Conditions: Postoperative Depression
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 32
Healthy volunteers: no

Brief summary:
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.

Detailed description:
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.

Arms:
arm 1: 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. arm 2: Following surgery and extubation, patients will receive normal saline at an equal rate to that used in the ketamine arm.

Interventions: intervention 1: Ketamine intervention 2: Normal saline
Intervention descriptions: intervention 1: NMDA antagonist intervention 2: IV fluid acting as a placebo

Protocol document:
Prot_SAP_000.pdf: 
Ketamine for Postoperative Avoidance of Depressive 
Symptoms: The K-PASS Feasibility Trial 
Protocol Number: 2.0 
National Clinical Trial (NCT) Identified Number:  NCT05233566 
Principal Investigator: Bradley A. Fritz, MD, MSCI 
Funded by: Center for Perioperative Mental Health 
Version Number:  v.2.1 
December 12, 2022 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
8.1 
Post-operative MADRS assessments may be 
performed *approximately* on the specified 
days. 
After hospital discharge, sometimes it is not 
possible to reach the patient by phone for a 
follow-up assessment on the specified day. 
When this happens, we would like to 
attempt to reach the patient on a 
subsequent day rather than leaving the data 
point as missing data. 
8.1 
Dreem data collection in preoperative holding 
has been added. 
Because most patients are now providing 
consent via a telephone conversation and 
DocuSign rather than in person, the 
opportunity to send the patient home with a 
Dreem headband for preoperative data 
collection is no longer available. To identify 
preoperative electroencephalogram markers 
of treatment responsiveness, we would like 
to obtain a short period of 
electroencephalogram data collection in 
preoperative holding. 


  
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Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 2 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 4 
2 
INTRODUCTION ............................................................................................................................................ 4 
2.1 
Study Rationale .................................................................................................................................... 4 
2.2 
Background........................................................................................................................................... 5 
2.3 
Risk/Benefit Assessment .................................................................................................................... 6 
2.3.1 
Known Potential Risks ..................................................................................................... 6 
2.3.2 
Known Potential Benefits ................................................................................................ 6 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 7 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 7 
4 
STUDY DESIGN ............................................................................................................................................. 8 
4.1 
Overall Design ...................................................................................................................................... 8 
4.2 
Scientific Rationale for Study Design................................................................................................ 9 
4.3 
Justification for Dose ........................................................................................................................... 9 
4.4 
End of Study Definition ..................................................................................................................... 10 
5 
STUDY POPULATION ................................................................................................................................ 10 
5.1 
Inclusion Criteria ................................................................................................................................ 10 
5.2 
Exclusion Criteria ............................................................................................................................... 10 
5.3 
Lifestyle Considerations .................................................................................................................... 11 
5.4 
Screen Failures .................................................................................................................................. 11 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 11 
6 
STUDY INTERVENTION ............................................................................................................................ 12 
6.1 
Study Intervention(s) Administration ............................................................................................... 12 
6.1.1 
Study Intervention Description ..................................................................................... 12 
6.1.2 
Dosing and Administration ............................................................................................ 13 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 13 
6.2.1 
Acquisition and accountability ...................................................................................... 13 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 14 
6.2.3 
Product Storage and Stability ....................................................................................... 14 
6.2.4 
Preparation ...................................................................................................................... 14 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 14 
6.4 
Study Intervention Compliance ........................................................................................................ 15 
6.5 
Concomitant Therapy ........................................................................................................................ 15 
6.5.1 
Rescue Medicine ............................................................................................................ 15 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 15 
7.1 
Discontinuation of Study Intervention ............................................................................................. 15 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 16 
7.3 
Lost to Follow-Up ............................................................................................................................... 16 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 17 
8.1 
Efficacy Assessments ....................................................................................................................... 17 
8.2 
Safety and Other Assessments ....................................................................................................... 18 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 19 


  
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8.3.1 
Definition of Adverse Events (AE) ............................................................................... 19 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 19 
8.3.3 
Classification of an Adverse Event .............................................................................. 19 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 21 
8.3.5 
Adverse Event Reporting .............................................................................................. 21 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 21 
8.3.7 
Reporting Events to Participants ................................................................................. 22 
8.3.8 
Events of Special Interest ............................................................................................. 22 
8.3.9 
Reporting of Pregnancy ................................................................................................ 22 
8.4 
Unanticipated Problems .................................................................................................................... 22 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 22 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 22 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 23 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 23 
9.1 
Statistical Hypotheses ....................................................................................................................... 23 
9.2 
Sample Size Determination .............................................................................................................. 23 
9.3 
Populations for Analyses .................................................................................................................. 24 
9.4 
Statistical Analyses............................................................................................................................ 24 
9.4.1 
General Approach .......................................................................................................... 24 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 24 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 25 
9.4.4 
Safety Analyses .............................................................................................................. 26 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 26 
9.4.6 
Planned Interim Analyses ............................................................................................. 26 
9.4.7 
Sub-Group Analyses ..................................................................................................... 27 
9.4.8 
Tabulation of Individual participant Data .................................................................... 27 
9.4.9 
Exploratory Analyses ..................................................................................................... 27 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 27 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 27 
10.1.1 
Informed Consent Process ........................................................................................... 27 
10.1.2 
Study Discontinuation and Closure ............................................................................. 27 
10.1.3 
Confidentiality and Privacy ........................................................................................... 28 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 28 
10.1.5 
Key Roles and Study Governance .............................................................................. 29 
10.1.6 
Safety Oversight ............................................................................................................. 29 
10.1.7 
Clinical Monitoring .......................................................................................................... 29 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 29 
10.1.9 
Data Handling and Record Keeping ............................................................................ 30 
10.1.10 
Protocol Deviations ........................................................................................................ 30 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 30 
10.1.12 
Conflict of Interest Policy .............................................................................................. 31 
10.2 
Additional Considerations ................................................................................................................. 31 
10.3 
Abbreviations ...................................................................................................................................... 32 
10.4 
Protocol Amendment History ........................................................................................................... 34 
11 
REFERENCES ............................................................................................................................................. 35 
 


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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 
CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title:
Ketamine for Postoperative Avoidance of Depressive Symptoms: The K-
PASS Feasibility Trial 
Study Description:
This trial will evaluate the feasibility of conducting a larger placebo-
controlled randomized clinical trial focused on the use of a postoperative, 
sustained low-dose ketamine infusion to reduce depressive symptoms.  
Objectives:
 
Primary Objectives: 
1. To evaluate the feasibility of recruiting participants to the 
randomized trial. 
2. To evaluate the feasibility of delivering the study medication. 
3. To evaluate the feasibility of collecting participant outcomes. 
Secondary Objectives: 
1. To estimate the effect size for the difference in postoperative 
depressive symptoms between the intervention and control 
groups. 
2. To estimate the effect size for the difference in delta sleep ratio 
between the intervention and control groups. 
Endpoints:
Primary Endpoints:
1. Fraction of approached patients who enroll and are randomized 
2. Fraction of randomized patients who complete the study 
medication infusion 
3. Fraction of data points with successful capture of depressive 
symptom data and with successful capture of EEG data 
Secondary Endpoints: 


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1. Change in Montgomery-Asberg Depression Rating Scale score 
between pre-operative time point and post-infusion day 4 
2. Delta sleep ratio on electroencephalogram obtained postoperative 
day 1 
Study Population:
Adult patients with past medical history of depression undergoing non-
ambulatory surgery scheduled for at least 2 hours. 
Phase:
3
Description of 
Sites/Facilities Enrolling 
Participants: 
Single-center (Washington University in St. Louis School of Medicine)  
Description of Study
Intervention: 
After extubation, patients in the intervention group will receive ketamine 
0.5 mg/kg over 10 minutes followed by a sustained infusion at 0.3 mg/kg/h 
for an additional 2 hours 50 minutes. 
Study Duration:
1 year
Participant Duration:
4 weeks
1.2 
SCHEMA 
 


