Conditions: Depression Major Depressive Disorder Dysthymic Disorder Depressive Symptoms Type 2 Diabetes PreDiabetes Insulin Resistance
Keywords: Primary Care Cognitive-Behavioral Therapy Computer-Based Psychotherapy Antidepressant Medications
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 46
Healthy volunteers: no

Brief summary:
This pilot randomized controlled trial seeks: (1) to determine the preliminary efficacy of our modernized collaborative care intervention for depression in improving the diabetes risk markers of hemoglobin A1c and insulin resistance and (2) to explore whether somatic depressive symptoms - i.e., hyperphagia (increased appetite/weight) and/or hypersomnia (increased sleep) - moderate the effect of the eIMPACT-DM intervention on diabetes risk markers.

Detailed description:
Diabetes affects 31 million (12%) U.S. adults, and another 82 million (34%) adults have prediabetes, a precursor to diabetes. The ramifications of diabetes are grave and include cardiovascular disease, disability, and death. While these statistics highlight the importance of diabetes prevention, current approaches have only partial effectiveness. This has created a clear need to identify new primary prevention targets and approaches for diabetes, and depression and depression treatment are strong candidates in this regard. Over 20 years of evidence indicates that depression is an independent, clinically important, robust, biobehaviorally plausible, and modifiable risk factor for diabetes. However, research has yet to determine whether depression treatment can prevent the development of diabetes in people with prediabetes. Given that depression is still receiving limited attention in settings where diabetes prevention occurs (e.g., primary care), there is a large cohort of patients with an underdetected or undertreated diabetes risk factor (depression). This status quo and the strong state of the depression-to-diabetes science create the need for a pilot randomized controlled trial to evaluate the utility of depression treatment as a new diabetes prevention strategy. Thus, we propose a pilot RCT of 64 primary care patients (50% minority) with a depressive disorder and prediabetes. Patients will be randomized to 6 months of eIMPACT-DM (intervention) or Active Control (comparator). eIMPACT-DM is our 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 diabetes risk reduction. Our preliminary data establish the feasibility and antidepressive efficacy of eIMPACT-DM. The Active Control consists of depression education, symptom monitoring, and primary care for depression. Our primary aim is to determine the preliminary efficacy of eIMPACT-DM in improving the diabetes risk markers of hemoglobin A1c (primary outcome) and insulin resistance (secondary outcome). Our exploratory aim is to explore whether somatic depressive symptoms - i.e., hyperphagia (increased appetite/weight) and/or hypersomnia (increased sleep) - moderate the effect of eIMPACT-DM on diabetes risk markers. A positive pilot trial would pave the way to an R01-level RCT by: (1) generating critical proof-of-concept data (eIMPACT-DM can improve A1c) to support the premise of the definitive trial; (2) providing preliminary effect sizes for eIMPACT-DM on diabetes risk markers to help justify future power analyses; (3) identifying a potentially important moderator of eIMPACT-DM efficacy that may need to be incorporated into the definitive trial. Ultimately, demonstrating that depression treatment reduces diabetes risk would identify a novel target (depression) for diabetes prevention efforts, and it would equip healthcare providers with a new practical, scalable, and disseminable intervention (eIMPACT-DM) to help lower diabetes risk for a large cohort of high-risk patients. These practice changes should translate into reduced diabetes morbidity, mortality, and costs.

Arms:
arm 1: eIMPACT-DM is a 6-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 diabetes 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 Good Days Ahead, 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 (PCPs). arm 2: Active Control (AC) consists of depression education (study staff), symptom monitoring (study staff), and primary care for depression (clinical staff).

Interventions: intervention 1: Good Days Ahead (GDA) intervention 2: Problem Solving Treatment in Primary Care (PST-PC) intervention 3: Antidepressant Medications intervention 4: Active Control
Intervention descriptions: intervention 1: GDA (Empower Interactive) is an empirically supported, HIPAA compliant, computerized CBT for depression appropriate for primary care patients and people with little computer experience. GDA uses an interactive, multimedia format to deliver 9 45-minute sessions, the structure and content of which mirror face-to-face CBT. General topics include identifying and modifying automatic thoughts, using behavioral activation and other behavioral methods, identifying and modifying schemas, using effective coping strategies, and employing other core CBT methods. GDA is empirically supported - it is acceptable to patients, achieves superior depression outcomes to waitlist comparators, and yields equivalent (noninferior) depression outcomes to standard face-to-face CBT. To minimize time/transportation barriers, GDA sessions occur at the PI's lab or a location with internet access selected by the patient (patient's, family member's, or friend's home). intervention 2: PST-PC is an established, manualized, empirically supported CBT developed for primary care. During the 6-10 30-minute sessions, patients are taught skills for solving problems contributing to depression. We will deliver PST-PC by phone, which has been found to be feasible and efficacious. intervention 3: We first considered all FDA-approved antidepressants and excluded those with weight gain effects (tricyclics, paroxetine, mirtazapine) and those rarely used in primary care (MAOIs). Then, we used existing evidence to inform the structure. We made bupropion (an aminoketone) and fluoxetine (an SSRI) our first-line and second-line antidepressants, as meta-analyses indicate that their use is associated with weight loss. We made other SSRIs (escitalopram, sertraline) and SNRIs (desvenlafaxine, duloxetine, venlafaxine) our third-line antidepressants, given their negligible effects on weight. Our team will make recommendations to the patient's PCP, who will write prescriptions. Our team and the PCP will then collaboratively manage pharmacotherapy. intervention 4: (1) The graduate research assistant (RA) will have a 50-minute call with AC patients to review depression materials. The RA will provide a list of Eskenazi Health mental health services and will encourage patients to follow-up with their PCP. We will then send an electronic health record message to the PCP encouraging them to address their patient's depression, note that there are no care restrictions, and provide the same list of services. (2) The RA will call AC patients every 4 weeks to assess depressive symptoms and will notify clinical staff to encourage additional care when indicated. (3) AC patients will receive current primary care for depression. The Eskenazi Health primary care clinics utilize a team care approach, with PCPs supported by embedded behavioral health clinicians and affiliated psychiatrists.

Protocol document:
Prot_SAP_000.pdf: 
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eIMPACT-DM Pilot Trial: 
Depression Treatment to Reduce the Excess Diabetes Risk 
of People with Depression and Prediabetes 
 
5.19.21 
 
Jesse C. Stewart, PhD 
Principal Investigator 
Department of Psychology 
Indiana University-Purdue University Indianapolis (IUPUI) 
402 N. Blackford St., LD 100E 
Indianapolis, IN 46202 
 
Daniel R. Bateman, MD 
Co-Investigator 
Department of Psychiatry 
Indiana University School of Medicine 
355 W. 16th St., Suite 2800  
Indianapolis, IN 46202 
 
Zeb I. Saeed, MBBS  
Co-Investigator 
Department of Endocrinology 
Indiana University School of Medicine 
541 Clinical Dr. 
Indianapolis, IN 46202 
 
Chandan Saha, PhD 
Co-Investigator 
Department of Medicine 
Indiana University School of Medicine 
410 W. 10th St. 
Indianapolis, IN 46202 
 
Support Provided by: 
NIH/NIDDK (R21 DK123582) 
 
ClinicalTrials.gov Identifier:  
NCT04437485 
 
 
 


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Table of Contents:  
 
Study Schema 
1.0 
Background & Rationale 
2.0 
Objectives 
3.0 
Outcome Measures 
4.0 
Eligibility Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Design 
7.0 
Study Procedures 
8.0 
Study Calendar 
9.0 
Reportable Events and Data Safety Monitoring 
10.0 
Study Withdrawal/Discontinuation 
11.0 
Statistical Considerations 
12.0 
Data Management 
13.0 
Privacy/Confidentiality Issues 
14.0 
Follow-up and Record Retention 
15.0 
References 
16.0 
Appendix: Suicidal Ideation Protection Protocol 


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1.0 
Background & Rationale 
 
A. Significance 
 
A1. Diabetes, prediabetes, and depression are highly prevalent, disabling, and deadly. 
Diabetes and prediabetes affect 31 million (12%) and 82 million (34%) U.S. adults, 
respectively.1,2 The ramifications of diabetes include CVD, renal disease, amputations, 
blindness, neuropathy, reduced functional status, and death.1,3,4 These statistics highlight the 
need for new prevention targets and approaches, especially for T2D, to augment current 
efforts.5 The lifetime prevalence of major depressive disorder (MDD) is 16%.6 Depression is the 
2nd leading cause of disability7 and predicts multiple chronic diseases8-12 and death.13  
 
A2. Depression is an independent, clinically important, and robust risk factor for 
diabetes. 
Twenty years of evidence shows that depression is a diabetes risk factor, independent of 
established diabetes risk factors. A 2013 meta-analysis14 (23 studies) found that depressed 
adults have 56% (unadjusted) and 38% (adjusted for established risk factors) greater risk of 
developing diabetes than nondepressed adults. This risk conferred by depression is clinically 
important, as it is on par with established diabetes risk factors, such as smoking.15-17 In addition 
to clinical diabetes onset, a 2013 meta-analysis18 (18 studies) revealed that depression is 
associated with insulin resistance, a sign of prediabetes. This finding supports intervening on 
depression at the prediabetes stage. Finally, the depression-diabetes relationship is robust, as it 
has been observed in major demographic groups.8,10,14 A 2008 meta-analysis10 found that risk 
ratios for depression predicting diabetes were comparable for women (1.26), men (1.57), older 
adults (1.50), younger adults (1.96), samples with higher minority representation (1.79), and 
samples predominantly White (1.65).  
 
A3. The depression-to-diabetes relationship is biobehaviorally plausible. 
Although the exact pathways through which depression contributes to diabetes 
development have yet to be determined, several candidate mechanisms have been identified. 
The leading biological mechanisms are HPA axis hyperactivity, autonomic dysfunction, and 
systemic inflammation. Substantial literatures indicate that depression is accompanied by HPA 
axis hyperactivity19,20 and autonomic dysfunction.21 Depression-related dysfunction in these two 
systems that normally exert anti-inflammatory effects could explain why depression is also 
reliably associated with elevated inflammatory markers.22-25 Moreover, HPA axis hyperactivity, 
autonomic dysfunction, and systemic inflammation are all implicated in the pathogenesis of 
insulin resistance and T2D.26-30 The leading behavioral mechanisms are increased adiposity, 
poor diet, physical inactivity, smoking, and medical nonadherence. Compared to nondepressed 
adults, depressed adults have a 58% greater risk of future obesity,9 a major T2D risk factor.31 
Maladaptive behaviors common in depressed people – i.e., high calorie diets,32-35 physical 
inactivity,36 smoking,36,37 and nonadherence to medical regimens38,39 – also promote insulin 
resistance and T2D.14,17,18,40 Of note, current conceptual frameworks27 view systemic 
inflammation as a final common pathway through which many candidate mechanisms promote 
insulin resistance and T2D. 
 
Our team's published studies further support the biobehavioral plausibility of the 
depression-to-diabetes relationship. We have found that: (1) depression is positively associated 
with the inflammatory markers interleukin-6 (IL-6) and C-reactive protein (CRP) and predicts 
inflammatory marker increases over 6 years;41-43 (2) depression predicts future obesity 
development;44 (3) depression is linked with poorer adherence to primary prevention 
recommendations;45 and (4) depression is positively associated with insulin resistance and 


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predicts insulin resistance increases over 6 years, and CRP and BMI are mediators of these 
relationships.46,47 
 
A4. Many patients have a modifiable diabetes risk factor that is going underdetected or 
undertreated. 
In primary care, the prevalence of depression is 16-19%.48,49 Depression is receiving 
increased, but still limited, attention in settings where diabetes prevention occurs, including 
primary care. Because depression screening is not routine, first-line interventions other than 
antidepressants are often not available, and the outcomes achieved are suboptimal,50 there is a 
large cohort of primary care patients with an underdetected or undertreated diabetes risk factor. 
This status quo could represent a major missed opportunity to prevent T2D. 
 
