Phase 1 Clinical Trial Study to Evaluate Pharmacokinetics and Safety Profile of BZ371A in a Gel Formulation, Applied on Healthy Men and Women Genitals
Phase: PHASE1
Conditions: Erectile Dysfunction Following Radical Prostatectomy, Erectile Dysfunction, Prostate Cancer, Radical Prostatectomy
Sponsor: Biozeus Biopharmaceutical S.A.

 
 
 
 
 
 
 
 
 
 
 
BZ-371 – SUPPORTIVE THERAPY TO MAINTAIN 
PENILE INTEGRITY IN PROSTATE CANCER PATIENTS 
SUBMITED TO RADICAL PROSTATECTOMY 
 
BZ371CLI003 STUDY 
(NCT05332340)  
 
"Phase 1 Clinical Trial to evaluate safety and 
pharmacokinetic of BZ371A in a gel form applied in 
the genitalia of healthy men and women” 
 
 
 
 
Version 3.1 de 20/October/2022 
 
VERSION CONTROL 
 

BZ371CLI003 - Phase 1 BZ371A 
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2 
 
 
 
 
Status 
Version 
Data 
Document revision/version explanation 
IR 
1.0 
11/01/2021 
Document creation 
IR 
1.0 
11/09/2021 
Document revision 
Finalized 
1.0 
11/10/2021 
Document termination 
IR 
2.0 
05/26/2022 
Review according to ANVISA requirements: addition of new 
inclusion and exclusion criteria, method for evaluating 
causality, explanation and information about the code that 
will be generated for participants, a section on special interest 
adverse events, notification of serious adverse events to 
ANVISA, a subsection on regulatory agency audits, and 
clarification on the qualitative analysis of adverse events.  
IR 
3.0 
08/30/2022 
Update of the analytical laboratory hired to perform 
pharmacokinetic analysis; revision according to suggestions 
from the principal investigator: better description of the 
procedures and timepoints for blood collection regarding 
laboratory and pharmacokinetic exams; update of an 
exclusion criteria (item 1) by adding pregnant women 
(confirmed by β-HCG test); addition of β-HCG test at visit V-1; 
correction of the visit number in which the ECG will be 
collected after application of the IP; better definition of vital 
sign measurement times; description addition regarding 
unscheduled visits; and addition of a section regarding 
participant's feeding.  
IR 
3.1 
10/20/2022 
Change related to tubes specification for biological samples 
collection that will be used in the pharmacokinetics study.  
 
IR: Internal Revision 
 
 
 
 
 
 

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INDEX 
 
RESPONSIBLE PERSONNEL & INSTITUITIONS INVOLVED .............................................................................................. 7 
PHASE I SYNOPSIS ........................................................................................................................................................ 9 
ABREVIATIONS ............................................................................................................................................................ 11 
LIST OF CHARTS .......................................................................................................................................................... 14 
LIST OF FIGURES ......................................................................................................................................................... 14 
LIST OF TABLES ........................................................................................................................................................... 14 
1. 
INTRODUCTION .................................................................................................................................................. 15 
1.1 
Medical need and study justification ............................................................................................... 15 
2. 
STUDY GOALS ..................................................................................................................................................... 16 
2.1 
Primary goals .................................................................................................................................. 16 
2.2 
Endpoints ....................................................................................................................................... 17 
3. 
STUDY PLAN ....................................................................................................................................................... 17 
3.1 
General study design ....................................................................................................................... 17 
3.2 
Study location ................................................................................................................................. 19 
4. 
STUDY POPULATION .......................................................................................................................................... 19 
4.1 
Participant eligibility ....................................................................................................................... 19 
4.1.1 
Inclusion Criteria ................................................................................................................................. 19 
4.1.2 
Exclusion Criteria ................................................................................................................................ 20 
4.2 
Screening and recruitment .............................................................................................................. 20 
5. 
STUDY PROCEDURES .......................................................................................................................................... 20 
5.1 
Research participants identity preservation ..................................................................................... 20 
5.2 
Safety analysis and tolerability procedures ...................................................................................... 21 
5.2.1 
Clinical and physical evaluation .......................................................................................................... 21 
5.2.2 
Vital signs and anthropometric .......................................................................................................... 21 
5.2.3 
Physical and genitalia exam ............................................................................................................... 22 
5.2.4 
Blood and urine sample collection ...................................................................................................... 22 
5.2.5 
Electrocardiogram .............................................................................................................................. 22 
5.2.6 
Participants food ................................................................................................................................. 23 
5.3 
Pharmacokinetics analysis procedure .............................................................................................. 23 
5.3.1 
Blood sample collection procedure ..................................................................................................... 23 

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5.3.2 
Blood sample processing and storage ................................................................................................ 24 
5.3.3 
Blood sample transportation and analysis ......................................................................................... 24 
6. 
STUDY MEDICATION .......................................................................................................................................... 25 
6.1 
Medication preparation .................................................................................................................. 25 
6.2 
Packaging and labelling ................................................................................................................... 26 
6.3 
Medication storage ......................................................................................................................... 26 
6.4 
Receiving, dispensing and accounting of the IP ................................................................................ 27 
6.5 
Investigational Product application procedure ................................................................................. 27 
7. 
SAFETY ................................................................................................................................................................ 28 
7.1 
AE definition ................................................................................................................................... 28 
7.2 
AE classification according to predictability ..................................................................................... 29 
7.3 
AE classification according to intensity ............................................................................................ 30 
7.4 
AE classification according to frequency .......................................................................................... 30 
7.5 
AE classification according to intensity ............................................................................................ 30 
7.6 
AE classification according to causality ............................................................................................ 31 
7.7 
Information regarding the action taken regarding the IP .................................................................. 32 
7.8 
Information regarding participants development ............................................................................. 32 
7.9 
AE reports follow-up ....................................................................................................................... 32 
7.10 
Ethics Committee notification ......................................................................................................... 33 
7.11 
ANVISA notification ........................................................................................................................ 33 
7.12 
Clinical Research Center notification to Sponsor .............................................................................. 33 
7.13 
Consistency of the data shared from the Clinical Research Center to the Sponsor ............................. 33 
7.14 
Financing and Insurance .................................................................................................................. 34 
8. 
ETHICAL ASPECTS / HUMAN PROTECTION ........................................................................................................ 34 
8.1 
Ethical Committee ........................................................................................................................... 34 
8.2 
ICF .................................................................................................................................................. 34 
8.3 
Participant confidentiality ............................................................................................................... 35 
8.4 
Confidential Information and Publications ....................................................................................... 35 
8.5 
Risk/benefit analysis ....................................................................................................................... 36 
8.5.1 
Expected benefits ................................................................................................................................ 36 
8.5.2 
Risks related to the intervention ......................................................................................................... 36 
8.5.3 
Contraceptives methods ..................................................................................................................... 36 
8.6 
Safety monitoring ........................................................................................................................... 36 
8.6.1 Study Suspension ............................................................................................................................ 36 
8.6.2 Participants removal ....................................................................................................................... 37 

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8.6.3 Criteria for participants discontinuation........................................................................................... 37 
8.7 
Criterions for change in the approved Protocol ................................................................................ 37 
8.7.1 
Amendments ....................................................................................................................................... 37 
8.7.2 
Corrections .......................................................................................................................................... 38 
8.8 
Protocol deviations and violations ................................................................................................... 38 
9. 
STATISTICAL ANALYSIS PLAN ............................................................................................................................. 38 
10. 
DATA QUALITY CONTROL MANAGEMENT .................................................................................................... 39 
10.1 
Source document ............................................................................................................................ 39 
10.2 
Data acquisition - Clinical file ........................................................................................................... 39 
10.3 
Data validation ............................................................................................................................... 40 
10.4 
Audit .............................................................................................................................................. 40 
11. 
REFERENCES ................................................................................................................................................... 40 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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I have read this project, the experimental protocol and the Informed Consent Form and I agree to 
conduct this study in compliance with the protocol, Resolution nº 466 of December 12, 2012, Resolution 
nº 251 of August 7, 1997 of the National Health Council - Ministry of Health, and according to the Helsinki 
Declaration (1964) and the revisions of Tokyo (1975), Venice (1983), Hong Kong (1989), Somerset West 
(1996), Edinburgh (2000), Tokyo (2004) and Seoul (2008). 
 
INVESTIGATOR 
SIGNATURE 
DATE 
Dr. Regina Mayumi Doi 
 
 
 
 
SPONSOR 
SIGNATURE 
DATE 
BIOZEUS Biopharmaceutical S.A. 
 
 
 
 
CLINICAL RESEARCH CENTER  
SIGNATURE 
DATE 
Azidus Brasil Pesquisa Científica e 
Desenvolvimento LTDA. 
 
