Evaluation of the Clinical and Molecular Efficacy of Daily Avanafil in Egyptian Males With Erectile and Endothelial Dysfunction (Randomized Placebo-Controlled Study)
Phase: PHASE4
Conditions: Erectile Dysfunction
Sponsor: University of Alexandria

Official title: Evaluation of the clinical and molecular efficacy of 
daily avanafil in Egyptian males with erectile and endothelial 
dysfunction (Randomized Placebo-Controlled study) 
 
NCT number:  NCT04374994 
Document date: 20-9-2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

2. 
 
INTRODUCTION 
 
Penile erection is a neurovascular process that occurs in response to the 
activation of pro-erectile autonomic pathways and is controlled by numerous 
tightly regulated events. Pathologic alteration in the endothelium of penile 
vasculature and/or erectile tissue and/or impairment of neurovascular processes 
can result in erectile dysfunction (ED). (1) 
 
Erectile dysfunction, the persistent inability to achieve or maintain an 
erection for satisfactory sexual performance, is a highly prevalent disorder 
associated with a significant burden of illness. The prevalence and incidence of 
ED are strongly age-related, affecting more than half of men >60 years. (2-4) 
 
Erectile dysfunction is an early symptom or alert of cardiovascular 
disease, due to the common risk factors and pathophysiology mediated through 
endothelial dysfunction that may explain the association between ED and other 
vascular disease e.g., DM, CVD, and atherosclerosis. (4) 
 
The vascular endothelium is involved in numerous physiologic functions 
and its dysfunction leads to impaired vasodilatation. This is attributed to 
decreased bioavailability of nitric oxide (NO) which is a molecule with a key 
role in vascular tone regulation and thus impaired NO bioactivity is a major 
pathogenic mechanism of ED. (5,6) 
 
Endothelin‐1 (ET-1) is a 31‐amino‐acid peptide with potent and 
prolonged vasoconstrictor activity. It exerts its biological effect through the 
activation of specific endothelin receptors. Endothelin receptors have been 
found in human corporal smooth muscle membranes. ED was suggested to be 

3. 
 
the result of impaired endothelium‐dependent smooth muscle relaxation due to 
increased release of ET-1. (7,8) 
 
Oral phosphodiesterase type 5 (PDE5) inhibitors are recommended as 
first‐line therapy for ED of varying aetiology and severity. (9,10) 
 
However, many patients are dissatisfied with available therapies due to 
high cost, adverse events and perceived lack of efficacy. Therefore, the 
development of novel PDE5 inhibitors with enhanced selectivity, faster onset of 
action, increased potency and improved tolerability is desirable. (11,12) 
 
Recently, a new PDE5ì, avanafil, has become available worldwide. The 
evaluation of safety profile suggests that avanafil is associated with a lower 
incidence of side effects and approved for the treatment of ED by both the US 
Food and Drug Administration (FDA) and the European Medicines Agency 
(EMA) in April 2012 and in June 2013, respectively.(13-15) 
 
The most important characteristic of avanafil, in comparison to the first-
generation PDE5is, is its high selectivity for PDE5, particularly in relation to 
PDE6, PDE1, and PDE11. Avanafil has selectivity for PDE5 over PDE1 and 
PDE6 similar to tadalafil, but, unlike tadalafil, has negligible affinity for 
PDE11. (14,15) 
 
 
 
 
 
 

4. 
 
AIM OF THE WORK 
 
The aim of the work is to investigate the impact of daily avanafil on the 
function and levels of some soluble molecular markers of penile endothelium in 
men with erectile dysfunction. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

5. 
 
PATIENTS 
 
The study will be conducted on 140 adult males complaining of ED 
associated with diseases that may affect endothelial function such as diabetes 
mellitus, hypertension and/or dyslipidemia from outpatient clinic of 
Dermatology, Venereology and Andrology Department of the Alexandria main 
University Hospital. 
 
They will be randomized into two groups: 
Intervention group: will include seventy adult males and will receive 
daily avanafil for four weeks. 
 
Control group: will include seventy adult males and will receive a 
placebo instead. 
 
• An informed consent will be taken from all subjects prior to the onset 
of the study. 
• Approval of the medical ethics committee of Alexandria Faculty of 
Medicine will be obtained. 
 
Exclusion criteria: 
1. Patients aged < 18 years. 
2. Patients with contraindications to treatment by PDE inhibitors. 
3. Patients with diseases that increase the risk of priapism (eg, leukemia 
and multiple myeloma). 
 
 
 

6. 
 
