Randomized Control Trial of Low Intensity Shockwaves for the Treatment of Erectile Dysfunction. 12- Month Follow-Up of a Double-Blinded, Sham-Controlled Study.
Phase: NA
Conditions: Erectile Dysfunction
Sponsor: University of Miami

 
 
Randomized Control Trial of Low Intensity Shockwaves for the Treatment of Erectile 
Dysfunction. 12- Month Follow-Up of a Double-Blinded, Sham-Controlled Study.  
_________________________________________________________________________________________________ 
 
 
PRINCIPAL INVESTIGATOR 
 
 
Ranjith Ramasamy, M.D 
Assistant Professor 
Department of Urology 
1400 N.W. 10th Avenue 
Miami, Florida 33136 
Phone: 305-243-6596 
Fax: 305-243-4562 
Email: Ramasamy@miami.edu 
         
BIOSTATICIAN: 
 
 
 
Research Assistant Professor,  
Department of Public Health Sciences, Division of 
Biostatistics 
Clinical Research Bldg, R-669 
1120 NW 14th Street, Room 1061 
Miami, FL 33136 
Phone: (305) 243-9694   
Fax: (305) 243-5544   
rrb28@miami.edu 
 
 
 
 
 
 
 
 
 
 
STUDY COORDINATOR: 
 
 
Manuel Molina, M.D 
305-243-4873 
                                                                                  m.molina.leyba@miami.edu 
 
SPONSOR: 
 
 
 
 
Direx System Corp 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL #:  
 
 
 
20180651 
 
NCT #:  
 
 
 
 
NCT03670628 
 
 
 

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TABLE OF CONTENTS 
 
1. BACKGROUND ................................................................................................................................. 6 
1.1 
Study Disease ....................................................................................................................................... 6 
1.2 
Study Interventions ........................................................................................................................... 6 
1.3 
Rationale ................................................................................................................................................ 7 
1.4 
Preliminary Studies ........................................................................................................................... 7 
2. HYPOTHESIS .................................................................................................................................... 8 
2.1 
Alternate Hypothesis (HA): ............................................................................................................. 8 
2.2 
Null Hypothesis (HO): ....................................................................................................................... 8 
3. OBJECTIVES ...................................................................................................................................... 8 
3.1 
Primary Efficacy Objective ............................................................................................................. 8 
3.2 
Secondary Objectives ....................................................................................................................... 8 
4. STUDY DESIGN ................................................................................................................................ 9 
4.1 
Accrual goal .......................................................................................................................................... 9 
4.2 
Duration of Study Participation ................................................................................................... 9 
5. STUDY ENTRY AND ENROLLMENT AND WITHDRAWAL .............................................. 9 
5.1 
Study Entry ........................................................................................................................................... 9 
5.2 
Enrollment Procedure ...................................................................................................................... 9 
5.3 
Cancellation Guidelines ................................................................................................................... 9 
6. PATIENT SELECTION/ELIGIBILITY CRITERIA ................................................................ 10 
6.1 
Inclusion (Eligibility) Criteria .................................................................................................... 10 
6.2 
Exclusion (Eligibility) Criteria ................................................................................................... 10 
6.3 
Study Population ............................................................................................................................. 11 
7. STUDY DESIGN, CLINICAL, RADIOLOGICAL, LABORATORY AND SURGICAL 
EVALUATIONS ...................................................................................................................................... 11 
7.1 
Study Design ..................................................................................................................................... 11 
7.2 
Screening Evaluations and Procedures .................................................................................. 11 
7.3 
Pre-Treatment Procedures and Evaluations ........................................................................ 11 
7.4 
Treatment Procedures .................................................................................................................. 13 
7.5 
Follow-Up Procedures and Evaluations: ................................................................................ 13 
8. ADVERSE EVENTS ....................................................................................................................... 13 
8.1 
Expected Adverse Events ............................................................................................................. 13 
8.2 
Serious Adverse Events ................................................................................................................ 13 
9. DATA AND SAFETY MONITORING PLAN ........................................................................... 13 
10. STATISTICAL CONSIDERATIONS .......................................................................................... 14 
10.1 
Primary Study Endpoints ............................................................................................................. 14 
10.2 
Secondary Endpoints ..................................................................................................................... 14 
10.3 
Endpoint definitions ...................................................................................................................... 14 
10.4 
Sample size, accrual and study duration................................................................................ 14 
10.5 
Statistical Analysis and Power calculation ............................................................................ 15 
10.6 
Randomization: ................................................................................................................................ 15 
11. INVESTIGATORS RESPONSIBLITIES.................................................................................... 16 
11.1 
Investigator Responsibility/Performance ............................................................................ 16 

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11.2 
Confidentiality .................................................................................................................................. 16 
11.3 
Informed Consent and Permission to Use Protected Health Information ................ 16 
11.4 
Source Documentation and Investigator Files..................................................................... 17 
11.5 
Recording and Processing of Data ............................................................................................ 17 
11.6 
Non-Protocol Research ................................................................................................................. 17 
11.7 
Ethics ................................................................................................................................................... 18 
11.8 
Essential Documents for the conduct of a clinical trial .................................................... 18 
12. Appendix I International Index of Erectile Function (IIEF – EF) Questionnaire. 920 
13. Appendix II Sexual Encounter Profile (SEP- Questions 2 and 3)10 ........................... 20 
14. Appendix III Global Assessment Question (GAQ)10 ........................................................ 21 
15. Appendix IV EHS- Erection Hardness Score.11 ................................................................. 21 
16. List of Abbreviations .................................................................................................................. 21 
17. Study Calendar ............................................................................................................................. 22 
18. Study Design Flowchart: ........................................................................................................... 24 
19. References: ..........................................................................Error! Bookmark not defined.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Investigator’s Statement 
 
 
 
This clinical trial shall be conducted in compliance with the protocol, as referenced herein 
and all applicable local, national, and international regulatory requirements to include, but 
not be limited to: 
 
• International Conference on Harmonization (ICH) Guidelines on Good Clinical 
Practice (GCP) 
• Ethical principles that have their origins in the Declaration of Helsinki  
• Food and Drug Administration (FDA) Code of Federal Regulation (CFR): 
o 
Title 21CFR Part 50 and 45 CFR Part 46, Protection of Human Patients 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards 
o 
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA) 
 
As the Principal Investigator, I understand that my signature on the protocol constitutes 
my agreement and understanding of PI responsibilities to conduct the clinical trial in 
accordance to the protocol and applicable regulations.  Furthermore, it constitutes my 
understanding and agreement that any changes initiated by myself, without prior 
agreement in writing from the Sponsor, shall be defined as a deviation from the protocol, 
and shall be formally documented as such. 
 
 
I understand that my signature constitutes agreement and understanding of acceptance of 
the defined responsibilities of a Sponsor-Investigator as defined by the protocol, applicable 
FDA Regulations, and/or business contracts, but does not in any capacity relieve me of my 
responsibilities as the Sponsor-Investigator.  Additionally, my signature constitutes my 
understanding and agreement that any changes to the protocol shall be implemented 
timely with my review and approval prior to implementation. 
 
 
 
 
 
 
 
 
 
 

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INVESTIGATOR'S AGREEMENT 
 
I confirm that I have read this protocol, I understand it, and I will work according to this 
protocol and to the ethical principles stated in the latest version of the Declaration of 
Helsinki, the applicable ICH guidelines for good clinical practices, and the applicable 
federal, state, and local laws, rules, and regulations relating to the conduct of the protocol.   
I have read and understand the information in the Instructions for Use (and/or other such 
pertinent safety information) regarding the risks and potential benefits.   
I agree to inform all those who assist/collaborate with me in the conduct of this study of 
their responsibilities and obligations.  
Once the protocol has been reviewed and approved by the Institutional Review Board 
(IRB) I understand that any change(s) made during the course of the study must also (first) 
be approved by the IRB prior to implementation, except when such modification is made to 
remove any immediate hazard(s) to the subject(s).   
I certify that I and the study staff responsible, have received the requisite training to 
conduct this research protocol.   
I agree to maintain adequate and accurate records in accordance with the University of 
Miami policies, federal, state and local laws and regulations.   
I agree to maintain the confidentiality of all information received and/or developed in 
connection with this protocol. 
 
RANJITH RAMASAMY  
 
 
Print Name of Physician 
 
 
 
 
 
 
 
 
 
March 28, 2018 
 
Physician’s Signature 
Date 
 
 
 
 
 
 

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1. 
BACKGROUND 
 
1.1 
Study Disease  
 
Erectile Dysfunction (ED) is a condition with an inability to develop or maintain an erection 
of the penis upon sexual stimulation. It occurs in association with aging, chronic illnesses 
and various modifiable risk factors. Amongst the modifiable risk factors, ED shares the most 
common risk factors with Coronary Artery Disease (CAD) which are smoking, hypertension 
and hyperlipidemia1. Even though it is not a part of normal aging, it is seen in 52% men in 
the age group 40 to 70 years, with a higher rate in the men more than 70 years2.  
 
Penile erections are because of an interaction of the normal physiologic processes involving 
the central and peripheral nervous system, endocrine and vascular systems. Any imbalances 
in these processes will lead to the development of ED.  
 
The phases of erection are, 
▪ 
Dilation of the arterioles and arteries because of increased blood flow. 
▪ 
Trapping of incoming blood by the expanding sinusoids. 
▪ 
Compression of the venous plexuses reducing venous outflow. 
 
 
▪ 
Stretching of the tunica to its maximum capacity, occluding the emissary 
veins and decreasing the venous outflow to a minimum. 
▪ 
Erections occurs 
 
ED can be classified in to two groups, Organic and Psychogenic. 
 
Vasculogenic ED which belongs to the Organic group, can be either due to arteriogenic, or 
venogenic or mixed2. 
 
Arteriogenic ED is caused due to a narrowed lumen due to increased resistance of the 
arteries, enhanced basal and myogenic tone leading to vasoconstriction, and endothelial 
dysfunction resulting in impaired endothelium dependent vasodilation. 
 
Venogenic ED occurs mainly due to failure of adequate venous occlusion.  
 
The inadequate venous occlusion can be due to: 
 
▪ 
Development of large venous channels draining the corpora cavernosa. 
▪ 
Degenerative disease (old age, Diabetes) or penile fracture (traumatic injury 
to the tunica albuginea) resulting in the inadequate compression of the 
veins. 
▪ 
Alteration in the structure of the fibroelastic components resulting in venous 
leak. 
▪ 
Acquired venous shunts. 
1.2 
Study Interventions 
 

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MoreNova is a Linear Shockwave (LISW) device, which incorporates a shockwave 
transducer operable to deliver shockwaves to a treatment region confined to a narrow 
rectangle. Shockwaves generation follows the electromagnetic principle.  
 
Linear Shockwaves (LISW), as a treatment for ED has been in evaluation in contemporary 
medicine (see section 1.4). It has been in use for the last five years. 
 
The present study will utilize a device called “MoreNova”, in which shockwaves are focused 
onto line segments for improved organ coverage. Shockwaves produced by "MoreNova" are 
aimed at the left and right corpora cavernosa and the crura. The study is aimed at 
determining the safety and effectiveness of this new type of LISW in the treatment of ED. 
 
1.3 
Rationale 
 
LISW has been known to bolster angiogenesis by increasing the levels of vascular 
endothelial growth factor.  
 
Principal mode of action used in other disease: 
 
Coronary Artery Disease: Kikuchi et al.3 found significantly improved symptoms and 
decreased nitroglycerin use in patient who had a coronary artery bypass grafting and were 
suffering from stable angina. 
 
Bone Healing: Haupt et al.4 demonstrated that Low intensity shock waves treated group 
showed radiological signs of faster healing.  
 
Calcifying tendinitis: Rompe et al.5 showed that shock wave to patients suffering from 
calcifying tendinitis resulted in a 62.5% partial and complete disintegration of the deposits. 
Moreover, 85% of the patients reported improvement at 24-week follow up period. 
 
 
Diabetic Foot Ulcers: Wang et al.6 found that Extracorporeal Shock Wave Therapy (ESWT) 
to patients with diabetic foot ulcer showed complete improvement in 31% and partial 
improvement in 58%. Moreover, ESWT showed significantly better clinical results and local 
blood flow perfusion, higher cell concentration, and activity than a comparative group that 
received hyperbaric oxygen.  
 
1.4 
Preliminary Studies  
 
Contemporary literature shows two important studies in this field both conducted by Vardi 
et al7,8.  
  
The efficacy trial study published in 2010 recruited 20 men with vasculogenic ED and were 
given serial 2 sessions of treatment for about 3 weeks followed by 3  week no intervention 
period. At 1-month duration there was a significant improvement in their erectile function 
measured by International Index of Erectile Function ED (IIEF-ED) domain scores (20.9 5.8 

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vs 13.5 4.1, p < 0.001). This significant result was consistent at 6-month follow up. 
Moreover, no pain or adverse event was noted during the follow-up period.  
 
The second randomized, double-blind, sham controlled study showed that the treatment 
group had better outcome than control group on the International Index of Erectile 
Function-Erectile Function domain (mean SEM 6.7 0.9 vs 3.0 1.4, p 0.0322) at the first 
follow-up. Additionally, penile hemodynamics improve significantly in the treatment group 
in comparison to control group (maximal post-ischemic penile blood flow 8.2 vs 0.1 ml per 
minute per dl, p 0.0001).  
 
Our own preliminary phase 2 trial has demonstrated that MoreNova has demonstrated a 
clinically significant improvement in erectile function, measured by IIEF-ED, erection 
hardness score at 6 (n = 16) and 3 months (n = 32). 
2. 
HYPOTHESIS 
 
2.1 
Alternate Hypothesis (HA): 
 
Active Treatment groups will show a > 3-point increase in the IIEF-EF score from baseline 
in patients with mild to moderate erectile dysfunction, as well as an improvement in 
secondary endpoints outlined below.  
 