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Screening/ 
Enrollment 
 
 
 
 
 
 
 
 
 
 
Day after  
Extubation 
 
 
Post-Infusion 
Day 1 
 
 
Post-Infusion 
Day 2 
 
 
Post-Infusion 
Day 4 
 
 
Post-Infusion 
Day 7 
 
 
Post-Infusion 
Day 14 
 
 
 
N = 32. Screen potential participants by inclusion and exclusion criteria; obtain informed 
consent; obtain history, document. Baseline assessments (see Section 1.3) 
Administer study medication. 
Assessments as noted in Section 1.3, Schedule of Activities. 
Saline 
N = 16 
Ketamine 
N = 16 
Follow-up assessments as noted in Section 1.3, Schedule of Activities. 
Randomize (blocks of 4)
Follow-up assessments as noted in Section 1.3, Schedule of Activities. 
Follow-up assessments as noted in Section 1.3, Schedule of Activities. 
Follow-up assessments as noted in Section 1.3, Schedule of Activities. 
Follow-up assessments as noted in Section 1.3, Schedule of Activities. 


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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening/Enrollment 
Day -7 to -1 
Day of Surgery 
Day of Extubation 
  
Post-Infusion Day 1 
Post-Infusion Day 2 
Post-Infusion Day 4 
Post-Infusion Day 7 
Post-Infusion Day 14 
Informed consent
X
Demographics
X
Medical history
X
Alcohol Use Disorders 
Identification Test 
X 
 
 
 
 
 
 
Drug Abuse Screening Test
X
Childhood Trauma 
Questionnaire 
X 
 
 
 
 
 
 
Montgomery-Asberg -
Depression Rating Scale 
X 
 
X 
X 
X 
X 
X 
Clinical Global Impression
X
X
X
X
X
X
Quick Inventory of Depressive 
Symptomatology 
X 
 
X 
X 
X 
X 
X 
Pain assessment
X
X
X
X
X
X
DREEM device instructions
X
EEG collection
X
X
X
Retrieve DREEM device
X
X
X
Randomization
X
Administer study medication
X
Brief Psychiatric Rating Scale
four-item positive subscale 
 
 
X
 
 
 
 
 
Clinical Administered 
Dissociative State Scale 
 
 
X
 
 
 
 
 
Clinical and Adverse Events 
Checklist 
 
 
X
 
 
 
 
X 
Concomitant medication 
review 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event review and 
evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Case Report Forms 
(CRFs) 
X 
X 
X 
X 
X 
X 
X 
X 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Depression is a disorder characterized primarily by depressed mood and loss of interest or pleasure, 
with additional symptoms such as changes in weight or appetite, slow thought or movement, fatigue, 
feelings of worthlessness or guilt, poor concentration, or suicidal ideation. Approximately 25-50% of 
patients presenting for surgery have a history of depression.1-5 Patients with a history of preoperative 
depression are at elevated risk for experiencing depressive symptoms after surgery. In a cohort of 248 
neurosurgical patients, lifetime history of depression was an independent predictor of postoperative 
depressive symptoms.6 Similar results have been observed in cardiac surgery.1 When scores on various 
depression scales are analyzed as continuous variables, higher preoperative scores have consistently 


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been significant predictors of higher postoperative scores.7-9 Increased postoperative depressive 
symptoms have been linked to increased pain,10 more frequent hospital readmissions within six 
months,11 as well as increased mortality in short-term and long-term follow-up.12 
 
Currently, prevention and treatment of postoperative depressive symptoms generally focuses on 
continuation, resumption, or initiation of oral antidepressants. For general treatment of depression in 
adults and older adults, the American Psychiatric Association recommends second-generation 
antidepressants such as selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake 
inhibitors as first-line pharmacotherapy.13 Following initiation or dose titration, these medications take 
several weeks to achieve their full effect,14-16 limiting their effectiveness to prevent acute depressive 
symptoms after surgery. Furthermore, it may not be possible to give these medications in some 
instances due to impaired gastrointestinal absorption or motility or due to concern for medication 
interactions such as serotonin syndrome. 
 
Ketamine is a promising prophylactic agent for postoperative depressive symptoms because it has 
shown efficacy for treatment-resistant depression and provides relief of depressive symptoms more 
rapidly than traditional biogenic amine-based antidepressants (e.g., selective serotonin reuptake 
inhibitors).  
 
2.2 
BACKGROUND  
The NMDA receptor antagonist ketamine has shown promise as a novel, rapid-acting therapy for 
treatment-resistant depression. In 2006, Zarate and colleagues published an 18-patient randomized trial 
that demonstrated improved Hamilton Depression Rating Scale scores following 0.5 mg/kg ketamine 
infused over 40 minutes compared to placebo.17 Since then, this finding has been replicated multiple 
times, with a recent meta-analysis of 19 studies reporting that a single infusion of ketamine led to 
improved depressive symptoms compared to placebo at 4 hours and 24 hours.18 This is a much faster 
effect than oral antidepressants such as selective serotonin reuptake inhibitors, which take weeks to 
achieve maximum effect. Additional trials have demonstrated superiority of ketamine compared to 
active comparators such as midazolam.19,20 
The antidepressant properties of ketamine are potentially mediated by a sequence of events that lead to 
synaptogenesis and increased electroencephalogram (EEG) slow wave activity (SWA). Ketamine 
administration results in increased extracellular glutamate in the prefrontal cortex,21-23 initiating a chain 
of events24,25 that leads to increased prefrontal synaptic density.26 Enhanced synapse creation during 
wakefulness is followed by enhanced synapse pruning during subsequent sleep, which can be observed 
as SWA (1-4 Hz total EEG power) during non-rapid eye movement (NREM) sleep.27 Low SWA during 
baseline sleep predicts ketamine responsiveness in depressed patients,28 and increases in SWA following 
ketamine infusion correlate with symptom response.29 
Although ketamine achieves its antidepressant effect rapidly, the effect of a single bolus wanes over the 
first week, and strategies to achieve longer effects have been explored. A common strategy has been to 
use repeated intravenous ketamine boluses administered two or three times per week,30,31 although 
intranasal administration of the S enantiomer of ketamine has also been reported.32-34 Symptoms can be 
controlled for multiple weeks, but ongoing therapy is needed to sustain the effect.35 An alternative 
strategy that eliminates the need for repeated dosing is to use a long-duration of infusion. Pilot studies 
have demonstrated that a 96-hour ketamine infusion titrated to a goal of 0.6 mg/kg/h leads to a rapid 


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reduction in depressive symptoms that can be sustained in a large majority of responders for up to 8 
weeks after the end of infusion.36,37 
Lessons learned from treatment-resistant depression may guide the prevention of postoperative 
depressive symptoms. Ketamine is already familiar in this setting because it is sometimes used to 
provide sedation or to augment analgesia.38,39 Boluses of 0.25-0.5 mg/kg during Cesarean section have 
been associated with either no effect40 or with reductions in postpartum depression.41,42 In surgery with 
general anesthesia, ketamine boluses near the time of induction have been associated with reduced 
postoperative depressive symptoms among patients with a history of depression43,44 but not in a general 
population of older adults.45 In those studies where a significant beneficial effect was observed, the 
effect quickly waned over the first few days after surgery. Treatment strategies that produce longer-
lasting effects are desirable, but the longer-duration infusion that has shown promise in treatment-
resistant depression has not been tested around the time of surgery.  
Therefore, we hypothesize that a postoperative sustained, low-dose ketamine infusion can prevent 
postoperative depressive symptoms compared to placebo, when administered to a targeted 
population of surgical patients with a history of depression. 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
The risks associated with ketamine have been observed in studies evaluating its use for general 
anesthesia (as a sole agent, for induction, or as a supplement to other agents), which general involve 
higher doses than those to be used in this study.46 
 
