Conditions: Covid19 SARS (Severe Acute Respiratory Syndrome)
Keywords: Proxalutamide Androgen Anti-androgen
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 645
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy and safety of Proxalutamide as a treatment for hospitalized COVID-19 male and female patients.

Detailed description:

Arms:
arm 1: Proxalutamide + usual care as determined by care provider arm 2: Placebo + usual care as determined by care provider

Interventions: intervention 1: Proxalutamide intervention 2: Placebo
Intervention descriptions: intervention 1: Proxalutamide 300mg q.d intervention 2: Placebo pill

Protocol document:
Prot_SAP_001.pdf: 
   
Study Protocol and Statistical Analysis Plan 
 
Proxalutamide Treatment for 
Hospitalized COVID-19 Patients 
 
 
 
 
 
Protocol: 
KP-DRUG-SARS-003 
Date: 
01 February, 2021 
EDMS number: 
Brazilian National Ethics Committee (4.513.425) 
NCT number: 
NCT04728802 
 
 
Document Contents: 
 
1. Original protocol 
Note: A protocol planned for males, begins with protocol version 1.0.  
2. Final protocol (v8) with summary of all changes. 
3. Final statistical analysis plan with summary of all changes.  
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is confidential and proprietary to the 
principal investigator. 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. 


CLINICAL STUDY 
PROTOCOL 
Proxalutamide (GT0918) 
Treatment for Hospitalized 
COVID-19 Male Patients 
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: Proxalutamide Treatment for Hospitalized COVID-19 Male Patients 
PROTOCOL IDENTIFYING NUMBER:  
KP-DRUG-SARS-003 
PROTOCOL VERSION NUMBER: 
1.00 
PROTOCOL VERSION DATE: 
December 27, 2020 




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Protocol signature page 
Investigator’s Agreement 
Clinical Study: Proxalutamide Treatment for Hospitalized COVID-19 Male Patients 
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 .................................................................................................................. 1 
1. 
Overview 
1 
1.1. 
Investigational Drug 
2 
1.1. 
Pre-Clinical and Prior Clinical Data 
3 
1.1.1. Prior Pre-Clinical and Clinical Safety Data 
3 
1.2. 
Risks/Benefits 
14 
1.3. 
Trial Conduct 
15 
1.4. 
Population 
15 
1.5. 
Literature 
15 
2. 
TRIAL OBJECTIVES ...................................................................................................... 17 
3. 
TRIAL DESIGN ................................................................................................................ 17 
3.1 
Primary Study Endpoints/Secondary Endpoints 
17 
3.2 
Study Design/Type 
17 
3.3 
Randomization 
18 
3.4 
Records 
19 
3.5 
Duration 
19 
3.6 
Discontinuation 
19 
3.7 
Product Accountability 
19 
3.8 
Data Identification 
20 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS .................................................. 20 
4.1 
Inclusion Criteria 
20 
4.2 
Exclusion Criteria 
20 


 
 
 
 
 
 
 
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4.3 
Subject Withdrawal 
21 
4.4 
Treatment of Subjects 
21 
4.5 
Medication 
21 
4.6 
Monitoring for subject compliance 
21 
5 
ASSESSMENT OF EFFICACY ....................................................................................... 22 
5.1 
Efficacy Parameters 
22 
5.2 
Method and Timing 
22 
6 
ASSESSMENT OF SAFETY ........................................................................................... 23 
6.1 
Safety Parameters 
23 
6.2 
Method and Timing 
23 
6.3 
Adverse Event Reporting 
23 
6.4 
Definitions 
24 
6.5 
Adverse Event Follow-up 
25 
7 
STATISTICAL PLAN ...................................................................................................... 25 
7.1 
Statistical Methods 
25 
7.2 
Sample Size Estimates 
26 
7.3 
Subject Population(s) for Analysis 
27 
7.4 
Interim Analysis 
27 
7.5 
Termination Criteria 
27 
7.6 
Accountability Procedure 
27 
7.7 
Deviation Reporting 
27 
8 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION .................................. 27 
9 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................... 27 
10 
ETHICAL CONSIDERATIONS ..................................................................................... 28 


 
 
 
 
 
 
 
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11 
DATA HANDLING AND RECORD KEEPING ........................................................... 28 
12 
FINANCE AND INSURANCE ......................................................................................... 29 
 
 
 


 
 
 
 
 
 
 
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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  
 
 
 
 
 
 


 
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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 
exhibiting pharmacological effects of inducing the down-regulation of AR expression; the 


 
 
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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. 
 
In December 2020, we completed a double-blinded, randomized, prospective, investigational 
study of Proxalutamide Treatment for Non-Hospitalized COVID-19 Male Patients 
(NCT04446429). 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. 
 
Based on the results of the Proxalutamide Treatment for Non-Hospitalized COVID-19 Male 
Patients study (NCT04446429), the purpose of this study is to assess the efficacy and safety 
of Proxalutamide as a treatment for hospitalized COVID-19 male patients.  
1.1. Investigational Drug 
 
Proxalutamide (300 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. 


 
 
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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 
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 


 
 
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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 
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 


 
 
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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 
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 


 
 
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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 
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 


 
 
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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. 


 
 
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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. 
 
 
 
Specific Populations 
 


 
 
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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.  
 
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: 


 
 
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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.  
 
 
 
1.1.4 Prior Clinical Efficacy Data  
 




 
 
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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. 
 
Further, the research team conducting the NCT04446429 study had previously 
administered to five COVID-19 male patients Proxalutamide at dosages as high as 400mg 
q.d. These patients did not qualify to be enrolled in the study due to age <50.  In the 
assessment of the research team, these patients were at an imminent threat of 
hospitalization due to COVID-19. All patients have exhibited shortness of breath, 
coughing and oxygen saturation <=93%. A marked improvement in symptoms was 
observed 24 hours following administration of 400mg Proxalutamide. None of the 
imminent were subsequently hospitalized. No treatment related adverse events were 
observed. 
 
As such, we believe that Proxalutamide 300mg q.d.is likely to provide efficacy in the 
treatment of hospitalized COVID-19 male patients without increasing the rate of 
treatment related adverse events (none observed in NCT04446429) 
 
1.1.6 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 hospitalized COVID-19 male patients; therefore, we assess below the risks/benefits for 
the proposed study.  
 
Benefit(s) of the Proposed Clinical Study 
To-date no therapy for hospitalized COVID-19 patients has demonstrated significant clinical 
benefit. Proxalutamide demonstrated clinical efficacy in non-hospitalized COVID-19 male 
patients (NCT04446429). As such, subjects enrolled in this study could potentially benefit from 
reduced hospitalization time as well as lower risk of experiencing progressively more severe  
COVID-19 related symptoms. In addition, if Proxalutamide demonstrates clinical efficacy in 
this study, it is likely to improve the standard of care for hospitalized COVID-19 male patients 
world-wide. 
 
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 14 days, we believe the risk of serious adverse events is lower 
than described in Phase I studies.  Further, during 14 days of dosing 134 subjects with 200mg 
q.d. of Proxulatimde no drug related adverse events were observed. 