 
2.2 
Null Hypothesis (HO):  
 
There is no difference between the sham and treatment groups in erectile function based on 
the IIEF-EF score and secondary endpoints outlined below. 
3. 
OBJECTIVES 
 
3.1 
Primary Efficacy Objective 
 
To evaluate the change of IIEF-EF score9 from baseline to follow-ups at 1, 3, 6, 9 and 12 
months’ post treatment (appendix I). 
3.2 
Secondary Objectives 
 
To study sexual activity improvement leading to optimal penetration at follow-ups 
according to: 
 
SEP- Sexual Encounter Profile: Questions 2 and 3 (appendix II) 
GAQ- Global Assessment Questions (appendix III) 
EHS- Erection Hardness Score (appendix IV) 

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4. 
STUDY DESIGN 
4.1 
Accrual goal 
 
A total of 120 patients with ED meeting the eligibility criteria will be recruited from the 
Department of Urology clinic.  
4.2 
Duration of Study Participation 
 
The total duration of the study will be for 13 months – including 1-month pretreatment 
(washout for all patient's previously on Phosphodiesterase Inhibitors) followed by a period 
of 12 months’ follow-up after the treatment. 
5. 
STUDY ENTRY AND ENROLLMENT AND WITHDRAWAL 
 
5.1 
Study Entry 
 
Study entry, as used in this protocol, will be defined as a subject signing informed consent.  
Study enrollment, as used in this protocol, will be defined as the investigator’s confirmation 
of the subject’s eligibility by signing an eligibility checklist.  As per University of Miami 
policy, each study participant, including participants who have screened failed, who signs 
an informed consent form shall be entered into the study database.  
 
 
5.2 
Enrollment Procedure 
 
Completed and signed protocol-specific eligibility checklist; All pages of the original signed 
informed consent forms (ICFs), including HIPAA Form B; Relevant source documents or 
medical records such as:  subject medical history and physical exam, admission or discharge 
notes, diagnostic reports, pathologic confirmation of diagnosis, and relevant subject-specific 
written communication. Documentation from the Investigator that he/she has determined 
the subject meets eligibility criteria.  
 
5.3 
Cancellation Guidelines 
 
The following are reasons for withdrawal of subjects from the study: 
 
▪ 
A subject does not meet the eligibility criteria; (the subject will be 
considered a screen failure).   
▪ 
A subject withdraws consent,  
▪ 
A subject die’s during protocol participation from causes other than the 
study treatment (not due to adverse events) or  
▪ 
A study investigator decides the subject should be withdrawn from the 
study (e.g. subject non-compliance)  

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Regardless of reason for withdrawal, once a patient has been randomized to an arm, an 
intention to treat analysis will be performed.  
 
All subjects who either screen fails, is withdrawn from the study or has completed all visits 
should be de-enrolled from the research database within 48 hours.   
6. 
PATIENT SELECTION/ELIGIBILITY CRITERIA 
6.1 
Inclusion (Eligibility) Criteria 
 
• The patient must be able willing and able to provide informed consent.  
• The patient is a male between >30 and <70 years of age. 
• The patient has ED based of IIEF scores.  
• The patient has been in a stable relationship for over 3 months prior to enrollment. 
• A minimum of 2 sexual attempts per month for at least one month prior to 
enrollment – as documented by International Index of Erectile Dysfunction (IIEF)  
• The patient is suffering from erectile dysfunction lasting for over 6 months and not 
more than 5 years as per history provided by patient.  
• IIEF-EF score between 16 and 25.  
• Testosterone level 300-1000 ng/dL within 1 month prior to enrollment. 
• A1C level ≤ 7% within 1 month prior to enrollment. 
 
6.2 
Exclusion (Eligibility) Criteria 
 
• The patient is currently or has participated in another study within the past three 
months that may interfere with the results or conclusions of this study. 
• The patient is under judicial protection (prison or custody).  
• The patient is an adult under guardianship. 
• The patient refuses to sign the consent.  
• History of radical prostatectomy or extensive pelvic surgery. 
• Evidence of venous leak. 
• Past radiation therapy of the pelvic region within 12 months prior to enrollment. 
• Recovering from any cancer within 12 months prior to enrollment. 
• Neurological disease such as Alzheimers or Parkinson’s disease which affects 
erectile function at the discretion of the investigator.  
• Psychiatric diagnosis or medications such as antidepressants, anxiolytic, 
antipsychotic that affects erectile function or any other medications at the discretion 
of the investigator. 
• Anatomical malformation of the penis, including Peyronie's disease. 
• Testosterone level <300 or >1000 ng/dL within 1 month prior to enrollment. 

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• A1C level > 7% within 1 month prior to enrollment or history of Insulin dependent 
diabetes. 
• The patient is taking blood thinners and has an international normalized ratio >3. 
• Received shockwave treatment at least 6 months before enrollment.  
 
 
6.3 
Study Population 
 
120 males suffering from ED.  
7. 
STUDY DESIGN, CLINICAL, RADIOLOGICAL, LABORATORY AND SURGICAL 
EVALUATIONS 
7.1 
Study Design  
 
This is a prospective, randomized, clinical study aimed to evaluate the safety and efficacy of 
the two treatment schedules on symptomatic ED patients. The patients are randomized in a 
2:1 ratio of active to sham treatment groups. (Refer section 18) 
 
7.2 
Screening Evaluations and Procedures 
 
The first visit of the patients will be for screening and medical evaluation. Patient’s medical 
history will be collected and documented and a physical examination will be performed.  
 