Immediate risk of ketamine use may include 
 
Hypertension and tachycardia – These are common events at higher doses. Ketamine is 
contraindicated in patients for whom a significant elevation of blood pressure would constitute 
a serious hazard. (Of note, the low doses to be used in this study have not previously been 
associated with clinically significant changes in blood pressure or heart rate.36) 
 
Psychotomimetic effects – These have occurred in approximately 12% of patients following 
anesthetic doses. These may range from pleasant dream-like states to vivid imagery, 
hallucinations, and emergence delirium. 
 
Respiratory depression – This is an uncommon event and may occur with overdosage or too 
rapid a rate of administration. 
 
Nystagmus, diplopia – These are common events. Rarely these may be associated with increases 
in intraocular pressure. 
 
Enhanced skeletal muscle tone 
 
Anorexia, nausea, vomiting 
 
Anaphylaxis 
 
Long-range risks of ketamine include 
 
Pediatric neurotoxicity - Animal studies demonstrate increased neuronal apoptosis in 
developing juvenile brains and long-term cognitive deficits when used for longer than 3 hours.  
 
2.3.2 KNOWN POTENTIAL BENEFITS  


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Participants may experience direct benefits from participation in this study. These benefits are described 
below. 
 
Reduced Incidence of Depressive Symptoms – As described in section 2.2, ketamine has been used 
successfully to improve symptoms in patients with treatment-resistant depression. Boluses of ketamine 
have been associated with reduced incidence of postpartum depression and transient reductions in 
depressive symptoms following general anesthesia. Patients in this study may experience reduced 
incidence of depressive symptoms following surgery if randomized to the intervention group. 
 
Analgesia – Patients who receive ketamine may benefit from improved pain control. In a 2018 Cochrane 
meta-analysis including 8,341 patients from 130 studies who underwent surgery with general 
anesthesia, ketamine was associated with improved pain scores at rest and with movement at 24 hours 
and 48 hours postoperatively.38 Patients who received ketamine also had reduced opioid consumption 
at 24 hours and 48 hours.38 Lower pain scores and decreased opioid consumption were similarly 
reported in a meta-analysis of 1,737 patients from 20 trials examining the effect of ketamine on pain 
following Cesarean section.39  
 
In addition to the direct benefits to patients, there will be benefits to society. When successfully 
completed, this line of research will yield knowledge about whether a postoperative ketamine infusion 
can prevent or mitigate subsequent depression. Investigation of concurrent EEG markers may also yield 
insights regarding the effects of ketamine infusion on sleep architecture and potential mechanistic 
associations between sleep architecture and postoperative depressive symptoms. This knowledge will 
benefit future patients by informing treatment decisions that will enhance mental health following 
surgery.  
 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
We have taken steps to reduce the potential risks to the fullest extent possible. By using a lower dose of 
ketamine than is commonly used for general anesthesia and by using a dosing protocol that avoids rapid 
boluses, we reduce the likelihood of hypertension, tachycardia, psychotomimetic effects, and 
respiratory depression. Furthermore, we reduce the risks associated with hypertension by excluding 
patients for whom a significant elevation of blood pressure would constitute a serious hazard. We 
reduced the likelihood of pediatric neurotoxicity by excluding pregnant patients and by excluding 
subjects less than 18 years of age. By conducting a small feasibility study prior embarking on a larger 
randomized clinical trial, we will maximize our ability to test the primary hypothesis and generate 
knowledge that will benefit society. Given these facts, we feel the benefits to patients and to society 
outweigh the risks associated with this study. 
 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
Primary
To evaluate the feasibility of 
recruiting participants to the 
randomized trial. 
Fraction of patients approached who 
enroll and are randomized. 
This endpoint provides 
an evaluation of how 
long it would take to 


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OBJECTIVES
ENDPOINTS
JUSTIFICATION FOR 
ENDPOINTS
 
complete enrollment in 
a full-scale clinical trial. 
To evaluate the feasibility of 
delivering the study medication. 
Fraction of randomized patients who 
complete the study medication 
infusion. 
This endpoint provides 
an evaluation of 
whether infusions were 
missed for logistical 
reasons and whether 
infusions were stopped 
early due to side 
effects. 
To evaluate the feasibility of 
collecting participant outcomes. 
Fraction of randomized patients with 
Montgomery-Asberg Depression 
Rating Scale (MADRS) scores 
available at all specified time points. 
This endpoint provides 
an evaluation of 
whether the primary 
outcome for the full-
scale clinical trial can 
be measured. 
Secondary
 
To estimate the effect size for the 
difference in postoperative 
depressive symptoms between 
patients receiving ketamine and 
patients receiving placebo. 
Change in MADRS score between the 
preoperative assessment and post-
infusion day 4 
The MADRS is a 
reliable, valid 
measurement tool for 
depressive symptoms. 
To estimate the effect size for the 
difference in delta sleep ratio 
between the intervention and 
control groups. 
Delta sleep ratio on EEG obtained on 
post-infusion night 1 
The delta sleep ratio, 
defined as the ratio 
between 1-4 Hz SWA 
during the first and 
second non-rapid eye 
movement epochs 
during sleep, has 
previously been 
associated with 
ketamine 
responsiveness.  
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
The primary hypothesis underlying this work is that a postoperative sustained, low-dose ketamine 
infusion can prevent postoperative depressive symptoms when administered to a targeted population 
of surgical 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, 


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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. Additional details about dosing and 
administration are found in section 6.1.2. Patients, research staff performing assessments, and research 
staff performing data analysis will be blinded to treatment allocation. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
A saline placebo has been selected for the control group because the study intervention (ketamine) 
represents an addition to the usual postoperative care plan rather than a replacement for an existing 
therapy. One potential problem with this choice of control is that patients in the ketamine group may be 
able to guess their treatment allocation if they experience side effects such as hallucinations or diplopia. 
To assess for the presence of this problem, we will ask patients to guess which treatment they received. 
Despite this potential problem, a saline placebo remains preferable to an active placebo such as a 
benzodiazepine because it is a better approximation of current usual care. 
 
4.3 
JUSTIFICATION FOR DOSE 
In the intervention group, the dosing regimen has been designed to quickly achieve the desired blood 
level of ketamine of 225 ng/mL and then maintain that level throughout the infusion. A desired blood 
level of 225 ng/mL has been selected because this is half of the serum concentration obtained during 
steady state for a 96-hour infusion.36 This level is also only slightly higher than the peak blood level 
obtained after patients receive a 0.5 mg/kg bolus dose delivered over 40 minutes, first described by 
Krystal in 199447 and used frequently in subsequent studies. Such a dosing approach would address the 
question of clinical utility in prolonging the length of anticipated NMDA receptor blockade from several 
minutes to 8 hours. 
 
Loading Dose – The alpha distribution half-life for ketamine is about 10 minutes.  A load over 10 minutes 
instead of an immediate bolus should be feasible in that this would lessen the likelihood of significant 
sedation, and it would provide time to detect the rare instances of more moderate sedation with the 
load. Thus, this loading approach carries minimal risk of unintended over-sedation. Also given the beta 
half-life of about 2.3 hours, there would not be substantial loss of ketamine during the 10-minute load. 
 