A5. There is a need to evaluate if depression treatment is a new diabetes prevention 
strategy. 
The state of the science (see A2 and A3) and the status quo (see A4) create the current 
need for a pilot RCT to begin to evaluate the utility of depression treatment as a new diabetes 
prevention strategy. Because no such trial has been conducted, it is unknown if depression 
treatment improves A1c and prevents T2D in people with prediabetes. Even so, three smaller 
studies provide initial indirect support for such an approach. In 20 depressed patients without 
diabetes, 3 months of antidepressant treatment was linked with improved insulin resistance.51 In 
two RCTs of 80 and 51 depressed inpatients without diabetes, depression remission after 
antidepressant treatment was associated with improved insulin resistance.57,58 Our post hoc 
analysis also provides initial indirect support. In 18 depressed patients without diabetes, we 
found that those randomized to computerized CBT for depression, vs. usual care, exhibited 
improvements in fasting glucose (see C1). Unfortunately, none of these studies was designed to 
test our hypotheses. First, some used pre/post designs with no randomization or control 
group,51 while others randomized patients to different antidepressants but did not have a control 
group.52,53 Second, none targeted patient groups with the greatest need for diabetes prevention, 
such as those with prediabetes. Third, none had A1c, an indicator of high clinical relevance, as 
an outcome. These key limitations, combined with the strong state of the science and the 
problematic status quo, create the need for the proposed pilot RCT of 64 depressed patients 
with prediabetes (1) to determine the preliminary efficacy of our depression intervention 
(eIMPACT-DM) on A1c and insulin resistance and (2) to explore whether somatic depressive 
symptoms moderate the intervention effect on A1c and insulin resistance. 
The scientific premise of the proposed trial is strong, as: (a) current diabetes prevention 
approaches have only partial effectiveness;5,54-56 (b) the depression-to-diabetes relationship is 
independent of established diabetes risk factors, is clinically important (i.e., of sufficient 
magnitude that effective intervention could meaningfully lower diabetes risk), is robust, and is 
biobehaviorally plausible (see A2 and A3); (c) many patients have a modifiable diabetes risk 
factor (depression) that is going underdetected or undertreated (see A4); (d) initial evidence, 
including our post hoc analysis, suggests that depression treatment can improve insulin 
resistance and fasting glucose (see A5 and C1); and (e) our preliminary data suggests that 
depressed people with somatic depressive symptoms are a subgroup at particularly elevated 
diabetes risk (see C3). 
 
A6. Establishing that depression treatment reduces diabetes risk would have a major 
positive impact.  
A positive pilot trial would pave the way to an R01-level RCT by yielding three expected 
outcomes: (1) generating critical proof-of-concept data (depression treatment can improve A1c) 
to support the premise; (2) providing preliminary effect sizes for eIMPACT-DM on diabetes risk 
markers to help justify future power analyses; (3) identifying a potentially important moderator 


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(somatic depressive symptoms) of eIMPACT-DM efficacy. If evidence of moderation by somatic 
depressive symptoms is observed, it would have implications for recruitment (enroll 50% with 
and 50% without these symptoms), randomization (stratify on presence of these symptoms), 
and the sample size (ensure sufficient power to detect 3-way interactions) of the future RCT. 
Ultimately, demonstrating that depression treatment reduces diabetes risk would have a 
major positive impact. In the scientific domain, it would identify depression as a causal diabetes 
risk factor. In the clinical domain, it would identify a novel target for prevention efforts, likely 
leading to the inclusion of depression in diabetes guidelines. Moreover, it would equip 
healthcare providers with a new intervention (eIMPACT-DM) to simultaneously treat depression 
and lower diabetes risk for a large cohort of high-risk patients. Finally, positive results – 
combined with our practical, scalable intervention – would facilitate dissemination and 
implementation of eIMPACT-DM. These three clinical practice changes should reduce diabetes 
morbidity, mortality, and costs. 
 
B. Innovation 
 
B1. Our trial would be the first to evaluate depression treatment as a diabetes prevention 
strategy. 
This RCT would be the first to test the effect of a depression intervention on A1c in 
depressed people with prediabetes. Our focus on a psychological factor is a major departure 
from current prevention efforts.5 
 
B2. eIMPACT-DM has innovative aspects that support broader dissemination and 
implementation. 
Although collaborative care for depression in primary care is an established approach,57 
only one trial58 besides our eIMPACT Trial (see C2) has incorporated computerized CBT. 
Moreover, no trials have used an antidepressant algorithm optimized for diabetes risk reduction. 
To achieve our long-term goal, large-scale dissemination and implementation must be possible. 
eIMPACT-DM fits very well in primary care, where behavioral health staff and space are limited, 
as it harnesses technology to minimize personnel and space requirements. In addition, because 
eIMPACT-DM uses computerized CBT, it is more scalable, easier to deliver with high fidelity, 
and likely more cost effective59 than current collaborative care models. Finally, eIMPACT-DM 
can reach patients with logistical barriers, as many components are internet or phone delivered. 
Pew data show that 89% of adults (87% for non-Hispanic Blacks; 81% for lower income 
households) use the internet. 
 
B3. Using a statewide information exchange to identify incident T2D is unique and has 
advantages. 
The Indiana Network for Patient Care (INPC),60,61 the nation’s largest clinical data 
repository, is a secure statewide health information exchange operated by Regenstrief Institute. 
In addition to extensive data provided by healthcare systems, INPC gathers data from Indiana 
Medicaid and commercial payers and death data from the Indiana State Department of Health. 
Advantages of using INPC seen in our past studies62-64 are an easily extended follow-up and 
minimal attrition (no patient participation required).    
 
C. Preliminary Studies 
 
C1. The Beating the Blues for Your Heart Trial (PI: Stewart; ClinicalTrials.gov Identifier: 
NCT01605552) 
This small pilot RCT provides initial proof-of-concept data. Although its primary outcome 
was a CVD risk marker, it allowed for a diabetes-related post hoc analysis. 29 Eskenazi Health 


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primary care patients with depression were randomized to Beating the Blues (BtB) – an 
empirically supported computerized CBT – or usual primary care for depression. 22 patients 
(76%) attended the 3-month post-treatment visit. For this analysis, we selected the 18 patients 
free of diabetes to parallel the targeted prediabetes population. BtB patients (-3.6 mg/dL), vs. 
usual care patients (+3.2 mg/dL), exhibited greater improvements in fasting glucose (see table). 
While this difference fell short of significance due to low power, the effect size of d=0.90 is 
large.65 BtB patients also showed large improvements in SCL-20 depression score, moderate-
to-large improvements in CRP, and moderate improvements in IL-6 (see table).  
The major limitation of these data is the fasting glucose outcome, which is a point 
estimate of glycemia highly susceptible to acute influences.66 Unfortunately, we did not bank 
whole blood samples to assess A1c. NIH reviewers previously noted that an R01-level RCT is 
premature due to our lack of preliminary data showing a promising effect of depression 
treatment on A1c. Another limitation of these data is post hoc selection of patients free of 
diabetes. These key limitations underscore the need for the proposed pilot RCT. 
 
 
 
 
 
 
 
 
 
 
 
C2. eIMPACT Trial (PI: Stewart; R01HL122245; ClinicalTrials.gov Identifier: NCT02458690) 
This phase II RCT provides data supporting the feasibility of recruitment, intervention, 
and assessment and the efficacy of eIMPACT-DM for depression. The eIMPACT Trial's 
objective is to determine if treating depression, before CVD onset, reduces CVD risk. We 
randomized Eskenazi primary care patients with depression and CVD risk factors to eIMPACT 
or usual primary care for depression. eIMPACT is identical to the proposed intervention, except 
the antidepressant algorithm is optimized for CVD risk reduction. We are now in Year 4. We 
have met our recruitment goal by randomizing 216 patients (56% non-White) and have 
executed the intervention/usual care procedures with high fidelity and minimal impact on clinic 
operations. Attrition has been low, with 93% of the intervention arm and 91% of the usual care 
arm attending the 12-month post-treatment visit. Checks indicate that the data are of high 
quality with minimal missingness. To evaluate eIMPACT efficacy, we selected all 135 patients 
whose post-treatment visits have come due. eIMPACT patients (-7.0 points), versus usual care 
patients (-3.5 points), showed significantly greater and moderate-to-large improvements in 
PHQ-9 depression score (see table). The clinical response data yielded similar results – 51% of 
eIMPACT patients, versus 20% of usual care patients, had a 50% PHQ-9 reduction. 
While these results establish the feasibility of our approaches and the efficacy of our 
intervention for depression, this ongoing trial is not appropriate for achieving our aims for three 
reasons: (1) the sample is problematic (~1/3 have diabetes), (2) the antidepressant algorithm 
(optimized for CVD risk reduction) includes medications that could increase weight and A1c, 
and (3) we cannot assess A1c (no whole blood samples). 
 
Beating the Blues 
Mean (SD) 
Usual Care    
Mean (SD) 
P-
value 
d 
Pre-Treatment Level 
 
 
 
 
Fasting Glucose, mg/dL 
105.7 (10.2) 
107.6 (10.7) 
0.72 
--- 
SCL-20 (range: 0-4) 
1.47 (0.64) 
1.67 (0.98) 
0.66 
--- 
CRP, mg/L 
4.90 (2.19) 
3.17 (2.66) 
0.19 
--- 
IL-6, pg/mL 
4.15 (2.55) 
4.42 (5.34) 
0.91 
--- 
 
 
 
 
 
Post-Treatment Level 
 
 
 
 
Fasting Glucose, mg/dL 
102.1 (12.6) 
110.8 (9.8) 
0.10 
0.90 
SCL-20 (range: 0-4) 
0.79 (0.47) 
1.48 (0.78) 
0.06 
1.03 
CRP, mg/L 
2.91 (3.11) 
3.94 (2.83) 
0.16 
0.76 
IL-6, pg/mL 
3.88 (1.78) 
5.14 (3.17) 
0.41 
0.46 
P-values and effect sizes (d’s) are adjusted for pre-treatment level. 


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C3. Somatic Depressive Symptoms and Elevated Diabetes Risk 
Our evidence suggests that depressed people with the somatic symptoms of 
hyperphagia (increased appetite/weight) and/or hypersomnia (increased sleep) may be a 
subgroup at particularly elevated diabetes risk. First, in our analysis of the NESARC data 
(N=17,787), we found that depressed adults with hyperphagia and hypersomnia had a greater 
odds (OR=1.51; p<.001) of developing obesity and exhibited greater increases in BMI (+0.40 
kg/m2; p=.009) over the 3-year follow-up than depressed adults without these symptoms.44 
Obesity is a major T2D risk factor.31 Second, in the eIMPACT pre-treatment data, we found that 
hyperphagia (β=0.348, p=.004), but not the other depressive symptoms, is associated with 
greater insulin resistance. The cohort for this analysis was the 135 depressed patients with 
post-treatment visits due minus those with baseline diabetes (final n=78, 63% with hyperphagia 
and/or hypersomnia). The outcome was the Homeostatic Model of Assessment 2 (HOMA2) 
Score67 computed from fasting glucose and insulin from banked plasma samples. Together, our 
results raise the intriguing possibly that depressed adults with hyperphagia and/or hypersomnia 
may show greater improvement in diabetes risk markers after depression treatment due to their 
higher baseline diabetes risk. We will explore this possibility in the proposed RCT. 
 
2.0 
Objectives 
 
Diabetes and prediabetes are top public health priorities in the U.S. Diabetes affects 31 
million (12%) adults, and another 82 million (34%) adults have prediabetes, a precursor to frank 
diabetes.1,2 The ramifications of diabetes are grave and include cardiovascular disease (CVD), 
renal disease, amputations, blindness, neuropathy, reduced functional status, and death.1,3,4 
While these statistics highlight the importance of diabetes prevention, current approaches have 
only partial effectiveness.5,54-56 This has created a clear need for new primary prevention targets 
and approaches, especially for type 2 diabetes (T2D; 90-95% of diabetes cases in U.S. adults1). 
Thus, our focus is on augmenting the overall effectiveness of diabetes prevention efforts by 
identifying and treating novel primary prevention targets that are unaddressed in current 
approaches. 
Depression, another top priority, is a diabetes risk factor. A 2013 meta-analysis14 found 
that depressed adults have 56% (unadjusted) and 38% (adjusted for established diabetes risk 
factors) greater risk of diabetes than nondepressed adults. The risk conferred by depression is 
on par with established diabetes risk factors,15-17 and the depression-to-diabetes relationship 
has been observed in major demographic groups.8,10,14 Plausible biobehavioral mechanisms 
have also been identified.27 Collectively, these literatures form the scientific premise for the 
proposed pilot trial by demonstrating that the depression-to-diabetes relationship is independent 
of established diabetes risk factors, is clinically important (i.e., of sufficient magnitude that 
effective intervention could meaningfully lower diabetes risk), is robust, and is biobehaviorally 
plausible. However, research has yet to determine whether depression treatment can prevent 
the development of T2D in people with prediabetes. 
Depression is receiving increased, but still limited, attention in settings where diabetes 
prevention occurs, such as primary care. Thus, there is a large cohort of primary care patients 
with an underdetected or undertreated diabetes risk factor (depression). This status quo could 
represent a major missed opportunity to prevent diabetes. Together, the state of the depression-
 
eIMPACT 
Mean (SD) 
Usual Care    
Mean (SD) 
P-value 
d / OR 
Pre-Treatment Level 
 
 
 
 
PHQ-9 score (range: 0-27) 
15.0 (5.1) 
15.4 (4.6) 
0.62 
--- 
Post-Treatment Level 
 
 
 
 
PHQ-9 score (range: 0-27) 
8.0 (6.4) 
11.9 (5.8) 
<0.001 
0.68 
50% Reduction in PHQ-9 
50.8% 
20.3% 
0.001 
4.06 
P-values and effect sizes (d’s) are adjusted for pre-treatment level. 


