Conditions: Sperm DNA Fragmentation Infertility, Male
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 75
Healthy volunteers: yes

Brief summary:
Double-blind placebo-controlled randomized trial of daily escitalopram for 6 weeks in healthy men with normal semen analyses and no psychiatric history of depression, bipolar, mania or suicidal ideation. Hormone profiles, semen analysis, sperm DNA fragmentation, and sexual function will be measured at baseline, after 6 weeks of therapy, and 4 weeks after discontinuation of therapy (10 weeks into study).

Detailed description:
SSRI medications, specifically escitalopram is a very commonly prescribed medication among men of reproductive age. Significant evidence exists that they may be harmful for paternal fertility potential in both animal and human studies. However, high quality data is lacking, particularly among commonly used SSRI's such as escitalopram. As such, it is important to properly evaluate the potential effect of escitalopram in a randomized placebo controlled fashion. Results will be important in guiding urologists, psychiatrists and family practitioners regarding discussion surrounding SSRI use in their patients interested in fertility.

Arms:
arm 1: 10mg by mouth daily for 6 weeks arm 2: Matched placebo control by mouth for 6 weeks.

Interventions: intervention 1: Escitalopram intervention 2: Placebo
Intervention descriptions: intervention 1: 10mg by mouth daily for 6 weeks intervention 2: matched placebo control by mouth for 6 weeks

Protocol document:
Prot_SAP_000.pdf: 
Study Title: Impact of Escitalopram on Sperm DNA Fragmentation 
NCT number: NCT03527043 
Date: 05/09/2023 


TITLE: SSRI Impact On Sperm Quality: A Randomized Placebo Controlled Trial 
IRB Protocol #: 1608017504   
IND/IDE # (if applicable): IND exempt 
Version Date:  May 9, 2023
Principal Investigator: 
Jonathan Gal, MD 
525 East 68th Street, Starr 900 Pavillion 
New York, NY 10065 
jog4018@med.cornell.edu 
Co-Investigators: 
Peter Schlegel, MD 
525 East 68th Street, Starr 946 Pavillion 
New York, NY 10065   
T 212-746-
5491   
F 212-746-8425  
pnschleg@med.cornell.edu   
Nahid Punjani, MD 
Jessica Marinaro, MD 
525 East 68th Street, Starr 900 Pavillion 
525 East 68th Street, Starr 900 Pavillion 
New York, NY 10065  
New York, NY 10065 
917-755-1702
jam9375@med.cornell.edu 
nap4001@med.cornell.edu
Caroline Kang, MD, PhD 
1300 York Avenue A900 
New York, NY 10065  
cak4005@med.cornell.edu 
Study Coordinator/Data Managers: 
Thomas Flynn 
525 E 68th St K901 New York, NY 10065 
thf3001@med.cornell.edu   
Akeem Noziere 
525 E 68th St New York, NY 10065 
212.746 5454 
akn4001@med.cornell.edu 
Grace Tan  
525 East 68th Street  
grt2008@med.cornell.edu 


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Statistician:           
 
Clara Oromendia   
402 East 67th Street,   
New York, NY 10065 
646-962-8009 
mco2004@med.cornell.edu     
 
 


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Responsible Research Nurse: NA  
 
Participating Sites:  Weill Cornell Medical College, Department of Urology.   
 
Confidentiality Statement 
   
This document is confidential and is to be distributed for review only to investigators, 
potential investigators, consultants, study staff, and applicable independent ethics 
committees or institutional review boards. The contents of this document shall not be 
disclosed to others without written authorization from WCM.   


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List of Abbreviations    
   
   
   
 
AE   
Adverse Event   
 
CFR   
Code of Federal Regulations   
 
CRF   
Case Report Form   
 
CTSC   
Clinical Translational Science Center   
 
DSMB   
Data Safety Monitoring Board   
 
DSMP   
Data Safety Monitoring Plan   
 
FDA   
Food and Drug Administration   
 
GCP   
Good Clinical Practice   
 
HIPAA   
   Health Insurance Portability and Accountability Act of 1996  
 
HRBFA   
Human Research Billing Analysis Form   
 
HUD   
Humanitarian Use Device   
 
ICF   
Informed Consent Form   
 
IIEF   
International Index of Erectile Function   
 
IDE   
Investigational Device Exemption   
 
IND   
Investigational New Drug   
 
IRB   
Institutional Review Board   
 
PHI   
Protected Health Information   
 
PI   
Principal Investigator   
MSHQ   
 
        Male Sexual Health Questionnaire   
REDCap    
        Research Electronic Data Capture   
 
SAE   
Serious Adverse Event   
 
SUSAR   
Suspected Unexpected Serious Adverse Reaction   
 
UAP   
Unanticipated Problem   
 
WCM   
Weill Cornell Medicine  
 


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Protocol Summary 
  
Full Title:                   
SSRI Impact On Sperm Quality: A Randomized Placebo  
Controlled Trial   
Short Title:   
SSRI Impact on Sperm   
Clinical Phase:   
II   
Principal Investigator:   
Jonathan Gal, MD 
Sample Size:   
N=45 per arm. 2 arms, placebo and study drug. Thus, N=90 in  
                                             total.   
Accrual Ceiling:   
Samples size required is 45 per arm (90 total), however, 
anticipating a 20% attrition or non-eligibility rate, 108 will be 
screened and consented.   
Study Population:   
Healthy men aged 18-65 years of age, with normal semen 
analyses (semen analyses with at least 5 million sperm) and no 
psychiatric history of depression, bipolar, mania or suicidal 
ideation. These men must be willing to engage in at least 
weekly sexual activity, with a partner or alone for the duration 
of the 10- week study   
Accrual Period:   
We anticipate accrual will take 1 year with 9 patients per 
month.  
   
