CVD event. Patients will be censored at non-CVD 
death or the end date. We expect to observe a HR ≤ 0.75. Aim 2. We will test our hypotheses that eIMPACT 
patients will exhibit greater decreases in the candidate mechanisms (Hypotheses 2-5) by performing two-
sample t-tests with SCL-20 score, high-frequency heart rate variability, IL-6, CRP, BTG, and PF4 at 12 months 
as the dependent variables. If baseline group differences are found, ANCOVAs adjusting for baseline level will 


Revision Date: July 13, 2018 
also be performed. To explore whether decreases in the candidate mechanisms are associated with 
improvements in endothelial dysfunction, we will compute correlations between 12-month change in each 
mechanism and in FMD. To explore whether decreases in the candidate mechanisms are partial mediators of 
eIMPACT’s hypothesized cardioprotective effect, we will conduct exploratory mediation analyses using 
MacKinnon’s approach, which has greater power than others.209 First, to quantify the treatment effect on each 
mechanism (“a" coefficients), we will perform linear regressions with treatment group predicting 12-month level 
of each mechanism. Second, to quantify the effect of each candidate mechanism on endothelial dysfunction 
("b" coefficients), we will perform linear regressions with 12-month level of each mechanism predicting 12-
month FMD in the presence of treatment group. Third, the significance of each mediation effect will be tested 
using MacKinnon and Lockwood’s product of coefficients (“ab”) method employing asymmetric confidence 
limits.209,210 If this test is significant, the selected mechanism is a partial mediator of the treatment effect on 12-
month FMD. Of note, we will also explore (a) if changes in depressive symptoms are correlated with changes 
in the atherogenic physiologic factors and (b) if changes in FMD predict CVD events. 
 
Supplemental, Hypothesis-Generating Analyses 
 
(1) We will explore atherogenic behavioral factors, conventional CVD risk factors, and depression care 
variables as potential mechanisms of eIMPACT’s effect on FMD by repeating Aim 2 analyses. (2) To explore 
the separate effects of intervention components (which likely have shared and unique pathways; Figure 1), Aim 
1 and 2 analyses will be repeated after coding the treatment variable as follows: eIMPACT both components, 
eIMPACT antidepressants only, eIMPACT psychotherapy only, eIMPACT neither component, and usual care. 
(3) We will explore sex and race/ethnicity as moderators of the treatment effect on the outcomes. (4) We will 
estimate the cost per patient of providing eIMPACT, including charges for BtB, DCS, psychiatrist and primary 
care expert supervision, materials, and a telephone line. 
 
9.0 Privacy/Confidentiality Issues 
 
Participants will be screened and consented in the privacy of their homes via telephone and/or in private rooms 
at the targeted primary care clinics or the CRC. All procedures will take place in private rooms at the CRC, Dr. 
Stewart’s Cardiovascular Behavioral Medicine Laboratory, the targeted primary care clinics, or a location 
selected by the patient, such as their home or a family member’s/friend’s home (for the follow-up calls and the 
telephonic and computerized components of the eIMPACT intervention). All research material will be kept 
strictly confidential. All study personnel have completed Collaborative Institutional Training Initiative (CITI) 
courses in human subjects research and will make every effort to ensure confidentiality. All electronic and hard 
copy data will be identified using only the unique participant number assigned when each individual is enrolled 
in this study (participant identifying information will not be included). All electronic data will be saved on 
password-protected and encrypted computers and secure servers, and all hard copy data will be stored in 
secure and locked file cabinets. The key linking participant names with the participant numbers will be kept in a 
separate secure and locked file cabinet. Data will be analyzed and reported as an aggregate, with no individual 
identifying information. 
 
10.0 Follow-Up and Record Retention 
 
For Usual Care patients who score in the “severe depression” range (20-27) on the PHQ-9 at the mid-
treatment (6 months) or post-treatment (12 months) assessments, the DCS (a) will contact the patient's 
primary care provider in person or by phone to notify the provider of the patient's high depressive symptoms 
and to urge the provider to follow-up and (b) will provide a list of local mental health services, including referral 
to a psychiatrist outside of the study team. In addition, participants in both treatment groups who continue to 
exhibit elevated depressive symptoms (PHQ-9 ≥10) at post-treatment will be will urged to follow-up with their 
primary care providers regarding their depression. Their providers will also receive a letter from the study team 
indicating that their patient has completed participation in the treatment phase of the trial and continues to have 
elevated depressive symptoms. This letter will also urge physicians to follow-up with their patients and will 
provide a list of local mental health services. 
 


Revision Date: July 13, 2018 
While the study duration is five years, all study documents will be kept up to seven years after study 
completion. After this time, we will permanently delete patient identifying data and shred all paper records, per 
Indiana State law. This process prevents any opportunity for a breach of confidentiality to occur.  
 
 


Revision Date: July 13, 2018 
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ICF_001.pdf: 
IRB Study 1411802537 
 
Version 5 6/15/2018 
eIMPACT Trial: 
Modernized Collaborative Care to Reduce the Excess CVD Risk of Older Depressed Patients 
(ClinicalTrials.gov ID: NCT02458690) 
 
Informed Consent Statement 
7/13/2018 
 
 
 


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INDIANA UNIVERSITY INFORMED CONSENT STATEMENT FOR 
 
eIMPACT Trial: 
Modernized Collaborative Care to Reduce Excess CVD Risk of Older Depressed Patients 
 
You are invited to participate in a research study examining whether a new depression treatment can help 
prevent cardiovascular disease (CVD).  You were selected as a possible participant because your medical 
records showed that you are a patient at an Eskenazi Health or Indiana University Health primary care clinic, 
are 50 years or older, and have one or more risk factors for CVD but have not developed CVD.  Your responses 
to our depression questions also show that you may have a depressive disorder.  Before you decide if you want 
to be a part of this study, we want you to know about it. 
 
The study is being conducted by Dr. Jesse C. Stewart from the Department of Psychology at Indiana University-
Purdue University Indianapolis (IUPUI) and other researchers from the Indiana University School of Medicine.  
It is supported by a research grant from the National Institutes of Health. 
 
This is a consent form.  It gives you information about this study.  The study staff will talk with you about this 
information.  You are free to ask questions at any time.  You will have as much time as you need to decide if 
you would like to participate.  If you agree to participate, you will be asked to sign this consent form, and you 
will get a copy to keep. 
 
STUDY PURPOSE 
 
CVD is the leading cause of death of American men and women.  Medical research has shown that people who 
are depressed today have a higher risk of CVD in the future, similar to people with high cholesterol.  In other 
words, depression is a new risk factor for CVD.  The main symptoms of depression are (1) feeling down, 
depressed, or hopeless and (2) having little interest or pleasure in doing things.  The purpose of this study is to 
compare a new depression treatment to standard depression treatment to see if our new treatment lowers the risk 
of developing CVD. 
 
People who agree to participate will be randomly assigned to one of two groups, as if a coin were flipped to 
decide.  If you are assigned to Group A (standard depression treatment), you will be referred back to your 
primary care provider, and he or she will decide how to treat your depression.  If you are assigned to Group B 
(new depression treatment), you will receive up to a year of our eIMPACT treatment.  A licensed mental health 
counselor (LMHC) will work with you and your primary care provider to treat your depression.  Established 
treatments will be available to you, like antidepressant medications and talk therapy.  You will also have the 
opportunity to receive newer treatments, like talk therapy on a computer or over the phone.  If your depression 
does not improve, the treatment will be changed to see if another one works better for you. 
 
We plan to use the data from this study to develop depression treatments that could be easily used in primary 
care clinics.  We hope that these depression treatments will help prevent CVD. 
 
STUDY PARTICIPANTS 
 
This trial will include primary care patients who are at least 50 years old, have one or more risk factors for CVD 
but have not developed CVD, and screened positive for a depressive disorder.   
 
