A Phase II, Randomized, Double-blind, Trial Comparing Escitalopram to Placebo in Patients With Localized Pancreatic Cancer
Phase: PHASE2
Conditions: Pancreatic Ductal Adenocarcinoma, Periampullary Cancer
Sponsor: Case Comprehensive Cancer Center

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STUDY NUMBER:  CASE6220  
ClinicalTrials.gov NCT #:  NCT05289830 
Protocol Date:  11/07/2022 
STUDY TITLE:  A Phase II, Randomized, Double-Blind Trial Comparing Escitalopram to 
Placebo in Patients with Localized Pancreatic Cancer 
 
PRINCIPAL INVESTIGATOR: Jordan Winter, MD 
 
 
 
 
Case Comprehensive Cancer Center 
University Hospitals Cleveland Medical Center 
 
 
 
 
Seidman Cancer Center 
11100 Euclid Avenue  
 
 
 
Cleveland, OH 44106 
  
 
 
 
 
 
CO-INVESTIGATORS:              University Hospitals Seidman Cancer Center    
 
 
 
 
John Ammori, MD 
                                                      Puja Arora, MD 
 
 
 
 
David Bajor, MD 
  
 
 
 
Mukesh Bhatt, MD 
                                                      Jennifer Brandstetter, MD 
 
 
 
 
Sakti Chakrabarti, MD 
 
 
 
 
Colleen Castelein, CNP 
 
 
 
 
Gordon Goolamier, CNP 
 
 
 
 
Jeffrey Hardacre, MD 
 
 
 
 
Amit Mahipal, MBBS 
 
 
 
 
Suresh Mendpara, MD 
 
 
 
 
Amr Mohamed, MD 
 
 
 
 
Lee M. Ocuin, MD, FSSO 
 
 
 
 
Kristy Rostocil, CNP 
 
 
 
 
Jennifer Selfridge, MD 
                                                      Lois Teston, MD 
 
 
 
 
Maria Tomaro, CNP 
 

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STATISTICIAN:  
 
  
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
STUDY COORDINATOR: 
 
 
 
 
 
 
 
 
 
 
 
      
                
      
                                                            
                                          
   
                                          
 
                                          
 
                                          
 
 
SPONSOR:  
 
 
Case Comprehensive Cancer Center  
 
 
 
 
 
SUPPORT/FUNDING: 
 
The Fred and Britt DiSanto Fund 
 
AGENT:  
    
 
Escitalopram and placebo   
 
IND #:  
 
 
 
Exempt 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Title:  A Phase II, Randomized, Double-Blind Trial Comparing Escitalopram to Placebo in 
Patients with Localized Pancreatic Cancer 
 
Principal Investigator:   Jordan Winter, MD 
 
PRINCIPAL INVESTIGATOR SIGNATURE: 
 
 
 
_______________________________________ 
 
Date: ___________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SUMMARY OF CHANGES 
Protocol 
Date 
Section 
Change 
1/12/2022 
 
Initial IRB approval 
4/14/2022 
v.2 
Cover page 
Addition of Co-Investigators Jennifer Brandstetter, MD, Kristy Rostocil, 
CNP  Removal of Co-Investigators Richard Lee, MD, Susan Padrino, 
MD. Corrections to Funding and Agent information 
 
Protocol 
Summary 
Added pancreatic cancer to objectives for clarity 
 
Abbreviations 
Added IDS 
 
3.1  
Updated blinding procedures 
 
3.4 
Revised to align criteria for patient removal from study with Table 7.1 
 
6.1 
Clarified that research blood draw is to take place before first dose of 
escitablopram/placebo. 
Corrected days FACT-Hep is completed 
Revised unblinding criteria to include Gr. 4 hyponatremia.  
Added: Patients who are unblinded before they complete all study visits 
will be asked to continue to have study-related phone calls with study 
staff and complete all study-related questionnaires. 
 
6.2 
Added to second bullet:  or patient inability to swallow 
escitalopram/placebo capsules, 
 
6.3 
Clarified that long-term survival follow-up starts after Week 25 
 
7.1 
Corrected name and email for Psycho-Oncology Provider 
 
Table 7.1 
Added hyponatremia 
 
9.1  
Revised to reflect new drug supplier information and changes to drug 
packaging 
 
11.1.1 
Screening visit updated to include ECOG performance status. Week 1, 
Day 1 updated to include toxicity assessment. 
 
14.2 
Correction made – added word “treatment”. 
 
Appendix II 
Small revision to Pill Diaries made for clarity.  

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Protocol 
Date 
Section 
Change 
8/31/2022 
V2.1 
Cover page 
Updated version date.  Updated study staff and made corrections to add 
staff who were erroneously not included or not removed when they left 
UH: Added Mukesh Bhatt, MD, Sakti Chakrabarti, MD, Amit Mahipol, 
MD., Gordon Goolamier, CNP Removed: Richard Chang, MD, 
Katherine Daunov CNP and Jennifer Dorth, MD 
10/21/2022 
V3.0 
Cover page 
Update version date to 10/21/2022 
 
Section 6.1 
The following line has been removed:  “and the patient is being treated 
at UH Main campus”.  This line no longer relevant as study procedures 
will take place at satellites. 
 
Study Calendar 
Updated to remove the following footnote as this amendment allows 
patients to be enrolled and have study procedures at satellites:  *Patients 
who receive chemotherapy at satellites sites are required to come to 
Main campus for D1, 15, 71 and End of Treatment visits to receive 
pills/return unused pills and to collect/return their pill diary. 
11/07/2022 
v4.0 
Cover page 
Updated version date to 11/07/2022 
 
Section 7 
Table 7.1:  The CTCAE grading reference ranges for hyponatremia have 
been corrected. 
 
Section 8 
Revisions are being made to clarify that only study related SAEs and 
AESI are to be recorded and reported.  SAEs related to chemo are not 
entered into the Oncore database or reported on a MedWatch form. The 
following revision have been made to this section:  
 
8.2.3 Adverse Event Evaluation changed: 
From: The investigator or designee is responsible for ensuring that  
adverse events of interest (both serious and non-serious as defined in 
previous sections) observed by the study staff or reported by the subject 
that are determined to be related to escitalopram/placebo which occur 
after the initiation of escitalopram/placebo are fully recorded in the 
subject’s medical record.  Source documentation must be available to 
support all adverse events.  
 
To: The investigator or designee is responsible for ensuring that all  
adverse events, (both serious and non-serious as defined in previous 
sections) observed by the study staff or reported by the subject that are 
determined to be related or possibly related to escitalopram/placebo 
which occur after the initiation of escitalopram/placebo are fully recorded 
in the subject’s medical record and reported according to AE reporting 
policies of the IRB of record.  Adverse events attributed to 
chemotherapy and/or underlying disease will not be recorded for this 
study.   Source documentation must be available to support all adverse 
events.  
 
8.4 Reporting Procedures for Serious Adverse Events changed 

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Protocol 
Date 
Section 
Change 
From:  For the purposes of safety reporting, all adverse events of interest 
will be reported that occur from the initiation of escitalopram/placebo on 
Day 1 until the Week 25 study visit. Adverse events of interest, both 
serious and non-serious, and deaths that occur during this period will be 
recorded in the source documents. All SAEs should be monitored until 
they are resolved or are clearly determined to be due to a subject’s stable 
or chronic condition or intercurrent illness(es). Related AEs will be 
followed until resolution to baseline or grade 1 or stabilization.  
 
To: For the purposes of safety reporting, all adverse events determined 
to be related or possibly related to escitalopram/placebo will be reported 
that occur from the initiation of escitalopram/placebo on Day 1 until the 
Week 25 study visit. Adverse events both serious and non-serious, and 
deaths that occur during this period will be recorded in the source 
documents and reported according to AE reporting policies of the IRB 
of record. All SAEs should be monitored until they are resolved or are 
clearly determined to be due to a subject’s stable or chronic condition or 
intercurrent illness(es). Related AEs will be followed until resolution to 
baseline or grade 1 or stabilization.  
 
8.4.1 
SAE Reporting Requirements 
Language was added to clarify that only SAEs related to 
escitalopram/placebo are to be reported. 
 
8.5 
SAEs and OnCore revised 
From:  All SAEs will be entered into OnCore.   
 
To: All SAEs related or possibly related to escitalopram/placebo will be 
entered into OnCore.   
 
Section 8.3 
Revised to state that the SAE Report Form to be used for this study is  
the FDA Form 3500A (MedWatch for Industry Form FDA 3500A –
Mandatory Reporting) This form can be found at the following link:   
https://www.fda.gov/safety/medical-product-safety-
information/medwatch-forms-fda-safety-reporting.  
 
 
 

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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 

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PROTOCOL SUMMARY 
Protocol Number/Title 
CASE6220:  A Phase II, Randomized, Double-blind, Trial 
Comparing Escitalopram to Placebo in Patients with Resectable 
Pancreatic Cancer 
Study Phase 
II 
Brief Background/Rationale 
 
 
 
Anti-depressants have been shown to be beneficial in cancer 
patients. They reduce depressive symptoms and improve 
quality of life. Randomized trials have shown that 
antidepressants can reduce the development of depression in 
non-depressed patients with breast, melanoma and head and 
neck cancers.    In this trial, we will test the role of anti-
depressants in patients with localized pancreatic and 
periampullary cancer receiving neoadjuvant therapy. It has 
been shown that treating depression can impact survival in 
cancer patients. Additionally, depressed pancreatic cancer 
patients have a worse survival. Therefore, anti-depressants 
may also have implications for cancer treatment. 
Primary Objective  
Primary Endpoint(s) 
To determine if patients with localized pancreatic and 
periampullary cancer have a decreased risk of depression with 12 
weeks of escitalopram treatment. 
Secondary Objective(s) 
Secondary Endpoint(s)  
To determine if patients with localized pancreatic and 
periampullary cancer have improved quality of life with 12 
weeks of escitalopram treatment.  
Correlative Objective(s) 
 
Correlative Endpoint(s) 
To collect serum, and tissue samples of metabolites related to 
serotonin metabolism, and determine if levels correlate with 
depression, quality of life, or benefit of escitalopram 
Sample Size 
46 patients including 23 patients in each arm (escitalopram and 
placebo)  
Disease sites/Conditions 
Localized pancreatic ductal adenocarcinoma or other 
periampullary adenocarcinoma (bile duct, duodenal, 
ampullary).  
Interventions 
Escitalopram or placebo for 12 weeks as follows:  
2 weeks: 10 mg/day (1 capsule) 
8 weeks: 20 mg/day (2 capsules) 
2 weeks: 10 mg/day (1 capsule) 

