Conditions: Gastrointestinal Cancer Depression Anxiety
Keywords: Ketamine Assisted Therapy Existential Distress
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
The goal of this open-label clinical trial is to assess the feasibility of Ketamine-assisted psychotherapy (KAP) studies for adults with non-operable GI cancers suffering with existential distress. The main questions it aims to answer are:

* Is it feasible to conduct a KAP study with this population?
* What is the safety and tolerability of KAP in this population?
* How prevalent is existential distress in this population?

Participants will undergo KAP administered as standard of care at the HMHI Park City Ketamine-Assisted Psychotherapy Clinic and will complete health assessments over the course of the study, as well as during the therapy.

Detailed description:

Arms:
arm 1: Three 2.5-3 hour Ketamine Assisted Psychotherapy sessions, each 2-7 days apart

Interventions: intervention 1: Ketamine
Intervention descriptions: intervention 1: Ketamine, 0.5-1.2mg/kg, administered intramuscularly

* Doses can range 0.5-1.2 mg/kg. Starting dose for all participants will be 0.5mg/kg.
* Dose can be titrated up to maximum of 1.2 mg/kg or titrated down to 0.5 mg/kg based on response and clinical judgement.
* Dose will be administered by injecting into large muscle mass (eg, deltoid, gluteal muscle, thigh)

Protocol document:
Prot_SAP_000.pdf: 
Page 1 of 68 
 
TREK: Ketamine-assisted Psychotherapy (KAP) for Patients 
with Existential Distress associated with Non-operable GI 
Cancers 
 
Principal Investigator 
Benjamin Lewis, MD 
Huntsman Mental Health Institute 
501 Chipeta Way 
Salt Lake City, UT 84112 
Ben.Lewis@hsc.utah.edu  
Co-Investigator 
Laura A. Lambert, MD, FACS 
Huntsman Cancer Institute 
2000 Circle of Hope 
Salt Lake City, UT 84112 
Laura.Lambert@hci.utah.edu 
Statistician 
Kenneth M. Boucher, PhD  
Huntsman Cancer Institute  
2000 Circle of Hope Room 1710 
Salt Lake City, UT 84112 
Email: Kenneth.Boucher@hci.utah.edu 
Sponsor  
Huntsman Cancer Institute 
Investigational Product(s) 
Ketamine 
IND  
Exempt 
NCT number 
NCT06001372 


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HCI IRB number 
160227 
Protocol Version 
Version 2: 09FEB2024 
 


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DOCUMENT HISTORY 
Document 
Date 
Overall Rationale 
Original Protocol  
21JUL2023 
Not applicable  
Amendment 1 
09FEB2024 
Updated eligibility criteria, 
removed MQOL 
questionnaire, and updated 
questionnaire time points 
 
 


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Table of Contents 
DOCUMENT HISTORY ................................................................................................................................ 3 
STATEMENT OF COMPLIANCE ................................................................................................................. 6 
1 
PROTOCOL SUMMARY .................................................................................................................... 10 
1.1 
Synopsis ...................................................................................................................................... 10 
1.2 
Schema ....................................................................................................................................... 13 
1.4 
Schedule of Events ..................................................................................................................... 14 
2 
OBJECTIVES AND ENDPOINTS....................................................................................................... 17 
2.1 
Primary Objective ........................................................................................................................ 17 
2.2 
Secondary Objectives ................................................................................................................. 17 
2.3 
Exploratory Objectives ................................................................................................................ 17 
3 
BACKGROUND AND RATIONALE ................................................................................................... 18 
3.1 
Ketamine ..................................................................................................................................... 19 
3.2 
Patient Population Background ................................................................................................... 19 
3.3 
Storyline Health Assessments .................................................................................................... 20 
4 
STUDY DESIGN ................................................................................................................................. 23 
4.1 
Study Duration............................................................................................................................. 23 
4.2 
End of Study ................................................................................................................................ 23 
5 
STUDY POPULATION ....................................................................................................................... 24 
5.1 
Inclusion Criteria ......................................................................................................................... 24 
5.2 
Exclusion Criteria ........................................................................................................................ 26 
5.3 
Registration ................................................................................................................................. 28 
5.4 
Screen Failures ........................................................................................................................... 28 
5.5 
Strategies for Recruitment .......................................................................................................... 29 
6 
STUDY INTERVENTION .................................................................................................................... 29 
6.1 
Ketamine Assisted Psychotherapy ............................................................................................. 29 
6.2 
Ketamine Administration Schedule ............................................................................................. 29 
6.3 
Ketamine ..................................................................................................................................... 32 
6.4 
Adverse Event Management ....................................................................................................... 32 
6.5 
Supportive Care .......................................................................................................................... 33 
6.6 
Concomitant Medications and Therapies .................................................................................... 33 
6.7 
Duration of Therapy .................................................................................................................... 33 
6.7.4 
Lost to Follow-Up .................................................................................................................... 35 
7 
STUDY ASSESSMENTS .................................................................................................................... 35 
7.1 
General Assessments ................................................................................................................. 35 
7.2 
Safety Assessments .................................................................................................................... 36 
7.3 
Patient Reported Outcomes ........................................................................................................ 37 
7.4 
Remote Visits/Telehealth ............................................................................................................ 39 
8 
ADVERSE EVENTS ........................................................................................................................... 39 
8.1 
Definitions .................................................................................................................................... 39 
8.2 
Adverse Event Reporting ............................................................................................................ 40 


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8.3 
Special Situations ........................................................................................................................ 43 
8.4 
Data Safety Monitoring Committee ............................................................................................. 44 
9 
STATISTICAL CONSIDERATIONS ................................................................................................... 45 
9.1 
Sample size determination .......................................................................................................... 45 
9.2 
Population for Analyses .............................................................................................................. 45 
9.3 
Primary Endpoint ......................................................................................................................... 45 
9.4 
Secondary Endpoints .................................................................................................................. 45 
9.5 
Exploratory Objectives ................................................................................................................ 45 
10 
ETHICAL AND REGULATORY CONSIDERATIONS .................................................................... 46 
10.1 
Human Subjects Protection ......................................................................................................... 46 
10.2 
Institutional Review ..................................................................................................................... 46 
10.3 
Investigator Responsibilities ........................................................................................................ 47 
10.4 
Protocol Amendments ................................................................................................................. 47 
10.5 
Protocol Deviations ..................................................................................................................... 47 
10.6 
FDA Reporting............................................................................................................................. 47 
11 
DATA HANDLING .......................................................................................................................... 47 
11.1 
Recording and Collection of Data ............................................................................................... 47 
11.2 
Data Management ....................................................................................................................... 49 
12 
PUBLICATION PLAN ..................................................................................................................... 49 
13 
REFERENCES ................................................................................................................................ 50 
 
List of Tables 
Table 1: Laboratory Assessments .......................................................................................................... 37 
Table 2: Severity assessment .................................................................................................................. 40 
 
List of Appendices 
Appendix 1: ECOG Performance Status12 .............................................................................................. 51 
Appendix 2: Existential Distress Scale (EDS) ........................................................................................ 52 
Appendix 3: Quick Inventory of Depressive Symptomatology (QIDS-SR-16) .................................... 53 
Appendix 4: Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening ....................... 56 
Appendix 5: Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit ............................. 59 
Appendix 6: FACIT-Sp (Version 4) .......................................................................................................... 62 
Appendix 7: Nondual Awareness Dimensional Assessment (NADA) ................................................. 65 
Appendix 8: Mystical Experiences Questionnaire (MEQ-30) ................................................................ 66 
Appendix 9: Death and Dying Distress Scale (DADDS) ........................................................................ 68 
 
 
 


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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR). 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take 
place without prior agreement from the Investigational New Drug (IND) or Investigational Device 
Exemption (IDE) sponsor, funding agency and documented approval from the Institutional 
Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial 
participants. All personnel involved in the conduct of this study 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 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. 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. 
 


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ABREVIATIONS 
Abbreviation 
Definition/Explanation 
ACI 
As clinically indicated 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
BCVA 
Best-corrected distance visual acuity 
BICR 
Blinded Independent Central Review 
β-HCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CMP 
Comprehensive metabolic panel 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
CYP 
Cytochrome P450 
CQ 
Chloroquine 


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Abbreviation 
Definition/Explanation 
DILI 
Drug-Induced Liver Injury 
DoR 
Duration of Response 
DSMB 
Data Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
Eg 
Exempli Gratia (for example) 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyltransferase 
GI 
Gastrointestinal  
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
i.e. 
Id est (that is) 
IEC 
Independent ethics committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional review board 
LDH 
Lactate dehydrogenase 
MRI 
Magnetic resonance imaging 
NIH 
National Institute of Health 
KAP 
Ketamine-assisted Psychotherapy 
PD 
Pharmacodynamic(s) 
PDAC 
Pancreatic Ductal Adenocarcinoma  
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic(s) 


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Abbreviation 
Definition/Explanation 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTc 
QT interval corrected  
QTcF 
QT interval corrected using Fredericia equation 
RBC 
Red blood cell 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious adverse event 
SD 
Stable disease 
SD-OCT 
Spectral-domain ocular coherence tomography 
T1/2 
Terminal elimination half-life 
TdP 
Torsades de Pointes 
Tmax 
Time of maximum observed concentration 
ULN 
The upper limit of normal 
VF 
Visual field 
WBC 
White blood cell 
  
 


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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Title: 
TREK: Ketamine-assisted Psychotherapy (KAP) for Patients with 
Existential Distress associated with Non-operable GI Cancers 
Protocol Short Title 
TREK 
Study Description: 
Open label, Pilot  
Phase: 
Pilot 
Objectives: 
 
Primary Objective:  
To assess the feasibility of recruiting, consenting, enrolling, and 
completing the study intervention in 12 patients. 
Secondary Objectives: 
To assess the safety and tolerability of ketamine-assisted therapy in 
the study population. 
To determine the prevalence of existential distress in patients with 
non-operable GI cancers. 
Endpoints: 
Primary Endpoint:  
The recruitment, consent, enrollment, and study completion of 12 
patients.  Study completion defined as participating in at least 2/3 of 
the 3 KAP sessions. 
Secondary Endpoints: 
The frequency of adverse events (AEs) and serious adverse events 
(SAEs) characterized by type, severity (as defined by the NIH 
CTCAE, version 5.0), seriousness, duration, and relationship to study 
treatment. 
The proportion of screened patients that meet criteria on the 
Existential Distress Scale (EDS: Single domain ≥ 3 or total score ≥ 6) 
Study Population: 
Key Inclusion Criteria: 
• 
Subjects with non-operable GI cancers who requiring multi-
modal treatment (e.g. surgery +/- chemo +/-radiation) and 
have a a high likelihood of recurrence and/or treatment failure 
in the opinion of the treating investigator 


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• 
Screen positivity for existential distress on the EDS, defined 
as scoring ≥ 3 on any of the 10 component domains, or a total 
score ≥ 6 
• 
ECOG Performance Status ≤ 2. 
Key Exclusion Criteria: 
• 
Personal history or first- or second-degree relatives with 
schizophrenia, bipolar affective disorder, delusional disorder, 
schizoaffective disorder, psychosis, or other psychotic 
spectrum illness. 
• 
Currently meeting DSM-5 criteria for Dissociative Disorder, or 
other psychiatric conditions judged to be incompatible with the 
establishment of rapport or safe exposure to ketamine. 
• 
Currently meeting DSM-5 criteria for Cluster B Personality 
Disorder. 
• 
Severe depression requiring immediate standard-of-care 
treatment (e.g., hospitalization). 
• 
Suicidal ideation over the past month as assessed as a yes to 
question 3, 4, or 5 on the Columbia-Suicide Severity Rating 
Scale, Suicidal Ideation section 
• 
Cancer with known CNS involvement, previously treated brain 
metastasis, or other major CNS disease. 
Current or history within the last two years of meeting DSM-V 
criteria of substance use disorder (excluding caffeine and 
nicotine). Current substance use disorders may be identified 
through the drug urine screening test. 
• 
Congestive heart failure, including all New York Heart 
Association Classes.  
• 
Angina pectoris, cardiac hypertrophy, cardiac ischemia, 
myocardial infarction  
• 
Uncontrolled hypertension at the time of enrollment (BP>140 
systolic or 90 diastolic), coronary artery disease, artificial heart 
valve  
• 
Prolonged or congenital long QT syndrome (>450 ms), 
serious cardiac arrhythmias, tachycardia, a clinically 
significant screening ECG abnormality  
• 
History of hypersensitivity to ketamine 
• 
Receiving ketamine treatments for psychiatric condition within 
the past 6 months 
• 
Seizure disorder 
• 
Moderate to severe dementia 
• 
History of significant traumatic brain injury 
• 
Requires the use of supplemental oxygen. 


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• 
Any other condition that would, in the Investigator’s judgment, 
contraindicate the subject’s participation in the clinical study 
due to safety concerns or compliance with clinical study 
procedures (e.g., infection/inflammation, intestinal obstruction, 
unable to swallow medication, [patients may not receive the 
drug through a feeding tube], social/ psychological issues, 
etc.)  
• 
Subjects taking prohibited medications. A washout period of 
prohibited medications for a period of at least five half-lives 
should occur prior to study registration.  These medications 
include antipsychotic medications, doses of benzodiazepines 
in excess of 20mg diazepam equivalents per day. 
 
Study Intervention: 
Ketamine, 0.5-1.2mg/kg, IM 
Study Duration: 
1 year 
Participant 
Duration: 
6 months 


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1.2 
Schema  
 
 
 
 
 
 
 
 
 


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1.4 
Schedule of Events
Activity 
Screening 
Preparatory 
Session 
(Baseline) 
Ketamine Sessions1 
Integration 
Session 
Follow-Up2 
Visit 
1 
2 
3 
14 
Days 
30 
Days 
90 
Days 
(Window in days) 
-60 
0 
 
 
 
0 
(±3) 
(±7) 
(±7) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
Registration3 
X 
 
 
 
 
 
 
 
 
Clinical and Laboratory Assessments4 
Vital Signs5 
X 
 
X6 
X4 
X4 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
ECOG Score 
X 
 
 
 
 
 
 
 
 
ECG 
X 
 
ACI 
 
 
 
 
Adverse event collection7 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
 
Complete Metabolic Panel 
X 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
Pregnancy Test8 
X 
 
 
 
 
 
 
 
 
Study Intervention 
Evaluation and Screening9 
 
 
X 
X 
X 
 
 
 
 


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Activity 
Screening 
Preparatory 
Session 
(Baseline) 
Ketamine Sessions1 
Integration 
Session 
Follow-Up2 
Visit 
1 
2 
3 
14 
Days 
30 
Days 
90 
Days 
(Window in days) 
-60 
0 
 
 
 
0 
(±3) 
(±7) 
(±7) 
Ketamine Administration10 
 
 
X 
X 
X 
 
 
 
 
Psychotherapy 
 
X 
X 
X 
X 
X 
 
 
 
Assessments 
EDS11 
X 
X 
X 
X 
X 
 
X 
X 
X 
QIDS-SR-1612 
 
X 
X 
X 
X 
 
X 
X 
X 
C-SSRS Baseline/Screening13 
X 
 
 
 
 
 
 
 
 
C-SSRS Since Last Visit14 
 
X 
X 
X 
X 
X 
X 
 
 
MEQ-3015 
 
 
X 
X 
X 
 
 
 
 
NADA16 
 
 
X 
X 
X 
 
 
 
 
DADDS17 
 
X 
X 
X 
X 
 
X 
X 
X 
FACIT-Sp18 
 
X 
 
 
 
 
X 
X 
X 
Storyline Integrative 
Assessment19 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 


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1 Ketamine will be given during three sessions, 2 to 7 days apart. Questionnaires, with the exception of the MEQ, may be completed up to 1 day prior to the 
ketamine session. 
2 Follow-up will be based on time since completion of the integration session. 
3 To register eligible patients on study, complete a Clinical Trials Office Subject Registration Form and submit to CTORegistrations@hci.utah.edu.  
4 Laboratory assessments should be completed within 28 days of enrollment. 
5 Vital signs include systolic/diastolic blood pressure, heart rate, respiration rate, pulse oximetry andweight.  
6 Cardiovascular measures during KAP session (blood pressure, O2 sat, heart rate) will be completed within ten minutes prior to session and at 40 min and 2 
hours post-administration. Vitals will be reviewed by an on-site MD with ACLS certification. A crash cart and code response team will be available. 
7 Adverse events and conmeds will be recorded at the time of the session. Subjects may also be contacted by study staff after the session to assess for any 
additional adverse events or conmed changes. 
8 Pregnancy test (serum or urine) must be obtained at screening and ≤ 8 days prior to ketamine administration for all women of childbearing potential and as 
clinically indicated while on trial. 
9 Evaluation and screening to include the items listed in Section 6.1.2. 
10 Ketamine will be administered according to Section 6.1.3. 
11 Existential Distress Scale (EDS). See Appendix 2. 
12 Quick Inventory of Depressive Symptomatology (QIDS-SR-16). See Appendix 3. 
13 Columbia-Suicide Severity Rating Scale Baseline/Screening (C-SSRS). See Appendix 4. 
14 Columbia-Suicide Severity Rating Scale since Last Visit (C-SSRS). To be completed at any time during study participation if a subject is rated as of 
moderate or high risk on the Baseline/Screening C-SSRS. See Appendix 5.  
15 Mystical Experiences Questionnaire (MEQ-30) should be completed after ketamine administration. See Appendix 8. 
16 Nondual Awareness Dimensional Assessment. See Appendix 7. 
17 Death and Dying Distress Scale. See Appendix 9. 
18 The Functional Assessment of Chronic Illness Therapy. See Appendix 6.   
19 See Section 3.3. 


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2 
OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
To assess the feasibility of recruiting, consenting, enrolling, and completing the study 
intervention for 12 patients. 
Primary endpoint: The recruitment, consent, enrollment, and study completion of 12 patients.  
Study completion defined as participating in at least 2/3 of the 3 KAP sessions. 
2.2 
Secondary Objectives 
2.2.1 To assess the safety and tolerability of ketamine-assisted therapy in the study 
population. 
Secondary Endpoint: The frequency of adverse events (AEs) and serious adverse 
events (SAEs) characterized by type, severity (as defined by the NIH CTCAE, version 
5.0), seriousness, duration, and relationship to study treatment. 
2.2.2 To determine the prevalence of existential distress in patients with non-operable 
GI cancers.  
Secondary Endpoint: The proportion of screened patients that meet criteria on the 
Existential Distress Scale (EDS: Single domain ≥ 3 or total score ≥ 6). 
2.3 
Exploratory Objectives 
2.3.1 To assess the effect that KAP has on symptoms of existential distress and 
depression in patients with non-operable GI cancers as measured by the EDS and 
QIDS-SR-16. 
Exploratory Endpoint: Mean change in score on EDS and QIDS-SR-16 from baseline to 
2 weeks post completion of intervention.   
2.3.2 To assess the effect that qualitative experiential aspects of the ketamine 
experience have on subsequent change to depression and existential distress 
measures using the Mystical Experiences Questionnaire (MEQ-30) and Nondual 
Awareness Dimensional Assessment (NADA) 
Exploratory Endpoint: Correlation between total score on the MEQ-30 and NADA and 
change in the EDS score at the 2 week primary outcome time point. 
2.3.3 To assess the effect that KAP has on symptoms of existential distress and 
depression in patients with non-operable GI cancers as measured by the Spiritual 
Well-Being (FACIT-Sp)  
Exploratory Endpoint: Mean change in score on FACIT-Sp from baseline to Day 30 post 
completion of intervention.   


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2.3.4 To develop an algorithm with Storyline Health technology to rapidly discover the 
most predictive and information rich components in the assessment of existential 
distress and its treatment response.   
Exploratory Endpoint: Identification of a behavioral phenotype that better predicts a 
response to ketamine intervention. 
2.3.5 To evaluate the completion rate of questionnaires using the Storyline platform. 
Exploratory Endpoint: The percentage of questionnaires completed. 
3 
BACKGROUND AND RATIONALE 
Symptoms of existential distress in patients with life-threatening cancer diagnoses are common, 
difficult to meaningfully treat, and cause extensive suffering at the end of life.1 Rates of 
existential distress in this population in general are estimated to be as high as 25% to 50%2. 
Existential distress, along with associated symptoms of anxiety and depression, have been 
shown to predict poor longitudinal outcomes, reduced quality of life (QoL), higher utilization of 
opioid analgesics, and care-provider burnout.3-5 There is evidence to suggest that existential 
distress- as measured by validated tools- is a distinguishable phenomenon from other current 
recognized DSM diagnoses such as depressive and anxiety disorders.6,7 
In patients with cancers of the GI tract, surgery is essential for curative intent. In patients for 
whom curative surgical resection is not an option, whether due to distant metastatic spread, 
local tumor invasion or patient comorbidities, the absence of curative options further contributes 
to the development of existential distress, potentially leading to decreased QoL, higher pain 
scores and even shorter survival. In patients with advanced non-small-cell lung cancer, several 
previous reports have suggested that early palliative intervention may increase overall survival8-
11 and/or QoL. This may be partially mediated by resources that address aspects of existential 
distress.  
Current treatments for existential distress in this population are limited. Usually, sedative 
medications are utilized initially to control symptoms, primarily GABA agonist medications. In 
severe cases patients are rendered minimally conscious utilizing intravenous infusions of 
medications such as propofol or phenobarbital.  This is referred to as terminal sedation 
(Rousseau, 2001). These interventions serve to lessen individual distress, but come at a cost of 
diminished awareness and limited meaningful interaction with family and friends at end of life. 
 
A variety of types of therapy are utilized in addition to medications, most of which seek to 
normalize and validate the symptoms, whether as an individual or group. Multiple other options, 
such as dignity therapy, seek to help elucidate the legacy that will be left after the patient’s 
death (Vuksanovic et al., 2017). These therapies have been shown to be effective (Cuevas et 
al., 2021) but the availability of experienced practitioners, short duration of effect and duration of 
therapy (8 weeks) limits the utility in those with severe symptoms or limited life expectancy. 
Given advances in medical therapies, the number of people living with terminal illnesses is 
increasing (Etkind et al., 2017). Additional therapies will be necessary to deal with the 
increasing burden of mental health issues that will invariably accompany this rise.  
 


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3.1 
Ketamine 
Ketamine, one of the most used anesthetic medications in the world and one of the World 
Health Organization’s essential medications, is a dissociative anesthetic that exerts 
pharmacological actions through antagonism at the NMDA receptor, altering glutamatergic tone 
in the brain (Zorumski et al., 2016). Intranasal ketamine in the form of Spravato, or the s-
enantiomer of racemic ketamine, recently received FDA approval for the treatment of 
depression, and multiple trials have shown the effectiveness of intravenous ketamine infusions 
for acute depression and suicidality (Abbar et al., 2022; Andrade, 2017; Ekstrand et al., 2022; 
Fava et al., 2020; Mandal et al., 2019; Singh et al., 2016). 
There is evidence that ketamine infusions can have a beneficial effect on mental health disorders 
without associated psychotherapy, including for the treatment of major depressive disorder. 
Ketamine-assisted psychotherapy (KAP) delivers this treatment in the context of a 
psychotherapeutic process and seems to increase the positive benefits of this intervention, by 
modulating the self-awareness and self-referential processing of the participant and potentially 
prolonging therapeutic effect (Bottemanne et al., 2022; Dore et al., 2019; Krupitsky & Grinenko, 
1997; Mathai et al., 2022). There is a strong reason to believe that this aberrant self-referential 
processing plays a part in existential distress. Currently there is limited literature regarding the 
use of ketamine and existential distress, but initial case reports point to the need for larger more 
focused studies to ascertain benefits.  In a case series and an in an open label-trial, oral ketamine 
was found to be a rapid, safe, and tolerable treatment for depression in patients receiving hospice 
care (S. A. Irwin & Iglewicz, 2010; Stefanczyk-Sapieha et al., 2008).  Ketamine’s anti-nociceptive 
properties also suggest it may be an effective treatment for patients often dealing with intractable 
pain symptoms (Castellanos et al., 2020) 
Ketamine has a favorable pharmacological profile as it relates to drug interactions, side effects, 
and time to therapeutic response. It is used in the adult and pediatric population as an 
anesthetic and analgesic in surgery, acute care, and trauma and pain management.  It has been 
used in management of chronic pain in hospice and palliative care populations for breakthrough 
and chronic pain.   IM Ketamine has a 90-95% bioavailability, has a short half-life, and it does 
not depress the respiratory drive.  Many of those suffering from existential distress are currently 
taking at least one SSRI, SNRI or MAOI anti-depressant, which may take 4-6 weeks to full 
therapeutic response and relief of symptoms, time which a population of patients with limited life 
expectancy lacks.  Ketamine’s antidepressant effects can be observed and measured within 
hours to days of administration.   
This study will contribute to the knowledge base around the use ketamine as a medicine used in 
alleviating emotional suffering at the end of life.  There are currently limited tools for this 
condition.  This study will inform a larger randomized controlled trial.  
 
3.2 
Patient Population Background 
Patients with advanced cancers of the GI tract often have limited treatment options and poor 
prognosis. These cancers can originate from a wide variety of sources and include hepatic, 
biliary, pancreatic, small bowel, colon and rectal cancers.   


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Treatment modalities such as chemotherapy, immunotherapy or surgical resection often carry 
significant morbidity. Patients for whom curative surgical resection is not an option, whether due 
to distant metastatic spread, local tumor invasion or patient co-morbidities, may have significant 
physical symptoms as well as concomitant existential distress.   
Existential distress is distress that originates from complexities and contradictions within one’s 
lived experience and relationship to the world around them. It occurs when meaning and value 
become “unclear” (Lo 2018). Existential distress appears to be a distinguishable phenomenon 
from other current recognized DSM diagnoses such as depressive and anxiety disorders.6,7 
Symptoms of existential distress in patients with life-threatening cancer diagnoses are common, 
difficult to meaningfully treat, and cause extensive suffering at the end of life.1 Rates of 
existential distress patients with advanced cancer are estimated to be as high as 25% to 50% 
(Grassi 2017).  
Existential distress, along with associated symptoms of anxiety and depression, have been 
shown to predict poor longitudinal outcomes, reduced quality of life, higher utilization of opioid 
analgesics, and care-provider burnout.3-5  
3.3 
Storyline Health Assessments 
3.3.1 Overview 
Storyline is a flexible research platform that will be used to deliver assessments during the 
course of the study. Storyline extracts features from video, audio, and natural language and 
overlays it with other data sources like patient records, genome data and outcomes. 
Participants are owners of their data and can access it at any time, and even delete it. However, 
the study will not be able to provide direct meaningful interpretations for participants. Note, that 
participants may be able to choose some non-research interactions within the Storyline app, 
such as what celebrities they look like. This is not considered a benefit nor will be included in 
the research data, it’s for entertainment purposes for the participants. 
3.3.2 Storyline Core Questions of Health  
The baseline assessment is designed to mimic a typical clinical psychiatric diagnostic interview 
and a neurological assessment. The psychiatric portion is a 60- minute program broken into six 
different 10-minute assessment sessions. The neurological portion is a 10-mintute assessment.  
Patients will be notified through the Storyline app on their smartphone or smart device to 
complete the various study assessments. Storyline manages reminders and makes the process 
simple.  
The objective is to create an effective and fast algorithm for feature selection and question 
selection to build assessments, diagnostic biobehavioral markers and predictive models from 
Storyline captured speech, vocal and facial data. The proposed algorithm has 3 components, 
including (1) rapid feature and question filtering based on variance, (2) feature selection using a 
method that integrates mutual information and random forest importance scores and (3) 
question selection using a deep learning method that ranks the predictive value of each 
question using the optimized features. The steps are as follows: 


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 Rapid Question Filtering – The first step in the Short Story algorithm will be to filter questions, 
assessments and A.I. features in the storyARC and storyTIME files that have little information 
content. To do this, we will compute the variance for each measured feature for each question 
in the data for all people in a customer’s pilot study. The variance is scaled to account for 
differences in units. We then sum the variance for each feature for each question, apply a min-
max absolute scale for interpretation that scores questions from 0 (low information content) to 
100 (high information content). The results will enable users to rapidly screen, rank and prune 
questions with little to no information content by pruning the bottom 25% of tested candidate 
questions. 
 Feature Selection: Storyline AI measures over 20,000 speech, vocal and facial features from 
the responses for each question and many are correlated or not useful for detecting some 
phenotypes of interest. Therefore, in this second step, Short Story technology performs a 
feature selection analysis that uncovers the most useful features for each tested question in an 
assessment for predicting a particular phenotype or outcome. The major objective is to uncover 
the best questions and features when the available data has limited sample size and classes 
are imbalanced. Our approach will involve implementing the qualitative mutual information 
(QMI) feature selection algorithm previously detailed by others and proven for high dimensional 
data, including microarray data for tens of thousands of genes (Nagpal and Singh, 2019). The 
algorithm will provide a score that combines random forest (RF) feature importance scores with 
mutual information to obtain a QMI value for each feature. QMI is more powerful than random 
forest (RF) importance or mutual information alone for feature selection, as previously described 
(Nagpal and Singh, 2018). In brief, RF will be applied to the speech, vocal and facial feature 
sets separately for each question and the importance scores of each feature will be calculated, 
as well as mutual information. RF importance scores will be converted to Preference scores and 
multiplied by the mutual information to define QMI values for each feature. The features will then 
be ranked by QMI values and features with a QMI > 0 will be retained. The results will return the 
most useful speech, facial and vocal features for each question. The usefulness of the features 
is determined from their ability to differentiate the two classes in a study, such as control versus 
sick patients. 
This approach has many advantages, including broad utility with few parameters to tune, 
applications to diverse data types with few samples and acceptable computational speed. RF 
importance scores are powerful for ranking correlated features. Mutual information, which 
determines the amount of information one random variable can provide about another variable, 
is then incorporated to further help remove irrelevant and redundant features. When accounting 
for accuracy and computational efficiency, this combined approach outperforms most methods, 
including filter, wrapper, embedded and hybrid feature selection strategies (Nagpal and Singh, 
2019). 
Question Selection: The final step of the Short Story algorithm will provide a score that 
determines the individual questions that should be retained in a new assessment and those that 
can be eliminated. In this approach, the input is all of the candidate questions and their 
optimized speech, vocal and facial features revealed from Short Story Score #2. The individual 
questions and question combinations that show the most value for predicting the classes of 
interest will then be determined. We will create a simple two-layer neural network that is 
architected to take Storyline speech, vocal and facial features as inputs to predict the 


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phenotypic classes of interest. The algorithm will be designed such that questions are tested in 
all possible pairwise combinations with 5-fold cross validation. The mean accuracy for predicting 
the target phenotype is determined for each question combination. Each pairwise question 
combination is then assigned an index. To compute the Short Story score for each question, we 
multiply the index and the mean classification accuracy for all question pairings in which that 
question was included in the predictive model. This vector of index*accuracy values is summed 
to yield a score and then the scores for all of the candidate questions are min-max scaled to 
create the final Short Story question ranking score from 0-to-100, where a high score indicates 
important questions, and a low score indicates questions that can be pruned. The final results 
will return the ranking for each question and the mean classification accuracy values for each 
question. 
3.3.3 Psychiatric and Psychology Assessment Components:  
This part of the assessment is a 60-minute program broken into six 10-minute assessments of 
(i) physical symptoms, (ii) mood & emotion, (iii) cognition, (iv) homeostasis (ie. eating, sleeping, 
activity patterns) (v) social support and (vi) psychological associations. The program was 
created, in part, with our collaborator, Dr. Brian Mickey MD PhD (clinical psychiatrist) from a 
proven set of psychiatric interview questions and methods for DSM-5 diagnoses of depression, 
bipolar, anxiety, psychosis, neurocognitive disorders (dementia and delirium), suicidality, 
addiction, trauma and physical health.  This interview uses open-ended questions that evaluate 
RDoC domains and create a caring and natural interview experience that is non-threatening 
using “normalization”, “reduction of guilt” and “symptom exaggeration” techniques, as well as 
providing safety, transparency, education and logical flow. Cognition is assessed, in part, using 
established clinical tests of cognitive functioning, including tests of (i) orientation (date, day of 
the week, location), (ii) short-term memory, (iii) long-term memory and recall, (iv) semantic 
fluency, (v) verbal fluency, (vi) working memory, (vii) attention and (viii) self-initiation. In addition, 
open-ended questions are included that ask for descriptions of (1) concerns about brain 
functioning, memory, concentration and fatigue, (2) any noticeable changes in memory or 
thinking, brain fog, headaches, (3) social interactions and perceived support, and (5) a 1-5-
minute story about “something that happened to you this week”. The psychological associations 
assessment uses open-ended descriptions (“What does this make you think of?”) to capture 
responses to neutral, positive and negative cues, including Eckman faces (neutral, happy, sad, 
angry, disgust, surprise, contempt), Open Affective Standardized Image Sets (OASIS) and 
Affective Norms for English Words (ANEW) with valence, arousal or dominance characteristics 
predictive of mental illness (ie. death, cruelty, trouble, carefree, good, and praise). Finally, the 
Storyline assessment includes the standard PHQ-2, GAD-2 and PCL-2 questionnaires of clinical 
depression, anxiety and trauma symptoms as internal controls for clinical symptomology.  
The neurological assessment developed by Storyline is 10 minutes long and is similar to a 
standard of care neurological exam. It includes questions that test eye movement, facial 
expression, speech, finger movements, hand movements, cognition and drawing. The material 
for this assessment is derived from the following leading clinical neurology textbook: 
"Neurological Examination Made Easy 6th Edition” by Geraint Fuller MD FRCP.  


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3.3.4 Deep Cognitive and Behavioral Assessments During Treatment 
Participants will be asked to perform a 10-minute “Well-being” assessment that includes open-
ended questions about major domains of health. Examples include how they are, concerns, 
physical symptoms, emotional symptoms, social interactions and perceived support, 
medications and missed pills, energy and activity, sleep, a 1-5-minute story describing 
something that happened to them during the week and tests of short-term memory, working 
memory and attention.  
4 
STUDY DESIGN 
This study is an open-label feasibility study that will enroll a total of 12 patients with non-
operable GI cancers suffering with existential distress. The study intervention for KAP will 
include a preparatory session, a total of three 2.5-3 hour therapy sessions which will occur 2-7 
days apart, an integration session, and follow-up visits at 14, 30, and 90 days. Ketamine will be 
administered at a starting does of 0.5 mg/kg and can be titrated up to 1.2 mg/kg based on 
patient response. The sessions will utilize eye-shades and a music track played over 
headphones. This will involve a therapist trained in KAP present 1:1 for all sessions with a 
physician available on site for medical evaluation, medication administration, support and 
backup. 
We hypothesize that this study design will be feasible and ketamine can be administered safely. 
This study will better characterize the category of ‘existential distress’ which is variably 
described in the literature, separable as a phenomenon from DSM 5 mood and anxiety 
disorders, and a set of symptoms that cause significant distress for patients and care givers. To 
better characterize and understand symptoms and predictors of existential distress we will 
administer an existential distress screening instrument (the Existential Distress Scale) along 
with a broad psychosocial assessment to screen for patient enrollment as well as examine 
psychosocial predictors.  We will then utilize the Storyline Health platform through the study 
process to build and refine a set of behavioral biomarkers to characterize existential distress. 
4.1 
Study Duration 
Study duration will be approximately 1 year. 
4.2 
End of Study  
A subject 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 
Events. 
The study will end when the last subject completes the last visit or last contact, discontinues 
from the study, or is lost to follow-up, whichever occurs first. In addition, the sponsor may 
terminate the study at any time. If at any time, the sponsor terminates the study any subjects 
receiving clinical benefit from the study intervention may roll over to an expanded access 
protocol, if available, to ensure continued access to the study medication.  
 
 


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5 
STUDY POPULATION 
Potential study participants must meet all inclusion criteria and no exclusion criteria to be 
deemed eligible for trial participation. To ensure subject safety, all subjects must be deemed 
eligible at the time of study registration and must continue to meet eligibility criteria up to 
ketamine dosing. This eligibility checklist is used to determine subject eligibility and will be filed 
with the enrolling investigator’s signature in the subject research chart. 
5.1 
Inclusion Criteria 
1. _____ Subject aged ≥ 18 years. 
2. _____ Subjects with non-operable GI cancers requiring multi-modal treatment (e.g. 
surgery +/- chemo +/-radiation) and have a a high likelihood of recurrence and/or 
treatment failure in the opinion of the treating investigator.  
3. _____ Screen positivity for existential distress on the EDS, defined as scoring ≥ 3 on any 
of the 10 component domains, or a total score ≥ 6 
4. _____ ECOG Performance Status ≤ 2. 
5. _____ Adequate hepatic function as defined as:  
• 
Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN) unless elevated 
bilirubin is related to Gilbert’s Syndrome 
• 
AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN 
 
Subjects with liver metastases will be allowed to enroll with 
AST and ALT levels ≤ 5 x ULN. 
6. _____ For subjects of childbearing potential: Negative pregnancy test or evidence of 
post-menopausal status. The post-menopausal status will be defined as having been 
amenorrheic for 12 months without an alternative medical cause. The following age-
specific requirements apply:  
• 
Subjects < 50 years of age:  
o Amenorrheic for ≥ 12 months following cessation of exogenous 
hormonal treatments; and  
o Luteinizing hormone and follicle-stimulating hormone levels in the 
post-menopausal range for the institution; or 
o Underwent surgical sterilization (bilateral oophorectomy or 
hysterectomy).  
• 
Subjects ≥ 50 years of age: 
o Amenorrheic for 12 months or more following cessation of all 
exogenous hormonal treatments; or 
o Had radiation-induced menopause with last menses >1 year ago; or 


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o Had chemotherapy-induced menopause with last menses >1 year 
ago; or 
o Underwent surgical sterilization (bilateral oophorectomy, bilateral 
salpingectomy, or hysterectomy). 
7. _____ Subjects of childbearing potential and subjects with a sexual partner of 
childbearing potential must agree to use a highly effective method of contraception as 
described in Section 5.3.1. 
8. _____ Subjects with a sexual partner of childbearing potential must agree to use a 
condom during intercourse for 24 hours post- ketamine dose. 
9. _____ Agree to refrain from using any psychoactive drugs, including alcoholic 
beverages, ondansetron, cannabis, and non-routine PRN medications within 24 hours of 
each ketamine administration. Exceptions include daily use of caffeine, nicotine, and 
opioid pain medication (see Section 6.5.1). 
 
