Conditions: COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 96
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if temporary androgen suppression improves the clinical outcomes of Veterans who are hospitalized to an acute care ward due to COVID-19.

Detailed description:
A novel coronavirus, now termed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), arose late in 2019. The first confirmed cases occurred in December in Wuhan, Hubei province, China. It now infects people on six continents, spreading person to person. The World Health Organization (WHO) classified it as a global pandemic on March 11, 2020. As of April 6, 2020, there are more than 1.2 million confirmed cases and more than 70,000 deaths attributed to this virus. Every person on Earth, as well as every United States Veteran, is at risk. This is the emergent public health threat of our time.

SARS-CoV-2 is a singled stranded RNA virus related to severe acute respiratory syndrome-related coronavirus (SARS-CoV-1). SARS-CoV-2 is thought to be transmissible largely by respiratory droplets or direct contact, but might also be transmitted through aerosolization. SARS-CoV-2 disease severity ranges from no to minimal symptoms, mildly symptomatic with cough and dyspnea, to severe respiratory distress with multi-organ failure requiring admission to an intensive care unit and emergent ventilator support. Although data are evolving, the severity of illness varies with age, co-existing comorbidities, and biological sex, with older age, people with pre-existing cardiovascular disease, and males manifesting greater disease severity.

A worldwide effort is in place to contain and suppress human-to-human transmission. These public-health strategies aim to slow the rate of spread and reduce the burden on critical care infrastructure. However, there is also a need effective therapeutics. Vaccine trials are underway but potential approvals are at least a year away. Development of new drugs de novo to treat SARS2-CoV-2 will likely take even longer. Thus, the most expedient therapeutic strategy to confront this pandemic will repurpose existing FDA-approved therapeutics. One potential strategy targets viral components directly, using existing antivirals and anti-infectives currently used for other diseases. Such efforts include trials of hydroxychloroquine, remdesivir, and ribavirin. Another strategy involves targeting the human proteins, rather than viral proteins, required for SARS CoV-2 entry and replication.

Arms:
arm 1: No active, only placebo (2 - prefilled syringes containing 3 ml of 0.9% saline) plus best supportive care. arm 2: Active Degarelix (2 - prefilled syringes containing 3 ml of reconstituted Degarelix concentrated to 40mg/ml) plus best supportive care.

Interventions: intervention 1: Degarelix intervention 2: Saline
Intervention descriptions: intervention 1: Degarelix is an FDA-approved drug for prostate cancer intervention 2: 09% Saline

Protocol document:
Prot_000.pdf: 
Hormonal Intervention for the Treatment in Veterans with COVID 19 Requiring Hospitalization 
NCT04397718 
February 9, 2021 


1 
HITCH Protocol: 20210209 
 
Hormonal Intervention for the Treatment in Veterans with COVID-
19 Requiring Hospitalization (HITCH): A Multicenter, Phase 2 
Randomized Controlled Trial of Best Supportive Care (BSC) vs 
BSC plus Degarelix  
 
 
Principal Investigator:   
 
Matthew B. Rettig, M.D. 
Chief, Hematology/Oncology, VA Greater Los Angeles Healthcare System (GLA) 
Professor of Medicine and Urology 
Medical Director, Prostate Cancer Program 
Institute of Urologic Oncology 
David Geffen School of Medicine at UCLA 
 
 
Study Drugs: Degarelix  
 
Funding Agency: VA CSR&D 
 
Protocol Version: 5.5., February 9, 2021 
 
 
 
 
 
 
 
 
 
Proprietary and Confidential 
 
The information in this document is considered privileged and confidential, and 
may not be disclosed to others except to the extent necessary to obtain 
Institutional Review Board approval and informed consent, or as required by 
Federal and State laws. Persons to whom this information is disclosed should be 
informed that this information is privileged and confidential and should not be 
further disclosed. 
 
 
 
 
 


2 
HITCH Protocol: 20210209 
PRINCIPAL INVESTIGATOR APPROVAL OF PROTOCOL  
 
The HITCH Trial will be carried out in accordance with the protocol, the principles of good 
clinical practice and in accordance to Veteran’s Affairs Medical Centers (VAMC), 
Research & Development (R&D) guidelines and regulations as well as national regulatory 
requirements.   
 
The undersigned has read and approve this protocol and agree to its content: 
 
Principal Investigator: 
 
 
Matthew Rettig, MD 
 
Name  
 
 
       Signature 
 
 
    Date 
 
 
 


3 
HITCH Protocol: 20210209 
PROTOCOL SITE INVESTIGATOR SIGNATURE SHEET 
 
I have read the HITCH Trial protocol, including all appendices, and I agree that it contains 
all necessary details for my staff and I to conduct this protocol as described. I will 
personally oversee protocol conduct as outlined herein.   
I will provide all study personnel under my supervision with copies of the protocol and 
access to all information provided for the study.   
Before commencement of this study at my clinical facility, the Central Institutional Review 
Board (IRB)/ethics committee must approve this protocol. I agree to make all reasonable 
efforts to adhere to the HITCH Trial protocol.   
I, or my designee, agree to be present at all site visits and Investigator meetings. I will 
ensure the presence of relevant study personnel under my supervision at these visits and 
meetings.  I will conduct the study according to the procedures specified herein, and 
according to the principles of Good Clinical Practice (GCP), VAMC research and 
development guidelines and regulations: 
 
 
Signature Site PI:  
 
Printed Name of Site PI:   
 
Site Location: 
 
Date:  
 
 
 
 


4 
HITCH Protocol: 20210209 
HITCH Trial Protocol Version and Amendment Tracking 
 
Version Number 
Date 
HITCH Protocol, v1.0, 20200407 
April 7, 2020 
HITCH Protocol, v2.0, 20200420 
April 20, 2020 
HITCH Protocol, v2.0, 20200423 
April 23, 2020 
HITCH Protocol, v2.0, 20200427 
April 27, 2020 
HITCH Protocol, v3.0, 20200505 
May 5, 2020 
HITCH Protocol, v4.0, 20200525 
May 25, 2020 
HITCH Protocol, v4.1, 20200525 
May 27, 2020 
HITCH Protocol, v5.1, 20200618 
June 18, 2020 
HITCH Protocol, v5.2, 20200714 
July 14, 2020 
HITCH Protocol, v5.3, 20200804 
August 4, 2020 
HITCH Protocol, v5.4, 20201103 
November 3, 2020 
HITCH Protocol, v.5.4.5, 20210115 
January 15, 2021 
HITCH Protocol, v.5.5, 20210209 
February 9, 2021 
 
 
 
 
 
 


5 
HITCH Protocol: 20210209 
STUDY TEAM ROSTER  
 
GLA 
Principal Investigator:  
Matthew Rettig, M.D. 
Chief, Division of Hematology-Oncology, GLA 
Professor of Medicine and Urology 
David Geffen School of Medicine at UCLA 
VA Greater Los Angeles HCS 
11301 Wilshire Blvd 
Building 500, Room 4237 
Los Angeles, CA 90073 
Ph: 310-268-3622; mobile: 310-569-1767 (best contact) 
e-mail: matthew.rettig@va.gov; mrettig@mednet.ucla.edu 
UCLA pager: 310-825-6301 (pager 14320) 
 
GLA Co-Investigators: 
Nicholas Nickols, MD, PhD 
Staff Physician, Radiation Oncology 
Associate Professor 
Department of Radiation Oncology 
David Geffen School of Medicine at UCLA 
Ph: 310-268-3390 
Cell: 818-421-5077 
Nicholas.nickols@va,gov; nnickols@mednet.ucla.edu  
VA pager: 310-478-3711 (pager 55053) 
Matthew Goetz, MD 
Chief, Infectious Diseases, GLA 
Professor of Medicine 
David Geffen School of Medicine at UCLA 
Ph: 310-478-3711 x 44716 
Matthew.goetz@va.gov 
 
Christopher Graber, MD 
Staff Physician, Division of Infectious Diseases, GLA 
Assistant Professor Medicine 
David Geffen School of Medicine at UCLA 
Ph: 310-478-3711 x40275 
Cell: 310-295-8376 
Christopher.Graber@va.gov 
Debika Bhattacharya, MD 
Staff Physician, Division of Infectious Diseases, GLA 
Assistant Clinical Professor 
David Geffen School of Medicine at UCLA 


6 
HITCH Protocol: 20210209 
Ph: 310-925-0137 
DebikaB@mednet.ucla.edu 
 
Guy Soo Hoo, MD 
Chief, Pulmonary and Critical Care, GLA 
Professor of Medicine 
David Geffen School of Medicine at UCLA 
Ph: (310)268-3021 
Mobile: (310)729-3273 
guysoohoo@va.gov; gsoohoo@ucla.edu 
 
 
Greg Orshansky, MD, FACP 
Chief, Clinical Informatics and Data Analytics  
Chief Health Informatics Officer 
VA Greater Los Angeles Healthcare Systems 
Ph: 310 478-3711 x43988 
Greg.Orshansky@va.gov  
 
GLA Study Coordinators 
Samantha Tran  
VA GLAHS 
11301 Wilshire Blvd 
Building 304, 2nd Floor, Room 2-304Ph: 310-478-3711 x44917 
Samantha.Tran@va.gov 
Leila Ghayouri 
VA GLAHS 
11301 Wilshire Blvd 
Building 304, 2nd Floor, Room 2-304 
Los Angeles, CA 90073 
Ph: 310-478-3711 x44386 
Leila@brentwoodresearch.orgMichelle Geelhoed, PA 
VA GLAHS 
11301 Wilshire Blvd 
Building 500, 4 East, Room 4237 
Los Angeles, CA 90073 
Ph: 310-478-3711 x40373 
Michelle.geelhoed@va.gov 
Sonny Tsai 
VA GLAHS 
11301 Wilshire Blvd 
Building 304, 2nd Floor, Room 2-304 
Los Angeles, CA 90073 
Ph: 310-478-3711 x44567 


7 
HITCH Protocol: 20210209 
Sonny.Tsai@va.gov 
 
Manhattan VA 
Manhattan Principal Investigator: 
Daniel Becker, MD, MPH 
Section Chief, Hematology-Oncology, VA-NYHHS, Manhattan Campus 
Assistant Professor of Medicine 
NYU School of Medicine 
Daniel.Becker@nyulangone.org 
Daniel.Becker2@va.gov 
212-686-7500 x3303 
Manhattan Co-Investigator: 
Jun-Chieh (James) Tsay, MD, MS 
Staff Physician, Division of Pulmonary and Critical Care, VA-NYHHS, Manhattan Campus 
Assistant Professor of Medicine 
NYU School of Medicine 
Jun-Chieh.Tsay@nyulangone.org 
Manhattan Study Coordinators: 
Melissa Diamond 
Program Manager 
Ph: 22-686-7500 x3924 
Cell: 917-821-9106 (best contact number) 
Melissa.diamond@va.gov 
 
Asha George 
Research Coordinator 
212-686-7500 x3922 
Asha.George@va.gov 
 
Brooklyn VA 
Brooklyn Principal Investigator: 
Daniel Becker, MD, MPH 
Section Chief, Hematology-Oncology, VA-NYHHS, Manhattan Campus 
Assistant Professor of Medicine 
NYU School of Medicine 
212-686-7500 x3303 
Daniel.Becker@nyulangone.org 
Daniel.Becker2@va.gov 
Brooklyn Co-Investigators: 
Mohammad Al-Ajam, MD, FCCP 
Section Chief, Pulmonary/Critical Care/Sleep Simulation  
Department of Medicine 


8 
HITCH Protocol: 20210209 
Ph: 718-630-3722 
Cell: 917-859-9604 
Mohammad.Al-Ajam@va.gov 
Pooja Belligund, MD 
Attending Physician, Pulmonary/Critical Care 
Department of Medicine 
Ph 718-836-6600 x6080 
Pooja.Belligund@va.gov 
Puget Sound VA 
Puget Sound Principal Investigator 
 
Bruce Montgomery, MD 
Attending Physician, Division of Hematology-Oncology 
Ph: 206-598-0860 
rbmontgo@uw.edu 
 
Puget Sound Co-Investigator 
 
Elahe Mostaghel, MD 
Attending Physician, Division of Hematology-Oncology 
Ph: 206-277-1657 
emostagh@fredhutch.org  
elahe.mostaghel@va.gov 
 
Puget Sound Coordinator 
 
Carlie Sulpizio 
(206) 762-1010 Ext 6-7190 
Carlie.Sulpizio@va.gov 
 
Philadelphia VA Medical Center 
 
Philadelphia Principal Investigator 
 
Kyle Robinson, MD 
Staff Physician, Hematology and Oncology 
Ph: 267-239-4924 
Kyle.Robinson3@va.gov 
 
 
Charleston VA Medical Center 
 
Charleston Principal Investigator 
 
John Huggins, MD 
Staff Physician, Pulmonology 


9 
HITCH Protocol: 20210209 
Ph: 843-789-6392 
John.Huggins@va.gov  
 
Long Beach VA Medical Center 
 
Long Beach Principal Investigator 
 
Ellis Levin, MD 
Chief, Endocrinology 
Ph: 562-826-8000 x14147 
Ellis.Levin@va.gov  
 
Houston VA Medical Center 
 
Houston Principal Investigator 
 
Reina Villareal, MD 
Staff Physician, Endocrinology 
Ph: 713-794-7534 
Reina.Villareal@va.gov  
 
Phoenix VA Medical Center 
 
Phoenix Principal Investigator 
 
Samuel Aguayo, MD 
Staff Physician, Endocrinology 
Ph: 602-277-5551 x7808 
Samuel.Aguayo@va.gov  
 
Memphis VA Medical Center 
 
Memphis Principal Investigator 
 
Muthiah Muthiah, MD 
Staff Physician, Pulmonology 
Ph: 901-523-8990 x5050 
Muthiah.Muthiah@va.gov  
 
Miami VA Medical Center 
 
Miami Principal Investigator 
 
Mehdi S. Mirsaeidi, MD 
Staff Physician, Pulmonology 
Ph: 305-575-7000 x4594 


10 
HITCH Protocol: 20210209 
Mirsaeidi.Mehdi@va.gov  
 
North Texas VA Medical Center 
 
North Texas Principal Investigator 
 
Roger Bedimo, MD 
Chief, Infectious Disease  
Ph: 241-857-0397 
Roger.Bedimo@va.gov  
 
Palo Alto VA Medical Center 
 
Palo Alto Principal Investigator 
 
Brian T. Dietrich, MD 
Staff Physician, Hematology  
Ph: 650-493-5000 
Brian.Dietrich2@va.gov  
 
 
 
Cooperative Studies Program 
 
Kousick Biswas, Ph.D. 
Director 
Cooperative Studies Program Coordinating Center 
Office of Research and Development 
U.S. Department of Veterans Affairs 
VA Medical Center, Perry Point, MD 21902 
Associate Professor 
Department of Epidemiology and Public Health 
School of Medicine, University of Baltimore 
Baltimore, Maryland 21201 
Kousick.Biswas@va.gov 
 
Zhibao Mi, Ph.D. 
Biostastician 
Cooperative Studies Program Coordinating Center 
Office of Research and Development 
U.S. Department of Veterans Affairs 
VA Medical Center, Perry Point, MD 21902 
Zhibao.Mi@va.gov 
 
Ellen De Matt, MA 
Chief Statistical Programmer 


11 
HITCH Protocol: 20210209 
Cooperative Studies Program Coordinating Center 
Office of Research and Development 
U.S. Department of Veterans Affairs 
VA Medical Center, Perry Point, MD 21902 
Ellen.DeMatt@va.gov 
 
Joseph Tadalan, MS 
Chief Database Programmer 
Cooperative Studies Program Coordinating Center 
Office of Research and Development 
U.S. Department of Veterans Affairs 
VA Medical Center, Perry Point, MD 21902 
Joseph.Tadalan@va.gov 
 
Erin Norman, MSW 
Project Manager 
Cooperative Studies Program Coordinating Center 
Office of Research and Development 
U.S. Department of Veterans Affairs 
VA Medical Center, Perry Point, MD 21902 
Leslie.Norman@va.gov 
 
Daniel Briones, BA 
Clinical Data Manager 
Cooperative Studies Program Coordinating Center 
Office of Research and Development 
U.S. Department of Veterans Affairs 
VA Medical Center, Perry Point, MD 21902 
Daniel.Briones@va.gov 
 
Christina E. Clise, Pharm.D. 
Clinical Research Pharmacist 
VA CSPCRPCC 
Office of Research and Development 
U.S. Department of Veterans Affairs 
Albuquerque, NM  87106 
Christina.Clise@va.gov  
 
Zachary Taylor, BS 
Computer Scientist 
VA CSPCRPCC 
Office of Research and Development 
U.S. Department of Veterans Affairs 
Albuquerque, NM  87106 
Zachary.Taylor@va.gov 
 


12 
HITCH Protocol: 20210209 
Jeffrey Huminik, BA 
Project Manager 
VA CSPCRPCC 
Office of Research and Development 
U.S. Department of Veterans Affairs 
Albuquerque, NM  87106 
Jeffrey.Huminik@va.gov 
 
 
 
 
 
 
 


13 
HITCH Protocol: 20210209 
SYNOPSIS 
Study Title:  
 
Hormonal Interventions for the Treatment in Veterans with COVID-19 Requiring 
Hospitalization (HITCH): A Multicenter Phase 2 Randomized Controlled Trial of Best 
Supportive Care (BSC) vs BSC plus Degarelix. 
Rationale 
SARS-CoV-2 entry into lung epithelium requires the TMPRSS2 cell surface 
receptor. Pre-clinical and correlative data in humans strongly suggest that anti-
androgenic therapies can reduce the expression of TMPRSS2 on lung epithelium. 
Accordingly, we hypothesize that therapeutic targeting of androgen receptor signaling will 
suppress viral infection and thereby ameliorate the severity of symptomatic COVID-19. 
Purpose:  
The purpose of this study is to determine if temporary androgen suppression 
improves the clinical outcomes of Veterans who are hospitalized to an acute care ward 
due to COVID-19.   
Target Population:  
 
Male Veterans, ≥18 - ≤ 85 years old (patients > 85 can be enrolled if there is no 
history of chronic obstructive pulmonary disease (COPD), asthma, cardiovascular 
disease, hypertension, diabetes mellitus or active malignancy), who have been admitted 
to acute care ward due to COVID-19. 
Objectives: 
The primary objective of this study is to determine if temporary androgen 
suppression induced by degarelix improves the clinical outcomes of Veterans who are 
hospitalized to an acute care ward due to COVID-19 as defined by a reduction in mortality, 
ongoing need for hospitalization, or requirement for mechanical ventilation/extracorporeal 
membrane oxygenation (ECMO). 
The secondary objectives of this study are to determine if temporary androgen 
suppression induced by degarelix reduces time to clinical improvement, inpatient 
mortality, length of hospitalization, duration of intubation for mechanical ventilation, time 
to achieve a normal temperature,  or the maximum severity of COVID-19 illness.   
Endpoints:  
 
Primary Endpoint: 
  


14 
HITCH Protocol: 20210209 
Determine if degarelix + best supportive care (BSC) as compared to placebo + 
BSC reduces the composite endpoint of mortality, ongoing need for hospitalization, or 
requirement for mechanical ventilation/extracorporeal membrane oxygenation (ECMO) at 
Day 15 after randomization.   
 
Secondary Endpoints: 
 
• Determine if degarelix + best supportive care (BSC) as compared to placebo + 
BSC reduces the composite endpoint of mortality, ongoing need for 
hospitalization, or requirement for mechanical ventilation/extracorporeal 
membrane oxygenation (ECMO) at Day 30 after randomization.   
• Determine if degarelix + BSC as compared to placebo + BSC reduces time to 
clinical improvement as defined by a decline of 2 categories or more from the 
baseline on the modified 7-category ordinal scale of clinical status of 
hospitalized influenza patients (influenza scale, see Appendix A).1 or hospital 
discharge, whichever comes first. 
• Determine if degarelix + BSC as compared to placebo + BSC reduces inpatient 
mortality. 
• Determine if degarelix + BSC as compared to placebo + BSC shortens the 
duration of hospitalization.  
• Determine if degarelix + BSC as compared to placebo + BSC shortens the 
duration of intubation for mechanical ventilation. 
• Determine if degarelix + BSC as compared to placebo + BSC reduces the time 
to normalization of temperature (T < 37.5℃ for ≥ 48 hours).  
• Determine if degarelix + BSC as compared to placebo + BSC reduces the 
maximum severity of COVID-19 illness based on the influenza severity scale 
(see Appendix A). 
 
 
Exploratory Endpoints 
 
• Determine if age, use of angiotensin converting enzyme inhibitors, the duration 
of pre-hospitalization symptoms, or the presence or absence of hypertension, 
cardiovascular disease, asthma, diabetes mellitus, or COPD are prognostically 
associate with clinical outcome defined by the primary endpoint or any 
secondary endpoint. 
 
• Determine if baseline, Day 8 or Day 15 values for D-dimer, IL-6, LDH, ferritin, 
total WBC, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), 
or testosterone are predictive of clinical outcome defined by the primary 
endpoint or any secondary endpoint. 
 
• Determine if degarelix + BSC as compared to placebo + BSC reduces  
nasopharyngeal (NP) epithelial or peripheral blood mononuclear cell (PBMC) 
TMPRSS2 expression, NP and plasma viral load, or serum cytokine (TNF, IL-
1, IL-6) levels.  


15 
HITCH Protocol: 20210209 
• Determine whether germline genomic factors are predictive of clinical outcome 
defined by the primary endpoint or any secondary endpoint. This analysis is 
optional and is contingent on obtaining adequate number of samples. 
 
• To determine the temporal onset of anti-viral antibodies.  
 
Design  
 
 
This is a randomized phase 2, placebo-controlled, double blind clinical trial to 
compare the efficacy of degarelix + BSC to the placebo + BSC on improving the clinical 
outcomes of male Veterans who have been hospitalized due to COVID-19. Enrolled 
patients must have documented infection with SARS-Cov-2 based on a positive reverse 
transcriptase polymerase chain reaction (RT-PCR) result performed on a nasopharyngeal 
swab and have a severity of illness of level 3-5 (see Appendix A). Patients will be centrally 
randomized 2:1 (degarelix + BSC: placebo + BSC) to the study arms. BSC consists of 
supplemental oxygen, antibiotics, vasopressor support, peritoneal or hemodialysis, 
antibiotics, intravenous fluids, etc.  
 
 
Statistical Considerations 
 
Expected Treatment Effects 
 
In a recent antiviral drug trial to treat adults hospitalized with severe COVID-19 
published in the New England Journal of Medicine (NEJM) on March 18, 2020 (Cao et al. 
2020), the results showed a mortality rate of 17%, hospital stay rate of 50%, and ECMO 
or  mechanical intubation rate of 11% among the patients managed with BSC after two-
week follow-up. In the current study, we propose a composite endpoint of mortality, 
hospital stay rate, and ECMO or mechanical intubation at 15 days after randomization. 
We are expecting to reduce the composite endpoint rate to 35% after the degarelix 
treatment plus BSC from 60% for patients treated placebo plus BSC.    
 
Sample Size Calculation and Power Analysis 
 
The sample size estimation and power analysis shown in Table 2 are based on the 
hypothesis testing of the primary endpoint, which is the composite endpoint of mortality, 
hospital stay rate, and ECMO or mechanical intubation at 15 days after randomization 
(Day 15).  
 
 
 
Based on the composite primary endpoint, we assume that an effect size for the 
primary endpoint of 42% can be anticipated in the degarelix group. The other assumptions 
include a three-month accrual time and one-month follow-up time, and 2:1 sample 
allocation of degarelix: placebo treatment group. The sample size for the study is 
estimated based on a superiority trial design. To have 90% power of detecting the 
expected 42% reduction using a two-sided two proportion test with a significance level of 
0.05 in the degarelix compared to the placebo group will require 186 evaluable patients 
total (i.e. 124 evaluable patients in the degarelix group and 62 evaluable patients in the 


16 
HITCH Protocol: 20210209 
placebo group).  Based on an assumed 5% attrition rate, 198 patients will be required 
(i.e. 132 in the degarelix group and 66 in the placebo group) to achieve actual statistical 
significance at alpha level of 0.05 and power of 90%.   
 
