A Trial of Sertraline vs. CBT for End-stage Renal Disease Patients With Depression {ASCEND}

Study Overview
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Brief Summary
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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
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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.

Official Title
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ASCEND: A Trial of Sertraline vs. CBT for End-stage Renal Disease Patients With Depression

Conditions
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Depression, End Stage Renal Disease

Intervention / Treatment
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* Behavioral: Engagement Interview
* Behavioral: Cognitive Behavioral Therapy
* Drug: Antidepressant Drug Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 21 years; Undergoing thrice-weekly maintenance HD for ≥ 3 months; Able to speak either English or Spanish; BDI-II score ≥ 15; and Meets diagnostic criteria for either current major depressive episode or dysthymia on the MINI. Exclusion Criteria: Active suicidal intent; Ongoing psychotherapy or current treatment with certain anti-depressant drugs; Evidence of cognitive impairment on Mini-Cog; Present or past psychosis or bipolar disorder I or II on the MINI; Alcohol or substance abuse diagnosed on the MINI or history of such abuse in the past three months; Life expectancy < 3 months, in the judgment of the site principal investigator; Anticipated to receive living related donor kidney transplantation within 3 months; Pregnancy, or lactation, or women of childbearing age not willing to use adequate birth control; Clinical and/or laboratory evidence of chronic liver disease; History of significant active bleeding in the past three months, such as hospitalization for gastrointestinal bleeding; Current use of class I anti-arrhythmic medications (e.g., propafenone, flecainide), pimozide, monoamine oxidase inhibitors, reserpine, guanethidine, cimetidine, tri-cyclic anti-depressants, triptans, tramadol, linezolid, tryptophan, and St. John's wort; and Known hypersensitivity to sertraline.

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Engagement Interview<br>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. | Behavioral: Engagement Interview<br>* 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.<br>|
| No Intervention: Control Visit<br>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. | |
| Active Comparator: Cognitive Behavioral Therapy<br>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. | Behavioral: Cognitive Behavioral Therapy<br>* 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).<br>* Other names: CBT;|
| Active Comparator: Antidepressant Drug Therapy<br>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. | Drug: Antidepressant Drug Therapy<br>* 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.<br>* Other names: Sertraline, Zoloft;|
| No Intervention: Observational Cohort<br>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. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Initiated Depression Treatment | The primary measure of efficacy of the Engagement Interview will be the number 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 establishing a diagnosis of major depression and/or dysthymia. Receiving a supply of anti-depressant drug either as a part of the clinical trial or the treating physician within four weeks of establishing a diagnosis of major depression and/or dysthymia. | within four weeks of engagement interview or control visit | 
| QIDS-C Score | The Quick Inventory of Depressive Symptomatology Clinician-rated (QIDS-C) scale ranges from 0-27, higher scores indicate worse depression. The primary measure of efficacy of Intervention will be the mean difference in QIDS-C score at Week 12 between treatment groups. | Week 12 of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Accepted Depression Treatment | The secondary measure of efficacy of the Engagement Interview 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. Receiving a prescription for anti-depressant drug therapy from primary care physician and/or treating nephrologist within two weeks of establishing a diagnosis of major depression/dysthymia. | within two weeks of engagement interview or control visit | 
| BDI-II | Beck Depression Inventory-II, range 0-63, higher scores indicate worse depression | Week 12 | 
| GAD-7 | Generalized Anxiety Disorder 7-item Scale, range 0-21, higher scores indicate worse anxiety | Week 12 | 
| Sheehan Disability Scale | range 0-30, higher scores indicate worse disability | Week 12 | 
| SF-36 Energy/Vitality | Energy/vitality subscale of the 36-Item Short Form Health Survey, range 0-100, higher scores indicate better energy/vitality | Week 12 | 
| Global Quality of Life Scale | range 0-10, higher scores indicate better quality of life | Week 12 | 
| Satisfaction With Life Scale | range 1-35, higher scores indicate better satisfaction | Week 12 | 
| Perceived Social Support | Multi-Dimensional Scale of Perceived Social Support, range 1-7, higher scores indicate better social support | Week 12 | 
| PSQI | Pittsburgh Sleep Quality Index, range 0-21, higher scores indicate worse sleep quality | Week 12 | 
| Exercise | Single item activity measure, range 1-6, higher indicates less activity | Week 12 | 
| Percentage of Dialysis Treatment Sessions Skipped and/or Shortened | Treatment 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. | Over 12 Weeks | 
| Percent Inter-dialytic Weight Gain | Treatment Adherence with Fluid Intake as defined by inter-dialytic weight gain (as % of post-dialysis weight) during Week 12 of the study | Week 12 | 
| Serum Phosphorus Level | Treatment 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. | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Comorbid Depression, Major Depressive Disorder, Dysthymia, Cognitive Behavioral therapy (CBT), Sertraline, Engagement Interview, End Stage Renal Disease (ESRD), Hemodialysis