Ketamine for Severe Adolescent Depression: Intermediate-term Safety and Efficacy (SAD-KIDS)

• ClinicalTrials.gov Identifier: NCT03889756
• Recruitment Status: Not yet recruiting
• First Posted: March 26, 2019
• Last Update Posted: September 25, 2019
• Sponsor: Yale University
• Information provided by (Responsible Party): Yale University

Tracking Information

• First Submitted Date: March 22, 2019
• First Posted Date: March 26, 2019
• Last Update Posted Date: September 25, 2019
• Estimated Study Start Date: September 2019
• Estimated Primary Completion Date: September 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 22, 2019)

• Evaluate the efficacy of a multiple-dosing ketamine infusion paradigm (2 infusions per week for 3 weeks) compared to midazolam in adolescents with treatment resistant depression [ Time Frame: Day 18 ]
  Establish if repeated ketamine will be efficacious medically and psychiatrically, as measured by a significant reduction in CDRS score in those treated with ketamine at the end of the dosing paradigm
• Evaluate the tolerability of a multiple-dosing ketamine infusion paradigm (2 infusions per week for 3 weeks) compared to midazolam in adolescents with treatment resistant depression [ Time Frame: Day 18 ]
  Establish if repeated ketamine will be tolerated as measured by drop-out rates

• Original Primary Outcome Measures: Same as current
• Change History: Complete list of historical versions of study NCT03889756 on ClinicalTrials.gov Archive Site
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Ketamine for Severe Adolescent Depression: Intermediate-term Safety and Efficacy
• Official Title: Ketamine for Severe Adolescent Depression: Intermediate-term Safety and Efficacy
• Brief Summary: The purpose of this study is to evaluate the intermediate-term efficacy and tolerability of a multiple-dosing ketamine infusion paradigm for the treatment of medication-refractory major depressive disorder (MDD). We are using a two-phase design. The first phase is a 3-week double blind parallel design clinical trial comparing 6 infusions of ketamine compared to 6 infusions of midazolam in 24 adolescents with treatment resistant depression. The primary outcome of this phase will be Children's Depression Rating Scale (CDRS) score at Day 18. The second phase is a 6-month open phase in which patients who received midazolam and remain depressed with be offered open ketamine treatment (6 infusions over 3 weeks). All participants will be followed weekly for 6 months and tracked for time to relapse.
• Detailed Description: The purpose of this study is to evaluate the intermediate-term efficacy and tolerability of a multiple-dosing ketamine infusion paradigm for the treatment of medication-refractory major depressive disorder (MDD). The specific aims of the study are: To evaluate the efficacy and tolerability of a multiple-dosing ketamine infusion paradigm (2 infusions per week for 3 weeks) compared to midazolam in adolescents with treatment resistant depression (TRD), . To test these aims we have designed a two-phase trial. The first phase is a 3-week double blind parallel design clinical trial comparing 6 infusions of ketamine compared to 6 infusions of midazolam in 24 adolescents with TRD. The primary outcome of this phase will be Children's Depression Rating Scale (CDRS) score at Day 18. The second phase is a 6-month open phase in which patients who received midazolam and remain depressed with be offered open ketamine treatment (6 infusions over 3 weeks). All participants will be followed weekly for 6 months and tracked for time to relapse. In those who initially responded to ketamine, symptom triggered maintenance infusions will be offered during this 6-month time period. All participants will receive standard of care treatment in addition to experimental procedures, and will be tracked monthly with extensive neurocognitive assessments.
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Phase 1 is a double-blind, midazolam-controlled parallel design trial; Phase 2 is an open extension.

Masking: Double (Participant, Outcomes Assessor)
Masking Description:

Participants will not be told what medication they are receiving; physicians absent from the infusion paradigm will perform blinded clinical efficacy ratings.

Primary Purpose: Treatment

• Condition: Major Depressive Disorder

Intervention

• Drug: Ketamine infusion
  The dose of ketamine established in prior research (0.5 mg/kg over 40 minutes) will be used in this study to minimize risks. The maximum total single dose allowed in this study will be 40mg, corresponding to a weight of 80kg.
• Drug: Midazolam infusion
  The weight-based midazolam dosing established in prior ketamine trials in adults (0.045mg/kg) will be used to minimize risks, as this is considered a very low dose compared to the sedation literature. The maximum total dose allowed in this study will be 3.6mg per infusion, corresponding to a weight of 80kg.

Study Arms

• Experimental: Ketamine
  Ketamine is an FDA-approved anesthetic agent that is commonly used to induce surgical anesthesia due to its low incidence of significant respiratory depression and hypotension. It as a N-methyl-D-aspartate (NMDA) receptor antagonist and glutamatergic modulator, and has been demonstrated in multiple controlled clinical trials to have rapidly acting antidepressant and anti-suicidal effects in adults.
  Intervention: Drug: Ketamine infusion
• Placebo Comparator: Midazolam
  Midazolam, the active control in this study, is a medication that is approved by the Food and Drug Administration as a sedative for both children and adults.It is a benzodiazepine with a short half-life that was chosen so as to blind the psychotomimetic effects of Ketamine.
  Intervention: Drug: Midazolam infusion

Publications *

• Richmond TK, Rosen DS. The treatment of adolescent depression in the era of the black box warning. Curr Opin Pediatr. 2005 Aug;17(4):466-72. Review.
• Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994 Mar;51(3):199-214.
• Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006 Aug;63(8):856-64.
• Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM, Iqbal S, Pillemer S, Foulkes A, Shah A, Charney DS, Mathew SJ. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013 Oct;170(10):1134-42. doi: 10.1176/appi.ajp.2013.13030392.
• Wilkinson ST, Toprak M, Turner MS, Levine SP, Katz RB, Sanacora G. A Survey of the Clinical, Off-Label Use of Ketamine as a Treatment for Psychiatric Disorders. Am J Psychiatry. 2017 Jul 1;174(7):695-696. doi: 10.1176/appi.ajp.2017.17020239.

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: March 22, 2019): 24
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 2022
• Estimated Primary Completion Date: September 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Male or female ages 13-17 years
2. Meet DSM-5 (Diagnostic and Statistical Manual 5 ) criteria for Major Depressive Disorder by structured interview (MINI-KID)
3. Children's Depression Rating Scale, Revised CDRS score ≥40 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. Stable psychiatric medications and doses for the month prior to enrollment. Subjects may continue to engage in any ongoing psychotherapy.
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.

Exclusion Criteria:

1. History of psychotic disorder, manic episode, 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 treatment with ketamine for depression or prior recreational use of ketamine.
6. Inability to provide written informed consent according to the Yale Human Investigation Committee (HIC) guidelines in English.

Sex/Gender

• Sexes Eligible for Study: All

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

Contacts

Contact: David Zakur; 203 785-6906; pedidepression@yale.edu

Contact: Jennifer Dwyer, MD; 203 737-4809; jennifer.dwyer@yale.edu

• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT03889756
• Other Study ID Numbers: 2000023857
• Has Data Monitoring Committee: Not Provided

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: Not Provided
• Responsible Party: Yale University
• Study Sponsor: Yale University
• Collaborators: Not Provided

Investigators

• Principal Investigator: Michael H. Bloch, MD; Yale University
• Study Director: Jennifer Dwyer, MD; Yale University

• PRS Account: Yale University
• Verification Date: September 2019