 
 
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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 hospital sites. This exact protocol will be 
followed. There will be one or more PIs. The study will be approved by each hospital’s 
Ethics Committee. 
 
The population for this study will be hospitalized COVID-19 male patients 18 years or older 
of any ethnicity.  Approximately, 300 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 14 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 
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 


 
 
16 | P a g e  
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This material is the property of the Applied Biology Inc.  Do not disclose or use except as authorized.  
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. 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 


 
 
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This material is the property of the Applied Biology Inc.  Do not disclose or use except as authorized.  
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 hospitalized COVID-19 male patients. 
3. Trial Design 
3.1 Primary Study Endpoints/Secondary Endpoints 
 
Primary Outcome Measure: 
 
1. Treatment efficacy of Proxalutamide relative to placebo arm as assessed by the COVID-
19 ordinal scale (defined in Section 5.1)  [Time Frame: Day 14]  
 
Secondary Outcome Measures: 
 
1. Mean change in clinical symptoms assessed by the COVID-19 ordinal scale (defined in 
Section 5.1)  [Time Frame: Day 1, 14, 28]  
A negative change indicates improvement in symptoms and a positive change indicates 
worsening symptoms 
 
2. Time to recovery [Time Frame: Day 1 through Day 28] 
Recovery is defined as the first day on which the subject satisfies one of the following 
two categories from the ordinal scale (defined in Section 5.1): 2) Not hospitalized, 
limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations 
on activities. 
 
3. Treatment efficacy of Proxalutamide relative to placebo arm as assessed by the COVID-
19 ordinal scale (defined in Section 5.1)  [Time Frame: Day 28]  
 
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: 
 
Arm 1: Subjects administered Nitazoxanide 500 mg b.i.d for 5 days + azithromycin 500mg 
q.d for 5 days + Proxalutamide 300mg q.d for 14 days  
 
Arm 2: Subjects administered Nitazoxanide 500 mg b.i.d for 5 days + azithromycin 500mg 
q.d for 5 days + Proxalutamide placebo 300mg q.d for 14 days  


 
 
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Study Environment: 
 
This is a multi-center study to be conducted at multiple hospitals (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 (within 24 hours of admission to hospital): 
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 administered the intervention                      
 
7. All information will be recorded in the appropriate CRFs 
 
Phase II: Outcome Assessment at Site (days 1-14): 
 
1. Each subject will be evaluated daily by the PI for the outcomes of this study 
2. Based on the Arm assignment, each subject will be administered the intervention                      
3. The PI will assess each subject for any treatment related adverse events 
4. 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.  
 
Arm 1: Subjects administered Nitazoxanide 500 mg b.i.d for 5 days + azithromycin 500mg 
q.d for 5 days + Proxalutamide 300mg q.d for 14 days  
 


 
 
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Arm 2: Subjects administered Nitazoxanide 500 mg b.i.d for 5 days + azithromycin 500mg 
q.d for 5 days + Proxalutamide placebo 300mg q.d for 14 days  
 
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 28 days. There will be no study related follow-up treatment. 
3.6 Discontinuation 
In the event that a subject reports any drug related adverse event (not ARDS symptom) we 
will discontinue the study for that particular subject. 
In the event a subject in any arm experiences a serious adverse event 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 


 
 
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hospital standard protocol. 
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. Admitted to the hospital with symptoms of COVID-19  
2. Male age  ≥18 years old 
3. Laboratory confirmed positive SARS-CoV-2 rtPCR test in the past 7 days 
4. Clinical status on the COVID-19 Ordinal Scale (defined in Section 5.1) of 3, 4 or 5 
5. Coagulation: INR ≤ 1.5×ULN, and APTT ≤ 1.5×ULN  
6. Subject (or legally authorized representative) gives written informed consent prior to 
performing any study procedures 
7. 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. Requires mechanical ventilation 
3. Subject taking an anti-androgen of any type including: androgen depravation therapy, 5-
alpha reductase inhibitors, etc… 
4. Patients who are allergic to the investigational product or similar drugs (or any excipients); 
5. 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 
6. 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  
7. Subjects with uncontrolled medical conditions that could compromise participation in 
the study(e.g. uncontrolled hypertension, hypothyroidism, diabetes mellitus) 
8. Known diagnosis of human immunodeficiency virus(HIV) , hepatitis C, active hepatitis 
B, treponema pallidum (testing is not mandatory） 
9. Subject likely to transfer to another hospital within the next 14 days 


 
 
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10.    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, the PI or the PI’s assistant will administer the assigned treatment 
on a daily basis at the hospital site. 
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. 
Therapy prior to enrollment with any other treatment for COVID-19 or the SARS-CoV-2 
infection are permitted but must be discontinued on enrollment. There is no waiting period 
between discontinuation of these treatments and administration of the study intervention; 
however, these prior treatments and their end date should be documented in the Concomitant 
Medication CRF.  
4.6 Monitoring for subject compliance 
The PI will monitor each subject’s chart to assure daily administration of the treatment by the 
study staff. 


 
 
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5 Assessment of Efficacy 
5.1 Efficacy Parameters 
The following efficacy parameters will be assessed and recorded in the CRF. 
 
I. COVID-19 Ordinal Scale: 
The ordinal scale is an assessment of the clinical status of each subject.  The scale is defined 
as follows: 
 
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  
 
II. Time to Recovery: 
Time to recovery is defined as the first day on which the subject satisfies one of the 
following three categories from the ordinal scale (defined in Section 5.1): 3) 
Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical 
care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; or 1) Not 
hospitalized, no limitations on activities. 
5.2 Method and Timing 
For each study day while the subject is hospitalized, the PI will record the clinical assessment 
on an 8- point ordinal scale as follows: 
• 
Day 1 – The clinical assessment at the time of enrollment.  
• 
Day 2 - The most severe clinical assessment occurring any time between enrollment and 
midnight the day following enrollment.  
• 
Day 3-14 (or until discharged) - The most severe assessment occurring from midnight to 
midnight of the prior day (e.g., the value recorded on Day 3 will be the most severe 
outcome that occurred on Day 2).  
If the subject is no longer hospitalized at day 14, a clinical assessment will be made by an in-
person or phone visit. 


 
 
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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. Clinical Laboratory Evaluations: 
The following tests will be conducted: WBC, differential, Hgb, PLT, creatinine, glucose, 
total bilirubin, AST, ALT and coagulation PT.  
 
III. 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 
The assessment will occur at screening. The information will be recorded in the appropriate 
CRF. 
II. Clinical Laboratory Evaluations: 
The assessment will occur upon admission to the hospital as well as at day 14. Additional 
laboratory tests or timing may be ordered as deemed necessary by the PI. 
III. Adverse Events: 
Adverse events will be assessed daily during the 14-day duration of the trial.  The 
information will be recorded in the appropriate CRF.  
 
The methods employed for completing assessments are described in section 6.1 
6.3 Adverse Event Reporting 
We will comply with any EC/IRB and/or FDA requirements for adverse events reporting. 
 