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to-diabetes science and this status quo create the need for a pilot RCT to evaluate the utility of 
depression treatment as a new diabetes prevention strategy.  
The long-term goal of our transdisciplinary team is to develop, evaluate, and disseminate 
new diabetes prevention strategies targeting novel psychosocial risk factors. This project’s 
objective is to perform a preliminary evaluation of the efficacy of our existing primary care-based 
intervention for depression (eIMPACT-DM) in improving diabetes risk markers. eIMPACT-DM is 
a modernized collaborative stepped care intervention consisting of (1) computerized and 
telephonic cognitive-behavioral therapy (CBT) for depression and (2) select antidepressant 
medications included in an algorithm optimized for diabetes risk reduction. Our preliminary data 
(see C2) establish the feasibility and antidepressive efficacy of eIMPACT-DM. We propose a 
pilot RCT of 64 primary care patients with a depressive disorder and prediabetes. Patients will 
be randomized to 6 months of eIMPACT-DM or the active control (depression education, 
symptom monitoring, and primary care for depression). The primary outcome is hemoglobin A1c 
– the gold standard glycemic outcome,68 a strong predictor of diabetes development,69,70 and a 
potent indicator of improvement in diabetes endpoints.5,69,71,72 
 
Primary Aim: Determine the preliminary efficacy of eIMPACT-DM in improving diabetes 
risk markers among depressed primary care patients with prediabetes. Depressed patients 
randomized to eIMPACT-DM, versus the active control, will exhibit greater improvement in A1c 
(primary outcome; H1) and insulin resistance (HOMA score; secondary outcome; H2) from pre-
treatment to post-treatment 6 months later.  
 
Exploratory Aim: Explore whether the effect of eIMPACT-DM on diabetes risk markers is 
greater among patients with a somatic presentation of depression at pre-treatment 
(baseline) than among patients without such a presentation. A somatic presentation of 
depression at baseline is defined as having hyperphagia (increased appetite/weight) and/or 
hypersomnia (increased sleep) at pre-treatment. Our preliminary data (see C3) suggest that, in 
people with depression, those with hyperphagia (increased appetite/weight) and/or hypersomnia 
(increased sleep) are a subgroup at particularly elevated diabetes risk. Because our findings 
raise the intriguing possibly that this subgroup may show greater improvement in diabetes risk 
markers after depression treatment, we will explore if effect sizes for eIMPACT-DM on A1c and 
insulin resistance are larger for patients with versus without hyperphagia and/or hypersomnia. 
 
There is a tight fit between our aims and PA-18-405, which requests applications for pilot 
therapeutic trials that will “lay the foundation for larger clinical trials related to the prevention 
and/or treatment of diabetes” by “acquiring data to support the rationale and/or feasibility of a 
definitive study and to develop and/or refine power calculations.” These trials could “test a new 
disease prevention strategy” and/or “explore the differential responses to interventions amongst 
subpopulations.” A positive pilot trial would pave the way to an R01-level RCT by: (1) generating 
critical proof-of-concept data (eIMPACT-DM can improve A1c) to support the premise of the 
definitive trial; (2) providing preliminary effect sizes for eIMPACT-DM on diabetes risk markers 
to help justify future power analyses; (3) identifying a potentially important moderator of 
eIMPACT-DM efficacy that may need to be incorporated into the definitive trial. Ultimately, 
demonstrating that depression treatment reduces diabetes risk would have a substantial 
positive impact. It would identify a novel target (depression) for diabetes prevention efforts, and 
it would equip healthcare providers with a new practical, scalable, and disseminable intervention 
(eIMPACT-DM) to help lower diabetes risk for a large cohort of high-risk patients. 
 
 


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3.0 
Outcome Measures/Endpoints 
 
Primary Outcome (A1c) 
The primary outcome is 6-month change in hemoglobin A1c. A1c will be measured at 
pre- and post-treatment by an immunoturbidimetric method on a Randox Daytona Clinical 
Analyzer in the Translation Core Analyte Lab of the Indiana CTSI. A1c is the best choice for our 
primary outcome for many reasons. First, A1c is considered the gold standard assessment of 
glycemic control and is a common surrogate endpoint in diabetes trials.16 Also, A1c ≥6.5% is 
diagnostic of diabetes.86 Second, A1c strongly predicts future diabetes.17 A systematic review18 
found that the 5-year incidence of diabetes increased sharply with A1c, from <9% incidence for 
A1c 5.0-5.5% to 9-25% incidence for A1c 5.5-6.0% and 25-50% incidence for A1c 6.0-6.5%. 
The diabetes incidence rate for A1c 5.0-5.5%, 5.5-6.0%, and 6.0-6.5% was approximately 2 
times, 5 times, and 20 times greater than for A1c <5.0%, respectively.18 Third, interventions 
producing A1c improvements have been shown to also improve clinical diabetes endpoints,19,20 
and diabetes prevention interventions targeting glycemic control result in reduced rates of 
progression from prediabetes to T2D.8,17 Thus, A1c is associated with clinical benefit. Fourth, 
A1c has statistical advantages. As a continuous measure, it provides greater statistical power 
than clinical events and thus requires smaller samples and shorter follow-ups. Also, because 
A1c reflects average glucose over the preceding 90-120 days,139 it is more stable than 
alternative measures, such as fasting glucose and oral glucose tolerance tests.86 For all of these 
reasons, A1c is well suited to evaluate if a new intervention approach holds promise, and it is 
appropriate and feasible for pilot trials. 
 
Secondary Outcome (HOMA Score) 
The secondary outcome is 6-month change in insulin resistance, as indicated by HOMA 
score. HOMA scores80 will be derived from fasting glucose (glucose oxidase method on a 
Randox Daytona Clinical Analyzer) and insulin (two antibody immunoassay on a Roche cobas 
e411 Analyzer). Fasting glucose and insulin assays will be performed in Translation Core 
Analyte Lab of the Indiana CTSI. HOMA score is an established index of insulin resistance that 
correlates highly with the more invasive euglycemic clamp (r=0.85-0.88) and is appropriate for 
assessing change.111-114 
 
Exploratory Outcome (Incident Diabetes) 
 
The exploratory outcome is time to T2D onset, defined as the first occurrence of the 
following between the participant's enrollment date and five years after their post-treatment visit 
date: T2D diagnosis (ICD-10 E11), fasting glucose ≥126 mg/dL, A1c ≥6.5%, or death due to 
T2D. The Regenstrief programmer will identify incident T2D cases by searching INPC – the 
statewide health information exchange (see B3) – blinded to group assignment. Our 
endocrinologist (Dr. Saeed), also blinded, will use standardized criteria to adjudicate all incident 
T2D cases. As we are doing in the eIMPACT Trial, we will obtain authorization from participants 
to conduct INPC searches to identify incident diabetes until five years after their post-treatment 
visit date. We will assess this outcome annually, with the first assessment at post-treatment. 
Because only a large Phase III trial would be powered for clinical events, incident T2D is an 
exploratory outcome. Based on our prediabetes inclusion criterion and the review described 
above,70 we expect a diabetes incidence rate of ≥25% over 5 years. Dr. Stewart will use his 
faculty development funds ($4K/year) and/or his research account ($50K) to cover INPC 
searches after the project period. 
 
Somatic Depressive Symptoms 
Total depressive symptoms will be assessed by the 20 depression items (response 
options: 0-4) of the Symptom Checklist-90 (SCL-20), a reliable and valid scale,115-118 at the pre- 


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and post-treatment visit. Patients with a score ≥2 to the hyperphagia item and/or hypersomnia 
item at pre-treatment will be coded as “yes” for the presence of somatic depressive symptoms. 
All others will be coded as “no.” 
 
Other Factors 
Weight, height, blood pressure, heart rate, respiration rate, and temperature will be 
measured by CRC nurses (pre, post). Validated questions/scales will assess demographics, 
medical/psychiatric history, current medications, alcohol use (AUDIT),73 tobacco use (BRFSS 
Tobacco Use Questionnaire),119,120 physical activity (International Physical Activity 
Questionnaire),121 OHA adherence (Morisky Medication Adherence Scale-8),122-124 depressive 
symptoms (PHQ-9),74,75 anxiety (GAD-7),125 hostility/anger (Buss-Perry Aggression 
Questionnaire),76 trait positive affect (Positive Affect subscale of the PANAS),77,78 life satisfaction 
(Satisfaction with Life Scale),79 insomnia symptoms (Insomnia Severity Index),80 sleep quality 
(PSQI),126 eating behaviors (Dutch Eating Behavior Questionnaire),81quality of life (SF-20)82 (all 
pre, post), and expectancy of benefit83 (pre). Attention will be determined from the intervention 
database for eIMPACT-DM patients and from EMR chart review for AC patients (post). 
Depression care variables (e.g., antidepressant dose/duration and psychotherapy session 
number/type) will be determined from the treatment delivery database for eIMPACT-DM patients 
and from EMR chart review for Active Control patients (post). Patients will complete a brief 
interview to assess depression care received outside of the trial (post). We will assess 
depression treatment acceptability (post). Diabetes prevention care received outside the trial will 
be assessed by EMR chart review (post) and a brief interview (post). We will also assess for the 
occurrence of any potential adverse events using a brief questionnaire and will administered the 
Techniques for Overcoming Depression Questionnaire84 (post). 
 
Type 
Name 
Time Frame 
Brief Description 
Hemoglobin 
A1c 
Primary 
Baseline, 6 
months 
The primary outcome is 6-month change in 
hemoglobin A1c, which will be measured at pre- 
and post-treatment by an immunoturbidimetric 
method on a Randox Daytona Clinical Analyzer 
in the Translation Core Analyte Lab of the 
Indiana CTSI. A1c is the gold standard glycemic 
outcome,16 a strong predictor of future diabetes 
development,17,18 and a potent indicator of 
improvement in clinical diabetes 
endpoints.8,17,19,20 
HOMA score 
Secondary 
Baseline, 6 
months 
The secondary outcome is 6-month change in 
insulin resistance, as indicated by HOMA score. 
HOMA scores80 will be derived from fasting 
glucose (glucose oxidase method on a Randox 
Daytona Clinical Analyzer) and insulin (two 
antibody immunoassay on a Roche cobas e411 
Analyzer). Fasting glucose and insulin assays 
will be performed in Translation Core Analyte 
Lab of the Indiana CTSI. HOMA score is an 
established index of insulin resistance that 
correlates highly with the more invasive 
euglycemic clamp (r=0.85-0.88) and is 
appropriate for assessing change.111-114 
 
 


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4.0 
Eligibility Criteria 
 
Inclusion Criteria 
• 
Current primary care patient in Eskenazi Health: a clinic visit in the past two years at one 
or more of the 8 Eskenazi primary care clinics (Clinics: Blackburn, Cottage Corner, 
Forest Manor, Grassy Creek, North Arlington, OCC, Westside, W. 38th St, Center for 
Senior Health) 
• 
Age ≥18 years 
• 
Current depressive disorder: During screening, ResNet assistants will administer the 
Patient Health Questionnaire-9 (PHQ-9),81 a validated depression diagnostic measure 
designed for primary care patients.82-85 We will consider patients to have a depressive 
disorder if (a) they have a PHQ-9 ≥1081 and (b) they meet criteria for a PHQ-9 MDD 
diagnosis (2 or more of the 9 depressive symptoms, including depressed mood or 
anhedonia, present in the past 2 weeks).83 The PHQ-9 cut point of ≥10 has 88% 
sensitivity and 88% specificity for MDD diagnosed by a clinical interview.81  The 
combination of a PHQ-9 ≥10 and a PHQ-9 MDD 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 identified in clinical practice, (b) recent successful trials have used 
similar approaches,106,132,133 and (c) we observed initial evidence of a signal of 
depression treatment on fasting glucose levels in our pilot trial, in which we used PHQ-9 
≥10 as the depression inclusion criterion (see C1). 
• 
Prediabetes: (a) a prediabetes diagnosis (ICD-10 code R73.03) ever in the patient’s 
EMR before enrollment or the most recent A1c in the past 2 years between 5.70-6.49% 
in the patient’s EMR before enrollment and (b) a finger-stick A1c <6.5%86 at the start of 
the pre-treatment visit 
 
Exclusion Criteria 
• 
History of diabetes: a self-reported type 1 or 2 diabetes diagnosis during screening or 
any of the following in the patient’s EMR before enrollment: type 1 or 2 diabetes 
diagnosis (ICD-9 250.X; ICD-10 E10.X or E11.X), fasting glucose ≥126 mg/dL, A1c 
≥6.5%, or insulin prescription. Patients with a pre-treatment A1c ≥6.5% will also be 
coded as having a history of diabetes, and their PCP will be notified. Of note, OHA use 
is not exclusionary, as practice guidelines recommend OHAs for prediabetes in some 
situations.86 
• 
HIV/AIDS 
• 
Chronic kidney disease 
• 
Active cancer/current cancer treatment 
• 
Ongoing treatment for an inflammatory condition (e.g., rheumatoid arthritis, lupus, 
Crohn's disease, and ulcerative colitis) in the past 3 months (daily use of NSAIDS is 
allowed) 
• 
Current pregnancy: Women able to become pregnant will complete a urine pregnancy 
test at the pre-treatment visit, and those with a positive pregnancy test will not continue 
in the trial. 
• 
Severe cognitive impairment: ≥3 errors on a validated 6-item cognitive screen87 during 
screening 
• 
Acute risk of suicide: Patients will be coded as at acute risk of suicide if: (a) they trigger 
the Suicidal Ideation Protection Protocol (see 16.0 Appendix) during screening or at the 
start of the pre-treatment visit and (b) after the situation is properly handled, the patient’s 
PCP or other clinical provider considers the patient to be at acute risk of suicide. 


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• 
History of bipolar disorder or psychosis or current use of an atypical antipsychotic 
medication: a self-reported diagnosis of bipolar disorder or a psychotic disorder during 
screening or a bipolar disorder diagnosis [ICD-9 code 296.X (all); ICD-10 codes F30X 
(all), F31X (all), F34.0] in the patient’s EMR before enrollment or a psychotic disorder 
diagnosis [ICD-9 code 295.X (all); ICD-10 codes F20.X (all), F21, F22, F23, F24, F25.X 
(all), F29] in the patient’s EMR before enrollment or current use of aripiprazole, 
aripiprazole lauroxil, asenapine, asenapine transdermal, brexiprazole, cariprazine, 
clozapine, iloperidone, lumateperone, lurasidone, olanzapine, paliperidone, paliperidone 
palmitate, pimavanserin, quetiapine, risperidone, or ziprasidone in the patient’s EMR at 
screening. 
• 
Participation in the eIMPACT Trial: All patients who participated in the eIMPACT Trial 
will be removed from the recruitment lists of eligible patients. Thus, none will be 
contacted during screening. 
 
Inclusion of Women and Minorities 
None of the inclusion/exclusion criteria of the proposed pilot RCT pertain to sex, gender, 
race, or ethnicity, except that pregnant women will be excluded due to the potential influence of 
pregnancy on depression and diabetes risk markers. We conducted a preliminary EMR search 
and identified 47,361 demographically and medically eligible Eskenazi primary care patients 
with no history of diabetes (63% women, 48% non-Hispanic Black, 20% Hispanic/Latino), of 
whom 9,876 (21%) fell on the high priority list (positive for a prediabetes marker). Moreover, in 
our eIMPACT Trial involving older Eskenazi primary care patients, we have had success 
recruiting and retaining racial/ethnic minorities with a depressive disorder, as 49% of the 216 
randomized patients identify as non-Hispanic Black, 4.6% as Hispanic/Latino, and 3.2% as 
multiracial. Because <3% of Indianapolis residents are American Indian/Alaskan Native, Asian, 
or Native Hawaiian/Other Pacific Islander (see www.stats.indiana.edu), we do not expect these 
racial groups to be well-represented in the proposed trial. Based on these data, we anticipate 
that participants in the proposed trial will be 64 primary care patients aged ≥18 years with a 
depressive disorder and prediabetes, of whom 60% will be women, ≥40% will be non-Hispanic 
Black, ≥10% will be Hispanic/Latino. We expect that, due to randomization, groups based on 
sex, gender, race, and ethnicity will be approximately equally represented in the two trial arms. 
It is worth noting that the inclusion of a high percentage of women and racial/ethnic minorities 
will enhance the external validity of the findings of the proposed trial. 
 
Inclusion of Children 
Participants in the proposed pilot RCT will be 64 primary care patients aged ≥18 years 
with a depressive disorder and prediabetes. Children (<18 years) will not be eligible because a 
separate, age-specific study of children is warranted and preferable for at least two reasons. 
One, evidence indicates that depression is experienced and expressed differently in children 
and adolescents (e.g., with increased irritability and suicidal ideation) versus in adults. Two, the 
major components of our modernized collaborative stepped care intervention for depression 
called eIMPACT-DM – namely, Good Days Ahead (computerized cognitive-behavioral therapy), 
Problem-Solving Treatment in Primary Care (telephonic cognitive-behavioral therapy), and our 
antidepressant algorithm optimized for diabetes risk reduction – were designed for adults and 
have not been fully evaluated in children. Thus, the appropriateness, acceptability, and 
effectiveness of eIMPACT-DM in children are unknown. 
 
5.0 
Enrollment/Randomization 
 
Participants will be 64 primary care patients (≥18 years, 50% minority) with a depressive 
disorder and prediabetes but no history of diabetes.  


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Recruitment Plan 
We will use the successful 3-stage process of our R01-funded eIMPACT Trial to recruit 
patients. In the eIMPACT Trial (see C2), we met our recruitment goal of randomizing 216 
Eskenazi primary care patients with a current depressive disorder and CVD risk factors (78% 
women, 56% non-White) but no history of clinical CVD. First, a Regenstrief Institute data 
manager will search the Eskenazi EMR in accordance with HIPAA and IRB regulations to 
generate lists of potentially eligible patients. To optimize recruitment, we will have high and low 
priority lists. Patients will be placed on the high priority list and screened first if there is a 
prediabetes marker (A1c 5.70-6.49% or prediabetes ICD-10 code R73.03) present in their EMR 
in the last 2 years. All others will be placed on the low priority list and screened second. To 
ensure that patients who participated in the eIMPACT Trial are not enrolled, we will remove all 
such patients from these recruitment lists prior to screening. Second, ResNet personnel will 
obtain permission to approach for screening from each patient's PCP. ResNet, Indiana 
University’s primary care practice-based research network, is the sole mechanism through 
which primary care patients can be contacted. Third, ResNet personnel will conduct high-
intensity phone screening. Through administering the eligibility interview refined in the eIMPACT 
Trial, they will assess depression status, medical/psychiatric status, and cognitive function. For 
patients who are eligible and remain interested in participating, ResNet personnel will provide a 
brief summary of key information from the informed consent statement at the end of the call. 
Specifically, they will summarize: the voluntary nature of participation, the study rationale, the 
structure and duration of study visits/contacts, the potential risks and benefits of participation, 
and payment for participation. Written informed consent and authorization will be obtained from 
each participant at the start of the pre-treatment visit. 
Using the 4.8% randomization rate from our eIMPACT Trial, we estimate that we will 
need to screen ≈26/week to randomize 64 patients over the 1-year recruitment period. In the 
eIMPACT Trial, which has similar but more restrictive eligibility criteria, 4.8% (216/4539) of 
approached patients were randomized. Most ineligible patients did not meet the current 
depressive disorder inclusion criterion. We conducted an EMR search and identified 47,361 
demographically and medically eligible Eskenazi primary care patients with no history of 
diabetes (63% women, 48% non-Hispanic Black, 20% Hispanic/Latinx), of whom 9,876 (21%) 
fell on the high priority list (positive for a prediabetes marker). ResNet leadership agrees that 
our approach and our randomization rate and target are feasible. We will be able to start 
recruitment immediately because personnel and protocols are in place from the eIMPACT Trial. 
 
Randomization 
1:1 randomization88 will be stratified by A1c (≤6.09%, 6.10-6.49%) and somatic 
depressive symptoms (yes, no) at pre-treatment using random number sequences.88 
Sequentially numbered, opaque, sealed envelopes containing group assignment will be 
prepared by the study statistician (Dr. Saha). 
 
Blinding 
All outcomes assessors will be blinded to group assignment to ensure unbiased results. 
The investigators and interventionists will have no data collection responsibilities, and the 
patients will be explicitly instructed not to reveal their group assignment to the outcomes 
assessors. 
 
Retention Plan 
We will use the successful practices of our eIMPACT Trial to retain participants over the 
6-month study period. First, we will implement Mason's procedures for minimizing attrition – 
e.g., collecting extensive contact information for patients and at least two secondary contacts, 
stressing the study timeline and scientific importance of study completion at enrollment, and 


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providing consistent incentives ($75 for attending the pre-treatment visit and $75 for attending 
the post-treatment visit). Second, we will make reminder calls and/or send reminder texts before 
the pre- and post-treatment visits according to patient preference (e.g., one day before, one 
week before, or both). Third, for all study visits, we will cover parking or transportation 
expenses, including arranging taxis or ride shares (e.g., Uber and Lyft) and providing bus 
vouchers. Fourth, we will maintain at least monthly contact with participants in both arms 
throughout the study period. Fifth, we will mail a mid-treatment newsletter to participants in both 
arms with study updates. The low attrition observed in the eIMPACT Trial indicates that our 
retention practices are effective, as 93% of participants in the intervention arm and 91% of 
participants in the usual care arm have attended the 12-month post-treatment visit. 
 
6.0 
Study Design 
 
We propose a pilot RCT of 64 primary care patients with a depressive disorder and 
prediabetes. Patients will be randomized to 6 months of eIMPACT-DM (our modernized 
collaborative stepped care intervention for depression) or the active control (depression 
education, symptom monitoring, and primary care for depression). The primary outcome is 
hemoglobin A1c – the gold standard glycemic outcome,68 a strong predictor of diabetes 
development,69,70 and a potent indicator of improvement in diabetes endpoints.5,69,71,72 The 
secondary outcome is HOMA score, an established index of insulin resistance that correlates 
highly with the more invasive euglycemic clamp (r=0.85-0.88) and is appropriate for assessing 
change.85-88 We will also explore whether the presence of somatic depressive symptoms 
moderates the effect of eIMPACT-DM on diabetes risk markers (A1c and HOMA score). 
 
 
 
 
 
 
 
 
 
 
In line with current conceptual frameworks,27 we predict that eIMPACT-DM will improve 
A1c and insulin resistance by decreasing depressive symptoms and downstream factors (see 
figure). These downstream factors (grey boxes) are the leading candidate mechanisms by 
which depression treatment could reduce diabetes risk. First, substantial literatures indicate that 
depression is associated with each downstream factor (see A3). Second, intervention studies 
indicate that depression treatment (CBT or antidepressants) is related to improvements in 
autonomic dysfunction,89-92 smoking,93,94 inflammatory markers,95-98 and insulin resistance.51-53 
Third, our post hoc analysis suggests that computerized CBT is associated with improvements 
in inflammatory markers and fasting glucose (see C2). While we expect that intervention-related 
reductions in depressive symptoms (paths a and b) will result in decreases in downstream 
factors (paths c, d, and e), some antidepressants could reduce A1c and insulin resistance via 
their direct effects on inflammation99 and weight loss.100,101 We are not testing mechanisms in 
the proposed RCT (mechanistic trials are not allowed under PA-18-405); however, we plan to 
do so in the future definitive trial. Blue boxes indicate factors to be assessed in the proposed 
trial. 
 
