Ketamine for Treatment Resistant Late-Life Depression

• ClinicalTrials.gov Identifier: NCT02556606
• Recruitment Status: Completed
• First Posted: September 22, 2015
• Results First Posted: August 9, 2021
• Last Update Posted: January 11, 2022
• Sponsor: VA Office of Research and Development
• Information provided by (Responsible Party): VA Office of Research and Development

Tracking Information

• First Submitted Date: June 25, 2015
• First Posted Date: September 22, 2015
• Results First Submitted Date: April 13, 2021
• Results First Posted Date: August 9, 2021
• Last Update Posted Date: January 11, 2022
• Actual Study Start Date: October 1, 2015
• Actual Primary Completion Date: March 31, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 15, 2021)

Percentage of Participants Demonstrating at Least a 50% Reduction on Montgomery-Asberg Depression Rating Scale Scores [ Time Frame: Day 7 post-infusion ]

To determine the best performing intervention among three sub-anesthetic doses of a single ketamine (0.1 mg/kg, 0.25 mg/kg, and 0.50 mg/kg) and midazolam (0.03 mg/kg) in Veterans with LL-TRD as measured by the percentage of participants demonstrating at least a 50% reduction from pre-treatment baseline on Montgomery-Asberg Depression Rating Scale (MADRS; score range 0 - 60, higher scores meaning more severe depression) scores at 7 days post-infusion.

Original Primary Outcome Measures (submitted: September 18, 2015)

time to relapse [ Time Frame: four-week, post-infusion follow-up ]

the durability of benefit of a single KET 0.5 mg/kg infusion is superior to (0.1 mg/kg, 0.25 mg/kg, and MID 0.03 mg/kg) time to relapse as measured by repeated measurements using the Montgomery-Asberg Depression Rating Scale during a four-week, post-infusion follow-up.

Current Secondary Outcome Measures (submitted: July 15, 2021)

Percentage of Patients With Continuation From Day 7 to Day 28 Post-infusion of at Least a 50% Improvement in MADRS [ Time Frame: 28 days post-infusion follow-up ]

Patients with a day 7 treatment response (at least a 50% improvement from baseline in Montgomery-Asberg Depression Rating Scale [MADRS]) are followed until day 28 post-infusion; day 7 non-responders are not followed. Outcome measure is the percentage of patients who continue to be responder at day 28, and is interpreted as a measure of durability of efficacy.

Original Secondary Outcome Measures (submitted: September 18, 2015)

proportion of participants demonstrating > 50% reduction on Montgomery-Asberg Depression Rating Scale scores [ Time Frame: at 72-hour post-infusion ]

To evaluate and compare the antidepressant efficacy of the best performing of three sub-anesthetic doses of a single ketamine (0.1 mg/kg, 0.25 mg/kg, and 0.50 mg/kg) and midazolam (0.03 mg/kg) infusion in veterans with LL-TRD, using a triple blind (patient, rater, anesthesiologist) Bayesian adaptive randomization design to determine if a single KET 0.5 mg/kg infusion will be superior to a single infusion of KET (0.1 mg/kg), KET (0.25 mg/kg), and MID 0.03 mg/kg) as measured by the proportion of participants demonstrating > 50% reduction on Montgomery-Asberg Depression Rating Scale scores at 72-hour post-infusion.

Current Other Pre-specified Outcome Measures (submitted: December 15, 2021)