The following events will be reported within 10 days (unless otherwise indicated below): 
• Any serious event (including on-site and off-site adverse events, injuries, side effects, 
deaths or other problems) which in the opinion of the local investigator was 
unanticipated, involved risk to subjects or others, and was possibly related to the 
research procedures will be reported within 24 hours. 


 
 
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• Any serious accidental or unintentional change to the IRB-approved protocol that 
involves risk or has the potential to recur will be reported within 24 hours. 
• Any deviation from the protocol taken without prior IRB review to eliminate apparent 
immediate hazard to a research subject.  
• Any publication in the literature, safety monitoring report (including Data and Safety 
Monitoring Reports), interim result or other finding that indicates an unexpected 
change to the risk/benefit ratio of the research.  
• Any breach in confidentiality that may involve risk to the subject or others.  
• Any complaint of a subject that indicates an unanticipated risk or that cannot be 
resolved by the research staff will be reported within 24 hours. 
• Any other serious and possibly related event which in the opinion of the investigator 
constitutes an unanticipated risk will be reported within 24 hours. 
In the event of any adverse event during or after the trial we will keep records of such events 
in the appropriate CRFs, report to the IRB/FDA and any treating physician if necessary. 
6.4 Definitions 
• 
Unanticipated (unexpected) problems/events are those that are not already described as 
potential risks in the consent form, not listed in the Investigator’s Brochure or not part of 
an underlying disease. Anticipated (expected) problems/events do NOT meet the IRB’s 
definition of UPIRTSO.  
• 
Serious problems/events are those which in the opinion of the local investigator involve 
risk to subjects or others. Examples may include death, hospitalization, disability as well 
as breach of confidentiality. Non-serious problems/events do NOT meet the IRB’s 
definition of UPIRTSO.  
• 
Problems/events that are unanticipated and serious should be reported to the IRB within 
10 working days only if in the opinion of the local investigator they are possibly, 
probably or definitely related to the research procedures. Those serious, unanticipated 
problems/events that the local investigator deems unlikely or not related do NOT meet 
the IRB’s definition of UPIRTSO.  
• 
Follow-up reports on previous events should be reported as UPIRTSOs if the initial event 
itself met the IRB’s definition of UPIRTSO AND in the local investigator’s judgment, 
this follow-up report adds value to the initial report. 
• 
Reports of off-site events on studies that are now closed at this site should be reported as 
UPIRTSOs if the event meets the IRB’s definition of UPIRTSO AND in the local 
investigator’s judgment, this event may affect risk to subjects who have completed the 
study. 
• 
For reports involving blinded study drug, the assessment of relatedness will often be “at 
least possibly related” as relatedness cannot always be ruled out. If there are numerous 
reports on the same blinded drug and these reports all meet the 3 criteria for UPIRTSO, 
they may be reported on one UPIRTSO form with an accompanying table/spreadsheet. A 


 
 
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narrative regarding whether risk is altered or subjects should be notified may be provided 
for each group of similar events.  
6.5 Adverse Event Follow-up 
 
Follow-up daily for the first 30 days following drug related adverse event; thereafter, every 7 
days up to an additional 90 days. 
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 
• 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 distribution of clinical assessments on the COVD-19 ordinal 
scale at  day 14. The primary outcome will be analyzed using the Wilcoxon rank sum test. 
The Null Hypothesis (H0) is that the distribution of clinical assessments on the COVD-19 
ordinal scale at day 14 among hospitalized COVID-19 male subjects treated with 
Proxalutamide is equal to the distribution of clinical assessments on the COVD-19 ordinal 
scale at day 14 among hospitalized COVID-19 male subjects treated with the Proxalutamide 
placebo 
The Alternative Hypothesis (HA) is that the distribution of clinical assessments on the 
COVD-19 ordinal scale at day 14 among hospitalized COVID-19 male subjects treated with 
Proxalutamide is not equal to the distribution of clinical assessments on the COVD-19 
ordinal scale at day 14 among hospitalized COVID-19 male subjects treated with the 
Proxalutamide placebo 
Mathematically written as: 
H0: P(X >Y) = P(Y > X) 


 
 
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HA: P(X >Y) ≠ P(Y > X) 
Where X and Y are randomly selected clinical assessments from the two treatment arms in 
the study.  
III. Primary Efficacy Analysis: 
• The non-parametric Wilcoxon rank sum test (Mann Whitney U) 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. 
7.2 Sample Size Estimates 
 
Assumptions: 
 
• The sample size estimation is based on the results reported in the placebo arm of the 
Adaptive COVID-19 Treatment Trial (NCT04280705) 
• On day 15, 61% of subjects in NCT04280705 placebo group remained hospitalized. 
• The odds ratio of improvement in the ordinal scale in the Proxalutamide arm compared to 
the Proxalutamide placebo is at least 2.0  
• The study has two arms with randomization at 1:1 ratio 
• 90% power to detect an odds ratio of 2.0 using a two-tailed test with a type I error rate of 
5% 
• According to NCT04280705 protocol “The sample size to detect a given odds ratio for 
1:1 randomization using a 2-tailed test at level α is estimated by the equation below. λ is 
the log odds ratio, !! is the overall probability (combined over both arms) of being in the 
ith category of the K ordinal outcomes, and "α/2 and "" are the 1 − α/2 and 1 − β 
quantiles of the standard normal distribution.” 
 
• The estimated distribution is based on NCT04280705 protocol scenario 4 
• 3.5% of the subjects will not complete the study based on  NCT04280705 
 
Sample Size Estimate: 
 
Based on the assumptions above, we calculated that at a minimum we would need to recruit 
294 subjects i.e., 147 subjects in each arm 


 
 
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7.3 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 (294 subjects) to reach our 
confidence level 
 
• Termination of Arm 1: Serious adverse event due to treatment with Proxalutamide 
 
• 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 


 
 
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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. 
 
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. 


 
 
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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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Revision History 
Revision Description of Change 
Date 
Signature 
1 
New draft release 
Andy Goren 
Dec 27, 2020 
2 
 
 
 
 


 
 
  
 
CLINICAL STUDY 
PROTOCOL 
Proxalutamide (GT0918) 
Treatment for Hospitalized 
COVID-19 Patients 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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: Proxalutamide Treatment for Hospitalized COVID-19 Patients 
PROTOCOL IDENTIFYING NUMBER:  
KP-DRUG-SARS-003 
PROTOCOL VERSION NUMBER: 
8.0
PROTOCOL VERSION DATE: 
February 1, 2021 




 
 
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Protocol signature page 
Investigator’s Agreement 
 
Clinical Study: Proxalutamide Treatment for Hospitalized COVID-19 Patients 
 
 
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 
 
 
Daniel Fonseca, MD 
 
 
 
 
 


 
 