10.  _____ Able to provide informed consent and willing to sign an approved consent form 
that conforms to federal and institutional guidelines. 
11. _____ Agree that for one week preceding the ketamine session, he/she will refrain from 
taking any nonprescription medication, nutritional supplement, or herbal supplement 
except when approved by the research team. Exceptions will be evaluated by the 
research team and will include acetaminophen, non-steroidal anti-inflammatory drugs, 
and common doses of vitamins and minerals. 
12. _____ Agree not to use nicotine for at least 2 hours before the ketamine administration 
or for the duration of the ketamine session. 
13. _____ Agree to consume approximately the same amount of caffeine-containing 
beverage (e.g., coffee, tea) that he/she consumes on a usual morning, before arriving at 
the research unit on the morning of the ketamine session. If the subject does not 
routinely consume caffeinated beverages, he or she must agree not to do so on the day 
of ketamine administration. 
14. _____ Subjects requiring opioid use for pain are on a stable pain management regimen 
or do not experience clinically significant sedation during opioid use. 
• 
Note: Long-acting opioid medications (e.g., oxycodone sustained-release, morphine 
sustained release) will be allowed if the last dose occurred at least 6 hours before 
ketamine administration; such medication will not be taken again until at least 6 
hours after ketamine administration. 
15. _____ Fluent in English. 
16. _____Reading literacy and comprehension sufficient for understanding the consent form 
and study questionnaires, as evaluated by study staff obtaining consent. 
17. _____ Have a support person who is be able to escort the subject home from the 
ketamine dosing sessions. 
• 
Note: The use of ride services will not be permitted (e.g., Uber, Lift, taxi, etc.) 


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5.2 
Exclusion Criteria 
 
1. _____ Received ketamine treatments for a psychiatric condition within 6 months of 
enrollment. 
2. _____ Personal history or first- or second-degree relatives with schizophrenia, bipolar 
affective disorder, delusional disorder, schizoaffective disorder, psychosis, or other 
psychotic spectrum illness. 
3. _____ Currently meeting DSM-5 criteria for Dissociative Disorder, or other psychiatric 
conditions judged to be incompatible with the establishment of rapport or safe exposure 
to ketamine. 
4. _____Currently meeting DSM-5 criteria for Cluster B Personality Disorder. 
5. _____ Severe depression requiring immediate standard-of-care treatment (e.g., 
hospitalization). 
6. _____ Suicidal ideation over the past month as assessed as a yes to question 3, 4, or 5 
on the Columbia-Suicide Severity Rating Scale, Suicidal Ideation section 
7. _____ Cancer with known CNS involvement, previously treated brain metastasis, or 
other major CNS disease. 
8. _____ Current or history within the last two years of meeting DSM-V criteria of 
substance use disorder (excluding caffeine and nicotine). Current substance use 
disorders may be identified through the drug urine screening test. 
9. _____ Current evidence of uncontrolled, significant intercurrent illness including, but not 
limited to, the following conditions: 
• 
Cardiovascular disorders: 
o Any grade congestive heart failure, unstable angina pectoris, serious 
cardiac arrhythmias including tachycardia, or clinically significant 
screening ECG abnormalities.  
o Cardiac hypertrophy or artificial heart valve. 
o Stroke (including transient ischemic attack [TIA]), myocardial 
infarction (MI), or other ischemic events, or thromboembolic event (eg, 
deep venous thrombosis, pulmonary embolism), and/or significant 
coronary artery disease within 3 months before the first dose.  
o QTc prolongation defined as a QTcF > 450 ms. 
o Known congenital long QT. 
o Uncontrolled hypertension defined as ≥ 140/90 as assessed from the 
mean of three consecutive blood pressure measurements taken over 
10 minutes. 


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• 
Seizure disorder 
• 
Moderate to severe dementia 
• 
History of significant traumatic brain injury 
• 
Requires the use of supplemental oxygen. 
• 
Renal insufficiency as defined as creatinine clearance < 40 mL/min 
calculated by Cockcroft-Gault formula 
• 
Any other condition that would, in the Investigator’s judgment, contraindicate 
the subject’s participation in the clinical study due to safety concerns or 
compliance with clinical study procedures (e.g., infection/inflammation, 
intestinal obstruction, unable to swallow medication, [subjects may not 
receive the drug through a feeding tube], social/ psychological issues, etc.) 
10. _____ Known HIV infection with a detectable viral load within 6 months of the anticipated 
start of treatment. 
Note: Subjects on effective antiretroviral therapy with an undetectable viral load within 6 
months of the anticipated start of treatment are eligible for this trial. 
11. _____ Active infection including tuberculosis (clinical evaluation that includes clinical 
history, physical examination, radiographic findings, and TB testing in line with local 
practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis 
C.  
Note: Subjects with a past or resolved HBV infection (defined as the presence of 
hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects 
positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is 
negative for HCV RNA. 
12. _____ Medical, psychiatric, cognitive, or other conditions that may compromise the 
subject's ability to understand the subject information, give informed consent, comply 
with the study protocol or complete the study. 
13. _____ Known prior severe hypersensitivity to ketamine or any component in its 
formulations (NCI CTCAE v5.0 Grade ≥ 3). 
14. _____ Subjects taking prohibited medications as described in Section 6.5.1. A washout 
period of prohibited medications for a period of at least five half-lives or as clinically 
indicated should occur before the start of treatment. 
I certify that this patient meets all inclusion and exclusion criteria for enrollment onto 
this study.  
_______________________________________ 
______________ 
____________ 
Investigator Signature  
 
 
 
 
Date 
 
 
Time 
 


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5.3 
Registration 
Subjects must complete all screening procedures and meet all of the eligibility requirements 
before registration. Study-related screening procedures can only begin once the subject has 
signed the consent form. Subjects must not begin protocol treatment prior to registration. 
Treatment should start as soon as logistically possible after registration. 
To register eligible subjects on study, complete a Clinical Trials Office Subject Registration 
Form and submit to CTORegistrations@hci.utah.edu. 
For sites outside of Huntsman Cancer Institute, submit registration forms to 
MultisiteRegistrations@hci.utah.edu  
5.3.1 Contraception 
Non-clinical and clinical data describing the effects ketamine on lactation, sperm, and 
teratogenicity are limited. Therefore, subjects of childbearing potential should have a negative 
pregnancy test at the time of screening and use a highly effective form of contraception for the 
duration of study treatment and for at least 14 days after ketamine administration.  
Subjects should be instructed to use a condom for 24 hours after the ketamine dose. 
Acceptable highly effective contraceptive methods include: 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Intra-uterine devise (IUD) or hormone-releasing system (IUS) 
• 
Any hormonal (estrogen combined with progesterone or progesterone alone) 
contraception associated with inhibition of ovulation: implanted, oral, intravaginal, 
transdermal, or injectable. 
• 
Spermicide with a compatible barrier method (i.e. diaphragm, sponge, or male or female 
condoms). 
• 
Abstinence from heterosexual intercourse.  
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but do 
not meet subject eligibility criteria. These subjects will not be entered into the study or begin 
study intervention. However, minimal information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements. Minimal information includes, but may not be limited to, demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE) experienced 
during screening, but prior to being deemed ineligible. Adverse events and SAEs will not be 
collected after a subject is deemed ineligible. Any AEs/SAEs related to a screening procedure 
will be followed until resolution.  
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened at the Investigator’s discretion.  


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5.5 
Strategies for Recruitment 
Potential patients will be identified by Investigators in the setting of their outpatient clinics. Social 
work team members on each oncology service will help identify potential patients during routine 
clinic encounters. 
5.5.1 Number of Subjects 
The study will enroll 12 subjects. 
5.5.2 Number of Study Sites 
This will be a single-center trial run at the Huntsman Cancer Institute at the University of Utah. 
6 
STUDY INTERVENTION 
6.1 
Ketamine Assisted Psychotherapy 
Ketamine-assisted psychotherapy will be administered standard of care by the therapist team in 
the HMHI Park City Ketamine-Assisted Psychotherapy Clinic.  This team has been trained 
specifically in this modality of treatment by the Psychedelic Research and Training Institute 
(PRATI).  This modality of therapy involves an initial experiential phase following ketamine 
administration of approximately 1 hour that is supportive and non-directive in nature and may 
utilize eye-shades and music playlists via headphones.  Interventions during this phase of the 
session are minimal, supportive, and largely directed towards helping the patient move through 
any difficult emotions or experiences arising.  The next phase of the 3 hour session involves 
more directed psychotherapeutic engagement where participants begin to explore and discuss 
content that arose during their experience, how this content may be related to underlying issues 
that bring them into this study (existential distress, grief, depressive symptoms, anxiety), and 
strategies to integrate this material or insights gained into their everyday lives. Modalities 
employed by our therapist team largely center around Acceptance and Commitment Therapy 
(ACT) techniques however also include – as clinically indicated- other modalities such as CBT, 
psychodynamic approaches, and Internal Family Systems (IFS), and Internal Family Systems 
(IFS).   
6.2 
Ketamine Administration Schedule 
Ketamine and all other supportive medications described in this guideline will be stored in 
accordance with State and Federal regulations. Medication retrieval, documentation, and 
wasting will follow applicable organizational policies and guidelines related to automated 
dispensing cabinets, controlled substances, and the storage, labeling, and discarding of drugs. 
Each vial of ketamine will be used to provide the desired dose for a single patient, and the 
remainder of the vial will be promptly wasted. 
6.2.1 Personnel required for administration of ketamine: 
o Medical doctor will be in the same room as the patient or onsite and immediately 
available throughout ketamine administration and the monitoring period 


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o Vital signs will be performed by either a medical assistant, clinic therapist, nurse, 
or medical doctor. All vital signs will be reviewed by an MD during the session at 
the time they are taken. 
6.2.2 Screening prior to ketamine-assisted psychotherapy: 
o Evaluation and screening prior to first visit 
 
Psychiatric evaluation and review of medical history 
 
Physical exam 
o Evaluation and screening immediately prior to each administration 
 
Confirm allergy list 
 
Confirm patient has been NPO (except for water) for at least 4 hours prior 
to treatment 
 
Medication history 
• 
Confirm no use of sedatives or psychostimulants for 12 hours prior 
to treatment 
• 
Confirm no use of MAO inhibitors for 2 weeks prior to treatment 
 
Brief physical assessment 
• 
Blood pressure 
o If blood pressure > 140/90 mmHg, then make a clinical 
decision regarding risks/benefits of administration of 
ketamine 
o If blood pressure > 160/100 then hold ketamine and re-
check after five minutes.  May repeat this process twice. 
o If blood pressure remains over 160/100 then ketamine will 
not be given. 
• 
Other parameters that must be met for ketamine administration 
o Oxygen saturation > 92% on room air 
o Respirations > 8 breaths per minute 
o Patient must be fully awake 
o Patient must be able to move all extremities 
 
Verify the patient has a responsible adult to escort them home 
• 
Patients may take any mode of transportation as long as they are 
accompanied by an escort 
• 
Ketamine will not be administered if an escort cannot be identified 
6.2.3 Administration of ketamine 
o To be administered by a medical doctor or nurse 
 
Double check of dose/volume to be administered to the patient 
o Intramuscular administration 
 
Doses can range 0.5-1.2 mg/kg. Starting dose for all participants will be 
0.5mg/kg. 
 
Dose can be titrated up to maximum of 1.2 mg/kg or titrated down to 0.5 
mg/kg based on response and clinical judgement.  
 
Dose will be administered by injecting into large muscle mass (eg, deltoid, 
gluteal muscle, thigh) 


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6.2.4 Monitoring after administration 
o During KAP session 
 
Check blood pressure 40 minutes and 2 hours after ketamine 
administration 
• 
Give clonidine 0.1 mg po in clinic if blood pressure is greater than 
180/110. If blood pressure remains elevated 1 hour after clonidine 
administration, transfer patient to a higher level of care. 
• 
Initiate emergency response procedures if blood pressure is 
greater than 180/110 and the patient develops symptoms of 
hypertensive crisis (eg, headache, vision changes) 
 
Severe emotional distress or agitation as determined by MD. 
• 
Lorazepam 0.5 mg po/im will be available on demand. This may 
be repeated once after one hour for ongoing severe emotional 
distress or agitation. 
 
Check respiratory rate at 40 minutes and 2 hours after ketamine 
administration 
• 
Initiate emergency response procedures and start continuous 
oxygen saturation monitoring if respiratory rate is < 8 breaths per 
minute or obtunded 
• 
Oxygen per nasal cannula available for oxygen saturation < 92% 
• 
Bag ventilation available 
 
Nausea or vomiting 
• 
Ondansetron 4 mg po/im will be available on demand. This may 
be repeated once after one hour for ongoing nausea and vomiting. 
o Following 3-hour KAP session 
 
The patient must have an adult escort with them for at least 3 hours post-
treatment 
 
The medical doctor or medical assistant will assess for suicidal ideation or 
other safety concerns 
 
The patient must avoid driving and operating machinery for at least 12 
hours post-treatment 
o Patient must meet the following objective criteria prior to leaving clinic (≥ 2 hours 
following ketamine administration) 
 
Patient must have oxygen saturation > 92% on room air 
 
Patient must have respirations > 8 breaths per minute 
• 
Patient must be able to take a deep breath and cough. 
 
Patient must have systolic blood pressure  +/- 20 mmHg of pre-
administration measurement 
 
Patient must be fully awake 
 
Patient must be able to move all extremities 
Ketamine is stored at the HMHI KAP Clinic and administered by an MD study investigator. The 
HMHI KAP Clinic employs a log of ketamine administration in accordance with DEA standards.  
Appropriate records will be kept to accurately show all dispensing activities including the return 
of any unused Investigational Product (IP). IP will be supplied only to subjects deemed eligible 
for study therapy. IP may not be dispensed to patients who have not been enrolled in the trial. 


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Patients will be advised to refrain from the following for 24 hours before ketamine: 
• 
Cannabis  
• 
Alcoholic beverages 
• 
Psychoactive drugs 
• 
Non-routine PRN medications 
• 
Grapefruit, grapefruit juice, and other CYP4A inhibitors 
On the day of ketamine administration, patients on opioids should not take any long-acting 
opioids within 6 hours prior to or 6 hours proceeding ketamine administration. Patients should 
consume approximately the same amount of caffeine-containing beverage (e.g., coffee, tea) 
that he/she consumes on a usual morning, before arriving at the research unit. If the subject 
does not routinely consume caffeinated beverages, he or she must agree not to do so on the 
day of ketamine administration. Patients should also not use nicotine for at least 2 hours before 
ketamine administration.  
All doses of ketamine will be administered at the investigational site by qualified medical staff. 
The time of administration will be recorded in the patients’ research charts. Any reason for 
deviation from the protocol-specified dose or schedule will be documented in the subject’s 
research chart. 
6.2.5 Accountability and Compliance 
Ketamine is currently stored at the HMHI KAP Clinic in a secure and locked medication safe in 
accordance with DEA standards and is overseen by HMHI Pharmacy staff with regular 
inspections.  This involves logging of dose, bottle # of ketamine, patient MRN, and amount of 
ketamine wasted per administration day with signatures of 2 clinic members present to observe 
the wasting of medication. 
6.3 
Ketamine 
6.3.1 Investigational Product Supplies 
Ketamine will be sourced from the current commercial supply stored at the HMHI KAP Clinic. 
6.3.2 Preparation and Dispensing 
The investigator or qualified personnel will prepare and dispense all investigational supplies. 
Appropriate records will be kept to accurately show all dispensing activates and Investigational 
Product (IP) will be supplied only to subjects deem eligible for study therapy. IP may not be 
dispensed to subjects who have not been enrolled in the trial. 
The time of administration will be recorded in the patients’ research charts. Any reason for 
deviation from the protocol-specified dose or schedule will be documented in the subject’s 
research chart. 
6.4 
Adverse Event Management 
Adverse events will be managed as outlined in Section 6.1.4. 


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6.5 
Supportive Care 
All supportive measures consistent with optimal patient care may be given throughout the study 
as deemed necessary by the treating investigator. 
6.6 
Concomitant Medications and Therapies 
All supportive measures consistent with optimal subject care may be given throughout the 
study.  
All administered concomitant medications (including herbal supplements) and non-medicinal 
therapies (including transfusions) used 28 days prior to registration, and until 30 days after the 
last dose of study therapy will be recorded in the subject’s research chart and corresponding 
eCRF, if applicable.  
6.6.1 Prohibited Therapy 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the active treatment period. Patients are prohibited from receiving the following therapies 
during the treatment phase of this trial:  
• 
Other investigational agents  
• 
Herbal remedies known to potentially interfere with major organ function (e.g., hypericin) 
• 
Monoamine oxidase inhibitors 
• 
Sedatives – any opioid, benzodiazepine, sedative hypnotic, or alcohol 
• 
Theophylline or Aminophylline 
• 
Sympathomimetics (excluding albuterol) and Vasopressin 
Patients will be advised to refrain from the following for 12 hours before ketamine: 
• 
Cannabis  
• 
Psychostimulants-includes methylphenidate, any amphetamines, modafinil, or 
armodafinil 
• 
Non-routine PRN medications 
On the day of ketamine administration, patients on opioids should not take any long-acting 
opioids within 12 hours prior to or 6 hours proceeding ketamine administration. Patients should 
consume approximately the same amount of caffeine-containing beverage (e.g., coffee, tea) 
that he/she consumes on a usual morning, before arriving at the research unit. If the subject 
does not routinely consume caffeinated beverages, he or she must agree not to do so on the 
day of ketamine administration. Patients should also not use nicotine for at least 2 hours before 
ketamine administration. .  
6.7 
Duration of Therapy 
Subjects will receive combined treatment until treatment discontinuation criteria is met. Upon 
meeting treatment discontinuation criteria, subjects will continue on the study in follow-up until 
study discontinuation criteria are met.  


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6.7.1 Criteria for the Discontinuation of Treatment 
Subjects may withdraw from treatment or the study overall at any time at their request, or they 
may be withdrawn at the discretion of the Investigator or Sponsor for safety, behavioral reasons, 
or the inability of the subject to comply with the protocol-required schedule of study visits or 
procedures. In addition to the drug-specific discontinuation criteria listed in section 6, the 
following will result in treatment discontinuation: 
• 
Completion of treatment study visits outlined in the Schedule of Events 
• 
The subject or legally authorized representative requests to discontinue the study 
treatment and/or study procedures;  
• 
Clinical deterioration that, in the opinion of the investigator, increases the risk to the 
subject; 
• 
Adverse events or intercurrent illness that in the opinion of the investigator warrants the 
subject’s withdrawal from study treatment; 
• 
Significant noncompliance with the protocol schedule or treatment administration in the 
opinion of the investigator; 
• 
Pregnancy 
6.7.2 Criteria for the Discontinuation of Study  
Subjects will be taken off study for the following: 
• 
Completed study follow-up period; 
• 
Participant or legally authorized representative requests to be fully withdrawn from the 
study;  
• 
If, in the investigator's opinion, the continuation of the trial would be harmful to the 
subject's well-being; 
• 
The subject is lost to follow-up;  
• 
Screen failure; 
• 
Death. 
6.7.3 Withdrawal of consent 
Subjects are free to withdraw from the study at any time without prejudice to further treatment. 
Subjects who withdraw consent for further participation in the study will not receive any further 
study medications or further study observation.  
If a subject withdraws consent, they will be specifically asked if they are withdrawing consent to 
all further participation in the study including any further follow-up (e.g., survival contact 
telephone calls). Survival status may be obtained from public records for subjects who have 
withdrawn from any further follow-up contact. 


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6.7.4 Lost to Follow-Up 
Subjects will be considered lost to follow-up only if no contact has been established by the time 
the study is completed, such that there is insufficient information to determine the subject’s 
status at that time. Subjects who refuse to continue participation in the study, including 
telephone contact, should be documented as “withdrawal of consent” rather than “lost to follow-
up.” Investigators should document attempts to re-establish contact with missing subjects 
throughout the study period. If contact with a missing subject is re-established, the subject 
should not be considered lost to follow-up and evaluations should resume according to the 
protocol. 
When a subject is lost to follow-up, site personnel should check hospital records, the subjects’ 
current physician, and a publicly available death registry to obtain a current survival status.  
In the event that the subject has actively withdrawn consent, the survival status of the subject 
can be obtained by site personnel from publicly available death. 
7 
STUDY ASSESSMENTS 
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that there may be circumstances, outside of 
the control of the Investigator that may make it unfeasible to perform the test. In these cases, 
the Investigator will take all steps necessary to ensure the safety and well-being of the subject. 
When a protocol-required test cannot be performed, the Investigator will document the reason 
for this and any corrective and preventive actions that he or she has taken to ensure that normal 
processes are adhered to as soon as possible. 
7.1 
General Assessments 
7.1.1 Participant Consent 
Before the initiation of any study procedures, all potential subjects or their legal representative 
must be fully informed of the risks and potential benefits of trial participation and demonstrate 
understanding. An informed consent document must be signed and dated by the participant or 
their legal representative indicating that they understand the risks and consent to participation 
and treatment on the study. The Principal Investigator or their appropriately trained and 
delegated study personnel conducting the informed consent discussion must also sign and date 
the document. A copy of the signed document should be provided to the subject. 
Procedures, laboratory tests, or imaging performed as part of the standard of care prior to 
subject consent may contribute to the assessment of eligibility and/or screening procedures if 
performed during the screening period.  
7.1.2 Medical History 
The investigator or appropriately trained and delegated study personnel will collect medical 
history to the extent that supports the assessment of eligibility. The medical history will include 
any active conditions and any conditions deemed to be clinically significant by the treating 
investigator. The use of symptom terms should be discouraged; if possible, terms describing the 
principal condition or syndrome should be used.  


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When collecting medical history specific attention should be given to: 
• 
History of Coronary Artery Disease 
• 
Alcohol history (never used alcohol, current alcohol user, former alcohol user) 
• 
Smoking history (never smoked, current smoker, former smoker) 
• 
Pack years (average number of packs per day and number of years smoked) 
• 
Current employment status (employed, retired, student, unknown, other) 
• 
Insurance status (private insurance, Medicare, Medicaid, VA, military, not insured, self-
pay, unknown, other) 
• 
Substance use history; including prior history with psychedelics including ketamine. 
7.1.3 Cancer History 
 The oncologic history of the malignancy understudy will be collected at the screening visit and 
will include prior regimens (duration of therapy, the best response on therapy, date of 
discontinuation, and reason for discontinuation), surgery, radiation therapy, and sequence.  
7.1.4 Concomitant Medications 
All medications currently being used by a study participant, regularly or as needed, must be 
reviewed and documented by the investigator or qualified designee. Specific attention should be 
given to medications with a protocol required washout as described in the exclusion criteria and 
any medication taken 28 days prior to ketamine. Refer to Section 6.5.1 for prohibited 
medications.  
During protocol therapy, any medications taken by the patient or used to treat an adverse event 
will be documented in the subject’s research chart and the corresponding eCRF. If a new 
anticancer therapy is initiated during study follow-up, the new therapy should also be recorded 
in the subject’s research chart and corresponding eCRF. .  
7.2 
Safety Assessments 
7.2.1 Physical Examinations and Vital Signs 
Subjects will have physical examinations to include major body systems, vital signs (blood 
pressure, heart rate, respiration rate, and pulse oximetry), assessment of ECOG performance 
status (see Appendix 1). and weightat the time points described in the Schedule of Events. If 
necessary to facilitate scheduling, the physical exam may occur one day before study treatment.  
7.2.2 Adverse Events 
Adverse events experienced during trial participation will be collected per the Schedule of 
Events and Adverse Events Section. Each study participant will be questioned about the 
occurrence of adverse events in a non-leading manner.  


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7.2.3 Laboratory Assessments 
Samples for all laboratory assessments will be drawn at the time points indicated in the Study 
Calendar and when clinically indicated. Laboratory tests may be performed up to 3 days before 
the scheduled clinic visit. All safety laboratory analyses will be performed by the local laboratory 
for each study center. When applicable, all safety laboratory assessments must be reviewed by 
the treating investigator before study drug administration. When applicable, results from the 
pregnancy test must also be available for review before dosing.  
Table 1: Laboratory Assessments 
Laboratory Assessments 
 Chemistry 
• 
Complete Metabolic Panel 
o Sodium 
o Potassium 
o Chloride 
o Carbon Dioxide 
o Alkaline Phosphatase 
o Aspartate Aminotransferase 
o Alanine Aminotransferase 
o Urea Nitrogen 
o Glucose 
o Creatinine 
o Calcium 
o Protein 
o Albumin 
o Bilirubin 
Urine Drug Test 
• 
Drug abuse panel 
• 
THC urine screen 
Pregnancy 
• 
Beta-hCG Qualitative Urine or Serum 
 
7.2.4 12-Lead Electrocardiograms 
A standard 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs. All subjects 
will require a single 12-lead ECG measurement according to the Schedule of Events only if 
clinically indicated. The parameters to be recorded are QT, QTc, PR, and QRS. All ECGs 
should be conducted pre-dose and Fridericia's formula will be used for all QT correction 
calculations.  
If at any time the QTcF > 500 ms, a triplicate ECG will be performed with tracings approximately 
one-minute apart.  
7.3 
Patient Reported Outcomes 
The response to study therapy will be assessed utilizing the Existential Distress Scale (EDS), 
Quick Inventory of Depressive Symptomatology (QIDS-SR-16), Patient Health, Columbia-
Suicide Severity Rating Scale Baseline/Screening and Since Last Visit (C-SSRS), Death 


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Transcendence Scale (DTS), Functional Assessment of Chronic Illness Therapy - Spiritual Well-
Being (FACIT-Sp), , Nondual Awareness Dimensional Assessment (NADA), Mystical 
Experiences Questionnaire (MEQ-30), Storyline Integrative Assessment, Patient-Reported 
Experience on Study Therapy, at the time points indicated in the Schedule of Events.  
7.3.1 Storyline 
 Psychiatric and Psychology Assessment Components:  
This part of the assessment is a 60-minute program broken into six 10-minute assessments of 
(i) physical symptoms, (ii) mood & emotion, (iii) cognition, (iv) homeostasis (ie. eating, sleeping, 
activity patterns) (v) social support and (vi) psychological associations. The program was 
created, in part, with our collaborator, Dr. Brian Mickey MD PhD (clinical psychiatrist) from a 
proven set of psychiatric interview questions and methods for DSM-5 diagnoses of depression, 
bipolar, anxiety, psychosis, neurocognitive disorders (dementia and delirium), suicidality, 
addiction, trauma and physical health.  This interview uses open-ended questions that evaluate 
RDoC domains and create a caring and natural interview experience that is non-threatening 
using “normalization”, “reduction of guilt” and “symptom exaggeration” techniques, as well as 
providing safety, transparency, education and logical flow. Cognition is assessed, in part, using 
established clinical tests of cognitive functioning, including tests of (i) orientation (date, day of 
the week, location), (ii) short-term memory, (iii) long-term memory and recall, (iv) semantic 
fluency, (v) verbal fluency, (vi) working memory, (vii) attention and (viii) self-initiation. In addition, 
open-ended questions are included that ask for descriptions of (1) concerns about brain 
functioning, memory, concentration and fatigue, (2) any noticeable changes in memory or 
thinking, brain fog, headaches, (3) social interactions and perceived support, and (5) a 1-5-
minute story about “something that happened to you this week”. The psychological associations 
assessment uses open-ended descriptions (“What does this make you think of?”) to capture 
responses to neutral, positive and negative cues, including Eckman faces (neutral, happy, sad, 
angry, disgust, surprise, contempt), Open Affective Standardized Image Sets (OASIS) and 
Affective Norms for English Words (ANEW) with valence, arousal or dominance characteristics 
predictive of mental illness (ie. death, cruelty, trouble, carefree, good, and praise). Finally, the 
Storyline assessment includes the standard PHQ-2, GAD-2 and PCL-2 questionnaires of clinical 
depression, anxiety and trauma symptoms as internal controls for clinical symptomology.  
The neurological assessment developed by Storyline is 10 minutes long and is similar to a 
standard of care neurological exam. It includes questions that test eye movement, facial 
expression, speech, finger movements, hand movements, cognition and drawing. The material 
for this assessment is derived from the following leading clinical neurology textbook: 
"Neurological Examination Made Easy 6th Edition” by Geraint Fuller MD FRCP.  
 Deep Cognitive and Behavioral Assessments During Treatment 
Participants will be asked to perform a 10-minute “Well-being” assessment that includes open-
ended questions about major domains of health. Examples include how they are, concerns, 
physical symptoms, emotional symptoms, social interactions and perceived support, 
medications and missed pills, energy and activity, sleep, a 1-5-minute story describing 
something that happened to them during the week and tests of short-term memory, working 
memory and attention.  


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7.4 
Remote Visits/Telehealth 
Some study visits and/or procedures may be conducted remotely in the following 
circumstances: 
• 
Telehealth visits do not present an increased risk to the participant. 
• 
All necessary data for the trial can be collected. 
• 
Procedures do not include research related imaging, lab samples, and/or pathology 
which should be conducted in person. 
Note: The method of telehealth should be documented in the participants’ charts.  
8 
ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 Adverse events 
21 CRF 312.32, ICH GCP, and OHRP define an adverse event as any untoward medical 
occurrence whether or not considered treatment-related. This definition extends to the 
worsening of any preexisting condition or symptom. All adverse events experienced during trial 
participation should be documented in the subject’s research chart and corresponding eCRF 
Laboratory abnormalities should not be listed as adverse events unless deemed clinically 
significant by the investigator or qualified designee. An abnormal test result or findings should 
not be recorded as an adverse event unless the following conditions are met: 
• 
Associated with clinical symptoms; and/or 
• 
Requires intervention (medical, surgical, or additional diagnostic testing); and/or 
• 
Results in a change in study drug dosing; and/or 
• 
Deemed by the investigator or qualified designee to be an adverse event. 
While disease progression should be noted in the subject’s research chart, it should not be 
reported as an adverse event. 
8.1.2 Serious Adverse Events 
 A serious adverse event is defined as any untoward event that is: 
• 
Fatal; 
• 
Life-threatening; 
• 
Results in persistent or significant disability/incapacity; 
• 
Medically significant; 
• 
Causes a congenital abnormality or birth defect; 
• 
Requires or prolongs inpatient hospitalization. 


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Investigator judgment must be used to assess an event as medically significant. The event may 
not be life-threatening or cause disability but may jeopardize the subject and require intervention 
to prevent the other SAE outcomes. 
The following situations should not be reported as an SAE: 
• 
Hospital admission not associated with a precipitating AE such as: 
o Treatment for a preexisting condition not associated with a new AE or the 
worsening of a preexisting condition; 
o Admission for social or administrative reasons; 
o Optional admission or elective surgery; 
o Observation; 
o Preplanned treatments or surgical procedures as noted at baseline; 
o Admission for the administration of blood products. 
8.2 
Adverse Event Reporting 
The investigator and qualified designees are responsible for the detection, documentation, 
reporting, and follow-up of all adverse events experienced by subjects during trial participation. 
AEs and SAEs will be recorded from consent until 30 days after the last dose of study 
medication or until new cancer therapy is started. The following information will be required for 
each adverse event: 
• 
Event severity as graded by the CTCAE v.5;  
• 
The causality assessment to study medication per the below definitions; 
• 
Expectedness 
• 
Event duration; 
• 
Any action taken to treat or manage the event; 
• 
Event outcome. 
8.2.1 Severity Assessment 
The severity of adverse events should be assessed by CTCAE v.5. If an event is not listed in 
CTCAE v.5 then the assessment of severity should follow the general guidelines listed in Table 
3. 
Table 2: Severity assessment 
Grade 
Severity Description 
1 
Mild event that generally does not require intervention. 
2 
Moderate event that may require intervention. 


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3 
Severe event that requires intervention. 
4 
Life-threatening event that requires urgent intervention. 
5 
Death. 
Events meeting grade 4 or 5 severity description should be reported promptly as SAEs unless 
otherwise indicated in Section 8.1.2. 
8.2.2 Causality Assessment 
The Investigator should assess the causality or relationship of AEs and SAEs to study therapy. 
The Investigator should consider if there is evidence that the investigational product caused the 
event taking into consideration timing, organ system affected, type of event, and possible 
alternative etiologies. The relationship of the AE to study treatment will be reported as listed 
below. These categories will be defined as follows: 
• 
Definitely related – a clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to drug administration, and which cannot be explained by 
concurrent disease or other drugs or chemicals. The response to the withdrawal of the 
drug (dechallenge) should be clinically plausible. The event must be definitive 
pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if 
necessary. 
• 
Probably related – a reasonable time sequence to the administration of the drug, unlikely 
to be attributed to concurrent disease or other drugs or chemicals, and which follows a 
clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 
• 
Possibly related – a reasonable time sequence to administrations of the drug, but which 
could also be explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal may be lacking or unclear. 
• 
Unlikely related –a temporal relationship to drug administration which makes a causal 
relationship improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanations. 
• 
Not related – there is no evidence of a causal relationship between the study drug and 
the event and in which other drugs, chemicals or underlying disease explain the event. 
Adverse events reported as definitely, probably, and possible, related to study therapy will be 
reported as related. In cases when the Investigator is unsure of the causality of an AE, the event 
will be considered related to study therapy unless deemed otherwise by the DSMC. 
8.2.3 Expectedness 
The Investigator will be responsible for determining whether or not an adverse event was 
expected or unexpected. Expected adverse events are those adverse events that are listed or 
characterized in the Package Insert (PI) or current Investigator Brochure (IB). Unexpected 
adverse events are those not listed in the PI or current IB or not identified. This includes 


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adverse events for which the specificity or severity is not consistent with the description in the PI 
or IB. For example, under this definition, hepatic necrosis would be unexpected if the PI or IB 
only referred to elevated hepatic enzymes or hepatitis. 
8.2.4  Action Taken and Outcome 
Start and stop dates will be required for all adverse events and serious adverse events. The 
action taken in response to the event should also be recorded in the subject’s research chart 
and corresponding eCRF. Event action terms include none, medication administered, non-drug 
therapy administered, surgery, hospitalization, or other with the option to specify. If a new 
medication is added the medication should also be added to the concomitant medications log. 
All adverse events should be followed until stabilization or resolution. Event outcomes may be 
classified as resolved, resolved with sequelae, ongoing, or death.  
8.2.5 Reporting Serious Adverse Events 
All serious adverse events should be reported as soon as possible but no later than one 
business day after the Investigator becomes aware. All SAEs must be reported via the HCI 
CTMS (OnCore) and submitted to HCI-RCO@utah.edu. The HCI Clinical Site Monitor will in 
turn, submit the report to the Medical Monitor. The RCO will summarize and present all reported 
SAEs according to the Data and Safety Monitoring Plan at the monthly DSMC meeting. 
At a minimum, initial SAE reports must include a description of the event, assessment of event 
causality, event grade, and the expectedness of the event. Although the Investigator may not 
know all the information at the time of the event, the available information should be reported. 
An SAE follow-up may be submitted at a later date once more information is known. It is 
required that follow-up reports be submitted until the SAE is resolved. 
Follow-Up Information 
It is recommended that follow-up reports be submitted as new information becomes available, 
however, a follow-up report should be submitted within 3 days of knowledge of event resolution. 
Follow-up information will be added to the SAE in OnCore and submitted to the DSMC via RCO.   
8.2.6 FDA Notifications 
This study will not hold an IND. 
8.2.7 IRB Notification 
The University of Utah IRB requires any unanticipated problems that may increase the risk to 
research participants be promptly reported. All study-therapy related, unexpected adverse 
events whose nature, severity, or frequency is not consistent with either: 
• 
The unknown or foreseeable risk of adverse events that are described in the protocol 
related-documents, such as the IRB-approved research protocol, applicable investigator 
brochure, the current IRB-approved informed consent document, and/or other relevant 
sources of information, such as product labeling and package inserts; or 


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• 
The expected natural progression of any underlying disease or condition of the 
subject(s) experiencing the adverse event. 
Adverse events meeting this criterion must be promptly reported to the IRB within 10 business 
days of awareness.  
8.3 
Special Situations 
8.3.1 Pregnancy or Breastfeeding  
Although pregnancy is not considered an adverse event, any exposure to the investigational 
products during pregnancy or breastfeeding must be reported promptly. Exposure may occur by 
a woman actively receiving study therapy or the partner of a male subject actively receiving 
study therapy becomes pregnant. Any possible pregnancy or breastfeeding exposure during 
study therapy and up to 30 days after the last dose of study therapy or up to the start of 
subsequent anticancer therapy (whichever happens first) must be reported within one business 
day of awareness regardless of the occurrence of an SAE. Should a woman on study therapy 
become pregnant, she should immediately discontinue study treatment. 
Women exposed to IP during pregnancy or while breastfeeding will be followed for pregnancy 
outcome and neonate health. Pregnancy outcomes may meet criteria as an SAE if ectopic 
pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital 
anomaly occurs. Congenital anomalies that occur in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death should be reported as an SAE. Any neonatal 
deaths that occur up to 30 days after birth or breastfeeding exposure should be reported as an 
SAE. Further follow-up on birth outcomes and neonate health will be handled on a case-by-case 
base. 
8.3.2 Hy’s Law Cases 
It is important to identify possible cases of Drug-Induced Liver Injury (DILI) early. Total bilirubin, 
AST, and ALT should be regularly monitored for elevations indicative of liver damage. Subjects 
who experience a transaminase elevation above three times the ULN should be monitored 
frequently to determine if the elevation is transient. Transient elevations are an indication of 
adaption and these subjects may be identified as “adaptors.” However, should a transaminase 
elevation be followed by total bilirubin (TBili) increase, a DILI could be occurring. Any laboratory 
abnormalities meeting the following criteria should be reported within 24 hours of awareness: 
• 
AST or ALT elevation > 3 x ULN; and 
• 
Total bilirubin > 2 x ULN; and 
• 
Absence of cholestasis; and  
• 
No alternative explanation for the elevations (e.g., impaired glucuronidation capacity 
caused by genetic [Gilbert syndrome]; viral hepatitis A, B, or C, preexisting or acute liver 
disease; or another drug capable of causing the observed injury). 
Investigators should conduct reasonable investigations to rule out other possible etiologies. 
Investigators should take into consideration the subject's use of ethanol, acetaminophen, 


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recreational drugs, herbal supplements, and medical history. A potential Hy’s Law case will not 
be considered a confirmed case until all results and considerations have excluded alternative 
etiologies.  
Possible cases of DILI will be promptly reported to the FDA prior to full work up to rule out other 
etiologies. Reporting should be completed on a MedWatch 3500A form and should include all 
available information, including the likelihood that the drug caused the event. Subjects should 
be closely followed until the resolution of the event.  
8.4 
Data Safety Monitoring Committee 
A Data Safety Monitoring Committee (DSMC) at HCI is charged with ensuring the risk/benefit 
balance for subjects undergoing study therapy. The purpose of the DSMC is to ensure subject 
safety and make recommendations for study conduct to ensure subject safety and data integrity. 
The DSMC is chaired by a medical oncologist and may include, but is not limited to, 
representatives from medical oncology, oncological sciences, biostatistics, and pharmacy. 
The roles and responsibilities of the DSMC are described in the NCI-approved Data and Safety 
Monitoring (DSM) plan. The activities of the committee include reviewing adverse events 
(including SAEs), deviations, important medical events, and approving cohort/dose escalations. 
Amendments that increase risk, increase treatment exposure, or impact study objectives will 
also be reviewed by the DSMC. If the DSMC and/or the PI have concerns about unexpected 
safety issues or AE trends, the study may be stopped and an unplanned safety data analysis 
may be conducted. Enrollment will not resume until the issues are resolved. The DSMC also 
reviews and approves audit reports generated by the Research Compliance Office. 
All trials will be assigned and an oncologist member of the DSMC to serve as a medical monitor. 
In rare cases, an external medical monitor may be assigned. The Medical Monitor will be 
notified of all serious adverse events (SAEs). Specific notifications will also be issued when a 
dose-limiting toxicity is encountered and when the RP2D is defined. Approval from the Medical 
Monitor is required for all dose escalations. All serious adverse events (SAEs) occurring in 
subjects treated at HCI or its affiliates will also be reviewed by the full DSMC monthly.  
Each trial is assigned a research compliance officer who will be responsible for monitoring the 
trial and reporting to the DSMC. The assessed risk level of the trial will determine the frequency 
with which monitoring occurs. The Research Compliance Officer monitor will review the study 
status and summarize enrollment, toxicities, SAEs, dose-escalation, statistical endpoints (e.g., 
stopping rules), deviations, and any other pertinent information for the full DSMC membership at 
the regularly scheduled meetings.  
Audits will be conducted for all trials one year after enrollment begins and annually thereafter. 
Audits may be conducted more frequently as requested by the DSMC, Institutional Review 
Board (IRB), Protocol Review and Monitoring Committee (PRMC), Research Compliance Office 
management, or the Principal Investigator.  
DSMC oversite will be tailored to the assessed risk level of the trial. Trials are categorized 
amongst three risk levels: high, moderate, and low.  
This trial has been classified as high risk and therefore will be monitored by RCO and reviewed 
by DSMC after the first subject is enrolled and then quarterly thereafter. 


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9 
STATISTICAL CONSIDERATIONS 
9.1 
Sample size determination 
 This is a descriptive study. The planned sample size is 12 enrolled subjects. For the study to be 
a success, at least 9 of 12 subjects must be consented, enrolled and complete the study. If at 
least 9 of 12 subjects complete the study, the lower bound of the 95% exact binomial 
confidence interval for the completion rate will exceed of 34%.  
9.2 
Population for Analyses 
A modified intent-to-treat data set will be used for both safety and efficacy endpoint analysis. All 
subjects who have received one dose of study medication will be included in all efficacy and 
safety data sets. Subjects who fail to begin study therapy will be replaced.  
9.3 
Primary Endpoint 
To assess the feasibility of recruiting, consenting, enrolling, and completing the study 
intervention for 12 patients. 
Primary endpoint: The recruitment, consent, enrollment, and study completion of 12 patients.  
Study completion defined as participating in at least 2/3 of the 3 KAP sessions. 
All subjects who enroll on the study will be considered evaluable. The completions rate will be 
reported along with a 95% exact binomial confidence interval (Clopper-Pearson method). 
9.4 
Secondary Endpoints 
9.4.1 The frequency of adverse events (AEs) and serious adverse events (SAEs) 
characterized by type, severity (as defined by the NIH CTCAE, version 5.0), 
seriousness, duration, and relationship to study treatment. 
All subjects who receive any study treatment will be included in the final summaries and listings 
of safety data. The detailed information collected for each AE will include a description of the 
event, duration, severity, relatedness to study drugs, action taken, and clinical outcome. The 
severity of the AEs will be graded according to the CTCAE v5.0. The statistical analysis of the 
safety data will be descriptive and tabular. 
9.4.2 The proportion of screened patients that meet criteria on the Existential Distress 
Scale (EDS: Single domain ≥ 3 or total score ≥ 6). 
All patients who have been consented to the study will be included in the final analysis.  
The observed proportion will be reported along with a 95% exact confidence interval. 
9.5 
Exploratory Objectives  
Exploratory endpoints include 1) the mean change in score on EDS and QIDS-SR-16 from 
baseline to 2 weeks post completion of intervention; 2) the correlation between total score on 
the MEQ-30 and NADA and change in the EDS score at the 2 week primary outcome time point; 


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and 3) the mean change in score on FACIT-Sp from baseline to Day 30 post completion of 
intervention.   
An additional exploratory objective is to develop an algorithm with Storyline Health technology to 
rapidly discover the most predictive and information rich components in the assessment of 
burnout and its treatment response. The associated endpoints are 7) the identification of a 
behavioral phenotype that better predicts a response to ketamine intervention; and 8) the 
Storyline questionnaire completion rate.  
Analysis of the above exploratory endpoints will be descriptive. Continuous variables will be 
summarized by the minimum, maximum, mean, standard deviation, and 95% confidence 
interval. The Storyline completion rate and 95% exact binomial confidence interval will be 
reported. Spearman rank correlation coefficients will be used to summarize the correlation 
between the total score on the MEQ-30 and NADA and change in the EDS score at the 2-week 
primary outcome time point. 
 
10 ETHICAL AND REGULATORY CONSIDERATIONS 
10.1 Human Subjects Protection 
The study will be conducted in accordance with the protocol, 21 CFR, HIPAA regulations, the 
Belmont Principles, ICH Guidelines for Good Clinical Practice (GCP), and the Declaration of 
Helsinki. Informed consent will be obtained from all research participants or their legally 
authorized representative before performing any study procedures using the most recent IRB 
approved version.  
10.1.1 Personal Data Protection 
All parties will take all necessary actions required for the protection of subject personal data. 
Subjects enrolled in the study will be assigned a subject number and will be reference by this 
number. Directly identifiable data will be omitted from reports, publications, and other 
disclosures. All personal data will be store at the study site in encrypted electronic and/or paper 
form stored in a locked and secured facility. The site will be responsible for maintaining a list of 
subjects linking each subject with their subject number. Data will only be accessed by 
appropriate personnel and will be password protected or securely stored in a locked room. In 
the case of a potential breach of personally identifiable data, the site will take responsibility to 
ensure appropriate action is taken according to institutional practice and applicable laws and 
regulations.  
10.2 Institutional Review 
Before the initiation of the study, the Investigator will have prospective approval of the study 
protocol, protocol amendments, informed consent documents, and other relevant documents, 
(e.g., recruitment advertisements, questionnaires, if applicable), from the IRB. All 
correspondence with the IRB should be retained in the Investigator’s regulatory file. Changes to 
the protocol or approved documents may not be made until IRB approval has been received. 


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However, if a change is necessary to eliminate immediate hazards to the subjects, prospective 
approval is not necessary.  
The investigator or designee should provide the IRB with reports, updates and other information 
(e.g., expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures. 
10.3 Investigator Responsibilities 
The Investigator is responsible for ensuring the trial is conducted in compliance with the current 
IRB approved version of the protocol, GCP, the Declaration of Helsinki, and any applicable 
national and local laws and regulations.   
10.4 Protocol Amendments 
Any amendments or administrative changes to an IRB approved protocol will not be initiated 
without submission of an amendment for IRB review and approval. However, prospective IRB 
approval will not be sought when an amendment is required to eliminate immediate risk to 
subjects on study. In these cases, amendments will be retrospectively submitted to the IRB for 
review and approval. 
Any amendments to the protocol that significantly affect the safety of subjects, the scope of the 
investigation, or the scientific quality of the study will be submitted to the FDA for review. 
10.5 Protocol Deviations 
A deviation will be defined as any noncompliance with ICH GCP or the clinical protocol 
requirements. The noncompliance may be either on the part of the participant, the Investigator, 
or the study staff. As a result of the deviation, a corrective action must be implemented to 
ensure future deviation does not occur. It is the Investigator’s responsibility to identify and report 
deviations from ICH GCP or protocol requirements. These deviations and corrective action 
should be documented in the subject’s research chart, the associated eCRF, and reported to 
the IRB per their policy.  
10.6 FDA Reporting  
This study will not hold an IND. 
11 DATA HANDLING 
11.1 Recording and Collection of Data 
Primary source documentation will come directly from the subject’s medical record. All source 
documentation should be attributable, legible, contemporaneous, original, accurate, complete, 
and available. All documentation should be signed and dated by applicable personnel. Relevant 
source data will be transcribed into the electronic case report forms (eCRFs) and should be 
completed as soon as possible after data availability. The eCRFs will be part of a computerized 
database grounded in the protocol requirements and study objectives. The database will be 
designed to comply with 21 CFR Part 11.  


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The Investigator has ultimate responsibility for ensuring that all data collected and recorded is 
accurate and consistent. He/she will need to sign off on all eCRFs to attest that all data 
recorded on them is true. A separate screening log of all the subjects screened for participation 
in the study must also be maintained and should include gender, age, eligibility status, the 
reason for ineligibility (if applicable), and study allocated subject number (if applicable). 
11.1.1 Storyline Health Data Confidentiality and Security  
The individuals who can view participant videos will only include the participant and the 
University of Utah and Storyline Health researchers involved in the study. Participant videos will 
never be shared with individuals outside of the study.  
All study videos will be collected and stored in the Storyline Health Vault Database, which is an 
ultra-secure, cloud based data storage platform specially designed for protecting participant 
videos and related data. It has the following technical features that will protect all data for the 
study:  
 HTTPS Communication Protocol 
 All Storyline participant data is transferred and accessed in an encrypted and secure manner. 
The Storyline Health database API is only available on port 443 via HTTPS and their public 
websites force HTTPS with HSTS. This is the most secure system available and prevents 
unauthorized access.  
 Access Management 
No one else can access participant data other than the participant and researchers involved in 
the study. Storyline Health ensures this by maintaining robust defense at each layer of the 
platform to secure data. The features include immutable audit logs, restrictive network rules, 
and per-record encryption, which all prevent unauthorized access to personal data.  
 Encryption / Decryption 
All participant records are encrypted with 256-bit AES encryption keys as soon as they enter 
Storyline Health's infrastructure. Every record is encrypted with a unique initialization vector by a 
unique encryption key to achieve semantic security. Storyline verifies each record's integrity on 
a regular basis and on each record request using a hash-based authentication code (HMAC) 
calculated using its own unique 256-bit HMAC key. Encryption keys, initialization vectors and 
HMAC keys are re-keyed and each record re-encrypted on a regular basis.  
 Network Security 
Multiple subsystems combine to power Storyline Health and secure your data. Each subsystem 
is totally and completely segmented from one another by software and network security rules to 
maximize protection. Storyline does not store encrypted records and their encryption keys in the 
same server cluster. Each subsystem can only be accessed by another subsystem via specific 
network routes and specific inbound and outbound port rules. These features make Storyline’s 
system ultra-secure for participant data storage.  
Participant videos only exist within the ultra-secure Storyline Health system, where individual 
participants will have access to their own data and have control over them. The videos will not 
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(such as a researcher laptop). The Storyline Health platform ensures that video data is never 
left on a device that can be lost or stolen.  
Participants will be given ownership of their data. The Storyline Health platform will make it easy 
for individual participants to view and delete their videos at any time if they choose. If they 
choose to delete a video, they will be informed about the impact on the study, the importance of 
their contributions and the major privacy protection measures in place and confidentiality rules 
governing their data.  
Any facial or speech micro-features extracted from participant videos using artificial intelligence 
and other data mining approaches will be stored in specially designed, de-identified Storyline 
Health StoryARC formatted files that maintain participant confidentiality. StoryARC files are text 
files containing letters and numbers that detail measures extracted from the videos and enable 
researchers to analyze study participant behavior patterns using mathematical approaches 
without revealing participant identity or personal information 
11.2 Data Management 
To accommodate evaluations, inspections, and/or audits from regulatory authorities, the 
Investigator must maintain all study records including subject identity, source documentation, 
original signed consent form, safety reporting forms, monitoring logs, IP accountability records, 
relevant correspondence (e.g., letters, emails, meeting minutes, etc.), and any other documents 
pertaining to the conduct of the study. The Investigator must also agree to the maintain source 
documents for a minimum of two years after regulatory approval of the investigational product 
per 21 CFR 312.57. For the duration of record maintenance, records must be stored in a secure 
location and protected from the elements.  
12 PUBLICATION PLAN 
In accordance with U.S. regulations and the best interest of research ethics and transparency, 
this study will be registered on ClinicalTrials.gov before subject enrollment. US Basic Results 
will also be reported and available on ClinicalTrials.gov within one year of the primary 
completion date, regardless of formal journal publication. All results will be reported objectively, 
accurately, balanced, and completely, regardless of the study outcome.  
 
 


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13 REFERENCES 
 
1. 
Mitchell AJ, Chan M, Bhatti H, et al: Prevalence of depression, anxiety, and 
adjustment disorder in oncological, haematological, and palliative-care settings: a meta-analysis 
of 94 interview-based studies. Lancet Oncol 12:160-74, 2011 
 
2. 
Nanni MG, Caruso R, Travado L, et al: Relationship of demoralization with 
anxiety, depression, and quality of life: A Southern European study of Italian and Portuguese 
cancer patients. Psychooncology 27:2616-2622, 2018 
 
3. 
Laird B, Colvin L, Fallon M: Management of cancer pain: basic principles and 
neuropathic cancer pain. Eur J Cancer 44:1078-82, 2008 
 
4. 
Daly LE, Dolan RD, Power DG, et al: Determinants of quality of life in patients 
with incurable cancer. Cancer 126:2872-2882, 2020 
 
5. 
Sanso N, Galiana L, Oliver A, et al: Palliative Care Professionals' Inner Life: 
Exploring the Relationships Among Awareness, Self-Care, and Compassion Satisfaction and 
Fatigue, Burnout, and Coping With Death. J Pain Symptom Manage 50:200-7, 2015 
 
6. 
Lo C, Panday T, Zeppieri J, et al: Preliminary psychometrics of the Existential 
Distress Scale in patients with advanced cancer. Eur J Cancer Care (Engl) 26, 2017 
 
7. 
Vehling S, Kissane DW: Existential distress in cancer: Alleviating suffering from 
fundamental loss and change. Psychooncology 27:2525-2530, 2018 
 
8. 
Gade G, Venohr I, Conner D, et al: Impact of an inpatient palliative care team: a 
randomized control trial. J Palliat Med 11:180-90, 2008 
 
9. 
Irwin KE, Greer JA, Khatib J, et al: Early palliative care and metastatic non-small 
cell lung cancer: potential mechanisms of prolonged survival. Chron Respir Dis 10:35-47, 2013 
 
10. 
Temel JS, Greer JA, Muzikansky A, et al: Early palliative care for patients with 
metastatic non-small-cell lung cancer. N Engl J Med 363:733-42, 2010 
 
11. 
Temel JS, Greer JA, Admane S, et al: Longitudinal perceptions of prognosis and 
goals of therapy in patients with metastatic non-small-cell lung cancer: results of a randomized 
study of early palliative care. J Clin Oncol 29:2319-26, 2011 
 
12. 
Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. American journal of clinical oncology 5:649-655, 1982 
 
 
 


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Appendix 1: ECOG Performance Status12 
 
Score 
Definition 
0 
Fully active, able to carry on all pre-disease activities without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light housework or office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hour 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled.  Cannot carry on any self-care. Confined to bed or chair 
5 
Dead 
 
 
 


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Appendix 2: Existential Distress Scale (EDS) 
We would like to better understand how you’re feeling so that we can be more helpful to you. 
We would like to ask you some questions about some distressing thoughts that people with 
cancer may worry about. These questions are about whether you have been feeling badly 
about yourself or feeling lonely, and whether you have been questioning the sense of 
meaning in your life. Please tell us if you have been distressed by any of these concerns and 
if so, how much distress you have been experiencing. 
 
How distressed have you been by the thought: 
Not 
distressed 
Mildly 
distressed 
Moderately 
distressed 
Greatly 
distressed 
Unbearably 
distressed 
1. That you are all alone? 
0 
1 
2 
3 
4 
2. That no one will miss you when you are gone? 
0 
1 
2 
3 
4 
3. That no one cares about you? 
0 
1 
2 
3 
4 
4. That you are or will be a burden to others? 
0 
1 
2 
3 
4 
5. That you have nothing to offer others? 
0 
1 
2 
3 
4 
6. That you don’t matter? 
0 
1 
2 
3 
4 
7. That you are worthless? 
0 
1 
2 
3 
4 
8. That your life is empty? 
0 
1 
2 
3 
4 
9. That your life is meaningless? 
0 
1 
2 
3 
4 
10. That you have nothing to live for? 
0 
1 
2 
3 
4 
 
 
 
 
___________________________________________ 
 
 
 
__________________ 
Participant Signature 
 
 
 
 
 
 
 
Date  
 
___________________________________________ 
Study ID 
 


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Appendix 3: Quick Inventory of Depressive Symptomatology (QIDS-SR-16) 
Please circle the one response to each item that best describes you for the past seven days. 
1.  
Falling Asleep:  
 
0  
I never take longer than 30 minutes to fall asleep. 
  
1  
I take at least 30 minutes to fall asleep, less than half the time. 
 
2  
I take at least 30 minutes to fall asleep, more than half the time. 
  
3  
I take more than 60 minutes to fall asleep, more than half the time. 
2.  
Sleep During the Night: 
 
0 
I do not wake up at night. 
 
1 
I have a restless, light sleep with a few brief awakenings each night. 
 
2  
I wake up at least once a night, but I go back to sleep easily. 
 
3  
I awaken more than once a night and stay awake for 20 minutes or more, more than half the 
time. 
3.  
Waking Up Too Early: 
 
0  
Most of the time, I awaken no more than 30 minutes before I need to get up. 
 
1  
More than half the time, I awaken more than 30 minutes before I need to get up. 
 
2  
I almost always awaken at least one hour or so before I need to, but I go back to sleep 
eventually. 
 
3  
I awaken at least one hour before I need to, and can’t go back to sleep. 
4.  
Sleeping Too Much: 
 
0  
I sleep no longer than 7–8 hours/night, without napping during the day. 
 
1  
I sleep no longer than 10 hours in a 24-hour period including naps. 
 
2  
I sleep no longer than 12 hours in a 24-hour period including naps.  
 
3  
I sleep longer than 12 hours in a 24-hour period including naps. 
5.  
Feeling Sad: 
 
0  
I do not feel sad 
 
1  
I feel sad less than half the time. 
 
2  
I feel sad more than half the time. 
 
3  
I feel sad nearly all of the time. 
6.  
Decreased Appetite: 
 
0  
There is no change in my usual appetite. 
 
1  
I eat somewhat less often or lesser amounts of food than usual. 
 
2  
I eat much less than usual and only with personal effort. 
 
3  
I rarely eat within a 24-hour period, and only with extreme personal effort or when others 
persuade me to eat. 
 


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7. 
Increased Appetite: 
 
0  
There is no change from my usual appetite. 
 
1  
I feel a need to eat more frequently than usual. 
 
2  
I regularly eat more often and/or greater amounts of food than usual. 
 
3  
I feel driven to overeat both at mealtime and between meals. 
8.  
Decreased Weight (Within the Last Two Weeks): 
 
0  
I have not had a change in my weight. 
 
1  
I feel as if I’ve had a slight weight loss. 
 
2  
I have lost 2 pounds or more. 
 
3  
I have lost 5 pounds or more. 
9.  
Increased Weight (Within the Last Two Weeks): 
 
0  
I have not had a change in my weight. 
 
1  
I feel as if I’ve had a slight weight gain. 
 
2  
I have gained 2 pounds or more. 
 
3  
I have gained 5 pounds or more. 
10. Concentration/Decision Making: 
 
0  
There is no change in my usual capacity to concentrate or make decisions. 
 
1  
I occasionally feel indecisive or find that my attention wanders. 
 
2  
Most of the time, I struggle to focus my attention or to make decisions. 
 
3  
I cannot concentrate well enough to read or cannot make even minor decisions. 
11. View of Myself: 
 
0  
I see myself as equally worthwhile and deserving as other people. 
 
1  
I am more self-blaming than usual. 
 
2  
I largely believe that I cause problems for others. 
 
3  
I think almost constantly about major and minor defects in myself. 
12. Thoughts of Death or Suicide: 
 
0  
I do not think of suicide or death. 
 
1  
I feel that life is empty or wonder if it’s worth living. 
 
2  
I think of suicide or death several times a week for several minutes. 
 
3  
I think of suicide or death several times a day in some detail, or I have made specific plans for 
suicide or have actually tried to take my life. 
13. General Interest: 
 
0  
There is no change from usual in how interested I am in other people or activities. 
 
1  
I notice that I am less interested in people or activities. 
 
2  
I find I have interest in only one or two of my formerly pursued activities. 
 
3  
I have virtually no interest in formerly pursued activities. 


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14. Energy Level: 
 
0  
There is no change in my usual level of energy. 
 
1  
I get tired more easily than usual. 
 
2  
I have to make a big effort to start or finish my usual daily activities (for example, shopping, 
homework, cooking or going to work). 
 
3  
I really cannot carry out most of my usual daily activities because I just don’t have the energy. 
15. Feeling Slowed Down: 
 
0  
I think, speak, and move at my usual rate of speed. 
 
1  
I find that my thinking is slowed down or my voice sounds dull or flat 
 
2  
It takes me several seconds to respond to most questions and I’m sure my thinking is slowed.  
 
3  
I am often unable to respond to questions without extreme effort. 
16. Feeling Restless: 
0  
I do not feel restless. 
 
1  
I’m often fidgety, wringing my hands, or need to shift how I am sitting. 
 
2  
I have impulses to move about and am quite restless. 
 
3  
At times, I am unable to stay seated and need to pace around. 
 
To Score: 
1. 
Enter the highest score on any 1 of the 4 
sleep items (1-4) 
______ 
2. 
Item 5 
______ 
3. 
Enter the highest score on any 1 1 appetite/ 
weight item (6-9) 
______ 
4. 
Item 10 
______ 
5. 
Item 11 
______ 
6. 
Item 12 
______ 
7. 
Item 13 
______ 
8. 
Item 14 
______ 
9. 
Enter the highest score on either of the 2 
psychomotor items (15 and 16) 
______ 
TOTAL SCORE (Range 0–27) 
______ 
 
 
___________________________________________ 
 
 
 
__________________ 
Participant Signature 
 
 
 
 
 
 
 
Date  
 
___________________________________________ 
Study ID 
 
 


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Appendix 4: Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening 
 
 
 
 
 
___________________________________________ 
 
 
____________________ 
Interviewer Signature 
 
 
 
 
 
 
Date  
 
___________________________________________ 
Study ID 


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Appendix 5: Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
 
 
 
 
___________________________________________ 
 
 
____________________ 
Interviewer Signature 
 
 
 
 
 
 
Date  
 
___________________________________________ 
Study ID 


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Appendix 6: FACIT-Sp (Version 4) 
 
 
 


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___________________________________________ 
 
 
____________________ 
Participant Signature 
 
 
 
 
 
 
Date  
 
___________________________________________ 
Study ID 


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Appendix 7: Nondual Awareness Dimensional Assessment (NADA) 
 
 
 
NADA-S SCORING 
Full Scale Score: Average all items. 
 
 
 
 
 
 
 
 
 
 
 
___________________________________________ 
 
 
 
__________________ 
Participant Signature 
 
 
 
 
 
 
 
Date  
 
___________________________________________ 
Study ID 
 
NONDUAL AWARENESS DIMENSIONAL ASSESSMENT – STATE 
Please read each statement and indicate the extent to which you agree 
with each statement. In other words, how well does the statement 
describe what you just experienced, just now? 
Not at all 
 
Very much 
1. I experienced all things seeming to unify into a single whole. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
2. I experienced all sense of self and identity dissolve away. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
3. I felt surrounded and filled with a blissful warmth or energy. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 


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Appendix 8: Mystical Experiences Questionnaire (MEQ-30) 
Instructions: Looking back on the entirety of your session, please rate the degree to which at 
any time during that session you experienced the following phenomena. Answer each question 
according to your feelings, thoughts, and experiences at the time of the session. In making each 
of your ratings, use the following scale: 
0 – none; not at all 
1 – so slight cannot decide 
2 – slight 
3 – moderate 
4 – strong (equivalent in degree to any other strong experience) 
5 – extreme (more than any other time in my life and stronger than 4) 
______ 1. Loss of your usual sense of time. 
______ 2. Experience of amazement. 
______ 3. Sense that the experience cannot be described adequately in words. 
______ 4. Gain of insightful knowledge experienced at an intuitive level. 
______ 5. Feeling that you experienced eternity or infinity. 
______ 6. Experience of oneness or unity with objects and/or persons perceived in your 
surroundings. 
______ 7. Loss of your usual sense of space. 
______ 8. Feelings of tenderness and gentleness. 
______ 9. Certainty of encounter with ultimate reality (in the sense of being able to “know” and 
“see” what is really real at some point during your experience. 
______ 10. Feeling that you could not do justice to your experience by describing it in words. 
______ 11. Loss of usual awareness of where you were. 
______ 12. Feelings of peace and tranquility. 
______ 13. Sense of being “outside of” time, beyond past and future. 


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______ 14. Freedom from the limitations of your personal self and feeling a unity or bond with 
what was felt to be greater than your personal self. 
______ 15. Sense of being at a spiritual height. 
______ 16. Experience of pure being and pure awareness (beyond the world of sense 
impressions). 
______ 17. Experience of ecstasy. 
______ 18. Experience of the insight that “all is One”. 
______ 19. Being in a realm with no space boundaries.  
______ 20. Experience of oneness in relation to an “inner world” within. 
______ 21. Sense of reverence. 
______ 22. Experience of timelessness. 
______ 23. You are convinced now, as you look back on your experience, that in it you 
encountered ultimate reality (i.e., that you “knew” and “saw” what was really real). 
______ 24. Feeling that you experienced something profoundly sacred and holy. 
______ 25. Awareness of the life or living presence in all things. 
______ 26. Experience of the fusion of your personal self into a larger whole. 
______ 27. Sense of awe or awesomeness. 
______ 28. Experience of unity with ultimate reality. 
______ 29. Feeling that it would be difficult to communicate your own experience to others who 
have not had similar experiences. 
______ 30. Feelings of joy. 
 
 
___________________________________________ 
 
 
 
__________________ 
Participant Signature 
 
 
 
 
 
 
 
Date  
 
___________________________________________ 
Study ID 
 
 


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Appendix 9: Death and Dying Distress Scale (DADDS)