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Ketamine for Treatment Resistant Late-Life Depression

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ClinicalTrials.gov Identifier: NCT02556606
Recruitment Status : Active, not recruiting
First Posted : September 22, 2015
Last Update Posted : August 29, 2019
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Tracking Information
First Submitted Date  ICMJE June 25, 2015
First Posted Date  ICMJE September 22, 2015
Last Update Posted Date August 29, 2019
Actual Study Start Date  ICMJE October 1, 2015
Estimated Primary Completion Date March 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02556606 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: April 1, 2016)
  • 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 MATRICS Consensus Cognitive Battery (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 brain-derived neurotrophic factor (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.
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  ICMJE Ketamine for Treatment Resistant Late-Life Depression
Official Title  ICMJE 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 and lasts the longest, 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 and evaluate the durability of benefit of the best performing of 3 sub-anesthetic doses of a single ketamine (0.1 mg/kg, 0.25 mg/kg, and 0.50 mg/kg) and midazolam (MID) (0.03 mg/kg) infusion in up to 72 Veterans with Late-Life Treatment Resistant Depression (LL-TRD).

Hypothesis 1: 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 (MADRS) during a four-week, post-infusion follow-up.

Secondary Aim: To evaluate and compare the antidepressant efficacy of the best performing of 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 vets with LL-TRD, using a triple blind (patient, rater, anesthesiologist) Bayesian adaptive randomization design.

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 72-hour post-infusion.

Tertiary Aim: To evaluate the immediate and longer-term safety and tolerability of the most effective KET infusion (0.5 mg/kg) relative to MID (0.03 mg/kg) in vets with LL-TRD.

Hypothesis 3: KET infusion at the most effective dose (0.5 mg/kg) 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 (0.50 mg/kg) relative to MID (0.03 mg/kg) on neurocognitive performance.
  2. 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 and inflammation.
  3. 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Treatment Resistant Depressive Disorder
Intervention  ICMJE
  • 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  ICMJE
  • 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 * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: September 18, 2015)
72
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 30, 2020
Estimated Primary Completion Date March 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 55 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02556606
Other Study ID Numbers  ICMJE 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  ICMJE
Plan to Share IPD: No
Responsible Party VA Office of Research and Development
Study Sponsor  ICMJE VA Office of Research and Development
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Sanjay Mathew, MD Michael E. DeBakey VA Medical Center, Houston, TX
PRS Account VA Office of Research and Development
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP