The Effect of Combination Therapy Using Li-ESWT (Low Intensity Extracorporeal Shockwave Therapy) and PDE-5 Inhibitor in Patients With Erectile Dysfunction
Phase: NA
Conditions: Erectile Dysfunction
Sponsor: Dr. Soetomo General Hospital

NCT  : 1690/KEPK/XII/2019 
Title 
: The Effect of Combination Therapy Using Li-ESWT and PDE-5 Inhibitor 
     Compared to PDE-5 Inhibitor Alone in Patients With Erectile Dysfunction 
Date 
: December 1, 2019 
 
 
Study Protocol and Statistical Analysis Plan

Study Summary 
 
 
Title 
The Effect of Combination Therapy Using Li-ESWT and PDE-5 Inhibitor in 
Patients With Erectile Dysfunction 
Methodology 
Randomized, controlled trial, blind study 
Study Duration Estimated duration for the main protocol (e.g. from start of screening to last 
subject processed and finishing the study) is approximately 9 months 
Study Centre 
Dr. Soetomo General Hospital, Surabaya - Indonesia 
Objectives 
To evaluate the effectiveness of combination therapy for mild to moderate 
erectile dysfunction using combination therapy (Li ESWT and tadalafil) 
versus tadalafil alone 
Number of 
Subjects 
30 randomized patients in two arms; test (combination therapy) and control 
(tadalafil monotherapy) 
Diagnosis and 
Main Inclusion 
Criteria 
Inclusion Criteria: 
 
Mild to Moderate Erectile dysfunction 
 
Married 
 
Sexually active 
 
Consenting to participate in the trial 
Exclusion Criteria: 
 
Psychological problems 
 
Spinal injury 
 
History of malignancy 
 
Penile anatomy abnormalities 
 
Allergic and Contraindications to tadalafil 
 
On anti-mitotic drugs 
Study Product, 
Dose, Route, 
Regiment 
Test group : receive tadalafil 2.5 mg once daily for 28 days combined with 
LiESWT twice weekly (energy density 0.09, frequency 5Hz, 600 pulse per 
location, in 5 locations : corpus penis distal, medial, and proximal, crux 
dextra et sinistra, 3 minutes of duration each location) 
 
Control group :  receive tadalafil 2.5 mg once daily for 28 days 
Statistical 
Methodology 
EndPoint : Improve Erectile Dysfunction clinically, measured using Erectile 
Hardness Score and IIEF-5 (International Index of Erectile Function); 
Laboratory (measured using VEGF level); and Ultrasonographically 
(measured using PSV (Peak Systolic Velocity) of the blood flow in 
cavernous arteries) 

Purpose : 
To evaluate the effectiveness of combination therapy for mild to moderate erectile dysfunction 
using combination therapy (Li ESWT and tadalafil) versus tadalafil alone 
 
Background : 
Erectile dysfunction (ED) is defined as the inability to achieve and maintain penile erection 
sufficient for satisfactory sexual performance that last for at least three months. The majority of 
the cases are organic ED. And, to be specific, the origin of organic ED were due to vasculogenic 
causes, which the main culprit is thought to be the endothelial dysfunction.  
PDE-5 Inhibitor is still the first line therapeutic options for this kind of ED. The mechanism of 
PDE-5 Inhibitor mainly to enable the vessels to dilate by inhibiting the PDE enzyme. Tadalafil 
is one kind of long acting PDE-5 Inhibitor. But still, some patients do not respond to the first 
line therapy. 
Li-ESWT is generally Low intensity Shock Wave that is given Extracorporeal-ly. In this 
particular study, the site is the penis. Li-ESWT is thought to be able to induce angiogenesis 
which leads to the increase of PSV resulting increase in EHS and IIEF-5. 
Addition of Li-ESWT regimen is expected to increase the respond of the standard PDE-5 
Inhibitor therapy. 
 
Goals of the study : 
1. Improve Erectile Dysfunction clinically, measured using Erectile Hardness Score 
and IIEF-5 (International Index of Erectile Function); compared to the control 
group  
2. To evaluate the angiogenesis effect laboratory (measured using VEGF level); 
compared to the control group 
3. To evaluate blood flow in cavernous arteries ultrasonographically (measured using 
PSV (Peak Systolic Velocity); compared to the control group 
 
Duration of the Study : 
Duration for the main protocol (e.g. from start of screening to last subject processed and finishing 
the study) is approximately 9 months 
 
 

Methods : 
Study Design 
Blind study involving thirty (30) subjects with mild to moderate erectile dysfunction will be placed 
in two randomized arms. One control group of fifteen (15) subjects will be given a standard first 
line therapy of tadalafil 2.5mg once daily. The other fifteen (15) subjects will be given a standard 
first line therapy, combined with LiESWT twice weekly (energy density 0.09, frequency 5Hz, 600 
pulse per location, in 5 locations : corpus penis distal, medial, and proximal, crux dextra et sinistra, 
3 minutes of duration each location). 
Data will be collected manually from patient respons, and from radiology unit and laboratory. A 
dedicated hard-copy paper system specific to each patient will serve as secondary data collection. 
Each patient will be contacted by members of the research staff at each follow up point. 
 
Study population and selection criteria 
All aspects of the study and consents form will be IRB approved prior to implementation. All 
participants will require full informed consent, be willing and able to comply with all study 
requirements and will meet the following criteria;  40-55 years old, mild to moderate erectile 
dysfunction, married, sexually active. 
Subjects will be excluded from the study based on the following criteria; 
 
Psychological problems 
 
Spinal injury 
 
History of malignancy 
 
Penile anatomy abnormalities 
 
Allergic and Contraindications to tadalafil 
 
On anti-mitotic drugs 
 
Recruitment methods 
Subjects are the new patients of Andrology Clinic of Dr. Soetomo General Hospital, with chief 
complaint of erectile dysfunction, categorized as mild to moderate, without any prior 
medication for the erectile dysfunction. 
 
 

Data collecting and reporting 
Data will be collected prior the therapeutic regiment, and after finishing the therapeutic 
regiment (28 days), consist of the EHS score, IIEF-5 Score, PSV value and VEGF level. EHS 
scores were obtained directly by asking the subjects after brief explanation. IIEF-5 scores were 
gained from the IIEF questionnaires which were filled by all subjects. PSV value based on the 
Doppler ultrasonography done by the radiology unit, and the VEGF level obtained from the 
blood test done by the laboratory. 
Data of the study will be maintained for two (2) years after the investigation completed. A 
description of this clinical trial will be available on http://www.ClinicalTrials.gov 
 
Expected outcomes 
The expected outcome is improvement of the combination therapy is better than the standard 
therapy, clinically, and laboratory and radiologically. 
 
Adverse reactions 
There is no expectations of adverse outcomes or reactions due to patients treated with tadalafil 
and LiESWT. Possible adverse reactions of tadalafil as stated by the manufacturer already being 
infoermed to all subjects. Possible adverse reactions of LiESWT consist of pain in the impacted 
area has already been informed to all subjects. All participants will be given access to contact 
info of the PI, co-investigators, and andology clinic staffs. Any adverse reactions should be 
reported immediately. 
 
Reasons for Withdrawal or Termination 
A subject may be discontinued from the study at any time if the subject, the Investigator, or the 
Sponsor feels that it is not in the subject’s best interest to continue. 
The following is a list of possible reasons for study treatment discontinuation:  
 Screening Failure 
 Subject withdrawal of consent  
 Subject is not compliant with study procedures 
 Adverse Event that in the opinion of the Investigator would be in the best interest of the 
subject to discontinue study participation 
 Protocol violation requiring discontinuation  
 Lost to follow-up 
 Subject death 

All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. Reasonable attempts will be made by the Investigator to 
provide a reason for subject withdrawals. The reason for the subject’s withdrawal from the 
study will be specified in the subject’s source documents and the Case Report Form (CRF). If 
a subject is withdrawn from treatment due to an AE (adverse Event), the subject will be followed 
and treated by the Investigator until the abnormal parameter or symptom has resolved or 
stabilized. The Investigator must make every effort to contact subjects who are lost to follow-
up. Attempts to contact such subjects must be documented in the subject’s records (e.g., times 
and dates of attempted telephone contact, receipt for sending a registered letter, etc.). 
 
Handling of Participant Withdrawals of Termination: 
Although subjects may withdraw from the study at any time and for any reason, (or may be 
withdrawn at the Investigator’s discretion), subject withdrawal should be avoided as much as 
reasonably possible. In any case, appropriate follow-up for endpoints should be continued. 
Subjects who prematurely discontinue are not to be replaced. For subjects considered lost to 
follow-up, the CRF must be completed up to the last visit performed. 
 
Methods and Study Schedule: 
Subjects eligible for the study will review and undergo informed consent. Once consented, 
subjects will be randomly assigned on a 1:1 basis to undergo:  
- Test Group, blind:  
Tadalafil 2.5mg once daily, and LiESWT twice weekly regiment as described 
- Control Group, blind:  
Tadalafil 2.5mg once daily as the standard first line therapy. 
 
Baseline/Screening Visit (-2 days from Day 0 prior to therapy) 
The following procedures will be performed at the Baseline/Screening visit: 
- 
Review the study with the subject and obtain written informed consent and  
- 
Assign the subject a unique screening/enrollment number 
- 
Review and record medical history, surgical history, and medication history to 
determine eligibility based on inclusion/exclusion criteria 
- 
Record demographics (age, race, ethnicity, gender) 
- 
Document vitals  

- 
Document all current medications, including medications over-the-counter and herbal 
medications 
- 
Perform physical examination 
- 
Assess IIEF-5 and EHS 
- 
Perform blood VEGF test and Doppler ultrasonography 
 
Treatment Visit (Day 0) 
Control group (blind) 
The fifteen (15) member of control group will receive three (3) tablets of tadalafil 2.5mg, to be 
taken once daily 
Treatment Group (blind):  
The fifteen (15) member of control group will receive three (3) tablets of tadalafil 2.5mg, to be 
taken once daily, plus the LiESWT procedure. 
 
Folluw-up Visits 
After initial treatment, all the subjects will have to follow the schedule for follow up at day 3, 
7, 10, 14, 17, 21, 24 
 
The following procedures will be performed at day 3, 10, 17, 24 
Control group (blind) 
The fifteen (15) member of control group will receive four (4) tablets of tadalafil 2.5mg, to be 
taken once daily, and assessment for adverse events and complications following treatments. 
Treatment Group (blind):  
The fifteen (15) member of control group will receive four (4) tablets of tadalafil 2.5mg, to be 
taken once daily, plus the LiESWT procedure, and assessment for adverse events and 
complications following treatments. 
 
The following procedures will be performed at day 7, 14, 21 
Control group (blind) 
The fifteen (15) member of control group will receive three (3) tablets of tadalafil 2.5mg, to be 
taken once daily, and assessment for adverse events and complications following treatments. 

Treatment Group (blind):  
The fifteen (15) member of control group will receive three (3) tablets of tadalafil 2.5mg, to be 
taken once daily, plus the LiESWT procedure, and assessment for adverse events and 
complications following treatments. 
 
Final Study Visit 
The following procedures will be performed at the final post treatment visit at day 28: 
- 
Assess for adverse events 
- 
Assess for complications following treatments 
- 
Perform physical examination 
- 
Assess IIEF-5 and EHS 
- 
Perform blood VEGF test and Doppler ultrasonography 
 
Randomization 
Subjects who meet all inclusion and exclusion criteria will be randomized on Treatment Day in 
a 1:1 ratio to either the Treatment Group or the Control Group, in accordance with a computer-
generated schedule prepared by a biostatistician. Randomization will then be performed by the 
randomization personnel in charge. Study personnel will be instructed not to randomize until 
subject has been confirmed to meet all inclusion/exclusion criteria on treatment day. 
 
SAMPLE SIZE JUSTIFICATION 
Sample Size Calculations 
 
𝑛1 = 𝑛2 = 2 𝑆𝐷2 (𝑍𝛼+ 𝑍𝛽)2 
(𝑥1 −𝑥2)2
 
 
-   SD  = 10,5   (Vardi et al., 2010) 
-   Zα = α 0,05 = 1,96. 
-   Zβ = β 0,10 = 1,28. 
 
n1 = n2 = 10,2   11 
 
 
 

 
Minimal sample for each group is eleven (11) subjects. Anticipation for drop-out was 
assumed 20%, adjusting the sample size calculation to fifteen (15) subjects for each group. 
Totalling thirty (30) participants. 
 
 
STATISTICAL ANALYSIS PLAN 
Endpoint 
EHS score (Ordinal)  
IIEF -5 score (Ordinal) measured from the standardized IIEF-5 questionnaire 
VEGF level (Interval) obtained from blood test done in the lab 
PSV (Interval) obtained from the result of Doppler ultrasonography done by the radiology unit  
All analyses will be performed using per-protocol population. 
 
EHS and IIEF-5 will be using median, VEGF ang PSV will be using mean. 
For statistical analysis of comparisons were done using paired t test or Wilcoxon signed-rank 
test as appropriate for the between group pre and post test comparisons. As for between group 
experimental and control comparisons, independent t test or Mann-Whitney test were used as 
appropriate. Significance was set at 5% (p < 0.05). Statistical software used is EZR (Easy R) 
 
ASSESSMENT OF SAFETY 
Adverse events (AE) will be monitored and collected by the study team from the point of signed 
consent until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation. For each AE, a detailed explanation will be obtained from the subject and 
subject’s medical record. All AEs will be recorded on the CRFs.   
 
Definition of Adverse Event 
An AE is defined as any unanticipated medical occurrence regardless to relationship of the 
investigative arm of the trial. An AE can be any unintended sign, lab abnormality, symptom, or 
disease associated with the trial. Any abnormality that presents during a medical test are to be 
defined as an AE if it produces clinical signs and/or symptoms, requires intervention, or deemed 
clinically significant by the Investigator. 

 
Definition of Serious Adverse Event 
An adverse event is considered serious if it results in any of the following: 
1. Death 
2. A life-threatening AE 
3. Requires inpatient hospitalization or prolongs existing hospitalization 
4. Persistent disability/incapacity  
5. Medically important event by the Investigator 
 
Severity of Event 
The Investigator will be asked to assess the severity of the AE using the following categories: 
Mild:  
Events require minimal or no treatment and 
do not interfere with the participant’s daily 
activities. 
Moderate:  
Events result in a low level of inconvenience 
or concern with the therapeutic measures. 
Moderate 
events 
may 
cause 
some 
interference with functioning.  
Severe:  
Events interrupt a participant’s usual daily 
activity and may require systemic drug 
therapy or other treatment. Severe events are 
usually 
potentially 
life-threatening 
or 
incapacitating 
 
Expectedness 
The Investigator will be responsible for determining whether an AE is expected or unexpected. 
An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study products. 
 
Time Period and Frequency for Event Assessment and Follow-Up 
The PI will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of 

study participation.  At each study visit, the Investigator will inquire about the occurrence of 
AE/SAEs since the last visit.  Events will be followed for outcome information until resolution 
or stabilization. 
 
 
 
SAE Reporting 
In the case of a SAE, the IRB must be notified according to their notification policies within 
one (1) day. 
 
Data Safety Monitoring 
As the treatments are currently being used as standard of care, the study team does not anticipate 
subjects experiencing any adverse events solely due to being in the study. This is simply a 
proposal to formally randomize and follow subjects undergoing two commonly performed 
procedures, both of which have been shown to be safe and approved. Therefore, a formal Data 
Safety Monitoring Board will not be needed for this study. 
 
DATA MONITORING 
The Principal Investigator will be responsible to ensure the study is conducted in accordance 
with the protocol, Good Clinical Practice (GCP), applicable regulatory requirements, and that 
the data recorded is valid. To achieve this objective, the study will be continuously monitored 
and reviewed on a monthly basis by the study team.  
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
GCP, and with applicable regulatory requirement(s). 
A Clinical Monitoring Plan will be created by the IRB and describe in detail who will conduct 
the monitoring, at what frequency monitoring will be done, at what level of detail monitoring 
will be performed, and the distribution of monitoring reports.  
 
