Clinical trial NCT04446429
Conditions: COVID-19 SARS-CoV2 Androgenetic Alopecia Prostate Cancer Benign Prostatic Hyperplasia SARS (Severe Acute Respiratory Syndrome)
Keywords: Anti-Androgen Proxalutamide
Sponsor: Applied Biology, Inc.
Start date: 2020-10-21; Completion date: 2021-01-21
Enrollment: 268 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is intended to explore the possible protective role of anti-androgens in SARS-CoV-2 infection

Detailed description:
During the continuing SARS-CoV-2 (COVID-19) pandemic, several studies have reported a significant difference in the rate of severe cases between adult females and adult males (42% vs 58%).Among children under the age of 14, the rate of severe cases was reported to be extremely low. To explain this difference, several theories have been proposed including cigarette smoking and lifestyle habits. However, no theory fits both the gender difference in severe cases as well as reduced risk in pre-pubescent children. Our past research on male androgenetic alopecia (AGA) has led us to investigate an association between androgens and COVID-19 pathogenesis. In normal subjects, androgen expression demonstrates significant variation between men and women as well as between adults and pre-pubescent children.

SARS-CoV-2 primarily infects type II pneumocytes in the human lung. SARS-CoV-2 enters pneumocytes, by anchoring to the ACE2 cell surface receptor. Prior to receptor binding, viral spike proteins undergo proteolytic priming by the transmembrane protease, serine 2 (TMPRSS2). TMPRSS2 inhibition or knock down reduces ability of SARS-CoV-1 (a related virus to SARS-CoV-2) to infect cells in vitro. Additionally, TMPRSS2 also facilitates entry of influenza A and influenza B into primary human airway cells and type II pneumocytes.

The human TMPRSS2 gene has a 15 bp androgen response element and in humans, androgens are the only known transcription promoters for the TMPRSS2 gene. In a study of androgen-stimulated prostate cancer cells (LNCaP), TMPRSS2 mRNA expression increase was mediated by the androgen receptor. Further, the ACE2 receptor, also critical for SARS-CoV-2 viral infectivity, is affected by male sex hormones with higher activity found in males.

Androgenetic alopecia (AGA), often referred to as male pattern hair loss, is the most common form of hair loss among men. The development of androgenetic alopecia is androgen mediated and is dependent on genetic variants found in the androgen receptor gene located on the X chromosome; thus, it is hypothesized that men with AGA would be more prone to severe COVID-19 disease. The investigators conducted a preliminary observational study of hospitalized COVID-19 patients at two Spanish tertiary hospitals between March 23-April 6, 2020 to test this theory. In total, 41 Caucasian males admitted to the hospitals with a diagnosis of bilateral SARS-CoV-2 pneumonia were analyzed. The mean age of patients was 58 years (range 23-79). Among them, 29 (71%) were diagnosed with AGA (16 (39%) were classified as severe AGA (Hamilton IV or above)) and 12 (29%) did not present clinical signs of AGA. The diagnosis of AGA was performed clinically by a dermatologist. The precise prevalence of AGA among otherwise healthy Spanish Caucasian males is unknown; however, based on published literature, the expected prevalence of a similar age-matched Caucasian population is approximately 31-53%.

Based on the scientific rationale combined with this preliminary observation, the investigators propose to test an anti-androgen as a treatment for patients recently diagnosed with COVID-19.

We have chosen the use of the novel second generation androgen receptor (AR) antagonist proxalutamide as a means for rapid reduction in AR activity. Proxalutamide (GT0918) demonstrates a dual mechanism of action. It is highly effective in inhibiting AR as well as exhibiting pharmacological effects of inducing the down-regulation of AR expression; the mechanism that is not present in bicalutamide and enzalutamide. Additionally, it has been reported that Proxalutamide lowers the expression of ACE2. Both would be beneficial for preventing SARS-CoV-2 entry into lung cells.

This study is intended to explore the possible protective role of anti-androgens in SARS-CoV-2 infection. Provided anti-androgens are effective in reducing the rate of COVID-19 hospitalization, subjects enrolled in this study may experience a lower rate of hospitalization.

Arms: arm 1: Usual care as determined by the PI arm 2: Proxalutamide + Usual care as determined by the PI
Interventions: intervention 1: Proxalutamide intervention 2: Standard of Care
Intervention descriptions: intervention 1: 200 mg q.d. intervention 2: Standard of care as determined by the PI

Protocol documents:
Prot_SAP_001.pdf: 
 
 
  
 
CLINICAL STUDY 
PROTOCOL 
Anti-Androgen 
Treatment for COVID-19 
(Proxalutamide - GT0918) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Proprietary and Confidential 
 
The information contained in this document is confidential and proprietary to Applied Biology, 
Inc. It is offered with the express agreement that you will not disclose this document to any other 
person(s), or discuss the information contained herein or make reproduction by any means 
electronic or mechanical, or use it for any purpose other than the evaluation of the proposed 
clinical study for approval by an Institutional Review Board. 


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PROTOCOL NAME: 
Clinical Study: Anti-Androgen Treatment for COVID-19 
PROTOCOL IDENTIFYING NUMBER: 
KP-DRUG-SARS-001 
PROTOCOL VERSION NUMBER: 
1.00 
PROTOCOL VERSION DATE: 
September 17, 2020 


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GENERAL INFORMATION 
Name and address of the person(s) authorized to sign the protocol and amendments 
Andy Goren, MD 
Flavio A. Cadegiani, MD, MSc, PhD 
Carlos Wambier, MD 
Name and address of study monitor 
Carlos Wambier, MD 
Name, title, address and telephone number(s) of the medical expert for the trial 
Flavio A. Cadegiani, MD, MSc, PhD 
Applied Biology, Inc. 
SGAS 915 Centro Clínico Advance, Rooms 260/262/264 
Brasilia, Brazil, 70390-150 
Name and title of the investigator(s) and sub-investigators responsible for the trial with 
address and phone number(s)   
Flavio A. Cadegiani, MD, MSc, PhD 
Andy Goren, MD 
Carlos Wambier, MD 
Principal Investigator (s) 
Flavio A. Cadegiani, MD, MSc, PhD 
Andy Goren, MD 
Site Supervisor 
Andy Goren, MD 
Investigator Assistant 
TBD 


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Protocol signature page 
Investigator’s Agreement 
Clinical Study: Anti-Androgen Treatment for COVID-19 
The information contained in this document is CONFIDENTIAL and, except to the extent 
necessary to obtain informed consent, may not be disclosed unless such disclosure is required by 
government regulation or state/local customs or law. Persons to whom the information is 
disclosed must be informed that the information is CONFIDENTIAL and not be further 
disclosed by them. By my signature below I agree to conduct this clinical study in accordance 
with the protocol, Good Clinical Practice, the Declaration of Helsinki, government regulations 
and state/local customs or laws, including those applying to institutional/ethics review and 
informed consent. I have read the protocol. I agree to ensure the confidentiality of my patients; 
however I agree to make available to the CROs, the Sponsor of this clinical study, relevant 
regulatory authorities, my patients’ medical records. I am aware of my responsibilities as 
investigator as provided to me by the CROs. 
Name 
Signature 
Date 
Flavio A. Cadegiani, MD, MSc, PhD 
Andy Goren, MD 


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TABLE OF CONTENTS 
1. BACKGROUND....................................................................................................................... 8
1. Overview
1
1.1. Preclinical Data 
1
1.2. Risk/Benefits 
1
1.3. Trial Conduct 
2
1.4. Population 
2
1.5. Literature  
2
2. TRIAL OBJECTIVES........................................................................................................... 22 
3. TRIAL DESIGN..................................................................................................................... 22 
3.1. Primary Study Endpoints/Secondary Endpoints 
3
3.2. Study Design/Type 
3
3.3. Randomization 
4
3.4. Records 
4
3.5. Duration 
4
3.6. Discontinuation 
4
3.7. Product Accountability 
4
3.8. Data Identification 
4
4. SELECTION AND WITHDRAWAL OF SUBJECTS ...................................................... 26 
4.1 Inclusion Criteria 
5
4.2 Exclusion Criteria 
5
4.3 Subject Withdrawal 
5
4.4 Treatment of Subjects 
5


 
 
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4.5 Medication 
5 
4.6 Monitoring for subject compliance 
5 
5. ASSESSMENT OF EFFICACY ........................................................................................... 27 
5.1 Efficacy Parameters 
5 
5.2 Method and Timing 
6 
6. ASSESSMENT OF SAFETY................................................................................................ 28 
6.1 Safety Parameters 
6 
6.2 Method and Timing 
6 
6.3 Adverse Event Reporting 
6 
6.4 Definitions 
7 
6.5 Adverse Event Follow-up 
8 
7. STATISTICAL PLAN............................................ERROR! BOOKMARK NOT DEFINED. 
7.1 Statistical Methods 
8 
7.2 Subject Population(s) for Analysis 
8 
7.3 Significance 
8 
7.4 Termination Criteria 
8 
7.5 Accountability Procedure 
8 
7.6 Deviation Reporting 
8 
8. DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION....................................... 36 
9. QUALITY CONTROL AND QUALITY ASSURANCE ................................................... 36 
10. ETHICAL CONSIDERATIONS......................................................................................... 36 
11. DATA HANDLING AND RECORD KEEPING ............................................................... 36 
12. FINANCE AND INSURANCE ............................................................................................ 37 
 


 
 
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List of Abbreviations 
 
 
CFR 
 
Code of Federal Regulations 
 
CRF 
 
Case Report Form 
 
FDA  
Food and Drug Administration 
 
GCP 
 
Good Clinical Practice 
 
IRB 
 
Institutional Review Board 
 
EC 
 
Ethics Committee 
 
HCP   
Healthcare Professional 
 
CDC  
US Center for Disease Control  
 
SAE   
Serious Adverse Event 
 
AE 
 
Adverse Event 
 
ARDS  
Acute Respiratory Distress Syndrome  
 
UP 
 
Unanticipated Problem 
 
 
 
 
 
 
 
 
 


 
 
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1. Background 
1. Overview 
During the continuing SARS-CoV-2 (COVID-19) pandemic, several studies have reported a 
significant difference in the rate of severe cases between adult females and adult males (42% 
vs 58%).1 Among children under the age of 14, the rate of severe cases was reported to be 
extremely low.1 To explain this difference, several theories have been proposed including 
cigarette smoking and lifestyle habits. However, no theory fits both the gender difference in 
severe cases as well as reduced risk in pre-pubescent children.  Our past research on male 
androgenetic alopecia (AGA) has led us to investigate an association between androgens and 
COVID-19 pathogenesis.2 In normal subjects, androgen expression demonstrates significant 
variation between men and women as well as between adults and pre-pubescent children. 
 
SARS-CoV-2 primarily infects type II pneumocytes in the human lung. SARS-CoV-2 enters 
pneumocytes, by anchoring to the ACE2 cell surface receptor.  Prior to receptor binding, 
viral spike proteins undergo proteolytic priming by the transmembrane protease, serine 2 
(TMPRSS2).3–5 TMPRSS2 inhibition or knock down reduces ability of SARS-CoV-1 (a 
related virus to SARS-CoV-2) to infect cells in vitro.6 Additionally, TMPRSS2 also 
facilitates entry of influenza A and influenza B into primary human airway cells and type II 
pneumocytes.7   
 
The human TMPRSS2 gene has a 15 bp androgen response element and in humans, 
androgens are the only known transcription promoters for the TMPRSS2 gene.8-10 In a study 
of androgen-stimulated prostate cancer cells (LNCaP), TMPRSS2 mRNA expression 
increase was mediated by the androgen receptor.10 Further, the ACE2 receptor, also critical 
for SARS-CoV-2 viral infectivity, is affected by male sex hormones with higher activity 
found in males.11 
 
Previously, we have reported the results from two retrospective cohort analysis 
demonstrating the protective effect of 5-alpha-reductase inhibitors (5ARi) for men with 
COVID-19.17   In a study of 77 men hospitalized with COVID-19 we found among men 
taking 5ARis, 8% were admitted to the ICU compared to 58% of men not taking 5ARis (P = 
0.0015).  In the cohort, 5ARis were associated with reduced risk for ICU admissions RR 0.14 
(95% CI: 0.02–0.94).17 Similarly, we have demonstrated that the frequency of COVID-19 
symptoms was drastically reduced for men using 5ARis in an outpatient setting.  A 
statistically significant (p<0.05) reduction in the frequency of 20 of the 29 clinical symptoms 
was observed in AGA men using 5ARis compared to AGA men not using 5ARis. For 
example, 38% and 2% of men presented with low-grade fever, 60% and 6% with dry cough, 
and 88% and 15% reported anosmia in the non-5ARi and 5ARi groups, respectively.18   
 
One limitation of 5ARis is the time course required to achieve systemic DHT reductions. As 
such, we explored the use of a novel second generation androgen receptor antagonist 
Proxalutamide as a means for rapid reduction in AR activity. Proxalutamide (GT0918) 
demonstrates a dual mechanism of action.  It is highly effective in inhibiting AR as well as 


 
 
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exhibiting pharmacological effects of inducing the down-regulation of AR expression; the 
mechanism that is not present in bicalutamide and enzalutamide. Because of the dual 
mechanism of action, it is expected to be a more effective and less toxic second-generation 
anti-androgen drug therapy. Clinical evidence has demonstrated that Proxalutamide lowers 
AR expression and activity.  Additionally, it has been reported that Proxalutamide lowers the 
expression of ACE2. Both would be beneficial for preventing SARS-CoV-2 entry into lung 
cells. 
 
1.1. Investigational Drug 
 
Proxalutamide (200 mg) q.d. 
 
 
Proxalutamide (GT0918) demonstrates a dual mechanism of action.  It is highly effective in 
inhibiting AR as well as exhibiting pharmacological effects of inducing the down-regulation 
of AR expression; the mechanism that is not present in bicalutamide and enzalutamide. 
Because of the dual mechanism of action, it is expected to be a more effective and less toxic 
second-generation anti-androgen drug therapy. Clinical evidence has demonstrated that 
Proxalutamide lowers AR expression and activity.  Additionally, it has been reported that 
Proxalutamide lowers the expression of ACE2. Both would be beneficial for preventing 
SARS-CoV-2 entry into lung cells. 
 
The Proxalutamide tablets (100mg per tablet) will be manufactured by: 
 
TOT BIOPHARM International Company Limited. No. 120 changyang Street, Suzhou 
Industrial Park,  Suzhou City, Jiangsu Province, China 


 
 
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1.1. Pre-Clinical and Prior Clinical Data 
1.1.1. Prior Pre-Clinical and Clinical Safety Data  
 
No prior pre-clinical safety data exists as to the use of Proxalutamide for the treatment of 
COVID-19; however, pre-clinical studies have been conducted in support of the US FDA 
IND approval of Phase-1 human trials of Proxalutamide in castration resistant prostate 
cancer.  Selected pre-clinical animal studies conducted with Proxalutamide are provided 
below. 
 
Tissue Distribution and Excretion of GT0918 in Rats 
The tissue distribution of GT9018 in male SD rats was determined at 0.5, 3 and 12 hours 
following an oral single administration (20 mg/kg). Proxalutamide was extensively 
distributed to most of the tissues/organs with high concentrations found in fat tissue and 
liver, followed by stomach, pancreas and intestine in rats. Proxalutamide distribution was 
also observed in bone marrow in rats. Peak Proxalutamide concentrations were achieved 
in most tissues at 3 hours following the administration and a certain degree of elimination 
was observed in these tissues at 12 hours following the administration. 
The excretion profiles (bile, urine and feces) following a single oral dose of 
Proxalutamide (20 mg/kg) to 6 male SD rats was studied. The data indicated that 
following a single oral administration of Proxalutamide to rats, the cumulative fractional 
excretion of Proxalutamide in bile within 36 hours was 0.010 ± 0.006%, the cumulative 
fractional excretion of Proxalutamide in urine within 72 hours was 0.014 ± 0.009% and 
the cumulative fractional excretion of Proxalutamide in feces within 72 hours was 10.785 
± 4.547%. Proxalutamide was mainly excreted in the feces (about 10%) and in trace 
amounts through bile and urine (0 to 0.1%) in rats. 
 
Pharmacokinetic Profiles of Proxalutamide in SD Rats 
Pharmacokinetic properties of Proxalutamide were studied in SD rats following single 
oral dosing at 10, 20, 40 and 80 mg/kg, single IV dosing at 5 mg/kg and repeated PO 
dosing at 20 mg/kg daily for 8 consecutive days. After single oral dosing, Proxalutamide 
reached maximal plasma concentrations in 3 to 5 hours and then decreased with the 
elimination half-life 2.0 to 2.5 hours. Both AUC and Cmax were proportional to dose. 
The absolute bioavailability was 74 - 100%. After repeated dosing for 8 days, AUC and 
Cmax increased about 50% comparing to single dose at the same level, indicating some 
drug accumulation after repeated dosing. 
 
Pharmacokinetic Profiles of Proxalutamide in Beagle Dogs 
Pharmacokinetic properties of Proxalutamide were studied in Beagle dogs following 
single oral dosing at 2, 5 and 10 mg/kg under fasting conditions, single IV dosing at 1 
mg/kg, a single oral dosing at 20 mg/kg (with two different API processes) under fed 
conditions, and repeated PO dosing at 20 mg/kg daily for 7 consecutive days. After single 


 
 
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oral dosing, Proxalutamide reached maximal plasma concentrations in 2 to 2.5 hours and 
then decreased with the elimination half-life 9.5 to 11.8 hours. Both AUC and Cmax 
were proportional to dose. The absolute bioavailability was 36.5 – 52.5%. Under fed 
conditions, Cmax markedly decreased about 60% with Tmax increase from 3 hours to 8.3 
hours but slightly increased in AUC compared to those respective PK parameters under 
fasting conditions at the same dose. After repeated dosing for 8 days, AUC and Cmax 
increased about 70% and 150%, respectively comparing to single dose at the same level, 
indicating drug accumulation after repeated dosing. 
 
1.1.2 Prior Clinical Safety Data 
 
Study 1: Proxalutamide Treatment for Non-Hospitalized COVID-19 Male Patients 
(NCT04446429)  
A  double-blinded, randomized, prospective, investigational study of Proxalutamide 
Treatment for Non-Hospitalized COVID-19 Male Patients (NCT04446429) was 
completed in December 2020. The length of the study was 30 days. Proxalutamide was 
administered 200mg q.d. for 14 days. Men enrolled in the study were 50 years and older. 
Two hundred and sixty two men completed the study. 134 men were assigned to the 
Proxalutamide group and 128 men were assigned to the control group.  Thirty five 
subjects were hospitalized in the control group compared to zero in the Proxalutamide 
group. The proportion of COVID-19 patients hospitalized was significantly different 
between the Proxalutamide and control arms;  χ2 (1) = 42.051, p<.0001. The difference 
in proportions was 27.30% with a 95%CI: [19.79%, 35.59%]. No subject receiving 
Proxalutamide died compared to 2 (1.56%) in the control group. There were no treatment 
related adverse event reported during the course of the study. 
 
Study 2: Phase 1 study in 16 males with prostate cancer.   
The data from the study was published in a peer review journal.  The identifier GT0918 
was used to denote Proxalutamide. The abstract from the publication is below: 
 
 
Abstract     Purpose:  We conducted  preclinical experiments  and phase I clinical trial 
to investigate the safety, pharmacokinetics (PK) and  antitumour effects of 
GT0918 in castration- resistant  prostate  cancer (CRPC). 
Experimental  design: An androgen  receptor  (AR) competitive  binding  assay was 
performed,  followed by evaluation  of GT0918 on AR protein  expression.  The 
efficacy of GT0918 was investigated  in a castration-resistant xenograft  model.  A 
phase  I dose-escalation  study of GT0918 in CRPC  was also carried out to evaluate 
its safety, PK and antitumour efficacy. Results: GT0918 was demonstrated to 
inhibit the binding of androgen  to AR more potently than  MDV3100,  and to 
effectively reduce the AR protein  level. GT0918 inhibited the tran- scriptional  
activity of wild-type AR and AR with clinically relevant  ligand-binding  domain 
mutations. Furthermore, GT0918 significantly inhibited the growth of prostate  
cancer. A total of 16 patients  was treated  with GT0918 at five dose levels. Among 


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these 16 patients,  10 and 2 patients,  respectively, completed a three-cycle and six-
cycle treatment, in which MTD  was not reached.  All the treatment-related adverse 
events were grade I, including hypercholesterolemia, hypertriglyceridemia, fatigue 
and anemia.  PK parameters showed that drug exposure increased with dose 
proportionally from 50 to 300 mg and a saturation was observed between 300mg 
and 400 mg. 
The most significant adverse events from the study are summarized in the following 
table: 
Study 3: Phase 1 study conducted in 40 males with prostate cancer.  
A summary of the study is provided below: 
Demographics: All 40 patients in the Safety Analysis Set were male with the mean age at 
70.1 years. Three (7.5%) patients were Hispanic or Latino and 37 (92.5%) were not 
Hispanic or Latino. Thirty-five (87.5%) patients were white, 4 (10%) were black or 
African American and 1 (2.5%) was Asian. Of the 40 patients with mCRPC tumors, all 
patients (100%) had received at least two lines of hormone therapies, with 11 (27.5%) 
having 3 lines and 20 (50%) having 4 lines or more. Most patients (70%) had also 
undergone chemotherapies, with 20 (50%) receiving one line and 8 (20%) receiving 2 or 
more lines of chemotherapies. 
Disposition: The distribution of 40 patients by dose cohort was as follows: 3 at the 50 
mg, 6 at the 100 mg, 6 at the 200 mg, 7 at the 300 mg, 7 at the 400 mg, 6 at the 500 mg 
and 5 at the 600 mg per day dose levels. Of the 40 patients, 1 (2.5%) did not complete 1 
cycle, 14 (35%) completed 1 cycle, 10 (25%) completed 2 cycles, 3 (7.5%) completed 3 
cycles, 3 (7.5%) completed 4 cycles, 5 (12.5%) completed 5 cycles, and 4 (10%) 
completed at least 6 cycles of treatment. The primary reason for discontinuation was 
progressive disease (28/40 patients, 70%). Other discontinuation reasons included the 


 
 
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following: unacceptable toxicity or AE (6/40, 15%), withdrawal of consent (4/40, 10%) 
and patient lost to follow-up (2/40, 5%).  
Efficacy: Of the 40 patients, no PSA response with more than 50% reduction from 
baseline was observed. CR or PR are not required as per phase 1 study data analyses. 
Treating physicians will do imaging scan to see if patients have with SD allowing for 
continuing the treatment. The mean number of dosing duration was 12.5 weeks (87.6 
days) across all dose cohorts from 50 mg/day to 600 mg/day, and the mean dosing 
duration for individual dose cohorts ranged from 8.3 weeks (57.7 days) to 15.6 weeks 
(109.4 days). Patients with treatment duration longer than 22.9 weeks (160 days) were 
from the following dose cohorts: 1 in the 50 mg/day, 1 in the 100 mg/day, and 2 in the 
400 mg/day cohorts. A total of 9 patients had completed between 4 and 6 cycles (28 days 
per cycle) of treatment, belonging to these dose cohorts: 200 mg/day (1/6), 400 mg/day 
(4/7), 500 mg/day (2/6), and 600 mg/day (2/5). 
Safety: The results from this study showed that the safety profile of GT0918 was 
generally favorable in patients with mCRPC whose disease progressed after multi-lines 
of therapies. The mean number of dosing duration was 87.6 days across all dose cohorts 
from 50 mg/day to 600 mg/day, and the mean dosing duration for individual dose cohorts 
ranged from 57.7 to 109.4 days. Of the 40 patients, 39 (98%) experienced at least 1 
TEAE during the study, with the most frequent AEs being fatigue, nausea, decreased 
appetite, anemia, weight decrease, diarrhea, constipation, back pain and dizziness. Most 
of patients reported TEAEs that were considered related to the study drug, with the most 
common drug-related AEs being fatigue (42.5%), decreased appetite (20%), nausea 
(15%), dizziness (12.5%), constipation (12.5%), anemia (10%), weight decrease (10%), 
dysgeusia (10%), and diarrhea (7.5%). Most TEAEs were Grade 1 or 2. Twenty patients 
across all dose cohorts reported TEAEs of Grade 3 or higher. Each individual TEAE of 
Grade 3 or higher occurred sporadically in 1 or 2 patients, except for the following: 
anemia (7/40), fatigue (5/40) and sepsis (3/40). The majority of Grade 3 or higher TEAEs 
were considered not related to the study drug. Overall, nine patients (9/40, 22.5%) 
reported at least one SAE. The nine patients were distributed in nearly all dose cohorts 
except the 100 mg/day cohort. The majority of SAEs were Grade 3 or 4, and two Grade 5 
deaths were reported. Both deaths were due to disease progression and they were not 
related to the study drug. Most SAEs were not drug-related, except for one event of 
Grade 4 increased creatine phosphokinase (CK). Five patients with SAEs, including 
sepsis, worsening dehydration, pneumonia and increased CK, were permanently 
discontinued from the study. Other drug-related AEs that led to study discontinuation 
included: fatigue (Grade 3 and Grade 2), anemia (Grade 3) and decreased white blood 
cell (Grade 3). No DLT was reported in any of the dose cohort. Therefore, MTD was not 
established in this study. Overall, GT0918 was generally well-tolerated in mCRPC 
patients. 
 
 
 
 
 
 
A summary of AEs are given in the following tables: 


 
 
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Study 4:  Phase II dose escalating study of Proxalutamide (100-300 mg) in 108 patients 
with prostate cancer.   
A table of adverse events observed in the trial are described below. 
 


 
 
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Drug Interactions 
Inhibition Potential Assessment of Proxalutamide on Cytochrome P450 Enzymes in 
Pooled Human Liver Microsomes 
The inhibition of human liver CYPs: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 
and CYP3A4/5, was assessed with Proxalutamide at concentrations of 0.2, 0.8, 2, 10, 50, 
100 and 200 µM. The metabolite formation from CYP catalyzed probe substrate 
metabolism was analyzed with LC-MS/MS. The results showed that Proxalutamide 
showed no significant inhibition on CYP1A2 and CYP2E1, weak inhibition on CYP2D6, 
CYP2C9, CYP2C19 and CYP3A (midazolam), but marked inhibition on CYP3A4 
(testosterone). 
The results indicate that there is an inhibitory effect of Proxalutamide on CYP3A4 in 
vitro and the corresponding in vivo drug interaction potential needs to be further 
investigated. 
*No interaction has been reported between Proxalutamide, nitazoxanide, and 
azithromycin. 
Evaluation of Cytochrome P450 Induction Potential of Proxalutamide in Human 
Hepatocytes 
Proxalutamide was evaluated for induction of drug metabolizing enzymes in primary 
human hepatocytes. No inductive effects on CYP1A2 and CYP3A4 were observed in the 
level of enzymatic activity. 


 
 
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Specific Populations 
 
Pediatric 
Proxalutamide pharmacokinetics have not been investigated in subjects younger 
than 18 years. 
  
Geriatric 
No dose adjustment is necessary in the elderly. The pharmacokinetics and 
pharmacodynamics of Proxalutamide were evaluated in 40 patients with an 
average age of 70.1 (Study 2, Section 1.1.2.4.). 
 
Gender 
Proxalutamide is not indicated for use in women.  The palnned interventional 
study will be conducted in men only. 
 
Race 
The effect of race on Proxalutamide pharmacokinetics has not been studied.  
 
Renal Impairment 
The effect of renal impairment on Proxalutamide pharmacokinetics has not been 
studied.  
 
Hepatic Impairment 
The effect of hepatic impairment on Proxalutamide pharmacokinetics has not 
been studied.  


 
 
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1.1.3 Prior Pre-clinical Efficacy Data 
 
No prior pre-clinical data exists as to the use of Proxalutamide as a treatment for COVID-
19.; however, two studies highlight the possible benefit of the dual anti-androgen activity 
of Proxalutamide .   
 
Proxalutamide inhibition of androgen binding to AR and AR protein expression   
A study by Zhou et al19 reported that: “GT0918 inhibited the binding of androgen to AR 
in a dose-dependent manner, and the Ki value of GT0918 (1.4 x 10-8 M) in binding to AR 
was 3.4-fold lower than that of MDV3100 (4.8 x 10-8 M) (Fig. 1A). It indicated that 
GT0918 was more potent than MDV3100 in inhibiting the binding of androgen to AR.”  
Additionally, in cultures of C4-2B cells, “the protein expression of AR was significantly 
reduced by GT0918”. Data depicting the inhibition androgen binding to AR and the 
reduced AR protein expression in C4-2B cells is shown below: 
 
Proxalutamide suppression ACE2 and TMPRSS2 in A549 lung cells   
 
A study by Wu et al 20 reported that “In LNCaP and A549 cells, we showed that androgen  
induced the ACE2 and TMPRSS2 expression, and GT0918 could suppress the ACE2 and 
TMPRSS2 expression”.  The data from the study is depicted in the figure below.  


 
 
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1.1.4 Justification for Dosage  
 
According to a phase I study of Proxalutamide conducted by Zhou et al19 pK 
parameters showed that drug exposure increased with dose proportionally from 50 
to 300 mg and a saturation was observed between 300mg and 400 mg. In addition, 
according to Zhou et al: “Of note, patients treated with a 400-mg dose in the present 
study showed greater PSA response (100%) than those treated with a 300-mg dose 
(50%) or a 200-mg dose (67%). Although several previous studies demonstrated that a 
30% PSA decline at 3 months was associated with a decreased risk of death from PCa” 
 
Assuming the PSA reduction is linearly correlated with the dosage of Proxalutamide; 
to achieve a clinically meaningful PSA reduction, a dosage of 200mg should suffice 
for the treatment of PCa. As we have no prior data on dosing of Proxalutamide for the 
treatment of COVID-19, we chose the same dosage used for the treatment of PCa. 
 
1.1.5 Other Data 
 
The PI has not identified any additional data related to the safety or efficacy of this study.  
1.2. Risks/Benefits 
 
This study is designed as a prospective, interventional, placebo controlled, double-blinded, 
randomized parallel assignment study to assess the efficacy of Proxalutamide as a treatment 
for COVID-19; therefore, we assess below the risks/benefits for the proposed study.  
 
Benefit(s) of the Proposed Clinical Study 
The study is intended to explore the theory that COVID-19 infection and disease severity is 
driven by androgens. As such, anti-androgen therapy is hypothesized to provide protection 
against COVID-19 disease progression. Provided anti-androgen therapy is effective, subjects 
enrolled in this study will possibly experience mild COVID-19 related symptoms.  


 
 
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Risk(s) of the Proposed Clinical Study 
Treatment with any drug carries risk. Treatment with Proxalutamide caries the risk of the 
adverse events reported in Phase I clinical trials with Proxalutamide; however, due to the 
short treatment duration of 15 days, we believe the risk of serious adverse events is lower 
than described in Phase I studies.   
1.3. Trial Conduct 
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board (Ethics Committee), and according to Good Clinical Practice standards. No 
deviation from the protocol will be implemented without the prior review and approval of the 
IRB (EC) except where it may be necessary to eliminate an immediate hazard to a research 
subject.  In such case, the deviation will be reported to the IRB (EC) as soon as possible. 
1.4. Population 
This is a multi-center study to be conducted at outpatient clinics. This exact protocol will be 
followed at each site. There will be one PI. The study will be approved by the national Ethics 
Committee.  
 
The population for this study will be non-hospitalized SARS-CoV-2 confirmed subjects 
previously presented to an outpatient hospital and/or clinic participating in the local health 
care electronic record exchange (SUS). Approximately, 260 male subjects who meet all the 
eligibility criteria will be enrolled. The estimated time from screening to end of the study for 
each subject is approximately 30 days. 
1.5. Literature  
1. Guan W-J, Ni Z-Y, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in 
China. N Engl J Med. February 2020:NEJMoa2002032. doi:10.1056/NEJMoa2002032 
2. Goren A, Mc Coy J, Wambier CG, et al. WHAT DOES ANDROGENETIC ALOPECIA 
HAVE TO DO WITH COVID-19? AN INSIGHT INTO A POTENTIAL NEW THERAPY. 
Dermatol Ther. April 2020:e13365. doi:10.1111/dth.13365 
3. Shieh WJ, Hsiao CH, Paddock CD, et al. Immunohistochemical, in situ hybridization, 
and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of 
severe acute respiratory syndrome in Taiwan. Hum Pathol. 2005. 
doi:10.1016/j.humpath.2004.11.006 
4. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on 
ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. March 
2020:1-10. doi:10.1016/j.cell.2020.02.052 
5. Glowacka I, Bertram S, Muller MA, et al. Evidence that TMPRSS2 Activates the Severe 
Acute Respiratory Syndrome Coronavirus Spike Protein for Membrane Fusion and Reduces 
Viral Control by the Humoral Immune Response. J Virol. 2011. doi:10.1128/jvi.02232-10 
6. Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pohlmann S. TMPRSS2 
and ADAM17 Cleave ACE2 Differentially and Only Proteolysis by TMPRSS2 Augments 
Entry Driven by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein. J Virol. 
2014;88(2):1293-1307. doi:10.1128/JVI.02202-13 


 
 
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This material is the property of the Applied Biology Inc.  Do not disclose or use except as authorized.  
7. Limburg H, Harbig A, Bestle D, et al. TMPRSS2 Is the Major Activating Protease of 
Influenza A Virus in Primary Human Airway Cells and Influenza B Virus in Human Type II 
Pneumocytes. Schultz-Cherry S, ed. J Virol. 2019;93(21). doi:10.1128/JVI.00649-19 
8. Lucas JM, Heinlein C, Kim T, et al. The Androgen-Regulated Protease TMPRSS2 
Activates a Proteolytic Cascade Involving Components of the Tumor Microenvironment and 
Promotes Prostate Cancer Metastasis. Cancer Discov. 2014;4(11):1310-1325. 
doi:10.1158/2159-8290.CD-13-1010 
9. National Institutes of Health. TMPRSS2 transmembrane serine protease 2 [ Homo 
sapiens (human) ] Gene ID: 7113. Gene ID: 7113, updated on 13-Mar-2020. 
https://www.ncbi.nlm.nih.gov/gene/7113. Published 2020. Accessed April 2, 2020. 
10. Lin B, Ferguson C, White JT, et al. Prostate-localized and androgen-regulated expression 
of the membrane- bound serine protease TMPRSS2. Cancer Res. 1999. 
11. Dalpiaz PLM, Lamas AZ, Caliman IF, et al. Sex Hormones Promote Opposite Effects on 
ACE and ACE2 Activity, Hypertrophy and Cardiac Contractility in Spontaneously 
Hypertensive Rats. Bader M, ed. PLoS One. 2015;10(5):e0127515. 
doi:10.1371/journal.pone.0127515 
12. Gan DCC, Sinclair RD. Prevalence of male and female pattern hair loss in Maryborough. 
J Investig Dermatol Symp Proc. 2005;10(3):184-189. doi:10.1111/j.1087-0024.2005.10102.x 
13. Goren et al. A PRELIMINARY OBSERVATION: MALE PATTERN HAIR LOSS 
AMONG HOSPITALIZED COVID-19 PATIENTS IN SPAIN – A POTENTIAL CLUE TO 
THE ROLE OF ANDROGENS IN COVID-19 SEVERITY. J. Cos. Derm (accepted April 
2020) 
14. Severi G, Sinclair R, Hopper JL, English DR, McCredie MR, Boyle P, Giles GG. 
Androgenetic alopecia in men aged 40-69 years: prevalence and risk factors. Br J Dermatol. 
2003; 149(6): 1207-1213. 
15. Hamilton JB. Patterned loss of hair in man: Types and incidence. Ann N Y Acad 
Sci. 1951;53:708–728. 
16. Montopoli M, Zumerle S, Vettor R, Rugge M, Zorzi M, Catapano CV, Carbone GM, 
Cavalli A, Pagano F, Ragazzi E, Prayer-Galetti T, Alimonti A, Androgen-deprivation 
therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study 
(n=4532), Annals of Oncology (2020), doi: https://doi.org/10.1016/j.annonc.2020.04.479 
17. Goren A, Wambier CG, Herrera S, McCoy J, Vaño-Galván S, Gioia F, Comeche B, Ron 
R, Serrano-Villar S, Ramos PM, Cadegiani FA, Kovacevic M, Tosti A, Shapiro J, Sinclair R. 
Anti-androgens may protect against severe COVID-19 outcomes: results from a prospective 
cohort study of 77 hospitalized men. J Eur Acad Dermatol Venereol. 2020 Sep 
25:10.1111/jdv.16953. doi: 10.1111/jdv.16953. Epub ahead of print. PMID: 32977363; 
PMCID: PMC7536996. 
18. McCoy J, Cadegiani FA, Wambier CG, Herrera S, Vaño-Galván S, Mesinkovska NA, 
Ramos PM, Shapiro J, Sinclair R, Tosti A, Goren A. 5-Alpha-Reductase Inhibitors are 
Associated with Reduced Frequency of COVID-19 Symptoms in Males with Androgenetic 
Alopecia. J Eur Acad Dermatol Venereol. 2020 Nov 2. doi: 10.1111/jdv.17021. Epub ahead 
of print. PMID: 33135263. 
19. Zhou T, Xu W, Zhang W, Sun Y, Yan H, Gao X, Wang F, Zhou Q, Hou J, Ren S, Yang 
Q, Yang B, Xu C, Zhou Q, Wang M, Chen C, Sun Y. Preclinical profile and phase I clinical 
trial of a novel androgen receptor antagonist GT0918 in castration-resistant prostate cancer. 


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CONFIDENTIAL 
This material is the property of the Applied Biology Inc.  Do not disclose or use except as authorized. 
Eur J Cancer. 2020 Jul;134:29-40. doi: 10.1016/j.ejca.2020.04.013. Epub 2020 May 24. 
PMID: 32460179. 
20. Wu, Siqi and Miao, Liyan and Zhou, Qianxiang and Gao, Chang and Liu, Jialin and
Zhan, Qingyuan and Guo, Binbin and Li, Fang and Wang, Yirong and Xu, Hongyang and
Yan, Honghua and Wu, Rui and Zhang, Shenghua and Zheng, Jiangnan and Yang, Jianfei
and Wang, Shanshan and Yu, Wenkui and Niu, Haitao and Li, Fengyuan and Yang, Ling and
Huang, Jianan and Lu, Xiaoting and Chen, Jiahao and Tong, Youzhi and Ma, Liandong and
Zhou, Yifeng and Guo, Qiang, Suppression of Androgen Receptor (AR)-ACE2/TMPRSS2
Axis by AR Antagonists May Be Therapeutically Beneficial for Male COVID-19 Patients
(April 20, 2020). Available at
SSRN: https://ssrn.com/abstract=3580526 or http://dx.doi.org/10.2139/ssrn.3580526
2. Trial Objectives
The primary purpose of this study is to evaluate the efficacy of Proxalutamide as a treatment
for COVID-19.
3. Trial Design
3.1 Primary Study Endpoints/Secondary Endpoints
Primary Outcome Measures: 
1. COVID-19 hospitalization [Time Frame: 30 days]
Percentage of subjects hospitalized due to COVID-19
Secondary Outcome Measures: 
1. COVID-19 Ordinal Outcomes Scale on Day 15, 30 [Time Frame: assessed on study day
15, 30]
We will determine the COVID Ordinal Scale for all patients on study day 15, 30 
COVID Ordinal Scale defined as: 
8. Death;
7. Hospitalized, on invasive mechanical ventilation or ECMO;
6. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
5. Hospitalized, requiring supplemental oxygen;
4. Hospitalized, not requiring supplemental oxygen- requiring ongoing medical care
(COVID-19 related or otherwise);
3. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical
care;
2. Not hospitalized, limitation on activities;
1. Not hospitalized, no limitations on activities


 
 
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3.2 Study Design/Type 
 
This study is designed as a prospective, interventional, placebo controlled, double-blinded, 
randomized parallel assignment study. The study will have 2 arms: 
 
For the first 15 days: 
 
Arm 1: Subjects administered Proxalutamide 200mg q.d for 15 days (or until remission) + 
standard of care as determined by the PI at the site 
 
Arm 2: Subjects administered Proxalutamide placebo q.d for 15 days (or until remission) + 
standard of care as determined by the PI at the site 
 
Starting at day 15 +/- 3 (if patients have not experienced full remission) 
 
Arm 1: Subjects administered Proxalutamide placebo 200mg q.d for 15 days (or until 
remission) + standard of care as determined by the PI at the site 
 
Arm 2: Subjects administered Proxalutamide placebo 200mg q.d for 15 days (or until 
remission) + standard of care as determined by the PI at the site 
 
Study Environment: 
 
This is a multi-center study to be conducted at multiple outpatient clinics (the sites). This 
exact protocol will be followed during the study. There will be one or more PIs. The study 
will be approved by the appropriate Ethics Committees (IRBs). Data collection will be 
performed at each site by study personnel under the supervision of the PI. 
 
Study Design: 
 
 
Phase I: Enrollment (first site visit or consultation by phone): 
1. Each subject will be evaluated for the inclusion and exclusion criteria  
 
2. Each subject will undergo a physical examination 
 
3. Each subject (or legally authorized representative) will complete and sign the Informed 
Consent Form 
 
4. Each subject will be assigned a subject study number  
 
5. Each subject will be randomly assigned to an Arm (Section 3.3) 
 
6. Based on the Arm assignment, each subject will be given a 15 days supply of the       
intervention  
 


 
 
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7. All information will be recorded in the appropriate CRFs 
 
Phase II: Treatment Administration at Home (day 0-15) 
1. Each subject will self-administer the assigned treatment orally once per day 
Phase III: Outcome Assessment at Site (day 15+/-3): 
 
1. Each subject will be evaluated by the PI for the primary and secondary outcomes 
 
2. The PI will assess each subject for any treatment related adverse events 
 
3. All information will be recorded in the appropriate CRFs 
 
Phase IV: Treatment Administration at Home (day 16-30) 
1. Each subject will self-administer the assigned treatment orally once per day 
Phase V: Outcome Assessment at Site (day 30+/-3): 
 
1. Each subject will be evaluated by the PI for the primary and secondary outcomes 
 
2. The PI will assess each subject for any treatment related adverse events 
 
3. All information will be recorded in the appropriate CRFs 
 
3.3 Randomization 
 
Subjects will be randomized into 1 of 2 arms each will receive an interventional treatment.  
 
For the first 15 days: 
 
Arm 1: Subjects administered Proxalutamide 200mg q.d for 15 days (or until remission) + 
standard of care as determined by the PI at the site 
 
Arm 2: Subjects administered Proxalutamide placebo q.d for 15 days (or until remission) + 
standard of care as determined by the PI at the site 
 
Starting at day 15 +/- 3 (if patients have not experienced full remission) 
 
Arm 1: Subjects administered Proxalutamide placebo 200mg q.d for 15 days (or until 
remission) + standard of care as determined by the PI at the site 
 
Arm 2: Subjects administered Proxalutamide placebo 200mg q.d for 15 days (or until 
remission) + standard of care as determined by the PI at the site 
 


 
 
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During the enrollment phase (admission to hospital), each subject will be assigned a subject 
study number. The first subject will be assigned the number 001 and each subject thereafter 
will be assigned a consecutive number i.e., 002, 003, etc. The randomization plan is based on 
a 1:1 ratio for each arm. Since the study is double-blinded, the following randomization 
schedule will be used but the identification of the Arm assignment will be known only to the 
sponsor: 
 
Subjects 001-020 will be assigned to Arm 1 
Subjects 021-040 will be assigned to Arm 2 
Subjects 041-060 will be assigned to Arm 1 
Subjects 061-080 will be assigned to Arm 2 
Subjects 081-100 will be assigned to Arm 1 
Subjects 101-120 will be assigned to Arm 2 
etc.……. 
3.4 Records 
Each subject will be assigned a number. The numbers will be consecutive starting at 001. 
 
A record will be created for each subject. Each record will contain a medical history, and the 
subject’s efficacy parameters copied from the subject’s charts and documented in the 
appropriate CRF. 
 
The subjects’ records will be stored and handled in the same manner as the PI’s other 
clinical study patients’ records are stored i.e., in a locked research storage area. 
 
No other data will be recorded. No personal information will be kept outside the study site. 
 
Data compiled at the end of the study will not include any information that can be used to 
identify individuals. 
3.5 Duration 
The duration of the study is 30 days. There will be no study related follow-up treatment. 
3.6 Discontinuation 
In the event that a subject experiences a SAE or an AE grade 3 or 4 (defined in Section 6) 
we will discontinue the study for that particular subject.  
In the event a subject in any arm experiences a SAE defined as death not due to respiratory 
failure (presents with clear lung CT and no ARDS symptoms) the study will be 
discontinued. The reminder of the study shall continue. 
3.7 Product Accountability 
All interventional treatments for this study will be stored and monitored according to each 
hospital standard protocol. 


 
 
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3.8  Data Identification 
The subject records kept by the PI will be stored and handled in the same manner as the PI’s 
other clinical research subject records. Only authorized personnel named in this study, or 
medical professional retained by the PI in case of an adverse event, will have access to the 
subject records. 
 
No other data will be recorded. No personal information will be kept outside the study site. 
 
Data compiled at the end of the study will not include any information that can be used to 
identify individuals. 
4. Selection and Withdrawal of Subjects 
4.1 Inclusion Criteria 
1. Male age  ≥18 years old 
2. Laboratory confirmed positive SARS-CoV-2 rtPCR test within 7 days prior to 
randomization 
3. Clinical status on the COVID-19 Ordinal Scale (defined in Section 5.1) of 1 or 2 
4. Coagulation: INR ≤ 1.5×ULN, and APTT ≤ 1.5×ULN  
5. Subject (or legally authorized representative) gives written informed consent prior to any 
study screening procedures 
6. Subject (or legally authorized representative) agree that subject will not participate in 
another COVID-19 trial while participating in this study 
4.2  Exclusion Criteria 
1. Subject enrolled in a study to investigate a treatment for COVID-19  
2. Subject taking an anti-androgen of any type including: androgen depravation therapy, 5-
alpha reductase inhibitors, etc… 
3. Patients who are allergic to the investigational product or similar drugs (or any 
excipients); 
4. Subjects who have malignant tumors in the past 5 years, with the exception of completed 
resected basal cell and squamous cell skin cancer and completely resected carcinoma in 
situ of any type 
5. Subjects with known serious cardiovascular diseases, congenital long QT syndrome, 
torsade de pointes, myocardial infarction in the past 6 months, or arterial thrombosis, or 
unstable angina pectoris, or congestive heart failure which is classified as New York 
Heart Association (NYHA) class 3 or higher, or left ventricular ejection fraction (LVEF) 
< 50%, QTcF > 450 ms  
6. Subjects with uncontrolled medical conditions that could compromise participation in 
the study(e.g. uncontrolled hypertension, hypothyroidism, diabetes mellitus) 
7. Known diagnosis of human immunodeficiency virus(HIV) , hepatitis C, active hepatitis 
B, treponema pallidum (testing is not mandatory） 
8. Alanine Transaminase (ALT) or Aspartate Transaminase (AST) > 5 times the upper limit 
of normal. 
9. Estimated glomerular filtration rate (eGFR) < 30 ml/min  


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10. Severe kidney disease requiring dialysis
11. Subject unlikely to return for day 15 site visit for reasons other then remission
12. Subject (or legally authorized representative) not willing or unable to provide informed
consent
4.3 Subject Withdrawal
Subjects may withdraw at any time for any reason. In the event the principal investigator or 
the site monitor believes a subject is at risk of injury the subject will be withdrawn from the 
study and: 
(a) If the subject has not completed the study
(b) The subject will be replaced with another subject
(c) The PI will follow-up with the subject every day for 14 days
(d) The information will be reported in the appropriate CRF
4.4 Treatment of Subjects
Once enrolled in the study, each subject will self-administer the assigned treatment at home 
in the form of a daily oral tablet.
4.5 Medication
Proxalutamide showed no significant inhibition on CYP1A2 and CYP2E1, weak inhibition 
on CYP2D6, CYP2C9, CYP2C19 and CYP3A (midazolam), but obvious inhibition on 
CYP3A4 (testosterone). Potential inducer on CYP3A4 at a concentration of 10μM. No
inductive effects on CYP1A2 and CYP2B6 were observed in the level of enzymatic activity. 
Co-administration of strong/moderate CYP3A4 inducer, strong/moderate CYP3A4 inhibitor, 
sensitive CYP3A4/ CYP2D6 substrates and narrow therapeutic index with Proxalutamide
should be used cautiously (See Appendix 1).
Note: No interaction has been reported between Proxalutamide, Nitazoxanide, and
azithromycin. 
4.6 Monitoring for subject compliance 
During each site visit, the PI will ask each subject to confirm if he adhered to the daily 
administration of the treatment. 
5 Assessment of Efficacy
5.1 Efficacy Parameters 
The following efficacy parameters will be assessed and recorded in the CRF. 
I. COVID-19 Hospitalization:
1. COVID-19 hospitalization [Time Frame: 30 days]


 
 
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Percentage of subjects hospitalized due to COVID-19  
 
II. COVID-19 Ordinal Outcome Scale: 
 
1. COVID-19 Ordinal Outcomes Scale on Day 15, 30 [Time Frame: assessed on study day 
15, 30] 
We will determine the COVID Ordinal Scale for all patients on study day 15, 30 
COVID Ordinal Scale defined as: 
8. Death;  
7. Hospitalized, on invasive mechanical ventilation or ECMO;  
6. Hospitalized, on non-invasive ventilation or high flow oxygen devices;  
5. Hospitalized, requiring supplemental oxygen;  
4. Hospitalized, not requiring supplemental oxygen- requiring ongoing medical care 
(COVID-19 related or otherwise);  
3. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical 
care;  
2. Not hospitalized, limitation on activities;  
1. Not hospitalized, no limitations on activities  
5.2 Method and Timing 
The assessments, as described in section 5.1, will occur as follows: 
The PI will assesses each subject and record the efficacy parameters at baseline, days 15 and 
30 following enrollment (+/-3 days). 
6 Assessment of Safety 
6.1 Safety Parameters 
Safety parameters will be assessed as follows: 
 
I. Physical Examination: 
The PI will conduct a thorough physical examination during screening. The assessment will 
be recorded in the appropriate CRF.  
 
