Conditions: Prostate Cancer Metastatic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 93
Healthy volunteers: no

Brief summary:
Randomized, double-blind, placebo controlled, dose finding Phase 2 study comparing oral daily dosing of VERU-944 after a week of loading (daily dosing) with placebo to ameliorate the vasomotor symptoms resulting from androgen deprivation therapy in men with advanced prostate cancer

Detailed description:
This study is a multicenter, randomized, double-blind, placebo controlled, dose finding study of VERU-944 to treat hot flashes (vasomotor symptoms) in men with advanced prostate cancer on ADT. The study will have four arms with 30 subjects per arm. The subjects participating in the study will have advanced prostate cancer and will be undergoing androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone (LHRH) therapy (agonist or antagonist) for at least the three months prior to randomization and be experiencing regular moderate to severe hot flashes while on ADT. Subjects will all continue to receive ADT and will be randomized to receive, for the first four days, a loading dose followed by daily doses of placebo or VERU-944 (10 mg, 50 mg or 100 mg) orally for a total period of 12 weeks.

Arms:
arm 1: Veru-944 10 mg daily arm 2: Veru-944 50 mg daily arm 3: Placebo daily

Interventions: intervention 1: Veru-944 intervention 2: Placebo
Intervention descriptions: intervention 1: Treat hot flashes (vasomotor symptoms) in men with advanced prostate cancer on ADT intervention 2: Placebo

Protocol document:
Prot_000.pdf: 
Veru Inc 
CONFIDENTIAL 
Protocol V72203 – FINAL Version 9.0 
 
FINAL: AMENDMENT 4 30 October 2019 
- 1 - 
 
CLINICAL TRIAL PROTOCOL: V72203 
 
Protocol Number: 
V72203 
Protocol Date:  
FINAL/ 09 July 2018 
 
 
 
Amendment 1/ 29 October 2018 (version 6.0) 
 
 
 
Amendment 2/17 January 2019 (version 7.0) 
 
 
 
Amendment 3/22 February 2019 (version 8.0) 
 
 
 
Amendment 4/30 October 2019 (version 9.0) 
Protocol Title: 
Randomized, double-blind, placebo controlled, dose finding Phase 2 
study comparing oral daily dosing of VERU-944 after a week of 
loading (daily dosing) with placebo to ameliorate the vasomotor 
symptoms resulting from androgen deprivation therapy in men with 
advanced prostate cancer 
IND number:  
134105 
EudraCT number: 
 
Clinical Phase: 
2 
Study Sponsor: 
Veru Inc. 
48 NW 25th St 
Suite 102 
Miami, FL 33127 
Telephone: (305) 509-6986 
 
CONFIDENTIAL 
This document is a confidential communication of Veru Inc. All information and data 
contained within this document is confidential. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein may be divulged or disclosed 
to third parties without prior written approval. 


Veru Inc 
CONFIDENTIAL 
Protocol V72203 – FINAL Version 9.0 
 
FINAL: AMENDMENT 4 30 October 2019 
- 2 - 
TABLE OF CONTENTS 
1.0 
LIST OF ABBREVIATIONS ...................................................................... 5 
2.0 
PROTOCOL SUMMARY .......................................................................... 7 
3.0 
INTRODUCTION .................................................................................... 10 
3.1 
Background ............................................................................................... 10 
3.2 
Target Indication and Pharmacologic Activity ............................................... 10 
3.3 
Study Rationale .......................................................................................... 12 
4.0 
STUDY OBJECTIVES ............................................................................. 13 
4.1 
Primary Objective ...................................................................................... 13 
4.2 
Secondary Objectives ................................................................................. 13 
4.3 
Exploratory Objectives................................................................................ 13 
4.4 
Safety Objective ......................................................................................... 13 
5.0 
STUDY DESIGN ...................................................................................... 13 
5.1 
Treatment Groups and Allocation of Subjects ................................................ 13 
5.2 
Study Duration ........................................................................................... 14 
5.3 
Efficacy Endpoints ..................................................................................... 14 
5.3.1 
Primary Endpoints ...................................................................................... 14 
5.3.2 
Secondary Endpoints .................................................................................. 14 
5.3.3 
Exploratory Endpoints ................................................................................ 14 
6.0 
SUBJECT POPULATION ........................................................................ 15 
6.1 
Number of Subjects .................................................................................... 15 
6.2 
Selection Criteria ........................................................................................ 15 
6.2.1 
Inclusion Criteria ........................................................................................ 15 
6.2.2 
Exclusion Criteria ....................................................................................... 16 
7.0 
STUDY MEDICATION ............................................................................ 17 
7.1 
Enrollment and Blinding ............................................................................. 17 
7.2 
Drug Supply .............................................................................................. 17 
7.2.1 
Placebo Capsules ........................................................................................ 17 
7.2.2 
VERU-944 Capsules, 10, 50 and 100 mg ...................................................... 17 
7.2.3 
Drug Dose Justification ............................................................................... 18 
7.2.4 
Drug Accountability ................................................................................... 20 
7.3 
Drug Administration ................................................................................... 20 
8.0 
STUDY PROCEDURES ........................................................................... 21 
8.1 
Clinic Visits ............................................................................................... 21 
8.2 
Screening .................................................................................................. 21 
8.3 
Enrollment ................................................................................................. 23 
8.4 
Day 1 Visit ................................................................................................ 23 
8.5 
Day 14 Visit .............................................................................................. 24 


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FINAL: AMENDMENT 4 30 October 2019 
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8.6 
Day 30 and Day 60 Visit ............................................................................. 24 
8.7 
Day 84 Visit (End of Study Visit)................................................................. 25 
8.8 
Follow-up Visit .......................................................................................... 26 
8.9 
Pharmacokinetic Sampling .......................................................................... 26 
8.9.1 
Blood Samples ........................................................................................... 26 
8.9.2 
Plasma Sample Labels ................................................................................ 26 
8.10 
Rules for Subjects that Become at High Risk for the Development of Venous 
Thromboembolic Events during the Study ..................................................... 27 
8.11 
Subject Stopping Rules ............................................................................... 27 
8.12 
Early Discontinuation of Study Treatment ..................................................... 28 
8.13 
Adverse Events .......................................................................................... 28 
8.13.1 
Intensity of Adverse Events ......................................................................... 29 
8.13.2 
Test Medication Causality ........................................................................... 30 
8.13.3 
Serious Adverse Events ............................................................................... 31 
8.13.4 
Initial Reports ............................................................................................ 31 
8.13.5 
Precautions ................................................................................................ 32 
8.13.6 
Reporting of Adverse Events Associated with Study Drug Overdose, Misuse, 
Abuse or Medication Error .......................................................................... 32 
8.14 
Concomitant Medications and Concomitant Therapies ................................... 32 
8.15 
Prohibited Medications ............................................................................... 33 
8.16 
Withdrawal of Subjects ............................................................................... 33 
9.0 
STATISTICAL ANALYSIS ...................................................................... 34 
9.1 
Sample Size Calculation .............................................................................. 34 
9.2 
Populations ................................................................................................ 34 
9.3 
Efficacy Analyses ....................................................................................... 34 
9.3.1 
Primary Analyses ....................................................................................... 35 
9.3.1.1 
Hot Flash Frequency, Week 6 (Day 42) ........................................................ 35 
9.3.2 
Secondary Analyses .................................................................................... 36 
9.3.2.1 
Hot Flash Frequency (Weeks 4, 8, 10 and 12) and Severity (Weeks 4, 6, 8, 10, and 
12) ............................................................................................................ 36 
9.3.2.2 
Bone Turnover Markers .............................................................................. 37 
9.3.3 
Exploratory Analyses .................................................................................. 37 
9.3.3.1 
Serum PSA ................................................................................................ 37 
9.3.3.2 
Change in Serum Total and Free Testosterone Concentration .......................... 37 
9.3.3.3 
Serum SHBG ............................................................................................. 37 
9.3.3.4 
Pharmacokinetic Assessments ...................................................................... 37 
9.3.4 
Safety Analysis .......................................................................................... 38 
9.3.4.1 
Data Safety Monitoring Board ..................................................................... 38 
10.0 
ADMINISTRATION PROCEDURES ....................................................... 38 
10.1 
Study Conduct and Compliance ................................................................... 38 


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FINAL: AMENDMENT 4 30 October 2019 
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10.2 
Informed Consent ....................................................................................... 39 
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 ................................................................................................. 41 
10.5.3 
Medical Information Coding ........................................................................ 41 
10.5.4 
Data Validation .......................................................................................... 41 
10.5.5 
Record Keeping ......................................................................................... 41 
10.6 
Data Quality .............................................................................................. 41 
10.7 
Regulatory Approval .................................................................................. 42 
10.8 
Publication Policy ...................................................................................... 42 
10.9 
Clinical Study Report .................................................................................. 43 
10.10 
Contractual and Financial Details ................................................................. 43 
10.11 
Insurance and Indemnity ............................................................................. 43 
11.0 
REFERENCES ......................................................................................... 43 
12.0 
APPENDICES .......................................................................................... 47 
12.1 
Appendix A: Clinical Laboratory Tests (central laboratory) ............................ 47 
12.2 
Appendix B: Schedule of Study Evaluationse ................................................ 48 
11.3 
Appendix C: Hot Flash Assessments ............................................................ 49 
12.3 
Appendix D: Caprini Venous Thromboembolism Risk Factor Assessment ....... 50 
 


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FINAL: AMENDMENT 4 30 October 2019 
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1.0 
LIST OF ABBREVIATIONS 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CTX 
C-Telopeptide cross-links of type I collagen 
eCRF 
Electronic Case report form 
DHEA 
Dehydroepiandrosterone 
DHEAS 
Dehydroepiandrosterone sulfate 
DHT 
Dihydrotestosterone 
ECOG 
Eastern Cooperative Oncology Group 
ER 
Estrogen receptor 
ES 
Elastic stockings 
FXaI 
Factor X inhibitor 
GCP 
Good clinical practice 
GGT 
Gamma-glutamyl transferase 
hERG 
Human ether-à-go-go related gene 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
IPC 
Intermittent pneumatic compression 
IRB 
Institutional review board 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
IWRS 
LDH 
Interactive Web Response System 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LDUH 
Low dose unfractionated heparin 
LH 
Luteinizing hormone 
LHRH 
Luteinizing hormone releasing hormone 
LMWH 
Low molecular weight heparin 
MedDRA 
MRI 
Medical dictionary of regulatory activities 
Magnetic resonance imaging 


Veru Inc 
CONFIDENTIAL 
Protocol V72203 – FINAL Version 9.0 
 
FINAL: AMENDMENT 4 30 October 2019 
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MMRM 
Mixed Models Repeated Measures  
NSAID 
Nonsteroidal anti-inflammatory drug 
OTC 
Over the Counter 
PCWG2 
Prostate Cancer Working Group 2 
PRN 
Pro re nata ± As Needed 
PSA 
Prostate specific antigen 
SAE 
Serious adverse event 
SHBG 
Sex hormone binding globulin 
SRE 
Skeletal related event 
T½  
Plasma concentration elimination half-life 
TNM 
Tumor staging, T = primary tumor, N = lymph nodes, M = 
distant metastases 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Veru Inc 
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Protocol V72203 – FINAL Version 9.0 
 
FINAL: AMENDMENT 4 30 October 2019 
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2.0 
PROTOCOL SUMMARY 
Study 
Number: 
 
 
V72203 
Title: 
Randomized, double-blind, placebo controlled, dose finding Phase 2 study 
comparing oral daily dosing of VERU-944 after a week of loading (daily 
dosing) with placebo to ameliorate the vasomotor symptoms resulting from 
androgen deprivation therapy in men with advanced prostate cancer 
 
Primary 
Objective: 
 
 
 
 
 
 
 
 
Secondary 
Objectives: 
 
 
 
 
 
 
 
 
 
 
 
Exploratory 
Objectives: 
 
 
 
 
 
 
Safety 
Objective: 
 
To determine an effective dose of VERU-944 (from among 10 mg, 50 mg, 
and possibly 100 mg PO q day), after a loading dose, for the treatment of 
vasomotor symptoms commonly known as hot flashes by assessing its 
effect on: 
 
1. the frequency of moderate to severe hot flashes at week 6 
 
 
 
To assess the effect of VERU-944 on: 
1. the severity of moderate to severe hot flashes at week 6 
2. the frequency of moderate to severe hot flashes at week 8 
3. the frequency of moderate to severe hot flashes at week 10 
4. the frequency of moderate to severe hot flashes at week 12 
5. the severity of moderate to severe hot flashes at week 8 
6. the severity of moderate to severe hot flashes at week 10 
7. the severity of moderate to severe hot flashes at week 12 
8. the frequency of moderate to severe hot flashes at week 4 
9. the severity of moderate to severe hot flashes at week 4 
10. bone turnover markers 
To assess the effect of VERU-944 on: 
1. serum PSA concentrations 
 
2. serum total and free testosterone concentrations 
 
3. serum SHBG concentrations 
 
To assess the safety and tolerability of VERU-944 


Veru Inc 
CONFIDENTIAL 
Protocol V72203 – FINAL Version 9.0 
 
FINAL: AMENDMENT 4 30 October 2019 
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Design: 
This study is a multicenter, randomized, double-blind, placebo controlled, 
dose finding study of VERU-944 to treat hot flashes (vasomotor 
symptoms) in men with advanced prostate cancer on ADT. The study will 
be conducted as a staged study with Stage 1 being a three-arm evaluation 
of placebo, 10 mg and 50 mg of VERU-944. When all subjects have 
completed Week 6 (Day 42) of dosing, an evaluation of the efficacy of the 
doses administered in Stage 1 will be made (safety will be assessed in a 
blinded review) and Stage 2, a two-arm evaluation of placebo and 100 mg 
VERU-944 may be initiated. Stage 1 of the study will have three arms 
(placebo, 10 mg VERU-944, and 50 mg VERU-944) and Stage 2 of the 
study will have two arms (placebo and 100 mg VERU-944) with 
approximately 30 subjects per arm. The subjects participating in the study 
will have advanced prostate cancer and will be undergoing androgen 
deprivation therapy (ADT) with a luteinizing hormone releasing hormone 
(LHRH) therapy (agonist or antagonist) for at least the three months prior 
to randomization and be experiencing regular moderate to severe hot 
flashes while on ADT.  Subjects will all continue to receive ADT and will 
be randomized to receive, for the first four days, a loading dose followed 
by daily doses of placebo or VERU-944 (10 mg, 50 mg or 100 mg) orally 
for a total period of 12 weeks.   
Subjects: 
Approximately, ninety (90) subjects will be randomized into Stage 1 of this 
study and approximately 60 subjects are planned to be randomized into 
Stage 2 of this study. Subjects with advanced prostate cancer who have 
experienced moderate to severe vasomotor symptoms (hot flashes) for at 
least one month prior to study entry will be enrolled.  Subjects must have 
been maintained on ADT with an LHRH agonist or antagonist for at least 
the 3 months prior to randomization will be screened for the study and if 
these subjects meet the other inclusion/exclusion criteria, will be 
randomized into the study.   
Treatments: 
Subjects will be maintained on ADT with an LHRH agonist or antagonist 
while on the study.  In addition to ADT, each subject will be orally 
administered either placebo, 10, or 50 mg of VERU-944 daily after they 
have completed a four day loading dose as outlined in Section 7.3 in Stage 
1 of the study. Each subject in Stage 2 of the study will receive either 
placebo or 100 mg of VERU-944 daily after they have completed a four 
day loading dose as outlined in Section 7.3.  


Veru Inc 
CONFIDENTIAL 
Protocol V72203 – FINAL Version 9.0 
 
FINAL: AMENDMENT 4 30 October 2019 
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Procedures: 
 
Potential study participants will undergo a series of screening evaluations 
within 28 days prior to randomization.  Subjects who give written informed 
consent and satisfy the selection criteria will be enrolled into the study.   
The frequency and severity of hot flashes will be recorded daily beginning 
with screening and through week 12 (Day 84). Assessments of serum total 
and free testosterone, serum SHBG and serum PSA will be made at 
baseline (Day 1), Days 30, 60 and 84.  Bone turnover markers will be 
assessed at baseline (Day 1) and Day 84.   
Safety evaluations including assessment of adverse events, serum PSA, 
periodic monitoring of vital signs, 12-lead electrocardiogram (single) and 
clinical laboratory results (including hematology, serum chemistry 
(including LDH) will be conducted at every visit. 
Patients that have been previously screened for this study and could not 
complete screening for reasons other than not meeting the inclusion and 
exclusion criteria, may be rescreened into the study. Laboratory testing 
conducted under this protocol (Appendix A) within 45 days prior to 
randomization into this study, may be used as the baseline laboratory 
values for this study and repeat laboratory testing is not required unless 
new coadministered medication(s) has been started, unless the investigator 
determines that retesting is warranted. 
Stage 2 
dosing 
evaluation: 
After the last subject has completed Day 42 of Stage 1, an unblinded 
assessment of the Week 6 (Day 42) hot flashes frequency (primary 
endpoint), hot flash severity (first secondary endpoint),and a blinded 
assessment of safety of VERU-944 will be conducted. 
If an effective dose of VERU-944 has been identified in Stage 1, Sponsor 
reserves the right to not initiate Stage 2 of this protocol. 
If an unacceptable safety profile is observed in Stage 1, Sponsor reserves 
the right to not initiate Stage 2 of this protocol. 


Veru Inc 
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FINAL: AMENDMENT 4 30 October 2019 
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3.0 
INTRODUCTION 
3.1 
Background 
Veru Inc. is developing VERU-944 (cis-clomiphene), a nonsteroidal estrogen, as a hormonal 
therapy for the alleviation of vasomotor symptoms, commonly known as hot flashes in men 
undergoing ADT. Cis-clomiphene is one of two geometric isomers of clomiphene, which is 
approved as Clomid® (clomiphene citrate oral capsules, 50 mg; NDA 016131; Sanofi Aventis 
US) for the treatment of ovulatory dysfunction in women desiring pregnancy. While trans-
clomiphene is anti-estrogenic, cis-clomiphene is an estrogen agonist at pharmacologic 
concentrations (Turner et al., 1998; Fitzpatrick et al., 1999; Kaminetsky et al., 2013). 
Furthermore, cis-clomiphene has a half-life of 5±7 days (Mikkelson et al., 1986; Mürdter et 
al., 2012). VERU-944 is expected to be effective and safe in men with prostate cancer 
undergoing ADT based on the established efficacy of low dose estrogens in the treatment of 
vasomotor symptoms (hot flashes) and safety of off-label clomiphene use for male infertility. 
3.2 
Target Indication and Pharmacologic Activity 
Introduction 
Prostate cancer is the most common cancer in men with over 160,000 new cases expected in 
2017 (American Cancer Society. Cancer Facts & Figures 2017).  As advanced prostate cancer 
is hormone sensitive, androgen deprivation therapy (ADT) is the standard of care for patients 
with metastatic or locally advanced prostate cancer, either alone or in combination with other 
drug treatments or radiation (National Comprehensive Cancer Network, 2016). The main 
objective of ADT is to lower the serum testosterone level to castrate level of approximately 
1.7 nmol/L (< 50 ng/dL) (Djavan et al., 2012). ADT is usually achieved either by surgical 
orchiectomy (castration) or by medically administering LHRH (luteinizing hormone releasing 
hormone) agonists and antagonists.  
One of the main side effects of low testosterone levels in men is vasomotor symptoms, 
commonly known as hot flashes.  Hot flashes are experienced by about 75% of men receiving 
ADT (Holzbeierlein et al., 2004) aQd aUe a VigQificaQW cRmSRQeQW iQ meQ¶V perception of their 
quality of life (Holzbeierlein et al., 2004).  One study found 38% of men who had experienced 
hot flashes over the past four weeks were distressed about them (Holzbeierlein et al., 2004).  
These hot flashes can have a long duration.  For example, in men experiencing hot flashes 
while on ADT, 70% of them continued to experience them five years later (Karling 1994).  
Men describe their experience of hot flashes with physical as well as emotional descriptors 
(Isbarn et al., 2008).  Up to 80% of men have described hot flashes that range from mild to 
very severe, lasting up to 30 minutes and accompanied by feelings of anxiety, irritability and 
being out of control. (Schow 1998). Hot flashes for men, as for women, often require some 
sort of action such as changing clothes or taking a shower (Isbarn et al., 2008). Hot flashes in 
men who have advanced prostate cancer being treated by ADT have detrimental effects on 
overall quality of life such that cancer-related distress caused by hot flashes are a contributing 
factor in the discontinuation of ADT (Engstrom, 2008; Ulloa et al., 2009; Frisk, 2010). 