 
 
Trial Design 
 
Screening, Enrollment, & Pre-Treatment Visit 
 
1:1 Randomization (N=64) 
 
eIMPACT-DM (n=32) 
-Good Days Ahead 
-Problem Solving Therapy 
-Antidepressants 
 
Active Control (n=32) 
-Depression Education 
-Symptom Monitoring 
-Current Primary Care 
 
6-Month Post-Treatment Visit (A1c, HOMA Score) 


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7.0 
Study Procedures 
 
Trial Overview 
Patients will attend the pre-treatment visit at the Clinical Research Center (CRC). They 
will fast and avoid tobacco and exercise for ≥8 hours. A finger-stick blood sample will be 
obtained to ensure patients have an A1c of <6.5%. Those with an A1c outside of this range will 
not continue. Women able to become pregnant will also complete a urine pregnancy test, and 
those with a positive pregnancy test will not continue in the trial. Patients will complete 
questionnaires, an interview, anthropometric measurements, vital signs assessments (blood 
pressure, heart rate, respiration rate, and temperature), and standard venipuncture (to test A1c, 
HOMA scores, and insulin levels). Finally, randomization will occur. Six months after 
randomization, patients will return to the CRC for the post-treatment visit following the same 
procedures as the pre-treatment visit.  
 
Trial Setting 
The setting is the 8 primary care clinics of our clinical partner, Eskenazi Health, which is 
affiliated with Indiana University and is the second largest safety net healthcare system in the 
U.S. Eskenazi provides special opportunities to study diseases, like T2D,1 that 
disproportionately affect lower SES (~90% are underinsured/ uninsured) and minority (~50% are 
racial/ethnic minorities) populations. 
 
Participants 
 
Please see sections 4.0 and 5.0 above. 
 
Treatment Groups 
1:1 randomization102 will be stratified by A1c (≤6.09%, 6.10-6.49%) and somatic 
symptoms (yes, no).  
 
eIMPACT-DM is our eIMPACT intervention (see C2), except that Good Days Ahead has 
replaced Beating the Blues and the antidepressant algorithm has been optimized for diabetes 
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 intervention50 by harnessing technology to 
minimize staff and space requirements. Interventions are Good Days Ahead (GDA), Problem 
Solving Treatment in Primary Care (PST-PC), and antidepressants. Critically, each intervention 
has a strong evidence base supporting its efficacy, and the IMPACT results50 and our data (see 
C2) support efficacy of the intervention structure. Our treatment team consists of a depression 
clinical specialist (DCS; Ms. MacDonald), a supervising psychiatrist with expertise in primary 
care (Dr. Bateman), and the patients' PCPs. The PI will monitor treatment fidelity. 


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(1) GDA (Empower Interactive; video tutorial) is an empirically supported, HIPAA 
compliant, computerized CBT for depression appropriate for primary care patients and people 
with little computer experience.103 GDA was created by Dr. Jesse Wright (University of 
Louisville), Dr. Andrew Wright (University of Washington), and Dr. Aaron Beck (University of 
Pennsylvania). Dr. Beck is widely recognized as the father of CBT. Dr. Jesse Wright is also a 
co-founder of Empower Interactive. GDA uses an interactive, multimedia format (including 
video, exercises, calls to action, newsfeeds, and customized feedback) to deliver 9 45-minute 
sessions, the structure and content of which mirror face-to-face CBT. Although session content 
is tailored to each patient, general topics include identifying and modifying automatic thoughts, 
using behavioral activation and other behavioral methods, identifying and modifying schemas, 
using effective coping strategies, and employing other core CBT methods. Characters 
appearing in GDA represent diverse racial, ethnic, age, and cultural backgrounds. GDA includes 
a clinician portal to allow clinicians to track progress, view completed exercises, and check 
comprehension. GDA is empirically supported – it is acceptable to patients,104 achieves superior 
depression outcomes to waitlist comparators (effect size = 1.60),105 and yields equivalent 
(noninferior) depression outcomes to standard face-to-face CBT (effect size = 0.05).105,106 GDA 
is being evaluated further in ongoing trials in new settings.103 
To minimize time/transportation barriers, GDA sessions will occur at the PI’s lab or a 
location with internet access selected by the patient (e.g., patient’s, family member’s, or friend’s 
home). In our eIMPACT Trial, most patients have elected to complete BtB remotely. For those 
with lower confidence in using GDA, the DCS and patient will work through the first few 
sessions together over the phone, via IU Zoom Health, or in the PI’s lab. IU Zoom Health is a 
HIPAA-aligned version of Zoom for use by individuals who host Zoom meetings where Personal 
Health Information (PHI) is shared or discussed. It is currently in use at many medical centers. 
Patients can install it for free onto their smartphones, tablets, or computers. 
(2) PST-PC is an established, manualized, empirically supported CBT developed for 
primary care.107-112 During the eight weekly 30-minute sessions, patients are taught skills for 
solving problems contributing to depression. We will deliver PST-PC by phone or IU Zoom 
Health, which we (see C2) and others113 have found to be feasible and efficacious.  
(3) Antidepressants. We first considered all FDA-approved antidepressants and 
excluded those with weight gain effects (tricyclics, paroxetine, mirtazapine73,74) and those rarely 
used in primary care (MAOIs114). Then, we used existing evidence to inform the structure. We 
made bupropion (an aminoketone) and fluoxetine (an SSRI) our first-line and second-line 
antidepressants, as meta-analyses indicate that their use is associated with weight loss.100,101 
We made other SSRIs (escitalopram, sertraline) and SNRIs (desvenlafaxine, duloxetine, 
venlafaxine) our third-line antidepressants, given their negligible effects on weight.100,101 As we 
did in the IMPACT and eIMPACT trials, our team will make recommendations to the patient’s 
PCP, who will write prescriptions. Our team and the PCP will then collaboratively manage 
pharmacotherapy. 


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Treatment Process. At the end of the pre-treatment visit, 
our DCS will speak to the patient for 20 minutes via IU 
Zoom Health to orient them to depression materials and 
schedule the intake interview. Future DCS contacts will 
be over the phone or via IU Health Zoom, consistent 
with patient preference. Our DCS will contact the patient 
for the intake interview. At meetings every 2 weeks, the 
DCS will present cases to our team, who will formulate a 
Step 1 plan with PCP input. The DCS will work with the 
PCP to implement this plan. Step 1 will be 2 months of 
psychotherapy or an antidepressant. GDA and PST-PC 
are our first- and second-line psychotherapies; 
bupropion and fluoxetine are our first- and second-line 
antidepressants (others are third-line). For patients on 
an antidepressant at entry, the dosage may be increased, psychotherapy may be added, or a 
different antidepressant may be prescribed. For patients who want psychotherapy but have 
major barriers to GDA, PST-PC will be offered at Step 1. Our DCS will follow patients for 6 
months, while monitoring response and staffing cases with the team at least every 2 months. At 
the start, the DCS will have sessions at least every 2 weeks. For patients who achieve 
remission (≥50% PHQ-9 reduction and <3 symptoms50), the DCS will develop a relapse 
prevention plan and follow-up monthly. Step 2 – augmenting Step 1 with psychotherapy or an 
antidepressant or switching to another psychotherapy or antidepressant – will be delivered to 
patients not in remission. If remission is not achieved after Step 2, Step 3 will be initiated, which 
will involve additional psychotherapy and/or antidepressants. 
Active Control (AC) consists of depression 
education (study staff), symptom monitoring (study 
staff), and primary care for depression (clinical staff). 
(1) At the end of the pre-treatment visit, the RA 
responsible for Active Control delivery (a clinical 
psychology PhD mentee of the PI) will speak to the 
patient for 20 minutes via IU Zoom Health to review 
depression materials,115 including their PCP's role in 
its management and treatment options. In addition, 
patients will be provided with a list of Eskenazi 
mental health services, and the RA will encourage patients to follow-up with their PCP. To 
engender expectancy of benefit, the RA will stress that our notifications should prompt PCP 
actions and that the available treatments are effective. We will then send an EMR message to 
the PCP indicating that their patient has a depressive disorder and was randomized to the AC 
group. This message will encourage the PCP to address their patient’s depression, note that 
there are no care restrictions, and provide the same list of Eskenazi services. (2) The RA will 
call AC patients every 4 weeks (i.e., at the end of Months 1, 2, 3, 4, and 5) to assess depressive 
symptoms (PHQ-9) and will notify clinical staff to encourage additional care when indicated (see 
table). (3) AC patients will receive current primary care for depression. The Eskenazi primary 
care clinics utilize a team care approach for behavioral health issues, as PCPs are supported by 
embedded behavioral health clinicians and affiliated psychiatrists available for brief counseling 
and antidepressant management. 
We chose an AC comparator116 for several reasons. (1) Because we plan to use an AC 
group in the R01-level RCT, we need to use it here to obtain accurate effect size estimates. 
Other approaches (no comparator or usual care comparator) could overestimate effect sizes. (2) 
Our AC group will help to ensure that the groups have similar expectancy of benefit and clinical 
eIMPACT-DM Treatment Process 
 
Intake Interview with DCS 
Review depression education materials 
Orient patient to the intervention 
Assess patient treatment preferences 
 
Treatment Team Meeting & PCP Input 
Formulate Step 1 treatment plan 
 
Step 1 Treatment (months 0-2) 
Deliver GDA/PST-PC and/or  
antidepressant therapy 
 
Step 2 Treatment (months 3-4) 
Deliver GDA/PST-PC and/or  
antidepressant therapy 
 
Step 3 Treatment (months 5-6) 
Deliver GDA/PST-PC and/or  
antidepressant therapy 
PHQ-9 Score 
Action (within 24 hours) 
<10  
(minimal) 
Results will be reported in a note added 
to the EMR. 
10-19  
(minor/ 
moderate) 
RA will encourage patient to seek 
treatment at their primary care clinic 
and will notify the patient’s PCP and the 
embedded behavioral health clinician. 
20-27  
(severe) 
RA will strongly encourage patient to 
seek treatment at their primary care 
clinic and will notify the patient’s PCP, 
the embedded behavioral health 
clinician, and the affiliated psychiatrist. 


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attention. We will assess expectancy83 and attention and will adjust for them in a sensitivity 
analysis. (3) Our AC group is feasible. As eIMPACT-DM uses a flexible approach, each patient 
will have their own treatment path within the intervention structure. Thus, it is not possible to 
develop a comparator that exactly parallels the attention for each eIMPACT-DM patient.  
 
Type 
Name 
Description 
Behavioral (e.g., 
Psychotherapy, 
Lifestyle 
Counseling) 
eIMPACT-DM 
(intervention) 
eIMPACT-DM is a 6-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 diabetes 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 
Good Days Ahead, 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' 
PCPs. 
Behavioral (e.g., 
Psychotherapy, 
Lifestyle 
Counseling) 
Active Control 
(comparator) 
Active Control (AC) consists of depression education (study 
staff), symptom monitoring (study staff), and primary care for 
depression (clinical staff). (1) The RA (a clinical psychology PhD 
mentee of the PI) will have a 50-minute call with AC patients to 
review depression materials, including their PCP's role and 
treatment options. We will send an EMR message to the 
patient’s PCP to encourage the PCP to address their patient’s 
depression. (2) The RA will call AC patients every 4 weeks to 
assess depressive symptoms and will notify clinical staff to 
encourage additional care when indicated. (3) AC patients will 
receive current primary care for depression. The Eskenazi 
primary care clinics utilize a team care approach for behavioral 
health issues, as PCPs are supported by embedded behavioral 
health clinicians and affiliated psychiatrists available for brief 
counseling and antidepressant management. 
 
Potential for Crossover Effects: Because randomization will occur at the patient level, 
it is possible that a PCP could have patients in both the eIMPACT and Active Control groups. 
Even so, crossover effects (i.e., diffusion of treatment) are unlikely for several reasons. One, 
PCPs do not attend eIMPACT treatment team meetings and do not have access to the 
eIMPACT treatment protocol, including the antidepressant algorithm. Instead, if treatment with 
an antidepressant is pursued for a particular patient, the PCP will receive a specific medication 
recommendation from the eIMPACT-DM treatment team via the DCS. Two, the behavioral 
health clinicians embedded in the targeted primary care clinics do not have the capacity or 
resources to deliver the intensity or modes (computerized) of psychotherapy of the eIMPACT 
treatment team. Three, we have not observed any evidence of crossover effects in our ongoing 
eIMPACT Trial, which utilizes a similar design. Moreover, our preliminary data from that trial 
(see C2) – i.e., 51% of eIMPACT patients, versus 20% of usual care patients, had a 50% 
reduction in depressive symptoms – argue against the existence of meaningful crossover 
effects. For these reasons, we believe that crossover effects (i.e., diffusion of treatment) are not 
a threat to the internal validity of the proposed pilot RCT. 
 


