Cognitive Behavioral Therapy Following Esketamine for Major Depression and Suicidal Ideation for Relapse Prevention (ENDURE)

CBT-ENDURE: Cognitive Behavioral Therapy Following Esketamine for Major Depression and Suicidal Ideation for Relapse Prevention

This is a rater-blinded, randomized controlled trial. All patients will receive esketamine for treatment of Major Depression with Suicidal Ideation (MDSI). Subjects will be randomized (1:1) to receive CBT (computer-assisted) or TAU alone following esketamine.

Study Overview

• Status: Recruiting
• Conditions: Depression and Suicide
• Intervention / Treatment: Behavioral: Cognitive Behavioral Therapy CBT

Detailed Description

Specific Aim 1: To determine the feasibility and safety of performing a larger study examining the effectiveness and mechanism of action of CBT to improve the longer-term outcomes following esketamine treatment in patients hospitalized for suicidal ideation or suicide attempt.

Specific Aim 2: To evaluate the appropriateness and utility of the proposed tests of cognitive control measures in exploring the mechanisms underlying the effects on depression of esketamine and the combination of esketamine+CBT.

Specific Aim 3: To examine the efficacy of esketamine+CBT combination compared to esketamine+TAU in reducing suicidal ideation.

In August 2022, the targeted enrollment was expanded to include outpatient participants, the anticipated enrollment was increased from 60 to 100 participants as a result.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Cindy Voghell; Phone Number: 203-764-9131; Email: cynthia.voghell@yale.edu
• Study Contact Backup: Name: Julie Holub; Phone Number: 203-764-9131; Email: julie.holub@yale.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Recruiting
      • UAB Medicine | Heersink School of Medicine
      • Contact: Samantha White, BS, CCRC; Phone Number: 205-934-9189; Email: swwhite@uabmc.edu
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Recruiting
      • Yale University
      • Contact: Cindy Voghell; Email: cynthia.voghell@yale.edu
      • Principal Investigator: Samuel T Wilkinson, MD
      • Contact: Julie Holub; Phone Number: (475) 306-4188; Email: julie.holub@yale.edu
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Recruiting
      • Emory University
      • Contact: Valeriya C Tsygankova; Phone Number: 404-712-6947; Email: vtsygan@emory.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants are eligible for the study if they meet all the following criteria:

  1. Written informed consent before any study procedures are performed
  2. Meeting criteria for inpatient admission for suicidal ideation or attempt at one of the study sites
  3. Recommended by a physician for esketamine treatment
  4. Males or females ages 18 through 65 years of age
  5. Diagnosis of major depressive disorder as confirmed by the MINI (inpatient) or the HAM-D-17 (outpatient)
  6. Willing to adhere to a reliable form of contraception throughout the trial and for one month following completion of the trial (for subjects who are sexually active)
  7. In the opinion of the investigator, the patient is willing and able to comply with scheduled visits, treatment plan, and other trial procedures for the duration of the study

Exclusion Criteria:

• Participants are excluded if they meet any of the following criteria:

  1. Active substance use disorder (except tobacco) within 6 months of screening date
  2. Meets DSM-5 criteria for bipolar disorder, schizophrenia, schizophreniform disorder, schizoaffective disorder, or pervasive development disorder
  3. Dementia or other cognitive disorder or intellectual disability that would impair the subject's ability to meaningfully engage in CBT (per investigator judgment)
  4. Any other medical or psychiatric comorbidity that the investigator judges would put the participant at additional undue risk due to study participation or would impair subject's ability to participate in the study.
  5. Current or planned participation in a formal CBT program defined by the following characteristics, each session has an agenda, a homework assignment is given at each session, and the homework assignment from the previous session is reviewed at the following appointment.

  6. Previous Esketamine or ketamine treatment that did not produce a clinical response as outlined below.

     • 6 treatments with Esketamine at a dose of 56 mg or more with no clinical response
     • 6 treatments of IV ketamine at a dose between 0.4 mg/kg and 0.7mg /kg with no clinical response Patients must not have received Esketamine or ketamine treatment within the past 12 weeks of time of enrollment.
  7. The patient is pregnant or breastfeeding
  8. Unable to give informed consent
  9. Was previously enrolled/randomized into the trial