Study Design:   
Double-blind placebo-controlled randomized trial of daily 
escitalopram for 6 weeks in healthy men. Hormone profiles, 
semen analysis and sperm DNA fragmentation, and sexual 
function will be measured at baseline, after 6 weeks of 
therapy, and 4 weeks after discontinuation of therapy (10 
weeks into study).   
Study Duration:   
Total length for each subject will be 10 weeks. This includes 
Baseline, 6-week assessment and 10 week assessment. The full 
study will be 78 months long, from June 2017 through 
December 31, 2028.   
Study Agent/   
Intervention Description:   Escitalopram 10mg by mouth daily for 6 weeks or a matched 
placebo control by mouth for 6 weeks.   
   
Primary Objective:   
The primary objective of this analysis is to determine the 
negative effect of Escitalopram on sperm DNA fragmentation. 
Specifically, to determine the proportion of patients who 
convert from normal to abnormal DNA fragmentation levels as   


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measured by TUNEL (abnormal defined as >7%) following 6 
weeks of escitalopram therapy.   
  Secondary Objectives:   
Secondary objectives will include assessing absolute change in 
DNA fragmentation via TUNEL assay from baseline to 6 weeks 
and 10 weeks. Other objectives include: changes in semen 
analysis parameters (motility, progressive motility, viability, 
and concentration) by bright field microscopy from baseline to 
6 and 10 weeks.   
Exploratory Objectives:   
  
Exploratory objectives include assessing for change in serum 
testosterone, LH, FSH, estrogen, prolactin, as well as sexual and 
erectile function using the International Index for Erectile 
Function (IIEF), Male Sexual Health Questionnaire (MSHQ) 
questionnaires from baseline to 6 and 10-week time points.   
Endpoints:   
The primary endpoint will be the proportion of subjects treated 
with Escitalopram that develop an abnormal TUNEL (>7%) 
following 6 weeks of therapy compared to placebo subjects.   
   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


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SCHEMA   
  


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Table of Contents   
1. 
STUDY OBJECTIVES ............................................................................. 6  
1.1 
Primary Objectives ......................................................................6  
1.2 
Secondary Objectives ...................................................................6  
1.3 
Exploratory Objectives ................................................................. 6  
2. 
BACKGROUND ................................................................................... 6  
2.1 
Disease.....................................................................................6  
2.2 
Investigational Agent or Device ........................................................8  
2.3 
Rationale ..................................................................................8   
2.4 
Risk/Benefit Assessment ............................................................... 8   
3. 
SUBJECT SELECTION ........................................................................... 9   
3.1 
Study Population ........................................................................ 9    
3.2 
Inclusion Criteria ........................................................................ 9    
3.3 
Exclusion Criteria ....................................................................... 9  
4. 
REGISTRATION PROCEDURES ................................................................ 10   
4.1 
Patient Registration ................................................................... 10   
5. 
STUDY PROCEDURES .......................................................................... 10   
5.1 
Schedule of Evaluations ............................................................... 11   
5.1.1 
Screening Visit................................................................ 11   
5.1.2 
Treatment Phase ............................................................ 11  
5.1.2.1 Visit 1 (baseline)………………………………………………………………………. 11  
5.1.2.2 Telephone call after 1 week of medication…………………………… 11  
5.1.2.3 Visit 2: 6 weeks (± 7 days) ……………………………………………………… 12  
5.1.2.4 Visit 3: 10 weeks (± 7 days)……………………………………………………. 12  
5.2 
Treatment Administration ............................................................ 12 
5.3 
General Concomitant Medication and Supportive Care Guidelines ............. 12   
5.4 
Duration of Therapy and Criteria for Removal from Study ...................... 12   
5.5 
Duration of Follow Up ................................................................. 13   
6. 
DOSING DELAYS/DOSE MODIFICATIONS .................................................... 13   
7. 
PHARMACEUTICAL INFORMATION ........................................................... 13   
7.1 
Investigational Agent .................................................................. 13  
7.2 
Availability .............................................................................  13   
7.3 
Agent Ordering ......................................................................... 14   
7.4 
Agent Accountability .................................................................. 14   
8. 
CORRELATIVE/SPECIAL STUDIES ............................................................ 14   
8.1 
Laboratory Correlative Studies ...................................................... 14   
8.1.1 
(Title – Laboratory Correlative Study #1) ................................ 14   
8.2 
Special Studies ......................................................................... 14   
8.2.1 
(Title – Special Correlative Study #1) ..................................... 14  
9. 
MEASUREMENT OF EFFECT ................................................................... 14   
9.1 
Response Criteria ...................................................................... 14  
9.2 
Duration of Response (modify as necessary) ....................................... 14  
9.3 
Progression-Free Survival (if applicable) ........................................... 14   
9.4 
Other Response Parameters..........................................................  14   


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10. DATA REPORTING/REGULATORY CONSIDERATIONS ...................................... 15   
10.1 
Data Collection ......................................................................... 15   
10.1.1 
REDCap .......................................................................  15   
10.2 
Regulatory Considerations ............................................................ 15   
11. STATISTICAL CONSIDERATIONS .............................................................. 15   
11.1 
Study Design/Endpoints ............................................................... 15  
11.2 
Sample Size/Accrual Rate ............................................................ 16 
11.3 
Stratification Factors .................................................................  16   
11.4 Analysis of Endpoints .....................................................................  16   
11.4.1 
Analysis of Primary Endpoints ............................................. 16   
11.4.2 
Analysis of Secondary Endpoints .......................................... 16  
11.5 Interim Analysis ............................................................................ 17   
11.6 Reporting and Exclusions ................................................................. 17    
11.6.1 Evaluation of toxicity..........................................................  17   
11.6.2 Evaluation of response.......................................................... 17   
12. ADVERSE EVENT REPORTING REQUIREMENTS ............................................. 17  
12.1 
Adverse Event Definition ............................................................. 17   
12.1.1 
Investigational Agent or Device Risks ..................................... 17   
12.1.2 
Adverse Event Characteristics and Related Attributions ............... 18   
12.1.3 
Recording of Adverse Events ............................................... 18   
12.1.4 
Reporting of AE to WCM IRB ................................................ 18   
12.2 
Definition of SAE ....................................................................... 18   
12.2.1 
Reporting of SAE to IRB ..................................................... 19   
12.2.2 
Reporting of SAE to FDA……………………………………………………………………. 19  
12.2.3 
Reporting of SAE to Insert Pharmaceutical Company Name ........... 19   
 
12.4  
AE/SAE Follow Up ..................................................................... 19   
13. DATA AND SAFETY MONITORING PLAN (DSMP) ............................................ 19 
REFERENCES ......................................................................................... 21   
APPENDIX A .......................................................................................... 22   
  
 
 
 
 
 
 
 
 
 
 
 


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1. Study Objectives   
To determine if 6 weeks of Escitalopram therapy increases DNA fragmentation and decreases sperm 
quality compared to placebo.   
   
1.1 Primary Objectives   
   
To assess the proportion of patients who convert from normal to abnormal DNA 
fragmentation levels as measured by TUNEL (abnormal defined as >7%) following 6 weeks 
of Escitalopram therapy.   
   
1.2 Secondary Objectives   
   
To assess the proportion of patients who convert from abnormal to normal DNA fragmentation 
levels as measured by TUNEL (abnormal defined as >7%) 4 weeks after discontinuing 6 weeks 
of Escitalopram therapy (10 week visit vs 6 week visit). Other objectives include to assess the 
absolute change in DNA fragmentation via TUNEL assay from baseline to 6 weeks and 10 
weeks. Other objectives include: changes in semen analysis parameters (motility, progressive 
motility, viability, and concentration) by bright field microscopy from baseline to 6 and 10 
weeks.   
   
1.3 Exploratory Objectives   
   
To assess for change in serum testosterone, LH, FSH, estrogen, and prolactin from study 
baseline to 6 week duration. Further, to assess sexual and erectile function using the IIEF, 
MSHQ questionnaires from baseline to 6 weeks of treatment and after 4 weeks of 
discontinuation of therapy (10-weeks total study time).   
   
  
2.   
Background   
   
2.1 Disease   
   
In an early series, 2 patients initially on antidepressants with infertility were found to have 
improved semen analysis (SA) parameters 1-2 months following cessation of therapy. In the 
first patient taking citalopram, he had marked oligospermia and 1% motility; 1 month after 
cessation of citalopram, his SA parameters were normal. He was then started on bupropion, 
which induced a decrease in concentration to 21million/ml, 10% motility, and he had a high 
DNA fragmentation of 76%. One month following bupropion cessation, his SA improved with 
75% motility, concentration of 41million/ml which was stable at 2-months post cessation of 
citalopram. The second patient was taking sertraline and found to have a concentration of 
20,000 with no motile sperm. 3 months after cessation of sertraline, all parameters were normal 
with 40 million total motile sperm. With bupropion added after this, then venlafaxine for 
refractory symptoms, SA revealed no motile sperm. One month following cessation of these 
medications SA results again normalized1. Similarly, a report of a 30 year old man on 


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citalopram discontinued the SSRI with improvement of concentration, motility, progressive 
motility and normal morphology at the first time point 4 months following cessation of SSRI2.   
   
In a cohort-control study, 74 fertile but depressed men on SSRI’s were compared to 44 
healthy fertile volunteers. Semen analyses were performed revealing sperm concentration of 
61.2+/-11.4 million vs 186+/- 31.4 million in SSRI and controls respectively, 48.2%+/-4.6% 
vs 66.2%+/-4.4%, normal morphology in 19% vs 52.3%, DNA fragmentation rate by SCSA of 
43.2% +/-11.4% vs 21.4% +/-10.6% respectively. A variety of SSRI’s were used by the 
patient population including citalopram, escitalopram, fluoxetine, paroxetine, sertraline and no 
differential correlations were made by SSRI type. A correlation was also present between 
SSRI duration and effect on SA parameters3.   
   
In a prospective series of 35 patients, healthy men provided a SA prior, during and 1 month 
after a 5-week duration of paroxetine. DNA fragmentation using TUNEL was measured at 
baseline and after 4 weeks of paroxetine; TUNEL was higher on paroxetine (30.3%) 
compared to baseline (13.8%), with an associated OR of 9.33 (95% CI, 2.3-37.9). SA 
parameters such as volume, concentration, motility, and morphology did not change with 
therapy. Testosterone decreased form 844ng/dL to 605ng/dL4. Another series of 25 patients 
with premature ejaculation (PE) received a 12 week intervention of escitalopram. After 3 
months of therapy, sperm concentration (68+/-27.1 vs 26.4 +/-16.1 million), motility 
(58.2+/5.2 vs 23.4+/-7.5%), and normal morphology (19.2+/-4.8 vs 7.3+/-3.3%) decreased 
compared to normal values5.   
   
In a single blinded clinical trial of 60 men with premature ejaculation, men were randomized 
into sertraline or behavioral therapy. Men in the sertraline group demonstrated decreased sperm 
concentration (118.61+/-54.47 vs 147.47+/-75.73 million/ml) compared to baseline, as well as 
reduced normal morphology (24.80+/-3.28 vs 44.19+/-3.94 %) and had higher DNA 
fragmentation (31.10+/-3.22 vs 15.73+/-3.50%) using the SCD method6.   
   
SSRI & Sperm Effects in the Lab   
SSRI’s have been postulated to potentially impair spermatogenesis through central actions as 
well as exerting effects on spermatozoa. SSRI’s have been demonstrated in a rat model to 
induce secretion of prolactin in female rats prior to ovulating due to inhibition of dopamine7. 
A human study demonstrated that fluoxetine potentiates a 5-HT induced increase in plasma 
cortisol and prolactin secretion among those with depression or OCD8. Hyperprolactinemia is 
thought to decrease GnRH secretion via negative feedback, leading to decreased LH & FSH 
secretion from the anterior pituitary, which are integral in promoting and maintaining 
spermatogenesis9.   
   
SSRI’s have also been demonstrated to bind sulfhydryl groups, which exist on spermatozoa10. 
This may have implications in sperm capacitation because sulfhydryl carrying proteins have 
been shown to be important during the process of sperm capacitation11. An in vitro experiment 
exposed semen to varying concentrations of SSRI’s, each fluoxetine, sertraline, fluvoxamine, 
paroxetine and citalopram demonstrated spermicidal activity12. Mice given citalopram doses 


Protocol 1608017504  
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also demonstrated increased DNA fragmentation among sperm13. Mice given fluoxetine in 
escalating doses demonstrated decreased sperm count and motility as well as increased sister-
chromatid exchanges14. Rats given fluoxetine for 60 days demonstrated decreased sperm 
counts, motility, testicular weights, decreased testosterone and FSH levels15.   
   
2.2 Investigational Agent or Device   
   
Escitalopram is commonly used as an antidepressant and anxiolytic. Dosage is between 10 
and 20mg daily16. The effects of escitalopram on sperm and fertility are largely unknown, but 
limited data available is mentioned above. Risks and side effects related to Escitalopram 
include: nausea (17%), sweating (8%), diarrhea (7%), insomnia (7%), somnolence (5%), 
erectile dysfunction (5%), dry mouth (5%), rhinitis (5%), upper respiratory tract infections. 
The rate of withdrawal of Escitalopram is 17.3%18. Common symptoms of withdrawal of 
similar SSRI type drugs include: flu-like symptoms, fatigue, weakness, tiredness, headache, 
tachycardia, dyspnea, gait instability, ataxia, dizziness, light-headedness, vertigo, paresthesia, 
and electric shock sensations.  Withdrawal symptoms may last days to weeks19.  
Antidepressants of the SSRI class have been shown to increase the risk of suicidal attempts 
among depressed patients20. Escitalopram is absolutely contraindicated in combination with 
the use of monoamine oxidase inhibitors (MAOIs)16.   
 
Lexapro (Escitalopram) is an FDA approved drug that is being used off-label for research purposes 
to investigate effects on sperm quality in healthy men with no depression. As no changes in labelling 
are being requested (ie. no change in dose, route of administration, or population) researchers are 
requesting an IND exemption. 
 
  
2.3 Rationale   
SSRI medications, specifically escitalopram is a very commonly prescribed medication 
among men of reproductive age. Significant evidence exists that they may be harmful for 
paternal fertility potential in both animal and human studies. However, high quality data is 
lacking, particularly among commonly used SSRI’s such as escitalopram. As such, it is 
important to properly evaluate the potential effect of escitalopram in a randomized placebo 
controlled fashion. Results will be important in guiding urologists, psychiatrists and family 
practitioners regarding discussion surrounding SSRI use in their patients interested in fertility.   
   
2.4 Risk/Benefit Assessment   
Risks to the subjects largely include side effects of Escitalopram as well as the potential for 
withdrawal symptoms. Side effects include: nausea (17%), sweating (8%), diarrhea (7%), 
insomnia (7%), somnolence (5%), erectile dysfunction (5%), dry mouth (5%), rhinitis (5%), 
upper respiratory tract infections. Withdrawal symptoms include: flu-like symptoms, fatigue, 
weakness, tiredness, headache, tachycardia, dyspnea, gait instability, ataxia, dizziness, 
lightheadedness, vertigo, paresthesia and electric shock sensations. Withdrawal symptoms may 
last days to weeks19. Antidepressants of the SSRI class, like Escitalopram, have been shown to 
increase the risk of suicidal attempts among depressed patients20. Other risks to subject are 


Protocol 1608017504  
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minimal and include discomfort and potential bruising associated with venipuncture for serum 
hormone testing.   
  
The potential benefit to the subject includes the financial stipend per each study visit and the 
benefit of a fertility evaluation at no cost to the patient. More significantly, the benefit in 
knowledge will contribute the highest quality data in shaping care in future patients and clinical 
care pathways and guidelines. SSRI’s and specifically Escitalopram are very commonly used 
among men of reproductive ages. Thus, these results may help physicians and care providers 
appropriately counsel couples who may be taking antidepressants such as Escitalopram 
regarding the potential risks. These findings will be published in an internationally accessible 
journal to help shape care globally.   
   
  
3.   
Subject Selection   
3.1 Study Population   
Healthy men aged 18-65 years of age, with normal semen analyses, or semen analyses with at 
least 5 million sperm, with no psychiatric history of depression, bipolar, mania, or suicidal 
ideation. These men must be willing to engage in at least weekly sexual activity, with a partner 
or alone for the duration of the 10-week study.   
   
3.2 Inclusion Criteria   
1. Healthy men aged 18-65 years of age   
2. Normal semen analyses, or semen analyses with at least 5 million sperm   
3. Willing to engage in at least weekly sexual activity, with a partner or alone for the duration of 
the 10-week study   
   
3.3 
Exclusion Criteria   
1. Azoospermia or severe oligospermia   
2. Presently attempting to conceive pregnancy   
3. Sexual dysfunction preventing ability to provide semen analysis throughout study or engage in 
weekly sexual activity   
4. Current psychiatric disorder including: bipolar, mania, depression, generalized anxiety, social 
phobia, panic attacks, obsessive compulsive disorder, and schizophrenia.   
5. Family history of bipolar disorder, or suicide (including 2nd degree relatives)  
6. Present use of psychotropic agents (prescription or herbal) or anticonvulsants   
7. Use of sleeping pills.   
8. Alcohol consumption greater that 2oz/day   
9. Use of illicit drugs   
9. Inability to read, follow instructions or complete questionnaires in English.   
10. Use of hormonal medications in past 3 months (androgens, androgen blockade, anabolic steroids, 
estrogens, herbal)   
11. History of chemotherapy or pelvic radiation in past 12 months   
12. Use of Monoamine Oxidase inhibitors (MAOI) or tricyclic antidepressants (TCA) within 14 days   
13. Liver disease   


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4.   
Registration Procedures   
  
4.1 Patient Registration   
   
Patients will be centrally registered with the Office of Billing Compliance. To register a patient, 
submit the following documents via the JIRA Registration Process:   
   
• 
Legible copy of the HRBAF   
• 
First and last page of signed informed consent form   
   
Registration must be completed within 24 hours of the signing of informed consent.   
   
 
  
5.   
Study Procedures   
   
Healthy subjects will be recruited from internet sources and study flyers. Inclusion and exclusion 
criteria will be screened if agreed. Eligible subjects will be brought into the clinic for a baseline 
assessment. In short, patients will be given 6 weeks of Escitalopram at baseline and will be evaluated 
at the end of the treatment. They will again be evaluated after 4 weeks of discontinuation (week 10).   
   
At baseline, subjects will be consented, interviewed for past medical history, and randomly assigned 
to Escitalopram or placebo treatment groups in a 1:1 ratio using a computer-generated randomization 
scheme developed by the study statistician. Subjects will be given a 6-week supply of their study 
drug which they have been assigned to. They will then have serum testing for testosterone, estrogen 
and prolactin. Semen specimen will also be collected to perform a semen analysis, and TUNEL 
assay. Subjects will also complete IIEF and MSHQ questionnaires. Subjects will complete the Ask 
Suicide-Screening Questionnaire – Suicide Risk Screening Tool to establish a baseline for suicide 
ideation.  
 
At 1-week, subjects will be called to review adverse events and complete the Ask Suicide-Screening 
Questionnaire – Suicide Risk Screening Tool.  
   
At 6-weeks, subjects will have just completed their 6-week duration of study drug (Escitalopram or 
placebo) given at the baseline visit. Subjects will be interviewed for adverse events or 
signs/symptoms of withdrawal, suicide ideation, and any left-over pills will be counted. Subjects 
will undergo serum testing for LH, FSH, testosterone, estrogen and prolactin. Semen specimen will 
also be collected to perform a semen analysis, and TUNEL assay. Subjects will also complete IIEF 
and MSHQ questionnaires. Subjects will be asked questions from the standardized Ask Suicide-
Screening Questionnaire – Suicide Risk Screening Tool to screen for suicide ideation.  
   
At 10-weeks, subjects will be interviewed for adverse events or signs/symptoms of withdrawal and 
suicide ideation. Subjects will undergo serum testing for testosterone, estrogen and prolactin. Semen 
specimen will also be collected to perform a semen analysis, and TUNEL assay. Subjects will once 
again complete IIEF and MSHQ questionnaires. Subjects will be asked questions from the 


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standardized Ask Suicide-Screening Questionnaire – Suicide Risk Screening Tool to screen for suicide 
ideation.   
   
  
  
  
  
5.1 Schedule of Evaluations   
Table 1. Schedule of trial events   
  
Baseline   
Wk 1   
Wk 6   
Wk 10   
Drug Administration   
X   
  
  
  
Informed consent   
X   
   
   
   
Demographics   
X   
   
   
   
Medical history   
X   
   
   
   
Serum (testosterone, Estradiol, 
Prolactin, LH, FSH)   
X   
   
X   
   
Semen Analysis   
X   
   
X   
X   
TUNEL Assay   
X   
   
X   
X   
Compliance (pill counting)   
   
   
X   
   
Adverse Events Interview   
   
X   
X   
X   
IIEF & MSHQ Questionnaires   
X   
   
X   
X   
Ask Suicide-Screening 
Questionnaire – Suicide Risk 
Screening Tool 
X 
X 
X 
X 
   
5.1.1 Screening Visit   
   
Screening will take place over the telephone.   
• 
Medical, Psychiatric, Fertility history   
• 
Medication history   
• 
Inclusion and Exclusion Criteria will be reviewed   
• 
Study overview provided.   
  
5.1.2 Treatment Phase   
This section will list all of the necessary study procedures by visit day.   
   
5.1.2.1 Visit 1 (baseline)   
• 
Review of inclusion & exclusion Criteria   


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• 
Informed Consent   
• 
Serum Testosterone, Estrogen, Prolactin, LH, FSH   
• 
Semen analysis, Sperm TUNEL assay   
• 
MSHQ & IIEF questionnaires   
• 
Medical History assessing for exclusion criteria & contraindications to 
Escitalopram   
   
 
  
5.1.2.2  Telephone call after 1 week of medication   
• 
Assess for medication side effects and suicide ideation   
 
  
5.1.2.3  Visit 2: 6 weeks (± 7 days)   
• 
Interview for adverse events, suicide ideation, and pill count   
• 
Serum Testosterone, Estrogen, Prolactin, LH, FSH   
• 
Semen analysis, Sperm TUNEL assay   
• 
MSHQ & IIEF questionnaires   
   
 
  
5.1.2.4  Visit 3: 10 weeks (± 7 days)   
• 
Interview for adverse events, suicide ideation, and signs or symptoms of withdrawal   
• 
Semen analysis, Sperm TUNEL assay   
• 
MSHQ & IIEF questionnaires   
  
  
 
  
5.2  Treatment Administration   
   
Treatment will be administered on an outpatient basis. Reported adverse events and potential risks 
are described in Section 7. Appropriate dose modifications for Investigational agent are described in 
Section 6.   
   
Patients will receive 1 bottle of study pills. These pills will either be Escitalopram 10mg pill, or a 
matched placebo. A complete supply of: 2 pills daily for 4 weeks and 1 pill daily for the final 2 
weeks (week 5 & 6) will be provided to each subject. Escitalopram may be taken with or without 
food.   
   
 
  
5.3  General Concomitant Medication and Supportive Care Guidelines   
   
Escitalopram is absolutely contraindicated in patients taking MAOi’s. Other agents patients will be 
warned to avoid include those that may increase SSRI toxicity: alcohol, St. John’s wort, 
pseudoephedrine, zolpidem, sibutramine, lithium and diuretic type medications such as furosemide 
or hydrochlorothiazide. These may lead to elevated serotonin levels and risk of serotonin syndrome. 
Drugs at risk of altered metabolism or drug levels include the following: warfarin, digoxin, 
propafenone, flecainide, propranolol, metoprolol, alprazolam, diazepam, midazolam, triazolam, 
carbamazepine, cisapride, clozapine, cyclosporine, haloperidol, thioridazine, phenytoin, pimozide, 


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tramadol, theophylline, arsenic, cimetidine, halofantrine, nilotinib, omeprazole, phenothiazines, 
aripiprazole, clozapine, and risperidone.   
   
 
  
5.4  Duration of Therapy and Criteria for Removal from Study   
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 6 weeks or 
until one of the following criteria applies:   
• 
Intercurrent illness that prevents further administration of treatment,   
• 
Unacceptable event(s)    
• 
Patient decides to end treatment. Patients will be encouraged here to return for 
follow up visits if able and willing.   
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator.     
  
 
  
5.5  Duration of Follow Up   
   
Patients will be followed for 10 weeks from start of treatment.   
   
 
  
6.   
Dosing Delays/Dose Modifications   
   
Escitalopram 10mg PO daily will be given for 4 weeks. Subjects will then be asked to take 
Escitalopram 5mg daily to wean the medication for the final 2 weeks of the intervention period. The 
same procedure will occur for the placebo group. No additional changes will be made to study dose.     
  
 
  
7.   
Pharmaceutical Information   
 
                       Table 2. Pharmaceutical Information 
 
 
Group                  AGENT(S)          DOSE    ROUTE   Frequency   Duration    Start date   
 
 Intervention  Escitalopram  10 mg   PO   
   Daily   
        4 weeks       Baseline visit   
Escitalopram   5mg     PO          Daily   
       2 weeks       5th week of trial   
 Placebo            Placebo 
10mg     PO          Daily   
       4 weeks       Baseline visit   
 
Placebo   
 5mg   
PO   
    Daily   
        2 weeks       5th week of trial   
                                 
7.1 Investigational Agent   
Escitalopram will be supplied in capsule form. Dose will be 5 mg capsules. No special handling or 
storage instructions are required.   
   
Escitalopram is absolutely contraindicated in patients taking MAOi’s. Other agents with which 
caution should be taken include those that may increase SSRI toxicity: alcohol, St. John’s wort, 


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pseudoephedrine, zolpidem, sibutramine, lithium and diuretic type medications such as furosemide 
or hydrochlorothiazide. These may lead to elevated serotonin levels and risk of serotonin syndrome. 
Drugs at risk of altered metabolism or drug levels include the following: warfarin, digoxin, 
propafenone, flecainide, propranolol, metoprolol, alprazolam, diazepam, midazolam, triazolam, 
carbamazepine, cisapride, clozapine, cyclosporine, haloperidol, thioridazine, phenytoin, pimozide, 
tramadol, theophylline, arsenic, cimetidine, halofantrine, nilotinib, omeprazole, phenothiazines, 
aripiprazole, clozapine, and risperidone.   
   
7.2 Availability   
Escitalopram is commercially available and is supplied to the investigators by Vividus pharmacy.   
7.3 Agent Ordering   
Escitalopram and matching placebo pills will be ordered from Kenneth Zielinski at Sentrix 
pharmacy:   
Sentrix Pharmacy   
3285 W McNab Rd.   
Pompano Beach, FL 33069   
(855)472-1894   
   
Orders will require at least 10 days to process and ship. Shipments will be prepared and shipped 
prior to enrollment of the first patient.   
   
7.4 Agent Accountability   
Escitalopram Inventory Records – The investigator, or a responsible party designated by the 
investigator, will maintain a careful record of the inventory and disposition of all agents received 
from Sentrix on a Drug Accountability Record Form (DARF).   
   
 
  
8.   
Correlative/Special Studies   
No correlative or special studies will be conducted.   
   
 
  
9.   
Measurement of Effect   
Response to therapy will be measured by the sperm DNA fragmentation TUNEL assay. A negative 
response will be demonstrated by increasing the proportion of men in the Escitalopram group with 
a TUNEL score (>7%). Other negative responses that will be measured are the percent change in 
TUNEL score.   
   
9.1 Response Criteria   
Number of men converting from a normal TUNEL result (<7%) to an abnormal TUNEL result (> 
7%).   
   
9.2 Duration of Response   
Duration of overall response: Primary response will be measured at 6 weeks from start of treatment. 
Duration of response will be assessed at 10 weeks (4 weeks beyond cessation of treatment) to 
determine if the effects of Escitalopram are still present 4 weeks after discontinuation.    


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9.4 Other Response Parameters   
   
Additional response parameters include absolute and percent changes in TUNEL DNA 
fragmentation percentage, as well as, changes in semen analyses parameters such as motility, 
viability, concentration and total motile count. Further parameters include: serum LH, FSH, 
testosterone, estrogen and prolactin levels at 6 weeks, as well as questionnaire responses to IIEF 
and MSHQ at 6 and 10-week study time points.   
   
 
  
10.  Data Reporting / Regulatory Considerations   
   
10.1 Data Collection   
The data collection plan for this study is to utilize REDCap to capture all treatment, toxicity, 
efficacy, and adverse event data for all enrolled patients.   
   
10.1.1 REDCap   
REDCap (Research Electronic Data Capture) is a free data management software system that is 
fully supported by the Weill-Cornell Medical Center CTSC. It is a tool for the creation of 
customized, secure data management systems that include Web- based data-entry forms, reporting 
tools, and a full array of security features including user and group based privileges, authentication 
using institution LDAP system, with a full audit trail of data manipulation and export procedures. 
REDCap is maintained on CTSC-owned servers that are backed up nightly and support encrypted 
(SSL-based) connections. Nationally, the software is developed, enhanced and supported through 
a multi-institutional consortium led by the Vanderbilt University CTSA.   
   
10.2 Regulatory Considerations   
All protocol amendments and consent form modifications will be made by the Principal  
Investigator.   
   
 
  
11.   Statistical Considerations   
   
11.1 Study Design/Endpoints   
The primary endpoint of this analysis is the proportion of patients who convert from normal to 
abnormal DNA fragmentation levels as measured by TUNEL (abnormal defined as >7%) 
following 6 weeks of escitalopram therapy. Patients with normal TUNEL (lower than 7%) will be 
randomized to escitalopram or placebo. Patients will return to the clinic 6-weeks after 
randomization (+/- 3 days) and will have their DNA fragmentation re-tested. A Fisher’s exact test 
will be used to compare the proportion of patients whose TUNEL increased after 6 weeks of 
escitalopram treatment sufficiently to become abnormal (all were normal at baseline), in the 
treatment and placebo arms. With 45 patients per arm, we will have 88% power to detect a 24% 
absolute increase in the proportion of patients with a TUNEL becomes abnormal after 6 weeks of 
escitalopram therapy (5% in placebo and 31% in treatment patients).   
   


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Secondary analyses will include comparing the proportion in each arm at week 10 (4 weeks after 
discontinuation) as well as baseline to 10 weeks. We will also similarly compare baseline to 
6week values and 10 week values of semen analysis, testosterone, LH, FSH, estrogen, prolactin, 
IIEF, MSHQ. Categorical and continuous values will be summarized with proportions and 
medians, and analyzed with Chi- squared or Fisher’s exact and Kruskal-Wallis tests, respectively. 
Exploratory linear regression analyses of change in TUNEL over 6 weeks will be used to adjust 
for clinical and demographic variables found to be imbalanced within each arm. All tests will be 
two-sided with significance considered at the 0.05 level. All analyses will be performed using R 
3.2.3.   
11.2 Sample Size/Accrual Rate   
   
Sample size has been calculated to be 45 patients per arm, 90 total. However, accounting for an 
attrition rate of 20%, our total number of patients screened is anticipated to be 108. Patients with 
normal TUNEL (lower than 7%) will be randomized to escitalopram or placebo using varying block 
sizes (2,4,6). Patients will return to the clinic 6-weeks after randomization (+/- 3 days) and will 
have their DNA fragmentation re-tested. A Fisher’s exact test will be used to compare the 
proportion of patients whose TUNEL increased after 6 weeks of escitalopram treatment sufficiently 
to become abnormal (all were normal at baseline), in the treatment and placebo arms. With 45 
patients per arm, we will have 88% power to detect a 24% absolute increase in the proportion of 
patients with a TUNEL becomes abnormal after 6 weeks of escitalopram therapy (5% in placebo 
and 31% in treatment patients).   
We anticipate accruing about 9 patients per month, leading to a 1-year accrual for 108 patients.   
   
11.3 Stratification Factors   
   
Patients will not be stratified.   
   
11.4 Analysis of Endpoints   
   
11.4.1 Analysis of Primary Endpoints   
   
The primary endpoint in this study is the proportion of patients who have abnormal (>7%) TUNEL 
DNA fragmentation levels after 6 weeks of treatment (all men have normal levels at baseline).  
Fisher’s exact test will be used to estimate 95% confidence intervals for the difference and perform 
a two-sided test with an alpha level of 5%. Response rates for each arm will also be estimated at 
this level.   
   
11.4.2 Analysis of Secondary Endpoints   
   
There are two secondary endpoints in this study. First, we will compare the proportion of patients 
who have abnormal DNA fragmentation levels at 10 weeks (4 weeks following cessation of 
treatment). Secondly, we will compare the absolute increase in DNA fragmentation percentage 
across treatment groups at both 6 and 10 weeks. This will be done using a Kruskal Wallis test for 
location shift as non- normal data are expected.   


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Exploratory analyses will include comparison across arms of semen parameters including motility, 
viability, concentration, and total motile count. Comparisons will be done at 6 and 10 weeks (4 
weeks post cessation of treatment). Fisher’s exact and Kruskal Wallis tests will be used for 
categorical and continuous variable, respectively. Furthermore, comparisons across arms of serum 
LH, FSH, testosterone, estrogen and prolactin will be compared at baseline, and 6 weeks. Responses 
to both the IIEF and MSHQ questionnaires will be compared at baseline to 6 and 10 weeks.   
   
11.5 Interim Analysis   
   
No interim analysis is planned for this study.   
   
11.6 Reporting and Exclusions   
   
11.6.1 Evaluation of toxicity   
All patients will be evaluable for toxicity from the time of their first treatment with Escitalopram. 
Patients will be asked to report any adverse events experienced at each follow up visit. The research 
team will call the patient after 1 week of therapy to ensure they are tolerating the drug. Counts and 
rates of all adverse events will be reported in the final analysis and SAEs reported immediately as 
required.   
   
11.6.2 Evaluation of response   
The primary analysis will include all patients randomized for whom 6-week data are available. 
Additional per-protocol analyses may be done, excluding patients who have missed 7 or more days 
of treatment, determined either by self-report or pill count.   
  
12. Adverse Event Reporting Requirements   
   
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe use 
of the drug or device under investigation. Safety will be monitored by evaluation of adverse events 
reported by patients or observed by investigators or research staff, as well as by other investigations 
such as clinical laboratory tests, x-rays, electrocardiographs, etc.   
   