 
 
 
 
 
 
 
 

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RESPONSIBLE PERSONNEL & INSTITUITIONS INVOLVED 
 
STEPS 
LOCATION 
RESPONSIBLE 
QUALIFICATIONS 
SPONSOR 
 
Biozeus Biopharmaceutical S.A. 
Av. Visconde de Pirajá, 623 – 9o 
andar 
Ipanema – Rio de Janeiro – RJ, 
Brazil 
ZIP: 22410-003 
Tel: (21) 2523-9089 
Dr. Paulo Lacativa  
Medical Doctor  
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR 
 
Azidus Brasil Pesquisa Científica e 
Desenvolvimento LTDA.  
Rua General Osório, 507 
Vila Martina – Valinhos – SP, Brazil 
ZIP: 13271-130 
Tel: (19) 3829-6160 
Dr. Regina Mayumi Doi 
 
 
 
Medical Doctor 
 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH COORDINATOR 
Azidus Brasil Pesquisa Científica e 
Desenvolvimento LTDA.  
Rua General Osório, 507 
Vila Martina – Valinhos – SP, Brazil 
ZIP: 13271-130 
Tel: (19) 3829-6160 
Graziela Fileti  
Biologist 

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CLINICAL RESEARCH CENTER Azidus Brasil Pesquisa Científica e 
Desenvolvimento LTDA.  
Rua General Osório, 507 
Vila Martina – Valinhos – SP, Brazil 
ZIP: 13271-130 
Tel: (19) 3829-6160 
Dr. Luciana Ferrara 
Pharmacist 
 
 
 
 
 

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PHASE I SYNOPSIS 
 
TITLE 
Phase 1 clinical study to evaluate the pharmacokinetics and safety of BZ371A in gel form applied to the 
genitals of healthy men and women. 
Study Identification 
BZ371CLI003 
Study description 
Single dose, single center, non-blinded 
Dosage and 
Administration 
BZ371A, at a concentration of 5 mg/mL, applied to the genital area (entire penis including glans, clitoris, 
labia majora and minora) in a volume of 1.5 mL. The genital area should be washed with water and mild 
soap beforehand, followed by drying. The product should be applied using gloves. 
Objectives 
• Determine safety and tolerability of BZ371A qhen topically Applied to genitália of healthy men and 
women  
• Evaluate systemic presence of BZ371A, or its fragments, through a pharmacokinetics study using blood, 
when BZ371A is topically applied.  
Outcomes 
• Safety 
o Adverse Events Report  
o Physical Exam in the genital region 
o Vital signs, including heart rate and systolic blood pressure 
o Electrocardiogram (ECG) 
o Laboratorial Exam, including (i) complete blood count, including platelets; (ii) coagulation profile, 
including prothrombin time (PT) and activated partial thromboplastin time (aPTT); (iii) biochemistry, 
including glucose, sodium, potassium, urea, creatinine, chloride, total calcium, phosphorus, total 
proteins and fractions (albumin and globulin), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase, gamma-glutamyl transferase (GGT), total cholesterol, 
HDL cholesterol, triglycerides, pH; (iv) urinalysis for abnormal elements and sediment (AES). 
 
• PK analysis 
o Detection of BZ371A and its fragments in the blood at the following collection times: pre-dose, 15, 30, 
60, 180, and 360 minutes.  
o If detected, determine the pharmacokinetic parameters: maximum concentration (Cmax), half-life 
(t1/2), area under the curve (AUC), clearance (CL), distribution volume (Vd). 
Study Population 
Healthy research participants, without any injuries that could compromise the study results. 
 
Inclusion Criteria: 
1. Men or Woman older than 18 years old; 
2. Body Mass Index > 19 and < 28,5 Kg/m2; 
3. Ability to understand the Informed Consent Form (ICF). 
 
Exclusion Criteria: 
1. Women who are menstruating or pregnant (confirmed by a positive β-HCG test); 
2. Diseases that interfere with drug absorption, distribution and excretion, such as a history or 
presence of liver or kidney diseases; 
3. Presence of genital lesions or active sexually transmitted diseases (such as herpes, gonorrhea, 
candidiasis, HPV, among others) that impair local adverse effects analysis in the genital area; 
4. Presence of lesions that may compromise the study outcome or diseases that may compromise 
their safety; 
5. Use of topical medications in the genital area that may interfere with the evaluation of the 
experimental drug; 
6. History of symptomatic hypotension or diseases that increase the risk of symptomatic 
hypotension, such as patients with heart disease (including a history of angina and/or heart 
failure) and kidney disease; 
7. Findings on ECG and/or laboratory tests that, at the investigator's discretion, are considered 
significant and pose a risk to the research volunteer's participation or may interfere with the 
study's analyses; 

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8. Blood pressure (BP) outside the safe limits: systolic BP less than 90 mmHg or greater than 140 
mmHg; or diastolic BP less than 60 mmHg or greater than 90 mmHg, except in situations such as 
"white coat syndrome". 
9. Any disease or finding in which the investigator considers significant, and/or that increases the 
volunteer risk on participating in the trial or that could interfere with the results. 
 
The research participant will be eligible if they meet all inclusion criteria and none of the exclusion criteria. 
Number of 
participants  
Total of 12 research participants, 6 men and 6 women. 
Study duration 
The study will have three visits and 7 days of duration for each participant. 
 
 

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ABREVIATIONS 
°C: degrees celsius 
ADR: Adverse Drug Reaction 
AE: Adverse events 
AES: Abnormal Elements and Sediments 
ALT: pyruvate transaminase 
ANVISA: Agência Nacional de Vigilância Sanitária 
API: Active Pharmaceutical Ingredient  
Art.: Article 
AST: oxalacetic transaminase  
AUC: area under the curve 
BMI: body mass index  
BP: Blood pressure 
CL: clearance 
Cmax: maximum concentration 
CONEP: Comissão Nacional de Ética em Pesquisa 
CONITEC: Comissão Nacional de Incorporação de Tecnologias no Sistema Único de Saúde 
CPC: Chinese Peptide Company 
CRF: Clinical Report File  
D0: Study initiation day 
D-1: Screening day 
D7: Safety evaluation after study (7 after study initiation) 
DBP: Diastolic Blood Pressure 
EC: Ethics Committee 
ECG: Electrocardiogram 

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ED: Erectile Dysfunction 
GCP: Good Clinical Practice 
GMP: Good Manufacture Practice 
GOT: glutamic oxaloacetic transaminase 
GT: glutamyl transpeptidase 
HDL: high density lipoprotein 
HPV: Human Papillomavirus  
HR: heart rate 
ICF: Informed Consent Form  
ICH: International Council Harmonization 
INCA: Instituto Nacional do Câncer 
iNOS: inducible nitric oxide synthase  
IP: investigational product 
IU: international units 
Kg: kilogram 
m: meter  
mg: milligram  
ml: milliliter 
mM: millimolar 
mmHg: milligrams of mercury 
nNOS: neuronal nitric oxide synthase  
NO: nitric oxide 
NOS: nitric oxide synthase 
PDE5i: phosphodiesterase 5 inhibitor 
PK: pharmacokinetics 
POT: piruvic oxaloacetic transaminase 

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PTT: Part time tromboplastine 
RDC: Resolução da Diretoria Colegiada 
RP: radical prostatectomy  
RR: respiratory rate 
SAE: Serious Adverse Events 
SBP: Systemic Blood Pressure 
SMC: smooth muscle cells 
SOP: Standard Operational Procedure  
STD: sexually transmitted diseases  
T oC: temperature 
t1/2: half-life 
TAP: prothrombin activation time 
V0: study visit 
V1: post study safety visit  
V-1: screening visit  
Vd: distribution volume  
WHO: world health organization  
 
 
 
 
 
 
 
 
 

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LIST OF CHARTS 
Chart 1. Visits and BZ371CLI003 study procedures ............................................................................................................ 18 
Chart 2. IP identification ..................................................................................................................................................... 25 
Chart 3. Composition of the finished product .................................................................................................................... 25 
Chart 4. IP monitoring during clinical studies ..................................................................................................................... 30 
 
LIST OF FIGURES 
Figure 1. Label model for products intended for clinical research (ANVISA) ............................................................. 26 
Figure 2. Possible AE from the IP ........................................................................................... Error! Bookmark not defined. 
 
LIST OF TABLES 
Table 1. Possible AE from the IP ......................................................................................................................................... 29 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. INTRODUCTION 
1.1 
Medical need and study justification  
Apart from non-melanoma skin cancer, which is of very low aggressiveness, prostate cancer is the 
most prevalent cancer in men. In Brazil, an estimated 65,840 new cases are expected each year, 
corresponding to an estimated risk of about 63 new cases per 100,000 men (INCA, 2021). This number 
has been progressively increasing due to higher diagnosis rates and longer life expectancy. The 
advancement of early diagnosis and treatment, both medicinal and surgical, has resulted in relatively low 
mortality, despite significant prevalence. In Brazil, there were about 16,000 deaths in 2019 (INCA, 2021). 
This means that the risk of a man having prostate cancer in Brazil is 16%, but the risk of dying from this 
cancer is 3.4% (CONITEC, 2018). However, this technological advancement and longer patient survival has 
also resulted in significant morbidity. 
One of the most recent technological advances refers to the radical prostatectomy (RP) 
techniques. This surgical procedure is the complete removal of the prostate, including the prostatic 
urethra, seminal vesicles and ampullae of the vas deferens, with or without bilateral lymphadenectomy. 
It is currently considered the gold standard for the treatment of non-metastatic prostate cancer (CONITEC, 
2018). The surgical approach can be perineal, retropubic, or laparoscopic; and can also be robotically 
assisted or not (CONITEC, 2018). 
RP, although curative for prostate cancer, can result in damage to the cavernous nerves and thus, 
result in erectile dysfunction (ED). The cavernous autonomic nerves travel posterolateral to the prostate, 
entering the penis, and regulating blood flow and consequently erection. 
In the past, virtually all men undergoing RP had permanent ED. With the introduction of the 
"nerve-sparing" technique, possibly depending on the size and local invasion of the tumor, this number 
has decreased. However, in any type of RP, even robotically assisted, the surgical manipulation of the 
neurovascular bundles causes a neuropraxia, and the vast majority of men lose complete sexual function 
immediately after RP, regardless of whether the nerves were spared or not. The return of the erectile 
function will be determined by a series of factors such as age, type of surgery, sexual function pre-surgery 
(Gabrielsen, 2018; Salonia, 2016). 
Some authors consider it almost impossible for men to return to the same preoperative erectile 
function, except in rare cases - only 6.7% of patients undergoing RP report that their erection was 
comparable to before the surgery (Vaznesensky, 2016). However, even inferior to preoperative 
performance, some can recover erectile function, which is defined as the ability to have an erection 
sufficient for penetration. This recovery is slow, usually occurring between 6 and 48 months. However, 30 
to 60% of RP patients never regain sexual function (Salonia, 2016; Rambhatla, 2008). 
The definitive loss of sexual function is explained by the loss of penile mass, caused by the lack of 
blood flow. The preservation of nocturnal erections is a good sign of returning to some sexual function. 

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However, no existing treatment method is able to preserve penile integrity. Due to the lack of therapeutic 
options, phosphodiesterase 5 inhibitors (PDE5i), such as Viagra® and Tadalafil®, have been used, but 
without definitive scientific evidence to support their use. PDE5i acts by maintaining the relaxation of 
smooth muscle cells (SMCs) (and consequently blood flow) initiated by nitric oxide (NO). With the 
neuropraxia caused by RP, NO is not released and, therefore, PDE5i are not able to act. 
BZ371A is a topical agent that increases nitric oxide synthase (NOS), an enzyme responsible to 
produce NO. BZ371A is a synthetic peptide composed of 19 amino acids, derived from the venom of the 
Brazilian spider Armadeira (Phoneutria nigriventer), found near banana trees (Silvia, 2015). When injected 
into small boys, the venom of this spider causes priapism, a strong and painful involuntary erection 
(Shigehara 2016). However, in addition, the natural venom causes vascular congestion in various organs. 
Based on bioinformatics study, BZ371A was developed and modified to exclude deleterious effects, 
maintain the vasodilator effect, and at the same time make its degradation more difficult. 
BZ371A increases the expression of inducible NOS (iNOS), an enzyme that produces NO and is 
present in all cells, including the smooth muscle cells of the corpus cavernosum, which need to be 
distended to achieve an erection. It also increases the action of neuronal NOS (nNOS), present in the nerve 
endings of the penis. By acting independently of the autonomic nerves and the integrity of the pelvic 
vessels, BZ371A can act in prostatectomized patients, increasing local NO production and preventing 
penile mass loss. This combined dual action allows for a rapid onset and long-lasting effect necessary for 
the treatment of prostatectomized patients. 
In addition, by increasing NO, BZ371A will present a synergistic effect with PDE5i, allowing this 
class of drugs to perform their action of maintaining blood flow, once stimulated by NO. 
According to preclinical studies, BZ371A is a gel, considered safe, practical, and tolerable for topical 
use. In these studies, when applied topically, BZ371A did not show systemic bioavailability and, therefore, 
did not cause typical side effects of systemic vasodilators, such as arterial hypotension. 
The aim of this study is to confirm whether BZ371A topically applied, is safe, tolerable, and does 
not show systemic bioavailability in humans. 
 
2. STUDY GOALS 
2.1 
Primary goals 
The objectives of this study are: 
• To determine the safety and tolerability of BZ371A when topically applied to the genitals of men 
and women; 

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• To determine the systemic presence of BZ371A and/or its fragments, through a pharmacokinetic 
study in the blood, when topically applied to the genitalia of men and women. 
 
2.2 
Endpoints 
For safety and tolerability analysis of BZ371A, the following outcomes were considered: 
• Report of adverse events (AE); 
• Local physical examination of the genital area; 
• Vital signs, including systemic blood pressure (BP) and heart rate (HR); 
• Electrocardiogram (ECG); 
• Laboratory tests, including (i) complete blood count, including platelets; (ii) coagulation profile, 
including prothrombin time (PT) and activated partial thromboplastin time (aPTT); (iii) 
biochemistry, including glucose, sodium, potassium, urea, creatinine, chloride, total calcium, 
phosphorus, total protein and fraction (albumin and globulin), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), alkaline phosphatase, gamma-glutamyl transferase (GGT), total 
cholesterol, HDL cholesterol, triglycerides, and pH; (iv) urinalysis for abnormal elements and 
sediments (EAS). 
For pharmacokinetics analysis of BZ371A, the following outcomes will be considered: 
• Detection of BZ371A and its fragments in the blood at the following timepoints: pre-dose, 15, 30, 
60, 180, and 360 minutes; 
• If detected, determination of the pharmacokinetic parameters: maximum concentration (Cmax), 
half-life (t1/2), area under the curve (AUC), clearance (CL), volume of distribution (Vd). 
 
3. STUDY PLAN  
3.1 
General study design  
Open-label study, conducted at a single center, with the aim of being the first human trial with the 
new BZ371A formulation in order to guide future clinical studies such as to understand safety, tolerability, 
and systemic bioavailability of the peptide topically applied. 
The study will comprise only one group, consisting of 6 men and 6 women.  
The formulation will be administered in a single dose, topically, followed by medical and laboratory 
analyses for safety assessment, and blood collections for pharmacokinetic analysis. 
The concentration of BZ371A and its fragments in the blood will be measured by an appropriate 
analytical method, developed for this purpose and previously validated. The collected blood will be 

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analyzed by the company Unidade Integrada de Farmacologia e Gastroenterologia (UNIFAG), the same 
company that validated the analytical method, and will not be stored or used for any other purpose. 
The visits and procedures are illustrated in the table below: 
CHART 1. VISITS AND BZ371CLI003 STUDY PROCEDURES 
Visit 
V-1 
V0 
V1 
Day 
D-1 
D0 
D7 
Interval 
-7 a 0 
0 
+2 a -2 
Visit Name 
Screening 
PK 
Safety revision 
ICF 
X 
 
 
Demogrphic data 
X 
 
 
Medical history 
X 
X 
 
Physical exam 
X 
 
X 
Ganitalia exam 
X 
X / X (*) 
X 
Antropometric data 
X 
 
 
Vital Signs 
X 
X / X (**) 
X 
Concomitant medication 
X 
X 
X 
Blood collection for laboratory analysis 
X 
X (*) 
 
Urine collection 
X 
X (*) 
 
Electrocardiogram 
X 
X (*) 
X 
Elegibility 
X 
X 
 
Blood sample collection for PK 
 
X 
 
BZ371A application 
 
X 
 
AE collection  
 
X 
X 
Next visit schedueling  
X 
X 
 
Study dismissal  
 
 
X 
*: after 360 minutes after IP application 
**: after IP application at 30, 60, 180 and 360 
 
At the screening visit (V-1), the first procedure will be the administration of the Informed Consent 
Form (ICF). Subsequently, procedures that will support determining participant eligibility will be 
performed, including the collection, recording of demographic, medical history, and concomitant 
medication data; physical examination including genital examination, anthropometric data and vital signs; 
collection of blood and urine for laboratory analysis; and ECG. The participant will be scheduled for the 
next visit, which must occur within one week. 
At visit V0, the actual study visit, participant eligibility for the study will be confirmed by 
reanalyzing medical history and concomitant medication history. Before administration of the 
investigational product (IP), vital signs should be collected and recorded. After administration of the IP, 
serial collections for pharmacokinetic analysis will be performed; blood and urine will be collected for 
laboratory analysis; an electrocardiogram will be performed; vital signs and genital region analysis will be 

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conducted. Any adverse events (AEs) should be recorded. The participant will be scheduled for the next 
visit, which should occur within 5 to 9 days after V0. 
Visit V1 aims to evaluate participant safety after participation in the study. At this visit, a physical 
examination, including genital examination and vital signs, should be performed. In addition, it should 
also be confirmed the use of medication used during study period and AEs should be registered. If there 
are no complaints, they should be instructed of the end of the study. 
Unscheduled visits may be made for orientation, treatment, and evaluation of discontinuation 
criteria, at the Investigator's discretion in the event that a participant presents any significant sign or 
symptom, as well as AEs, that result in a return to the Research Center before regular visits. Unscheduled 
visits should be numbered according to the last regular study visit, for example, if one of these visits is 
performed after Visit 1, it will be considered as Visit 1.1, and so on until the next regular visit is conducted. 
All information collected during an unscheduled visit should be recorded in source documents and in the 
individual Clinical Record of each research participant. If the unscheduled visit results in discontinuation 
of the participant from the clinical protocol study or interruption of the use of the investigational product, 
it will be considered a study discontinuation visit and all procedures related to the final study visit should 
be performed. 
 
3.2 
Study location 
The study will be conducted at a single center, at the headquarters of Azidus Brasil Pesquisa 
Científica e Desenvolvimento, located in the city of Valinhos. Azidus Brasil is a Clinical Research Center 
that has a highly qualified team with 20 years of experience in developing drugs and health products. It 
has certified and equipped units for conducting Phase I clinical research studies. Participants will receive 
specialized assistance and care throughout the treatment period of this protocol. 
 
4. STUDY POPULATION 
4.1 
Participant eligibility 
The study group will consist of 12 healthy adults, 6 males and 6 females, with no restrictions on 
ethnicity, social class, or group. Participants should not have injuries that could compromise the study 
results, nor diseases that could compromise their safety. 
4.1.1 
Inclusion Criteria 
 
1. Men or women above 18 years of age; 
2. Body mass index (BMI) > 19 and < 28.5 kg/m2; 

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3. Ability to understand the informed consent form. 
 
4.1.2 
Exclusion Criteria 
 
1. Women who are menstruating or pregnant (confirmed by a positive β-HCG test); 
2. Diseases that interfere with the absorption, distribution, and excretion of drugs, such as a history or 
presence of liver or kidney diseases; 
3. Presence of genital lesions or active sexually transmitted diseases (STDs) (such as herpes, gonorrhea, 
candidiasis, HPV, among others) that impair the analysis of local adverse effects on the genitalia; 
4. Presence of lesions that may compromise the study results, or diseases that may compromise their 
safety; 
5. Use of topical medications in the genital region that may interfere with the evaluation of the 
experimental medication; 
6. History of symptomatic hypotension, or diseases that increase the risk of symptomatic hypotension, 
such as patients with heart disease (including a history of angina and/or heart failure) and kidney 
disease; 
7. Findings on ECG and/or laboratory tests that, at the investigator's discretion, are considered 
significant and pose a risk to the research participant's participation or may interfere with the 
study's analyses; 
8. Blood pressure (BP) outside the considered safe limits: systolic BP less than 90 mmHg or greater 
than 140 mmHg; or diastolic BP less than 60 mmHg or greater than 90 mmHg, except in situations 
such as "white coat syndrome." 
9. Any disease or condition or physical finding that the investigator considers significant and that 
increases the risk of the research participant's participation or may interfere with the results. 
The research participant will be eligible if they meet all inclusion criteria and no exclusion criteria. 
 
4.2 
Screening and recruitment 
The study participants will be recruited from the healthy volunteer database from the Clinical 
Research Center. They will be invited to come to the center, where the first mandatory procedure must 
be the explanation of the research and all activities related to it, and all participant's doubts must be 
clarified. Those who agree to participate must sign the Informed Consent Form (ICF) (ANNEX 1). 
 
5. STUDY PROCEDURES 
5.1 
Research participants identity preservation 

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In order to maintain participants' right of privacy, a unique identification code will be assigned to 
each participant during the screening visit, which must be used in all study documentation until the end 
of the study. The identification code will be generated according to the order of participant inclusion in 
an ascending order. This code will start with the identification of the clinical study (BZCLI003) followed by 
participant's entry order into the study. 
Example: Participant 1: BZCLI003P01; Participant 2: BZCLI003P02; Participant 3: BZCLI003P03; etc. 
 
5.2 
Safety analysis and tolerability procedures  
5.2.1 
Clinical and physical evaluation 
Demographic data, medical history, current medication, and adverse events will be collected 
through direct interviews with the research participant and/or their family members when necessary. 
The use of any concomitant medication should be recorded, including its indication. 
5.2.2 
Vital signs and anthropometric  
The collection of vital signs aims to detect the presence of any AE, especially hypotension. In order 
to evaluate safety, the following parameters should be collected and recorded: systolic blood pressure 
(SBP), diastolic blood pressure (DBP), heart rate (HR), respiratory rate (RR) and axillary temperature (T°C). 
Before evaluation period, participants should remain at rest (sitting and without physical effort) 
for at least 5 minutes in a room at room temperature. Blood pressure measurement should be obtained 
in only one of the participant's arms (right or left), which should be selected as a reference for subsequent 
measurements. The examiner should perform three measures with an interval of one minute between 
them; the first measurement should be discarded and the real blood pressure that should be considered 
is the average between the last two measurements. 
The normal values are: SBP between 90-140 mmHg and DBP between 60-90 mmHg. Values outside 
these ranges will be considered as medical history or AE (whether before or afterIPadministration) and 
should be reported as such if there is clinical significance in the physician's opinion. 
Vital signs should be collected at V-1, V0, and V1. At V0, they will be collected before IP 
administration (concomitant with medical evaluation); and in 30, 60, 180, and 360 minutes after IP 
administration. 
Arterial hypotension should be recorded as an AE. Its occurrence should be associated with the 
following values: 20 mmHg reduction in SBP, 10 mmHg reduction in DBP, and/or 20% increase in HR. These 
values should all be related to the data recorded on the same day, before IP administration. 

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Weight, height, and body mass index (BMI) will be measured only at V-1 for eligibility and 
characterization of the evaluated sample. 
 
5.2.3 
Physical and genitalia exam 
In order to be completed, physical examination must be performed at V-1 and V1 to capture 
diseases and AEs, respectively. The assessment includes a general inspection (skin, oropharynx, and 
appendages), and cardiovascular, pulmonary, digestive, musculoskeletal, peripheral, and neurological 
exams. 
Physical examination of the male or female genitalia must be performed at all visits: at V-1, for 
eligibility assessment; at V0, before and 360 minutes afterIPadministration, for AE assessment; and at V1, 
for AE assessment. 
 
5.2.4 
Blood and urine sample collection  
In order to evaluate the systemic safety of the PSI, blood and urine will be collected before (at V-
1) and after the application of theIP(at V0 at the 360-minute time point), for analysis of the following 
laboratory tests: (i) complete blood count, including platelets; (ii) coagulogram, including PT and PTT; (iii) 
biochemistry, including glucose, sodium, potassium, urea, creatinine, chloride, total calcium, phosphorus, 
total and fractionated proteins (albumin and globulin), TGO, or AST, TGP or ALT, alkaline phosphatase, 
gamma GT, total cholesterol, HDL cholesterol, triglycerides, pH; (iv) urinalysis. 
In addition, blood will be collected from women during the V-1 visit for the β-HCG test and 
confirmation of absence of pregnancy, allowing the participant to be included in the study. 
Approximately 20 ml of blood will be collected per evaluation (V-1 and V0), totaling 40 ml of blood 
for laboratory tests. 
Any difference between the baseline and post-application of theIPshould be evaluated by the 
examiner and, if clinically significant, should be noted as an AE. 
 
5.2.5 
Electrocardiogram  
In order to evaluate the cardiac safety of PSI, an ECG examination will be performed at all visits. 
At V0, it should be performed 360 minutes after the administration of PSI, with a window of +/- 30 
minutes. At V-1 and V1, the cardiac evaluation can be performed concurrently with the clinical evaluation. 