The risk of over-sedation may be larger in patients with elevated body mass index (BMI), due to a higher 
peak concentration prior to redistribution throughout all tissue (including the excess adipose). To reduce 
the peak concentration without decreasing the expected plasma concentration at the end of the bolus 
load, the bolus load duration will be increased to 20 minutes in patient with BMI > 40. 
 
We want to load the patient with an amount equal to 100% of the desired steady state. Thus, the 
loading dose is equal to the product of the volume of distribution and the desired plasma concentration. 
Per Wagner and O’Hara,48 the volume of distribution of ketamine is 2.4 L/kg. As noted above, the 
desired plasma concentration is 225 ng/mL, which is equal to 0.225 mg/L. Therefore, the loading dose 
will be 
2.4
L
kg × 0.225
mg
L = 0.54
mg
kg
 


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Thus, we will plan to load with a bolus of 0.5 mg/kg over 10 minutes (or over 20 minutes if BMI > 40). 
 
Infusion Dose – In a previous study of 23 patients with treatment-resistant depression who received a 
96-hour infusion of intravenous ketamine, serum ketamine levels were directly measured.37 An infusion 
of 0.6 mg/kg/h produced a steady-state blood level of about 450 ng/mL. Therefore, an infusion at half 
that rate (0.3 mg/kg/h) would be expected to produce a 50% lower steady-state blood level of 225 
ng/mL.  
 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3. 
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
globally. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Able to provide written, informed consent 
2. Aged 18 or older 
3. Scheduled for non-ambulatory surgery scheduled to last at least 2 hours at Barnes-Jewish 
Hospital 
4. Past medical history of depression, defined as one or more of the following criteria 
a. Previous diagnosis by a psychiatrist or primary care physician in an outpatient or 
inpatient setting, by patient report or chart documentation 
b. Prescription of an oral antidepressant by a psychiatrist or primary care physician for a 
mood disorder 
 
 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Bipolar depression 
2. Concurrent use of a medication contraindicated with ketamine 
3. Emergent surgery 
4. Known or suspected elevation in intracranial pressure 
5. Current subarachnoid hemorrhage 
6. Carotid endarterectomy or arteriovenous malformation repair 
7. Allergy to ketamine 
8. Any condition in which a significant elevation of blood pressure would constitute a serious 
hazard (e.g., aortic dissection, pheochromocytoma) 
9. Known history of dementia 
10. Pregnancy or lactation 
11. Inability to converse in English 


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12. Concurrent enrollment in another interventional trial 
 
Comorbid anxiety and outpatient anxiolytic use will be neither inclusion criteria nor exclusion criteria. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
Not applicable. 
 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
 
Examples of situations that may result in screen failure include patient death, surgery cancellation, and 
postoperative mechanical ventilation for > 72 hours. In the case of surgery cancellation, the patient may 
be rescreened if they are scheduled for another surgery during the trial period. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Anticipated Patient Population – The target sample size will be 32 patients. 
Patients will be enrolled at a single site (BJH/Washington University School of 
Medicine). The expected accrual rate was estimated by examining 
characteristics (obtained via Epic Slicer Dicer at the population level only) of a 
retrospective cohort of patients who had non-emergent surgery at BJH 
between 1/1/2021 and 6/30/2021, had an ICU admission, and had an ICD 
grouper corresponding to depression documented in the diagnosis list or the 
past medical history. The query was limited to the cardiac, neurosurgery, and 
vascular services because many of the patients from other services (e.g., 
trauma, orthopedic) were suspected to have initially had emergent surgery 
followed by an ICU admission and then a non-emergent surgery. Exclusion 
criteria for the retrospective query included age < 18. During that 6-month 
time period, there were 307 patients who met these criteria (Figure 2). If we 
conservatively estimate that 20% of these patients enroll in the trial, that 
results in an accrual of 10 patients per month.  
 
The gender, race and ethnicity, and age distributions are expected to follow 
the gender, race and ethnicity, and age distributions served by the Barnes-
Jewish Hospital. These distributions were observed in the retrospective 
cohort seen in Figure 2. The anticipated characteristics of the study 
population are shown in Table 1. 
 
Table 1. Anticipated Demographic Characteristics of the Study Population 
Racial  
Categories 
Ethnic Categories
Not Hispanic or Latino
Hispanic or Latino
Total
Female
Male
Female
Male
Figure 2. Number of 
potentially eligible patients 
in a 6-month period. 


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American Indian/ 
Alaska Native 
1
0
0
0
1
Asian
1
0
0
0
1
Native Hawaiian or 
Other Pacific Islander
0
0
0
0
0
Black or African 
American 
2
2
0
0
4
White
13
11
1
1
26
More than One Race
0
0
0
0
0
Total
17
13
1
1
32
 
Recruitment Strategy – Patients will primarily be recruited at the Center for Preoperative Assessment 
and Planning (CPAP). Potentially eligible patients will be identified by screening the CPAP schedule. 
Patients identified via screening will be approached by telephone prior to their CPAP appointment or in 
person at CPAP. 
 
In addition, the operating room schedule will be reviewed to identify potentially eligible patients 
admitted to the hospital before surgery who did not visit CPAP. These patients will be approached in 
person in the hospital prior to the day of surgery. 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
The study intervention is ketamine. Per the package insert, “Ketamine is a nonbarbiturate general 
anesthetic chemically designated dl 2-(0-chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride. 
It is formulated as a slightly acid (pH 3.5-5.5) sterile solution for intravenous or intramuscular injection in 
concentrations containing the equivalent of either 10, 50, or 100 mg ketamine base per milliliter and 
contains not more than 0.1 mg/mL Phemerol® (benzethonium chloride) added as a preservative. The 10 
mg/mL solution has been made isotonic with sodium chloride.”46 
 
Ketamine is indicated as the sole anesthetic agent for diagnostic and surgical procedures that do not 
require skeletal muscle relaxation, for the induction of anesthesia prior to the administration of other 
general anesthetic agents, and for supplementation of low-potency agents such as nitrous oxide.46 It is 
frequently used off-label for other purposes such as sedation in the intensive care unit and for analgesia. 
 
This trial involves use of an FDA-approved drug for a purpose not listed on the package insert. This trial 
is exempt from IND requirements because it meets all the criteria in CRF 312.2(b): 
 
The investigation is not intended to be reported to the FDA to support a new indication or to 
change the drug labeling. 
 
The drug is lawfully marketed in the United States as a prescription drug product. 
 
The investigation does not involve a route of administration, a dosage level, or a patient 
population that significantly increases the risks compared to the labeled indication. 
 
The investigation complies with the requirements for IRB review and informed consent. 
 
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6.1.2 DOSING AND ADMINISTRATION 
The study intervention consists of a bolus loading dose followed by a continuous infusion. For patients in 
the intervention group, the bolus loading dose will consist of ketamine 0.5 mg/kg administered 
intravenously over 10 minutes (or over 20 minutes if BMI > 40). This will be followed by a continuous 
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. The bolus loading dose will 
consist of normal saline 0.1 mL/kg administered intravenously over 10 minutes (or over 20 minutes if 
BMI > 40). This will be followed by a continuous infusion at 0.06 mL/kg/h for an additional 2 hours 50 
minutes. 
 
Study intervention dosing will be based on actual body weight. 
 
