Clinical trial NCT04842747
Conditions: SARS-CoV Infection
Sponsor: Veru Inc.
Start date: 2021-05-18; Completion date: 2022-07-06
Enrollment: 204 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To demonstrate the efficacy of VERU-111 in the treatment of SARS-Cov-2 Infection by assessing its effect on the proportion of patients who die on study (prior to Day 60).

Detailed description:
This study is a multicenter, randomized, placebo-control, efficacy and safety study of VERU-111 for the treatment of COVID-19. Subjects will receive either 9mg of VERU-111 or matching placebo orally or through nasogastric tube daily for up to 21 days or until the subject is discharged from the hospital, whichever comes first. The primary efficacy endpoint of the study will be the proportion of subjects that die prior to Day 60.The total study duration for a subject from screening to follow up visit is planned to be 62 days. In addition to the safety of VERU-111, an evaluation of the efficacy of VERU-111 on SARS-CoV-2 (COVID-19) compared to the placebo control will be evaluated as part of the Independent Data Monitoring Committee (IDMC).

Arms: arm 1: 9mg of VERU-111 arm 2: Subjects in the Placebo treatment group will receive standard of care, plus a placebo capsule for 21 days or until released from hospital.
Interventions: intervention 1: VERU-111
Intervention descriptions: intervention 1: Subjects in the VERU-111 treatment groups will receive standard of care, plus oral daily VERU-111 9mg for 21 days or until released from hospital.

Protocol documents:
Prot_000.pdf: 
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Protocol V3011902 – FINAL Version 7.0 
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CLINICAL TRIAL PROTOCOL: V3011902 
 
Protocol Number: 
V3011902 
 
Protocol Date: 
Original Protocol (Version 1.0)/ 8 March 2021 
Protocol Amendment 1 (Version 2.0)/27 April 2021 
Protocol Amendment 2 (Version 3.0)/12 May 2021 
Protocol Amendment 3 (Version 4.0)/ 3 August 2021 
Protocol Amendment 4 (Version 5.0)/ 10 September 2021 
Protocol Amendment 5 (Version 6.0)/ 9 January 2022 
Protocol Amendment 6 (Version 7.0)/ 18 March 2022 
 
Protocol Title: 
Phase 3, Randomized, Placebo-Controlled, Efficacy and Safety Study 
of VERU-111 for the Treatment of Severe Acute Respiratory 
Syndrome Coronavirus 2 (SARS-CoV-2) in Patients at High Risk for 
Acute Respiratory Distress Syndrome (ARDS). 
 
IND number: 
149282 
 
EudraCT number: 2021-001194-24 
Clinical Phase: 
3 
 
Study Sponsor: 
Veru Inc. 
48 NW 25th St 
Suite 102 
Miami, FL 33127 
Telephone: (305) 509-6986 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1.0 
LIST OF ABBREVIATIONS ............................................................................... 5 
2.0 
PHASE 3 PROTOCOL SUMMARY .................................................................. 6 
3.0 
INTRODUCTION ............................................................................................... 10 
3.1 
Background............................................................................................................ 10 
3.2 
Target Indication and Pharmacologic Activity ...................................................... 13 
3.3 
Study Rationale ..................................................................................................... 13 
4.0 
STUDY OBJECTIVES ....................................................................................... 16 
4.1 
Primary Objectives ................................................................................................ 16 
4.2 
Secondary Objectives ............................................................................................ 16 
4.3 
Safety Objective .................................................................................................... 16 
5.0 
STUDY DESIGN ................................................................................................. 17 
5.1 
Treatment Groups and Allocation of Subjects ...................................................... 17 
5.2 
Study Duration ...................................................................................................... 17 
5.3 
Efficacy Endpoints ................................................................................................ 17 
5.3.1 
Primary Endpoint .................................................................................................. 17 
5.3.2 
Secondary Endpoints ............................................................................................. 17 
6.0 
SUBJECT POPULATION .................................................................................. 18 
6.1 
Number of Subjects ............................................................................................... 18 
6.2 
Selection Criteria ................................................................................................... 18 
6.2.1 
Inclusion Criteria ................................................................................................... 18 
6.2.2 
Exclusion Criteria .................................................................................................. 19 
7.0 
STUDY MEDICATION ...................................................................................... 20 
7.1 
Enrollment and Blinding ....................................................................................... 20 
7.2 
Drug Supply .......................................................................................................... 20 
7.2.1 
VERU-111 Capsules.............................................................................................. 20 
7.2.2 
Placebo Control ..................................................................................................... 20 
7.2.3 
Drug Accountability .............................................................................................. 21 
7.3 
Drug Administration .............................................................................................. 21 
8.0 
STUDY PROCEDURES ..................................................................................... 21 
8.1 
Screening ............................................................................................................... 21 
8.2 
Enrollment ............................................................................................................. 22 
8.3 
Day 1 ..................................................................................................................... 22 
8.4 
Day 2 through Day 21 or day of discharge from the hospital (whichever 
comes first) ............................................................................................................ 23 
8.5 
Day 3, Day 9, and Day 15 ..................................................................................... 23 
8.6 
Day 22 ± 3 days (these assessments will also be done at Early Termination 
from the study) ...................................................................................................... 23 


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8.7 
Day 29 ± 3 days ..................................................................................................... 24 
8.8 
Follow up visits at Day 45 (± 3 days) and Day 60 (± 3 days) (conducted via 
phone/teleconference) ............................................................................................ 24 
8.9 
Subject Stopping Rules ......................................................................................... 24 
8.10 
Early Discontinuation of Study Treatment or Early Termination from the 
Study ...................................................................................................................... 25 
8.11 
Adverse Events ...................................................................................................... 26 
8.11.1 
Intensity of Adverse Events .................................................................................. 27 
8.11.2 
Test Medication Causality ..................................................................................... 27 
8.11.3 
Serious Adverse Events ......................................................................................... 28 
8.11.4 
Initial Reports ........................................................................................................ 29 
8.11.5 
Precautions ............................................................................................................ 29 
8.11.6 
Reporting of Adverse Events Associated with Study Drug Overdose, Misuse, 
Abuse or Medication Error .................................................................................... 29 
8.12 
Concomitant Medications and Concomitant Therapies ......................................... 30 
8.13 
Prohibited Medications .......................................................................................... 30 
8.14 
Pharmacokinetic Sampling and Handling ............................................................. 30 
8.15 
Plasma Sample Labels for Pharmacokinetic Samples ........................................... 31 
9.0 
STATISTICAL ANALYSIS ............................................................................... 31 
9.1 
Sample Size Calculation ........................................................................................ 31 
9.2 
Analysis Sets.......................................................................................................... 32 
9.3 
Analysis Scope ...................................................................................................... 32 
9.4 
Efficacy Analyses .................................................................................................. 33 
9.4.1 
Primary Endpoint .................................................................................................. 33 
9.4.2 
Secondary Analyses of the Primary Endpoint ....................................................... 33 
9.4.2.1 
Sensitivity Analyses .............................................................................................. 33 
9.5 
Secondary Endpoint............................................................................................... 34 
9.5.1 
Proportion of patients alive and free of respiratory failure at Day 29, Day 15 
and Day 22 ............................................................................................................. 34 
9.5.1.1 
Days in ICU ........................................................................................................... 34 
9.5.1.2 
Change from baseline in WHO Ordinal Scale for Clinical Improvement at Day 15, 
Day 22 and Day 29 ................................................................................................ 35 
9.5.1.3 
Days on mechanical ventilation ............................................................................. 36 
9.5.1.4 
Days in hospital ..................................................................................................... 36 
9.5.1.5 
Mean change from baseline in Viral load to Day 9 ............................................... 36 
9.6 
Pharmacokinetic Analysis ..................................................................................... 36 
9.7 
Safety Analysis ...................................................................................................... 36 
9.7.1 
Independent Data Monitoring Committee (IDMC) ............................................... 37 
9.7.2 
Interim Analysis .................................................................................................... 37 
10.0 
ADMINISTRATION PROCEDURES .............................................................. 38 


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10.1 
Study Conduct and Compliance ............................................................................ 38 
10.2 
Informed Consent .................................................................................................. 38 
10.3 
Protocol Amendments ........................................................................................... 39 
10.4 
Protocol Deviations ............................................................................................... 40 
10.5 
Data Handling and Recordkeeping ........................................................................ 40 
10.5.1 
Data Handling ........................................................................................................ 40 
10.5.2 
Data Entry.............................................................................................................. 40 
10.5.3 
Medical Information Coding ................................................................................. 40 
10.5.4 
Data Validation ...................................................................................................... 41 
10.5.5 
Record Keeping ..................................................................................................... 41 
10.6 
Data Quality .......................................................................................................... 41 
10.7 
Regulatory Approval ............................................................................................. 41 
10.8 
Publication Policy .................................................................................................. 42 
10.9 
Clinical Study Report ............................................................................................ 42 
10.10 
Contractual and Financial Details ......................................................................... 42 
10.11 
Insurance and Indemnity........................................................................................ 43 
11.0 
REFERENCES .................................................................................................... 43 
12.0 
APPENDICES ..................................................................................................... 45 
12.1 
Appendix A: Clinical Laboratory Tests (local laboratory) .................................... 45 
12.2 
Appendix B: Schedule of Study Evaluations ........................................................ 46 


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1.0 
LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic Case report form 
ECOG 
Eastern Cooperative Oncology Group 
GCP 
Good clinical practice 
GGT 
Gamma-glutamyl transferase 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
LAR 
Legally Authorized Representative 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LMWH 
Low molecular weight heparin 
MedDRA 
Medical dictionary of regulatory activities 
NSAID 
Nonsteroidal anti-inflammatory drug 
OTC 
Over the Counter 
PRN 
Pro re nata – As Needed 
RRT 
Renal replacement therapy 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


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2.0 
PHASE 3 PROTOCOL SUMMARY 
 
Study 
Number: 
V3011902 
Title: 
Phase 3, Randomized, Placebo-Controlled, Efficacy and Safety Study of 
VERU-111 for the Treatment of Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2) in Patients at High Risk for Acute 
Respiratory Distress Syndrome (ARDS) 
Primary 
Objectives: 
To demonstrate the efficacy of VERU-111 in the treatment of SARS-Cov- 
2 Infection by assessing its effect on the proportion of patients who die on 
study (prior to Day 60). 


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Secondary 
Objectives: 
The secondary objectives/endpoints on this study are: 
1. The proportion of subjects that are alive without respiratory failure 
at Day 15, Day 22 and Day 29. Day 29 is the key secondary 
endpoint in this study. Respiratory failure is defined as 
endotracheal intubation and mechanical ventilation, extracorporeal 
membrane oxygenation, high-flow nasal cannula oxygen delivery, 
noninvasive positive pressure ventilation, clinical diagnosis of 
respiratory failure with initiation of none of these measures only 
when clinical decision making is driven solely by resource 
limitation. 
2. Days in ICU 
3. WHO Ordinal Scale for Clinical Improvement change from 
baseline to Day 15, Day 22, and Day 29 
4. Days on mechanical ventilation 
5. Days in hospital 
6. Proportion of subjects that die on study at Day 15, Day 22, and Day 
29. 
7. Change from baseline in viral load (baseline to Day 9) 
Safety 
Objective: 
To assess the safety, tolerability, and risk/benefit of VERU-111 
Patient State 
Descriptor 
Score 
Uninfected 
No clinical or virological evidence 
of infection 
0 
Ambulatory 
No limitation of activities 
1 
Limitation of activities 
2 
Hospitalized, Mild disease 
Hospitalized, no oxygen therapy 
3 
Oxygen by mask or nasal prongs 
4 
Hospitalized, Severe 
disease 
Non-invasive ventilation or high- 
flow oxygen 
5 
Intubation and mechanical 
ventilation 
6 
Ventilation + additional organ 
support – pressors, RRT, ECMO 
7 
Death 
Death 
8 


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Design: 
This study is a multicenter, randomized, placebo-control, efficacy and 
safety study of VERU-111 for the treatment of COVID-19. Subjects will 
receive either 9 mg of VERU-111 or matching placebo orally or through 
nasogastric tube daily for up to 21 days or until the subject is discharged 
from the hospital, whichever comes first. 
The primary efficacy endpoint of the study will be the proportion of 
subjects that die prior to Day 60. 
The total study duration for a subject from screening to follow up visit is 
planned to be 62 days. 
In addition to the safety of VERU-111, an evaluation of the efficacy of 
VERU-111 on SARS-CoV-2 (COVID-19) compared to the placebo control 
will be evaluated as part of the Independent Data Monitoring Committee 
(IDMC). 
Subjects: 
Approximately, 210 subjects are planned to be randomized at a 2:1 ratio 
into two treatment arms (140 subjects in the VERU-111 treated group and 
70 subjects in the Placebo treated group). 
Randomization will be stratified by baseline WHO Ordinal Scale score of 
4, 5 and 6 such that subjects with a WHO Ordinal Scale of 4, 5 and 6 at 
baseline are approximately equally distributed between the treatment 
groups. 
NOTE: Throughout this protocol the terms “patients” and “subjects” are 
used interchangeably. 
Treatments: 
Subjects in the VERU-111 treatment groups will receive standard of care, 
plus oral daily VERU-111 9 mg for 21 days or until released from hospital, 
whichever comes first. 
Subjects in the Placebo treatment group will receive standard of care, plus 
a placebo capsule for 21 days or until released from hospital, whichever 
comes first. 
Procedures: 
Potential study participants will undergo a series of screening evaluations, 
including the collection of demographic information, within 3 days prior to 
randomization. Subjects who give written informed consent and satisfy the 
selection criteria will be enrolled into the study. 
SpO2 levels will be taken at screening, baseline (Day 1) and on Days 3, 9, 
15, 22, and 29. 


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Safety evaluations including assessment of adverse events (Days 1-22, Day 
29, Day 45, and Day 60), 12-lead electrocardiogram (single) (screening, 
Day 15, Day 22, and Day 29) and clinical laboratory results: urinalysis 
(screening, baseline, Day 22, and Day 29), hematology (screening, 
baseline, Day 3, Day 9, Day 15, Day 22, and Day 29), and serum chemistry 
(screening, baseline, Day 3, Day 9, Day 15, Day 22 and Day 29). 


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3.0 
INTRODUCTION 
 
3.1 
Background 
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is an enveloped, 
nonsegmented, positive-sense, single stranded RNA virus with an unusually large RNA 
genome, a nucleocapsid, and club-like spikes (S protein) that project from their surface and 
from which they are named. It belongs to the betacoronavirus category which includes 
SARS-CoV and MERS-CoV. These viruses have been responsible for epidemics with 
variable severity with both respiratory and extra-respiratory clinical manifestations, highly 
contagious, and mortality rates between 10-35% (Cascella 2020). The coronavirus 
superfamily (Coronaviridae) includes several human pathogens with large RNA genomes, 
e.g., influenza and viral encephalitis and they are classified into alpha, beta, delta and gamma 
coronavirus families and then further divided into Lineages A, B, C and D. SARS-CoV-2 is a 
Lineage B betacoronavirus (Gorbalenya 2020). 
 
Starting in December 2019, SARS-CoV-2 infection resulted in Coronavirus Disease 2019 
(COVID-19) and consequently has been declared a global pandemic with 98,050,801 cases 
and 2,098,174 deaths worldwide as of 22 January 2021 at 1:44 GMT (January 22, 2021; 
Worldometers.info). 
Viruses have efficient mechanisms that take control of their host’s cellular machinery to carry 
out viral replication, assembly and to exit from the cell to spread infectious virions. Given the 
spatial distances between the point of virion entry at the plasma membrane to the location in 
the cell where RNA replication (nucleus) and viral assembly occur in the ER and Golgi and 
then the newly generated virions have to travel back out to the plasma membrane to egress out 
of the cell, it is no wonder that the virus’s most critical task is to hijack the host’s internal 
transportation system, the cytoskeleton (Ward 2011). The cytoskeleton has three major types 
of protein filaments: microfilaments (actin), microtubules (tubulin), and intermediate 
filaments. The principal ones involved in viral replication and trafficking (transport) are 
microtubules and actin since these are the two main filament systems involved in cellular 
transport (Ward 2011). 
Microtubules are important for cell shape, transport, motility, and cell division (Heald 2002). 
Microtubules are dynamic long polar fibers/filaments that result from the polymerization of α 
and β tubulin heterodimer subunits with a positive end located at the plasma membrane and a 
minus end facing the nucleus at the microtubule organizing center (MTOC). From the MTOC, 
microtubule fibers radiate out from the nuclear area towards the periphery of the cell. 
Microtubules are dynamic network systems, meaning that, they undergo rapid polymerization 
(add α and β tubulin subunits heterodimers) to grow, and subsequent rapid depolymerization 
(remove α and β tubulin subunits heterodimers) to shrink. This “dynamic” growing and 
shrinking serves the constantly changing transportation requirements of the cell. Large 
macromolecules, like viruses, engage with specialized motor proteins (kinesins and dyneins) 
(Dohner 2005; Biswas 2014; Han 2012; Hara 2009). Kinesins and dyneins attach, carry, and 
move the virus cargo up and down these microtubule tracks to travel long distances to reach 
the different compartments within the cell (Ward 2011; Simpson 2020; Cooper 2000). 


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Microtubule based transportation is a critical aspect of viral replication (Naghavi 2017; 
Dohner 2005). In fact, viral infection or expression of viral proteins alters the organization of 
the microtubular networks to serve their need to replicate and spread infectious virion. 
Microtubules not only facilitate infection, but microtubules are actively manipulated by 
viruses (Naghavi 2017). Furthermore, microtubule inhibiting agents that disrupt microtubule 
networks suppress viral infection (Rudiger 2016). 
Virus-cell surface interactions, virus entry and internalization- 
Although microtubules are located within the cell, they are able to influence the viral infection 
from the onset. Viruses utilize specific sites and proteins to attached to the cell surface. The 
spatial organization of these surface receptors and entry factors are controlled in part by the 
polarization of the microtubular array (Naghavi 2017). When added early, nocodazole, a 
microtubule depolymerizing drug, decreased mouse hepatitis coronavirus virus infection by 
affecting plasma membrane entry by endocytosis (Burkard 2014). There are apparently other 
ways that entry and internalization may occur as human coronavirus NL63 internalization and 
vesicle entry was not affected by nocodazole (Milewska 2018). 
In the case of SARS-CoV, the first stage of interaction with the microtubule cytoskeleton 
occurs when the Spike (S) protein mediated attachment to the cell surface (Ren 2015). After 
binding, the virus particles actively rearrange the cytoskeleton by regulating the 
FAK/Cofilin/Rac/Cdc42 pathway (Lv 2019). 
Virus intracellular transport via microtubules to the perinuclear region- 
Many viruses require microtubules at cell entry for efficient nuclear targeting (Dohner 2005). 
Vesicular transport occurs via microtubule trafficking and the corresponding specialized 
motor proteins. In the case of the Mouse Hepatitis Coronavirus Virus, the early secretory 
pathway is important in the formation of the replication complex (Knoops 2010; Oostra 
2007). Intracellular transport of the endocytosed vesicles containing coronavirus utilizes S- 
protein bound to β- tubulin on microtubules to locate to the perinuclear region of the cell. 
Viruses can also modulate microtubular dynamics to promote rapid transport to nucleus 
(Naghavi 2017; Suomalainen 2001). Coronaviruses may also have interactions of S proteins 
with the specialized motor proteins like kinesins and dyneins (Rudiger 2016). 
Virion replication and assembly and egress of infectious viral particles out of the cell- 
Virus particle assembly occurs in the ER-Golgi intermediate compartment (ERGIC) and is 
orchestrated by the M protein. M provides the scaffold for virion morphogenesis and M-S and 
M-N interactions facilitate the recruitment of structural components to the assembly site. 
Coronavirus particles budding into the ERGIC are transported in smooth walled vesicles and 
trafficked via microtubules for release by exocytosis. Host factors, specifically, the 
interactions between the cytoskeleton and other structural proteins are essential in this 
process. Interactions between tubulin and the cytosolic domain of the S protein of human 
coronavirus-229E, human coronavirus-NL63, and TGEV are required for successful assembly 
and release of viral particles (Reviewed in Fung 2019). RNA viruses utilize diverse structures 
within the cytoskeleton for their replication which rely on microtubules to form and function 
(Naghavi 2017). Nocodazole, a microtubule depolymerizing agent, blocks the movement and 


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fusion of capsids and nucleoprotein particles to the budding ER/Golgi compartments to form 
virions as well as the secretory microtubule trafficking to egress new virions resulting in 
reduced virus yields (Eichwald 2012; Criglar 2014; Dohner 2005). 
To evaluate early assembly events, alpha (HCoV-229E, HCoV-NL63, and TGEV) and beta 
(SARS-CoV) coronaviruses S proteins were treated with nocodazole. The pharmacological 
action of nocodazole is the inhibition of tubulin polymerization. Untreated cells had long and 
filamentous tubulin structures (microtubules) and the S protein accumulated near the nucleus 
(ERGIC) and less S protein distributed in the cytosol, whereas the nocodazole treated cells 
had dispersed and patchy tubulin fragments and the S proteins were “differentially 
distributed”, or scattered throughout the cytoplasm (Rudiger 2016). Also, following 
nocodazole treatment, M protein amount was decreased and there was a reduced 
colocalization of S and M proteins (Rudiger 2016). Nocodazole treatment resulted in both a 
significant reduction in viral particles and these particles had very little S protein, and thus, 
the virions were less infectious as well (Rudiger 2016). In fact, nocodazole treatment at all 
time points resulted in significantly lower virus titers in cell culture supernatant versus 
untreated infected cells (Rudiger 2016). 
In summary, tubulin interacts with the cytoplasmic domain of alphacoronavirus and 
betacoronavirus SARS-CoV spike S proteins. Rudiger et al. (2016) conclude that the 
reduction in infectious virus titer following treatment with a drug that causes microtubule 
depolymerization is mainly because there is less S protein present at the assembly site due to 
impaired S protein-microtubule transport and that the incorporation process of S protein itself 
into virions is tubulin-dependent. Furthermore, disruption of microtubule trafficking impaired 
the egress of these poorly assembled virions with less surface spike S proteins, less infectious, 
out of the cell. A microtubule depolymerizing agent may be effective in treating in treating 
coronavirus infection to disrupt microtubule trafficking critical for virus replication cycle. 
 
Colchicine-like Activity 
The central mechanism of colchicine clinical anti-inflammatory and anti-viral activities is 
based on its ability to bind the “colchicine binding” sites on alpha and beta tubulin which 
when incorporated into microtubule block subsequent microtubule polymerization 
(Slobodnick 2018). Inhibition of tubulin polymerization is responsible for the effects of 
colchicine on cell migration, cytokine release, and intracellular trafficking (antiviral) and 
disruption of inflammatory cell activities seen for acute gout and familial Mediterranean 
fever. Colchicine modulates leucocyte mediated inflammatory activities including inhibition 
of leucocyte production of superoxides and release of various cytokines and pyrogens 
(Slobodnick 2018). Colchicine-like agents may be useful to treat the “cytokine storm” seen 
with SARS-CoV 2. IL-18 is a member of the IL-1 cytokine family and unopposed elevated 
levels of IL-18 concentrations have been associated with macrophage activation syndrome 
and poor clinical outcomes in severe inflammatory and septic shock conditions (Verweyen 
2020). Interestingly, colchicine abrogates IL-1β and IL-18 overexpression by reducing its 
transcription to reduce severe inflammation and septic shock. Verweyen et al. (2020) also 
showed that colchicine as well as nocodazole abrogated IL-18 expression confirming that 
microtubule depolymerization is the mechanism. 


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3.2 
Target Indication and Pharmacologic Activity 
VERU-111 is orally bioavailable bis-indole that binds the “colchicine binding site” of α and β 
tubulin and inhibits tubulin polymerization at low nanomolar concentrations. VERU-111 is 
neither a substrate for MDRs including P-gp, MRPs, and BCRP, nor CYP3A4. VERU-111 
also decreases the transcription of βI, βIII, and βIV-tubulin isoforms (Li 2012). VERU-111 is 
currently under development for the treatment of metastatic castration resistant prostate 
cancer in patients who have failed an androgen receptor targeting agent. 
 
3.3 
Study Rationale 
In a Phase 2, double-blind, placebo-controlled clinical study the safety and efficacy of VERU- 
111 in the treatment of SARS-CoV-2 in patients at high risk for ARDS was assessed. Thirty- 
nine (39) hospitalized patients at high risk for ARDS were randomized to 18 mg of VERU- 
111 (powder in capsule formulation) or matching placebo. The primary efficacy endpoint for 
the study was the proportion of patients alive without respiratory failure at Day 15, Day 22, 
and Day 29. The key secondary endpoints in the study were days on mechanical ventilation, 
days in intensive care unit (ICU), and proportion of patients discharged from the hospital on 
Day 15, Day 22, and Day 29. The efficacy conclusions in the Intent-to-Treat (ITT) population 
from a post-hoc analysis from the Phase 2 study are: 
 
• 
VERU-111 reduced the proportion of patients who died on study (up to Day 60) from 
30% (6/20) in the placebo group to 5% (1/19) in the VERU-111 treated group. This is 
an approximately 82% reduction in mortality in the VERU-111 treated group. 
• VERU-111 reduced the proportion of patients that are treatment failures, i.e. death or 
respiratory failure from 35.0% in the placebo group to 15.8% in the VERU-111 treated 
group at Day 15 and from 30.0% in the placebo group to 10.5% in the VERU-111 
treated group at Day 29. This represents an approximately 55% reduction in treatment 
failures at Day 15 and a 65% reduction in treatment failures at Day 29 in the VERU- 
111 treated group compared to placebo. 
• VERU-111 reduced the days on mechanical ventilation from an average of 5.4 days in 
the placebo group to 1.6 days in the VERU-111 treated group. This represents a 3.4- 
fold increase in the days on mechanical ventilation in the placebo group compared to 
the VERU-111 treated group. 
• VERU-111 reduced the days in ICU from an average of 9.6 days in the placebo group 
to 3.0 days in the VERU-111 treated group. This represents a 3.2-fold increase in the 
days in the ICU in the placebo group compared to the VERU-111 treated group. 
• There is an imbalance in the gender distribution between the treatment group such that 
the placebo group is 85% male (17/20) and the VERU-111 treated group is 53% male 
(10/19). This imbalance was evaluated as a covariate in the analysis but did not have a 
significant effect on the conclusions of the study. 
• The use of remdesivir and dexamethasone did not have a significant effect on patient 
outcomes in the study. 
• In patients with a WHO disease severity score of ≥5 at baseline, the proportion of 
patients that died on study (up to Day 60) in the placebo group was 46% compared to 
10% in the VERU-111 treated group. This represents a 78% reduction in death in the 


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VERU-111 treated group compared to placebo. It is important to note that in the Phase 
2 study, the 6 patients in the placebo group and the 1 patient in the VERU-111 treated 
group that died on study all had a WHO disease severity score of ≥5 at baseline. 
Therefore, randomization into the Phase 3 study will be stratified by WHO scale at 
baseline such that patients who have a WHO disease severity score of 4, 5, and 6 at 
baseline are approximately equally distributed between the treatment groups. This is a 
similar population as was used in the Phase 2 study and accounts for patients that 
move from WHO severity score of 4 to 5 and then from WHO severity score of 5 to 6 
to 7 quickly. 
 
The Phase 2 clinical study was hypothesis generating. A 78-82% reduction in mortality, a 55- 
65% reduction in death or respiratory failure, 3.2-fold higher mean days in ICU and 3.4-fold 
higher mean days on mechanical ventilation in the Placebo group compared to the VERU-111 
treated group are all clinically relevant observations and warrant the continued development 
of VERU-111 in the treatment of SARS-CoV-2 in patients at high risk for ARDS. 
 
There were no drug related serious adverse events (SAEs) observed in the Phase 2 clinical 
study of VERU-111 in SARS-CoV-2 infected patients. There were no drug related serious 
adverse reactions (≥Grade 3). 
 
The relative bioavailability (pharmacokinetics) of the VERU-111 powder in capsule (PIC) 
formulation has been assessed and compared to a to-be-marketed VERU-111 formulated 
capsule (FC) formulation. Additionally, the effect of high fat meal (food effect) was also 
assessed for both formulations. The data are presented in Table 1. 
 
Table 1 
The Steady State Pharmacokinetics of VERU-111 Powder in Capsule (PIC) 
and Formulated Capsule (FC) Under Fasted and Fed Conditions 
 
63 mg PIC (fasted) 
63 mg PIC (fed) 
31.5 mg FC (fasted) 
31.5 mg FC (fed) 
N 
6 
6 
6 
6 
Cmax (ng/mL) 
148.1±64.7 
97.8±53.5 
182.2±32.6 
169.9±104.2 
Tmax (hr) 
2.17±0.98 
7.67±2.66 
1.67±1.21 
4.08±2.69 
AUC0-24h (ng*hr/mL) 
1006.16±376.29 
984.80±519.62 
973.58±307.87 
1011.27±512.54 
T½ (hr) 
7.38±4.59a 
5.06±1.53b 
5.11±1.24 
4.89±1.09c 
AUC = area under the curve; FC = formulated capsule; PIC = powder in capsule. 
a. 
One patient had an aberrant T½ of 16.09 hours. If this value is removed from the analysis, then the T½ is 5.64 hours 
(±1.90) 
b. 
The terminal T½ was calculable in 3 of 6 subjects in the 63 mg PIC fed group. 
c. 
The terminal T ½ was calculable in 5 of 6 subject in the 31.5 FC fed group. 
 
The conclusions from this study are: 
 
1. The T1/2 of VERU-111 is approximately 5 hours and steady state is reached within 5 days 
of daily dosing. 
 
2. Administration of VERU-111 FC formulation with a high fat meal has minimal effect on 
the AUC0-24 or Cmax at steady state. However, the shape of the curve appears to be 


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different with a high fat meal with the Tmax shifted to the right. Based on these data, the 
instructions for use will be VERU-111 FC may be taken without regard to food. 
 
3. The relative bioavailability of the VERU-111 FC formulation compared to the VERU-111 
PIC formulation shows that a 31.5 mg dose of the VERU-111 FC formulation shows 
similar pharmacokinetics compared to the 63 mg dose of the VERU-111 PIC formulation. 
The dose of VERU-111 PIC used in the Phase 2 study was 18 mg. Therefore, for the 
VERU-111 dose for treatment of SARS-CoV-2 in patients at high risk for ARDS, a 9 mg 
dose of VERU-111 FC will be used. 


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4.0 
STUDY OBJECTIVES 
 
4.1 
Primary Objectives 
To demonstrate the efficacy of VERU-111 in the treatment of SARS-CoV-2 infection by 
assessing its effect on the proportion of subjects that die on study (up to Day 60). 
 
4.2 
Secondary Objectives 
The secondary objectives/endpoints on this study are: 
 
1. The proportion of subjects that are alive without respiratory failure at Day 15, Day 22, 
and Day 29. Day 29 is the key secondary endpoint. Respiratory failure is defined as 
endotracheal intubation and mechanical ventilation, extracorporeal membrane 
oxygenation, high-flow nasal cannula oxygen delivery, noninvasive positive pressure 
ventilation, clinical diagnosis of respiratory failure with initiation of none of these 
measures only when clinical decision making is driven solely by resource limitation. 
2. Days in ICU 
3. WHO Ordinal Scale for Clinical Improvement change from baseline to Day 15, Day 
22, and Day 29 
Patient State 
Descriptor 
Score 
Uninfected 
No clinical or virological evidence 
of infection 
0 
Ambulatory 
No limitation of activities 
1 
Limitation of activities 
2 
Hospitalized, Mild disease 
Hospitalized, no oxygen therapy 
3 
Oxygen by mask or nasal prongs 
4 
Hospitalized, Severe 
disease 
Non-invasive ventilation or high- 
flow oxygen 
5 
Intubation and mechanical 
ventilation 
6 
Ventilation + additional organ 
support – pressors, RRT, ECMO 
7 
Death 
Death 
8 
 
4. Days on mechanical ventilation 
5. Days in hospital 
6. Proportion of subjects that die on study at Day 15, Day 22, and Day 29. 
7. Change from baseline in viral load (baseline to Day 9) 
 
4.3 
Safety Objective 


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To assess the safety, tolerability, and risk/benefit of VERU-111 
 
5.0 
STUDY DESIGN 
 
5.1 
Treatment Groups and Allocation of Subjects 
 
This randomized, placebo-control clinical study consists of two treatment arms: VERU-111 9 
mg treated group, and Placebo treated group. Subjects will be randomized in a 2:1 fashion to 
the VERU-111 treated group and Placebo treated group, respectively. 
 
All patients will receive standard of care for the treatment of SARS-CoV-2 infection 
(COVID-19). 
 
Randomization will be stratified by baseline WHO Ordinal Scale score of 4, 5 and 6 such that 
subjects with a WHO Ordinal Scale of 4, 5 and 6 at baseline are approximately equally 
distributed between the treatment groups. 
 
5.2 
Study Duration 
 
The study will require that each subject in the study receive 9 mg daily oral dose of VERU- 
111 or placebo for up to 21 days (Day 21) or until the patient is discharged from the hospital 
(whichever comes first) with efficacy and safety follow up continuing to Day 60 of the study. 
The total duration of the study for a subject in the study from screening to follow-up visit 
(approximately Day 60 on study) will be approximately 62 days. 
 
5.3 
Efficacy Endpoints 
 
5.3.1 
Primary Endpoint 
 
The primary endpoint for the study is the proportion of subjects that die on study (up to Day 
60). 
 
5.3.2 
Secondary Endpoints 
 
The secondary endpoints on this study are: 
 
1. The proportion of subjects that are alive without respiratory failure at Day 15, Day 22, 
and Day 29. Day 29 is the key secondary endpoint. Respiratory failure is defined as 
endotracheal intubation and mechanical ventilation, extracorporeal membrane 
oxygenation, high-flow nasal cannula oxygen delivery, noninvasive positive pressure 
ventilation, clinical diagnosis of respiratory failure with initiation of none of these 
measures only when clinical decision making is driven solely by resource limitation. 
2. Days in ICU 
3. WHO Ordinal Scale for Clinical Improvement change from baseline to Day 15, Day 
22, and Day 29 
4. Days on mechanical ventilation 


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5. Days in hospital 
6. Proportion of subjects that die on study at Day 15, Day 22, and Day 29. 
7. Change from baseline in viral load (baseline to Day 9) 
 
6.0 
SUBJECT POPULATION 
 
6.1 
Number of Subjects 
Approximately 210 subjects are planned to be randomized at a 2:1 ratio into two treatment 
arms (approximately 140 subjects in the VERU-111 treated group and approximately 70 
subjects in the Placebo treated group). 
 
6.2 
Selection Criteria 
6.2.1 Inclusion Criteria 
Subjects accepted for this study must: 
 
1. 
Provide informed consent from the subject or the subject’s Legally Authorized 
Representative (LAR) 
2. 
Aged ≥18 years 
3. 
Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) infection confirmed by 
polymerase chain reaction (PCR) test 
4. 
Patients with a WHO Ordinal Scale for Clinical Improvement score of 4 at high risk for 
ARDS, must have at least one of the known comorbidities for being at high risk, such as, 
Asthma (moderate to severe), Chronic Lung Disease, Diabetes, Hypertension, Severe 
Obesity (BMI ≥40), 65 years of age or older, primarily reside in a nursing home or long- 
term care facility, or immunocompromised and patients with a WHO Ordinal Scale for 
Clinical Improvement score of 5 or 6 regardless of presence of comorbidities. 
5. 
WHO Ordinal Scale for Clinical Improvement score of 4 (Oxygen by mask or nasal 
prongs), 5 (Non-invasive ventilation or high-flow oxygen) or 6 (Intubation and 
mechanical ventilation) 
6. 
Peripheral capillary oxygen saturation (SpO2) ≤ 94% on room air at screening. If patient 
is on oxygen therapy at the time of presentation for screening and the SpO2 levels were 
≤94% prior to introduction to oxygen therapy with proper documentation example EMT 
notes or ER/ED notes, then the patient is considered to have met this inclusion criterion. 
If patient is on oxygen therapy at the time of presentation for screening and the SpO2 
levels prior to introduction to oxygen therapy are unknown, the patient may be 
considered to have met this inclusion criterion if oxygen therapy is removed and the 
SpO2 levels fall to ≤94%, then the patient is considered to have met this inclusion 
criterion. However, removal of the oxygen therapy should only be done if it is considered 
medically reasonable. 
7. 
Subjects must agree to follow doctor’s recommendation for oxygen supplementation. 
8. 
Subjects must agree to use acceptable methods of contraception: 
• If female of childbearing potential or a male subject’s partner could become 
pregnant, use acceptable methods of contraception from the time of the first 
administration of study medication until 6 months following administration of 


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the last dose of study medication. Acceptable methods of contraception are as 
follows: Condom with spermicidal foam/gel/film/cream/suppository [i.e., barrier 
method of contraception], surgical sterilization (vasectomy with documentation 
of azospermia) and a barrier method {condom used with spermicidal 
foam/gel/film/cream/suppository}, the female partner uses oral contraceptives 
(combination estrogen/progesterone pills), injectable progesterone or subdermal 
implants and a barrier method (condom used with spermicidal 
foam/gel/film/cream/suppository) 
• If the female partner of a male subject has undergone documented tubal ligation 
(female sterilization), a barrier method (condom used with spermicidal 
foam/gel/film/cream/suppository) should also be used 
• If female partner of a male subject has undergone documented placement of an 
intrauterine device (IUD) or intrauterine system (IUS), a barrier method 
(condom with spermicidal foam/gel/film/cream/suppository) should also be used 
9. Subject is willing to comply with the requirements of the protocol through the end of the 
study 
 
6.2.2 Exclusion Criteria 
Any of the following conditions are cause for exclusion from the study: 
 
1. Known hypersensitivity or allergy to colchicine 
2. Pregnant or currently breast feeding 
3. Participation in any other clinical trial of an experimental treatment for COVID-19. 
Convalescent plasma, dexamethasone and remdesivir are allowed in this study. 
4. Concurrent treatment with other experimental agents with actual or possible direct acting 
antiviral activity against COVID-19 is prohibited <24 hours prior to study drug dosing 
(except standard of care). Remdesivir, dexamethasone and convalescent plasma are allowed 
in the study. 
5. Requiring ventilation + additional organ support – pressors, RRT, ECMO (WHO Ordinal 
Scale for Clinical Improvement – Score of 7). NOTE: short term (PRN) use of pressors is 
allowed. 
6. Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) >3 X upper limit of 
normal (ULN) 
7. Total bilirubin > ULN 
8. Creatinine clearance < 60 mL/min 
9. Documented medical history of liver disease, including but not limited to, prior diagnosis 
of hepatitis of any etiology, cirrhosis, portal hypertension, or confirmed or suspected 
esophageal varices 
10. Moderate to severe renal impairment 
11. Hepatic impairment 
12. History of hepatitis (Hepatitis B and C) NOTE: treated and controlled hepatitis C is allowed. 
13. Any comorbid disease or condition (medical or surgical) which might compromise the 
hematologic, cardiovascular, gastrointestinal, hepatic, or central nervous system; or in PI’s 


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opinion other conditions that may interfere with the absorption, distribution, metabolism or 
excretion of study drug, or would place the subject at increased risk. 
14. Participants must agree to refrain from prolonged exposure to the sun or agree to use at 
least SPF 50 on all exposed skin and protective clothing during prolonged sun exposure 
throughout participation in this study and/or treatment with VERU-111. 
 
7.0 
STUDY MEDICATION 
 
7.1 
Enrollment and Blinding 
The study will be a randomized, double-blind, placebo-controlled study. 
 
Randomization will be stratified by baseline WHO Ordinal Scale score of 4, 5 and 6 such that 
subjects with a WHO Ordinal Scale of 4, 5 and 6 at baseline are approximately equally 
distributed between the treatment groups. 
 
An emergency code break will be available to the investigator / pharmacist / investigational 
drug storage manager. This code break option in IWRS may only be disclosed in emergency 
situations when the identity of the trial drug must be known to the investigator in order to 
provide appropriate medical treatment or if required to assure safety of trial participants. If the 
code break for a patient is opened, the sponsor and CRO will be informed immediately via 
IWRS notification. The reason for the IWRS unblinding of the subject must be documented 
on the appropriate eCRF page along with the date and the initials of the person who broke the 
code. 
 
7.2 
Drug Supply 
7.2.1 VERU-111 Capsules 
VERU-111 9 mg dose will be supplied as capsules containing 9 mg of VERU-111. Capsules 
will be supplied in bottles containing 21 capsules in each bottle. Patients will take one VERU- 
111 capsule per day. 
 
The VERU-111 capsules should be stored at controlled room temperature, 20°C to 25°C 
(68°F to 77°F) with excursions permitted between 15°C to 30°C (59°F to 86°F). 
 
7.2.2 Placebo Control 
Placebo capsules containing zero (0) mg VERU-111 drug substance will be supplied in bottles 
containing 21 capsules each. These capsules are identically appearing to the VERU-111 
capsules. Patients will take one Placebo capsule per day. 
 
The Placebo capsules should be stored at controlled room temperature, 20°C to 25°C (68°F to 
77°F) with excursions permitted between 15°C to 30°C (59°F to 86°F). 


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7.2.3 Drug Accountability 
Subjects should not take a replacement dose if a dose is missed. Study medication should not 
be taken more than once a day. If the patient vomits after dosing, the dose will not be 
replaced. 
 
The pharmacists or other site personnel as delegated by the Investigator are responsible for 
accountability of all used and unused study drug supplies. A study drug dosing log should be 
kept current and should contain the dates and times drug dosing the subject, the subject’s 
identification (i.e., subject number), the initials of the dispensing persons. Veru Inc., shall be 
immediately notified of any unexpected occurrences during the dispensing or dosing of study 
drug. 
 
7.3 
Drug Administration 
Study drug should be taken daily at approximately the same time every day with 
approximately 240 mL (a full glass) of non-alcoholic liquid (drink). Dosing may be taken 
with or without food. Subjects will take the entire daily dose at once. In subjects with a 
nasogastric feeding tube, the contents of the capsules may be emptied into the tube and 
appropriately flushed through the tube. 
 
8.0 
STUDY PROCEDURES 
 
8.1 
Screening 
Potential subjects will be screened for this study in the 3 days prior to enrollment. The 
following activities will be conducted at screening: 
 
1. 
Signed informed consent and HIPAA form (or legal documents as directed based on the 
region outside of the United States) will be obtained prior to any study-specific 
procedures and a copy of the signed consent form will be given to the subject. 
2. 
Assess subject eligibility for inclusion into this study based on protocol 
inclusion/exclusion criteria. 
3. 
Pregnancy test (women of childbearing potential only) 
4. 
Medical history will be obtained, including diagnosis of COVID-19 infection (date of 
diagnosis), details and dates of treatments received, documentation of symptoms 
related to COVID-19 infection, and COVID-19 vaccination status. 
5. 
WHO Ordinal Scale score assessment 
6. 
The use of any medications will be recorded. This will include medications currently 
being taken and those taken since COVID-19 symptoms started. Over-the-counter 
(OTC) medications as well as medications taken on an as-needed basis (PRN) should 
be recorded. 
7. 
Vital signs (temperature/pulse/supine, if possible, blood pressure) 
8. 
SpO2 level (%) 


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9. 
Physical examination including height and weight 
10. 
Electrocardiogram- 12 lead (single) 
11. 
Clinical Laboratory Tests 
• Hematology (Appendix A) 
• Serum chemistry (Appendix A) 
• Urinalysis 
8.2 
Enrollment 
Enrollment should be done after the subject has completed the screening assessments and 
after it has been determined that the subject meets all the eligibility criteria. 
 
Subject will be randomized into one of two treatment groups. 
 
8.3 
Day 1 
The Day 1 visit assessments will serve as the baseline assessments. 
 
1. 
The medical history should be reviewed and updated to include any changes occurring 
since the screening visit. This will include the following: 
a. Number of days from onset of COVID-19 symptoms to Day 1 
b. Specific reason for hospitalization 
2. 
Assessment of eligibility - the WHO Ordinal Scale score at Screening will be used as 
the eligibility criteria for the study. The WHO Ordinal Scale score on Day 1 prior to 
dosing will be considered the baseline WHO Ordinal Scale score. 
3. 
WHO Ordinal Scale score assessment (prior to dosing) 
4. 
Pregnancy test (women of childbearing potential only) 
5. 
Vital signs (temperature/pulse/supine, if possible, blood pressure) 
6. 
SpO2 level (%) 
7. 
Physical examination (including weight) 
8. 
Chest X-ray or Computed Tomography (CT) scan 
9. 
Viral load 
10. 
Clinical Laboratory Tests 
a. Hematology (Appendix A) 
b. Serum chemistry (Appendix A) 
c. Urinalysis 
11. 
Record the usage of any concomitant medications and ongoing treatments. 
12. 
Adverse events (ongoing on Day 1) 
13. 
PK sample prior to dosing 
14. 
First dose of study drug 


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8.4 
Day 2 through Day 21 or day of discharge from the hospital (whichever comes 
first) 
The following assessments will be conducted on each of Day 2 to Day 21 or up to the day of 
discharge from the hospital, whichever comes first: 
 
1. 
Vital signs (temperature/pulse/supine, if possible, blood pressure) 
2. 
Record the usage of any concomitant medications and ongoing treatments. This should 
include the following: 
a. Documentation of the standard of care 
b. The clinical rationale for initiation of mechanical ventilation, if necessary 
c. Documentation of supportive measures for ARDS (e.g., proning, paralytics, 
etc.) 
d. Care decisions that are based on limitations of resources at the clinical site 
3. 
Adverse events 
4. 
Dose study drug 
5. 
At the time of discharge from the hospital, patients should be advised to use refrain 
from prolonged exposure to the sun or use at least SPF 50 on all exposed skin and 
protective clothing during prolonged sun exposure until the Day 60 adverse event 
assessment. 
 
8.5 
Day 3, Day 9, and Day 15 
The following additional assessment will be conducted on Days 3, Day 9 and 15: 
 
1. SpO2 level (%) (or day of discharge if prior to Day 15) 
2. Serum Chemistry – (Appendix A) (or day of discharge if prior to Day 15) 
3. Hematology – (Appendix A) (or day of discharge if prior to Day 15) 
4. Viral load (Day 9 only or day of discharge if prior to Day 9) 
5. WHO Ordinal Scale score assessment (Day 15 only or day of discharge if prior to Day 15) 
6. Physical examination (including weight) (Day 15 only or day of discharge if prior to Day 
15) 
7. Pregnancy test (Day 15 only or day of discharge if prior to Day 15) (women of 
childbearing potential only) 
8. 12 lead ECG (single) (Day 15 only or day of discharge if prior to Day 15) 
9. Plasma samples for pharmacokinetic assessment will be taken prior to dosing on Day 3 
and Day 9. 
 
8.6 
Day 22 ± 3 days (these assessments will also be done at Early Termination from the 
study) 
The following assessments will be performed on Day 22 (± 3 days): 
 
1. 
Vital Signs (temperature/pulse/supine blood pressure) 
2. 
SpO2 level (%) 
3. 
Physical examination (including weight) 
4. 
12-lead ECG (single) 


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5. 
Chest X-ray or CT scan 
6. 
Clinical Laboratory tests 
a. Hematology (Appendix A) 
b. Serum chemistry (Appendix A) 
c. Urinalysis 
7. 
Adverse events 
8. 
Pregnancy test (women of childbearing potential only) 
9. 
Record the usage of any concomitant medications and ongoing treatments. 
10. WHO Ordinal Scale score assessment (at Day 22 or day of discharge if prior to Day 22) 
 
8.7 
Day 29 ± 3 days 
The following assessments will be performed at approximately Day 29 (± 3 days): 
 
1. Vital Signs (temperature/pulse/supine blood pressure) 
2. SpO2 level (%) 
3. 
Physical examination (including weight) 
4. 
12-lead ECG (single) 
5. 
Chest X-ray or CT scan 
6. 
Clinical Laboratory tests 
a. Hematology (Appendix A) 
b. Serum chemistry (Appendix A) 
c. Urinalysis 
7. 
Adverse events 
8. 
Pregnancy test (women of childbearing potential only) 
9. 
Record the usage of any concomitant medications and ongoing treatments. 
10. WHO Ordinal Scale score assessment (at Day 29 or day of discharge if prior to Day 29) 
 
8.8 
Follow up visits at Day 45 (± 3 days) and Day 60 (± 3 days) (conducted via 
phone/teleconference) 
1. Adverse events 
2. WHO Ordinal Scale score assessment 
 
8.9 
Subject Stopping Rules 
If, in the opinion of the investigator, the participation in the study is or is becoming 
detrimental to the well-being of a particular subject, this issue should be discussed with the 
Medical Monitor for this study and dosing may be discontinued. 
 
In subjects that experience an adverse event of Grade 4 or greater severity according to the 
Common Terminology Criteria for Adverse Events (CTCAE) version 5 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0_2010-06-14_QuickReference_5x7.pdf) that 
is deemed to be possible, probably or definitely related to study drug dosing with study drug 
will be discontinued. Prior to discontinuation of study drug, the grading of the event and 
causal relationship should be discussed with the Medical Monitor for the study. 


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Subjects will be discontinued from dosing if AST or ALT levels are >5 times the upper limit 
of normal, or if AST or ALT levels are >3 times the upper limit of normal along with a total 
bilirubin elevation of >2 times the upper limit of normal. 
 
Subjects will be discontinued from dosing if Grade 3 diarrhea is observed. 
Subjects will be discontinued from dosing if Grade 3 neutropenia is observed. 
NOTE: These subject stopping rules are related to the discontinuation of study drug, not 
discontinuation from the study. Subjects should be followed for efficacy and safety even if 
study drug is stopped based on these stopping rules. 
 
8.10 Early Discontinuation of Study Treatment or Early Termination from the Study 
Subjects may prematurely discontinue study treatment for any of the following reasons: 
 
1. 
Consent withdrawn for further study treatment (specify the reason). 
2. 
Significant and unacceptable adverse event – specify the adverse event leading to 
discontinuation of study drug 
3. 
Investigator decision (specify the reason), must be approved by the Medical Monitor 
4. 
Non-compliance by subject with protocol requirements, must be approved by the Medical 
Monitor 
5. 
Lost to follow-up (record the date of last contact) 
6. 
Death (specify the following information) 
a. Date of death 
b. Death due to primary disease? Yes or no 
c. Death due to study drug? Yes or no 
d. Death due to adverse event? Yes or no 
7. 
Lack of efficacy 
8. 
Study terminated by the Sponsor 
9. 
Other reason (specify the reason) should be approved by the Medical Monitor 
 
The reason for discontinuation of study treatment will be documented for each subject. 
Subjects who discontinue study drug prematurely will not be replaced. At the time of 
discontinuation, please fill out the End of Study case report forms (eCRFs) and subject 
disposition eCRF pages. 
 
Every effort will be made for the patient to complete all study related procedures at Day 15, 
Day 22, Day 29, Day 45, and Day 60. Every effort will be made to determine patient status 
(alive or dead) at Day 15, Day 22, Day 29, and Day 60. This determination can be made via 
telephone contact or public search records. 


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OF NOTE: For subjects who are terminated from the study prematurely, every effort should 
be made to have the subject complete all Early Termination Assessments (same as day 22 
assessments). The reason for early termination from the study will be documented for each 
subject. Subjects who are early terminations will not be replaced. At the time of early 
termination, please fill out the Early Termination and End of Study case report forms. 
 
Every effort should be made to determine patient status (alive or dead) at Day 60. This 
determination can be made via telephone contact or public search records. 
 
8.11 Adverse Events 
An adverse event (AE) is any unfavorable or unintended change in body structure (signs) or 
body function (symptoms), abnormal laboratory result that is associated with symptoms or 
requires treatment or worsening of a pre-existing condition. This includes all such events 
regardless of the presumed relationship between the event and the study medication(s). 
 
Any AE that occurs after the informed consent is signed but prior to dosing on Day 1 will be 
captured as part of the medical history and will be documented on the appropriate eCRF. This 
would include AEs resulting from concurrent illnesses, reactions to concomitant medications 
or progressive disease states. 
 
Each subject will be assessed for the development of any adverse events. Adverse events 
should be assessed daily during the time in the hospital and at each visit to the clinic after 
discharge. This information should be obtained in the form of non-leading questions (e.g., 
"How are you feeling?") and from signs and symptoms detected during each examination, 
observations of the study personnel or spontaneous reports from the subjects. 
 
Any AEs such as complaints, signs, or symptoms that occur during the course of the study or 
designated follow-up periods will be recorded on the subject's case report form (eCRF). This 
would include AEs resulting from concurrent illnesses, reactions to concomitant medications, 
or progressive disease states. 
 
Whenever possible, the AE will be described on the case report form using standard medical 
terminology consistent with Common Terminology Criteria for Adverse Events (CTCAE) 
version 5 in order to avoid the use of vague, ambiguous or colloquial expressions. The 
investigator will evaluate all adverse events as to their intensity, relation to test medication, 
outcome and action taken. 
 
Each AE will be evaluated for duration, intensity, and relationship to (or association with) the 
study treatment (or other causes). Additionally, the actions taken (e.g., reduction of dosage, 
discontinuation of study medication, administration of treatment, etc.) and the resulting 
outcome of the AE will be indicated on the case report form. 
 
Any subject who is withdrawn from the study drug due to an adverse event will be followed 
until the outcome of the event is determined, and the investigator will prepare a written 


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summary of the event and document the available follow-up information on the case report 
form. 
 
8.11.1 
Intensity of Adverse Events 
The intensity of the AEs will be graded according to CTCAE version 5. For any adverse event 
that is not specifically covered in CTCAE version 5, the following criteria should be used: 
 
Grade 
Description 
 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
 
2 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
 
3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living 
 
4 
Life-threatening consequences: urgent intervention indicated. 
 
5 
Death related to AE 
 
If the intensity (Grade) changes within a day, the maximum intensity (Grade) should be 
recorded. If the intensity (Grade) changes over a longer period of time, the changes should be 
recorded as separate events (having separate onset and stop dates for each grade). 
 
8.11.2 
Test Medication Causality 
The relationship (or association) of each AE to the test medication will be assessed by the 
investigator according to the following definitions: 
 
Unrelated: 
There is no chance that the study medication caused the AE; other conditions, 
including concurrent illnesses, progression or expression of the disease state, or a reaction to a 
concomitant medication best explain the event. 
 
Unlikely: 
There is little chance that the study medication caused the AE; other 
conditions, including concurrent illnesses, progression or expression of the disease state, or a 
reaction to a concomitant medication best explain the event. 
 
Possible: 
The association of the AE with the study medication is unknown; however, the 
AE is not clearly due to another condition. 
 
Probable: 
A reasonable temporal association exists between the AE and treatment 
administration and, based on the investigator's clinical experience, the association of the AE 
with the study treatment seems likely. 


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Definite: 
The association of the AE with the study medication has a direct relationship. 
 
For the purpose of safety analyses, all AEs which are classified as "Possible," "Probable" or 
“Definite” will be considered treatment-related events. 
 
8.11.3 
Serious Adverse Events 
A serious adverse event (SAE) is defined as any experience that suggests a significant 
clinical hazard, contraindication, side effect, or precaution. This includes any event which: 
 
• Results in death. 
• Is life-threatening. 
• Requires inpatient hospitalization or causes prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity. 
• Results in congenital abnormality/birth defect. 
• Requires intervention to prevent permanent impairment or damage 
 
An SAE also may include other events, based on medical judgment, which jeopardize the 
subject and require medical or surgical intervention to prevent one of the outcomes listed 
above. 
 
Any SAE, including death due to any cause, which occurs during the study or within 60 days 
following initiation of dosing on study medication, whether or not related to the study 
medication, must be reported immediately via telephone (within 24 hours) to Veru Inc. Drug 
Safety. 
 
In addition, the investigator must immediately complete a Serious Adverse Event eCRF report 
form and electronically submit the form. The investigator will promptly notify the 
Institutional Review Board (IRB). 
 
If additional information regarding a previously submitted SAE is obtained, a follow-up SAE 
eCRF report should be completed and submitted as indicated above. Supporting source 
documentation should be provided to 
 Drug Safety at the contact 
information below. 
 
 
 
 
 
 
 
 
 
 


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8.11.4 
Initial Reports 
SAEs will be collected from the time of first study drug administration through 60 days after 
first study drug administration. SAEs and events of clinical interest must be reported to the 
Sponsor (or designee) within 24 hours of the knowledge of the occurrence. 
 
In the event an SAE is observed or reported, the SAE report will be completed as thoroughly 
as possible including all available details about the event and the signature of the Investigator. 
If the Investigator does not have all information about an SAE, the Investigator will not wait 
to receive additional information before notifying the Sponsor of the event and completing the 
form. The form will be updated when additional information is received. 
 
8.11.5 
Precautions 
Adverse events should be treated in accordance with standard medical practice. During the 
course of the study, the overall safety, and tolerability of all study treatments will be reviewed 
by the sponsor and the investigator. 
 
8.11.6 
Reporting of Adverse Events Associated with Study Drug Overdose, Misuse, 
Abuse or Medication Error 
AEs associated with study drug overdose, misuse, abuse, and medication error refer to AEs 
associated with uses of the study drug outside of that specified by the protocol. Overdose, 
misuse, abuse, and medication error are defined as follows: 
 
Overdose: Accidental or intentional use of the study drug in an amount higher than the 
protocol-defined dose 
 
Misuse: Intentional and inappropriate use of study drug not in accordance with the protocol 
 
Abuse: Sporadic or persistent intentional excessive use of study drug accompanied by harmful 
physical or psychological effects 


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Medication error: Any unintentional event that causes or leads to inappropriate study drug use 
or subject harm while the study drug is in the control of site personnel or the subject. 
 
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event eCRF and also reported using the procedures detailed in Reporting of 
SAEs even if the AEs do not meet serious criteria. Abuse is always to be captured as an AE. If 
the AE associated with an overdose, misuse, abuse, or medication error does not meet serious 
criteria, it must still be reported using the SAE form and in an expedited manner but should be 
noted as non-serious on the SAE form and the Adverse Event eCRF. 
 
8.12 Concomitant Medications and Concomitant Therapies 
Any medication (including OTC medications) taken by a subject within 30 days prior to the 
Screening Visit and during the course of the study and the reason for use of the medication 
will be recorded on the eCRF. Upon entering the study, each subject will be instructed to 
report the use of any medication (including OTC medications) to the investigator. 
 
 
8.13 Prohibited Medications 
The following medications are prohibited with the appropriate washout period, if any, for 
each prohibited medication: 
 
• Retroviral/antiretroviral medications, except for remdesivir 
• Any experimental drug/clinical trial, except for remdesivir and convalescent plasma 
• colchicine 
8.14 Pharmacokinetic Sampling and Handling 
The limited sampling schedule is used due to limitations on study personnel entering the 
patient’s room during the day. 
 
The blood sample should be collected in a 6 mL K2EDTA blood collection tube at each 
collection time. 
 
Immediately after collection, the tube will be gently inverted several times to mix the 
anticoagulant with the blood sample. The blood sample should be kept at room temperature 
until processed. The blood samples should be processed within 60 minutes after collection. 
The plasma fraction will be separated by placing the collection tube into a centrifuge for 10 
minutes at 1,500 x g (at room temperature). The plasma fraction will be withdrawn by pipette 
and divided into two polypropylene freezing tubes (with each tube receiving approximately 
equal aliquots). All plasma samples will be placed into a freezer at -20oC (or below) within 90 
minutes after collection. (NOTE: A flash freezing in dry ice or liquid nitrogen is NOT 
required under this protocol but may be used.) 


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8.15 Plasma Sample Labels for Pharmacokinetic Samples 
The plasma freezing tube labels will contain the following information: 
 
• Subject Number 
• Study Number 
• Site Number 
• Prior Dosing time (hour and minute) 
• Sample time (hour and minute) 
• Aliquot Number: Aliquot A or B 
• Species and Matrix: Human Plasma 
• Sample Sequence Number 
• Barcode Number 
Labels will be fixed to freezing tubes in a manner that will prevent the label from becoming 
detached after freezing. 
 
All plasma samples will be stored frozen (-20°C or below). Details of the method validation 
and sample analysis will be included with the final report. 
 
9.0 
STATISTICAL ANALYSIS 
 
9.1 
Sample Size Calculation 
In the Phase 2, the VERU-111 treated group showed a 5.3% mortality rate compared to a 30% 
mortality rate in the Placebo group in the same patient population. 
 
Approximately, 210 subjects are planned to be randomized at a 2:1 ratio into two treatment 
arms (140 subjects in the VERU-111 treated group and 70 subjects in the Placebo treated 
group). Randomization will be stratified by baseline WHO Ordinal Scale score of 4, 5 and 6 
such that subjects with a WHO Ordinal Scale of 4, 5 and 6 at baseline will be approximately 
equally distributed between the treatment groups. Assuming a rate of mortality of 5% in the 
VERU-111 treated group and 25% in the Placebo treated group, the above sample sizes will 
yield 95% confidence interval of [--0.308, -0.092] for the risk difference between treatment 
groups. Other scenarios are shown in the table below. 
 
Confidence interval = (p1 – p2) +/- z*√(p1(1-p1)/n1 + p2(1-p2)/n2) 
where: 
• 
p1, p2: sample 1 proportion, sample 2 proportion 
• 
z: the z-critical value based on the confidence level 
• 
n1, n2: sample 1 size, sample 2 size 


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Table of Alternative 95% Confidence intervals for the difference between Treatment Groups: 
Mortality at Day 60 
 
VERU-111 
Placebo 
Difference 
LOWER 95% CI 
UPPER 95% CI 
0.05 
0.15 
-0.1 
-0.191107629 
-0.008892371 
0.05 
0.2 
-0.15 
-0.250420118 
-0.049579882 
0.05 
0.25 
-0.2 
-0.307672652 
-0.092327348 
0.05 
0.3 
-0.25 
-0.363261644 
-0.136738356 
0.1 
0.15 
-0.05 
-0.147297482 
0.047297482 
0.1 
0.2 
-0.1 
-0.206067903 
0.006067903 
0.1 
0.25 
-0.15 
-0.262958399 
-0.037041601 
0.1 
0.3 
-0.2 
-0.318297929 
-0.081702071 
0.15 
0.15 
0 
-0.102449012 
0.102449012 
0.15 
0.2 
-0.05 
-0.160812454 
0.060812454 
0.15 
0.25 
-0.1 
-0.21742487 
0.01742487 
0.15 
0.3 
-0.15 
-0.27256998 
-0.02743002 
 
With significance level α=0.05, and a 2:1 ratio of enrollment into the VERU-111 and Placebo 
arms respectively, the sample size is adequate to achieve >92% power assuming the treatment 
estimates stated above. 
 
NOTE: The IDMC will monitor efficacy and safety and may make a recommendation to stop 
the study based on treatment success according to the statistical analysis plan and IDMC 
charter for this study. 
 
9.2 
Analysis Sets 
Intent-to-Treat (ITT) population: All randomized subjects will be included in this 
population. 
 
Modified Intent-to-Treat (mITT) analysis set: All randomized subjects who do not have 
any major protocol violations will be included in the mITT population. 
 
Safety (SAF) analysis set: All randomized subjects who received at least one dose of study 
medication (VERU-111 or Placebo) will be included in this population The SAF population 
will be used as the safety population. 
 
9.3 
Analysis Scope 
The Intent-to-Treat (ITT) analysis scope will include all data collected from randomization to 
the end of the study at Day 60. This will be considered the primary analysis scope for the 
primary analysis. 


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9.4 
Efficacy Analyses 
A statistical analysis plan will be written for this Phase 3 clinical study. A detailed description 
of the analyses that will be conducted will be included in that document. 
 
9.4.1 Primary Endpoint 
The primary endpoint for the study will be the proportion of subjects that die on study (up to 
Day 60). 
 
The number and percentage of deaths will be summarized by treatment group. Mortality rates 
will be analyzed using a logistic regression model. This model will include treatment as a 
factor and study site, gender, remdesivir use (No/Yes), dexamethasone use (No/Yes) and 
WHO Ordinal Scale for Clinical Improvement at baseline as a covariates. The model will be 
fitted using logit link function. Odds ratios, standard errors, 95% confidence intervals and p- 
values for the treatment difference will be presented. 
 
The primary analysis will be performed on the ITT analysis set and the ITT data scope 
regardless of patient’s use of rescue medications, protocol violations or investigational 
product discontinuation consistent with the treatment policy strategy. Every effort will be 
made to collect vital status up to the end of the study period. Missing data for subjects who 
are lost to follow up will be imputed using multiple imputation methods. Details for the 
imputation will be given in the Statistical Analysis Plan (SAP). 
 
9.4.2 Secondary Analyses of the Primary Endpoint 
The primary endpoint, mortality rate, will also be assessed in the subset of mITT patients. 
 
To obtain risk differences between treatment groups, the same analysis as described above 
will be fitted except identity link function will be used. 
 
Additionally, mortality rates will be summarized using Kaplan-Meier (KM) survival curves 
and equality of treatment groups will be tested using log-rank test. Hazard ratios will be 
calculated using the Cox proportional hazards model including terms for treatment, study site, 
gender, remdesivir use (No/Yes), dexamethasone use (No/Yes) and WHO Ordinal Scale for 
Clinical Improvement at baseline. Any subjects that are lost to follow-up or terminated early 
prior to death will be censored at the day of their last observed assessment or last captured 
event. 
 
9.4.2.1 Sensitivity Analyses 
A sensitivity analysis using the tipping-point approach will be conducted to assess the 
robustness of the primary analysis approach. 
 
Missing endpoints will be re-assigned in a series of analyses that are progressively more in 
favor of placebo. 


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The tipping point analysis will consider the full range of possible response rates in the 
subjects with missing data in the primary analysis. This will be done by systematically 
changing assumed response rates from 0% to 100% in a stepwise manner. The imputation will 
be performed independently within the two treatment groups so that, in the most extreme 
case, the imputed response rate in the VERU-111 arm will be 0% and 100% in the placebo 
arm. 
 
Multiple imputation will be used for each pair of response rates under consideration. Both the 
imputation model and the analysis model will incorporate the covariates as used in the 
primary analysis. 
 
Details for the imputation will be given in the SAP. 
 
9.5 
Secondary Endpoint 
Primary analysis of secondary endpoints will be performed on the ITT analysis set and the 
ITT data scope regardless of patient’s use of rescue medications, protocol violations or 
investigational product discontinuation consistent with the treatment policy strategy. 
 
Full details for the handling of missing data, and consideration of subjects that die during the 
study for those endpoints that do not directly incorporate death, will be included in the 
Statistical Analysis Plan. 
 
9.5.1 Proportion of patients alive and free of respiratory failure at Day 29, Day 15 and 
Day 22 
Respiratory failure is defined as endotracheal intubation and mechanical ventilation, 
extracorporeal membrane oxygenation, high-flow nasal cannula oxygen delivery, noninvasive 
positive pressure ventilation, clinical diagnosis of respiratory failure with initiation of none of 
these measures only when clinical decision making is driven solely by resource limitation. 
 
This analysis will compare the percentage of subjects that are alive without respiratory failure 
(responder) on Day 29 and on Day 15 and on Day 22. 
 
Proportion of subjects alive and free of respiratory failure will be analyzed separately at each 
timepoint using the same logistic regression methodology as primary endpoint (section 9.4.1). 
 
9.5.1.1 Days in ICU 
Days in ICU will be summarized using descriptive statistics (n, mean, standard deviation, 
median, minimum, and maximum) by treatment group. 
 
For subject who die, days in ICU will be set to the worst possible outcome (29 days) to give 
deaths unfavorable value in the analysis. 
 
Treatment comparison will be based on analysis of covariance (ANCOVA) model including 
treatment as a factor and study site, gender, remdesivir use (No/Yes), dexamethasone use 


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(No/Yes) and WHO Ordinal Scale for Clinical Improvement at baseline as covariates. 
Treatment difference, standard error, 95% confidence interval and p-value will be presented. 
 
9.5.1.2 Change from baseline in WHO Ordinal Scale for Clinical Improvement at Day 
15, Day 22 and Day 29 
Baseline for WHO Ordinal Scale for Clinical Improvement will be the last available record 
prior to first dose of study medication. 
 
For subject who die, WHO Ordinal Scale for Clinical Improvement will be set to the worst 
possible outcome (8 – death) for the following planned timepoints to give deaths unfavorable 
value in the analysis. For subjects who are discharged early, or are otherwise having missing 
values, following timepoints use data from multiple imputation. Details for the imputation 
will be given in the SAP. 
 
WHO Ordinal Scale for Clinical Improvement will be summarized using frequencies and 
percentages by treatment group and timepoint. Also change from baseline will be 
summarized. 
 
Change from baseline will be analyzed as ordinal response using proportional odds logistic 
regression. Analysis will be performed separately for each timepoint (Day 15, Day 22, Day 
29). Proportionality of odds will be tested and if the proportionality assumption does not hold, 
then non-proportional odds model will be fitted. Model will include treatment as fixed effect 
and study site, gender, remdesivir use (No/Yes), dexamethasone use (No/Yes) and WHO 
Ordinal Scale for Clinical Improvement at baseline as covariate. Odds ratio, 95% confidence 
interval and p-value for the treatment difference will be presented. Distribution of change 
from baseline will be plotted in stacked bar plot by treatment group and time point. 
 
Proportional (or non-proportional) odds model will be performed only using the imputed data 
to include all subjects in the analysis. 
 
Additionally, descriptive statistics (n, mean, standard deviation, median, minimum and 
maximum) will be summarized for absolute values and change from baseline by treatment 
group and visit. 
 
Additionally, change from baseline will be analyzed using mixed model for repeated 
measures (MMRM) including treatment, visit and treatment-by-visit interaction as fixed 
effects and study site, gender, remdesivir use (No/Yes), dexamethasone use (No/Yes) and 
WHO Ordinal Scale for Clinical Improvement at baseline as covariate. The resulting F-tests 
will be based on Kenward-Roger’s adjusted degrees of freedom. Least squares means, 
standard errors, 95% confidence intervals and p-values for treatments and treatment 
differences at each visit will be presented. 
 
MMRM analysis will be performed only using the imputed data to include all subjects in the 
analysis. 


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9.5.1.3 Days on mechanical ventilation 
Days on mechanical ventilation will be summarized using descriptive statistics (n, mean, 
standard deviation, median, minimum and maximum) by treatment group. 
 
For subject who die, days on mechanical ventilation will be set to the worst possible outcome 
(29 days) to give deaths unfavorable value in the analysis. 
 
Days on mechanical ventilation will be analyzed using the same methodology as for Days in 
ICU (section 9.5.1.2). 
 
9.5.1.4 Days in hospital 
Days in hospital will be summarized using descriptive statistics (n, mean, standard deviation, 
median, minimum and maximum) by treatment group. 
 
For subject who die, days in hospital will be set to the worst possible outcome (29 days) to 
give deaths unfavorable value in the analysis. 
 
Days in hospital will be analyzed using the same methodology as for Days in ICU (section 
9.5.1.2). 
 
9.5.1.5 Mean change from baseline in Viral load to Day 9 
The mean change in viral load from baseline to Day 9 will be assessed. 
 
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) will be 
summarized for absolute values, and change from baseline by treatment group. 
 
Change from baseline will be analyzed using the same methodology as for change from 
baseline in WHO score (section 9.5.1.3). 
 
9.6 
Pharmacokinetic Analysis 
The pharmacokinetic samples for assessment of VERU-111 levels will be taken at baseline 
(prior to dosing on Day 1) and then prior to dosing on Days 3 and 9. 
 
An evaluation of baseline levels versus effectiveness of VERU-111 will be conducted. 
 
Pharmacokinetic concentration data will be summarized using descriptive statistics (n, mean, 
standard deviation, median, minimum and maximum). CV%, geometric mean, geometric SD 
and geometric CV% will be presented. 
 
All PK data will be listed. 
 
9.7 
Safety Analysis 
The frequency of adverse events (AEs) will be tabulated by MedDRA term and system organ 
class. The incidence of AEs and the maximum intensity and frequency of AEs will be 


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summarized. A new onset AE is defined as an AE that was not present prior to treatment with 
study medication but appeared following treatment or was present at treatment initiation but 
worsened during treatment. An AE that was present at treatment initiation but resolved and 
then reappeared while the subject was on treatment is a new-onset AE (regardless of the 
intensity of the AE when the treatment was initiated). 
 
All laboratory results, vital sign measurements, and other safety variables will be summarized 
using appropriate descriptive statistics. Changes from baseline will be computed and will be 
summarized using appropriate descriptive statistics. 
 
A summary of the number of subjects developing treatment emergent values of ALT and AST 
≥3x ULN, 5x ULN, and 10x ULN, respectively and a shift table for individual subjects shifts 
from baseline to maximum observed value by category: <3x ULN, ≥3x ULN, ≥5x ULN and 
≥10x ULN will be provided. Additionally, a summary of patients that develop Drug Induced 
Liver Injury by Hy’s Law will be provided. 
 
Safety data will be summarized utilizing the SAF analysis set. 
 
9.7.1 Independent Data Monitoring Committee (IDMC) 
An Independent Data Monitoring Committee (IDMC) will review the unblinded safety data 
from this Phase 3 study, including all SAEs, approximately every 4 weeks. The efficacy data 
will be reviewed at the specified timepoint for the interim efficacy analysis when 
approximately 50% of the subjects have completed Day 60. 
 
The recruitment of this Phase 3 study is expected to be completed within 9 months of first 
patient, first dose. 
 
9.7.2 Interim Analysis 
An efficacy interim analysis of the primary endpoint, all-cause mortality at Day 60, will be 
conducted when approximately 71.4% of the subjects (~150 subjects) have completed Day 
60, died or withdrawn for other reasons. The first 150 patients randomized into the study will 
be included in the planned interim analysis. The interim and final analyses will follow an 
O’Brien-Fleming group sequential design, with a plan of stopping the trial at the interim 
analysis if the results are statistically significant in favor of VERU-111. The criterion for 
efficacy at the interim analysis will be a two-sided 0.0160 p-value (a one-sided p-value 
<=0.0080 in favor of VERU-111). If the criterion is not met, the trial will continue, and the 
final analysis will have a criterion for efficacy of a two-sided p-value <=0.0452 (one-sided 
0.0226 in favor of VERU-111). 
 
In addition, an estimate of the conditional power that the trial will be positive (statistically 
significant difference for final analysis) will be provided to the IDMC at regular intervals. If 
the conditional power is below 0.30 this may suggest termination for futility. However, this 
would not be a binding rule. Factors other than the conditional power will be considered by 
the IDMC when weighing the futility of the study as a whole after carefully evaluating 
various factors, including among others, enrolment rate and safety. 


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The interim analyses will be conducted by an independent statistician and provided to the 
IDMC. The sponsor will not be unblinded to the data and will only be notified of the 
recommendation of the IDMC to stop or continue the trial for futility. The sponsor will make 
such a decision after carefully evaluating various factors, including among others, enrolment 
rate and safety. 
 
10.0 
ADMINISTRATION PROCEDURES 
 
10.1 Study Conduct and Compliance 
The study will be conducted in accordance with the Code of Federal Regulations (21 CFR 
parts 50, 54, 56, 312, and 314), which originates from the ethical principles laid down in the 
Declaration of Helsinki. Good Clinical Practices (GCPs) and the policies and procedures of 
the Sponsor and/or its authorized representative will also be followed. This clinical trial will 
be overseen and managed by a contract research organization (CRO) and the Sponsor. The 
CRO will be responsible for data management, data handling, clinical monitoring, statistical 
analysis, quality assurance and the final study report. The Sponsor will be responsible for 
project management of the CRO. 
 
Sponsor Emergency Contact Info: 
 
 
Before initiating a trial, the Investigator/Institution should have written and dated 
approval/favorable opinion from the Independent Ethics Committee (IEC)/IRB for the trial 
protocol/amendment(s), written informed consent form, any consent form updates, subject 
recruitment procedures (e.g., advertisements), any written information to be provided to 
subjects and a statement from the IEC/IRB that they comply with GCP requirements. The 
IEC/IRB approval must identify the protocol version as well as the documents reviewed. 
 
After IEC/IRB approval, changes will require a formal amendment. Once the study has 
started, amendments should be made only in exceptional circumstances. Changes that do not 
affect subject safety or data integrity are classified as administrative changes and generally do 
not require ethical approval. If ethically relevant aspects are concerned, the IEC/IRB must be 
informed and, if necessary, approval sought prior to implementation. Ethical approval on 
administrative changes will be obtained if required by local/site IEC/IRB. 
 
10.2 Informed Consent 
Prior to study entry, the Investigator, or a person designated by the Investigator, will explain 
the nature, purpose, benefits and risks of participation in the study to each subject, subject’s 
LAR or impartial witness. Written informed consent must be obtained prior to the subject 
entering the study (before initiation of any study-related procedure and administration of the 


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investigational medicinal product (IMP). Sufficient time will be allowed to discuss any 
questions raised by the subject. 
 
The Sponsor will provide a sample informed consent form. The final version-controlled form 
must be agreed to by the Sponsor and the IEC/IRB and must contain all elements included in 
the sample form, in language readily understood by the subject. Each subject’s original 
consent form, personally signed and dated by the subject or by the subject’s LAR, and by the 
person who conducted the informed consent discussion, will be retained by the Investigator. 
The Investigator will supply all enrolled subjects with a copy of their signed informed 
consent. 
 
The consent form may need to be revised during the trial should important new information 
become available that may be relevant to the safety of the subject or as a result of protocol 
amendments. In this instance approval should always be given by the IEC/IRB. It is the 
Investigator’s responsibility to ensure that all subjects subsequently entered into the study and 
those currently in the study sign the amended form. This is documented in the same way as 
previously described. Subjects who have completed the study should be informed of any new 
information that may impact on their welfare/wellbeing. 
 
The Investigator should, with the consent of the subject, inform the subject’s primary 
physician about their participation in the clinical trial. 
 
10.3 Protocol Amendments 
In the event that an amendment to this protocol is required, it will be classified into one of the 
following three categories: 
 
• 
Non-Substantial Amendments are those that are not considered ‘substantial’ (e.g., 
administrative changes) and as such only need to be notified to the IECs/IRBs or 
Competent Authorities (CA) for information purposes. 
 
• 
Substantial Amendments are those considered ‘substantial’ to the conduct of the clinical 
trial where they are likely to have a significant impact on: 
 
- the safety or physical or mental integrity of the subjects; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of the IMP used in the trial. 
 
Substantial amendments must be notified to the IECs/IRBs and CA. Prior to 
implementation, documented approval must be received from the IECs/IRBs. In the case 
of the CA in the EU member states, approval or ‘favorable opinion’ can be assumed if the 
CA has raised no grounds for non-acceptance during an allocated time period (to be 
confirmed with the Sponsor’s Regulatory Affairs (RA) representative) following 
acknowledgment of receipt of a valid application to make a substantial amendment. 


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• 
Urgent Amendments are those that require urgent safety measures to protect the trial 
subjects from immediate hazard and as such may be implemented immediately by the 
Sponsor with subsequent IECs/IRBs and CA notification, forthwith. 
 
10.4 Protocol Deviations 
It is the responsibility of the Investigator and Sponsor to ensure compliance with the study 
protocol. When the protocol is not followed, it can put the safety of study subjects at risk as 
well as jeopardize the accuracy and reliability of the study results which could lead to a 
rejection of the data by regulatory authorities. 
 
All identified deviations from the protocol must be documented and reported to the Sponsor 
using the appropriate electronic form to be supplied by the Sponsor. Deviations will be 
categorized into minor deviations or major deviations; definitions and examples of deviations 
will be provided by the Sponsor. The Sponsor will be reviewing all deviations on an ongoing 
basis. 
 
10.5 Data Handling and Recordkeeping 
10.5.1 Data Handling 
Data will be recorded at the site on the eCRF and reviewed by the clinical research associate 
(CRA) during monitoring visits. The CRA will verify data recorded in the EDC system with 
source documents. All corrections or changes made to any study data must be appropriately 
tracked in an audit trail in the EDC system. An eCRF will be considered complete when all 
missing, incorrect, and/or inconsistent data has been accounted for and electronically signed 
by the Investigator or assignee. 
 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
 
10.5.2 Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel 
must log into the system using their secure username and password in order to enter, review, 
or correct study data. These procedures must comply with Title 21 of the Code of Federal 
Regulations (21 CFR Part 11) and other appropriate international regulations. All passwords 
will be strictly confidential. 
 
10.5.3 Medical Information Coding 
For medical information, the following thesauri will be used: 
• Latest version of MedDRA (version 18.1 or higher) for medical history and AEs, and 
• World Health Organization Drug Dictionary Enhanced (Sept. 2015 or later) for prior and 
concomitant medications. 


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10.5.4 Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the data, will be applied to the data in order to ensure accurate, 
consistent, and reliable data. Data identified as erroneous, or data that are missing, will be 
referred to the site for resolution through data queries. 
 
The eCRFs must be reviewed and electronically signed by the Investigator in order to be 
considered complete. 
 
10.5.5 Record Keeping 
Records of subjects, source documents, monitoring visit logs, eCRFs, inventory of study 
drugs, regulatory documents, and other Sponsor correspondence pertaining to the study must 
be kept in the appropriate study files at the site. Source data is defined as all information in 
original records and certified copies of original records of clinical findings, observations, or 
other activities in a clinical study necessary for the evaluation and reconstruction of the 
clinical study. Source data are contained in source documents (original records or certified 
copies). These records will be retained in a secure file for the period as set forth in the Clinical 
Study Agreement. Prior to transfer or destruction of these records, the Sponsor must be 
notified in writing and be given the opportunity to further store such records. 
 
10.6 Data Quality 
Monitored eCRFs transferred from the investigational site to the assigned Data Management 
group will be reviewed (secondary monitoring) for completeness, consistency, legibility and 
protocol compliance. 
 