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ABBREVIATIONS 
 
AE 
Adverse Event/Adverse Experience 
CCCC 
Case Comprehensive Cancer Center 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSTC 
Data, Safety and Toxicity Committee 
DSMP 
Data and Safety Monitoring Plan 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IDS 
Investigational Drug Services Pharmacy 
IRB 
Institutional Review Board 
N 
Number (typically refers to participants) 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
PDA 
Pancreatic Ductal Adenocarcinoma 
PHQ-9 
Patient Health Questionnaire 
PI 
Principal Investigator 
QA 
Quality Assurance 
QIDS 
Quick Inventory of Depressive Symptoms 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOC 
Standard of Care 
UH 
University Hospitals 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
1.0  
INTRODUCTION  
 
1.1 
Background Information  
1.2  
Rationale for Proposed Study 
1.3  
Correlative Studies 
1.4 
Potential Risks and Benefits 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2  
Secondary Objective(s) 
2.3 
Exploratory Objectives(s) 
2.4 
Endpoints/Outcome Measures 
 
3.0 
STUDY DESIGN 
3.1 
Study Characteristics 
3.2 
Number of Subjects 
3.3 
Replacement of Subjects 
3.4 
Expected Duration of Treatment and Subject Participation 
 
 
4.0  
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
 
5.0 
REGISTRATION  
 
6.0  
TREATMENT PLAN 
6.1 
Treatment Regimen Overview  
6.2 
Criteria for Removal from Study 
6.3 
Duration of Follow-Up 
 
7.0 
DOSE DELAYS / DOSE MODIFICATIONS 
 
8.0 
ADVERSE EVENTS AND POTENTIAL RISKS 
8.1  
Escitalopram Adverse events 
8.2 
Definitions 
8.3 
Serious Adverse Event Report Form 
8.4 
Reporting Procedures for Serious Adverse Event  
8.5 
Serious Adverse Events and OnCoreTM    
8.6 
Data Safety Toxicity Committee 
8.7 
Data and Safety Monitoring Plan 
 
 

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9.0 
PHARMACEUTICAL INFORMATION  
9.1 
Investigational Agent(s) 
 
 
10.0 
EXPLORATORY/CORRELATIVE  
10.1     Special Assays or Procedures  
 
10.2 
Specimen Preparations, Handling and Storage  
 
11.0 
STUDY PARAMETERS AND CALENDAR 
11.1 
Study Parameters 
11.2 
Calendar 
 
12.0 
MEASUREMENT OF EFFECT  
 
13.0 
RECORDS TO BE KEPT/REGULATORY CONSIDERATIONS 
13.1 
Data Reporting 
13.2 
Regulatory Considerations  
 
 
14.0 
STATISTICAL CONSIDERATIONS 
REFERENCES 
 
APPENDICES  
 
 
APPENDIX I  
 
             ECOG / Karnofsky Performance Status Criteria  
 
 
 
APPENDIX II 
 
Subject Diary (pill, injectable, etc) 
 
 
APPENDIX III 
 
Clinical Medication Compliance Form for Investigational Studies 
 
 
APPENDIX IV 
 
QIDS-SR16 
 
 
APPENDIX V 
 
Fact –Hep (Version 4) 
 
 
APPENDIX VI 
 
FIBSER Scale 
 
            APPENDIX VII 
 
PHQ-9 
 
 
APPENDIX VIII 
 
Tumor Profile Assessment 
 

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 1.0 
Introduction  
1.1 
Background Information  
The diagnosis of major depressive disorder (MDD) is typically made clinically according to the 
DSM-5 diagnostic criteria. The prevalence in the general United States population is 6% 1, and the 
lifetime risk is about 17% 2. The risk is in fact lowest in older patients, with a point prevalence 
around 1% in individuals over 65 years 3. Thus, the high rate of depression in patients with cancer 
is striking, particularly since it is so widely undertreated. The rate of depression in patients 
diagnosed with cancer is increased by 4-fold over the general population by some estimates, with 
a point-prevalence as high as 12% 4. This has major implications for patients and their families. 
The comorbid incidence of depression in cancer patients leads to worse survival, longer and more 
frequent hospitalizations, decreased treatment compliance, and worse quality of life 5, 6. In most 
instances, depressive symptoms develop within the first year of a cancer diagnosis7, yet, 
unfortunately almost 73% of eligible patients do not receive appropriate therapy8. Other studies 
have demonstrated that almost all inpatients 9, and 50% of outpatients with cancer have 
undiagnosed depression 10. There is a growing body of evidence that targeted interventions in 
cancer patients can improve depressive symptoms and quality of life, including behavioral therapy 
11 and antidepressants12-18. Therefore, in light of the high risk of depression in cancer patients, the 
low risk of treatment, and the potential benefit of antidepressant treatment, there is a strong 
argument to be made in favor of broad depression screening. Even further, the evidence supports 
a line of investigation to examine the utility of anti-depression treatment as a new standard of care 
in patients with high-risk cancers. Herein, we propose testing the use of anti-depressants in all 
patients with localized pancreatic and related cancer, with the primary goal to prevent worsening 
depression at 12 weeks. 
1.2  
Rationale for Proposed Study 
A recent randomized study of patients with head and neck cancer offers pioneering insights into 
the potential benefit of this approach. Lydiatt et al. randomized 148 patients with head and neck 
cancer of varying stages to escitalopram (Lexapro, an SSRI, 20 mg/day, except 10 mg/day during 
week 1) or placebo. Patients were included in the study if they were not depressed or had mild 
depression at the start of treatment, as indicated by a QIDS-SR score < 11. There were minimal 
adverse effects in both treatment groups. Depression was more common at later time points in the 
placebo group compared to the treatment group (24% vs. 10%), and the benefit persisted in a 
multivariable analysis. Thus, the number needed to treat to prevent a single case of depression was 
just 7 people. Additionally, there was better quality of life noted in patients in the treatment group 
at every time point in the study, and as early as after 1 month of treatment. Based on this study, 
we will administer the same dose of study drug. We will administer escitalopram at 10 mg/day for 
2 weeks, 20 mg/day for 8 weeks, and 10 mg/day for the final 2 weeks (ramp up and ramp down 
periods) for a total of 12 weeks.  
Due to the fact that depression is more common in pancreatic cancer than any other cancer type 
(40% of patients), depression symptoms overlap with presenting signs and symptoms of pancreatic 
cancer, and depression screening is currently not standard practice for patients undergoing 
treatment for pancreatic cancer, the QIDS survey (nor any other tool) has been validated in the 

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pancreatic cancer population, we will include all patients with localized pancreatic cancer in this 
trial, regardless of depression score. Importantly, patients noted to have either severe 
depression per the QIDS screen or suicidal ideation will be referred to a study psychiatrist 
for a more thorough evaluation and care plan with consideration of starting a second 
pharmacologic agent. However, these patients will continue on study in a blinded fashion 
taking placebo or escitalopram.  
We will look at QIDS scores at 12 weeks as the primary study outcome. We hypothesize that 
patients receiving escitalopram will have a lower rate of moderate (or worse) depression, compared 
to patients receiving placebo. 
QIDS (Quick inventory of depressive symptomatology) 
QIDS is a 16-item survey that addresses each of the nine symptom domains covered in the DSM-
V criteria for Major depressive disorder (depressed mood, loss of interest or pleasure, 
concentration/decision making, self-outlook, suicidal ideation, energy/fatigability, sleep, 
weight/appetite change, and psychomotor changes) 19. The tool is used both for depression 
screening, and to measure depression severity, and has been heavily validated against established 
surveys. Its effectiveness is proven. The tool is straight forward, and is administered in either a 
self-reported form (SR), or a clinician-rated (CR) form, and requires minimal training. The QIDS 
scores range from 0-27. Scores are interpreted as follows 20:  
0-5 
No depression 
6-10 
Mild depression 
11-15 
Moderate depression 
16-20 
Severe depression 
21-27 
Very severe depression 
 
In this study, we will be using the QIDS to measure the rate of depression at each time point, with 
the incidence of worsening depression at 12 weeks as a primary outcome. Patients with a QIDS 
score ≥16 at any time point will be referred to a psychiatrist for a more thorough evaluation and 
consideration for additional therapy. 
PHQ-9 
This survey has just 9 questions with respect to the past 2 weeks of life, and each question is 
scored on a 4-point scale: not at all = 0; several days =1; more than half the days = 2; and nearly 
every day = 3. Scores are added up to determine if patients have depression. The 9th question 
asks about suicidal ideation. The tool mirrors the 9 criteria in DSM V and has been extensively 
validated 21. 
0-4 
Minimal depression 
5-9 
Mild depression 
10-14 
Moderate depression 
15-19 
Moderately severe depression 
20-27 
Very severe depression 
 
 

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FACT-Hep (Quality of life survey) 
The fact scales are quality of life surveys that can be administered by patients or by 
clinician/coordinators as an interview. The FACT-Hep has 27 general questions, and 18 questions 
that are specific to hepatopancreatobiliary cancer, for a total of 45 questions. The general questions 
span four domains: physical, social/family, emotional, and functional well-being 21. It requires less 
than 10 minutes to complete and targets the 6th grade reading level. Answers are given in the form 
of a five-point Likert scale as follows: 0 (Not at all), 1 (A little bit), 2 (Somewhat), 3 (Quite a bit), 
and 4 (Very much). Points are re-calibrated and compiled, such that high scores indicate a higher 
quality of life (opposite to the grading scheme of QIDS or PHQ-9 where a high score reflects 
depression). The additional 18 questions in the FACT-Hep address a subscale to estimate 
hepatopancreatobiliary quality of life issues. From these 45 answers, several different scores can 
be computed, including a FACT-global score (G), a hepatobiliary cancer subscale (HCS) score, a 
FACT-Hep total score (a sum of the prior two scores), and a FACT-Hep Trial Outcome Score 
(TOI) which is a summary of the physical + functional + HCS scores. The FACT form has been 
validated for use in patients with advanced and localized pancreatic cancer 21-24. 
1.3  
Correlative Studies 
The serotonin theory of depression is supported through clinical experience. Selective serotonin 
reuptake inhibitors (SSRIs) remain the most common class of medicines used to treat depression. 
Mechanistically, these drugs increase serotonin levels at brain synapses 25.  Tryptophan is the 
principal substrate for serotonin synthesis, and therefore, tryptophan breakdown may have biologic 
implications on clinical depression in patients with dysregulated tryptophan catabolism. We and 
others have demonstrated that the enzymes responsible for tryptophan metabolism are 
dysregulated in pancreatic cancer 26, 27. Specifically, the enzymes that divert tryptophan into 
kynurenine and related metabolites are overexpressed, including IDO1, IDO2, and TDO (. This 
pathway effectively shunts tryptophan away from serotonin synthesis.  
 