Timing of study medication administration will be the same for both groups. For patients who are 
extubated in the operating room, the study medication will be initiated prior to leaving the operating 
room. For patients who remain intubated and transfer to the intensive care unit, the study medication 
will be administered based on the following criteria: 
 
If the patient is extubated before 07:00am on postoperative day 1, the study medication will be 
administered between 05:00am and 08:00am on postoperative day 1. 
 
If the patient is extubated after 07:00am on postoperative day 1 and before 07:00am on 
postoperative day 2, the study medication will be administered between 05:00am and 08:00am 
on postoperative day 2. 
 
If the patient is extubated after 07:00am on postoperative day 2 and before 07:00am on 
postoperative day 3, the study medication will be administered between 05:00am and 08:00am 
on postoperative day 3. 
 
If the patient remains intubated at 07:00am on postoperative day 3, the patient will be 
withdrawn from the study. 
 
In the operating room, the study medication will be administered by the anesthesiology clinician (MD or 
certified registered nurse anesthetist). In the PACU or ICU, the study medication will be administered by 
the patient’s bedside nurse. 
 
Richmond Agitation and Sedation Scale (RASS) scores will be monitored per standard nursing protocols, 
as described in section 8.2. If the patient experiences sedation to a RASS score ≤ -2, then the study 
medication will be halted and the procedures documented in section 7.1 will be followed.  
 
If the RASS score is ≤ -2 before initiation of the study medication, then the study medication will not be 
initiated at that time. The patient will be re-evaluated the following day, and the study medication will 
be initiated when the RASS is no longer ≤ -2. If RASS remains ≤ -2 on postoperative day 3, the patient will 
be withdrawn from the study. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
Ketamine will be purchased in multidose vials through the BJH Investigational Drug Service. The study 
medication (ketamine or normal saline) will be prepared by the Investigational Drug Service after an 
order has been placed in Epic by the research team. The study medication will be delivered to the 


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patient’s bedside nurse by the Investigational Drug Service utilizing a controlled substance chain of 
custody form. Any unused study medication will be returned to the Investigational Drug Service and 
destruction of unused ketamine will be done in accordance with federal, state, and institutional 
regulations. 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
Ketamine hydrochloride is a 50 mg/mL sterile solution that is clear, colorless, and free of visible 
particles. It will be purchased in multidose vials containing 500 mg in 10 mL. Ketamine will be 
manufactured by PAR Pharmaceuticals. 
 
Normal saline is a sterile, preservative free solution that is clear, colorless, and free of visible particles. It 
will be manufactured by Baxter Healthcare. 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
Per the package insert, ketamine is to be stored at a temperature between 20°C and 25°C (68°F to 77°F) 
and is to be protected from light.46 The product will be stored by BJH Investigational Drug Service in a 
secure location under proper & monitored environmental conditions. 
 
Each multi-dose vial has a beyond-use date of 28 days after initial use. 
 
 
6.2.4 PREPARATION 
Medication preparation will be performed by the BJH Investigational Drug Service using proper aseptic 
technique in accordance with USP Chapter 797. Ketamine will be diluted using normal saline to a 
concentration of 5 mg/mL (e.g., 500 mg in 100 mL). Both ketamine and normal saline placebo will be 
delivered in 100 mL bags that have identical appearance except for a unique study identifier. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Randomization will occur postoperatively at the time of study medication preparation. Patients will be 
randomized in a 1:1 ratio to ketamine or normal saline placebo. Randomization will occur in blocks of 4. 
The randomization scheme will be held by the Investigational Drug Service. 
 
Patients, research team members, and clinical staff (nurses, physicians) will be blinded to treatment 
allocation. To facilitate blinding, study medication for both the ketamine group and the control group 
will be delivered in 100 mL bags with identical appearance except for a unique study identifier. 
 
Intentional unblinding of the clinical staff may occur in the case of serious adverse events if the 
attending physician feels knowledge of the treatment allocation will impact clinical decision making. The 
principal investigator will be notified of all instances of intentional unblinding. 
 
Inadvertent unblinding may occur if the patient experiences side effects such as nystagmus, 
hallucinations, sedation, or hypertension/tachycardia. To detect inadvertent unblinding of the patient, 
we will ask the patient during the final study visit if they believe they received ketamine or placebo. To 
minimize the effects of inadvertent unblinding on study results, endpoints will be measured by study 
staff who were not present during the study medication infusion. 
 
 


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6.4 
STUDY INTERVENTION COMPLIANCE 
Because the study medication will be ordered in Epic and administered by the clinical bedside nurse, 
medication administration will be documented in Epic per usual nursing policies. Compliance will be 
assessed via review of the electronic health record documentation. 
 
6.5 
CONCOMITANT THERAPY 
Intraoperatively, enrolled participants should not receive open-label ketamine. Otherwise, all 
components of the anesthetic care plan will be at the discretion of the attending anesthesiologist. 
 
Postoperatively, enrolled participants should not receive open-label ketamine. During the study 
medication infusion, concurrent infusions of propofol, midazolam, or other sedative agents with GABA 
receptor activity will not be permitted. Concurrent dexmedetomidine is permitted. During the study 
medication infusion, administration of benzodiazepines or gabapentin will not be permitted. All other 
components of postoperative care will occur as directed by the clinical team. 
 
Medications administered to the patient will be retrieved by the research team from the electronic 
health record. In particular, administrations of the following medication classes between 05:00am on 
the day of the study medication infusion and 06:00am on post-infusion day 2 will be retrieved: 
 
Benzodiazepines 
 
Anticonvulsants 
 
Alpha agonists (dexmedetomidine, clonidine) 
 
Hypnotic agents 
 
Antihypertensive agents 
 
Antiarrhythmic agents 
 
Administrations of the following medication classes between 06:00am on the day of the study 
medication infusion and 06:00am on post-infusion day 7 will be retrieved: 
 
Opioid analgesics 
 
Non-opioid analgesics 
 
Antiemetics 
 
6.5.1 RESCUE MEDICINE 
Not applicable 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Infusion of the study medication may be halted if the patient experiences sedation to a Richmond 
Agitation and Sedation Scale (RASS) score of -2 (light sedation: briefly awakens <10 sec with eye contact 
to voice) or lower. Once the patient has returned to a RASS of -1 (drowsy: sustained awakening >10 sec 
with eye contact to voice) or greater, the study medication may be restarted as noted below: 
 
If the medication was halted during the bolus loading dose, then the bolus will not be resumed. 
After recovery to RASS ≥ -1, the continuous infusion will be started at 0.3 mg/kg/h ketamine or 
0.06 mL/kg/h normal saline. 


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 
If the medication was halted during the continuous infusion of 0.3 mg/kg/h ketamine or 0.06 
mL/kg/h normal saline, then the infusion will be restarted at 0.2 mg/kg/h ketamine or 0.04 
mL/kg/h normal saline after recovery to RASS ≥ -1. 
 
If the medication was halted during an infusion at 0.2 mg/kg/h ketamine or 0.04 mL/kg/h 
normal saline, then the infusion will be restarted at 0.15 mg/kg/h ketamine or 0.03 mL/kg/h 
normal saline after recovery to RASS ≥ -1. 
 
If the medication was halted during an infusion at 0.15 mg/kg/h ketamine or 0.03 mL/kg/h 
normal saline, then the infusion will not be restarted. 
 
Discontinuation of the study medication as described in this section may result in inadvertent unblinding 
of the patient and clinical staff. We will assess for inadvertent unblinding as described in section 6.3.  
 
If 3 patients require the study medication to be halted, then the principal investigator will consider 
revising the dosages and/or infusion rates listed in section 6.1.2. 
 
