Stepped Care for Depression in Heart Failure
Phase: NA
Conditions: Heart Failure, Depressive Disorder, Major
Sponsor: Washington University School of Medicine

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Grant # RO1HL131524
clinicaltrials.gov record # NCT02997865
Stepped Care for Depression in Heart Failure
Kenneth E. Freedland, PhD, Principal Investigator
Washington University School of Medicine in St. Louis
Study Protocol
Version Date: 08/26/2018
PRINCIPAL INVESTIGATOR’S NOTE: The final, DSMB- and IRB-approved protocol for this study was completed on
08/26/2018.  The current version was submitted to clinicaltrials.gov on 12/29/2022.  There are no substantive
differences between the 08/26/2018 version and the 12/29/2022 document. The differences are limited to formatting
changes that were needed to meet clinicaltrial.gov formatting requirements.

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RO1HL131524 Stepped Care for Depression in Heart Failure
Kenneth E. Freedland, PhD, Principal Investigator
Study Protocol
ORIGINAL PLAN
Study Design
This is a two-arm, parallel groups, single-blind RCT. Both groups will receive usual care from their own
nonstudy health care providers throughout the trial, and both will receive a nurse-directed, individually tailored
intervention to address deficits in HF self-care (TSC). The difference between the groups is that the intervention
arm will receive stepped care for depression (SCD) before TSC, whereas the comparison arm will not. Thus, the
trial will compare (UC + SCD + TSC) to (UC + TSC). For simplicity, the following sections will refer to the former
as the intervention arm, and the latter as the UC arm.
We selected this design after weighing its pros and cons against those of several alternatives. A key
advantage of UC is that it will probably be chosen for a future Phase III multicenter trial. However, since the goal
of this study is to achieve better outcomes than we obtained in our recent trial, an alternative would be to compare
SCD to CBT instead of to UC. This would permit a direct test of the hypothesis that SCD is superior to CBT, but
it is outweighed by two disadvantages. First, if SCD turns out to be superior to CBT, the advantage is likely to
be incremental rather than dramatic. There was a 4.5-point difference on the BDI-II and a difference of 27
percentage points in remission rates between the CBT and UC arms of our recent trial, and our goal is to surpass
these outcomes. Much larger differences would be desirable, of course, but sample size calculations are based
on the minimum clinically significant effect size80, not on the largest effect one might hope to achieve. Whereas
a comparison of SCD vs. UC can be powered to detect differences at least as large as the ones found in our
previous trial, an SCD vs. CBT comparison would have to be powered to detect a much smaller difference, so a
much larger sample would be need. The second disadvantage is that our findings would be less relevant to a
future Phase III trial if we were to choose CBT as the comparator instead of UC.
Another alternative would be to use a Sequential Multiple Assignment Randomized Trial (SMART) design81,
which would support rigorous evaluation of the branches within the SCD intervention. A relatively complex
SMART design would enable us to compare CBT monotherapy vs. antidepressant monotherapy vs. UC at the
initial step. Unfortunately, even a less complex SMART design would require a much larger sample than would
be feasible in a single-site study with a standard R01 budget. Thus, a SMART trial would be impractical at this
stage of our research. Depending upon the results of the proposed study, however, it might be desirable to test
the SCD algorithm in greater detail in a future trial with a SMART design.
A final alternative would be to compare SCD to an attention control (AC) condition instead of to UC. This
would determine whether SCD is superior to nonspecific clinical attention. However, the primary purpose of this
study is to determine whether SCD yields better outcomes than approaches that have already been tried, not to
evaluate the extent to which the effects of stepped care are due to clinical attention. The UC comparator will not
determine how much of the effect of SCD is due to clinical attention and how much of it is due to other therapeutic
ingredients, but it is a more clinically relevant comparator than an AC control group.
As a single-blind RCT, this study meets the NIH guidance on robust and unbiased design. The outcome
assessors will be blinded to group assignment, and we will aim to maintain equipoise, enroll a representative
sample, conceal the randomization sequence, maximize adherence and retention, and minimize potential biases,
especially ones that can arise post-randomization such as differential attrition and co-intervention bias.
Subjects
Patients with HF and comorbid MD (n=180, approximately 50% women and 50% minorities) will be
enrolled. The inclusion criteria are 1) stable Class I-III HF, 2) a current major depressive episode, and 3) a
baseline BDI-II score >14. Identification of HF will be based on a documented clinical diagnosis, clinical test
results consistent with HF (chest x-ray, echocardiography, and/or elevated BNP), and a documented response
to medications for HF. Patients with preserved ejection fraction (EF) will be eligible as will those with reduced
EF, since neither major depression nor self-care deficits are exclusive to either one of these forms of HF. The
presence of MD will be documented by a structured clinical interview at the baseline evaluation. Patients who

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have been on a stable dose of an antidepressant for at least two months will be eligible as long as they meet the
study’s depression criteria, as will patients who are not taking an antidepressant at baseline.
The exclusion criteria are: 1) dementia or other cognitive or communication deficits; 2) terminal illness
other than HF, 3) insurmountable logistical barriers to participation, 4) age under 25 years, 5) current alcoholism
or clinically significant substance abuse, bipolar disorder, schizophrenia, or other psychotic disorder, 6) high risk
of suicide, 7) current participation in nonstudy psychotherapy or counseling for depression or other psychiatric
conditions, 8) initiation or modification of antidepressant therapy within the past two months, and 9) renal or
hepatic conditions that would preclude the use of antidepressants. Patients under 25 years old will be excluded
due to the FDA black box warning on SSRI antidepressants for patients younger than 25.82
Screening and Recruitment
Outpatients with HF will be recruited from the Heart Failure, General Cardiology, and Primary Care Clinics
at Washington University Medical Center (WUMC) in St. Louis, as well as from WU faculty cardiology group
practices in the St. Louis metropolitan area. We will use clinic schedules to identify potential candidates, work
with the staff to facilitate physician referrals, and place study recruitment brochures in the waiting rooms.