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The standard 12-lead ECG examination will be performed and an analytical report must be 
provided descriptively and/or conclusively in accordance with the Guidelines of the Brazilian Society of 
Cardiology on Electrocardiographic Analysis and Reports. The interpretation of the tracing should be 
performed by a physician and clinically significant abnormalities (and/or those related to the current 
health condition) should be recorded as relevant medical history and/or current conditions during the 
screening visit, which should be analyzed by the Investigator physician as a risk or not for inclusion in the 
study. Other clinically significant abnormalities found after the administration ofIPshould be reported and 
evaluated by the Investigator physician as EA. All ECG reports should be kept as part of the study 
documentation. 
 
5.2.6 
Participants food 
In order to maintain standardization of blood collection for pharmacokinetics, unbalanced feeding 
will follow the same pattern for all participants. 
• Fluids: water intake is free during the study. 
• Food: At visit V-1, participants must fast for at least 6 hours and a maximum of 10 hours before 
blood collection for laboratory tests. After this collection, participants can eat without restrictions. 
At visit V0, participants can receive a light breakfast before starting blood collection for 
pharmacokinetics and after 2 hours ofIPapplication. 
 
5.3 
Pharmacokinetics analysis procedure 
5.3.1 
Blood sample collection procedure 
The collection of blood samples will be done through a heparinized catheter inserted into the 
superficial vein of the volunteer's forearm. After each blood collection, the catheter will be washed with 
1 mL of sodium heparin solution (5000 IU/mL in 0.90% sterile NaCl). Samples will be collected at the 
following times: immediately before the application of PSI, and 15, 30, 60, 180, and 360 minutes after the 
application of PSI. 
In total, 6 samples of approximately 4.9 mL (5 mL tube) of blood will be collected from each 
participant for the BZ371A dosage. Thus, approximately 29.40 mL of blood will be used for the 
pharmacokinetic study. In addition, adding to the 40 mL for laboratory tests before and after the 
application of PSI, a total of approximately 69.40 mL of blood will be collected during the study period for 
each participant. 
The absolute real time of each blood sample collection should be recorded in the Clinical Record 
Forms (CRF) using a 24-hour clock. The absolute real time of the IP application should also be recorded, 

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so that the actual time interval between the application of IP and the respective collections can be 
computed. Any loss of sample collection should also be recorded. The collected samples should allow for 
the unequivocal identification of the study, research subject (identification code), collection period, and 
time. 
In this study, yellow tubes with clot activator and gel separator will be used for blood sample 
collection. These two components cause the blood to clot more quickly, and after clotting, the gel 
performs the physical separation between the cellular and liquid (serum) portions. After collection, the 
samples should be kept in an ice bath at 4ºC ± 2ºC from collection until centrifugation. 
5.3.2 
Blood sample processing and storage 
The blood samples will be centrifuged at approximately 3,000 rpm for 10 minutes at 4°C (±2ºC). 
Immediately after centrifugation, a minimum of 1.2 mL of serum from each sample will be collected and 
aliquoted into 3 transparent Eppendorf LoBind tubes with a maximum capacity of 1.5 mL. The minimum 
volume of serum collected will be 1.2 mL and will be divided equally among the 3 tubes (e.g., if exactly 
1.2 mL of serum is collected, each Eppendorf LoBind tube will have approximately 400 μL of volume). The 
remaining serum will be transferred to another cryogenic tube as a reserve sample. 
Lo Bind Eppendorf tubes will be stored in polypropylene boxes labeled with the study name, study 
code, period, and subject number. These boxes will be stored at a temperature < -70°C ± 5ºC in a specific 
freezer for the storage of biological samples, at the research center. 
The period between sample collection, centrifugation, and storage in the freezer should not 
exceed 30 minutes. 
5.3.3 
Blood sample transportation and analysis 
The transportation of samples from the storage unit to the analytical unit will be carried out in 
thermal boxes containing dry ice and a digital thermometer where the maximum and minimum 
temperatures reached are recorded. 
The company Unidade de Integração Farmacologia e Gastroenterologia (UNIFAG) is the analytical 
company that will quantify BZ371A and its fragments in the samples. 
If the peptide or its fragments are detected, the following pharmacokinetic parameters must be 
determined: maximum concentration (Cmax), half-life (t1/2), area under the curve (AUC), clearance (CL), 
volume of distribution (Vd). 
 
 

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6. STUDY MEDICATION 
6.1 
Medication preparation 
The PSI, named BZ371A, will be incorporated into a gel formulation. The formulation will be 
produced and stored according to good manufacturing practices (GMP), following the RDC 301 of August 
21, 2019. The pharmaceutical characteristics of theIPare listed in the table below: 
 
CHART 2. IP IDENTIFICATION 
Active ingrediente 
BZ371A 
Commercial name  
Non Aplicable 
Batch 
21051801 
Therapeutci class 
Nitric Oxide Synthase Enhancer 
Administration method 
Topical 
Pharmaceutical form 
Gel 
Concentration 
5 mg/ml 
Presentation 
Seringes with single dose 
Dosage regimen 
1,5 ml, single dose 
API fabrication 
CPC (Chinese Peptide Company) 
IP production  
BIOLAB Farmacêutica 
Responsible company 
Biozeus Biopharmaceutical S.A. 
 
The active pharmaceutical ingredient (API) was produced in accordance with good manufacturing 
practices (GMP) by the company CPC - Chinese Peptide Company, lot 21051801, and stored in a -20°C 
freezer. The API will be transported in thermal boxes containing dry ice and a digital thermometer where 
the maximum and minimum temperatures reached are recorded. 
BIOLAB, a Brazilian pharmaceutical company, will receive the API and produce the formulation 
also in accordance with GMP. The finished product formulation has the following components: 
CHART 3. COMPOSITION OF THE FINISHED PRODUCT 
Compounds 
Quantity 
Sodium Acetate Buffer 20mM 
60% 
Propilenoglycol 
30% 
Pluronic F-127 
10% 
BZ371A Acetate (Batch 21051801) 
5 mg/ml 
 
The choice of BZ371A dose for this clinical study was based on physicochemical studies that 
determined the maximum viable concentration of the compound in this formulation. In addition, in vivo 

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26 
 
 
studies of pharmacodynamics, biodistribution, and toxicology confirmed the efficacy and safety of this 
formulation, respectively. 
The study drugs will be sent by the sponsor, along with all relevant documentation, in an adequate 
quantity for the study, including an additional quantity for sample retention and potential losses. 
 
6.2 
Packaging and labelling  
TheIPwill be available in 3ml syringes containing 1.5ml of the formulation, for single-dose 
administration. All syringes will be provided in individual laminated bags, of the stand-up pouch type 
weighing 250 grams, with the label containing the necessary information for clinical research according 
to the regulations in force in the country. 
The label model to be used will contain all the labeling information required by ANVISA for 
products intended for clinical research, as shown in Figure 1 below: 
 
 
FIGURE 1. LABEL MODEL FOR PRODUCTS INTENDED FOR CLINICAL RESEARCH (ANVISA) 
 
6.3 
Medication storage 

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TheIPmust be stored in a secure location equipped with locked cabinets and restricted access, 
protected from light and moisture, and at room temperature between 20 to 25ºC. Only authorized 
personnel will have access to the products, and a document controlling access to the storage area must 
be available for inspection during possible monitoring and/or audits. 
Deviation from storage requirements, including any actions taken, must be documented and 
immediately reported to the Sponsor. Once the deviation is identified, theIPshould be placed in 
quarantine, and it should not be used until the Sponsor provides specific documentation permitting its 
use. 
All drug packaging (used or unused) should be stored at the Research Center, so that at the end of 
the study, they can be sent for final disposal, which is the responsibility of the Sponsor. 
 
6.4 
Receiving, dispensing and accounting of the IP 
The IP for the study will be transported to the Research Center accompanied by an invoice and a 
shipping form, which should contain all the necessary information to fill in the receipt form and check by 
the Research Center. If the quantity of the medication sent is inconsistent with the quantity described on 
its shipping invoice or form, or if the product is damaged in any way, the sponsor must be immediately 
contacted, and the products segregated until a favorable opinion is issued by the sponsor. 
A designated pharmacist from the Research Center will be responsible for both receiving and 
storing the study medications, as well as dispensing, collecting, and accounting for those dispensed to 
research participants, through the completion of the IP Dispensing and Return Control Form provided by 
the Sponsor. In case of discrepancies, these must be properly documented in a specific field of the form, 
as well as the reason why they occurred. The dispensing of study medications will be carried out in 
sufficient quantities, as allocated in the research. 
During monitoring visits, checks will be made between the information contained in the dispensing 
and control forms and the physical quantity of study medications. All medications used or unused, as well 
as empty packaging, during the study must be returned to the Sponsor at the end of the study to be 
destroyed in accordance with current legislation. 
6.5 
Investigational Product application procedure 
At visit V0, prior to the application of PSI, an analysis of the genital area and registration of vital 
signs should be done. The genital area should be washed beforehand with water and neutral soap, 
followed by drying. TheIPshould be applied with gloves on the entire surface of the genital organ: from 
the glans to the base of the penis in the case of men, and on the clitoris and labia majora in the case of 
women. 

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The application will be performed by a trained nursing professional. The characteristics of irritation 
and sensitivity on the applied skin (AE of the formulation on the skin) will be observed and recorded from 
this moment on. 
7. SAFETY 
7.1 
AE definition  
An AE is defined as "any unfavorable medical occurrence in a patient, or clinical trial participant, 
to whom a pharmaceutical product has been administered, which does not necessarily have a causal 
relationship with the treatment." All AEs observed after the signing of the ICF, regardless of the possible 
causal relationship with the investigational product, must be reported on the AE page(s) of each individual 
participant's CRF. AEs can be considered as the following: 
• Suspected adverse drug reactions (SADRs); 
• AEs due to medication’s quality deviations; 
• AEs due to unapproved use of medication; 
• Medication interactions; 
• Therapeutic ineffectiveness, total or partial; 
• Medication-related intoxications; 
• Medication abuse; 
• Potential and actual medication errors. 
If the research participant has a relevant previous medical history, the Investigator must specify in 
the participant's individual CRF the date of diagnosis, history of follow-up, and the treatment followed. 
Pre-existing conditions will not be considered as AE, except when there is/are: 
• Decompensation of the controlled chronic disease before starting the clinical study; 
• Symptoms Increased frequency or intensity of symptoms of the disease described in the medical 
history related to the use of the study medication; 
• Need for discordant treatment compared to the treatment usually used for the disease 
described in the medical history; 
• Specified in the clinical study protocol. 
The following will not be considered AE: 
• Planned elective procedures before the start of the clinical study, even when performed during 
its duration, except for any complications that occur during the procedure. 
The Sponsor will be responsible for all expenses related to examination procedures, especially 
those for diagnosis, treatment, hospitalization of the participant, and other necessary actions for the 
resolution of AEs related to the clinical trial (Art. 12, ANVISA RDC 09/2015). 

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The safety of treatments will be evaluated throughout the study by the incidence and classification of AEs 
occurring between treatments in terms of type, frequency, and intensity. 
 
7.2 
AE classification according to predictability 
For the classification of predictability of AEs reported during the clinical trial, the Investigator will 
use the Investigator's Brochure (IB) as the reference safety document. 
• Unexpected: an AE whose nature or intensity is not consistent with the information provided in 
the Investigator's reference safety document for the investigational product, meaning it is 
unexpected based on the product's characteristics; 
• Expected: an AE whose nature or intensity is consistent with the information provided in the 
Investigator's reference safety document for the investigational product. 
 
 
The expected AEs are referred to as "AEs of interest" because they are actively sought during 
clinical trials. They have been defined based on the results of previous animal studies and exploratory 
studies in humans. The expected AEs of the investigational product can be divided according to their origin 
(Table 1). 
 
TABLE 1. POSSIBLE AE FROM THE IP 
Origin 
Potential side effects 
Local allergy reaction or sensibility due to formulation components 
Pruritus, erythema, urticaria, skin 
rash, edema. 
Outcomes based on systemic vasodilation  
Headache, hypotension 
Outcomes based on excessive local vasodilation 
Priapism 
Outcomes resulted from peptide excretion by the kidneys  
Tubulopathy 
Other effects, with no clear rationale, detected in preclinical studies. 
Diarrhea 
 
Among the potential risks described above, two main effects were observed during preclinical 
studies: i) the development of renal tubulopathies, observed only in a study in rats with high systemic 
doses of BZ371A; ii) and diarrhea, observed in female pigs with topical application of IP. In addition to 
these AEs, in exploratory studies, pruritus was the only effect reported by study participants, with only 
one case of mild severity and complete spontaneous resolution identified. 
Therefore, for safety monitoring during the clinical trial development, the evaluation of risks 
related to the proposed formulation containing BZ371A will be carried out through (I) clinical and physical 
assessment (demographic data, medical and current history, concomitant medications); (II) vital signs 

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(SBP, DBP, HR, RR and T oC) and anthropometric measurements; (III) complete physical examination, 
including genitalia; and (IV) laboratory analysis (Table 4). 
CHART 4. IP MONITORING DURING CLINICAL STUDIES 
Possible AE 
Monitoring 
Unkown side effects 
AE report and general physical exam; Complete 
blood count analysis, biochemistry, and urinalysis. 
Local reaction: pruritus itching, redness, urticaria, skin rash, edema 
Local physical evaluation (genitália) 
Hypotension (or arrhythmia caused by hypotension) 
BP, HR (ECG) analysis 
Priapism 
Local physical evaluation (genitália) 
Tubulopathy 
Biochemistry and urinalysis 
Diahrrea 
AE report 
 
7.3 
AE classification according to intensity  
The classification of the intensity of AEs will be performed according to the World Health 
Organization's grading of intensity for health conditions described below: 
• Mild: a problem is present less than 25% of the time, with an intensity that a person can tolerate 
and that rarely occurs in the last 30 days. 
• Moderate: means that a problem is present less than 50% of the time, with an intensity that 
interferes with people's daily life and that occasionally occurs in the last 30 days. 
• Severe: means that a problem is present more than 50% of the time, with an intensity that partially 
alters people's daily life and that frequently occurs in the last 30 days. 
• Complete impairment: means that a problem is present more than 95% of the time, with an 
intensity that completely alters the person's daily life and occurs every day in the last 30 days. 
• Not specified: means that there is not enough information to specify the intensity. 
• Not applicable: means that it is inappropriate to use a grading (e.g. menstrual functions). 
 
7.4 
AE classification according to frequency  
• Once: the AE occurred only once; 
• Continuous: AE persists or worsens, without resolution between treatment courses or cycles; 
• Intermittent: AE occurs and resolves during one treatment cycle/course, and then occurs again in 
another treatment cycle/course. 
 
7.5 
AE classification according to intensity  
The AEs will be considered as serious (SAEs), regardless of the administered medication dose, in 
situations that result in any of the following clinical outcomes: 

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• Deaths; 
• Life-threatening; there is a risk of death at the time of the event; 
• Hospitalization or prolongation of existing hospitalization: hospitalization will be considered as 
hospital care requiring participant admission, as well as their stay for a period less than 24 hours 
in a hospital unit; 
• Significant or persistent disability: substantial interruption of a person's ability to perform normal 
life functions; 
• Congenital anomaly and birth defect; 
• Any suspicion of transmission of an infectious agent through a drug; 
• Clinically significant event: any event resulting from drug use that requires medical intervention 
to avoid death, life-threatening situations, significant disability, or hospitalization. 
All situations that do not result in the clinical outcomes mentioned above will be considered as 
non-serious AEs. 
 
7.6 
AE classification according to causality  
To determine causality, the Investigator should use the World Health Organization's (modified) 
system. In this way, three criteria will be evaluated to define the causal relationship: 
• Temporal relationship - The AE occurred after the use of the investigational product (IP), within at 
least 10 times its half-life; 
• Other causes - Strong presence of other causes that may be related to the AE; 
• Known effect - The effect is known or physiologically related to any of the components of the IP. 
 
CHART 5. MONITORING OF THE IP THROUGHOUT THE STUDY 
Classification 
Time related 
Other causes 
Known effect 
Improbable 
No 
NA 
NA 
Yes 
Yes 
No 
Possible 
Yes 
No 
No 
Yes 
Yes 
Yes 
Probable 
Yes 
No 
Yes 
 
• Probable: a reaction that follows a reasonable temporal sequence between medication 
administration and the appearance of the AE. It follows a known pattern of response to the 
suspected medication. It cannot be reasonably explained by the participant's known clinical state 
characteristics. 

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• Possible: a reaction that follows a reasonable temporal sequence between medication 
administration and the appearance of the AE. It follows a known pattern of response to the 
suspected medication, but it could have been produced by the participant's clinical state or other 
therapies administered concomitantly. 
• Unlikely: a reaction that does not follow a reasonable temporal sequence between medication 
administration and the appearance of the AE; or that does not follow a known pattern of response 
to the IP, and can be explained by the participant's known clinical state characteristics. 
 
If there is not enough data available to correctly establish the causality of the AE (due to 
insufficient evidence, conflicting data, or poor documentation), the Investigator should classify it as non-
evaluable. 
AEs classified as "Probable" and "Possible" will be considered "related" to the PSI, and those 
classified as "Unlikely" will be considered "not related". 
 
 
7.7 
Information regarding the action taken regarding the IP 
The investigator must report in both source documents and the participant's CRF what action was 
taken regarding the use of theIPat the time they became aware of the AE. The investigator must report if 
there was a need for clinical, pharmacological, or surgical treatment, as well as any other medical 
management required to resolve the presented AEs. 
7.8 
Information regarding participants development 
The investigator must report the evolution of the condition (clinical outcome), considering the 
following progression: 
• Recovered: when the AE is no longer present; 
• Recovering: when the AE is present but improving compared to its initial state; 
• Not recovered: when the AE is present and/or getting worse; 
• Recovered with sequelae: when the AE is no longer present, but the patient presents associated 
sequelae; 
• Ignored: when the condition of the AE is unknown; 
• Death: when the AE in question has led the patient to death. 
In cases of death, it is essential to record the date related to cause of death, to provide a death 
certificate, or medical autopsy report, when possible. 
7.9 
AE reports follow-up 

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The Investigator shall monitor the symptoms presented, whether or not they are related to the IP. 
This monitoring should be continued until the symptoms disappear or if they persist, the Investigator 
should initiate classical medical procedures to treat the symptom and evaluate the participant's continued 
participation in the study. A follow-up report shall be submitted to the Sponsor, with data regarding the 
monitoring of these reports, in accordance with current regulations. 
7.10 Ethics Committee notification  
The research Ethics Committee (EC) must be notified of all Serious Adverse Events (SAEs) occurring 
with the research participant from the center under its responsibility within a maximum period of 24 
hours, after the center becomes aware of the event through its responsible investigators. 
 
7.11 ANVISA notification  
The sponsor must ensure that all relevant information about unexpected serious adverse events 
that are fatal or life-threatening occurring in the national territory are documented and notified to 
ANVISA, through an electronic form within a maximum of 7 (seven) consecutive days from the date of 
knowledge of the case by the sponsor. In addition, additional information about the follow-up of these 
adverse events must be included in the form within 8 (eight) consecutive days from the date of 
notification. All other serious unexpected adverse events, whose causality is possible, probable, or 
definite in relation to the investigational products, must be reported to ANVISA within 15 (fifteen) 
consecutive days from the date of knowledge of the case by the sponsor. 
 
7.12 Clinical Research Center notification to Sponsor 
Non-serious AE reports should be forwarded to the Sponsor's Clinical Research Department 
through the AE pages in the CRF by the clinical research monitor after monitoring has been conducted. 
Serious AE reports should be sent to the Sponsor within 24 hours of the Research Center's 
knowledge via the specific AE reporting form provided by the Study Sponsor. This form should be sent to 
the Clinical Study Monitor and to the Sponsor. 
This submission to the Sponsor's Clinical Research Department is independent of the relationship 
between the AE and the investigational product. 
 
7.13 Consistency of the data shared from the Clinical Research Center to the Sponsor 

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34 
 
 
If there are any inconsistencies in the information about the AE in the CRFs or forms, a clarification 
note will be sent by email directly to the Investigator responsible for recording the AE for updates. A 
follow-up will be scheduled with the Investigator to monitor the progress of the condition. 
 
7.14 Financing and Insurance 
The Investigator, the Sponsor, and the institutions and/or organizations involved in the different 
phases of the research must provide immediate assistance, as well as take responsibility for the 
comprehensive care of the research participants regarding the complications and damages arising from 
the research. 
 
8. ETHICAL ASPECTS / HUMAN PROTECTION 
This research protocol was designed according to resolution 466/12 and subsequent regulations. 
Researchers must ensure that this study is conducted in full compliance with the principles of the "Helsinki 
Declaration", the principles described in the "Guidelines for Good Clinical Practice" of the International 
Conference on Harmonization (ICH), and the regulations of resolution 466/12. 
 
8.1 
Ethical Committee 
The clinical study must be previously approved in writing, according to applicable legislation, by 
an Ethics Committee (EC) indicated by the National Commission for Ethics in Research (CONEP) through 
the issuance of a Substantiated Opinion. The submission of the clinical study protocol to theECis the 
responsibility of the Principal Investigator, as well as the monitoring of the status of this evaluation. No 
activity involving research participants may be initiated before the approval of this clinical protocol by the 
EC. 
Any changes to the clinical protocol as well as to the informed consent form (ICF), or any other 
written information provided to research participants, must be previously approved by the CEP, with the 
new approval of this documentation being forwarded to the Sponsor. Records of review and approval of 
all documents related to the study must be filed by the Investigator, since they may be requested in 
inspections carried out during and after the study. 
 
8.2 
ICF 
The Investigator will protect the integrity of the participants, following all applicable regulations. 

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It is the responsibility of the researcher, or a person designated by the researcher, to obtain the 
signed informed consent form (ICF) from each patient, before any study-related procedures are 
performed. The participant must be informed of all pertinent aspects of the study and the elements of 
the ICF, including the objectives, methods, anticipated benefits, and potential risks of the study. The 
participant should have sufficient time to ask questions and think about the decision to participate or not. 
If the participant agrees to voluntarily participate in the study, they must sign and date two copies of the 
same approved version of the ICF provided by the EC. 
The researcher or designated person must also explain that patients are entirely free to refuse to 
be included in the study or to withdraw from it at any time, for any reason. 
The ICF used during the study must be reviewed by the Sponsor, approved by the EC, and made 
available for inspection. If new safety information results in significant changes in the risk/benefit 
assessment, the ICF must be reviewed and updated, if necessary. All patients (including those already 
being treated) must be informed of the new information, provided with a copy of the revised form, and 
give their consent to continue in the study. 
 
8.3 
Participant confidentiality  
Considering the privacy of the research participant, all data related to the participant will be 
identified only by the initials of their name and the corresponding code for the clinical study phase. All 
personal data will be omitted in any analysis of results. 
However, it is necessary for the Investigator to allow the study monitor (in the presence or absence 
of the Investigator) to review the part of the research participant's records related to the clinical study. 
This should include all documentation containing the research participant's medical history to verify 
eligibility, laboratory test results, diagnoses, summaries of the research participant's admission or non-
admission to the hospital during the period of the clinical study, as well as death certificates and/or 
autopsy reports. 
 
8.4 
Confidential Information and Publications 
Confidential Information is considered for any and all information that has not been previously 
published and provided to the Investigator and members of their team by the Sponsor. This includes, but 
is not limited to, the investigator's brochure, basic scientific data, clinical research protocol, amended 
protocols/amendments (when applicable), case report forms, and experimental methods. Any data 
obtained during the course of the clinical study is also considered confidential. All confidential information 
is the property of the Sponsor, however, it will be available to government health authorities. 

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At the end of the clinical study, after data analysis and submission to regulatory authorities, the 
results will be published by the Sponsor following the current regulations in the country. 
8.5 
Risk/benefit analysis  
8.5.1 
Expected benefits 
This is a phase 1 study in healthy individuals, so individual benefits are not expected. This study 
may benefit many patients in the future if the proposed intervention proves to be safe and effective. 
8.5.2 
Risks related to the intervention   
Pre-clinical studies did not demonstrate any occurrence of local or systemic side effects related to 
the IP. Therefore, possible adverse effects for IP are limited to the possibility of local reactions such as 
allergy, irritation or sensitivity, which may manifest as skin rash, urticaria and edema; and effects based 
on vasodilation resulting from products that act on the NO pathway, such as hypotension, headache and 
priapism. 
Regarding procedures, blood collection may cause bruising. The participant will fast for blood 
collection at V-1. 
8.5.3 
Contraceptives methods  
To avoid any safety issues for research participants, the following contraceptive methods will be 
considered acceptable when used correctly: oral contraceptives, contraceptive patches and/or injections, 
male condoms, diaphragms or cervical caps with spermicide, contraceptive vaginal ring, intrauterine 
device, surgical sterilization (bilateral tubal ligation, vasectomy), or sexual abstinence. 
The Investigator and the participant will decide on the appropriate contraceptive method to be 
used. 
8.6 
Safety monitoring  
8.6.1 
Study Suspension 
The Sponsor may suspend or terminate a study, or part thereof, at any time, for any reason. 
After the decision to suspend or cancel, the Sponsor must notify the Ethics Committee within a 
maximum of 15 calendar days, except in cases of temporary suspension as a safety measure, when the 
deadline is 7 calendar days from the date of suspension. It should be noted that cancellations under RDC 
09/2015 are final and apply only to ongoing clinical trial protocols, with no possibility of reactivation 
later. 
If the Investigator suspends or terminates the study, he/she must immediately inform the 
Sponsor and the Ethics Committee and provide them with detailed written information. The Investigator 
shall also return to the Sponsor all investigational products, their containers, and other study materials. 