If the clinical team feels it is necessary to halt the study medication for a reason other than RASS < -1, 
this will be discussed with the principal investigator or a qualified designee. 
 
Discontinuation of the study medication does not mean discontinuation from the study, and remaining 
study procedures should be completed as indicated by the study protocol.  If a clinically significant 
finding is identified (including, but not limited to changes from baseline) after enrollment, the 
investigator or qualified designee will determine if any change in participant management is needed. 
Any new clinically relevant finding will be reported as an adverse event (AE). 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive 
the study intervention may be replaced.  Subjects who sign the informed consent form, and are 
randomized and receive the study intervention, and subsequently withdraw, or are withdrawn or 
discontinued from the study, will not be replaced. 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she is unable to be contacted by the study site 
staff after hospital discharge for three consecutive follow-up assessments. 
 
For each post-discharge follow-up assessment, the following actions will be taken if the patient is unable 
to be contacted: 


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 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s study file.  
 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
Depressive Symptom Measurement 
Depressive symptoms will be measured using the Montgomery-Asberg Depression Rating Scale (MADRS) 
preoperatively and on post-infusion days 1, 2, 4, 7, and 14. The MADRS rates the severity of 10 
depressive symptoms based on a targeted clinical interview, yielding a total score 0 (no symptoms) and 
60 (severe symptoms).49,50 The scale has been found to correlate highly with a global clinician 
assessment (Pearson correlation = 0.71)51 and to have high inter-rater reliability.49 The MADRS has been 
modified to assess symptoms over the previous day rather than the previous week.36,37  This modified 
version will be used on the post-infusion days. 
 
The MADRS will be administered by a trained research team member. Post-infusion assessments will be 
conducted between 07:00am and 12:00pm approximately on the specified days. The time of day for the 
preoperative assessment will be variable, depending on the time of the patient’s CPAP appointment or 
in-hospital visit. If the patient is discharged from the hospital before the day of the final study 
assessment, the MADRS will be conducted over the telephone. 
 
Concurrent with each MADRS assessment, the research team member will use the Clinical Global 
Impression (CGI) to rate the overall severity of the patient’s mental illness.52 At each postoperative 
follow-up, the CGI will also be used to rate the overall level of improvement compared to the previous 
assessment. 
Concurrent with each MADRS assessment, self-reported depressive symptoms will be collected using 
the Quick Inventory of Depressive Symptomatology (QIDS).53 
 
The MADRS includes questions about suicidal ideation. If the patient reports any suicidal ideation, then 
the Suicide Risk Management Protocol will be initiated. This includes a structured assessment allowing 
stratification of the risk for self-harm, notification of the principal investigator, and (if risk is moderate or 
high) notification of an on-call psychiatrist.  
 
Electroencephalogram (EEG) Measurement 
EEG will be captured using the Dreem headband (DREEM, Rhythm, New York, NY), a consumer-grade 
wireless device using dry electrodes. The device uses five EEG channels (F7, F8, FpZ, O1, O2), 
accelerometry, and pulse oximetry. It samples EEG electrode potentials at a rate of 250 Hz and applies a 
0.4-30 Hz bandpass filter. 
 
At the baseline visit, the research team member will teach the participant how to use the Dreem 
headband for data collection. If the participant is recruited in the CPAP clinic, then the participant will 
take the Dreem headband home with them. They will be instructed to wear the headband and activate 
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on the day of surgery. If the participant is recruited in the hospital, then the participant will wear the 
headband and activate data collection while sleeping the night following enrollment. The headband will 
be retrieved the following day. 
 
Additional data collection using the Dreem headband will occur in preoperative holding, during the 
study medication infusion, the night following the study medication infusion, and the night following 
post-infusion day 1. 
 
Postoperative Pain 
Pain will be measured at the baseline visit and on post-infusion days 1, 2, 4, 7, and 14 using the visual 
analog scale. The participant will rate their pain at rest, when taking a deep breath, and with movement. 
 
If the participant is discharged from the hospital before the day of the final study assessment, pain will 
be assessed over the telephone using an 11-point numeric rating scale at each remaining study time 
point. Pain will be rated at rest, when taking a deep breath, and with movement. 
 
Postoperative Delirium 
Delirium is assessed routinely by the ICU nurses using the Confusion Assessment Method for the ICU 
(CAM-ICU) once per shift. CAM-ICU scores between the day of the infusion and post-infusion day 5 will 
be retrieved from the electronic health record. 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
Psychotomimetic Side Effects 
Psychotomimetic effects will be quantified using the Brief Psychiatric Rating Scale (BPRS) four-item 
positive symptom subscale36,54 and using the modified 6-item Clinical Administered Dissociative State 
Scale (CADSS-6).55 The BPRS four-item subscale yields a score between 4 (no symptoms) and 28 
(extremely severe). The CADSS-6 yields a score between 0 (no symptoms) and 24 (severe symptoms). 
Both scales will be administered by a research team member midway through the study medication 
infusion (approximately 1-2 hours after the start of the bolus loading dose). 
 
Clinical and Adverse Events Checklist 
Additional side effects of ketamine will be detected using the Clinical and Adverse Events Checklist.56 
This checklist will be administered by a research team member midway through the study medication 
infusion (approximately 1-2 hours after the start of the bolus loading dose). The checklist will be 
repeated on post-infusion day 14 to monitor for resolution of any side effects. 
 
Level of Sedation 
Although the doses of ketamine used in this study are not expected to produce clinically significant 
sedation, patients will be monitored for sedation using the Richmond Agitation and Sedation Scale 
(RASS). RASS assessments will be conducted by the clinical bedside nurse per standard nursing protocols 
of the ICU. The nurse will also be asked to perform one extra RASS assessment at the end of the 10-
minute bolus loading dose. If the RASS score is ever -2 or lower, the study medication will be held 
according to the protocol described in section 7.1. 
 
Vital Signs during Study Medication Infusion 
During the infusion, participants will receive vital sign monitoring per intensive care unit standard of 
care. This will include continuous telemetry, continuous pulse oximetry, and either intermittent 


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noninvasive blood pressure (at least hourly) or continuous invasive blood pressure (if an arterial 
catheter is present). Vital signs will be documented in the electronic health record by the clinical bedside 
nurse per unit standard of care. The research team will retrieve vital signs from the electronic health 
record. 
 
Safety events will include significant hypertension during the infusion, defined as systolic blood pressure 
> 180 mmHg or the administration of an antihypertensive medication that is not one of the patient’s 
home medications. Another safety event will be tachycardia, defined as heart rate > 100 beats per 
minute, during the infusion. 
 
Nausea and Vomiting 
At each post-infusion study visit, participants will be asked if they have experienced nausea or vomiting 
in the past 24 hours. If present, the patient will be asked to classify the event as mild, moderate, or 
severe. In addition, the electronic medical record will be reviewed for administration of antiemetic 
medication. 
 
Baseline Factors Potentially Related to Depression 
At the time of enrollment, the patient will complete several surveys evaluating factors that may be 
related to their depressive history or that may predict treatment responsiveness. These surveys will 
include the Generalized Anxiety Disorder 7-item scale (GAD-7),57 the Alcohol Use Disorders Identification 
Test (AUDIT),58 the Drug Abuse Screening Test (DAST-10),59 and the Childhood Trauma Questionnaire 
(CTQ).60 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 


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For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
  
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
  
8.3.3.3 EXPECTEDNESS  


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The principal investigator will be responsible for determining whether an adverse event (AE) is expected 
or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The principal investigator will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of 
study participation.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs 
since the last visit.  Events will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
Adverse events will be reported to the Washington University IRB according to the timeframes set forth 
by the IRB: 
 
An event that meets the definition of an unanticipated problem involving risk to participants or 
others and results in the death of a participant: will be reported within 1 working day. 
 
An event that meets the definition of an unanticipated problem involving risk to participants or 
others and does NOT result in the death of a participant: will be reported within 10 working 
days. 
 
Adverse events and serious adverse events that do not also meet the definition of an 
unanticipated problem involving risks to participants or others: will be reported annually during 
continuing review. 
 
An unexpected adverse drug event that result in the death of a participant: will be reported 
within 1 working day. 
 
An unexpected adverse drug events that does NOT result in the death of a participant: will be 
reported within 10 working days. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  


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The study clinician will immediately report to the sponsor any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the study intervention 
caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal relationship 
between the study intervention and the event (e.g., death from anaphylaxis). In that case, the 
investigator must immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the study sponsor and should be provided as soon as possible. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
Individual participants will be notified of any serious, unanticipated adverse events probably related to 
study interventions. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
Not applicable 
 
8.3.9 REPORTING OF PREGNANCY  
Not applicable 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  


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• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
 
UPs involving risk to participants or others and results in the death of a participant will be 
reported to the IRB within 1 working day. 
 
UPs involving risk to participants or others and does NOT result in the death of a participant will 
be reported to the IRB within 10 working days. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
Participants will be informed of UPs if/when recommended by the IRB. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
The primary endpoints of this trial will be descriptive outcomes measuring feasibility rather than 
hypothesis-driven efficacy outcomes. The primary endpoints will include 
 
Primary Endpoint 1: Fraction of approached patients who enroll in the trial 
 
Primary Endpoint 2: Fraction of planned study medication infusions that are completed 
 
Primary Endpoint 3: Fraction of participants with MADRS scores available at all specified time 
points 
 
The secondary endpoints of this trial will be efficacy outcomes, designed to test the following 
hypotheses with two-sided superiority comparisons. This feasibility trial is intended to provide estimates 
of effect sizes, but it will not be powered to test these hypotheses. 
 
Secondary Endpoint 1: Change in MADRS score between the preoperative assessment and post-
infusion day 4 
o Null Hypothesis: The change in MADRS score will be the same in the ketamine group 
and in the control group. 
o Alternative Hypothesis: The change in MADRS score will be smaller in the ketamine 
group than in the control group. 
 
Secondary Endpoint 1: Delta sleep ratio on EEG obtained on the second night following the 
study medication infusion 
o Null Hypothesis: There will be no difference in delta sleep ratio between the ketamine 
group and the control group. 
o Alternative Hypothesis: The delta sleep ratio will be greater in the ketamine group 
compared to the control group. 
 
9.2 
SAMPLE SIZE DETERMINATION 
The sample size of 32 has been selected to allow the primary descriptive endpoints to be measured with 
acceptable levels of precision: 
 
Primary Endpoint 1: Fraction of approached patients who enroll in the trial 


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o Conservatively assuming that 25% of approached patients will enroll, then n = 32 
patients will allow this proportion to be measured with a 95% confidence interval width 
of ±15%: 
95%CI = ±1.96ඨ𝑝(1 −𝑝)
𝑛
= ±1.96ඨ(0.25)(0.75)
32
= ±0.15 
 
Primary Endpoint 2: Fraction of planned study medication infusions that are completed 
o If we assume that 90% of planned infusions are completed, then n = 32 patients will 
allow this proportion to be measured with a 95% confidence interval width of ± 10%: 
95%CI = ±1.96ඨ𝑝(1 −𝑝)
𝑛
= ±1.96ඨ(0.90)(0.10)
32
= ±0.10 
 
Primary Endpoint 3: Fraction of participants with MADRS scores available at all specified time 
points 
o If we assume that 95% of participants will have scores available at all specified time 
points, then n = 32 patients will allow this proportion to be measured with a 95% 
confidence interval width of ± 7%: 
95%CI = ±1.96ඨ𝑝(1 −𝑝)
𝑛
= ±1.96ඨ(0.95)(0.05)
32
= ±0.07 
 
This sample size does not provide power to test the secondary endpoints for superiority. However, the 
observed values will be used to determine effect sizes, as well as standard deviations for the observed 
values. These quantities will inform the sample size calculation for the full-scale clinical trial. A minimum 
of 24-30 patients has previously been recommended for estimating effects sizes,61,62 so this feasibility 
trial should be large enough to provide the necessary estimates. 
 
9.3 
POPULATIONS FOR ANALYSES 
The population for Primary Endpoint 1 will include all patients who are approached for enrollment in the 
trial. Primary Endpoints 2 and 3 will be analyzed in an intention-to-treat population that includes all 
patients who are randomized. The secondary endpoints will also be analyzed in the intention-to-treat 
population of all patients who are randomized. 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
For descriptive statistics, categorical data will be presented using frequency counts and percentages, 
normally distributed continuous data will be presented using means and standard deviations, and non-
normally distributed continuous data will be presented using medians and interquartile ranges. 
Normality will be assessed using visual analysis of histograms and using the Kolmogorov-Smirnoff test. 
All inferential tests will be two-tailed, and p-values < 0.05 will be considered statistically significant. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
Primary Endpoint 1: 
The fraction of approached patients who enroll in the trial will be described using a proportion. A 95% 
confidence interval will be used to present uncertainty around this proportion. 
 


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The numerator will include all participants who are randomized to receive either ketamine or the 
placebo. 
 
The denominator will include all patients who are approached by the research team to evaluate 
eligibility and offer consent. This will include patients approached by telephone in advance of their CPAP 
appointment, patients approached in person at CPAP, and patients approached in person in the hospital 
prior to the day of surgery. 
 
Primary Endpoint 2: 
The fraction of randomized participants who complete the study medication infusion will be described 
using a proportion. A 95% confidence interval will be used to present uncertainty around this 
proportion. 
 
The numerator will include all participants who receive the study medication for at least 7 of the 
planned 8 hours (if enrolled under protocol version 1) or for at least 2 of the planned 3 hours (if enrolled 
under protocol version 2). If the study medication is temporarily halted but later restarted, the 
participant will still be included in the numerator if the total time with an active infusion is above the 
threshold defined above. 
 
The denominator will include all participants who are randomized to receive either ketamine or the 
placebo. 
 
Primary Endpoint 3: 
The fraction of participants with MADRS scores available at all the specified time points will be described 
using a proportion. A 95% confidence interval will be used to present uncertainty around this 
proportion. 
 
The numerator will include all participants with MADRS scores documented at all of the following time 
points: preoperative baseline, post-infusion days 1, 2, 4, 7, and 14. 
 
The denominator will include all participants who are randomized to receive either ketamine or the 
placebo. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Secondary Endpoint 1: 
For each randomized participant, the difference in MADRS score on post-infusion day 4 and at the 
preoperative baseline visit will be calculated. Participants with missing MADRS scores at either time 
point will be excluded. (No imputation of MADRS scores will be performed.) 
 
The distribution of delta MADRS scores in the population will be assessed for normality using visual 
analysis of histograms and using the Kolmogorov-Smirnoff test. If the delta MADRS scores are normally 
distributed, then the mean delta scores in the two groups will be compared using a two-sample t-test. If 
the delta MADRS scores are not normally distributed, then the median delta scores in the two groups 
will be compared using a Wilcoxon rank sum test. 
 