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Justification for Intervention and Comparator Components: We chose to 
incorporate only components addressing depression specifically into our intervention and active 
control groups. We chose not to incorporate components directly targeting factors known to 
improve A1c (e.g., diet, physical activity, or weight) into our intervention or active control groups, 
as doing so would severely cloud interpretation and undermine our ability to determine whether 
improving depression lowers A1c and other diabetes risk markers – the primary aim of the 
proposed research.  
 
Training and Treatment Fidelity: Before launch, the treatment team will complete 
training with the PI on the eIMPACT-DM model and antidepressant algorithm. The DCS will also 
complete trainings for GDA with Empower Interactive and PST-PC with the AIMS Center. The 
PI will provide annual refresher trainings. At bi-monthly treatment team meetings, fidelity to 
eIMPACT-DM will be assessed by the PI. In addition, the PI will also audit a random subset of 
20% of eIMPACT-DM and Active Control patients every 6 months and perform an assessment 
of treatment fidelity using our adherence checklists. We have developed a treatment delivery 
REDCap database for the eIMPACT Trial, which we will use here. This database, which will 
include the DCS’s de-identified notes and EMR messages, will allow for assessments of 
treatment fidelity. To maintain high fidelity, the PI will provide timely feedback to the DCS and 
any needed training. Our approaches are in line with the NIH Treatment Fidelity Workgroup 
recommendations.138 
 
Assessments 
Please see sections 3.0 above. 
 
8.0 
Study Calendar 
 
The timeline for study activities is shown below. In Quarter 1 of Year 1, we will complete 
trial start-up tasks, including obtaining regulatory approvals from the Indiana University IRB, the 
Indiana CTSI Clinical Research Center, and Eskenazi Health Research Committee; forming the 
DSMB and obtaining the board's feedback on the trial protocol; finalizing all trial manuals, 
protocols, questionnaire batteries, databases, and meetings; and registering this study on 
ClinicalTrials.gov. Of note, through the eIMPACT Trial, we have already developed many 
materials (treatment manuals, safety protocols, questionnaire batteries, and REDCap 
databases), processes (treatment team meeting structure and preferred methods of 
communicating with PCPs), and relationships (Eskenazi leadership, PCPs, and clinic staff). We 
have also obtained permission from the IMPACT PI (Dr. Unützer) to modify the IMPACT 
intervention and manuals. During the 1-year recruitment period (Quarter 2 in Year 1 through 
Quarter 1 in Year 2), we will recruit and randomize (at the end of the pre-treatment visit) 64 
primary care patients with a depressive disorder and prediabetes. During the 1.5-year treatment 
period (Quarter 2 in Year 1 through Quarter 3 in Year 2), the eIMPACT-DM and Active Control 
interventions will be delivered. The post-treatment visits will begin 6 months after the first pre-
treatment visit and will be completed from Quarter 4 in Year 1 through Quarter 3 in Year 2. 
Upon completion of the last pre-treatment visit, we will begin data management and analysis in 
Quarter 2 of Year 2, which will run through Quarter 4 of Year 2. Finally, in Quarters 3 and 4 of 
Year 2, we will prepare the R01 application to support the definitive RCT for which this pilot trial 
is designed to generate preliminary data. 
 
 
 
 
 
Year 1 
Year 2 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Trial Start-Up Phase 
 
 
 
 
 
 
 
 
Recruitment & Pre-Treatment Visits 
 
 
 
 
 
 
 
 
Intervention Delivery 
 
 
 
 
 
 
 
 
Post-Treatment Visits 
 
 
 
 
 
 
 
 
Data Management & Analysis  
 
 
 
 
 
 
 
 
R01 Preparation 
 
 
 
 
 
 
 
 


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9.0 
Reportable Events and Data Safety Monitoring 
 
We have developed a Data and Safety Monitoring Plan and Board to ensure the safety 
of participants and to monitor participant recruitment, accrual, randomization, and retention; 
treatment delivery and fidelity; and data collection and quality.  
 
Data and Safety Monitoring Plan (DSMP) 
 
Adverse Event Monitoring  
As we are doing in our ongoing eIMPACT Trial (see C2), we will systematically identify 
potential adverse events (AEs): (a) by conducting Eskenazi Health EMR searches every 6 
months (before DSMB meetings) for all emergency department visits, hospitalizations, and 
deaths that occurred among randomized patients and (b) by reviewing responses on a self-
report questionnaire assessing for the occurrence of any potential adverse events since the pre-
treatment visit administered at the post-treatment visit. The eIMPACT-DM depression clinical 
specialist will also receive alerts through the Eskenazi Health EMR when any randomized 
patient has a new emergency department visit or hospitalization, which will provide real-time 
monitoring. Finally, any potential adverse events spontaneously reported by participants (e.g., 
during a study visit or call) will be evaluated. We will fully investigate, rate, and prepare a Case 
Report Form for those events that are plausibly related to depression, depression treatment, 
suicidal ideation, or any study procedures and for all deaths. For all other captured events 
(emergency department visits or hospitalizations typically for chronic medical conditions that are 
unrelated to study involvement), we will provide frequency counts for the eIMPACT-DM and 
Active Control arms. We will fully investigate these events only if there is evidence of group 
imbalance. It is worth noting that that: (a) we are delivering safe and established depression 
interventions, (b) we are not delivering any new or experimental interventions or restricting usual 
care, and (c) all study procedures are noninvasive (except for the blood draw) and standard. 
 
Adverse Event Rating and Reporting 
All events plausibly related to depression, depression treatment, suicidal ideation, or any 
study procedures and all deaths will be promptly rated using the anticipation, severity, and 
attribution scales below. These ratings will be included in the Case Report Form for the adverse 
event signed by Dr. Stewart (principal investigator) and Dr. Bateman (trial psychiatrist). 
 
Anticipation 
1. Anticipated 
2. Unanticipated 
 
Severity 
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  
4. Life-Threatening: Immediate risk of death from the reaction as it occurred 
 
Attribution 
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 
 


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All AEs that meet the IUPUI IRB prompt reporting requirements (unanticipated; 
definitely, probably, or possibly related to study involvement; and suggest that the research 
places participants or others at a greater risk of harm than was previously known or recognized) 
will be immediately reported the IUPUI IRB, DSMB, CRC Research Subject Advocate, and NIH. 
All severe or life-threatening AEs will be immediately reported to and reviewed by the DSMB. All 
other AEs will be reported to these entities at the time of continuing review. A summary of AE 
data (e.g., frequency, types, and corrective actions) will be provided to the IUPUI IRB, DSMB, 
CRC Research Subject Advocate, and NIH at the time of continuing review. 
 
Data and Safety Monitoring Board (DSMB) 
As we did in our ongoing eIMPACT Trial (see C2), we will form a DSMB to provide 
independent oversight. None of the DSMB members will be involved in the proposed trial other 
than serving on this board. The DSMB will consist of a psychiatrist, an endocrinologist, and a 
clinical trialist from the Indiana University School of Medicine. All AEs that are severe/life-
threatening or that raise questions about the risks posed to other participants will be 
immediately reviewed by the DSMB. In addition, every 6 months, Dr. Stewart (principal 
investigator) will submit a written report to the DSMB describing study updates; participant 
recruitment, accrual, randomization, and retention; treatment delivery and fidelity; data collection 
and quality; suicidal ideation protection protocol triggers; any adverse events; any protocol 
deviations; and any IRB amendments. At that time, the DSMB will have a closed meeting to 
determine whether the trial should continue unchanged, be modified, or be stopped, and the 
DSMB Chair will provide a written response with all recommendations. The IUPUI IRB, CRC 
Research Subject Advocate, and NIH will receive copies of all DSMB reports and responses at 
the time of continuing review. 
 
10.0 
Study Withdrawal/Discontinuation 
 
All participants will be considered enrolled at the start of the pre-treatment visit after 
written informed consent and authorization are obtained. 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. 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 the 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 exhibits evidence of a psychotic disorder or bipolar disorder (both of 
which are exclusionary conditions and could interfere with treatment delivery/effectiveness) 
during the 6 month 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 diabetes) 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. 
 
 


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11.0 
Statistical Considerations 
 
Sample Size Justification and Power Analysis 
 
This pilot RCT is not designed to detect statistically significant differences. We chose 
N=64, as it is sufficient to yield the expected outcomes and is feasible within the R21 
constraints. Assuming an attrition rate of ≤20%,117 we will have ≥50 completers (25/arm). With 
50 completers and type I error rate=5%, we will have 55%, 68%, 79%, and 88% power to detect 
a d=0.60, 0.70, 0.80, and 0.90, respectively. We observed a d=0.90 for CBT for depression on 
fasting glucose in depressed primary care patients (see C2). 
 
Primary Aim Analytic Plan 
 
Analyses will use the intent-to-treat approach.118 Tests will be two-tailed with p<.05 
considered statistically significant. Supplemental analyses of completers and analyses 
employing multiple imputation (SAS mi and mianalyze) will be performed. We will assess for 
group differences in baseline factors. Due to randomization, we do not expect differences. Even 
so, baseline differences will be taken into account when interpreting results, and baseline 
factors that differ between groups will be added as covariates in sensitivity analyses. We will 
also add expectancy and attention as covariates in sensitivity analyses. 
 
We will evaluate H1 and H2 (eIMPACT-DM patients will exhibit greater improvement in 
A1c and HOMA score) using linear mixed modeling (SAS proc mixed) with an unstructured 
covariance matrix. Subject will be a random effect, and treatment group, time, and their 
interaction will be fixed effects. Separate models will be run for the primary (A1c) and secondary 
(HOMA score) outcomes. Treatment group x time interactions would indicate statistically 
significant treatment effects. For both A1c and HOMA score, we will report the group means and 
standard errors; regression coefficients, 95% CIs, and p-values; and effect sizes (d’s). We will 
consider an absolute group difference in post-treatment A1c of ≥0.3% (d=0.50) to be clinically 
important (e.g., 5.9% for eIMPACT-DM group versus 6.2% for AC group; d=0.50). This A1c 
difference corresponds to annualized diabetes incidence rate of 4.0% for the eIMPACT-DM 
group versus 7.0% for the AC group.70 Because there is no absolute cut point distinguishing 
between normal and abnormal HOMA scores,119 we will consider a d≥0.50 (moderate effect 
size65) as clinically important. If we find that the eIMPACT-DM produces clinically important 
improvements in A1c and HOMA score (d’s ≥0.50), it would pave the way to an R01-level RCT 
by (1) generating critical proof-of-concept data to support the premise and (2) providing 
preliminary effect sizes for eIMPACT-DM on A1c and HOMA score. Of note, the effect size 
estimate used in the primary power analysis for the future RCT will be based on the minimal 
clinically important difference in A1c instead of solely on this RCT’s results, as pilot studies tend 
to overestimate or underestimate true effect sizes.120 We will use this RCT’s results, along with 
other relevant data, to make a strong case that the selected effect size estimate is plausible and 
achievable. 
A set of planned subgroup analyses will be performed including only participants with 
pre-treatment A1c values between 5.70%-6.49%. Another set of planned subgroup analyses will 
explore whether history of COVID-19 infection (defined as history of a positive COVID-19 test at 
trial entry) moderates the effect of eIMPACT-DM on A1c and HOMA score. 
 
Exploratory Aim Analytic Plan 
 
To explore whether somatic depressive symptoms moderate the effect of eIMPACT-DM 
on A1c and HOMA score, we will rerun the Primary Aim models stratified by somatic symptoms 
group. We expect ~60% of patients to have hyperphagia and/or hypersomnia and thus be 
coded as “yes” on the somatic symptoms group variable (see C3). The remaining patients will 
be coded as “no.” We anticipate larger effect sizes for the somatic symptoms group. We will 
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d=0.75 vs. 0.25). We will compute effect sizes of treatment group x somatic symptoms group x 
time interactions for A1c and HOMA score; however, we expect these to be nonsignificant due 
to lower power. If we find clinically important effect size differences between those with vs. 
without somatic depressive symptoms, we will modify the design of the R01-level RCT as 
follows – recruitment: enroll 50% with and 50% without these symptoms; randomization: stratify 
on presence of these symptoms; and sample size: ensure sufficient power to detect 3-way 
interactions. 
A set of planned subgroup analyses will be performed including only participants with 
pre-treatment A1c values between 5.70%-6.49%. Another set of planned subgroup analyses will 
explore whether history of COVID-19 infection (defined as history of a positive COVID-19 test at 
trial entry) moderates the effect of eIMPACT-DM on A1c and HOMA score. 
 
