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This protocol describes a feasibility trial that will evaluate the feasibility of conducting a full-scale phase 3 trial testing the hypothesis that a postoperative sustained, low-dose ketamine infusion can prevent postoperative depressive symptoms when administered to a targeted population of neurosurgical patients with a history of depression.
This protocol describes a feasibility trial that will evaluate the feasibility of conducting a full-scale phase 3 trial. Both the feasibility trial and the full-scale trial will follow a randomized, placebo-controlled, double-blinded, parallel design. The trial will follow a superiority design. This trial will take place at a single site (Washington University in St. Louis School of Medicine/Barnes-Jewish Hospital).
Following extubation, patients will be randomized to the intervention (ketamine group) or to control (control group). Patients in the ketamine group will receive a bolus of ketamine 0.5 mg/kg intravenously over 10 minutes, followed by an infusion at 0.3 mg/kg/h for an additional 2 hours 50 minutes. Patients in the control group will receive an equal volume of normal saline. Patients, research staff performing assessments, and research staff performing data analysis will be blinded to treatment allocation.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ketamine Arm | Experimental | Following surgery and extubation, patients will receive ketamine 0.5 mg/kg over 10 minutes followed by an infusion of 0.3 mg/kg/h for 2 hours 50 minutes. |
|
| Control Arm | Placebo Comparator | Following surgery and extubation, patients will receive normal saline at an equal rate to that used in the ketamine arm. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ketamine | Drug | NMDA antagonist |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Fraction of Approached Patients Who Enroll and Are Randomized | The numerator will include all patients who are randomized to receive either ketamine or placebo. The denominator will include all patients who are approached by the research team to evaluated eligibility and offer consent. | 3 days after surgery |
| Fraction of Randomized Patients Who Complete the Study Infusion | The numerator will include all participants who received the entire study medication infusion as planned. The denominator will include all participants who are randomized to receive either ketamine or the placebo. | 3 days after surgery |
| Fraction of Randomized Patients With Depression Rating Scale Scores at All Specified Time Points | Depression will be measured using the Montgomery-Asberg Depression Rating Scale (MADRS) at pre-operative baseline and on post-infusion days 1, 2, 4, 7, and 14. MADRS scores range 0 to 60, with higher scores representing worse depression. The numerator will include all patients with MADRS scores documented at all 6 time points. The denominator will include all participants who are randomized to receive either ketamine or the placebo. | 14 days after the intervention |
| Measure | Description | Time Frame |
|---|---|---|
| Depressive Symptoms on Day 4 | Depression will be measured using the Montgomery-Asberg Depression Rating Scale (MADRS) at pre-operative baseline and on post-infusion days 1, 2, 4, 7, and 14. MADRS scores range 0 to 60, with higher scores representing worse depression. The distribution of MADRS scores in the population will be assessed for normality using visual analysis of histograms and using the Kolmogorov-Smirnoff test. If the MADRS scores are normally distributed, then the mean scores in the two groups on post-infusion day 4 will be compared using linear regression, adjusting for preoperative score. If the MADRS scores are not normally distributed, then the median delta scores in the two groups will be compared using median regression, adjusting for preoperative score. Participants with missing MADRS scores at either time point (preoperative baseline or post-infusion day 4) will be excluded. |
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Inclusion Criteria:
Able to provide written, informed consent
Aged 18 or older
Scheduled for non-ambulatory surgery scheduled to last at least 2 hours at Barnes-Jewish Hospital
Past medical history of depression, defined as one or more of the following criteria
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington University School of Medicine | St Louis | Missouri | 63110 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38179107 | Derived | Fritz BA, Tellor Pennington BR, Dalton C, Horan C, Palanca BJA, Schweiger JA, Griffin L, Tumwesige W, Willie JT, Farber NB. Ketamine for postoperative avoidance of depressive symptoms: the K-PASS feasibility randomised trial. BJA Open. 2023 Dec 15;9:100245. doi: 10.1016/j.bjao.2023.100245. eCollection 2024 Mar. | |
| 37483552 | Derived |
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| ID | Title | Description |
|---|---|---|
| FG000 | Ketamine Arm | Following surgery and extubation, patients will receive ketamine 0.5 mg/kg over 10 minutes followed by an infusion of 0.3 mg/kg/h for 2 hours 50 minutes. Ketamine: NMDA antagonist |
| FG001 | Control Arm | Following surgery and extubation, patients will receive normal saline at an equal rate to that used in the ketamine arm. Normal saline: IV fluid acting as a placebo |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Ketamine Arm | Following surgery and extubation, patients will receive ketamine 0.5 mg/kg over 10 minutes followed by an infusion of 0.3 mg/kg/h for 2 hours 50 minutes. Ketamine: NMDA antagonist |
| BG001 | Control Arm |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Fraction of Approached Patients Who Enroll and Are Randomized | The numerator will include all patients who are randomized to receive either ketamine or placebo. The denominator will include all patients who are approached by the research team to evaluated eligibility and offer consent. | The analysis population for this outcome includes all patients who were approached by the research team, including those who decided not to participate in the trial and those who were excluded from the trial prior to randomization. Because these patients were never randomized, it is not possible to report results for this outcome separately for the Ketamine Arm and the Control Arm. | Posted | Count of Participants | Participants | 3 days after surgery |
|
30 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Ketamine Arm | Following surgery and extubation, patients will receive ketamine 0.5 mg/kg over 10 minutes followed by an infusion of 0.3 mg/kg/h for 2 hours 50 minutes. Ketamine: NMDA antagonist |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Seizure | Nervous system disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Transient Ischemic Attack | Nervous system disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Bradley Fritz | Washington University School of Medicine | 3142733453 | bafritz@wustl.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Dec 12, 2022 | Feb 15, 2024 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Aug 10, 2022 | Jan 23, 2026 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D007649 | Ketamine |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
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| Normal saline |
| Drug |
IV fluid acting as a placebo |
|
| 4 days after the intervention |
| Delta Sleep Ratio on Night 1 Following Study Medication | Electroencephalograms (EEG) will be captured during sleep using the Dreem headband (DREEM, Rhythm, New York, NY), a consumer-grade wireless device using dry electrodes. Sleep stages (e.g., non-rapid eye movement [NREM], rapid eye movement, wakefulness) will be detected using the Dreem headband's built-in automated sleep scoring algorithm. During each time epoch, slow wave activity will be defined as the EEG power in the range 1-4 Hz. The delta sleep ratio (DSR) will be defined as the ratio of slow wave activity during the first NREM epoch to slow wave activity during the second NREM epoch. Because it is a ratio, the DSR is a dimensionless number. In normal sleep, slow wave activity is greatest at the beginning of the night and decreases throughout the night. Therefore, higher DSR values reflect a more normal sleep architecture. | 2 days after intervention |
| Fritz BA, Tellor Pennington BR, Palanca BJA, Schweiger JA, Willie JT, Farber NB. Protocol for the Ketamine for Postoperative Avoidance of Depressive Symptoms (K-PASS) feasibility study: A randomized clinical trial. F1000Res. 2022 May 11;11:510. doi: 10.12688/f1000research.121529.1. eCollection 2022. |
Following surgery and extubation, patients will receive normal saline at an equal rate to that used in the ketamine arm.