 
Study Schematic 
 
 
 
Study Treatments 
 
 
Patients assigned to the degarelix arm will receive degarelix 240 mg 
subcutaneously (SQ) in the periumbilical area. The degarelix or matched placebo will be 
administered within 24 hours of randomization (i.e. within 24 hours of Day 1). Patient in 
the BSC alone arm will receive placebo. Patients, investigators, and treating physicians 
will be blinded to treatment assignment (i.e. double blinding). 
 
 
Screening 
 
 
Male Veterans who have been hospitalized or are in the process of being admitted 
to an acute care ward from the outpatient setting or emergency department (ED) and 
have a positive nasopharyngeal swab for SARS-Cov-2 based on an approved RT-PCR 
assay will be screened. Patients will complete screening within 72 hours of signing the 
informed consent form (ICF).   
Eligibility Criteria 
 
Inclusion Criteria 
 
1. Male Veterans admitted to a VA hospital.  
2. Age ≥ 18  
3. Hospitalized on an acute care ward with a diagnosis of COVID-19 contributing to 
hospitalization.  
4. Positive RT-PCR assay for SARS-CoV-2 on a nasopharyngeal swab sample. 
5. Severity of COVID-19 illness of level 3, 4 or 5 on the influenza severity scale (see 
Appendix A) at the time of randomization.  


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HITCH Protocol: 20210209 
6. The subject (or legally acceptable representative if applicable) must provide 
informed consent for the trial. 
Exclusion Criteria 
1. History of severe hypersensitivity to degarelix or any component of their respective 
formulation 
2. History of congenital long QT syndrome or known history of prolonged QT interval 
OR Fridericia correction formula (QTcF) > 500 msec on electrocardiogram 
performed at screening.   
3. Planned discharge within 24 hours of treatment initiation.  
4. Subject is planning to conceive or father children within the projected duration of 
the study, starting with the screening visit through 120 days after the last dose of 
study treatment.  
1. Ongoing usage of a Class IA or Class III antiarrhythmic agent (see Appendix D). 
At least 5 half-lives must elapse since any prior use of a Class IA or III 
antiarrhythmic agent prior to administration of study drug.  
5. Baseline electrolyte abnormalities of Grade 3 or higher (based on CTCAE v5.0 
criteria). Patients may be included if baseline electrolyte abnormalities are 
corrected to Grade 2 or lower prior to study drug administration.  
6. Myocardial infarction in the past 6 months, severe or unstable angina, or New York 
Heart Association (NYHA) Class III or IV heart disease. 
7. Enrollment in another investigational study within 30 days of Day 1.  
8. Known psychiatric or substance abuse disorder that would interfere with the 
requirements of the trial.  
9. Child-Pugh Class C liver disease. 
10. Use of any of the following hormonal agents: 
• Androgen receptor antagonists or agonists within 4 weeks of study 
enrollment, 
• Ketoconazole or abiraterone acetate within 2 weeks of study enrollment,  
• Estrogens or progestins within 2 weeks of study enrollment,  
• Herbal products that contain hormonally active agents within 2 weeks of 
study enrollment. 
• Any prior use of an LHRH analogue unless a serum total testosterone 
measured within 30 days of study enrollment is ≥ 150 ng/dL. 
• Other hormonal agents listed in Appendix B within one day of study 
enrollment. 
11. Unwilling or unable to comply with the study protocol.  
12. Any condition, which in the opinion of the investigator, would preclude participation 
in the trial.  


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HITCH Protocol: 20210209 
 
 
LIST OF ABBREVIATIONS 
 
AE = adverse event 
ALT = alanine aminotransferase 
ANC = absolute neutrophil count 
AR = androgen receptor 
AST = aspartate aminotransferase 
BSC = best supportive care 
CBC = complete blood count 
CDMS = clinical data management system 
CFR = Code of Federal Regulations 
COPD = chronic obstructive pulmonary disease 
CRF = case report form 
CSPCC = Cooperative Studies Program Coordinating Center 
CTCAE v5.0 = Common Terminology Criteria for Adverse Events version 5.0 
CT = computed-tomography 
DSMB = Data Safety Monitoring Board 
ECMO = extracorporeal membrane oxygenation 
eCRF = electronic case report form 
eDC = electronic data capture 
FDA = Food and Drug Administration 
Hgb = hemoglobin 
ICF = informed consent form 
IL-1 = interleukin-1 beta 
IL-6 = interleukin-6 
LAR = legally authorized representative 
IRB = institutional review board 
LDH = lactate dehydrogenase 
LFTs= liver function tests 
LHRH = luteinizing hormone releasing hormone 
MRI = magnetic resonance imaging 
NP = nasopharyngeal 
PaO2 = partial pressure of oxygen 
QT = electrocardiogram interval from onset of the QRS complex to the end 
of the T wave representing duration of repolarization 
QTCF = electrocardiogram interval for QT interval corrected by the Fridericia correction 
formula 
PI= principal investigator 
SAE = serious adverse event 
SaO2 = oxygen saturation 
SQ = subcutaneously 
TNF = tumor necrosis factor alpha 
 


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HITCH Protocol: 20210209 
TABLE OF CONTENTS 
Page 
 
STUDY TEAM ROSTER ..................................................................................................... 5 
 
SYNOPSIS......................................................................................................................... 13 
 
LIST OF ABBREVIATIONS .............................................................................................. 18 
 
1. 
INTRODUCTION ........................................................................................................ 19 
2. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................... 24 
3. 
STUDY POPULATION .............................................................................................. 26 
4. 
STUDY ENROLLMENT PROCEDURES .................................................................. 28 
5. 
STUDY DESIGN ........................................................................................................ 33 
6. 
STUDY TREATMENT ................................................................................................ 35 
7.     STUDY PROCEDURES 
8. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..................................... 43 
9. 
SAFETY MONITORING ............................................................................................ 47 
10. 
STATISTICAL CONSIDERATIONS ...................................................................... 48 
11. 
DATA COLLECTION AND QUALITY ASSURANCE .......................................... 57 
12. 
PATIENT RIGHTS AND CONFIDENTIALITY ...................................................... 60 
13. 
FUNDING AND INSURANCE ............................................................................... 61 
14. 
PUBLICATION OF RESEARCH FINDINGS......................................................... 61 
15. 
REFERENCES ....................................................................................................... 62 
16.  
APPENDICES ........................................................................................................ 66 
 
1. 
INTRODUCTION  
Background 
 
A novel coronavirus, now termed Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2), arose late in 2019.2 The first confirmed cases occurred in 
December in Wuhan, Hubei province, China. It now infects people on six continents, 


20 
HITCH Protocol: 20210209 
spreading person to person. The World Health Organization (WHO) classified it as a 
global pandemic on March 11, 2020. As of April 6, 2020, there are more than 1.2 million 
confirmed cases and more than 70,000 deaths attributed to this virus. Every person on 
Earth, as well as every United States Veteran, is at risk. This is the emergent public health 
threat of our time. 
 
SARS-CoV-2 is a singled stranded RNA virus3 related to severe acute respiratory 
syndrome-related coronavirus (SARS-CoV-1).4 SARS-CoV-2 is thought to be 
transmissible largely by respiratory droplets or direct contact,5 but might also be 
transmitted through aerosolization.6 SARS-CoV-2 disease severity ranges from no to 
minimal symptoms, mildly symptomatic with cough and dyspnea, to severe respiratory 
distress with multi-organ failure requiring admission to an intensive care unit and 
emergent ventilator support.7 Although data are evolving, the severity of illness varies 
with age, co-existing comorbidities, and biological sex, with older age, people with pre-
existing cardiovascular disease, and males manifesting greater disease severity.8 
 
A worldwide effort is in place to contain and suppress human-to-human 
transmission.9 These public-health strategies aim to slow the rate of spread and reduce 
the burden on critical care infrastructure. However, we also need effective therapeutics. 
Vaccine trials are underway but potential approvals are at least a year away.10 
Development of new drugs de novo to treat SARS2-CoV-2 will likely take even longer. 
Thus, the most expedient therapeutic strategy to confront this pandemic will repurpose 
existing FDA-approved therapeutics. One potential strategy targets viral components 
directly, using existing antivirals and anti-infectives currently used for other diseases. 
Such efforts include trials of hydroxychloroquine, remdesivir, and ribavirin.11,12 Another 
strategy involves targeting the human proteins, rather than viral proteins, required for 
SARS CoV-2 entry and replication.  
 
Study Rationale  
 
SARS-CoV-2 recognizes host cell membrane proteins and relies upon their 
enzymatic activity to infect host cells. Like SARS-CoV-1, SARS-CoV-2 has four 
structural proteins: E (envelop), M (membrane), N (nucleocapsid), and S (spike).13 The S 
protein recognizes and binds the ACE2 receptor expressed on target cells. Binding of S 
protein to ACE2 facilitates attachment of the virus to the host cell. However, entry of the 
virus into the host cell requires catalytic cleavage of the S protein (a process termed S 
protein priming) by the host cell membrane protein TMPRSS2.14 Thus, TMPRSS2 is 
required for viral entry and infection. This mechanism is similar to that used by SARS-
CoV-1.14 SARS-CoV-2 and SARS-CoV-1 can also use the host membrane protein 
cathepsin B and L (CatB/L) for S protein priming in vitro. However, TMPRSS2 appears to 
be required for SARS-CoV priming in the infected host whereas CatB/L is not.14,15  
 
TMPRSS2 is expressed in the aero-digestive tract. TMPRSS2 is expressed 
within the nasal mucosa, respiratory sinuses, buccal mucosa, tracheal epithelia, bronchial 
epithelia, lung type 2 pneumocytes, and alveolar macrophages.16–18 In addition to the 


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HITCH Protocol: 20210209 
aero-digestive tract, TMPRSS2 is highly expressed on prostate, kidney, and pancreatic 
epithelia.18 
 
Inhibition of TMPRSS2 reduces SARS-CoV-2 entry into target cells. Camostat 
mesylate is a small molecule inhibitor of TMPRSS2 currently approved in Japan for 
pancreatitis. Pharmacologic inhibition of TMPRSS2 with camostat mesylate prevented 
SARS-CoV-2 entry into cultured human lung cells.14 Importantly, effective abrogation of 
SARS-CoV-2 entry did not require co-targeting of CatB/L, supporting the notion that 
targeting TMPRSS2 alone is sufficient to block SARS-CoV-2. This is consistent with prior 
investigations that demonstrated pharmacologic inhibition of TMPRSS2 was sufficient to 
eliminate lethal SARS-CoV-1 infection in murine models, whereas pharmacologic 
inhibition of CatB/L was not.15 Moreover, murine models deficient in TMPRSS2 (tmprss2 
knockout mice) were more resistant to SARS-CoV-1 infection than wildtype controls, 
exhibited reduced viral replication within lung tissue, and profoundly reduced lung 
immunopathology after infection, suggesting that loss of the tmprss2 gene in humans may 
be protective against SARS-CoV-2 infection.19 The tmprss2 knockout mice appeared 
normal, indicating loss of tmprss2 by itself is not pathogenic.19 Camostat mesylate is 
currently being evaluated in a randomized, double-blind study for hospitalized SARS-
CoV-2+ patients (NCT04321096) in Denmark. In an entirely separate line of investigation, 
a chemical library screen of small molecule inhibitors of TMPRSS2 for an entirely 
unrelated purpose identified the drug bromhexine.20 Bromhexine demonstrated 
submicromolar inhibition of TMPRSS2 and suppressed TMPRSS2 driven metastatic 
progression in murine models.20 The mechanism of bromhexine is not entirely clear, but 
it is sold over the counter in other countries, available both by mouth and via inhalation 
for respiratory disorders. 
 
In contrast, ACE2 is considered loss-of-function intolerant in humans.21  In 
addition, SARS-CoV-mediated down-regulation of ACE2 is thought to contribute to the 
severity of lung pathologies, indicating that down-regulation of ACE2 may further harm 
the lungs of infected patients.22 
 
For all of the aforementioned reasons, it seems that transcriptional regulation of 
TMPRSS2 is the highest priority for clinical evaluation. 
 
Transcriptional regulation of TMPRSS2. The transcriptional regulation of the 
TMPRSS2 gene has been extensively characterized, most rigorously within the prostate. 
The TMPRSS2 gene is located on chromosome 21 and is under the control of the 
androgen receptor (AR). Binding of androgens (e.g. testosterone or dihydrotestosterone) 
to the AR results in homodimerization and translocation of the AR to the nucleus, where 
it binds to its cognate androgen response element in the regulatory regions of its target 
genes, and thereby regulates gene expression.23,24 It is firmly established that 
suppression of AR transcriptional activity through reduction in circulating androgens or 
direct antagonism of AR-androgen binding using AR competitive antagonists reduces 
expression and protein levels of TMPRSS2 within the prostate, as well as prostate 
cancers.25 Remarkably, expression of TMPRSS2 also appears to be hormonally 
regulated within the lung and bronchial cells. Notably, the AR is expressed in type II 


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HITCH Protocol: 20210209 
pneumocytes and the bronchial epithelium.26 Androgens enrich AR binding at the 
TMPRSS2 enhancer and upregulate expression of TMPRSS2 in human lung cells, in a 
fashion similarly to that found in the prostate.26  
 
In addition, our query of publicly available gene expression databases 
demonstrated that TMPRSS2 appears to have a high variability of expression amongst 
individuals.27 To identify the most promising therapeutic opportunities, we performed a 
literature-wide screen of RNA-seq datasets in the NCBI Sequence Read Archive (SRA) 
that incorporated keywords relating to drug treatments. We identified differentially 
expressed genes from 3,089 distinct case-control comparisons featuring a drug 
treatment. Notably, anti-androgenic compounds and estrogens were among the strongest 
and most consistent down-regulators of TMPRSS2 expression, while androgens 
consistently led to up-regulated TMPRSS2 gene expression.27 In other words, these 
studies suggest that the AR induces TMPRSS2 expression, whereas ER transcriptional 
activity is associated with suppression of TMPRSS2 expression.  However, there was an 
initial surge in TMPRSS2 expression after estrogen treatments, followed by a gradual 
decrease in TMPRSS2 expression. Moreover, the highly variable expression pattern of 
TMPRSS2 suggests a provocative and plausible, although unproven, explanation for the 
wide range in disease severity for patients infected by SARS-Cov-2, as well as the higher 
rate of severe infections among males and the reduced rate and severity of infection in 
pre-pubertal children. A link between TMPRSS2 expression and susceptibility to viral 
infection was discovered by a recent genome wide association study that identified 
genetic variants with higher TMPRSS2 expression also had more severe H1N1 and H7N9 
influenza.28 Notably, H1N1 and H7N9 influenza, but not all influenza subtypes, require 
TMPRSS2 for priming.29,30 
 
Identification of drugs that suppress TMPRSS2 expression. Based on the 
aforementioned data that TMPRSS2 is hormonally regulated in the lung by the AR and 
estrogen receptor (ER), it is hypothesized that drugs that interfere with AR driven 
transcription or enhance ER driven transcription will reduce TMPRSS2 expression. An 
informatics analysis of publicly available gene expression data to identify drugs that affect 
TMPRSS2 expression levels identified several existing FDA approved drugs.27 
Unsurprisingly, these included antagonists of the AR an agonists of the ER. A possible 
protective effect from estrogenic agonism in the context of another coronavirus was 
suggested from murine models whereby female mice exhibited reduced susceptibility and 
mortality to SARS-CoV-1 infection as compared to males. Furthermore, anti-estrogen 
treatments of the female mice increased their susceptibility and mortality to SARS-CoV-
1.31  
 
Thus, either suppression of AR or activation of ER may reduce expression of 
TMPRSS2. We chose to focus on suppression of AR, rather than activation of ER, 
because we are concerned that a potential initial estrogen-induced surge in TMPRSS2 
expression could acutely worsen viral infections. Fortuitously, a wealth of FDA approved 
drugs block AR signaling. These include the GnRH analogs that reduce pituitary release 
of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby potently 
suppressing testosterone production, and anti-androgens that interfere with binding of 


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HITCH Protocol: 20210209 
androgens to the AR. These drugs are predominantly used in the treatment of prostate 
cancer, have well known and generally tolerable side effect profiles, and exhibit 
reversibility of their biologic effects. As such, we contend that androgen suppression will 
reduce TMPRSS2 expression in the target cells of SARS-CoV-2 and reduce the severity 
of illness. 
 
Hypothesis and Overarching Objective 
 
➢ Our overarching objective is to investigate if temporary androgen suppression 
that suppresses expression of TMPRSS2 will reduce severity of COVID-19 
disease due to SARS-CoV-2 infection. 
 
➢ Our specific hypothesis is that the GnRH antagonist degarelix reduces the 
mortality, the need for hospitalization and/or the need for intubation/ECMO at Day 
15.  
 
Relevance to the VA and VA Population 
 
 
The COVID-19 pandemic is affecting a wide swath of the US population. Mortality 
from COVID-19 is higher in older, male patients. Given the demographics of the Veteran 
population, there is a critical need to develop therapies that can reduce the severity, 
mortality and duration of hospitalization for our Veteran population. 
 
Selection and Description of Study Drug 
 
Degarelix is an FDA-approved drug for prostate cancer. Of all the FDA-approved 
agents that inhibit AR signaling, degarelix exhibits the most rapid and robust effects. One 
loading dose of 240 mg subcutaneously (SQ) serves as a 30-day depot. As a luteinizing 
hormone releasing hormone (LHRH) antagonist, degarelix acts at the level the pituitary 
to rapidly reduce LH secretion, thereby decreasing testosterone production within the 
testes. A rapid reduction in circulating total testosterone to castrate levels is achieved in 
the majority of patients within 24 hours and virtually all patients in 2-3 days (see attached 
degarelix package insert). The testosterone level recovers after the 30-day depot is 
cleared. Degarelix was selected among other GnRH analogs due to its rapid effect on 
circulating testosterone, safety profile, and availability. For example, LHRH agonists (e.g. 
leuprolide) achieve castrate levels of testosterone over 2-3 weeks; the potent androgen 
receptor antagonists (e.g. enzalutamide and apalutamide) achieve steady-state in the 
serum over approximately 4 weeks. Clearly, these time frames for LHRH agonists and 
AR antagonists are not suited to testing in acutely ill patients with COVID-19.  
Importantly, although LHRH analogs, including LHRH agonists and antagonists 
are well-tolerated in patients with advanced prostate cancer who represent an older 
population (median age ~66-68), there may be increased risk of cardiovascular 
complications. Risk of cardiovascular complication is associated with duration of 
exposure. For example, in a randomized controlled trial involving degarelix for patients 
with pre-existing cardiovascular disease with a median age of 72, ischemic cardiovascular 
events occurred in 3.4% of patients over 12 months of continuous therapy (DOI: 


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HITCH Protocol: 20210209 
10.1200/jco.2015.33.7_suppl.151 Journal of Clinical Oncology 33, no. 7_suppl (March 
01, 2015) 151-151). In a single dose study such as the current study, cardiovascular 
complications are expected to occur at an even lower frequency. Given that the patients 
to be enrolled in this study are acutely ill, daily monitoring and correction of electrolytes 
and blood counts will be performed to mitigate risk. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives: 
The primary objective of this study is to determine if temporary androgen 
suppression induced by degarelix improves the clinical outcomes of Veterans who are 
hospitalized to an acute care ward due to COVID-19 as defined by a reduction in mortality, 
ongoing need for hospitalization, or requirement for mechanical ventilation/extracorporeal 
membrane oxygenation (ECMO). 
The secondary objectives of this study are to determine if temporary androgen 
suppression induced by degarelix reduces time to the clinical improvement, inpatient 
mortality, length of hospitalization, duration of intubation for mechanical ventilation, time 
to achieve a normal temperature, or the maximum severity of COVID-19 illness.   
Endpoints:  
 
Primary Endpoint: 
  
Determine if degarelix + best supportive care (BSC) as compared to placebo + 
BSC reduces the composite endpoint of mortality, need for ongoing hospitalization, or 
requirement for mechanical ventilation/extracorporeal membrane oxygenation (ECMO) at 
Day 15 after randomization. 
 
Secondary Endpoints: 
 
• Determine if degarelix + best supportive care (BSC) as compared to placebo + 
BSC reduces the composite endpoint of mortality, ongoing need for 
hospitalization, or requirement for mechanical ventilation/extracorporeal 
membrane oxygenation (ECMO) at Day 30 after randomization.   
• Determine if degarelix + BSC as compared to placebo + BSC reduces time to 
the clinical improvement as defined by a decline of 2 categories or more from 
the baseline on the modified 7-category ordinal scale of clinical status of 
hospitalized influenza patients (influenza scale, see Appendix A)1, or hospital 
discharge, whichever comes first. 
• Determine if degarelix + BSC as compared to placebo + BSC reduces inpatient 
mortality. 
• Determine if degarelix + BSC as compared to placebo + BSC shortens the 
duration of hospitalization.  


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HITCH Protocol: 20210209 
• Determine if degarelix + BSC as compared to placebo + BSC shortens the 
duration of intubation for mechanical ventilation. 
• Determine if degarelix + BSC as compared to placebo + BSC reduces the time 
to normalization of temperature (T < 37.5℃ for ≥ 48 hours).  
• Determine if degarelix + BSC as compared to placebo + BSC reduces the 
maximum severity of COVID-19 illness based on the influenza severity scale 
(see Appendix A). 
 
 
Exploratory Endpoints 
 
• Determine if age, use of angiotensin converting enzyme inhibitors, the duration 
of pre-hospitalization symptoms, or the presence or absence of hypertension, 
cardiovascular disease, asthma, diabetes mellitus, or COPD are predictive of 
clinical outcome defined by the primary endpoint or any secondary endpoint. 
 
• Determine if baseline, Day 8 or Day 15 values for D-dimer, IL-6, LDH, ferritin, 
total WBC, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), 
or testosterone are predictive of clinical outcome defined by the primary 
endpoint or any secondary endpoint. 
 
• Determine if degarelix + BSC as compared to placebo + BSC reduces 
nasopharyngeal (NP) epithelial or peripheral blood mononuclear cell (PBMC) 
TMPRSS2 expression, NP and plasma viral load, or serum cytokine (TNF, IL-
1, IL-6) levels.  
 
• Determine whether germline genomic factors are predictive of clinical outcome 
defined by the primary endpoint or any secondary endpoint. This analysis is 
optional and is contingent on obtaining adequate number of samples.  
 
• To determine the temporal onset of anti-viral antibodies.  
 
Definition of Need for Ongoing Hospitalization (i.e. discharged): Patients who no 
longer require hospitalization on an acute bed ward for COVID-19 or its complications will 
be considered discharged (i.e. do not need ongoing hospitalization). For example, if a 
patient does not require ongoing hospitalization on an acute care ward due to COVID-19 
but has remained on a non-acute inpatient unit (e.g. physical rehabilitation unit), the 
patient will be considered discharged for the purpose of the endpoints of this study. 
However, if the patient has a major complication of the hospitalization for COVID-19 (e.g. 
stroke) and requires ongoing hospitalization for this complication in an acute care bed, 
then this the patient will be considered as hospitalized for the purpose of endpoint 
definition even if the COVID-19 itself is deemed to have been adequately treated (i.e. no 
ongoing signs and symptoms that are directly due to COVID-19). 
 
 
 


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HITCH Protocol: 20210209 
3. 
STUDY POPULATION 
Rationale for Patient Selection 
 
We have selected to study male patients, ≥18 - ≤ 85 years old (patients > 85 can 
be enrolled if there is no history of COPD, asthma, cardiovascular disease, hypertension, 
diabetes mellitus or active malignancy), who manifest symptoms and a disease severity 
that warrant hospitalization for supportive care. In this patient population, the virus itself 
still drives the severity of the disease, whereas a hyperinflammatory response is thought 
to mediate from ARDS, SIRS, and respiratory failure that underlie the severity of COVID-
19 in critically ill, intubated ICU patients. (A separate study has been designed for patients 
with mild severity COVID-19). Female patients will not be included in this study because 
female androgen suppression reduces endogenous estrogenic activity and thereby 
induces TMPRSS2 expression, which in turn could exacerbate COVID-19. Studies of pre- 
and post-menopausal women are planned in other studies.  
Although it is recognized that older patients are more susceptible to the most severe 
complications of COVID-19, younger patients (e.g. < 40 years old) were not excluded 
because such patients have a clinically significant risk of adverse outcomes including the 
requirement for mechanical ventilation and death. In addition, long-term complications of 
degarelix on fertility are not expected from the single dose of degarelix so that in balance 
and based on a risk-benefit profile of the degerilex, it was decided to include younger 
patients. 
 
Recruitment 
Patient Identification 
Establishment and coordination of site-specific active surveillance mechanisms for 
patient identification are the responsibility of the LSI and local site study team members. 
The general recruitment strategy for all sites requires the early identification, screening, 
and contact of patients seen by the medical center’s primary care and sub-specialty 
medical clinics, other clinics, and inpatient units responsible for the evaluation and 
treatment of patients with likely or confirmed diagnoses of COVID-19.  
 
Male Veterans who are admitted or transferred from an outpatient clinic or the 
emergency department to an acute care bed will be identified by any of the following 
clinical services: 
1. the admitting team, 
2. the emergency department staff caring for a patient who is being admitted 
to acute care, non-ICU bed, or 
3. the outpatient care team caring for a patient who is being admitted to acute 
care, non-ICU bed. 
IRB approved flyers that indicate the contact information, including phone 
numbers, pager numbers, and email of study staff will be posted on the wards and in the 
emergency department and outpatient clinics.  
The PI, one of the sub-investigators, or a study coordinator will be contacted about 
potential patients. Potential patients will then be approached by study staff about the 
study to initiate the informed consenting process.  


27 
HITCH Protocol: 20210209 
 
Eligibility Criteria 
 
Inclusion Criteria 
 
1. Male Veterans admitted to a VA hospital.  
2. Age ≥ 18. 
3. Hospitalized on an acute care ward with a diagnosis of COVID-19 contributing to 
hospitalization. 
4. Positive RT-PCR assay for SARS-CoV-2 on a nasopharyngeal swab sample. 
5. Severity of COVID-19 illness of level 3, 4 or 5 on the influenza severity scale (see 
Appendix A) at the time of randomization.  
6. The subject (or legally acceptable representative if applicable) must provide written 
informed consent for the trial. 
Exclusion Criteria 
 
2. History of severe hypersensitivity to degarelix or any component of its formulation. 
3. History of congenital long QT syndrome or known history of prolonged QT interval 
OR Fridericia correction formula (QTcF) > 500 msec on electrocardiogram on 
electrocardiogram performed during screening .     
4. Planned discharge within 24 hours of treatment initiation.  
5. Subject is planning to conceive or father children within the projected duration of 
the study, starting with the screening visit through 120 days after the last dose of 
study treatment.  
6. Ongoing usage of a Class IA or Class III antiarrhythmic agent (see Appendix D). 
At least 5 half-lives must elapse since any prior use of a Class IA or III 
antiarrhythmic agent prior to administration of study drug.  
7. Baseline electrolyte abnormalities of Grade 3 or higher (based on CTCAE v5.0 
criteria). Patients may be included if baseline electrolyte abnormalities are 
corrected to Grade 2 or lower prior to study drug administration.  
8. Enrollment in another investigational study within 30 days of Day 1.  
9. Myocardial infarction in the past 6 months, severe or unstable angina, or New York 
Heart Association (NYHA) Class III or IV heart disease. 
10. Known psychiatric or substance abuse disorder that would interfere with the 
requirements of the trial.  
11.  Child-Pugh Class C liver disease. 
12. Use of any of the following hormonal agents: 
a. Androgen receptor antagonists or agonists within 4 weeks of study 
enrollment, 
b. Ketoconazole or abiraterone acetate within 2 weeks of study enrollment,  
c. Estrogens or progestins within 2 weeks of study enrollment,  


28 
HITCH Protocol: 20210209 
d. Herbal products that contain hormonally active agents within 2 weeks of 
study enrollment.  
e. Any prior use of an LHRH analogue unless a serum total testosterone 
measured within 30 days of study enrollment is ≥ 150 ng/dL. 
f. Other hormonal agents listed in Appendix B within one day of study 
enrollment. 
13. Unwilling or unable to comply with the study protocol.  
14. Any condition, which in the opinion of the investigator, would preclude participation 
in the trial.  
 
NOTE: We will not be excluding patients based upon renal or hepatic dysfunction, except 
for patients with Child-Pugh Class C liver disease; according to the degarelix package 
insert, degarelix has been safely administered to patients with Child-Pugh class A and B 
liver disease. Moreover, grade 3 and higher liver enzyme abnormalities occur in <1% of 
patients treated with degarelix (degarelix package insert). In clinical practice, degarelix is 
used at full dose in the setting of creatinine clearance <50 ml/min and severe liver disease 
without excess toxicity. In addition, the study population will receive one and only one 
dose of degarelix, which will result in temporary androgen suppression. Most of the side 
effects of degarelix are attributable to the chronic suppression of serum testosterone as 
is typically done for prostate cancer patients, so it is predicted that study patients will likely 
have fewer side effects from degarelix than prostate cancer patients.  
 
4. 
STUDY ENROLLMENT PROCEDURES 
 
Screening  
 
 
Patients will undergo a screening evaluation during a 72-hour window. The 
screening period begins when the patient or his legally authorized representative (LAR) 
has signed the informed consent form.  
Informed Consent  
 
 
 
The Investigator must obtain documented consent from each potential study 
patient prior to conducting any research activities. Patients will be provided complete 
informed consent that will be conducted by site PIs, designated sub-investigators, and/or 
study staff. Subjects will have the option of having family and/or anyone else they deem 
appropriate present during the informed consent process. The PI and/or co-investigators 
will verbally discuss the study with the patient and/or the patient’s legally authorized 
representative (LAR). The patient or LAR will be given the informed consent form (ICF) 
and encouraged to carefully read and review the document. After reading the informed 
consent form, the patient or  LAR will be encouraged to ask any and all questions. The 
investigators will in turn pose questions that will evaluate their understanding of the nature 
and risks of the study. The copy of the ICF can be an electronic iMED, DocuSign or hard 
copy.  
  


29 
HITCH Protocol: 20210209 
 
Although the consenting process can be done in the patient’s room, due to the 
nature of the risks of exposure to a COVID-19 patient, direct communication with the 
patient may not be feasible or safe. Accordingly, the investigator or delegated research 
staff will obtain the patient’s phone number (e.g. bedside phone or cell phone), and 
arrange a three-way call or video conference with the patient (or LAR), an impartial 
witness, and if desired and feasible, additional patients requested by the patient or LAR 
(e.g. next of kin). To ensure that patients are approached in a consistent fashion, a 
standard process should be used when contacting the patient remotely that will 
accomplish the following:  
• Identification of who is on the call.  
• Review of the ICF with the patient by the investigator (or their designee) and 
response to any questions the patient may have,  
• Confirmation by the witness that the patient’s questions have been answered, 
• Confirmation by the investigator that the patient is willing to participate in the trial 
and sign the informed consent document while the witness is listening on the 
phone, 
• Verbal confirmation by the patient that they would like to participate in the trial and 
that they have signed and dated the informed consent document that is in their 
possession. 
If the signed informed consent document will not be able to be collected from the 
patient’s location and included in the study records, the following two options are 
acceptable to provide documentation that the patient signed the informed consent 
document: 
 
• Option #1: Attestations by the witness who participated in the call and by the 
investigator that the patient confirmed that they agreed to participate in the study 
and signed the informed consent, 
  
Please note: It is recommended that the documented verbal confirmation include 
information on the version of the IRB-approved informed consent document that was 
used, such as IRB-approved informed consent date and version 1.0, or other type of 
designation such as IRB-approval date. 
  
• Option #2:  A photograph of the informed consent document with attestation by 
the person entering the photograph into the study record that states how that 
photograph was obtained and that it is a photograph of the ICF signed by the 
patient. 
  
A copy of the informed consent document signed by the investigator and witness 
should be placed in the patient’s trial source documents, with a notation by the 
investigator of how the consent was obtained, e.g. telephone. The trial record at the 
investigational site should document how it was confirmed that the patient signed the ICF 
(i.e., either using attestation by the witness and investigator or the photograph of the 
signed consent). The note should include a statement of why the ICF signed by the patient 
was not retained, e.g., due to contamination of the document by infectious material.  
  


30 
HITCH Protocol: 20210209 
If the patient is unable to provide informed consent and there is a LAR, 
investigators should obtain consent from the patient’s LAR.  
 
The ICF, any subsequent revised written ICF and any written information provided 
to the patient must receive the IRB approval in advance of use. The patient or his/her 
legally acceptable representative should be informed in a timely manner if new 
information becomes available that may be relevant to the patient’s willingness to 
continue participation in the trial. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form 
that captures the patient’s dated signature or by the patient’s legally acceptable 
representative’s dated signature. Specifics about a trial and the trial population will be 
added to the consent form template at the protocol level. 
 
 
The informed consent will adhere to IRB requirements, applicable laws and 
regulations and Sponsor requirements. 
 
 
Subjects will be informed that they may refuse participation in or withdraw from this 
study at any time without prejudice or any negative effect on subsequent care. In addition, 
subjects will be informed that their health care provider may be one of the investigators 
on this study and a conflict of interest may therefore exist in that the investigator may be 
interested in both the patient’s welfare and in the conduct of the study.  
 
LAR and Surrogate Consent  
 
 
The study will utilitze the assent process for patients who are unable to give 
informed consent. The PI and/or co-investigators will verbally discuss the study with the 
patient and/or the patient’s legally authorized representative (LAR)/surrogate. In the event 
that an LAR is needed, the study team will educate the LAR/surrogate on the consent 
process. It will be explained that the LAR/surrogate is being asked to act on behalf of the 
patient because he lacks capacity and is unable to consent on his own behalf in this 
situation. It will be emphasized to the LAR/surrogate that he/she should determine what 
he/she believes is best for the patient. It will also be explained that even though the 
LAR/surrogate consents to the patient’s being in the study, if the patient expresses that 
he does not want to participate in the study, his dissent will be honored and respected, 
even if the LAR/surrogate wants him to participate in the study. The patient or 
LAR/surrogate will be given the informed consent form (ICF) and encouraged to carefully 
read and review the document. After reading the ICF, the patient or his LAR/surrogate 
will be encouraged to ask any and all questions. The investigators will in turn pose 
questions that will evaluate the LAR/surrogate’s understanding of the nature and risks of 
the study. Before obtaining consent from the LAR/surrogate, study team will ask the 
patient if he wishes to participate in the study. If the patient agrees to participate in the 
study, then the informed consent process will be completed by the LAR/surrogate. If the 
patient does not want to participate in the study, then his dissent will be honored and 
respected.  
 


31 
HITCH Protocol: 20210209 
 
However, there are situations where assent cannot be obtained due to either the 
patient’s having disorders involving disturbances of cognitive or intellectual functioning 
(for instance, in mentally challenged patients, or in patients with dementia or patients in 
confused states), rendering them incapable of understanding the disclosed information at 
that time.  
 
 
For patients who are diagnosed with a cognitive disorder (e.g. dementia, 
Alzheimer’s Disease, bi-polar,  schizophrenia or mentally challenged), or in a state of 
delirium due to superimposed complications of COVID, every effort will be made to obtain 
assent. However, due to Legally Authorized Representatives (LARs)/surrogate not being 
allowed in the COVID ward, these individuals may not have an accurate perception of the 
patient’s mental and physical capacity. In this situation, the study will solicit the help of an 
“honest broker” (a provider who is not part of the study team) within the unit to help the 
LAR/surrogate understand the patient’s capacity to participate in the study. 
 
If the investigator(s) conclude(s) that assent may not be possible, an honest broker will 
be asked to witness the process. The honest broker and the investigator(s) will provide 
input on the patient’s capacity to participate in the study to the LAR/surrogate so he/she 
can make an informed decision as to whether the surrogate/LAR should provide consent 
for the patient to participate in the research study. If the LAR/surrogate provides consent 
for the patient to participate, then we study will only obtain consent from the 
LAR/surrogate if assent is not possible.   
 
Randomization Procedure 
 
Patients will be randomized after the investigator has verified that all eligibility 
criteria have been met and the patient has been enrolled.  Patients will be randomized 
2:1 to BCS + degarelix, or BCS + placebo using a block randomization scheme.  Random 
block sizes of 3 and 6 will be used to reduce the chances of guessing future 
allocations.  Randomization will be performed using the Interactive Web Response 
System (IWRS), a computerized system that will allow authorized study personnel to 
randomize patients and obtain study treatment assignments.  Following randomization, 
the site coordinator will obtain a randomization certificate containing the assigned 
randomization number.  Following randomization, the randomization certificate will be 
given to the site pharmacy.  The site pharmacist will then log into the IWRS and use the 
information on the randomization certificate to obtain a treatment assignment certificate 
which will indicate whether the patient has been assigned to degarelix or placebo. The 
URL for the IWRS is:  
https://vaww.abq.csp.va.gov/csp/ctsc/HITCH/main.cfm/logins/welcome 
 
All patients should commence assigned treatment as soon as possible and no later 
than 48 hours (2 calendar days) after randomization.  
Stratification Factors 
 
 
Patients will be stratified according to 3 factors: 
• Age: <65 vs. ≥65 
• History of hypertension prior to hospitalization: yes vs. no 


32 
HITCH Protocol: 20210209 
• Influenza severity scale: 3 vs 4/5 
 
Study site is not a stratification factor because the participating sites will be in close 
communication to minimize variability in providing BSC. Other potential factors that can 
influence clinical outcome include COPD, asthma, and cardiovascular disease will be 
assessed for their relationship to clinical outcome in exploratory analyses.  
 
Blinding  
 
This is a randomized, double-blind study. Patient treatment assignments will 
remain blinded. The study biostatisticians and clinical research pharmacist may access 
treatment assignment information as necessary.  
The investigational drug blind will be maintained using the IWRS. The drug and 
placebo injections will be dispensed by the research pharmacy and packaged to be made 
indiscernible from one another. To maintain the blind, the IWRS will ensure the 
investigator or designee is unaware of the treatment arm assigned to the subject.   Prior 
to dispensing the study medications, the research pharmacist will verify the appropriate 
treatment arm assignment using the IWRS cross-referencing the patient’s randomization 
number. The study drug will be delivered to an unblinded administrator of the study drug 
who is not part of the study team and who will not disclose information regarding study 
drug administration to any member of the study team, the patient or anyone else. 
 
Unblinding Procedure 
The CSPCRPCC will not provide Emergency Code Envelopes to the Research 
Pharmacy for HITCH. Emergency unblinding will be managed through the 24-hour 
emergency call service (505-248-3203). This number is also listed on the patient ID cards 
given to each patient participating in HITCH. The system managed by the CSPCRPCC 
will electronically capture up-to-date study drug assignment information gathered from 
the HITCH IWRS.  
 
Authorization to Break the Blind 
Under unusual circumstances, chiefly related to patient safety and emergency 
medical necessity, unblinding may be necessary if knowledge of the study treatment 
assignment will influence the medical treatment of the patient. This is usually done after 
consultation with the Study Chair.  
If emergency unblinding becomes necessary during local business hours, a 
treating provider should contact the LSI. The LSI should then contact the Study Chair to 
discuss the situation before requesting that a patient be unblinded by the CSPCRPCC. 
Outside of local business hours, a treating provider or LSI may contact the CSPCRPCC 
directly at a number that is available 24 hours per day, 7 days per week (505-248-3203) 
to discuss the need for unblinding and to have the unblinding performed if indicated. 
Efforts should be made to avoid unblinding unless medically necessary for emergency 
treatment decisions. Emergency unblinding procedures are further detailed in the Study 
Operations Manual. 
 


33 
HITCH Protocol: 20210209 
Patients will be provided with a Patient Identification Card that lists local study 
staffs’ telephone numbers, a 24-hour PCC contact number, and contacts for the Study 
Chairs. The research facility’s name and the study drugs are also provided on the card. 
The Patient Identification Card will include the patient’s Randomization Number, which 
can be used to determine the patient’s treatment assignment should emergency 
unblinding be required for patient safety. 
5. 
STUDY DESIGN 
Study Design Overview  
 
This is a randomized phase 2, placebo-controlled, double blind clinical trial to 
compare the efficacy of degarelix + BSC to placebo + BSC on improving the clinical 
outcomes of male Veterans who have been hospitalized due to COVID-19. Enrolled 
patients must have documented infection with SARS-Cov-2 based on a positive RT-PCR 
result performed on a nasopharyngeal swab. Patients will be centrally randomized 2:1 to 
the study arms. BSC consists of supplemental oxygen, antibiotics, vasopressor support, 
peritoneal or hemodialysis, antibiotics, intravenous fluids, etc. The primary endpoint is to 
determine if degarelix + best supportive care (BSC) as compared to placebo + BSC 
reduces the composite endpoint of mortality, ongoing need for hospitalization, or 
requirement for mechanical ventilation/extracorporeal membrane oxygenation (ECMO) at 
Day 15 after randomization. 
 
 
 
 
 
 
 
 
 
 
 
 
Study Schema 
 
 
 
 


34 
HITCH Protocol: 20210209 
 
 
Sample Size 
 
A total of 198 patients will be enrolled with 2:1 ratio for degarelix + BSC versus 
placebo + BSC (n = 132 for degarelix + BSC and n= 66 for placebo + BSC).  
 
Study Duration 
• Study enrollment = estimated 90 days (i.e. first patient in [FPI] → last patient in 
[LPI] = 90 days).  
• Assessment of response and additional follow-up for primary endpoint = date of 
LPI + estimated -60 days. 
• Completion of data analysis = date of LPI + estimated 60 days.  
• Total study duration = estimated 210 days.  
 
Feasibility of Accrual 
 
The planned total accrual is 198 patients, including a 5% drop out rate. As of April 
7, 2020, the sites have the following number of confirmed COVID-19 patients: 
• Brooklyn: 83 
• GLA: 22. There are an addition 11 patients whose COVID status is pending. 
• Manhattan: 51 
• Puget Sound: 9 
 
The number of hospitalizations for confirmed COVID-19 is increasing. For example, 


35 
HITCH Protocol: 20210209 
the Brooklyn VA had 54 patients as of 4/02/2020. Given the anticipated increase in 
number of hospitalized patients, we expect to reach our accrual goal within the planned 
90-day period of enrollment.  
 
Duration of Patient Follow-up 
 
Patients will be followed until death or 60 days after randomization, whichever 
comes first. If a patient dies or refuses to continue participation, he will be terminated. A 
termination form will be used to record the termination information for these patients. If a 
patient remains hospitalized beyond Day 30, the patient will continue to be followed for 
clinical endpoints, but no additional research labs will be obtained.  
6. 
STUDY TREATMENT 
Degarelix 
Degarelix (as the acetate) is formulated as a sterile lyophilized powder for injection. 
Degarelix forms a depot upon subcutaneous administration, from which it is released to 
the circulation.  The long half-life after subcutaneous administration is a consequence of 
a very slow release of degarelix from the depot formed at the injection site(s). The 240 
mg dosage is achieved by the administration of two 120 mg SQ doses in the deep 
abdominal subcutaneous tissue. 
The 240 mg dosage was chosen because it results in rapid suppression of serum 
testosterone levels. This rapid testosterone suppression is predicted to result in 
downregulation of TMPRSS2 expression, which can inhibit further viral infection and 
propagation and thereby reduce the clinical severity of COVID-19. One and only one dose 
was selected because the suppressive effect on testosterone will endure for at least four 
weeks, which will allow for the potential disease remitting effects to be observed amongst 
hospitalized COVID-19 patients, who have a median time to clinical improvement of 15 
days (Remdesivir study). 
The normal target population for this drug is men. In this study, only men will 
receive the drug. The indication in the package insert is patients with advanced prostate 
cancer. The study population does not target men with prostate cancer. Men with prostate 
cancer get one loading dose and then are continued indefinitely on a lower dose of the 
medication. The study population will receive one and only one dose of degarelix (loading 
dose), which is expected to result in temporary androgen suppression. Most of the side 
effects of degarelix are attributable to the chronic suppression of serum testosterone as 
is typically done for prostate cancer patients, so it is predicted that study patients will likely 
have fewer side effects from degarelix than prostate cancer patients. 
Degarelix is well tolerated. Most side effects are attributable to suppression of 
serum testosterone levels, such as hot flashes and erectile dysfunction. Degarelix and 
other LHRH analogues have been associated with an increase risk of cardiovascular 
complications, although these effects are observed with chronic administration of 
degarelix; the increased risk appears to be restricted to patients with pre-existing 


36 
HITCH Protocol: 20210209 
cardiovascular disease. The current study involves one and only one dose of degarelix, 
which will temporarily suppress serum testosterone. In addition, 
A prolonged QTcF interval may occur in patients on LHRH analogues, but is 
more frequent in patients receiving LHRH agonists as opposed to LHRH antagonists 
like degarelix. In a randomized controlled trial, the incidence of prolongation in the QTcF 
to >500 msec was <1% over 12 months of continuous therapy with degarelix; ventricular 
arrhythmias including torsades de pointes did not occur in any patient over 12 months. 
Thus, although cardiotoxicity represents a potential complication of degarelix, we expect 
that the potential benefit of degarelix is greater than the cardiovascular risk especially 
given the one-time nature of the degarelix administration in the current study. 
Nonetheless, we have included ongoing assessments of adverse events of special 
interest, including arrhythmias and thromboembolic events (please see Adverse Events 
and Serious Adverse Events, Safety Monitoring and Statistical Considerations sections 
for detailed discussion). In a phase 2 study involving two months of degarelix (one 
loading dose of 240 mg followed by one maintenance dose of 80 mg), no grade 3 
toxicities were observed amongst 45 patients who were monitored until gonadal 
recovery (UCLA abstract). 
Moreover, an 80 patient trial was conducted for the explicit purpose of 
determining if single dose degarelix at supratherapeutic concentrations has an intrinsic 
effect on cardiac repolarisation and the QT interval (Olsson et al. Clin Drug Investig . 
2017 Sep;37(9):873-879. DOI: 10.1007/s40261-017-0547-7). The conclusion was that 
degarelix by itself does not have any effect on the QT interval and cardiac repolarization 
even at supratherapeutic concentrations. 
Systemic allergic reactions from degarelix are rare. In a randomized controlled 
trial that included over 400 patients chronically treated with degarelix, no systemic 
allergic reaction including anaphylaxis was observed (BJU Int. 2008; 102(11):1531–
1538) 
Best Supportive Care 
Best supportive care will include all treatments that would be applied irrespective 
of patient enrollment and includes but is not limited to supplemental oxygen, antibiotics, 
vasopressor support, peritoneal or hemodialysis, antibiotics, intravenous fluids. The 
treatment landscape for COVID-19 is rapidly evolving. Accordingly, the clinical trial will 
allow for updates to the allowed treatments. For example, emergency authorization of 
remdesivir was recently granted, so remdesivir usage is allowed prior to or during study 
enrollment. In addition, use of convalescent plasma is not uncommon, is available 
through an expanded access program and will be allowed prior to or during study 
enrollment. New treatments will have a drug utilization report assessment prior to use to 
identify overlapping toxicities prior to use of a new treatment. 
Off-label use of other agents or interventions will be allowed. For example, anti-
coagulation is recommended by various societies, including the American Society of 


37 
HITCH Protocol: 20210209 
Hematology. Off-label use of IL-6 antibodies will also be allowed on study; however, 
formal enrollment to another investigational study involving IL-6 antibodies is prohibited. 
The development of novel treatments and interventions for COVID-19 will be 
monitored by lead site investigators (Drs. Rettig and Nickols) as well as other study 
team members. Appropriate changes to allowed treatments and interventions will be 
instituted accordingly. 
Description of Treatment Regimens 
 
Patients will be randomly assigned to receive a one-time dose of degarelix 240 mg 
SQ or matching placebo on day 1.  The matching placebo will contain equal volume 0.9% 
saline.   
No dose modifications are allowed for degarelix. 
 
Prescribing and Dispensing Study Products 
 
Study medication (Degarelix (Firmagon) 240 mg or placebo) will be dispensed by 
the local research pharmacist at each site after careful confirmation of treatment 
assignment. 
  
In addition to best supportive care, each patient will receive a one-time dose of 
study medications supplied as 2 – 3ml syringes for deep SQ administration on either side 
of the anterior abdomen in the general periumbilical area. 
 
Treatment 1 - Active Degarelix (2 – prefilled syringes containing 3 ml of reconstituted 
Degarelix concentrated to 40mg/ml) 
 
Treatment 2 - No active, only placebo (2 – prefilled syringes containing 3 ml of 0.9% 
saline) 
 
The Local Research Pharmacist will dispense  study medications according to the 
treatment assignment in IWRS. Upon receipt of an approved study medication order, the 
Local Research Pharmacist will use the IWRS to verify the correct treatment assignment 
prior to dispensing the study medication to the unblinded administrator. Each study 
medication order must be logged.  
  
Sixty Minute Rule: If the study medication (degarlix or placebo) cannot be 
administered within 60 minutes from the time of reconstitution/preparation, the medication 
cannot be administered. Even though the placebo is not affected, procedures should be 
in place, that maintain the blind. In such cases, the Local Research Pharmacist will need 
to document the reasons for delay and replacement. 
 


38 
HITCH Protocol: 20210209 
Method of Administration 
Degarelix is administered as a subcutaneous injection in the abdominal region. 
Injections should be given in areas of the abdomen that will not be exposed to pressure, 
e.g., not close to waistband or belt nor close to the ribs. 
Degarelix should not be administered IV. 
The degarelix or placebo will be administered deep SQ in the abdominal area by 
pinching skin and elevating SQ tissue by a study-approved clinician; 
• Insert the needle at a 45-degree angle.  
• Gently pull plunger back to check for aspiration  
o (if blood is aspirated into syringe, do not inject; discard and reconstitute a 
new dose)  
• Slowly inject over 30 seconds, remove needle and then release skin.  
• Repeat this procedure for both doses.  
Each dose should be administered on either side of the anterior abdomen in the general 
periumbilical area.  
 
Source and Handling of Study Drug  
 
The local VA pharmacy will be supplying the degarelix (Study Drug) and matched 
SQ placebo. The placebo will consist of normal saline. The local VA Pharmacy will 
purchase a supply of degarlix for exclusive use in the study. The Pharmacy will be 
reimbursed for the cost of degarlix from by the study. The placebo (normal saline) will be 
supplied by the pharmacy. 
 
Degarelix for injection (Firmagon ®) 240 mg for subcutaneous use can be obtained 
from VA National Prime Vendor. The site pharmacy must ensure that adequate supplies 
of degarlix are available for dispensing and/or administering to study patients and should 
account for lead times in drug procurement.  A minimum amount of degarelix will be kept 
on hand at all times (enough drug to treat 20 patients with degarelix for the maximum 
duration of treatment = degarelix x 1 dose administered within 24 hours of randomization). 
 
Degarelix is a commercially available product with expiration dating assigned by 
the manufacturer. The research pharmacy will monitor the dating of all study drug to 
ensure that the drug will not expire through the anticipated administration and use by the 
patient. 
  
Study drug must be stored in a secure, limited-access location under the storage 
conditions specified on the label. Site pharmacies are responsible for providing secure 
storage for study drugs in the Pharmacy or elsewhere as directed by federal and local 
laws, regulations, policies, and procedures. Investigational drugs must be stored 
separately from non-study drug inventory to avoid co-mingling of investigational and 
clinical drug products. 


39 
HITCH Protocol: 20210209 
  
Receipt and dispensing of trial medication must be recorded by an authorized 
person at the trial site. Drug will be stored per manufacturers’ recommendations in the 
VA Clinical Research Pharmacy. The VA Clinical Research Pharmacy will maintain an 
inventory of the study drug, including the lot number, expiration date, amount shipped, 
date of shipment, dates/amounts dispensed, and remaining amounts of drug. Site 
pharmacists should consult VHA Handbook 1108.04 “Investigational Drugs and supplies. 
 
Degarelix requires special hazardous agent handling. (NIOSH 2016 [group 1]). 
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves 
(single) should be worn during receiving, unpacking, and placing in storage. 
 
Degarelix supplies may not be used for any purpose other than that stated in the 
protocol. The investigational drug will be dispensed and administered only for the 
purposes of HITCH. The LSI is responsible for assuring that the HITCH investigational 
drug is administered only to HITCH study patients by qualified and approved study 
personnel. The LSI is ultimately responsible for all study drug at their clinical site. 
  
If any dispensing errors or discrepancies are discovered, the sponsor must be 
notified immediately. The investigator or designee must record the current inventory of all 
study medications (degarelix 240 mg) on a sponsor-approved drug accountability log. The 
following information will be recorded at a minimum: protocol number and title, name of 
investigator, site identifier and number, description of study medications, expiry date and 
amount dispensed including initials, seal, or signature of the person dispensing the drug, 
and the date and amount returned to the pharmacy by the site (if applicable), including 
the initials, seal, or signature of the person receiving the study medications. The log 
should include all required information as a separate entry for each subject to whom study 
medications is dispensed. Prior to site closure or at appropriate intervals, a representative 
from the sponsor or its designee will perform study medications accountability and 
reconciliation before study medications are returned or locally destroyed. The investigator 
or designee will retain a copy of the documentation regarding study medications 
accountability, return, and/or destruction, and originals will be sent to the sponsor or 
designee.  
Packaging and Labeling Information 
Drugs or matched placebos will be supplied to the research staff in a manner that 
does not identify the active versus placebo drug. The research staff will remain blinded to 
the treatment group assignment. 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the 
storage conditions specified on the label.  Site pharmacies are responsible for providing 
secure storage for study drugs in the Pharmacy or elsewhere as directed by federal and 
local laws, regulations, policies, and procedures. Investigational drugs must be stored 
separately from non-study drug inventory to avoid co-mingling of investigational and 


40 
HITCH Protocol: 20210209 
clinical drug products.  Site pharmacists should consult VHA Handbook 1108.04 
“Investigational Drugs and supplies”   
 
Clinical supplies may not be used for any purpose other than that stated in the 
protocol. The investigational drug will be dispensed and administered only for the 
purposes of HITCH. The LSI is responsible for assuring that the HITCH investigational 
drug is administered only to HITCH study patients by qualified and approved study 
personnel. The LSI is ultimately responsible for all study drug at their clinical site.  Receipt 
and dispensing of trial medication must be recorded by an authorized person at the trial 
site. Drug will be stored per manufacturers’ recommendations in the VA Clinical Research 
Pharmacy. The VA Clinical Research Pharmacy will maintain an inventory of the study 
drug, including the lot number, amount shipped, date of shipment, dates/amounts 
dispensed, and remaining amounts of drug. A minimum amount of drug will be kept on 
hand at all times (enough drug to treat 20 patients with degarelix for the maximum 
duration of treatment = degarelix x 1 dose administered within 24 hours of randomization).  
 
The study drugs are commercially available products with expiration dating 
assigned by the manufacturer. The research pharmacy will monitor the dating of all study 
drug to ensure that the drug will not expire through the anticipated administration and use 
by the patient.  
Hazardous Drugs Handling Considerations 
Degarelix requires special hazardous agent handling.  (NIOSH 2016 [group 1]).  
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves 
(single) should be worn during receiving, unpacking, and placing in storage.   
Adverse Reactions 
 
Degarelix (see Appendix F) 
 
o >10%: 
Central nervous system: Fatigue (3% to ≥10%) 
Endocrine & metabolic: Hot flash (26%), increased gamma-glutamyl transferase 
(≥10%), weight loss (≥10%), weight gain (9% to ≥10%) 
Hepatic: Increased serum transaminases (47%) 
Local: Injection site reactions (35%, grade 3: ≤2%; pain at injection site [28%], 
erythema/bruising at injection site [17%], swelling at injection site [6%], 
induration at injection site [4%], injection site nodule [3%], injection site infection 
[including abscess, 1%]) 
Miscellaneous: Fever (1% to ≥10%) 
o 1% to 10%: 
Cardiovascular: Hypertension (6%) 
Central nervous system: Chills (5%), dizziness (1% to 5%), headache (1% to 5%), 
insomnia (1% to 5%) 
Dermatologic: Diaphoresis 
Endocrine & metabolic: Hypercholesterolemia (3%), gynecomastia 
Gastrointestinal: Constipation (5%), nausea (1% to 5%), diarrhea 


41 
HITCH Protocol: 20210209 
Genitourinary: Urinary tract infection (5%), erectile dysfunction, testicular atrophy 
Hepatic: Increased serum ALT (10%; grade 3: <1%), increased serum AST (5%; 
grade 3: <1%) 
Immunologic: Antibody development (antidegarelix: 10%) 
Neuromuscular & skeletal: Back pain (6%), arthralgia (5%), weakness (1% to 5%) 
Miscellaneous: Night sweats (1% to 5%) 
o <1%, postmarketing, and/or case reports. 
  
Bone 
metastases 
(worsening), 
cerebrovascular 
accident, 
depression, 
hypersensitivity reaction (including anaphylaxis, urticaria, and angioedema), itching 
at injection site, local soreness/soreness at injection site, malignant lymphoma, 
mental status changes, myocardial infarction, osteoarthritis, prolonged Q-T interval 
on ECG, squamous cell carcinoma, unstable angina pectoris. 
 
Dose Modification 
 
 
No dose modifications will be allowed.  Degarelix will be administered as a one-
time dose, so dose modification does not apply. 
 
Prohibited Concurrent Treatments and Medications 
 
• Medications listed in the exclusion criteria. 
• Any medication that can serve as pro- or anti-androgen, -estrogen, or -progestin (See 
Appendix B). Dexamethasone was recently reported to reduce COVID-19 severity, so 
glucorticoids for the purpose of treating COVID-19 are permitted. 
• Use of other investigational drugs for COVID-19 treatment within 28 days (or five half-
lives whichever is shorter; with a minimum of 14 days from the last dose) preceding 
the Day 1 of treatment. Use of hydroxychloroquine or chloroquine is permitted.  
• Use of hydroxychloroquine and chloroquine are prohibited 
• Use of drugs known to prolong QT interval are prohibited 
 
 
 
 
 
 


42 
HITCH Protocol: 20210209 
7. 
STUDY PROCEDURES  
Table 1. Schedule of Events 
 
Assessment 
Screening
A 
Day 1 
Day 8 
Day 15 
Day 22 
Day 30 
Day 60 
Informed consent 
X 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Vital signs/Medical/interval 
historyB  
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
Clinical assessment of statusC 
X 
X 
X 
X 
X 
X 
 
Serum total testosterone levelD 
X 
 
X 
X 
 
X 
 
D-dimer, LDHD 
X 
 
X 
 
 
 
 
CBC with differential, chem 
panel and electrolytes, 
coagulation tests, cardiac blood 
tests,  and LFTsE 
X 
 
 
Daily 
 
 
 
Inflammatory testsD,K 
X 
Weekly 
 
Research blood collectionD,F,G,H 
 
 
X 
X 
X 
 
X 
 
NP swabD,F,G,H 
 
X 
X 
X 
 
 
 
Degarelix or matched placebo 
 
X 
 
 
 
 
 
EKGI 
X 
 
 
 
 
 
 
Post Discharge Follow upJ 
 
 
 
 
 
X 
X 
 
A Screening studies should be performed within 72 hours of Day 1.  
B Vital signs, medical history and physical exam data can be accessed from the electronic 
medical record so as to minimize exposure to patients.  This assessment should continue 
so long as the patient is hospitalized.  
C Based on modified 7-category ordinal scale of clinical status of hospitalized influenza 
patients (see Appendix A). This assessment should continue so long as the patient is 
hospitalized. 
D All labs should be performed in the local VA laboratory. The window for labs is +/- 2 
days.  The collection of labs will discontinue when the participant is discharged.  
E Chem panel = Sodium, potassium, chloride, CO2, blood urea nitrogen, creatinine. 
Electrolytes = Calcium, magnesium, phosphorus. LFTs = AST, ALT, albumin, total 
bilirubin, alkaline phosphatase, LDH. Cardiac blood tests = troponin, CPK. Coagulation 
tests = D-dimer, PT/INR and aPTT. Some of these labs are collected for the purposes of 
safety assessments and risk mitiagation and will not necessarily be collected in CRFs. 
F Research blood collection will be performed at GLA only. Research blood should include 
1 gold top and 1 Streck tube; each tube will contain 5 mL of blood. The Day 1 collection 
can be performed up to 72 hours prior to study drug administration. The window for 
research blood collection on Days 8, 15, and 30 is +/- 2 days,. 


43 
HITCH Protocol: 20210209 
G NP swabs will be collected at GLA, only. The Day 1 NP swab can be obtained up to 24 
hours prior to study drug administration. The window for the Day 8 and 15 NP swab is +/- 
2 days. All NP swabs will be placed immediately in the supplied vial containing formalin. 
H Collection of research blood and NP swabs will be attempted at the indicated time 
points, but it is understood that some of these samples may not be obtained due to 
logistical reasons, such as safety. Accordingly, the failure to collect the research blood or 
NP swabs will not be considered a protocol deviation.  
I EKG. EKGs beyond the screening window will be performed per standard of care.  
J Upon discharge, patients will be followed for vital status, need for re-hospitalization, and 
adverse events. 
K Inflammatory blood tests = CRP, IL-6, ferritin and pro-calcitonin. 
 
Laboratory abnormalities observed during study enrollment will be managed 
according to local hospital practices and good standard of care. Study teams will focus 
on electrolyte abnormalities that could impact risk for cardiac events. 
 
Handling of Research Specimens 
 
 
The research specimens will be transported to UCLA for analysis on the same day 
of collection whenever possible. If samples cannot be transported to UCLA on the same 
day of collection, then the samples will be stored within the GLA Medical Center Building 
500 Clinical Research Center. In the Clinical Research Center, the NP swabs will be 
stored at room temperature, and blood specimens will be stored at -20℃.  
8. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Overview of Adverse Event Reporting 
Timely and complete reporting of safety information assists study management in 
identifying any untoward medical occurrence. This contributes to patient safety, regulatory 
compliance and improvements in study design or procedures. In addition, close attention 
to AEs provides valuable information about the safety and tolerability of study drugs. This 
study specific safety plan is designed to collect information on the safety and tolerability 
of the study medications; thus, reporting will be conducted in accordance with the 
requirements of GCP and other regulatory requirements governing clinical research in the 
US. 
Definitions and recording requirements for this trial are based on the International 
Conference on Harmonisation Efficacy Guideline 2a: Pharmacovigilance: Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting (ICH-E2A), the 
Code of Federal Regulations (21 CFR 312.32) and CSP Global Standard Operation 
Procedure (SOP) 3.6. 
In HITCH, patients will receive a regimen of FDA approved commercially available 
degarelix for injection (Firmagon ®) 240 mg for subcutaneous use or matching placebo.  
Local Study Investigators, with assistance from their local SC, are responsible for 
collecting AE and SAE information regarding the patients at their sites. 


44 
HITCH Protocol: 20210209 
Non-serious AEs and SAEs will be collected from the time of randomization until 
60 days after the last dose of study medication.  Throughout the specified duration of AE 
and SAE collection, data will be collected through spontaneous local SC/LSI/Co-I contact, 
during in-person study visits, and gathered during telephone contacts and medical record 
reviews when performed (see Table of Scheduled Events). AEs will be collected based 
on a review of the electronic medical record. If a patient receives care at a non-VA facility 
for an AE or SAE, study staff should obtain the requisite release of information form(s) 
from the patient and acquire the pertinent medical records from the facility. 
Adverse events that are open will require follow-up reports (if necessary) every 30 
days until resolved or until the end of the trial. 
Adverse events reported to study staff and deemed related to the study drug(s) 
and all SAEs will be recorded on an AE or SAE form (respectively) and documented in 
source records (e.g., the electronic VA medical record and/or the patient's study record). 
In this way, the site creates a permanent record that provides information on the patient’s 
clinical course while in the study. 
Adverse Events (AEs) 
An AE is any untoward physical or psychological occurrence in a human 
participating in research or associated with the use of a drug in a human. An AE can be 
any unfavorable and unintended event, including an abnormal laboratory finding, 
symptom, or disease associated with the research or the use of a medical investigational 
test article. An AE does not necessarily have to have a causal relationship with the 
research or medical investigational test article. (See 21 CFR 312.32(a) and VHA 
Handbooks 1058.01 and 1200.05) 
Severity of an Adverse Event 
Adverse events will be graded according to CTCAE v5.0. 
All adverse events that are related to the study intervention or procedures are 
recorded at each research assessment visit (description, severity, relationship to study 
intervention, date onset, date resolution).  
The following categories are used to convey the severity of an adverse event: 
• Grade 1 Mild; – Events require minimal or no treatment and do not interfere with 
the patient’s daily activities. 
• Grade 2 Moderate; – Events result in a low level of inconvenience or concern 
with the therapeutic measures. Interferes with normal daily activities to some 
extent. 
• Grade 3 Severe; – Events interrupt a patient’s usual daily activity and may require 
systemic drug therapy or other treatment. May severely interfere with or prevent 
normal daily activities 
• Grade 4 Life-threatening consequences; – Events requiring urgent intervention 
• Grade 5 Death related to AE. 
Serious Adverse Event (SAEs) 


45 
HITCH Protocol: 20210209 
An AE is considered an SAE if, in the view of either the investigator or sponsor, it results 
in any of the following outcomes:  
• Death: 
• A life-threatening AE; 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it were more severe. 
• Inpatient hospitalization or prolongation of existing hospitalization; 
• A persistent, significant, or permanent incapacity or substantial disruption in the 
patient's body function/structure, physical activities and/or quality of life; 
• Congenital anomaly/birth defect; or 
• Important medical events that may not be immediately life-threatening, result 
in death, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Such events include intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug 
abuse. (See 21 CFR 312.32(a) and VHA Handbooks 1058.01 and 1200.05) 
A serious problem is a problem in human research or research information security 
that may reasonably be regarded as: 
1. Presenting a genuine risk of substantive harm, to the safety, rights, or welfare of 
human research subjects, research personnel, or others, including their rights to 
privacy and confidentiality of identifiable private information; or 
2. Substantively compromising a facility’s Human Research Protection Program 
(HRPP) or research information security program. 
Relatedness 
Relatedness involves an assessment of the degree of causality (attributability) 
between the study intervention and the event. Site investigators will be asked to provide 
an assessment of relatedness of the event to the study intervention. The assessment 
provided by the site investigator is part of the information used by the sponsor (CSP) to 
determine if the event represents an alteration in the safety profile of the study 
intervention. All events with a reasonable causal relationship to the study intervention 
should be considered “related”. A definite relationship does not need to be established. 
This study will use the following relatedness scale to categorize an event: 
 
• Definitely Related: The event is clearly related to the study intervention – i.e. an 
event that follows a reasonable temporal sequence from administration of the 
study intervention follows a known or expected response pattern to the suspected 
intervention that is confirmed by improvement on stopping and reappearance of 
the event on repeated exposure and that could not be reasonably explained by the 
known characteristics of the patient’s clinical state. 


46 
HITCH Protocol: 20210209 
• Possibly Related: An event that follows a reasonable temporal sequence from 
administration of the study intervention follows a known or expected response 
pattern to the suspected intervention, but that could readily have been produced 
by a number of other factors. 
• Not Related: The event is clearly not related to the investigational agent/procedure. 
- i.e. another cause of the event is most plausible; and/or a clinically plausible 
temporal sequence is inconsistent with the onset of the event and the study 
intervention and/or a causal relationship is considered biologically implausible. 
Unanticipated Adverse Event: 
An AE that is new or greater than previously known, in terms of nature, severity, 
or frequency of occurrence, or any other unanticipated serious problem associated with 
the investigation that relates to the rights, safety, or welfare of subjects, as documented 
in the protocol or other materials approved by the IRB of record or the characteristics of 
the study population. Such materials may include but are not limited to: the informed 
consent form, safety plan, clinical investigator’s brochure (or CSPCPRCC’s Drug 
Information Report), and product labeling (see VHA Handbook 1058.01). The Sponsor 
(Cooperative Studies Program) will concur or disagree with the site investigator’s 
assessment as to whether an adverse event is anticipated or unanticipated (sometimes 
referred to as expected/unexpected, respectively). 
Expedited Reporting of Serious Adverse Events 
All SAEs will be reported by submission of the event into the HITCH reporting 
system within 3 calendar days of the Study Site Personnel becoming aware of the event. 
The reporting system will immediately inform the Study Biostatisticians, Clinical Research 
Pharmacists and Study Chairs. All SAEs found to be attributable or related to the study 
intervention will be documented as “possibly related” or “related” within the SAE Form. 
Expedited Reporting of Adverse Events of Special Interest 
 
Cardiac arrhythmias and thromboembolic events will be considered AEs of special 
interest. Any cardiac arrhythmia or thromboembolic event of grade 3-5 according to 
Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0; see 
Appendix C) will be reported in a manner similar to SAEs, whereby the event will be 
reported to the HITCH reporting system within 3 calendar days of the Study Site 
Personnel becoming aware of the event.  
Reporting of Related and Unexpected Serious Adverse Events 
All SAEs will be assessed by the study Sponsor to determine if an event is 
anticipated or unanticipated. The source of information that will be utilized in the 
determination of expectedness will include the HITCH Drug Information Report, the 
HITCH Informed Consent, published literature, and the FDA Adverse Event Reporting 
System (AERS). SAEs found by the Sponsor  to be both related to the investigational 
treatment and unexpected will be reported to the VA Chief Research and Development 
Officer, the FDA, and site investigators after review by the Study Chairs, VA Central IRB, 
the CSPCRPCC Director and the Perry Point CSPCC Director. 
Reporting of Adverse and Serious Adverse Events to the DMC 


47 
HITCH Protocol: 20210209 
The HITCH Biostatisticians, with coordination from CSPCRPCC, will tabulate and 
summarize all study intervention related AEs and all SAEs (intervention related or not 
related) for the DMC on a schedule set by the DMC, but no less than annually. The DMC 
will also determine when the committee should be unblinded to treatment assignment in 
reviewing AE/SAE data. The DMC will advise the CSP Director whether the study should 
continue or be stopped for safety reasons. 
Reporting Requirements of the VA Central or Local IRB 
Sites are additionally responsible for following the VA Central IRB policy in 
submitting safety data, unanticipated serious problems, and protocol deviations. The VA 
Central IRB’s most recent policy including a Table of Reporting Requirements, 
instructions, and forms can be found at 
http://www.research.va.gov/vacentralirb/policies.cfm.  
VHA Handbook 1058.01 requires that the VA CIRB must be notified orally and 
immediately upon becoming aware of any research death that is both unanticipated and 
related (includes possibly related) to the research. In addition to the oral notification, site 
personnel must also ensure that a written notification is sent to the VA CIRB within 5 
business days of becoming aware of the death (Note: this is different than the 3 calendar 
day reporting requirement to CSP). 
Reporting to the FDA 
Any FDA reporting requirements will be handled by the sponsor (CSP), not by 
individual sites. In addition to prompt reporting to appropriate VA personnel, 
CSPCRPCC will report SAEs that are both related to study intervention and unexpected 
to the FDA no later than 15 days from when they are notified. If the SAE is a death or a 
life-threatening event, this notification will happen within 7 days. In addition, the FDA will 
be notified (1) for any subject who is withdrawn for safety reasons and (2) for any DMC 
decision to pause enrollment or terminate the study. 
 
9. 
SAFETY MONITORING 
 
Data and Safety Monitoring Plan 
 
The VA Clinical Sciences Research and Development (CSR&D) centralized Data 
Monitoring Committee (DMC) will monitor this study. The CSR&D DMC provides an 
ongoing independent evaluation of the progress of studies, including patient accrual and 
retention, adverse events monitoring, and analysis plan. This is a service that is provided 
by CSR&D to ensure independent oversight of the safety and integrity of this project. No 
other DMC or Data and Safety Monitoring Board (DSMB) review is needed. 
The DMC office is located within the Cooperative Studies Program Coordinating 
Center (CSPCC) at the Edward Hines, Jr. VA Hospital in Hines, IL. The DMC Office at 
Hines then communicates directly with the PI to provide DMC related information. 
After the DMC has recommended approval for this trial to begin and the first patient 
has been randomized, a progress report will be due in approximately one month and then 
monthly thereafter. The PI typically will not need to call in for the DMC review after the 


48 
HITCH Protocol: 20210209 
initial review. The DMC makes recommendations to the director of CSR&D for 
endorsement.  The recommendations range from approval (unconditionally or with 
conditions to be addressed) to probation to termination. 
Following each DMC meeting, the PI will receive meeting minutes containing any 
action items for which a response will be requested typically within 30 days.  Then the 
process starts all over again for the next reporting period. In addition to the quarterly 
progress reports, all Serious Adverse Events are to be reported to the DMC. 
 
Additional Safety Monitoring for AEs of Special Interest 
 
 
Whereas the DMC serves as the entity with primary oversight responsibility for the 
study, additional real-time monitoring will be conducted to capture AEs of special interest, 
including cardiac arrhythmias and thromboembolic events that may result from degarelix. 
In particular, cardiac arrhythmias and thromboembolic complications of grades 3-5 
according to CTCAE v5.0 (see Appendix C) will be closely monitored through not only 
ongoing, daily review of AE and SAE reports, but also through regular, planned 
teleconference calls to include: 
 
• The study chair (Dr. Rettig), co-chair (Dr. Nickols), and the lead site coordinator 
(Ms. Samantha Tran), 
• One or more investigators from each site and/or one or more site coordinators. 
 
The teleconferences will occur on Tuesday of each week until the LPI + 30 days. 
In addition, study sites should report the onset arrhythmias of thromboembolic events of 
grade 3-5 according to CTCAE v5.0 within 72 hours by contacting the study chair or co-
chair by email and voice call (see page 5 for contact information). 
10. 
STATISTICAL CONSIDERATIONS 
 
This is a randomized, placebo-controlled, double-blind phase 2 study that will 
compare the effects of degarelix + BCS to placebo + BCS on the clinical outcomes of 
patients hospitalized due to COVID-19.  
Expected Treatment Effects 
 
In a recent antiviral drug trial to treat adults hospitalized with severe COVID-19 
published in the New England Journal of Medicine (NEJM) on March 18, 2020 (Cao et al. 
2020), the results showed that a mortality rate of 17%, hospital stay rate of 50%, and 
ECMO or  mechanical intubation rate of 11% among the patients managed with BSC after 
two-week follow-up. In the current study, we propose a composite endpoint of mortality, 
ongoing need for hospitalization, and ECMO or mechanical intubation at 15 days after 
randomization. We are expecting to reduce the composite endpoint rate to 35% after the 
degarelix treatment plus BSC from 60% for patients treated placebo plus BSC.    
 
Sample Size Calculation and Power Analysis 
 


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HITCH Protocol: 20210209 
The sample size estimation and power analysis shown in Table 2 are based on the 
hypothesis testing of the primary endpoint, which is the composite endpoint of mortality, 
hospital stay rate, and ECMO or mechanical intubation at 15 days after randomization 
(Day 15).  
 
According to the composite endpoint outlined in the previous section, we assume 
that an effect size for the primary endpoint of 42% can be anticipated in the degarelix 
group. The other assumptions include a three-month accrual time and one-month follow-
up time, and 2:1 sample allocation of degarelix: placebo treatment group. The sample 
size for the study is estimated based on a superiority trial design. To have 90% power of 
detecting the expected 42% reduction using a two-sided two proportion test with a 
significance level of 0.05 in the degarelix compared to the placebo group will require 186 
evaluable patients total (i.e. 124 evaluable patients in the degarelix group and 62 
evaluable patients in the placebo group). Based on an assumed 5% attrition rate, 198 
patients will be required (i.e. 132 in the degarelix group and 66 in the placebo group) to 
achieve actual statistical significance at alpha level of 0.05 and power of 90% (see Table 
2).   
 
 
Table 2: Sample Size Estimation and Power Analysis 
 
 
 
Duration of Study and Number of Participating Sites 
 
To estimate the expected study duration and resources, we assume that the 
recruitment rate will be half of what we anticipate. Under this assumption, various 
scenarios were examined in order to identify an optimal combination between the number 
of sites, the study duration (which includes recruitment period and follow-up period) and 
the estimated budget. The study will include four VA medical centers and each center will 
randomize 17 patients per month on average; however, estimated recruitment rate will 
vary depending on the patient volume of each participating center as the disease evolves. 
Based on these assumptions, the recruitment period was found to be approximately three 


50 
HITCH Protocol: 20210209 
months. This will be followed by approximately one month of follow up for the last patients 
randomized into the study followed by one month of data analysis. Thus, the study 
duration including start-up will be approximately five months. 
 
Interim Analysis and Criteria for Study Termination 
 
A mid-term interim analysis of the primary endpoint will be performed at half of the 
patients or 99 randomized patients complete or are terminated the study. If the mid-term 
analysis of the primary endpoint indicates that the null hypothesis can be rejected with a 
boundary value of 2.77 (standardized Z >  2.77 or  < - 2.77) at an α-level of 0.006 or 
accepted with a boundary value of 0.44 ( - 0.44 ≤ standardized Z ≤ 0.44 ) based on O’Brien 
and Fleming criteria, the study will be recommended for trial termination for efficacy and 
futility reasons (shown in the Figure 1). Enrollment will be paused if the interim analysis 
results indicate crossing of the threshold for futility or efficacy until the final DMC 
recommendation is rendered. 
 
Meanwhile, the drug toxicity will be closely monitored and analyzed. As described 
in previous sections, arrythmia and thromboembolic complications are adverse events of 
special interest that will be monitored closely and graded according to on CTCAE 5.0. 
Once the toxicity markers reach a threshold of 25% (Ray and Rai 2011), a statistical 
analysis of the toxicity will be performed. If the experimental (degarelix) group has a 
significant higher toxicity compared to the placebo group at an α-level of 0.01, then results 
will be reported to the DMC for a recommendation for trial termination.  
 
 
 
Figure 1. Interim analysis stopping boundaries for efficacy and futility 
 
 
Data Analysis Plan 


51 
HITCH Protocol: 20210209 
 
The primary analysis will be performed to test the null hypothesis of no difference 
in composite outcome of mortality, hospital stay rate, and ECMO or mechanical intubation 
at 15 days after randomization between the degarelix + BSC versus placebo + BSC, i.e. 
odds ratio equals one. If the null hypothesis is not rejected, a 95% confidence interval will 
be constructed about the difference observed to inform the medical community as to how 
large the difference is likely to be in either direction.  All statistical tests will be two-sided, 
and the primary outcome will be tested at 5% level of significance. SAS 9.4 or higher will 
be used to conduct all the statistical analyses. A variety of analytic methods will be used 
for the primary endpoint, secondary endpoints, exploratory endpoints analyses, and other 
analyses (Table 3).   
 
Analysis Populations 
 
Intent-to-Treat (ITT) – This population is defined as the population of patients who 
will be randomized to either of the treatment groups – degarelix or placebo. The patients 
will be categorized (in terms of their treatment assignment) based on their initial 
randomized group and will be included in analyses irrespective of their status – completer 
or drop out of the study before completion. The testing power for the primary endpoint is 
estimated as 90% in this population. 
 
Safety – This population includes all patients who will be randomized to either of 
the treatment groups – degarelix or placebo. 
 
The primary analysis of the study will be performed on the primary endpoint on the 
ITT population. SAEs will be analyzed based on the Safety population. 
 
Primary Endpoint Analysis 
 
The primary study endpoint will be the composite outcome of mortality, ongoing 
need for hospitalization, and ECMO or mechanical intubation at 15 days after 
randomization. This outcome will be compared according to assigned treatment groups, 
using Pearson 2 test. The test for differences between the treatment groups in the 
primary outcome will be conducted at an overall α-level of 0.05 (i.e. α = 0.006 for mid-
term interim analysis, α = 0.044 for the final analysis). If a patient drops out from the study, 
then he will be considered as a failure. Additional analyses will be conducted using logistic 
models to adjust for other clinical factors, such as age, hypertension, and COPD. Logistic 
regression will be used for the primary endpoint (y = 1 if a composite outcome, otherwise 
y = 0) analysis with the treatment group as the testing factor (x). The following covariates 
will be included in the model: age (z1), hypertension (z2), and COPD (z3), site (z4). Given 
the composite outcome probability 𝑝= 𝑝 (𝑦= 1|𝑥, 𝑧1, 𝑧2,𝑧3), the basic model is defined 
as follows: 
𝐿𝑜𝑔𝑖𝑡(𝑝) = 𝑙𝑛(
𝑝
1 −𝑝) = 𝛽0 + 𝛽1𝑥+ 𝛽2𝑧1 + 𝛽3𝑧2 + 𝛽4𝑧3 
Odds ratio and 95% confidence interval (CI) will be presented using SAS PROC 
GENMOD or PROC LOGSTIC. If the coefficient for treatment effect is significant, then 


52 
HITCH Protocol: 20210209 
the null hypothesis will be rejected. Logistic models will be tested for goodness of fit.  We 
will assess goodness-of-fit using the statistic -2 log likelihood, which has a 2 distribution 
under the null hypothesis that all the explanatory variables in the model are zero. We will 
also consider the Akaike Information Criterion statistic and the Schwartz Criterion statistic, 
both of which adjust the -2-log likelihood for the number of items in the model. Models 
that show lack of fit will be reconsidered for the inclusion of additional variables or use of 
alternate models with assumptions that are better met by the study data.  One alternate 
model if model fit is poor for logistic regression is a log-linear model. 
Further, Cochran Mantel-Haenszel method will be used to adjust for three 
randomization stratification factors (Age: <65 vs. ≥65, History of hypertension: yes vs. no, 
and Influenza severity scale: 3 vs 4/5) using SAS PROC FREQ as one of the sensitivity 
analyses for the primary efficacy endpoint. 
 
Secondary Endpoint Analyses 
 
Secondary endpoints included in the data analysis are the composit endpoint at 
30 days after randomization, time to clinical improvement, inpatient mortality, length of 
hospital stay, length of intubation for mechanical ventilation, time to normal temperature, 
and the maximum severity of COVID-19 illness, which are defined in the endpoint section. 
The secondary endpoint analyses will be adjusted for multiplicity with a α-level of 0.0071 
for each endpoint. 
 
The composite outcome of mortality, ongoing need for hospitalization, and ECMO 
or mechanical intubation at 30 days after randomization as a secondary endpoint will be 
analyzed using the methods described in the the primary endpoint analysis.  
 
For the time to clinical improvement as defined by a decline of 2 categories or more 
from the baseline on the modified 7-category ordinal scale of clinical status of hospitalized 
influenza patients (influenza scale, see Appendix A) or hospital discharge (see section 2 
for definition of discharge) whichever comes first, survival analysis techniques will be 
used to analyze the time-to-event data for this endpoint. Patients whose conditions getting 
worse or died or withdraw from the study without clinical improvement will be censored. 
Kaplan-Meier analysis will be used to compare the two curves of the time to the clinical 
improvement over the patient follow-up time between the two treatment groups and a log-
rank statistic will be used to test the equality of the survival function estimates of the two 
treatment groups using SAS PROC LIFETEST. Kaplan-Meier curves will be created. 
Additional analysis will be conducted using the Cox’s Proportional Hazards model to test 
the treatment efficacy of the treatment intervention on the time until endpoint events 
adjusted for three prognostic factors: age, hypertension, and COPD. The hazard ratio and 
95% confidence interval (CI) will be presented using SAS PROC PHREG. If the coefficient 
for treatment effect is significant, then the null hypothesis will be rejected. The regression 
model will be checked for the model assumption, adequacy, and the goodness of fit. If 
the model shows lack of fit, then alternate models with assumptions that are better met 
by the study data will be considered. 
For mortality endpoint data analysis, the treatment effect will be analyzed initially 
with a Pearson 2 test and logistic regression will also be performed using SAS PROC 


53 
HITCH Protocol: 20210209 
LOGISTIC by taking account of prognostic factors described in the primary endpoint 
analysis.  
 
For the length of hospital stay data analysis, medians (interquartile ranges) will be 
presented and Wilcoxon tests, a nonparametric method, will be performed to compare 
the medians of the length of hospital stay between the two treatment groups using SAS 
PROC NPAR1WAY. In addition, a quantile regression will be used to test the effect of the 
treatment on the time until the clinical event adjusted for prognostic factors described in 
the primary endpoint analysis. 
 
For the length of intubation for mechanical ventilation data analysis, nonparametric 
analyses will be performed as described in the length of hospital stay analysis. 
 
For time to normal temperature data analysis, survival analysis techniques will be 
used as described in the time to the clinical endpoint analysis using SAS PROC 
LIFETEST and PROC PHREG.  
 
For the maximum severity of COVID-19 illness data analysis, Pearson 2 test will 
be performed for this categorical endpoint using SAS PROC FREQ initially. Given the 
endpoint is also an ordinal variable, Cochran–Armitage test will be performed to test the 
ordinal trend tendency using SAS PROC FREQ. in addition to the frequency analysis, 
proportional odds logistic regression will also be performed using SAS PROC LOGISTIC 
by taking account of the factors of age, hypertension, COPD, and the baseline influenza 
scale (see Appendix A). 
 
Exploratory Endpoint Analyses 
 
Clinical and Laboratory Prognostic Factors 
 
Exploratory analyses will be performed to identify the impact of clinical and 
laboratory prognostic factors on the primary endpoint or any secondary endpoint. Clinical 
factors include age, presence or absence of COPD, hypertension, or cardiovascular 
disease, or use of angiotensin converting enzyme inhibitors. Laboratory measurements 
including D-dimer, IL-6, LDH, ferritin, total WBC, absolute neutrophil count (ANC), 
absolute lymphocyte count (ALC), and testosterone are measured during the patient’s 
hospital stay. Further germline genomic factors will also be analyzed if feasible as 
prognostic factors for the study outcomes for part of the patients. 
 
For continuous variables, the sample size, mean, SD, median, minimum, and 
maximum values for each intervention will be presented for each parameter at each data 
collection time point and tested using SAS PROC TTEST between the treatment groups. 
If a variable is not normally distributed the non-parametric method will be applied using 
SAS PROC NPAR1WAY. For categorical variables, the number and percentage of 
patients by the treatment group will be tabulated and tested based on Pearson 2 test 
using SAS PROC FREQ.  
 


54 
HITCH Protocol: 20210209 
Univariate correlation with the primary endpoint or any categorical secondary 
endpoint will be assessed for each clinical and laboratory factor based on logistic 
regressions using SAS PROC LOGISTIC. For the secondary endpoints of time to events 
data, univariate analysis will be performed based on Cox regressions using SAS PROC 
PHREG. For the secondary endpoints of length of hospital stay and length of intubation 
for mechanical ventilation, nonparametric univariate analysis will be performed based on 
Spearman correlation method using SAS PROC CORR for the continuous prognostic 
factors, whereas Mann–Whitney U or Wilcoxon rank-sum test will be performed for the 
categorical prognostic factors using SAS PROC NPAR1WAY. For those prognostic 
factors significantly associated with the primary and secondary outcomes from the 
univariate analyses, multiple regressions will be performed by adjusting some other 
prognostic factors identified from the univariate analyses. The multiple regressions will be 
performed as described in the primary analysis and each corresponding secondary 
endpoint analysis. 
 
Viral Load, Cytokines Levels, and TMPRSS2 Expression  
 
To explore the mechanisms that underlie treatment effect, nasopharyngeal (NP) 
epithelial or peripheral blood mononuclear cell (PBMC) TMPRSS2 expression, NP and 
plasma viral load, or serum cytokine (TNF-α, IL-1β, IL-6) levels will be tested among the 
patients from the Great Los Angeles site, only.   
 
Viral load kinetics in the two treatment groups over patients’ critical period will be 
monitored from baseline to Day 15. The viral load in plasma will be assessed by the viral 
RNA measured by a reverse-transcriptase–polymerase chain--reaction (RT-PCR) assay 
and quantified as log10 copies/ml. Mean change from baseline in SARS-CoV-2 viral RNA 
load across each sample collection time point will be compared by the treatment groups. 
The mean value for log10 copies/ml for each week will be calculated and summarized. 
Log10 copies/ml changes from baseline to each week will be summarized. For each week, 
the sample size, mean, SD, median, minimum, and maximum values for each treatment 
will be presented. A mixed-effect model of repeated measure (MMRM) for overall 
changes across all the time point between the two treatment groups using SAS PROC 
MIXED. A longitudinal graph of Log10 copies/ml will be created and presented by 95% 
confidence intervals of the means.   
 
Serum cytokines TNF-α, IL-1β, and IL-6, as well as TMPRSS2 expression and 
anti-viral antibodies will be tested by immunoassays. Mean change from baseline in the 
cytokine and TMPRSS2 levels, and antibody titers across each sample collection time 
point will be compared by the treatment groups. The mean value for each week will be 
calculated and summarized. Mean changes from baseline to each week will be 
summarized. For each week, the sample size, mean, SD, median, minimum, and 
maximum values for each treatment will be presented. A mixed-effect model of repeated 
measure (MMRM) for overall changes across all the time point between the two treatment 
groups using SAS PROC MIXED. A longitudinal graph of each measurement level will be 
created and presented by 95% confidence intervals of the means. If a measurement level 


55 
HITCH Protocol: 20210209 
is not normally distributed, then a non-parametric method will be used as an alternative 
analysis approach.    
 
The exploratory analyses will not be adjusted for multiplicity.   
 
AE and SAE analyses 
 
Adverse events (AE) and serious adverse events (SAEs) are defined by the ICH 
for Clinical Safety Data Management (ICH-E2A), the Food and Drug administration as 
described in the section 9. Incidence of AE/SAEs will be summarized for each treatment 
group by body system and MedDRA term. The number and percentage of subjects with 
each body system and MedDRA term will be presented for each group. Pearson 2 test 
and/or Fisher Exact test were used to compare the frequency difference of AE and SAE 
between the treatment groups in System of Body (SOC) and Preferred Terms (PT) levels. 
Tables to summarize the incidence rates will be created for each of the following groups: 
Total AE and SAE, AE and SAE by relationship to study intervention, AE and SAE leading 
to premature discontinuation, AE and SAE presented in descending order of frequency 
by MedDRA term (no body systems shown). AE and SAE that led to premature 
discontinuation from the study will be listed. These listings will contain details about the 
SAEs such as outcome and relationship to study treatments. Other supportive data, such 
as the subject’s age, will be given. All AE and SAE will be coded with MedDRA (updated 
version) and listed by subject.  
 
Other analyses 
 
Baseline characteristics 
 
The patient demographics and pre-treatment baseline characteristics will be 
summarized for each treatment group and for all patients. The patient demographics such 
as age, race, gender, ethnicity etc. and baseline test results such as D-dimer, IL-6, LDH, 
ferritin, total WBC, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), 
and testosterone will be analyzed. For continuous variables, the sample size, mean, 
median, SD, minimum, and maximum values will be calculated and tested either by 
Student t or Wilcoxon test depending on data distributions using SAS PROC TTEST and 
SAS PROC NPAR1WAY, respectively. For categorical variables, the number and 
percentage of patients by the intervention group will be tabulated and tested based on 
Pearson 2 test using SAS PROC FREQ. 
 
Disposition status 
 
Subject disposition will be summarized for the ITT population. The number and 
percentage of patients who completed or discontinued prematurely from the study by the 
treatment group will be tabulated and tested using Pearson 2 test. The number and 
percentage of patients who discontinued for each reason will be presented for each 
intervention group. The number and percentage of patients who completed or 
discontinued prematurely in each intervention group will also be displayed graphically. 


56 
HITCH Protocol: 20210209 
 
Adherence 
 
Patients who change the treatment groups after randomization or have protocol 
violations will be identified as non-adherence to the treatment. The number and 
percentage of non-adherence patients will be summarized by the treatment group and 
tested using Pearson 2 test. 
 
Site Effect 
 
Site effect will be evaluated for four participating sites. Balances of the treatment 
of assignment and the primary and secondary outcomes will be assessed among the four 
sites. If there is significant associations between the site and treatment assignment and 
a study outcome at significance level of 0.05 without multiplicity adjustment, the site effect 
will be adjusted in the corresponding the primary or any secondary outcome along with 
the other prognostic factors described in the primary and secondary analyses. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3: Summary of Data Analysis Plan 
 


57 
HITCH Protocol: 20210209 
 
 
Handling of Missing Data 
 
Every effort will be made to minimize the occurrence of missing data, particularly 
for the primary and the secondary endpoints. In the event of a potential drop out, every 
effort will be made to capture missed data from the patient record and VA databases. For 
patients who drop out during the study the missing values for the primary endpoint 
analysis will be considered as failures. However multiple imputation (MI) method may be 
used for certain secondary endpoint analyses. Multiple imputations will be performed 
using SAS PROC MI under missing at random assumption. If the assumption does not 
hold, then imputations will be performed. Sensitivity analysis will be performed to compare 
the results from the various imputation scenarios. 
 
 11. 
DATA COLLECTION AND QUALITY ASSURANCE 
Data Collection Forms 


58 
HITCH Protocol: 20210209 
 
Data will be collected for each patient as described in the Table of Schedule of 
Events. Electronic case report forms (eCRFs) will be completed for screening, Days 1, 8, 
15, 22, and 30 and then weekly until discharge (discharge being defined as no longer 
requiring hospitalization for COVID-19) or death.   
Data Management 
 
Access to individual identifiable patient information will be available to the PI, the 
co-PIs, and study staff. eCRFs will be generated to track clinical, laboratory, and 
radiographic data. Each study site will maintain records for its patients. Each site will have 
access only to data entered at its respective site. Investigators will not have access to 
unblinded study data.  
The Perry Point CSPCC will serve as the Data Coordinating Center for this trial. 
Data collection will be accomplished using the Clinical Data Management System 
(CDMS), iDataFax, licensed by DF/Net. iDataFax is a hybrid data management system 
that can collect data from both paper and electronic sources, as well as allow for direct 
data entry. Direct data entry will be permitted in this study. Data will be entered from 
corresponding source documentation and from paper case report forms (CRFs) designed 
for this trial. Patient medical records and case report forms will serve as the original 
sources of data for verification. Data from these sources will be entered and submitted 
and after submission will be reviewed by Perry Point Clinical Data Managers.  The end 
users will access the CDMS with credentials issued to them from the Perry Point CSPCC; 
these credentials are dependent on their roles at the site and on their completion of 
required data management, privacy protection, human subjects protection (HSP), and 
good clinical practices (GCP) training.  
 
Given the urgency of this trial and the impossibility of holding face-to-face 
meetings, there will be no formal kick-off meeting for HITCH. Moreover, due to the 
anticipated duration of the study, there will be no annual meeting. Rather, the study PI 
will have teleconference meetings with each of the site investigators, as a group or 
individually depending on availability, and the study staff. The study will be read in detail 
by all site investigators prior to the teleconferences. The study site investigators will 
complete online good clinical practices (GCP) and information security training. Data 
management training will take place via teleconference. A comprehensive Data 
Management Handbook will be furnished as part of the study’s approved Operations 
Manual. These tools will be made available to site personnel via SharePoint, an online 
file sharing system selected for use in this study because of its acceptance within the VA 
and its ability to store study documents behind the security of the VA firewall. Blank 
original CRFs and related source document templates will also be furnished to 
participating clinical sites via Microsoft SharePoint, so that they may be accessed and 
duplicated on demand, dependent on individual sites’ needs and rates of recruitment.  
Site personnel are expected to enter source data into the CDMS on an ongoing 
basis in this study, timed as closely with the required visits and procedures as possible. 
The Perry Point CSPCC will monitor the timeliness and accuracy of data submission and 
will provide performance data to the study’s Principal Investigator for routine review, or 
upon request.  


59 
HITCH Protocol: 20210209 
Following submission to the CDMS, CRF data must pass through a series of 
quality filters before it is deemed acceptable into the main study database. First, a series 
of automated logic and range checks will be applied to the data upon data entry and 
submission and will result in automated requests for confirmation or correction by site 
personnel. A second series of Quality Checks (QCs) will occur after data submission and 
will consist of more sophisticated validity checks customized by the clinical data 
programming staff at the Perry Point CSPCC. These checks may compare values across 
several different CRFs for consistency; they may trigger requirements for additional 
forms; or they may calculate necessary values or scores. Reports and listings of data 
requiring clarifications may also be issued by the data management staff at the Perry 
Point CSPCC when potential data integrity issues are identified outside of automated 
means, through a centralized monitoring approach. The Clinical Research Monitors 
assigned to verify CRF data submissions with source documentation may also issue 
requests to site personnel for data confirmation, clarification or correction.  
If incomplete or inaccurate data or data practices are found, site personnel will be 
notified and given the opportunity to confirm, correct or clarify the data at the earliest time 
possible following detection. Only data that have undergone these quality control 
procedures will be accepted into the study’s final database. All confirmations, 
clarifications and corrections made to CRF data must accord with existing source 
documentation and must be made in accordance with the ICH guidelines for good clinical 
practice (GCP). The procedures for confirming, clarifying, or correcting CRF data will be 
demonstrated at the study’s teleconference training meetings and will be detailed within 
the Data Management Handbook, part of the study’s Operations Manual.  
All local site investigators (LSI) are responsible for maintaining accurate, legible, 
complete and up-to-date source documentation and corresponding CRF entries for each 
patient, including any films, lab reports, ECG tracings, and electronic storage media. All 
known deviations from the approved study protocol must be documented by site 
personnel on the protocol deviation CRF and must be acknowledged with a signature 
from the LSI.  Corrections or other changes to the CRFs must made in line with GCP 
guidelines using established Perry Point CSPCC procedures. 
Upon the completion of this clinical trial when all data have been entered and all 
queries and requests for data clarifications have been resolved, or the attempts to resolve 
them have been exhausted, the CDMS will be locked from further editing. Following lock 
of the trial database, data management staff at the Perry Point CSPCC will furnish final 
analytical datasets to the study’s biostatistician for analysis. Statistical analysis of the data 
will be performed in accordance with the study’s protocol.  
Patient Discontinuation: 
 
Patients will be discontinued from study participation under the following 
circumstances: 
• Death or Day 60 (whichever comes first) 
• Patient withdraws consent for any reason 
Quality Assurance 
Training  


60 
HITCH Protocol: 20210209 
All staff has and will continue to undergo appropriate training related to human 
subjects. Access to study data is limited to only personnel listed as research staff.  All 
study staff must be compliant with all required VA human subjects’ trainings (Privacy and 
HIPAA, Information Security Awareness & Rules of Behavior, CITI GCP).   
Protocol Deviations 
Protocol deviations will be recorded by site personnel at the site at which they 
occur and will be documented both with a note to chart and on the Protocol Deviation 
CRF. Deviations will be submitted via CRF to the VA CSPCC, Perry Point and will become 
part of the study’s database.  The VA CSPCC will report out protocol deviations to the PI 
at the coordinating site (VA GLA) on a routine (monthly) basis, or upon request. 
12. 
PATIENT RIGHTS AND CONFIDENTIALITY 
 
This study will be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent 
with GCP and all applicable regulatory requirements. The Investigator must comply with 
the applicable regulations in Title 21 of the Code of Federal Regulations (21 CFR §50, 
§54, and §312), GCP/ICH guidelines, and all applicable regulatory requirements.  The 
IRB must comply with the regulations in 21 CFR §56 and applicable regulatory 
requirements. 
 
Institutional Review Board (IRB) Review 
 
This protocol and the informed consent document and any subsequent 
modifications will be reviewed and approved by the VA IRB responsible for oversight of 
the study.  Subject recruitment materials and any other written information to be provided 
to subjects are also reviewed and approved by the IRB before any protocol related 
procedures are performed on any subjects.  
Informed Consent Form 
 
A signed research consent form (VA Form 10-1086) must be obtained from each 
patient, or from his legally authorized representative (LAR), if the patient is unable to 
provide informed consent.  The consent form will describe the purpose of the study, the 
procedures to be followed, and the risks and benefits of participation as well as the 
required elements per VHA regulation.  A copy will be given to each patient or LAR and 
this fact will be documented in the patient’s record. 
 
The legally authorized representative (LAR) may only provide informed consent 
for the patient to participate in the study.  Examples of a LAR include, but may not be 
limited to, a spouse, parent, adult child over 18 years of age, or court-appointed individual 
(i.e. legal guardian, POA).   
Patient Confidentiality 
All patient reports and clinical samples will be identified by an assigned coded 
number/letter to maintain patient confidentiality (e.g. sample 1B). The PI will maintain a 


61 
HITCH Protocol: 20210209 
log of patients’ codes, names, and contact information, which will be kept in a locked 
cabinet in his office, which in turn will remain locked in his absence. The PI has a large, 
heavy-duty combination code protected safe in his office for the storage of these 
documents.  Every effort will be made to keep all documents with patient identifiers under 
the strictest confidentiality. Information that is collected during the study will be stored at 
the research site:  paper copies will be kept in the safe, and computer files will be 
protected by passwords. 
 
 
The study was granted a waiver of HIPAA Authorization for the entire study,    
authorizing the use and disclosure of identifiable health information relevant to this study. 
This information comes from medical records and research study-specific information that 
is obtained for the purposes of this study.   
Patient records, the research information, and the informed consent forms may be 
inspected by a representative of the Department of Veteran Affairs, Office of Human 
Research Protections, the Government Accountability Office, the Office of the Inspector 
General, the VA Office of Research Oversight, the VA Central IRB, local Research and 
Development Committee, Food and Drug Administration, and U.S. Governmental 
Agencies. Thus, because of the possibility that information may be released to one of 
these regulatory institutions, absolute confidentiality cannot be guaranteed. Results of 
this study may be published, but the names or identities of subjects will not be revealed, 
and medical records will remain confidential unless the disclosure is required by law.  
 
Research study files will be kept in accordance with the VA Records Control 
Scheduled (RCS 10-1). At study closure, data and samples will be deidentified.  
Remaining samples will be stored indefinitely for other, potential research, unless a 
patient indicates in the informed consent form that remaining samples must be destroyed 
upon completion of the research study. 
Study Discontinuation 
 
The study may be discontinued at any time by the IRB, the OHRP, the FDA, or 
other government agencies as part of their duties to ensure that research patients are 
protected. 
Clinical Criteria for Early Trial Termination 
 
The VA Data Monitoring Committee will oversee the trial and make 
determinations related to early trial termination.  
13. 
FUNDING AND INSURANCE 
 
This study is funded by the Department of Veterans Affairs through a Merit Review 
grant. This grant and the VA cover the costs of executing this study. 
14. 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by the policies and 


62 
HITCH Protocol: 20210209 
procedures of the Human Research Protections Programs (HRPPs) of the participating 
sites. Patient confidentiality will be maintained in any presentation, abstract, or 
manuscript.  
15. 
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Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients 
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8.  Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential Effects of 
Coronaviruses on the Cardiovascular System: A Review. JAMA Cardiol. 2020 Mar 
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9.  Patrick Walker. The Global Impact of COVID-19 and Strategies for Mitigation and 
Suppression.WHO Collaborating Centre for Infectious Disease Modeling. Institute 
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Overview. Curr Trop Med Rep. 2020 Mar 3;1–4. PMCID: PMC7094941 
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understanding of the Coronavirus Disease 2019. J Med Virol. 2020 Mar 26; PMID: 
32219882 
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J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola 
B, Rolain J-M, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a 
treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J 
Antimicrob Agents. 2020 Mar 20;105949. PMID: 32205204 
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Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020 Mar 6; 
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Schiergens TS, Herrler G, Wu N-H, Nitsche A, Müller MA, Drosten C, Pöhlmann S. 
SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a 
Clinically Proven Protease Inhibitor. Cell. 2020 Mar 4; PMID: 32142651 
15.  Zhou Y, Vedantham P, Lu K, Agudelo J, Carrion R, Nunneley JW, Barnard D, 
Pöhlmann S, McKerrow JH, Renslo AR, Simmons G. Protease inhibitors targeting 
coronavirus and filovirus entry. Antiviral Res. 2015 Apr;116:76–84. PMCID: 
PMC4774534 
16.  Bertram S, Heurich A, Lavender H, Gierer S, Danisch S, Perin P, Lucas JM, Nelson 
PS, Pöhlmann S, Soilleux EJ. Influenza and SARS-coronavirus activating proteases 
TMPRSS2 and HAT are expressed at multiple sites in human respiratory and 
gastrointestinal tracts. PloS One. 2012;7(4):e35876. PMCID: PMC3340400 
17.  Yamaya M, Shimotai Y, Hatachi Y, Lusamba Kalonji N, Tando Y, Kitajima Y, Matsuo 
K, Kubo H, Nagatomi R, Hongo S, Homma M, Nishimura H. The serine protease 
inhibitor camostat inhibits influenza virus replication and cytokine production in 
primary cultures of human tracheal epithelial cells. Pulm Pharmacol Ther. 2015 
Aug;33:66–74. PMID: 26166259 
18.  Vaarala MH, Porvari KS, Kellokumpu S, Kyllönen AP, Vihko PT. Expression of 
transmembrane serine protease TMPRSS2 in mouse and human tissues. J Pathol. 
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19.  Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N. 
TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of 


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Murine Models after Coronavirus Infection. J Virol. 2019 15;93(6). PMCID: 
PMC6401451 
20.  Lucas JM, Heinlein C, Kim T, Hernandez SA, Malik MS, True LD, Morrissey C, Corey 
E, Montgomery B, Mostaghel E, Clegg N, Coleman I, Brown CM, Schneider EL, Craik 
C, Simon JA, Bedalov A, Nelson PS. The androgen-regulated protease TMPRSS2 
activates a proteolytic cascade involving components of the tumor microenvironment 
and promotes prostate cancer metastasis. Cancer Discov. 2014 Nov;4(11):1310–
1325. PMCID: PMC4409786 
21.  Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-
Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, 
Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, 
Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta 
N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso 
GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson 
PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won H-H, Yu D, 
Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, 
Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, 
McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, 
Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins 
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18;536(7616):285–291. PMCID: PMC5018207 
22.  Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, 
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23.  Clinckemalie L, Spans L, Dubois V, Laurent M, Helsen C, Joniau S, Claessens F. 
Androgen regulation of the TMPRSS2 gene and the effect of a SNP in an androgen 
response element. Mol Endocrinol Baltim Md. 2013 Dec;27(12):2028–2040. PMCID: 
PMC5426606 
24.  Chen Z, Song X, Li Q, Xie L, Guo T, Su T, Tang C, Chang X, Liang B, Huang D. 
Androgen Receptor-Activated Enhancers Simultaneously Regulate Oncogene 
TMPRSS2 and lncRNA PRCAT38 in Prostate Cancer. Cells [Internet]. 2019 Aug 9 
[cited 
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25.  Lin B, Ferguson C, White JT, Wang S, Vessella R, True LD, Hood L, Nelson PS. 
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26.  Mikkonen L, Pihlajamaa P, Sahu B, Zhang F-P, Jänne OA. Androgen receptor and 
androgen-dependent gene expression in lung. Mol Cell Endocrinol. 2010 Apr 
12;317(1–2):14–24. PMID: 20035825 
27.  Wang, X et al. Transcriptional Inhibition of Host Viral Entry Proteins as a Therapeutic 
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Identification of TMPRSS2 as a Susceptibility Gene for Severe 2009 Pandemic 
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S, Schughart K. Tmprss2 is essential for influenza H1N1 virus pathogenesis in mice. 
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W, Klenk H-D, Gabriel G, Böttcher-Friebertshäuser E. TMPRSS2 is a host factor that 
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Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, 
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J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, 
Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. 
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33.  Ray HE and Rai SN. An evaluation of a Simon 2-Stage phase II clinical trial design 
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16.  
APPENDICES 
APPENDIX A: 7-category Ordinal Scale of Clinical Status of Hospitalized Influenza 
Patients  
 
1: Not hospitalized with resumption of normal activities.   
 
2: Not hospitalized, but unable to resume normal activities, 
 
3: Hospitalization, not requiring supplemental oxygen.  
 
4: Hospitalization, requiring supplemental oxygen. 
 
5: Hospitalization, requiring nasal high-flow oxygen therapy and/or noninvasive 
mechanical ventilation. 
  
6: Hospitalization, requiring extracorporeal membrane oxygenation and/or invasive 
mechanical ventilation.  
 
7: Death.  
 
 
 


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HITCH Protocol: 20210209 
APPENDIX B: Prohibited agents/treatments that can affect androgen, estrogen 
and progestin signaling 
 
Androgen receptor antagonists 
- Flutamide 
- Bicalutamide 
- Nilutamide 
- Apalutamide 
- Darolutamide 
- Enzalutamide 
 
LHRH antagonists  
- Degarelix 
- Abarelix 
- Cetrorelix 
 
LHRH agonists 
- Leuprolide 
- Goserelin 
- Triptorelin 
- Historelin 
 
CYP17 inhibitors 
- Abiraterone 
- Ketoconazole 
 
-  
 
Estrogenic agents 
- Oral contraceptives 
- Post-menopausal hormone replacement therapy  
 
Progestins 
- Cyproterone acetate 
- Medroxyprogesterone acetate 
- Progesterone 
 
Androgens 
- Testosterone (enanthate, cypionate and propionate) 
- Testosterone undecanoate 
- DHT 
 
Aromatase inhibitors 
- Formestane 
- Exemestane 
- Anastrozole 


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HITCH Protocol: 20210209 
- Letrozole 
 
Miscellaneous 
- Spironolactone 
- Cimetidine 
- Genistein 
- Orchiectomy 
 
More info: https://www.cancer.org/cancer/prostate-cancer/treating/hormone-
therapy.html 
 
 
APPENDIX C: CTCAE v5.0 
 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCA
E_v5_Quick_Reference_5x7.pdf 
 
Degarelix Prescribing Information (see attached separate document). 
 
APPENDIX D: Class IA and III Antiarrhythmic Agents 
 
Class IA 
 
Quinidine 
 
Disopyramide 
 
Procainamide 
 
Ajmaline 
 
Class III 
 
Ambasilide 
Amiodarone 
Dronedarone  
Dofetilide  
Ibutilide  
Sotalol  
Vernakalant 
Nicorandil  
Pinacidil 
 

SAP_001.pdf: 
Hormonal Intervention for the Treatment in Veterans with COVID 19 Requiring Hospitalization 
NCT04397718 
August 5, 2021 


HITCH Study                                                                                                CONFIDENTIAL                           
 
SAP (08.05.2021) 
Page 0 
 
 
 
 
HITCH Protocol  
 
Hormonal Intervention for the Treatment in Veterans with COVID-19 
Requiring Hospitalization (HITCH): A Multicenter, Phase 2 Randomized 
Controlled Trial of Best Supportive Care (BSC) vs BSC plus Degarelix  
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 
Prepared by: 
VA CSPCC  
CSPCC  151E, Research Bldg. 4 
Boiler House Rd 
PO BOX 1010 
Perry Point, MD 21902 
 
 
 
 


HITCH Study                                                                                                CONFIDENTIAL                           
 
SAP (08.05.2021) 
Page i 
 
 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
Responsibility 
Name 
Signature 
Date 
(DDMMMYYYY) 
Biostatistician  
Zhibao Mi 
 
 
Co-Chairman 
Matthew B. Rettig 
 
 
Co-Chairman 
Nicholas Nickols 
 
 
Center Director 
Kousick Biswas 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


HITCH Study                                                                                                CONFIDENTIAL                           
 
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Page ii 
 
 
TABLE OF CONTENTS 
 
STATISTICAL ANALYSIS PLAN APPROVAL ........................................................... i 
TABLE OF CONTENTS  ........................................................................................... ii 
LIST OF ABBREVIATIONS  .................................................................................... vi 
1.0 SUMMARY.......................................................................................................... 1 
2.0 INTRODUCTION  ............................................................................................... 2 
2.1 Background  ........................................................................................................ 2 
2.2 Objective  ............................................................................................................ 6 
2.3 Study Design  ...................................................................................................... 6 
2.4 Study Outcome Variables  .................................................................................. 8 
2.4.1 Primary Outcome Variable  .............................................................................. 8 
2.4.2 Secondary Outcome Variables  ....................................................................... 8 
2.4.2 Exploratory Outcome Variables  ...................................................................... 8 
2.4.4 Safety Outcome Variables ............................................................................... 9 
2.5 Study Assessments Used in the Analysis ........................................................... 9 
2.5.1. Baseline Assessment ...................................................................................... 9 
2.5.2. Follow-up Assessment .................................................................................... 9 
2.5.5.  Safety Assessment ........................................................................................ 9 
2.6 Sample Size Consideration  .............................................................................. 12 
3.0 STATISTICAL METHODS  ............................................................................... 13 
3.1 Statistical Handling Policy  ................................................................................ 13 
3.1.1 Missing Data and Imputations  ....................................................................... 13 
3.1.2 Analysis Conventions  .................................................................................... 13 
3.2 Participant Disposition  ..................................................................................... 15 
3.3 Analysis Populations  ........................................................................................ 15 
3.4 Study Protocol Adherence ................................................................................ 16 
3.5 Participant Demographics and Characteristics  ................................................ 16 
3.5.1 Demographics  ............................................................................................... 16 


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3.5.2 Baseline Characteristics ................................................................................ 17 
3.5.3 Medical History .............................................................................................. 17 
3.6 Concomitant Medications .................................................................................. 17 
3.7 Efficacy Analysis  .............................................................................................. 18 
3.7.1 Primary Endpoint Analysis ............................................................................. 18 
3.7.2 Secondary Endpoint Analyses ....................................................................... 19 
3.7.3 Exploratory Endpoint Analyses ...................................................................... 21 
3.7.4 Site Effect Analysis ........................................................................................ 24 
3.7.5 Long Term Effect Analysis ............................................................................. 24 
3.8 Safety Analyses ................................................................................................ 25 
3.8.1 AE and SAE Analyses  .................................................................................. 25 
3.8.2. Drug Toxicity Analysis ................................................................................... 26 
3.9 Interim Analysis ................................................................................................. 26 
4.0 REFERENCES  ................................................................................................ 27 
5.0 APPENDICES  .................................................................................................. 33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation           Definition 
AE  
adverse event 
ALT  
alanine aminotransferase 
ANC  
absolute neutrophil count 
AR  
androgen receptor 
AST  
aspartate aminotransferase 
BSC  
best supportive care 
CBC  
complete blood count 
CDMS  
clinical data management system 
CFR  
code of federal regulations 
CRF  
case report form 
CSPCC  
Cooperative Studies Program Coordinating Center 
CT  
computed tomography 
DMC 
data monitoring committee 
eCRF  
electronic case report form 
eDC  
electronic data capture 
FDA  
Food and Drug Administration 
Hgb  
hemoglobin 
ICF  
informed consent form 
IL-6  
interleukin-6 
LAR  
legally authorized representative 
IRB  
institutional review board 
LDH  
lactate dehydrogenase 
LFTs  
liver function tests 
LHRH  
luteinizing hormone releasing hormone 
MRI  
magnetic resonance imaging 
PaO2  
partial pressure of oxygen 
QT 
QT = electrocardiogram interval from onset of the QRS complex to 
the end of the T wave representing duration of repolarization 
QTCF  
electrocardiogram interval for QT interval corrected by the 
Fridericia correction formula 
PI  
principal investigator 
SAE  
serious adverse event 
SaO2  
oxygen saturation 
SAP 
Statistical Analysis Plan 
SQ  
subcutaneously 
 
 
 
 


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1.0 
SUMMARY 
The overall goal of the proposed study is to determine whether if temporary 
androgen suppression improves the clinical outcomes of Veterans who are hospitalized 
to an acute care ward due to COVID-19. This study will compare degarelix + best 
supportive care (BSC) to placebo + BSC for the participants’ clinical improvement. The 
study will randomize 198 patients from four participating VA sites (another four backup 
sites) over a 90-day recruitment period.  The primary end point of the study is a 
composite endpoint of mortality, ongoing need for hospitalization, or requirement for 
mechanical ventilation/extracorporeal membrane oxygenation (ECMO) at 15 days after 
the randomization. The study hypothesis is that the degarelix treatment group will 
reduce the event rate of the composite primary endpoint. Secondary objectives of this 
study include: 1). the composite endpoint of mortality, ongoing need for hospitalization, 
or requirement for mechanical ventilation/extracorporeal membrane oxygenation 
(ECMO) at 30 days after the randomization.2). time to clinical improvement as defined 
by a decline of 2 categories or more from the baseline on the modified 7-category 
ordinal scale of clinical status of hospitalized influenza patients (influenza scale, see 
Appendix 5.1) or hospital discharge1, 3). inpatient mortality, 4). duration of 
hospitalization, 5). duration of intubation for mechanical ventilation, 6). time to normal 
temperature (T < 37.5℃ for ≥ 48 hours), and 7). maximum severity of COVID-19 illness 
based on the influenza severity scale. 
This statistical analysis plan (SAP) is drafted after review of the current HITCH 
study protocol and case report forms (CRFs), but before any analysis of the data has 
begun. Detailed information is given to aid in the production of the statistical output and 
the statistical section of the final study report, and potential manuscripts for publication. 
This document provides background of the study based on the protocol and describes 
the populations that will be analyzed. All participant characteristics and the efficacy and 
safety parameters that will be evaluated, along with the specific statistical methods, are 
described. The SAP is an independent statistical document in accordance to the 
updated version of the study protocol and it serves the guideline for the statistical 
analyses of the data collected during the study.  


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2.0 
INTRODUCTION 
 
2.1 Background  
A novel coronavirus, now termed Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2), arose late in 20192. The first confirmed cases occurred 
in December in Wuhan, Hubei province, China. It now infects people on six continents, 
spreading person to person. The World Health Organization (WHO) classified it as a 
global pandemic on March 11, 2020. As of April 6, 2020, there are more than 1.2 
million confirmed cases and more than 70,000 deaths attributed to this virus. Every 
person on Earth, as well as every United States Veteran, is at risk. This is the 
emergent public health threat of our time. 
SARS-CoV-2 is a singled stranded RNA virus3 related to severe acute 
respiratory syndrome-related coronavirus (SARS-CoV-1).4 SARS-CoV-2 is thought to 
be transmissible largely by respiratory droplets or direct contact,5 but might also be 
transmitted through aerosolization.6 SARS-CoV-2 disease severity ranges from no to 
minimal symptoms, mildly symptomatic with cough and dyspnea, to severe respiratory 
distress with multi-organ failure requiring admission to an intensive care unit and 
emergent ventilator support.7 Although data are evolving, the severity of illness varies 
with age, co-existing comorbidities, and biological sex, with older age, people with pre-
existing cardiovascular disease, and males manifesting greater disease severity.8 
A worldwide effort is in place to contain and suppress human-to-human 
transmission.9 These public-health strategies aim to slow the rate of spread and reduce 
the burden on critical care infrastructure. However, we also need effective therapeutics. 
Vaccine trials are underway but potential approvals are at least a year away.10 
Development of new drugs de novo to treat SARS2-CoV-2 will likely take even longer. 
Thus, the most expedient therapeutic strategy to confront this pandemic will repurpose 
existing FDA-approved therapeutics. One potential strategy targets viral components 
directly, using existing antivirals and anti-infectives currently used for other diseases. 
Such efforts include trials of hydroxychloroquine, remdesivir, and ribavirin.11,12 Another 


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strategy involves targeting the human proteins, rather than viral proteins, required for 
SARS CoV-2 entry and replication.  
SARS-CoV-2 recognizes host cell membrane proteins and relies upon their 
enzymatic activity to infect host cells. Like SARS-CoV-1, SARS-CoV-2 has four 
structural proteins: E (envelop), M (membrane), N (nucleocapsid), and S (spike).13 The 
S protein recognizes and binds the ACE2 receptor expressed on target cells. Binding 
of S protein to ACE2 facilitates attachment of the virus to the host cell. However, entry 
of the virus into the host cell requires catalytic cleavage of the S protein (a process 
termed S protein priming) by the host cell membrane protein TMPRSS2.14 Thus, 
TMPRSS2 is required for viral entry and infection. This mechanism is similar to that 
used by SARS-CoV-1.14 SARS-CoV-2 and SARS-CoV-1 can also use the host 
membrane protein cathepsin B and L (CatB/L) for S protein priming in vitro. However, 
TMPRSS2 appears to be required for SARS-CoV priming in the infected host whereas 
CatB/L is not.14,15 TMPRSS2 is expressed in the aero-digestive tract. TMPRSS2 is 
expressed within the nasal mucosa, respiratory sinuses, buccal mucosa, tracheal 
epithelia, bronchial epithelia, lung type 2 pneumocytes, and alveolar macrophages.16–18 
In addition to the aero-digestive tract, TMPRSS2 is highly expressed on prostate, 
kidney, and pancreatic epithelia.18 
Inhibition of TMPRSS2 reduces SARS-CoV-2 entry into target cells. Camostat 
mesylate is a small molecule inhibitor of TMPRSS2 currently approved in Japan for 
pancreatitis. Pharmacologic inhibition of TMPRSS2 with camostat mesylate prevented 
SARS-CoV-2 entry into cultured human lung cells.14 Importantly, effective abrogation of 
SARS-CoV-2 entry did not require co-targeting of CatB/L, supporting the notion that 
targeting TMPRSS2 alone is sufficient to block SARS-CoV-2. This is consistent with 
prior investigations that demonstrated pharmacologic inhibition of TMPRSS2 was 
sufficient to eliminate lethal SARS-CoV-1 infection in murine models, whereas 
pharmacologic inhibition of CatB/L was not.15  Moreover, murine models deficient in 
TMPRSS2 (tmprss2 knockout mice) were more resistant to SARS-CoV-1 infection than 
wildtype controls, exhibited reduced viral replication within lung tissue, and profoundly 
reduced lung immunopathology after infection, suggesting that loss of the TMPRSS2 


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gene in humans may be protective against SARS-CoV-2 infection.19 The TMPRSS2 
knockout mice appeared normal, indicating loss of tmprss2 by itself is not pathogenic.19 
Camostat mesylate is currently being evaluated in a randomized, double-blind study for 
hospitalized SARS-CoV-2+ patients (NCT04321096) in Denmark. In an entirely 
separate line of investigation, a chemical library screen of small molecule inhibitors of 
TMPRSS2 for an entirely unrelated purpose identified the drug bromhexine.20 
Bromhexine demonstrated submicromolar inhibition of TMPRSS2 and suppressed 
TMPRSS2 driven metastatic progression in murine models.20 The mechanism of 
bromhexine is not entirely clear, but it is sold over the counter in other countries, 
available both by mouth and via inhalation for respiratory disorders. In contrast, ACE2 
is considered loss-of-function intolerant in humans.21  In addition, SARS-CoV-mediated 
down-regulation of ACE2 is thought to contribute to the severity of lung pathologies, 
indicating that down-regulation of ACE2 may further harm the lungs of infected 
patients.22 For all of the aforementioned reasons, it seems that transcriptional 
regulation of TMPRSS2 is the highest priority for clinical evaluation. 
Transcriptional regulation of TMPRSS2. The transcriptional regulation of the 
TMPRSS2 gene has been extensively characterized, most rigorously within the 
prostate. The TMPRSS2 gene is located on chromosome 21 and is under the control of 
the androgen receptor (AR). Binding of androgens (e.g. testosterone or 
dihydrotestosterone) to the AR results in homodimerization and translocation of the AR 
to the nucleus, where it binds to its cognate androgen response element in the 
regulatory regions of its target genes, and thereby regulates gene expression.23,24 It is 
firmly established that suppression of AR transcriptional activity through reduction in 
circulating androgens or direct antagonism of AR-androgen binding using AR 
competitive antagonists reduces expression and protein levels of TMPRSS2 within the 
prostate, as well as prostate cancers.25 Remarkably, expression of TMPRSS2 also 
appears to be hormonally regulated within the lung and bronchial cells. Notably, the AR 
is expressed in type II pneumocytes and the bronchial epithelium.26 Androgens enrich 
AR binding at the TMPRSS2 enhancer and upregulate expression of TMPRSS2 in 
human lung cells, in a fashion similarly to that found in the prostate.26  


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In addition, our query of publicly available gene expression databases 
demonstrated that TMPRSS2 appears to have a high variability of expression amongst 
individuals.27 To identify the most promising therapeutic opportunities, we performed a 
literature-wide screen of RNA-seq datasets in the NCBI Sequence Read Archive (SRA) 
that incorporated keywords relating to drug treatments. We identified differentially 
expressed genes from 3,089 distinct case-control comparisons featuring a drug 
treatment. Notably, anti-androgenic compounds and estrogens were among the 
strongest and most consistent down-regulators of TMPRSS2 expression, while 
androgens consistently led to up-regulated TMPRSS2 gene expression.27 In other 
words, these studies suggest that the AR induces TMPRSS2 expression, whereas ER 
transcriptional activity is associated with suppression of TMPRSS2 expression.  
However, there was an initial surge in TMPRSS2 expression after estrogen treatments, 
followed by a gradual decrease in TMPRSS2 expression. Moreover, the highly variable 
expression pattern of TMPRSS2 suggests a provocative and plausible, although 
unproven, explanation for the wide range in disease severity for patients infected by 
SARS-Cov-2, as well as the higher rate of severe infections among males and the 
reduced rate and severity of infection in pre-pubertal children. A link between 
TMPRSS2 expression and susceptibility to viral infection was discovered by a recent 
genome wide association study that identified genetic variants with higher TMPRSS2 
expression also had more severe H1N1 and H7N9 influenza.28 Notably, H1N1 and 
H7N9 influenza, but not all influenza subtypes, require TMPRSS2 for priming.29,30 
Identification of drugs that suppress TMPRSS2 expression. Based on the 
aforementioned data that TMPRSS2 is hormonally regulated in the lung by the AR and 
estrogen receptor (ER), it is hypothesized that drugs that interfere with AR driven 
transcription or enhance ER driven transcription will reduce TMPRSS2 expression. An 
informatics analysis of publicly available gene expression data to identify drugs that 
affect TMPRSS2 expression levels identified several existing FDA approved drugs.27 
Unsurprisingly, these included antagonists of the AR an agonist of the ER. A possible 
protective effect from estrogenic agonism in the context of another coronavirus was 
suggested from murine models whereby female mice exhibited reduced susceptibility 


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and mortality to SARS-CoV-1 infection as compared to males. Furthermore, anti-
estrogen treatments of the female mice increased their susceptibility and mortality to 
SARS-CoV-1.31  
Thus, either suppression of AR or activation of ER may reduce expression of 
TMPRSS2. We chose to focus on suppression of AR, rather than activation of ER, 
because we are concerned that a potential initial estrogen-induced surge in TMPRSS2 
expression could acutely worsen viral infections. Fortuitously, a wealth of FDA 
approved drugs block AR signaling. These include the GnRH analogs that reduce 
pituitary release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), 
thereby potently suppressing testosterone production, and anti-androgens that interfere 
with binding of androgens to the AR. These drugs are predominantly used in the 
treatment of prostate cancer, have well known and generally tolerable side effect 
profiles, and exhibit reversibility of their biologic effects. As such, we contend that 
androgen suppression will reduce TMPRSS2 expression in the target cells of SARS-
CoV-2 and reduce the severity of illness. 
2.2 Objective  
The goal of the proposed study is to determine if temporary androgen 
suppression improves the clinical outcomes of Veterans who are hospitalized to an 
acute care ward due to COVID-19 as defined by an influenza severity scale or time to 
discharge. 
2.3 Study Design  
This study is a parallel, double-blind, placebo controlled, superiority trial in which 
participants will be randomized to the degarelix + BSC treatment group or to the 
placebo + BSC control group. The study will randomize 198 Veterans at four VA 
Medical Centers at a 2:1 treatment assignment ratio, i.e. 132 participants in the 
degarelix group and 66 participants in the placebo group. The total recruitment period 
will be approximately 90 days with an approximately follow-up period of 60 days. The 


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duration of the study will be approximately five months. Informed consent for the study 
will be obtained prior to participants’ enrollemnt eligibility screening. Randomization will 
be performed via an Interactive Web Response System (IWRS), a computerized 
system that will allow authorized study personnel to randomize patients and obtain 
study treatment assignments using a stratified random block method once a participant 
has eligible to the study. Study drug treatment will be given according to the 
randomization assignment within 48 hours after randomization. BSC consists of 
supplemental oxygen, antibiotics, vasopressor support, peritoneal or hemodialysis, 
antibiotics, intravenous fluids, etc. The participants will be followed up till their 
discharge. The study flow is shown in Appendix 5.2. Both the participants and the 
treating physicians/nurses as well site investigators/coordinators will be blinded of the 
treatment assignment.  
Participants will be followed until death or discharge, whichever comes first. If a 
patient dies or refuses to continue participation, he will be terminated.  A termination 
form will be used to record the termination information for these patients. If a patient 
remains hospitalized beyond day 30, the patient will continue to be followed for clinical 
endpoints, but no additional research labs will be obtained. 
Study treatment drug, degarelix (as the acetate) is formulated as a sterile 
lyophilized powder for injection. Degarelix forms a depot upon subcutaneous 
administration, from which it is released to the circulation.  The long half-life after 
subcutaneous administration is a consequence of a very slow release of degarelix from 
the depot formed at the injection site(s). The 240 mg dosage is achieved by the 
administration of two 120 mg SQ doses in the deep abdominal subcutaneous tissue. 
Participants will be randomly assigned to receive a one-time dose of degarelix 240 mg 
SQ or matching placebo on randomization day (day 1). The matching placebo will 
contain equal volume 0.9% saline by following the 60 minute rule after the drug 
reconstitution. No dose modifications are allowed for degarelix. 
Scheduled follow up forms will be filled out weekly after randomization upon till 
discharge after the randomization and Unschedued follow-up form will be filled out on 
the time whenever the event occurs during the follow-up time (see Appendix 5.3.1 ). 


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2.4 Study Outcome Variables  
2.4.1 Primary Outcome Variable 
The primary outcome is defined as a composite endpoint of mortality, ongoing 
need for hospitalization, or requirement for mechanical ventilation/extracorporeal 
membrane oxygenation (ECMO) at 15 days after the randomization.  
2.4.2 Secondary Outcome Variables 
There are five secondary outcome measures  
1. The composite endpoint of mortality, ongoing need for hospitalization, or 
requirement for mechanical ventilation/extracorporeal membrane oxygenation 
(ECMO) at 30 days after the randomization. 
2. The time to clinical improvement as defined by a decline of 2 categories or more 
from the baseline on the modified 7-category ordinal scale of clinical status of 
hospitalized influenza patients (influenza scale, see Appendix 5.1) or hospital 
discharge, whichever comes first. 
3.  Inpatient mortality 
4.  Length of hospital stay  
5.  Duration of intubation for mechanical ventilation 
6. Time to normal temperature (< 37.5℃ for ≥ 48 hours) 
7. The maximum severity of COVID-19 illness based on the influenza severity scale  
     (see Appendix 5.1) 
2.4.3 Exploratory Outcome Variables 
           Prognostic factors associated with clinical outcomes 
          Clinical Factors: Age, use of angiotensin converting enzyme inhibitors, the 
duration of pre-hospitalization symptoms, or the presence or absence of hypertension, 
cardiovascular disease, asthma, diabetes mellitus, or COPD 
Laboratory Factors D-dimer, IL-6, LDH, ferritin, total WBC, absolute neutrophil 
count (ANC), absolute lymphocyte count (ALC), or testosterone 
Treatment effect on viral load and cytokines (GLA site only) 


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Viral load NP epithelial cells, PBMC 
Serum cytokines TNF-α, IL-1β, IL-6 
Other TMPRSS2 expression, anti-viral Ab, genomic factors 
2.4.4 Safety Outcome Variables 
Safety measures include study-related adverse events (AE) and serious adverse 
events (SAE), and AE with special interest in the drug toxicity.   
 
2.5 Study Assessments Used in the Analysis 
2.5.1. Baseline Assessment  
Participants’ demographics, medical history, vital signs, and concomitant 
medication use are collected at the baseline time point. Other baseline assessments 
will be collected the time between identification of an eligible participant and the 
randomization including medical history, laboratory measurements of D-dimer, IL-6, 
LDH, ferritin, total WBC, ANC, ALC, testosterone, and participant clinical status. Data 
collected during this period is used primarily for the participants’ baseline 
characteristics used for the statistical analysis, monitoring recruitment, and 
randomization status. We will maintain the information of all identified potential 
participants. This will be accomplished by completing the screening form for every 
participant presenting to the clinical site for eligible operations including those who are 
excluded from the study for any reason.    
2.5.2. Follow-up Assessment  
Follow-up assessments will be collected after participants’ randomization and 
treatment at day 1, 8, 15, 22, 30, and 60 for the scheduled follow-up assessments of 
concomitant medications, medical status, laboratory measurements, and clinical 
assessment. The follow-up assessments also include those unscheduled protocol 
deviations, AEs and SAEs, and participants’ disposition status. The data collection 
schedule as shown in Appendix 5.3.2. 
2.5.3. Safety Assessment  
Timely and complete reporting of safety information assists study management 
in identifying any untoward medical occurrence. This contributes to patient safety, 


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regulatory compliance and improvements in study design or procedures. In addition, 
close attention to AEs provides valuable information about the safety and tolerability of 
study drugs. This study specific safety plan is designed to collect information on the 
safety and tolerability of the study medications; thus, reporting will be conducted in 
accordance with the requirements of GCP and other regulatory requirements governing 
clinical research in the US. In HITCH, patients will receive a regimen of FDA approved 
commercially available degarelix for injection (Firmagon ®) 240 mg for subcutaneous 
use or matching placebo. Local Study Investigators, with assistance from their local 
SC, are responsible for collecting AE and SAE information regarding the patients at 
their sites. Non-serious AEs and SAEs will be collected from the time of randomization 
until 30 days after the last dose of study medication. Throughout the specified duration 
of AE and SAE collection, data will be collected through spontaneous local SC/LSI/Co-I 
contact, during in-person study visits, and gathered during telephone contacts and 
medical record reviews when performed (see Table of Scheduled Events). AEs will be 
collected based on a review of the electronic medical record. Adverse events that are 
open will require follow-up reports (if necessary) every 30 days until resolved or until 
the end of the trial. Adverse events reported to study staff and deemed related to the 
study drug(s) and all SAEs will be recorded on an AE or SAE form (respectively) and 
documented in source records (e.g., the electronic VA medical record and/or the 
patient's study record).  
Severity of an Adverse Event The following categories are used to convey the 
severity of an adverse event: 
• Grade 1 Mild; – Events require minimal or no treatment and do not interfere 
with the patient’s daily activities 
• Grade 2 Moderate; – Events result in a low level of inconvenience or concern 
with the therapeutic measures. Interferes with normal daily activities to some extent 
• Grade 3 Severe; – Events interrupt a patient’s usual daily activity and may 
require systemic drug therapy or other treatment. May severely interfere with or 
prevent normal daily activities 
• Grade 4 Life-threatening consequences; – Events requiring urgent intervention 


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• Grade 5 Death related to AE. 
Serious Adverse Event (SAEs) An AE is considered an SAE if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization  
• A persistent, significant, or permanent incapacity or substantial disruption in 
the patient's body function/structure, physical activities and/or quality of life  
• Congenital anomaly/birth defect; or  
• Important medical events that may not be immediately life-threatening, result in 
death, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Such events include intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse 
Relatedness Relatedness involves an assessment of the degree of causality 
(attributability) between the study intervention and the event.  
• Definitely Related: The event is clearly related to the study intervention – i.e. 
an event that follows a reasonable temporal sequence from administration of the study 
intervention follows a known or expected response pattern to the suspected 
intervention that is confirmed by improvement on stopping and reappearance of the 
event on repeated exposure and that could not be reasonably explained by the known 
characteristics of the patient’s clinical state. 
• Possibly Related: An event that follows a reasonable temporal sequence from 
administration of the study intervention follows a known or expected response pattern 
to the suspected intervention, but that could readily have been produced by a number 
of other factors. 
• Not Related: The event is clearly not related to the investigational 
agent/procedure. - i.e. another cause of the event is most plausible; and/or a clinically 


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plausible temporal sequence is inconsistent with the onset of the event and the study 
intervention and/or a causal relationship is considered biologically implausible.   
  Unanticipated Adverse Event An AE that is new or greater than previously 
known, in terms of nature, severity, or frequency of occurrence, or any other 
unanticipated serious problem associated with the investigation that relates to the 
rights, safety, or welfare of participants, as documented in the protocol or other 
materials approved by the IRB of record or the characteristics of the study population.  
Adverse Events of Special Interest Cardiac arrhythmias and thromboembolic 
events will be considered AEs of special interest. Any cardiac arrhythmia or 
thromboembolic event of grade 3-5 according to Common Terminology Criteria for 
Adverse Events version 5.0 (CTCAE v5.0; see Appendix 5.4) will be reported in a 
manner similar to SAEs, whereby the event will be reported to the HITCH reporting 
system within 3 calendar days of the Study Site Personnel becoming aware of the 
event. 
All adverse events that are related to the study intervention or procedures are 
recorded at each research assessment visit (description, severity, relationship to study 
intervention, date onset, date resolution). 
2.6 Sample Size Consideration  
In a recent antiviral drug trial to treat adults hospitalized with severe COVID-19 
published in the New England Journal of Medicine (NEJM) on March 18, 202032, the 
results showed that a mortality rate of 17%, hospital stay rate of 50%, and ECMO or 
mechanical intubation rate of 11% among the patients managed with BSC after two-
week follow-up. In the current study, we propose a composite endpoint of mortality, 
ongoing need for hospitalization, and ECMO or mechanical intubation at 15 days after 
randomization. We are expecting to reduce the composite endpoint rate to 35% after 
the degarelix treatment plus BSC from 60% for patients treated placebo plus BSC. 
The sample size estimation and power analysis shown in Table 2 are based on 
the hypothesis testing of the primary endpoint, which is the composite endpoint of 
mortality, hospital stay rate, and ECMO or mechanical intubation at 15 days after 


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randomization (Day 15). According to the composite endpoint outlined in the previous 
section, we assume that an effect size for the primary endpoint of 42% can be 
anticipated in the degarelix group. The other assumptions include a three-month 
accrual time and one-month follow-up time, and 2:1 sample allocation of degarelix: 
placebo treatment group. The sample size for the study is estimated based on a 
superiority trial design. To have 90% power of detecting the expected 42% reduction 
using a two-sided two proportion test with a significance level of 0.05 in the degarelix 
compared to the placebo group will require 186 evaluable patients total (i.e. 124 
evaluable patients in the degarelix group and 62 evaluable patients in the placebo 
group). Based on an assumed 5% attrition rate, 198 patients will be required (i.e. 132 
in the degarelix group and 66 in the placebo group) to achieve actual statistical 
significance at alpha level of 0.05 and power of 90% (Appendix 5.5). 
3.0 
STATISTICAL METHODS 
3.1 Statistical Handling Policy 
3.1.1 Missing Data and Imputations  
Every effort will be made to minimize the occurrence of missing data, particularly 
for the primary and the secondary endpoints. In the event of a potential drop out, every 
effort will be made to capture missed data from the patient record and VA databases. 
For patients who drop out during the study the missing values for the primary endpoint 
analysis will be considered as failures. However multiple imputation (MI) method may 
be used for certain secondary endpoint analyses. Multiple imputations will be 
performed using SAS PROC MI under missing at random assumption. If the 
assumption does not hold, then imputations will be performed. Sensitivity analysis will 
be performed to compare the results from the various imputation scenarios. 
3.1.2 Analysis Conventions 
This section details general policies to be used for the statistical analyses. 
Departures from these general policies may be given in the specific detailed sections of 
this statistical analysis plan. When this situation occurs, the rules set forth in the 


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specific section take precedence over the general policies. The following policies will 
be applied to all data presentations and analyses. 
• 
All statistical tests will use a significance level of α = 0.05. Two-tailed tests 
will be performed for all analyses that use statistical testing. 
• 
All p-values will be rounded to 3 decimal places. All p-values that round to 
0.000 will be presented as ‘<0.001’ and p-values that round to 1.000 will be 
presented as ‘>0.999’. Any p-value ≤ α will be considered statistically 
significant. 
• 
Summary statistics will consist of the number and percentage of responses 
in each category for discrete variables, and the mean, median, standard 
deviation (SD), minimum, and maximum for continuous variables. 
• 
All mean and median values will be formatted to one more decimal place 
than the measured value. Standard deviation values will be formatted to two 
more decimal places than the measured value. 
• 
All percentages will be rounded to one decimal place. The number and 
percentage of responses will be presented in the form XX (XX.X), where the 
percentage is in the parentheses. The decimal of the percentage may be 
dropped due to space constraints when creating a table. 
• 
All listings will be sorted for presentation in order of treatment group, site 
number, participant number, and date of procedure or event. 
• 
All analysis and summary tables will have the population sample size for 
each treatment group in the column heading. 
• 
Calculating change from baseline to a visit will be done as follows: change = 
visit –baseline. 
• 
Baseline is defined as the last data point before the first treatment is 
administered. If baseline data are not available, screening data will be used. 
• 
Version 9.4 of SAS or higher will be the statistical software package used 
to produce all summaries, listings, statistical analyses, and graphs. 
• 
Updated version of MedDRA will be used for adverse event and pre-
treatment coding. 


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• 
The current version of the World Health Organization (WHO) drug dictionary 
will be used for the coding of medications. 
3.2 Participant Disposition 
Participant disposition will be summarized for the ITT population. 
• 
The number and percentage of participants who completed or discontinued 
prematurely from the study by treatment group will be tabulated and tested 
using Pearson 2 test (Table 3.2.1).  The number and percentage of participants 
who completed or discontinued prematurely in each treatment group will also be 
displayed graphically (Figure 3.2.1). 
• 
The number and percentage of participants who discontinued for each reason 
will be presented by treatment group (Table 3.2.2).  
• 
A listing of participants that discontinued prematurely from the study will be 
presented. The listing will include information about treatment, study center, 
participant number, age, race, number of days, and reason for discontinuation 
(Table 3.2.3). 
• 
The number and percentage of participants who completed or discontinued 
prematurely from the study by study center will be tabulated and tested using 
Pearson 2 test (Table 3.2.4).  The number and percentage of participants who 
completed or discontinued prematurely in each treatment group will also be 
displayed graphically (Figure 3.2.1). 
3.3 Analysis Populations 
Intent-to-Treat (ITT) – This population includes all participants randomized to 
either of the treatment groups – degarelix or placebo. The patients will be categorized 
(in terms of their treatment assignment) based on their initial randomized group and will 
be included in analyses irrespective of their status – completer or drop out of the study 
before completion. The testing power for the primary endpoint is estimated as 90% in 
this population. 


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Safety – This population includes all participants randomized to either of the 
treatment groups – degarelix or placebo. 
The number of participants in each population will be summarized for each 
treatment group and for all participants (Table 3.3.1). 
3.4 Study Protocol Adherence 
Study treatments and adherence will be summarized by treatment group and 
overall for the ITT population. The number and percentages of participants will be 
presented for each treatment group and overall (Table 3.4.1). The number and 
percentage of non-adherence participants will be summarized by the treatment groups 
and tested using Pearson 2 test. The following information will be presented for each 
treatment group and overall for adherence:   
• 
Summary of protocol non-adherence (Table 3.4.2) 
• 
Summary statistics (number of participants, mean, median, SD, minimum, and 
maximum) for study adherence (Table 3.4.3) 
3.5 Participant Demographics and Characteristics 
The patient demographics and pre-treatment baseline characteristics and 
medical history will be summarized for each treatment group and overall for the ITT 
population. For continuous variables, the sample size, mean, median, SD, minimum, 
and maximum value will be calculated and tested either by Student t or Wilcoxon test 
depending on data distributions using SAS PROC TTEST and SAS PROC 
NPAR1WAY, respectively. For categorical variables, the number and percentage of 
patients by the treatment group will be tabulated and tested based on Pearson 2 test 
using SAS PROC FREQ. 
3.5.1 Demographics 
The summary of demographics at baseline will include age, race, gender, 
ethnicity, marital status, military history, location of military service, branch of service, 
and pre-admission residence (Tables 3.5.1). 