Reasons should be given on the relevant eCRF for any missing data and other protocol 
deviations. Any electronic queries and items not adequately explained will require additional 
electronic manual queries to be raised to the Investigator by the monitor for 
clarification/correction. The Investigator must ensure that queries are dealt with promptly. All 
data changes and clarifications can be viewed in the audit trail function of the eCRF. 
 
Clinical site personnel must make themselves available for any potential audit by the Sponsor 
or Sponsor representative and regulatory authorities, such as, but not limited to, United States 
Food and Drug Administration. The clinical site personnel must be completely responsive and 
cooperative during these audits. 
 
10.7 Regulatory Approval 
As required by local regulations, the Sponsor’s Regulatory Affairs group will ensure all legal 
regulatory aspects are covered, and obtain approval of the appropriate regulatory bodies, prior 
to study initiation in regions where an approval is required. 


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10.8 Publication Policy 
The Sponsor encourages acknowledgement of all individuals/organizations involved in the 
funding or conduct of the study, including medical writers or statisticians subject to the 
consent of each individual and entity concerned, including acknowledgement of the Sponsor. 
 
The results of this study may be published or communicated to scientific meetings by the 
Investigators involved in the study. For multicenter studies, a plan for scientific publication 
and presentation of the results may be agreed and implemented by the study Investigators or a 
Steering Committee. The Sponsor requires that reasonable opportunity be given to review the 
content and conclusions of any abstract, presentation, or paper before the material is 
submitted for publication or communicated. This condition also applies to any amendments 
that are subsequently requested by referees or journal editors. The Sponsor will undertake to 
comment on the draft documents within the time period agreed in the contractual 
arrangements, including clinical trial agreements, governing the relationship between the 
Sponsor and authors (or the author’s institution). Requested amendments will be incorporated 
by the author, provided they do not alter the scientific value of the material. 
 
If patentability would be adversely affected by publication, this will be delayed until (i) a 
patent application is filed for the content of the publication in accordance with applicable 
provisions of the clinical trial agreement concerned, (ii) the Sponsor consents to the 
publication, or (iii) the time period as may be agreed in the contractual arrangements, 
including clinical trial agreements, governing the relationship between the Sponsor and 
authors (or authors’ institution) after receipt of the proposed publication by the Sponsor, 
whichever of (i), (ii) or (iii) occurs first. 
 
The author undertakes to reasonably consider the Sponsor's request for delay to the proposed 
publication should the Sponsor reasonably deem premature to publish the results obtained at 
the then stage of the study. 
 
10.9 Clinical Study Report 
A final clinical study report will be prepared according to the ICH guideline on structure and 
contents of clinical study reports. A final clinical study report will be prepared where any 
subject has signed informed consent, regardless of whether the trial is completed or 
prematurely terminated. Where appropriate an abbreviated report may be prepared. The CSR 
will be in compliance with any applicable regulatory requirements, national laws in force and 
will be in English. 
 
10.10 Contractual and Financial Details 
The Investigator (and/or, as appropriate, the hospital/institution authorized representative) and 
the Sponsor will sign a clinical study agreement prior to the start of the study, outlining 
overall Sponsor and Investigator responsibilities in relation to the study. Financial 
remuneration will cover the cost per included subject, based on the calculated costs of 
performing the study assessments and other activities in accordance with the protocol, and the 
specified terms of payment will be described in the contract. The contract should describe 


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Protocol V3011902 – FINAL Version 7.0 
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whether costs for pharmacy, laboratory and other protocol-required services are being paid 
directly or indirectly. 
 
10.11 Insurance and Indemnity 
The Sponsor will obtain Product Liability insurance providing coverage relating to the clinical 
study and subjects participating therein. 
 
11.0 
REFERENCES 
 
Biswas K et al. Effect of microtubule disruption on neuronal spread and replication of 
demyelinating and nondemyelinating strains of mouse hepatitis virus in vitro. J Virol 88:3-43- 
3047, 2014. 
 
Burkard C et al. Coronavirus cell entry occurs through the endo-/lysosomal pathway in a 
proteolysis-dependent manner. PLOS Pathogens 10:e1004502, 2014. 
 
Cascella M. et al. Features, evaluation, and treatment coronavirus (COVID-19) StatPearls 
2020 www.ncbi.nlm.nih.gov/books/NBK554776. 
 
Chen J et al. Discovery of novel 2-aryl-4-benzoyl-imidazole (ABI-III) analogues targeting 
tubulin polymerization as antiproliferative agents. J Med Chem 55:7285-7289, 2012. 
 
Cooper GM. The Cell: A Molecular Approach.2nd edition. Sunderland(MA): Sinauer 
Associates 2000. Microtubules. https://www.ncbi.nlm.nih.gov/books/NBK9932. 
 
Criglar JM et al. A novel form of rotavirus NSP2 and phosphorylation-dependent NSP2- 
NPS5 interactions are associated with viroplasm assembly. J Virol 88:786-798, 2014. 
 
Dohner K et al. Viral stop-and-go along microtubules: taking a ride with dynein and kinesins. 
Trends in Microbiology 13:320-327, 2005. 
 
Eichwald C et al. Rotavirus viroplasm fusion and perinuclear localization are dynamic 
processes requiring stabilized microtubules. PLoS One 7:e47947, 2012. 
 
Fung S et al. Human Coronavirus: host-pathogen interaction. Annu Rev Microbiol 73:529-57, 
2019. 
 
Gorbalenya AE et al. The species severe acute respiratory syndrome-related coronavirus: 
classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 2020. 
 
Han X et al. Influenza virus A/Beijing/501/2009 (H1N1) interacts with beta tubulin and 
induces disruption of the microtubule network and apoptosis on A549 cells. PLoS One:7, 
e48340, 2012. 
 
Hara Y et al. Propagation of swine hemagglutinating encelphalomyelitis virus and 
pseudorabies virus in dorsal root ganglia cells. J Vet Med Sci 71:595-601, 2009. 


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Heald R et al. Microtubule dynamics. J Cell Sci 115, 3-4, 2002. 
 
Knoops K et al. Integrity of the early secretory pathway promotes, but is not required for, 
severe acute respiratory syndrome coronavirus RNA synthesis and virus-induced remodeling 
of endoplasmic reticulum membranes. J Virol 84:833-846, 2010. 
 
Li CM et al. Orally bioavailable tubulin antagonists for paclitaxel-refractory cancer. Pharm 
Res 29:3053-3063, 2012. 
 
Lv et al. Porcine hemagglutinating encephalomyelitis virus activation of the integrin a5b1- 
FAK-cofilin pathway causes cytoskeleton rearrangement to promote its invasion of N2a cells. 
J Virol 93:1-19, 2019. 
 
Milewski A et al. Entry of human coronavirus NL63 into the cell. J Virology 92:e01933-17, 
2018. 
 
Naghavi MH et al. Microtubule regulation and function during virus infection. J Virol 
91:e00538-17, 2017. 
 
Oostra M et al. Localization and membrane topology of coronavirus nonstructural protein. 4: 
involvement of the early secretory pathway in replication. J Virol 81:12323-12336, 2007. 
 
Ren et al. Genetic drift of human coronavirus OC43 spike gene during adaptive evolution. 
Scientific Reports 5:11451, 2015. 
 
Rudiger AT et al. Tubulins interact with porcine and human S proteins of the genus 
alphacoronavirus and support successful assembly and release of infectious viral particles. 
Virology 497:185-197, 2016. 
 
Simpson C et al. Microtubules in influenza virus entry and egress. Viruses 12:117, 2020. 
Slobodnick A et al. Update on colchicine, 2017. Rheumatology 57:i4-i11, 2018. 
Suomalainen M et al. Adenovrius-activated PKA and p38/MAPK pathways boost 
microtubule-mediated nuclear targeting of virus. EMBO J 20:1310-1319, 2001. 
 
Verweyen E et al. Synergistic signaling of TLR and IFN alpha/beta facilitates escape of IL-18 
expression from endotoxin tolerance. American J Resp and Critical Care Medicine 201:526- 
539, 2020. 
 
Ward B. The taking of the cytoskeleton one two three: How viruses utilize the cytoskeleton 
during egress. Virology 411:244-250, 2011. 


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12.0 
APPENDICES 
 
12.1 Appendix A: 
Clinical Laboratory Tests (local laboratory) 
 
Hematology: 
Serum Chemistry: 
Hemoglobin 
Sodium 
Hematocrit 
Potassium 
Red Blood Cell Count 
Chloride 
White Blood Cell Count 
Bicarbonatea 
White Blood Cell Differential 
BUN 
Platelet Count 
Creatinine 
Reticulocyte Count 
Calcium 
Cardiac Troponin 
Phosphorus 
Total Protein 
Urinalysis: 
Albumin 
pH 
Total Bilirubin 
Specific Gravity 
SGOT (ALT) 
Protein 
SGPT (AST) 
Glucose 
Alkaline phosphatase 
Leucocytes 
LDH 
Nitrates 
GGT 
Ketones 
Glucose 
Blood 
Ferritin 
Microscopic Examination (only if urinalysis results are 
abnormal) 
D-dimer 
a Bicarbonate will be collected only if it is part of the standard local panel. 


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Veru Inc 
C
Protocol V3011902 – FINAL Version 7.0 
 
12.2 Appendix B: Schedule of Study Evaluations 
 
Day 
Screena 
Day 1 
Days 2-21 Days 3, 9, & 15 Days 22d and 29 
Days 45 and 60 
Informed Consent and 
HIPAA 
X 
Medical History 
X 
X 
Assessment of Eligibility 
X 
X 
Physical Exam 
X 
X 
Xf 
X 
Pregnancy test 
X 
X 
Xf 
X 
Vital signs 
X 
X 
X 
X 
12-lead ECG (single) 
X 
Xf 
X 
WHO Ordinal Scale score 
X 
X 
Xf 
X 
X 
Chest X-ray or CT 
X 
X 
Clinical Laboratory Tests 
Hematology 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
Serum Chemistry 
X 
X 
X 
X 
SpO2 
X 
X 
X 
X 
Dosingb,c 
X 
X 
Pharmacokinetic assessment 
X 
Xe 
Assessment of conmeds 
X 
X 
X 
X 
Assessment of AEs 
X 
X 
X 
X 
Viral load 
X 
Xg 
a Screening evaluations are to be conducted within 3 days prior to Day 1. 
b Subjects will be treated for 21 days OR until discharged from hospital, whichever comes first 
c Subjects can be discontinued from treatment if they are not responding to therapy, however patients should continue to be followed on study and have the study assessments as outlined herein. 
d Early termination assessments are the same as Day 22 assessments 
e Days 3 and 9 only 
f Day 15 only 
g Day 9 only (or day of discharge if prior to Day 9) 


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PROTOCOL SIGNATURE PAGE 
 
Protocol Number: 
V3011902 
 
Protocol Date: 
Protocol Amendment 6 (Version 7.0)/ 18 March 2022 
 
Protocol Title: 
Phase 3, Randomized, Placebo-Controlled, Efficacy and Safety 
Study of VERU-111 for the Treatment of Severe Acute Respiratory 
Syndrome Coronavirus 2 (SARS-CoV-2) in Patients at High Risk 
for Acute Respiratory Distress Syndrome (ARDS) 
 
 
 
 
SIGNATURE: 
 
3/18/2022 
 
Sponsor 
Date 
 
 
 
Chief Scientific Officer 
 
 
Name and Title of Sponsor Representative 
 
 
 
 
 
This signature of the Sponsor Representative constitutes approval of this protocol. 


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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
Protocol Number: 
V3011902 
 
Protocol Title: 
Phase 3, Randomized, Placebo-Controlled, Efficacy and Safety 
Study of VERU-111 for the Treatment of Severe Acute Respiratory 
Syndrome Coronavirus 2 (SARS-CoV-2) in Patients at High Risk 
for Acute Respiratory Distress Syndrome (ARDS) 
 
Protocol Date: 
Protocol Amendment 6 (Version 7.0)/ 18 March 2022 
 
 
 
 
SIGNATURE: 
 
 
 
 
 
Principal Investigator: 
Date 
 
 
 
Name of Principal Investigator (Please Print) 
 
 
 
 
 
Address of Principal Investigator 
 
 
 
The signature of the Principal Investigator constitutes approval of this protocol and an 
assurance that this study will be conducted according to all requirements of this protocol 
and according to Good Clinical Practices (GCP). 

SAP_001.pdf: 
Controlled Quality Management Document 
Sponsor: 
Veru Inc. 
Protocol Number: 
V3011902 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
 
 
 
 
Page 1 of 49 
 
 
 
Statistical Analysis Plan 
Title: Phase 3, Randomized, Placebo-Controlled, Efficacy and Safety Study of 
VERU-111 for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 
2 (SARS-CoV-2) in Patients at High Risk for Acute Respiratory Distress 
Syndrome (ARDS) 
Protocol Number: V3011902 
Protocol Version: 1.0 (08-MAR-2021), 2.0 (27-APR-2021), 3.0 (12-MAY-2021), 
4.0 (03-AUG-2021), 5.0 (10-SEP-2021), 6.0 (09-JAN-2022), 7.0 (18-MAR-2022) 
 
SAP Version 5.0 
SAP Issue Date: 30-JUN-2022 
SAP Author: 
 
 
Previous SAP Versions 
Version 1.0 (11-FEB-2022), Version 2.0 (16-MAR-2022), Version 3.0 (18-MAR-
2022), Version 4.0 (07-APR-2022) 
 
 


Controlled Quality Management Document 
Sponsor: 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
 
 
 
 
Page 2 of 49 
 
SAP Amendments before database lock 
Version  Issue Date 
Section 
Revision / Addition 
Rationale 
1.0 
11-FEB-2022 
 
 
First Version 
2.0 
16-MAR-2022 
1 and 5 
 
 
 
6.11.1, 
6.11.3, 
6.11.5.2 
 
6.11.1 
 
 
 
 
 
 
 
6.14.1 
 
6.14.1, 
11.1 
Reworded ‘screening’ to 
‘baseline’ in 
randomization strata. 
 
Allow model to include 
country as covariate 
instead of study site. 
 
Updated SAS code for 
imputation model. Added 
clarifications for study site 
variable. Added 
clarifications for 
DISCHARGE and 
DISCONT variables. 
 
Updated TEAE definition. 
 
Added tables for TEAEs 
leading to treatment 
modification, TEAEs 
leading to treatment 
discontinuation and Fatal 
TEAEs. 
Consistency with the 
protocol. 
 
 
To allow model 
modification i.e. if model 
does not converge. 
 
FDA request. 
 
 
 
 
 
 
 
FDA request. 
 
FDA request. 
3.0 
18-MAR-2022 
1 
 
 
 
4 
Added new version of the 
protocol. 
 
 
Updated for new sample 
size. 
Protocol update. Sample 
size changed from 300 to 
210. 
 
Protocol update. 
4.0 
07-APR-2022 
6.11.1, 
6.11.3, 
6.11.5.2 
In the statistical models 
allowing also region as 
covariate 
Some countries h
 only 
very few subjects so 


Controlled Quality Management Document 
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Veru Inc. 
Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
 
 
 
 
Page 3 of 49 
 
 
 
 
6.11.3, 
6.11.5.2, 
11.1 
 
 
 
Added subgroup analyses 
for primary endpoint 
model fitting might have 
issues. 
 
FDA request 
5.0 
30-JUN-2022 
6.2.1 
 
 
 
6.2.2 
 
 
 
 
 
6.2.4 
 
 
6.2.10 
 
 
 
 
6.11 
 
 
6.12 
 
 
 
6.14.2 
 
 
 
 
 
Updated baseline 
definition to match 
protocol. 
 
Allow study day 
derivation to use 
randomization date for 
those subjects who were 
not treated. 
 
Added imputation for 
COVID-19 vaccines. 
 
Updated handling of 
discharge, early 
termination and 
unscheduled visits. 
 
Small clarifications in the 
text. 
 
Added formulas for 
geometric mean, SD and 
CV. 
 
Added normalization of 
lab values to make results 
from different labs 
comparable. 
 
Clarifications during 
output production. 
 
 
Clarifications during 
output production. 
 
 
 
 
Clarifications during 
output production. 
 
Clarifications during 
output production. 
 
 
 
Clarifications during 
output production. 
 
Clarifications during 
output production. 
 
 
Clarifications during 
output production. 
 
 
 


Controlled Quality Management Document 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
 
 
 
 
Page 4 of 49 
 
6.14.6 
 
 
11 
Added section for chest x-
ray. 
 
Updated TFLs as needed. 
Clarifications during 
output production. 
 
Clarifications during 
output production. 
 
 
 


Controlled Quality Management Document 
Sponsor: 
Veru Inc. 
Protocol Number: 
V3011902 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
 
 
 
 
Page 5 of 49 
 
Table of Contents 
LIST OF ABBREVIATIONS .................................................................................... 8 
1 
INTRODUCTION ............................................................................................... 9 
2 
STUDY OBJECTIVES ....................................................................................... 9 
2.1 
Primary Objective ........................................................................................................... 9 
2.2 
Secondary Objectives...................................................................................................... 9 
2.3 
Safety Objective ............................................................................................................ 11 
3 
ENDPOINTS .....................................................................................................11 
3.1 
Primary Endpoint .......................................................................................................... 11 
3.2 
Secondary Endpoints .................................................................................................... 11 
4 
SAMPLE SIZE ..................................................................................................11 
5 
RANDOMIZATION .........................................................................................11 
6 
PLANNED ANALYSES ...................................................................................12 
6.1 
Analysis Sets ................................................................................................................. 12 
6.1.1 
Enrolled Set ............................................................................................................. 12 
6.1.2 
Intent-to-Treat (ITT) Analysis Set .......................................................................... 12 
6.1.3 
Modified Intent-to-Treat (mITT) Analysis Set ....................................................... 12 
6.1.4 
Safety (SAF) Analysis Set ...................................................................................... 13 
6.2 
Derived Data ................................................................................................................. 13 
6.2.1 
Baseline ................................................................................................................... 13 
6.2.2 
Duration / Study Day / Time ................................................................................... 13 
6.2.3 
Conventions for Missing and Partial Dates ............................................................ 13 
6.2.4 
Missing / Partial Start / Stop Date of Concomitant Medications ............................ 13 
6.2.5 
Missing Last Dates of Study Drug Dosing ............................................................. 15 
6.2.6 
Missing Diagnosis Dates......................................................................................... 15 
6.2.7 
Exposure to Study Drug .......................................................................................... 15 
6.2.8 
Inexact Values ......................................................................................................... 15 
6.2.9 
Area under curve (AUC) of WHO Ordinal Scale for Clinical Improvement ......... 15 
6.2.10 
Discharge, Early Termination and Unscheduled Visits .......................................... 16 
6.3 
Conventions .................................................................................................................. 16 
6.3.1 
Decimal Places ........................................................................................................ 16 


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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
 
 
 
 
Page 6 of 49 
 
6.4 
Subject Disposition ....................................................................................................... 17 
6.5 
Protocol Deviations ....................................................................................................... 17 
6.6 
Baseline Comparability ................................................................................................. 17 
6.7 
Medical History ............................................................................................................ 18 
6.8 
Prior and Concomitant Medications ............................................................................. 19 
6.9 
Exposure to Study Drug ................................................................................................ 19 
6.10 
Treatment Compliance .................................................................................................. 19 
6.11 
Efficacy Analyses ......................................................................................................... 20 
6.11.1 
Primary Efficacy Analysis ...................................................................................... 20 
6.11.2 
Sensitivity Analysis for the Primary Endpoint ....................................................... 22 
6.11.3 
Secondary Analyses for the Primary Endpoint ....................................................... 24 
6.11.4 
Exploratory Analysis for the Primary Endpoint ..................................................... 25 
6.11.5 
Secondary Efficacy Analyses ................................................................................. 25 
6.11.6 
Exploratory Efficacy Analyses ............................................................................... 28 
6.11.7 
Multiplicity ............................................................................................................. 28 
6.12 
Pharmacokinetic Analyses ............................................................................................ 29 
6.13 
Pharmacodynamic Analyses ......................................................................................... 29 
6.14 
Safety Analyses ............................................................................................................. 30 
6.14.1 
Adverse Events ....................................................................................................... 30 
6.14.2 
Laboratory Data ...................................................................................................... 31 
6.14.3 
Vital Signs ............................................................................................................... 32 
6.14.4 
Physical Examination.............................................................................................. 33 
6.14.5 
Electrocardiogram Data .......................................................................................... 33 
6.14.6 
Chest X-Ray ............................................................................................................ 34 
7 
INTERIM ANALYSIS ......................................................................................34 
8 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) ANALYSIS
 