Inpatients with HF at Barnes-Jewish Hospital (BJH) at WUMC will be identified via a daily Clinical
Investigation & Data Exploration Repository (CIDER) search engine query of the electronic medical record
system. With the permission of the patient’s physician, the study recruiter will give information about the study
to potentially eligible patients and ask for permission to contact them after discharge for further evaluation.
Feasibility: Approximately 3,200 patients with HF received services at WUMC last year. The prevalence
of MD in patients with HF is 15% to 20%, so an estimated 480 to 640 HF patients had comorbid MD. There are
approximately 600 new cases of HF per annum at WUMC, consistent with 90 to 120 new depressed cases.
Thus, we estimate that 795 to 1060 patients with HF and comorbid MD will be treated at WUMC during the
study’s 3½ year recruitment phase. The target sample of 180 patients represents between 17% and 23% of the
estimated pool of potentially eligible patients. This suggests that our enrollment plan is very feasible.
Screening and Consent: Patients who consent to be screened for depression will be asked to complete
the Patient Health Questionnaire (PHQ-9).83;84 Patients who score >10 on the PHQ will be asked for written
informed consent to participate in the trial and to complete a baseline evaluation. Patients who score >14 on the
BDI-II and who meet the DSM-5 criteria for MD will be eligible to participate unless any additional reasons for
exclusion (e.g., comorbid alcohol use disorder) are discovered at baseline. It will not be necessary to screen for
self-care deficits because virtually all depressed HF patients have self-care deficits. In our recent trial, for
example, the mean SCHFI Maintenance score at baseline was almost 40 points below the maximum on this
100-point scale and about 7 points below the mean score of patients seen at HF specialty clinics.1;85 A brief
motivational interview will be included in the enrollment process to promote retention.86
Randomization and Allocation Concealment
Eligible patients will be randomized immediately after the baseline evaluation. Randomization will be
stratified by nonstudy antidepressant use at enrollment. In our recent study, 33% of the participants were taking
a nonstudy antidepressant at enrollment, and all of them continued on their antidepressant throughout the trial,
regardless of group assignment. Thus, we anticipate that about 1 out of every 3 enrollees will be on nonstudy
antidepressants at baseline. Permuted block randomization with allocation concealment will be used to prevent
the study recruiter from guessing the group to which the next patient will be assigned. The study statistician will
generate a separate allocation sequence for each stratum, and the allocations will be concealed in sequentially
numbered, opaque, sealed security envelopes.87
Usual Care
Throughout the study, all participants in both groups will continue to receive medical care from their own
nonstudy physicians and other health care providers. Participation in the UC arm will not prevent patients from
seeking or obtaining nonstudy care for depression or other psychiatric problems, although few participants in
any of our previous trials have sought mental health specialty services during their participation in these studies.

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If there is a significant change in a patient’s psychiatric or medical status or nonstudy treatment during the trial
that would be incompatible with continued participation, the patient will be withdrawn from the study.
All enrollees will be given standard educational brochures about depression and heart failure at
enrollment. Assistance will be provided for patients who are unable to read the materials. With the patient’s
consent, the patient’s personal physician will be informed that the patient has met the criteria for MD and has
been enrolled in our trial. Thus, both groups will receive “minimally enhanced” usual care.88
Intervention
Overview
Adaptive interventions incorporate decision rules for dynamically modifying the intensity or type of
treatment based on the patient’s progress or lack thereof.81 As shown in Table 1, the timing of each intervention
component will depend on whether and how rapidly the patient’s depression has improved. Inadequate progress
will trigger individualized modifications of the CBT for depression (CBT-D) and antidepressant medication (ADM)
plans, whereas rapid progress will allow the patient to initiate CBT for residual insomnia (CBT-I) if indicated,
enter the CBT maintenance phase (CBT-M), and initiate the home-based physical exercise and other HF self-
care intervention components “ahead of schedule.”
Stepped care for depression (SCD) will include CBT administered by a trained therapist and
antidepressant medication prescribed by the study psychiatrist. The home-based physical exercise component
bridges the SCD and Tailored Self-Care (TSC) interventions, because exercise is a component of HF self-care
that is also helpful for reducing depressive symptoms.72 The exercise and other HF self-care components of TSC
will be administered in the intervention and UC arms by a trained nurse.
The SCD and TSC sessions will be conducted with individual patients, in person whenever possible and
by telephone whenever necessary (e.g., because of transportation barriers or illness exacerbations). The first
sessions of CBT and TSC, and evaluations by the study psychiatrist, will be held in person at our clinic.
The PHQ-9 criteria for initiating TSC are the same in both the intervention and UC arms. Thus, TSC will start
for patients in both arms as soon as their PHQ-9 total score has improved by >75%, at Week 12 if their score
has improved 50% to 74%, and Week 15 if their score has improved <50% by then.
Intervention
Action
Timing
PHQ-9 Criteria (Relative to Baseline)
SCD
TSC
Component
CBT-D
Modify
At
Week 06
if <10% improvement
At
Week 09
if <25% improvement
At
Week 12
if <50% improvement
At
Week 15
if <75% improvement
CBT-I
Initiate
Before Week 12
if >75% improvement + residual insomnia
At
Week 12
if >50% improvement + residual insomnia
At
Week 15
if <50% improvement + residual insomnia
CBT-M
Initiate
Before Week 18
if PHQ total score <5
At
Week 18
if PHQ total score >5
ADM
Initiate or
Modify
At
Week 06
if <10% improvement
At
Week 12
if <50% improvement
Exercise
Initiate
Before Week 12
if >75% improvement
At
Week 12
if >50% improvement
At
Week 15
if <50% improvement
Other
Self-Care
Initiate
3 weeks after initiating
exercise component
Table 1. Timing and criteria for initiating or modifying intervention components.
Acronyms: SCD = Stepped Care for Depression; TSC = Tailored Self-Care Intervention; CBT-D = CBT for
Depression; CBT-I = CBT for Insomnia; CBT-M = CBT Maintenance Phase;ADM = Antidepressant Medication

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Cognitive Behavior Therapy for Depression (CBT-D)
Treatment Manuals: As in our previous trial, the depression intervention will be guided by Cognitive
Therapy of Depression40 and Cognitive Therapy: Basics and Beyond.41 Heart Disease by Skala, Freedland, and
Carney42 will guide the adaptation of CBT to the cardiac patient population. Modifications of the CBT-D plan for
nonresponders will be guided by Cognitive Therapy for Challenging Problems.89
Clinical Assessments: The clinical evaluation for the first CBT session will include 1) the Dysfunctional
Attitudes Scale (DAS)90;91, the Dysfunctional Attitudes About Health scale42, 2) a structured problem identification
and goal-setting form, and 3) the Techniques for Overcoming Depression (TOD) scale92. Patients will also
complete an evaluation form after each session. Other clinical tools for CBT will be used as needed.
Treatment Fidelity: Therapists will develop a cognitive conceptualization diagram and a structured
treatment plan and revise it as needed, track the delivery of the intervention on a structured treatment process
data log and systematically track the use of specific cognitive-behavioral techniques on a session evaluation
form. With the patient’s permission, sessions will be recorded for supervisory reviews.
Brief Cognitive Behavior Therapy for Insomnia (CBT-I)
Rationale: Insomnia is one of the most common residual symptoms after treatment of major depression,
and it increases the risk of relapse.66;67 Thus, a residual insomnia module may help in many cases to improve
depression outcomes and prevent relapse. CBT-I is effective for primary insomnia93 and for comorbid insomnia
in MD.94 It has also been shown to reduce inflammatory markers in late-life insomnia.95 Consequently, it may
help to reduce systemic inflammation in HF with comorbid insomnia.
Treatment Manual: We will use Germain and Buysse’s Brief (3-4 session) Behavioral Treatment of
Insomnia protocol70, a form of CBT-I with proven efficacy.96;97 It emphasizes stimulus control and sleep restriction
procedures. It deemphasizes cognitive restructuring of distorted beliefs about insomnia, although these
cognitions will be addressed if clinically indicated as part of CBT for depression.
Clinical Assessments: A score >1 on PHQ-9 “sleep” item will be used to define the presence of residual
insomnia.The Pittsburgh Sleep Quality Index (PSQI)98 will be administered at the initiation of CBT-I (see Table
1). The PSQI will provide information about the patient’s sleep patterns that will guide the intervention.
CBT Maintenance Phase (CBT-M)
The maintenance phase of CBT will begin when the patient scores below 5 on the PHQ-9, if there is no
residual insomnia. If the patient scores below 5 on the PHQ-9 but has residual insomnia, the maintenance phase
will start when the CBT-I module has been completed. If the PHQ-9 score is still >5 at Week 18, the maintenance
phase will start at that point. This phase will consist of brief (10-20 minute) telephone contacts to assist the
patient in maintaining the gains that were achieved during CBT-D and CBT-I, and longer (20-40 minute)
telephone contacts if needed to address a relapse of depression.  The frequency of contacts will taper to biweekly
for the first month of CBT-M, and then monthly for three additional months.
CBT Supervision
A weekly CBT group supervision meeting will be held to discuss clinical issues and implementation of
the treatment protocol. Cases will be systematically reviewed at each “inadequate progress” decision point listed
in Table 1. These reviews will examine all relevant clinical assessments and the therapist’s cognitive case
conceptualization, treatment goals and plan, treatment fidelity measures, and treatment barriers. A modified
treatment plan will be developed based on the review, and its implementation will be discussed at the next
meeting. Brief reviews will also be conducted at decision points that are based on adequate or rapid progress,
to assist in planning the next steps. For example, one will be conducted at Week 12 if the patient’s PHQ score
has improved >50% and residual insomnia is present, and the patient’s CBT-I plan will be discussed.

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Pharmacotherapy
Nonstudy Antidepressants: A third of the patients in our recent trial were taking nonstudy antidepressants
at enrollment. The most common were fluoxetine (16%), citalopram (15%), escitalopram (11%), paroxetine
(11%), and sertraline (10%). SSRIs are likely to comprise the majority of nonstudy antidepressants in this trial.
Study Antidepressants: The study psychiatrist will choose from four antidepressants, including sertraline,
escitalopram, bupropion XL, and mirtazapine. Sertraline and escitalopram are SSRIs, mirtazapine is a tetracyclic,
and bupropion is an atypical antidepressant. All four are considered safe for most cardiac patients13;14;99-102 but
we will monitor side effects and adjust medications and dosages as needed. The choice will depend whether the
patient has prior experience with any of them, and if so, how well she or he tolerated and responded to the
medication. A favorable prior experience determine the drug of choice for the patient’s initial step, and an
unfavorable experience will eliminate it as an option. If there are no relevant prior experiences or potential drug-
drug interactions or other contraindications to consider, the selection order will be 1) sertraline, 2) escitalopram,
3) bupropion, and 4) mirtazapine, based on established safety and efficacy.