Incident Diabetes 
We will also explore whether eIMPACT-DM patients show a clinically relevant reduction 
(≥25% lower relative risk) in incident diabetes by performing a Cox model with treatment group 
predicting time to diabetes onset. 
 
Sex as a Relevant Biological Variable 
In exploratory analyses, we will examine sex as a moderator of treatment effects on all 
outcomes by testing treatment group x sex x time interactions in the Primary Aim models. In 
addition, we will examine whether there is sex difference in the likelihood of being classified as 
having a somatic presentation of depression (i.e., those with hyperphagia and/or hypersomnia) 
at baseline. If a sex difference is found, it would influence the design of the future definitive RCT 
– e.g., we would likely additionally stratify randomization by sex. 
 
12.0 
Statistical Data Management 
 
Research materials that will be directly obtained from the participants are: (1) 
questionnaires; (2) standard measures of height, weight, and waist circumference; (3) blood 
samples; and (4) urine specimens to determine pregnancy status (women only). Only members 
of the research team directly involved in the proposed trial will have access to individually 
identifiable private information about the participants. All research material collected during the 
proposed project will be used for research purposes only and will be kept strictly confidential. 
The only research materials that will be obtained from other sources are the recruitment data: 
potential participants’ medical records will be accessed in accordance with HIPAA and IRB 
regulations when the Eskenazi EMR is searched to generate a list of patients who satisfy the 
study inclusion/exclusion criteria. 
REDCap software will be used to obtain the questionnaire data and other data (e.g., 
height, weight, waist circumference, and urine pregnancy test results). Blood samples will be 
transferred from the Indiana CTSI Clinical Research Center (CRC) to Translation Core Analyte 
Lab of the Indiana CTSI for secure storage until the time of assay. An Excel file reporting assay 
results will be securely sent to Dr. Stewart from the Translation Core Analyte Lab. SPSS 
statistical software will be used for all data merging, cleaning, and reduction tasks. 
 
13.0 
Privacy/Confidentiality Issues 
 
 
Participants will be screenedco in the privacy of their homes via phone or the Indiana 
CTSI Clinical Research Center (CRC). All procedures will take place in private rooms at the 
CRC, Dr. Stewart’s Cardiometabolic 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 calls and the computerized and telephonic components of the treatment groups). All 


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research material will be kept strictly confidential. All study personnel have completed the 
required Collaborative Institutional Training Initiative (CITI) courses 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. Any leftover blood samples will be stored in 
Dr. Considine's laboratory. 
 
14.0 
Follow-up and Record Retention 
 
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. 
While the study duration (i.e., project period) is 2 years, all study documents will be kept 
up to 7 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.  
 
 


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16.0 
Appendix: Suicidal Ideation Protection Protocol 
 
Suicidal ideation protection protocols very similar to the one described below have 
previously been approved by the Indiana University IRB and were successfully implemented in 
three other depression trials conducted by our team (IRB #’s 1105005448, 1110007119, and 
1411802537). Those suicide management plans were constructed with input from Sandra 
Eskenazi Mental Health Center leadership (Dean Babcock, Associate Vice President, and 
Michael Hughes), who concluded that the plans provide a high level of protection while 
minimizing disruption to usual clinical activities. The informed consent form for this trial contains 
a section describing the steps that will be taken if an enrolled patient reports suicidal ideation on 
a questionnaire or spontaneously. 
 
ResNet Phone Screening Interview 
 
If a potential participant reports having thoughts of being better off dead or of hurting 
him/herself (i.e., responds with a 1, 2, or 3 to PHQ-9 Item #9 or spontaneously reports suicidal 
ideation) during a ResNet telephone interview, the interview will be immediately stopped, and 
the ResNet research assistant will interview the potential participant to complete the Patient 
Suicidality Form. If the potential participant answers “no” to the clarifying question, the interview 
will proceed as normal. If the potential participant answers “yes” to the clarifying question, the 
participant will be asked the three suicide questions. If the potential participant answers “no” to 
all three suicide questions or if the patient answers “yes” only to Question 3 (previous attempt) 
and the most recent attempt was ≥ 10 years ago, the interview will proceed as normal, and the 
completed Patient Suicidality Form will be given to the principal investigator. If the potential 
participant answers “yes” to any of the three questions (for Question #3 the previous attempt 
must be within the past 10 years), the ResNet research assistant will inform the patient that the 
interview must be stopped and that a behavioral health clinician must be contacted according to 
the study protocol. The patient will also be told that the behavioral health clinician will call them 
back before the end of that day. The ResNet research assistant will then contact a behavioral 
health clinician, who will contact the patient before the end of that day to determine the 
appropriate course of action (e.g., referral to the psychiatrist or to the Crisis Intervention Unit) 
and will notify the patient’s primary care provider. After the situation is handled, the ResNet 
research assistant will contact the behavioral health clinician. If the behavioral health clinician 
considers the patient to be at acute risk of suicide (an exclusion criterion), the patient will be 
coded as ineligible. If the behavioral health clinician considers the patient not to be at acute risk 
of suicide, ResNet will attempt to contact the patient again to readminister the screening 
interview. 
 
In-Person Study Visits 
 
Suicidal ideation will be assessed using Item #9 of the PHQ-9 at the pre- and post-
treatment visits. The PHQ-9 may also be administered periodically in person by the depression 
clinical specialist during the treatment phase.  Suicidal ideation will also be assessed using 
items #3 “thoughts of ending your life” and #14 “thoughts of death or dying” on the SCL-20 at 
pre- and post-treatment visits. 
If an enrolled patient reports having thoughts of being better off dead or of hurting 
him/herself (i.e., responds with a 1, 2, or 3 to PHQ-9 Item #9; responds with a 1, 2, 3, or 4 to 
SCL-20 Item #3 or #14; or spontaneously reports suicidal ideation) during an in-person study 
visit, the visit will be immediately stopped, and the research assistant or depression clinical 
specialist will interview the participant to complete the Patient Suicidality Form. If the potential 
participant answers “no” to the clarifying question, the visit will proceed as normal. If the 


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potential participant answers “yes” to the clarifying question, the participant will be asked the 
three suicide questions. If the participant answers “no” to all three suicide questions or if the 
patient answers “yes” only to Question 3 (previous attempt) and the most recent attempt was ≥ 
10 years ago, the visit will proceed as normal, and the completed Patient Suicidality Form will 
be given to the principal investigator. If the participant answers “yes” to any of the three 
questions (for Question #3 the previous attempt must be within the past 10 years), the research 
assistant or depression clinical specialist will immediately contact Dr. Stewart. If Dr. Stewart 
cannot be reached, contact Dr. Bateman. Dr. Stewart (a clinical psychologist) and Dr. Bateman 
(the trial psychiatrist) will review the case as soon as possible, but no later than the same day, 
to determine the appropriate course of action (e.g., interview the patient to obtain further 
information, immediately contact the patient’s primary care provider and/or behavioral health 
clinician to involve them in the decision-making process, consult with clinicians at Sandra 
Eskenazi Mental Health Center, escort the patient to the Crisis Intervention Unit, and/or contact 
the police if the patient is at imminent danger of harm and is refusing all care).  The depression 
clinical specialist will also notify the participant’s primary care provider if s/he was not involved in 
the decision-making process. Regardless of the exact course of action, the study team will 
ensure that the participant is connected to the appropriate existing clinical services. If the 
patient’s primary care provider no longer believes that the patient is appropriate for this trial 
following a situation, s/he will be withdrawn.  
   
Study Calls 
 
Suicidal ideation will be assessed using Item #9 of the PHQ-9 during most study calls 
completed by the depression clinical specialist responsible for intervention delivery and during 
most study calls competed by the research assistant responsible for active control delivery. 
If an enrolled patient reports having thoughts of being better off dead or of hurting 
him/herself (i.e., responds with a 1, 2, or 3 to PHQ-9 Item #9 or spontaneously reports suicidal 
ideation) during a study calls, the research assistant or depression clinical specialist will 
immediately interview the participant to complete the Patient Suicidality Form.  If the potential 
participant answers “no” to the clarifying question, the call will proceed as normal. If the potential 
participant answers “yes” to the clarifying question, the participant will be asked the three 
suicide questions. If the participant answers “no” to all three suicide questions or if the 
participant answers “yes” only to Question 3 (previous attempt) and the most recent attempt 
was >10 years ago, the call will proceed as normal, and the completed Patient Suicidality Form 
will be given to the principal investigator.  If the participant answers “yes” to any of the three 
questions (for Question #3 the previous attempt must be within the past 10 years) or 
prematurely terminates the call, the research assistant or depression clinical specialist will 
immediately contact Dr. Stewart. If Dr. Stewart cannot be reached, contact Dr. Bateman. Drs. 
Stewart and Bateman will review the case as soon as possible, but no later than the same day, 
to determine the appropriate course of action (e.g., interview the patient to obtain further 
information, immediately contact the patient’s primary care provider and/or behavioral health 
clinician to involve them in the decision-making process, consult with clinicians at Sandra 
Eskenazi Mental Health Center, refer the patient to the Crisis Intervention Unit, and/or contact 
the police if the patient is at imminent danger of harm and is refusing all care). The depression 
clinical specialist will also notify the participant’s primary care provider if s/he was not involved in 
the decision-making process. Regardless of the exact course of action, the study team will 
ensure that the participant is connected to the appropriate existing clinical services. If the 
patient’s primary care provider no longer believes that the patient is appropriate for this trial 
following a situation, s/he will be withdrawn. 
 
 


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Patient Suicidality Form 
 
 
Interviewer:_______________________________________ Date: ______________________ 
 
Patient’s Name: ___________________________________ Hospital ID: _________________ 
 
Patient’s Address: _____________________________________________________________ 
 
Patient’s Phone Number: ____________________________ Patient’s PCP: _______________ 
 
************************************************************************************************************* 
Clarifying Question 
Over the past 2 weeks, have you been having thoughts of hurting yourself in some way? 
 
Yes ____   
No ____ 
(Continue) 
(Stop, no SIPP trigger) 
 
Comments: 
 
*************************************************************************************************************
I’m going to ask you a few questions that are part of the study protocol, because we have 
seen that in some patients with these symptoms, these are important concerns. 
 
1. Do you have a suicide plan?   
 
Yes ____  No ____ 
 
Comments: 
 
 
2. Have you been struggling against thoughts about committing suicide? In other words, 
are you afraid you might act on these thoughts?   
 
Yes ____  No ____ 
 
Comments: 
 
 
3. Have you attempted suicide in the past?   
 
Yes ____  No ____ 
 
If YES, in what year was the most recent attempt? __________   
 
Comments: 
 
 
If the patient answers “yes” to any of the three questions (for Question #3 the previous 
attempt must be within the past 10 years), you must carefully follow the procedures 
described in the Suicidal Ideation Protection Protocol. 

ICF_001.pdf: 
 
 
V5.06.2021 
 
 
 
 
IRB Protocol# 1908716624 
IU IRB ICS Template - Biomedical v04.25.2019 
 
 
 
 
 
          Page 1 of 8 
INDIANA UNIVERSITY INFORMED CONSENT STATEMENT FOR RESEARCH 
 
eIMPACT-DM Pilot Trial:  
Depression Treatment to Reduce the Excess Diabetes Risk  
of People with Depression and Prediabetes 
 
National Institute of Diabetes and Digestive and Kidney Disease, 
National Institutes of Health 
(R21DK123582) 
 
ClinicalTrials.gov Identifier:  
NCT04437485 
 
5.6.21 
 
ABOUT THIS RESEARCH  
You are being asked to participate in a research study. Scientists do research to answer important 
questions which might help change or improve the way we do things in the future.  
 
This consent form will give you information about the study to help you decide whether you want to 
participate. Please read this form, and ask any questions you have, before agreeing to be in the study. 
 
TAKING PART IN THIS STUDY IS VOLUNTARY 
You may choose not to take part in the study or may choose to leave the study at any time. Deciding 
not to participate, or deciding to leave the study later, will not result in any penalty or loss of benefits 
to which you are entitled and will not affect your relationship with your regular healthcare providers or 
your relationship with the study team. 
 
WHY IS THIS STUDY BEING DONE? 
Diabetes is a common medical condition that can lead to disability, heart disease and other medical 
conditions, and death. People with depression have a higher chance of developing diabetes than 
people without depression. The main symptoms of depression are (1) feeling down or depressed and 
(2) having little interest or pleasure in doing things.   
 
The purpose of this study is to compare standard depression treatment to a new depression treatment 
to see if the new depression treatment lowers the chance of developing diabetes in the future. You 
were selected as a possible participant because your medical records show that you are a patient at an 
Eskenazi Health primary care clinic, are 18 years or older, and have one or more risk factors for 
diabetes but have not developed diabetes. Your responses to our depression questions also show that 
you may have a depressive disorder. 
 
The study is being conducted by Dr. Jesse 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. 
 


 
 
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We will use the data from this study to develop new depression treatments that could be easily used in 
primary care clinics. We hope that these new depression treatments will help prevent diabetes in 
people with prediabetes. 
 
HOW MANY PEOPLE WILL TAKE PART? 
If you agree to participate, you will be one of 64 people taking part in this research locally.   
 
WHAT WILL HAPPEN DURING THE STUDY? 
If you agree to be in the study, you will be asked to attend a pre-treatment visit and a post-treatment 
visit six months later. The pre-treatment visit is the start of the study, and the post-treatment visit is 
the end of the study. 
 
At the pre-treatment visit, 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 healthcare providers will continue to make your own treatment decisions. 
Neither you nor your healthcare providers will be able to choose your group assignment. 
 
If you are assigned to Group A (standard depression treatment), you will also be asked to complete five 
calls with a study assistant over the six months to review depression handouts and to measure your 
depression. The study assistant will send your depression results to your healthcare providers (primary 
care provider, counselor, and/or psychiatrist) at your usual primary care clinic at Eskenazi Health and 
encourage them to treat your depression. You and your usual healthcare providers at Eskenazi Health 
will decide how to treat your depression during the study.  
 
If you are assigned to Group B (new depression treatment), you will be asked to complete additional 
calls and visits to receive the new depression treatment called eIMPACT-DM over the six months. A 
study counselor will work with you and your usual primary care provider at Eskenazi Health to treat 
your depression during the study. Established depression treatments will be available to you, like 
antidepressant medicines 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.  
 
Each study visit and call is described in more detail below. Please note that we will not audio or video 
record any of your phone calls or visits in this study. 
 
Pre-Treatment Visit (All Participants) 
You will be asked to come to the Clinical Research Center at Indiana University Hospital for the 2½-
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 at the end of the visit. 
 
At the pre-treatment visit, the nurse will first obtain a finger-stick blood sample to make sure that you 
have an A1c below 6.5%, which is required for this study (6.5% and above is the diabetes range). 
Women able to become pregnant will also complete a urine pregnancy test. If you have an A1c in the 
diabetes range or a positive pregnancy test, your participation in this study will end, and you will be 


 
 
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paid for your time and effort. Next, the nurse will measure your height, weight, blood pressure, heart 
rate, respiration rate, and temperature. The nurse will then complete a standard blood draw to collect 
½ a tablespoon of blood. This is similar to what your doctor would collect for usual blood tests. This 
blood will be used to look at your A1c and your insulin resistance. After that, you will be asked to fill 
out questionnaires on a secure computer in a private room and complete an interview with the study 
assistant. These questionnaires and the interview will ask you for your basic background, physical and 
mental health history, and medicines. You will also be asked about your behaviors, mood, and sleep. 
 
Treatment for Group A 
If you are assigned to Group A, you will receive standard depression treatment over six months. You 
and your usual healthcare providers at Eskenazi Health will decide how to treat your depression during 
the study.  
 
At the end of your pre-treatment visit, you will speak to a study assistant for 20 minutes over IU Zoom 
Health to review depression materials, including treatment options. IU Zoom Health is a secure form of 
communication in use at many medical centers. You will also be given a list of mental health services 
available to Eskenazi patients and will be encouraged to follow-up with your usual primary care 
provider about your depression. Your primary care provider will also receive a letter from the study 
team informing them of your depression and assignment to Group A. This letter will also encourage 
your primary care provider to work with you to address your depression and will provide the same list 
of available mental health services. Second, you will also be asked to complete five calls with a study 
assistant over the six months. Each call will be 10 minutes to measure your depression and will occur 
each month. The study assistant will send your depression results to your healthcare providers 
(primary care provider, counselor, and/or psychiatrist) at your usual primary care clinic at Eskenazi 
Health and encourage them to treat your depression if your depression scores remain high. Please 
note that there are no restrictions on the care you can receive during the study, meaning that you will 
still 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, you will receive the new depression treatment called eIMPACT-DM over 
the six months. A licensed mental health counselor, called a depression clinical specialist (DCS), will 
work with you and your usual primary care provider at Eskenazi Health to treat your depression.  
 
At the end of your pre-treatment visit, you will speak to the DCS over IU Zoom Health for 20 minutes to 
review depression materials and schedule your first call. During your first call, the DCS will review 
additional depression materials and discuss your treatment options and preferences. The DCS will then 
work with you, the study psychiatrist, and your primary care provider to develop an initial treatment 
plan that is okay with everyone.  
 
The treatment options are: 
• Good Days Ahead: a talk therapy for depression on a computer 
• Problem-Solving Treatment for Primary Care (PST-PC): a talk therapy for depression over the 
phone or IU Zoom or in-person 
 
If Good Days Ahead is selected, you will have the opportunity to complete nine 45-minute sessions on 
a computer, about one per week. Sessions will take place at Dr. Stewart’s research office or a location 


 
 
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selected by you where you can access a computer with internet, like your home, your work, a family 
member’s or friend’s home, or a public library. Your preference will determine the location. Good Days 
Ahead is a computer program, so you will not be meeting face-to-face with a counselor. By 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 using 
effective coping strategies. 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 PST-PC is selected, you will have the opportunity to complete eight weekly 30-minute sessions with 
the DCS over the phone or IU Zoom or in-person at Dr. Stewart’s research office. By completing PST-PC 
sessions, you will learn skills for solving real-life problems contributing to your depression.  
 
No matter which option is selected (Good Days Ahead or PST-PC), you, the study psychiatrist, and your 
primary care provider will have the ability to decide if antidepressant medicine is a good idea for you to 
take in addition to participating in the treatment sessions. If an antidepressant medicine is selected, it 
will be recommended by the study psychiatrist and will be prescribed by your usual primary care 
provider. The DCS, the study psychiatrist, and your primary care provider will monitor the use of these 
medicines. 
 
Over the six months, the DCS will have regular contact with you to see how you are responding to the 
treatments. 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 DCS will call you to discuss other treatment options 
described above. The main idea is that, if your depression does not improve, your treatment will be 
changed to see if another option works better for you. Please note that there are no restrictions on the 
care you can receive during the study, meaning that you will still have access to and will receive any 
health services that are part of your usual care. 
 
Study Newsletter (All Participants) 
Three 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 healthy recipe, profiles for the team members, and a reminder to update the study 
team if your contact information has changed.  
 
Post-Treatment Visit (All Participants) 
Six months after the pre-treatment visit, you will be asked to come back to the Clinical Research Center 
at Indiana University Hospital for the 2½-hour post-treatment visit. This visit will be identical to the 
pre-treatment visit. If you are still screening positive for depression at the post-treatment visit, the 
study team will send your primary care provider a letter urging them to follow-up with you about your 
depression. 
 
Medical Records Review (All Participants) 
We are requesting permission to review your medical records from 5 years before the date you enroll 
in this study to 5 years after your last study visit (the post-treatment visit). To achieve the goals of this 
study, we need to review your medical history to make sure you are eligible, and we need to track your 


 
 
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health over time. We are examining the short- and long-term effects of depression treatment on 
physical health, especially diabetes. You do not need to do anything to complete this part of the study. 
 
WHAT ARE THE 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 interviews or questionnaires 
The study assistants and DCS 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 not to 
answer any question. 
 
Risks of the standard blood draws 
Trained and experienced nurses will use standard approaches (finger stick and inserting a needle into a 
vein) to obtain the needed blood samples. This can be mildly painful, and there is a very low risk of 
bruising, fainting, or a skin infection. You may terminate a blood draw at any time for any reason. 
 
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 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 behavioral health clinician in your primary care clinic. We may also 
consult with the Sandra Eskenazi Mental Health Center and escort you to the Crisis Intervention Unit at 
Eskenazi Hospital. If you prematurely terminate a 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. 
 
WHAT ARE THE POTENTIAL BENEFITS OF TAKING PART IN THE STUDY? 
By taking part in the study, you will learn about the relationship between depression and diabetes at 
the post-treatment visit when we review a handout with you. We hope that you will benefit from being 
in this study by getting treatment for your depression. We also hope that by treating your depression, 
your risk for diabetes will decrease, although there is no guarantee of that. Your involvement will 
generate knowledge that may help to treat depression and prevent diabetes in the future. 
 
 
 


 
 
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WHAT ARE THE OTHER TREATMENT OPTIONS? 
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 main treatments 
for depression are antidepressant medicines and talk therapy, such as cognitive-behavioral therapy. 
You may want to contact your primary care provider to discuss your treatment options. If you choose 
not to participate, your decision will not affect your relationship with your regular healthcare providers 
or your relationship with the study team. 
 
WILL I RECEIVE MY RESULTS? 
We may learn things about you from the study activities which could be important to your health or to 
your treatment. If this happens, this information will be provided to you. Specifically, depression 
results, blood sugar and A1c results, and vital signs (blood pressure, heart rate, respiration rate, and 
body temperature) will be shared with you and your usual primary care provider if the values fall 
outside of safety limits. If this occurs, you will be notified during that study visit or call. You may need 
to meet with professionals with expertise to help you learn more about your research results. The 
study team/study will not cover the costs of any follow-up consultations or actions. 
 
HOW WILL MY INFORMATION BE PROTECTED? 
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 Institute of Diabetes and Digestive and Kidney Disease/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 (ClinicalTrials.gov Identifier: 
NCT04437485), 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);  
(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. 
  


 
 
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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. 
 
WILL MY INFORMATION BE USED FOR RESEARCH IN THE FUTURE? 
Information or specimens collected from you for this study may be used for future research studies or 
shared with other researchers for future research. If this happens, information which could identify 
you will be removed before any information or specimens are shared. Since identifying information will 
be removed, we will not ask for your additional consent.  
 
We will not use the specimens collected as a part of this study for whole genome sequencing, which 
involves mapping all of your DNA.  
 
WILL I BE PAID FOR PARTICIPATION?  
You will receive payment for taking part in this study: a $75 Visa gift card (which can be used most 
places that accept debit cards) for completing the pre-treatment visit and another $75 Visa gift card  
for completing the post-treatment six months later. If you complete all visits, you will receive a total of 
$150 in Visa gift cards. You will not be paid for completing any visits or calls related to depression 
treatment. If you show up for your pre-treatment visit but do not pass the A1c screen (value is 6.5% 
and above) or pregnancy screen (positive test), you will receive a $15 Visa gift card for your time and 
effort. If needed, we will arrange for transportation (e.g., a taxi or ride share) to and from all study 
visits or provide vouchers to cover parking or public transportation costs. 
 
WILL IT COST ME ANYTHING TO PARTICIPATE?  
While there are no costs directly associated with participation in this study, you or your insurance 
company will be responsible for any depression treatments (therapy, medications, etc.) which you 
would receive if you were not participating in the study. The costs of all study-specific tests and 
procedures 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. If you have any questions about what costs you will be responsible for, 
please ask someone on the study team. 
 
WHO WILL PAY FOR MY TREATMENT IF I AM INJURED?  
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. 
 
WHO SHOULD I CALL WITH 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. In the 
event of an emergency, you may call 911 and/or your primary care provider.  
 


 
 
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For questions about your rights as a research participant, to discuss problems, complaints, or concerns 
about a research study, or to obtain information or to offer input, please contact the IU Human 
Subjects Office at 800-696-2949 or at irb@iu.edu. 
 
CAN I WITHDRAW FROM THE STUDY? 
If you decide to participate in this study, you can change your mind and decide to leave the study at 
any time in the future. The study team will help you withdraw from the study safely. If you decide to 
withdraw, you may do so by notifying any member of the research team (including the principal 
investigator) at any time by phone, email, 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. 
 
PARTICIPANT’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 document to keep for my records. I agree to take part in this 
study. 
 
Participant’s Printed Name: 
 
 
Participant’s Signature: 
Date: 
 
 
Printed Name of Person Obtaining Consent:  
 
 
 
Signature of Person Obtaining Consent: 
Date: