Conditions: Depression End Stage Renal Disease
Keywords: Comorbid Depression Major Depressive Disorder Dysthymia Cognitive Behavioral therapy (CBT) Sertraline Engagement Interview End Stage Renal Disease (ESRD) Hemodialysis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 184
Healthy volunteers: no

Brief summary:
Patients whose kidneys fail generally require dialysis treatments to sustain life. The ability of patients to make major adjustments in their lives for dialysis is hampered by depression that affects almost one-quarter of such individuals. There are no studies that have adequately tested whether treatment of depression is effective in dialysis patients and if there is any difference between the response to the two most commonly available forms of treatment, psychotherapy and anti-depressant drug therapy.

To fill this important gap in the investigators knowledge, the investigators propose to undertake (1) a randomized controlled clinical trial of 200 patients to test whether an engagement interview will result in a higher proportion of dialysis patients accepting treatment for depression; and (2) a randomized controlled clinical trial of 120 patients to determine whether there is any difference in the likelihood of improvement of depressive symptoms with psychotherapy or drug therapy among dialysis patients with depression. Patients in these studies will be enrolled from among individuals receiving care in 50 dialysis facilities in three metropolitan areas - Seattle, Dallas, and Albuquerque. The research proposal has been developed with the support of patients, caregivers, and stakeholders to ensure that the findings from the study are relevant to them and can be readily implemented in day-to-day clinical practice. Hence, the engagement interview and psychotherapy will be delivered in a dialysis facility to ease the burden on patients, and the dose of the study drug will be changed in partnership with the study participants. In addition to depressive symptoms, the effect of treatment on other meaningful outcomes such as fatigue and sleep will be determined.

The two forms of treatment for depression being tested in this clinical trial are very different from each other and patients differ with regards to the treatment option preferable and/or available to them. Successful completion of the clinical trial will provide patients, caregivers, and other stakeholders with the information that they would need when faced with a diagnosis of depression in patients undergoing hemodialysis. This will allow patients to select evidence-based treatments to improve outcomes that are relevant to them.

Detailed description:
BACKGROUND Patients with end-stage renal disease undergoing maintenance hemodialysis (HD) have to adjust to complex treatment regimens, and experience frequent care transitions. This is compounded by a four-fold higher prevalence of comorbid depression than in the general population, which is strongly associated with poor patient-centered outcomes. Yet, depression is often not diagnosed when present, not treated when identified, and many HD patients are reluctant to accept treatment. This is likely a result of lack of high-quality evidence for the efficacy of different treatment options for comorbid depression in HD patients. OBJECTIVES Conduct an open-label, randomized controlled clinical trial among HD patients with comorbid depression to (1) compare the efficacy of an engagement interview with usual care in increasing acceptability of treatment (n=200); and (2) compare the efficacy of 12 weeks of cognitive behavioral therapy (CBT) or anti-depressant drug therapy (sertraline) for reducing the severity of depressive symptoms, and other meaningful outcomes (n=120). METHODS HD patients in up to 50 dialysis facilities in three different regions (Albuquerque, NM; Dallas, TX; Seattle, WA) will be pre-screened for the presence of clinically significant depressive symptoms. Patients with a confirmed diagnosis of major depression or dysthymia will be randomly assigned to an engagement interview or usual care to determine efficacy in increasing acceptability of treatment (n=200). Individuals who agree to treatment will be randomly assigned to individual CBT or drug therapy. CBT will be administered in a dialysis facility by a trained therapist. Sertraline will be titrated to the maximum tolerated dose using Measurement Based Care, a model of shared-decision-making. Patient-reported outcomes will be measured by a single assessor for all three sites, blinded to the treatment assignment. The primary efficacy measure will be a change in severity of depressive symptoms; secondary outcome measures will assess other important patient-reported outcomes such as somatic symptom burden, functioning, and adherence with dialysis treatment, diet, and medications. The longitudinal evolution of symptoms in patients who refuse to accept any treatment either within or outside the clinical trial will also be studied (n=40). PATIENT OUTCOMES (PROJECTED) This study will provide answers to three questions faced by HD patients with clinically significant depressive symptoms: (1) "Given my preferences, what should I expect will happen to me?"; (2) "What are my options, and what are the potential benefits and harms of these options?"; and (3) "What can I do to improve the outcomes that are most important to me?" Oversight of study will be provided by separate Patient Council and Stakeholder Council to align with PCORI's mission of generating high-integrity, evidence-based information from research guided by patients, caregivers, and broader health care community.

Arms:
arm 1: Subjects will be randomly assigned to engagement interview or a control visit.Trained CBT therapists at each of the three sites will conduct the engagement interview. The session will be aimed at improving the acceptance of the diagnosis of depression by patients and treatment for the same. arm 2: Subjects will be randomly assigned to engagement interview or a control visit. Individuals assigned to control visit will be scheduled for a follow-up discussion with a member of the research team. During this session, they will be informed of the diagnosis of major depression or dysthymia, the options for treatment available through the clinical trial, and alternatives should they decline participation in the clinical trial. arm 3: The subjects will be randomly assigned to individual CBT or sertraline drug therapy using block randomization.

Individuals will undergo 10 CBT sessions of 60 minutes each, by a trained therapist in the dialysis facility (8 weekly sessions; then every other week x 2). The CBT will be administered while the patient is undergoing HD; however, alternative arrangements will be made upon individual patient's preferences. arm 4: The subjects will be randomly assigned to individual CBT or sertraline drug therapy using block randomization. Anti-Depressant Drug Therapy will be delivered with sertraline, a selective serotonin reuptake inhibitor, and the dose will be titrated using the Measurement Based Care Protocol. arm 5: Subjects who (1) are not willing to participate in the clinical trial and (2) do not find any treatment acceptable outside the clinical trial will be invited to participate in the prospective observational cohort for serial assessment of depressive symptoms.These subjects will only undergo assessment of severity of depressive symptoms at weeks 0, 6, and 12 using QIDS-C.

Interventions: intervention 1: Engagement Interview intervention 2: Cognitive Behavioral Therapy intervention 3: Antidepressant Drug Therapy
Intervention descriptions: intervention 1: An Engagement Interview will comprise a one-on-one session with the patient, during which the health-care provider will use reflective statements and non-judgmental listening techniques, will explore barriers to treatment, and will help patient articulate ambivalence about engaging in treatment. This session will be enhanced with a 40-minute DVD that the subject will watch with the therapist in the dialysis facility. The subject will be encouraged to take the DVD home with them and watch it with their family members as well. intervention 2: Cognitive Behavioral Therapy (CBT) is a short-term psychotherapy that will focus on how the individual is thinking, behaving, and communicating today rather than on their childhood experience. The therapist will assist the patient in identifying specific distortions (cognitive assessment) and biases in thinking and will provide guidance on how to change this thinking. During the course of intervention, study subjects will undergo assessment of severity of depressive symptoms using Quick Inventory of Depressive Symptoms - Self-Report (QIDS-SR) every two weeks for the first six weeks (weeks 0, 2, 4, and 6) and every three weeks for the next six weeks (weeks 9 and 12). intervention 3: The site investigators will prescribe sertraline drug at a starting dose of 25 mg oral tablets. Dose titration will be implemented using standardized assessments of depressive symptoms and drug side effects; and the research team and the patient make joint decisions to maintain, increase, or decrease the dose. This will help establish the highest effective but tolerable dose tailored for each patient. The QIDS-SR scale will be used to assess the clinical response for dose titration. The FIBSER scale will be used to assess side effects and the degree to which they interfere with day-to-day functions. The participant-specific dose at week 6, up to a maximum of 200 mg/d, will be continued for the remaining 6 weeks.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
Version: V2.6, 16-June-2017 
 
ASCEND: A Trial of Sertraline vs. CBT for 
End-stage Renal Disease Patients with 
Depression 
Study Protocol 
Treatment Options for Depression in Patients 
Undergoing Hemodialysis 
Funding Agency:  
 
Patient-Centered Outcome Research Institute 
 
 
 
 
CER-1310-07253 
Investigators: 
 
 
University of Washington:  
Rajnish Mehrotra (PI)  
Patrick Heagerty  
Wayne Katon 
Bessie Young 
SUNY Downstate Medical Center 
Daniel Cukor 
University of Texas Southwestern 
Susan Hedayati 
University of New Mexico  
Mark Unruh  
George Washington University 
Scott Cohen 
 
 
 
University of Pennsylvania  
Laura Dember 
University of Utah 
 
Tom Greene 
Emory University  
 
Nancy Kutner 
 
 
 
University of Pittsburgh 
 
Steve Weisbord 
NIDDK   
 
 
Paul Kimmel 
 
 
 
 
 
 


 Study Protocol; Version 2.6 
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Table of Contents 
List of Abbreviations ................................................................................................................. 5 
Study Summary .........................................................................................................................6 
1. 
Introduction ..................................................................................................................... 10 
1.1  
Background ................................................................................................................... 10 
1.2 
Rationale for Study ........................................................................................................12 
1.2.1 
Engagement Interview........................................................................................12 
1.2.2 
Comparative Efficacy of individual CBT and anti-depressant drug therapy ... 13 
1.2.3 
Evolution of depressive symptoms without any treatment in patients 
undergoing hemodialysis ................................................................................................. 15 
2. 
Study Objective and Aims ............................................................................................... 16 
2.1 
Efficacy of the Engagement Interview ..................................................................... 16 
2.2 
Comparative Efficacy of individual CBT and sertraline drug therapy ....................17 
2.2.1 
Primary Measure of Efficacy...............................................................................17 
2.2.2 
Secondary Measure of Efficacy...........................................................................17 
3. 
Study Design and Overview ............................................................................................ 18 
4. 
Participant Selection and Withdrawal............................................................................ 20 
4.1 
Study Population ...................................................................................................... 20 
4.1.1 Pre-Screening:........................................................................................................... 20 
4.1.2 Subjects for Engagement Interview and Treatment of Comorbid Depression: ... 20 
4.2 
Participant Pre-Screening and Recruitment ............................................................21 
4.2.1 
Pre-Screening and Enrolling Subjects in Engagement Interview Phase ..........21 
4.2.2 
Enrollment of Subjects in Comparative Efficacy Trial of individual CBT and 
Anti-Depressant Drug Therapy ........................................................................................21 
4.2.3 
Enrollment of Subjects in Observational Cohort Study with no Active 
Treatment ......................................................................................................................... 22 
4.3 
Early Termination of Study Treatment and Withdrawal of Subjects .................... 22 
5. 
Study Interventions ......................................................................................................... 22 
5.1 
Engagement Interview Phase ................................................................................... 22 
5.1.1 
Engagement Interview....................................................................................... 23 
5.1.2 
Control Visit ....................................................................................................... 24 


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5.2 
Comparative Efficacy of individual CBT vs Anti-Depressant Treatment Drug 
Therapy ................................................................................................................................ 24 
5.2.1 
Individual CBT in Dialysis Facility .................................................................... 24 
5.2.2 
Anti-Depressant Drug Therapy......................................................................... 26 
5.2.2.1 Overview of the Intervention ............................................................................... 26 
5.2.2.2 
Training of Investigators in Measurement Based Care ................................ 26 
5.2.2.3 
Drug Procurement and Dispensation ........................................................... 26 
5.2.2.4 
Monitoring Drug Adherence ......................................................................... 26 
6. 
Ascertainment of Outcomes ........................................................................................... 27 
6.1 
Engagement Interview vs. Control .......................................................................... 27 
6.2 
Comparative Efficacy of individual CBT and anti-depressant drug therapy ......... 27 
6.3 
Observational Cohort Study of Patients Who Find Treatment Unacceptable ...... 28 
7. 
Study Visits ...................................................................................................................... 28 
7.1 
Pre-Screening ............................................................................................................ 28 
7.2 
Screening (within 10 days of completion of BDI-II) ................................................ 28 
7.3 
Engagement Interview vs. Control Visit (within 10 days of screening) ................. 29 
7.4 
Baseline Visit/Week 0 (within 7 days of engagement interview) .......................... 30 
7.5 
Weeks 2, 4, and 9 ...................................................................................................... 30 
7.6 
Week 6 and 12 ........................................................................................................... 30 
7.7  
Study Exit ................................................................................................................... 31 
7.8  
Post-Study Follow-up (within four weeks of completion of the study 
intervention) ......................................................................................................................... 31 
8. 
Statistical Analyses .......................................................................................................... 32 
8.1 
Preliminary Analyses ................................................................................................ 32 
8.2 Statistical Analysis for the Engagement Interview Phase ............................................ 32 
8.2.1 Statistical Power for Primary Analysis of the Engagement Interview Phase ......... 32 
8.3 
Statistical Analysis for the Comparative Evaluation Phase ..................................... 32 
8.3.1 Plan for Handling Missing Data .............................................................................. 33 
8.3.2 Sample size/detectable effect size in the Comparative Evaluation of CBT and 
Drug Therapy ................................................................................................................... 33 


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8.3.3 Overall Approach for Avoidance of bias in the Comparative Efficacy of CBT and 
drug therapy ..................................................................................................................... 34 
8.4  
Statistical analysis of data from observational cohort of patients who refuse to 
accept any treatment for comorbid depression ................................................................. 34 
9. 
Adverse Events ................................................................................................................. 34 
9.1 Potential Adverse Events from Study Interventions .................................................... 34 
9.2 Anticipated Adverse Events in the Hemodialysis Population .................................... 35 
9.3 Monitoring for Adverse Events ..................................................................................... 35 
9.4 Reporting of Adverse Events ........................................................................................ 36 
9.5 Management of Active Suicidal Intent ......................................................................... 36 
10. 
Data Management ........................................................................................................ 37 
10.1 Data Coordinating Center and Data Entry Overview ................................................. 37 
10.2 Computer and Data Security ....................................................................................... 38 
10.3 Training Procedures ..................................................................................................... 38 
10.4 Responsibilities of the Clinical Sites ........................................................................... 38 
11. 
Study Oversight ............................................................................................................ 38 
Appendix One: Study Schedule ........................................................................................... 43 
Appendix Two: Highest Dose Level Eligible for Enrollment ................................................44 
Appendix Three: Measurement Based Care Protocol ...........................................................44 
Appendix Four:  Membership of Oversight Groups .............................................................. 47 
Appendix Five CBT manual Pages 1-4 ................................................................................... 49 
Appendix Six: DSMB Charter ................................................................................................. 58 
Appendix Seven: Data Safety Monitoring Plan ..................................................................... 73 
 
 
 


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List of Abbreviations 
AAKP  
 
American Association of Kidney Patients 
BDI-II  
 
Beck Depression Inventory 
CATI  
 
Computer Assisted Telephone Interviewing 
CBT 
 
 
Cognitive Behavioral Therapy 
DPC  
 
Dialysis Patient Citizens 
ESRD  
 
End-Stage Renal Disease 
FIBSER 
 
Frequency, Intensity, and Burden of Side Effects Rating 
MINI  
 
Mini International Neuropsychiatric Interview 
QIDS-C 
 
Quick Inventory of Depressive Symptomatology, Clinician Rating 
QIDS-SR 
  
Quick Inventory of Depressive Symptomatology, Self-Report 
QOL  
 
Quality of Life 
SCID  
 
Structured Clinical Interview for DSM-IV 
SF-36  
 
Short-Form 36 
 
 


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Study Summary 
Title 
A Trial of Sertraline vs. CBT for End-Stage Renal Disease Patients 
with Depression (ASCEND)  
Short Title 
ASCEND Trial 
Protocol Number 
 PCORI CER-1310-07253 
Phase 
Phase III 
Methodology 
Randomized, open-label trial 
Study Duration 
3 years 
Clinical Sites 
University of New Mexico, Albuquerque, NM 
University of Texas Southwestern, Dallas, TX 
University of Washington, Seattle, WA 
Data Coordinating 
Center 
Center for Biomedical Statistics, University of Washington, 
Seattle, WA 
Primary Objectives 
• Compare the efficacy of engagement interview with a control 
visit in patients undergoing HD with comorbid current major 
depressive episode or dysthymia in increasing treatment for 
the condition. 
• Compare the efficacy of 12-week treatment with sertraline 
with individual CBT for the treatment of depressive symptoms 
in patients undergoing HD with comorbid current major 
depression or dysthymia. 
Secondary 
Objectives 
• Compare the efficacy of sertraline with individual CBT in 
improving patient-reported outcomes and adherence with 
treatment in patients undergoing HD with comorbid major 
depression or dysthymia. 
• Undertake a longitudinal evaluation of depressive symptoms 
over 12 weeks in patients undergoing HD with comorbid major 
depression or dysthymia who refuse to accept any treatment. 
Number of 
Participants 
• Engagement interview vs. control visit:      200 
• Sertraline vs. CBT:                                         120 
• Cohort study of untreated patients:             40 


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Diagnosis and 
Main Inclusion 
Criteria 
ESRD patients undergoing HD with major depression or 
dysthymia  
Interventions 
• Engagement Interview 
• Sertraline drug therapy 
• Individual CBT 
Duration of study 
Up to 16 weeks 
Primary Outcomes 
• Efficacy of Engagement Interview: Initiate treatment for co-
morbid depression 
• Comparative Efficacy of Sertraline vs. CBT: Change in 
depressive symptoms as per QIDS-C   
Statistical 
Methodology 
• Efficacy of Engagement Interview: Fisher’s exact test to 
compare the proportions of patients who initiate treatment 
for comorbid depression. 
• Comparative Efficacy of Sertraline and CBT: Longitudinal 
mixed effects analyses will be applied to QIDS-C to compare 
means at Weeks 6 and 12 assessments between the CBT and 
Sertraline groups with the treatment group and clinical center 
as fixed effects in the model. An unstructured covariance 
matrix will account for serial correlations in outcome 
measurements within patients and the model will constrain 
baseline means of the outcome to be equal in the treatment 
groups. Linear contrasts will be constructed to estimate for 
each outcome variable: (a) mean difference in outcome 
between the treatment groups at Week 12 (primary 
assessment of treatment effect); (b) mean difference in 
outcome between groups at Week 6 (early treatment effect); 
(c) the average of the treatment effect estimates from (a) and 
(b) over Weeks 6 and 12 (persistence of early effect to 12 
weeks); and (d) the difference in the estimated treatment 
effects from (a) and (b) between Week 6 and Week 12 (overall 
assessment of the treatment effect incorporating both follow-
up visits). 


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Study Oversight 
• Local Institutional Review Boards 
• Data Safety Monitory Board (Chair: Alan Kliger, MD) 
• Patient Advisory Council (Chair: Lori Hartwell) 
• Stakeholder Council (Chair: Thomas Parker, MD) 


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Reviewed and approved by: 
 
Rajnish Mehrotra, Principal Investigator 
 
 
 
Alan Kliger 
Chair, Data Safety Monitoring Board 
 
 
 
Lori Hartwell 
Chair, Patient Council 
 
Thomas Parker 
Chair, Stakeholder Council 


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1. Introduction 
 
The prevalence of comorbid depression is about four-fold higher in patients undergoing 
maintenance HD than in the general population. A large number of studies have 
demonstrated that comorbid depression in patients undergoing HD is associated with 
worse patient-centered outcomes such as lower health-reported quality of life (QOL), 
greater burden of somatic symptoms, sexual dysfunction, cardiac events, hospitalizations, 
mortality, and withdrawal from dialysis [1-17]. Yet, there is wide variability in the diagnosis 
and treatment of comorbid depression in HD patients: the condition is not diagnosed in 
most patients, and when diagnosed, invariably not treated. This may, in part, be because 
of patients’ reluctance to accept the diagnosis and/or therapy and lack of evidence for 
efficacy of different treatments for depression in patients undergoing HD [18, 19].  ASCEND, 
‘A Trial of Sertraline vs. CBT for End-stage Renal Disease Patients with Depression’, is the 
first multi-center randomized controlled trial that will enroll a racially/ethnically diverse 
group of English and Spanish-speaking individuals undergoing HD with comorbid major 
depression or dysthymia in up to 50 dialysis facilities in three metropolitan areas in the 
United States. The study will (1) compare the efficacy of engagement interview vs. a control 
visit for patients’ probability of starting treatment for comorbid depression; (2) compare the 
efficacy of sertraline vs. individual CBT for improvement of depressive symptoms in patients 
undergoing HD with comorbid major depression or dysthymia; and (3) study the 
evolution of depressive symptoms in a prospective longitudinal cohort of individuals who 
find all forms of treatment for the condition unacceptable. The results of the study will 
provide patients and healthcare providers with much needed information when weighing 
treatment options for comorbid depression. 
1.1  
Background 
 
In the United States, over 400,000 individuals are undergoing HD for the treatment of 
ESRD in over 5000 dialysis facilities at an annual societal cost of $50 billion[20]. Most ESRD 
patients have multi-morbidity and report significant impairments in their quality of life 
(QOL) [1, 20-25]. They experience frequent care transitions as they are hospitalized on an 
average for 12 days every year, and one-third are re-hospitalized within 30 days of 
discharge[20]. In addition to the burden from disease, these individuals have a high burden 
of treatment. They receive HD treatments at least three times every week and each session 
is 3-4 hours long. They need to make numerous dietary changes including limiting daily 
fluid intake, and prescribed 10-12 medications with a median of 17 pills daily [23, 26]. With 
such a high burden of both disease and its treatment, it is imperative to identify effective 


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interventions to improve patient-centered outcomes for HD patients and to enhance their 
ability to adhere to complex treatment regimens. 
Depression is the most common psychiatric disorder in HD patients. In a recent 
systematic review of 198 cohorts with 46,505 patients, the summary prevalence of 
depression using the most stringent criteria for diagnosis, a structured clinical interview, 
was 23% [27]. This prevalence is over four-fold higher than in the general population [27]. 
Several studies have demonstrated a strong association between the severity of depressive 
symptoms and somatic symptom burden, sexual dysfunction, unemployment, and poor 
QOL in HD patients [1-6]. These outcomes are highly relevant to patients and influence 
their sense of wellbeing. Numerous studies have also consistently shown an association 
between the severity of depressive symptoms and cardiac events, hospitalizations, 
mortality, and withdrawal from dialysis [7-17]. Two potential mechanisms may explain these 
latter associations: First, depression is associated with systemic inflammation, which may 
be the proximate cause of morbidity and mortality [28, 29]. Second, depression makes self-
management difficult leading to challenges in adherence with the complex treatment 
regimens for ESRD[30]; depressive symptoms are associated with higher likelihood of 
patients’ shortening the length of and/or skipping dialysis treatments, excessive fluid 
intake, and lower medication adherence [31-35]. Moreover, depression makes navigating 
care transitions, as frequently experienced by HD patients, difficult.  
There is wide variability in the diagnosis and treatment of comorbid depression in HD 
patients. Even though HD patients have numerous symptoms that affect their well-being 
(viz., lack of energy, insomnia), physicians often do not recognize them and hence, don’t 
make any attempts to alleviate these symptoms [36]. Consistent with this, only 40% of 1089 
HD patients with clinically significant depressive symptoms had been diagnosed and/or 
treated [10]. In the USRDS Special Study (ACTIVE-ADIPOSE), 25% of the participants had a 
CES-D score ≥ 18; only 5.6% of these individuals were receiving anti-depressants (Kutner, 
personal communication). While this may suggest the need for systematic screening for 
depression in the routine care of HD patients, even when implemented, an appropriate 
intervention is made infrequently [14, 37]. In a recent clinical trial, treatment was instituted 
in only 17% of patients, even though the diagnosis of depression was communicated to 
physicians directly or through nurses trained to offer treatment recommendations[38]. 
Hence, despite the high prevalence and robust data associating it with poor patient-
centered outcomes, comorbid depression is neither diagnosed when present nor treated 
when identified in HD patients. This is likely due to lack of high-level generalizable 
evidence for the efficacy of treatment for the condition in this population.  


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1.2 
Rationale for Study 
1.2.1 
Engagement Interview 
Past studies have also shown that many HD patients with comorbid depression do not 
wish to receive any form of treatment in part because of the lack of their understanding 
about depression, and the stigma associated with mental illnesses[38]. In a recent cluster 
randomized controlled clinical trial, 220 HD patients were randomly assigned to provide 
direct feedback along with evidence-based treatment algorithms, or to specific 
recommendations from nurses trained in symptom assessment and algorithms to 
patients. There was no significant difference in the implementation of treatment in the 
feedback arm (11 of 37) or the nurse recommendation arm (6 of 28). Consistent with this 
observation, the patients that responded to a survey administered to dialysis patients 
through our two patient advocacy partners, AAKP and DPC,  over 60% ranked “no 
specific intervention” as their top choice were they to suffer from comorbid depression. 
Similarly, over 40% of patients approached for participation in a recently completed trial of 
individual CBT in Brooklyn did not wish to undergo treatment for clinically significant 
depressive symptoms [39]. Hence, it is necessary to determine whether an engagement 
interview prior to discussing options increases the frequency of treatment for depressive 
symptoms. 
A large number of clinical trials have tested the efficacy of collaborative care for the 
treatment of depression in primary care in individuals with comorbid illnesses such as 
diabetes mellitus. An engagement interview, which is based on principles of motivational 
interviewing, is an integral component of the collaborative care arm of the studies. At 
least one study was shown to increase acceptance of evidence-based treatment of 
depression in low-income minority women who are new mothers[40]. In another recent 
study, 925 adult patients treated by 135 primary care clinicians were randomized to watch 
a depression engagement video, or a tailored interactive multimedia computer program, 
or a control visit [41]. The primary outcome was a composite measure of patient-reported 
anti-depressant drug recommendation, mental health referral, or both. Individuals 
randomized to interactive multimedia program were significantly more likely to achieve 
the primary outcome compared to controls (26% vs.26.3%); there was no significant 
difference between the use of depression engagement video and controls (17.5% vs. 
16.3%). There are no data on the efficacy of this approach for the increasing the likelihood 
of treatment for depressive symptoms among patients undergoing HD.  
The intervention to be tested in this study is the same as the one being used in studies of 
collaborative care for the treatment of depression and will include the presentation of a 
video along with motivational interviewing.   


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1.2.2 
Comparative Efficacy of individual CBT and anti-depressant drug therapy 
There are two distinct approaches to treat depression – cognitive behavioral therapy (CBT, 
or psychotherapy), and anti-depressant drug therapy. While developing the research plan, 
responses from 61 ESRD patients indicated that not all treatment options for depression 
are equally acceptable to every HD patient, since the two approaches for treatment are 
very different; CBT necessitates multiple encounters with a therapist for patients who 
already need to go to a healthcare facility for dialysis sessions thrice weekly. Similarly, 
anti-depressant drug therapy would add to the already high pill burden for HD patients 
and may result in adverse effects in some patients. Moreover, the availability of each of 
these treatments varies, in part, by insurance coverage and out-of-pocket costs to patients. 
Hence, the current study will compare two different treatments that, if found to be 
comparably efficacious, would offer options for treatment that are most acceptable and/or 
available to them and their providers. There is a paucity of data for the efficacy of either of 
these approaches for the treatment of comorbid depression in HD patients[42]. There is 
only one clinical trial that has compared the efficacy of citalopram and psychological 
training for improving depression and anxiety symptoms in patients undergoing 
hemodialysis [43]. In this single-center study, 44 patients undergoing hemodialysis in Iran 
who scored 8 or more on the Hospital Anxiety and Depression Scale were randomly 
assigned to either 20 mg/d of citalopram or six one-hour sessions of psychological training. 
While both treatments resulted in improvement in both anxiety and depressive symptoms, 
there was no significant difference in the efficacy of these two interventions. This study 
will compare the efficacy of CBT with anti-depressant drug therapy in a multi-center study 
in a larger multi-ethnic population to ensure high external validity.  
Cognitive Behavioral Therapy (CBT): CBT is a short-term focused psychotherapy for 
many psychological problems including depression[44]. The focus of the therapy is on how 
the individual is thinking, behaving, and communicating today rather than on their 
childhood experiences. The therapist assists the patient in identifying specific distortions 
(cognitive assessment) and biases in thinking and provides guidance on how to change 
this thinking[45]. Thus, CBT helps the patients learn effective self-help skills that are used 
in homework assignments that target change in the way they think, feel, and behave now. 
CBT is action-oriented, practical, rational, and helps the patient gain independence and 
effectiveness in dealing with real-life issues. 
Numerous studies show that CBT is a first-line treatment for depression, is endorsed by 
clinical practice guidelines from the American Psychiatry Association, and does not have 
the negative side-effects of medications [42, 44]. It would also be expected to reduce relapse 
because patients may learn self-management techniques during therapy. The efficacy of 
CBT has been demonstrated in two pilot single-center studies of HD patients with 


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comorbid depression, setting the stage for a larger-scale testing in a multi-center clinical 
trial (n=85 and 63) [39, 46]. In the first clinical trial conducted in Brazil, 41 patients in the 
intervention group received 12 weekly sessions of group CBT by a trained psychologist over 
three months and 44 patients received the usual treatment [39]. After three months of 
treatment, there was a significant improvement in depressive symptoms with BDI-II (3 
month score, 14.1 ± 8.7 vs. 21.2 ± 9.1), major depression module on the MINI (3 month 
score, 1.9 ± 2.8 vs. 4.3 ± 2.9), burden of kidney disease, quality of social interaction, sleep, 
and mental component summary of health-related quality of life. In the second clinical 
trial conducted in Brooklyn, New York, 65 patients were randomly assigned to treatment 
first or wait-list control group [46]. Individual CBT was administered chair side while the 
patient underwent hemodialysis for three months. The intervention was associated with a 
significant improvement in depressive symptoms (Beck’s Depression II and Hamilton 
Depression Rating Scale), quality of life (Kidney Disease Quality of Life Short Form), and 
treatment adherence (inter-dialytic weight gain).  This study will test the efficacy of 
individual CBT, as tested in the latter clinical trial, among patients treated in up to 50 
dialysis facilities operated by 7 providers in a geographically, ethnically, and culturally 
diverse and broader array of patients across a wider age range than done thus far. 
Anti-Depressant Drug Therapy with Sertraline:  Anti-depressant drugs are also a first-
line treatment for depression in the general population [42, 47]. The data for anti-depressant 
drugs are even more limited, as patients with kidney diseases have been excluded from all 
major clinical trials [18, 19]. The benefits with drug therapy in otherwise healthy individuals 
cannot be extrapolated to those with chronic medical illnesses as evident from the lack of 
efficacy of anti-depressant drugs in large clinical trials of patients with asthma and 
congestive heart failure [48, 49]. Only two randomized trials of drug therapy for the 
treatment of depression have been reported for HD patients; only one tested the effect on 
depressive symptoms [48]. In a placebo-controlled trial of 14 patients undergoing 
hemodialysis, the improvement in depressive symptoms with 8-weeks of treatment with 
fluoxetine did not reach statistical significance [48]. At least nine non-randomized 
uncontrolled studies with 7-44 HD patients with comorbid depression each, treated with 
anti- depressant drugs, have been published, most of which demonstrated improvement 
in depressive symptoms [49-57]. These limited data allow us to posit a significant 
improvement in patient- reported outcomes with treatment of comorbid depression in 
HD patients.  
Clinical practice guidelines indicate that only selective serotonin-reuptake inhibitors, 
serotonin-norepinephrine reuptake inhibitors, and bupropion meet the balance between 
efficacy and tolerability[42]. In ESRD patients, loss of renal excretory capacity further 
complicates drug selection [18]. A recent systematic review of 28 studies for 24 anti-


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depressant drugs in patients with kidney disease indicates that both serotonin-
norepinephrine reuptake inhibitors and bupropion require dose reduction [18]. However, 
the magnitude of dose reduction cannot be readily determined as it is influenced by 
residual kidney function, which has not been considered in any study. These complicated 
dosing considerations are likely to make it difficult to balance efficacy and safety for these 
two drug classes for HD patients, and will likely preclude widespread adoption in clinical 
practice. Hence, sertraline, a selective serotonin reuptake inhibitor, will be used as the 
anti-depressant for this clinical trial. 
The drug is metabolized to an inactive form before being excreted via the kidneys; is safe 
in patients with heart disease (SADHART trial); and available in generic form [18, 19]. In a 
study of ten HD patients receiving 200 mg sertraline/day for 21 days, the 
pharmacokinetics were no different than 12 age-matched healthy volunteers[58]. At least 
six studies including 128 dialysis patients treated with sertraline have been published [50, 56, 
57, 59-61]; three reported improved hemodynamic stability during dialysis, and none 
reported any intolerability.  
1.2.3 
Evolution of depressive symptoms without any treatment in patients 
undergoing hemodialysis  
In any individual, a diagnosis of major depression or dysthymia requires treatment. 
However, some patients are reluctant to either accept a diagnosis or treatment for 
depression. Over 60% of the patients with kidney disease that we surveyed ranked “no 
specific intervention” as their top preference for managing clinically significant depressive 
symptoms. In other patients, the available treatment options may not be feasible or 
tolerated; this may be from availability and/or insurance coverage for such treatment or 
unacceptable pill burden and/or adverse effects. As such, there is a need for us to 
understand the natural course of depressive symptoms in patients undergoing 
maintenance hemodialysis. Such data are extremely sparse. In a single center 
observational cohort study, the data on the presence and severity of depressive symptoms 
using SCID-1 Depression module were available at two different time points, 16-months 
apart [62]. Of the 47 patients with sufficient follow-up data, 12 had a depressive disorder 
and 2 had dysthymia.  Upon follow-up, 7 of the 12 subjects with depressive disorder no 
longer qualified for a SCID diagnosed depressive disorder while 5 had persistent 
depression. Of the two patients with dysthymia, they met the SCID criteria for major 
depression at the second time point. In the SMILE study, 286 subjects completed at least 
one depression or pain assessment [63]. The subjects completed a median of 16 and total of 
4452 monthly PHQ-9 assessments; moderate to severe depressive symptoms were 
reported on 788 (18%). At baseline, 73 patients (26%) reported moderate to severe 
depressive symptoms, 50% on at least one assessment, and 9% on ≥ 755 of assessments 


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[63]. In this multi-center study, patients that do not find any form of treatment acceptable 
either within or outside the scope of the clinical trial will be followed for the presence 
and/or severity of depressive symptoms for up to 12 weeks. This will generate evidence to 
inform patients on what they should expect if they were to decide not to accept any form 
of treatment.   
2. Study Objective and Aims 
 
With the ASCEND study, we seek to test two hypotheses:  
• 
Hypothesis One: In HD patients with comorbid current major depressive episode or 
dysthymia, an engagement interview significantly increases the frequency of 
treatment for comorbid depression. 
• 
Hypothesis Two: In HD patients with comorbid current major depressive episode or 
dysthymia, there is no significant difference in the efficacy of 12-week treatment 
with individual CBT in a dialysis facility or anti-depressant drug therapy. 
 
2.1 
Efficacy of the Engagement Interview 
The primary measure of efficacy will be % of patients undergoing hemodialysis with co-
morbid depression who initiate treatment for the condition. This will be defined as one of 
the following: 
• Completing at least one psychotherapy session either as a part of the clinical trial or in 
the community within four weeks of the engagement/control visit. 
• Receiving a supply of anti-depressant drug either as a part of the clinical trial or the 
treating physician within four weeks of the engagement/control visit. 
 
The secondary measure of efficacy will be the % of patients undergoing hemodialysis 
with co-morbid depression who are willing to accept treatment. This will be measured by 
the patient’s intent and will be defined as one of the following: 
• Signing the informed consent to be randomly assigned to individual CBT or drug 
therapy. 
• Receiving a referral by the research team and/or primary care physician and/or 
treating nephrologist to a therapist for psychotherapy in the community within two 
weeks of establishing an engagement/control visit. 


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• Receiving a prescription for anti-depressant drug therapy from primary care physician 
and/or treating nephrologist within two weeks of establishing an engagement/control 
visit. 
 
2.2 
Comparative Efficacy of individual CBT and sertraline drug therapy 
2.2.1 Primary Measure of Efficacy 
The primary measure of efficacy will be the mean difference in QIDS-C score at 
Week 12 between treatment groups.  
2.2.2 Secondary Measure of Efficacy 
Two groups of secondary measures of efficacy will be examined – Patient Reported 
Outcomes and Treatment Adherence. 
2.2.2.1 Patient-Reported Outcomes 
The mean difference in the scores for each of the following scales at Week 12 between 
treatment groups: 
• Depressive Symptoms:  
o Global Improvement Scale 
o Beck Depression Inventory-II 
• Anxiety Symptoms: 
o Generalized Anxiety Disorder 7- item (GAD-7) scale 
• Effect of Disease on Well-Being: 
o Sheehan Disability Scale 
• Fatigue: 
o Short-Form 36- Energy/Vitality Sub-scale 
• Health-Related Quality of Life: 
o One-item global quality of life scale 
o Satisfaction with Life Scale 
• Perceived Social Support: 
o Multi-Dimensional Scale of Perceived Social Support 
• Sleep: 
o Pittsburgh Sleep Quality Index 
• Exercise: 
o Single item Activity Measure 
 
2.2.2.2 Treatment Adherence 
This will comprise: 


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• Non-Adherence with Dialysis as defined by the percentage of all dialysis sessions 
skipped and/or requested by the patient to be shortened by ≥ 10 minutes over the 
12-week intervention period. Dialysis sessions missed due to hospitalization will 
not be included as a skipped treatment.  
• Non-Adherence with Fluid Intake as defined by inter-dialytic weight gain (as % of 
post-dialysis weight) during Week 12 of the study. 
• Non-Adherence with Diet and/or Medications as defined by serum phosphorus 
level measured as a part of routine clinical care during the third month of 
participation in the study. 
3. Study Design and Overview 
The ASCEND study is an open- label, randomized, controlled clinical trial of HD patients 
with comorbid depression, with accrual of participants over 24 months, comparing (1) a 
single engagement interview with a control visit for initiating treatment for comorbid 
depression in 200 patients; and (2) individual CBT with drug therapy for 12 weeks in 120 
HD patients for depressive symptoms at three clinical sites - Seattle, Dallas, and 
Albuquerque (Figure 1 and Appendix 1). The length of intervention is selected based upon 
considerable data from the general population that indicate that individuals, who do not 
respond to CBT or anti-depressant drug therapy within 12 weeks, are highly unlikely to do 
so with continued treatment. In addition, up to 40 patients who refuse to accept 
treatment either within or outside the clinical trial, will also be followed for 12 weeks. 
These patients will not be a part of the clinical trial, will be offered treatment at each 
evaluation, and will undergo longitudinal assessment of depressive symptoms. 
An Engagement Interview will comprise a one-on-one session with the patient, during 
which the health-care provider will use reflective statements and non-judgmental listening 
techniques, will explore barriers to treatment, and will help the patient articulate 
ambivalence about engaging in treatment. This session will be enhanced with a 20-minute 
DVD that the subject will watch with the therapist in the dialysis facility [64]. The subject will 
be encouraged to take the DVD home with them and watch it with their family members as 
well.   
Cognitive Behavioral Therapy (CBT) is a short-term psychotherapy that will focus on 
how the individual is thinking, behaving, and communicating today rather than on their 
childhood experience. The therapist will assist the patient in identifying specific 
distortions (cognitive assessment) and biases in thinking and will provide guidance on how 
to change this thinking [45]. Thus, CBT will help the patients to learn effective self-help 
skills that will target change in the way they think, feel, and behave. CBT will be 


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administered while the patient is undergoing the HD procedure; however, alternative 
arrangements will be made for individual patients based upon their preferences.  
Anti-Depressant Drug Therapy will be delivered with sertraline, a selective serotonin 
reuptake inhibitor, and the dose will be titrated using the Measurement Based Care 
Protocol. 
 
 Figure 1 Study Overview 
Pre-Screen with BDI-II 
Screening 
Randomization
Engagement 
Interview 
Control Visit 
Patient accepts treatment 
and clinical trial 
Patient does not accept 
treatment even outside study 
Randomization 
CBT 
Sertraline 
Follow-Up 
Hypothesis One 
Hypothesis Two 


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4. Participant Selection and Withdrawal 
4.1 
Study Population 
4.1.1 Pre-Screening:  
All patients with ESRD being treated in participating dialysis facilities that meet the 
following three criteria, will be eligible to participate in pre- screening: (1) age ≥ 21 years; 
(2) undergoing maintenance HD ≥ 3 months; and (3) speak either English or Spanish. 
These individuals will be invited to complete the 21-item Beck Depression Inventory 
(BDI). Individuals with BDI score ≥ 15 will be invited to participate in subsequent study-
related activities.  
4.1.2 Subjects for Engagement Interview and Treatment of Comorbid Depression:  
Inclusion Criteria: 
1. Age ≥ 21 years; 
2. Undergoing thrice-weekly maintenance HD for ≥ 3 months; 
3. Able to speak either English or Spanish; 
4. BDI-II score ≥ 15; and 
5. Meets diagnostic criteria for either current major depressive episode or dysthymia on 
the MINI [65]. 
Exclusion Criteria: 
1. Active suicidal intent; 
2. Intensive psychotherapy (once weekly) for the treatment of depression;  
3. Current drug therapy for the treatment of depression with serotonin receptor uptake 
inhibitors or serotonin norepinephrine reuptake inhibitors at doses higher than listed in 
Appendix Two; 
4. Evidence of cognitive impairment on Mini-Cog[66]; 
5. Present or past psychosis or bipolar disorder I or II on the MINI[65]; 
6. Alcohol or substance abuse diagnosed on the MINI or history of such abuse in the 
past three months [65]; 
7. Life expectancy < 3 months, in the judgment of the site principal investigator; 
8. Anticipated to receive living related donor kidney transplantation within 3 months; 
9. Pregnancy, or lactation, or women of childbearing age not willing to use adequate 
birth control; 
10. Clinical and/or laboratory evidence of chronic liver disease; 
11. History of significant active bleeding in the past three months, such as 
hospitalization for gastrointestinal bleeding; 


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12. Current use of class I anti-arrhythmic medications (e.g., propafenone, flecanide), 
pimozide, monoamine oxidase inhibitors, reserpine, guanethidine, cimetidine, tri-
cyclic anti-depressants, triptans, tramadol, linezolid, tryptophan, and St. John’s 
wort; and 
13. Known hypersensitivity to sertraline. 
4.2 
Participant Pre-Screening and Recruitment  
4.2.1 Pre-Screening and Enrolling Subjects in Engagement Interview Phase 
All eligible patients with ESRD being treated in participating dialysis facilities will be 
invited to complete the 21-item Beck Depression Inventory (BDI). Study personnel will 
provide all patients with an information sheet that will describe the purpose and nature 
of pre-screening and provide patients with an option to opt-out of the pre-screening.  
Once the patient completes the BDI-II, it will be reviewed immediately upon receipt for 
subjects’ response to question 9 to determine the presence of suicidal intent; those who 
answer either “I would like to kill myself” or “I would kill myself if I had the chance” will be 
emergently triaged.  
The summary score on BDI-II will be computed within 48 hours of receipt and subjects 
will be managed based on the summary score: 
• Score ≥ 15 will be approached for their willingness to complete the modules of MINI, 
and undergo other screening activities. Subjects that agree will be invited to sign a 
consent form (ICF-1) and those individuals with a diagnosis of major depression or 
dysthymia on the MINI will be randomly assigned to (1) an engagement interview with 
a trained therapist, or (2) brief discussion with study staff. 
• The information on subjects with score ≥ 15 who refuse to undergo additional 
screening activities will be communicated to the patients’ treating nephrologist. 
Subjects will also be presented with a list of mental health care providers and resources 
in their community. This will include providers who serve safety-net populations like 
those with Medicaid insurance and those that provide charity care. 
• Information on subjects with score < 15 will also be communicated to the patients’ 
treating nephrologist. 
4.2.2 Re-Administration of Pre-Screening 
Some subjects may complete the 21-item Beck Depression Inventory (BDI) additional 
time(s). These include when a subject: 
• Scores ≥15, but is unable to be screened within the 10 day window. A second BDI 
will be administered for a valid score prior to screening. 
• Scores < 15, 3 months have passed since previous administration. 


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4.2.3 Enrollment of Subjects in Comparative Efficacy Trial of individual CBT and Anti-
Depressant Drug Therapy 
The clinical trial will be limited to patients with major depression or dysthymia, with no 
additional psychiatric co-morbidity. Subjects with (1) confirmed diagnosis of major 
depression or dysthymia on the MINI, (2) are willing to receive treatment for comorbid 
depression, and (3) who meet the inclusion and exclusion criteria, will be approached for 
their willingness to be randomly assigned to either individual CBT or anti-depressant 
drug therapy as a part of the clinical trial.  All subsequent study-related activities will 
begin only upon the subjects’ signing an informed consent form (ICF-2).  
4.2.4 Enrollment of Subjects in Observational Cohort Study with no Active Treatment 
Subjects who (1) are not willing to participate in the clinical trial and (2) do not find any 
treatment acceptable outside the clinical trial will be invited to participate in the 
prospective observational cohort for serial assessment of depressive symptoms. 
4.2.5 Patients 
4.6 
Early Termination of Study Treatment and Withdrawal of Subjects  
Active treatment with the study interventions (individual CBT or sertraline drug therapy) 
will be terminated if the patient: 
• Withdraws informed consent 
• Unable to follow study procedures 
• Undergoes kidney transplantation 
• Transfers to home dialysis  
• Transfers care to a dialysis facility outside the participating metropolitan areas.  
Under each of these circumstances all attempts will be made to continue to ascertain 
primary and secondary patient-reported outcomes with computer assisted telephone 
interviewing (CATI).  
5. Study Interventions 
5.1 
Engagement Interview Phase 
Subjects will be randomly assigned to engagement interview or a control visit using block 
randomization within each site based on variable blocks of size 6 to 10. This will ensure 
that equal numbers of participants are randomized to each group, and that the two groups 
are balanced at periodic enrollment intervals. Randomization assignment will be 
obtained via the secure study web portal hosted at the Data Coordinating Center at the 
University of Washington.  


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5.1.1 Engagement Interview 
5.1.1.1  Overview of the Intervention 
Trained CBT therapists at each of the three sites will conduct the engagement interview. 
The session will be aimed at improving the acceptance of the diagnosis of depression by 
patients and treatment for the same. The therapist will invite patients to tell their story of 
recent stress (including medical symptoms) and possible connection to depression. The 
therapist will use reflective statements and non-judgmental listening techniques so that 
the patient feels heard. Potential barriers to acceptance of treatment and how to overcome 
them will be discussed. Motivational interviewing techniques will be used to help the 
patient articulate potential ambivalence about treatment and therapists will reflect back 
to the patients their expression of wanting life to be different despite ambivalence about 
treatment. The session is anticipated to last an hour and maybe supplemented with a 40- 
minute DVD entitled “Depression Self Care Companion for Better Living” in an effort to 
improve health literacy regarding depression and its treatment. The subject can watch 
salient portions of the video along with the therapist, or watch it at home or in the 
dialysis unit. 
5.1.1.2 Training and Certification Prior To Implementation in Trial 
Each of the therapists will undergo a one-day in-person training to be scheduled in 
Seattle prior to implementing the intervention. The training will be led by Nancy Grote at 
the School of Social Work at the University of Washington, supported by Yaminette Diaz 
Linehart; the latter will focus on adapting the intervention culturally to Latinos.  
Following the completion of training, each therapist will be required to complete mock 
interventions prior to implementation of the intervention in the clinical trial. These mock 
sessions will be audio recorded and will be reviewed by Drs. Grote and Linehart using a 
structured fidelity adherence form. Once the therapists are deemed competent in the 
intervention, they will be ready to implement the intervention in a clinical trial.  In the 
event of staff turnover, any new therapist will need to undergo training procedures prior 
to start of intervention for the clinical trial. 
5.1.1.3  
Monitoring the Fidelity of the Intervention 
During the conduct of the trial, bi-weekly conference calls will be scheduled with all the 
therapists during which clinical issues and implementation will be discussed and cases 
reviewed.  All sessions of the engagement interview will also be audio-taped and a 10% 
random sample will be periodically reviewed to provide rating for treatment fidelity using 
forms that outline the major skills and intervention pieces.  


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5.1.2 Control Visit 
Individuals assigned to control visit will be scheduled for a follow-up discussion with a 
member of the research team. During this session, they will be informed of the diagnosis 
of major depression or dysthymia, the options for treatment available through the clinical 
trial, and alternatives should they decline participation in the clinical trial. The time spent 
in providing this information will be recorded for the control visit. 
5.2 
Comparative Efficacy of individual CBT vs Anti-Depressant Treatment Drug 
Therapy 
The subjects will be randomly assigned to individual CBT or sertraline drug therapy using 
block randomization as for the engagement interview. The randomization will occur 
using the secure study web portal. 
5.2.1 
Individual CBT in Dialysis Facility 
5.2.1.1  Overview of the Intervention 
Individuals will undergo 10 CBT sessions of 60 minutes each, by a therapist in the dialysis 
facility (8 weekly sessions; then every other week x 2). The CBT will be administered 
while the patient is undergoing HD; however, alternative arrangements will be made upon 
individual patient’s preferences. To the extent possible, each session will be scheduled on 
the same day of the week for any given patient.  Standard CBT intervention for 
depression will be modified for the challenges associated with HD treatment to include 
psycho-education, adherence with the dialysis prescription, adapting behavioral 
activation, and identification and challenging ESRD specific cognitive distortions and 
maladaptive thought patterns (detailed manual in Appendix Five). 
During the course of intervention, study subjects will undergo assessment of severity of 
depressive symptoms using Quick Inventory of Depressive Symptoms – Self-Report 
(QIDS-SR) every two weeks for the first six weeks (weeks 0, 2, 4, and 6) and on weeks 9 
and 11. The results of these assessments will be available to the therapist as they will be for 
titration of the drug therapy. 
5.2.1.2  
Training and Certification Prior To Implementation in Trial 
The training of the therapists in the implementation of the CBT will be held in 
conjunction with the training for the engagement interview. This training is expected to 
last two days, will be held in-person in Seattle, and led by Daniel Cukor.  
Following the completion of training, each therapist will be required to complete mock 
interventions prior to implementation of the intervention in the clinical trial. These mock 
sessions will be audio recorded and will be reviewed by Dr. Cukor using a structured 
fidelity adherence form. Once the therapists are deemed competent in the intervention, 
they will be ready to implement the intervention in a clinical trial.  


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Table 2 Overview of individual CBT for the study 
Sessions 1-2 
Assessment – Assess patient’s motivation for change, goals for treatment, 
‘stage of change’. Evaluate need for patient to modify fluid intake, 
adherence with medical regimen. 
Psycho-education – highlight similarities/differences between depression 
and medical illness. 
Behavioral Intervention – Behavioral activation – increase patients’ 
enjoyable activities. 
Sessions 3-6 
Cognitive Intervention – Train participants in relationship between 
dysfunctional automatic thoughts and negative perceptions and outcomes; 
Improve patient’s ability to categorize distorted thoughts and provide 
rational behavioral responses; Identify recurring patterns of maladaptive 
thinking and challenge negative schemas. 
Sessions 7-8 
Health Behaviors – Teach and practice healthy living (adherence) skills for 
HD treatment; Increase positive social contacts – initiating contact, 
building support network; Teach and practice strategies for managing 
anxiety 
Sessions 9-10 
Termination – Review newly learned skills and practice eliciting, 
challenging, and modifying maladaptive thoughts; Plan for termination of 
therapy – identify which interventions were helpful and which were not, 
and focus on relapse prevention 
 
5.2.1.3  
Monitoring the Fidelity of the Intervention 
During the conduct of the trial, bi-weekly conference calls will be scheduled with all the 
therapists during which clinical issues and implementation will be discussed and cases 
reviewed. All individual CBT sessions will be audio-taped and a 10% random sample 
periodically reviewed to provide rating for treatment fidelity using forms that outline the 
major skills and intervention pieces.  
5.2.1.4  
Monitoring Adherence to Intervention 
A structured form will be developed for therapists to monitor patients’ adherence with 
health behaviors and/or homework at the start of each session following the first session. 
This will generate data to describe the association between adherence with skills taught 
during CBT with observed efficacy with the intervention. 


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5.2.2 Anti-Depressant Drug Therapy 
5.2.2.1 Overview of the Intervention 
The site investigators will prescribe sertraline drug therapy and dose titration will be 
implemented using “Measurement-Based Care”, a model of patient-centered shared-
decision making (Appendix Three). This protocol incorporates standardized assessments 
of depressive symptoms and drug side effects, and the research team and the patient make 
joint decisions about the next steps in titration – to maintain, increase, or decrease the 
dose[19, 67]. This will help establish the highest efficacious but tolerable dose tailored for 
each patient and minimize the risk of under-dosing. The QIDS-SR scale will be used to 
determine the clinical response for dose titration [68]. Side effects will be assessed using 
the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) scale, a self-report 
three-item scale to assess side effects and the degree to which they interfere with day-to-
day functions[69].  The assessments will occur every two weeks for the first six weeks (Weeks 0, 2, 
4 and 6) and on Weeks 9 and 12 in the dialysis facility while the patient is undergoing HD. To 
the extent possible, the assessments will be done on the first dialysis day of the week 
(Monday or Tuesday, respectively, for subjects on Monday-Wednesday-Friday or Tuesday-
Thursday-Saturday / Sunday-Tuesday-Thursday schedules). The participant-specific dose 
at week 6, up to a maximum of 200 mg/d, will be continued for the remaining six weeks.  
 
5.2.2.2 Training of Investigators in Measurement Based Care 
The investigators, sub-investigators, or any personnel with privileges to prescribe drug 
therapy at each of the three sites will undergo formal training in the implementation of 
Measurement Based Care prior to implementation of the study protocol. This training 
will led by Drs. Hedayati and Katon.  
 
5.2.2.3 Drug Procurement and Dispensation 
The drug will be procured as 25 mg, 50 mg, and 100 mg tablets by the Kidney Research 
Institute at the University of Washington and shipped to each of the three clinical sites. 
The drug will be stored at the Investigational Drug Services at each of the three sites and 
will be dispensed for individual patients at two-week periods for the first six weeks and 
three-week periods for the second six weeks. The dose for each dispensation will be 
determined by assessments made on the first dialysis day of the week and drugs will be 
dispensed to the patient on the second dialysis day of the week.  
 
5.2.2.4 Monitoring Drug Adherence 
At weeks 2, 4, 6, 9, and 12 subjects will be asked to bring in the bottles that were provided 
to them at the preceding study visit. Pill count will be done to monitor adherence to drug 
therapy and all unused drug will be destroyed by IDS.  


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6. Ascertainment of Outcomes 
6.1 
Engagement Interview vs. Control 
The primary outcome will be assessed six weeks from the time of completion of the 
engagement interview or control visit. This will be assessed as: 
• Subjects enrolled in comparative efficacy trial: Completion of at least one CBT 
session or receiving at least one dispensation of sertraline. 
• Subjects not enrolled in comparative efficacy trial: This will be ascertained with a 
single telephone call and subjects will be asked if, since the completion of 
engagement interview or control visit, they have either (1) completed one 
psychotherapy session, or (2) filled a prescription of anti-depressant drug therapy. 
The secondary outcome will be ascertained upon completion of the engagement 
interview or control visit by the therapist or research coordinator, respectively. Patients 
will be asked to report whether they are willing to (1) enroll in the clinical trial of 
comparative efficacy of CBT or anti-depressant drug therapy, (2) receive a referral for 
psychotherapy, or (3) receive a prescription of anti-depressant drug therapy.  
6.2 
Comparative Efficacy of individual CBT and anti-depressant drug therapy 
The primary and secondary patient reported outcomes will be ascertained by CATI 
at weeks 0, 6, and 12. If there are individuals that do not have access to a telephone, the 
study staff will work to make that available to them to complete the CATI.  The CATI will 
run out of Albuquerque, NM under the direction of Mark Unruh who will train the 
interviewers. All the interviews will be audio recorded and up to 10% of all interviews will 
be audited to ensure the integrity of the assessment. The CATI interviewers will be 
blinded to study assignment. Bilingual CATI operators will conduct the assessments using 
scripts available in both English and Spanish, using the language preferred by the study 
subject. The interview is expected to last about 30 minutes. The baseline assessment will 
be performed prior to the first scheduled session of CBT or receiving anti-depressant drug 
therapy. Each of the three sessions will be scheduled on the day following the first dialysis 
treatment of the week (Tuesday for subjects on a Monday-Wednesday-Friday schedule, 
and Wednesday for subjects on a Tuesday-Thursday- Saturday / Sunday-Tuesday-
Thursday schedule). If, however, the CATI could not be completed on the designated day, 
it would be acceptable to complete it during the subsequent non-dialysis days.  If the 
subject is not available for the call on a non-dialysis day, then it is permissible for it to be 
done within the first hour of the dialysis session according to the subject’s treatment 
schedule as noted above.  The calls for the 6 and 12 weeks should be done on a dialysis vs. 
non-dialysis day based on which was chosen for the baseline call, consistently for each 
subject. 


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Measures of adherence will be ascertained by a structured data extraction from the 
medical records maintained in the dialysis facility at each site at weeks 0, 6, and 12 of the 
study. The study staff at each site will be trained in the process prior to the start of the 
clinical trial. Adherence with dialysis regimen will be determined for the preceding six 
weeks as a composite of % of treatments in which patient requested early termination of 
HD (≥ 10 minutes) or skipped a session (excluding missed due to hospitalization or 
changes by dialysis facility). Adherence with diet and medications will be determined 
by (1) weight gain between each of the completed HD treatments over the preceding six 
weeks; and (2) each measurement of serum phosphorus in the preceding six weeks.  
6.3 
Observational Cohort Study of Patients Who Find Treatment Unacceptable 
These subjects will only undergo assessment of severity of depressive symptoms at weeks 
0, 6, and 12 using QIDS-C and they will be ascertained using CATI as described above. 
7. Study Visits 
 
All study visits will occur in the participating dialysis facility and a summary of the 
screening procedures prior to start of treatment are summarized as: 
 
 
 
 
 
7.1 
Pre-Screening 
• Information sheet will be handed to patients to invite them to complete BDI-II 
• Patients who agree will be invited to complete BDI-II 
• Study staff will review response to question 9 of BDI-II and emergently triage 
patients with suicidal intent 
• BDI-II scores will be computed within 48 hours of receipt of surveys 
7.2 
Screening (within 10 days of completion of BDI-II) 
• Patients with BDI-II score ≥ 15 will be invited to sign consent form to complete 
screening activities (ICF-1). 
BDI-II 
MINI 
Engagement Interview vs 
Control 
Enrolled to 
Treatment; 
BDI and 
QIDS-C 
Up to 10 d 
Up to 10 d 
Up to 7 d 


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• For subjects that consent to participate in the study, the following information will 
be recorded: 
o Registered on to the online study portal. 
o Demographic Data 
o 7 modules of MINI 
o Mini-COG 
o Health literacy questions: 
§ How often do you have someone help you read hospital materials? 
(Never, Occasionally, Sometimes, Often, Always) 
§ How confident are you filling out medical forms by yourself? 
(Extremely, Quite a bit, Somewhat, Little Bit, Not at all) 
§ How often do you have problems learning about your medical 
condition because of difficulty understanding written information? 
(Never, Occasionally, Sometimes, Often, Always) 
o Review Inclusion and Exclusion Criteria 
• Subjects that meet the inclusion and exclusion criteria will be randomly assigned 
to engagement interview or control visit through the secure study web portal. 
7.3 
Engagement Interview vs. Control Visit (within 10 days of screening) 
• Engagement interview will be conducted by the study therapist and control visit 
will be delivered by another member of the research team. 
• Upon completion of the intervention, subjects will be asked about their preference 
for treatment :  
o “Both antidepressant medication and a type of counseling called cognitive 
behavioral therapy can be successful in treating depression. Antidepressant 
medication involves taking one or more pills once daily which may have 
only minor side effects. Counseling involves speaking with a therapist once 
a week during dialysis for approximately 50 minutes to work on patterns of 
thinking and emotions that are involved in depression. Which of these two 
treatments would you prefer?  
§ Medication 
§ Counseling 
§ Either 
§ Neither” 
 


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7.4 
Baseline Visit/Week 0 
• , Within 7 days of engagement interview or on the day of the control visit, subjects 
will be approached for their willingness to enroll in the clinical trial of comparative 
efficacy of treatment options for depression (ICF-2). 
• CATI will be scheduled for the non-dialysis day (or the next dialysis session, if the 
subject is not available on a non-dialysis day) following the day the consent form 
was signed (within 7 days of signing the consent form). 
• Consenting subjects will be randomly assigned to individual CBT or anti-
depressant drug therapy at the beginning of the week following the CATI call. 
• During Week 0, the following data will be recorded for consenting study subjects: 
o Medical History 
o Concomitant Medications 
o QIDS-SR 
• Study Intervention will start during the same week: 
o The first session for individual CBT will be scheduled on the second or third 
dialysis day of the week 
o Patients on sub-therapeutic doses of anti-depressant drugs will be asked to 
discontinue the drug, in consultation with the physician who initially 
prescribed the drug (See Appendix Two). 
o Sertraline will be made available on the second dialysis day of the week and 
the first dose (25 mg) administered under supervision of study staff 
7.5 
Weeks 2, 4, and 9 
• On the first dialysis day of the week, the following will be completed 
o QIDS-SR 
o FIBSER (for subjects in the anti-depressant drug therapy arm) 
• On the second dialysis day of the week, subjects in the anti-depressant drug 
therapy arm will: 
o Return the supply of medications at the prior visit to research staff 
o Receive a new supply of medications from research staff 
7.6 
Week 6, 11 and 12 
• On the first dialysis day of the weeks 6 and 11, the following will be completed 
o QIDS-SR 
o FIBSER (for subjects in the anti-depressant drug therapy arm) 
• On the first non-dialysis day (or dialysis day, if subject is not available on a non-
dialysis day) of the week 6 and 12: 
o CATI 


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• On the second dialysis day of Week 6, subjects in the anti-depressant drug therapy 
arm will: 
o Return the supply of medications at the prior visit from research staff 
o Receive a new supply of medications from research staff 
7.7  
Study Exit 
 
At 12 weeks, study patients will be deemed either to have achieved a response (≥ 50% 
decrease in baseline depressive symptoms) or remission (QIDS-C < 5), or not. The 
approach to managing participants upon conclusion of the study will depend upon the 
treatment arm: 
• 
CBT Arm: In individuals with clinically significant depressive symptoms (QIDS-C ≥ 
11), the 12-week score and its interpretation will be communicated to the patients’ 
treating nephrologist, along with a list of mental health care providers and 
resources in their community. 
• 
Drug Therapy: Patients that demonstrate either a response or achieve remission 
will be offered continued treatment in consultation with the treating nephrologist. 
If patients and/or treating nephrologists do not want continued treatment, 
sertraline will be gradually tapered by 50 mg/week. In patients that don’t achieve a 
50% improvement in depressive symptoms, the drug will be gradually tapered to 
off after 12-weeks. The failure to respond to sertraline will be communicated to the 
treating nephrologist with information on resources as listed above. 
The study team will provide the supply for and oversee the care should the patient and/or 
treating physician choose to discontinue sertraline. On the other hand, should the 
treating physician and patient decide to continue with sertraline drug therapy, the study 
staff will ensure a smooth transition for patients to receive the drug from their pharmacy 
as a part of their routine clinical care.  
7.8  
Post-Study Follow-up (done on week 12 by CATI) 
• Semi-structured interview will be conducted to elicit the experience of patients 
with the study intervention. This will be included as the last question on the CATI 
call done on week 12 of the study 
• At 30 days from the end of the study, the research staff will ascertain by reviewing 
the patient’s medical records or calling the patient, the occurrence of following 
events: 
o Death or 
o Hospitalization 


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8. Statistical Analyses 
8.1 
Preliminary Analyses 
Descriptive statistics will be provided for continuous data and frequency distributions for 
categorical data. Pre-treatment characteristics of the two randomized groups in both the 
engagement interview phase and evaluation of comparative efficacy of CBT and drug 
therapy will be compared to assess chance imbalances. If differences are found, these 
variables will be used as covariates in secondary analyses to evaluate the sensitivity of the 
primary analysis.  
8.2 Statistical Analysis for the Engagement Interview Phase 
The primary analysis will employ logistic regression adjusting for recruitment site to 
compare the proportions of patients who initiate treatment for comorbid depression 
between the engagement interview and control visit groups. The primary analyses will be 
based on a likelihood ratio test. In secondary analyses, we will compare the proportions of 
patients who report that they would be willing to initiate treatment for comorbid depression 
upon completion of engagement interview phase.  
8.2.1 Statistical Power for Primary Analysis of the Engagement Interview Phase 
Randomized evaluation of an engagement interview will be conducted with 400 patients. 
In the pilot study by Dr. Cukor, 40% of HD patients accepted treatment for comorbid 
depression and in studies by Dr. Katon, the engagement interview increases the rate by 10-
20% [39]. Based on recent updated assessment of sample size considerations and statistical 
power, we have updated our target sample size to a total of 120 patients randomized to 
cognitive behavioral therapy or sertraline drug therapy. Therefore our study design is well 
powered to detect the anticipated effect of an engagement interview. 
8.3 
Statistical Analysis for the Comparative Evaluation Phase 
Longitudinal mixed effects analyses will be applied to the QIDS-C primary outcome and to 
other continuous secondary outcomes to compare outcome means at the 6 and 12 Week 
assessments between the CBT and Sertraline groups[70]. Treatment group and the Clinical 
Center will be fixed effects in the model. An unstructured covariance matrix will account 
for serial correlations in outcome measurements within patients[71]. The model will 
constrain baseline means of the outcome to be equal in the treatment groups based on 
randomization. Such an analysis is known to correspond to an ANCOVA when only one 
follow-up measure is evaluated. Linear contrasts will be constructed to estimate for each 
outcome variable: (a) the mean difference in the outcome between the treatment groups 
at Week 12 (primary assessment of treatment effect); (b) the mean difference in the 


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outcome between groups at Week 6 (early treatment effect); (c) the average of the 
treatment effect estimates from (a) and (b) over Weeks 6 and 12 (persistence of early effect 
to 12 weeks); and (d) the difference in the estimated treatment effects from (a) and (b) 
between Week 6 and Week 12 (overall assessment of the treatment effect incorporating 
both follow-up visits). 
In addition, we will describe the following proportions for each of the two treatment 
arms: 
• % of patients in each of the two treatment arms that have at least 50% improvement 
in severity of depressive symptoms from baseline 
• % of patients in each of the two treatment that achieve remission at end of follow-up 
(QIDS-C < 5). 
8.3.1 Plan for Handling Missing Data  
The potential for bias due to loss-to-follow-up is a concern as poor adherers who 
discontinue either intervention are at risk both for loss to follow up and poor outcomes. 
The mixed effects modeling approach will mitigate the effects of loss-to-follow-up after 
the Week 6 visit by incorporating information from baseline and the Week 6 
measurements for patients who subsequently drop out of the study when estimating 
treatment effects at Week 12. Multiple imputations will be used to further limit the effects 
of missing outcome measurements. Baseline and follow-up factors beyond the analyzed 
outcome can be incorporated into the imputation model to account for dependence of the 
missing data mechanism on other measured factors, including measures of patient 
adherence to the intervention. Data augmentation using Markov Chain Monte Carlo 
(MCMC) simulation will be applied to generate imputed values[72]. Secondary analyses will 
examine the association between participation in engagement interview prior to 
randomization, health literacy at baseline, and adherence with the respective intervention 
on treatment efficacy. 
8.3.2 Sample size/detectable effect size in the Comparative Evaluation of CBT and Drug 
Therapy  
The sample size for this phase is 120 patients. The serial correlation in self-reported 
depression scales in data from published and unpublished studies in HD patients or those 
with advanced kidney disease by members of this consortium, over approximately 12 
weeks, typically ranges between R = 0.40 and 0.70[38, 39, 73]. Assuming a loss- to-follow-up of 
≤ 15%, 120 randomized participants will provide 80% power with 2-sided α = 0.05 to detect 
a difference in the mean 12-Week QIDS-C between the treatment groups of between 0.40 
(if R = 0.70) and 0.51 (if R = 0.40) of 1 standard deviation in the QIDS-C. This range of 
detectable effect sizes is well within the range of differences observed in the randomized 
and non-randomized trials of CBT or anti-depressant drug therapy for comorbid 


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depression in HD patients[46, 50, 51, 56, 57]. Moreover, the magnitude of effect size that is 
detectable is in the range of what is considered to be a clinically meaningful improvement 
in depressive symptoms. Smaller effect sizes may exist that may be statistically significant 
in larger studies. However, they are unlikely to be clinically meaningful or relevant to 
patients in the selection of treatment options. 
8.3.3 Overall Approach for Avoidance of bias in the Comparative Efficacy of CBT and drug 
therapy  
Several features of study design will minimize bias. First, a randomized controlled study 
design will generate the highest level of evidence for treatment efficacy. Second, all HD 
patients in participating dialysis facilities will be systematically screened, which will assure 
the selection of a cohort highly representative of the HD patient population with 
comorbid depression. Third, the primary and secondary outcomes will be measured at two 
time points after randomization, and hence data on intermediate time points will be 
available for participants who may drop out. Fourth, computer-assisted telephone 
interviewing will maximize patient participation and the assessor will be blinded to 
treatment assignment, both of which will minimize bias in an open-label clinical trial. 
Fifth, procedures to minimize missing data will be implemented, such as training and 
certification of study personnel, careful design of data collection forms, documentation of 
procedures, and implementation of a management system that minimizes data entry 
errors and patient tracking procedures[74]. Should there still be missing data, multiple 
imputation methods will be utilized as described above[74]. 
8.4  
Statistical analysis of data from observational cohort of patients who 
refuse to accept any treatment for comorbid depression 
Longitudinal mixed effects analyses will be performed to describe the change in depressive 
symptoms for this cohort; no comparisons will be made with data from the clinical trial. 
The proportion of patients who begin treatment during follow-up will be described as 
well. If sufficient numbers of patients initiate CBT or treatment with Sertraline then we 
will generate propensity scores for treatment and use these to conduct observational data 
based estimates of treatment effects, and compare these estimates with those obtained 
from the randomized trial. 
9. Adverse Events 
9.1 Potential Adverse Events from Study Interventions  
1. Adverse Effects from CBT: The risk classification for this arm is “not greater than 
minimal”. There is risk of experiencing discomfort in exploring psychologically 


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difficult material. Some people feel temporarily worse when they begin to disclose 
their intimate feelings, but this is usually mild and transient. Additional potential 
risks include breach of confidentiality if participants choose CBT to be done while 
undergoing HD. 
2. Adverse Effects from Sertraline:  
a. Common side effects (>10%) are transient and include nausea, decrease in 
appetite, diarrhea, dry mouth, dizziness, headache, insomnia, somnolence, 
decreased libido, sweating and tremors.  
b. Less common side effects (1-10%) include chest pain, palpitations, agitation, 
nervousness, pain, rash, impotence, increased appetite, constipation, 
vomiting, weakness, visual problems, yawning, and tinnitus.  
c. Rare (<1%) potential risks include bleeding, extrapyramidal reactions, 
neuroleptic malignant syndrome and suicide.  
d. Withdrawal symptoms such as agitation, anxiety, confusion, headache and 
seizures could occur if sertraline is stopped abruptly.  
e. Use of serotonin reuptake inhibitors has been reported to increase risk for 
bleeding; this risk may potentially be amplified in the presence of ESRD due 
to platelet dysfunction with uremia and use of heparin with each HD 
treatment. However, this adverse event has not been reported in any of the 
studies with this class of drugs in dialysis patients to date [48-50, 54-57]. 
Nevertheless, participants will be closely monitored for the occurrence of 
this complication. 
3. Worsening of depressive symptoms. 
4. Psychological discomfort from completing patient-reported scales 
5. Loss of patient confidentiality 
9.2 Anticipated Adverse Events in the Hemodialysis Population 
Patients undergoing hemodialysis experience a large number of adverse events from their 
underlying health, co-existing illnesses, and concomitant medications. These adverse 
events include (1) death, (2) fluid overload, (3) congestive heart failure, (4) vascular access 
events such as thrombosis or infection or dysfunction, (5) atherosclerotic cardiovascular 
events, (6) infections such as pneumonia, and (6) laboratory abnormalities such as 
anemia, hyperphosphatemia, and hyperparathyroidism. 
9.3 Monitoring for Adverse Events 
The subjects will be monitored for the occurrence of adverse events as:  
• 
The study staff will evaluate the subjects every two weeks for the first six weeks 
and every three weeks for the next six weeks.  


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• 
At these visits, tolerability of sertraline drug therapy will be monitored with the use 
of FIBSER. Patients assigned to the sertraline arm will be withdrawn if (1) they 
experience a serious adverse event attributable to the study drug and in the 
judgment of the site PI, the medication cannot be safely reinstituted; (2) the 
patient has intolerable side effects despite reducing dose to 50 mg/d; or (3) patient 
becomes pregnant. 
• 
The informed consent document will provide the name of a study staff with a 
phone number to be contacted in the case of an emergency or if an adverse event 
occurred outside the time frame of study visits. 
9.4 Reporting of Adverse Events 
All adverse events experienced by study subjects from the time of registration into the 
study (screening visit for engagement interview phase of study) will be recorded and 
summarized by random assignment group. The summary will be submitted to oversight 
groups at periodic intervals. 
All serious or unanticipated adverse events will be reported by each of the clinical site to 
the Data Coordinating Center within 24 hours of becoming aware of these events using a 
structured reporting form. Each site will also be expected to follow local reporting policies 
such as to the Institutional Review Board. Serious adverse events are ones that result in 
death, or are life threatening, or lead to or prolong hospitalization, or result in disability 
or incapacity. Unanticipated adverse events are unexpected events, which in the opinion 
of the investigator, could be reasonably be considered to be associated with participation 
in the research study.  The DCC will be responsible for communicating these to the 
DSMB consistent with the policies agreed upon and outlined in the DSMB charter. 
9.5 Management of Active Suicidal Intent 
The overall incidence of suicide is extremely low. However, since individuals with 
comorbid depression are at risk for committing suicide and individuals with ESRD are at 
a higher risk for committing suicide than the general population, care will be exercised to 
identify and provide help to individuals with suicidal intent. 
The suicidal intent could be ascertained by: 
• Study Coordinator (initial pre-screen with BDI-II or monitoring with QIDS-SR) 
• Therapist (Engagement Interview or CBT sessions) 
• CATI (while completing QIDS-C or CATI) 
The subjects will be deemed to have active suicidal intent if they answer the following 
questions: 


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• BDI-II (question 9): “I will like to kill myself” or “I will like to kill myself if I had the 
chance” 
• QIDS-SR (question 12): “I think of suicide/death several times a week for several 
minutes” OR “I think of suicide/death several times a day in some detail, or I have 
made specific plans for suicide or have actually tried to take my life”. 
Each site will be asked to provide three emergency telephone numbers of study 
personnel; these telephone numbers will be made available to the therapist, CATI 
operator, and dialysis facility staff. Upon being informed of study subjects with an active 
suicidal intent, the following process will be followed: 
• If the subject is at immediate risk for self-harm, call 911 
• If the subject is not at immediate risk for self-harm, site clinician would be 
immediately contacted by telephone along with an electronic communication to 
the site study team and DCC. 
• The site clinician will assess the suicidal risk using the “Suicidality” module of the 
MINI, classify the individual’s risk as low, medium, or high, and manage as 
follows: 
o High (≥ 17 points): Arrange for immediate help 
o Medium (9-16 points): State concern for subject, encourage patient to 
contact provider, and provide three emergency telephone numbers. 
o Low (1-8 points):  Provide three emergency telephone numbers and suggest 
subject call the numbers if continued symptoms/concerns.  
10. Data Management 
10.1 Data Coordinating Center and Data Entry Overview 
The DCC will be based at the Center for Biomedical Statistics (CBS) at the University of 
Washington. Data collection and management of the clinical trial will be web-based and 
the DCC will support https-secured study-specific ‘.NET’ web page that will provide a 
centralized location for public information about the project for participants, 
investigators, and institutional agencies. The web page will contain a link to a study-
specific portal. Study personnel will log on to the private portal with individual 
Shibboleth-based user names and passwords to securely perform data management 
activities. Shibboleth is a standards-based, open source software package for web single 
sign-on across organizational boundaries. The web portal will serve as the wrapper for all 
data management tools and software utilized in the project, including: study ID 
assignment, screening, randomization, prospective data collection, and study operations 
reporting.  


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10.2 Computer and Data Security  
Access to research data will be restricted to study team members at each site and DCC 
personnel. The clinical recruitment sites will maintain a secure electronic database that 
links the study participant ID generated by the portal to participant contact information. 
Efforts made by clinical sites to contact patients for follow-up visits will be documented in 
this database. The database will be stored on a secure electronic server with user name and 
passwords log in for individual users and will be backed up nightly.  
10.3 Training Procedures 
After the planning phase and before the recruitment begins, a training session will be held 
to train study staff on data collection procedures, including orientation to the Manual of 
Operations, data entry and management principles, review of study interventions, and 
quality control procedures.  
10.4 Responsibilities of the Clinical Sites 
Each of the clinical sites will be responsible for maintaining a regulatory binder and 
maintaining source documents for all data entry. The web portal will generate queries 
and the sites will be responsible for completing these queries in a timely manner.  
11.  
Study Oversight 
The research will operate under the oversight provided by: 
• Data Safety and Monitoring Board (DSMB); 
• Patient Council; and  
• Stakeholder Council. 
The membership of each of these oversight bodies is listed in Appendix Four. Each of 
the bodies will review and approve the study protocol prior to implementation. Each of 
the three groups will develop a charter outlining their role in monitoring the progress of 
the study (The DSMB Charter and the Data Safety Monitoring Plan is available as 
Appendices Six and Seven, respectively). Each group will convene via a teleconference at 
least once every six months, or more frequently if deemed necessary.  
 
 
 


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open trial of antidepressant therapy. J Clin Psychiatry, 1989. 50(2): p. 60-3. 
54. 
Koo, J.R., et al., Treatment of depression and effect of antidepression treatment on 
nutritional status in chronic hemodialysis patients. Am J Med Sci, 2005. 329(1): p. 1-5. 
55. 
Lee, S.K., et al., The effects of antidepressant treatment on serum cytokines and nutritional 
status in hemodialysis patients. J Korean Med Sci, 2004. 19(3): p. 384-9. 
56. 
Turk, S., et al., Treatment with antidepressive drugs improved quality of life in chronic 
hemodialysis patients. Clin Nephrol, 2006. 65(2): p. 113-8. 
57. 
Wuerth, D., et al., Identification and treatment of depression in a cohort of patients 
maintained on chronic peritoneal dialysis. Am J Kidney Dis, 2001. 37(5): p. 1011-7. 
58. 
FDA Approved Labeling for Zoloft. 
59. 
Brewster, U.C., et al., Addition of sertraline to other therapies to reduce dialysis-associated 
hypotension. Nephrology (Carlton), 2003. 8(6): p. 296-301. 
60. 
Dheenan, S., et al., Effect of sertraline hydrochloride on dialysis hypotension. Am J Kidney 
Dis, 1998. 31(4): p. 624-30. 
61. 
Yalcin, A.U., et al., Sertraline hydrochloride treatment for patients with hemodialysis 
hypotension. Blood Purif, 2002. 20(2): p. 150-3. 
62. 
Cukor, D., et al., Course of depression and anxiety diagnosis in patients treated with 
hemodialysis: a 16-month follow-up. Clin J Am Soc Nephrol, 2008. 3(6): p. 1752-8. 
63. 
Weisbord, S.D., et al., Associations of depressive symptoms and pain with dialysis 
adherence, health resource utilization, and mortality in patients receiving chronic 
hemodialysis. Clin J Am Soc Nephrol, 2014. 9(9): p. 1594-602. 
64. 
Katon, W.J., et al., Collaborative care for patients with depression and chronic illnesses. N 
Engl J Med, 2010. 363(27): p. 2611-20. 


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65. 
Sheehan, D.V., et al., The Mini-International Neuropsychiatric Interview (M.I.N.I.): the 
development and validation of a structured diagnostic psychiatric interview for DSM-IV and 
ICD-10. J Clin Psychiatry, 1998. 59 Suppl 20: p. 22-33;quiz 34-57. 
66. 
Borson, S., et al., The mini-cog: a cognitive 'vital signs' measure for dementia screening in 
multi-lingual elderly. Int J Geriatr Psychiatry, 2000. 15(11): p. 1021-7. 
67. 
Trivedi, M.H., et al., Medication augmentation after the failure of SSRIs for depression. N 
Engl J Med, 2006. 354(12): p. 1243-52. 
68. 
Rush, A.J., et al., The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), 
clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients 
with chronic major depression. Biol Psychiatry, 2003. 54(5): p. 573-83. 
69. 
Wisniewski, S.R., et al., Self-rated global measure of the frequency, intensity, and burden of 
side effects. J Psychiatr Pract, 2006. 12(2): p. 71-9. 
70. 
Verbeke, G., Molenberghs, A, Linear Mixed Models for Longitudinal Data2000, New York: 
Springer. 
71. 
Littell, R.C., J. Pendergast, and R. Natarajan, Modelling covariance structure in the analysis 
of repeated measures data. Stat Med, 2000. 19(13): p. 1793-819. 
72. 
Schafer, J.L., Multiple imputation: a primer. Stat Methods Med Res, 1999. 8(1): p. 3-15. 
73. 
Hedayati, S.S., et al., Validation of depression screening scales in patients with CKD. Am J 
Kidney Dis, 2009. 54(3): p. 433-9. 
74. 
Siegel, J., Innovative Methods in Stakeholder Engagement: An Environmental Scan. 2012. 
 
 
 
 


 
 
 
 
Version: V2.6, 16-June-2017 
 
Appendix One: 
Study Schedule 
 
Pre-
Screen 
Engagement 
Comparative Effectiveness of Treatment of Depression 
Screen 
Interview 
Screen 
ON STUDY 
Post-
Study 
WEEK 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Eligibility Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Information Sheet 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI-II 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI (7 modules) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess suicidal risk 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
Cognitive Function 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Health Literacy 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 1 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Engagement Interview/Control Visit  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Preferences 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Accepts Study Treatments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 2 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
HD treatment adherence 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Laboratory Test Results 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
CBT 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
Sertraline Dispense 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
Monitor Adherence to Sertraline 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
QIDS-SR 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
QIDS-C 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
FIBSER 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
CATI 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Semi-Structured Interview 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Does Not Accept Treatment 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 


 
 
 
 
Version: V2.6, 16-June-2017 
 
Appendix Two: Highest Dose Level Eligible for Enrollment 
Upper limit of doses for anti-depressant drugs for including patients in the clinical trial. 
Generic Name 
Brand Name 
Upper Dose limit for inclusion 
Selective Serotonin Reuptake Inhibitors (SSRI) 
sertraline 
Zoloft 
25 mg daily*** 
paroxetine 
Paxil, Pexeva 
10 mg daily*** 
fluoxetine 
Prozac 
10 mg daily*** 
fluvoxamine 
Luvox 
50 mg daily*** 
vortioxetine 
Brintellix 
5 mg daily*** 
citalopram 
Celexa 
10 mg daily*** 
escitalopram 
Lexapro 
5 mg daily*** 
Serotonin Norepinephrine Reuptake Inhibitors (SSRI/SNRI) 
duloxetine 
Cymbalta 
30 mg daily*** 
reboxetine 
Norebox 
2 mg daily*** 
venlafaxine 
Effexor or Effexor XR 
Extended release 75 mg daily; 
immediate release 75 mg twice daily*** 
desvenlafaxine 
Khedezla, Pristiq 
50 mg daily*** 
Other Antidepressants 
trazodone 
Desyrel, Oleptro 
100 mg daily or 50 mg twice daily 
nefazodone 
Serzone 
100 mg daily or 50 mg twice daily 
vilazodone 
Viibryd 
10 mg qd daily 
bupropion 
Aplenzin, Wellbutrin 
100 mg twice daily 
mirtazapine 
Remeron 
15 mg daily 
milnacipran 
Savella 
50 mg daily 
levomilnacipran Fetzima 
20 mg daily 
buspirone 
Buspar 
10 mg daily or 5 mg twice daily 
imipramine 
Tofranil 
25 mg daily 
clomipramine 
Anafranil 
25 mg daily 
desipramine 
Norpramin 
25 mg daily 
trimipramine 
Surmontil 
25 mg daily 
amoxapine 
Aventyl, Asendin 
50 mg daily 
amitriptyline 
Endep, Elavil, Etrafon, 
Limbitrol, Triavil 
50 mg daily 
nortriptyline 
Asendin HCI, Pamelor 
50 mg daily 
protriptyline 
Vivactil 
5 mg daily 
doxepin 
Adapin, Sinequan 
25 mg daily 


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Appendix Three: Measurement Based Care Protocol 
Week Clinical Status 
Recommended Sertraline Dosing 
 
QIDS-SR  
 
0 
 
 
Initiate sertraline treatment: 25 mg/d x 1 week, 
then 50 mg/d x 1 week 
2 
≤ 5 
Remission 
(FIBSERB , < 5) 
Increase dose to 100 mg/d 
 
 
Remission  
(FIBSERB , ≥ 5) 
Continue current dose and address SEs 
 
6-8 
Partial 
Response 
(FIBSERB , < 5) 
Increase dose to 100 mg/d 
 
 
Partial 
Response 
(FIBSERB , ≥ 5) 
Continue current dose and address SEs 
 
≥ 9 
Non-Response  
(FIBSERB , < 5) 
Increase dose to 100 mg/d 
 
 
Non-Response  
(FIBSERB , ≥ 5) 
Continue current dose and address SEs 
4 
≤ 5 
Remission 
(FIBSERB , < 5) 
Increase dose by 50 mg/d since last visit 
 
 
Remission  
(FIBSERB , ≥ 5) 
Continue current dose and address SEs OR 
Decrease dose by 50 mg 
 
6-8 
Partial 
Response 
(FIBSERB , < 5) 
Increase dose by 50 mg/d since last visit 
 
 
Partial 
Response 
(FIBSERB , ≥ 5) 
Continue current dose and address SEs OR 
Decrease dose by 50 mg 
 
≥ 9 
Non-Response  
(FIBSERB , < 5) 
Increase dose by 50 mg/d since last visit 
 
 
Non-Response  
(FIBSERB , ≥ 5) 
Continue current dose and address SEs OR 
Decrease dose by 50 mg 
6 
≤ 5 
Remission 
(FIBSERB , < 5) 
If sertraline dose < 150 mg, increase by 50 mg 
If sertraline dose ≥ 150 mg, continue current 
dose 
 
 
Remission  
(FIBSERB , ≥ 5) 
Continue current dose and address SEs OR 
Decrease dose by 50 mg 
 
6-8 
Partial 
Response 
(FIBSERB , < 5) 
Increase dose by mg (max. 200 mg/d) 


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Partial 
Response 
(FIBSERB , ≥ 5) 
Continue current dose and address SEs OR 
Decrease dose by 50 mg 
 
≥ 9 
Non-Response  
(FIBSERB , < 5) 
Increase dose by mg (max. 200 mg/d) 
 
 
Non-Response  
(FIBSERB , ≥ 5) 
Continue current dose and address SEs OR 
Decrease dose by 50 mg 
9 
≤ 5 
Remission 
(FIBSERB , < 5) 
Continue current dose 
 
 
Remission  
(FIBSERB , ≥ 5) 
Continue current dose and address SEs OR 
Decrease dose by 50 mg 
 
6-8 
Partial 
Response 
(FIBSERB , < 5) 
Continue current dose 
 
 
Partial 
Response 
(FIBSERB , ≥ 5) 
Continue current dose and address SEs OR 
Decrease dose by 50 mg 
 
≥ 9 
Non-Response  
(FIBSERB , < 5) 
Continue current dose 
 
 
Non-Response  
(FIBSERB , ≥ 5) 
Continue current dose and address SEs OR 
Decrease dose by 50 mg 
12 
 
 
Begin drug taper at rate of 50 mg/week until 
discontinued 
 
 


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Appendix Four:  Membership of Oversight Groups 
 
Data Safety Monitoring Board (DSMB) 
 
Alan Kliger (Chair), Yale University, New Haven, CT 
 
Michael Hollifield, VA Long Beach Health Care System, Long Beach, CA 
 
J Richard Landis, University of Pennsylvania, Philadelphia, PA 
 
Michael Rocco, Wake Forest University, Winston-Salem, NC 
 
Suzanne Watnick, Oregon Health Sciences Center, Portland, OR 
 
Patient Council 
 
Lori Hartwell (Chair) 
 
Monica Alfonzo 
 
Richard Blaine 
 
Diana Headlee 
 
Linda Oakford 
 
Heather Powell 
 
Glenda Roberts 
 
Nancy Spaeth 
 
Cal Sturdivant 
 
 


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Stakeholder Council  
 
Organization 
Representative 
Patient Organizations 
American Association of Kidney 
Patients 
Gary Green 
Diana Clynes 
Dialysis Patient Citizens 
Hrant Jamgochian 
Nancy L Scott 
Dialysis Providers 
DaVita 
Allen Nissenson 
Fresenius Medical Care 
Ravi Thadhani 
Ann Mooney 
Northwest Kidney Centers 
Leanna B. Tyshler 
Renal Ventures 
Tom Parker (Chair) 
Research 
National Institutes of Health 
Robert Star 
Clinical Professionals’ 
Representatives 
American Nephrology Nurses 
Association 
Leslie Dork 
Council for Nephrology Social 
Workers 
Leanne Peace 
National Renal Administrators’ 
Association 
Debbie Cote 
Helen Currier 
Nephrologists 
Greg Braden 
Arti Gupta 
Fred Finkelstein 
Psychiatrist 
Lewis Cohen 
 
 
 
 
 


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Appendix Five CBT manual Pages 1-4 
 
   
 


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CBT manual Pages 5-8 
   
  
 


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CBT manual Pages 9-12 
                 
 
     


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CBT manual Pages 13-16 
         
 
 
 


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CBT manual Pages 17-20 
       
 


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CBT manual Pages 21-24 
    
 


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CBT manual Pages 25-28 
Forms 
 
 
      
 


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CBT manual Pages 29-32 
       
 
      
 
 
 


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CBT manual Pages 33-37 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix Six: DSMB Charter 
 
Data and Safety Monitoring Board (DSMB) Charter 
Title: A Trial of Sertraline and CBT in End-stage Renal Disease Patients with 
Depression (ASCEND) Randomized Controlled Trial 
 
 
Funder Name: 
Patient Centered Outcomes Research Institute (PCORI) 
Principal 
Investigator: 
Rajnish Mehrotra, MD MS 
Date of Document: 
03/29/2017 
 
Version: 
1.1 
 
Reviewed and Accepted by DSMB Members: 
 
Alan Kliger, MD (Chair) 
Date 
Michael Hollifield, MD 
Date 
J Richard Landis, PhD (Biostatistician) 
Date 
Michael Rocco, MD 
Date 
Suzanne Watnick, MD 
Date 
Reviewed and Accepted by Funder by: 
 
Julie McCormack, MA, Project Officer 
Date 
 
 


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Terms used in this document related to the Data Safety Monitoring Board 
activities 
Term 
Definition 
Blinding Status 
Blinded 
Access to aggregate (i.e., total) results only. 
Semi-Blinded 
Access to results split by randomized treatment arm, but without 
knowledge of the actual treatment assignment (i.e., Treatment A 
versus Treatment B) 
Unblinded 
Access to the decode information for A and B as described in the 
Semi-Blinded definition 
Individuals and Groups 
Data Safety 
Monitoring Board 
(DSMB) 
Unblinded 
An independent group charged with monitoring the safety of 
patients in the ASCEND trial, and the scientific integrity of the 
trial 
Funder 
Initially Blinded 
The Funder is the organization that provides funding and other 
support, and oversees trial implementation. 
Principal 
Investigator 
Initially Blinded 
Prepared and Accepted by: 
 
Rajnish Mehrotra, MD MS, Principal Investigator for the 
ASCEND Trial  
Date 
Patrick Heagerty, PhD, Coordinating Center Statistical 
Advisor 
Date 
Tessa Rue, MS, Unblinded Coordinating Center 
Statistician 
Date 


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The Principal Investigator is the physician who serves as the 
scientific leader of the trial 
Coordinating 
Center / Study 
Management Team 
Initially Blinded 
The Coordinating Center and Study Management Teams are 
responsible for trial logistics, including interaction with sites, data 
collection and cleaning, supply of study materials and updates to 
the Funder. 
 Unblinded 
Coordinating 
Center Statistician* 
Initially Unblinded 
The unblinded statistician who prepared the Closed Report 
Coordinating 
Center Statistical 
Advisor** 
Initially Semi-Blinded 
The semi-blinded statistician who will assist with the 
interpretation of the Closed Report. 
Open and Closed Report, Session, Minutes 
Open 
The Open Session may be attended by all groups described above. 
The Open Report will be discussed, and Open Minutes will be 
recorded. 
Closed 
The Closed session may be attended by semi-blinded and 
unblinded persons only. The (Semi-Blinded) Closed Report will 
be discussed, and Closed Minutes will be recorded. 
* The Unblinded Coordinating Center Statistician is unblinded, but has no contact with 
patients or the day-to-day study activities.  
** The Coordinating Center Statistical Advisor is semi-blinded, but has no contact with 
patients or the day-to-day study activities. 
 
 
 


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A Trial of Sertraline and CBT in End-stage Renal Disease Patients with Depression 
(ASCEND) 
Data and Safety Monitoring Board (DSMB) Charter 
Table of Contents 
Part 1: Introduction 62 
1.1 
Charge to the DSMB 62 
1.2 
 Protocol Summary 62 
1.3 
 DSMB Membership and Responsibilities 63 
1.3.1 
DSMB Chair 64 
1.3.2 
DSMB Statistician 
65 
1.4 
Responsibilities of the Study Management Team and Coordinating Center 65 
1.4.1 
Principal Investigator 
65 
1.4.2 
Unblinded Coordinating Center Statistician 
65 
1.4.3 
Coordinating Center Statistical Advisor 66 
Part 2:  Procedures of the DSMB 
66 
2.1 
Blinding 
66 
2.2 
DSMB Report 66 
2.3 
Scheduled DSMB Meetings 67 
2.4 
DSMB Meeting Structure 
68 
2.4.1 
Open Session 68 
2.4.2 Closed Session 
68 
2.4.3 Executive Session 
68 
2.5 
DSMB Recommendations 69 
2.6 
Meeting Minutes 
69 


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2.6.1 
Open Minutes 
69 
2.6.2 Closed Minutes 
70 
Part 3: Appendices 71 
Appendix 1:  Rosters and Contact Information 
71 
 
Part 1: Introduction 
The Data and Safety Monitoring Board (DSMB) will be responsible for assessing safety 
and efficacy during conduct of the ASCEND trial, as well as ensuring the validity and 
scientific merit of the trial.  This charter describes the roles and responsibilities of the 
DSMB for this trial.  The DSMB will meet on a regular basis, and will provide 
recommendations to the Principal Investigator for the ASCEND study on whether to 
continue, modify, or terminate the study.  
1.1 
Charge to the DSMB 
The DSMB will monitor the conduct of the study and review interim results for the 
purpose of recommending whether or not to continue the trial as designed. The 
fundamental responsibilities of the DSMB are to assure: 
• The ongoing safety of study participants, and  
• The scientific integrity of the trial. 
In addition, the DSMB will use established guidelines to monitor the study for important 
safety variables suggesting harm.  
The DSMB is also charged to recommend whether to continue the study, terminate the 
study, continue the study with major or minor modifications (such as modifications to 
inclusion/exclusion criteria or criteria to determine eligibility for cross-over), or 
temporarily suspend enrollment and/or treatment in the study until uncertainty is 
resolved. 
1.2 
 Protocol Summary 
The ASCEND study is a two phase randomized, controlled trial randomizing 200 
depressed patients undergoing hemodialysis to receive either engagement interview or 
control visit, and the second phase randomizing 120 patients accepting intervention, to 


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either CBT or drug therapy. Those who do not accept treatment are followed 
observationally.  The goals of this study are to 1) evaluate the impact of an engagement 
interview on receiving treatment; and 2) compare the effectiveness of treatments for 
depression in patients undergoing hemodialysis.  The primary outcome for the first 
randomization will be at 6 weeks post-randomization assessing treatment (either 
psychotherapy or drug therapy) uptake.  The primary outcome for the second 
randomization will be at 12 weeks post-randomization assessing depressive symptoms. 
With N=200 patients, the ASCEND study will have 80% power to detect a 15% difference 
in uptake between the engagement interview group (55%) and the control visit group 
(40%). The primary analysis will employ logistic regression adjusting for recruitment site 
to compare the proportions of patients who initiate treatment for depression between the 
engagement interview and control visit groups. 
For the second phase of the trial (N=120), the study is powered on the Quick Inventory of 
Depressive Symptomatology-Clinician rated (QIDS-C) score, as measured at the primary 
study endpoint of 12 weeks.  The QIDS-C is a 16-item questionnaire used to assess 
depressive symptoms.  The primary analysis will utilize analysis of covariance (ANCOVA) 
to compare CBT to Sertraline with the following analysis parameters: 85% follow-up at 12 
weeks; two-sided Type 1 error rate of alpha=0.05; adjustment for recruitment site, first 
randomization, and the QIDS-C baseline score.  Depending on the within-person 
correlation from baseline to 12 weeks (estimated range .4-.7), the study will have 80% 
power to detect an effect size of 0.40(r=0.7) – 0.51 (R=0.4).   
1.3 
 DSMB Membership and Responsibilities 
The DSMB is an independent multidisciplinary group consisting of four clinicians in the 
fields of nephrology and psychiatry and one biostatistician who collectively have 
experience in the treatment of subjects with depression, and/or experience with care for 
patients with end stage renal disease, and/or in the conduct and monitoring of 
randomized clinical trials.  The duration of membership will span until six months after 
the end of patient recruitment.   
All DSMB Members have agreed by contract that proceedings from DSMB meetings and 
related activities are confidential.  DSMB Members will not act as investigators or sub-
investigators for these trials and will have no trial involvement outside their role on the 
DSMB.   
No Member of the DSMB will be an employee of PCORI.  DSMB Members must disclose 
all active agreements (direct or indirect) with pharmaceutical companies, biotechnology 


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companies, or contract research organizations.  Members of the DSMB will be responsible 
for advising the Board of any changes in their financial interests in the aforementioned 
companies. 
The DSMB membership has been restricted to individuals free of apparent significant 
conflict of interest.  The source of conflict may be financial, scientific and/or regulatory in 
nature.  Thus, neither study investigators nor individuals employed by the funder or 
regulatory agencies are to be Members of the DSMB. 
The DSMB will be responsible for deciding whether consultant agreements or financial 
interests of the members have the potential for conflict of interest.  Members of the 
DSMB who develop significant potential or perceived conflicts of interest will be asked to 
resign from the committee. 
The DSMB Members and Chair are listed in Appendix 1. 
 
As part of this study, the DSMB is established to provide an independent review and 
assessment of the accumulating safety and efficacy data, and to further safeguard the 
interests and safety of the participating subjects. The primary role of the DSMB is to make 
a recommendation to the Principal Investigator based on analysis of available data. 
The objective of the DSMB is to independently monitor and assess the study.  At each 
interim meeting, the DSMB will undertake a comprehensive review and assessment of the 
cumulative study safety data.  The DSMB will determine if safety of sertraline is sufficient 
to allow the trial to continue.  The DSMB will use a priori defined, and, where 
appropriate, ad hoc analyses to assess safety. The DSMB will utilize all available trial data 
when forming any recommendation to discontinue the study or unblind the results.  The 
Study Management Team will consult with the DSMB as needed on substantive changes 
to the protocol or study conduct once the trial begins. 
The DSMB will be responsible for ensuring the timely review of the accumulated safety 
data.  Based on the reviews and assessments of the data, the DSMB will inform the 
Principal Investigator of any safety concerns and will provide recommendations for 
appropriate actions. 
1.3.1 
DSMB Chair 
The DSMB Chair will have the following additional responsibilities: chair the meeting, 
confirm quorum, summarize recommendations, set an agenda for the Closed Session of 
the meeting, and record Open and Closed Minutes of the DSMB meetings. If a DSMB 


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member can no longer continue, the Chair is responsible for selecting his or her 
replacement. 
1.3.2 
DSMB Statistician  
The DSMB statistician will provide guidance to the voting Members of the DSMB on 
issues of a statistical nature. 
1.4 
Responsibilities of the Study Management Team and Coordinating Center 
The Coordinating Center and Study Management Team work in tandem but are distinct 
entities.  Representatives from the Study Management Team are charged with the day-to-
day management of the trial; the Unblinded Coordinating Center Statistician and 
Coordinating Center Statistical Advisor are not involved in these activities and have no 
contact with sites or patients.  The Study Management team and their roles are listed in 
Appendix. 
The Study Management Team is responsible for providing timely and accurate data to the 
Unblinded Coordinating Center Statistician for inclusion in reports to the DSMB.  In 
addition, the Study Management Team will review the Open Report and may present 
information about the status of the trial and any issues related to study execution during 
the Open Session. The Study Management Team must maintain an up-to-date, accurate 
study database by such processes as retrieving CRFs promptly, entering and validating the 
data, querying suspicious data, and coding adverse events. 
1.4.1 
Principal Investigator 
The Principal Investigator for the ASCEND study will be the physician leading the 
conduct of the clinical trial, and will oversee activities of the Study Management Team.  
The Principal Investigator must set an agenda for the Open portion of the meeting, and 
will receive the recommendations of the DSMB. The Principal Investigator will distribute 
the recommendations to the Study Management Team, Internal Review Boards, and 
others as appropriate. 
1.4.2 
Unblinded Coordinating Center Statistician 
The Unblinded Coordinating Center Statistician must produce and validate the DSMB 
report, keeping any potentially unblinding information confidential and out of reach of 
other members of the coordinating center (with the exception of unblinded 
programmers). This individual will also be responsible for delivering the Open and Closed 
Reports to the DSMB. 


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The Unblinded Coordinating Center Statistician will be responsible for getting approval 
from the DSMB in the event that personnel directly associated with the study must be 
given information that could potentially unblind them. 
1.4.3 
Coordinating Center Statistical Advisor 
The Coordinating Center Statistical Advisor must review and present the Closed Report 
during the Closed Session and answer questions from the DSMB that are of a statistical 
nature, or other questions as deemed appropriate by the DSMB.  
Due to potential for bias, the Coordinating Center Statistical Advisor should not make 
study design decisions after viewing the semi-blinded results; after the first data review, 
such decisions should be made by a blinded person as appointed by the Principal 
Investigator.  
Part 2: Procedures of the DSMB 
2.1 
Blinding 
The DSMB will be unblinded in its assessment of safety data.  The DSMB will have full 
access to all data as needed for safety assessment and will have access to comparative 
results of safety data, aggregated by treatment arm.  
To maintain the integrity of the trial, the Funder, Principal Investigator and the study 
investigators will not have access to any unblinded or semi-blinded summaries of interim 
data prior to the conclusion of the trial and the final database lock.  Access to semi-
blinded information will be restricted to the DSMB and Unblinded Coordinating Center 
Statistician and Coordinating Center Statistical Advisor.  The Unblinded Coordinating 
Center Statistician will generate an Open Report that includes aggregate information and 
a Closed Report that includes unblinded information by randomized treatment 
assignment.  
The DSMB may direct questions and request further data from the Unblinded 
Coordinating Center Statistician, Coordinating Center Statistical Advisor or Study 
Management Team directly. The DSMB will determine what is communicated to blinded 
persons regarding additional requests. 
2.2 
DSMB Report 
The DSMB Report should provide information that is accurate to the extent possible, 
although all data will not be clean.  Follow-up should be complete, if possible, to within 
three months of the date of the DSMB meeting, and the data snapshot should occur 


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approximately one month in advance of the meeting.  Some "last-minute" data (e.g., 
Serious Adverse Events, Enrollment, and Follow-up Rates) will be even more current.  
The reports should be sent to the DSMB Members at least eleven days prior to the date of 
the meeting.  Based upon the enrollment rate, the Study Management team will 
determine target dates for the DSMB meetings.  The report will be based mainly on 
monitored data, but will include all safety data available at the time the report is 
prepared.   If major changes occur due to data corrections, those changes will be 
highlighted in future DSMB Reports.   
Each DSMB Report will have two main sections:  an Open Section (blinded information) 
that contains information on recruitment, eligibility violations, baseline characteristics, 
data on completeness of follow-up and compliance, and other study management issues; 
and a Closed Section (unblinded information) which contains safety information 
displayed by treatment arm, analyses of Adverse Events, and efficacy data based on 
intent-to-treat analyses of primary endpoints.  The details of these reports can be found 
in the Data Safety Management Plan (DSMP).  DSMB Members will receive both the 
Open and Closed Sections of the Report.  The Principal Investigator may communicate 
information from the Open Section of the DSMB Report to the Study Management Team. 
This DSMB Report will be assembled by Unblinded Coordinating Center Statistician in 
consultation with the Coordinating Center Statistical Advisor. 
DSMB Members will return their Closed Reports to the Coordinating Center Statistical 
Advisor at the conclusion of each DSMB meeting.  The DSMB may retain their copies of 
the Open Report.  Open and Closed Minutes are recorded by the Chair of the DSMB.  
Copies of the Open Minutes are distributed to the Principal Investigator and DSMB.  
Copies of the Closed Minutes are distributed only to the DSMB, and are archived by the 
chair until after the study database has been locked and treatment results unblinded. 
The DSMB may wish to request clarification on existing reports or additional information.  
The Unblinded Coordinating Center Statistician will create ad hoc reports to address 
these questions. The Study Management Team and other persons may be informed about 
these ad hoc requests at the discretion of the DSMB. 
2.3 
Scheduled DSMB Meetings 
The following table depicts a proposed meeting schedule for the DSMB.  This schedule 
can be altered as necessary by the Principal Investigator or DSMB.  Alterations will be 
attached in Appendix 2 and will not require amendment to this charter. 
 


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Proposed 
Meeting Date 
Function 
Estimated 
Number of 
Subjects in Study 
Jul 2015 
Safety Looks 
50/22 
Jan 2016 
Safety Looks 
150/67 
Jul 2016 
Safety Looks 
250/112 
Jan 2017 
Safety Looks 
350/157 
 
Unscheduled DSMB meetings can be called as necessary by the DSMB.  To call an 
unscheduled meeting, the DSMB Chair will contact the Coordinating Center Statistical 
Advisor.  Typically, the Principal Investigator will not be told the reason for the meeting.  
Information to be communicated to the Principal Investigator regarding the meeting is 
determined by the DSMB. 
2.4 
DSMB Meeting Structure 
The meetings will typically begin with an Open Session, followed by a Closed Session. All 
Closed Sessions will also include an Executive Session. There may also be a final open 
session where the DSMB may verbally give recommendations and answers questions from 
the Principal Investigator and Study Management Team.  
2.4.1 
Open Session 
In order to allow the DSMB to have adequate access to insights from the Study 
Management Team, an Open Session of the DSMB meeting will be held during each 
DSMB meeting.  Members of the Study Management Team, and other persons as needed, 
may be present during the Open Sessions (either in person or by telephone). The blinded 
information covered in the Open Session will be contained in the Open Report. 
2.4.2 Closed Session 
Closed DSMB Sessions involving only DSMB Members and the Coordinating Center 
Statistical Advisor will be held after the Open Session to allow discussion of unblinded 
data from the Closed Report.  The information covered in the Closed Session will be 
contained in the Closed Report.  
2.4.3 Executive Session 


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Executive DSMB Sessions involving only DSMB Members will be held to allow discussion 
of study data without the members of the study team present. 
A representative of the Funder may be present at DSMB open sessions unless the DSMB 
Chair decides that the presence will inhibit free and open discussion or appear to 
compromise the DSMB’s independence.  The Funder may be permitted to attend Closed 
and Executive Sessions at the discretion of the DSMB Chair. 
2.5 
DSMB Recommendations 
During the DSMB meetings, issues relating to subject safety and scientific integrity of the 
trial will be reviewed and discussed.  Afterward, the DSMB may hold a brief meeting with 
the Principal Investigator to review the status of the study and make its 
recommendations.  These recommendations will primarily use the guidelines defined in 
this Charter or the DSMP.  The DSMB will also make recommendations, as appropriate, 
regarding the conduct and management of the trial.  
A quorum, defined as 3 DSMB Members including the Chair, must be present or available 
by teleconference in order for the DSMB to make any formal recommendations. Further, 
a recommendation to stop the trial must be made by a majority vote of the DSMB (i.e., 
either unanimously or four to one in favor of the recommendation). Other 
recommendations may be made by simple majority. 
Any recommendations which could compromise the blind will be communicated in 
writing to the Principal Investigator within 5 business days of the meeting.  
In the event that the study is recommended to be terminated, the Coordinating Center 
Statistical Advisor and the Principal Investigator will meet with the DSMB to review the 
semi-blinded report and discuss the reasons for this recommendation. At this time the 
Principal Investigator may become semi-blinded before deciding whether to accept the 
recommendation to terminate the study.  
2.6 
Meeting Minutes 
2.6.1 Open Minutes 
The Open Session Minutes will be recorded by the DSMB Chair and will summarize the 
DSMB's findings during the Open Session in addition to the overall recommendation 
from the Closed Session discussions as to whether the trial should continue, continue 
with modifications or be terminated.  A copy of the Open Minutes will be sent to the 


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Principal Investigator, who will disseminate the recommendations to the Study 
Management Team as appropriate.  
These Open Session Minutes must be devoid of any statements having the potential to 
compromise the blinding of the study, since these minutes will be distributed to the 
Principal Investigator.   
At a minimum, the following question should be addressed by the DSMB: 
• Does the DSMB feel that it is ethical to continue the trial as presently designed? 
The results of deliberations should be communicated to the Principal Investigator in 
writing following the meeting.  
2.6.2 Closed Minutes 
The Closed Session Minutes will be recorded by the DSMB Chair and will summarize the 
discussion of the semi-blinded data and other issues the DSMB wishes to document but 
keep in confidence.  
 
 
 
 


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Part 3: Appendices to Charter 
Appendix 1:  Rosters and Contact Information 
DSMB 
Name 
Address 
E-mail address 
Alan Kliger, MD 
(Chair) 
Yale University 
New Haven, CT 
alan.kliger@ynhh.org 
 
Michael Hollifield, 
MD 
VA Long Beach Health 
Care System 
Long Beach, CA 
Michael.Hollifield@va.
gov 
J Richard Landis, 
PhD 
University of 
Pennsylvania 
Philadelphia, PA 
landisjr@mail.med.upe
nn.edu 
Michael Rocco, MD 
Wake Forest University 
Winston-Salem, NC 
mrocco@wakehealth.e
du 
Suzanne Watnick, 
MD 
Oregon Health 
Sciences Center, 
Portland, OR 
watnicks@ohsu.edu 
 
Funder 
Funder Project Officer 
Name 
Address 
E-mail address 
Julie McCormack, 
MA 
PCORI 
Washington, DC  
jmccormack@pcori.org 
 
 


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Study Management Team and Coordinating Center 
Name 
Address 
E-mail address 
Phone & fax 
Principal Investigator for the ACEND Trial 
Rajnish Mehrotra, 
MD MS 
 
University of 
Washington 
Seattle, WA  98195-
6490 
mehrotr@uw.edu 
P: 206-744-
4933 
F: 206-744-
2252 
 
Unblinded Coordinating Center Statistician 
Tessa Rue, MS 
University of 
Washington 
Seattle, WA 98195-
9461 
ruet@uw.edu 
 
P: 206-543-
4246 
F: 206-543-5881 
Semi-blinded Coordinating Center Statistical Advisor 
Patrick Heagerty, 
PhD 
University of 
Washington Seattle, 
WA 98104-7232 
heagerty@uw.edu 
P: 206-616-
2720 
F: 206-543-
3286 
 
 


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Appendix Seven: Data Safety and Monitoring Plan 
1. Overview 
This Data Safety and Monitoring Plan (DSMP) defines the oversight and monitoring 
activities that will ensure and maintain both the safety of participants and the scientific 
integrity and validity of the trial data. The plan also describes the procedures for adverse 
event reporting and details guidelines for recommendations related to trial continuance.  
2. Data and Safety Monitoring Board 
Review of the ASCEND trial’s study performance and safety outcomes will be conducted 
by the Data Safety and Monitoring Board (DSMB). The DSMB consists of 5 members, 
(Chair: Dr. Alan Kliger MD, Dr. Michael Hollifield MD, Dr. J Richard Landis, PhD, 
Dr. Michael Rocco, MD, Dr. Suzanne Watnick, MD). The DSMB is expected to meet 
twice annually (every 6 months) to review study performance and safety outcomes in 
Open and Closed Reports, and to review study enrollment reports quarterly. Ad hoc 
sessions may be scheduled as required should a serious adverse event need to be reviewed 
as a group.  
Aggregate study performance and safety data will be presented during the open sessions 
of DSMB meetings. Safety and efficacy data will be presented by treatment arm during 
the closed sessions. Review by the DSMB provides assurances that the trial can continue, 
without jeopardizing patient safety. The DSMB is also responsible for protecting the 
confidentiality of the trial data and for monitoring the quality of both the data and study 
implementation procedures.   
3. Study Sample Size and Design  
Each recruitment site will enroll approximately 133 patients. The first randomization is 
block randomized on site, with random size block assignment within site to maintain 
balance between treatment groups. The second randomization is blocked on site and on 
treatment arm (engagement interview or control visit).   
Randomized evaluation of an engagement interview will be conducted with up to 400 
patients. In the pilot studies, 40% of HD patients accepted treatment for comorbid 
depression and the engagement interview increases the rate by 10-20. In order to have 
80% power to detect a difference in proportions of 40% versus 55% (a 15% increase) we 
would need to enroll 100 patients per arm, or a total of 200 participants. Therefore our 
study design is well powered to detect the anticipated effect of an engagement interview.  


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The sample size for the randomized comparison of Sertraline to CBT is 120 patients. The 
serial correlation in self-reported depression scales in data from published and 
unpublished studies in HD patients or those with advanced kidney disease by members of 
this consortium, over approximately 12 weeks, typically ranges between R = 0.40 and 0.70. 
Assuming a loss- to-follow-up of ≤ 15%, 120 randomized participants will provide 80% 
power with 2-sided α = 0.05 to detect a difference in the mean 12-Week QIDS-C between 
the treatment groups of between 0..40 (if R = 0.70) and 0.51 (if R = 0.40) of 1 standard 
deviation in the QIDS-C. This range of detectable effect sizes is well within the range of 
differences observed in the randomized and non-randomized trials of CBT or anti-
depressant drug therapy for comorbid depression in HD patients. Moreover, the 
magnitude of effect size that is detectable is in the range of what is considered to be a 
clinically meaningful improvement in depressive symptoms. Smaller effect sizes may exist 
that may be statistically significant in larger studies. However, they are unlikely to be 
clinically meaningful or relevant to patients in the selection of treatment options.   
4. Monitoring Guidelines  
Based on findings following review of study data by the DSMB, the Board may 
recommend: continuation of the trial, termination of the trial, or modifications to the 
protocol (e.g. adding new measurements for safety monitoring, discontinuing high risk 
subjects, extending the trial in time, increasing the trial sample). Decision guidelines in 
the ASCEND trial are based on group differences in adverse event rates as explained 
below.  
4.1 Performance Monitoring  
Performance monitoring will be an ongoing activity performed by the study principal 
investigator and statistician, and status reports will be reviewed by the DSMB during their 
regular meetings. Procedural reviews to address protocol compliance with respect to 
subject recruitment and eligibility, retention and follow-up, randomization and blinding, 
and quality of data will be conducted and monthly reports generated. Any protocol 
violation that affects patient safety will be reported to the DSMB immediately. 
Performance data will be reviewed in aggregate and by site. It is expected that: 
(1) the overall enrollment rate will not drop below the expected rate (15 patients 
per month for 24 months) by more than 50%. 
(2) missing treatment uptake will be no greater than 15% at the six-week follow-up; 
(3) the response rate for the QIDS-C will be no less than 85% at the 12-week time-
point among those randomized to Sertraline or CBT;  


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Data will be entered on-line into a REDCap database hosted at the Data Coordinating 
Center (DCC).  Data will be entered into fields with automated validation and logical 
checks built in.  Outcome measures will be collected by Computer Assisted Telephone 
Interview (CATI).  Compliance will be assessed based on the weekly conference calls and 
data submitted to the DCC on a weekly basis.  If it is determined by the study PI that 
either study protocol is not being followed or that reporting is inadequate at any site, 
further action will be taken to address these issues.  These actions may include additional 
in-person site visits if appropriate or additional educational/problem-solving sessions by 
phone or in person regarding the study protocol.  Compliance rates and any concerns 
regarding deviation from study protocol will be reported to the DSMB on a quarterly basis 
for review and determination if additional measures need to be employed such as 
protocol changes or discontinuing enrollment at that site.  
The ASCEND study aims to enroll up to 400 subjects with the following distribution 
among the sites: 167 subjects each at Seattle and Dallas and 66 subjects at Albuquerque. 
We plan to start screening subjects on March 17, 2015 and stop recruitment on March 16, 
2017. Tables 1 and 2 and Figure 1 are performance monitoring examples that will be 
included in future Open DSMB Reports. 
Table 1. Cumulative and Current Report Period Study Recruitment  
 
Current Report Period  
Cumulative 
Site 
Seattle 
Dallas Albuquerque 
Total 
 
Seattle 
Dallas Albuquerque 
Total 
Screened 
 
 
 
 
 
 
 
 
Eligible 
 
 
 
 
 
 
 
 
Enrolled 
 
 
 
 
 
 
 
 
Accepted 
treatment, 
randomized to 
CBT or 
Sertraline 
 
 
 
 
 
 
 
 
Not accepting 
treatment 
 
 
 
 
 
 
 
 
Table 2. Follow-up rates by site, n / N (%).  
 
Seattle Dallas 
Albuquerque 
Total 
Treatment uptake assessed at 6 weeks 
 
 
 
 
Accepted treatment, randomized to CBT or 
Sertraline 
 
 
 
 
     CATI assessment completed at 12 weeks 
 
 
 
 
Not accepting treatment 
 
 
 
 
     CATI assessment completed at 12 weeks 
 
 
 
 


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Figure 1. Cumulative Enrollment. 
 
Follow up rates will be further tabulated by treatment arm in the Closed DSMB report. 
Table 3. Follow-up rates by group, n / N (%)(closed report).  
12 week CATI assessment completed 
A 
B 
Total 
     Randomized to A’ 
 
 
 
     Randomized to B’ 
 
 
 
     Not accepting treatment 
 
 
 
     Total 
 
 
 
A/B blinding designations for engagement interview or control 
A’/B’ blinding designations for CBT or Sertraline 
4.2 Safety Monitoring:  
Safety reports will summarize adverse and serious adverse event data and will be reviewed 
at regular and ad hoc DSMB meetings. A serious adverse event is defined as any 
experience that is fatal or life-threatening, is permanently disabling, or requires inpatient 
hospitalization.  
Patients undergoing hemodialysis experience a large number of adverse events from their 
underlying health, co-existing illnesses, and concomitant medications. These adverse 
events include death, fluid overload, congestive heart failure, vascular access events such 
as thrombosis or infection or dysfunction, atherosclerotic cardiovascular events, 
infections such as pneumonia, and laboratory abnormalities such as anemia, 
hyperphosphatemia, and hyperparathyroidism. Adverse events possibly associated with 
use of Sertraline include suicide ideation and suicide attempts and bleeding. CBT is 
considered minimal risk to a patient, although there is a potential for a loss of patient 
0
100
200
300
400
Date
Patient Enrollment
2015-04-01
2015-09-28
2016-03-26
2016-09-22
2017-03-21
Planned Enrollment
Actual Enrollment
75% of Planned Enrollment
Target Enrollment: n=400


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confidentiality since CBT will be done while patient is undergoing HD. Among patients 
randomized to CBT or Sertraline, all adverse events possibly associated with Sertraline 
will be reported in Table 4. All serious adverse events regardless of possible association to 
intervention will be reported in Table 4. The research team will follow the participants for 
a period of 30 days from the end of 12 weeks of participation for the occurrence of death 
or hospitalization. Detailed reporting of serious adverse events will be given in Table 5, by 
treatment group sorted chronologically. If adverse or serious adverse events occur in 
different proportion in the study groups and there are concerns regarding the negative 
effects of either intervention, then the research team in consultation with both the study 
statistician and the DSMB may make protocol changes or discontinue the study.  
Any suicide attempt (occurring within six weeks of the study procedures) will be 
immediately reported by the PI to the DSMB chair. These events will prompt a review if 
the event rate in either study arm exceeds the indicated threshold.  
Table 4. Adverse event incidence rate (number of events / number at risk) and 
threshold for action (Closed Report) 
Event 
Group A’ 
Group B’ 
Expected* 
(over 4-
month period 
of 
participation) 
Threshold 
For Action 
p-value** 
 Adverse Event 
Suicide Ideation1 
 
 
10% 
20% 
 
Serious Adverse Event 
Major bleeding2 
 
 
2% 
5% 
 
Suicide Attempt 
 
 
<1% 
3% 
 
Death 
 
 
5% 
10% 
 
Any 
Hospitalization 
 
 
25% 
40% 
 
* Expected rates calculated based on expected number of events in a population 
** P-value calculated for the rate ratio comparing treatment Group A to Group B. 


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1Suicidal ideation is defined as scoring moderate (9-16 points) or high (>= 17 points) risk 
on the MINI suicidality module. Estimates obtained from Chen et al, Psychosomatics 
2010;51: 528-528e6 (prevalence of suicide plan or suicide attempt),  
2 Hospitalization or death for hemorrhage from any site, including gastrointestinal, 
vascular access, and central nervous system. The estimates are based on several published 
estimates of populations of patients undergoing hemodialysis such as from the DOPPS 
(Sood et al, Kidney Int 2013; 84: 600-608)  
Rates of death and hospitalization were estimated from annual rates reported in the 
USRDS Annual Data Report and projected for the 4-month study period  
 


 
 
 
 
Version: V2.6, 16-June-2017 
 
Table 5. Detailed tabulation of (Closed Report) Serious Adverse Events that have occurred during the ASCEND study. 
 
 
 
1Frequency:  
1. Single Episode 
 
 
2. Intermittent 
 
 
3. Continuous  
 
2Relationship:  1. Unrelated 
 
 
2. Unlikely 
 
 
3. Possibly related 
 
 
4. Probably related 
 
 
5. Definitely related 
 
3Action Taken:  1. None 
 
 
2. Conservative action 
 
 
3. Concomitant Medication 
 
 
4. Operative action 
 
 
 
4Outcome:  
1. Resolved, no residual effects 
 
 
2. Resolved, residual effects 
 
 
3. Continuing 
 
 
4. Subject lost to follow-up. No data available 
 
 
5. Subject died 
Ex2 
Hospitalization-CHF 
B’ 
70 
M 
30Oct2011 
30Nov2011 
1 
2 
4 
3 


 
 
 
 
Version: V2.6, 16-June-2017 
 
4.3 Treatment Efficacy Monitoring 
We will report aggregate 12-week QIDS-C scores by blinded treatment group for 
monitoring by the DSMB. We will also provide a z-score assessment of the evidence for 
the difference between treatment arms at 12 weeks. However, the DSMB is charged not to 
make a recommendation to terminate the study based on interim efficacy estimates. CBT 
and Sertraline are accepted standard of care treatments for depression. The study aims to 
provide valid estimates of treatment efficacy and early stopping for efficacy would 
jeopardize the primary analysis. Efficacy data is provided only to inform any safety or 
performance concerns that may arise.  
4.4 Procedures for minimizing research-associated risk 
A number of strategies for minimizing research-associated risk to subjects are built into 
the study protocol.  CBT and Sertraline are standard treatments frequently used in 
clinical practice.  This protocol only randomizes the choice of treatment.  The doses being 
used are also standard doses without any additional risks posed to subjects.  Subjects will 
also be monitored more frequently than in usual clinical practice and at all follow up time 
points, subjects will be asked about adverse events and unanticipated health events that 
may or may not be related to the study procedures.  
In this study, we have developed safety plans for addressing suicide ideation. We are also 
employing additional procedures for patients randomized to Sertraline to ensure safety 
for these patients. These procedures are described below.  
4.4.1 Patients who endorse suicide ideation 
Since we will ask patients about suicide ideation (SI) during the screening phase as well as 
during the study, there is a high likelihood of identifying patients experiencing SI. If a 
patient endorses an SI item during screening or at the baseline visit, the site investigator 
will be notified. These patients will not be randomized to either CBT or Sertraline and 
will be referred to their primary care provider. If an individual reports active suicidal 
ideation or intent at any point during the trial, a cascade of events will be triggered to 
explore the risk of-and protect the subject from-self-harm. The site clinician will be 
immediately contacted who will in turn assess risk using the suicidality module of the 
MINI.  
4.4.5 Patients randomized to Sertraline 
Tolerability of Sertraline will be monitored every two weeks for the first six weeks and 
every three weeks for the second six weeks with the use of FIBSER. Treatment for subjects 


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assigned to the Sertraline arm will be withdrawn if (1) they experience a serious adverse 
event attributable to the study drug and in the judgment of the site PI, the medication 
cannot be safely reinstituted; (2) the subject has intolerable side effects despite reducing 
dose to 50 mg/d; or (3) subject becomes pregnant. 
5. Scheduled Reporting 
One month prior to each DSMB review, the Data Coordinating Center (DCC) will 
summarize monthly administrative reports that describe study progress including subject 
accrual by site, demographics, and the sites’ adherence to inclusion/exclusion criteria and 
other protocol requirements, including retention rates at each follow up point. These 
reports are prepared monthly and reviewed internally by the study research team for 
ongoing quality control. The DCC will also produce safety reports that list adverse events, 
serious adverse events, deaths, and in aggregate to the DSMB. 
With each review the DSMB will decide to approve the study and protocol as is, 
recommend protocol changes in the interest of patient safety, or stop the study based on 
overwhelming evidence of safety concerns.  The DSMB will provide the recommendation 
in a written letter to the principal investigator.  In addition the DSMB will inform the 
investigator of any changes in the proposed timing of future DSMB reviews. The review 
may result in an amendment to the protocol, which must be approved by the IRB.  
The DSMB report will begin with a brief narrative section that describes the status of the 
study, progress or findings to-date, issues, and the procedures that produced the report 
(e.g., data obtained by a specific date). The report will provide a study description along 
with a current organization chart, current timetable and study schedule as well as a list of 
study clinical and administrative centers. Data will be presented that describe the 
administrative status of the study including recruitment and forms handling. Study data 
reports describe demographic and baseline clinical characteristics and provide a safety 
assessment. Tables will be provided by site as well as for the whole study population. 
AE/SAE rates for each group will be presented in the closed report. Finally, the report will 
include a brief evaluation by the DSMB, with recommendations as to whether or not the 
trial will continue.  
The DSMB will transmit a copy of their recommendations to the Principal Investigator 
who will disseminate to the clinical investigators at each recruitment site. The clinical 
investigators are responsible for forwarding the information to their local IRB.  
5.1 Serious Adverse Event Reporting 
Since reporting rules vary by institution, the following statements are a conservative 
guide to reporting adverse events for this trial and may be further amplified with DSMB 
guidance. 


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Any suicide attempt that occurs during a subject’s window of study participation in the 
CBT vs Sertraline trial is reportable to the principal investigator and DSMB within 24 
hours of the site investigator learning of the event. The notification to the DSMB and the 
IRB, will include a determination from the study Principal Investigator as to likelihood of 
relation to the study procedure. Every site IRB shall receive notification from the 
Principal Investigator, of any suicide attempt regardless of where the attempt occurred.  
Unexpected adverse events which are serious, but not life threatening, and have a causal 
relation to the research, (unexpected in this context means not mentioned in the 
informed consent) must be reported to the DSMB within 7 days and to the local IRB 
within two weeks of the event. Serious adverse events will be reported to the DSMB chair, 
as they occur. The DSMB may call an emergency meeting, if necessary.