The study psychiatrist will meet at Week 6 with patients in the intervention arm who have improved <10%
on the PHQ-9, and at Week 12 for those who have improved <50% by then. No patient will receive any study
medications between baseline and Week 6, although a dosage adjustment will be recommended if a patient
enters the study on subtherapeutic dose of a nonstudy antidepressant. Study medications may be initiated at
Week 6 or 12 depending upon the patient’s progress by these assessment points, and when necessary, the
study medication regimen will be modified at Week 12 for patients who initiated a study medication at Week 6.
Study medications will be initiated at the lowest therapeutic dosage for depression (sertraline 50 mg/day,
escitalopram 10 mg/day, bupropion XL 150 mg/day, mirtazapine 15 mg/day) and then increased if necessary up
to the maximum dosage (sertraline 200 mg/day, escitalopram 20 mg/day, bupropion 450 mg/day,  mirtazapine
45 mg/day). Inability to tolerate a particular medication will trigger a switch to a different one.
Medication Adherence: Patients will be asked to bring their bottles for pill counts at the 12- and 18-week
assessment visits. Counts will be conducted via follow-up telephone calls when patients forget to bring their pill
bottles to a visit. The adherence level will be defined as the percentage of doses taken as prescribed.
Tailored Self-Care (TSC) Intervention
Home-Based Exercise Component
Rationale: The ACCF/AHA heart failure guidelines state that “Exercise training (or regular physical
activity) is recommended as safe and effective for patients with HF who are able to participate to improve
functional status (Level of Evidence: A)”.103 The AHA self-care guideline also recommends individually tailored
exercise, even for patients with severe, symptomatic left ventricular dysfunction.10 Both guidelines cite the HF-
ACTION trial104 as providing the most definitive evidence. HF-ACTION showed that moderate exercise predicts
a >30% reduction in risk of all-cause mortality or hospitalization105 and significant improvements in perceived
health status.106 It also showed that physical exercise reduces depressive symptoms in patients with HF.71 Other
studies suggest that aerobic exercise reduces depressive symptoms in older adults with MD72 and that it is also
effective when used to augment antidepressant medications in clinically depressed adults.107
In short, aerobic exercise is a facet of HF self-care that also helps to decrease depression. Unfortunately,
depression predicts low physical activity and nonadherence to exercise in patients with heart failure.108;109 Thus,
it is difficult for depressed patients to engage in the very activities that could help to relieve their depression. The
sequential intervention strategy addresses this Catch-22 by treating the patient’s depression with CBT and with
antidepressant  medications before starting the home-based exercise component.
Protocol: The home-based exercise component of the intervention is a slightly modified version of the
HF-ACTION protocol for home-based exercise. The HF-ACTION protocol called for five 40-minute sessions per
week of walking or cycling, at 60-70% of the patient’s heart rate reserve (HRR). However, a cardiopulmonary
exercise test was required to determine the patient’s HRR. An alternative that does not require an exercise test
is to base the intensity target on the Borg Perceived Exertion Scale.110 The standard initial intensity level will be
a Borg rating of 11-12 (light exertion), e.g., “walking around a grocery store or similar activities that require some
effort but not enough to speed up your breathing.”  However, patients who are severely deconditioned or
symptomatic will be instructed to start with activities rated as 9-10 (very light), e.g., “chores like folding clothes
that seem to take little effort.” The target intensity will be activities that are rated 13-14 (moderate), e.g., “brisk

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walking or other activities that require moderate effort and speed your heart rate and breathing but don’t make
you out of breath.” Patients will start at the initial intensity for at least 10-15 minutes per day, at least 3 days per
week, and gradually progress over 2-3 weeks to 30 minutes of moderate exercise per day 5 days per week.111
Monitoring and Adherence: Patients will keep a physical activity log and record their daily pedometer
totals. The TSC nurse will schedule weekly 20 minute telephone contacts with the patient to formulate the initial
intensity, duration, and type of exercise, gradually increase the exercise program toward the target level, address
questions and concerns, use motivational interviewing to help the patient develop and maintain self-motivating
cognitions, and use standard problem-solving techniques to address barriers to exercise.
Other Self-Care Component
HF Self-Care: There are three dimensions of HF self-care: 1) maintenance behaviors that can prevent
acute exacerbations and help to slow the progression of HF, 2) management of acute exacerbations, and 3)
confidence in self-care knowledge and skills. According to the AHA Scientific Statement on HF self-care10,
maintenance includes, in addition to physical activity and exercise, dietary and medication adherence, symptom
monitoring, fluid restriction, alcohol restriction, weight management,  and smoking cessation. Deficits in HF
maintenance can precipitate acute exacerbations and hospitalizations. Effective HF self-management includes
appropriate responses to worsening signs and symptoms, particularly edema and dyspnea.
HF self-care requires patient education, but education alone is insufficient.112 It is necessary for patients
to develop knowledge, beliefs, and attitudes that support appropriate self-care behaviors, along with the requisite
skills. Deficits in any of these domains can interfere with self-care and affect HF outcomes.10
Assessment and Intervention: The Self-Care of Heart Failure Index (SCHFI)113;114 is the most widely used
questionnaire for assessing HF self-care behaviors and confidence. The TSC nurse will use the SCHFI to identify
self-care deficits, and then interview the patient to evaluate and prioritize the patient’s self-care deficits and
barriers to effective self-care. Based on this evaluation, the nurse will assemble an individually tailored packet of
educational materials and self-monitoring tools from the HF patient education libraries of the Heart Failure
Society of America115 and the American Heart Association116, as well as from several HF patient education
handouts that have been published in major medical journals.117-120 In addition, self-care materials for patients
with a left ventricular assist device (LVAD)121 will be provided when appropriate.
After an initial face-to-face session, weekly 20-minute TSC telephone sessions will start with the Exercise
component and continue through the Other Self-Care component. There will be up to 9 TSC contacts (3 for the
exercise phase and 6 for the other self-care phase). Contacts may be shortened (10-15 minutes) and the
frequency decreased to biweekly if all of the self-care goals have been met. TSC contacts will end by Week 24.
The Other Self-Care contacts will include 1) a brief review of physical exercise over the past week, along
with activity scheduling and problem-solving to promote maintenance of exercise; 2) collaborative prioritization
of other self-care goals; 3) development of specific plans to modify self-care maintenance behavior deficits (in
the order determined by the prioritization process); 4) cognitive restructuring to address low self-care confidence;
and 5) implementation of maintenance strategies for improvements in self-care behavior.
The Other Self-Care component of the TSC intervention will start with education about the role of self-care
in HF and motivational interviewing to strengthen self-care motivation and commitment to change.122;123 HF self-
care behavior change strategies that have been tested in previous trials10 will also be used. A structured
monitoring form will be used to track the specific targets of the intervention on a session-by-session basis.
Daily weight checks are necessary in HF to recognize edema124 and because weight change not due to
edema is a serious adverse sign and predictor of poor prognosis.125 Most patients have bathroom scales that
are accurate enough for self-monitoring, but one will be provided for patients who cannot afford one.
Outcome Measures
Beck Depression Inventory126 (BDI-II): Each BDI-II item assesses an individual symptom on a 0-3 scale,
for a total score range of 0-63. The BDI-II total score at 18 weeks is the trial’s primary outcome. Remission (total
score <9) and maintenance of gains over the follow-up phase are secondary outcomes.
Patient Health Questionnaire (PHQ-9): Patients in both arms of the trial will complete a PHQ-9
questionnaire every 3 weeks between baseline and Week 24 to track changes in the severity of depression.

8
Beck Anxiety Inventory (BAI): The BAI is a widely used measure of the self-reported severity of clinical
anxiety symptoms. Like the BDI, scores on the BAI range from 0-63. Continuous scores on the BAI will be
evaluated as a secondary outcome measure, to determine the degree of change in anxiety.
Hamilton Rating Scale for Depression127 (HAM-D-17): Total scores on the HAM-D-17 range from 0-50;
remission is defined as a score <7. The HAM-D will be derived from the Depression Interview and Structured
Hamilton (DISH)128 at baseline, 18, and 24 weeks. The DISH will also be used to diagnose DSM-5 major
depression. Total scores and remission on the HAM-D will be evaluated as secondary outcomes.
Self-Care of Heart Failure Index113;114 (SCHFI): The SCHFI is a 15-item self-report measure that assesses
HF self-care maintenance, confidence, and management. Each item is rated on a 1-4 scale. The Maintenance
score is the trial’s co-primary outcome and the Confidence score is a secondary outcome. Management scores
will be obtained only from the subgroup of patients who have had a  recent acute exacerbation of HF.
Kansas City Cardiomyopathy Questionnaire129 (KCCQ): The KCCQ is a 23-item self-report questionnaire
that assesses physical limitations, symptoms, self-efficacy, social interference, and quality of life in HF. Scores
range from 0-100, with higher scores representing better health and QOL.  It is widely used in clinical trials and
is more sensitive to change than other widely-used measures of health-related QOL in heart failure.130
NIH Patient-Reported Outcomes Measurement Information System131 (PROMIS): PROMIS measures
are available as short forms and as computerized adaptive tests (CATs) that typically require only 5-7 items to
yield an accurate score. Thus, multiple domains can be assessed while minimizing patient burden. The following
CATs that assess relevant aspects of functioning will be administered as secondary outcomes: 1) Sleep
Disturbance, 2) Sleep-Related Impairment, 3) Fatigue, 4) Satisfaction with Participation in Discretionary
Social Activities, and 5) Satisfaction with Participation in Social Roles. This adaptive test battery will include
between 25 and 35 items, depending upon the individual patient’s pattern of responses.
Actigraphy: Patients will be asked to wear a wrist actigraph for one week at baseline, 18 weeks, and 24
weeks to measure daily physical activity levels and sleep patterns. Secondary outcomes based on actigraphic
data will include the average daily activity level and a sleep efficiency index.
Assessment Schedule
The baseline, 18-, and 24-week assessments are the most extensive ones and they include an interview,
so they will be conducted at our clinical research center. The other assessments will be conducted via the Web
or by paper-and-pencil questionnaires, depending upon the patient’s preference. Paper-and-pencil PROMIS
short forms will be used instead of CATs when necessary. Table 2 presents the assessment schedule.
Measure
Baseline
Week Number
6
12
18
24
36
52
Beck Depression Inventory (BDI-II)
X
X
X
X
X
X
X
Beck Anxiety Inventory (BAI)
X
X
X
X
X
X
X
DISH: DSM-5 major depression diagnosis
X
X
X
DISH: Hamilton Rating Scale for Depression (HAM-D-17)
X
X
X
Self-Care of Heart Failure Index (SCHFI)
X
X
X
X
X
Kansas City Cardiomyopathy Questionnaire (KCCQ)
X
X
X
X
PROMIS measures
X
X
X
X
Actigraphy
X
X
X
Table 2. Assessment  schedule.
Statistical Analysis Plan
Data Management: The Research Electronic Data Capture (REDCap) system132 hosted by the Washington
University Biostatistics Division will be used for secure data management, quality assurance, and questionnaire
administration. Redcap data will be integrated into SAS 9.3 for all analyses and quality control reports, including
evaluation of model variable distributions, identification of outliers and invalid values, and examination of missing
data patterns to build efficient multiple imputation models for the intent-to-treat (ITT) analyses. All hypothesis
tests will be two-tailed with a Type I error rate of 0.05.

9
Hypothesis 1a (severity of depression) will be tested by fitting 18-week BDI-II scores to a linear mixed model
(LMM). Depression scores (YBDI) will be regressed on a within-time factor (βTIME), treatment (βTRT), antidepressant
stratum (βAD), baseline depression severity (βBDI), and the treatment x time interaction (βINT). The hypothesis will
be tested by a treatment contrast at 18 weeks (H0: µSCD=µUC vs. H1: µSCD≠µUC).
Hypothesis 1b (remission) will be tested by a binary logistic regression model of the conditional probability
of remission (Y) given treatment assignment (βTRT). The treatment effect odds ratio (θTRT=exp(βTRT)) hypothesis
test takes the form of H0: θTRT=1 (no relationship) vs. H1: θTRT≠1. The model includes treatment (βtrt),
antidepressant stratum (βAD), and baseline depression severity (βBDI). Model validity will be evaluated by residual
analyses, restrictions on overfitting, goodness-of-fit assessment via Nagelkerke, Cox-Snell pseudo-R2, and
Hosmer-Lemeshow tests, as well as by multicollinearity and overdispersion diagnostics.
Hypotheses 2a (superior TSC outcomes after SCD than after UC) and 2b (improvement in depression is
associated with better self-care outcomes regardless of group assignment) will be tested in a single LMM. SCHFI
Maintenance and Confidence scores at 24 weeks (YSC) will be regressed on time (βTIME), treatment (βTRT), BDI-
II change between baseline and 18 weeks (βΔdep), SCHFI scores at baseline (βsc(b)) and 18 weeks (βsc(18)), and
antidepressant stratum (βAD). The 24-week treatment contrast tests Hypothesis 2a (H0: µSCD=µUC vs. H1:
µSCD≠µUC), while a test of βΔdep tests Hypothesis 2b. Group differences in self-care trajectories will also be tested
in a secondary LMM with a treatment x time interaction term.
Hypotheses 3a-f are that SCD will be superior to UC on post-treatment scores: a) Beck Anxiety, b)
PROMIS Sleep Disturbance and Sleep-Related Impairment, c) PROMIS Fatigue, d) KCCQ, e) PROMIS Social
Activities and Roles, and f) activity level on actigraphy. Treatment  contrasts at 18 weeks of the form Ck=(H0k:
µSCD=µUC vs. H1k: µSCD≠µUC) will be tested for the kth outcome measure fitted to LMMs. KCCQ and PROMIS
scores at other occasions will be fitted to secondary LMMs to test for treatment differences over time.
Hypothesis 3g is that the one-year hospitalization rate will be lower in the SCD than in the UC arm. A
Poisson regression model will be fitted to test the hypothesized treatment effect, with antidepressant stratum,
baseline BDI-II, and baseline SCHFI Maintenance scores as covariates.
Consideration of Relevant Biological Variables: Planned moderator and subgroup analyses will augment the
models discussed above to determine whether the effects of treatment differ by sex, race, or age, as well as by
baseline severity of depression and antidepressant use. In addition, baseline levels of HF self-care Maintenance
and Confidence will be examined as moderators of the TSC outcomes.
Power Analysis and Sample Size
The analyses will follow the intention-to-treat (ITT) principle133, and multiple imputation (MI) will be used for
data that are missing at random (MAR). The MI model will include auxiliary correlates134;135 of the ITT model
variables, and tipping point analysis136 will be used to assess the assumptions of the missingness mechanism.
Primary Hypothesis 1a: The target sample size is
based on the Type 1 error rate (α), power, treatment effect
size (d=µSCD-µUC), and variance (σ2BSL, σ26mo, σ(BSL,6mo))
from an unstructured covariance structure, estimated from
a linear mixed-effects ANCOVA model fitted to BDI-II
scores from our previous HF trial. With α=0.05,
σ2BSL=72.4, σ26mo=108.9, and σ(BSL,6mo)=37.6, a MIXED
model simulation137 was used to create Figure 3, with
power estimates plotted against N for d=4.0, 4.5, and 5.0.
We are predicting a larger treatment effect than the 4.5-
point difference observed in our previous trial.  With 90%
power and up to 18% attrition138;139, 180 patients permit
detection of a treatment effect of d>5.0 BDI-II points. For
Hypothesis 1b (remission of depression), this target
sample size allows us to detect a >25% remission rate
difference between SCD and UC.
Secondary Hypotheses: We applied the same power procedures and assumptions (N=180 and up to 18%
attrition) to estimate the smallest detectable difference (SDD) for the other outcomes. Table 3 presents estimates
of the variance components (σ2BSL, σ26mo, σ(BSL,6mo)) along with the SDD for the continuously distributed secondary
Figure 3. Power curves.

10
outcomes at 80% and 90% power. For Hypothesis 3g, the Poisson model has 80% and 90% power to detect
55% and 60% decreases in hospitalization rates, respectively, in SCD relative to UC.
Outcome Measure
Covariance Estimates
SDD
σ2BSL
σ26mo
σ(BSL,6mo)
Power
0.80
0.90
Beck Anxiety Inventory (BAI)
115.0
97.9
57.6
4.2
4.8
Hamilton Rating Scale for Depression (HAM-D-17)
30.7
31.2
8.9
2.4
2.7
Self-Care of Heart Failure Index (SCHFI)
Maintenance
Confidence
253.9
467.6
241.6
364.3
184.0
217.6
6.5
8.0
7.6
9.2
Kansas City Cardiomyopathy Questionnaire (KCCQ)
443.6
512.0
338.9
9.5
11.0
PROMIS measures
Sleep Disturbance
Sleep-Related Impairment
Fatigue
Satisfaction with Discretionary Social Activities
Satisfaction with Social Role Participation
25.0
30.3
47.4
40.7
41.8
49.0
56.3
78.8
65.3
51.1
14.0
16.5
29.7
26.6
14.6
3.0
3.2
3.7
3.4
3.0
3.4
3.7
4.3
4.0
3.5
Actigraphy (average daily total activity count / minute)
2683
3015
1894
23.0
26.6
Table 3. Smallest detectable differences (SDDs) on the continuously distributed secondary outcome measures.