Previous month’s blood test results will be reviewed including a general chemistry panel, a 
Hemoglobin A1C and serum testosterone levels during chart review. 
 
Patients will sign an informed consent and will answer the IIEF-EF questionnaire to see if 
they fit the criteria for enrollment. In case they meet all inclusion criteria (and do not meet 
any exclusion criteria), they will be recruited to the study.  
 
Patients who have been using PDE5-i in the last 4 weeks will report on their medicine type 
and dosage, and this data will be recorded in their files (reported prior to consent and 
gathered from chart review).  
 
 
7.3 
Pre-Treatment Procedures and Evaluations  
 
Upon evaluating the inclusion/exclusion criteria, patients will be recruited to the study and 
randomized into one of the two groups in a 2:1 ratio (randomization will be performed by a 
computer software maintained by the Department of Urology). Patients randomized to the 
treatment group will be instructed to stop any use of PDE5i for 4 weeks prior to first 
treatment session and refrain from using any other ED therapy option during the study. 

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They will be instructed to undergo a PDE5i washout period of 4 weeks prior to treatment 
and to avoid using PDE5i or any other ED treatment during the entire study duration 
(shockwave treatment and follow-ups). After the washout period and before the first 
treatment session, patients will answer the IIEF-EF, SEP and EHS questionnaires for 
baseline evaluation. Penile Doppler ultrasound will be performed by the time of enrollment, 
at 1,3, 6, 9 and 12 months and after treatment.  
 
 
7.4 
Treatment Procedures  
 
The treatment session lasts approximately 20 minutes and may be performed in an office 
environment. Treatment is applied in the physician’s office. For session and treatment 
details (see below) 
 
 
 
 
 
 
 
In 
the 
treatment 
group, 
patients 
randomized 
will 
receive,  
5 daily sessions within a week (MTWThF), in which 720 shocks of treatment energy will be 
applied in every session to each treated region (left and right corpora cavernosa and crura). 
In the sham group, patients will have the same number of sessions, and the machine will be 
set to deliver 720 shock treatments, but the machine will not fire shockwaves.  
 
 
 

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7.5 
Follow-Up Procedures and Evaluations: 
 
Follow-up visits will be conducted at months: 1, 3, 6, 9 and 12  after the last treatment 
session and shall include:  
 
Measuring IIEF-EF, GAQ, SEP, and EHS scores of patients at the clinic at every follow-up 
visit, as well as reporting and recording adverse events.  
 
Doppler ultrasound will be performed at the time of enrollment, 3 and 6 month follow up.  
8. 
ADVERSE EVENTS 
 
8.1 
Expected Adverse Events  
 
In known studies where LISW was used for treatment of ED, there have been no reported 
adverse events (Ref. 2, Ref. 3). Additionally, in our own phase 2 trial no adverse events were 
reported. However minimal side effects like Transitory reddening of the skin, small bruising 
and swelling can be expected. 
 
8.2 
Serious Adverse Events  
 
Serious injury or death  
 
Any adverse event (penile hematoma or penile fracture) and eventual complication must be 
recorded at any time during the treatments and the follow up visits, and throughout the 
entire study duration. Patients will be instructed to alert the study investigator by 
telephone of any side effects occurring in the period after the treatment and until the study 
end.  
 
For Reporting of adverse events see section 9  
 
9. 
DATA AND SAFETY MONITORING PLAN 
 
The study investigators will report to a surgeon monitor Dr. Sanoj Punnen in the 
department of urology (who is not involved in the study) to ensure data quality and subject 
safety. The investigators will conduct continuous reviews of the data and subject safety, 
keeping track of the number of subjects, significant toxicities in accordance with the 
protocol and observed responses, which will be discussed at research committee meetings. 
All grade 3-5 adverse events (CTCAE v4.0), regardless of association with the LISW, will be 
entered into study database and reviewed at research committee meetings. In addition, all 
adverse reactions considered “serious” will be entered into research database and reviewed 
by the Surgeon monitor on an ongoing basis. If a death occurs within 30 days of LISW 
treatment and is determined to be related to the study, the investigators will notify the 

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Department Chair Dr. Dipen Parekh within 1 business day. If an increase in the frequency of 
grade 3 or 4 adverse events is noted in the study, a report will be submitted to the 
Department Chair Dr. Dipen Parekh at the time the increased rate is identified. If at any time 
the principal investigator stops enrollment or stops the study due to safety issues, the 
Department Chair (Dr. Dipen Parekh) will be notified within 1 business day and a formal 
letter will be sent to the Department Chair (Dr. Dipen Parekh) to be received within 10 
business days.  
10. STATISTICAL CONSIDERATIONS 
10.1 Primary Study Endpoints 
 
The IIEF-EF questionnaire (appendix I) was chosen as the primary clinical efficacy 
assessment tool in this study. The total score (range 0-30) will be used for statistical 
analysis. The lower the score the more severe the ED. 
 
