<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04422652</url>
  </required_header>
  <id_info>
    <org_study_id>STU-2020-0046</org_study_id>
    <secondary_id>R01DK124379</secondary_id>
    <nct_id>NCT04422652</nct_id>
  </id_info>
  <brief_title>Combination of Novel Therapies for CKD Comorbid Depression</brief_title>
  <acronym>CONCORD</acronym>
  <official_title>Combination of Novel Therapies for CKD Comorbid Depression (CONCORD)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Texas Southwestern Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Stony Brook University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Washington</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Texas Southwestern Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The overall goal of the study is to determine if treatment of a Major Depressive Disorder&#xD;
      (MDD) improves the outcomes of patients with chronic kidney disease (CKD). We showed that MDD&#xD;
      is present in 25% of CKD patients and independently associated with progression to End-Stage&#xD;
      Kidney Disease, hospitalization, and death. Depression is also associated with lower quality&#xD;
      of life (QOL), fatigue, poor sleep, and non-adherence to diet and medications. However,&#xD;
      evidence for efficacy and tolerability of commonly-used antidepressant medications or&#xD;
      nonpharmacologic treatments are limited in CKD patients. Our group was the first to conduct a&#xD;
      double-blind randomized controlled trial for MDD treatment in 201 patients with non-dialysis&#xD;
      CKD, and showed that sertraline, a commonly used selective serotonin reuptake inhibitor&#xD;
      (SSRI), was no more efficacious than placebo for improving depressive symptoms. It becomes&#xD;
      imperative to test novel strategies to treat MDD in CKD. We propose to compare with a control&#xD;
      group, the efficacy and tolerability of two novel treatment strategies - (1) Behavioral&#xD;
      Activation Teletherapy (BAT) for 16 weeks, with the addition of bupropion, a non-SSRI&#xD;
      antidepressant, at 8 weeks for patients whose depression has not remitted (non-remitters);&#xD;
      and (2) bupropion for 16 weeks, with the addition of BAT at 8 weeks for non-remitters. In Aim&#xD;
      1, we will investigate the efficacy and tolerability of these 2 strategies vs. control for&#xD;
      improvement in a primary endpoint of depressive symptoms in 201 patients (67 per group) with&#xD;
      non-dialysis CKD stages 3b-5 and MDD at 2 sites, randomized 1:1:1 to either strategy or a&#xD;
      control group of Clinical Management plus placebo. We hypothesize that either approach vs.&#xD;
      control will result in a minimal clinically important difference of 2 points improvement in&#xD;
      depressive symptoms, as ascertained blindly by the Quick Inventory of Depressive&#xD;
      Symptomatology. In Aim 2 we will investigate the efficacy and tolerability of 8 weeks of (1)&#xD;
      single-blind BAT plus placebo or (2) double-blind bupropion plus Clinical Management vs.&#xD;
      control for improvement in depressive symptoms. In Aim 3, we will compare the efficacy of&#xD;
      these 2 treatments strategies vs. control for improvement in CKD patient-centered outcomes&#xD;
      including a. adherence to medications and healthcare visits; b. fatigue; c. sleep; and d.&#xD;
      overall functioning. A clinical trial is urgently needed to address the evidence gap that&#xD;
      exists for MDD treatment in CKD patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Aim 1. Compare the efficacy and tolerability of two 16-week strategies vs. control for&#xD;
      treatment of CKD patients with MDD starting with (1) BAT or (2) bupropion, each augmented to&#xD;
      a combination of both in non-remitters. Primary hypothesis: Treatment with either strategy&#xD;
      will improve depression (primary endpoint) and be tolerable.&#xD;
&#xD;
      Patients with non-dialysis stages 3b-5 CKD and MDD (N=201) will be randomized 1:1:1 to 16&#xD;
      weeks of:&#xD;
&#xD;
      Strategy 1: Single-blind BAT plus placebo, augmented in non-remitters at 8 weeks with&#xD;
      single-blind bupropion; Strategy 2: Double-blind bupropion plus single-blind Clinical&#xD;
      Management (CM) attention control, augmented in non-remitters at 8 weeks with single-blind&#xD;
      BAT; Control: CM attention control plus placebo. There will be &gt;80% power to detect a minimal&#xD;
      clinically important difference (MCID) of 2 points on the Quick Inventory of Depressive&#xD;
      Symptomatology between each intervention and control, assuming a 14% attrition rate.&#xD;
&#xD;
      Exploratory aim (a): Explore if remote access to therapy via internet vs. travel to clinic&#xD;
      affects treatment efficacy.&#xD;
&#xD;
      Aim 2. Investigate efficacy and tolerability of 8 weeks (Phase 1) of (1) BAT plus placebo or&#xD;
      (2) bupropion plus CM, vs. control, for improvement in depression. Secondary hypothesis:&#xD;
      Treatment with 8 weeks of BAT or bupropion will improve depression. There will be 80% power&#xD;
      to detect a MCID of 2 points between each arm and control, assuming 10% attrition.&#xD;
&#xD;
      Exploratory aims:&#xD;
&#xD;
      (a) Investigate whether patient preference for BAT vs. drug affects treatment efficacy; (b)&#xD;
      compare efficacy of each combination in Phase 2 with control; (c) compare change from&#xD;
      baseline in plasma C-reactive protein in drug vs. BAT or control arms.&#xD;
&#xD;
      Aim 3. Investigate the efficacy of these two 16-week treatment strategies vs. control for&#xD;
      improvement in CKD patient-centered outcomes including: (a) adherence to medications and&#xD;
      healthcare visits; (b) fatigue; (c) sleep; (d) overall functioning. Secondary hypothesis:&#xD;
      Treatment with either strategy will result in clinically meaningful improvements in&#xD;
      adherence, fatigue, sleep and overall functioning in patients with CKD.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 24, 2020</start_date>
  <completion_date type="Anticipated">April 1, 2026</completion_date>
  <primary_completion_date type="Anticipated">April 1, 2025</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Those eligible will be randomized via a computerized random number generator 1:1:1 to BAT, bupropion, or control, using block randomization, stratified by site and CKD stage (3b, 4, or 5). Randomization assignment will be obtained via the secure study web portal hosted at UTSW. As in previous trials that involve therapy for MDD, it is challenging to double-blind aspects of this study that involve BAT. However, we have made every effort to maintain blind as much as possible. Bupropion for Strategy 2 and double-blind matching placebo for the control arm will be administered by concealed allocation. Participants in Strategy 1 will receive matching placebo by single-blind allocation. Although it is impossible to conceal the allocation of the BAT to the research team, it is intended for the participants to remain single-blinded to BAT vs. CM. Using Computer Assisted Telephone Interviewing, the same assessor, blinded to interventions, will assess outcomes for both sites.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Quick Inventory of Depressive Symptomatology-Clinician Rated scale (QIDS-C)</measure>
    <time_frame>Assessed at baseline and weeks 4, 6, 8, 12, and 16</time_frame>
    <description>Assess the change from baseline in the QIDS-C total score in each of the intervention arms vs. the control arm. The score on the QIDS-C ranges from 0-27, with higher scores indicating more severe depressive symptoms.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Serious adverse events</measure>
    <time_frame>Assessed at weeks 4, 6, 8, 12, and 16.</time_frame>
    <description>Pre-specified serious adverse events include death, hospitalization, renal replacement therapy (dialysis or kidney transplantation), and acute suicidal intent.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quick Inventory of Depressive Symptomatology-Clinician Rated scale (QIDS-C)</measure>
    <time_frame>Assessed at baseline and weeks 4, 6, and 8.</time_frame>
    <description>Assess the change from baseline in the QIDS-C total score in each of the intervention arms vs. the control arm during the first 8 weeks of the study when participants in the treatment arms will be receiving monotherapy with BAT or bupropion.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serious adverse events with monotherapy</measure>
    <time_frame>Assessed at weeks 4, 6, and 8.</time_frame>
    <description>Pre-specified serious adverse events include death, hospitalization, renal replacement therapy (dialysis or kidney transplantation), and acute suicidal intent during the first 8 weeks of the study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quick Inventory of Depressive Symptomatology-Clinician Rated scale (QIDS-C)</measure>
    <time_frame>Assessed at weeks 8, 12, and 16.</time_frame>
    <description>Assess the change from baseline in the QIDS-C total score in each of the intervention arms vs. the control arm during the second 8 weeks of the study when participants who did not respond to the treatment arms will be receiving combination therapy with BAT and bupropion.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>High sensitivity C-reactive protein</measure>
    <time_frame>Assessed at baseline and week 8</time_frame>
    <description>Change from baseline to Week 8 in the plasma level of high sensitivity C-reactive protein (hsCRP) in the intervention groups vs. control.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adherence to medications by Pill Count</measure>
    <time_frame>Assessed at weeks 4, 8, 12, and 16.</time_frame>
    <description>The proportion of participants in each arm that are adherent to antidepressant medications (or placebo, prescribed in the setting of the clinical trial). Adherence will be defined as 80% or greater of study drug taken.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fatigue assessed by the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) scale</measure>
    <time_frame>Assessed at baseline and weeks 4, 8, 12, and 16</time_frame>
    <description>Change from baseline in the FACIT-F scale in the intervention groups vs. control. The FACIT has 13 items, each on a Likert scale, with a score range of 0-52, and higher scores indicating a lower level of fatigue.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sleep assessed by the Insomnia Severity Index (ISI)</measure>
    <time_frame>Assessed at baseline and weeks 4, 8, 12, and 16</time_frame>
    <description>Change from baseline in the Insomnia Severity Index (ISI) in the intervention groups vs. control. The ISI has 7 items that measure insomnia severity, with higher scores indicating more severe insomnia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall functioning assessed by the Sheehan Disability Scale (SDS)</measure>
    <time_frame>Assessed at baseline and weeks 4, 8, 12, and 16</time_frame>
    <description>Change from baseline in the SDS in the intervention groups vs. control groups. The SDS assesses functional impairment in 3 domains: work, social life, and family, each evaluated on a 10-point visual analog scale, which are summed into a single dimensional measure of global functional impairment that ranges from 0 (unimpaired) to 30 (highly impaired).</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">201</enrollment>
  <condition>Chronic Kidney Diseases</condition>
  <condition>Major Depressive Disorder</condition>
  <arm_group>
    <arm_group_label>Strategy 1</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Strategy 1: Single-blind Behavioral Activation Therapy plus placebo for 8 weeks (Phase 1), augmented in non-remitters at 8 weeks with single-blind bupropion (Phase 2) for another 8 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Strategy 2</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Strategy 2: Double-blind bupropion plus single-blind Clinical Management (CM) attention control for 8 weeks (Phase 1), augmented in non-remitters at 8 weeks with single-blind BAT (Phase 2) for another 8 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Control: Clinical management attention control plus placebo for 16 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bupropion</intervention_name>
    <description>Bupropion is an anti-depressant medication.</description>
    <arm_group_label>Strategy 2</arm_group_label>
    <other_name>Wellbutrin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Behavioral activation therapy</intervention_name>
    <description>Brief behavioral activation treatments administered via video tele-conferencing.</description>
    <arm_group_label>Strategy 1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Double-blind placebo.</description>
    <arm_group_label>Control</arm_group_label>
    <arm_group_label>Strategy 1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Clinical Management</intervention_name>
    <description>Clinical management will serve as the attention control for the Behavioral Activation Therapy intervention.</description>
    <arm_group_label>Control</arm_group_label>
    <arm_group_label>Strategy 2</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female adults aged 18 years or greater. There will be no upper age limit.&#xD;
&#xD;
          2. Presence of CKD stages 3b, 4 or non-dialysis stage 5, with an estimated glomerular&#xD;
             filtration rate (GFR) of &lt;45 mL/min/1.73 m2 for a period of at least 3 months, as&#xD;
             defined by the National Kidney Foundation and determined using the four-variable&#xD;
             Modification of Diet for Renal Diseases Study formula.&#xD;
&#xD;
          3. Presence of a current Major Depressive Disorder (MDD) based on MINI DSM IV-based&#xD;
             criteria&#xD;
&#xD;
          4. Quick Inventory of Depressive Symptomatology-Self-report (QIDS-SR) score of ≥11 at&#xD;
             enrollment and ≥11 on QIDS-Clinician Rated (QIDS-C) at randomization.&#xD;
&#xD;
          5. Able to understand and sign informed consent after the nature of the study has been&#xD;
             fully explained&#xD;
&#xD;
          6. Kidney transplant patients that are at least 6 month post-transplantation (3 months&#xD;
             post-transplant, with at least another 3 months to confirm eGFR &lt;45)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Unable to understand or give informed consent.&#xD;
&#xD;
          2. Unwilling or unable to participate in the protocol or comply with any of its&#xD;
             components&#xD;
&#xD;
          3. Receiving chronic dialysis&#xD;
&#xD;
          4. Significant hepatic dysfunction or liver enzyme abnormalities 3 times or greater than&#xD;
             the upper limit of normal&#xD;
&#xD;
          5. Terminal chronic obstructive pulmonary disease or cancer&#xD;
&#xD;
          6. Presence of seizure disorder&#xD;
&#xD;
          7. Current use of class I anti-arrhythmic medications (such as 1C propafenone and&#xD;
             flecanide), pimozide, MAO inhibitors, reserpine, guanethidine, cimetidine, or&#xD;
             methyldopa; tri-cyclic anti-depressants, neuroleptics, or anti-convulsants&#xD;
&#xD;
          8. Use of serotonergic drugs or supplements such as triptans, tramadol, linezolid,&#xD;
             tryptophan, and St. John's Wort.&#xD;
&#xD;
          9. Use of medications known to cause QT prolongation on EKG&#xD;
&#xD;
         10. Ongoing use of antidepressant medications for depression treatment&#xD;
&#xD;
         11. Past treatment failure on bupropion&#xD;
&#xD;
         12. Initiation of depression-focused psychotherapy in the 3 months prior to study entry&#xD;
&#xD;
         13. Active alcohol or substance abuse or dependence that requires acute detoxification at&#xD;
             study entry&#xD;
&#xD;
         14. Present or past psychosis or Bipolar I or II disorder&#xD;
&#xD;
         15. Dementia or a Mini-Mental State Examination score &lt;23&#xD;
&#xD;
         16. Active suicidal intent&#xD;
&#xD;
         17. Pregnancy, lactation, or women of childbearing potential not willing to use adequate&#xD;
             contraception&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Susan Hedayati, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Texas</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Meredith McAdams, MD</last_name>
    <phone>214-645-5418</phone>
    <email>Meredith.McAdams@UTSouthwestern.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Stony Brook University Medical Center</name>
      <address>
        <city>Stony Brook</city>
        <state>New York</state>
        <zip>11794-8430</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
  </location>
  <location>
    <facility>
      <name>Parkland Health and Hospital System</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75235</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>UT Southwestern and Affiliates</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>University of Washington</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98195</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Hedayati SS, Gregg LP, Carmody T, Jain N, Toups M, Rush AJ, Toto RD, Trivedi MH. Effect of Sertraline on Depressive Symptoms in Patients With Chronic Kidney Disease Without Dialysis Dependence: The CAST Randomized Clinical Trial. JAMA. 2017 Nov 21;318(19):1876-1890. doi: 10.1001/jama.2017.17131.</citation>
    <PMID>29101402</PMID>
  </reference>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>June 5, 2020</study_first_submitted>
  <study_first_submitted_qc>June 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 9, 2020</study_first_posted>
  <last_update_submitted>August 28, 2023</last_update_submitted>
  <last_update_submitted_qc>August 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 31, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Texas Southwestern Medical Center</investigator_affiliation>
    <investigator_full_name>Susan Hedayati</investigator_full_name>
    <investigator_title>PROFESSOR, IM-Nephrology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Diseases</mesh_term>
    <mesh_term>Renal Insufficiency, Chronic</mesh_term>
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Depressive Disorder, Major</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bupropion</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04422652
org study id: STU-2020-0046
secondary id: R01DK124379
nct id: NCT04422652
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The overall goal of the study is to determine if treatment of a Major Depressive Disorder
      (MDD) improves the outcomes of patients with chronic kidney disease (CKD). We showed that MDD
      is present in 25% of CKD patients and independently associated with progression to End-Stage
      Kidney Disease, hospitalization, and death. Depression is also associated with lower quality
      of life (QOL), fatigue, poor sleep, and non-adherence to diet and medications. However,
      evidence for efficacy and tolerability of commonly-used antidepressant medications or
      nonpharmacologic treatments are limited in CKD patients. Our group was the first to conduct a
      double-blind randomized controlled trial for MDD treatment in 201 patients with non-dialysis
      CKD, and showed that sertraline, a commonly used selective serotonin reuptake inhibitor
      (SSRI), was no more efficacious than placebo for improving depressive symptoms. It becomes
      imperative to test novel strategies to treat MDD in CKD. We propose to compare with a control
      group, the efficacy and tolerability of two novel treatment strategies - (1) Behavioral
      Activation Teletherapy (BAT) for 16 weeks, with the addition of bupropion, a non-SSRI
      antidepressant, at 8 weeks for patients whose depression has not remitted (non-remitters);
      and (2) bupropion for 16 weeks, with the addition of BAT at 8 weeks for non-remitters. In Aim
      1, we will investigate the efficacy and tolerability of these 2 strategies vs. control for
      improvement in a primary endpoint of depressive symptoms in 201 patients (67 per group) with
      non-dialysis CKD stages 3b-5 and MDD at 2 sites, randomized 1:1:1 to either strategy or a
      control group of Clinical Management plus placebo. We hypothesize that either approach vs.
      control will result in a minimal clinically important difference of 2 points improvement in
      depressive symptoms, as ascertained blindly by the Quick Inventory of Depressive
      Symptomatology. In Aim 2 we will investigate the efficacy and tolerability of 8 weeks of (1)
      single-blind BAT plus placebo or (2) double-blind bupropion plus Clinical Management vs.
      control for improvement in depressive symptoms. In Aim 3, we will compare the efficacy of
      these 2 treatments strategies vs. control for improvement in CKD patient-centered outcomes
      including a. adherence to medications and healthcare visits; b. fatigue; c. sleep; and d.
      overall functioning. A clinical trial is urgently needed to address the evidence gap that
      exists for MDD treatment in CKD patients.
Aim 1. Compare the efficacy and tolerability of two 16-week strategies vs. control for
      treatment of CKD patients with MDD starting with (1) BAT or (2) bupropion, each augmented to
      a combination of both in non-remitters. Primary hypothesis: Treatment with either strategy
      will improve depression (primary endpoint) and be tolerable.

      Patients with non-dialysis stages 3b-5 CKD and MDD (N=201) will be randomized 1:1:1 to 16
      weeks of:

      Strategy 1: Single-blind BAT plus placebo, augmented in non-remitters at 8 weeks with
      single-blind bupropion; Strategy 2: Double-blind bupropion plus single-blind Clinical
      Management (CM) attention control, augmented in non-remitters at 8 weeks with single-blind
      BAT; Control: CM attention control plus placebo. There will be >80% power to detect a minimal
      clinically important difference (MCID) of 2 points on the Quick Inventory of Depressive
      Symptomatology between each intervention and control, assuming a 14% attrition rate.