Normal saline: IV fluid acting as a placebo
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Preoperative Depressive Symptoms - Montgomery-Asberg Depression Rating Scale | Count of Participants | Participants |
|
| OG001 | Protocol Version 2 | Under protocol version 2, the inclusion criteria included patients aged ≥18 yr with a history of depression undergoing non-ambulatory surgery scheduled for at least 2 h. |
|
|
| Primary | Fraction of Randomized Patients Who Complete the Study Infusion | The numerator will include all participants who received the entire study medication infusion as planned. The denominator will include all participants who are randomized to receive either ketamine or the placebo. | Posted | Count of Participants | Participants | 3 days after surgery |
|
|
|
| Primary | Fraction of Randomized Patients With Depression Rating Scale Scores at All Specified Time Points | Depression will be measured using the Montgomery-Asberg Depression Rating Scale (MADRS) at pre-operative baseline and on post-infusion days 1, 2, 4, 7, and 14. MADRS scores range 0 to 60, with higher scores representing worse depression. The numerator will include all patients with MADRS scores documented at all 6 time points. The denominator will include all participants who are randomized to receive either ketamine or the placebo. | Posted | Count of Participants | Participants | 14 days after the intervention |
|
|
|
| Secondary | Depressive Symptoms on Day 4 | Depression will be measured using the Montgomery-Asberg Depression Rating Scale (MADRS) at pre-operative baseline and on post-infusion days 1, 2, 4, 7, and 14. MADRS scores range 0 to 60, with higher scores representing worse depression. The distribution of MADRS scores in the population will be assessed for normality using visual analysis of histograms and using the Kolmogorov-Smirnoff test. If the MADRS scores are normally distributed, then the mean scores in the two groups on post-infusion day 4 will be compared using linear regression, adjusting for preoperative score. If the MADRS scores are not normally distributed, then the median delta scores in the two groups will be compared using median regression, adjusting for preoperative score. Participants with missing MADRS scores at either time point (preoperative baseline or post-infusion day 4) will be excluded. | Excludes participants with missing MADRS scores either at baseline or on post-infusion day 4. | Posted | Median | Inter-Quartile Range | score on a scale | 4 days after the intervention |
|
|
|
| Secondary | Delta Sleep Ratio on Night 1 Following Study Medication | Electroencephalograms (EEG) will be captured during sleep using the Dreem headband (DREEM, Rhythm, New York, NY), a consumer-grade wireless device using dry electrodes. Sleep stages (e.g., non-rapid eye movement [NREM], rapid eye movement, wakefulness) will be detected using the Dreem headband's built-in automated sleep scoring algorithm. During each time epoch, slow wave activity will be defined as the EEG power in the range 1-4 Hz. The delta sleep ratio (DSR) will be defined as the ratio of slow wave activity during the first NREM epoch to slow wave activity during the second NREM epoch. Because it is a ratio, the DSR is a dimensionless number. In normal sleep, slow wave activity is greatest at the beginning of the night and decreases throughout the night. Therefore, higher DSR values reflect a more normal sleep architecture. | Posted | Mean | Full Range | ratio (dimensionless number) | 2 days after intervention |
|
|
|
| 0 |
| 16 |
| 2 |
| 16 |
| 0 |
| 16 |
| EG001 | Control Arm | Following surgery and extubation, patients will receive normal saline at an equal rate to that used in the ketamine arm. Normal saline: IV fluid acting as a placebo | 1 | 16 | 5 | 16 | 3 | 16 |
| Ramsay Hunt syndrome | Nervous system disorders | Non-systematic Assessment |
|
| Postoperative Apnea | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Subjective arm/leg weakness | Nervous system disorders | Non-systematic Assessment |
|
| Surgical Site Infection | Infections and infestations | Non-systematic Assessment |
|
| Deep Venous Thrombosis | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Death (underlying etiology unable to be determined) | General disorders | Non-systematic Assessment |
|
| Blisters around incision | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Fever and chills | General disorders | Non-systematic Assessment |
|
| Nausea and vomiting | Gastrointestinal disorders | Non-systematic Assessment |
|
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| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |