Reducing Adolescent Suicide Risk: Safety, Efficacy, and Connectome Phenotypes of Intravenous Ketamine

• ClinicalTrials.gov Identifier: NCT04613453
• Recruitment Status: Not yet recruiting
• First Posted: November 3, 2020
• Last Update Posted: January 29, 2021
• Sponsor: Yale University
• Collaborator: National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): Jennifer Dwyer, MD, PhD, Yale University

Tracking Information

• First Submitted Date: October 27, 2020
• First Posted Date: November 3, 2020
• Last Update Posted Date: January 29, 2021
• Estimated Study Start Date: March 2021
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 27, 2020)

Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: 2 days ]

The C-SSRS is an assessment of suicidal ideation and behavior in clinical and research settings. The C-SSRS consists of 16 questions that ask about suicidal ideation and behaviors (the first 10 questions comprise the ideation subscale and the last 6 comprise the behavior subscale). This 5-item subscale ranges from a minimum of 0 (corresponding to no suicidal ideation) to a maximum of 5 (representing active suicidal ideation with plan and intent).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 26, 2021)

• Montgomery Asberg Depression Rating Scale [ Time Frame: 2 days ]
  Montgomery Asberg Depression Rating Scale is an 10-item scale examines depressive symptoms and will be assessed at baseline (prior to any experimental treatment), prior to each experimental treatment, and weekly during the open phase of the trial. This 10-item scale ranges from 0 to 60, with higher values representing more intensive depressive symptoms.
• Change in Children's Depression Rating Scale [ Time Frame: Baseline to Day 11 ]
  Children's Depression Rating Scale-Revised is a 17-item scale examines depressive symptoms in children and adolescents using the combined report of the adolescent and the parent, synthesized by a clinician. It will be administered at baseline (prior to any experimental treatment), at the end of the blinded phase of the trial (Day 11), and monthly during the open phase of the trial. This 17-item clinical scale creates scores that range from 17 to 113, with higher scores representing more intensive depressive symptoms

Original Secondary Outcome Measures (submitted: October 27, 2020)

• Montgomery Asberg Depression Rating Scale [ Time Frame: Baseline ]
  Montgomery Asberg Depression Rating Scale is an 10-item scale examines depressive symptoms and will be assessed at baseline (prior to any experimental treatment), prior to each experimental treatment, and weekly during the open phase of the trial. This 10-item scale ranges from 0 to 60, with higher values representing more intensive depressive symptoms.
• Change in Children's Depression Rating Scale [ Time Frame: Baseline to Day 11 ]
  Children's Depression Rating Scale-Revised is a 17-item scale examines depressive symptoms in children and adolescents using the combined report of the adolescent and the parent, synthesized by a clinician. It will be administered at baseline (prior to any experimental treatment), at the end of the blinded phase of the trial (Day 11), and monthly during the open phase of the trial. This 17-item clinical scale creates scores that range from 17 to 113, with higher scores representing more intensive depressive symptoms

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Reducing Adolescent Suicide Risk: Safety, Efficacy, and Connectome Phenotypes of Intravenous Ketamine
• Official Title: Reducing Adolescent Suicide Risk: Safety, Efficacy, and Connectome Phenotypes of Intravenous Ketamine

Brief Summary

The purpose of this study is to determine if intravenous ketamine reduces suicidal thinking compared to an active placebo (midazolam) in adolescents who have treatment resistant depression and a recent history of a suicide event (defined as a suicide attempt, emergency room evaluation for suicidal thinking, or a transition to inpatient care for suicidality in the past 120 days).

The primary objective of this study is to determine whether ketamine reduces suicidal ideation (as measured via the C-SSRS, recent ideation scale) relative to an active control, midazolam, 48-hours after first administration in adolescents with TRD at high suicide risk.

Detailed Description

The main purpose of the study is to examine the safety, efficacy, response predictors, and post-treatment trajectory of adolescents with TRD and high suicide risk following a highly conservative repeat dosing ketamine infusion paradigm (four infusions of 0.5mg/kg each over two weeks) compared to an active control, midazolam. Those who are randomized to midazolam and remain ill have the option to cross-over to ketamine in the open phase. All participants will be followed closely for four months post-treatment and treated with standard of care depression treatment (medication management and cognitive behavioral therapy). Brain-based predictors of anti-suicidal responses will be assessed via connectome predictive modeling (CPM), examining functional brain circuits via fMRI before and after treatment.

Given the unregulated use of ketamine in the community at widely varying doses and frequencies, the safety data gathered from this highly conservative repeat dosing paradigm is critical to inform the field about potential risks. Efficacy data at rapid, short-term, and intermediate-term (4 month) timepoints will be critical to determining whether a larger study is warranted in this population. The assessment of brain-based predictors of response through the integration of functional neuroimaging adds an important measure of biological engagement that will inform subsequent studies and stands to contribute towards the goal of personalized medicine (i.e. determining not only if a treatment works, but in whom).

Aim 1: To evaluate the safety of treating adolescents with TRD at high suicide risk with a conservative repeat-dosing ketamine paradigm followed by standard of care treatment over 4 months. Hypothesis: We anticipate no untoward effects on medical outcomes (cardiovascular function and bladder health) or cognitive function (measured via Cogstate).

Aim 2: To evaluate the 48-hour impact of ketamine on suicidal ideation compared to midazolam, and to identify connectome phenotypes predictive of ideation post-treatment. Hypothesis: Ketamine will reduce suicidal thinking (Columbia Suicide Rating Scale, recent ideation subscale) compared to midazolam. CPM will identify networks predictive of ideation, validated via k-fold or leave-one-out cross-validation within the sample. The network measures obtained at this fixed ketamine dose will inform the design of larger clinical trials.

Aim 3 (exploratory): To describe the trajectory of suicidal thinking, depressive symptoms, and use of mental health resources in both ketamine responders and non-responders over 4 months.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Adolescent Suicide

Intervention

• Drug: Ketamine Infusion
  Participants will receive four Ketamine infusions over two weeks, each 0.5mg/kg over 40 minutes.
• Drug: Midazolam Infusion
  Participants will receive four Midazolam infusions over two weeks, each 0.045mg/kg over 40 minutes.

Study Arms

• Experimental: Ketamine Infusion
  Participants will receive four Ketamine infusions over two weeks, each 0.5mg/kg over 40 minutes.
  Intervention: Drug: Ketamine Infusion
• Active Comparator: Midazolam Infusion
  Participants will receive four Midazolam infusions over two weeks, each 0.045mg/kg over 40 minutes.
  Intervention: Drug: Midazolam Infusion

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: October 27, 2020): 66
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2025
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Male or female ages 13-17 years, inclusive
2. Meet DSM-5 criteria for Major Depressive Disorder by structured interview (MINI-KID+)
3. Children's Depression Rating Scale, Revised (CDRS-R) score ≥45 at screening
4. Failure to achieve remission with at least 2 antidepressant trials (e.g. SSRI, SNRI or TCA), meaning at least 6 weeks at therapeutic dosing, including at least 4 weeks of stable dosing
5. Suicide event within the past 120 days (i.e. a suicide attempt (defined as an act of potentially self-injurious behavior with explicit or inferred intent to die) -OR- degree of suicidal ideation requiring an emergency evaluation or a transition to higher level of care (e.g. intensive outpatient program, partial hospital program, inpatient)
6. Medically and neurologically healthy on the basis of physical examination and medical history.
7. Parents able to provide written informed consent and adolescents must additionally provide assent.
8. Stated willingness to comply with all study procedures and availability for the duration of the study
9. Provision of signed and dated informed consent form

Exclusion Criteria:

1. History of psychotic disorder, manic episode, or autism spectrum disorder diagnosed by MINI-KID
2. History of substance dependence diagnosis by MINI-KID (excluding tobacco) or positive urine toxicology
3. Intellectual disability (IQ<70) per medical history
4. Pregnancy (urine pregnancy tests on the day of infusions for menstruating girls) or lactation
5. Prior participation in a ketamine study, prior clinical psychiatric treatment with ketamine, or prior recreational use of ketamine
6. Pre-existing cardiovascular disease or untreated or unstable hypertension
7. Body weight greater than 80 kgs
8. Currently taking benzodiazepines or other medications that may cause respiratory depression, or lamotrigine, which is hypothesized to interfere with ketamine's mechanism of action

9. Inability to provide written informed consent according to the Yale Human Investigation Committee (HIC) guidelines in English.

   For participation in the fMRI scans only (participants with contraindications to fMRI may still participate in all other portions of the trial, providing they meet all other inclusion/exclusion criteria):

10. Any contraindication to MRI including severe claustrophobia, or metal in the body (including mental dental braces)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 13 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: Jennifer Dwyer, MD; jennifer.dwyer@yale.edu

Contact: Brooke Rivera, MSW; brooke.rivera@yale.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04613453
• Other Study ID Numbers: 2000029003; 1R01MH125203-01 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

• Responsible Party: Jennifer Dwyer, MD, PhD, Yale University
• Study Sponsor: Yale University
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Not Provided
• PRS Account: Yale University
• Verification Date: January 2021