 
 


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NUMBER OF PEOPLE TAKING PART IN THE STUDY 
 
If you agree to participate, you will be one of up to 220 men and women participating in this study locally. 
 
PROCEDURES FOR THE STUDY 
 
If you agree to be in the study, you will be asked to attend a pre-treatment visit, a mid-treatment call 
approximately 6 months later, and a post-treatment visit approximately 12 months later.  For participants 
assigned to eIMPACT (Group B), you will be asked to complete additional visits and calls to receive the 
depression treatment.  Finally, all participants will be asked to complete yearly follow-up calls.  Each visit and 
call is described below. 
 
Pre-Treatment Visit (All Participants) 
Within two weeks, you will be asked to come to the Indiana Clinical Research Center (CRC) at Indiana 
University Hospital for the 3-hour pre-treatment visit.  You will need to fast (nothing to eat or drink, except for 
water) and avoid tobacco products or exercise for at least 8 hours before the visit.  You may use water with your 
medications, but if you need to take medications with food, please bring them with you so you can take them 
after the visit. 
 
At the pre-treatment visit, you will have your height, weight, blood pressure, heart rate, and temperature 
measured by a nurse.  The nurse will complete a standard blood draw to collect 1½ tablespoons of blood.  This 
is similar to what your doctor would collect for usual blood tests.  You will then be asked to fill out 
questionnaires on a secure computer in a private room.  These questionnaires will ask you for basic background 
information, your medical and psychiatric history, and your medications.  You will also be asked about your 
behaviors, such as smoking, exercise, and medication taking.  Finally, you will be asked about your mood and 
sleep. 
 
The research assistant will then place three small sensors on your shoulder and lower ribs to measure your heart 
rate.  You will then be asked to rest in a bed for 10 minutes.  The ultrasound test will then be completed to 
measure your blood vessel function.  An ultrasound scan, which is a standard medical test, is painless and 
involves bouncing sound beams off an artery in your arm so it can be seen on a computer screen.  A blood 
pressure cuff will then be placed on your lower arm and inflated for about 5 minutes.  While the cuff is inflated, 
your hand will be uncomfortable.  This is unavoidable and expected, and it will be relieved within a few 
minutes after the cuff is deflated.  Next, another ultrasound scan of the artery in your arm will be done. 
 
At the end of this visit, your mid-treatment phone call and post-treatment visit will be scheduled.  You will be 
randomly assigned to Group A or Group B, as if a coin were flipped to decide.  You will be notified of your 
group assignment.  No matter which group you are assigned to, you and your doctors will continue to make 
your own treatment decisions.  Neither you nor your doctors will be able to choose your group assignment.  If 
you are assigned to Group B (new depression treatment), you will briefly speak to the depression clinical 
specialist over FaceTime to learn about depression treatment materials and schedule your first session. 
 
Treatment for Group A 
If you are assigned to Group A (standard depression treatment), you will be informed that you screened positive 
for depression, will be provided with a list of mental health services available to Eskenazi patients, and will be 
encouraged to follow-up with your primary care provider regarding your depression. Your primary care 
provider will also receive a letter from our team informing him/her of your depression and assignment to Group 
A. This letter will also encourage your provider to work with you to address your depression and will provide 
the same list of available mental health services that we will give to you. Please note that, although we will pass 


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along information to your primary care provider, participants in Group A do not receive any depression 
treatments from the study team. Instead, depression treatments that participants in Group A receive during the 
study are from their usual providers, like their primary care provider. Also please note that there are no 
restrictions on the care that you can receive during the study, meaning that you will continue to have access to 
and will receive any health services that are part of your usual care.  
 
Treatment for Group B 
If you are assigned to Group B (new depression treatment), you will receive up to one year of our eIMPACT 
treatment.  A Master’s-level licensed mental health counselor, called a depression clinical specialist (DCS), will 
call you within two weeks of your pre-treatment visit.  During this call, the DCS will review depression 
materials and discuss treatment options.  The DCS will then work with your primary care provider to develop a 
treatment plan.  Initial treatment options include 2-3 months of Beating the Blues, a computerized therapy for 
depression, or an antidepressant medication, whichever you prefer. 
 
If you select Beating the Blues, you will have the opportunity to complete eight 50-minute therapy sessions, one 
per week.  Sessions will take place at Indiana University Hospital, at Dr. Stewart’s office, at your primary care 
clinic, or at a location selected by you where you can access a computer with internet, such as your home, your 
work, a family member’s/friend’s home, or a public library. Your preference will drive the location of the 
sessions. 
 
Beating the Blues is a computer program, so you will not be meeting face-to-face with a therapist.  Through 
completing the sessions on a computer, you will learn techniques that have been shown to improve depression.  
These techniques include examining unhelpful thoughts, scheduling pleasurable activities, and problem solving.  
The topics will be designed for your specific needs, and you can work through the sessions at your own pace.  
Between these sessions, you will be given projects to help you learn how to use the techniques.  This program 
can be used by people with little computer experience.  If you select an antidepressant medication, it will be 
prescribed by your primary care provider and monitored by the DCS and your provider. 
 
The DCS will be in regular contact with you during the 12 months to monitor your response to treatment.  The 
DCS will share your progress with your primary care provider.  Initially, the DCS will contact you at least every 
2 weeks.  After your depression improves, the DCS will contact you once a month.  If your depression does not 
improve, the DSC will call you to discuss other treatment options, including adding or switching to (a) Beating 
the Blues or talk therapy over phone or FaceTime or (b) another antidepressant medication.  If your depression 
still does not improve, you may be seen by the study psychiatrist to discuss other treatment options.  The main 
idea is that, if your depression does not improve, your treatment will be changed to see if another one works 
better for you.   
 
You will continue to have access to and will receive any health services that are part of your usual care.  There 
will be no restrictions on the care you can receive, although starting new depression treatments outside of the 
study is discouraged during the 1-year treatment period if you are assigned to Group B. 
 
On occasion, FaceTime will be used to make contact with the DCS. This program encrypts information that is 
sent and is a secure form of communication.  We will not record any sessions in this study, including FaceTime 
contacts. 
 
Mid-Treatment Call at 6 months (All Participants) 
About 6 months after the pre-treatment visit, you will be asked to complete questionnaires over the phone for 
about 45 minutes.  Many of the questionnaires completed at the start of the study will be repeated.  You will 


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also be asked about whether you have experienced any CVD events since the start of the study.  If you have had 
a CVD event, we may request medical records related to the event. 
 
Post-Treatment Visit at 12 months (All Participants) 
About 12 months after the pre-treatment visit, you will be asked to come back to the CRC at Indiana University 
Hospital for the 3-hour post-treatment visit.  This visit will be identical to the pre-treatment visit.  In addition, 
you will be asked about whether you have experienced any CVD events since the mid-treatment call.  If you 
have had a CVD event, we may request medical records related to the event. 
 
Annual Follow-up Calls (All Participants) 
Depending on when you enrolled in this study, you will be asked to complete 2-4 yearly follow-up calls.  These 
calls will be identical to the mid-treatment call. 
 
Study Newsletters at 3 and 9 months 
About 3 and 9 months after you enrolled in this study, the study team will mail a study newsletter to your home 
address.  Each newsletter will be one page and will include an update from the Principal Investigator, a heart 
healthy recipe, profiles for the eIMPACT team members, and a reminder to update the study team if your 
contact information has changed.   
 
RISKS OF TAKING PART IN THE STUDY 
 
Risk of a possible loss of confidentiality 
All study personnel are trained in human subjects protection and will make every effort to ensure that your 
confidential information is kept confidential and secure.  
 
Risk of possibly experiencing emotional discomfort when completing questionnaires or interviews 
The interviews and questionnaires will be completed in a private room.  The research assistants are experienced 
and will be sensitive to the nature of the questions.  You may terminate the interviews or questionnaires at any 
time for any reason.  You may choose to not answer any question. 
 
Risks of the standard blood draw 
Trained and experienced nurses will use the standard approach (inserting a needle into a vein) to obtain a blood 
sample.  This can be mildly painful, and there is a very low risk of bruising, fainting, or a skin infection.  You 
may terminate the blood draw at any time for any reason. 
 
Risks of the ultrasound scan 
The ultrasound scan is a painless test that has no short- or long-term risks.  The test usually causes a moderate 
uncomfortable feeling in your arm and hand because a blood pressure cuff is tightly inflated on your arm.  The 
cuff will be inflated to a level similar to what you would experience in your regular physician’s office.  The 
uncomfortable feeling is relieved within a few minutes after the cuff is deflated.  You may terminate the 
ultrasound scan at any time for any reason, including if the cuff becomes too uncomfortable. 
 
Suicidal Thoughts 
Because this study involves people with depression, some participants may report thoughts of being better off 
dead or of hurting themselves.  This could happen during a telephone call or an in-person visit.  IF this occurs, 
our protection plan will be used.  You will first be asked follow-up questions.  Dr. Stewart (a clinical 
psychologist) and the study psychiatrist will review the information the same day to determine the right course 
of action.  If we believe that you are in imminent danger of harm, we will have to report it, potentially to 
authorities including the police, for your own protection.  We may contact your primary care provider and the 


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behavioral health clinician in your primary care clinic.  We may also consult with Midtown Community Mental 
Health Center and escort you to the Crisis Intervention Unit at Eskenazi Hospital.  If you prematurely terminate 
a phone call after reporting suicidal thoughts, Dr. Stewart and the study psychiatrist will determine the right 
course of action and may carry out any of the steps described above.  After getting input from your primary care 
provider, we may decide that is important for your own safety to end your participation in this study. 
 
BENEFITS OF TAKING PART IN THE STUDY 
 
You may receive no direct benefits from participating in this study.  By taking part in the study, you will also 
learn about the relationship between depression and cardiovascular disease at the post-treatment visit.  In 
addition, participants in Group A will be informed that they screened positive for depression, and their provider 
will be encouraged to work with participants to address their depressive symptoms.  Participants in Group B 
will receive 12 months of our new depression treatment free of charge.  Finally, participants may feel satisfied 
knowing that their involvement will generate knowledge that may help to treat depression and prevent 
cardiovascular disease in the future. 
 
ALTERNATIVES TO TAKING PART IN THE STUDY 
 
Instead of being involved in this study, you have the option to not participate.  If you decide not to participate, 
you may choose to seek depression treatment outside of the study.  The leading treatments for depression are 
antidepressant medications and psychotherapy.  You may want to contact your primary care provider to discuss 
treatment options.  If you choose not to participate, your decision will not affect your regular healthcare or your 
relationship with the study team. 
 
CONFIDENTIALITY 
 
Efforts will be made to keep your personal information confidential.  We cannot guarantee absolute 
confidentiality.  Your personal information may be disclosed if required by law.  Your identity will be held in 
confidence in reports in which the study may be published. 
 
Organizations that may inspect and/or copy your research records for quality assurance and data analysis 
include the study investigators and their research associates, the Indiana University Institutional Review Board 
or its designees, the Indiana Clinical Research Center, the study sponsor (the National Heart Lung and Blood 
Institute/National Institute of Health), and state or federal agencies (for example, the Office for Human 
Research Protections). 
 
A description of this clinical trial is available on ClinicalTrials.gov, as required by U.S. Law.  This website will 
not include information that can identify you.  At most, the website will include a summary of the results.  You 
can search this website at any time. 
 