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TABLE OF CONTENTS 
 
1. BACKGROUND .................................................................................................................... 8 
1. Overview 
8 
1.1. Investigational Drug 
9 
1.1. Pre-Clinical and Prior Clinical Data 
10 
1.1.1. Prior Pre-Clinical and Clinical Safety Data 
10 
1.2. Risks/Benefits 
23 
1.3. Trial Conduct 
23 
1.4. Population 
23 
1.5. Literature 
23 
2. TRIAL OBJECTIVES ........................................................................................................ 25 
3. TRIAL DESIGN .................................................................................................................. 25 
3.1 Primary Study Endpoints/Secondary Endpoints 
25 
3.2 Study Design/Type 
26 
3.3 Randomization 
27 
3.4 Records 
28 
3.5 Duration 
28 
3.6 Discontinuation 
28 
3.7 Product Accountability 
28 
3.8 Data Identification 
28 
4. SELECTION AND WITHDRAWAL OF SUBJECTS .................................................... 29 
4.1 Inclusion Criteria 
29 
4.2 Exclusion Criteria 
29 
4.3 Subject Withdrawal 
30 


 
 
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4.4 Treatment of Subjects 
31 
4.5 Medication 
31 
4.6 Monitoring for subject compliance 
31 
5 ASSESSMENT OF EFFICACY .......................................................................................... 31 
5.1 Efficacy Parameters 
31 
5.2 Method and Timing 
32 
6 ASSESSMENT OF SAFETY .............................................................................................. 33 
6.1 Safety Parameters 
33 
6.2 Method and Timing 
33 
6.3 Adverse Events 
34 
7 STATISTICAL PLAN ......................................................................................................... 38 
7.1 Statistical Methods 
38 
7.2 Sample Size Estimates 
39 
7.3 Subject Population(s) for Analysis 
40 
7.4 Interim Analysis 
40 
7.5 Termination Criteria 
40 
7.6 Accountability Procedure 
40 
7.7 Deviation Reporting 
40 
8 DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ..................................... 40 
9 QUALITY CONTROL AND QUALITY ASSURANCE .................................................. 41 
10 ETHICAL CONSIDERATIONS ...................................................................................... 41 
11 DATA HANDLING AND RECORD KEEPING ............................................................ 41 
12 FINANCE AND INSURANCE .......................................................................................... 42 
 
 
 


 
 
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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. In addition, none of the 5ARis currently approved by the US FDA have been tested in 
phase I studies. As such, thet are not recommended for women. Phase I studies for 
Proxalutamide have been successfully completed in men and women.  
 
In December 2020, we completed a double-blinded, randomized, prospective, investigational 
study of Proxalutamide Treatment for Non-Hospitalized COVID-19 Male Patients 
(NCT04446429). The length of the study was 30 days. Proxalutamide was administered 
200mg q.d. for 15 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. 
 
Based on the results of the Proxalutamide Treatment for Non-Hospitalized COVID-19 Male 
Patients study (NCT04446429), the purpose of this study is to assess the efficacy and safety 
of Proxalutamide as a treatment for hospitalized COVID-19 male and female patients.  
1.1. Investigational Drug 
 
Proxalutamide (300 mg) q.d. 
 
 


 
 
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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 
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 and metastatic breast 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. 
 
 


 
 
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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 
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 15 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. 
 
 


 
 
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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 
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: 
 


 
 
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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 
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%) 


 
 
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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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Study 5:  Phase I dose escalating study of Proxalutamide (100-500 mg) in 67 female 
patients with metastatic breast cancer positive for androgen receptor (AR+)   
Background: Androgen receptor (AR) blocker has become an increased interest in the 
treatment of BC, in which about 60-80% patients showed AR positive. However, 
currently no AR blocker has been approved in mBC. GT0918 is a new chemical entity of 
AR blocker with possible AR down-regulation. This study is an open-label, single-center, 
dose escalation phase I trial to assess GT0918 in mBC female patients who have 
progressed after systemic treatments in China. The primary objectives are to identify the 
maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). The secondary 
objectives are to assess pharmacokinetics and pharmacodynamics of GT0918 with single 
and multiple dosage applications. (CTR20170757) Methods: Patients (pts) with 
historically confirmed mBC who had progressed after either chemotherapy, hormonal or 
targeted therapy, or could not tolerate currently standard therapies were eligible. With the 
starting dose at 100 mg of GT0918, the decision of dose escalation in the 3+3 design was 
based on the safety and tolerability assessments. GT0918 was administered orally once, 
followed by a 7-day off-treatment period for single dose PK analysis of drug elimination. 
Then GT0918 oral administration was resumed once daily for 28 consecutive days and 
multiple dose PK analysis was assessed at the end of first cycle (28 days). The first 28-
days on treatment (cycle 1) was defined as DLT period. Pts manifesting an objective 
response or stable disease and likely to have clinical benefit from continued treatment 
were continued on GT0918 thereafter until they experienced one of following events of 
intolerable toxicities, disease progression or withdrew consent. Results: 18 pts were 


 
 
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enrolled and treated with GT0918 since 9/6/2017 as defined in protocol at five dose 
levels: 100 mg (n = 3), 200 mg (n = 4), 300 mg (n = 4), 400 mg (n = 4) and 500 mg (n = 
3) (as to 7/2/2019). All pts progressed more than two lines of therapies with 83.3% 
(15/18) pts were treated ≥3rd lines. Out of 6 confirmed AR positive pts, two (33.3%) at 
300 mg cohort had finished 17 and 19 cycles individually and continue treatment (as 
7/2/19). No DLT was observed and MTD has not been reached. GT0918 related adverse 
events (AEs) were grade 1 or 2 as per CTCAE v4.03, including fatigue, 
hypertriglyceridemia, anemia, hypercholesterolemia, increased LDL, nausea, loss of 
appetite, increased ALT, increase of weight loss, constipation and thrombocytopenia. PK 
profile analysis showed that in the single-dose study, GT0918 showed a fast absorption 
profile. In the multiple-dose study, the steady-state serum concentration level of GT0918 
and its main metabolite were attained at 21 days. Conclusions: Proxalutamide (GT0918) 
administrated orally once a day is well tolerated in late-stage pts. No DLT has occurred at 
maximum dose 500 mg. Pts with AR positive biomarker could have better clinical 
outcomes with GT0918 treatment. GT0918 and its main metabolite exhibited a nonlinear 
pharmacokinetic profile over the dose range from 100mg to 500 mg. An expanded/phase 
Ib in AR positive mBC pts has launched in China to evaluate the anti-tumor activity and 
safety of GT0918. 200 mg and 300 mg were selected for dose expansion. 
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. 


 
 
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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.  
 
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: 


 
 
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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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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 hospitalized COVID-19 male and female patients; therefore, we assess below the 
risks/benefits for the proposed study.  
 
Benefit(s) of the Proposed Clinical Study 
To-date no therapy for hospitalized COVID-19 patients has demonstrated significant clinical 
benefit. Proxalutamide demonstrated clinical efficacy in non-hospitalized COVID-19 patients 
(NCT04446429). As such, subjects enrolled in this study could potentially benefit from 
reduced hospitalization time as well as lower risk of experiencing progressively more severe  
COVID-19 related symptoms. In addition, if Proxalutamide demonstrates clinical efficacy in 
this study, it is likely to improve the standard of care for hospitalized COVID-19 male and 
female patients world-wide. 
 
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 14 days, we believe the risk of serious adverse events is lower 
than described in Phase I studies.  Further, during 14 days of dosing 134 subjects with 200mg 
q.d. of Proxulatimde no drug related adverse events were observed. 
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 hospital sites. This exact protocol will be 
followed. There will be one or more PIs. The study will be approved by each hospital’s 
Ethics Committee. 
 
The population for this study will be hospitalized COVID-19 patients 18 years or older of 
any ethnicity.  Approximately, 600 (300 males and 300 females) 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 28 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 


 
 
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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 
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 


 
 
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This material is the property of the Applied Biology Inc.  Do not disclose or use except as authorized.  
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. 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 hospitalized COVID-19 male and female patients. 
3. Trial Design 
3.1 Primary Study Endpoints/Secondary Endpoints 
 
Primary Outcome Measure: 
 
1. Treatment efficacy of Proxalutamide relative to placebo arm as assessed by the COVID-
19 ordinal scale (defined in Section 5.1)  [Time Frame: Day 14]  
 
Secondary Outcome Measures: 
 


 
 
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1. Treatment efficacy of Proxalutamide relative to placebo arm as assessed by the COVID-
19 ordinal scale (defined in Section 5.1)  [Time Frame: Day 28]  
 
2. Time to recovery [Time Frame: Day 1 through Day 28] 
Recovery is defined as the first day on which the subject satisfies one of the following 
two categories from the ordinal scale (defined in Section 5.1): 2) Not hospitalized, 
limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations 
on activities. 
 
3. Proportion of death [Time Frame: Day 1 through Day 28] 
Defined as the number of subjects who have died in each arm divided by the numbers of 
subjects randomized to the treatment arm 
 
4. Duration of new oxygen use [Time Frame: Day 1 through Day 28 ] 
Duration of new oxygen use measured in days among subjects that did not require 
oxygen upon randomization.  
 
5. Proportion of subjects testing positive for SARS-CoV-2 [Time Frame: Day 14] 
Defined as the proportion of subjects in each arm with a qualitative positive rtPCR 
SARS-CoV-2 test from upper respiratory tract specimens  
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 cohorts: men and women and 2 
arms: 
 
Arm 1: Subjects administered Proxalutamide 300mg q.d for 14 days + standard of care as 
determined by the PI at the site 
 
Arm 2: Subjects administered Proxalutamide placebo 300mg q.d for 14 days + standard of 
care as determined by the PI at the site 
 
Study Environment: 
 
This is a multi-center study to be conducted at multiple hospitals (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 (within 5 days of admission to hospital): 
1. Each subject will be evaluated for the inclusion and exclusion criteria  
 


 
 
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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 administered the intervention                      
 
7. All information will be recorded in the appropriate CRFs 
 
Phase II: Outcome Assessment at Site (days 1-28): 
 
1. Each subject will be evaluated daily by the PI for the outcomes of this study 
2. Based on the Arm assignment, each subject will be administered the intervention                      
3. The PI will assess each subject for any treatment related adverse events 
4. All information will be recorded in the appropriate CRFs 
3.3 Randomization 
 
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.  
 
In each cohort, subjects will be randomized into 1 of 2 arms in a 1:1 ratio each receiving an 
interventional treatment.  
 
Arm 1: Subjects administered Proxalutamide 300mg q.d for 14 days + standard of care as 
determined by the PI at the site 
 
Arm 2: Subjects administered Proxalutamide placebo 300mg q.d for 14 days + standard of 
care as determined by the PI at the site 
 
In each cohort, each subject will be randomized using an interactive web software: 
Randomizer.at. The blinding table layout will be a single block. The randomization method 
used will be permuted blocks of size 4. 
 
This is a blinded study. Neither participants, nor investigators, nor the study team will be 
aware of treatment assignments prior to the final data base locks at the conclusion of the 
study (or the interim analysis). 


 
 
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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 28 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. 
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. 


 
 
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4. Selection and Withdrawal of Subjects 
4.1 Inclusion Criteria 
1. Admitted to the hospital with symptoms of COVID-19  
2. Male and females age  ≥18 years old 
3. Laboratory confirmed positive SARS-CoV-2 rtPCR test within 7 days prior to 
randomization or confirmed lung involvement by CT scan 
4. Clinical status on the COVID-19 Ordinal Scale (defined in Section 5.1) of 3 to 6 
5. Coagulation: INR ≤ 1.5×ULN, and APTT ≤ 1.5×ULN  
6. Subject (or legally authorized representative) gives written informed consent prior to 
performing any study procedures 
7. 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. Requires mechanical ventilation 
3. Subject taking an anti-androgen of any type including: androgen depravation therapy, 5-
alpha reductase inhibitors, etc… 
4. Patients who are allergic to the investigational product or similar drugs (or any 
excipients); 
5. 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 
6. 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  
7. Subjects with uncontrolled medical conditions that could compromise participation in the 
study(e.g. uncontrolled hypertension, hypothyroidism, diabetes mellitus) 
8. Known diagnosis of human immunodeficiency virus(HIV) , hepatitis C, active hepatitis 
B, treponema pallidum (testing is not mandatory） 
9. Alanine Transaminase (ALT) or Aspartate Transaminase (AST) > 5 times the upper limit 
of normal. 
10. Estimated glomerular filtration rate (eGFR) < 30 ml/min  
11. Severe kidney disease requiring dialysis 
12. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective contraception, as shown below, 
throughout the study and for 3 months after stopping GT0918 treatment. Highly effective 
contraception methods include:  
• Total Abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception, or  


 
 
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• Use of one of the following combinations (a+b or a+c or b+c):  
a: Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate < 
1%), for example hormone vaginal ring or transdermal hormone contraception.  
b: Placement of an intrauterine device (IUD) or intrauterine system (IUS) ; 
c: Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository ; 
• Female sterilization (have had prior surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow-up hormone level assessment ; 
• Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient; 
• In case of use of oral contraception women should have been stable for a minimum 
of 3 months before taking study treatment. Women are considered post-menopausal 
and not of child bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, 
history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy) or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment, is she considered not of child 
bearing potential; 
13. Sexually active males must use a condom during intercourse while taking the drug and 
for 3 months after stopping GT0918 treatment and should not father a child in this period. 
A condom is required to be used also by vasectomized men in order to prevent delivery 
of the drug via seminal fluid 
14. Subject likely to transfer to another hospital within the next 28 days 
15. 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  


 
 
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(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, the PI or the PI’s assistant will administer the assigned treatment 
on a daily basis at the hospital site. 
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. 
Therapy prior to enrollment with any other treatment for COVID-19 or the SARS-CoV-2 
infection are permitted but must be discontinued on enrollment. There is no waiting period 
between discontinuation of these treatments and administration of the study intervention; 
however, these prior treatments and their end date should be documented in the Concomitant 
Medication CRF.  
4.6 Monitoring for subject compliance 
The PI will monitor each subject’s chart to assure daily administration of the treatment by the 
study staff. 
5 Assessment of Efficacy 
5.1 Efficacy Parameters 
The following efficacy parameters will be assessed and recorded in the CRF. 
 