      Exploratory aim (a): Explore if remote access to therapy via internet vs. travel to clinic
      affects treatment efficacy.

      Aim 2. Investigate efficacy and tolerability of 8 weeks (Phase 1) of (1) BAT plus placebo or
      (2) bupropion plus CM, vs. control, for improvement in depression. Secondary hypothesis:
      Treatment with 8 weeks of BAT or bupropion will improve depression. There will be 80% power
      to detect a MCID of 2 points between each arm and control, assuming 10% attrition.

      Exploratory aims:

      (a) Investigate whether patient preference for BAT vs. drug affects treatment efficacy; (b)
      compare efficacy of each combination in Phase 2 with control; (c) compare change from
      baseline in plasma C-reactive protein in drug vs. BAT or control arms.

      Aim 3. Investigate the efficacy of these two 16-week treatment strategies vs. control for
      improvement in CKD patient-centered outcomes including: (a) adherence to medications and
      healthcare visits; (b) fatigue; (c) sleep; (d) overall functioning. Secondary hypothesis:
      Treatment with either strategy will result in clinically meaningful improvements in
      adherence, fatigue, sleep and overall functioning in patients with CKD.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Those eligible will be randomized via a computerized random number generator 1:1:1 to BAT, bupropion, or control, using block randomization, stratified by site and CKD stage (3b, 4, or 5). Randomization assignment will be obtained via the secure study web portal hosted at UTSW. As in previous trials that involve therapy for MDD, it is challenging to double-blind aspects of this study that involve BAT. However, we have made every effort to maintain blind as much as possible. Bupropion for Strategy 2 and double-blind matching placebo for the control arm will be administered by concealed allocation. Participants in Strategy 1 will receive matching placebo by single-blind allocation. Although it is impossible to conceal the allocation of the BAT to the research team, it is intended for the participants to remain single-blinded to BAT vs. CM. Using Computer Assisted Telephone Interviewing, the same assessor, blinded to interventions, will assess outcomes for both sites.
measure: Quick Inventory of Depressive Symptomatology-Clinician Rated scale (QIDS-C)
time frame: Assessed at baseline and weeks 4, 6, 8, 12, and 16
description: Assess the change from baseline in the QIDS-C total score in each of the intervention arms vs. the control arm. The score on the QIDS-C ranges from 0-27, with higher scores indicating more severe depressive symptoms.
measure: Serious adverse events
time frame: Assessed at weeks 4, 6, 8, 12, and 16.
description: Pre-specified serious adverse events include death, hospitalization, renal replacement therapy (dialysis or kidney transplantation), and acute suicidal intent.
measure: Quick Inventory of Depressive Symptomatology-Clinician Rated scale (QIDS-C)
time frame: Assessed at baseline and weeks 4, 6, and 8.
description: Assess the change from baseline in the QIDS-C total score in each of the intervention arms vs. the control arm during the first 8 weeks of the study when participants in the treatment arms will be receiving monotherapy with BAT or bupropion.
measure: Serious adverse events with monotherapy
time frame: Assessed at weeks 4, 6, and 8.
description: Pre-specified serious adverse events include death, hospitalization, renal replacement therapy (dialysis or kidney transplantation), and acute suicidal intent during the first 8 weeks of the study.
measure: Quick Inventory of Depressive Symptomatology-Clinician Rated scale (QIDS-C)
time frame: Assessed at weeks 8, 12, and 16.
description: Assess the change from baseline in the QIDS-C total score in each of the intervention arms vs. the control arm during the second 8 weeks of the study when participants who did not respond to the treatment arms will be receiving combination therapy with BAT and bupropion.
measure: High sensitivity C-reactive protein
time frame: Assessed at baseline and week 8
description: Change from baseline to Week 8 in the plasma level of high sensitivity C-reactive protein (hsCRP) in the intervention groups vs. control.
measure: Adherence to medications by Pill Count
time frame: Assessed at weeks 4, 8, 12, and 16.
description: The proportion of participants in each arm that are adherent to antidepressant medications (or placebo, prescribed in the setting of the clinical trial). Adherence will be defined as 80% or greater of study drug taken.
measure: Fatigue assessed by the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) scale
time frame: Assessed at baseline and weeks 4, 8, 12, and 16
description: Change from baseline in the FACIT-F scale in the intervention groups vs. control. The FACIT has 13 items, each on a Likert scale, with a score range of 0-52, and higher scores indicating a lower level of fatigue.
measure: Sleep assessed by the Insomnia Severity Index (ISI)
time frame: Assessed at baseline and weeks 4, 8, 12, and 16
description: Change from baseline in the Insomnia Severity Index (ISI) in the intervention groups vs. control. The ISI has 7 items that measure insomnia severity, with higher scores indicating more severe insomnia.
measure: Overall functioning assessed by the Sheehan Disability Scale (SDS)
time frame: Assessed at baseline and weeks 4, 8, 12, and 16
description: Change from baseline in the SDS in the intervention groups vs. control groups. The SDS assesses functional impairment in 3 domains: work, social life, and family, each evaluated on a 10-point visual analog scale, which are summed into a single dimensional measure of global functional impairment that ranges from 0 (unimpaired) to 30 (highly impaired).
arm group label: Strategy 1
arm group type: Active Comparator
description: Strategy 1: Single-blind Behavioral Activation Therapy plus placebo for 8 weeks (Phase 1), augmented in non-remitters at 8 weeks with single-blind bupropion (Phase 2) for another 8 weeks.
arm group label: Strategy 2
arm group type: Active Comparator
description: Strategy 2: Double-blind bupropion plus single-blind Clinical Management (CM) attention control for 8 weeks (Phase 1), augmented in non-remitters at 8 weeks with single-blind BAT (Phase 2) for another 8 weeks.
arm group label: Control
arm group type: Placebo Comparator
description: Control: Clinical management attention control plus placebo for 16 weeks
intervention type: Drug
intervention name: Bupropion
description: Bupropion is an anti-depressant medication.
arm group label: Strategy 2
other name: Wellbutrin
intervention type: Behavioral
intervention name: Behavioral activation therapy
description: Brief behavioral activation treatments administered via video tele-conferencing.
arm group label: Strategy 1
intervention type: Drug
intervention name: Placebo
description: Double-blind placebo.
arm group label: Control
arm group label: Strategy 1
intervention type: Other
intervention name: Clinical Management
description: Clinical management will serve as the attention control for the Behavioral Activation Therapy intervention.
arm group label: Control
arm group label: Strategy 2
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Susan Hedayati, MD
role: Principal Investigator
affiliation: University of Texas
last name: Meredith McAdams, MD
phone: 214-645-5418
email: Meredith.McAdams@UTSouthwestern.edu
facility: 
status: Not yet recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
country: United States
citation: Hedayati SS, Gregg LP, Carmody T, Jain N, Toups M, Rush AJ, Toto RD, Trivedi MH. Effect of Sertraline on Depressive Symptoms in Patients With Chronic Kidney Disease Without Dialysis Dependence: The CAST Randomized Clinical Trial. JAMA. 2017 Nov 21;318(19):1876-1890. doi: 10.1001/jama.2017.17131.
PMID: 29101402
responsible party type: Principal Investigator
investigator affiliation: University of Texas Southwestern Medical Center
investigator full name: Susan Hedayati
investigator title: PROFESSOR, IM-Nephrology
mesh term: Kidney Diseases
mesh term: Renal Insufficiency, Chronic
mesh term: Depressive Disorder
mesh term: Depressive Disorder, Major
mesh term: Bupropion
sharing ipd: No