Clinical trial NCT04422652: Combination of Novel Therapies for CKD Comorbid Depression
Official title: Combination of Novel Therapies for CKD Comorbid Depression (CONCORD)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Chronic Kidney Diseases
Major Depressive Disorder
Lead sponsor: Stony Brook University
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2020-06-09
Enrollment: 201
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Male or female adults aged 18 years or greater. There will be no upper age limit.
2. Presence of CKD stages 3b, 4 or non-dialysis stage 5, with an estimated glomerular filtration rate (GFR) of \<45 mL/min/1.73 m2 for a period of at least 3 months, as defined by the National Kidney Foundation and determined using the four-variable Modification of Diet for Renal Diseases Study formula.
3. Presence of a current Major Depressive Disorder (MDD) based on MINI DSM IV-based criteria
4. Quick Inventory of Depressive Symptomatology-Self-report (QIDS-SR) score of ≥11 at enrollment and ≥11 on QIDS-Clinician Rated (QIDS-C) at randomization.
5. Able to understand and sign informed consent after the nature of the study has been fully explained
6. Kidney transplant patients that are at least 6 month post-transplantation (3 months post-transplant, with at least another 3 months to confirm eGFR \<45)

Exclusion Criteria:

1. Unable to understand or give informed consent.
2. Unwilling or unable to participate in the protocol or comply with any of its components
3. Receiving chronic dialysis
4. Significant hepatic dysfunction or liver enzyme abnormalities 3 times or greater than the upper limit of normal
5. Terminal chronic obstructive pulmonary disease or cancer
6. Presence of seizure disorder
7. Current use of class I anti-arrhythmic medications (such as 1C propafenone and flecanide), pimozide, MAO inhibitors, reserpine, guanethidine, cimetidine, or methyldopa; tri-cyclic anti-depressants, neuroleptics, or anti-convulsants
8. Use of serotonergic drugs or supplements such as triptans, tramadol, linezolid, tryptophan, and St. John's Wort.
9. Use of medications known to cause QT prolongation on EKG
10. Ongoing use of antidepressant medications for depression treatment
11. Past treatment failure on bupropion
12. Initiation of depression-focused psychotherapy in the 3 months prior to study entry
13. Active alcohol or substance abuse or dependence that requires acute detoxification at study entry
14. Present or past psychosis or Bipolar I or II disorder
15. Dementia or a Mini-Mental State Examination score \<23
16. Active suicidal intent
17. Pregnancy, lactation, or women of childbearing potential not willing to use adequate contraception

Primary outcomes:
measure: Quick Inventory of Depressive Symptomatology-Clinician Rated scale (QIDS-C)
timeFrame: Assessed at baseline and weeks 4, 6, 8, 12, and 16
Secondary outcomes:
measure: Serious adverse events
timeFrame: Assessed at weeks 4, 6, 8, 12, and 16.
measure: Quick Inventory of Depressive Symptomatology-Clinician Rated scale (QIDS-C)
timeFrame: Assessed at baseline and weeks 4, 6, and 8.
measure: Serious adverse events with monotherapy
timeFrame: Assessed at weeks 4, 6, and 8.
measure: Quick Inventory of Depressive Symptomatology-Clinician Rated scale (QIDS-C)
timeFrame: Assessed at weeks 8, 12, and 16.
measure: High sensitivity C-reactive protein
timeFrame: Assessed at baseline and week 8
measure: Adherence to medications by Pill Count
timeFrame: Assessed at weeks 4, 8, 12, and 16.
measure: Fatigue assessed by the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) scale
timeFrame: Assessed at baseline and weeks 4, 8, 12, and 16
measure: Sleep assessed by the Insomnia Severity Index (ISI)
timeFrame: Assessed at baseline and weeks 4, 8, 12, and 16
measure: Overall functioning assessed by the Sheehan Disability Scale (SDS)
timeFrame: Assessed at baseline and weeks 4, 8, 12, and 16
Other outcomes:
Locations:
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Dallas
country: United States
facility: Parkland Health and Hospital System
state: Texas
city: Dallas
country: United States
facility: UT Southwestern and Affiliates
state: Texas
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: Stony Brook University
name: Susan Hedayati, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Briggs LC. Hominid evolution in Northwest Africa and the question of the North African "Neanderthaloids". Am J Phys Anthropol. 1968 Nov;29(3):377-85. doi: 10.1002/ajpa.1330290312. No abstract available.