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3.5.2 Baseline Characteristics 
Baseline comparability among the treatment groups will be evaluated by 
providing a summary of baseline test results (D-dimer, IL-6, LDH, ferritin, total WBC, 
absolute neutrophil count (ANC), absolute lymphocyte count (ALC), hemoglobin, 
hematocrit, platelet counts, and testosterone) and baseline medical status (fever, 
oxygen needs, and days symptoms started prior to hospitalization) (Tables 3.5.2). 
3.5.3 Medical History 
The number and percentage of participants reporting a medical history will be 
summarized by the following medical conditions: COPD, hypertension, cardiovascular 
disease, asthma, diabetes, use of angiotensin converting enzyme inhibitors within last 
30 days prior to hospitalization, and use of supplemental oxygen prior to hospitalization 
(Tables 3.5.3). 
3.6 Concomitant Medications 
 
Summaries for prior and concomitant medications will be done for the ITT 
population. Concomitant medications will be reported at screening, day 8,15,22, and 
30. Each summary below will be done for each treatment group and for all participants: 
•  Prior medications – medications taken prior to the study drug administration  
• Concomitant medications –medications taken on or after the study drug 
administration 
All medications recorded on the CRF will be coded to the therapeutic drug 
classes and generic drug names using the World Health Organization (WHO) drug 
classifications. The current version of the WHO drug dictionary will be used for the 
coding of medications. 
The number and percentage of participants who take medications that are 
coded to each generic drug name and therapeutic drug class will be tabulated by the 
treatment group and tested based on Pearson 2 test using SAS PROC FREQ (Tables 
3.6.1-2). If there are significant differences between the two treatment groups for 
certain study related drugs, these concomitant medication use will be adjusted for the 
endpoint efficacy analyses when it is necessary. 


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3.7 Efficacy Analyses 
The primary analysis of the study will be performed on the primary endpoint on 
the ITT population. The secondary analyses will be performed on the ITT population 
and available data. Both the primary and secondary endpoints analyses will be 
performed for the hypothesis testing. While the exploratory endpoints will be analyzed 
to generate new hypothesis unless otherwise specified. Potential difficulties of 
convergence of model fit, which arise in efficacy analyses that include covariates, will 
be handled using the method described in section 3.7.1. The analysis plan is 
summarized in the Appendix 5.6. 
3.7.1. Primary Endpoint Analysis 
The primary study endpoint will be the composite outcome of mortality, ongoing 
need for hospitalization, and ECMO or mechanical intubation at 15 days after 
randomization. This outcome will be compared according to assigned treatment 
groups, using Pearson 2 test. The test for differences between the treatment groups in 
the primary outcome will be conducted at an overall α-level of 0.05 (i.e. α = 0.006 for 
mid-term interim analysis, α = 0.044 for the final analysis). If a participant drops out 
from the study, then he will be considered as a failure. Additional analyses will be 
conducted using logistic models to adjust for other clinical factors, such as age, 
hypertension, and COPD. Logistic regression will be used for the primary endpoint (y = 
1 if a composite outcome, otherwise y = 0) analysis with the treatment group as the 
testing factor (x). The following covariates will be included in the model: age (z1), 
hypertension (z2), and COPD (z3). Given the composite outcome probability 
, the basic model is defined as follows: 
 
Odds ratio and 95% confidence interval (CI) will be presented using SAS PROC 
GENMOD or PROC LOGSTIC. If the coefficient for treatment effect is significant, then 
the null hypothesis will be rejected. Logistic models will be tested for goodness of fit.  
We will assess goodness-of-fit using the statistic -2 log likelihood, which has a 2 


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distribution under the null hypothesis that all the explanatory variables in the model are 
zero. We will also consider the Akaike Information Criterion statistic and the Schwartz 
Criterion statistic, both of which adjust the -2-log likelihood for the number of items in 
the model. Models that show lack of fit will be reconsidered for the inclusion of 
additional variables or use of alternate models with assumptions that are better met by 
the study data.  One alternate model if model fit is poor for logistic regression is a log-
linear model. The number and percentage of participants with the composite endpoint 
at the 15 day after the randomization will be summarized and compared using Pearson 
2 test (Table 3.7.1a). For logistic regression analysis, if the coefficient for treatment 
effect is significant (i.e., the confidence interval for the odds ratio does not include 1), 
then the null hypothesis will be rejected. The significant level for each covariate 
coefficient in the model will best determined by Wald test (Table 3.7.1b). Meanwhile, 
Cochran Mantel-Haenszel test will be used to adjust for three randomization 
stratification factors (Age: <65 vs. ≥65, History of hypertension: yes vs. no, and 
Influenza severity scale: 3 vs 4/5) using SAS PROC FREQ as one of the sensitivity 
analyses (Table 3.7.1c).  
3.7.2 Secondary Endpoint Analyses 
Secondary endpoints included in the data analysis are the composite outcome 
of mortality, ongoing need for hospitalization, and ECMO or mechanical intubation at 
30 days after randomization, time to clinical improvement, inpatient mortality, length of 
hospital stay, length of intubation for mechanical ventilation, time to normal 
temperature, and the maximum severity of COVID-19 illness, which are defined in the 
endpoint section. The secondary endpoint analyses will be adjusted for multiplicity with 
a α-level of 0.0071 for each endpoint.  
The composite outcome of mortality, ongoing need for hospitalization, and 
ECMO or mechanical intubation at 30 days after randomization as a secondary 
endpoint will be analyzed using the methods described in the primary endpoint analysis 
(Tables 3.7.2.1a-c). 
For the time to clinical improvement as defined by a decline of 2 categories or 
more from the baseline on the modified 7-category ordinal scale of clinical status of 


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hospitalized influenza patients (influenza scale, see Appendix 5.1) or hospital 
discharge (see section 2 for definition of discharge) whichever comes first, survival 
analysis techniques will be used to analyze the time-to-event data for this endpoint. 
Participants whose condition worsened, who died, or who withdrew from the study 
without clinical improvement will be censored. Kaplan-Meier analysis will be used to 
compare the two curves of the time to the clinical improvement over the patient follow-
up time between the two treatment groups and a log-rank statistic will be used to test 
the equality of the survival function estimates of the two treatment groups using SAS 
PROC LIFETEST. Kaplan-Meier curves will be created (Figure 3.7.2.1). Additional 
analysis will be conducted using the Cox’s Proportional Hazards model to test the 
treatment efficacy of the treatment on the time until endpoint events adjusted for three 
prognostic factors: age, hypertension, and COPD. The hazard ratio and 95% 
confidence interval (CI) will be presented using SAS PROC PHREG (Table 3.7.2.2). If 
the coefficient for treatment effect is significant, then the null hypothesis will be 
rejected. The regression model will be checked for the model assumption, adequacy, 
and the goodness of fit. If the model shows lack of fit, then alternate models with 
assumptions that are better met by the study data will be considered. 
For mortality endpoint data analysis, the treatment effect will be analyzed initially 
with a Pearson 2 test (Table 3.7.2.3a) and then logistic regression will be performed 
using SAS PROC LOGISTIC by taking account of prognostic factors described in the 
primary endpoint analysis (Table 3.7.2.3b).  
For the length of hospital stay data analysis, medians (interquartile ranges) will 
be presented and Wilcoxon tests, a nonparametric method, will be performed to 
compare the medians of the length of hospital stay between the two treatment groups 
using SAS PROC NPAR1WAY (Table 3.7.2.4a). In addition, a quantile regression will 
be used to test the effect of the treatment on the time until the clinical event adjusted 
for prognostic factors described in the primary endpoint analysis using a SAS PROC 
QUANTREG (Table 3.7.2.4b). 
For the length of intubation for mechanical ventilation data analysis, medians 
(interquartile ranges) will be presented and Wilcoxon tests, a nonparametric method, 


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will be performed to compare the medians of the length of hospital stay between the 
two treatment groups using SAS PROC NPAR1WAY (Table 3.7.2.5a). In addition, a 
quantile regression will be used to test the effect of the treatment on the time until the 
clinical event adjusted for prognostic factors described in length of hospital stay data 
analysis using SAS PROC QUANTREG (Table 3.7.2.5b). 
For time to normal temperature data analysis, survival analysis techniques will 
be used to analyze the time-to-event data for this endpoint. Participants whose 
temperature remains abnormal will be censored. Kaplan-Meier analysis will be used to 
compare the two curves of the time to the clinical improvement over the patient follow-
up time between the two treatment groups and a log-rank statistic will be used to test 
the equality of the survival function estimates of the two treatment groups using SAS 
PROC LIFETEST. Kaplan-Meier curves will be created (Figure 3.7.2.2). Additional 
analysis will be conducted using the Cox’s Proportional Hazards model to test the 
treatment efficacy of the treatment on the time until endpoint events adjusted for three 
prognostic factors: age, hypertension, and COPD. The hazard ratio and 95% 
confidence interval (CI) will be presented using SAS PROC PHREG (Table 3.7.2.6). If 
the coefficient for treatment effect is significant, then the null hypothesis will be 
rejected. The regression model will be checked for the model assumption, adequacy, 
and the goodness of fit. If the model shows lack of fit, then alternate models with 
assumptions that are better met by the study data will be considered. 
For the maximum severity of COVID-19 illness data analysis, Pearson 2 test 
will be performed for this categorical endpoint using SAS PROC FREQ initially. Given 
the endpoint is also an ordinal variable, Cochran–Armitage test will be performed to 
test the ordinal trend tendency using SAS PROC FREQ (Table 3.7.2.7a). in addition to 
the frequency analysis, proportional odds logistic regression will also be performed 
(Table 3.7.2.7b) using SAS PROC LOGISTIC by taking account of the factors of age, 
hypertension, COPD, and the baseline influenza scale (see Appendix 5.1). 
3.7.3 Exploratory Endpoint Analyses 
Clinical and Laboratory Prognostic Factors 


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Exploratory analyses will be performed to identify the impact of clinical and 
laboratory prognostic factors on the primary endpoint or any secondary endpoint. 
Clinical factors include age, presence or absence of COPD, hypertension, or 
cardiovascular disease, or use of angiotensin converting enzyme inhibitors. Laboratory 
measurements including D-dimer, IL-6, LDH, ferritin, total WBC, absolute neutrophil 
count (ANC), absolute lymphocyte count (ALC), hemoglobin, hematocrit, platelet 
counts, and testosterone are measured during the patient’s hospital stay. Further 
germline genomic factors will also be analyzed if feasible as prognostic factors for the 
study outcomes for part of the patients. 
For continuous variables, the sample size, mean, SD, median, minimum, and 
maximum values for each treatment will be presented for each parameter at each data 
collection time point and tested using SAS PROC TTEST between the treatment 
groups. If a variable is not normally distributed the non-parametric method will be 
applied using SAS PROC NPAR1WAY (Table 3.7.3.1). For categorical variables, the 
number and percentage of participants by the treatment group will be tabulated and 
tested based on Pearson 2 test using SAS PROC FREQ (Table 3.7.3.2).  
Univariate correlation with the primary endpoint or any categorical secondary 
endpoint will be assessed for each clinical and laboratory factor based on logistic 
regressions using SAS PROC LOGISTIC (Table 3.7.3.3). For the secondary endpoints 
of time to events data, univariate analysis will be performed based on Cox regressions 
using SAS PROC PHREG (Table 3.7.3.4). For the secondary endpoints of length of 
hospital stay and length of intubation for mechanical ventilation, nonparametric 
univariate analysis will be performed based on Spearman correlation method using 
SAS PROC CORR for the continuous prognostic factors, whereas Mann–Whitney U or 
Wilcoxon rank-sum test will be performed for the categorical prognostic factors using 
SAS PROC NPAR1WAY(Table 3.7.3.5). For those prognostic factors significantly 
associated with the primary and secondary outcomes from the univariate analyses, 
multiple regressions will be performed by adjusting some other prognostic factors 
identified from the univariate analyses. The multiple regressions will be performed as 


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described in the primary analysis and each corresponding secondary endpoint analysis 
(Table 3.7.3.6). 
Viral Load, Cytokines Levels, and TMPRSS2 Expression  
To explore the mechanisms that underlie treatment effect, nasopharyngeal (NP) 
epithelial or peripheral blood mononuclear cell (PBMC) TMPRSS2 expression, NP and 
plasma viral load, or serum cytokine (TNF-α, IL-1β, IL-6) levels will be tested among 
the participants from the Great Los Angeles site only.   
Viral load kinetics in the two treatment groups over participants’ critical period 
will be monitored from baseline to day 30. The viral load in plasma will be assessed by 
the viral RNA measured by a reverse-transcriptase–polymerase chain--reaction (RT-
PCR) assay and quantified as log10 copies/ml. Mean change from baseline in SARS-
CoV-2 viral RNA load across each sample collection time point will be compared by the 
treatment groups. The mean value for log10 copies/ml for each week will be calculated 
and summarized. Log10 copies/ml changes from baseline to each week will be 
summarized. For each week, the sample size, mean, SD, median, minimum, and 
maximum values for each treatment will be presented. A mixed-effect model of 
repeated measure (MMRM) for overall changes across all the time point between the 
two treatment groups using SAS PROC MIXED (Table 3.7.3.7). A longitudinal graph of 
Log10 copies/ml will be created and presented by 95% confidence intervals of the 
means (Figure 3.7.3.1).   
Serum cytokines TNF-α, IL-1β, and IL-6, as well as TMPRSS2 expression and 
antiviral antibodies will be tested by immunoassays. Mean change from baseline in the 
cytokine and TMPRSS2 levels, and antibody titers across each sample collection time 
point will be compared by the treatment groups. The mean value for each week will be 
calculated and summarized. Mean changes from baseline to each week will be 
summarized. For each week, the sample size, mean, SD, median, minimum, and 
maximum values for each treatment will be presented (Table 3.7.3.8). A mixed-effect 
model of repeated measure (MMRM) for overall changes across all the time point 
between the two treatment groups using SAS PROC MIXED. A longitudinal graph of 
each measurement level will be created and presented by 95% confidence intervals of 


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the means (Table 3.7.3.9). If a measurement level is not normally distributed, then a 
non-parametric method will be used as an alternative analysis approach.    
The exploratory analyses will not be adjusted for multiplicity.   
3.7.4 Site Effect Analysis 
Site effect will be evaluated for four participating sites. Balances of the treatment 
of assignment and the primary and secondary outcomes will be assessed among the 
four sites (Table 3.7.4.1). If there are significant associations between the site and 
treatment assignment and a study outcome at significance level of 0.05 without 
multiplicity adjustment, the site effect will be adjusted in the corresponding the primary 
or any secondary outcome along with the other prognostic factors described in the 
primary and secondary analyses.  
3.7.5 Long Term Effect Analysis 
The long-term analysis will be based on the data collected by following the 
randomized participants up to 60 days after randomization, which will include mortality, 
readmission to hospital, and oxygen use.    
For mortality analysis, the treatment effect will be analyzed initially with a 
Pearson 2 test (Table 3.7.5.1a) and then logistic regression will be performed using 
SAS PROC LOGISTIC by taking account of prognostic factors described in the primary 
endpoint analysis (Table 3.7.5.1b). 
 For hospital readmission rate analysis, the treatment effect will be analyzed 
initially with a Pearson 2 test (Table 3.7.5.2a) and then logistic regression will be 
performed using SAS PROC LOGISTIC by taking account of prognostic factors 
described in the primary endpoint analysis (Table 3.7.5.2b). Further, time to hospital 
readmission will also be analyzed based on survival analysis techniques using log-rank 
test and Kaplan-Meier curves (Figure 3.7.5.1) by PROC LIFETEST, and Cox 
regression model adjusted for the covariates as described in the secondary endpoint 
analyses (Tables 3.7.5.3a-b). 
For the oxygen use analysis, Pearson 2 test will be performed for this 
categorical endpoint using SAS PROC FREQ initially. Given the endpoint is also an 
ordinal variable, Cochran–Armitage test will be performed to test the ordinal trend 


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tendency using SAS PROC FREQ (Table 3.7.5.4a). in addition to the frequency 
analysis, proportional odds logistic regression will also be performed (Table 3.7.5.4b) 
using SAS PROC LOGISTIC by taking account of the factors of age, hypertension, 
COPD, and the baseline influenza scale (see Appendix 5.1). 
The long-term analyses will not be adjusted for multiplicity.   
3.8 Safety Analyses 
 
All safety analyses will be done for the safety population and reported in tabular 
forms.  These analyses include serious adverse events (SAE), study related to adverse 
events (AE), and AE with special interests to monitor drug toxicity. 
3.8.1 AE and SAE analyses 
Adverse events (AE) and serious adverse events (SAEs) are defined by the ICH 
for Clinical Safety Data Management (ICH-E2A), the Food and Drug administration as 
described in the section 9. Incidence of AE/SAEs will be summarized for each 
treatment group by body system and MedDRA term. The number and percentage of 
participants with each body system and MedDRA term will be presented for each 
group. Pearson 2 test and/or Fisher Exact test were used to compare the frequency 
difference of AE and SAE between the treatment groups in System of Body (SOC) and 
Preferred Terms (PT) levels. Tables to summarize the incidence rates will be created 
for each of the following groups: Total AE and SAE, AE and SAE by relationship to 
study treatment, AE and SAE leading to premature discontinuation, AE and SAE 
presented in descending order of frequency by MedDRA term (no body systems 
shown). AE and SAE that led to premature discontinuation from the study will be listed. 
These listings will contain details about the SAEs such as outcome and relationship to 
study treatments. Other supportive data, such as the participant’s age, will be given. All 
AE and SAE will be coded with MedDRA (updated version) and listed by participant. 
Tables to summarize the incidence rates will be created for each of the following 
groups: 
• 
AE and SAE (Table 3.8.1a-b) 
• 
AE and SAE by relationship to study treatment (Tables 3.8.2a-b) 


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• 
AE and SAE leading to premature discontinuation (Table 3.8.3a-b) 
• 
AE and SAE presented in descending order of frequency by MedDRA term (no 
body systems shown) (Table 3.8.4a-b) 
AE and SAE that led to premature discontinuation from the study will be listed. 
These listings will contain details about the AE/SAEs such as outcome and relationship 
to study treatment. Other supportive data, such as the participant’s age, will be given. 
All AE/SAEs will be coded with MedDRA (updated version) and listed by subject (Table 
3.8.5). 
3.8.2. Drug Toxicity Analysis 
The drug toxicity will be closely monitored and analyzed. Cardiac arrythmia and 
thromboembolic complications are adverse events of special interest (grade 3 and 
above) that will be monitored closely and graded according to on CTCAE 5.0. Once the 
toxicity markers reach a threshold of 25%33, a statistical analysis of the toxicity will be 
performed. The treatment difference will be analyzed initially with a Pearson 2 test 
using SAS PROC FREQ (Table 3.8.2.1) and logistic regression will also be performed 
using SAS PROC LOGISTIC by taking account of prognostic factors described in the 
primary endpoint analysis (Table 3.8.2.2). If the experimental (degarelix) group has a 
significant higher toxicity compared to the placebo group at an α-level of 0.01, then 
results will be reported to the DMC for a recommendation for trial termination. 
3.9 Interim Analyses 
 
A mid-term interim analysis of the primary endpoint will be performed when half 
of the participants (99 randomized participants) complete or are terminated from the 
study. If the mid-term analysis of the primary endpoint indicates that the null hypothesis 
can be rejected with a boundary value of 2.77 (standardized Z >  2.77 or  < - 2.77) at 
an α-level of 0.006 or accepted with a boundary value of 0.44 ( - 0.44 ≤ standardized Z 
≤ 0.44 ) based on O’Brien and Fleming criteria, the study will be recommended for trial 
termination for efficacy and futility reasons (shown in Appendix 5.7). The number and 
percentage of participants with the composite endpoint at day 15 will be summarized 
and compared using Pearson 2 test (Table 3.9.1a) using SAS PROC FREQ. For 


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logistic regression analysis, if the coefficient for treatment effect is significant (i.e., the 
confidence interval for the odds ratio does not include 1), then the null hypothesis will 
be rejected. The significant level for each covariate coefficient in the model will best 
determined by Wald test (Table 3.9.1b) using SAS RPOC LOGISTIC. The analysis will 
be done in the ITT population. The detailed analysis is described in the primary 
endpoint analysis in the section 3.7.1. 
4 
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5.0 APPENDICES 
 
APPENDIX 5.1 7-category Ordinal Scale of Clinical Status of Hospitalized 
Influenza Patients 
 
1: Not hospitalized with resumption of normal activities.   
 
2: Not hospitalized, but unable to resume normal activities, 
 
3: Hospitalization, not requiring supplemental oxygen.  
 
4: Hospitalization, requiring supplemental oxygen. 
 
5: Hospitalization, requiring nasal high-flow oxygen therapy and/or noninvasive 
mechanical ventilation. 
  
6: Hospitalization, requiring extracorporeal membrane oxygenation and/or invasive 
mechanical ventilation.  
 
7: Death.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 5.2 Study Flow 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 5.3.1 Data Collection Schema 
 
 


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Appendix 5.3.2 Data Collection Schedule  
 
1
Screening and Randomization
R
2
Demographics
R
3
Medical History
R
4
Baseline Medical Status
 R
5
Study Treatment
R
6
Concomitant Medication Log
 A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
7
Medical Status
R
RH
RH
RH
RH
RH
RH
RH
RH
8
Laboratory Measures
 R
R
R
RH
RH
RH
9
Ordinal Scale of Clinical Status**
 R
R
A
R
A
RH
A
RH
A
RH
RH
RH
RH
RH
RH
10
Protocol Deviation
 A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
11
Adverse Event
 A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
12
AE Follow-up
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
13
Serious Adverse Event
 A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
14
SAE Follow-up
 A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
15
Participant Termination
A
A
A
A
A
A
A
A
A
A
A
A
A
A
16
Research Blood and Nasal Swab 
Collection (GLA)
RH
17
Total Testosterone Measurement 
(CSP completion)
R
18
Post Discharge Follow-up
RD
RD
RH=Required if patient is still hospitalized (i.e. until discharge is noted on Form 07). 
RD=Required if patient was discharged
**Ordinal Scale of Clinical Status will be completed at screening, day 1 and whenever a status change occurs in the patient, but no less than 1x week. 
Visit 10-17 (if patient is 
still hospitalized complete 
weekly until discharge)
Visit 05 
(Day 30)
Visit 04 
(Assessments 02-
07)
Visit 07 
(Day 44)
Visit 08 
(Day 51)
Visit 09 
(Day 60)
Visit 06 
(Day 37)
A = As needed
Visit 01   
(Randomization / 
Day 1)
Visit 02 
(Day 8)
Visit 03 
(Day 15)
Visit 04 
(Day 22)
Visit 01  
(Assessments 02-
07)
Visit 02 
(Assessments 02-
07)
Visit 03  
(Assessments 02-
07)
Visit 00 
(Screening / 
Baseline)
Form 
#
Form Name
R = Required  
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 5.4 CTCAE v5.0 
 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCA
E_v5_Quick_Reference_5x7.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 5.5 Power Analysis  
Sample Size: 186 patients are required to have a 90% chance of detecting, as 
significant at the 5% level, a decrease 42% of the composite endpoint in the degarelix 
treatment group compared to the placebo treatment group. Assume 5% attrition rate, 
then the sample size would be 198 (i.e. 132 in the treatment group, 66 in the control 
group) to maintain 90% testing power 
 
 
 
 
 
 
 
 


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Appendix 5.6 Efficacy Analysis Schema  
 
 


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Appendix 5.7 Interim Analysis Boundary