34 
9 
CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................34 
10 REFERENCES ..................................................................................................36 
11 LIST OF TABLES, FIGURES AND LISTINGS .............................................37 
11.1 
Tables ............................................................................................................................ 37 


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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
 
 
 
 
Page 7 of 49 
 
11.2 
Figures........................................................................................................................... 47 
11.4 
Listings .......................................................................................................................... 48 
 


Controlled Quality Management Document 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ARDS 
Acute Respiratory Distress Syndrome 
AUC 
Area Under Curve 
ATC 
Anatomic Therapeutic Chemical 
COVID-19 
SARS-CoV-2 infection 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
electronic Case Report Form 
ICU 
Intensive Care Unit 
IDMC 
Independent Data Monitoring Committee 
ITT 
Intent-to-Treat (Analysis Set) 
LLOQ 
Lower Limit of Quantification 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary of Regulated Activities 
mITT 
Modified Intent-to-Treat (Analysis Set) 
MMRM 
Mixed Model for Repeated Measures 
NCS 
Not Clinically Significant 
RRT 
Renal Replacement Therapy 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
TEAE 
Treatment-Emergent Adverse Event 
WHO 
World Health Organization 
 
 
 


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1 INTRODUCTION 
This document details the planned statistical analyses for Veru Inc., protocol “V3011902” study 
titled “Phase 3, Randomized, Placebo-Controlled, Efficacy and Safety Study of VERU-111 for the 
Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Patients at 
High Risk for Acute Respiratory Distress Syndrome (ARDS)”. 
The proposed analyses are based on the contents of the final version of the protocol (dated 08-
MAR-2021), and amendments 1 (dated 27-APR-2021), 2 (12-MAY-2021), 3 (03-AUG-2021), 4 
(10-SEP-2021), 5 (09-JAN-2022), 6 (18-MAR-2022). 
This randomized, placebo-control clinical study consists of two treatment arms: VERU-111 9 mg 
treated group, and Placebo treated group. Subjects will be randomized in a 2:1 fashion to the 
VERU-111 treated group and Placebo treated group, respectively. 
All patients will receive standard of care for the treatment of SARS-CoV-2 infection (COVID-19). 
Randomization will be stratified by baseline WHO Ordinal Scale score of 4, 5 and 6 such that 
subjects with a WHO Ordinal Scale of 4, 5 and 6 at baseline are approximately equally distributed 
between the treatment groups. 
The study will require that each subject in the study receive 9 mg daily oral dose of VERU-111 or 
placebo for up to 21 days (Day 21) or until the patient is discharged from the hospital with efficacy 
and safety follow up continuing to Day 60 of the study. The total duration of the study for a subject 
in the study from screening to follow-up visit (approximately Day 60 on study) will be 
approximately 62 days. 
2 STUDY OBJECTIVES 
2.1 Primary Objective 
To demonstrate the efficacy of VERU-111 in the treatment of SARS-CoV-2 infection by 
assessing its effect on the proportion of subjects that die on study (up to Day 60). 
2.2 Secondary Objectives 
The secondary objectives/endpoints on this study are: 


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1. The proportion of subjects that are alive without respiratory failure at Day 15, Day 22, 
and Day 29. Day 29 is the key secondary endpoint. Respiratory failure is defined as 
endotracheal intubation and mechanical ventilation, extracorporeal membrane 
oxygenation, high-flow nasal cannula oxygen delivery, noninvasive positive pressure 
ventilation, clinical diagnosis of respiratory failure with initiation of none of these 
measures only when clinical decision making is driven solely by resource limitation 
2. Days in Intensive Care Unit (ICU) 
3. WHO Ordinal Scale for Clinical Improvement change from baseline to Day 15, Day 22, 
and Day 29. 
Patient State 
Descriptor 
Score 
Uninfected 
No clinical or virological evidence 
of infection 
0 
Ambulatory 
No limitation of activities 
1 
 
Limitation of activities 
2 
Hospitalized, Mild disease 
Hospitalized, no oxygen therapy 
3 
 
Oxygen by mask or nasal prongs 
4 
Hospitalized, Severe 
disease 
Non-invasive ventilation or high-
flow oxygen 
5 
 
Intubation and mechanical 
ventilation 
6 
 
Ventilation + additional organ 
support – pressors, Renal 
Replacement Therapy (RRT), 
Extracorporeal Membrane 
Oxygenation (ECMO) 
7 
Death 
Death 
8 
 
4. Days on mechanical ventilation 
5. Days in hospital 


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6. Proportion of subjects that die on study at Day 15, Day 22, and Day 29. 
7. Change from baseline in viral load (baseline to Day 9). 
2.3 Safety Objective 
To assess the safety, tolerability, and risk/benefit of VERU-111. 
3 ENDPOINTS 
3.1 Primary Endpoint 
The primary endpoint for the study is the proportion of subjects that die on study (up to Day 60). 
3.2 Secondary Endpoints 
The secondary endpoints on this study are: 
1. The proportion of subjects that are alive without respiratory failure at Day 15, Day 22, 
and Day 29. Day 29 is the key secondary endpoint. Respiratory failure is defined as 
endotracheal intubation and mechanical ventilation, extracorporeal membrane 
oxygenation, high-flow nasal cannula oxygen delivery, noninvasive positive pressure 
ventilation, clinical diagnosis of respiratory failure with initiation of none of these 
measures only when clinical decision making is driven solely by resource limitation. 
2. Days in ICU 
3. WHO Ordinal Scale for Clinical Improvement change from baseline to Day 15, Day 22, 
and Day 29 
4. Days on mechanical ventilation 
5. Days in hospital 
6. Proportion of subjects that die on study at Day 15, Day 22, and Day 29. 
7. Change from baseline in viral load (baseline to Day 9) 
4 SAMPLE SIZE 
Approximately 210 subjects are planned to be randomized at a 2:1 ratio into two treatment arms 
(approximately 140 subjects in the VERU-111 treated group and approximately 70 subjects in 
the Placebo treated group). 
5 RANDOMIZATION 


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Randomization will be stratified by baseline WHO Ordinal Scale score of 4, 5 and 6 such that 
subjects with a WHO Ordinal Scale of 4, 5 and 6 at baseline are approximately equally distributed 
between the treatment groups. 
6 PLANNED ANALYSES 
No statistical analysis plan (SAP) prepared in advance of the data can be absolutely definitive and 
the final Clinical Study Report (CSR) may contain additional tables or statistical tests if warranted 
by the data obtained. The justification for any such additional analyses will be fully documented 
in the final CSR. 
6.1 Analysis Sets 
Subjects excluded from the analysis sets and the reason for their exclusion will be summarized and 
listed. 
6.1.1 Enrolled Set 
All subjects who gave informed consent. 
6.1.2 Intent-to-Treat (ITT) Analysis Set 
All randomized subjects will be included in this analysis set. 
6.1.3 Modified Intent-to-Treat (mITT) Analysis Set 
All randomized subjects who completed the efficacy portion of the trial and who do not have any 
major protocol violations will be included in the mITT Analysis Set. Subjects who were 
randomized but did not receive study medication will be excluded from the mITT Analysis Set. 
All protocol deviations will be assessed and documented on a case-by-case basis before the 
database lock, and deviations considered to have a serious impact on the efficacy results will lead 
to the relevant subject being excluded from the mITT. Exclusion of subjects who were 
randomized using incorrect WHO scores will be evaluated. Also, exclusion of subjects who were 
randomized under original protocol (WHO strata 5 and 6) will be evaluated. 
Before database lock, potential subject exclusions from mITT will be reviewed by the Sponsor 
and documented in a subject evaluability document. 


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6.1.4 Safety (SAF) Analysis Set 
All randomized subjects who received at least one dose of study medication (VERU-111 or 
Placebo) will be included in this analysis set. 
6.2 Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
6.2.1 Baseline 
The Day 1 visit assessment will serve as the baseline assessments. 
6.2.2 Duration / Study Day / Time 
Study day will be calculated as the number of days from first dose of study drug. 
 date of event – date of first dose of study drug + 1, for events on or after first dose  
 date of event – date of first dose of study drug, for events before first dose. 
If subject does not get study drug then ‘Day 1’ visit date (or randomization date) can be used 
instead of the date of first dose of study drug. 
6.2.3 Conventions for Missing and Partial Dates 
All rules explained below for partial / missing dates will be followed unless contradicted by any 
other data recorded on the electronic Case Report Form (eCRF). 
All dates presented in the individual subject listings will be as recorded on the eCRF (i.e., not 
completed as per the below rules). 
6.2.4 Missing / Partial Start / Stop Date of Concomitant Medications 
For COVID-19 vaccines missing/partial dates will be imputed as follows: 
 Completely missing dates will be imputed using 01JAN2021 
 If month and day are missing then imputed using 01JAN of the year 
 If only day is missing then imputed using the first of the month. 


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If reported COVID-19 vaccine was a single shot then missing end date will be set to equal to start 
date. 
For other concomitant medications missing and partial start and stop date will be imputed for 
analysis purposes as follows. 
Partial or missing stop date will be imputed as follows: 
If the stop date is completely missing and the event has resolved, or the subject has stopped taking 
the concomitant medication, the stop date will be imputed as the date of the subject’s last clinic 
visit in the study. 
 If only the year is known, the stop date will be imputed as “31-Dec” of that year or as the 
date of the subject’s last clinic visit in the study if in the same year. 
 If the month and year are known, the stop date will be imputed as the last day of that month 
unless the stop date corresponds to the same month as the subject’s last clinic visit in which 
case the date of subject’s last clinic visit in the study will be used instead. 
Missing start date will be imputed as follows: 
 If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the date of the first dose of study 
drug.  
 If the stop date occurs before the start of study drug, the start date of the event / concomitant 
medication will be imputed as the subject’s screening date or the stop date of the event / 
concomitant medication whichever the earlier. 
Partial start date (year present, but month and day missing) 
 If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, and the year is the same as the year of first dosing the start date will 
be imputed as “01-Jan” of the same year or the date of the first dose of study drug 
whichever is latest. If the year is different from the year of first dosing “01-Jan” will be 
used. 
 If the stop date occurs before the start of study drug, the start date of the event / concomitant 
medication will be imputed as the “01-Jan” of the same year. 
Partial start date (month and year present, but day missing) 
 If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the first day of the same month and 


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year unless this partial start date is in same month as the first dose of study drug in which 
case the date of first dose of study drug will be used.  
 If the stop date occurs before the start of study drug, the start date will be imputed as the 
first day of the month and year of the partial stop date. 
If the start time is missing it will be imputed only in the case where the start date of the concomitant 
medication / event corresponds to the date of the first dose of study drug. The time will be imputed 
as the same time as the first dose of study drug. In all other cases the time will not be imputed. 
6.2.5 Missing Last Dates of Study Drug Dosing 
Missing dates for study drug dosing will not be imputed. 
6.2.6 Missing Diagnosis Dates 
If the month and year are present but the day is missing, the diagnosis date will be set to first day 
of the relevant month. If only the year is recorded the diagnosis date will be set as “01-Jan” for 
that year. 
6.2.7 Exposure to Study Drug 
Exposure to study drug will be calculated as the date of last dosing minus the first day of dosing + 
1. The exposure calculation will not take into account breaks in therapy. 
6.2.8 Inexact Values 
In the case where a variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value of x will be taken 
for analysis purposes. 
For pharmacokinetic data values below lower limit of quantification (LLOQ) will be handled as 
follows in summary tables: 
 If value collected before first dose of study treatment then set to 0. 
 If value collected on or after the first dose of study treatment then set to LLOQ/2. 
6.2.9 Area under curve (AUC) of WHO Ordinal Scale for Clinical 
Improvement 
Area under curve (AUC) of WHO Ordinal Scale for Clinical Improvement will be calculated from 
baseline up to Day 60 using trapezoidal rule. For each subject all available measurements up to 


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study day 60 are included in the calculations. If subject does not have record on Day 60 then the 
last observation carried forward (LOCF) will be used. If a patient dies on Day 10, then they would 
be an 8 from Day 10 to Day 60. If the patient is discharged as a 2 on Day 5 then they would be a 
2 from Day 5 to Day 60. Actual collection times will be used in the calculations. 
6.2.10 Discharge, Early Termination and Unscheduled Visits 
Only scheduled post-baseline values will be tabulated. Discharge, early termination and 
unscheduled visits will be mapped to the closest scheduled post-baseline time point. If subject then 
having more than one record mapped for specific visit then the closest value to the scheduled time 
point will be used in the analysis. 
All collected data will be presented in subject data listings. 
6.3 Conventions 
All data listings, summaries, figures and statistical analyses will be generated using SAS version 
9.4 or higher1. 
Summaries will be presented by treatment group. Treatment group labels will be displayed as 
follows: 
 VERU-111 9 mg 
 Placebo 
Listings will be sorted in the following order: treatment group, subject, parameter, and visit unless 
otherwise stated. All data will be listed, subjects who were not randomized will be displayed after 
the randomized treatment groups. 
Continuous variables will be summarized by the number of non-missing observations, mean, 
median, standard deviation, and minimum and maximum. 
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the subject population unless 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented. 
6.3.1 Decimal Places 


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Decimal places for derived data described in section 6.2 will be determined by the scale of 
measurement unless otherwise stated. No decimal places will be displayed if the smallest 
calculated value is ≥ 100; 1 decimal place will be displayed when the smallest value is within the 
interval (10, 100), with 10 being inclusive; 2 decimal places will be displayed when the smallest 
value is within (1, 10), with 1 being inclusive; and so on for even smaller scales of measurement.  
Derived data where it is known in advance the result will be an integer for example day, month, 
year, number of days and total scores (for rating scales) will be presented with zero decimal places.  
Means, medians and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (e.g. standard deviation) will have two more decimal places, and the minimum 
and maximum will be displayed to the same number of decimal places as reported in the raw data. 
Percentages will be displayed with one decimal place. 
P-values will be quoted to 4 decimal places. P-values < 0.0001 will be presented as p<0.0001. 
6.4 Subject Disposition 
Subject disposition will be summarized as follows: 
 The number of enrolled subjects overall in Enrolled Set. 
 The number of screen failures overall in Enrolled Set. 
 The number of subjects with inclusion/exclusion criteria violations overall in Enrolled Set. 
 Number of subjects in each Analysis Set by treatment group and overall in Enrolled Set. 
 The reasons for exclusion from the mITT Analysis Set will be summarized by treatment 
group and overall. 
 Study completion, early treatment withdrawal with reason, early study termination with 
reason and other disposition by treatment group and overall in ITT Analysis Set. 
6.5 Protocol Deviations 
Protocol deviations will be summarized and listed. 
6.6 Baseline Comparability 
The comparability of treatment groups with respect to subject demographics and baseline 
characteristics will be assessed in a descriptive manner, but no formal statistical testing will be 
performed. 


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Standard continuous or categorical variable summaries will be presented by randomized 
treatment group for the following variables based on the Safety Analysis Set and mITT Analysis 
Set: 
 Age (years) at Informed Consent 
 Age category (<60 years, >=60 years) 
 Sex (Female, Male) 
 Fertility Status for Women (Childbearing Potential, Post-menopausal, Surgically Sterile) 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White) 
 Weight (kg) at Baseline 
 Height (cm) at Baseline 
 Body Mass Index (BMI) (kg/m2) at Baseline 
 WHO Ordinal Scale for Clinical Improvement (descriptive statistics and frequencies for 
each score category). 
The following baseline conditions will be summarized: 
 Comorbidities, n (%) 
o Cancer 
o Diabetes 
o Hypertension 
o History of Heart Failure 
o Pneumonia, Renal Issues 
o Respiratory Issues 
o Asthma (subset of Respiratory Issues) 
 Oxygen Saturation (SpO2) (%) 
 Creatinine Clearance (mL/min) 
 Time from Admission to Randomization (days). 
6.7 Medical History 
Separate tabulations of previous and ongoing conditions at screening will be presented by 
randomized treatment group and overall for the Safety Analysis Set. 


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Previous conditions are all conditions which ended before the first dose of study drug. 
Ongoing conditions are all conditions which were ongoing at the time of the first dose of study 
drug. 
Conditions will be presented by Medical Dictionary of Regulated Activities (MedDRA, version 
24.0) primary system organ class and preferred term. 
6.8 Prior and Concomitant Medications 
Separate tabulations will be produced for prior and concomitant medications presented by 
randomized treatment group and overall for the Safety Analysis Set. Prior medications are defined 
as all medications ending before the date of first dose of study drug. Concomitant medications are 
defined as medications taken on or after the date of first dose of study drug. 
Concomitant medications will be summarized using Anatomic Therapeutic Chemical (ATC) Level 
2 and Drug Reference Names using the WHO dictionary (version B3 Mar 2021). 
6.9 Exposure to Study Drug 
Extent of exposure (number of days of exposure to study drug) will be presented by randomized 
treatment group for the Safety Analysis Set. 
6.10 Treatment Compliance 
All subjects will receive standard of care plus oral daily VERU-111 or Placebo. Subjects will take 
one capsule per day. 
Overall study drug compliance (%) will be summarized using descriptive statistics by treatment 
group and overall. Additionally, compliance (%) will be summarized as frequencies in ‘<80%’, 
’80-120%’ and ‘>120%’ categories. 
Overall study drug compliance will be calculated as follows: 
100 ∗
𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑡𝑎𝑘𝑒𝑛
𝑝𝑙𝑎𝑛𝑛𝑒𝑑 𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 
where planned number of capsules is 1 capsules/day in both VERU-111 and placebo groups. 
Planned number of capsules will be calculated as last dose date – date of first dose +1. 


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6.11 Efficacy Analyses 
All statistical tests will be performed using a two-tailed 5% overall significance level, unless 
otherwise stated. All comparisons between treatments will be reported with 95% confidence 
intervals for the difference. 
6.11.1 Primary Efficacy Analysis 
The primary endpoint for the study will be the proportion of subjects that die on study (up to Day 
60). Responders are subjects who are alive at Day 60. 
The number and percentage of deaths will be summarized by treatment group. 
Mortality rates will be analyzed using a logistic regression model. The model will include 
treatment as a factor and gender, study site (or country or region), remdesivir use (No/Yes), 
dexamethasone use (No/Yes) and WHO Ordinal Scale strata used in randomization as covariates. 
The model will be fitted using logit link function. Odds ratios, standard errors, 95% confidence 
intervals and p-values for the treatment difference will be presented. 
The primary analysis will be performed on the ITT analysis set and the ITT data scope regardless 
of patient’s use of rescue medications, protocol violations or investigational product 
discontinuation consistent with the treatment policy strategy. Every effort will be made to collect 
vital status up to the end of the study period. Missing data for subjects who are lost to follow up 
will be imputed using multiple imputation methods. 
Example SAS code for imputation is as follows: 
proc mi data=xxx out=imputed1 seed=1234 nimpute=50; 
class treatment sex site discharge discont remdesivir dexamethasone whostrata  
      imputedresponse; 
fcs logistic(imputedresponse / details likelihood=augment); 
var treatment sex site discharge discont remdesivir dexamethasone whostrata  
    imputedresponse; 
run; 
where IMPUTEDRESPONSE is the response variable to be imputed, TREATMENT is the 
randomized treatment group (veru/placebo), SEX is sex of the subject (male/female), SITE is study 
site (if there are issues fitting imputation model then this might be replaced with country or region), 
DISCHARGE is whether the subject was discharged from the hospital at any time during the study 


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(no/yes, populated as ‘no’ for subjects who were not discharged from the hospital prior to 
withdrawing from the study before Day 60), DISCONT is whether subject discontinued treatment 
early (no/yes), REMDESIVIR is the use of remdesivir at baseline (no/yes), DEXAMETHASONE 
is the use of dexamethasone at baseline (no/yes) and WHOSTRATA is the WHO Ordinal Scale 
strata used in randomization. If the imputation model does not converge when both DISCHARGE 
and DISCONT variables are included then will be checked if either of them alone can be included 
in the model. If model converges with DISCHARGE or DISCONT alone but the model with both 
DISCHARGE and DISCONT does not converge, then imputation model will include only 
DISCHARGE. 
The imputed data sets will be analyzed separately for each imputation using the logistic 
regression model. If all subjects have the mortality status at Day 60 then the imputation part 
above will not be used and observed data will be analyzed as such. Example SAS code for 
logistic regression is as follows: 
proc logistic data=imputed1 order=internal descending; 
by _imputation_; 
class imputedresponse treatment sex site remdesivir dexamethasone whostrata  
      / param=glm; 
model imputedresponse = treatment sex site remdesivir dexamethasone whostrata  
      / clodds=both firth; 
estimate 'Treatment A vs. Treatment B' treatment 1 -1 / cl e exp; 
lsmeans treatment / cl exp diff; 
ods output modelanova=imputed_modelanova1 
           lsmeans=imputed_lsmeans1 
           diffs=imputed_diffs1 
           parameterestimates=imputed_parmest1; 
run; 
If there are enough deaths to perform analysis without FIRTH option then it might be dropped 
out. Note that variable _IMPUTATION_ identifies each of the imputations created by PROC MI. 
Finally, results from individual imputations are pooled via Rubin’s rules using PROC 
MIANALYZE. Example SAS code for pooling log(odds) for each treatment group is as follows: 
 
proc mianalyze data=imputed_lsmeans1; 
by trt01pn; 
modeleffects estimate; 
stderr stderr; 
ods output parameterestimates=combined_odds1; 


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run; 
 
Example SAS code for pooling log(odds ratio) for each treatment group is as follows: 
proc mianalyze data=imputed_diffs1; 
modeleffects estimate; 
stderr stderr; 
ods output parameterestimates=combined_diffs1; 
run; 
6.11.2 Sensitivity Analysis for the Primary Endpoint 
A sensitivity analysis using the tipping-point approach will be conducted to assess the robustness 
of the primary analysis approach. This analysis will be performed only if primary efficacy 
analysis shows significant difference between treatment groups and at least some subjects have 
missing mortality status as Day 60. 
Missing endpoints will be re-assigned in a series of analyses that are progressively more in favor 
of placebo. 
The tipping point analysis will consider the full range of possible response rates in the subjects 
with missing data in the primary analysis. This will be done by systematically changing assumed 
response rates from 0% to 100% in a stepwise manner. The imputation will be performed 
independently within the two treatment groups so that, in the most extreme case, the imputed 
response rate in the VERU-111 arm will be 0% and 100% in the placebo arm. 
Multiple imputation will be used for each pair of response rates under consideration. Both the 
imputation model and the analysis model will incorporate the covariates as used in the primary 
analysis. 
The following algorithm will be used for the imputation; 
Step 1: Use efficacy data to identify subjects classed as non-responders due to missing 
data. 
Step 2: 121 pairs of response rates for VERU-111 and placebo in the table below will be 
used for the imputation. 
 
