Back to results

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

Primary Purpose

Adolescent Suicide, Adolescent Depression

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Ketamine Infusion

Midazolam Infusion

About this trial

This is an interventional treatment trial for Adolescent Suicide focused on measuring Intravenous Ketamine

Eligibility Criteria

13 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Ages 13-17 years, inclusive
Meet DSM-5 criteria for Major Depressive Disorder by structured interview (MINI-KID+)
Children's Depression Rating Scale, Revised (CDRS-R) score ≥45 at screening
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
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)
Columbia Suicide Severity Rating Scale ideation score of ≥ 1 at screening
Medically and neurologically healthy on the basis of physical examination, medical history, and the clinical judgement of the evaluating physician.
Parents able to provide written informed permission and adolescents must additionally provide assent.
Stated willingness to comply with all study procedures and availability for the duration of the study
Provision of signed and dated parental permission and adolescent assent form. If there are two parents or guardians, both must provide permission and each must sign a separate permission form.

Exclusion Criteria:

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

Sites / Locations

Yale New Haven HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Ketamine Infusion

Midazolam Infusion

Arm Description

Participants will receive four Ketamine infusions over two weeks, each 0.5mg/kg over 40 minutes.

Participants will receive four Midazolam infusions over two weeks, each 0.045mg/kg over 40 minutes.

Outcomes

Primary Outcome Measures

Columbia-Suicide Severity Rating Scale (C-SSRS)

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).

Secondary Outcome Measures

Montgomery Asberg Depression Rating Scale

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

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

Full Information

NCT ID

NCT04613453

First Posted

October 27, 2020

Last Updated

August 28, 2023

Sponsor

Yale University

Collaborators

National Institute of Mental Health (NIMH)

1. Study Identification

Unique Protocol Identification Number

NCT04613453

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Recruiting

Study Start Date

January 21, 2022 (Actual)

Primary Completion Date

December 2024 (Anticipated)

Study Completion Date

March 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Yale University

Collaborators

National Institute of Mental Health (NIMH)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Adolescent Suicide, Adolescent Depression

Keywords

Intravenous Ketamine

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

66 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Ketamine Infusion

Arm Type

Experimental

Arm Description

Participants will receive four Ketamine infusions over two weeks, each 0.5mg/kg over 40 minutes.

Arm Title

Midazolam Infusion

Arm Type

Active Comparator

Arm Description

Participants will receive four Midazolam infusions over two weeks, each 0.045mg/kg over 40 minutes.

Intervention Type

Drug

Intervention Name(s)

Ketamine Infusion

Intervention Description

Participants will receive four Ketamine infusions over two weeks, each 0.5mg/kg over 40 minutes.

Intervention Type

Drug

Intervention Name(s)

Midazolam Infusion

Intervention Description

Participants will receive four Midazolam infusions over two weeks, each 0.045mg/kg over 40 minutes.

Primary Outcome Measure Information:

Title

Columbia-Suicide Severity Rating Scale (C-SSRS)

Description

Time Frame

2 days

Secondary Outcome Measure Information:

Title

Montgomery Asberg Depression Rating Scale

Description

Time Frame

2 days

Title

Change in Children's Depression Rating Scale

Description

Time Frame

Baseline to Day 11

10. Eligibility

Sex

All

Minimum Age & Unit of Time

13 Years

Maximum Age & Unit of Time

17 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Ages 13-17 years, inclusive Meet DSM-5 criteria for Major Depressive Disorder by structured interview (MINI-KID+) Children's Depression Rating Scale, Revised (CDRS-R) score ≥45 at screening Continued clinically significant depressive symptoms despite an SRI trial (e.g. SSRI or SNRI) of adequate dose and duration, meaning at least 6 weeks at therapeutic dosing, including at least 4 weeks of stable dosing 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) Columbia Suicide Severity Rating Scale ideation score of ≥ 1 at screening Medically and neurologically healthy on the basis of physical examination, medical history, and the clinical judgement of the evaluating physician. Parents able to provide written informed permission and adolescents must additionally provide assent. Stated willingness to comply with all study procedures and availability for the duration of the study Provision of signed and dated parental permission and adolescent assent form. If there are two parents or guardians, both must provide permission and each must sign a separate permission form. Exclusion Criteria: History of psychotic disorder, manic episode, or autism spectrum disorder diagnosed by MINI-KID History of substance dependence diagnosis by MINI-KID (excluding tobacco) or positive urine toxicology Intellectual disability (IQ<70) per medical history Pregnancy (urine pregnancy tests on the day of infusions for menstruating girls) or lactation Prior participation in a ketamine study, prior clinical psychiatric treatment with ketamine, or prior recreational use of ketamine Pre-existing cardiovascular disease or untreated or unstable hypertension Body weight greater than 80 kgs Currently taking benzodiazepines or other medications that may cause respiratory depression, or lamotrigine, which is hypothesized to interfere with ketamine's mechanism of action 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): Any contraindication to MRI including severe claustrophobia, or metal in the body (including mental dental braces)

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Brooke Rivera, LMSW

Phone

203-785-7880

brooke.rivera@yale.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Michael Bloch, MD MS

michael.bloch@yale.edu

Facility Information:

Facility Name

Yale New Haven Hospital

City

New Haven

State/Province

Connecticut

ZIP/Postal Code

06510

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Michael Bloch, MD, MS

michael.bloch@yale.edu

First Name & Middle Initial & Last Name & Degree

Michael Bloch, MD, MS

12. IPD Sharing Statement

Plan to Share IPD

Yes

Learn more about this trial

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

We'll reach out to this number within 24 hrs