Secondary Endpoint 2: 
For each randomized participant, the EEG collected on the second night following the study medication 
infusion will be analyzed by an experienced sleep technician to identify sleep stages. Within each time 


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epoch captured, slow wave activity will be defined as the total power in the 1-4 Hz frequency band. The 
delta sleep ratio (DSR) will be defined as the ratio of SWA during the first non-rapid eye movement 
(NREM) epoch to SWA during the second NREM epoch. 
 
The distribution of DSRs in the population will be assessed for normality using visual analysis of 
histograms and using the Kolmogorov-Smirnoff test. If the DSRs are normally distributed, then the mean 
DSR in the two groups will be compared using a two-sample t-test. If the DSRs are not normally 
distributed, then the median DSR in the two groups will be compared using a Wilcoxon rank sum test. 
 
 
9.4.4 SAFETY ANALYSES 
Psychotomimetic Symptoms: 
The BPRS four-item positive symptom subscale score and the CADSS-6 score will be calculated for each 
patient. The distribution of scores will be assessed for normality using visual analysis of histograms and 
using the Kolmogorov-Smirnoff test. If the scores are normally distributed, then the mean score in the 
two groups will be compared using a two-sample t-test. If the scores are not normally distributed, then 
the median score in the two groups will be compared using a Wilcoxon rank sum test. 
 
Clinical and Adverse Events Checklist: 
The number of patients reporting each side effect during the study medication infusion will be 
determined. The incidence of each side effect will be compared between the two groups using a chi-
square test (or using a Fisher exact test in the case of rare side effects). 
 
Significant Hypertension during Infusion: 
The number of patients experiencing a systolic blood pressure > 180 mmHg during the study medication 
infusion or receiving an antihypertensive medication during the infusion that is not on the patient’s 
home medication list will be determined. The incidence of significant hypertension will be compared 
between the two groups using a chi-square test. 
 
Tachycardia during Infusion: 
The number of patients experiencing a heart rate > 100 beats per minute during the study medication 
infusion will be determined. The incidence of tachycardia will be compared between the two groups 
using a chi-square test. 
 
Nausea and Vomiting: 
The number of patients reporting nausea and vomiting will be determined. The incidence of nausea and 
vomiting will be compared between the two groups using a chi-square test. 
 
Other adverse events will be coded and reported as described in section 8.3. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Baseline descriptive statistics will include demographic characteristics, past medical history including 
previous psychiatric diagnoses, preoperative use of psychoactive medications, and type of surgery 
planned. Descriptive statistics will be stratified by randomization allocation, but no inferential statistics 
will be used. 
 
9.4.6 PLANNED INTERIM ANALYSES  


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No interim analyses are planned. 
 
9.4.7 SUB-GROUP ANALYSES 
The primary feasibility endpoints will also be assessed in sub-groups corresponding to surgical service 
(e.g., neurosurgery, cardiac surgery, etc.). 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual participant data will not be presented. 
 
9.4.9 EXPLORATORY ANALYSES 
Exploratory analyses will include postoperative pain, intensive care unit length of stay, and hospital 
length of stay. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  Written consent materials are submitted with this 
protocol. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 


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This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, funding agency, and 
regulatory authorities.  If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants  
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be stored on the Research Electronic Data Capture (REDCap) system managed by Washington University 
School of Medicine. This will not include the participant’s contact or identifying information. Rather, 
individual participants and their research data will be identified by a unique study identification number. 
The study data entry and study management systems will be secured and password protected. At the 
end of the study, all study databases will be de-identified and archived. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored at Washington University School of Medicine. 
After the study is completed, the de-identified, archived data will be transmitted to and stored at the 
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10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator
Bradley Fritz, MD, MSCI
Washington University School of 
Medicine
660 S Euclid Avenue, 
St. Louis, MO 63110
314-273-3453
bafritz@wustl.edu
In addition, an executive steering committee will serve as advisors to the principal investigator. 
10.1.6 SAFETY OVERSIGHT 
Safety oversight will be performed by an independent safety monitor (ISM). The ISM will be a physician 
with relevant expertise in the care of postoperative critically ill patients. The ISM will be independent 
from the study conduct and free of conflict of interest, or measures should be in place to minimize 
perceived conflict of interest.  The ISM will review adverse events as they reported, according to the 
timelines outlined in section 8.3.5. 
 
In addition to as-needed reviewing of reportable events, the ISM will review safety data every 6 months. 
This review will include the following safety outcomes described in section 8.2: psychotomimetic side 
effects, clinical and adverse events checklist, level of sedation, vital signs during study medication 
infusion, and nausea/vomiting. 
 
10.1.7 CLINICAL MONITORING 
Not applicable 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan will be 
developed to describe a site’s quality management.] 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 


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10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the source 
documents.  
 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into REDCap, a 21 CFR Part 11-compliant data capture 
system provided by Washington University School of Medicine. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the source 
documents. 
 
10.1.9.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 3 years. These documents should be retained for 
a longer period, however, if required by local regulations.  
 
10.1.10 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 10 working days of identification of the protocol deviation, or within 10 working days 
of the scheduled protocol-required activity.  All deviations must be addressed in study source 
documents and reported to the funding agency. Protocol deviations must be sent to the reviewing 
Institutional Review Board (IRB) per their policies. The site investigator is responsible for knowing and 
adhering to the reviewing IRB requirements. Further details about the handling of protocol deviations 
will be included in the MOP. 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 


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This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers 2 years after the 
completion of the primary endpoint by contacting the principal investigator.  
 
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial. 
 
10.2 ADDITIONAL CONSIDERATIONS 
Not applicable 
 
 
 


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10.3 ABBREVIATIONS 
 
AE 
Adverse Event  
AUDIT 
Alcohol Use Disorders Identification Test 
BJH 
Barnes-Jewish Hospital 
BMI 
Body Mass Index 
BPRS 
Brief Psychiatric Rating Scale 
CADSS 
Clinical Administered Dissociative State Scale 
CFR 
Code of Federal Regulations  
CGI 
Clinical Global Impression 
CMP 
Clinical Monitoring Plan 
CONSORT 
Consolidated Standards of Reporting Trials  
CPAP 
Center for Preoperative Assessment and Planning 
CRF 
Case Report Form  
CTQ 
Childhood Trauma Questionnaire 
DAST 
Drug Abuse Screening Test 
eCRF 
Electronic Case Report Forms  
EEG 
Electroencephalogram 
FDA 
Food and Drug Administration  
GABA 
Gamma-Aminobutyric Acid 
GCP 
Good Clinical Practice  
GLP 
Good Laboratory Practices  
GMP 
Good Manufacturing Practices  
HIPAA 
Health Insurance Portability and Accountability Act  
ICD 
International Classification of Disease 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
ICU 
Intensive Care Unit 
IND 
Investigational New Drug Application  
IRB 
Institutional Review Board  
ISM 
Independent Safety Monitor  
K-PASS 
Ketamine for Postoperative Avoidance of Depressive Symptoms 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures  
NIH  
National Institutes of Health  
NMDA 
N-Methyl-D-Aspartate 
OHRP 
Office for Human Research Protections  
PACU 
Post Anesthesia Care Unit 
PHQ-9 
Patient Health Questionnaire-9 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control  
QIDS 
Quick Inventory of Depressive Symptomatology 
RASS 
Richmond Agitation and Sedation Scale 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event  
SOA 
Schedule of Activities  
SOP 
Standard Operating Procedure  
SWA 
Slow Wave Activity 


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UP 
Unanticipated Problem  
US 
United States  
 
 
 


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10.4 PROTOCOL AMENDMENT HISTORY 
Version
Date
Description of Change
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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