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Upon completion of the study, the Investigator shall provide the Sponsor and the Ethics Committee with 
final reports and summaries, as required by applicable regulations. 
8.6.2 
Participants removal 
Request by the participant to withdraw from the study at any time: 
• Participant does not wish to continue in the study for personal reasons (or even without reason); 
• Participant does not wish to continue in the study due to AEs of the investigational drugs 
(undesirable effects possibly related to the investigational drugs); 
• Participant does not wish to continue for reasons other than AEs, for example, unavailability, 
intolerance to study procedures, or even personal will. 
The researcher may withdraw the participant from the study for one of the following reasons: 
• Positive response to reevaluation of any of the exclusion criteria, from admission to the 
first treatment period or on a subsequent occasion; 
• Non-adherence to the protocol requirements; 
• AEs, symptoms, or signs of possible toxicity; 
• Intercurrent illness requiring medication; 
• Any other condition that, in the researcher's judgment, is in the participant's best interest 
for maintaining health. 
The details and reasons for the participant's withdrawal from the study will be recorded in the CRF and 
must be reported to the sponsor. 
 
 
8.6.3 
Criteria for participants discontinuation 
In order to ensure the well-being of the participants, the study may be interrupted if, at the 
discretion of the Principal Investigator, or the Sponsor, it is established that the risks to which the 
participants are being subjected to, are greater than initially anticipated, or even at any time by the 
participant's own decision.  
Subjects may have their participation in the study prematurely terminated based on the 
withdrawal criteria described above. 
8.7 
Criterions for change in the approved Protocol  
8.7.1 
Amendments 

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Defined as changes that alter the potential safety risk to the participants and/or the study plan, 
such as changes in dosage regimen, alteration of the number of participants, or additional blood samples 
to be collected. Amendments can occur before and/or after the study commencement. 
Any change to the study plan requires an amendment to the protocol. The Investigator must not 
make any changes to the study without the approval of the Ethics Committee (EC) and the Sponsor, except 
when necessary to eliminate immediate obvious risks to the participants. An amendment to the protocol 
aimed at eliminating an immediate obvious risk to the participants can be promptly implemented, but the 
change must then be documented in an amendment, notified to the EC within 5 business days, and 
submitted to the appropriate regulatory agency within the required timeframe. All protocol amendments 
must be reviewed and approved following the same process as the original protocol. 
8.7.2 
Corrections 
Defined as changes before the study commencement that do not alter the potential safety risk to 
the participants and/or the study plan. 
Any necessary corrections to this protocol after its initial version approved by the Ethics 
Committee (EC) should be made with the approval of the sponsor. 
8.8 
Protocol deviations and violations 
The procedures described in the protocol must be followed in full, taking appropriate measures to 
prevent protocol deviations. However, in the event of any complications, it is the responsibility of the 
researchers to analyze and evaluate the situation, as well as take appropriate actions accordingly. 
Protocol deviation is defined as any failure to comply with the procedures or requirements defined 
in the version of the protocol approved by the Ethics Committee (EC) without significant implications for 
the study integrity, data quality, or participant rights and safety. On the other hand, protocol violation 
refers to a deviation from the protocol that may affect data quality, compromise the integrity of the study, 
or impact the safety or rights of the participants. In general, a significant deviation from the protocol is 
considered a protocol violation, while a minor deviation is considered a protocol deviation. 
Any deviation from the plan outlined in this protocol must be described, justified, and included in 
the Final Report. 
9. STATISTICAL ANALYSIS PLAN 
The statistical analyses will aim to describe the pharmacokinetic parameters. Adverse events (AEs) 
will be analyzed qualitatively. Therefore, every detected adverse event will be described in the results, 
characterized by: (i) identification, if possible, as a medical entity (sign, symptom, or disease); (ii) intensity 
(mild, moderate, or severe); (iii) severity, whether it is a serious adverse event (resulting in death, 
abortion, immediate risk of death, hospitalization or prolongation of hospitalization, or disability); (iv) 

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duration; (v) resolution (complete, partial, or unresolved); (vi) mode of resolution (spontaneous or 
requiring medicinal treatment); and (vii) causality with the investigational product (IP). 
Participants in whom the IP has been administered will be included in the analysis. 
A sample size of 12 participants is considered adequate for a pharmacokinetic curve. 
 
 
 
10. DATA QUALITY CONTROL MANAGEMENT 
The quality of the conducted clinical study will be ensured in accordance with the Standard 
Operating Procedures (SOPs) of the Research Center, which comply with regulatory requirements of the 
ICH (International Council for Harmonization), Good Clinical Practice (GCP) guidelines, and current 
national regulations. The study data management will be conducted in accordance with the applicable 
regulations. 
10.1 
Source document 
The source documents are all original documents in which the first record of collected data was 
made, including but not limited to: 
• Medical records; 
• Informed consent forms; 
• Questionnaires; 
• Dispensation control records and accounting of investigational product. 
The completion of source documents is the responsibility of the principal investigator and should 
be performed by either the principal investigator or a designated member of their team. Availability of 
the source documents for verification, by the sponsor's assigned monitor during monitoring visits, is 
mandatory. 
All documents related to the clinical study, including but not limited to source documents and the 
physical study file, should be archived under the responsibility of the Research Center for a period of 10 
years from the close-out visit of the clinical study. These documents are subject to auditing by the sponsor 
as well as regulatory authorities at any time within the aforementioned period. In the case archiving 
outside the Research Center, the storage location must be informed to the sponsor at the time of close-
out through a formal declaration. 
10.2 
Data acquisition - Clinical file 

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The raw data generated during the conduct of the study will be directly recorded in the study's 
paper Case Report Form (CRF). All data related to the study will be the responsibility of the Principal 
Investigator until its archiving. 
Clinical data will be collected by the investigator or delegated responsible party(ies), and the CRF 
should document each phase throughout the clinical study. All screened research participants will be 
recorded in the CRF, regardless of their randomization to the clinical protocol, ensuring traceability of the 
records for participants considered as selection failures. 
 
10.3 
Data validation 
Data verification will be carried out by the data management department, based on cross-checking 
between different fields of the CRF. The development of this process takes into account each field of the 
CRF and the cross-referencing of fields within the same visit and between visits, allowing for verification 
of all fields considered essential for statistical analysis and obtaining study results. This verification aims 
to ensure the quality of the collected data. 
10.4 
Audit  
During the study or after its completion, the conduct of the study and/or relevant documentation 
may be audited by the Sponsor or Regulatory Agencies through an independent visit, or by the Research 
Center through routine quality control audits. These audits aim to assess the conduct of the clinical study 
and compliance with the clinical protocol, SOPs, GCPs, and applicable regulatory requirements. 
 
 
11. REFERENCES 
• Agência Nacional de Vigilância Sanitária. Resolução de Diretoria Colegiada – RDC no 9, de 20 de 
Fevereiro de 2015. 
• CONITEC 2018. Relatório de recomendação: Sistema cirúrgico robótico para cirurgia 
minimamente invasiva: Prostatectomia radical. Ministério da Saúde 
• Gabrielsen JS, Penile Rehabiliation: the "up"- date. Curr Sex Health Rep 2018; 10(4): 287–92. 
• INCA, site acessado em 27 de março de 2021. https://www.inca.gov.br/estimativa/sintese-de-
resultadose-comentarios 
• Naranjo, C A et al. “A method for estimating the probability of adverse drug reactions.” Clinical 
pharmacology and therapeutics vol. 30,2 (1981): 239-45. doi:10.1038/clpt.1981.154 
• Rambhatla A et al. Rationale for phosphodiesterase 5 inhibitor use post-radical prostatectomy: 
experimental and clinical review. Inter J Impotence Res. 2008; 20:30–34 

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• Salonia A, et al. Sexual Rehabilitation After Treatment for Prostate Cancer—Recommendations 
From the Fourth International Consultation for Sexual Medicine (ICSM 2015). J Sex Med 2017; 
14: 285-315. 
• SHIGEHARA K, NAMIKI M. CLINICAL MANAGEMENT OF PRIAPISM: A REVIEW. WORLD J MENS 
HEALTH 2016; 34(1): 1-8. 
• Silva CN, Nunes KP, Torres FS et al. PnPP-19, a Synthetic and Nontoxic Peptide Designed from a 
Phoneutria nigriventer Toxin, Potentiates Erectile Function via NO/cGMP. J Urol 2015; 194(5): 
1481-90. 
• Voznesensky M, Annam K, Kreder KJ. Understanding and Managing Erectile Dysfunction in 
Patients Treated for Cancer. J Oncol Pract. 2016;12(4):297-304