II. Adverse Events: 
Safety will be assessed by summarizing the incidence and type of Adverse Events in a CRF 
form. 
6.2 Method and Timing 
The assessments, as described in section 6.1, will occur as follows: 
I. Physical Examination 


 
 
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The assessment will occur at screening. The information will be recorded in the appropriate 
CRF. 
II. Adverse Events: 
Adverse events will be assessed by the PI at baseline and during the site visits on days 15 and 
30 following enrollment (+/-3 days). 
The methods employed for completing assessments are described in section 6.1 
6.3 Adverse Events 
 
6.3.1 Definition of Adverse Event (AE)  
AE means any medical event associated with the use of an intervention, whether or not 
considered intervention-related. An AE can be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of medicinal (investigational) product.  
Any medical condition that is present at the time that the subject is screened will be 
considered as baseline and not reported as an AE. However, if the severity of any pre-
existing medical condition increases, it should be recorded as an AE.  
Given the nature of severity of the underlying illness, subjects will have many symptoms 
and abnormalities in vitals and laboratory. All Grade 3 and 4 AEs will be captured as 
AEs in this trial.  
6.3.2 Definition of Serious Adverse Event (SAE)  
An SAE is defined as “An AE or suspected adverse reaction is considered serious if, in 
the view of either the investigator or the sponsor, it results in any of the following 
outcomes: Death, a life-threatening AE, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.” “Life-
threatening” refers to an AE that at occurrence represents an immediate risk of death to a 
subject. An event that may cause death if it occurs in a more severe form is not 
considered life-threatening. Similarly, a hospital admission for an elective procedure is 
not considered a SAE.  All SAEs, as with any AE, will be assessed for severity and 
relationship to study intervention. All SAEs will be recorded on the appropriate SAE 


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CRF. All SAEs will be followed through resolution or stabilization by a licensed study 
physician (for IND studies, a physician listed on the Form FDA 1572 as the site PI or 
Sub-Investigator).  All SAEs will be reviewed and evaluated by DMID and will be sent to 
the SMC (for periodic review), and the IRB/IEC.  
6.3.3 Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is any SAE where a causal relationship with the study product is at least 
reasonably possible but is not listed in the Investigator Brochure (IB), Package Insert, 
and/or Summary of Product Characteristics.  
6.3.4 Classification of an Adverse Event 
The determination of seriousness, severity, and causality will be made by an on-site 
investigator who is qualified (licensed) to diagnose AE information, provide a medical 
evaluation of AEs, and classify AEs based upon medical judgment. This includes but is 
not limited to physicians, physician assistants, and nurse practitioners.  
6.3.5 Severity of Adverse Events 
All AEs and SAEs will be assessed for severity, according to the Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, version 
2.1 (July 2017). For AEs not included in the protocol defined grading system, the 
following guidelines will be used to describe severity.  
Mild (Grade 1): Events that are usually transient and may require only minimal or no 
treatment or therapeutic intervention and generally do not interfere with the subject’s 
usual activities of daily living.  
Moderate (Grade 2): Events that are usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research subject.  
Severe (Grade 3): Events interrupt usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. Severe events are 
usually incapacitating.  
Severe (Grade 4): Events that are potentially life threatening. 
AEs characterized as intermittent require documentation of onset and duration of each 
episode. The start and stop Duration of each reported AE will be recorded on the 
appropriate CRF. Changes in the severity of an AE will be documented to allow an 
assessment of the duration of the event at each level of intensity.  
6.3.6 Relationship to Study Intervention 


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For each reported adverse reaction, the PI or designee must assess the relationship of the 
event to the study product using the following guideline:  
Related – The AE is known to occur with the study intervention, there is a reasonable 
possibility that the study intervention caused the AE, or there is a temporal relationship 
between the study intervention and event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study intervention and the AE.  
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established.  
6.3.7 Time Period and Frequency for Event Assessment and Follow-Up 
For this study, all Grade 3 and 4 AEs and all SAEs occurring from the time the informed 
consent is signed through the Day 30 (end of study) visit will be documented, recorded, 
and reported.  
6.3.8 Investigators Reporting of AEs 
Information on all AEs should be recorded on the appropriate CRF. All clearly related 
signs, symptoms, and results of diagnostic procedures performed because of an AE 
should be grouped together and recorded as a single diagnosis. If the AE is a laboratory 
abnormality that is part of a clinical condition or syndrome, it should be recorded as the 
syndrome or diagnosis rather than the individual laboratory abnormality. Each AE will 
also be described in terms of duration (start and stop date), severity, association with the 
study product, action(s) taken, and outcome.  
6.3.9 Serious Adverse Event Reporting 
6.3.9.1 Investigators Reporting of SAEs 
Any AE that meets a protocol-defined criterion as a SAE must be submitted immediately 
(within 24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance 
Group, at the following address:  
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) SAE FAX 
Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) SAE Email Address: 
PVG@dmidcroms.com  
Other supporting documentation of the event may be requested by the DMID 
Pharmacovigilance Group and should be provided as soon as possible. The DMID 


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Medical Monitor will review and assess the SAE for regulatory reporting and potential 
impact on study subject safety and protocol conduct. At any time after completion of the 
study, if the site PI or appropriate sub-investigator becomes aware of an SAE, the site PI 
or appropriate sub-investigator will report the event to the DMID Pharmacovigilance 
Group.  
6.3.9.2 Regulatory Reporting of SAEs 
Following notification from the site PI or appropriate sub-investigator, DMID, as the IND 
sponsor, will report any SUSAR in an IND safety report to the FDA and will notify all 
participating site PIs as soon as possible. DMID will report to the FDA any unexpected 
fatal or life-threatening suspected adverse reaction as soon as possible, but in no case 
later than 7 calendar days after the sponsor’s initial receipt of the information. If the event 
is not fatal or life- threatening, the IND safety report will be submitted within 15 calendar 
days after the sponsor determines that the information qualifies for reporting as specified 
in 21 CFR Part 312.32. Relevant follow up information to an IND safety report will be 
submitted as soon as the information is available. Upon request from FDA, DMID will 
submit to the FDA any additional data or information that the agency deems necessary, as 
soon as possible, but in no case later than 15 calendar days after receiving the request.  
SAEs that are not SUSARs will be reported to the FDA at least annually in a summary 
format which includes all SAEs. Sites may have additional local reporting requirements 
(to the IRB and/or national regulatory authority).  
6.3.10 Reporting Events to Subjects 
Subjects will be informed of any severe AEs or SAEs that occur as part of their 
participation in this trial.  
6.3.11 Reporting of Pregnancy 
Pregnancy is not defined as an AE. However, any pregnancy that occurs during study 
participation should be reported to the sponsor on the appropriate CRF. Pregnancy should 
be followed to outcome.  
6.4 
Unanticipated Problems 
6.4.1 Definition of Unanticipated Problems (UP) 
An Unanticipated Problem is any event, incident, experience, or outcome that meets the 
following criteria:  
•
Unexpected in terms of nature, severity, or frequency given (a) the research
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the
characteristics of the subject population being studied;


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•
Related or possibly related to participation in the research (“possibly related” means
there is a reasonable possibility that the incident, experience, or outcome may have
been caused by the procedures involved in the research); and
•
Suggests that the research places subjects or others at a greater risk of harm
(including physical, psychological, economic, or social harm) than was previously
known or recognized.
6.4.2 Unanticipated Problem Reporting 
To satisfy the requirement for prompt reporting, unanticipated problems (UP) will be 
reported using the following timeline: UPs that are SAEs will be reported to the IRB and 
to the Statistical and Data Coordinating Center (SDCC)/study sponsor within 24 hours of 
the investigator becoming aware of the event per the above describe SAE reporting 
process. Any other UP will be reported to the IRB and to the SDCC/study sponsor within 
3 days of the investigator becoming aware of the problem.  
6.4.3 Reporting Unanticipated Problems to Subjects 
Subjects will be informed of any UPs that occur as part of their participation in this trial. 
7 Statistical Plan
7.1 Statistical Methods 
I. General Principles:
•
Double-blinded, placebo controlled randomized interventional study with a two-sided
type I error rate of 0.05.
•
Continuous variables will be expressed as median (interquartile range [IQR]) and
categorical variables will be expressed as a number
•
95% confidence intervals will be calculated for the primary outcome
•
Group comparisons will be analyzed by the Wilcoxon rank sum test or χ2 test for
independent proportions
•
The placebo arm will be used as a reference group when calculating treatment effects
•
Differences between rates of clinical improvement will be calculated using unadjusted
ordinal logistic regression or Cox proportional hazard models
•
Statistical analyses will be conducted using XLSTAT version 2020.5.1 (Addinsoft, Inc.)
II. Statistical Hypotheses:
The primary endpoint is the proportion of subjects hospitalized through day 30. The primary 
outcome will be analyzed using the χ2 test for independent proportions. 


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The Null Hypothesis (H0) is that the proportion of subjects hospitalized due to COVID-19 in 
Arm 1 (Proxalutamide) is equal to the proportion of subjects hospitalized due to COVID-19 
in Arm 2 (standard of care) 
The Alternative Hypothesis (HA) is that the proportion of subjects hospitalized due to 
COVID-19 in Arm 1 (Proxalutamide) is less than the proportion of subjects hospitalized due 
to COVID-19 in Arm 2 (standard of care) 
Mathematically written as: 
H0: p1 - p2= 0 
HA: p1 - p2<0 
Where p1 and p2 are the proportion of subjects hospitalized from arm1 and arm2 
respectively.   
III. Primary Efficacy Analysis:
•
The χ2 test for independent proportions will be used to assess the primary end point.
•
P-values <0.05 will be considered significant. All statistical analysis will be based on the
intent-to-treat (ITT) population. All missing data will be described.
7.1 Sample Size Estimates
Assumptions: 
•
Riccardo et al (2020)1 reported that in Italy the hospitalization rate was as high as 20%
among adults above the age of 65 tested positive for SARS-CoV-2. Further, Montopoli et
al (2020)2 reported that males represent 60% of hospitalized patients; therefore, we can
estimate that the rate of hospitalization of males over the age of 65% tested positive for
SARS-CoV-2 is approximately 30%.
•
To estimate the efficacy of Proxalutamide as a treatment for COVID-19,  we use the
results reported by Montopoli et al (2020)2. According to Montopoli et al: “Comparing
the total number of SARS-CoV-2 positive cases, patients with prostate cancer receiving
ADT had a significantly lower risk of SARS-CoV-2 infections compared to patients who
did not receive ADT (OR 4.05; 95% CI 1.55-10.59). Applying the 20% hospitalization
rate, we derive a probability of treatment efficacy of 50%
•
The study has two arms with randomization at 1:1 ratio
•
80% power to detect the difference in proportions using a two-tailed test with a type I
error rate of 5%


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•
5% of the subjects will not complete the study.
Sample Size Estimate: 
Based on the assumptions above, we calculated3 that at a minimum we would need to recruit 
254 subjects i.e., 127 subjects in each arm 
References: 
1.
https://doi.org/10.1101/2020.04.08.20056861
2.
Montopoli M, Zumerle S, Vettor R, Rugge M, Zorzi M, Catapano CV, Carbone GM,
Cavalli A, Pagano F, Ragazzi E, Prayer-Galetti T, Alimonti A, Androgen-deprivation
therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based
study (n=4532), Annals of Oncology (2020), doi:
https://doi.org/10.1016/j.annonc.2020.04.479.
3.
https://jamanetwork.com/journals/jama/fullarticle/2765184
4.
Machin D, Campbell MJ, Tan SB, Tan SH (2009) Sample size tables for clinical studies.
3rd ed. Chichester: Wiley-Blackwell.
7.2 Subject Population(s) for Analysis
•
The primary analysis will be based on the intent-to-treat (ITT) population. The data from
all subjects enrolled in the study will be analyzed.
•
The safety analysis will be based on a modified intent-to-treat (MITT) population i.e.,
subjects who received at least one dosage of the interventional treatment.
•
Subgroup analysis based on: 1) age stratification; and 2) androgen status as defined by
the “Gabrin sign” will be conducted for the primary and secondary outcomes.
7.4 Interim Analysis 
Interim efficacy and safety data will be made upon recruitment of 50% of the subjects. 
7.5 Termination Criteria
Upon occurrence of any one of the events listed below, the study will terminate or be 
modified accordingly: 
•
Completion of the study by a sufficient number of subjects (254 subjects) to reach our
confidence level
•
Termination of Arm 1: Serious adverse event due to treatment with Proxalutamide


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•
Substantial evidence of treatment difference between the arms. The study design will be
modified to an open-label study.
7.6 Accountability Procedure
The data will be analyzed by a bio-statistics expert. The data will also be independently 
verified by an outside expert consultant.  
7.7 Deviation Reporting
No deviation from the plan will be implemented without the prior review and approval of the 
EC/IRB.  
8 Direct Access to Source Data/Documentation
The PI and hospital will permit trial-related monitoring, audits, IRB/IEC(s) review and 
regulatory inspection(s) by providing direct access to source data/documentation. 
9 Quality Control and Quality Assurance
Every effort will be made to keep staff assignments consistent throughout the entire study. 
The PI who assesses the subject at baseline should follow the subject throughout the 
completion of the study.  This will ensure that this study is conducted – and that data is 
generated, documented (recorded), and reported - in compliance with this protocol, with 
GCP, and any other applicable regulatory requirements. The study monitor will audit the 
study procedures and CRFs throughout the study. 
10 Ethical Considerations
This study will be conducted according to US and international standards of Good Clinical 
Practice (FDA regulations 21 CFR 312 for IND studies and FDA guidance E6) for all 
studies.  Applicable government regulations and hospital research policies and procedures 
will also be followed. 
This protocol and any amendments will be submitted to the Institutional Review Board (IRB) 
for formal approval to conduct the study.  The decision of the IRB concerning the conduct of 
the study will be made in writing to the investigator.   
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  This consent form will be submitted with the protocol for review 
and approval by the IRB.  The formal consent of a subject, using the IRB-approved consent 
form, will be obtained before that subject is submitted to any study procedure.  This consent 
form must be signed by the subject or legally acceptable surrogate, and the investigator-
designated research professional obtaining the consent.  
11 Data Handling and Record Keeping
During enrollment, each subject will be assigned a number. The numbers will be consecutive 
starting at 001. 


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During enrollment a record will be created for each subject. Each record will contain the 
subject’s demographics, subject’s efficacy parameters and any adverse events or study 
related information. 
The subjects’ records will be stored and handled in the same manner as the PI’s patients’ 
records.  
The study monitor will keep a separate record at the monitor’s office of each subject’s 
identification number, the treatment administered to the subject (arm assignment), outcomes 
and any laboratory results.  
No other data will be recorded. No personal information will be kept outside the study site. 
Data compiled at the end of the study will not include any information that can be used to 
identify individuals. 
The site will keep all subject records for a minimum of 3 years after the completion of the 
study. 
12 Finance and Insurance
The Principal Investigator will be responsible for the cost of study. The site carries insurance 
for accidental injury. There is no other insurance. 


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APPENDIX 1 
Drugs that should be used cautiously with Proxalutamide 
Strong CYP3A4 inducer 
Avamibe, Carbamazepine, Phenytoin, Rifampicin, Mitotan, Nevirapine,  Phenobarbital, 
Rifabutin, Rifapentine, St. John's wort, Alfentanil, Ryclosporin, Dihydroergotamine / 
Ergotamine, Fentanyl, Irinotecan, Pimozit, Quinidine, Sirolimus, Tacrolimus 
Moderate CYP3A4 inducer 
Smacet, Tavern, Bosentan, Efaviron, Etruverin, Lopinavir, Modafinil, Nafcillin, Thalidazine, 
Tiranavir, Ritonavir 
Strong CYP3A4 inhibitor 
Posidovir, Clarithromycin, Conivatan, Indinavir, Itraconazole,            Ketoconazole, lopinavir / 
Ritonavir, Mibedil, Nefazodone, Nefenavir, Posaconazole, Ritonavir, Saquinavir, Trapivir, 
Taliomycin, Voriconazole, Etigavir / Ritonavir, Fluconazole, Tiranavir / Ritonavir, Acetamycin 
Moderate CYP3A4 inhibitors 
Apronavir, Aripitan, Azanavir, Casopitam, Cimetidine, Ciprofloxacin, Clazotinib, Cyclosporin, 
Dalunavir, Diltiazem, Dronedarone, Erythromycin, Imatinib, Tofesoyang, Verapamil 
Sensitive CYP3A4 substrates 
Remifentanil, Aripiptam, Budesonide, Buspirone, Conivatan,            Daphnesin, Darunavir, 
Dasatinib, Dronedarone, Eletroptan, Eplerenone, Everolimus, Felodipine, Indinavir, Fluticasone, 
Lopinavir, Lovastatin, Lulasidone, Maravelo, Midazolam, Nisoldipine, Quetiapine, Saquinavir, 
Sildenafil, Simvastatin,            Sirolimus, Tolvaptan, Tiranavir, Triazolam, Vardenafil 
Narrow therapeutic index CYP3A4 Substrate 
Astemizole, Cisapride, Cyclosporine, Dihydroergotamine, Fentanyl,            Pethidine, Quinidine, 
Tacrolimus, Terfenadine 
Sensitive CYP2D6 substrates 
Tomoxetine, Decipamine, Dextromethorphan, Metoprolol, Nebeprolol,
Perphenazine, 


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Tolterodine, Venlafaxine, Avamibe, Carbamazepine,            Phenytoin sodium, Rifampicin 
Narrow therapeutic index CYP2D6 Substrate 
Thioridazine