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The precise mechanism of hot flashes in men is not fully understood, but appears to be similar 
to postmenopausal hot flashes in women. Studies in postmenopausal women and women 
undergoing breast cancer treatment who experience hot flashes have shown that abrupt 
withdrawal of sex hormones leads to a dysfunctional hypothalamic thermoregulation resulting 
in vasomotor flushing (Kaplan and Mahon, 2014). In women, hormones (usually estrogen 
combined with progesterone), selective serotonin reuptake inhibitors (SSRIs) and serotonin-
noradrenalin reuptake inhibitors (SNRIs), clonidine, and gabapentin have been effective in 
treating hot flashes. Similar treatments have been attempted in men with inconsistent activity; 
overall, hormonal treatments (cyproterone and medroxyprogesterone) are generally thought to 
be more effective than non-hormonal treatments at reducing hot flashes in men on ADT 
(Loprinzi et al., 1994; Frisk, 2010; Irani et al., 2010; Vitolins et al., 2013). Hot flashes in men 
on ADT are typically treated by off-label treatments such as an SSRI, whereas hormones such 
as estrogen and megestrol are reserved for refractory cases (Smith and Crawford, 2017). 
Hot Flash Treatment for Men 
There are no approved therapies for the treatment of moderate to severe vasomotor symptoms 
in men with advanced prostate cancer on ADT. There have been few placebo controlled, 
multicenter studies evaluating possible drug interventions for hot flashes these men. 
Megestrol acetate, 20 mg twice a day (Loprinzi et al., 1994), depomedroxyprogesterone 400 
mg IM (Brosman S 1995), and venlafaxine 12.5 mg twice a day has been investigated as a 
tool to address hot flashes in men (Loprinzi et al., 1999).  A very small randomized trial was 
completed with 12 men after orchiectomy with cyproterone acetate (100 mg three times a 
day) which appeared to reduce hot flashes (Eaton and McGuire, 1993).  In addition to 
hormonal approaches, in women, the norepinephrine reuptake inhibitor, venlafaxine, has been 
studied and shown to be an effective non-hormonal treatment for hot flashes (Evans et al., 
2005) although there is no evidence that this approach will work in men.  
Another drug that has received some pilot testing, specifically in men, is sertraline as reported 
in a series of case studies (Roth and Scher 1997).  Five men who were being treated with 
androgen ablation therapy for prostate cancer exhibited symptoms of hot flashes, symptom 
distress, trouble sleeping, worsening mood, fatigue and illness concerns.  Patients were treated 
with sertraline, starting with 25 mg daily, and titrated up to 100 or 150 mg daily.  From these 
five cases, it appeared that improvement in hot flashes was not experienced until the dose was 
at least 50 mg daily and side effects were experienced at a dose of 150 mg daily.  Specific 
reductions in hot flashes were not provided for every case, but one man experienced a 75 % 
reduction in hot flashes while another experienced a 50% reduction.  In addition to hot flash 
reduction, the author reports improvement in mood and irritability (Roth and Scher 1997).  
Doses from 50 mg to 100 mg appeared to be tolerated very well in this small group of cases. 
Gabapentin for the treatment of hot flashes 
To date, there has only been one placebo-controlled, Phase 3 study of an agent to control hot 
flashes in men with prostate cancer on ADT.  This study, albeit non-regulatory, investigated 
the anti-seizure medication, gabapentin. In this trial, men with bothersome hot flashes as 


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FINAL: AMENDMENT 4 30 October 2019 
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defined as the occurrence of at least 14 times per week, were evaluated and of sufficient 
severity to make the patient desire therapeutic intervention, with the hot flashes being present 
for at least 1 month before study entry.  The study duration was four weeks and during this 
time, the patients on the highest gabapentin dose arm (900 mg/day) demonstrated a significant 
decrease in hot flash frequency (p=0.02) and a trend towards lower scores (p=0.10) (Loprinzi 
2009).  In a continuation phase of this study, those effects were maintained (Moraska et al., 
2007). Although these results were promising, gabapentin is not widely used for the treatment 
of hot flashes in this male population and the unmet medical need remains. 
 
Estrogens for the treatment of hot flashes in men with advanced prostate cancer on ADT 
 
As stated briefly above, vasomotor symptoms (hot flashes) occur in a majority of men 
receiving ADT for advanced prostate cancer.  Since decreasing estrogen levels as a result of 
the ADT are a contributing cause of the hot flashes, the off-label use of estrogenic compounds 
have historically been used.  For example, low doses of diethylstilbestrol (0.25 mg/day) 
appears to have efficacy but can result in significant breast swelling and tenderness along with 
an increase in cardiovascular side effects (Smith JA 1994; Smith JA 1996; Glashan 1981).  
Transdermal estrogen patches are another route of off-label administration of estrogens for 
this indication.  In a study of twelve men with moderate to severe hot flashes who were 
randomized to receive either low dose (0.05 mg) of high dose (0.10 mg) estrogen twice 
weekly for four weeks.  Although no placebo group was included in this study, a significant 
reduction in the severity and frequency of hot flashes was observed in the high dose arm and 
in severity only in the low dose arm (Gerber 2000).   
 
In conclusion, while the off-label use of estrogens appears to have benefit for the treatment of 
hot flashes in men with advanced prostate cancer, the type of most efficacious estrogen or 
estrogen preparation as well as dosing route or schedule is not known. Furthermore, the 
potential for safety issues with potent steroidal estrogens remains a significant limitation to 
their clinical utility.  These published data support the evaluation of VERU-944 to determine 
the optimal dose for efficacy and safety of a nonsteroidal estrogen to treat hot flashes in men 
with advanced prostate cancer on ADT. 
3.3 
Study Rationale 
Veru is evaluating cis-clomiphene (zuclomiphene), a nonsteriodal estrogen, as a hormonal 
therapy for the amelioration of hot flashes in men undergoing ADT for advanced prostate 
cancer. Cis-clomiphene is one of two geometric isomers of clomiphene, which is approved as 
Clomid® (clomiphene citrate oral tablets, 50 mg; NDA 016131; Sanofi Aventis US) for the 
treatment of ovulatory dysfunction in women desiring pregnancy. While trans-clomiphene is 
anti-estrogenic, cis-clomiphene is an estrogen agonist at pharmacologic concentrations 
(Turner et al., 1998; Fitzpatrick et al., 1999; Kaminetsky et al., 2013; Section 7.4.1.1). 
Furthermore, cis-clomiphene has a half-life of 5±7 days (Mikkelson et al., 1986; Mürdter et 
al., 2012). VERU-944 is expected to be effective and safe in men with prostate cancer 
undergoing ADT based on the established efficacy of low dose estrogens in the treatment of 
vasomotor symptoms (hot flashes) and safety of off-label clomiphene use for male infertility.  


Veru Inc 
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FINAL: AMENDMENT 4 30 October 2019 
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4.0 
STUDY OBJECTIVES 
4.1 
Primary Objective 
To determine an effective dose of VERU-944 (from among 10 mg, 50 mg, and possibly 100 
mg PO q day), after a loading dose, for the treatment of vasomotor symptoms commonly 
known as hot flashes by assessing its effect on:  
1. the frequency of moderate to severe hot flashes at week 6 
2.  
4.2 
Secondary Objectives 
To assess the effect of VERU-944 on: 
1. the severity of moderate to severe hot flashes at week 6 
2. the frequency of moderate to severe hot flashes at week 8 
3. the frequency of moderate to severe hot flashes at week 10 
4. the frequency of moderate to severe hot flashes at week 12 
5. the severity of moderate to severe hot flashes at week 8 
6. the severity of moderate to severe hot flashes at week 10 
7. the severity of moderate to severe hot flashes at week 12 
8. the frequency of moderate to severe hot flashes at week 4 
9. the severity of moderate to severe hot flashes at week 4 
10. bone turnover markers 
 
4.3 
Exploratory Objectives 
To assess the effect of VERU-944 on: 
1. serum PSA concentrations 
 
2. serum total and free testosterone concentrations 
 
3. serum SHBG concentrations 
4.4 
Safety Objective 
To assess the safety and tolerability of VERU-944 
5.0 
STUDY DESIGN 
5.1 
Treatment Groups and Allocation of Subjects 
This randomized, multicenter, double blind, placebo controlled clinical study consists of three 
treatment arms along with a placebo arm with approximately thirty (30) subjects enrolled in 
each of three treatment arms in a 1:1:1 fashion (placebo, 10 and 50 mg) in Stage 1 and 


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approximately thirty (30) subjects randomized in a 1:1 fashion to each of two treatment arms 
(placebo and 100 mg) in Stage 2.  Each subject will be randomized, and after a four-day daily 
loading dose, outlined in Section 7.3, will receive either placebo, 10 mg VERU-944 or 50 mg 
VERU-944 daily in Stage 1 and either placebo or 100 mg VERU-944 daily in Stage 2.  
5.2 
Study Duration 
The study will require that each subject receive a loading dose followed by a daily oral dose 
of placebo, 10 mg VERU-944, 50 mg VERU-944 or 100 mg VERU-944 for 12 weeks (84 
days).   
5.3 
Efficacy Endpoints 
5.3.1 
Primary Endpoints 
Patients will record frequency and severity of hot flashes using an electronic diary (eDiary) at 
home to ensure attributable, time stamped data collection in an unsupervised environment.  
This instrument will be used to assess the: 
1. Percentage change in frequency of moderate to severe vasomotor symptoms from baseline 
to Week 6 (Day 42)  
5.3.2 
Secondary Endpoints 
1. Percentage change in severity of vasomotor symptoms from baseline to Weeks 6 (Day 42)  
2. Percentage change in frequency of moderate to severe vasomotor symptoms from baseline 
to Week 8 (Day 56) 
3. Percentage change in frequency of moderate to severe vasomotor symptoms from baseline 
to Week 10 (Day 70) 
4. Percentage change in frequency of moderate to severe vasomotor symptoms from baseline 
to Week 12 (Day 84) 
5. Percentage change in severity of vasomotor symptoms from baseline to Week 8 (Day 56) 
6. Percentage change in severity of vasomotor symptoms from baseline to Week 10 (Day 70) 
7. Percentage change in severity of vasomotor symptoms from baseline to Week 12 (Day 84) 
8. Percentage change in frequency of moderate to severe vasomotor symptoms from baseline 
to Week 4 (Day 28) 
9. Percentage change in severity of vasomotor symptoms from baseline to Week 4 (Day 28) 
10. Percentage change in bone turnover marker concentrations at Day 84 compared with 
baseline 
5.3.3 
Exploratory Endpoints 
1.  Percentage change in serum PSA concentrations at Days 30, 60, and 84 compared with 
baseline 
 


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2. Percentage change in serum total and free testosterone concentrations at Days 30, 60, and 
84 compared with baseline 
 
3. Percentage change in serum SHBG concentrations at Days 30, 60, and 84 compared with 
baseline 
6.0 
SUBJECT POPULATION 
6.1 
Number of Subjects 
Approximately ninety (90) subjects will be enrolled into Stage 1 of the study, with 
approximately thirty (30) subjects in each of three treatment arms (placebo, 10 and 50 mg). 
Approximately sixty (60) subjects will be enrolled into Stage 2 of the study, with 
approximately thirty (30) subjects in each of two treatment arms (placebo and 100 mg).  
6.2 
Selection Criteria 
6.2.1 Inclusion Criteria 
Subjects accepted for this study must: 
1. 
Be over 18 years of age 
2. 
Be able to communicate effectively with the study personnel 
3. 
Have histologically confirmed prostate cancer 
4. 
Have been treated with an LHRH agonist or LHRH antagonist for at least the 2 months 
prior to randomization 
5. 
Be continued on an LHRH agonist or LHRH antagonist throughout this study (must be 
continuous therapy) 
6. 
Have experienced hot flashes for at least one month prior to study entry 
7. 
Have moderate or severe vasomotor symptoms (hot flashes) (defined as a minimum of 4 
moderate to severe hot flashes per day or 12 per week at baseline) 
8. 
ECOG performance status of 0 to 2 
9. 
Be willing to uses electronic data capture for the relevant medical events 
x Must be at least 80% compliant during the screening period (for the 14 
contiguous day hot flash assessment that is required during screening)  
10. Subjects must agree to use acceptable methods of contraception 
x If their female partners are pregnant or lactating, acceptable methods of 
contraception from the time of the first administration of study medication until 
6 months following administration of the last dose of study medication must be 
used. Acceptable methods are: Condom used with spermicidal 
foam/gel/film/cream/suppository. If the subject has undergone surgical 
sterilization (vasectomy with documentation of azospermia), a condom with 
spermicidal foam/gel/film/cream/suppository should be used 
x If Whe male VXbjecW¶V SaUWQeU cRXld becRme SUegQaQW, use acceptable methods of 
contraception from the time of the first administration of study medication until 
6 months following administration of the last dose of study medication. 
Acceptable methods of contraception are as follows: Condom with spermicidal 


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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) 
x If the female partner has undergone documented tubal ligation (female 
sterilization), a barrier method (condom used with spermicidal 
foam/gel/film/cream/suppository) should also be used 
x If the female partner 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 
11. 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. Have a serum total testosterone concentration > 50 ng/dL at screening 
2. Known hypersensitivity or allergy to estrogen or estrogen like drugs 
3. Any disease or condition (medical or surgical) which might compromise the hematologic, 
cardiovascular, endocrine, pulmonary, renal, gastrointestinal, hepatic, or central nervous 
system; or other conditions that may interfere with the absorption, distribution, 
metabolism or excretion of study drug, or would place the subject at increased risk 
4. Subjects with a personal history of abnormal blood clotting or thrombotic disease, 
including venous or arterial thrombotic events such as a history of stroke, deep vein 
thrombosis (DVT), and/or pulmonary embolus (PE) 
5. Any subjects, as determined by a central laboratory, that have a: 
x Factor V Leiden gene mutation  
x Prothrombin gene mutation 
6. Uncontrolled symptomatic congestive heart failure (NYHA Class III ± IV), unstable 
angina pectoris, cardiac arrhythmia, or uncontrolled atrial fibrillation 
7. History of MI in the past 12 months 
8. The presence of consistently abnormal laboratory values which are considered clinically 
significant. In addition, any subject with liver enzymes (ALT or AST) above 2 times the 
upper limit of normal, total bilirubin above 2 times the upper limit of normal, or serum 
creatinine above 1.5 times the upper limit of normal will NOT be admitted to the study 
9. Received an investigational drug within a period of 90 days prior to enrollment in the 
study 
10. Received the study medication (VERU-944) previously 
11. Have previously taken within 3 months prior to screening or are currently taking 
diethylstilbestrol, other estrogens; 


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12. Currently taking gabapentin, estrogen, diethylstilbestrol, medroxyprogesterone acetate, 
clomiphene, selective serotonin reuptake inhibitors (SSRIs), other treatments for hot 
flashes 
13. Recent hospitalization for more than 24 hours (within 30 days of screening) 
14. Recent surgery (within 30 days of screening) 
15. Have been previously diagnosed or treated for active cancer (other than prostate cancer or 
non-melanoma skin cancer) within the previous five years 
16. Have a BMI >40 
17. Have been randomized into Stage 1 of this protocol 
7.0 
STUDY MEDICATION 
7.1 
Enrollment and Blinding 
Stage 1 of the study will be a randomized (1:1:1) double blind, placebo controlled study with 
approximately thirty (30) subjects in each of the three treatment arms:  Subjects will be 
randomized (1:1:1) to receive oral doses of placebo, 10 mg VERU-944, or 50 mg VERU-944 
daily for 12 weeks. 
Stage 2 of the study will be a randomized (1:1) double blind, placebo controlled study with 
approximately thirty (30) subjects in each of the two treatment arms:  Subjects will be 
randomized (1:1) to receive oral doses of placebo or 100 mg VERU-944 daily for 12 weeks 
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 Placebo Capsules 
Placebo capsules are formulated with standard pharmaceutical excipients, such as 
pregelatinized starch and/or lactose monohydrate and will be supplied in a capsule that 
matches the VERU-944 capsules. The placebo should be stored at room temperature, 15°C to 
25°C (59°F to 77°F). 
7.2.2 VERU-944 Capsules, 10, 50 and 100 mg 
VERU-944 capsules, 10, 50 and 100 mg, are formulated with micronized VERU-944 drug 
substance and standard pharmaceutical excipients, such as pregelatinized starch and/or lactose 
monohydrate. The study drug will be supplied in 30-day kits. The study drug should be stored 
at room temperature, 15°C to 25°C (59°F to 77°F). 


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7.2.3 Drug Dose Justification 
The doses of VERU-944 (cis-clomiphene) selected in this dose finding study are 10, 50 and 
100 mg daily.  Support for the utilization of these doses results from published studies as well 
as additional work that the Sponsor has performed.  
In mouse studies, 40 mg/kg/day cis-clomiphene for 90 days results in a significant reduction 
in testicular weight as well as testicular degeneration (Fontenot GK et al., BJUI Int, 117:344-
350, 2016). Using the FDA published guidance on conversion from animal studies to humans 
(FDA, Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult 
Healthy Volunteers), the 40 mg/kg dose is multiplied by 0.08 resulting in an equivalent 
human dose of 3.25 mg/kg.  For an average weight adult (70 kg) this would correspond to 227 
mg.  In the same study, at 4 mg/kg/day there were no effects on testicular degeneration but 
seminal vesicle weights were somewhat reduced. This dose would correspond to a 22.7 mg in 
humans.  From this study, it appears that the efficacious range for cis-clomiphene will be 
above 22.7 mg with a maximum of 227 mg. 
In a study in baboons, administration of 1.5 mg/kg for 12 days resulted in mild 
reduction of total serum T levels, an estrogenic signal (Fontenot, unpublished 2001).  
Utilizing the FDA conversion from a baboon to a human dose (multiplication by 0.54), 
in an average adult, this would correspond to 56.7 mg further supporting our proposed 
dose range for the Phase 2 study.   
In ovariectomized female rats 3 mg/kg cis-clomiphene for 90 days results in the 
restoration of uterine weight to the pre-ovariectomized state similar to a 0.1 mg/kg 
dose of estradiol (Turner RT et al., Endo, 139:3712-3720, 1997).  A 3 mg/kg dose in 
rats would correspond to 33.6 mg daily dose in an average human.   
When hypogonadal men were treated with 25 mg daily clomiphene citrate for 6 
weeks, the median steady state level of cis-clomiphene was 44.0 ng/ml (Helo S et al., 
BJUI Int 119:171-176, 2017).  Assuming that clinically available clomiphene citrate 
contains 30% cis-clomiphene, that would equate to 7.5 mg daily cis-clomiphene 
resulting in these steady state levels.  Extrapolating the daily doses that will be used in 
this study, a 10 mg dose will result in steady state level of 59 ng/ml, a 50 mg dose 
would result in 293 ng/ml and a 100 mg dose would result in 1,173 ng/ml.   
In order to determine if these concentration ranges would result in estrogenic activity, 
in vitro assays were utilized.  In a transactivation assay, the effective concentration of 
cis-clomiphene appears to be in the range of 1.2 PM which correspond to a level 717.6 
ng/ml.  Based upon the Helo 2017 study, this blood level would be achieved within 
the dose finding range of 50 mg and 100 mg.  In a separate in vitro study utilizing a in 
a rat hypothalamic cell line they observed an EC50 of cis-clomiphene of 100 nM 
corresponds to a level of 60 ng/ml (Fitzpatrick SL Endo 140:3928-3937, 1999).  This 
cRQceQWUaWiRQ iV lRZeU WhaQ WhaW RbVeUYed iQ Whe SSRQVRU¶V VWXd\ aQd ma\ UeflecW, aV 
the authors point out, cell type specific differences.   
Low doses of estrogens have been shown to ameliorate vasomotor symptoms (hot 
flashes) in men who underwent bilateral orchiectomy or on ADT for advanced 


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prostate cancer.  A daily dose of 1 mg diethylstilbestrol (DES) over 12 weeks 
eliminates the hot flashes in 86% of these men (Atala A et al., Urology, 1992).  
VERU-944 is 400X less potent of an estrogen as DES based on the transactivation in 
vitro study, but does have a much longer half-life supporting the selected dose range to 
evaluate the activity of VERU-944 for the treatment of hot flashes in men who have 
advanced prostate cancer on ADT. 
VERU-944 is intended for daily maintenance dosing following a 4-day loading period. 
Due to the relatively long half-life of cis-clomiphene, the loading doses were included 
in the protocol to shorten the time to steady-state cis-clomiphene plasma levels in 
order to determine whether that dose level will have efficacy at Day 28 to treat hot 
flashes, the primary endpoint of the proposed study. During the first 4 days of 
treatment, the subjects will receive a loading dose that is determined by their 
maintenance dose (10, 50, or 100 mg). On day 1, subjects will take 5 times their 
maintenance dose at a single time; on days 2±4, subjects will take 3 times their 
maintenance dose at a single time. 
As mentioned above, the rationale for the loading dose is to achieve steady state 
quickly to meet the Food and Drug Administration (FDA) requirement for the 
demonstration of efficacy at Day 28 of dosing (FDA Draft Guidance for Industry, 
2003: Estrogen and Estrogen/Progestin Drug Products to Treat Vasomotor Symptoms 
and Vulvar and Vaginal Atrophy Symptoms ± Recommendations for Clinical 
Evaluation). Based upon the published 14.2±33.4 day half-life of cis clomiphene 
(Szutu et al., 1989), without a loading dose, evaluation of efficacy as reflected by the 
steady state will not be achieved until after Day 28. Therefore, Veru has developed a 
dosing regimen for this study that includes loading doses (see Table below).  
Cis-clomiphene, as part of the FDA approved product Clomid, has been used in men 
for off-label acute and chronic indications with limited reported safety observations. 
However, in an ongoing nonclinical toxicology study of VERU-944 in rats and beagle 
dogs, preliminary indications are that the dose of VERU-944 required to treat hot 
flashes in men with prostate cancer on ADT is between 10-50 mg (data on file). 
Moreover, at a high dose of cis-clomiphene of 20 mg/kg/day (a human equivalent dose 
of 667 mg in a 60 kg human) in male dogs, dose limiting toxicities have been 
observed. The dose limiting toxicities that have been observed include elevations in 
liver function tests (AST, ALT, alkaline phosphatase, GGT, and total bilirubin), 
weight loss and death. No significant toxicities have been observed in the ongoing 
study in rats. Due to the preliminary information that suggests a dose of VERU-944 up 
to 50 mg per day will show efficacy and safety in the proposed indication, Protocol 
V72203 has been amended so that the 100 mg dose of VERU-944 will not be used 
until and unless the dose of 50 mg VERU-944 has been shown to not be effective for 
the proposed indication and an acceptable side effect profile is determined at the 
blinded placebo, 10 mg and 50 mg doses of VERU-944 in Stage 1.   


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7.2.4 Drug Accountability 
Patients should not take a replacement dose if a dose is missed. Study medication should not 
be taken more than once a day. 
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 dispensing log should 
be kept current and should contain the dates and quantities of drug dispensed to the subject, 
Whe VXbjecW¶V ideQWificaWiRQ (i.e., VXbjecW QXmbeU), Whe initials of the dispensing persons and the 
date and quantity of drug returned. Drug accountability and reconciliation should be assessed 
and performed at each outpatient visit. At the end of the study, a final study drug 
reconciliation statement will be retrieved by the clinical monitor assigned to the site. Veru 
Inc., shall be immediately notified of any unexpected occurrences during the dispensing of 
study drug. 
7.3 
Drug Administration 
Dosing should occur greater than (1) hour before or greater than (1) hour after eating.  
Subjects will take the entire daily dose at once according to the dosing schedule below. 
Subjects randomized to the placebo group will receive placebo capsules daily. During the first 
four days of treatment, the subjects will receive a loading dose representing the dose arm that 
they have been randomized to.  On day one they will take five times their maintenance dose at 
a single time.  On days 2-4 they will take 3 times their maintenance dose at a single time each 
day.  Upon completion of the loading dose (Days 1-4), subjects in the 10 mg VERU-944 dose 
arm will receive one 10 mg capsule of VERU-944 daily.  Subjects in the 50 mg VERU-944 
dose arm will receive one 50 mg VERU-944 capsule daily. Subjects in the 100 mg VERU-
944 dose arm will receive one 100 mg VERU-944 capsule daily.  
Dosing Arm 
Day 1 
Days 2-4 
Days 5-84 
Stage 1 
Placebo 
(5 capsules) 
(3 capsules) 
(1 capsule) 
10 mg dosing arm 
50 mg (5 capsules) 
30 mg (3 capsules) 
10 mg (1 capsule) 
50 mg dosing arm 
250 mg (5 capsules) 
150 mg (3 capsules) 
50 mg (1 capsule) 
Stage 2 
Placebo 
(5 capsules) 
3 (capsules) 
(1 capsule) 
100 mg dosing arm 
500 mg (5 capsules) 
300 mg (3 capsules) 
100 mg (1 capsule) 
Amendment 4 of the protocol is implemented to change the primary endpoint from 
Week 4 (Day 28) to Week 6 (Day 42) due to the potential for some patients to have a 
longer T½ of cis-clomiphene up to 32 days. Patients with longer T½ will not reach 


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steady state within the first 2-3 weeks of dosing, even with the loading dose that is 
currently used in the protocol. Therefore, to adequately assess the effect of VERU-944 
on moderate to severe hot flashes at steady state, Week 6 (Day 42) is being named as 
the timepoint for the primary efficacy endpoint in this Phase 2 study.   
8.0 
STUDY PROCEDURES 
A summary of clinical laboratory tests (Appendix A) and a flow chart describing study 
procedures (Appendix B) can be found at the end of this document. 
8.1 
Clinic Visits 
Potential study participants will visit the clinical research facility as needed for screening 
evaluations in the 28 days prior to enrollment.  Subjects will have study related visits at Day 
1, Day 30, Day 60, and 84.  A follow-up visit will be conducted approximately 30 days after 
the last dose. 
8.2 
Screening 
Potential subjects will be screened for this study in the 28 days prior to enrollment. The 
following activities will be conducted at screening: 
1. 
Signed informed consent 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. 
Medical history will be obtained, including diagnosis of primary disease (date of 
diagnosis), clinical stage and Gleason score (individual scores and sum) at diagnosis, 
presence, date and extent of soft tissue and bone metastases, details and dates of 
primary treatment, and details and dates of prior therapies for prostate cancer, 
concurrent illnesses and family history. 
4. 
The use of any medications will be recorded (including radiation). This will include 
medications currently being taken and those taken within the last 30 days. This will 
also include the type of androgen deprivation therapy (ADT) utilized and when it was 
initiated.  Over-the-counter (OTC) medications as well as medications taken on an as-
needed basis (PRN) should be recorded. 
5. 
Vital signs (temperature/pulse/supine blood pressure) 
6. 
Physical examination including height and weight 
7. 
History of hot flash frequency and severity 
8. 
Thromboembolic risk assessment including: a) Factor V Leiden gene mutation; b) 
Lupus Anticoagulant assessment and Cardiolipin assessment; c) Prothrombin gene 
mutation; and Protein C and S.  


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NOTE: detection of lupus anticoagulant, cardiolipin antibody outside the normal 
range, prolonged PTT-LA, dRVVT and Protein C and/or Protein S deficiency are not 
exclusionary from the study. However, if a patient has lupus anticoagulant detected, 
cardiolipin outside the normal range, a prolonged PTT-LA, a prolonged dRVVT or is 
deficient for Protein C and/or Protein S, and remains eligible for participation in the 
study, prophylactic anticoagulation therapy should be considered. 
For Protein C or Protein S deficiency, consideration should be given to dietary 
changes to increase Vitamin K intake. 
9. 
Electrocardiogram- 12 lead (single) 
10. 
Caprini Venothromboembolism (VTE) Risk Assessment 
NOTE: Caprini VTE Risk is not an inclusion/exclusion criteria for the study. It is 
iQWeQded WR aVVeVV Whe SaWieQW¶V RYeUall UiVk fRU VTE aQd Whe chaQge Rf UiVk RYeU Whe 
course of the study.  
11. 
Clinical Laboratory Tests 
x Hematology (Appendix A) 
x Serum hormones (Appendix A) 
x Serum chemistry (Appendix A) 
x Urinalysis 
12. 
Measurement of frequency and severity of hot flashes utilizing electronic device 
(values over 14 contiguous days in order to establish a weekly baseline) 
x Must be at least 80% compliant during this assessment.  This translates into 
recording frequency and severity of hot flashes at least 11 of the 14 days. 
 
13. 
Bilateral Doppler ultrasound of the lower extremity (If the subject is diagnosed with a 
VTE in this assessment, the subject will not be eligible for the study under the 
exclusion criterion of history of a VTE). 
Patients that have been previously screened for this study and could not complete screening 
for reasons other than not meeting the inclusion and exclusion criteria, may be rescreened into 
the study. Laboratory testing conducted under this protocol (Appendix A) within 45 days 
prior to randomization into this study, may be used as the baseline laboratory values for this 
study and repeat laboratory testing is not required unless new coadministered medication(s) 
has been started, unless the investigator determines that retesting is warranted.  
Patients that failed screening under previous versions of the protocol due to a positive lupus 
aQWicRagXlaQW, bXW iQ ZhRm lXSXV aQWicRagXlaQW ZaV QRW ³deWecWed´ ma\ be UeVcUeeQed XQdeU 
Amendment 2, Version 7.0 of the protocol. 
Patients that failed screening under previous versions of the protocol due to indeterminant 
cardiolipin antibody, may be rescreened under Amendment 2, Version 7.0 of the protocol. 


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Patients that failed screening under previous versions of the protocol due a finding related to 
Protein C or Protein S, including patients that were excluded from participation 
inappropriately due to elevated levels of Protein S and/or Protein C above the upper limit of 
normal, may be rescreened under Amendment 2, Version 7.0 of the protocol. 
For patients that fall into the three categories outlined above, laboratory testing conducted 
under this protocol (Appendix A) within 45 days prior to randomization into this study, may 
be used as the baseline laboratory values for this study and repeat laboratory testing is not 
required unless new coadministered medication(s) has been started or if the investigator 
determines that retesting is warranted. 
 
8.3 
Enrollment 
Subjects will be enrolled from 2 to 5 days prior to the Day 1 visit. Enrollment should be done 
after the subject has completed the screening assessments and after it has been determined 
that the subject meets all the inclusion and exclusion criteria. 
Assess eligibility status for inclusion into the trial based on protocol inclusion/exclusion 
criteria, including results from screening lab assessments. 
8.4 
Day 1 Visit 
Subjects should fast for at least 8 hours (overnight) prior to this visit.  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. 
2. 
Assessment of eligibility 
3. 
Vital signs (temperature/pulse/supine blood pressure) 
4. 
Physical examination (including weight) 
5. 
Hematology (Appendix A) 
6. 
Serum chemistry (Appendix A) 
7. 
Urinalysis 
8. 
Serum hormones (Appendix A) 
9. 
Bone turnover markers (Appendix A) 
10. 
Record the usage of any concomitant medications and ongoing treatments. 
11. 
Adverse events (ongoing on Day 1) 
12. 
Caprini VTE Risk Assessment (Appendix D) 
13. 
Blood samples for pharmacokinetic assessment 
14. 
Assess hot flashes 


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15. 
Dispense study drug 
16. 
First dose- Instruct the subject to take his capsule at the same time each day 
8.5 
Day 14 Visit 
The following assessments will be conducted on Day 14 (± 3 days): 
1. Vital Signs 
2. Serum Chemistry ± (Appendix A) 
3. Record the usage of any concomitant medications and treatments 
4. Adverse events 
8.6 
Day 30 and Day 60 Visit 
Subjects should fast for at least 8 hours (overnight) prior to these visits. The following 
assessments will be conducted on Day 30 (± 7 days) and Day 60 (± 7 days): 
1. 
Vital Signs (temperature/pulse/supine blood pressure) 
2. 
Serum chemistry ± (Appendix A) 
3. 
Hematology ± (Appendix A) 
4. 
Serum hormones± (Appendix A) 
5. 
Blood samples for pharmacokinetic assessment 
6. 
Record the usage of any concomitant medications and treatments. 
7. 
Assess hot flashes (see Appendix C) 
8. 
Caprini Venothromboembolism Risk Assessment (Appendix D) 
x It is important to note that it is expected that the patient population included in this 
study will have some risk of VTE due to age, presence of a malignancy, and BMI. The 
purpose of this assessment is a change in risk from baseline. Also, while the 
questionnaire is designed for the patient to complete, in this study, the Caprini VTE 
risk assessment should be filled out by study personnel with information from the 
SaWieQW aQd SaWieQW¶V chaUW.  
If there is an increase in risk from baseline (Day 1) in this assessment, appropriate 
preventative actions should be taken. The subject should be consulted about the risk 
for VTE and actions that would increase their risk further such as long periods of 
inactivity and surgery. Prophylactic anticoagulation therapy should be considered.  
Prolonged PTT-LA, dRVVT and Protein C and/or Protein S deficiency are not 
exclusionary from the study. However, if a patient has a prolonged PTT-LA, a 
prolonged dRVVT or is deficient for Protein C and/or Protein S, and remains eligible 
for participation in the study, prophylactic anticoagulation therapy should be 
considered. 


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For Protein C or Protein S deficiency, consideration should be given to dietary 
changes to increase Vitamin K intake. 
9. 
Adverse events 
10. 
Collect capsule bottles and perform capsule accountability/compliance assessment 
11. 
Dispense study drug 
8.7 
Day 84 Visit (End of Study Visit) 
Subjects should fast for at least 8 hours (overnight) prior to this visit. The following 
assessments will be conducted on Day 84 (± 7 days): 
1. 
Vital Signs (temperature/pulse/supine blood pressure) 
2. 
Physical examination (including weight) 
3. 
Serum chemistry (Appendix A) (central laboratory) 
4. 
Hematology (Appendix A) (central laboratory) 
5. 
Serum hormones (Appendix A) (central laboratory) 
6. 
Blood samples for pharmacokinetic assessment 
7. 
Bone turnover markers 
8. 
Record the usage of any concomitant medications and treatments 
9. 
Adverse events 
10. 
Assess hot flashes (see Appendix C) 
11. 
Caprini Venothromboembolism Risk Assessment (Appendix D) 
x It is important to note that it is expected that the patient population included in this 
study will have some risk of VTE due to age, presence of a malignancy, and BMI. The 
purpose of this assessment is a change in risk from baseline. Also, while the 
questionnaire is designed for the patient to complete, in this study, the Caprini VTE 
risk assessment should be filled out by study personnel with information from the 
SaWieQW aQd SaWieQW¶V chaUW. 
If there is an increase in risk from baseline (Day 1) in this assessment, appropriate 
preventative actions should be taken. The subject should be consulted about the risk 
for VTE and actions that would increase their risk further such as long periods of 
inactivity and surgery. Prophylactic anticoagulation therapy should be considered. 
12. 
Collect capsule bottles and perform capsule accountability/compliance assessment 


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8.8 
Follow-up Visit 
The following assessments will be performed 30 days (± 7 days) after the End of Study visit 
(Day 84): 
1. 
Vital Signs (temperature/pulse/supine blood pressure) 
2. 
Physical examination (including height and weight) 
3. 
Adverse events 
8.9 
Pharmacokinetic Sampling 
8.9.1 
Blood Samples 
Samples of venous blood for the determination of trough plasma concentrations of VERU-944 
and related metabolites will be obtained on Days 1 (prior to dose), 30, 60 and 84. The sample 
should be taken prior to dosing with VERU-944 on these days. The time of the last dose of 
study drug prior to the clinic visit (day before visit) and the time of the blood samples should 
be carefully recorded. 
The blood samples should be collected in a 6 mL K2EDTA blood collection tube at each 
collection time.   
Immediately after collection, the tubes will be gently inverted several times to mix the 
anticoagulant with the blood sample. Blood samples may be kept on wet ice (the use of ice 
packs in a water bath is also acceptable) for up to 20 minutes until processed. The plasma 
fraction will be separated by placing the collection tube into a centrifuge for 10 minutes at 
1,500 x g. 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 1 hour after 
collection. (NOTE: A flash freezing in dry ice or liquid nitrogen is NOT required under this 
protocol but may be used.) 
Any remaining plasma samples after completion of the protocol outlined pharmacokinetic 
analysis may be used to identify and quantify the metabolites of VERU-944 or measure other 
biomarkers of safety or efficacy. 
8.9.2 
Plasma Sample Labels 
The plasma freezing tube labels will contain the following information: 
x Subject Number 
x Study Number 
x Site Number 
x Nominal Day Collection 
x Aliquot Number: Aliquot A or B 
x Species and Matrix: Human Plasma 
x Sample Sequence Number 


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x 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. 
8.10 Rules for Subjects that Become at High Risk for the Development of Venous 
Thromboembolic Events during the Study 
If a subject has any of the events listed below during the study, they are considered to have an 
increased risk of development of a VTE. The subject should be monitored closely and 
prophylactic anticoagulation therapy should be used if clinically indicated. These subjects are 
not required to discontinue the study if these events occur: 
1. 
Surgery 
2. 
Hospitalization 
3. 
Trauma, such as a broken long bone 
4. 
Radiation therapy to prostate for cancer control (radiation to bone to relieve pain is 
acceptable) 
5. 
Prolonged immobilization 
If a subject is expecting to have a prolonged immobilization such as a long car ride or plane 
ride or sitting at a desk for a long period of time, the subject should be instructed carefully 
about proper steps to take to prevent VTEs. Specifically, subjects should be instructed to, 
whenever possible, get up and walk around (at least every two hours) and flex your feet up 
and down while sitting by alternating raising your toes off the floor while keeping your heels 
on the floor and then pointing your toes. Subjects should also wear compression stockings if 
long periods of inactivity are expected. 
The Caprini Venothromboembolism Risk Assessment (Appendix E) rules and instructions 
should be followed. However, it is important to note that it is expected that the patient 
population included in this study will have some risk of VTE due to age, presence of a 
malignancy, and BMI. The purpose of this assessment is to monitor for increased risk from 
baseline. The events listed above will increase the risk of VTEs in these patients. 
8.11 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. 
Subjects that experience a Grade 3 or greater toxicity according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4 


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(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf) 
that is deemed to be possible, probably or definitely related to study drug will be discontinued 
from the study. Prior to discontinuation from the study, the grading of the event and causal 
relationship should be discussed with the Medical Monitor for the study. 
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. 
8.12 Early Discontinuation of Study Treatment 
A subject will be considered to have completed the trial if they received at least 84 days of 
treatment with VERU-944 or the study is terminated by the sponsor.  Subjects may 
prematurely discontinue study treatment for any of the following reasons: 
1.
Consent Withdrawn (specify the reason).
2.
Significant and unacceptable adverse event ± specify the adverse event leading to
discontinuation
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.
Study terminated by the Sponsor
8.
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 prematurely will not be replaced. If a subject is discontinued from 
the study, he will be asked to complete all End of Study visit assessments and return all study 
materials (study medication and electronic device). At the time of discontinuation, please fill 
out the End of Study case report forms (eCRFs) and subject disposition eCRF pages. 
8.13 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). 


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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. These AEs will be captured as part of the medical history. 
Each subject will be assessed for the development of any adverse events. Adverse events 
should be assessed at each visit to the clinic. 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 4 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 due to an adverse event will be followed until 
the outcome of the event is determined, and the investigator will prepare a written summary 
of the event and document the available follow-up information on the case report form. 
8.13.1 
Intensity of Adverse Events 
The intensity of the AEs will be graded according to CTCAE version 4. For any adverse event 
that is not specifically covered in CTCAE version 4, the following criteria should be used: 


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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). 
8.13.2 
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. 
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 
³DefiQiWe´ Zill be cRQVideUed WUeaWmeQW-related events. 


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8.13.3 
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: 
x Results in death. 
x Is life-threatening. 
x Requires inpatient hospitalization or causes prolongation of existing hospitalization 
x Results in persistent or significant disability/incapacity. 
x Results in congenital abnormality/birth defect. 
x Requires intervention to prevent permanent impairment or damage 
An SAE also may include other events, based on medical judgment, which jeopardize the 
patient or 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 30 days 
following cessation of 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 Worldwide Clinical Trials Drug Safety at the contact 
information below. 
Worldwide Clinical Trials Drug Safety Contact Information: 
Fax number: 1-866-387-5539 or +44 (0) 115 922 0960 
E-mail: 
drugsafety@worldwide.com 
Worldwide Clinical Trials Medical Monitor: 
Noor Khaskhely, MD, PhD Sr. Medical Director, Medical Affairs Worldwide 
Clinical Trials 
Office +1 610 632 8151Mobile +1 919 324 4351 
 noor.khaskhely@worldwide.com 
8.13.4 
Initial Reports 
SAEs will be collected from the time of first study drug administration through 30 days after 
receipt of final dose of study drug.  SAEs and events of clinical interest must be reported to 
the Sponsor (or designee) within 24 hours of the knowledge of the occurrence.  


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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.  
8.13.5 
Precautions 
Adverse events should be treated in accordance with standard medical practice. During the 
course of the study, the overall safety, tolerability and pharmacokinetics of all study 
treatments will be reviewed by the sponsor and the investigator. 
8.13.6 
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 
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. 
8.14 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. 
Any radiation therapy (linear beam or seeds) taken by the subject within 30 days prior to the 
Screening Visit and during the course of the study, including type of treatment, and duration 
of the treatment will be recorded on the eCRF. 


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8.15 Prohibited Medications 
The following medications are prohibited with the appropriate washout period, if any, for 
each prohibited medication: 
x All anabolic steroids and supplements containing anabolic steroids are prohibited from use 
during the study. This includes, but is not limited to, testosterone and testosterone-like 
compounds. Use of anabolic steroids and supplements containing anabolic steroids >6 
months prior to screening into the study is allowed. 
x Medroxyprogesterone acetate is prohibited from use during the study. Use of 
medroxyprogesterone >6 months prior to screening into the study is allowed. 
x Clomiphene (Clomid® or a generic equivalent to Clomid) is prohibited from use during 
the study. Use of clomiphene >6 months prior to screening into the study is allowed. 
x Diethylstilbestrol and estrogen therapy are prohibited from use during the study. Use of 
diethylstilbestrol and estrogen therapy >6 months prior to screening into the study is 
allowed. 
x Initiation of treatment with selective serotonin reuptake inhibitors not allowed during the 
study and 6 months prior to the study is not allowed. However, if a patient is on stable 
sSSRI for >6 months prior to screening and is still qualifies for the study, this is allowed. 
x Cytotoxic chemotherapy is prohibited from use during the study. 
x Saw Palmetto, Black Cohosh, soy pills and PC-SPES are prohibited from use during the 
study. However, a washout period of >90 days prior to screening is allowed. 
x Gabapentin is prohibited from use during the study. A washout period of >60 days from 
screening is allowed.  
x Other experimental study medications are prohibited from use during the study. A 
washout of > 90 days prior to screening is allowed. 
8.16 Withdrawal of Subjects 
a. 
Any subject found to have entered the study in violation of the protocol will be 
withdrawn from the study. 
b. 
An effort must be made to determine why any subject discontinues the study 
prematurely. This information will be recorded on the case report form. 
c. 
All subjects reserve the right to withdraw from the study at any time. The investigator 
will encourage all subjects who decide to withdraw from the study to complete all 
evaluations which may be necessary to assure that the subject is free of untoward effects 
and to seek appropriate follow-up for any continuing problems. 
d. 
Any subjects who develop a clinically significant medical condition, as judged by the 
investigator, so that the subject no longer meets the inclusion/ exclusion criteria. 
e. 
Any subject who requires the use of an unacceptable concomitant medication will be 
withdrawn from the study. 
The investigator will withdraw any subject from the study if, in the investigator's opinion, it is 
not in the subject's best interest to continue. No subject that discontinues from the study for 
any reason will be replaced. 


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The date the subject is withdrawn from the study and the reason for discontinuation will be 
recorded on the case report form. When a subject fails to return for scheduled study visits, the 
investigator will make a reasonable effort to contact the subject and determine why the 
subject failed to return. This information will be documented on the study records. When a 
subject is withdrawn from the study (regardless of the reason), all evaluations required at the 
final study visit should be performed. 
9.0 
STATISTICAL ANALYSIS 
9.1 
Sample Size Calculation 
The proposed trial sample size, n=30 per arm, total N=90 in Stage 1, is based on the mean 
change in hot flash frequency from baseline to Week 4 (Day 28) (the planned primary 
endpoint at the time of the original study design). Other assumptions include: one-sided 
Į=0.10; ȕ=0.10 (i.e., power=0.9), equal variances, the variance is equal to the mean of the 
active arm, and a frequency in at least one treated arm that is 40% less than that of the placebo 
arm on Week 4 (Day 28). The same assumptions hold for Stage 2 as well with proposed trial 
sample size of n=30 per arm, N=60 in Stage 2.  Total enrollment if both stages are completed 
will be approximately N=150.   
All patients in screening at the time that the 90th patient is randomized into Stage 1 of the 
study that qualify for the study will be randomized into the study up to a maximum of 120 
patients (40 per arm). In Stage 2, all patients in screening at the time the 60th patient is 
randomized into Stage 2 of the study that qualify for the study will be randomized into the 
study up to a maximum of 80 patients (40 per arm).  
9.2 
Populations 
Intent-to-Treat (ITT) population: All enrolled subjects who have taken at least one dose of 
study drug. 
Efficacy Evaluable (EE) population: All subjects in the ITT population who have 
analyzable baseline data and 12 weeks of hot flash data. Subjects must also be at least 80% 
compliant with taking study drug with no major protocol deviations, including no major 
inclusion/exclusion deviations. 
Efficacy Evaluable Interim Analysis (EEIA) population: All subjects in the ITT 
population who have analyzable baseline data and 6 weeks of hot flash data. Subjects must 
also be at least 80% compliant with taking study drug with no major protocol deviations, 
including no major inclusion/exclusion deviations. 
Safety population: All subjects that receive at least one dose of study medication. The safety 
analyses will be conducted on this population. 
9.3 
Efficacy Analyses 
The primary efficacy analyses will be among the EE (EEIA) population.  The comparison of 
percentage change in frequency from baseline to Week 6 between the placebo arm and each 


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of the 10 mg and 50 mg dose arms will be of primary interest in Stage 1. In Stage 2, the 
comparison of percentage change in frequency from baseline to Week 6 between the placebo 
arm and the 100 mg dose arm will be of primary interest.   
Subjects will record events of hot flashes (frequency and severity) utilizing an application on 
an electronic device (i.e. smartphone). An example of the specific questions asked and 
definitions of severity are included in Appendix C 
9.3.1 
Primary Analyses 
9.3.1.1 Hot Flash Frequency, Week 6 (Day 42) 
Mixed models repeated measures (MMRM) analyses that incorporate, treatment, time, 
and the treatment*time interactions will be the primary analytical method for the 
percentage change in the frequency of moderate to severe hot flashes.  The percentage 
change from baseline in frequency of moderate to severe hot flashes in each active 
arm will be compared to the placebo arm at Week 6 (Day 42). The analysis will be 
handled in two ways within the MMRM framework: (1) the means analysis comparing 
the change from baseline to Week 6, and (2) the slope analysis comparing the rate of 
change from baseline to Week 6. 
 
The primary endpoint in the study will be analyzed when the last patient reaches Day 
42. However, the clinical site and patients will remain blinded through the completion 
of the Day 84 efficacy assessments and the follow up safety visits. 
Each VXbjecW¶V hRW flaVh fUeTXeQc\ will be summed on a weekly basis. Because the 
MMRM is the primary analytical method, it will be possible to estimate Week 6 
changes from baseline by incorporating the preceding weeks¶ daWa, e.g., Week 6 
estimates will incorporate data from baseline and Week 1 through Week 6.  Analyses 
will be performed for the EE (EEIA) populations. 
If the MMRM model does not converge or has poor fit, T-tests or non-parametric 
tests, if the data are deemed non-normally distributed, will compare changes over time 
within (Paired T-test or Wilcoxon sign-rank test) an arm and between (T-test or 
Wilcoxon rank sum test) each active arm and the placebo arm, respectively.  
The Hochberg procedure (Hochberg Y, 1988) will be applied to control for the 
multiple comparisons associated with the comparisons between the two dose arms and 
placebo and the two different MMRM analyses (means, slope) in the primary analyses 
of frequency of hot flashes in Stage 1. The analyses for Stage 2 will be treated 
similarly to address the multiplicity of the MMRM analyses.  Note that the placebo 
arm in Stage 2 comprises a cohort of subjects distinct from those placebo subjects that 
were enrolled during Stage 1. 
 


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9.3.2 
Secondary Analyses 
9.3.2.1 Hot Flash Frequency (Weeks 4, 8, 10 and 12) and Severity (Weeks 4, 6, 8, 
10, and 12) 
Mixed models repeated measures (MMRM) analyses that incorporate, treatment, time, 
and treatment*time interactions will be the primary analytical method for the 
percentage change in both the frequency and severity of moderate to severe hot 
flashes:  frequency (severity).  The percentage change from baseline in frequency 
(severity) of moderate to severe hot flashes in each active arm will be compared to the 
placebo arm at Week 4 (Day 28), Week 8 (Day 56), Week 10 (Day 70), and Week 12 
(Day 84). Each analysis will be handled in two ways within the MMRM framework, 
as described for the primary analysis above. 
Each VXbjecW¶V hRW flaVh fUequency (severity) will be summed on a weekly basis. 
Because the  MMRM is the primary analytical method, it will be possible to estimate 
Weeks 4, 8, 10, and 12 changes from baseline by incorporating the precediQg ZeekV¶ 
data, e.g., Weeks 4, 8, 10, and 12 estimates will incorporate data from baseline and 
Week 1 through Weeks 4, 8, 10, and 12. Analyses will be performed for the ITT and 
PP populations. 
If the MMRM model does not converge or has poor fit, T-tests or non-parametric 
tests, if the data are deemed non-normally distributed, will compare changes over time 
within (Paired T-test or Wilcoxon sign-rank test) an arm and between (T-test or 
Wilcoxon rank sum test)  each active arm and the placebo arm, respectively.  
If the MMRM model does not converge or has poor fit, non-parametric tests will 
compare changes over time within (Wilcoxon sign-rank test) an arm and between 
(Wilcoxon rank sum test) active arms and the placebo arm, respectively.  
The Hochberg procedure (Hochberg Y, 1988) will be applied to control for the 
multiple comparisons associated with the comparisons between the two dose arms and 
placebo and the two different MMRM analyses in the analyses of frequency (severity) 
of hot flashes for Stage 1. The analyses for Stage 2 will be treated similarly to address 
the multiplicity of the two MMRM analyses.  Note that the placebo arm in Stage 2 
comprises a cohort of subjects distinct from those placebo subjects that were enrolled 
during Stage 1.  
The severity of hot flash analysis will be the average severity at baseline of only the 
moderate and severe hot flashes. The severity of hot flashes analysis at Weeks 4, 6, 8, 
10, and 12 will be the average severity of all hot flashes, i.e. mild, moderate, and 
severe hot flashes. 
 
See the Statistical Analysis Plan for the study for full and complete statistical analyses 
planned for the study. 


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9.3.2.2 Bone Turnover Markers 
Values at baseline and each scheduled assessment (Day 84) for each treatment group 
will be assessed. The mean, standard deviation, median, minimum, and maximum 
values will be summarized at each of these time points. The percentage change from 
baseline to Day 84 will be summarized as well. This will be done for the ITT 
population. T-tests or non-parametric tests, if the data are deemed non-normally 
distributed, will compare changes over time within (Paired T-test or Wilcoxon sign-
rank test) an arm and between (T-test or Wilcoxon rank sum test)  each active arm and 
the placebo arm, respectively.  
9.3.3 Exploratory Analyses 
9.3.3.1 Serum PSA 
Values at baseline and each scheduled assessment (Days 30, 60, and 84) in each 
treatment group will be assessed. The mean, standard deviation, median, minimum, 
and maximum levels will be summarized at each of these time points. The percentage 
change from baseline to each time point will be summarized as well. This will be done 
for the ITT population. T-tests or non-parametric tests, if the data are deemed non-
normally distributed, will compare changes over time within (Paired T-test or 
Wilcoxon sign-rank test) an arm and between (T-test or Wilcoxon rank sum test) each 
active arm and the placebo arm, respectively.  
9.3.3.2 Change in Serum Total and Free Testosterone Concentration  
Values at baseline and each scheduled assessment (Days 30, 60, and 84) for each 
treatment group will be assessed. The mean, standard deviation, median, minimum, 
and maximum lab values will be summarized at each of these time points. The 
percentage change from baseline to each time point will be summarized as well. This 
will be done for the ITT population. T-tests or non-parametric tests, if the data are 
deemed non-normally distributed, will compare changes over time within (Paired T-
test or Wilcoxon sign-rank test) an arm and between (T-test or Wilcoxon rank sum 
test) each active arm and the placebo arm, respectively.  
9.3.3.3 Serum SHBG 
Values at baseline and each scheduled assessment (Days 30, 60, and 84) for each 
treatment group will be assessed. The mean, standard deviation, median, minimum, 
and maximum lab values will be summarized at each of these time points. The 
percentage change from baseline to each time point will be summarized as well. This 
will be done for the ITT population. T-tests or non-parametric tests, if the data are 
deemed non-normally distributed, will compare changes over time within (Paired T-
test or Wilcoxon sign-rank test) an arm and between (T-test or Wilcoxon rank sum 
test) each active arm and the placebo arm, respectively.   
9.3.3.4 Pharmacokinetic Assessments 


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VERU-944 trough concentrations will be determined in each subject and used to 
calculate the mean, median, standard deviation, coefficient of variation, maxima and 
minima within each arm of the trough levels of VERU-944. 
9.3.4 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 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 patient 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. 
9.3.4.1 Data Safety Monitoring Board 
There will be no formal Data Monitoring Committee for this study. Safety data, 
including all SAEs, will be reviewed on an ongoing basis by a Safety Review Team 
comprised of the Medical Monitor, and representatives of the Sponsor. This Safety 
Review Team will meet at least monthly.  Additional ad hoc meetings will be 
scheduled if required to evaluate the safety and/or thromboembolic events further.     
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, statistical analysis, quality 
assurance and the final study report. The Sponsor will be responsible for project management 
of the CRO and clinical monitoring. 
Sponsor Emergency Contact Info: 
K. Gary Barnette, Ph.D. 
Chief Scientific Officer 
Veru Inc. 
 
Cell: 919-426-3611 
 


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FINAL: AMENDMENT 4 30 October 2019 
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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 
Whe QaWXUe, SXUSRVe, beQefiWV aQd UiVkV Rf SaUWiciSaWiRQ iQ Whe VWXd\ WR each VXbjecW, VXbjecW¶V 
legally acceptable representative 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 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 Ueadil\ XQdeUVWRRd b\ Whe VXbjecW. Each VXbjecW¶V RUigiQal 
cRQVeQW fRUm, SeUVRQall\ VigQed aQd daWed b\ Whe VXbjecW RU b\ Whe VXbjecW¶V legall\ acceSWable 
representative, 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 
IQYeVWigaWRU¶V UeVSRQVibiliW\ WR eQVXUe WhaW all VXbjecWV VXbVeTXeQWl\ eQWeUed iQWR Whe VWXd\ aQd 
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 VXbjecW, iQfRUm Whe VXbjecW¶V SUimaU\ 
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: 


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Protocol V72203 – FINAL Version 9.0 
 
FINAL: AMENDMENT 4 30 October 2019 
- 40 - 
x 
Non-Substantial Amendments aUe WhRVe WhaW aUe QRW cRQVideUed µVXbVWaQWial¶ (e.g., 
administrative changes) and as such only need to be notified to the IECs/IRBs or 
Competent Authorities (CA) for information purposes. 
x 
Substantial Amendments aUe WhRVe cRQVideUed µVXbVWaQWial¶ WR Whe cRQdXcW Rf Whe cliQical 
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 
Rf Whe CA iQ Whe EU membeU VWaWeV, aSSURYal RU µfaYRUable RSiQiRQ¶ caQ be aVVXmed if Whe 
CA has raised no grounds for non-acceptance during an allocated time period (to be 
cRQfiUmed ZiWh Whe SSRQVRU¶V RegXlaWRU\ AffaiUV (RA) UeSUeVeQWaWiYe) fRllRZiQg 
acknowledgment of receipt of a valid application to make a substantial amendment. 
x 
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. 


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FINAL: AMENDMENT 4 30 October 2019 
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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: 
x Latest version of MedDRA (version 18.1 or higher) for medical history and AEs, and 
x World Health Organization Drug Dictionary Enhanced (Sept. 2015 or later) for prior and 
concomitant medications. 
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 


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FINAL: AMENDMENT 4 30 October 2019 
- 42 - 
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 
AV UeTXiUed b\ lRcal UegXlaWiRQV, Whe SSRQVRU¶V RegXlaWRU\ 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. 
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 
SSRQVRU aQd aXWhRUV (RU Whe aXWhRU¶V iQVWiWXWiRQ). ReTXeVWed ameQdmeQWV Zill be iQcRUSRUaWed 
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 
aXWhRUV (RU aXWhRUV¶ iQVWiWXWiRQ) afWeU UeceiSW Rf Whe SURSRVed SXblicaWiRQ b\ Whe SSRQVRU, 
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. 


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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 
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  
1. 
American Cancer Society. Cancer Facts & Figures 2017. Atlanta: American Cancer 
Society; 2017. 
2. 
Brosman S.  1995 Depo-Provera as a treatment for hot flashes in men on androgen 
ablation therapy.  J Urol 153(4):448A. 
3. 
Djavan, B., Eastham, J., Gomella, L., Tombal, B., Taneja, S., Dianat, S.S., Kazzazi, A., 
Shore, N., Abrahamsson, P.-A., and Cheetham, P., et al. 2012. Testosterone in prostate 
cancer: the Bethesda consensus. BJU International 110, 344-352. 
4. 
Eaton A, McGuire N.  1993  Cyproterone acetate in treatment of post-orchidectomy hot 
Flushes.  Lancet 2:1336-1137. 
5. 
Engstrom, C.A. (2008). Hot flashes in prostate cancer: state of the science. American 
journal of men's health 2, 122-132. 
6. 
Evans ML, Pritts E, Vittinghoff E, McClish K, Morgan KS, Jaffe RB. 2005  Obstet 
Gynecol. 105(1):161-6. 


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7. 
Fitzpatrick, S.L., Berrodin, T.J., Jenkins, S.F., Sindoni, D.M., Deecher, D.C., and Frail, 
D.E. (1999). Effect of estrogen agonists and antagonists on induction of progesterone 
receptor in a rat hypothalamic cell line. Endocrinology 140, 3928-3937. 
8. 
Frisk J. (2010). Managing hot flushes in men after prostate cancer--a systematic review. 
Maturitas 65, 15-22. 
9. 
Gerber GS, Zagaja GP, Ray PS, Rukstalis DB.  2000  Transdermal estrogen in the 
treatment of hot flushes in men with prostate cancer.  Urology 55(1):97-101. 
10. Glashan RW and Robinson MR.  1981  Cardiovascular complications in the treatment of 
prostatic carcinoma.  Br J Urol. 53(6):624-627. 
11. Holzbeierlein JM, Castle E, Thrasher JB. 2004. Complications of Androgen Deprivation 
Therapy: Prevention and Treatment. Oncology (Williston Park) . Mar; 18(3):303-309, 
discussion 310, 315, 319-321. 
12. Irani, J., Salomon, L., Oba, R., Bouchard, P., and Mottet, N. (2010). Efficacy of 
venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for the treatment of 
vasomotor hot flushes in men taking gonadotropin-releasing hormone analogues for 
prostate cancer: a double-blind, randomized trial. The Lancet. Oncology 11, 147-154. 
13. Isbarn H, Boccon-Gibod L, Carroll PR, Montorsi F, Schulman C, Smith MR, Sternberg 
CN, Studer UE.  2009.  Androgen deprivation therapy for the treatment of prostate 
cancer: consider both benefits and risks.  Eur. Urol. 55(1):62-75. 
14. Kaminetsky, J., Werner, M., Fontenot, G., and Wiehle, R.D.  2013. Oral enclomiphene 
citrate stimulates the endogenous production of testosterone and sperm counts in men 
with low testosterone: comparison with testosterone gel. The journal of sexual medicine 
10, 1628-1635 
15. Kaplan, M., and Mahon, S. (2014). Hot flash management: update of the evidence for 
patients with cancer. Clinical journal of oncology nursing 18 Suppl, 59-67. 
16. Karling P, Hammar M, Varenhorst E. 1994. Prevalence and duration of hot flushes after 
surgical or medical castration in men with prostatic carcinoma. J Urol 152:1170±3.  
17. Larocca A, Cavallo F, Bringhen S, et al. 2012. Aspirin or enoxaparin 
thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with 
lenalidomide. Blood. Jan 26; 119(4):933-939; quiz 1093. Epub 2011 Aug 11. 
18. Loprinzi CL, Dueck AC, Khoyratty BS, Barton DL, Jafar S, Rowland KM, Atherton PJ, 
Marsa GW, Knutson WH, Bearden JD, Kottschade L and Finch TR.  1999  A phase III 
randomized, double-blind, placebo-controlled trial of gabapentin in the management of 
hot flashes in men (N00CB).  Ann Oncol. 20(3): 542-549. 


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Protocol V72203 – FINAL Version 9.0 
 
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19. Loprinzi CL, Michalak JC, Quella SK, et al.  1994 Megestrol acetate for the prevention 
of hot flashes.  N Engl J Med 331(6):347-352. 
20. Loprinzi CL, Quella SK, Sloan JA, et al.  1999 Preliminary data from a randomized 
evaluation of fluoxetine (Prozac) for treating hot flashes in breast cancer survivors.  Proc 
San Antonio Breast Cancer Society. 
21. Loprinzi, C.L., Michalak, J.C., Quella, S.K., O'Fallon, J.R., Hatfield, A.K., Nelimark, 
R.A., Dose, A.M., Fischer, T., Johnson, C., and Klatt, N.E. (1994). Megestrol acetate for 
the prevention of hot flashes. The New England Journal of Medicine 331, 347-352. 
22. Mense SM, Remotti F, Bhan A, et al. 2008. Estrogen-induced breast cancer: alterations in 
breast morphology and oxidative stress as a function of estrogen exposure. Toxicol Appl 
Pharmacol. Oct:232(1):78-85. Epub 2008 Jul 1. 
23. Moraska AR, Atherton PJ,  Szydlo DW, Barton DL, Stella PJ, Rowland KM, Schaefer 
PL, Krook J, Bearden JD and Loprinzi CL.  2010.  Gabapentin for the Management of 
Hot Flashes in Prostate Cancer Survivors: A Longitudinal Continuation Study ± NCCTG 
Trial N00CB.  J Support Oncol., 8(3):128-132. 
24. Mürdter, T.E., Kerb, R., Turpeinen, M., Schroth, W., Ganchev, B., Böhmer, G.M., Igel, 
S., Schaeffeler, E., Zanger, U., and Brauch, H., et al. (2012). Genetic polymorphism of 
cytochrome P450 2D6 determines oestrogen receptor activity of the major infertility drug 
clomiphene via its active metabolites. Hum. Mol. Genet. 21, 1145-1154. 
25. National Comprehensive Cancer Network (2016). NCCN Guidelines for Patients: 
Prostate Cancer (Fort Washington, PA). 
26. Roth A, Scher H.  1997 Sertraline relieves hot flashes secondary to medical castration as 
treatment of advanced prostate cancer.  Psychooncology 7:129-132. 
27. Schow DA, Renfer LG, Rozanski TA, Thompson IM. Prevalence of hot flushes during 
and after neoadjuvant hormonal therapy for localized prostate cancer. South Med 
J. 1998;91:855±857. 
28. Siegel R, Naishadham D, Jemal A. 2012. Cancer Statistics, 2012. CA Cancer J Clin. 
Jan-Feb; 62(1):10-29. Epub 2012 Jan 4. 
29. Smith JA. 1994  A prospective comparison of treatments for symptomatic hot flushes 
following endocrine therapy for carcinoma of the prostate.  J Urol.  152(1):132-134. 
30. Smith JA. 1996  Management of hot flushes due to endocrine therapy for prostate 
carcinoma.  Oncology (Willston Park) 10(9):1319-1322. 
31. Smith, M.R., and Crawford, E.D. (2017). Side Effects of Androgen Deprivation Therapy. 


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32. Szutu, M., Morgan, D.J., McLeish, M., Phillipou, G., Blackman, G.L., Cox, L.W., and
Dollman, W. (1989). Pharmacokinetics of intravenous clomiphene isomers. Br. J Clin
Pharmacol. 27, 639-640.
33. Turner, R.T., Evans, G.L., Sluka, J.P., Adrian, M.D., Bryant, H.U., Turner, C.H., and
Sato, M. (1998). Differential responses of estrogen target tissues in rats including bone to
clomiphene, enclomiphene, and zuclomiphene. Endocrinology 139, 3712-3720.
34. Ulloa E.W., Salup, R., Patterson, S.G., and Jacobsen, P.B. (2009). Relationship between
hot flashes and distress in men receiving androgen deprivation therapy for prostate
cancer. Psycho-oncology 18, 598-605.
35. Vitolins, M.Z., Griffin, L., Tomlinson, W.V., Vuky, J., Adams, P.T., Moose, D., Frizzell,
B., Lesser, G.J., Naughton, M., and Radford, J.E., JR, et al. (2013). Randomized trial to
assess the impact of venlafaxine and soy protein on hot flashes and quality of life in men
with prostate cancer. Journal of clinical oncology : official journal of the American
Society of Clinical Oncology 31, 4092-4098.
36. Hochberg, Y (1988).  A sharper Bonferroni procedure for multiple tests of significance.
Biometrika 75(4), 800-2.


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12.0 
APPENDICES 
12.1 Appendix A: 
Clinical Laboratory Tests (central laboratory) 
Hematology: 
Urinalysis: 
Hemoglobin 
pH 
Hematocrit 
Specific Gravity 
Red Blood Cell Count 
Protein 
White Blood Cell Count 
Glucose 
White Blood Cell Differential 
Leucocytes 
Platelet Count 
Nitrates 
Reticulocyte Count 
Ketones 
 
Blood 
³Serum Hormones´ 
Microscopic Examination (only if urinalysis 
results are abnormal) 
LH 
 
FSH 
 
Total testosterone (LC-MS/MS) 
Serum Chemistry: 
Free testosterone (LC-MS/MS) 
Sodium 
Sex Hormone Binding Globulin 
Potassium 
Serum PSA 
Chloride 
 
Bicarbonate 
 
BUN 
Bone turnover markers 
Creatinine 
C-telopeptide (CTX) 
Calcium 
Bone specific alkaline phosphatase 
Phosphorus 
 
Total Protein 
 
Albumin 
Thromboembolic Risk Assessment 
Total Bilirubin 
Factor V Leiden gene mutation 
SGOT (ALT) 
Antiphospholipid antibodies for Lupus  
SGPT (AST) 
Anticoagulant and Anticardiolipin  
Alkaline phosphatase 
Prothrombin gene mutation 
LDH 
Protein C and S 
GGT 
 
Glucose 
 
 
 
 


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12.2 Appendix B: 
Schedule of Study Evaluationse 
Day 
Screena 
 
Pre-
Randomiz
ation 
during 
screening 
period 
1 
14 
30 
60 
84 
End of 
study 
Follow-up 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
X 
 
 
 
 
 
Assessment of Eligibility (For 
Screening visit capture history of hot 
flashes frequency and severity 
X 
X 
X 
 
 
 
 
 
Physical Exam 
X 
 
X 
 
 
 
X 
X 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
12-lead ECG (single) 
X 
 
 
 
 
 
 
 
Clinical Laboratory Tests 
 
 
 
 
 
 
 
 
Hematology 
X 
 
X 
 
X 
X 
X 
 
Urinalysis 
X 
 
X 
 
 
 
 
 
Serum Chemistry 
X 
 
X 
X 
X 
X 
X 
 
Serum Hormones 
X 
 
X 
 
X 
X 
X 
 
Blood sample for pharmacokinetic 
assessmentc 
 
 
X 
 
X 
X 
X 
 
Bone turnover markers 
 
 
X 
 
 
 
X 
 
Thromboembolic risk assessment 
X 
 
 
 
 
 
 
 
Bilateral Doppler ultrasound of the 
lower extremities 
 
X 
 
 
 
 
 
 
Assess hot flashes (electronic diaries) 
 
X 
X 
 
X 
X 
X 
 
First dose 
 
 
X 
 
 
 
 
 
Dispense study drug 
 
 
X 
 
X 
X 
 
 
Collect capsule bottles (even if 
empty) and perform 
accountability/compliance 
assessment b 
 
 
 
 
X 
X 
X 
 
Assessment of conmeds 
X 
 
X 
X 
X 
X 
X 
 
Assessment of AEs 
 
 
X 
X 
X 
X 
X 
X 
Caprini VTE risk assessment d 
X 
 
X 
 
X 
X 
X 
 
a Screening evaluations to be conducted within 28 days prior to Day 1. 
b. Collect capsule bottles (even if empty) and perform accountability/compliance assessment throughout the participation of the subject in the 
study. 
c.  The pharmacokinetic blood samples should be done prior to receiving the dose of study drug for that day. 
d.  It is important to note that it is expected that the patient population included in this study will have some risk of VTE due to age, presence of a 
malignancy, and BMI. The purpose of this assessment is a change in risk from baseline. Also, while the questionnaire is designed for the 
patient to complete, in this study, the Caprini VTE risk assessment should be filled out by study personnel with information from the patient 
and SaWieQW¶V chaUW. 
e. The same schedule of study evaluations will be used in Stage 1 and Stage 2 of this protocol.


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11.3 
Appendix C: Hot Flash Assessments 
Assessments of hot flashes will be made at baseline (14 contiguous days during screening) 
and daily from Day 1 (first dose) to the end of the study. Patients will record frequency 
and severity of hot flashes using an electronic diary (eDiary) to ensure attributable, time 
stamped data collection in an unsupervised environment.  When experiencing a hot flash 
the subject will indicate on the app that they have had a hot flash and then will assign a 
severity to the hot flash based upon the following scale: 
A. MILD:  sensation of heat without sweating 
B. MODERATE:  sensation of heat with sweating, able to continue activity 
C. SEVERE:  sensation of heat with sweating, causing cessation of activity 
 
The hot flashes will then be compiled to examine the number of hot flashes during the 
period and their severity. 
 


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12.3 Appendix D: Caprini Venous Thromboembolism Risk Factor Assessment 
 
 


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PROTOCOL SIGNATURE PAGE 
 
Protocol Number: 
V72203 
Protocol Date: 
FINAL/ 09 July 2018 
 
AMENDMENT 1 FINAL/ 29 October 2018 
 
AMENDMENT 2 FINAL/17 January 2019 
 
AMENDMENT 3 FINAL/22 February 2019 
 
AMENDMENT 4 FINAL/30 October 2019 
Protocol Title: 
 
Randomized, double-blind, placebo controlled, dose finding Phase 2 
study comparing oral daily dosing of VERU-944 after a week of 
loading (daily dosing) with placebo to ameliorate the vasomotor 
symptoms resulting from androgen deprivation therapy in men with 
advanced prostate cancer 
 
 
 
 
 
 
SIGNATURE: 
 
 
 
Sponsor 
 
Date 
 
 
Name and Title of Sponsor Representative 
 
 
 
This signature of the Sponsor Representative constitutes approval of this protocol. 
 
 


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FINAL: AMENDMENT 4 30 October 2019 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: 
V72203 
Protocol Title: 
Randomized, double-blind, placebo controlled, dose finding Phase 2 
study comparing oral daily dosing of VERU-944 after a week of 
loading (daily dosing) with placebo to ameliorate the vasomotor 
symptoms resulting from androgen deprivation therapy in men with 
advanced prostate cancer 
Protocol Date:  
FINAL/ 09 July 2018 
 
AMENDMENT 1 FINAL/ 29 October 2018 
 
AMENDMENT 2 FINAL/17 January 2019 
 
AMENDMENT 3 FINAL/22 February 2019 
 
AMENDMENT 4 FINAL/30 October 2019 
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: 
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STATISTICAL ANALYSIS PLAN  
 
 
Veru Inc. 
48 NW 25th St., Suite 102 
Miami, FL 33127 
 
 
 
 
RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, 
DOSE FINDING PHASE 2 STUDY COMPARING ORAL DAILY 
DOSING OF VERU-944 AFTER A WEEK OF LOADING (DAILY 
DOSING) WITH PLACEBO TO AMELIORATE THE 
VASOMOTOR SYMPTOMS RESULTING FROM ANDROGEN 
DEPRIVATION THERAPY IN MEN WITH ADVANCED 
PROSTATE CANCER 
 
 
 
Protocol No: V72203 
Protocol Date/Version: 30OCT2019, Version 9.0, Amendment 4  
 
 
 
 
 
 
 
 
 
 
 
 
This document contains confidential information of Veru Inc.  Any viewing or disclosure of such 
information that is not authorized in writing by Veru Inc. is strictly prohibited.  Such information may be 
used solely for the purpose of reviewing or performing this study.  


Approval 
Veru Inc. 
STATISTICAL ANALYSIS PLAN 
Veru Inc. 
V72203 
Version: 2.0 300ct2019 
48 NW 25th St., Suite 102 
Miami, FL 33127 
Randomized, double-blind, placebo controlled, dose finding Phase 2 
study comparing oral daily dosing ofVERU-944 after a week of 
loading (daily dosing) with placebo to ameliorate the vasomotor 
symptoms resulting from androgen deprivation therapy in men with 
advanced prostate cancer 
arnette, PhD 
Chief Scientific Officer 
Vel'tdij~~ 
NJich~elL I:Jancqc~ NJS, CCRP 
Consultant Biostatistician 
Veru Inc. 
Protocol No: V72203 
· ~>!.J~ 
Confidential 
10/30/2019 
Approy~tl>ate 
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• lo/30/zo1~ 
Page 2 of 32 


 
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REVISION HISTORY 
 
Version 1: 7 February 2019 – Version 2, dated 30 October 2019 replaces Version 1 dated 7 
February 2019. The significant changes made between Version 1 and Version 2 are: 
1. The time of the primary endpoint is assessed is changed from Day 28 to Day 42. This 
change is being made to address the potentially long terminal half-life of cis-clomiphene 
in some patients (up to 30+ days). 
2. The severity of hot flashes is moved from a primary endpoint to secondary endpoints. 
3. Frequency and severity of the hot flashes will be conducted at Weeks 4, 6, 8, 10 and 12. 
4. Wilcoxon rank sum test and t-tests are added as prospective analyses in this Phase 2 
study. 
5. Other clarifying edits are made. 
 
 


 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................................6 
1. 
INTRODUCTION .............................................................................................................................8 
2. 
STUDY OBJECTIVES .....................................................................................................................8 
2.1 
Primary Objective .........................................................................................................................8 
2.2 
Secondary Objectives ....................................................................................................................8 
2.3 
Exploratory Objectives .................................................................................................................8 
2.4 
Safety Objective ............................................................................................................................9 
3. 
STUDY DESIGN ..............................................................................................................................9 
4. 
SCHEDULE OF ASSESSMENTS ...................................................................................................9 
4.1 
Screening.......................................................................................................................................9 
4.2 
Enrollment................................................................................................................................... 11 
4.3 
Day 1 Visit .................................................................................................................................. 11 
4.4 
Day 14 Visit ................................................................................................................................ 12 
4.5 
Day 30 and Day 60 Visits ........................................................................................................... 12 
4.6 
Day 84 Visit (End of Study Visit) ............................................................................................... 12 
4.7 
Follow-up Visit ........................................................................................................................... 13 
4.8 
eDiary Assessment ...................................................................................................................... 13 
5. 
ANALYSIS POPULATIONS ......................................................................................................... 13 
6. 
STATISTICAL METHODOLOGY ................................................................................................ 14 
6.1 
Statistical and Analytical Issues .................................................................................................. 14 
6.1.1 
Statistical Methods ............................................................................................................. 14 
6.1.2 
Handling of Dropouts and Missing Data ........................................................................... 14 
6.1.3 
Pooling of Investigative Sites ............................................................................................ 15 
6.1.4 
Determination of Sample Size ........................................................................................... 15 
6.2 
Subject Characteristics ................................................................................................................ 15 
6.2.1 
Subject Disposition ............................................................................................................ 15 
6.2.2 
Protocol Deviations ............................................................................................................ 15 
6.2.3 
Background and Demographic Characteristics .................................................................. 15 
6.2.4 
Treatment Exposure and Compliance ................................................................................ 16 
6.2.4.1 
eDiary Exposure .......................................................................................................... 16 
6.2.4.2 
Overall Exposure and Compliance .............................................................................. 16 
6.2.5 
Prior and Concomitant Medications and Therapies ........................................................... 16 
6.2.6 
Medical Histories ............................................................................................................... 17 


 
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6.3 
Efficacy Analyses ....................................................................................................................... 17 
6.3.1 
Analyses of all hot flash frequency and severity endpoints both Primary and Secondary . 17 
6.3.1.1 
Primary Efficacy Endpoint Analysis (Hot Flash Frequency at Week 6) ..................... 19 
6.3.1.1.1 
Additional frequency analyses ............................................................................... 20 
6.3.1.1.2 
Additional frequency analyses – sensitivity analyses among the ITT population .. 21 
6.3.1.1.1 
Additional frequency analyses – sensitivity analyses including all severity levels 21 
6.3.2 
Secondary Efficacy Variables ............................................................................................ 21 
6.3.2.1 
Percentage Change in severity of moderate and severe hot flashes from baseline to week 6
 
21 
6.3.2.2 
Percentage Change in frequency of moderate and severe hot flashes from baseline to week 8
 
21 
6.3.2.3 
Percentage Change in frequency of moderate and severe hot flashes from baseline to week 10
 
21 
6.3.2.4 
Percentage Change in frequency of moderate and severe hot flashes from baseline to week 12
 
21 
6.3.2.5 
Percentage Change in severity of moderate and severe hot flashes from baseline to week 8
 
21 
6.3.2.6 
Percentage Change in severity of moderate and severe hot flashes from baseline to week 10
 
22 
6.3.2.7 
Percentage Change in severity of moderate and severe hot flashes from baseline to week 12
 
22 
6.3.2.8 
Percentage Change in frequency of moderate and severe hot flashes from baseline to week 4
 
22 
6.3.2.9 
Percentage Change in severity of moderate and severe hot flashes from baseline to week 4
 
22 
6.3.2.10 
Bone Marker Turnovers ............................................................................................. 22 
6.3.3 
Exploratory Analysis ......................................................................................................... 22 
6.3.3.1 
Change in Serum PSA Concentrations ........................................................................ 22 
6.3.3.2 
Change in Serum Total Testosterone and Serum Free Testosterone Concentrations... 23 
6.3.3.3 
Change in Serum SHBG Concentrations ..................................................................... 23 
6.4 
Safety Analysis ........................................................................................................................... 24 
6.4.1 
Adverse Events .................................................................................................................. 24 
6.4.2 
Physical Examination ........................................................................................................ 25 
6.4.3 
Vital Signs ......................................................................................................................... 25 
6.4.4 
Electrocardiogram .............................................................................................................. 25 
6.4.5 
Laboratory Parameters ....................................................................................................... 25 
6.5 
PK Analysis ................................................................................................................................ 25 
6.6 
Caprini VTE Risk Assessment .................................................................................................... 25 


 
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6.7 
Interim Analysis .......................................................................................................................... 25 
6.8 
Data Monitoring Committee ....................................................................................................... 26 
6.9 
Changes to Methods Planned in the Protocol .............................................................................. 26 
7. 
TABLES, LISTINGS AND FIGURES ........................................................................................... 26 
7.1 
Stage 1 versus Stage 2 reporting ................................................................................................. 28 
8. 
REFERENCES ................................................................................................................................ 29 
9. 
APPENDICES ................................................................................................................................. 30 
9.1 
Schedule of Study Evaluations .................................................................................................... 30 
9.2 
Clinical Laboratory Tests (central laboratory) ............................................................................ 31 
9.3 
Hot Flash Assessments ................................................................................................................ 32 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
AIC 
Akaike’s Information Criteria 
ATC  
Anatomic therapeutic chemical (classification) 
BMI 
Body mass index 
ECG 
Electrocardiogram 
eCRF 
Electronic Case report form 
eDiary 
Electronic Diary 
EE 
Efficacy Evaluable (population) 
ITT 
Intent-to-treat (population) 
max 
maximum 
MedDRA 
Medical dictionary of regulatory activities 
mg 
Milligram 
min 
minimum 
MMRM 
Mixed Models Repeated Measures  
PK 
Pharmacokinetic 
PO q day 
Medication is taken orally once a day 
PSA 
Prostate specific antigen 
PT 
Preferred term 


 
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SAE 
Serious adverse event 
SD  
Standard deviation 
SHBG 
 
Sex hormone binding globulin 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TLF 
Tables, listings, and figures 
VTE 
Venothromboembolism (Caprini VTE Risk Assessment) 
WHODDE 
World health organization drug dictionary enhanced 
 


 
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1. INTRODUCTION 
Prostate cancer is the most common form of cancer in men, with androgen deprivation therapy (ADT) as 
the standard of care for many patients. The main objective of ADT is to lower the serum testosterone 
level in men which can result in a number of estrogen deficiency side effects the most common of which 
is known as hot flashes. Hot flashes are experienced by approximately 75% of men receiving ADT and 
are a significant component in assessing quality of life (Holzbeierlein et al., 2004). Men describe hot 
flashes with both physical and emotional descriptors. Men with advanced prostate cancer, being treated 
with ADT, have described their hot flashes as having detrimental effects on their overall quality of life to 
the extent that cancer-related distress caused by hot flashes is a contributing factor in the discontinuation 
of ADT (Engstrom, 2008; Ulloa et al., 2009; Frisk, 2010). 
The precise mechanism of hot flashes in men is not yet fully understood. There are currently no approved 
therapies for the treatment of moderate to severe hot flashes in men with advanced prostate cancer on 
ADT. As a result of ADT, decreasing estrogen levels appear to be a contributing cause of the hot flashes. 
A nonsteroidal estrogen, VERU-944, is a hormonal therapy that can be used to alleviate vasomotor 
symptoms (hot flashes) in men undergoing ADT. 
2. STUDY OBJECTIVES 
2.1 Primary Objective 
To determine an effective dose of VERU-944 (from among 10 mg, 50 mg, and possibly 100 mg PO q 
day), after a loading dose, for the treatment of vasomotor symptoms commonly known as hot flashes by 
assessing its effect on: 
1. the frequency of moderate to severe hot flashes at Week 6 
 
2.2 Secondary Objectives 
To assess the effect of VERU-944 on: 
1. the severity of moderate to severe hot flashes at Week 6 
2. the frequency of moderate to severe hot flashes at Week 8 
3. the frequency of moderate to severe hot flashes at Week 10 
4. the frequency of moderate to severe hot flashes at Week 12 
5. the severity of moderate to severe hot flashes at Week 8 
6. the severity of moderate to severe hot flashes at Week 10 
7. the severity of moderate to severe hot flashes at Week 12 
8. the frequency of moderate to severe hot flashes at Week 4 
9. the severity of moderate to severe hot flashes at Week 4 
10. bone turnover markers 
2.3 Exploratory Objectives 
To assess the effect of VERU-944 on: 
1. serum prostate-specific antigen (PSA) concentrations 
2. serum total and free testosterone concentrations 
3. serum sex hormone binding globulin (SHBG) concentrations 


 
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2.4 Safety Objective 
To assess the safety and tolerability of VERU-944 
3. STUDY DESIGN  
This is a randomized, multicenter, double-blind, placebo-controlled dose finding study of VERU-944 to 
treat hot flashes (vasomotor symptoms) in men with advanced prostate cancer on ADT. The study will be 
conducted as a staged study with Stage 1 consisting of 3 arms (placebo, 10 mg and 50 mg of VERU-944). 
When all subjects in Stage 1 have completed the Week 6 of dosing, an interim analysis will be conducted 
to assess efficacy (unblinded) and safety (blinded) of the doses administered in Stage 1 at Week 6 
frequency and severity – with the Week 6 frequency analysis being the primary analyses. Following 
review of the Stage 1 results, a decision will be made whether to progress with Stage 2 of the study. If 
initiated, Stage 2 will have 2 arms (placebo and 100 mg VERU-944). It is important to note that the 
placebo arm of Stage 2 will be enrolled with separate and distinct subjects from those subjects who 
receive placebo in Stage 1. There is no intent to combine these placebo arms for analysis purposes of this 
protocol. 
The subjects participating in the study will have advanced prostate cancer and will be undergoing ADT 
with a luteinizing hormone releasing hormone therapy (agonist or antagonist) for at least 3 months prior 
to randomization and be experiencing regular moderate to severe hot flashes while on ADT. Subjects will 
continue to receive ADT over the course of the study.  
Approximately 30 subjects will be enrolled into each arm, regardless of stage of study. Each subject will 
be randomized to receive placebo, 10 mg VERU-944, or 50 mg VERU-944 in Stage 1, and placebo, or 
100 mg VERU-944 in Stage 2. Following randomization, each subject will receive a 4-day loading dose 
of the treatment to which they have been randomized. On Day 1, each subject will receive 5 times their 
maintenance dose at a single time. On Days 2-4 each subject will receive 3 times their maintenance dose 
at a single time each day. Then on Days 5-84, each subject will receive 1 capsule per day. Dosing should 
occur greater than 1 hour before or 1 hour after eating and will continue for 12 weeks (84 days). 
4. SCHEDULE OF ASSESSMENTS 
The schedule of study evaluations are provided in the protocol (Appendix B) and are copied in Appendix 
9.1. 
4.1 Screening 
Potential subjects will be screened for this study in the 28 days prior to enrollment. The following 
activities will be conducted at screening: 
1. 
Signed informed consent 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. 
Medical history will be obtained, including diagnosis of primary disease (date of diagnosis), 
clinical stage and Gleason score (individual scores and sum) at diagnosis, presence, date and 
extent of soft tissue and bone metastases, details and dates of primary treatment, and details and 
dates of prior therapies for prostate cancer, concurrent illnesses and family history. 


 
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4. 
The use of any medications will be recorded (including radiation). This will include medications 
currently being taken and those taken within the last 30 days. This will also include the type of 
androgen deprivation therapy (ADT) utilized and when it was initiated.  Over-the-counter (OTC) 
medications as well as medications taken on an as-needed basis (PRN) should be recorded. 
5. 
Vital signs (temperature/pulse/supine blood pressure) 
6. 
Physical examination including height and weight 
7. 
History of hot flash frequency and severity 
8. 
Thromboembolic risk assessment including: a) Factor V Leiden gene mutation; b) Lupus 
Anticoagulant assessment and Cardiolipin assessment; c) Prothrombin gene mutation; and Protein 
C and S.  
NOTE: detection of lupus anticoagulant, cardiolipin antibody outside the normal range, 
prolonged PTT-LA, dRVVT and Protein C and/or Protein S deficiency are not exclusionary from 
the study. However, if a patient has lupus anticoagulant detected, cardiolipin outside the normal 
range, a prolonged PTT-LA, a prolonged dRVVT or is deficient for Protein C and/or Protein S, 
and remains eligible for participation in the study, prophylactic anticoagulation therapy should be 
considered. 
For Protein C or Protein S deficiency, consideration should be given to dietary changes to 
increase Vitamin K intake. 
9. 
Electrocardiogram- 12 lead (single) 
10. 
Caprini Venothromboembolism (VTE) Risk Assessment 
NOTE: Caprini VTE Risk is not an inclusion/exclusion criteria for the study. It is intended to 
assess the patient’s overall risk for VTE and the change of risk over the course of the study.  
11. 
Clinical Laboratory Tests 
• 
Hematology (Appendix A) 
• 
Serum hormones (Appendix A) 
• 
Serum chemistry (Appendix A) 
• 
Urinalysis 
12. 
Measurement of frequency and severity of hot flashes utilizing electronic device (values over 14 
contiguous days in order to establish a weekly baseline) 
• 
Must be at least 80% compliant during this assessment.  This translates into recording 
frequency and severity of hot flashes at least 11 of the 14 days. 
 
13. 
Bilateral Doppler ultrasound of the lower extremity (If the subject is diagnosed with a VTE in this 
assessment, the subject will not be eligible for the study under the exclusion criterion of history of 
a VTE). 
Patients that have been previously screened for this study and could not complete screening for reasons 
other than not meeting the inclusion and exclusion criteria, may be rescreened into the study. Laboratory 
testing conducted under this protocol (Appendix A) within 45 days prior to randomization into this study, 
may be used as the baseline laboratory values for this study and repeat laboratory testing is not required 


 
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unless new coadministered medication(s) has been started, unless the investigator determines that 
retesting is warranted.  
Patients that failed screening under previous versions of the protocol due to a positive lupus 
anticoagulant, but in whom lupus anticoagulant was not “detected” may be rescreened under Amendment 
2, Version 7.0 of the protocol. 
Patients that failed screening under previous versions of the protocol due to indeterminant cardiolipin 
antibody, may be rescreened under Amendment 2, Version 7.0 of the protocol. 
Patients that failed screening under previous versions of the protocol due a finding related to Protein C or 
Protein S, including patients that were excluded from participation inappropriately due to elevated levels 
of Protein S and/or Protein C above the upper limit of normal, may be rescreened under Amendment 2, 
Version 7.0 of the protocol. 
For patients that fall into the three categories outlined above, laboratory testing conducted under this 
protocol (Appendix A) within 45 days prior to randomization into this study, may be used as the baseline 
laboratory values for this study and repeat laboratory testing is not required unless new coadministered 
medication(s) has been started or if the investigator determines that retesting is warranted. 
4.2 Enrollment 
Approximately 90 subjects will be randomized into Stage 1 and 60 into Stage 2. Subjects will be 
randomized from 2 to 5 days prior to the Day 1 visit. Randomization should be done after the subject has 
completed the screening assessments and after it has been determined that the subject meets all the 
inclusion and exclusion criteria. 
Assess eligibility status for inclusion into the trial based on protocol inclusion/exclusion criteria, 
including results from screening lab assessments. 
4.3 Day 1 Visit 
Subjects should fast for at least 8 hours (overnight) prior to this visit. The Day 1 visit assessments will 
serve as the baseline assessments, unless otherwise specified. 
1. The medical history should be reviewed and updated to include any changes occurring since the 
screening visit. 
2. Assessment of eligibility 
3. Vital signs (temperature/pulse/supine blood pressure) 
4. Physical examination (including weight) 
5. Hematology  
6. Serum chemistry  
7. Urinalysis 
8. Serum hormones  
9. Bone turnover markers  
10. Record the usage of any concomitant medications and ongoing treatments 
11. Adverse events (ongoing on Day 1) 
12. Caprini VTE Risk Assessment  
13. Blood samples for pharmacokinetic (PK) assessment 
14. Assess hot flashes 
15. Dispense study drug 
16. First dose- instruct the subject to take his capsule at the same time each day 


 
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4.4 Day 14 Visit 
The following assessments will be conducted on Day 14 (±3 days): 
1. Vital Signs (temperature/pulse/supine blood pressure) 
2. Serum chemistry 
3. Record the usage of any concomitant medications and treatments 
4. Adverse events 
4.5 Day 30 and Day 60 Visits 
Subjects should fast for at least 8 hours (overnight) prior to these visits. The following assessments will 
be conducted on Day 30 (± 7 days) and Day 60 (± 7 days): 
1. Vital Signs (temperature/pulse/supine blood pressure) 
2. Serum chemistry  
3. Hematology  
4. Serum hormones 
5. Blood samples for PK assessment 
6. Record the usage of any concomitant medications and treatments 
7. Assess hot flashes  
8. Caprini Venothromboembolism Risk Assessment  
a. If there is an increase in risk from baseline (Day 1) in this assessment, appropriate 
preventative actions should be taken. The subject should be consulted about the risk for 
VTE and actions that would increase their risk further such as long periods of inactivity 
and surgery. Prophylactic anticoagulation therapy should be considered. 
b. If a subject has a prolonged PTT-LA or is deficient for Protein C and/or Protein S, but 
remains eligible for participation in the study, prophylactic anticoagulation therapy 
should be considered.  
c. For Protein C or Protein S deficiency, consideration should be given to dietary changes to 
increase Vitamin K intake.  
9. Adverse events 
10. Collect capsule bottles and perform capsule accountability/compliance assessment 
11. Dispense study drug 
 
4.6 Day 84 Visit (End of Study Visit) 
Subjects should fast for at least 8 hours (overnight) prior to this visit. The following assessments will be 
conducted on Day 84 (± 7 days): 
1. 
Vital Signs (temperature/pulse/supine blood pressure) 
2. 
Physical examination (including weight) 
3. 
Serum chemistry (Appendix 9.1) (central laboratory) 
4. 
Hematology (Appendix 9.1) (central laboratory) 
5. 
Serum hormones (Appendix 9.1) (central laboratory) 
6. 
Blood samples for pharmacokinetic assessment 
7. 
Bone turnover markers 


 
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8. 
Record the usage of any concomitant medications and treatments 
9. 
Adverse events 
10. 
Assess hot flashes (see Appendix 9.3) 
11. 
Caprini Venothromboembolism Risk Assessment (Appendix D) 
• 
It is important to note that it is expected that the patient population included in this study will 
have some risk of VTE due to age, presence of a malignancy, and BMI. The purpose of this 
assessment is a change in risk from baseline. Also, while the questionnaire is designed for the 
patient to complete, in this study, the Caprini VTE risk assessment should be filled out by study 
personnel with information from the patient and patient’s chart. 
If there is an increase in risk from baseline (Day 1) in this assessment, appropriate preventative 
actions should be taken. The subject should be consulted about the risk for VTE and actions that 
would increase their risk further such as long periods of inactivity and surgery. Prophylactic 
anticoagulation therapy should be considered. 
12. 
Collect capsule bottles and perform capsule accountability/compliance assessment 
4.7 Follow-up Visit 
The following assessments will be performed 30 days (± 7 days) after the End of Study visit (Day 84): 
1. Vital Signs (temperature/pulse/supine blood pressure) 
2. Physical examination (including height and weight) 
3. Adverse events 
4.8 eDiary Assessment 
Subjects will be provided with an Electronic Diary (eDiary) at the Screening Visit to collect data for hot 
flashes during screening. If enrolled, they will continue to use the eDiary to collect hot flash information 
for each hot flash through Day 84/Early Termination. All subjects should be instructed to return the 
eDiary to the study site. Subjects must be educated to record the hot flash assessments in the eDiary in 
real time. 
The table in Appendix 9.1 outlines the timing of assessments to be recorded throughout the study in the 
eDiary. Appendix 9.3 further elaborates on the hot flash assessment and provides a list of the three severity 
levels of hot flashes along with a description of the symptoms associated with each level. 
5. ANALYSIS POPULATIONS 
The subjects will be over the age of 18 and will have moderate to severe hot flashes, defined as a 
minimum of 4 moderate to severe hot flashes per day or 12 per week at baseline. The 4populations are as 
follows: 
Intent-to-Treat (ITT) 
population:   
All enrolled subjects who have taken at least 1 dose of study drug. 
Efficacy Evaluable (EE) 
population: 
All subjects in the ITT population who have analyzable baseline 
data and 12 weeks of hot flash data. Subjects must also be at least 
80% compliant with taking study drug with no major protocol 
deviations, including no major inclusion/exclusion deviations.  


 
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Efficacy Evaluable 
(EEIA) population for 
IA: 
All subjects in the ITT population who have analyzable baseline 
data and 6 weeks of hot flash data. Subjects must also be at least 
80% compliant with taking study drug with no major protocol 
deviations, including no major inclusion/exclusion deviations.  
Safety population: 
All subjects who receive at least 1 dose of study drug. The safety 
analyses will be conducted on this population. This population is 
the same as the ITT population. 
6. STATISTICAL METHODOLOGY 
6.1 Statistical and Analytical Issues 
6.1.1 Statistical Methods 
For quantitative variables, descriptive statistics will include the number of subjects (n), mean, standard 
deviation (SD), median, minimum and maximum. Categorical variables will be summarized using the 
number (n) and percentage (%) of subjects for each category. Unless otherwise specified, the denominator 
for all percentages will be the number of subjects in the respective treatment group who have data for the 
respective time point in the applied analysis population. Percentage change from baseline will be 
calculated using the non-missing (see section 6.1.2) data of both baseline and the respective post-baseline 
value. 
The primary efficacy analyses will only include efficacy data that were captured in the eDiary for hot 
flashes which were treated with study drug (VERU-944 or placebo). All baseline measurements for 
efficacy will be collected prior to dosing in the treatment period. By default the frequency and severity of 
hot flashes at baseline will be determined from the second week of the first two weeks of hot flash eDiary 
that were recorded; If a patient qualified for the study entry by number of hot flashes during the second 
week of screening, then data from that week will be used as their baseline. However, if a patient did not 
qualify for study entry based on the number of hot flashes during that second week then data from the 
screening week that was used to qualify the patient will be used as their baseline instead. Percentage 
change from baseline is defined as the post-baseline value of interest minus the baseline value then 
divided by the baseline value and finally converted to a percentage by multiplying by 100. 
A 1-sided alpha level equal to 0.10 will be used to determine statistical significance for the primary and 
secondary efficacy objectives related to hot flash frequency and severity.  
For the treatment period, baseline for the safety assessments will be defined as the Day 1 assessment, or if 
missing, the last assessment prior to dosing. 
All data processing, summarization, and analyses will be performed using SAS® Version 9.4 or higher. 
Specifications for table, graph, and data listing formats can be found in the tables, listings, and figures 
(TLF) specifications. Adverse events will be classified using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary, Version 18.1 or higher. All concomitant medications will be coded 
using the World Health Organization Drug Dictionary Enhanced (WHODDE), version Sep2015 or later. 
6.1.2 Handling of Dropouts and Missing Data 
Subjects must have entered hot flash data (frequency and severity) for 4 or more days in a given week for 
their data to be considered non-missing.  No other imputation procedures will be used to impute missing 
data.  If a subject enters that there are no hot flashes to report on a given day, then this will be considered 
a data point equal to zero. If a subject does not report any hot flash information across consecutive days, 


 
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the data management team will be alerted to query the situation. From a data perspective, if a subject fails 
to report hot flash information on a given day, then that day will be recorded as missing. 
For determining whether adverse events (AEs) are treatment-emergent when the start date of the AE is a 
partial date, refer to Section 6.4.1. 
For determining whether a medication is a prior medication or concomitant medication, refer to Section 
6.2.5.   
6.1.3 Pooling of Investigative Sites 
All site data will be combined and analyzed together.  
6.1.4 Determination of Sample Size 
The proposed trial sample size, n=30 per arm, total N=90 in Stage 1, is based on at least a 40% reduction 
in the mean weekly frequency of hot flashes in a treated arm versus placebo from baseline to Week 4 
(Day 28) [the planned primary endpoint at the time of the original study design]. Other assumptions to 
derive the sample size include a 1-sided α=0.10, a β=0.10 (i.e., power=0.9), and equal variances in the 
placebo and active arms. The variance was set to equal the mean of the active arm. The same assumptions 
hold for Stage 2, with a proposed sample size of n=30 per arm, N=60 in Stage 2. 
Note, all subjects in screening at the time the 90th subject is randomized into Stage 1 will qualify to be 
randomized into Stage 1 up to a maximum of 120 subjects (40 per arm). In Stage 2, all subjects in 
screening at the time the 60th subject is randomized into Stage 2 will qualify to be randomized into the 
study up to a maximum of 80 subjects (40 per arm). The total enrollment, if both stages are completed, 
will be a minimum of N=150.  
6.2 Subject Characteristics 
6.2.1 Subject Disposition 
The number of subjects who have been screened, screen failed, and randomized will be summarized by 
treatment group and overall. The number of subjects who discontinue study treatment or study follow-up 
will be summarized by treatment group, along with the reasons for discontinuation. The number of 
subjects in each analysis population will be summarized by treatment group. 
Listings of the subject disposition and enrollment eligibility, analysis populations, and treatment 
assignment will be provided. 
6.2.2 Protocol Deviations 
Protocol deviations will be presented in a data listing, by treatment group for the Safety population. 
Protocol deviations will be captured through data review and site monitoring. 
6.2.3 Background and Demographic Characteristics 
Demographic information (e.g., age, sex, race, height, weight, body mass index [BMI], and ethnicity) will 
be summarized for the ITT population, by treatment group and overall with summary statistics for 
continuous/categorical variables.  


 
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6.2.4 Treatment Exposure and Compliance 
6.2.4.1 eDiary Exposure 
Exposure will be collected in the eDiary, where for Days 1-7 subjects will be asked how many pills they 
take each day. A listing will be provided, for the ITT population, to report treatment exposure for Days 1-
7, where subjects are instructed to take 1 or more pills a day.  
6.2.4.2 Overall Exposure and Compliance 
Duration of exposure and compliance will be summarized for the ITT population by treatment group and 
overall for the active treatment groups using descriptive statistics.  
Duration of exposure will be summarized as time in days from first treatment to last dose, calculated as 
last dose date minus first dose date plus 1 day. 
Compliance will be summarized using data from the electronic case report form (eCRF). A percent 
compliance value (shown derived below) will be calculated and listed for each subject. 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑖𝑙𝑙𝑠 𝑡𝑎𝑘𝑒𝑛
𝐸𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑖𝑙𝑙𝑠 𝑡𝑎𝑘𝑒𝑛∗100 
 
6.2.5 Prior and Concomitant Medications and Therapies 
The start and stop of each medication will be recorded by calendar date. “Prior medications” are defined 
as medications that have been discontinued prior to the date of first dose of study drug. “Concomitant 
medications” are defined as medications taken any day from the first dose of study drug until the last dose 
of study drug, regardless of whether the medication was initiated prior to the first dose of study drug. 
The counts and percentages of subjects who took prior and concomitant medications will be summarized 
on the safety population, by treatment group and overall. Prior and concomitant medications will also be 
presented in subject data listings. 
For partial start or stop dates, the following considerations and imputations will be performed.  
• 
For a partial or missing start date where the stop date is recorded in full and is before the date of 
initial study treatment, it will be considered a prior medication. If the stop date is after the date of 
initial study treatment, it will be considered a concomitant medication.  
• 
For a partial or missing stop date where the start date is recorded in full and the start date is after 
the initial study treatment date, it will be considered a concomitant medication.  
• 
For instances where a medication has a partial stop date and a partial start date, the month and 
year of the stop date will be used to assess whether the medication is prior or concomitant. For 
instance, if month and year exist for the stop date, this data will be compared with the date of 
initial study treatment and if the month or year show evidence of being after this date or on the 
same date (same month/year), the medication will be considered concomitant.  
• 
For medications where both the start and stop dates are missing, these medications will be 
considered concomitant.  
The prior and concomitant medications taken during the study will be summarized using number of 
subjects (n) and percentage (%) in the safety population. All prior and concomitant medications will be 
coded using the WHODDE, version September 2015 or later, and then further coded against the 


 
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Anatomic Therapeutic Chemical (ATC) classification. Prior and concomitant medication data will be 
presented by ATC Level 2 and preferred term and will be presented by treatment group.  
6.2.6 Medical Histories 
General medical history and surgical history data will be captured during the screening period, both at 
screening and Day 1. A listing of medical and surgical history data will be provided on the Safety 
population. 
6.3 Efficacy Analyses 
6.3.1 Analyses of all hot flash frequency and severity endpoints both Primary and Secondary 
The following conventions apply to all analyses of hot flash frequency and severity data: 
Population: The EE population (efficacy evaluable) population will be the population of interest in the 
primary and all secondary endpoint analyses. The EEIA (efficacy evaluable interim analysis) population 
will be the population of interest for the analysis conducted at Week 6.  The ITT population will be used 
in the sensitivity analyses to verify that the findings remain consistent.  
Data Handling 
Baseline week will be determined from the second week of the first two weeks of hot flash eDiary that 
were recorded; if a patient qualified for study entry by number of hot flashes during the second week of 
screening, then data from that week will be used as their baseline. However, if a patient did not qualify for 
study entry based on the number of hot flashes during that second week then data from the screening 
week that was used to qualify the patient will be used as their baseline instead. A week’s data collection 
will be considered the 6 days prior to plus the day of week’s data.  For example, Week 6 data will include 
the data collected for the 7 days from Day 36 through Day 42, inclusive. For a subject’s data to be 
considered non-missing for a given week the subject must have recorded at least 4 days of data during the 
respective week. For subjects who report at least 4 days of data during a week, the weekly frequency of 
moderate and severe hot flashes will be the sum across those days of the number of moderate to severe 
hot flashes. The severity level reported for each of the reported hot flashes will be calculated as follows. 
Baseline severity level will be the number of severe hot flashes reported times 3 + the number of 
moderate hot flashes reported times 2 then divided by the number of moderate and severe hot flashes 
reported.  Post-baseline weeks will have their severity level calculated as above but with the addition of 
reported mild hot flashes so the post-baseline severity for a given week level will be the number of severe 
hot flashes reported times 3 + the number of moderate hot flashes reported times 2 + the number of mild 
hot flashes reported times 1 then divided by the number of mild, moderate and severe hot flashes 
reported. The percentage change from baseline of the frequency of moderate and severe hot flashes will 
be the number of moderate to severe hot flashes reported for the given week minus the number reported at 
baseline then divided by the number reported at baseline and converted to a percentage by multiplying by 
100.  The percentage change from baseline of the severity of moderate and severe hot flashes will be the 
calculated severity score reported for the given week minus the severity score at baseline then divided by 
the severity level reported at baseline and converted to a percentage by multiplying by 100.   
Adjustment for Multiple Comparisons 
The Hochberg procedure will be applied to control for multiplicity for each of the primary and secondary 
hot flash related endpoints. Each endpoint will have 4 analyses associated with them to account for the 
two active dose arms (10 mg and 50 mg) each compared to baseline by two methods each (MMRM test 
for slope and MMRM test for change from baseline at the specified week). These may be referred to as 
sets of analyses.  Hochberg is a step-up procedure based on univariate p-values. This procedure begins 


 
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with the least significant p-value and then examines the other p-values in sequential order, making alpha 
level adjustments along the way, until a significant p-value is observed. Once achieved, all following 
lower p-values in the sequence would be considered significant.  For example, if one has 4 hypotheses the 
following will be performed: 
• 
Step 1: Order the p-values from largest (least significant) to smallest (most significant) 
• 
Step 2: Using the pre-specified overall alpha level, α0=0.10, one-sided, compare the largest p-
value, P1, to the overall alpha level. If P1<0.10 then all (null) hypotheses are rejected; otherwise 
go to step 3. 
• 
Step 3: Compare the second largest p-value, P2, to α1=0.10/2=0.05.  If  P2<0.05  then this and  all  
further hypotheses are rejected; otherwise repeat for the third, P3, and fourth, P4, largest p-values 
compared with  α2=0.10/3=0.033 and α3=0.10/4=0.025 as necessary to either reject all remaining 
hypotheses or conclude no significant difference exists.  
 
For this study, during Stage 1, Hochberg’s procedure will rank the p-values from highest to lowest for 
each statistical test within each set of analyses:  10 mg versus placebo slope difference (through Week 6), 
50 mg versus placebo slope difference (through Week 6), 10 mg versus placebo mean difference at week 
6, 50 mg versus placebo mean difference at Week 6. Adjustment for the single comparison of 100 mg 
versus placebo in Stage 2 will be necessary only for the two MMRM modes, means and slopes. 
Overall, for the multiple tests of primary and secondary endpoint analyses alpha control will be achieved 
by a gate-keeping method such that the endpoints are ordered and the preceding endpoint must be shown 
to be significant in order for endpoints down the list to be eligible for significance. 
The order of the secondary endpoint assessments will be: 
1. Percentage change in severity of vasomotor symptoms from baseline to Weeks 6 (Day 42)  
2. Percentage change in frequency of moderate to severe vasomotor symptoms from baseline to 
Week 8 (Day 56) 
3. Percentage change in frequency of moderate to severe vasomotor symptoms from baseline to 
Week 10 (Day 70) 
4. Percentage change in frequency of moderate to severe vasomotor symptoms from baseline to 
Week 12 (Day 84) 
5. Percentage change in severity of vasomotor symptoms from baseline to Week 8 (Day 56) 
6. Percentage change in severity of vasomotor symptoms from baseline to Week 10 (Day 70) 
7. Percentage change in severity of vasomotor symptoms from baseline to Week 12 (Day 84) 
8. Percentage change in frequency of moderate to severe vasomotor symptoms from baseline to 
Week 4 (Day 28) 
9. Percentage change in severity of vasomotor symptoms from baseline to Week 4 (Day 28) 
10. Percentage change in bone turnover marker concentrations at Day 84 compared with baseline 
Common analytical methods for all hot flash related analyses 
The MMRM analyses shown in the following section with SAS code written specifically to address the 
primary analysis of difference in percentage change of the frequency of hot flashes at Week 6 between 
each of the active arms and placebo are the SAME for all hot flash related analyses, both frequency and 
severity, at all weeks of interest.  Simple changes to the data set to subset to the appropriate weeks of data 
and to the LSESTIMATE statements are all that is necessary to construct the appropriate tests.   MMRM 
models that test for MEAN difference between active arm(s) at Week 6 and placebo and separately for a 


 
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difference in SLOPE between active arm(s) at Week 6 and placebo.  There is no plan to compare the 
active arms to each other. 
If the MMRM models does not converge or have poor fit, T-tests or non-parametric tests, if the data are 
deemed non-normally distributed, will compare percentage changes over time between (T-test or 
Wilcoxon rank sum test) each active arm and the placebo arm, respectively. 
6.3.1.1 Primary Efficacy Endpoint Analysis (Hot Flash Frequency at Week 6) 
STAGE 1: 
The primary frequency efficacy endpoint is percentage change in frequency of moderate and severe hot 
flashes (vasomotor symptoms) from the baseline week to Week 6 (Day 42). The statistical tests for 
significant differences with regards to the percentage change between placebo and each of the active 
arms, 10 mg 50mg, and perhaps 100 mg comprise the main tests of interest. 
The SAS code for performing the MMRM analyses to test for a significant difference in the MEAN 
percentage change in frequency of moderate to severe hot flashes between each of the dose arms and 
placebo evaluated at Week 6 (primary analysis week) is shown below.  Note that this analysis will 
generate two of the four tests that are part of the primary analysis to which the Hochberg procedure will 
apply. 
 
PROC MIXED DATA= XXX; 
 
CLASS subjid tx week; 
 
MODEL cfb = tx week_2 tx*week_2; 
 
REPEATED week / type=AR(1) sub=subjid(tx); 
 
LSESTIMATE tx*week ‘10MG VS Placebo at Week 6’ [1, 10 6]  [-1, P 6];  
LSESTIMATE tx*week ‘50MG VS Placebo at Week 6’ [1, 50 6] [-1, P 6];  
WHERE week le 6; 
RUN; 
The variables used in the above model will be defined as follows: tx=treatment; week (1, 2… 6); 
cbf=change from baseline value, week_2=week (week will be treated as a categorical variable in the class 
statement and week_2 will be treated as a continuous variable in the model… effectively the values of 
these variables will be an exact match).  By creating week_2 in a preceding data step, this allows for 
LESTIMATES to be computed at a specific WEEK (treated as categorical in the CLASS statement) but 
allows week to be treated as a continuous variable, WEEK_2 in the model. 
This model will be run 3 separate times using 3 separate covariance structures to determine best fit. The 
same model will be run, with the following specified change on the REPEATED line: (1) type=AR(1); (2) 
type=CS; and (3) type=UN. If a model does not converge, then disregard that model. If more than 1 
model remains, then refer to the Akaike’s Information Criteria (AIC) score to determine model fit. The 
best fit model will be chosen as having the AIC value closest to zero. The model type chosen will be 
referenced in the footnote for each model output. 
Additional prespecified analysis of the data will be conducted regardless of whether the MMRM model(s) 
converge, and will be considered the definitive tests for significance in the event the MMRM model(s) do 
not converge: 
• 
T-tests will be generated to compare the percentage change from baseline to each of Week 6 in 
the placebo arm to each of the 10 mg and 50 mg arms. If the data are determined to be non-
normally distributed then the Wilcoxon rank sum test will be the definitive test of significance. 


 
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• 
Wilcoxon rank sum tests will be generated to compare the percentage change from baseline to 
Week 6 in the placebo arm to each of the 10 mg and 50 mg arms. 
The SAS code for performing the MMRM analyses to test for a significant difference in the SLOPES of 
the percentage change in frequency of moderate to severe hot flashes between each of the dose arms and 
placebo by Week 6 (primary analysis week) is shown below.  Note that these analyses will generate the 
remaining two of the four tests that are part of the primary analysis to which the Hochberg procedure will 
apply.   
 
The where statement in PROC MIXED has been used to simplify the interpretation of the output so that 
one model will be run for the 10 mg versus placebo slope analysis and a separate one for the 50 mg versus 
placebo slope analysis through Week 6. Variable have the same meaning as defined in the above analysis. 
 
PROC MIXED DATA=XXX; 
   CLASS subjid tx; 
   MODEL cfb= tx week tx*week / s; 
   RANDOM intercept week/ type=AR(1) sub=subjid g; 
             WHERE tx in (10, P) and week le 6; /* repeat for ‘tx in (50, P)’ */ 
RUN; 
 
This model allows for both the intercept and the slope to differ randomly for each subject but the overall 
p- value for the interaction term is interpreted as a test of the slope between the stated active arm and 
placebo.  Note, if the p-value is significant, the estimated coefficients must be in the appropriate direction 
to conclude the result is in favor of the active dose arm. 
 
STAGE 2: 
The analyses conducted in Stage 2 will be the exact same as in Stage 1, except the 10 mg and 50 mg dose 
of study drug will be replaced with a 100 mg dose of study drug. A separate and distinct placebo group 
will be used for Stage 2. The Hochberg procedure will have to address only two multiple comparisons, 
i.e., the MMRM slope models and the MMRM means models as there is now only one dose level 
comparison to placebo.  The two alpha levels that may be needed to assess significance will be only 
α0=0.10 and possibly α1=0.05.  Here is the appropriate code for the LSESTIMATE statement. 
LSESTIMATE tx*week ‘100MG VS Placebo at Week 6’ [1,100 6] [-1, P 6];  
Also, as a reminder, the SAS code shown for the primary analysis can be used in this second stage as well 
for its primary analysis of hot flash frequency as well as for all secondary hot flash related endpoints. 
6.3.1.1.1 Additional frequency analyses 
The t-test or the or the Wilcoxon rank-sum test, if the data are determined to be non-normally distributed,  
will be used for between group treatment comparisons comparing the percentage change from baseline in 
the placebo arm to the percentage change from baseline in each treatment group (10 mg and 50 mg) at 
Day 42. The paired t-test or the Wilcoxon signed-rank test, if the data are determined to be non-normally 


 
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distributed, will be used for comparing baseline and Day 42 within each treatment group. The 
comparisons are as follows: 
• 
Stage 1: Change from Baseline week to Week 6 between placebo and each of the 10 mg and 50 
mg arms  
• 
Stage 2: Change from Baseline week to Week 6 between placebo and the 100 mg 
• 
Stage 1: Baseline week versus Week 6 for each treatment arm (placebo, 10 mg, and 50 mg) 
• 
Stage 2: Baseline week versus Week 6 for each treatment arm (placebo and 100 mg) 
6.3.1.1.2 Additional frequency analyses – sensitivity analyses among the ITT population 
Sensitivity analyses will also be conducted on the ITT population as described above.   
6.3.1.1.1 Additional frequency analyses – sensitivity analyses including all severity levels 
Sensitivity analyses on the percentage change in frequency of hot flashes from baseline to Week 6 will be 
conducted where a subject’s frequency of hot flashes for a given week will include any hot flash 
designated as mild, moderate, or severe.  This will be conducted among subjects in the EEIA population 
and among those in the ITT population. 
6.3.2 Secondary Efficacy Variables 
As noted previously, the same MMRM models - one for means and one for slopes - specified for the 
primary analysis will be used for each of the following hot flash related secondary endpoints including 
both frequency of hot flashes and severity of hot flashes.   
6.3.2.1 Percentage Change in severity of moderate and severe hot flashes from baseline to week 6 
Analyzed with the same methods and considerations as for the analysis of frequency at week 6 (primary 
endpoint). Please see the data handling description (Section 6.3.1) for the specifics of severity calculation 
Repeat for Stage 2 as necessary. 
6.3.2.2 Percentage Change in frequency of moderate and severe hot flashes from baseline to week 8 
Analyzed with the same methods and considerations as for the analysis of frequency at week 6 (primary 
endpoint). Repeat for Stage 2 as necessary. 
6.3.2.3 Percentage Change in frequency of moderate and severe hot flashes from baseline to week 10 
Analyzed with the same methods and considerations as for the analysis of frequency at week 6 (primary 
endpoint). Repeat for Stage 2 as necessary. 
6.3.2.4 Percentage Change in frequency of moderate and severe hot flashes from baseline to week 12 
Analyzed with the same methods and considerations as for the analysis of frequency at week 6 (primary 
endpoint). Repeat for Stage 2 as necessary. 
6.3.2.5 Percentage Change in severity of moderate and severe hot flashes from baseline to week 8 
Analyzed with the same methods and considerations as for the analysis of frequency at week 6 (primary 
endpoint). Please see the data handling description (Section 6.3.1) for the specifics of severity calculation 
Repeat for Stage 2 as necessary. 


 
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6.3.2.6 Percentage Change in severity of moderate and severe hot flashes from baseline to week 10 
Analyzed with the same methods and considerations as for the analysis of frequency at week 6 (primary 
endpoint). Please see the data handling description (Section 6.3.1) for the specifics of severity calculation 
Repeat for Stage 2 as necessary. 
6.3.2.7 Percentage Change in severity of moderate and severe hot flashes from baseline to week 12 
Analyzed with the same methods and considerations as for the analysis of frequency at week 6 (primary 
endpoint). Please see the data handling description (Section 6.3.1) for the specifics of severity calculation 
Repeat for Stage 2 as necessary. 
6.3.2.8 Percentage Change in frequency of moderate and severe hot flashes from baseline to week 4 
Analyzed with the same methods and considerations as for the analysis of frequency at week 6 (primary 
endpoint). Repeat for Stage 2 as necessary. 
6.3.2.9 Percentage Change in severity of moderate and severe hot flashes from baseline to week 4 
Analyzed with the same methods and considerations as for the analysis of frequency at week 6 (primary 
endpoint). Please see the data handling description (Section 6.3.1) for the specifics of severity calculation 
Repeat for Stage 2 as necessary. 
6.3.2.10 Bone Marker Turnovers 
STAGE 1:  
The secondary efficacy endpoint for bone marker turnovers is percentage change in bone turnover marker 
concentrations at Day 84 compared with baseline (Day 1, pre-dose). The bone markers to be assessed will 
include: serum C-telopeptide and bone specific alkaline phosphatase. For each marker, the mean, SD, 
median, minimum, and maximum will be summarized at each time point by treatment. The percentage 
change from baseline to Day 84 will also be summarized.  
The t-test or the Wilcoxon rank-sum test, if the data are determined to be non-normally distributed, will 
be used for between group treatment comparisons comparing the percentage change from baseline in the 
placebo arm to the percentage change from baseline in each treatment group (10 mg and 50 mg) at Day 
84. The paired T-test or the Wilcoxon signed-rank test, if the data are determined to be non-normally 
distributed, will be used for comparing baseline and Day 84 within each treatment group. Analyses will 
be conducted on the ITT population. 
STAGE 2:  
The same methods and analyses described directly above for Stage 1, will be repeated in Stage 2 for the 
placebo and 100 mg dose. 
6.3.3 Exploratory Analysis 
6.3.3.1 Change in Serum PSA Concentrations 
STAGE 1: 
A percentage change in serum PSA concentrations comparing baseline (Day 1, pre-dose) and each 
scheduled assessment (Days 30, 60, and 84) will be reported for each treatment group. The mean, SD, 
median, minimum, and maximum will be summarized at each time point by treatment. The percentage 
change from baseline to each scheduled assessment will also be summarized.  