I. COVID-19 Ordinal Scale: 
The ordinal scale is an assessment of the clinical status of each subject.  The scale is defined 
as follows: 
 
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;  


 
 
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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  
 
II. Time to Recovery: 
Time to recovery is defined as the first day on which the subject satisfies one of the 
following three categories from the ordinal scale (defined in Section 5.1): 3) 
Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical 
care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; or 1) Not 
hospitalized, no limitations on activities. 
 
III. “Multiple Combined Sensitive Outcome Detect Method” (combining items I and 
II): 
 
1.  (WHO COVID ORDINAL OUTCOMES SCALE):  
a. 1 dia; b: 2 dias; c. 3 dias; d. 7 dias; e. 14 dias; f. 21 dias; g. 30 dias (cuja escala é 
plenamente contemplada por alguns dos desfechos descritos abaixo) 
2. TEMPO ATÉ RECURAÇÃO – regressão aos níveis 1 e 2 da WHO COVID Ordinal 
Outcomes Scale (dias) 
3. POSITIVIDADE DA rtPCR-SARS-CoV-2 a. 7 dias; b. 14 dias; c. 30 dias (%) 
4. TEMPO ATÉ REMISSÃO DE CADA SINTOMA (dias) 
5. TEMPO ATÉ REMISSÃO COMPLETA DOS SINTOMAS (dias) 
6. TEMPO ATÉ RECUPERAÇÃO DA CAPACIDADE DE REALIZAÇÃO DE 
ATIVIDADES DIÁRIAS DEVIDO AOS SINTOMAS DE COVID-19 (Nível 1 da 
WHO COVID Ordinal Outcomes Scale) (dias) 
7. NECESSIDADE DE UNIDADE INTENSIVA (%) 
8. NECESSIDADE DE VENTILAÇÃO MECÂNICA (%) 
9. TEMPO DE HOSPITALIZAÇÃO (dias) 
10. TEMPO DE OXIGENIOTERAPIA (dias) (se necessário) 
11. TEMPO DE UNIDADE DE TERAPIA INTENSIVA (dias) (se necessário) 
12. TEMPO DE VENTILAÇÃO MECÂNICA (dias) (se necessário) 
13. NECESSIDADE DE USO DE VASOATIVOS (%) 
14. MORTE (%) 
 
5.2 Method and Timing 
For each study day while the subject is hospitalized, the PI will record the clinical assessment 
on an 8- point ordinal scale as follows: 
• 
Day 1 – The clinical assessment at the time of enrollment.  


 
 
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• 
Day 2 - The most severe clinical assessment occurring any time between enrollment and 
midnight the day following enrollment.  
• 
Day 3-28 (or until discharged) - The most severe assessment occurring from midnight to 
midnight of the prior day (e.g., the value recorded on Day 3 will be the most severe 
outcome that occurred on Day 2).  
If the subject is no longer hospitalized at day 28, a clinical assessment will be made by an in-
person or phone visit; otherwise, it would be recorded as missing data. 
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. Clinical Laboratory Evaluations: 
The following tests will be conducted: WBC, differential, Hgb, PLT, creatinine, glucose, 
total bilirubin, AST, ALT and coagulation PT.  
 
III. 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 
The assessment will occur at screening. The information will be recorded in the appropriate 
CRF. 
II. Clinical Laboratory Evaluations: 
The assessment will occur upon admission to the hospital as well as at day 14. Additional 
laboratory tests or timing may be ordered as deemed necessary by the PI. 
III. Adverse Events: 
Adverse events will be assessed daily during the 28 day duration of the trial.  The 
information will be recorded in the appropriate CRF.  
 
The methods employed for completing assessments are described in section 6.1 


 
 
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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 
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)  


 
 
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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  
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.  


 
 
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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 28 (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 
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  


 
 
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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;  
• 
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  


 
 
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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 
• 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 distribution of clinical assessments on the COVD-19 ordinal 
scale at  day 14. The primary outcome will be analyzed using the Wilcoxon rank sum test. 
The Null Hypothesis (H0) is that the distribution of clinical assessments on the COVD-19 
ordinal scale at day 14 among hospitalized COVID-19 subjects treated with Proxalutamide is 
equal to the distribution of clinical assessments on the COVD-19 ordinal scale at day 14 
among hospitalized COVID-19 subjects treated with the Proxalutamide placebo 
The Alternative Hypothesis (HA) is that the distribution of clinical assessments on the 
COVD-19 ordinal scale at day 14 among hospitalized COVID-19 subjects treated with 
Proxalutamide is not equal to the distribution of clinical assessments on the COVD-19 
ordinal scale at day 14 among hospitalized COVID-19 subjects treated with the 
Proxalutamide placebo 


 
 
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Mathematically written as: 
H0: P(X >Y) = P(Y > X) 
HA: P(X >Y) ≠ P(Y > X) 
Where X and Y are randomly selected clinical assessments from the two treatment arms in 
the study.  
III. Primary Efficacy Analysis: 
• The non-parametric Wilcoxon rank sum test (Mann Whitney U) 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. 
7.2 Sample Size Estimates 
 
Assumptions: 
 
• The sample size estimation is based on the results reported in the placebo arm of the 
Adaptive COVID-19 Treatment Trial (NCT04280705) 
• On day 15, 61% of subjects in NCT04280705 placebo group remained hospitalized. 
• The odds ratio of improvement in the ordinal scale in the Proxalutamide arm compared to 
the Proxalutamide placebo is at least 2.0  
• The study has two arms with randomization at 1:1 ratio 
• 90% power to detect an odds ratio of 2.0 using a two-tailed test with a type I error rate of 
5% 
• According to NCT04280705 protocol “The sample size to detect a given odds ratio for 
1:1 randomization using a 2-tailed test at level α is estimated by the equation below. λ is 
the log odds ratio, 푝푖 is the overall probability (combined over both arms) of being in the 
ith category of the K ordinal outcomes, and 푧α/2 and 푧훽 are the 1 − α/2 and 1 − β 
quantiles of the standard normal distribution.” 
 
• The estimated distribution is based on NCT04280705 protocol scenario 4 
• 3.5% of the subjects will not complete the study based on NCT04280705 
 
Sample Size Estimate: 
 


 
 
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Based on the assumptions above, we calculated that at a minimum we would need to recruit 
for each cohort 294 subjects (147 subjects in each arm) i.e., a total of approximately 600 
subjects. 
7.3 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” or “PCOS signs” 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 (294 subjects) to reach our 
confidence level 
 
• Termination of Arm 1: Serious adverse event due to treatment with Proxalutamide 
 
• 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. 


 
 
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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. 
 
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. 
 


 
 
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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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Revision History 
Revision Description of Change 
Date 
Signature 
1 
New draft release 
Andy Goren 
Dec 27, 2020 
2 
Amendments to end points 
Andy Goren 
Dec 29, 2020 
3 
Amended AE section 
Andy Goren 
Dec 30, 2020 
4 
Amended to include 
female cohort 
Flavio Cadegiani 
Jan 10, 2021 
5 
Final review for female 
cohort 
Andy Goren 
Jan 10. 2021 
6 
Added exclusions for 
sexual activity and minor 
corrections 
Andy Goren 
Jan 11, 2021 
7 
Changed randomization 
model 
Andy Goren 
Jan 19, 2021 
8 
Amended inclusion criteria Andy Goren 
February 1, 2021 


 
1 
FINAL STATISTICAL PLAN WITH SUMMARY OF CHANGES FROM THE FINAL 
PROTOCOL 
 
 
We had to make minor adjustments to the statistical plan of the final protocol while writing 
the manuscript to make the statistical plan more stringent and clearer. The rationale for each 
change or no change is also presented. 
 