• Change in Clinician-Administered Dissociative States Scale (CADSS) [ Time Frame: Baseline to 40 minutes after start of infusion ]
  Change from pre-infusion baseline to end of infusion at 40 minutes after start of infusion on the Clinician-Administered Dissociative States Scale (CADSS; scale form 0 [no psychosis-like symptoms] to 90 [severe psychosis-like symptoms]) to assess psychosis-like side effect on day of infusion.
• Change in Resting-state Quantitative Electroencephalography (EEG) Frontal Gamma Band Power (Log of Microvolt Squared) [ Time Frame: Baseline to 30 minutes after start of infusion ]
  Change in EEG frontal gamma power from pre-infusion baseline to 30 minutes after start of infusion to assess engagement of the study drug with the N-methyl-D-aspartate receptor.
• Change in Systolic Blood Pressure (Millimeters of Mercury, mm Hg) [ Time Frame: Baseline to 30 minutes after start of infusion ]
  Change in systolic blood pressure from pre-infusion baseline to 30 minutes after start of infusion
• Change in Diastolic Blood Pressure (Millimeters of Mercury, mm Hg) [ Time Frame: Baseline to 30 minutes after start of infusion ]
  Change in systolic blood pressure from pre-infusion baseline to 30 minutes after start of infusion

Original Other Pre-specified Outcome Measures (submitted: September 18, 2015)

• psychoactive side effect rating scales [ Time Frame: during and up to four week post study infusion ]
  To evaluate the immediate and longer-term safety and tolerability of the most effective KET infusion (0.5 mg/kg) relative to midazolam (0.03 mg/kg) by assessing psychoactive side effect rating scales using the Clinician-Administered Dissociative States Scale (CADSS) during and up to four week post study infusion.
• performance on neurocognitive assessments [ Time Frame: Screening phase through four weeks post study infusion ]
  To measure the effects of the most effective dose of KET (0.50 mg/kg) relative to MID (0.03 mg/kg) on neurocognitive performance assessed with the MCCB and MMSE assessment tools.
• peripheral biomarkers of cellular plasticity [ Time Frame: day of the infusion at baseline, 120 minutes, 240 minutes, 8 hours, and 7 days post infusion and four weeks post infusion ]
  To measure the effects the most effective dose of KET (0.50 mg/kg) relative to MID (0.03 mg/kg) on peripheral biomarkers of cellular plasticity by BDNF measures from blood samples taken.
• resting-state quantitative electroencephalography [ Time Frame: pre-infusion, 28 and 60 minutes after start of infusion, 2 and 3 hours after end of infusion and 1, 3, and 7 days after ketamine infusion. ]
  To measure the effects the most effective dose of KET (0.50 mg/kg) relative to MID (0.03 mg/kg) on resting-state quantitative electroencephalography. Pharmaco-EEG (12 minutes of alternating 1-minute eyes open and closed) will be assessed pre-infusion, 28 minutes after start of infusion, 60 minutes after start of infusion, and 2 and 3 hours after end of infusion and 1, 3, and 7 days after ketamine infusion.
• general side effect rating scales [ Time Frame: during and up to four weeks post study infusion ]
  To evaluate the immediate and longer-term safety and tolerability of the most effective KET infusion (0.5 mg/kg) relative to midazolam (0.03 mg/kg) by assessing general side effect rating scales using the PRISE assessment tool during and up to four week post study infusion.
• peripheral biomarkers inflammation [ Time Frame: day of the infusion at baseline, 120 minutes, 240 minutes, 8 hours, and 7 days post infusion and four weeks post infusion ]
  To measure the effects the most effective dose of KET (0.50 mg/kg) relative to MID (0.03 mg/kg) on peripheral biomarkers of inflammation by measuring Interleukin from blood sample taken.

Descriptive Information

• Brief Title: Ketamine for Treatment Resistant Late-Life Depression
• Official Title: Ketamine for Treatment Resistant Late-Life Depression
• Brief Summary: The purpose of this study is to examine the effectiveness of a single infusion of ketamine (KET), to determine which dose is optimal 7 days after infusion using Bayesian Adaptive Randomization, and to learn about how ketamine works in the body and brain in persons with late-life treatment resistant depression.

Detailed Description

Primary Aim: To identify the best performing condition across a single intravenous infusion of ketamine (KET) 0.1 mg/kg, KET 0.25 mg/kg, KET 0.50 mg/kg) and midazolam (MID) 0.03 mg/kg on Montgomery-Asberg Depression Rating Scale (MADRS) treatment response (at least a 50% improvement in depression from baseline) 7 days after the infusion in up to 72 Veterans with Late-Life Treatment Resistant Depression (LL-TRD) , using a triple blind (patient, rater, anesthesiologist) Bayesian adaptive randomization design.

Hypothesis 1: Single KET 0.5 mg/kg infusion is superior to KET 0.1 mg/kg, KET 0.25 mg/kg, and MID 0.03 mg/kg measured by the proportion of participants demonstrating > 50% reduction on MADRS scores 7 days post-treatment.

Secondary Aim: To evaluate the durability of day 7 treatment response across 3 sub-anesthetic doses of a single KET (0.1 mg/kg, 0.25 mg/kg, and 0.50 mg/kg) and MID (0.03 mg/kg) infusion in veterans with LL-TRD during a 4 week follow-up.

Hypothesis 2: a single KET 0.5 mg/kg infusion will be superior to a single infusion of KET 0.1 mg/kg, KET 0.25 mg/kg, and MID 0.03 mg/kg as measured by the proportion of participants demonstrating > 50% reduction on MADRS scores at 28 days post-infusion.

Tertiary Aim: To evaluate the immediate and longer-term safety and tolerability of the most effective KET infusion relative to MID in vets with LL-TRD.

Hypothesis 3: KET infusion at the most effective dose will be safe and well tolerated compared to MID, as assessed by psychoactive and general side effect rating scales during and up to 4 weeks post study infusion.

Exploratory Aims:

1. To measure the effects of the most effective dose of KET relative to MID on neurocognitive performance.
2. To measure the effects the most effective dose of KET relative to MID on peripheral biomarkers of cellular plasticity and inflammation.
3. To measure the effects the most effective dose of KET relative to MID on resting-state quantitative electroencephalography.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

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

We use a Bayesian, adaptive, randomized design initially allocating subjects to 2 arms in a 1:3 ratio: ARM 1: MID 0.03 mg/kg (active placebo); ARM 2: four conditions KET 0.1 mg/kg, KET 0.25 mg/kg, KET 0.5 mg/kg or MID 0.03 mg/kg. After 1:1:1:1 allocation of the first 20 subjects to ARM 2, Bayesian adaptive randomization may stop for superiority, change randomization ratios and/or prune arms for futility based on the probability of a day 7 treatment response. ARM 1 remains open for allocation to ensure a placebo group sufficiently large for comparison with best dose KET. For analyses, MID of ARM 1 and ARM 2 will be combined so that there are 4 conditions (or arms) for final statistical analyses. We expected to enroll a maximum 72 patients.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

• Condition: Treatment Resistant Depressive Disorder

Intervention

• Drug: Ketamine
  randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg
• Drug: Ketamine
  randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg
• Drug: Ketamine
  randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg
• Drug: Midazolam
  single 40 min infusion of MID 0.03mg/Kg

Study Arms

• Experimental: Ketamine 0.10 mg/kg
  randomly assigned to a single 40 min infusion of either KET 0.1mg/Kg
  Intervention: Drug: Ketamine
• Experimental: Ketamine 0.25 mg/kg
  randomly assigned to a single 40 min infusion of either KET 0.25mg/Kg
  Intervention: Drug: Ketamine
• Experimental: Ketamine 0.50 mg/kg
  randomly assigned to a single 40 min infusion of either KET 0.50mg/Kg
  Intervention: Drug: Ketamine
• Active Comparator: Midazolam 0.03 mg/kg
  randomly assigned to a single 40 min infusion of either MID 0.03mg/Kg
  Intervention: Drug: Midazolam

• Publications *: Murphy N, Lijffijt M, Ramakrishnan N, Vo-Le B, Vo-Le B, Iqbal S, Iqbal T, O'Brien B, Smith MA, Swann AC, Mathew SJ. Does mismatch negativity have utility for NMDA receptor drug development in depression? Braz J Psychiatry. 2022 Jan-Feb;44(1):61-73. doi: 10.1590/1516-4446-2020-1685.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 15, 2021): 33
• Original Estimated Enrollment (submitted: September 18, 2015): 72
• Actual Study Completion Date: March 31, 2020
• Actual Primary Completion Date: March 31, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male or female patients, 55 years of age,
• Participants must fulfill DSM 5 criteria for a Major Depressive Episode (Unipolar), based on a structured diagnostic interview, the DSM 5 M.I.N.I. 7.0
• Participants must have a history of at least one previous episode of depression prior to the current episode (recurrent MDD) or have chronic MDD (of at least two years' duration),
• Participants have not responded to two or more adequate trials of FDA-approved antidepressants, determined by Antidepressant Treatment Response Questionnaire (ATRQ) criteria.
• Participants must score 14 or greater on the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), and score 27 on the Montgomery Asberg Depression Rating Scale (MADRS),
• Each participant must have a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign an informed consent document.

Exclusion Criteria:

• Patients currently on fluoxetine,
• History of schizophrenia, schizoaffective disorder or any psychotic disorder, or bipolar disorder,
• Documented history of a psychotic disorder in a first-degree relative,
• Current diagnosis of obsessive-compulsive disorder (OCD) or eating disorder [bulimia nervosa or anorexia nervosa],
• Alcohol or substance use [except nicotine] within the preceding 6 months,
• Patients with any clinically significant personality disorder that would, in the investigator's judgment, preclude safe study participation,
• Patients judged to be at serious and imminent suicidal or homicidal risk,
• Serious, unstable medical illnesses including respiratory [obstructive sleep apnea, or history of difficulty with airway management during previous anesthetics], cardiovascular [including ischemic heart disease and uncontrolled hypertension], and neurologic [including history of severe head injury],
• For study entry, patients must be reasonable medical candidates for ketamine or midazolam infusion, as determined by a board-certified physician co-investigator during study Screening,
• Clinically significant abnormal findings of laboratory parameters [including urine toxicology screen for drugs of abuse], physical examination, or ECG,
• Hypertension (systolic BP >160 mm Hg or diastolic BP >90 mm Hg),
• Patients with one or more 11 seizures without a clear and resolved etiology,
• Patients starting hormonal treatment (e.g., estrogen) in the 3 months prior to Screening,
• Past intolerance or hypersensitivity to ketamine, or history of recreational use of phencyclidine (PCP) or ketamine,
• Past intolerance or hypersensitivity to midazolam,
• Age-related cognitive decline or mild dementia suggested by a score of < 25 on the Mini-Mental State Examination (MMSE) at Screening,
• Patients taking medications with known activity at the N-methyl-D-aspartate receptor (NMDA) or AMPA glutamate receptor [e.g., riluzole, amantadine, lamotrigine, memantine, topiramate, dextromethorphan, D-cycloserine], or the muopioid receptor,
• Patients taking any of the following medications: St John's Wort, theophylline, tramadol, metrizamide,
• Patients who demonstrate > 25% decrease in depressive symptoms as reflected by the QIDS-SR score from Screening to Randomization,
• Patients who have received electroconvulsive therapy (ECT) in the past 6 months prior to Screening,
• Patients currently receiving treatment with vagus nerve stimulation (VNS) or repetitive transcranial stimulation (rTMS).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 55 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02556606
• Other Study ID Numbers: CLNA-001-14F
• 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
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: VA Office of Research and Development
• Original Responsible Party: US Department of Veterans Affairs
• Current Study Sponsor: VA Office of Research and Development
• Original Study Sponsor: US Department of Veterans Affairs
• Collaborators: Not Provided

Investigators

• Principal Investigator: Sanjay Mathew, MD; Michael E. DeBakey VA Medical Center, Houston, TX

• PRS Account: VA Office of Research and Development
• Verification Date: December 2021