Placebo Response Rate 
0 
0.1 
0.2 
0.3 
0.4 
0.5 
0.6 
0.7 
0.8 
0.9 
1.0 


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VERU-111 9 mg 
Response Rate 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
0.1 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
0.2 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
0.3 
34 
35 
36 
37 
38 
39 
40 
41 
42 
43 
44 
0.4 
45 
46 
47 
48 
49 
50 
51 
52 
53 
54 
55 
0.5 
56 
57 
58 
59 
60 
61 
62 
63 
64 
65 
66 
0.6 
67 
68 
69 
70 
71 
72 
73 
74 
75 
76 
77 
0.7 
78 
79 
80 
81 
82 
83 
84 
85 
86 
87 
88 
0.8 
89 
90 
91 
92 
93 
94 
95 
96 
97 
98 
99 
0.9 
100 
101 
102 
103 
104 
105 
106 
107 
108 
109 
110 
1.0 
111 
112 
113 
114 
115 
116 
117 
118 
119 
120 
121 
 
For each of the 121 pairs of response rates in the table above, (e.g. for pair number 46, response 
rate for Placebo = 0.1, while response rate for VERU-111 = 0.4.): 
 For each subject identified in Step 1, generate a continuous response score between 0 
(non-response) and 1 (response) using SAS PROC MI adjusting for the same covariates 
as in the primary analysis. Example SAS code is as follows: 
proc mi data=a out=xxx seed=1234 nimpute=50 
        minimum=. . . . . . . . 0 maximum=. . . . . . . . 1; 
class treatment sex site discharge discont remdesivir dexamethasone 
whostrata; 
fcs reg(imputedresp / details); 
var treatment sex site discharge discont remdesivir dexamethasone 
whostrata imputedresp; 
run; 
 Assign the imputed response (1=response, 0=non-response) based on the response score 
and the current tipping point. Using the example values above: 
o Given a VERU-111 tipping point response rate of 0.1, subjects in the VERU-111 
group with a response score ≥ 0.9 would be imputed as responders and non-
responders otherwise. 
o Given a placebo tipping point response rate of 0.4, subjects in the placebo group 
with a response score ≥ 0.6 would be imputed as responders and non-responders 
otherwise. 
 Then same model as in primary analysis will be run for each pair of response rates and p-
values reported in the table. From the table the robustness of results can be evaluated.  


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6.11.3 Secondary Analyses for the Primary Endpoint 
The primary endpoint, mortality rate at Day 60, will also be assessed in the subset of mITT 
patients and Safety Analysis Set (all treated subjects). 
Additionally, similar analysis to primary analysis will be performed in subgroups for region, 
standard of care, WHO Ordinal Scale at baseline and vaccination status. 
To obtain risk differences between treatment groups, the same analysis as described above for 
primary efficacy analysis will be performed except identity link function will be used. Example 
SAS code is as follows: 
proc genmod data=a order=internal; 
class treatment sex site remdesivir dexamethasone whostrata; 
model response=treatment sex site remdesivir dexamethasone whostrata  
      / type3 dist=bin link=identity; 
lsmeans treatment / e diff exp cl; 
run; 
 
Additionally, mortality rates will be summarized using Kaplan-Meier (KM) survival curves and 
equality of treatment groups will be tested using log-rank test. Hazard ratios will be calculated 
using the Cox proportional hazards model including terms for treatment, gender, study site (or 
country or region), remdesivir use (No/Yes), dexamethasone use (No/Yes) and WHO Ordinal 
Scale strata used in randomization. Any subjects for whom survival status is not available at day 
60 will be censored at the day of their last observed assessment or last captured event. 
Example SAS code for log-rank test is as follows: 
proc lifetest data=XXX outsurv=surv1 
              plots=survival(atrisk=0 to 60 by 1); 
time time*cens(1); 
strata treatment; 
run; 
 
Example SAS code for proportional hazards model is as follows: 
proc phreg data=XXX; 
class treatment sex site remdesivir dexamethasone whostrata; 
model time*cens(1)=treatment sex site remdesivir dexamethasone 
whostrata; 


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hazardratio treatment; 
assess ph / resample seed=1234; 
 run; 
6.11.4 Exploratory Analysis for the Primary Endpoint 
Not applicable. 
6.11.5 Secondary Efficacy Analyses 
6.11.5.1 The proportion of subjects that are alive without respiratory failure at Day 15, Day 
22, and Day 29. 
This analysis will compare subjects that are alive without respiratory failure on the visit 
(responder) to subjects who died before the visit or had respiratory failure (non-responder) on the 
visit. 
Responders are subjects who are alive and have Grade 0-4 on the WHO Ordinal Scale for 
Clinical Improvement on the visit. If subject was discharged from the hospital prior to the visit 
and WHO Ordinal Scale for Clinical Improvement is not collected at the specific visit then the 
last available observation before or at the time of discharge will be used. If subject’s vital status 
is not known then missing information will be imputed using multiple imputation. 
Non-responders are subjects who died before the visit or has Grade 5, 6, 7, or 8 on the WHO 
Ordinal Scale for Clinical Improvement on the visit. 
The number and percentage of responders will be summarized by treatment group and visit. 
Responders will be analyzed using the same methodology as for the primary endpoint (separate 
analysis will be performed for each visit): 
 Multiple imputation + logistic regression model 
6.11.5.2 Days in ICU 
‘Days in ICU’ will be summarized using descriptive statistics (n, mean, standard deviation, 
median, minimum and maximum) by treatment group. 
‘Days in ICU’ will be the number of days in ICU up to Day 60. In this analysis the worst 
possible endpoint will be assigned to those subjects who died at any time up to Day 60. For 
subjects who died the days in ICU will be set to 60. Even for those who were never in the ICU. If 


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subject did not report any days in the ICU then their days will be set to zero except for those who 
died. 
Same analysis will be performed in subgroups for region, standard of care and WHO Ordinal 
Scale at baseline. 
A sensitivity analysis will be performed using the actual number of days in ICU. If subject was 
never in the ICU then days in ICU will be set to 0 even if subject died. 
Treatment comparison will be based on analysis of covariance (ANCOVA) model including 
treatment as a factor, and study site (or country or region), remdesivir use (No/Yes), 
dexamethasone use (No/Yes) and WHO Ordinal Scale strata used in randomization as covariates. 
Treatment difference, standard error, 95% confidence interval and p-value will be presented. 
Example SAS codes for the analysis are as follows: 
proc mixed data=XXX order=internal; 
class trt01pn site remdesivir dexamethasone; 
model response=trt01pn site remdesivir dexamethasone whostrata /  
               ddfm=kr; 
lsmeans trt01pn / cl diff; 
ods output tests3=tests lsmeans=lsmeans diffs=diffs 
run; 
6.11.5.3 WHO Ordinal Scale for Clinical Improvement change from baseline to Day 15, Day 
22, and Day 29 
WHO Ordinal Scale for Clinical Improvement will be summarized in frequency table by visit 
and treatment group. 
Additionally, response status for each subject will be defined based on WHO Ordinal Scale for 
Clinical Improvement. This analysis will compare subjects that have WHO score 0 or 1 
(responder) on the visit to subjects who have WHO score >=2 (non-responder) on the visit. 
Baseline for WHO Ordinal Scale is the last available record up to and including Day 1. If subject 
was discharged from the hospital prior to Day 15, 22 or 29 and WHO Ordinal Scale for Clinical 
Improvement is not collected or record is otherwise missing at those timepoints then the last 
available observation before or at the time of death/discharge will be carried forward. If subject 
dies then following time points will be set to the worst possible outcome (score=8). 


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The number and percentage of responders will be summarized by treatment group and visit. 
Responders will be analyzed using similar logistic regression model except not planning multiple 
imputation as the above algorithm provides responder status for all subjects. 
6.11.5.4 Days on mechanical ventilation 
Mechanical ventilation is defined as subject having ‘Intubation and mechanical ventilation’ or 
‘Ventilation + additional organ support – pressors, RRT, ECMO’. 
‘Days on mechanical ventilation’ will be summarized using descriptive statistics (n, mean, 
standard deviation, median, minimum and maximum) by treatment group. 
‘Days on mechanical ventilation’ will be defined using two different algorithms similarly to 
‘Days in ICU’. 
‘Days on mechanical ventilation’ will be analyzed using the same methodology as for ‘Days in 
ICU’ and the same sensitivity analysis will be performed. 
6.11.5.5 Days in hospital 
‘Days in hospital’ will be summarized using descriptive statistics (n, mean, standard deviation, 
median, minimum and maximum) by treatment group. 
‘Days in hospital’ will be defined using two different algorithms similarly to ‘Days in ICU’. 
‘Days in hospital’ will be analyzed using the same methodology as for ‘Days in ICU’ and the 
same sensitivity analysis will be performed except the subgroup analyses will not be performed. 
6.11.5.6 The proportion of subjects that die on study at Day 15, Day 22, and Day 29. 
The number and percentage for all-cause mortality will be summarized by treatment group and 
visit. 
These endpoints will be analyzed using the same methodology as for the primary endpoint 
(separate analysis will be performed for each visit): 
 Multiple imputation + logistic regression model 
 Risk differences between treatment groups (using identity link function). 


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6.11.5.1 Change from baseline in viral load (baseline to Day 9) 
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) will be 
summarized for absolute values and change from baseline by treatment group and visit. For viral 
load post-BL time points for summary and analysis will be ‘Last On-Study’ and ‘Day 9 only’. 
Change from baseline in viral load will be analyzed using the same methodology as for ’Days in 
ICU’ but including also viral load at baseline as covariate. 
6.11.6 Exploratory Efficacy Analyses 
AUC of WHO Ordinal Scale for Clinical Improvement will be summarized using descriptive 
statistics by treatment group. 
6.11.7 Multiplicity 
Holm (1979) step-down procedure will be used to control multiplicity for selected key secondary 
endpoints (days in ICU and days on mechanical ventilation). 
If the primary analysis of the primary endpoint is significant at the <0.05 level key secondary 
endpoints days in ICU and days on mechanical ventilation will be tested using the Holm step-
down procedure.  In this way an overall type 1 (false-positive) error rate of 5% will be maintained 
so that no statistical significance for the key secondary efficacy endpoints will be claimed unless 
the principal analysis of the primary efficacy endpoint using the ITT set is statistically significant 
at the 5% level. 
Holm procedure will be applied as follows: 
1. If the p-value for primary endpoint >= 0.05 then testing will stop and key secondary 
endpoints will not be tested. If p-value <0.05 then testing continues to key secondary 
endpoints. 
2. P-values for key secondary endpoints will be sorted from smallest to greatest (ascending 
order). 
3. The smallest p-value for key secondary endpoints will be compared to 0.025. 
4. If the smallest p-value yields significant result at 0.025 level then sequential testing 
continues to the next largest p-value and adjusted alpha value of 0.05. Otherwise the testing 
will stop. 
Data from all analyses, regardless of the level of significance, will be presented for review. 


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6.12 Pharmacokinetic Analyses 
Pharmacokinetic concentration data will be summarized using descriptive statistics (n, mean, 
standard deviation, median, minimum and maximum) at each time point. Also CV%, geometric 
mean, geometric SD and geometric CV% will be presented. 
Geometric mean is calculated as 
𝜇𝑔= √𝑥1𝑥2𝑥3 … 𝑥𝑛
𝑛
, 
where n is the number of observations and xi are the observed data. This can be expressed also in 
the following form 
𝜇𝑔= exp (
∑
ln 𝑥𝑖
𝑛
𝑖=1
𝑛
), 
which is easier for the practical calculation. This would simply be the exponent of the arithmetic 
mean from logarithmically transformed data. 
Geometric standard deviation (SD) 
Geometric SD is calculated as 
𝜎𝑔= exp (√∑
(ln 𝑥𝑖−ln 𝜇𝑔)
2
𝑛
𝑖=1
𝑛
). 
This would simply be the exponent of the arithmetic standard deviation from logarithmically 
transformed data. 
Geometric coefficient of variation (CV) 
Geometric CV is calculated as 
𝐶𝑉𝑔= √𝑒(ln 𝜎𝑔)
2
−1, 
where ln σg is the arithmetic standard deviation from logarithmically transformed data. 
Geometric CV can be multiplied by 100 if CV displayed in percentage. 
6.13 Pharmacodynamic Analyses 


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Not applicable. 
6.14 Safety Analyses 
The safety analyses will be presented by the treatment received for the Safety Analysis Set. 
6.14.1 Adverse Events 
A treatment emergent adverse event (TEAE) is defined as: 
 Any AE that has an onset on or after the first dose of study drug. 
 Any pre-existing AE that has worsened in severity on or after the first dose of study drug. 
A treatment-related AE is defined as an AE with causality collected as ‘POSSIBLY RELATED’, 
‘PROBABLY RELATED’ or ‘RELATED’ in the CRF. 
The intent is to collect all data, in a rare cases data might be incomplete for AE relationship and/or 
standard toxicity grade. This is not anticipated to cause any issues in the analysis and in these cases 
values will be imputed using worst-case scenario for analysis as follows: 
 If an AE has missing relationship it is assumed to be ‘RELATED’ to the study drug for 
analysis purposes. 
 If an AE has missing standard toxicity grade it is assumed to be ‘GRADE 3 (SEVERE)’ 
for analysis purposes. This is not worst case but more meaningful to impute as severe 
compared to life-threatening or death. 
AEs will be summarized according to the MedDRA (version 24.0) system organ class and 
preferred term. 
The following tables will be presented for AEs: 
 Overall incidence and the number of events in the following categories: 
o TEAEs 
o Treatment-Related TEAEs 
o Serious TEAEs 
o Treatment-Related Serious TEAEs 
o TEAEs leading to treatment modification (drug interrupted / dose increased / dose 
reduced) 


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o TEAEs leading to treatment discontinuation (drug withdrawn) 
o Fatal TEAEs 
 For the above AE categories tables including incidence and number of events will be 
presented by system organ class and preferred term 
 TEAEs by system organ class, preferred term and maximum toxicity grade (incidence, no 
event counts) 
 TEAEs by system organ class, preferred term and strongest relationship grade (incidence, 
no event counts) 
 Listing of Deaths (presented in the Table section of the appendices) 
 Listing of Serious TEAEs (presented in the Table section of the appendices). 
In counting the event number of AEs reported, a continuous event (i.e. reported more than once 
and which did not cease), will be counted only once; non-continuous AE reported several times by 
the same subject will be counted as multiple events. 
All AEs will be listed. 
6.14.2 Laboratory Data 
Laboratory data will be collected in local labs and the units need to be made consistent before 
presenting in summary tables. 
Even when same units are used in different labs the normal ranges can vary within each lab 
parameter. Also in these cases normalization of the data need to be performed. 
Laboratory data shift tables (low/normal/high) will be done based on the original ranges used in 
the local laboratories. 
For descriptive statistics, local laboratory results are normalized using location-scale 
normalization or scale normalization formulas given by Karvanen (2003). 
 
Result Normalization 
Location-scale normalization is used when both central lab and local lab have both lower and 
upper limits for normal specified in the data: 


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𝑠location-scale = 𝐿𝑆+ (𝑥−𝐿𝑋) (𝑈𝑆−𝐿𝑆)
(𝑈𝑋−𝐿𝑋) 
If location-scale normalization reaches negative value for a parameter then for that parameter 
scale normalized value will be used instead (giving priority for value using upper normal limit). 
Scale normalization is used when either central lab or local lab have and only lower or upper 
limits for normal specified in the data (or location-scale normalization reaches negative value): 
 
𝑠scale(upper) = 𝑥
𝑈𝑆
𝑈𝑥     or     𝑠scale(lower) = 𝑥
𝐿𝑆
𝐿𝑥 
 
The notation in the above formulas are as follows: 
 
s 
normalized result 
x 
local laboratory result 
LX 
lower normal limit in local lab 
UX 
upper normal limit in local lab 
LS 
lower normal limit in central lab 
US 
upper normal limit in central lab. 
As this study does not have central laboratory then the most common range will be used instead 
of central lab values in the formula above. This keeps the number of normalized values as low as 
possible. 
Descriptive statistics of the observed values and change from baseline (continuous data) will be 
presented by treatment group and visit for each chemistry, hematology and urinalysis parameter.  
Each measurement (continuous data) will be classed as below, within, or above normal range, 
based on ranges supplied by the laboratory used. Shift tables in relation to the normal range from 
baseline to each timepoint will be presented. 
A listing of any clinically significant laboratory measurements recorded throughout the study 
will be presented in tables section. 
All laboratory data will be listed. Listings will show the normalized values. 
6.14.3 Vital Signs 


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Descriptive statistics for observed values and changes from baseline in the following vital signs 
will be presented by treatment group and visit: 
 Systolic blood pressure (mmHg) 
 Diastolic blood pressure (mmHg) 
 Pulse rate (bpm) 
 Respiration rate (breath / min) 
 Body weight (kg) 
 Body temperature (degrees Celsius) 
 SpO2 (%) 
When study day has more than one record (i.e. vital sign log data) then summary table will use the 
average within the day. 
Data for body temperature and SpO2 log will be presented in plot where individual subjects will 
be overlaid in one figure (spaghetti plot) by treatment group. 
All vital sign data will be listed. 
6.14.4 Physical Examination 
Shift tables for each body system from baseline to worst post-baseline record will be presented 
(Normal, Abnormal NCS and Abnormal CS). NCS = Not Clinically Significant, CS = Clinically 
Significant. 
All physical examination data will be listed. 
6.14.5 Electrocardiogram Data 
Descriptive statistics for observed values and changes from baseline in the following ECG 
variables will be tabulated at each follow-up visit: 
 Heart rate (bpm) 
 PR interval (ms) 
 RR interval (ms) 
 QRS duration (ms) 
 QT interval (ms) 


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 QTc interval (ms) 
 QTc interval (ms) [Bazett’s formula - QTcB] 
 QTc interval (ms) [Fridericia’s formula - QTcF] 
Shift tables in relation to the overall interpretation (Normal, Abnormal NCS and Abnormal CS) 
from baseline to worst post-baseline record will be presented. 
All ECG data will be listed. 
6.14.6 Chest X-Ray 
Shift tables for chest X-ray from baseline to each timepoint will be presented (Normal, 
Abnormal. 
All chest X-ray data will be listed. 
7 INTERIM ANALYSIS 
Interim analyses are described in separate IDMC SAP. 
8 INDEPENDENT DATA MONITORING COMMITTEE (IDMC) 
ANALYSIS 
Independent Data Monitoring Committee (IDMC) analyses and interim analyses are described in 
separate IDMC analysis plan. 
9 CHANGES TO PLANNED PROTOCOL ANALYSIS 
Original protocol stated that randomization will be stratified by WHO scores 5 and 6 but it was 
updated to include WHO scores 4, 5 and 6 in protocol version 3.0 (amendment 2)(dated 12-MAY-
2021). 
In the protocol WHO score was planned to be analyzed as continuous variable using MMRM. 
However this was changed into responder type of analysis in the SAP. 
Holm step-down procedure was added to control multiplicity for primary endpoint and key 
secondary endpoints. 
 