For the protection of your privacy, this research is covered by a Certificate of Confidentiality from the National 
Institutes of Health. The researchers may not disclose or use any information, documents, or specimens that 
could identify you in any civil, criminal, administrative, legislative, or other legal proceeding, unless you 
consent to it. Information, documents, or specimens protected by this Certificate may be disclosed to someone 
who is not connected with the research: 
 
(1) If there is a federal, state, or local law that requires disclosure (such as to report child abuse or 
communicable diseases);  


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(2) if you consent to the disclosure, including for your medical treatment;  
(3) if it is used for other scientific research in a way that is allowed by the federal regulations that 
protect research subjects 
(4) for the purpose of auditing or program evaluation by the government or funding agency 
  
 
You should understand that a Certificate of Confidentiality does not prevent you from voluntarily releasing 
information about yourself. If you want your research information released to an insurer, medical care 
provider, or any other person not connected with the research, you must provide consent to allow the 
researchers to release it. 
 
 
COSTS 
 
There are no costs directly associated with participation in this study.  The costs of all study-related tests will be 
provided by the study.  However, taking part in this study may lead to added costs to you or your insurance 
company in the unlikely event of physical or emotional injury resulting from participation in this study.  You or 
your insurance company will be responsible for all standard of care procedures, drugs, tests, etc. 
 
PAYMENT 
 
You will receive payment for taking part in this study: $100 cash for completing the pre-treatment visit, a $25 
gift card for completing the mid-treatment call, $100 cash for completing the post-treatment visit, and a $20 gift 
card for completing the each of the annual follow-up calls.  Gift cards will be mailed once the call is completed.  
If you complete all visits and calls, you will receive a total of $265 to $305, depending on the number of follow-
up calls.  You will not be paid for completing any visits or calls related to depression treatment, although if you 
are in Group B, treatment will be provided free of charge.  You will also receive up to $10 per assessment visit 
to cover parking or transportation costs.   
 
COMPENSATION FOR INJURY 
 
In the event of physical injury resulting from your participation in this research, necessary medical treatment 
will be provided to you and billed as part of your medical expenses.  Costs not covered by your health insurance 
will be your responsibility.  It is also your responsibility to determine the extent of your healthcare coverage.  
There is no program in place for other monetary compensation for research-related injuries.  However, you are 
not giving up any legal rights or benefits to which you are otherwise entitled. 
 
CONTACTS FOR QUESTIONS OR PROBLEMS 
 
You are encouraged to ask questions any time during the study.  For questions about the study or a research-
related injury, contact the principal investigator, Dr. Jesse Stewart, at (317) 274-6761.  If you cannot reach the 
Dr. Stewart during regular business hours (8:00 AM to 5:00 PM), please call the Indiana University Human 
Subjects Office at (317) 278-3458 or (800) 696-2949.  In the event of an emergency, you may call 911 and/or 
your primary care provider.  For questions about your rights as a research participant or to discuss problems, 
complaints, or concerns about a research study or to obtain information or offer input, contact the Indiana 
University Human Subjects Office at (317) 278-3458 or (800) 696-2949. 
 
 


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VOLUNTARY NATURE OF STUDY 
 
Taking part in this study is voluntary.  You may choose not to take part or may leave the study at any time.  You 
may do so by notifying any member of the research team (including the principal investigator) at any time by 
email, telephone, or in person.  Not taking part in this study will not affect your general healthcare.  Leaving the 
study will not result in any penalty or loss of benefits to which you are entitled.   
 
The study investigators may need to take you off the study without your permission if we believe that it is not in 
your best interest for you to participate. 
 
SUBJECT’S CONSENT 
 
In consideration of all of the above, I give my consent to participate in this research study.   
 
I will be given a copy of this informed consent statement to keep for my records. 
 
SUBJECT’S SIGNATURE: 
Date: 
 
 
 
(must be dated  by subject) 
 
SUBJECT’S PRINTED NAME:___________________________________________________ 
 
 
      
SIGNATURE OF PERSON OBTAINING CONSENT: 
Date: 
 
 
PRINTED NAME OF PERSON  
OBTAINING CONSENT:________________________________________________________ 
Form date: July 13, 2018