 
  
12.1   
Adverse Event Definition   
   
An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended 
sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a drug, and does not imply any judgment about causality. An adverse event can arise with any 
use of the drug (e.g., off-label use, use in combination with another drug) and with any route of 
administration, formulation, or dose, including an overdose.   
   


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12.1.1 Investigational Agent or Device Risks   
  
Adverse events for Escitalopram that have been previously described include the following: Risks 
and side effects related to Escitalopram include: nausea (17%), sweating (8%), diarrhea (7%), 
insomnia (7%), somnolence (5%), erectile dysfunction (5%), dry mouth (5%), rhinitis (5%), upper 
respiratory tract infections. Patients may also have symptoms of withdrawal: flu-like symptoms, 
fatigue, weakness, tiredness, headache, tachycardia, dyspnea, gait instability, ataxia, dizziness, 
light-headedness, vertigo, paresthesias, electric shock sensations, myalgias, neuralgias, tinnitus, 
altered taste, pruritis, visual changes, blurred vision, tremor, myoclonus, ataxia, muscle rigidity, 
jerkiness, muscle aches, facial numbness, sweating, flushing, chills insomnia, vivid dreams, 
nightmares, hypersomnia, lethargy, nausea, vomiting, diarrhea, anorexia, abdominal pain, anxiety, 
agitation, tension, panic, depression, intensification of suicidal ideation, irritability, impulsiveness, 
aggression, anger, bouts of crying, mood swings, de- realization and depersonalization, visual and 
auditory hallucinations, confusion, decreased concentration, amnesia, genital hypersensitivity, 
premature ejaculation. Withdrawal symptoms may last days to weeks19. Antidepressants of the 
SSRI class have been shown to increase the risk of suicidal attempts among depressed patients20   
   
12.1.2 Adverse Event Characteristics and Related Attributions   
  
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
web site (http://ctep.cancer.gov).   
  
Attribution of the AE:   
- Definite – The AE is clearly related to the study treatment.   
- Probable – The AE is likely related to the study treatment.   
- Possible – The AE may be related to the study treatment.   
- Unlikely – The AE is doubtfully related to the study treatment.   
- Unrelated – The AE is clearly NOT related to the study treatment.   
   
 12.1.3 Recording of Adverse Events   
   
All adverse events will be recorded on a patient specific AE log. The AE log will be maintained 
by the research staff and kept in the patient’s research chart.   
   
12.1.4 Reporting of AE to WCM IRB   
   
All AEs occurring on this study will be reported to the IRB according to the IRB policy, which 
can be accessed via the following link: 
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Policy 
.pdf       
   


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12.2   
Definition of SAE   
   
SAE’s include death, life threatening adverse experiences, hospitalization or prolongation of 
hospitalization, disability or incapacitation, overdose, congenital anomalies and any other serious 
events that may jeopardize the subject or require medical or surgical intervention to prevent one 
of the outcomes listed in this definition.  
   
12.2.1 Reporting of SAE to IRB   
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, which 
can 
be 
accessed 
via 
the 
following 
link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Policy 
.pdf     
  
12.2.2 Reporting of SAE to FDA [For protocols where WCMC is the Sponsor- 
Investigator]   
   
If an SAE occurs on this study, the event will be filed on a MedWatch form with the FDA. The 
investigator must notify the FDA of any SAE’s as soon as possible but no later than 7 calendar 
days after the initial receipt of the information   
   
Select appropriate reporting branch below   
CDER INDs:   
Food and Drug Administration   
Center for Drug Evaluation and Research   
Division of Human Drug information Products   
5901-B Ammendale Road   
Beltsville, MD 20705-1266   
CDER-only Biologic INDs:   
Food and Drug Administration   
Center for Drug Evaluation and Research   
Therapeutic Biologic Products Document Room   
5901-B Ammendale Road   
Beltsville, MD 20705-1266      
  
12.4 AE/SAE Follow Up   
   
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. This 
requirement indicates that follow-up may be required for some events after the patient discontinues 
participation from the study.   
  


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13.  Data and Safety Monitoring Plan (DSMP)   
   
In this section, please include a written plan of the measures that will be taken to ensure the safety 
of clinical research subjects and protect the validity and integrity of research data. The following 
questions should be addressed as a part of the DSMP and must be incorporated into your WCM 
eIRB application:   
1. We will not use the ‘Data and Safety Monitoring Plan’ external to the study personnel as the 
study agent is an FDA approved drug being used off-label and  has reported adverse effects such 
as nausea, fatigue, increased sweating, somnolence (tiredness), diarrhea, dizziness, anorexia 
(loss of appetite), impotence (unable to get an erection) constipation, weight increase, yawning, 
decreased libido (desire for sex), unable to ejaculate, suicidal thoughts, and serotonin syndrome. 
The study agent is also commercially available.   
2. Subjects will be interviewed for adverse events and side effects at 6 and 10 week follow ups. 
They will also be provided with the contact number of study personnel to contact if they are 
experiencing any unwanted side effects.   
3. Serious adverse events that are life threatening or require significant medical or surgical 
intervention will be considered and reviewed for termination of the study.   
4. All serious adverse events as previously identified will be reported within the timeframe 
mentioned in section 12. Minor adverse events will be reported every 6 months and study end.   
5. Monitoring for adverse events will be performed semi-annually.   
6. The monitoring entity’s comments/review will be disseminated to the IRB at the time of 
continuing review, at interim analysis and study end.   
   
For additional information and guidance on developing a DSMP, please contact the Quality  
 
Assurance Unit (JCTOQAU@med.cornell.edu).    
 
 
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2. Elnazer HY, Baldwin DS. Treatment with citalopram, but not with agomelatine, adversely 
affects sperm parameters: a case report and translational review. Acta Neuropsychiatr. 
2014;26(2):125-129.   
3. Safarinejad MR. Sperm DNA damage and semen quality impairment after treatment with 
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6. Akasheh G, Sirati L, Noshad Kamran AR, Sepehrmanesh Z. Comparison of the effect of 
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