In this study, we will examine the expression of each of these tryptophan degrading enzymes in 
resected PDAs (25 of 46 patients in the trial are expected to have resected specimens for analysis). 
We will determine if a correlation exists between expression levels of these enzymes in the tumor 
and 1) depression at baseline, and 2) the development of depression in patients on trial. 
Additionally, plasma levels of specific tryptophan metabolites will be measured in patients at the 
start of treatment. Patients undergoing resection will have repeat levels taken 1-2 months after 
resection to determine how tumor burden impacts metabolite levels. 
1.4 
Potential Risks and Benefits 
The study drug, escitalopram, is FDA approved for the treatment of depression. It is safe and 
well tolerated.  
 
Potential Risks 
Adverse side effects include:44  
Nausea (15%) 

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Ejaculatory disorder (9%) 
Insomnia (9%) 
Diarrhea (8%) 
Dry mouth (6%) 
Somnolence (6%) 
Dizziness (5%)  
Hyperhidrosis (5%)  
Fatigue (5%)  
Rhinitis (5%) 
Influenza-like symptoms (5%) 
 
Benefits 
Potential benefits of the study for the patient include prevention of depression, improved quality 
of life, and improved cancer survival. For the field, the study may demonstrate that prophylactic 
anti-depressant use is beneficial and provide a justification for a larger, phase III trial. 
2.0  
Objectives 
Anti-depressants have been shown in multiple studies to be beneficial in cancer patients 29-33. They 
reduce depressive symptoms and improve quality of life. Moreover, anti-depressants have been 
shown in randomized trials of breast cancer, melanoma, and head and neck cancer to reduce the 
development of depression in non-depressed cancer patients 34-36. In this trial, we will test the role 
of anti-depressants in patients with localized pancreatic and periampullary cancer receiving 
neoadjuvant therapy. It has also been shown that treating depression can impact survival in cancer 
patients 37, 38. Additionally, depressed pancreatic cancer patients have a worse survival 39. 
Therefore, anti-depressants may also have implications for cancer treatment. 
 
2.1  
Primary Objective  
To obtain preliminary evidence of the efficacy of daily escitalopram in reducing depression in 
patients with localized pancreatic or periampullary cancer receiving neoadjuvant therapy. The 
primary endpoint will be a reduction in the rate of depression at 12 weeks using a QIDS survey. 
 
2.2 
Secondary Objectives 
• To determine depression rates in patients with resected pancreatic cancer at baseline and 
at 12 weeks.  
• To determine if daily escitalopram improves the quality of life in patients with localized 
pancreatic and periampullary cancer. 
o To determine if daily escitalopram improves survival in patients with resected 
pancreatic cancer. 
o Study tissues and serum to determine if molecular markers of the serotonin-
tryptophan-kynurenine pathway are associated with depression scores. 
o Study tissues and serum to determine if molecular markers of the serotonin-
tryptophan-kynurenine pathway are associated with the efficacy of anti-depressants 
in patients with pancreatic cancer. 

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o Test for an association between tryptophan intermediates and immune profile in 
tumors and blood of patients with pancreatic cancer. 
 
2.3 
Exploratory Objective 
We will also examine the impact of IDO2 polymorphisms in depression rates and response to anti-
depressants. 
 
2.4        Endpoints/Outcome Measures 
Endpoints will include depression, quality of life, survival endpoints, and biomarkers. 
Primary: 
The primary outcome measure will be depression rates, based on answers from the QIDS form. 
Depression is reflected by a score ≥ 11 (moderate depression or worse). 
 
Secondary: 
The secondary outcome measures will include: 
• Quality of life, as measured by the FACT-Hep total score, and FACT-Hep subscores. 
• Measurements of overall survival  
 
Exploratory: 
Exploratory endpoints include: 
• genetic biomarkers 
• tissue biomarkers of resected specimens 
• tissue biomarkers in the plasma or blood  
• early PDA recurrence or clinical evidence of disease after resection or radiographic 
progression in patients who have not yet had surgery (early recurrence is defined as 
progression of disease within 8 months after the start of systemic chemotherapy) 
 
3.0 
Study Design 
This trial is a phase II, prospective, randomized, placebo controlled trial, evaluating escitalopram 
(vs. placebo) in patients with localized pancreatic or periampullary cancer. 
 
3.1  
Study Characteristics  
Patients may be non-depressed or depressed. Those who are severely depressed according to the 
Quick Inventory of Depression Survey (QIDS ≥16 points) will be referred to a psychiatrist for 
further evaluation and possibly additional therapy, based on clinical judgement. The study will be 
started at University Hospitals Cleveland Medical Center with the possibility that it can be opened 
at alternative sites if needed for patient accrual. 
 
At the time of study enrollment, the treating physician must have the intent to treat the patient with 
12 weeks of neoadjuvant chemotherapy as standard of care cancer treatment.  For this study, 
patients will be randomized in a 1:1 ratio to receive escitalopram or placebo using a  randomization 
table prepared by the study statistician.  This randomization table will be shared by the statistician 
only with the Investigational Drug Services Pharmacy (IDS) personnel and will detail for all 55 
patients/study IDs whether that patient is to receive escitalopram or placebo.  Each patient will be 

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assigned a study number, in sequential order, only after all eligibility criteria have been confirmed 
by the study coordinator, treating physician (Investigator or Co-investigator) involved in the case, 
and by a member of the Clinical Trials Unit’s Quality Assurance department.    
 
It is possible that burden of disease could influence mood.  Therefore, patients will also be 
stratified according to whether they have resectable disease or locally advanced disease (borderline 
resectable or unresectable) according to NCCN criteria. A pancreatic surgeon (PI or Co-
Investigator) will determine this status using the Tumor Profile Assessment (see Appendix VIII). 
The Tumor Profile Assessment is to be filled out by the PI or by the Co-investigator prior to 
randomization. 
 
3.2 
Number of Subjects 
The clinical trial is powered for 46 patients, including 23 patients in each arm (escitalopram and 
placebo).  However, 55 patients will be enrolled, in order to achieve the desired number due to 
expected attrition both before and after initiation of therapy or due to removal from study due to 
reasons noted in Section 6.2. 
 
3.3 
Replacement of Subjects  
Patients will not be replaced.   
 
3.4  
Expected Duration of Treatment and Subject Participation 
Patients will be treated with escitalopram or placebo for 12 weeks. An end of treatment visit and 
assessment will be conducted at Week 13 and another at Week 25. After Week 25, patients will be 
followed every three months for three years for treatment details and to document disease and 
survival status.   
 
The typical course of neoadjuvant therapy for resectable or unresectable patients is virtually always 
≥ 12 weeks. Patients whose cancer progresses during that time will remain on study unless the 
patient meets criteria for removal from study as noted in Table 7.1 or if the patient becomes unable 
to swallow oral medications.  
 
The first day of medication will be considered day = zero with respect to the depression (QIDS-
SR, PHQ-9) and QOL (FACT-Hep) survey time points (Survival analyses however will be dated 
back to the date of consent). Surveys will be performed biweekly for 12 weeks. The FACT-Hep 
will be administered at a slightly less frequent interval (once per month). In the follow-up phase, 
beginning after Week 25, subjects will be followed for up to 3 years, for recurrence, treatment 
details, and survival information. Follow-up information will be obtained every 3 months. 
 
4.0 
Subject Selection 
Each of the criteria in the sections that follow must be met in order for a subject to be considered 
eligible for this study. Use the eligibility criteria to confirm a subject’s eligibility.  
Subject’s Name _____________________________________________________________ 
 
Medical Record # ___________________________________________________________ 

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Research Nurse / Study Coordinator Signature:  
 
_________________________________________________ 
 
 
Date __________ 
 
 
Treating Physician [Print] ____________________________________________________ 
 
 
Treating Physician Signature: _________________________________________________ 
 
 
Date __________ 
 
4.1 
Inclusion Criteria 
 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment:  
 
 
4.1.1 Patients must have histologically or cytologically confirmed localized or locally 
advanced pancreatic ductal adenocarcinoma or other periampullary adenocarcinoma (bile 
duct, duodenal, ampullary) 
 
 
 
4.1.2  Patients must not currently be on an antidepressant, anti-anxiety, anti-bipolar, or anti-
psychotic medicine 
 
 
 
4.1.3  Aged 18-80 years.  
 
 
 
4.1.4  ECOG PS score of 0-2 
 
 
 
4.1.5  Planned to have at least 12 weeks of neoadjuvant chemotherapy as standard of care 
cancer treatment   
 
 
 
4.1.6  No diagnosis of bipolar disease 
 
 
 
4.1.7  Willing to comply with all study procedures and be available for the duration of the 
study 
 
 
 
4.1.8 Patient must be mentally competent and must have the ability to understand and the 
willingness to sign a written informed consent document 
 
 
 
4.1.9  Patients must be able to speak English 
 
4.2 
Exclusion Criteria 
The presence of any of the following will exclude a subject from study enrollment. 
 
 
4.2.1 Patients under the age of 18 or over age of 80 
 

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4.2.2  Metastatic pancreatic or other periampullary cancer 
 
 
 
4.2.3 Resection of pancreatic cancer within the past year prior to study enrollment or 
planned surgery within the next 12 weeks  
 
 
 
4.2.4 Currently on an antidepressant, anti-anxiety, anti-bipolar or anti-psychotic medicine.  
Patients who have taken MAOI inhibitors within the past 6 months are excluded. 
 
 
 
4.2.5  Patients with a diagnosis of bipolar disease 
 
 
 
 4.2.6  Patients with a history of seizure disorder  
 
 
 
4.2.7   Patients with a recent medical history of myocardial infarction or unstable heart  
disease 
 
     4.2.8   Patients with a history of QTc prolongation or torsade de points, a baseline QTc  
             interval of > 500ms, a history of drug-induced QTc prolongation or congenital long QT  
             syndrome 
 
_
 
4.2.9  Patients with Child-Pugh score of B or C 
 
_
 
4.2.10  Patients with moderate to severe renal disease with a GFR < 45.  
 
_
 
4.2.11  Patients who cannot ingest oral medication  
 
_
 
4.2.12 Patients with any history of mania  
 
_
 
4.2.13 Patients with known allergy to escitalopram    
 
_
 
4.2.14  Patients who are pregnant or lactating 
 
_
 
l.2.15   Patients who do not speak English 
 
 
4.3 
Inclusion of Women and Minorities  
Both men and women and members of all races and ethnic groups are eligible for participation in 
this trial. Children (under 18) will be excluded. Note that escitalopram is safe and effective in the 
elderly 40. 
 
5.0 
Registration 
All subjects who have been consented are to be registered in the OnCore™ Database. For those 
subjects who are consented, but not enrolled, the reason for exclusion must be recorded. 
All subjects will be registered through University Hospitals Cleveland Medical Center and will be 
provided a study number by contacting the study coordinator listed on the cover page.    
 
 
 

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6.0  
Treatment Plan 
6.1 
Treatment Regimen Overview 
This interventional trial involves the administration of a safe and well-tolerated oral antidepressant. 
Patients will take escitalopram or placebo, at the standard dose, with a ramp-up and ramp-down 
interval, as previously described in a similar trial in head and neck cancer 18.  
The schedule is as follows: 
2 weeks: 10 mg/day (1 capsule) 
8 weeks: 20 mg/day (2 capsules) 
2 weeks: 10 mg/day (1 capsule) 
Patients will come to the clinic on Day 1 and will be given a pill diary and enough blinded 
escitalopram/placebo for the first 2 weeks of the study. The patient will taught how/when to take 
the pills and how to complete the pill diary.  The patients will be given pill bottles for Weeks 1-2.    
Patients will take their first dose of escitalopram/placebo and have blood drawn for serum 
metabolites at this visit (prior to dosing). The QIDS-SR depression survey, PHQ-9, FACT-Hep 
QOL and FIBSER Side Effect Questionnaires (see Appendices IV, V, VI and VII) will be 
completed.   A member of the study staff will give the questionnaires to the patient to complete in 
a private area. The study staff member will remain with the patient during completion of the 
questionnaires to assist, if necessary, and to ensure that the patient is answering all questions on 
their own.  
 
There will be study-related clinic visits scheduled for Days 15 and 71. On Day 15, patients will be 
given pill bottles for Weeks 3-10.  On Day 71, patients will be given pill bottles for Weeks 11-12.  
The Week 11-12 pill diary along with any unused pills will be collected at the end of treatment 
clinic visit (Week 13, Day 85). All other visits will be conducted via phone call from the study 
staff every two weeks beginning on Day 8.  Phone visits will be conducted on Days 8, 22, 36, 50, 
64 and 78 (+/- 7 days).  However, if a patient’s scheduled chemotherapy-related visit, clinic visit 
or hospital visit for any other reason happens to fall on (or within the 7 day window of) a planned 
study visit, the visit may be conducted in person with study staff. During these visits (phone or in-
person), the study staff will perform a toxicity assessment and ask questions to determine if the 
patient is being compliant with taking the pills and completing the pill diary.  The study staff 
member will verbally conduct the QIDS-SR, PHQ-9, and FIBSER with the patient and record the 
patient’s answers and the FACT-Hep will be given directly to the patient to complete (if not done 
over the phone). The FACT-Hep will be performed monthly on Days 1, 22, 50 78, and 85.    
 
Unblinding Procedures: 
• Patients will be unblinded if study drug is discontinued for the Adverse Events of 
Special Interest (hemorrhage, suicidal ideation and mania) as described in Table 7.1.   
• Patients will be unblinded if study drug is discontinued due to Grade 4 hyponatremia 
as described in Table 7.1. 

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• Patients will be unblinded if they meet the criteria for removal from study as defined 
in Section 6.2. 
• Patients will be unblinded at the time of their Day 85 (Week 13) end of treatment visit.   
 
Patients will be unblinded by IDS staff as outlined in the Unblinding Manual.  Patients who are 
unblinded before they complete all study visits will be asked to continue to have study-related 
phone calls with study staff and complete all study-related questionnaires.  Patients who are 
unblinded prior to the end of treatment visit and undergo tumor resection will be required to have 
the research tissue sample and post-surgery research blood samples taken. 
  
An assessment of depression will be made by the treating physician. Based on the assessment, 
patients who received escitalopram may be given the option of continuing the medication either 
under the supervision of their medical oncologist or primary care provider.  If this occurs, the 
patient will obtain escitalopram from commercial supply at the dose prescribed by the patient’s 
medical oncologist, primary care physician or other provider.    
 
6.2 
Criteria for Removal from Study 
Withdrawal Visit/Discontinuation of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for 12 weeks or 
until one of the following criteria applies: 
• Patient misses more than four consecutive weeks of escitalopram. 
• Intercurrent illness that prevents further administration of treatment or patient inability to 
swallow escitalopram/placebo capsules, 
• The investigator considers it, for safety reasons, to be in the best interest of the patient.  
• Unacceptable adverse event(s):  
 
-NCI CTCAE version 5.0 Grade 2 or higher hemorrhage that occurs within the  
 first four weeks of treatment 
-NCI CTCAE version 5.0 Grade 4 suicidal ideation  
-NCI CTCAE version 5.0 Grade 3 or higher mania  
-NCI CTCAE version 5.0 Grade 4 hyponatremia 
 
     
Patients who experience severe depression will be referred to a psychiatrist. They will  
            also continue, if agreeable, on the study and with scheduled surveys according to the  
            defined schedule (QIDS, PHQ-9, FACT-Hep, FIBSER).  
 
Patients will be withdrawn if they are deemed at high risk for suicide or if they wish to 
voluntarily withdraw from the study. 
 
• Patient decision to withdraw from treatment (partial consent) or from the study (full 
consent), 
• Pregnancy during the course of the study  
• Death 

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• The Principal Investigator and/or the Case Comprehensive Cancer Center Data Safety 
Toxicity Committee (DSTC) reserve the right to temporarily suspend or prematurely 
discontinue this study if unacceptable study-related risks are identified. The date and reason 
for discontinuation must be documented. Every effort should be made to complete the 
appropriate assessments.  
 
Handling of Participant Withdrawals and Participant Discontinuation of Study  
Intervention 
 
Patients who withdraw from treatment will have an end of study visit as described in Section 6.3. 
They will continue to be followed with surveys at the scheduled intervals and for cancer-specific 
outcomes, unless patients refuse this follow-up by withdrawal of consent. 
 
6.3 
Duration of Follow-Up 
 
End of Treatment Study Procedures 
An end of treatment visit will be conducted on Day 85 (Week 13).  This will be a clinic visit and 
will include a physical exam, collection of pill diary and any unused pills, toxicity assessment, 
QIDS-SR, PHQ-9, Fact-Hep and FIBSER.  The patient’s disease and treatment status will also be 
assessed.  
 
During Week 25 (12 weeks after the end of treatment), a phone visit will be conducted which will 
include a toxicity assessment, QIDS-SR, PHQ-9, Fact-Hep and FIBSER.  Patients who screen 
above 11 on the QIDS-SR or above 9 on the PHQ-9 will be referred by the study team to a social 
worker, who will then conduct their own assessment and make appropriate referrals to psychiatry 
if necessary.  Patients who give an affirmative reply to Question 12 on the QIDS-SR or 9 on the 
PHQ-9 indicating thoughts of suicide, will be referred to Seidman Psychiatry Service for 
evaluation (please see Section 7.0). 
 
Post-treatment/Follow-Up 
Patients will call the research coordinator, their doctor, or the study PI if they experience 
depression-related symptoms. 
 
Long Term/Survival Follow-up  
After the Week 25 visit, cancer-specific information will be obtained for three years to assess 
disease and survival status.  The information will be obtained every three months either by a review 
of the patients’ medical record or by phone. Patients who undergo tumor resection after completion 
of the study will have tumor and blood samples collected for research studies.   
 
7.0  
Dose Delays/Dose Modifications 
The starting dose will be one pill (10mg of escitalopram/placebo) during Weeks 1 and 2 followed 
by two pills daily (20mg of escitalopram/placebo) during Weeks 3-10 then one pill (10mg of 
escitalopram/placebo) during Weeks 11-12. Drug toxicities will be assessed based upon responses 
to questionnaires and from entries on pill diaries every two weeks by the clinical staff during the 
scheduled phone calls or in-person visits. There will be no dose reductions.  Drug will be 
discontinued for the Adverse Events of Special Interest (hemorrhage, suicidal ideation and mania) 

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and for Grade 4 hyponatremia as described in Table 7.1. Drug may also be discontinued, at the 
discretion of the treating physician, for other adverse events determined by the PI to be related to 
escitalopram/placebo. If the event takes place in the first four weeks of starting treatment, the 
patient will be removed from study and will not be followed.   
 
Patients who discontinue drug for any reason will continue to complete all questionnaires as 
outlined on the Study Calendar.  The study team will make every effort to ensure that patients stay 
on schedule.  
 
Table 7.1 Criteria for dosing delays and re-initiation of treatment due to study drug-related 
toxicity  
CTCAE Grade* Patient report or from any 
assessment scale 
Dose Discontinuation 
Guidelines 
Hemorrhage 
(any site) 
Grade 1:  Mild symptoms; 
intervention not indicated  
Grade 2:  Moderate symptoms; 
intervention indicated  
Grade 3:  Transfusion indicated; 
invasive intervention indicated; 
hospitalization  
 
Grade 4:  Life-threatening 
consequences; urgent intervention 
indicated  
Grade 2 or greater:  
Discontinue drug, inform 
treating physician and PI 
immediately upon discovery.  
 
(if this happens within first 4 
weeks remove patient from 
study) 
Suicidal 
ideation** 
 
 
Grade 1:  Increased thoughts of death 
but no wish to kill oneself  
Grade 2:  Suicidal ideation with no 
specific plan or intent  
Grade 3:  Specific plan to commit 
suicide without serious intent to die 
which may not require hospitalization 
Grade 4:  Specific plan to commit 
suicide with serious intent to die 
which requires hospitalization  
Grade 1-3: inform treating 
physician immediately upon 
discovery  
Grade 4:  discontinue drug and 
remove from study.  
 
See Table 7.2 
Mania 
 
 
Grade 1:  Mild manic symptoms 
(e.g., elevated mood, rapid thoughts, 
rapid speech, decreased need for 
sleep)  
Grade 2:   Moderate manic symptoms 
(e.g., relationship and work 
difficulties; poor hygiene)  
Grade 3-4: discontinue drug 
and remove from study, notify 
treating physician and PI 
immediately.   

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Grade 3:  Severe manic symptoms 
(e.g., hypomania; major sexual or 
financial indiscretions); 
hospitalization not indicated; new 
onset  
Grade 4:  Life-threatening 
consequences, threats of harm to self 
or others; hospitalization indicated  
Hyponatremia 
Grade 1:  <LLN - 130.0 mmo/L 
Grade 2: 125-129 mmol/L and 
asymptomatic 
Grade 3:  125-129 mmol/L 
symptomatic; 120-124 mmol/L 
regardless of symptoms 
Grade 4:  <120 mmo/L; life-
threatening consequences 
Grade 4:  discontinue drug and 
remove from study.  
 
*CTCAE Version 5.0 
**Please see safety guidelines section below regarding patients exhibiting suicidal 
ideation 
 
Safety Assessment 
Patients will not be allowed to participate or will be withdrawn if at any point in the trial they are 
found to be at high risk for suicide.  Patients who provide an affirmative response (checks 1, 2 or 
3) on Question 12 of QIDS will be referred and evaluated by a UH/Seidman Psychiatrist to assess 
whether high risk for suicide is present.   Patients who are severely  or moderately severely 
depressed by QIDS (≥16) or PHQ-9 greater than 14 will be referred and evaluated by a 
UH/Seidman psychiatrist. They will not be discontinued from the trial, but may be offered 
additional therapy as part of standard of care, according to the judgement of the evaluating 
psychiatrist. 
For a referral to a Psycho-Oncology Provider call 
 or email   
, 
  
 
Table 7.2 Suicidal Ideation Safety Guidelines   
Response to Question 
12 on QIDS-SR* 
Response to Question 9 on 
the PHQ-9 
Action to be taken 
0  
0 
No action 
1  
1 
Immediately inform treating physician 
and PI* 

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2  
2 
Immediately inform social worker to 
perform assessment or send patient to 
ED (also inform treating physician and 
PI)* 
3  
3 
Immediately inform social worker to 
perform assessment or send patient to 
ED (also inform treating physician and 
PI)* 
* If positive response discovered via phone assessment, clinical team must be informed within 4 
hours.  If a patient is at acute risk for self-harm, hospital/system suicide safety plan will be 
followed. 
 
8.0 
Adverse Events and Potential Risks  
8.1 
Escitalopram 
Adverse side effects include:44 
Nausea (15%) 
Ejaculatory disorder (9%) 
Insomnia (9%) 
Diarrhea (8%) 
Dry mouth (6%) 
Somnolence (6%) 
Dizziness (5%)  
Hyperhidrosis (5%)  
Fatigue (5%)  
Rhinitis (5%) 
Influenza-like symptoms (5%) 
 
Please refer to the escitalopram package insert for a comprehensive list of adverse events.  
 
8.2 
Definitions  
8.2.1    Adverse Event   
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to a research participant as a result 
of the participant’s involvement in a research study. The event can include abnormal laboratory 
findings, symptoms, or disease associated with the research study. The event does not necessarily 
have to have a causal relationship with the research, any risk associated with the research, the 
research intervention, or the research assessments.  
 
Adverse events may be the result of the interventions and interactions used in the research; the 
collection of identifiable private information in the research; an underlying disease, disorder, or 
condition of the subject; and/or other circumstances unrelated to the research or any underlying 
disease, disorder, or condition of the subject.  

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The measurement of side effects of escitalopram in not an endpoint of this study and escitalopram 
has been studied extensively in patients 28, 41-43. This drug has also been studied as prophylactic 
antidepressant in the cancer populations18.  All patients enrolled to this study will be receiving 
chemotherapy at the time of treatment and will be under clinical care during this interval.   Adverse 
events attributed to chemotherapy and/or underlying disease will not be recorded for this study. 
 
Akathisia, or restlessness, is a serious but uncommon side effect, which patients will be alerted to 
report.  Other common side effects typically go away on their own. Patients will be educated on 
possible symptoms, as is routinely done when patients are started on an anti-depressant off-of trial. 
They will contact the PI if the symptom becomes debilitating and referred to psychiatry for 
consideration of removal from the study.  
 
Suicidal ideation will be queried every 2 weeks and prompt an immediate referral to psychiatry.  
 
8.2.2   Serious Adverse Events  
A serious adverse event (SAE) is any adverse experience occurring at any dose that results in any 
of the following outcomes:  
• Results in death.  
• Is a life-threatening adverse experience.  The term life-threatening in the definition of 
serious refers to an adverse event in which the subject was at risk of death at the time 
of the event.  It does not refer to an adverse event which hypothetically might have 
caused death if it were more severe.  
• Requires inpatient hospitalization or prolongation of existing hospitalization.  Any 
adverse event leading to hospitalization or prolongation of hospitalization will be 
considered as Serious, UNLESS at least one of the following expectations is met: 
o The admission results in a hospital stay of less than 24 hours OR 
o The admission is pre-planned (e.g., elective or scheduled surgery arranged 
prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any hospitalization may fulfill 
the criteria of “medically important” and as such may be reportable as a serious adverse 
event dependent on clinical judgment.  In addition where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedent.  
• Results in persistent or significant disability/incapacity.  The definition of disability 
is a substantial disruption of a person’s ability to conduct normal life’s functions. 
• Is a congenital anomaly/birth defect.  
• Is an important medical event.  Important medical events that may not result death, 
be life-threatening, or require hospitalization may be considered a serious adverse 
experience when, based upon appropriate medical judgment, they may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  Examples of such medical events include allergic 

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bronchospasm requiring intensive treatment in an emergency room or at home, blood 
disease or disorders, or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. The development of a new cancer is 
always considered an important medical event. 
 
8.2.3 Adverse Event Evaluation  
The investigator or designee is responsible for ensuring that all adverse events, (both serious and 
non-serious as defined in previous sections) observed by the study staff or reported by the subject 
that are determined to be related or possibly related to escitalopram/placebo which occur after the 
initiation of escitalopram/placebo are fully recorded in the subject’s medical record and reported 
according to AE reporting policies of the IRB of record.  Adverse events attributed to 
chemotherapy and/or underlying disease will not be recorded for this study.  Source documentation 
must be available to support all adverse events.  
 
The investigator or sub-investigator (treating physician if applicable) will provide the following 
for all adverse events (both serious and non-serious): 
• Event term (as per CTCAE) 
• Description of the event 
• Date of onset and resolution 
• Expectedness of the toxicity 
• Grade of toxicity  
• Attribution of relatedness to the investigational agent- (this must be assigned by an 
investigator, sub-investigator, or treating physician) 
• Action taken as a result of the event, including but not limited to; no changes, dose 
interrupted, reduced, discontinued, etc. or action taken with regard to the event, i.e. no 
action, received conmed or other intervention, etc. 
• Outcome of event 
 
Descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 will be utilized for AE reporting.  
 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the subject. 
The event is usually listed in the Investigator Brochure, consent form or research protocol.  
 
An unexpected adverse event is an adverse event not previously known or anticipated to result 
from the research study or any underlying disease, disorder, or condition of the subject.  
 
Attribution is the relationship between an adverse event or serious adverse event and the study 
drug.  Attribution will be assigned as follows: 
• Definite – The AE is clearly related to the study drug. 
• Probable – The AE is likely related to the study drug. 
• Possible – The AE may be related to the study drug. 

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• Unlikely – The AE is doubtfully related to the study drug. 
• Unrelated – The AE is clearly NOT related to the study drug. 
 
Protocol must specify if attribution is required for individual components of the treatment regimen 
or the treatment regimen as a whole. 
8.2.4   Adverse Events of Special Interest  
The following adverse events must be recorded, evaluated, and reported according to reporting 
policies of the IRB of record.  Procedures related to these events will be followed as noted in 
Tables 7.1 and 7.2.  Events are graded using CTCAE v5.0. 
• Serious bleeding event (Grade 2 or greater).  Will prompt discontinuation of escitalopram 
or placebo and removal from study.  
• Mania.  Symptoms consistent with mania will prompt referral to psychiatry. 
• Suicidal ideation.  Patients will be evaluated for suicidal ideation every 2 weeks using the 
QIDS and referred to psychiatry if present.  
 
8.3  
SAE Report Form 
SAEs (including AEs of special interest, as applicable) related or at least possibly related to 
escitalopram/placebo will be recorded on the FDA Form 3500A (MedWatch for Industry Form 
FDA 3500A –Mandatory Reporting) but should only be reported as instructed below.  This form 
can be found at the following link:  https://www.fda.gov/safety/medical-product-safety-
information/medwatch-forms-fda-safety-reporting 
 
The electronic FDA SAE reporting forms should not be used. 
   
The PI will evaluate all SAEs for relationship to study participation and report to IRB of record 
per applicable reporting policies. 
 
8.4  
Reporting Procedures for Serious Adverse Events 
For the purposes of safety reporting, all adverse events determined to be related or possibly related 
to escitalopram/placebo will be reported that occur from the initiation of escitalopram/placebo on 
Day 1 until the Week 25 study visit. Adverse events both serious and non-serious, and deaths that 
occur during this period will be recorded in the source documents and reported according to AE 
reporting policies of the IRB of record. All SAEs should be monitored until they are resolved or 
are clearly determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). 
Related AEs will be followed until resolution to baseline or grade 1 or stabilization.  
 
8.4.1 SAE Reporting Requirements 
• Participating investigators (all sites) must report all serious adverse events related to 
escitalopram/placebo to the Principal Investigator (e.g. Sponsor-Investigator) within 24 
hours of discovery or notification of the event. The participating investigator must also 
provide follow-up information on the SAE until final resolution.  
o Jordan Winter, MD, Jordan.winter@uhhospitals.org  

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• The Lead Site Principal Investigator will review the SAE and report the event to external 
collaborator(s), and IRB as applicable. 
• It is the Sponsor-Investigator’s responsibility (e.g. lead site PI) to ensure that ALL serious 
adverse events related to escitalopram/placebo that occur on the study (e.g. ALL SAEs that 
occur at each enrolling institution) are reported to all participating sites. 
 
8.5 
SAEs and OnCore 
• All SAEs related or possibly related to escitalopram/placebo will be entered into OnCore.   
• A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded into 
Oncore. 
 
8.6  
Data Safety and Toxicity Committee 
It is the responsibility of each site PI to ensure that all SAEs related to escitalopram occurring on 
this trial (internal or external) are reported to the Case Comprehensive Cancer Center’s Data and 
Safety Toxicity Committee. This submission is simultaneous with their submission to the sponsor 
and/or other regulatory bodies.  
 
The sponsor-investigator is responsible for submitting an annual report to the DSTC as per CCCC 
Data and Safety Monitoring Plan. 
 
8.7 
Data and Safety Monitoring Plan (DSMP) 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and 
Safety Monitoring Plan in accordance with NCI guidelines.  
 
9.0 
PHARMACEUTICAL INFORMATION  
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 8.  
 
9.1 Investigational Agents 
 
9.1.1  Name of Agent 
Escitalopram 
Other Names:   
Lexapro 
Product description:   Escitalopram and placebo will be supplied as 10 mg capsules 
 
Formulation, Packaging and Labeling: All aspects of drug and placebo manufacturing, 
preparation, packaging, and  labeling will be managed by Buderer Drug Co.   Escitalopram will be 
supplied as a 10mg oblong white tablet, commercially manufactured pharmaceutical by 
Aurobindo, supplied by Buderer Drug, over-encapsulation in a #1 dark blue capsule.  Twenty (20) 
capsules placed into a labeled child resistant prescription vial.  Eight (8) bottles will be supplied 
for each patient. Placebo is a white capsule containing microcrystalline cellulose, compounded (to 
match the weight of the escitalopram 10mg tablet) over-encapsulation into a #1 dark blue capsule.  
Twenty capsules placed into a labeled child resistant prescription vial.  Eight (8) bottles will be 

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supplied for each patient. A batch will be prepared every 180 days or sooner as required.  Bottles 
will be labeled with the patient’s study number, blinded ID (B or D) and drug storage information.  
 
Storage requirements and stability:  Stability will be for six months duration, and stable at room 
temperature 15°-30°C (59°-86°F). 
Route of administration:  There will be no mixing or added preparation by pharmacists, 
technicians or nurses once the finished clinical supply is received from Budrer. Patients will take 
escitalopram or placebo at the standard dose, with a ramp up and ramp down interval as follows:  
2 weeks:  10 mg (1 capsule) 
8 weeks:  20 mg (2 capsules) 
2 weeks:  10 mg (1 capsule)  
Drug Procurement:    Escitalopram and placebo for this study will be obtained from Buderer 
Drug Co.  
  
Drug Accountability:  Orders will be placed by study staff and product shipped by Buderer and 
stored at University Hospital’s Investigational Drug Services Pharmacy at room temperature for 
the duration of the trial. Patients will be given one bottle of escitalopran/placebo upon study 
initiation for the first two weeks on study. At Day 15 patients will be given six bottles for the next 
eight weeks and at Day 71 patients will be given one bottle for the remainder of the study.   
Investigational Drug Services Pharmacy is responsible for maintaining accurate dispensing records 
of the study drug.  
Drug Destruction:  
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, 
and drug remaining. This reconciliation will be logged on the drug reconciliation form, signed and 
dated. Any discrepancies noted will be investigated, resolved, and documented prior to destruction 
of unused study drug. All unused investigational product/placebo will be destroyed at the site per 
institutional policy. Drug destroyed on site will be documented in the study files. 
 
10.0 
EXPLORATORY or CORRELATIVE STUDIES 
 
 
10.1   Serum Metabolites 
10.1.1 Background 
Tryptophan is the principal substrate for serotonin synthesis, and therefore, tryptophan breakdown 
may have biologic implications on clinical depression in patients with dysregulated tryptophan 
catabolism.  We and others have demonstrated that the enzymes responsible for tryptophan 
metabolism are dysregulated in pancreatic cancer 26, 27.  Specifically, the enzymes that divert 
tryptophan into kynurenine and related metabolites are overexpressed, including IDO1, IDO2, and 
TDO. This pathway effectively shunts tryptophan away from serotonin synthesis.  
 
 

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10.1.2 Rationale 
We will determine if a correlation exists between expression levels of these enzymes in the tumor 
and 1) depression at baseline, and 2) the development of depression in patients on trial. 
Additionally, serum levels (or plasma levels are a suitable alternative) of specific tryptophan 
metabolites will be measured in patients at the start of treatment. Patients undergoing resection 
will have repeat levels taken 1-2 months after resection to determine how tumor burden impacts 
metabolite levels. 
 
10.1.3 Collection of Specimens 
Blood samples will be collected on Day 1.  For patients who undergo resection, samples will also 
be collected between one and three months after surgery to account for half-life of metabolites and 
determine if tumor burden influences metabolite levels.  Approximately 30 ml blood will be 
collected into three red top tubes from each patient via venipuncture or port.  
 
10.1.4 Handling of Specimens 
Samples will be left at room temperature for two hours to coagulate.  Samples will then be 
centrifuged at 1000 g for 15-20 minutes and serum collected. 
 
All specimens will be handled according to universal precautions. They will be stored in the Winter 
lab.  Samples will be labeled with the patient’s study number and will not contain any patient 
identifiers.  
 
10.1.5  Analytical Laboratory 
Once samples are collected, contact 
 to inform her that samples are ready for pick-up 
and delivery to the Winter lab. 
 
 
 
 
Wolstein Research Building (WRB 
) 
Lab phone #: 
 
10.1.6  Methods 
• ELISA kits should be brought to room temperature prior to assays (at least 30 minutes) 
• All samples will be run fresh 
• ELISAs will be carried out according to kit protocol. All necessary reagents are provided 
within kits. 
o Kynurenine ELISA - Biovision (E4629-100) 
o Melatonin ELISA - Biovision (E4630-100) 
o Serotonin ELISA - Biovision (E4294-100) 
 
(ELISA kits are suited for either plasma or serum). 
 
• Standards should be run in triplicate 
• Optimal dilution factor should be determined for human subjects (1:10 for mice) 
• Samples are analyzed using a microplate reader, absorbance (450 nm) 

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10.2  Tissue Specimen Assays 
 
10.2.1 Background 
The serotonin theory of depression is supported through clinical experience. Selective serotonin 
reuptake inhibitors (SSRIs) remain the most common class of medicines used to treat depression. 
Mechanistically, these drugs increase serotonin levels at brain synapsis 25.  Tryptophan is the 
principal substrate for serotonin synthesis, and therefore, tryptophan breakdown may have biologic 
implications on clinical depression in patients with dysregulated tryptophan catabolism. We and 
others have demonstrated that the enzymes responsible for tryptophan metabolism are 
dysregulated in pancreatic cancer 26, 27. Specifically, the enzymes that divert tryptophan into 
kynurenine and related metabolites are overexpressed, including IDO1, IDO2, and TDO. This 
pathway effectively shunts tryptophan away from serotonin synthesis.  
 
10.2.2  Rationale 
In this study, we will examine the expression of each of these tryptophan degrading enzymes in 
resected PDAs (25 of 46 patients in the trial are expected to have resected specimens for analysis). 
We will determine if a correlation exists between expression levels of these enzymes in the tumor 
and 1) depression at baseline, and 2) the development of depression in patients on trial. 
 
10.2.3  Collection of Specimens 
Patients undergoing resection after completion of the study will have tumors collected and assayed 
for IDO1, IDO2, and TDO2 expression. This will be performed on sections prepared from resected 
specimens.  Blocks will be requested from pathology and pulled for each patient and 
immunohistochemical staining will be performed. 
 
10.2.4  Handling of Specimens  
All specimens will be handled according to universal precautions.  They will be stored in paraffin 
embedded blocks in the Winter lab.  Samples will labeled with the patient’s study number and will 
not contain any patient identifiers. Samples will be stored for up to two years.  
 
10.2.5 Analytical Laboratory 
Once samples are collected, contact 
 to inform her that samples are ready for pick-up 
and delivery to the Winter lab. 
 
 
 
 
 
Wolstein Research Building (WRB 
) 
Lab phone #:
 
 
10.2.6 Methods 
Collected tumors will be assayed for ID01, ID02 and TD02 expression.  We will test to see if 
expression of these enzymes correlate with depression scores or response to treatment. 
 
 

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11.0  STUDY PARAMETERS AND CALENDAR  
11.1 
Study Parameters 
11.1.1 Screening Evaluation: 
The following must be completed within 28 days of initiating treatment:  
• Informed consent 
• Medical history 
• Review of current medications 
• Physical exam to include head and neck, pulmonary, cardiovascular, gastrointestinal, 
musculoskeletal, cognitive and cutaneous systems 
• Electrocardiogram 
• Pregnancy test for patients of child-bearing potential (ie. women who are pre-menopausal 
or not surgically sterile) 
• ECOG 
 
The following must be completed Week 1, Day 1 (clinic visit): 
• ECOG performance status  
• Blood collection for plasma metabolites 
• FIBSER Side effect questionnaire 
• QIDS-SR baseline survey for depression 
• PHQ-9 Patient Health Questionnaire 
• FACT-Hep quality of life survey 
• Provide supply of blinded escitalopram/placebo and pill diary to patient 
• Explain study procedures including dosing, completion of pill diary and questionnaires 
• Toxicity assessment 
 
11.1.2 Treatment Period (these visits have window of +/- 7 days) 
Daily:  
• Escitalopram (Lexapro) is an SSRI (1 capsule) 10mg/ day for 2 weeks followed by 
Escitalopram (Lexapro) is an SSRI (2 capsules) 20mg/ day for 8 weeks followed by 
Escitalopram (Lexapro) is an SSRI (1 capsule) 10mg/ day for 2 weeks 
• Patients randomized to the placebo arm will receive the same dose schedule but no active 
drug. 
• Pill diary. 
 
Every 2 weeks (phone call or clinic visit):   
• QIDS-SR  
• PHQ-9 
• FIBSER  
• Toxicity assessment  
• Review drug diary compliance  
 
Weeks 3 and 11 (clinic visit) 
• Turn in unused pills and pick up new supply 

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• Review pill diary and pick up new diary 
 
Once per month (phone call or clinic visit):  
• FACT-Hep  
 
Week 13 (end of treatment clinic visit): 
• Collect pill diary 
• Medical History  
• Physical exam 
• ECOG Performance Status 
• QIDS-SR (via phone or mail) 
• PHQ-9 
• FIBSER (via phone or mail) 
• FACT-Hep 
• Toxicity Assessment 
 
 
Week 25 (phone call or clinic visit) 
• QIDS-SR (via phone or mail) 
• PHQ-9 
• FIBSER (via phone or mail) 
• FACT-Hep 
• Toxicity Assessment 
 
Follow-up (every 12 weeks, via EMR review, patient visit or phone call) 
• Assessment of disease and survival status, treatment details 
• Tissue will be obtained from patients who undergo resection and stored in paraffin 
embedded blocks 
• Patients who undergo tumor resection will have blood samples drawn for plasma 
metabolites 1-3 month after surgery 
 
 

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11.1.2 Study Calendar  
 
 
 
Assessments 
 
Screening 
(within 28 
days 
before 
treatment) 
D1 
D85  
Wk2 
D15  
Wk 3 
(increase  
to 20mg) 
D225
Wk4 
D365
Wk6 
D505
Wk8 
D645
Wk 
10 
 
D71
Wk11 
(decrease 
to 10mg) 
D785
Wk12 
D855
Wk13 
(end of 
treatment) 
Wk 
25  
Follow-
up: 
every 3 
mos x 3 
years7  
1-3 mos 
after 
surgery (if 
applicable) 
Informed 
consent 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
/physical1 
√ 
 
 
 
 
 
 
 
 
 
√ 
 
 
 