METHODS 
 
ALL studied groups will be subjected to: 
1. Full history taking with complete general and genital examination. 
2. Diagnosis and severity of ED was determined according to IIEF-5 
questionnaire. Erectile dysfunction will be defined as a score of < 22 
in the self reported International Index of Erectile Function-5 
questionnaire (IIEF-5). (16) 
 
The International Index of Erectile Function (IIEF-5) Questionnaire 
Over the past 6 months: 
1. How do you rate 
your confidence that 
you could get and 
keep an erection? 
Very low 1 Low 2 
Moderate 
3 
High 4 Very high 5 
2. When you had 
erections 
with 
sexual 
stimulation, how 
often were 
your 
erections 
hard 
enough 
for 
penetration? 
Almost 
never/never 
1 
A few 
times 
(much 
less 
than 
half the 
time) 2 
Sometimes 
(about half 
the time) 3 
Most 
times 
(much 
more 
than 
half the 
time) 4 
Almost 
always/always 
5 
3. 
During 
sexual 
intercourse, how 
often were you able 
Almost 
never/never 
1 
A few 
times 
(much 
Sometimes 
(about half 
the time) 3 
Most 
times 
(much 
Almost 
always/always 
5 

7. 
 
The International Index of Erectile Function (IIEF-5) Questionnaire 
to 
maintain 
your 
erection after you 
had 
penetrated 
(entered) 
your 
partner? 
less 
than 
half the 
time) 2 
more 
than 
half the 
time)4 
 
 
 
 
 
 
 
4. 
During 
sexual 
intercourse, how 
difficult was it to 
maintain 
your 
erection 
to 
completion 
of 
intercourse? 
Extremely 
difficult 1 
Very 
difficult 
2 
Difficult 3 Slightly 
difficult 
4 
Not difficult 5 
5. 
When 
you 
attempted 
sexual 
intercourse, how 
often was 
it 
satisfactory for you? 
Almost 
never/never 
1 
A few 
times 
(much 
less 
than 
half the 
time) 2 
Sometimes 
(about half 
the time) 3 
Most 
times 
(much 
more 
than 
half the 
time) 4 
Almost 
always/always 
5 
IIEF-5 scoring: 
The IIEF-5 score is the sum of the ordinal responses to the 5 items. 
22-25: No erectile dysfunction 
17-21: Mild erectile dysfunction 

8. 
 
The International Index of Erectile Function (IIEF-5) Questionnaire 
12-16: Mild to moderate erectile dysfunction 
8-11: Moderate erectile dysfunction 
5-7: Severe erectile dysfunction 
 
3. The patients in the intervention group will receive avanafil 50 mg 
orally for 4 weeks. They will be instructed to take their medication on 
an empty stomach every evening. A total of 28 pills will be prescribed 
at study entry and patients will be asked to count and report any 
unused medication at the end-of-study visit.  
4. The patients in the control group will receive placebo tablets for 4 
weeks. 
5. Markers of endothelial function will be measured in plasma at 
baseline and end of treatment using standard methods and 
commercially available kits (Human Endothelin 1(ET-1) ELISA Kit, 
Nitric oxide (NO) ELISA Kit and Human Cyclic guanosine 
monophosphate(cGMP) ELISA Kit).(17-19) 
6. The primary outcome will be the percentage of change of NO, cGMP 
and ET1 serum levels from baseline to 4 weeks posttreatment with 
avanafil. 
7. The secondary outcome will be comparing avanafil with placebo 
group regarding posttreatment NO, cGMP and ET1 serum levels and 
percentage of change from baseline. 
 
 
 
ETHICS OF RESEARCH 

9. 
 
 
Research on human or human products: 
 Prospective study: informed consent will be taken from patients. In 
case of incompetent patients the informed consent will be taken 
from the guardians. 
 Retrospective study: confidentiality of records will be considered. 
 DNA/genomic material: informed consent for DNA / genomic test 
and for research will be taken from patients. No further test will be 
carried out except with further approval of committee and patients. 
If the samples will travel outside Egypt the researcher will be 
responsible for transportation and security approval. 
 All drugs used in the research are approved by the Egyptian 
Ministry of Health. 
 
 
Research on animal: 
 The animal species are appropriate for the test. 
 After test, if animal will suffer, it will be euthanized and properly 
disposed. 
 After operation, it will have a proper postoperative care. 
 
RESULTS 

10. 
 
 
The data will be recorded, tabulated, statistically analyzed and 
represented in appropriate figures and diagrams to fulfill the aim of the work.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DISCUSSION 

11. 
 
 
The findings will be discussed in view of achievement of the aim. The 
results of other related studies will be compared to those of the current one.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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