DATA HANDLING AND RECORD KEEPING 

The collection of personal patient information will be limited to the amount necessary to 
achieve the aims of the research, so that no unneeded sensitive information is being collected.  
Only study personnel will collect data.  Hard copy documents will be retained for the duration 
of the study until data entry.  All hard copy documents will be kept in a locked cabinet in the 
research coordinator’s office (which will cover all the created CRFs) which will then be used 
for data analysis. Only de-identified data will be used for data analysis. All hard copy 
documents will be shredded within five years after completion of the study Collected de-
identified data will be sent to a biostatistician for statistical analysis.   
INSTITUTIONAL REVIEW BOARD 
The protocol, informed consent form(s), and all participant materials will be submitted to the 
IRB for review and approval.  Approval of both the protocol and the consent form must be 
obtained before any participant is enrolled.  Any amendment to the protocol will require review 
and approval by the IRB before the changes are implemented to the study.  All changes to the 
consent form will be IRB approved; a determination will be made regarding whether previously 
consented participants need to be re-consented. 
 
CONSENT PROCESS 
Subjects will be approached when they come through the clinic being evaluated and considered 
for therapy for mild to moderate erectile dysfunction. Each potential subject must provide 
written consent with full knowledge of the procedures involved. The informed consent, 
approved by the IRB and in accordance with regulatory guidelines, must be fully explained by 
the Investigator or member of the study staff including the study aims, methods, benefits and 
risks, and signed by the subject before enrollment into the study. Potential subjects will be 
informed that study participation is voluntary and that they may withdraw at any time. The 
subjects will be told that choosing against participation will not affect the care received for 
treatment. The subjects will be informed that they will be authorizing access of investigational 
staff to confidential medical records. The subject will be given sufficient time to read the 
consent and ask any questions. Once the informed consent is signed, the subject will be given 
a copy of the document. 
 
PROTOCOL DEVIATION  
A protocol deviation is any noncompliance with the clinical trial protocol or GCP requirements. 
The noncompliance may be either on the part of the participant, the Investigator, or the study 
site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly.   

All 
protocol 
deviations/violations 
should 
be 
documented 
using 
the 
Protocol 
Deviations/Violations CRF and submitted to the IRB according to their reporting guidelines.    
 
LAWS AND REGULATIONS 
This clinical study will be conducted in compliance with all national laws and regulations of 
the countries in which the clinical trial is performed, as well as any applicable guidelines. The 
trial will be registered on www.clintrials.gov and on other sites, as appropriate. 
PUBLICATION AND DATA SHARING POLICY 
The preparation and submittal for publication of manuscripts containing the study results shall 
be in accordance with a process determined by mutual written agreement among investigators.  
 
CONFLICTS OF INTEREST 
No conflicts of interest have been reported. 
 
STUDY PERSONNEL AND ROLES 
1. Andrian Japari, M.D.  ; Principal Investigator 
2. Androniko Setiawan, M.D. ; Co-Investigator 
3. Rosy Nur Febriani, M.D. ; Co-Investigator 
4. Tjahjo Djojo Tanojo, M.D. ; Study Coordinator 
5. M. P. B. D. Pramesti, M.D. ; Study Coordinator 
6. Agustinus, M.D. ; Project Manager 
7. Dr. Budi Utomo, M.D. ; Data Manager 
 
 

APPENDIX I 
The trial will be conducted in accordance with the Indonesian Health Research 
regulatory, and applicable to clinical studies (45 CFR Part 46, 21 CFR Part 91, 21 CFR 
Part 56, and 21 CFR Part 812). The Principal Investigator will assure that no deviation 
from, or changes to the protocol will take place without prior agreement from the 
Sponsor and documented approval from the Institutional Review Board, except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel 
involved in the conduct of this study have completed Human Subjects Protection 
Training.  
I agree to ensure that all staff members involved in the conduct of this study are informed 
about their obligations in meeting the above commitments. 
 
Signature Of Principal Investigator 
Date (12/01/2019) 
 
 
Printed Name 
Andrian Japari, M.D. 
Name of Institution 
Dr. Soetomo General Hospital