Figure 4. Study Timeline
POST-FUNDING PROTOCOL REVISIONS APPROVED BY DSMB
Note: This section describes the protocol revisions that were made during the start-up phase of the study, before
any patients were enrolled. It also includes revisions related to the decision to suspend the psychiatric component
of the intervention as of September 2018, due to underutilization. Following this decision, patients were referred
to their own (nonstudy) physicians to discuss antidepressant medication options.
Revised Intervention Schedule
This revision supersedes Table 1 and the associated descriptive information in the Intervention section of the
original Research Plan.
In the original study design, the active CBT phase lasted up to 18 weeks, and in both arms, the initiation of the
Tailored Self Care (TSC) intervention was based on improvement in depression scores. In the revised schedule,
the active CBT phase lasts up to 16 weeks and the TSC intervention starts at 8 weeks regardless of the patient’s
depression score. This revision will make the protocol simpler, more predictable, and less burdensome, and it
will also facilitate the primary statistical analyses. Figure 1 (below) displays the revised schedules for the Stepped
Care for Depression (SCD) and Enhanced Usual Care (EUC) arms.
0
12
24
36
48
60
Close-out
Follow-up
Treatment
Recruitment
Start-up
Months

11
Group
Component
Weeks After Randomization
SCD
CBT active
CBT maintenance
ADM if indicated
~~~~~~~
~~~
~~~
~~~~~~~~ ~ ~ ~ ~ ~~~~~~~~ ~~~~~~~~ ~~~~~~~~
TSC active
IC
TSC maintenance
EUC
ADM if indicated
~~~~~~~
~~~~~~~~ ~~~~~~~~ ~~~~~~~~ ~~~~~~~~ ~~~~~~~~ ~~~~~~~~
TSC active
IC
TSC maintenance
0                4                 6                 8                12               16               24            32
Table R1.  Revised Intervention Schedule. The red bars are points when patients may be referred to their
primary care physician to discuss antidepressant medication options. The “~” marks are non-study
antidepressant prescriptions (if indicated). Note that some patients may already be taking a nonstudy
antidepressant at enrollment, and others may start during the trial.
Stepped Care for Depression: In the SCD arm, the active (weekly) CBT phase will last at least 8 weeks. It will
end when the participant meets the study’s clinical improvement criteria (i.e., PHQ-9 total score <5 and
ENRICHD CBT Performance Criteria Scale [CBT-PCS] score = 12) OR at Week 16. The CBT maintenance
phase will begin when the patient has met the study’s clinical improvement criteria OR at Week 16, but no sooner
than Week 8. The CBT maintenance phase will end at Week 32.
The original proposal called for a brief CBT for Insomnia (CBT-I) phase to be “tacked on” to the end of the active
CBT phase for patients with residual insomnia. The revised protocol eliminates the CBT-I phase. Therapists will
instead incorporate CBT-I techniques into the treatment plan as needed, at any point during the active CBT
phase for patients with insomnia. This gives the therapists greater flexibility to address depression-related
insomnia, when indicated, as a collaborative treatment goal.
If a patient in the SCD arm has not improved >25% on the PHQ-9 by Week 5, the therapist will refer the patient
to his or her primary care physician for evaluation and antidepressant medication, if indicated. Referral to the
PCP may also occur at Week 10 if the patient has not improved >50% by then. (The original plan was to refer
SCD participants at Week 5 or 10 to the study psychiatrist for evaluation and a study-provided antidepressant
medication if needed. This part of the plan was dropped as of September 2018 due to underutilization.)
Enhanced Usual Care: Patients randomized to EUC will be asked to call or schedule an appointment with their
personal physician as soon as possible to discuss nonstudy depression treatment options.
Tailored Self-Care (TSC): For all participants in both arms of the trial, the weekly (active) TSC intervention
phase will start at Week 8 and end between Week 12 and Week 16, depending upon the “dosage” of intervention
that the patient needs to address his or her HF self-care deficits and goals. Starting at Week 12, the active TSC
phase will end when the patient achieves all self-care goals OR at Week 16. The TSC maintenance phase will
start no sooner than Week 12, and it will run through Week 32.
The original Research plan divided the TSC intervention into two phases (Exercise and Other). The revised
protocol combines these phases. Exercise will still be one of the first self-care goals, but work on other self-care
goals can now begin concurrently with exercise, depending on the participant’s needs and goals.
Adaptive CBT and Medication Milestones
This revision supersedes the improvement criteria listed in Table 1 of the original Research Plan.
Based on a literature review including studies published after the grant submission, and a secondary analysis of
DASH-1 data, we now know that rapid progress in CBT predicts successful depression outcomes and,
conversely, that lack of early progress predicts poor outcomes. We examined the DASH-1 data to refine the
progress milestones for the SCD arm in DASH-2. The following table displays the milestones and shows the
steps that will be taken if a participant in the SCD arm misses a milestone. Note: the baseline PHQ-9 score (not
the Initial Clinical Evaluation [ICE] score) is the denominator for the improvement milestone percentages.

12
Week
PHQ-9
Improvement
Milestone
CBT
PHQ-9
Improvement
Milestone
Antidepressant Medication
2
>10%
Implement adaptive strategy
4
>20%
Implement adaptive strategy
5
>25%
Implement adaptive strategy
>25%
If on nonstudy ADM: evaluate, possibly
recommend change.