  10. Patients who have a contraindication to receiving Esketamine including any of the following:

      • aneurysmal vascular disease
      • arteriovenous malformation
      • history of intracerebral hemorrhage
      • hypersensitivity to esketamine or ketamine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CBT Cognitive Behavioral Therapy; Participants will receive CBT, which will consist of in-person and computer-based component (based on Good Days Ahead). This will consist of 20 sessions given over 16 weeks.	Behavioral: Cognitive Behavioral Therapy CBT; CBT: In-person and computer-based components (Good Days Ahead) First 4 weeks of CBT are twice weekly; thereafter weekly CBT
Other: TAU Treatment As Usual; Participants will undergo Treatment as usual (TAU). These patients will undergo standard, post-hospitalization clinical treatments, which many include physician visits and psychotherapy (except for formal CBT).	Behavioral: Cognitive Behavioral Therapy CBT; CBT: In-person and computer-based components (Good Days Ahead) First 4 weeks of CBT are twice weekly; thereafter weekly CBT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the feasibility of performing a larger study with similar design by measuring of recruitment rates.	Feasibility will be evaluated by measures of recruitment rates measured by attaining 80% of recruitment target will be considered feasible.	Recruitment rates will be assessed at 18 months.
To determine the feasibility of performing a larger study with similar design by measuring attrition.	Feasibility will be evaluated by measures of attrition rates by attaining 80% of retention will of 70% of participants will be considered feasible.	Attrition will be assessed at 18 months.
Reasons for discontinuation	Feasibility will be evaluated by measures of reasons for discontinuation regardless of clinical state, to Week 18 or later will be considered feasible.	Discontinuation will be assessed at 18 months.
To determine the safety of performing a larger study with similar design.	Safety will be evaluated by measures of the number by type of protocol deviations.	Safety will be assessed at 18 months.
Evaluate the appropriateness of the proposed tests of cognitive control measures in exploring the mechanisms of change.	Appropriateness will be evaluated by the proportion of patients who are able to complete the cognitive control assessments. As this is a feasibility study, we do not have pre-specified quantitative cutoffs.	The appropriateness will be assessed at the end of study (18 months).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of esketamine/CBT combination compared to esketamine/TAU in reducing the risk of suicide.	Efficacy will be measured by the response to the MADRS (Montgomery-Asberg Depression Rating Scale). The MADRS is a 10 question assessments conducted in an interview setting.	Measured at Baseline, study day 2, study day 15, study day 30, weeks 7 - 17, week 18, week 26. The primary observation will be the last observation carried forward per protocol at Week 18.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the depression assessments BDI-II (Beck Depression Inventory).	The BDI-II range of values is 0-42 and the clinical interpretation are indicated with higher scores indicating greater severity of illness.	BDI-II will be measured at Baseline, study day 2, study day 15, study day 30, weeks 7 - 17, week 18, week 26. The primary assessment of this outcome will be at Week 18.
To evaluate the depression assessments CGI (Clinical Global Impression for Severity of Suicidality).	The CGI range of values is 1-5 and the clinical interpretation is indicated with higher scores indicating greater severity of illness.	CGI will be measured at Baseline, study day 2, study day 15, study day 30, weeks 7 - 17, week 18, week 26. The primary assessment of this outcome will be at Week 18.
To evaluate the Suicide Ideation assessments CSSRS (COLUMBIA-SUICIDE SEVERITY RATING SCALE).	The CSSRS range of values 0-5 and the clinical interpretation is indicated with higher score indicating greater severity.	The CSSRS will be measured at Baseline, study day 2, study day 15, study day 30, weeks 7 - 17, week 18, week 26. The primary assessment of this outcome will be at Week 18.
To evaluate the BSI (Beck Scale for Suicidal Ideation).	The BSI range of values 0-63 and the clinical interpretation is indicated with higher scores indicating greater severity of illness.	The BSI will be measured at Baseline, study day 2, study day 15, study day 30, weeks 7 - 17, week 18, week 26. The primary assessment of this outcome will be at Week 18.
To evaluate the RRS (Ruminative Responses Scale).	RRS range of values is 22-88, with higher scores indicating greater severity.	We will compare at Week 18 using last observation carried forward per protocol.
To evaluate the SoCT (Skills of Cognitive Therapy.	SoCT range of values is 8-40, with higher scores indicating greater mastery of CBT.	We will compare at Week 18 using last observation carried forward per protocol.
To evaluate CTAS (Computer-Assisted Cognitive-Behavior Therapy for Depression).	CTAS range of values is 0-40, with higher scores indicating greater knowledge of CBT.	We will compare at Week 18 using last observation carried forward per protocol.

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Samuel T Wilkinson, MD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2021
• Primary Completion (Estimated): August 31, 2024
• Study Completion (Estimated): August 31, 2024

Study Registration Dates

• First Submitted: February 4, 2021
• First Submitted That Met QC Criteria: February 15, 2021
• First Posted (Actual): February 18, 2021

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 18, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Depression; Suicide
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Self-Injurious Behavior; Depression; Depressive Disorder; Suicide; Suicidal Ideation
• Other Study ID Numbers: 2000029473; 1265736169 (Other Identifier: National Provider Identifier (NPI) #); 1R01MH125205-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No