Ketamine Versus Midazolam for Recurrence of Suicidality in Adolescents

Sponsor

University of Texas Southwestern Medical Center (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT04592809

Collaborator

National Institute of Mental Health (NIMH) (NIH)

264

Enrollment

Location

Arms

24.8

Anticipated Duration (Months)

10.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study design is a double-blind, randomized, active-control trial of adolescents (ages 13-18 years) with recent suicidal behaviors (suicide attempt or increased suicidal ideation). All participants will be treated through a suicide prevention IOP (typically 6-8 weeks), as well as clinically indicated psychosocial and/or psychopharmacological treatments. Ketamine/midazolam treatment will occur twice weekly during the first two weeks of the study, followed by weekly assessments through week 12.

Condition or Disease	Intervention/Treatment	Phase
Suicide, Attempted Suicide and Depression Suicide Threat	Drug: Ketamine Hydrochloride Drug: Midazolam Hydrochloride	Phase 3

Detailed Description

Youth patients (ages 13-18) who have recent suicidality (defined as suicidal ideation or behavior), and who are enrolled or expected to be enrolled in an intensive outpatient program (IOP) will be recruited for participation in the study. Upon informed consent/assent, baseline data will be collected regarding mood symptoms, suicidal ideation and behavior, associated comorbidities, and treatment history. Youth participants will be randomized to ketamine or midazolam, which will be provided twice weekly for two weeks. Participants will then have follow-up assessments visits through week 12 to continue to monitor outcomes. Participants may be recruited directly from the IOP or from the ED or inpatient psychiatric unit, provided they have undergone evaluation and are confirmed to begin IOP treatment. The baseline visit and first infusion must be +/- 10 days of IOP enrollment.

Enrollment of 264 subjects is expected to take place over a period of approximately 36 months. Enrolled participants will be involved in the study for approximately 14 weeks (screening plus 12 weeks of study follow-up visits). Visits include a Screening Visit, a Baseline, 4 Study Intervention Visits, and 10 Follow-Up Visits. Multiple streams of outcome measures will be utilized for this protocol, including self-report measures, research assessor-completed measures, clinic level measures, and behavioral measures.

Aim 1. Evaluate reduction in frequency of suicidal events associated with two-week twice-weekly course of ketamine treatment versus midazolam.

Aim 2. Evaluate reduction in implicit suicidal cognition with ketamine.

Aim 3. Evaluate reduction in depressive symptoms and suicidality with ketamine.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

264 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Youth will be randomized in 1:1 fashion to either intravenous ketamine (0.5 mg/kg) or midazolam (0.02 mg/kg) twice weekly for 2 weeks followed by weekly visits for 10 weeks (for a total of 12-week post-randomization observation period).Youth will be randomized in 1:1 fashion to either intravenous ketamine (0.5 mg/kg) or midazolam (0.02 mg/kg) twice weekly for 2 weeks followed by weekly visits for 10 weeks (for a total of 12-week post-randomization observation period).

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

The investigator, patient, and study staff will be blinded. Packaging and labeling of the study drugs will be performed by the research pharmacy in a way to ensure blinding throughout the study. No members of the study team will have access to the randomization scheme during the conduct of the study. The Research Pharmacist and the CDRC (Center for Depression Research and Clinical Care) Program Manager will have access to the treatment assignment in the event of an emergency. The treatment code must not be broken except in medical emergencies when the appropriate management of the patient necessitates knowledge of the treatment randomization. The investigator retains the right to break the code for serious adverse events (SAEs) that are unexpected and are suspected to be causally related to a study drug and that potentially require expedited reporting to regulatory authorities.

Primary Purpose:

Treatment

Official Title:

Double-Blind Randomized Controlled Trial of Acute-Course of Ketamine Versus Midazolam for Recurrence of Suicidality in Adolescents

Anticipated Study Start Date :

Dec 6, 2022

Anticipated Primary Completion Date :

Dec 31, 2024

Anticipated Study Completion Date :

Dec 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Ketamine 0.5 mg/kg intravenous ketamine will be administered 4 times in a 2 week period. Ketamine will be dissolved in 0.9% sodium chloride in a total volume of 100ml and administered with a syringe infusion pump at a constant rate.	Drug: Ketamine Hydrochloride infused over a 40 minute period Other Names: Ketalar Drug: Midazolam Hydrochloride infused over a 40 minute period Other Names: Versed
Active Comparator: Midazolam 0.02 mg/kg midazolam will be administered 4 times in a 2 week period. Midazolam will be dissolved in 0.9% sodium chloride in a total volume of 100ml and administered with a syringe infusion pump at a constant rate.	Drug: Ketamine Hydrochloride infused over a 40 minute period Other Names: Ketalar Drug: Midazolam Hydrochloride infused over a 40 minute period Other Names: Versed

Arm

Intervention/Treatment

Active Comparator: Ketamine

0.5 mg/kg intravenous ketamine will be administered 4 times in a 2 week period. Ketamine will be dissolved in 0.9% sodium chloride in a total volume of 100ml and administered with a syringe infusion pump at a constant rate.

Drug: Ketamine Hydrochloride

infused over a 40 minute period

Other Names:

Ketalar

Drug: Midazolam Hydrochloride

infused over a 40 minute period

Other Names:

Versed

Active Comparator: Midazolam

0.02 mg/kg midazolam will be administered 4 times in a 2 week period. Midazolam will be dissolved in 0.9% sodium chloride in a total volume of 100ml and administered with a syringe infusion pump at a constant rate.