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10 REFERENCES 
1. SAS Institute Inc., Cary, NC, 27513, USA 
2. Holm SA. A simple sequentially rejective multiple test procedure. Scandanavian Journal 
of Statistics 1979; 6: 65-70. 
3. Karvanen J. The Statistical Basis of Laboratory Data Normalization. Drug Information 
Journal, Vol. 37, pp. 101–107, 2003, 0092-8615/2003 
 
 
 


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11 LIST OF TABLES, FIGURES AND LISTINGS 
The following table includes details of the tables, figures and listings to be included within each 
section of the eCTD. The following validation methods maybe used:  
 Independent programming of numbers and manual review of format (IP) 
 Independent programming by statistician of numbers and manual review of format (Stat 
IP) 
 Manual review (MR) 
 Code review (CR) 
11.1 Tables 
Table 
Number 
Table Title 
Validatio
n Method 
Shell 
Number (if 
repeat) 
14.1.1.1 
Subject Enrollment 
Enrolled Set 
IP 
 
14.1.1.2 
Screen Failures 
Enrolled Set 
IP 
 
14.1.1.3 
Inclusion/Exclusion Criteria Violations 
Enrolled Set 
IP 
 
14.1.1.4 
Analysis Sets and Subject Disposition 
ITT Set 
IP 
 
14.1.1.5 
Protocol Deviations 
ITT Set 
IP 
 
14.1.1.6 
Reasons for Exclusion from Per-Protocol Set 
ITT Set 
IP 
 
14.1.1.7 
Randomization by Country and Site 
ITT Set 
IP 
 
14.1.2.1 
Demographics 
ITT Set 
IP 
 
14.1.2.2 
Demographics 
Safety Set 
IP 
 


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Table 
Number 
Table Title 
Validatio
n Method 
Shell 
Number (if 
repeat) 
14.1.2.3 
Demographics 
mITT Set 
IP 
14.1.2.1 
14.1.2.4 
Baseline Condition 
ITT Set 
IP 
 
14.1.2.5 
Baseline Condition 
Safety Set 
IP 
 
14.1.2.6 
Baseline Condition 
mITT Set 
IP 
14.1.2.3 
14.1.3.1 
Previous Medical History by System Organ Class and Preferred 
Term 
ITT Set 
IP 
 
14.1.3.2 
Ongoing Medical History by System Organ Class and Preferred 
Term 
ITT Set 
IP 
14.1.3.1 
14.1.4.1 
Prior Medications by ATC Level 2 and Preferred Term 
ITT Set 
IP 
 
14.1.4.2 
Concomitant Medications by ATC Level 2 and Preferred Term 
ITT Set 
IP 
14.1.4.1 
14.1.4.3 
Background Standard of Care by Country 
ITT Set 
IP 
 
14.1.5.1 
Treatment Exposure 
Safety Set 
IP 
 
14.1.5.2 
Treatment Compliance 
Safety Set 
IP 
 
14.2.1.1 
Proportion of Subjects Alive by Visit 
ITT Set 
IP 
 
14.2.1.2 
Logistic Regression for Proportion of Subjects Alive by Visit 
ITT Set 
Stat IP 
 


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Table 
Number 
Table Title 
Validatio
n Method 
Shell 
Number (if 
repeat) 
14.2.1.3 
Proportion of Subjects Alive by Visit 
Safety Set 
IP 
14.2.1.1 
14.2.1.4 
Logistic Regression for Proportion of Subjects Alive by Visit 
Safety Set 
Stat IP 
14.2.1.2 
14.2.1.5 
Proportion of Subjects Alive by Visit 
mITT Set 
IP 
14.2.1.1 
14.2.1.6 
Logistic Regression for Proportion of Subjects Alive by Visit 
mITT Set 
Stat IP 
14.2.1.2 
14.2.1.7 
Tipping Point Analysis for Proportion of Subjects Alive at Day 60 
ITT Set 
Stat IP 
 
14.2.1.8 
Logistic Regression for Proportion of Subjects Alive by Visit - 
Identity Link 
ITT Set 
Stat IP 
14.2.1.2 
14.2.1.9 
Kaplan-Meier Estimates for Overall Mortality 
ITT Set 
Stat IP 
 
14.2.1.10 
Cox Proportional Hazards Model for Overall Mortality 
ITT Set 
Stat IP 
 
14.2.1.11 
Proportion of Subjects Alive by Region, Country and Site,  and Visit 
ITT Set 
IP 
14.2.1.1 
14.2.1.12 
Logistic Regression for Proportion of Subjects Alive by Region and 
Visit 
ITT Set 
Stat IP 
14.2.1.2 
14.2.1.13 
Proportion of Subjects Alive by Standard of Care and Visit 
ITT Set 
IP 
14.2.1.1 
14.2.1.14 
Logistic Regression for Proportion of Subjects Alive by Standard of 
Care and Visit 
ITT Set 
Stat IP 
14.2.1.2 


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Table 
Number 
Table Title 
Validatio
n Method 
Shell 
Number (if 
repeat) 
14.2.1.15 
Proportion of Subjects Alive by WHO Ordinal Scale at BL and Visit 
ITT Set 
IP 
14.2.1.1 
14.2.1.16 
Logistic Regression for Proportion of Subjects Alive by WHO 
Ordinal Scale at BL and Visit 
ITT Set 
Stat IP 
14.2.1.2 
14.2.1.17 
Proportion of Subjects Alive by Vaccination Status (All Vaccinated 
(at Least One Shot) vs. All Unvaccinated) and Visit 
ITT Set 
IP 
14.2.1.1 
14.2.1.18 
Proportion of Subjects Alive by Vaccination Status (All Vaccinated 
with US Acceptable Vaccine vs. the Rest of the Population) and 
Visit 
ITT Set 
IP 
14.2.1.1 
14.2.1.19 
Proportion of Subjects Alive by Vaccination Status (All Vaccinated 
with at Least One Shot within 6 Months of the First Dose on 
V3011902 vs. the Rest of the Population) and Visit 
ITT Set 
IP 
14.2.1.1 
14.2.2.1 
Proportion of Subjects Alive and Free of Respiratory Failure by 
Visit 
ITT Set 
IP 
14.2.1.1 
14.2.2.2 
Logistic Regression for Proportion of Subjects Alive and Free of 
Respiratory Failure by Visit 
ITT Set 
Stat IP 
14.2.1.2 
14.2.3.1 
Descriptive Statistics for Days in Intensive Care Unit (ICU) - Death 
Assigned to Worst Possible Outcome 
ITT Set 
IP 
 
14.2.3.2 
Analysis of Covariance (ANCOVA) for Days in Intensive Care Unit 
(ICU) - Death Assigned to Worst Possible Outcome 
ITT Set 
Stat IP 
 


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Table 
Number 
Table Title 
Validatio
n Method 
Shell 
Number (if 
repeat) 
14.2.3.3 
Descriptive Statistics for Days in Intensive Care Unit (ICU) by 
Region - Death Assigned to Worst Possible Outcome 
ITT Set 
IP 
14.2.3.1 
14.2.3.4 
Analysis of Covariance (ANCOVA) for Days in Intensive Care Unit 
(ICU) by Region - Death Assigned to Worst Possible Outcome 
ITT Set 
Stat IP 
14.2.3.2 
14.2.3.5 
Descriptive Statistics for Days in Intensive Care Unit (ICU) by 
Standard of Care - Death Assigned to Worst Possible Outcome 
ITT Set 
IP 
14.2.3.1 
14.2.3.6 
Analysis of Covariance (ANCOVA) for Days in Intensive Care Unit 
(ICU) by Standard of Care - Death Assigned to Worst Possible 
Outcome 
ITT Set 
Stat IP 
14.2.3.2 
14.2.3.7 
Descriptive Statistics for Days in Intensive Care Unit (ICU) by WHO 
Ordinal Scale at BL - Death Assigned to Worst Possible Outcome 
ITT Set 
IP 
14.2.3.1 
14.2.3.8 
Analysis of Covariance (ANCOVA) for Days in Intensive Care Unit 
(ICU) by WHO Ordinal Scale at BL - Death Assigned to Worst 
Possible Outcome 
ITT Set 
Stat IP 
14.2.3.2 
14.2.3.9 
Descriptive Statistics for Days in Intensive Care Unit (ICU) - Actual 
Days 
ITT Set 
IP 
14.2.3.1 
14.2.3.10 
Analysis of Covariance (ANCOVA) for Days in Intensive Care Unit 
(ICU) - Actual Days 
ITT Set 
Stat IP 
14.2.3.2 
14.2.4.1 
Frequencies for WHO Ordinal Scale for Clinical Improvement by 
Visit 
ITT Set 
IP 
 
14.2.4.2 
WHO Ordinal Scale for Clinical Improvement Responders by Visit 
ITT Set 
IP 
 


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Table 
Number 
Table Title 
Validatio
n Method 
Shell 
Number (if 
repeat) 
14.2.4.3 
Logistic Regression for WHO Ordinal Scale for Clinical 
Improvement Responders by Visit 
ITT Set 
Stat IP 
14.2.4.1 
14.2.5.1 
Descriptive Statistics for Days on Mechanical Ventilation - Death 
Assigned to Worst Possible Outcome 
ITT Set 
IP 
14.2.3.1 
14.2.5.2 
Analysis of Covariance (ANCOVA) for Days on Mechanical 
Ventilation - Death Assigned to Worst Possible Outcome 
ITT Set 
Stat IP 
14.2.3.2 
14.2.5.3 
Descriptive Statistics for Days on Mechanical Ventilation by Region 
- Death Assigned to Worst Possible Outcome 
ITT Set 
IP 
14.2.3.1 
14.2.5.4 
Analysis of Covariance (ANCOVA) for Days on Mechanical 
Ventilation by Region - Death Assigned to Worst Possible Outcome 
ITT Set 
Stat IP 
14.2.3.2 
14.2.5.5 
Descriptive Statistics for Days on Mechanical Ventilation by 
Standard of Care - Death Assigned to Worst Possible Outcome 
ITT Set 
IP 
14.2.3.1 
14.2.5.6 
Analysis of Covariance (ANCOVA) for Days on Mechanical 
Ventilation by Standard of Care - Death Assigned to Worst Possible 
Outcome 
ITT Set 
Stat IP 
14.2.3.2 
14.2.5.7 
Descriptive Statistics for Days on Mechanical Ventilation by WHO 
Ordinal Scale at BL - Death Assigned to Worst Possible Outcome 
ITT Set 
IP 
14.2.3.1 
14.2.5.8 
Analysis of Covariance (ANCOVA) for Days on Mechanical 
Ventilation by WHO Ordinal Scale at BL - Death Assigned to Worst 
Possible Outcome 
ITT Set 
Stat IP 
14.2.3.2 


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Table 
Number 
Table Title 
Validatio
n Method 
Shell 
Number (if 
repeat) 
14.2.5.9 
Descriptive Statistics for Days on Mechanical Ventilation - Actual 
Days 
ITT Set 
IP 
14.2.3.1 
14.2.5.10 
Analysis of Covariance (ANCOVA) for Days on Mechanical 
Ventilation - Actual Days 
ITT Set 
Stat IP 
14.2.3.2 
14.2.6.1 
Descriptive Statistics for Days in Hospital - Death Assigned to 
Worst Possible Outcome 
ITT Set 
IP 
14.2.3.1 
14.2.6.2 
Analysis of Covariance (ANCOVA) for Days in Hospital - Death 
Assigned to Worst Possible Outcome 
ITT Set 
Stat IP 
14.2.3.2 
14.2.6.3 
Descriptive Statistics for Days in Hospital by Region - Death 
Assigned to Worst Possible Outcome 
ITT Set 
IP 
14.2.3.1 
14.2.6.4 
Analysis of Covariance (ANCOVA) for Days in Hospital by Region - 
Death Assigned to Worst Possible Outcome 
ITT Set 
Stat IP 
14.2.3.2 
14.2.6.5 
Descriptive Statistics for Days in Hospital by Standard of Care - 
Death Assigned to Worst Possible Outcome 
ITT Set 
IP 
14.2.3.1 
14.2.6.6 
Analysis of Covariance (ANCOVA) for Days in Hospital by Standard 
of Care - Death Assigned to Worst Possible Outcome 
ITT Set 
Stat IP 
14.2.3.2 
14.2.6.7 
Descriptive Statistics for Days in Hospital by WHO Ordinal Scale at 
BL - Death Assigned to Worst Possible Outcome 
ITT Set 
IP 
14.2.3.1 
14.2.6.8 
Analysis of Covariance (ANCOVA) for Days in Hospital by WHO 
Ordinal Scale at BL - Death Assigned to Worst Possible Outcome 
ITT Set 
Stat IP 
14.2.3.2 


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Table 
Number 
Table Title 
Validatio
n Method 
Shell 
Number (if 
repeat) 
14.2.6.9 
Descriptive Statistics for Days in Hospital - Actual Days 
ITT Set 
IP 
14.2.3.1 
14.2.6.10 
Analysis of Covariance (ANCOVA) for Days in Hospital - Actual 
Days 
ITT Set 
Stat IP 
14.2.3.2 
14.2.7.1 
Viral Load Descriptive Statistics 
ITT Set 
IP 
 
14.2.7.2 
 Analysis of Covariance (ANCOVA) for Change from Baseline in 
Viral Load 
ITT Set 
Stat IP 
14.2.3.2 
14.2.8.1 
Area Under Curve of WHO Ordinal Scale for Clinical Improvement 
ITT Set 
IP 
 
14.2.9.1 
Summary of Primary and Key Secondary Efficacy Endpoints (Holm 
Step-down Procedure) 
ITT Set 
Stat IP 
 
14.3.1.1.1 
Overall Summary of Adverse Events 
Safety Set 
IP 
 
14.3.1.2.1 
TEAEs by System Organ Class and Preferred Term 
Safety Set 
IP 
 
14.3.1.2.2 
Treatment-Related TEAEs by System Organ Class and Preferred 
Term 
Safety Set 
IP 
14.3.1.2.1 
14.3.1.2.3 
Serious TEAEs by System Organ Class and Preferred Term 
Safety Set 
IP 
14.3.1.2.1 
14.3.1.2.4 
Treatment-Related Serious TEAEs by System Organ Class and 
Preferred Term 
Safety Set 
IP 
14.3.1.2.1 


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Table 
Number 
Table Title 
Validatio
n Method 
Shell 
Number (if 
repeat) 
14.3.1.2.5 
TEAEs Leading to Treatment Modification (drug interrupted / dose 
increased / dose reduced) by System Organ Class and Preferred 
Term 
Safety Set 
IP 
14.3.1.2.1 
14.3.1.2.6 
TEAEs Leading to Treatment Discontinuation (drug withdrawn) by 
System Organ Class and Preferred Term 
Safety Set 
IP 
14.3.1.2.1 
14.3.1.2.7 
Fatal TEAEs by System Organ Class and Preferred Term 
Safety Set 
IP 
14.3.1.2.1 
14.3.1.3.1 
TEAEs by System Organ Class, Preferred Term and Maximum 
Toxicity Grade 
Safety Set 
IP 
 
14.3.1.3.2 
TEAEs by System Organ Class, Preferred Term and Strongest 
Relationship to Study Treatment 
Safety Set 
IP 
 
14.3.2.1 
Listing of Deaths 
Safety Set 
IP 
 
14.3.2.2 
Listing of Serious TEAEs 
Safety Set 
IP 
14.3.2.1 
14.3.4.1 
Listing of Abnormal Laboratory Values 
Safety Set 
IP 
 
14.3.5.1.1 
Hematology Descriptive Statistics 
Safety Set 
IP 
14.2.7.1 
14.3.5.1.2 
Hematology Shift Table 
Safety Set 
IP 
 
14.3.5.2.1 
Chemistry Descriptive Statistics 
Safety Set 
IP 
14.2.7.1 
14.3.5.2.2 
Chemistry Shift Table 
Safety Set 
IP 
14.3.5.1.2 


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Page 46 of 49 
 
Table 
Number 
Table Title 
Validatio
n Method 
Shell 
Number (if 
repeat) 
14.3.5.3.1 
Urinalysis Descriptive Statistics (Continuous) 
Safety Set 
IP 
14.2.7.1 
14.3.5.3.2 
Urinalysis Descriptive Statistics (Categorical) 
Safety Set 
IP 
14.2.1.1 
14.3.5.3.3 
Urinalysis Shift Table 
Safety Set 
IP 
14.3.5.1.2 
14.3.6.1.1 
Vital Signs Descriptive Statistics 
Safety Set 
IP 
14.2.7.1 
14.3.7.1.1 
Physical Examination Shift Table 
Safety Set 
IP 
14.3.5.1.2 
14.3.8.1.1 
ECG Descriptive Statistics 
Safety Set 
IP 
14.2.7.1 
14.3.8.1.2 
ECG Shift Table 
Safety Set 
IP 
14.3.5.1.2 
14.3.9.1.1 
Chest X-Ray / CT Shift Table 
Safety Set 
IP 
14.3.5.1.2 
14.4.1.1 
Descriptive Statistics for Pharmacokinetic Concentrations of Veru-
111 (ng/mL) 
Safety Set 
IP 
 
 
 
 


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11.2 Figures 
Figure 
Number 
Figure Title 
Validatio
n Method 
Shell 
Number 
(if 
repeat) 
14.2.1.1 
Time to Death 
ITT Set 
IP 
 
14.2.2.1 
Mean Profile for WHO Ordinal Scale for Clinical Improvement - with 
LOCF Values 
ITT Set 
IP 
 
14.2.2.2 
Mean Change from Baseline Profile for WHO Ordinal Scale for Clinical 
Improvement - with LOCF Values 
ITT Set 
IP 
14.2.1.1 
14.3.1.1 
Mean Profile for Body Temperature 
ITT Set 
IP 
14.2.2.1 
14.3.2.1 
Mean Profile for SpO2 
ITT Set 
IP 
14.2.2.1 
 
 
 


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11.4 Listings 
Listing 
Number 
Listing Title 
Validatio
n Method 
Shell 
Number 
(if 
repeat) 
16.2.1.1 
Screen Failures 
Enrolled Set 
IP 
 
16.2.1.2 
Inclusion/Exclusion Criteria Violations 
Enrolled Set 
IP 
 
16.2.1.3 
Treatment Completion 
Safety Set 
IP 
 
16.2.1.4 
Study Completion 
ITT Set 
IP 
 
16.2.2.1 
Protocol Deviations 
ITT Set 
IP 
 
16.2.3.1 
Analysis Sets 
Enrolled Set 
IP 
 
16.2.4.1 
Demographics 
ITT Set 
IP 
 
16.2.4.2 
Medical History 
ITT Set 
IP 
 
16.2.4.3 
Prior and Concomitant Medications 
ITT Set 
IP 
 
16.2.5.1 
Drug Accountability 
ITT Set 
IP 
 
16.2.5.2 
Dosing 
ITT Set 
IP 
 
16.2.5.3 
Standard of Care 
ITT Set 
IP 
 
16.2.5.4 
Pharmacokinetic Concentrations 
Safety Set 
IP 
 


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Listing 
Number 
Listing Title 
Validatio
n Method 
Shell 
Number 
(if 
repeat) 
16.2.6.1 
Responder Endpoints 
ITT Set 
IP 
 
16.2.6.2 
WHO Ordinal Scale for Clinical Improvement 
ITT Set 
IP 
 
16.2.6.3 
Time-to-Event and 'Days on/in' Endpoints 
ITT Set 
IP 
 
16.2.6.4 
Viral Load 
ITT Set 
IP 
 
16.2.7.1 
Adverse Events 
ITT Set 
IP 
 
16.2.8.1 
Hematology 
ITT Set 
IP 
 
16.2.8.2 
Serum Chemistry 
ITT Set 
IP 
 
16.2.8.3 
Urinalysis 
ITT Set 
IP 
 
16.2.8.4 
Pregnancy Test 
ITT Set 
IP 
 
16.2.8.5 
Vital Signs 
ITT Set 
IP 
 
16.2.8.6 
Physical Examination 
ITT Set 
IP 
 
16.2.8.7 
ECG 
ITT Set 
IP 
 
16.2.8.8 
Chest X-Ray 
ITT Set 
IP