ECOG 
performance 
status  
√ 
√ 
 
 
 
 
 
 
 
 
√ 
 
 
 
ECG 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study visits* 
 
√  
clinic  
√ 
phone 
√ 
clinic 
√ 
phone 
√ 
phone 
√ 
phone 
√ 
phone 
√ 
clinic 
√ 
phone 
√  
clinic 
√ 
phone 
 
 
Serum 
metabolites2  
 
√ 
 
 
 
 
 
 
 
 
 
 
√8 
Treatment 
escitalopram 
vs. placebo 
(10mg or 
20mg) per day3 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
 
Pill diary4
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
Toxicity 
assessment 
 
√ 
√6 
 
√6 
√6 
√6 
√6 
 
√6 
√ 
√6
 
 
QIDS-SR 
(Depression) 
 
√ 
√6 
 
√6 
√6 
√6 
√6 
 
√6 
√ 
√6
 
 
PHQ-9 Health 
Questionnaire 
 
√ 
√6 
 
√6 
√6 
√6 
√6 
 
√6 
√ 
√6 
 
 
FACT-Hep 
(Quality of 
Life) 
 
√ 
 
 
√,6 
√,6 
 
 
√6 
√,
√6
 
 

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FIBSER side 
effect 
questionnaire) 
  
√ 
√,6 
 
√6 
√6 
√6 
√6 
 
√6 
√,
√6
 
 
Tissue obtained 
if resection 
done 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
 
Disease/ 
survival 
status/treatment 
details 
 
 
 
 
 
 
 
 
 
 
√ 
√ 
√
 
 
1History must include a review of current medications.  Physical must include head and neck, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 
cognitive and cutaneous systems 
2Collect 30ml in three 10ml red top tubes prior to dosing. 
3Blinded escitalopram vs placebo is to be taken daily days 1 through 84 (10mg wks 1-2., 20mg wks 3-10, 10mg wks 11-12) unless dose reduction/drug 
discontinuation is required.  
4Diary is to be completed daily by patients and reviewed with clinical study staff during study visits to confirm compliance. Patients are required to come to the 
clinic on Days 15 and 71 to pick up drug supply and new pill diary.  Unused pills and final pill diary will be returned at the end of treatment visit (Day 85).   
5 +/- 7 days 
6QoL assessments and Toxicity assessment will be completed with clinical study staff over the phone or in person if the patient’s regular chemotherapy visit 
coincides with a study visit. 
7Patients will continue to be followed for survival for three years or until deceased (whichever occurs first).   
8Patients who undergo tumor resection will have repeat correlative plasma samples collected one to three months after surgery. 

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12.0  MEASUREMENT OF EFFECT  
Efficacy will be defined as the prevention of incidents of moderate or greater depression defined 
as a QIDS-SR score greater than 11 at 12 weeks. 
 
13.0     DATA REPORTING / REGULATORY CONSIDERATIONS  
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 
(Adverse Events: List and Reporting Requirements). 
 
13.1       Data Reporting  
The OnCore™ and Forte EDC Databases will be utilized, as required by the Case Comprehensive 
Cancer Center, to provide data collection for accrual entry. OnCore™ is a Clinical Trials 
Management System housed on secure servers maintained at Case Western Reserve University. 
OnCore™ has the capability to facilitate study setup, activation, tracking, reporting, data 
monitoring and review, and eligibility verification.   
 
The investigators are responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents must be completed in a neat, legible manner 
to ensure accurate interpretation of data. The investigators will maintain adequate case histories of 
study participants, including accurate case report forms (CRFs), and source documentation. 
 
Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study staff under the 
supervision of the investigator. All source documents and laboratory reports must be reviewed by 
the study team and data entry staff, who will ensure that they are accurate and complete. 
Unanticipated problems and adverse events must be reviewed by the investigator or designee.  
 
Data Capture Methods 
The University Hospitals Research Information System (REDCap) database will be used for this 
study to record clinical data and toxicity-related data. 
 
Types of Data 
Data will be maintained on paper source documents and entered into REDCap for data analysis. 
Captured data include patient medical history, laboratory values, treatment data and compliance, 
toxicity data, survival and outcome data, survey data, and radiographic data. 
 
Study Records Retention 
Data will be maintained for at least two years after closure of the study and final data analysis. 
 
13.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws. 
 
13.2.1   Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related procedures. The 
Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study as well as the 

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subject’s financial responsibility. Subjects must also be notified that they are free to discontinue 
from the study at any time. The subject should be given the opportunity to ask questions and be 
allowed time to consider the information provided.  
 
The original, signed written Informed Consent Form must be kept with the Research Chart in 
conformance with the institution’s standard operating procedures. A copy of the signed written 
Informed Consent Form must be given to the subject. Additionally, documentation of the 
consenting process should be located in the research chart. 
 
13.2.2   Subject Data Protection 
The study subjects will be assigned a unique study identification number that will be used on all 
study data forms, and other study records. Patient names, initials and/or hospital IDs will not be 
used as protocol identifiers. Randomization records will be maintained by the Seidman Cancer 
Center, Clinical Trials Unit Quality Assurance Team at a secure location at 6700 Euclid Ave. 
Cleveland, OH 44106. 
 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a subject 
must sign an authorization to release medical information to the sponsor and/or allow the sponsor, 
a regulatory authority, or Institutional Review Board access to subject’s medical information that 
includes all hospital records relevant to the study, including subjects’ medical history.  
 
13.2.3     Retention of records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of 
all documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence for as long as needed to comply with local, national and international regulations. 
No records will be destroyed until the Principal Investigator confirms destruction is permitted.  
 
13.2.4     Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform audits or 
inspections, including source data verification. The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to determine 
whether these activities were conducted, and data were recorded, analysed, and accurately reported 
according to the protocol, Good Clinical Practice (GCP), guidelines of the International 
Conference on Harmonization (ICH), and any applicable regulatory requirements.  For multi-
center studies, participating sites must inform the sponsor-investigator of pending audits.  
 
14.0  STATISTICAL CONSIDERATIONS  
14.1     Study Hypotheses 
The primary hypothesis is that the incidence of depression in patients with localized pancreatic 
and related cancer will be lower with treatment with escitalopram compared to placebo at 12 
weeks. 

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14.2    Analysis Plans 
The primary endpoint of the study is depression by QIDS at 12 weeks.  
 
Depression 
The primary outcome is moderate or greater depression defined as a QIDS-SR score greater 
than 11. All patients will have localized disease, but be stratified by extent of disease: 
resectable vs. unresectable, based on imaging and as determined by the PI Based on the 
Tumor Profile Assessment. Under Generalized Linear Model (GLM) framework, a 
modified Poisson model can be constructed as the working model to directly estimate the 
relative risk of depression at each measurement time through 12 weeks (Zou and Donner 
2013). Measurement time will be treated as a categorical/ordinal variable to allow for 
differing risk of depression in controls at each time point. The model will adjust for baseline 
QIDS-SR score as a continuous covariate and the stratification variable. Generalized 
Estimating Equation (GEE) will be used to account for correlation among the 6 repeated 
post-randomization measurements through month 3 for each participant. A time by 
randomization assignment interaction variable will be included to allow for estimation of 
the relative risk at each measurement time. The primary interest is to compare the two 
treatment groups at 12 weeks. This comparison will be performed at the one-sided 
alpha=0.10 level.   
 
Since the GEE estimates are only valid under the Missing At Random (MAR) assumption 
if the working correlation structure is correctly specified, missing dichotomous outcomes 
will be imputed using Multiple Imputation (MI) prior to analysis (Li et al 2006). Estimates 
using this method are consistent under the MAR assumption (Beunckens et al 2008).   
 
  
Analytical Plan for PHQ-9 Outcome 
PHQ-9 outcomes can be summarized into ordinal statistics or dichotomized variables, thus 
the same analytical procedure for QIDS outcomes can be adapted here. We expect the same 
statistical power for data analysis using a similar Generalized Linear Model (GLM) 
framework for depression risk estimation and correlation control using Generalized 
Estimating Equation (GEE). Therefore, detailed statistical power justification is omitted.  
Equivalence of Results 
Analyses using QIDS and PHQ-9 will be conducted separately. The results from them will 
be compared for equivalence of results purpose. The comparison will include directions of 
effective size, level of significance of the potential changes, and biological dispersion of 
estimations from both metrics.  
 
Quality of life 
The FACT-Hep will be utilized to assess quality of life at the pre-determined time intervals 
specified above. Longitudinal measurements of FACT-Hep scores will be modeled using 
mixed effects linear regression. Randomization assignment, time, and randomization by 
time interaction terms will be included in the model as fixed effects. An appropriate 

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correlation structure will be assumed for the residual covariance matrix to account for 
within-subject correlation. Groups will be compared with respect to average scores at 12 
weeks using a linear contrast of model parameters. Missing data will not be imputed for 
this analysis.  
 
Survival 
Overall survival will be measured from the date of randomization to date of death or last 
follow-up, and adjusted for staging. The distribution of survival time will be estimated 
using the Kaplan-Meier method, and randomization groups will be compared using a 
stratified log-rank test.   
 
The primary and secondary analyses will be performed on all randomized patients. Patients 
will be analyzed according to randomization assignment, regardless of the treatment 
actually received.   
 
Treatment failures 
Patients with high risk for suicide, suicide attempts, or a score of ≥ 16 points on the QIDS-
SR at 12 weeks will be considered “treatment failures” and will be provided referrals for 
more optimal depression treatment throughout the duration of the study.  Patient scores and 
adverse events will be reviewed by clinical study staff (RN or MD) within 24 hours of 
collecting information from patients to determine if additional action is needed per Section 
7.  Cases of suspected suicidal ideation will be reviewed within four hours as noted in 
Section 7, and study staff will immediately take action as appropriate upon review.  
14.3       Sample Size Considerations 
The primary objective of this study is to obtain preliminary evidence of efficacy of the treatment 
in preventing incident moderate or greater depression defined as a QIDS-SR score greater than 11 
at 12 weeks. Assuming 23 subjects per arm and a true rate of depression in the control arm of 40%, 
we have 80% power to detect a difference if the true rate in treatment arm is 13.8% using a one-
sided alpha of 0.10. Assuming an observed rate of 40% in the control arm, the upper limit of the 
80% confidence interval for the risk ratio ranges from 0.56 when the observed treatment arm rate 
is 10% to 1.09 when the observed treatment arm rate is 25%.  Any patient who has less than 65% 
compliance rate after four weeks of escitalopram/placebo (as determined during bi-weekly pill 
diary review) will be considered not evaluable and will be replaced.  Any patient who experiences 
a serious adverse event that requires discontinuation of study drug within the first four weeks of 
treatment will be considered not evaluable and will be replaced. 
To achieve a final sample size of 46 (23 per arm) at 12 weeks we will randomize 55 patients 
allowing for up to 15% attrition.  
Replacement Policy 
Patients will not be replaced.  Based on prior experience, we anticipate that we can comfortably 
accrue 36 patients per year and complete the study within 2 years.  

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14.4 
Evaluation of Safety 
In light of the well reported safety of escitalopram, there will be no statistical aspect to safety 
review. We will closely measure side effects as part of this clinical trial, but will not specifically 
have this as a secondary endpoint, since escitalopram has been studied extensively in patients 28, 
41-43, and even as a prophylactic antidepressant in the cancer population18. Standard toxicity 
recording will be performed through phone interviews at monthly intervals at a minimum, using 
the CTCAE 5.0 grading system. 
 

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35. 
Gusev Y, Riggins RB, Bhuvaneshwar K, et al. In silico discovery of mitosis regulation 
networks associated with early distant metastases in estrogen receptor positive breast 
cancers. Cancer Inform 2013;12:31-51. 
36. 
Moskovitz B, Ross M, Bolkier M, et al. The use of distilled water as an irrigating fluid in 
patients undergoing transurethral resection of the prostate. Eur Urol 1989;16:267-70. 
37. 
Huang YH, Peng W, Furuuchi N, et al. Delivery of Therapeutics Targeting the mRNA-
Binding Protein HuR Using 3DNA Nanocarriers Suppresses Ovarian Tumor Growth. 
Cancer Res 2016;76:1549-59. 
38. 
Spiegel D, Bloom JR, Kraemer HC, et al. Effect of psychosocial treatment on survival of 
patients with metastatic breast cancer. Lancet 1989;2:888-91. 
39. 
Boyd CA, Benarroch-Gampel J, Sheffield KM, et al. The effect of depression on stage at 
diagnosis, treatment, and survival in pancreatic adenocarcinoma. Surgery 2012;152:403-
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40. 
Kasper S, Lemming OM, de Swart H. Escitalopram in the long-term treatment of major 
depressive disorder in elderly patients. Neuropsychobiology 2006;54:152-9. 
41. 
Gupta VK, Park JO, Kurihara T, et al. Selective gene expression using a DF3/MUC1 
promoter in a human esophageal adenocarcinoma model. Gene Ther 2003;10:206-12. 
42. 
Maity N, Ghosal MK, Gupta A, et al. Clinical effectiveness and safety of escitalopram and 
desvenlafaxine in patients of depression with anxiety: a randomized, open-label controlled 
trial. Indian J Pharmacol 2014;46:433-7. 
43. 
Si T, Wang G, Yang F, et al. Efficacy and safety of escitalopram in treatment of severe 
depression in Chinese population. Metab Brain Dis 2017;32:891-901. 
44.       Polychroniou, P, Mayberg, H, Craighead, W, Rakofsky, J, Rivera, V, Haroon, E, Dunlap, 
B. Temporal Profiles and Dose-Responsiveness of Side Effects with Escitalopram and 
Duloxetine in Treatment-Naïve Depressed Adults. Behav Sci (Basel). 2018 Jul; 8(7): 
64.Published online 2018 Jul 17. doi: 10.3390/bs8070064 
   
 
 

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APPENDIX I 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade
Description 
Percent 
Description 
 
0 
 
Normal activity. Full active, able to carry 
on all pre-disease performance without 
restriction.  
 
100 
 
Normal, no complaints, no evidence 
of disease. 
 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
 
1 
Symptoms, but ambulatory. Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of 
a light or sedentary nature (e.g., light 
housework, office work). 
 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
 
2 
In bed < 50% of the time.  Ambulatory 
and capable of all self-care, but unable to 
carry out any work activities. Up and 
about more than 50% if waking hours. 
 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
 
50 
Requires considerable assistance 
and frequent medical care. 
 
3 
In bed > 50% of the time.  Capable of 
only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
 
40 
 
Disabled, requires special care and 
assistance. 
 
30 
 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care. Totally 
confined to bed or chair. 
 
20 
Very sick, hospitalization indicated. 
Death not imminent.  
 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead 

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APPENDIX II 
 
SUBJECT PILL DIARY 
Subject Name ________________________Protocol # CASE6220  Subject Study ID __________ 
Weeks #: 1 and 2   (Days 1-14) 
INSTRUCTIONS FOR THE SUBJECT: 
1. You will take one 10mg capsule of escitalopram/placebo each day.  You should take your pill in the morning or evening.  
You may take the pill with or without food, as you wish. 
 
   2.  Record the date, the number of tablets you took, and what time you took them. 
   3.  If you have any comments or side effects please record them in the “Comments” column below.  
   4. If you have bleeding, please record in the “Bleeding” column below. 
   5.  Please bring your pill bottle and this form to your physician when you come for your next appointment.   
       6.  Please sign your name at the bottom of the diary. 
Date 
Day 
# of 10mg 
pills and time 
taken  
 
Comments 
Bleeding 
Type of bleeding: nose bleed, cut that won’t 
stop bleeding, bruising, blood in urine, red or 
black stool, Other (please describe) 
State if:  Mild, Moderate, Severe 
 
(Wk 1) 1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
(Wk 2) 8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
Subject’s Signature: ________________________________________ Date: ___________ 
 
 
 
 

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SUBJECT PILL DIARY 
Subject Name ______________________Protocol # CASE6220     Subject Study ID __________ 
Weeks #: 3 through 10 (Days 15 through 70) Page 1 
INSTRUCTIONS FOR THE SUBJECT: 
   1.  You will take two 10mg capsules of escitalopram/placebo each day.  You should take your pill in the morning or evening.  
You may take the pill with or without food, as you wish. 
   2.  Record the date, the number of tablets you took, and what time you took them. 
   3.  If you have any comments please record them in the “Comments” column below. 
   4. If you have bleeding, please record in the “Bleeding” column below. 
   5.  Please bring your pill bottle and this form to your physician when you come for your next appointment.   
      6.  Please sign your name at the bottom of the diary. 
Date 
Day 
# of 10 mg 
pills and 
time taken 
 
Comments 
Bleeding 
Type of bleeding: nose bleed, cut that won’t 
stop bleeding, bruising, blood in urine, red or 
black stool, Other (please describe) 
State if:  Mild, Moderate, Severe 
 
(Wk 3) 15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
(Wk 4) 22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
(Wk 5) 29 
 
 
 
 
30 
 
 
 
 
31 
 
 
 
 
32 
 
 
 
 
33 
 
 
 
 
34 
 
 
 
 
35 
 
 
 
 
(Wk 6) 36 
 
 
 
 
37 
 
 
 
 
38 
 
 
 
 
39 
 
 
 
 
40 
 
 
 
 
41 
 
 
 
 
42 
 
 
 
Subject’s Signature: _________________________________________ Date: ___________ 
 

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SUBJECT PILL DIARY 
 
Subject Name ______________________Protocol # CASE6220     Subject Study ID __________ 
 
Weeks #: 3 through 10 (Days 15 through 70) Page 2 
 
INSTRUCTIONS FOR THE SUBJECT: 
   1.  You will take two 10mg capsules of escitalopram/placebo each day.  You should take your pill in the morning or evening.  
You may take the pill with or without food, as you wish. 
   2.  Record the date, the number of tablets you took, and what time you took them. 
   3.  If you have any comments please record them in the “Comments” column below. 
   4. If you have bleeding, please record in the “Bleeding” column below. 
   5.  Please bring your pill bottle and this form to your physician when you come for your next appointment.   
      6.  Please sign your name at the bottom of the diary. 
Date 
Day 
# of 10 mg 
pills and 
time taken 
 
Comments 
Bleeding 
Type of bleeding: nose bleed, cut that won’t 
stop bleeding, bruising, blood in urine, red or 
black stool, Other (please describe) 
State if:  Mild, Moderate, Severe 
 
(Wk 7) 43 
 
 
 
 
44 
 
 
 
 
45 
 
 
 
 
46 
 
 
 
 
47 
 
 
 
 
48 
 
 
 
 
49 
 
 
 
 
(Wk 8) 50 
 
 
 
 
51 
 
 
 
 
52 
 
 
 
 
53 
 
 
 
 
54 
 
 
 
 
55 
 
 
 
 
56 
 
 
 
 
(Wk 9) 57 
 
 
 
 
58 
 
 
 
 
59 
 
 
 
 
60 
 
 
 
 
61 
 
 
 
 
62 
 
 
 
 
63 
 
 
 
 
(Wk 10) 64 
 
 
 
 
65 
 
 
 
 
66 
 
 
 
 
67 
 
 
 
 
68 
 
 
 
 
69 
 
 
 
 
70 
 
 
 
Subject’s Signature: ________________________________________ Date: ___________ 

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SUBJECT PILL DIARY 
 
Subject Name ________________________Protocol # CASE6220  Subject Study ID __________ 
 
 
Weeks #: 11 and 12   (Days 71-84) 
INSTRUCTIONS FOR THE SUBJECT: 
1. You will take one 10mg capsule of escitalopram/placebo each day.  You should take your pill in the morning or evening.  
You may take the pill with or without food, as you wish. 
   2.  Record the date, the number of tablets you took, and what time you took them. 
   3.  If you have any comments or side effects please record them in the “Comments” column below.  
   4. If you have bleeding, please record in the “Bleeding” column below. 
   5.  Please bring your pill bottle and this form to your physician when you come for your next appointment.   
       6.  Please sign your name at the bottom of the diary. 
Date 
Day 
# of 10mg 
pills and 
time taken 
 
Comments 
Bleeding 
Type of bleeding: nose bleed, cut that won’t 
stop bleeding, bruising, blood in urine, red or 
black stool, Other (please describe) 
State if:  Mild, Moderate, Severe 
 
(Wk 11) 71 
 
 
 
 
72 
 
 
 
 
73 
 
 
 
 
74 
 
 
 
 
75 
 
 
 
 
76 
 
 
 
 
77 
 
 
 
 
(Wk 12) 78 
 
 
 
 
79 
 
 
 
 
80 
 
 
 
 
81 
 
 
 
 
82 
 
 
 
 
83 
 
 
 
 
84 
 
 
 
Subject’s Signature: ________________________________________ Date: ___________ 
 
 
 
 
 
 
 

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APPENDIX III 
Clinical Medication Compliance Form for Investigational Studies
 

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APPENDIX IV 
QIDS-SR16 
 
 

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APPENDIX  V 
Fact –Hep (Version 4) 
 
 
 
 

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APPENDIX VI 
FIBSER Scale 
 
 

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APPENDIX VII 
 

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