10.2 Secondary Endpoints 
 
Sexual activity improvement leading to optimal penetration at follow-ups will be done 
according to: 
 
SEP 2 & 3 at follow-ups 
GAQ at follow-ups 
EHS at follow-ups. 
 
Endpoint Measurements: using CRF/questionnaire analysis 
 
10.3 Endpoint definitions 
 
IIEF-EF Questionnaire see appendix I 
SEP 2 & 3 Questionnaire see appendix II 
GAQ Questionnaire see appendix III 
EHS Questionnaire see appendix IV 
 
10.4 Sample size, accrual and study duration 
 
TOTAL SAMPLE SIZE: 120 
TOTAL ACCRUAL: 120  
ACCURAL DURATION: 24 months 
STUDY DURATION: 13 months 
 
 
 
 

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10.5 Statistical Analysis and Power calculation   
 
The average and standard deviation of all relevant variables, including demographic and 
baseline characteristics, primary and secondary outcomes will be calculated.  
 
IIEF-EF and EHS scores will be analyzed using ANOVA with repeated measures throughout 
the study, in order to compare the trends between the treatment and sham group. 
 
GAQ, SEP and success rates will be analyzed and compared between the groups according to 
Fisher's exact test in each of the endpoints. The statistical significance will be set at P<0.05.    
  
Demographic characteristics such as age and ED duration will be compared between 
treatment group and sham group using student's T-Test. Other demographic characteristics, 
such as medical background and risk factors will be compared between these groups using 
Fisher's Exact Test. 
 
A sample of 120 men with failing scores on the IIEF survey will be randomized 2:1 into a 
treatment or sham arm using a permuted random block algorithm. We hypothesize that 
following treatment, both the treatment and sham groups will have increases in IIEF scores 
from baseline, but that the treatment group will have a greater statistically significant 
increase compared to the sham group. Our hypothesis will be tested using a repeat 
measures ANOVA test, with a 0.025 alpha error level to allow for a 0.05 experiment wide 
type I error rate. Using follow up data from our phase 2 trial, we expect a minimum of a 3.5 
point improvement in IIEF scores from baseline in the treatment group with a standard 
deviation of approximately 4.5. Additionally, we assume a small 0.5 improvement in the 
placebo arm based on placebo responses in prior ED studies. With this information power 
calculations done in r 3.3.0 suggest that with 41 participants in each group we will have an 
85% 
power 
to 
detect 
the 
difference 
between 
our 
treatment 
and 
placebo 
groups. Furthermore, if our non-compliance/drop-out rate remains above 10% will have at 
least 80% power (see Figure 1). 
  
Figure 1: Sample size needed for 80% 85% and 90% power for a 1-Way ANOVA Pairwise, 2-Sided Equality 
with alpha = 0.025. 
Power 
Sample 
Size 
0.8 
36 
0.85 
41 
0.9 
48 
 
 
 
10.6 Randomization: 
 
 

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120 patients will be randomized . 2:1 to treatment vs placebo groups with 80 patients in the 
treatment arm and 40 patients in the placebo arm. An online based randomization tool 
called randomized.org will be used. The PI will not have the knowledge of patient’s 
treatment group beforehand. However, the study coordinator will be aware of treatment vs 
sham group; because the sham probe needs to be applied once a patient is randomized into 
the sham arm.   
11. INVESTIGATORS RESPONSIBLITIES 
11.1 Investigator Responsibility/Performance 
 
The investigator (or a person designated by the investigator) should inform the patient of 
all pertinent aspects of the study, including the written information. 
 
The investigator should provide the patient ample time and opportunity to inquire about 
details of the study and to decide whether or not to participate in the study.  All questions 
about the study should be answered to the satisfaction of the patient. Neither the 
investigator, nor the study staff, should coerce or unduly influence a patient to participate 
or to continue to participate in a study. 
 
11.2 Confidentiality 
 
The identity of the patients in this study will be treated as confidential. Patients eligible to 
participate in the study following the pre-treatment visit will be assigned a unique patient 
code. The results of the study, including any other data, may be published for scientific 
purposes but will not give the patients' name or include any identifiable references to them. 
 
However, any records or data obtained as a result of the patient participation in this study 
may be inspected by the sponsor, by any relevant governmental agency, by the Hospital 
Ethics Committee, or by the persons conducting this study, provided that such inspectors 
are legally obligated to protect any identifiable information from public disclosure, except 
where disclosure is otherwise required by law or a court of competent jurisdiction. These 
records will be kept private in so far as permitted by law.  
 
11.3 Informed Consent and Permission to Use Protected Health Information  
 
It is the responsibility of the investigator to obtain written informed consent from each 
subject participating in this study after adequate explanation, in lay language, of the 
methods, objectives, anticipated benefits, and potential hazards of the study.  The 
investigator must also explain that the subject is completely free to refuse to enter the study 
or to discontinue participation at any time (for any reason) and receive alternative 
conventional therapy as indicated.  Prior to study participation, each subject will sign an IRB 
approved informed consent form and receive a copy of same (and information leaflet, if 
appropriate).  
 

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The investigator or designee must explain to the subject before enrollment into the study 
that for evaluation of study results, the subject’s protected health information obtained 
during the study may be shared with the study sponsor, regulatory agencies, and the IRB.  It 
is the investigator’s (or designee’s) responsibility to obtain permission to use protected 
health information per HIPAA from each subject, or if appropriate, the subjects’ parent or 
legal guardian. 
 
11.4 Source Documentation and Investigator Files 
 
The investigator will maintain adequate and accurate records to document the conduct of 
the study and to ensure that study data can be subsequently verified.  These documents will 
be classified into two separate categories: (1) investigator study file and (2) subject clinical 
source documents that corroborate data collected on the CRF’s.  Subject clinical source 
documents would include hospital/clinic patient records; physician's and nurse's notes; 
original laboratory, radiology, pathology, and special assessment reports; QOL forms, signed 
informed consent forms.  When the CRF or any form is used as the source document, this 
will be clearly stated in the investigator study file. 
 
At a minimum, the following be documented in source documents: 
 
• 
Medical history/physical condition and diagnosis of the subject before involvement 
in the study sufficient to verify protocol entry criteria. 
• 
Study number, assigned subject number, and verification that written informed 
consent was obtained (each recorded in dated and signed notes on the day of entry 
into the study) 
• 
Progress notes for each subject visit. 
• 
Laboratory test results. 
• 
Condition and response of subject upon completion of or early termination from the 
study. 
• 
Quality of Life Surveys. 
 
11.5 Recording and Processing of Data 
 
Data for this study will be entered into electronic CRFs in research database (a web-based 
clinical research management application).  A CRF is required for every patient who 
received any study intervention.  The investigator will ensure that the CRF’s are accurate, 
complete, legible and timely. Separate source records are required to support all CRF 
entries.  All corrections to study data will be made by drawing a single line through the 
information to be corrected without obscuring it.  All corrections will be initialed, dated and 
explained, if necessary. Do not use “white-out” or obscuring correction tape.   
 
11.6 Non-Protocol Research 
 
No investigative procedures other than those described in this protocol will be undertaken 
on the enrolled subjects without the agreement of the IRB. 

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11.7 Ethics 
 
The investigator agrees to conduct the study in compliance with the protocol, current good 
clinical practices, and all applicable (local, FDA) regulatory guidelines and standard of ethics 
 
11.8 Essential Documents for the conduct of a clinical trial 
 
Essential documents are those documents with individually and collectively permit 
evaluation of the conduct of a trial and the quality of the data produced. 
 
The following documents will be on file: 
 
• 
CV’s and license of all investigators. 
• 
IRB documentation/correspondence. 
• 
Documentation of IRB certification. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12. Appendix I International Index of Erectile Function (IIEF – EF) 
Questionnaire. 9 
 
 
Name:  
Date: 
Write the number that best describes your erectile function for the past 4 weeks in the 
spaces provided 
Over the past four weeks:  
1. How often were you able to get an 
erection during sexual activity? 
0 = No sexual activity 
1 = Almost never/never 
2 = A few times (much less than half the 
time) 
3 = Sometimes (about half the time) 
4 = Most times (much more than half the 
time) 
5 = Almost always/always 
2. When you had erections with sexual 
stimulation, how often were your erections 
hard enough for penetration? 
0 = No sexual activity 
1 = Almost never/never 
2 = A few times (much less than half the 
time) 
3 = Sometimes (about half the time) 
4 = Most times (much more than half the 
time) 
5 = Almost always/always 
3. When you attempted sexual intercourse, 
how often were you able to penetrate 
(enter) your partner? 
0 = Did not attempt intercourse 
1 = Almost never/never 
2 = A few times (much less than half the 
time) 
3 = Sometimes (about half the time) 
4 = Most times (much more than half the 
time) 
5 = Almost always/always 
4. During intercourse, how often were you 
able to maintain your erection after you had 
penetrated (entered) your partner? 
0 = Did not attempt intercourse 
1 = Almost never/never 
2 = A few times (much less than half the 
time) 
3 = Sometimes (about half the time) 
4 = Most times (much more than half the 
time) 
5 = Almost always/always 
5. During sexual intercourse, how difficult 
was it to maintain your erection to 
completion of intercourse? 
0 = Did not attempt intercourse 
1 = Extremely difficult 
2 = Very difficult 
3 = Difficult 
4 = Slightly difficult 

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5 = Not difficult 
15. How would you rate your confidence 
that you could get and keep an erection? 
1 = Very low 
2 = Low 
3 = Moderate 
4 = High 
5 = Very high 
 
 
13. Appendix II Sexual Encounter Profile (SEP- Questions 2 and 3)10 
 
SEP-Q2:  Over the past 4 weeks, were you able to insert your penis into your partner's 
vagina? 
Yes………                                        No……… 
SEP-Q3: Over the past 4 weeks, did your erection last long enough for you to have 
successful intercourse? 
Yes………                                        No……… 
 
 
 
 
 
 
 

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14. Appendix III Global Assessment Question (GAQ)10 
 
GAQ-Q1: Over the past 4 weeks, has the treatment you have been taking improved your 
erectile function? 
Yes………                                        No……… 
GAQ-Q2: If yes, has the treatment improved your ability to engage in sexual activity over 
the past 4 weeks? 
Yes………                                        No……… 
15. Appendix IV EHS- Erection Hardness Score.11 
 
How would you rate the hardness of your erection? 
• 
0: Penis does not enlarge 
• 
1: Penis is larger but not hard 
• 
2: Penis is hard but not hard enough for penetration 
• 
3: Penis is hard enough for penetration but not completely hard 
• 
4: Penis is completely hard and fully rigid 
16. List of Abbreviations 
 
ED 
Erectile Dysfunction 
AE 
Adverse Event 
EHS 
Erection Hardness Score 
GAQ 
Global Assessment Questions 
IIEF-EF 
The International Index of Erectile Function – Erectile Function 
LISW 
Low Intensity Shock Wave 
PDE5i 
Phosphodiesterase type 5 inhibitor 
SEP 
Sexual Encounter Profile 
 
 

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1. 
Study Calendar 
 
 
 
 
 
 
 
 
          Visit #, Time 
 
 
 
 
Activity 
Visit 1 
Screening 
Visit 2 
Pre-Treatment 
Week 1  
Visits 3-7 
 5 Sessions  
Visit 8 
1 Mo FU 
Visit 9 
3  Mo FU 
Visit 10 
6 Mo FU 
Visit 11 
9 Mo FU 
Visit 12  
12 Mo FU 

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          Visit #, Time 
 
 
 
 
Activity 
Visit 1 
Screening 
Visit 2 
Pre-Treatment 
Week 1  
Visits 3-7 
 5 Sessions  
Visit 8 
1 Mo FU 
Visit 9 
3  Mo FU 
Visit 10 
6 Mo FU 
Visit 11 
9 Mo FU 
Visit 12  
12 Mo FU 
Medical & Urological 
History 
● 
 
 
 
 
 
 
 
Physical Examination 
● 
 
 
 
 
 
 
 
Informed Consent 
● 
 
 
 
 
 
 
 
Inclusion & Exclusion 
Criteria 
● 
 
 
 
 
 
 
 
IIEF-EF, GAQ, SEP, EHS 
● 
 
 
● 
● 
● 
 
● 
 
● 
Penile Doppler 
ultrasound 
    ● 
 
 
 
 
● 
 
 
● 
Study Recruitment  
& Group 
Randomization 
 
● 
 
 
 
 
 
 
 
Record Treatment 
Parameters 
 
 
Group A = 
Treatment 
Group B = 
Sham 
● 
● 
● 
 
● 
 
● 
Report Complications 
 
 
● 
● 
● 
● 
 
● 
 
● 

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1. 
Vlachopoulos C, Rokkas K, Ioakeimidis N, et al: Prevalence of Asymptomatic 
Coronary Artery Disease in Men with Vasculogenic Erectile Dysfunction: A 
Prospective Angiographic Study. European Urology 2005; 48: 996–1003. 
2. 
MELMAN A and GINGELL JC: THE EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF 
ERECTILE DYSFUNCTION. The Journal of Urology 1999; 161: 5–11. 
3. 
Kikuchi Y, Ito K, Ito Y, et al: Double-Blind and Placebo-Controlled Study of the 
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4. 
Haupt G, Haupt A, Ekkernkamp A, et al: Influence of shock waves on fracture healing. 
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5. 
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6. 
Wang C-J, Kuo Y-R, Wu R-W, et al: Extracorporeal shockwave treatment for chronic 
diabetic foot ulcers. J. Surg. Res. 2009; 152: 96–103. 
7. 
Vardi Y, Appel B, Jacob G, et al: Can low-intensity extracorporeal shockwave therapy 
improve erectile function? A 6-month follow-up pilot study in patients with organic 
erectile dysfunction. European Urology 2010; 58: 243–248. 
8. 
Vardi Y, Appel B, Kilchevsky A, et al: Does low intensity extracorporeal shock wave 
therapy have a physiological effect on erectile function? Short-term results of a 
randomized, double-blind, sham controlled study. The Journal of Urology 2012; 187: 
1769–1775. 
9. 
Rosen RC, Riley A, Wagner G, et al: The international index of erectile function (IIEF): 
a multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49: 
822–830. 

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10. 
Agency for Healthcare Research and Quality (AHRQ): Diagnosis and Treatment of 
Erectile Dysfunction. In: Diagnosis and Treatment of Erectile Dysfunction. 2009; pp 
1–770. 
11. 
Mulhall, John P., et al. "OUTCOMES ASSESSMENT: Validation of the Erection 
Hardness Score." The journal of sexual medicine 4.6 (2007): 1626-1634.