 
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The t-test or the or the Wilcoxon rank-sum test, if the data are determined to be non-normally distributed,  
will be used for between group treatment comparisons comparing the percentage change from baseline in 
the placebo arm to the percentage change from baseline in each treatment group (10 mg and 50 mg) at 
Days 30, 60, and 84. The paired t-test or the Wilcoxon signed-rank test, if the data are determined to be 
non-normally distributed, will be used for comparing baseline and Day 84 within each treatment group. 
Analyses will be conducted on the ITT population. 
. 
STAGE 2:  
The same methods and analyses described directly above for Stage 1, will be repeated in Stage 2 for the 
placebo and 100 mg dose. 
6.3.3.2 Change in Serum Total Testosterone and Serum Free Testosterone Concentrations 
STAGE 1: 
A percentage change in serum total testosterone concentrations comparing baseline (Day 1, pre-dose) and 
each scheduled assessment (Days 30, 60, and 84) will be reported for each treatment group. The mean, 
SD, median, minimum, and maximum will be summarized at each time point by treatment. The 
percentage change from baseline to each scheduled assessment will also be summarized.  
The t-test or the or the Wilcoxon rank-sum test, if the data are determined to be non-normally distributed,  
will be used for between group treatment comparisons comparing the percentage change from baseline in 
the placebo arm to the percentage change from baseline in each treatment group (10 mg and 50 mg) at 
Days 30, 60, and 84. The paired t-test or the Wilcoxon signed-rank test, if the data are determined to be 
non-normally distributed, will be used for comparing baseline and Day 84 within each treatment group. 
Analyses will be conducted on the ITT population. 
Similar analyses will be implemented for serum free testosterone concentrations. 
STAGE 2:  
The same methods and analyses described directly above for Stage 1, will be repeated in Stage 2 for the 
placebo and 100 mg dose. 
6.3.3.3 Change in Serum SHBG Concentrations 
STAGE 1: 
A percentage change in serum SHBG concentrations comparing baseline (Day 1, pre-dose) and each 
scheduled assessment (Days 30, 60, and 84) will be reported for each treatment group. The mean, SD, 
median, minimum, and maximum will be summarized at each time point by treatment. The percentage 
change from baseline to each scheduled assessment will also be summarized.  
The t-test or the or the Wilcoxon rank-sum test, if the data are determined to be non-normally distributed,  
will be used for between group treatment comparisons comparing the percentage change from baseline in 
the placebo arm to the percentage change from baseline in each treatment group (10 mg and 50 mg) at 
Days 30, 60, and 84. The paired t-test or the Wilcoxon signed-rank test, if the data are determined to be 
non-normally distributed, will be used for comparing baseline and Day 84 within each treatment group. 
Analyses will be conducted on the ITT population. 
STAGE 2:  


 
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The same methods and analyses described directly above for Stage 1, will be repeated in Stage 2 for the 
placebo and 100 mg dose. 
6.4 Safety Analysis 
6.4.1 Adverse Events 
A treatment-emergent adverse event (TEAE) is defined as any event not present before the date of 
treatment with the first dose of study drug, or any event already present that worsens in severity on or 
after the date of the first dose of study drug.  
The calendar date is to be collected for the start and stop of each AE. In the event that only a partial end 
date (month/year) is available, and the month/year occurs before Day 1 in the treatment period of the 
study, the AE will not be considered treatment-emergent. However, if the onset date is a partial date 
(month/year) and the month/year occurs on or after Day 1 in the treatment period of the study, the 
following cases will be considered: 
• 
The AE will be considered as treatment-emergent if: 
o The month/year of the onset date is later than the month/year of Day 1 in the treatment 
period.   
o The month/year of the onset date is equal to the month/year of Day 1 in the treatment 
period of study, and the AE is ongoing at the end of study or the end date and time are 
present in full or are partially provided such that they place the stop of the AE after the 
start of exposure to study treatment on Day 1 in the treatment period of the study. 
Otherwise, the AE will be considered to be not treatment-emergent and will not be summarized; 
however, it will be included in the listing. 
 
AEs will be summarized based on subjects having at least 1 occurrence of the AE at the level of the 
MedDRA preferred term, with the subject as the unit of analysis. If a subject has more than 1 AE of the 
same preferred term and there are different grades of severity, only the highest grade will be represented 
in the summary of severity. If the severity assessment is missing, the severity will be reported as 
‘unknown’, and the known severity will be reported over the unknown severity. Each AE will be assessed 
for relatedness to the study treatment. If a subject has more than 1 AE of the same preferred term and 
there are different levels of relatedness to study treatment, only the highest level of relatedness for each 
will be represented in the summary of relatedness. Missing relationships will be included as related. 
The following summaries of TEAEs by system organ class (SOC) and preferred term (PT) for the safety 
population will be provided. Summaries will be displayed by number of subjects with the event, 
percentage of subjects with the event and number of events reported by treatment group and overall for   
the following groups: 
• 
TEAEs  
• 
Serious adverse events (SAEs) 
Similarly, summaries will also be displayed by number and percentage of subjects with the event reported 
by treatment group and overall for the following groups:  
• 
TEAEs by maximum severity and incidence 
• 
TEAEs by strongest relationship to study treatment number and incidence 


 
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Any adverse events, serious adverse events, actions taken due to adverse events, discontinuation from the 
study due to adverse events, adverse event outcomes, and adverse events resulting in study 
discontinuation will be listed. 
Summary tables and listings will be presented by treatment group for the safety population. 
6.4.2 Physical Examination 
Physical exam data will be listed for the safety population. The listing will include exam date, body 
system, and result. 
6.4.3 Vital Signs 
The following vital sign test results and changes from baseline will be descriptively summarized by study 
visit for the safety population. Summaries will be displayed by treatment group and overall. 
• 
Temperature (ºF)  
• 
Systolic and diastolic blood pressure (mmHg) 
• 
Heart Rate (beats/minute) 
A listing of the vital signs and weight for each study visit will be presented. 
6.4.4 Electrocardiogram 
An electrocardiogram (ECG) is performed at screening. A listing of ECG date, parameters and 
interpretation will be provided for each subject in the ITT population.  
6.4.5 Laboratory Parameters 
Laboratory data (Section 9.2) will be displayed by treatment group and overall for the safety population. 
Continuous data for laboratory tests of serum chemistry, hematology, urinalysis, and serum hormone 
including change from baseline will be descriptively summarized at each visit, and urinalysis categorical 
data will be summarized by visit. The number of subjects who have values outside the normal range will 
also be displayed descriptively at each time point.  
A listing of serum chemistry, hematology, urinalysis, and serum hormone test results will be presented 
separately by visit. The numeric values will be flagged/indicated with LN = Low Normal, LP = Low 
Panic, N = Normal, HN = High Normal, HP = High Panic in the listing.  
6.5 PK Analysis 
Samples of venous blood for the determination of trough plasma concentrations of VERU-944 will be 
collected on Days 1 (prior to dose), 30, 60, and 84. VERU-944 trough concentrations will be determined 
in each subject and summarized by mean, median, standard deviation, and coefficient of variation, 
maximum, and minimum for each treatment arm. 
6.6 Caprini VTE Risk Assessment 
The VTE risk assessment data will be summarized for the safety population at each visit, by treatment 
group and overall. 
6.7 Interim Analysis 
During Stage 1, after the last subject has completed the Day 42 visit, an unblinded interim analysis (IA) of 
the Week 6 (Day 42) hot flash primary endpoint (frequency) and first secondary endpoint (severity) of 
VERU-944 will be conducted. A blinded analysis of the safety will also be conducted. Both the Sponsor 
and CRO study team will remain blinded to patient level data until completion of the study stage. An 


 
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unblinded statistical support group, independent of the study team (within the CRO), along with a 
representative of Veru Inc., will review the IA results and determine steps forward. It is of note that due to 
the material nature of the IA results of this study in the business of Veru Inc., a publicly traded company, 
these results may be required to be released in a press release prior to the completion of Stage 1 of this 
study. 
The analyses to be included in the IA will be the analyses of hot flash frequency at Week 6 (Section 
6.3.1.1) and the hot flash severity at Week 6. These analyses will include the summary statistics and 
MMRM model for both the ITT and EEIA populations. The sensitivity analyses associated with these 
sections will not be conducted during the IA. 
In addition to the efficacy analyses, a blinded safety report will be reviewed to assess drug safety. All IA 
analyses will be conducted on the EEIA population. 
If an effective dose of VERU-944 is achieved in Stage 1, as defined as a statistically significant result), 
the Sponsor reserves the right to not initiate Stage 2 of the protocol. However, if an effective dose is not 
achieved in the Stage 1 IA, then the study will commence with Stage 2. 
Regardless of IA outcome, unless safety issues are observed, the Stage 1 section of the study will 
continue to completion at 12 Weeks with Follow-up. 
Assuming Stage 2 is implemented, an additional replicate IA will be conducted after the last subject in 
Stage 2 has completed the Day 42 visit. This IA will follow the same procedures as done for Stage 1.  
6.8 Data Monitoring Committee  
There will be no formal Data Monitoring Committee for this study. Safety data, including all SAEs, will 
be reviewed on an ongoing basis by a Safety Review Team comprised of the Medical Monitor, and 
representatives of the Sponsor. This Safety Review Team will meet at least monthly. Additional ad hoc 
meetings will be scheduled if required to evaluate the safety and/or thromboembolic events further 
6.9 Changes to Methods Planned in the Protocol  
At the time the SAP was finalized, there were no changes to methods planned in the protocol. Any other 
changes from the SAP, including any ad-hoc analysis, will be detailed in the clinical study report. 
7. TABLES, LISTINGS AND FIGURES 
The standard operating procedures of Worldwide Clinical Trials will be followed in the creation and 
quality control of all tables, listings and figures. 
 
Format of Output 
1. Unless otherwise specified, all computer-generated output should be produced in landscape mode.  
Required margins: 1.25 inches on top and bottom and 1.00 inch on the left and right; required font: 
Courier New; and required font size: 9.  All output should have the following header at the top of the 
page: 
 
VERU Inc. 
 
 
 
 
 
Page n of N 
Protocol Number: V72203 
 


 
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All output should have date (date output was generated) and page number. Tables/listings/figures 
should be internally paginated in relation to total length (i.e., page number should appear sequentially 
as page n of N, where N is the total number of pages in the table).    
   
2. Each output should be identified by a numeral, and the output designation (e.g., Table 1) should be 
listed on the same line, before the title. A decimal system (x.y and x.y.z) should be used to identify 
tables and listings with related contents. The title is centered in initial capital characters. 
 
Table No. 
Table Title 
Study Population 
 
The study population should be identified immediately following the title. 
 
3. Column headings should be in initial upper-case characters. 
4. For numeric variables, include “unit” in column or row headings when appropriate. 
5. Footnotes should be single spaced, but separated by at least a double space from the bottom line of the 
table. The notes are aligned vertically by the left vertical border of the table.    
6. If the categories are not ordered (e.g., race), then only those categories for which there is at least 1 
subject represented in 1 or more groups should be included. 
7. An Unknown or Missing category should be added to any parameter for which information is not 
available for 1 or more subjects. 
8. Listings should be sorted by subject number and study visit. 
9. In a listing, display the subject number only once for the subject with multiple records. If a subject’s 
records run across multiple pages, display the subject number once for every page. 
Data format 
1. Unless otherwise specified, the estimated mean and median for a set of values should be printed out 
to 1 more significant digit than the individual units of measurement and the standard deviation for a 
set of values should be printed out to 2 more significant digits than the individual units of 
measurement.  The minimum and maximum should report the same significant digits as the original 
values.  For example, for age (with raw data in whole years): 
 
           n                                    XX 
           Mean (STD) 
XX.X (XX.XX) 
           Median 
    XX.X 
           Min, Max 
  XX, XX 
2. Unless otherwise specified, data in columns of a table should be formatted as follows: 
• 
Alphanumeric values are left-justified.  
• 
Whole numbers (e.g., counts) are right-justified. 
• 
Numbers containing fractional portions are decimal aligned. 


 
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3. Unless otherwise specified, percentage values should be printed with 1 digit to the right of the 
decimal point (e.g., 12.8%, 5.4%).  Less-than-signs “0.1%” should be printed when values are 0.0 
and 0.1% (not 0.0%). 
4. Unless otherwise specified, missing data should be represented on subject listings as either a hyphen 
(“-“) with a corresponding footnote (“ - = unknown or not evaluated”), or as “N/A,” with the footnote 
“N/A = not applicable,” whichever is appropriate.  
5. Dates should be printed in SAS® DATE9.format (“DDMMMYYYY”: 01JUL2000).  Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000).  Dates that are 
missing because they are not applicable for the subject are output as “N/A”, unless otherwise 
specified. 
 
Unless otherwise specified, time should be printed in SAS® TIME5.format (“HH:MM”: 17:30). Missing 
portions of time should be represented on subject listings as dashes (--:30). Times that are missing 
because they are not applicable for the subject are output as “N/A”, unless otherwise specified. 
7.1 Stage 1 versus Stage 2 reporting 
TLFs reported for Stage 1 will be as shown in the TLF specification document, reporting only for Stage 1 
of the study. Assuming Stage 2 is implemented, all data for Stage 1 and 2 will be combined for safety and 
demographic tables and listings. However, the placebo groups for Stage 1 and Stage 2 will not be 
combined and will remain treated as 2 separate treatment groups. See TLF specifications for more detail 
on reporting. 
 
 


 
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8. REFERENCES 
1. 
Engstrom, C.A. (2008). Hot flashes in prostate cancer: state of the science. American journal of 
men's health 2, 122-132. 
2. 
Frisk J. (2010). Managing hot flushes in men after prostate cancer--a systematic review. Maturitas 
65, 15-22. 
3. 
Holzbeierlein JM, Castle E, Thrasher JB. 2004. Complications of Androgen Deprivation Therapy: 
Prevention and Treatment. Oncology (Williston Park). Mar; 18(3):303-309, discussion 310, 315, 
319-321. 
4. 
Ulloa E.W., Salup, R., Patterson, S.G., and Jacobsen, P.B. (2009). Relationship between hot flashes 
and distress in men receiving androgen deprivation therapy for prostate cancer. Psycho-oncology 18, 
598-605. 
 
 


 
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9. APPENDICES 
9.1 Schedule of Study Evaluations 
Day 
Screena 
Pre-
Randomization 
during 
screening period 
1 
14 
30 
60 
84 
End of 
study 
Follow-
up 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
X 
 
 
 
 
 
Assessment of Eligibility (For 
Screening visit capture history of hot 
flashes frequency and severity 
X 
X 
X 
 
 
 
 
 
Physical Exam 
X 
 
X 
 
 
 
X 
X 
Vital signs 
X 
 
X 
X 
X 
X 
X 
X 
12-lead ECG (single) 
X 
 
 
 
 
 
 
 
Clinical Laboratory Tests 
 
 
 
 
 
 
 
 
Hematology 
X 
 
X 
 
X 
X 
X 
 
Urinalysis 
X 
 
X 
 
 
 
 
 
Serum Chemistry 
X 
 
X 
X 
X 
X 
X 
 
Serum Hormones 
X 
 
X 
 
X 
X 
X 
 
Blood sample for pharmacokinetic 
assessmentc 
 
 
X 
 
X 
X 
X 
 
Bone turnover markers 
 
 
X 
 
 
 
X 
 
Thromboembolic risk assessment 
X 
 
 
 
 
 
 
 
Bilateral Doppler ultrasound of the 
lower extremities 
 
X 
 
 
 
 
 
 
Assess hot flashes (electronic 
diaries) 
 
X 
X 
 
X 
X 
X 
 
First dose 
 
 
X 
 
 
 
 
 
Dispense study drug 
 
 
X 
 
X 
X 
 
 
Collect capsule bottles (even if 
empty) and perform 
accountability/compliance 
assessment b 
 
 
 
 
X 
X 
X 
 
Assessment of conmeds 
X 
 
X 
X 
X 
X 
X 
 
Assessment of AEs 
 
 
X 
X 
X 
X 
X 
X 
Caprini VTE risk assessment d 
X 
 
X 
 
X 
X 
X 
 
a. Screening evaluations to be conducted within 28 days prior to Day 1. 
b. Collect capsule bottles (even if empty) and perform accountability/compliance assessment throughout the participation of the subject in the 
study. 
c.  The pharmacokinetic blood samples should be done prior to receiving the dose of study drug for that day. 
d.  It is important to note that it is expected that the patient population included in this study will have some risk of VTE due to age, presence of a 
malignancy, and BMI. The purpose of this assessment is a change in risk from baseline. Also, while the questionnaire is designed for the 
patient to complete, in this study, the Caprini VTE risk assessment should be filled out by study personnel with information from the patient 
and patient’s chart. 
e. The same schedule of study evaluations will be used in Stage 1 and Stage 2 of this protocol. 
 
 
 


 
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9.2 Clinical Laboratory Tests (central laboratory) 
Hematology: 
Urinalysis: 
Hemoglobin 
pH 
Hematocrit 
Specific Gravity 
Red Blood Cell Count 
Protein 
White Blood Cell Count 
Glucose 
White Blood Cell Differential 
Leucocytes 
Platelet Count 
Nitrates 
Reticulocyte Count 
Ketones 
 
Blood 
“Serum Hormones” 
Microscopic Examination (only if urinalysis 
results are abnormal) 
LH 
 
FSH 
 
Total testosterone (LC-MS/MS) 
Serum Chemistry: 
Free testosterone (LC-MS/MS) 
Sodium 
Sex Hormone Binding Globulin 
Potassium 
Serum PSA 
Chloride 
 
Bicarbonate 
 
BUN 
Bone turnover markers 
Creatinine 
C-telopeptide (CTX) 
Calcium 
Bone specific alkaline phosphatase 
Phosphorus 
 
Total Protein 
 
Albumin 
Thromboembolic Risk Assessment 
Total Bilirubin 
Factor V Leiden gene mutation 
SGOT (ALT) 
Antiphospholipid antibodies for Lupus  
SGPT (AST) 
Anticoagulant and Anticardiolipin  
Alkaline phosphatase 
Prothrombin gene mutation 
LDH 
Protein C and S 
GGT 
 
Glucose 
 
 
 


 
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9.3 Hot Flash Assessments 
Assessments of hot flashes will be made at baseline (14 contiguous days during screening) and daily from 
Day 1 (first dose) to the end of the study. Patients will record frequency and severity of hot flashes using 
an electronic diary (eDiary) to ensure attributable, time stamped data collection in an unsupervised 
environment. When experiencing a hot flash the subject will indicate on the app that they have had a hot 
flash and then will assign a severity to the hot flash based upon the following scale: 
 
• 
MILD: sensation of heat without sweating 
• 
MODERATE: sensation of heat with sweating, able to continue activity 
• 
SEVERE: sensation of heat with sweating, causing cessation of activity 
 
The hot flashes will then be compiled to examine the frequency and severity of hot flashes over the course 
of the study.