If not on an ADM: evaluate, possibly
refer for nonstudy ADM
6
>30%
Implement adaptive strategy
8
>40%
Implement adaptive strategy
10
>50%
Implement adaptive strategy
>50%
If on nonstudy ADM: evaluate, possibly
recommend change.
If not on an ADM: evaluate, possibly
refer for nonstudy ADM
12
>60%
Implement adaptive strategy
14
>70%
Implement adaptive strategy
16
Start maintenance phase if it
hasn’t already started,
regardless of PHQ-9 score
Recommend antidepressant evaluation
by personal physician if clinically
indicated.
24
32
End CBT maintenance phase
Table R2. Revised Improvement Milestones for the CBT Arm
Note:  Adaptive strategies for CBT are described in the next section.
The intensive (weekly) phase of CBT will end when the criteria for successful completion have been met (PHQ<5
and CBT-PCS=12), or at 16 weeks, whichever comes first. If the successful completion criteria are met between
Weeks 8 and 16, the frequency and duration of CBT sessions will be tapered and the focus will shift to
maintenance of gains and relapse prevention.
If the patient has not met the criteria for successful completion by Week 16, the frequency and duration of CBT
sessions will be gradually tapered but will continue to focus on achievement of remission until the depression is
in remission OR at Week 24, whichever comes first. After this point, the focus will shift to self-therapy skills,
maintenance of gains, and relapse prevention.
The therapist will determine whether the ADM milestones have been met at Weeks 5 and 10.  If a milestone is
missed either time, the therapist will refer the patient to his or her primary care physician to discuss
antidepressant medication options, in addition to continuing CBT.
Adaptive CBT Strategies
At each “milestone” week (e.g, Weeks 2, 4, 5, 6, etc. in Table R2, above), the therapist will determine whether
the patient has met the PHQ-9 improvement milestone. If the milestone has been achieved, the therapist will
continue with the original CBT treatment plan.
If the milestone has not been achieved, the therapist will determine whether the patient is adherent to the CBT
protocol. This will entail clinical evaluation of several factors including understanding and acceptance of the
cognitive-behavioral model, session attendance, and completion of “homework” assignments, among others.

13
If adherence is not satisfactory, a strategy to improve adherence will be devised and implemented.  Alternatively,
if the patient is not making sufficient progress despite satisfactory adherence, the CBT treatment plan will be
revised. The revision will usually involve addressing barriers to improvement and/or shifting the focus of
treatment to therapeutic goals that the patient is more likely to be able to achieve.
The adaptive strategies will be based on the approaches presented in Strategic Decision-Making in Cognitive
Behavioral Therapy (Wenzel, 2013) and in Cognitive Therapy for Challenging Problems:  What to Do When the
Basics Don’t Work (J.S. Beck, 2005). The adaptive CBT algorithm is displayed in Figure R1, below.
Figure R1.  Adaptive CBT Algorithm.
PHQ-9 Score
Meets PHQ-9
Improvement
Milestone
Continue As Planned
Does Not Meet PHQ-9
Improvement
Milestone
Implement
Adherence-
Improvement
Strategy
Adherent
to CBT
Revise CBT Treatment
Goals and Plan
Nonadherent
to CBT

14
Revised Assessment Schedule
This section supersedes Table 2 and some of the details of the Outcome Measures section of the original
Research Plan.
The assessment schedule was revised to ensure compatibility with the revised intervention schedule and to
reduce participant and staff burden.  This included dropping the PROMIS measures which were originally
included as exploratory outcomes, and dropping some nonessential assessment points.
Measure
Baseline
Weeks After Randomization
8
16
32
40
52
Beck Depression Inventory (BDI-II)
X
X
X
X
X
X
Beck Anxiety Inventory (BAI)
X
X
X
X
X
X
DISH: DSM-5 major depression diagnosis
X
X
DISH: Hamilton Rating Scale for Depression (HAM-D-17)
X
X
Self-Care of Heart Failure Index (SCHFI)
X
X
X
X
X
Kansas City Cardiomyopathy Questionnaire (KCCQ)
X
X
X
X
X
Actigraphy
X
X
X
Patient Health Questionnaire (PHQ-9)
X
Generalized Anxiety Disorder Questionnaire (GAD-7)
X
Table R3.  Revised Assessment Schedule.
Primary Outcomes
The revised primary depression outcome is the BDI-II total score at Week 16.  In the original Research Plan, it
was the BDI-II score at Week 18.
The revised primary HF Self-Care outcome is the Maintenance Scale score from the Self-Care of Heart Failure
Index (SCHFI) at Week 16.  In the original research plan, it was the Maintenance score at Week 24.
Interpretation of Co-Primary Outcomes
If the BDI-II score is significantly lower in the SCD than the EUC arm at Week 16, this will be interpreted as
showing that stepped care for depression is superior to enhanced usual care for depression, regardless of the
self-care outcomes.
If the SCHFI Maintenance score is significantly higher in the SCD than the EUC arm at Week 16, this will be
interpreted as showing that self-care outcomes can be improved in patients with major depression by pre-treating
their depression with a stepped care intervention. However, this interpretation is contingent on the superiority of
SCD to EUC for depression on the BDI-II at Week 16.  If the SCD intervention does not yield superior depression
outcomes, pre-treatment with SCD will not be recommended for depressed patients who are going to receive a
tailored HF self-care intervention.
It should be noted that Hypothesis 2b under Specific Aim #2 is that regardless of group assignment, improvement
in depression prior to initiating the TSC intervention will predict better self-care outcomes. If improvement in
depression does predict better self-care outcomes, but the SCD intervention is not superior to EUC, the
interpretation will be that it is helpful to treat depression before intervening in HF self-care BUT that stepped care
for depression is not superior to usual care for depression in patients with HF.