Clinical trial NCT03067987: Safety and Efficacy of Low Intensity Shockwave for the Treatment of Erectile Dysfunction
Official title: Safety and Efficacy of Low Intensity Shockwave for the Treatment of Erectile Dysfunction- Comparison of Two Treatment Schedule
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Vasculogenic Erectile Dysfunction
Lead sponsor: University of Miami
Sponsor class: OTHER
Collaborators: name: DIREX SYSTEMS CORPORATION
First posted: 2017-03-01
Enrollment: 103
Sex: MALE
Minimum age (years): 30
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Renova- Erectile Dysfunction (ED) is a Linear Shockwaves (LISW) device which incorporates a unique shockwave transducer operable to deliver shockwaves to a treated region. Shockwaves 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 LISW in the relief of erectile dysfunction.

HYPOTHESIS Alternate Hypothesis (HA): Active Treatment groups will show a \>2-point increase in the IIEF-EF score from baseline for mild erectile dysfunction, and \>5 points for moderate erectile dysfunction and will show significant change.

Null Hypothesis (HO): There is no difference from baseline and after-treatment in Treatment groups for alleviating erectile dysfunction measured using International Index of Erectile Function score (IIEF-EF).

Primary Efficacy Objective: To evaluate change of International Index of Erectile Function score Questionnaire score from baseline to follow-ups 1, 3 and 6 months' post treatment.

Secondary Objectives:To study sexual activity improvement leading to optimal penetration at follow-ups according to:

* SEP- Sexual Encounter Profile Questionnaire.
* GAQ- Global Assessment Questionnaire.
* EHS- Erection Hardness Score.

Detailed description: Renova-Erectile dysfunction (ED) is a Linear Shockwaves (LISW) device which incorporates a unique shockwave transducer operable to deliver shockwaves to a treated region confined to a narrow rectangle. Shockwaves generation follows the electromagnetic principle.

Linear Shockwaves (LISW), as a treatment for erectile dysfunction has been in evaluation in contemporary medicine, It has been in use for the last three years.

The present study is about a device called "Renova-erectile dysfunction", in which shockwaves are focused onto line segments for improved organ coverage. Shockwaves produced by "Renova-erectile dysfunction" 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 LISW in the relief of erectile dysfunction.

Rationale:Linear Shockwaves 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 showed 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 showed that Low intensity shock waves treated group showed radiological signs of faster healing.
* Calcifying tendinitis: Rompe et al.5 showed that shock wave to patient suffering from calcifying tendinitis showed a 62.5% partial and complete disintegration of the the deposits. Moreover, 85% of the patients reported improvement at 24-week follow up period.
* Diabetic Foot Ulcers: Wang et al.6 showed that Extracorporeal Shock Wave Therapy (ESWT) to patients with diabetic foot ulcer showed complete improvement in 31% and partial improvement in 58%.Moreover,Extracorporeal Shock Wave Therapy showed significantly better clinical results and local blood flow perfusion, higher cell concentration, and activity than the Hyperbaric Oxygen group.

Preliminary Studies:

Contemporary literature shows two important studies in this field both conducted by Verdi et al.

The efficacy trial study published in 2010 recruited 20 men with vasculogenic erectile dysfunction 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 domain scores (20.9 5.8 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 by showed that treatment group showed better outcome than control group measured using International Index of Erectile Function-Erectile Function domain (mean square root of sample size 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).

Primary Efficacy Objective:To evaluate change of Erectile Function-Erectile Function score 9 from baseline to follow-ups 1, 3 and 6 months' post treatment.

Secondary Objectives:To study sexual activity improvement leading to optimal penetration at follow-ups according to:

* SEP- Sexual Encounter Profile.
* GAQ- Global Assessment Questions.
* EHS- Erection Hardness Score.

STUDY DESIGN Accrual goal: A total of 80 patients with Vasculogenic erectile dysfunction meeting the eligibility criteria will be recruited from the Department of Urology clinic.

Duration of Study Participation: The total duration of the study will be for 7 months- including 1-month pretreatment (washout) followed by a period of 6 months' follow-up after the treatment.

Screening Evaluations and Procedures: The first visit of the patients will be for screening and medical evaluation. Patient's medical co-medication 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 lipid profile, hemoglobin A1C and testosterone levels during chart review.

Patients will sign an informed consent and will answer the Erectile Function-Erectile Function 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 phosphodiesterase 5 inhibitor (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).

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 1:1 ratio (randomization will be performed by a computer software maintained by the Department of Urology). Patients randomized to the treatment groups will be instructed to stop any use of phosphodiesterase 5 inhibitor for 4 weeks prior to first treatment session and refrain from using any other erectile dysfunction therapy option during the study. They will be instructed to undergo a phosphodiesterase 5 inhibitor washout period of 4 weeks prior to treatment and to avoid using phosphodiesterase 5 inhibitor or any other erectile dysfunction 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.

Treatment procedure: 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)

During the treatment, the same total number of shocks will be delivered according to the two treatment schedules as follows:

Group A:

5 daily sessions within a week (Monday, Tuesday, Wednesday, Thursday, Friday (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).

Group B:

Three sessions per week Monday, Wednesday, Friday (MWF) for 2 consecutive weeks, in which 600 shocks of treatment energy will be applied in every session to each treated region (left and right corpora cavernosa and crura)

Following the last treatment session, each patient will resume his baseline consumption of phosphodiesterase 5 inhibitor, in terms of type and dose of drug, for the remainder of study duration.

Follow-Up Procedures and Evaluations:Follow-up visits will be conducted at month 1, month 3 and month 6 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

Reporting and recording adverse events at every follow-up visit.

Eligibility criteria: Inclusion Criteria:

* The patient must be willing and able to provide informed consent.
* The patient is a male between \>30 and \<80 years of age.
* PDE5i responsive or non-responsive. If on PDE5i patient will discontinue medication for 4 weeks before IIEF.
* Stable sexual relationship for over 3 months prior to enrollment.
* A minimum of 2 sexual attempts per month for at least one month prior to enrollment.
* Erectile dysfunction lasting for over 6 months and not more than 5 years.
* Baseline IIEF-EF score between 11 and 25. If taking PDE5i, stop medication for at least 4 weeks before baseline IIEF-EF.
* Testosterone level 300-1000 ng/dL.
* If diabetic, HgbA1C level ≤ 7.5% within 1 month prior to enrollment.

Exclusion 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 ever.
* 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 Parkinsons disease which affects erectile function at the discretion of the investigator.
* Psychiatric diagnosis or medications such as antidepressants which 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.
* HgbA1C level \> 7.5% within 1 month prior to enrollment.
* Androgen deprivation treatment in the last year.
* History of spinal cord injury.
* The patient is taking blood thinners (eg Coumadin, Plavix)

Primary outcomes:
measure: International Index of Erectile Function (IIEF-EF) Questionnaire
timeFrame: 7 months
Secondary outcomes:
measure: Erection Hardness Score (EHS)
timeFrame: 7 months
measure: Sexual Encounter Profile (SEP)
timeFrame: 7 months
measure: Global Assessment Question (GAQ)
timeFrame: 7 months
Other outcomes:
Locations:
city: Miami
country: United States
facility: University of Miami
state: Florida
Study officials:
affiliation: University of Miami
name: Ranjith Ramasamy, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mulhall JP. Defining and reporting erectile function outcomes after radical prostatectomy: challenges and misconceptions. J Urol. 2009 Feb;181(2):462-71. doi: 10.1016/j.juro.2008.10.047. Epub 2008 Dec 13.
citation: Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997 Jun;49(6):822-30. doi: 10.1016/s0090-4295(97)00238-0.
citation: Vardi Y, Appel B, Kilchevsky A, Gruenwald I. 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. J Urol. 2012 May;187(5):1769-75. doi: 10.1016/j.juro.2011.12.117. Epub 2012 Mar 15.
citation: Vardi Y, Appel B, Jacob G, Massarwi O, Gruenwald I. Can low-intensity extracorporeal shockwave therapy improve erectile function? A 6-month follow-up pilot study in patients with organic erectile dysfunction. Eur Urol. 2010 Aug;58(2):243-8. doi: 10.1016/j.eururo.2010.04.004. Epub 2010 May 6.
citation: Wang CJ, Kuo YR, Wu RW, Liu RT, Hsu CS, Wang FS, Yang KD. Extracorporeal shockwave treatment for chronic diabetic foot ulcers. J Surg Res. 2009 Mar;152(1):96-103. doi: 10.1016/j.jss.2008.01.026. Epub 2008 Mar 7.
citation: Rompe JD, Rumler F, Hopf C, Nafe B, Heine J. Extracorporal shock wave therapy for calcifying tendinitis of the shoulder. Clin Orthop Relat Res. 1995 Dec;(321):196-201.
citation: Haupt G, Haupt A, Ekkernkamp A, Gerety B, Chvapil M. Influence of shock waves on fracture healing. Urology. 1992 Jun;39(6):529-32. doi: 10.1016/0090-4295(92)90009-l.
citation: Kikuchi Y, Ito K, Ito Y, Shiroto T, Tsuburaya R, Aizawa K, Hao K, Fukumoto Y, Takahashi J, Takeda M, Nakayama M, Yasuda S, Kuriyama S, Tsuji I, Shimokawa H. Double-blind and placebo-controlled study of the effectiveness and safety of extracorporeal cardiac shock wave therapy for severe angina pectoris. Circ J. 2010 Mar;74(3):589-91. doi: 10.1253/circj.cj-09-1028. Epub 2010 Feb 4.
citation: Melman A, Gingell JC. The epidemiology and pathophysiology of erectile dysfunction. J Urol. 1999 Jan;161(1):5-11.
citation: Vlachopoulos C, Rokkas K, Ioakeimidis N, Aggeli C, Michaelides A, Roussakis G, Fassoulakis C, Askitis A, Stefanadis C. Prevalence of asymptomatic coronary artery disease in men with vasculogenic erectile dysfunction: a prospective angiographic study. Eur Urol. 2005 Dec;48(6):996-1002; discussion 1002-3. doi: 10.1016/j.eururo.2005.08.002. Epub 2005 Aug 24.
citation: Katz JE, Molina ML, Clavijo R, Prakash NS, Ramasamy R. A Phase 2 Randomized Trial To Evaluate Different Dose Regimens of Low-intensity Extracorporeal Shockwave Therapy for Erectile Dysfunction: Clinical Trial Update. Eur Urol Focus. 2018 Apr;4(3):336-337. doi: 10.1016/j.euf.2018.07.011. Epub 2018 Jul 17.