 
 
Table of contents: 
 
1. 
Primary Outcome Measure ....................................................................................... 1 
2. 
Secondary Outcome Measures ................................................................................. 2 
3. 
General principles ..................................................................................................... 4 
4. 
Statistical hypothesis ................................................................................................ 5 
5. 
Primary analysis efficacy .......................................................................................... 6 
6. 
Sample size calculation ............................................................................................ 7 
 
 
 
 
1. Primary Outcome Measure  
 
 
 
 
Proposed in the final protocol 
Final statistical Plan 
Rationale 
Treatment efficacy of 
proxalutamide relative to 
placebo arm as assessed by the 
COVID-19 ordinal scale [time 
frame: day 14]  
No change 
The distribution analysis of all the 
COVID-19 8-point ordinal scale scores 
at day 14 covers all possible scores, 1 
to 8. This is better illustrated 
graphically for group comparison. 
 
No specific measure of effect 
was appointed for the Primary 
efficacy analysis (quantitative 
efficacy measure).  
 
 
Recovery ratio was defined as 
the measure of effect for the 
primary outcome. The treatment 
efficacy of proxalutamide was 
assessed by the proportion of 
recovered patients in both study 
arms [time frame: 14 days].  
Recovery was defined as 
reaching scores 1 and 2 in the 
COVID-19 ordinal scale 
Scores 1-2 represent a clear cut for 
recovery (alive hospital discharge).  


 
2 
2. Secondary Outcome Measures  
 
As proposed in the final 
protocol 
Done in the final statistical 
Plan 
Rationale 
Treatment efficacy of 
Proxalutamide relative to 
placebo arm as assessed by 
the COVID- 19 ordinal scale 
(defined in Section 5.1) 
[Time Frame: Day 28] 
A clear cut-off point was used 
in the COVID-19 scale 
(scores 1 and 2) so that we 
were able to measure the 
effect size recovery ratio 
[time frame: 28 days].  
All scores at Day 28 are informative and is 
better presented in a graph. 
As reported for the primary outcome, we 
clarified a measure of effect within this 
secondary outcome measure. 
Time to recovery [Time 
Frame: Day 1 through Day 
28] Recovery is defined as 
the first day on which the 
subject satisfies one of the 
following two categories 
from the ordinal scale.1): 2) 
Not hospitalized, limitation 
on activities and/or requiring 
home oxygen; 1) Not 
hospitalized, no limitations 
on activities. 
 
Name changed to post-
randomization time to 
recover/alive hospital 
discharge [time frame: day 1 
to day 28] in median days 
(interquartile range).  
Recovery was defined as the 
first day on which the subject 
reached scores 1 and 2 in the 
COVID-19 ordinal scale. 
We needed to be more specific in this 
outcome to make it clearer and 
reproducible. 
Proportion of death [Time 
Frame: Day 1 through Day 
28] Defined as the number of 
subjects who have died in 
each arm divided by the 
numbers of 
subjects randomized to the 
treatment arm 
 
Name changed to 28-day all-
cause mortality rate. The 
proportion of patients who 
reached score 8 in the 19-
COVID ordinal scale after 
randomization. [Time frame: 
28 days] 
The outcome is still the same described in 
the statistical plan of the final protocol, 
however we just clarified that it refers to 
all-cause mortality. All-cause mortality is a 
more stringent measure, and therefore this 
change goes against the direction of the 
bias. Although mortality at 14 days could 
be contemplated in the original Primary 
outcome (score 8), we decided to analyze 
mortality at 28 days only, which is more 
stringent and reflects the intention-to-treat. 
Duration of new oxygen use 
[Time Frame: Day 1 through 
Day 28] 
 
Excluded 
This outcome measure was not adequately 
reported by the hospital sites, and therefore 
we have not included it in the final 
statistical plan.  
Proportion of subjects testing 
positive for SARS-CoV-2 
[Time Frame: Day 14] 
 
Excluded 
This outcome also needed to be abandoned 
because we lacked financial resources to 
test all patients again for SARS-CoV-2 at 
day 14. 
Subgroup analysis based on: 
1) age stratification; and 2) 
androgen status as defined by 
“Gabrin sign” or “PCOS 
signs” will be conducted for 
the primary and secondary 
outcomes. 
 
Changed to include the 
subgroup analysis per 1) 
baseline score (severity of the 
disease), 2) gender and 3) 
hospital site. No hypothesis 
testing was performed in these 
subgroup analyses to avoid 
finding significant p-values by 
chance due to multiple 
comparisons. 
Androgen status was excluded 
from the subgroup analysis. 
Several reasons led us to make these new 
subgroup analyses: 
 
1. Age was lower than expected, lower 
age cut-offs did not show relevant 
findings to be reported, possibly in 
the future we may plan for a 
multivariate analysis with factors 
such as women post-menopause. 
Also, pre-determining age cut-offs for 
analyses were needed. Age 


 
3 
 
 
 
distribution graphs were included in 
the supplement. 
2. Since the randomization scheme was 
changed in the small hospital located 
in the remote Amazon areas to 
control for sharing and unblinding in 
these regions (see randomization 
details in the supplement), we needed 
to evaluate if there was interaction 
between the overall effect size 
[recovery ratio, and all-cause 
mortality ratio] per city of sites. 
Important to say here that in the 
hospital centers located in the capital 
of the state of Amazonas, 
randomization scheme was performed 
as planned. 
3. Since men are by definition more 
androgenic it was important to 
evaluate the effects specifically. 
4. Finally, we checked if there were an 
interaction effect between the patients 
with more severe presentations such 
as baseline score 6 compared to 5, 4, 
3.  


 
4 
3. General principles 
 
As proposed in the final 
protocol 
Done in the final statistical 
Plan 
Rationale 
Continuous variables will be 
expressed as median 
(interquartile range [IQR]) 
and categorical variables will 
be expressed as a number 
Continuous variables were 
expressed as median (IQR) 
and categorical variables were 
expressed as a number and in a 
risk percentage. 
Expression of the categorical 
variables only as a number is not 
sufficient to allow for calculation 
of risk ratios. Then, absolute risk 
ratios were calculated for primary 
(14-day Overall Recovery rate) 
and secondary outcomes (28-day 
recovery rate and 28-day all-
cause mortality) 
95% confidence intervals 
will be calculated for the 
primary outcome 
95% confidence intervals will 
be calculated for the primary 
outcome, secondary outcomes 
and subgroup analysis. 
All secondary outcomes expressed 
in ratios were reported along with 
the 95% confidence interval to 
allow for a better understanding of 
the effect sizes. 
Group comparisons will be 
analyzed by the Wilcoxon 
rank sum test or χ2 test 
For all categorial effect sizes, 
hypothesis testing was 
performed with the χ2 test, 
including risk ratios. 95% 
Confidence intervals were 
reported in results tables, for 
the primary endpoint Overall 
Recovery Ratio), along with 
the P value. For the Adverse 
AE table, P-values were 
included. Other outcomes 
described as median and IQR 
were compared with the 
Wilcoxon rank sum test. 
The primary hypothesis testing 
previously stated was maintained. 
However, we explained in which 
cases the different tests were 
applied to increase transparency. 
Differences between rates of 
clinical improvement will be 
calculated using unadjusted 
ordinal logistic regression or 
Cox proportional hazard 
models 
We used Kaplan-Meier’s 
survivor function for estimates 
of proportion surviving, and 
failure function for estimates 
of alive hospital discharges. 
Cox proportional hazards 
model was kept only to 
calculate hazard ratio (HR) for 
death and its 95% confidence 
interval (CI). Graphical 
assessment and Kaplan-Meier 
versus predicted survival 
showed that of the 
proportional-hazards 
assumption has not been 
violated 
For better demonstration of the 
95% CI and timeline of the 
evolution of the outcomes in 
figures. For measure of effect, as 
stated in the Primary and 
Secondary outcomes, we adopted 
relative risk (or Risk Ratio) for 
easier understanding. 
Statistical analyses will be 
conducted using XLSTAT 
version 2020.5.1 (Addinsoft, 
Inc.) 
Statistical analysis was 
conducted using Stata/SE 
version 16.1 for Mac 
(StataCorp LLC, College 
Station, TX, USA). 
Preference of the team performing 
statistical analysis 
 
 


 
5 
4. Statistical hypothesis 
 
As proposed in the final 
protocol 
Done in the final statistical 
Plan 
Rationale 
The primary endpoint is the 
distribution of clinical 
assessments on the COVID-
19 ordinal scale at day 14. 
The primary outcome will be 
analyzed using the Wilcoxon 
rank sum test. 
The primary efficacy 
endpoint was described as 
the overall 14-day recovery 
ratio. This effect measure 
was obtained after 
dichotomization of the 
COVID-19 ordinal scale for 
scores 2 and 1, representing 
patients that were discharged 
from hospital. 
Although the distribution is 
still presented graphically, 
and tested for statistical 
significance, a clear cut-off 
point in the COVID-19 
ordinal scale was used to 
obtain the Overall Recovery 
Ratio. Recovery ratio is a 
clinically meaningful effect 
measure.  
The Null Hypothesis (H0) is 
that the distribution of 
clinical assessments on the 
COVD-19 ordinal scale at 
day 14 among hospitalized 
COVID-19 subjects treated 
with Proxalutamide is equal 
to the distribution of clinical 
assessments on the COVD-
19 ordinal scale at day 14 
among hospitalized COVID-
19 subjects treated with the 
Proxalutamide placebo 
The null hypothesis applied 
to the primary endpoint 
Overall Recovery Ratio is 
that there is no association 
between the recovery risk 
rates of the study arms and 
the type of treatment 
(proxalutamide or placebo) 
in the hospitalized patients 
with COVID-19 
Since the primary outcome 
was refined with a clear 
efficacy endpoint, defined as 
a binary measure, the null 
hypothesis was rephrased to 
be in line with the chi-square 
test. 
The Alternative Hypothesis 
(HA) is that the distribution 
of clinical assessments on the 
COVD-19 ordinal scale at 
day 14 among hospitalized 
COVID-19 subjects treated 
with Proxalutamide is not 
equal to the distribution of 
clinical assessments on the 
COVD-19 ordinal scale at 
day 14 among hospitalized 
COVID-19 subjects treated 
with the 
Proxalutamide placebo 
The alternative hypothesis 
applied to the primary 
endpoint Overall Recovery 
Ratio is that the there is an 
association between the 
recovery risk rates of the 
study arms and the type of 
treatment (proxalutamide or 
placebo) in the hospitalized 
patients with COVID-19, 
meaning that the 
experimental treatment may 
affect the Overall Recovery 
Ratio. 
The primary outcome was 
refined with a clear efficacy 
endpoint, defined as a binary 
measure the alternative 
hypothesis was rephrased to 
be in line with the chi-square 
test. 
 
 
 


 
6 
 
5. Primary analysis efficacy 
 
As proposed in the final 
protocol 
Done in the final statistical 
Plan 
Rationale 
The non-parametric 
Wilcoxon rank sum test 
(Mann Whitney U) 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. 
The non-parametric 
Wilcoxon rank sum test was 
used to assess some of the 
secondary outcomes 
described above.  
 
The intention-to-treat 
protocol was performed in 
the final analysis. Missing 
data was reported. 
The primary outcome was 
refined with a clear efficacy 
endpoint, defined as a binary 
measure, and thus, Wilcoxon 
Rank Sum test was not 
appropriate for such type of 
variable. 
No measure of effect 
Included measure of effect: 
Overall Recovery Ratio 
[time frame: 14 days] 
Although we meant to 
calculate the overall recovery 
ratio, the outcome was not 
clearly described in the 
statistical plan of the 
protocol, and sample size 
was based on odds ratio for 
recovery. 
 
 
 


 
7 
6. Sample size calculation 
 
As proposed in the final 
protocol 
Done in the final statistical 
Plan 
Rationale 
The sample size estimation is 
based on the results reported 
in the placebo arm of the 
Adaptive COVID-19 
Treatment Trial 
(NCT04280705) protocol 
scenario 4: On day 15, 61% 
of subjects in NCT04280705 
placebo group remained 
hospitalized. For 90% power 
to detect an odds ratio of 2.0 
using a two-tailed test with a 
type I error rate of 5%, and 
3.5% of the subjects will not 
complete the study based on 
NCT04280705 
No change. 
 
However, we noticed that the 
way the sample size 
estimation was described 
may be hard for many 
readers to follow it.  
 
An odds ratio for 
improvement of 2 over a 
baseline recovery risk of 
39% (NCT04280705, 
scenario 4), results in a 
difference of 14% in the 
absolute recovery rate.  
The sample size was 
calculated to be able to detect 
a difference of 14% in 
Overall Recovery Rate at 14 
days (risk ratio of 1.36) with 
a power of 90% and a type I 
error of 5%, over the 
estimated 39% recovery rate 
for the placebo group, and 
3.5% non-compliance/cross 
over in the study groups.  
 
Although no change was 
done in the sample size 
estimate, we rewrote it using 
simpler and more direct 
terms. 
Sample size estimate: Based 
on the assumptions above, 
we calculated that at a 
minimum we would need to 
recruit for each cohort 294 
subjects (147 subjects in each 
arm) i.e., a total of 
approximately 600 subjects. 
No change 
We verified that the sample 
size was still 90% powered 
after inclusion of baseline 
score 6 to the final protocol. 
 
 
These minor changes in the statistical analysis plan were performed while writing the 
manuscript. 
 
Researchers involved in the statistical analysis that implemented the changes: 
 
Dr. Carlos Wambier, MD, PhD 
 
Dr Alessandra Reis, DDS, PhD