Drug: Ketamine Hydrochloride

infused over a 40 minute period

Other Names:

Ketalar

Drug: Midazolam Hydrochloride

infused over a 40 minute period

Other Names:

Versed

Outcome Measures

Primary Outcome Measures

Number of participants with suicidal event, which is defined as suicide attempt, or emergency department visit, or inpatient hospitalization due to suicidality [12 weeks]
Concise Health Risk Tracking Clinician-Rated Behavior Module (CHRT-C) will be used to identify suicidal events. The CHRT-C consists of nine clinician-rated yes/no items about specific behaviors (i.e., suicidal ideation, suicidal attempt, preparatory acts, non-suicidal self-injury (NSSI), other injuries, etc.). At the initial administration, this instrument captures lifetime information; at subsequent administrations, it will capture information since the last visit.

Secondary Outcome Measures

Death/Suicide Implicit Association Test (IAT) [2 weeks]
The IAT is a performance-based measure of cognition that has demonstrated good reliability and sensitivity to change. The IAT measures associations based on response latency where the response time is compared across categorization tasks.
Depression symptoms as measured by CHRT-SR a self report measure [2 weeks]
(specify for each) Concise Health Risk Tracking Self-Report (CHRT-SR) consists of 14 questions with responses ranging from 0 (strongly disagree) to 4 (strongly agree). 1) the Propensity subscale, which consists of 9 questions and 4 factors (pessimism, helplessness, social support, and despair) and a score range of 0-36; and the Suicidal Thoughts subscale, which consists of 3 questions and a score range of 0-9 (which will serve as the primary suicidal behavior outcome in this study); and 3) Impulsivity, which consists of 2 questions and a score range of 0-6. A total score is also calculated, ranging from 0 to 56.
Number of participants with suicidal events/behaviors as measured by CHRT-C a self report measure [2 week]
Concise Health Risk Tracking Clinician-Rated Behavior Module (CHRT-C). consists of nine clinician-rated yes/no items about specific behaviors (i.e., suicidal ideation, suicidal attempt, preparatory acts, non-suicidal self-injury (NSSI), other injuries, etc.). At the initial administration, this instrument captures lifetime information; at subsequent administrations, it will capture information since the last visit. a yes on any of the 9 questions indicates presence of suicidal event/behaviors (ideation, attempt, preparatory acts, non suicidal self injury, other injury).
Depression symptoms as measured by QIDS-A-SR, self report measure [2 weeks]
Quick Inventory of Depressive Symptomatology - Adolescent, Self-Report (QIDS-A-SR) is a depressive symptom severity measure that rates all nine criterion symptoms of MDD. A score of 0-51 will be calculated, with 51 indicating the highest severity.
Depression symptoms as measured by QIDS-A-SR, Parent report measure [2 weeks]
Quick Inventory of Depressive Symptomatology - Adolescent, Parent Report (QIDS-A-SR) is a depressive symptom severity measure that rates all nine criterion symptoms of MDD. A score of 0-51 will be calculated, with 51 indicating the highest severity.

Eligibility Criteria

Criteria

Ages Eligible for Study:

13 Years to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria

Study participants must:

Be adolescents (aged 13-18 years);
Have had a recent suicidal event (suicide attempt or significant suicidal ideation with a plan or intent warranting emergency evaluation or inpatient hospitalization within the past 30 days);
Receiving standard of care treatment that includes clinically indicated psychosocial and/or psychopharmacological treatment;
Have a current primary diagnosis of a depressive disorder based on the MINI-KID (other psychiatric disorders are acceptable, but must not be primary);
Be able to complete assessments in English.
Use effective method of contraception during and for 90 days following the end of treatment for female and male participants. Recommended methods of birth control are namely, consistent use of an approved hormonal birth control (pill/patches, rings), an intrauterine device (IUD), contraceptive injection, double barrier methods, sexual abstinence, or sterilization.

Exclusion Criteria:

• Study participants must not:

Have lifetime schizophrenia, psychotic disorder, pervasive developmental disorder, or mental retardation;
Have current mania, hypomania, mixed episode, or obsessive-compulsive disorder;
Have a primary diagnosis other than a depressive disorder;
Have moderate to severe alcohol or substance use disorder within the past six months (based on MINI-KID). If there is a positive urine drug screen at screening, the urine drug screen will be repeated at each infusion visit. Positive urine drug screen will be reviewed by study physician and infusion will proceed as long as no safety risk was identified;
If female, be pregnant, lactating, or nursing. Women of childbearing potential must have a negative urine pregnancy test prior to all infusions;
Have unstable medical conditions or with clinically significant laboratory values or an electrocardiogram (ECG) that would pose significant risk;
Be at serious suicidal risk that cannot be managed in the outpatient setting;
Have prior treatment for depression with or contraindications to ketamine, esketamine, or, midazolam;
Currently being treated with benzodiazepines, non-benzodiazepine sleeping medication (including zolpidem, eszopiclone, zaleplon, suvorexant, and ramelteon), barbiturates, dextromethorphan and opioids will be asked to discontinue for at least 1 week or 5 half-lives whichever is longer. This applies to the screening period. During this 2-week period, these medications will be avoided, and their use permitted to manage any new side effects as long as their use does not increase the risk of study-drug infusion. ADHD stimulant medications will be permitted with last dose at least 24 hours prior to infusion. All concomitant medications will be evaluated by the study physician to determine if the type and dose of concomitant medication requires discontinuation and will be excluded if the concomitant medication could substantially increase the risk of study infusion.