Study of IV Ketamine for Emergency Department Treatment of Adolescent Suicidal Ideation (KSI)

A Double Blinded, Randomized, Placebo Controlled, Parallel Arm Pilot Trial of Intravenous Ketamine for Emergency Department Treatment of Suicidal Ideation in a Pediatric Population.

Approximately 20% of Canadian adolescents experience thoughts of suicide, or suicidal ideation (SI), and suicide is the second leading cause of death among Canadians aged 15-19 years. The emergency department at CHEO sees approximately four patients per day with SI. Even though this is a medical emergency, there are no fast-acting treatments available.

Ketamine is a medication that is commonly used to safely sedate children who require painful procedures in the emergency department. For nearly ten years, intravenous ketamine has also been shown to rapidly reduce SI in adults. However, ketamine as a treatment for SI has never been studied in adolescents. The primary study objective is to pilot a clinical trial that investigates intravenous ketamine to emergently treat SI in adolescents.

If intravenous ketamine can relieve symptoms of SI for youth, this would have tremendous effects on patients and would dramatically change how physicians treat adolescent mental health emergencies. If ketamine is effective for several weeks, as it is in adults, it will help temporize patients until they receive more long-term psychiatric care. At the system level, it has the potential to reduce emergency visits and lengthy admissions. The investigators feel that the results of this study will be generalizable to pediatric centres across Canada and beyond.

Study Overview

• Status: Recruiting
• Conditions: Suicidal Ideation; Suicidal Ideas
• Intervention / Treatment: Drug: Ketamine Hydrochloride; Drug: Normal saline

Detailed Description

Suicidal ideation (SI) is a common and often severe cause of morbidity in adolescents. Patients frequently present to the emergency department (ED) with severe and distressing thoughts of self-harm or suicide, and yet, there is currently no acute therapeutic intervention to offer them. The standard of care for patients who do not require admission is to discharge them home with resources for websites, apps, or telephone help lines. These interactions fail to address the underlying suicidal thoughts and leave patients, families and providers feeling very dissatisfied. Medications are nearly never initiated in the ED and patients who are already taking anti-depressants experience a very slow therapeutic onset, and often with unfavourable side effects that make medication compliance difficult and sometimes impossible.

For nearly ten years, intravenous ketamine has been shown to be an efficacious acute therapy in adult patients with suicidal ideation. A single dose of intravenous (IV) ketamine can rapidly reduce the severity of suicidal ideation by moderate to large effect sizes (Cohen's d = 0.5-0.8) during an ED visit, in an adult population. However, it has never been studied in a pediatric population. The study primary objective is to determine the feasibility of conducting a trial that investigates the efficacy of IV ketamine to reduce suicidal ideation in adolescents in the pediatric emergency department.

If intravenous ketamine can rapidly alleviate the severity of SI for adolescents, this would have tremendous effects on patients and families and dramatically change how ED physicians treat pediatric mental health emergencies. It would increase patient safety, reduce patient distress, morbidity, possibly mortality and alleviate family stress. If the therapeutic effect of ketamine is maintained for several days, as it is in adults, it will help temporize patient symptoms while they are connected with more long-term psychiatric care. At the system level, it may reduce rates of ED visits and, often lengthy, admissions to hospital. The investigators feel that the results of this study will be generalizable to pediatric centres across Ontario, Canada and beyond.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Maala Bhatt, MD; Phone Number: 6137377600; Email: mbhatt@cheo.on.ca

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L1
      • Recruiting
      • Children's Hospital of Eastern Ontario
      • Contact: Tyrus Crawford; Phone Number: 4178 6137377600; Email: tcrawford@cheo.on.ca
      • Contact: Maala Bhatt, MD, MSc.; Phone Number: 4178 6137377600; Email: mbhatt@cheo.on.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Responds "yes" to Ask Suicide Screening Question (ASQ) #5 at triage, which asks; "Are you having thoughts of killing yourself right now?"
2. Moderate to severe suicidal ideation, defined as score ≥ 3 on the first 5 questions of the Beck Scale for Suicidal Ideation (SSI5)
3. Age 12 to 17 years, inclusive
4. Medically clear (deemed fit for participation in the trial), as judged by the treating physician. Minimum criteria required to be deemed medically clear are: a) No evidence of serious physical injury requiring urgent intervention b) No evidence of acute ingestion requiring monitoring, blood tests, imaging or ECG or in the context of acute ingestion they have satisfied the requisite number of hours of post-ingestion monitoring with no further need for intervention.

Exclusion Criteria:

1. Acute intoxication from any substance, including alcohol
2. Previously enrolled in the current study or currently enrolled in another clinical trial
3. History of intellectual disability or autism spectrum disorder by patient/parent report
4. Active, or history of, psychosis or psychotic disorder
5. History of non-psychiatric neurologic disorder (e.g., epilepsy)
6. Any of the following contraindications to ketamine based on the drug monograph: a) Known allergy or hypersensitivity to ketamine by patient history b) History of cerebrovascular accident (stroke or aneurysm) c) History of elevated intracranial pressure or idiopathic intracranial hypertension d) Significant hypertension requiring daily medication e) Severe cardiac decompensation
7. On an involuntary psychiatric hold
8. Requires physical or chemical restraint
9. History of violence while in hospital
10. Pregnant or breastfeeding
11. Received opioids in the 2-hours prior to study screening

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketamine; Participants in the intervention group will receive 0.5mg/kg of 1mg/mL intravenous ketamine (50 mg maximum) over 40 minutes.	Drug: Ketamine Hydrochloride; See arm description; Other Names: Ketamine
Placebo Comparator: Normal Saline; Participants in the control group will receive 0.5mL/kg intravenous normal saline (50 ml maximum) over 40 minutes	Drug: Normal saline; See arm description

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of eligible participants who complete the study protocol	This is a feasibility measure; the investigators will report the number of patients who are screened for participation, are eligible, eligible and consent, complete the intervention, complete study follow-up	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline distribution of responses to the first 5 questions of Beck Scale for Suicidal Ideation (SSI5)	Estimates of central tendency (mean) and variance (standard deviation) from participant responses to the SSI5 at baseline will be measured and reported. These parameters will aid with sample size estimates for the larger definitive trial. The first 5 questions of Beck Scale for Suicidal Ideation (SSI5) is a five item questionnaire scored from 0 to 10, with higher scores indicating more severe suicidal ideation.	Baseline
Baseline distribution of responses to the suicide item (#9) from the Beck Depression Index (BDI9).	Estimates of central tendency (mean) and variance (standard deviation) from participant responses to the BDI9 at baseline will be measured and reported. These parameters will aid with sample size estimates for the larger definitive trial. The Beck Depression Inventory is a 21 item depression questionnaire. Item 9 rates suicidal ideation from 0 (I don't have thoughts of killing myself) to 3 (I would kill myself if I had the chance) with higher scores indicating more severe suicidal ideation.	Baseline
Baseline pragmatic assessment of the first 5 questions of the Beck Scale for Suicidal Ideation (SSI5), the suicide item (#10) from the Montgomery-Asberg Depression Rating Scale (MADRS10), and the suicide item (#9) from the Beck Depression Index (BDI9).	Pragmatic assessment of the tool validity by asking each participant, which of the three tools best captures how they are feeling at baseline.	Baseline
Baseline distribution of responses to the suicide item (#10) from the Montgomery-Asberg Depression Rating Scale (MADRS10)	Estimates of central tendency (mean) and variance (standard deviation) from participant responses to the MADRS10 at baseline will be measured and reported. These parameters will aid with sample size estimates for the larger definitive trial. The MADRS is a 10 item, 6-point, depression scale. Item 10 rates suicidal ideation from 0 (Enjoys life or takes it as it comes), to 6 (Explicit plans for suicide when there is an opportunity. Active preparations for suicide) with higher scores indicating more severe suicidal ideation.	Baseline
Assessment of blinding	Blinding adequacy will be measured by asking each participant which intervention they think they received at the end of the 40 minute study drug infusion.	Baseline
Treatment efficacy measured by the Beck Scale for Suicidal Ideation (SSI5)	Change in suicidal ideation severity from baseline at the end of the 40-minute medication infusion will be measured using SSI5. The first 5 questions of Beck Scale for Suicidal Ideation (SSI5) is a five item questionnaire scored from 0 to 10, with higher scores indicating more severe suicidal ideation.	40 minutes after the beginning of the infusion
Treatment efficacy measured by the suicide item (#10) from the Montgomery-Asberg Depression Rating Scale (MADRS10)	Change in suicidal ideation severity from baseline at the end of the 40-minute medication infusion will be measured using MADRS10. The MADRS is a 10 item, 6-point, depression scale. Item 10 rates suicidal ideation from 0 (Enjoys life or takes it as it comes), to 6 (Explicit plans for suicide when there is an opportunity. Active preparations for suicide) with higher scores indicating more severe suicidal ideation.	40 minutes after the beginning of the infusion
Treatment efficacy measured by the suicide item (#9) from the Beck Depression Index (BDI9)	Change in suicidal ideation severity from baseline at the end of the 40-minute medication infusion will be measured using BDI9. The Beck Depression Inventory is a 21 item depression questionnaire. Item 9 rates suicidal ideation from 0 (I don't have thoughts of killing myself) to 3 (I would kill myself if I had the chance) with higher scores indicating more severe suicidal ideation.	40 minutes after the beginning of the infusion
Treatment durability measured by the Beck Scale for Suicidal Ideation (SSI5)	The durability of a treatment effect on suicidal ideation will be measured by SSI5 at 80 minutes, 120 minutes, 24 hours, and seven days post treatment start. The first 5 questions of Beck Scale for Suicidal Ideation (SSI5) is a five item questionnaire scored from 0 to 10, with higher scores indicating more severe suicidal ideation.	40, 80, 120 minutes after the beginning of the infusion as well as 24 hours and 7 days post enrollment
Treatment durability measured by the suicide item (#10) from the Montgomery-Asberg Depression Rating Scale (MADRS10)	The durability of a treatment effect on suicidal ideation will be measured by MADRS10 at 80 minutes, 120 minutes, 24 hours, and seven days post treatment start. The MADRS is a 10 item, 6-point, depression scale. Item 10 rates suicidal ideation from 0 (Enjoys life or takes it as it comes), to 6 (Explicit plans for suicide when there is an opportunity. Active preparations for suicide) with higher scores indicating more severe suicidal ideation.	40, 80, 120 minutes after the beginning of the infusion as well as 24 hours and 7 days post enrollment
Treatment efficacy measured by the suicide item (#9) from the Beck Depression Index (BDI9)	The durability of a treatment effect on suicidal ideation will be measured by BDI9 at 80 minutes, 120 minutes, 24 hours, and seven days post treatment start. The Beck Depression Inventory is a 21 item depression questionnaire. Item 9 rates suicidal ideation from 0 (I don't have thoughts of killing myself) to 3 (I would kill myself if I had the chance) with higher scores indicating more severe suicidal ideation.	40, 80, 120 minutes after the beginning of the infusion as well as 24 hours and 7 days post enrollment
Admission to Hospital	Proportion of patients who require hospital admission at the enrolment ED visit	Enrollment visit
Length of Stay in Hospital	The mean and standard deviation of length of hospital stay for patients admitted at the enrollment visit	30 days post enrollment
ED revisits	Proportion of patients who have an ED visit(s) for mental health complaints within 30 days following enrolment	30-days post enrollment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Outcome 3: Vomiting	Vomiting during or after the infusion	Enrollment visit
Safety Outcome 5: Death	Death from any cause within 30 days following enrolment	30-days post enrolment
Safety Outcome 1: Clinically significant tachycardia	Present at 120 minutes post infusion and requires intervention by the treating team	Enrollment visit
Safety Outcome 2: Clinically significant hypertension	Present at 120 minutes post infusion and requires intervention by the treating team	Enrollment visit
Safety Outcome 4: Dissociation	Clinician-Administered Dissociative States Scale (CADSS; minimum score 0, maximum score 24) - total score of 6 or more OR 4 on any single question AND clinically dissociated	During the infusion

Collaborators and Investigators

• Sponsor: Children's Hospital of Eastern Ontario
• Investigators: Study Director: Tyrus Crawford, BA, CHEO

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2024
• Primary Completion (Actual): May 29, 2024
• Study Completion (Estimated): June 28, 2024

Study Registration Dates

• First Submitted: April 10, 2024
• First Submitted That Met QC Criteria: April 12, 2024
• First Posted (Actual): April 15, 2024

Study Record Updates

• Last Update Posted (Actual): June 5, 2024
• Last Update Submitted That Met QC Criteria: June 4, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Pathologic Processes; Disease Attributes; Self-Injurious Behavior; Suicide; Emergencies; Suicidal Ideation; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: 23/02E

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