LI-ESWT Versus Sham Therapy in Men With ED

Study Overview
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Brief Summary
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Hong Kong has an aging population. By the year of 2036, more than 30% of our population will be older than 65 years old1. Aging in male has been shown to correlate with the risk of erectile dysfunction(ED). The demand in ED treatment is expected to increase. Several ED treatment options are available, ranging from oral or intracavernosal drug treatments, to vacuum erection therapy or even penile prosthesis implantation. However, none of these treatment are curative nor rectify the pathophysiology of ED. Low-intensity extra-corporeal shockwave therapy(LI-ESWT) has been introduced since 2010 for treatment of ED. The first randomized-controlled trial by Vardi et al. had proved the efficacy of ESWT in improving the International Index of Erectile Function(IIEF) score3. The International Index of Erectile Function-Erectile Function domain score(IIEF-EF) was significantly greater in the treatment group compared with the sham therapy group. The efficacy of LI-ESWT was also confirmed in meta-analyses. Nonetheless, the available studies were criticized for the variations in shockwave generators, energy parameters and treatment protocol. Most studies used focused electrohydraulic machines, did not include NPT as part of the outcomes assessment, and only reported the short-term outcomes. Currently LI-ESWT machine was used in few Hong Kong public hospitals for the treatment of erectile dysfunction. In KEC, few pilot cases have been done using the linear LI-ESWT machine. No adverse events were seen. Local published data is lacking. Yee et al. has published a double-blinded randomized placebo-controlled trial on LI-ESWT in 20144. Using an electrohydraulic machine with a focused shockwave source, they concluded no significant differences in IIEF-EF and Erectile Hardness Score(EHS) between treatment and sham therapy after 13 weeks of treatment. In subgroup analysis significant improvement was noted in men with severe baseline erectile dysfunction (LI-ESWT IIEF-EF improvement: 10.1 ± 4.1 vs sham therapy IIEF-ED domain improvement: 3.2 ± 3.3; P = 0.003). There were several limitations in this study. These include the small number of participants included in the subgroup analysis (ranges from 18 to 21 men in each subgroups), the lack of physical measurement of erectile function. The percentage of patients with 5 points or more IIEF-EF improvement and the Erection Hardness Score(EHS) were also not reported. They have also used an old design with focused energy source, instead of the linear energy source. In light of the limitations of the previous international and local studies, the investigators plan to investigate the efficacy of a linear electromagnetic LI-ESWT machine in men with moderate and severe ED. In addition, the intermediate-term outcomes would be studied, in terms of patients-reported erection scores and nocturnal tumescence and rigidity measurement.

Detailed Description
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Objectives To investigate the efficacy and safety of LI-ESWT in treatment of moderate and severe ED To investigate the effect of LI-ESWT on nocturnal penile tumescence and rigidity. Research Plan and Methodology Study Design This is a prospective, two-centre randomized controlled trial involving United Christian Hospital and Tseung Kwan O Hospital. The study will be conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation, Good Clinical Practice Guidelines (ICH-GCP). This RCT will be registered with ClinicalTrials.gov. Patient selection and recruitment Patients would be recruited in the urology outpatient clinics. Subjects who fulfilled selection criteria would be counselled to participate in the study. Written consent would be obtained. Randomisation, allocation concealment and blinding Patients are randomised to either LI-ESWT or sham therapy in a ratio of 1:1. Randomisation is performed with a random number table. The designated operator who perform the procedure is not blinded. Patients were blinded throughout the procedures, during clinical follow-up and data analysis. Study Intervention Patients would undergo a 4-week washout period of oral phosphodiesterase inhibitors after recruitment. Severity of ED would be assessed by the International Index of Erectile Function - Erectile Function Domain (IIEF-EF) & International Index of Erectile Function (IIEF-5) questionnaires and Erection Hardness Score(EHS) after the washout. Nocturnal penile tumescence (NPT) and rigidity would be measured by the Rigiscan at the night prior to the first treatment. All procedures would be performed by a designated nurse consultant(co-investigator) in an office setting using an electromagnetic linear shockwave machine. The nurse consultant has received overseas andrology training, as well as on-hand machine operation training by ESWT product specialist. Patient would be positioned in a supine position. Shockwaves would be delivered to the stretched penis at proximal, mid and distal penile shaft and bilateral crura of penis. (Energy: 0.1-0.25 mJ/mm2; 3000pulses per session; Frequency 3Hz) Treatment consists of 6 sessions over 5 weeks in total. It would be a twice-weekly treatment with one-week interval of resting period. Patient would be discharged home after each treatment session. Sham therapy would be given with a modified probe which no shockwave would be emitted. A working noise would still be generated which mimicked active treatment. Post-procedure management Clinical assessment would be conducted at week 4, week 26 and week 52 after completion of treatment. NPT would be measured at week 4. At all follow-up the IIEF-EF and EHS would be assessed. Any complications would be assessed and documented according to Clavien-Dindo classification. Sample Size Calculation In a recent meta-analysis, the mean improvement in IIEF-EF was 4.23. At 5% significance level and 80% power, 33 subjects were needed in each treatment and sham group (Total 66 subjects). Overall 84 subjects would be recruited with 20% of drop out expected (i.e. 42 subjects in each group). Study Period The expected study period would last for 44 months, including 30 months of subject enrolment, 2 months of treatment and 12 months of follow-up. Statistical Analysis The results would be analysed according to intention-to-treat principle. Mann-whitney U test would be used to study the IIEF-EF results, as well as all other non-parametric continuous variables in secondary outcomes. Chi-square test would be used for categorical variable, independent samples t-test would be used for parametric continuous variable. Ethical Concern All identifiable personal data will be anonymised and will follow the HA policy on handling of patient data privacy.

Official Title
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Efficacy of Low-Intensity Extracorporeal Shockwave Therapy in Treatment of Erectile Dysfunction - A Randomized Controlled Trial With Sham Therapy

Conditions
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Erectile Dysfunction

Intervention / Treatment
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* Device: Low-intensity Extracorporeal Shockwave Therapy
* Device: Sham Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 50 years old ED > 6 months Stable heterosexual relationship > 6 months Sexual Health Inventory for Men (SHIM) score <= 16 Suboptimal response after first line phosphodiesterase type 5 inhibitor treatment Exclusion Criteria: Penile anatomical abnormality History of pelvic radiotherapy History of radical prostatectomy History of penile implantations Neurological diseases Hypogonadism or on anti-androgen therapy Unstable psychiatric conditions or under active psychiatric treatment

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low-intensity ESWT<br>Patient would be positioned in a supine position. Shockwaves would be delivered to the stretched penis at proximal, mid and distal penile shaft and bilateral crura of penis. (Energy: 0.1-0.25 mJ/mm2; 3000pulses per session; Frequency 3Hz) Treatment consists of 6 sessions over 5 weeks in total. It would be a twice-weekly treatment with one-week interval of resting period. Patient would be discharged home after each treatment session. | Device: Low-intensity Extracorporeal Shockwave Therapy<br>* Low intensity shockwave energy would be delivered to stimulate angiogenesis in corporal tissue. Therapy would be delivered through a linear probe in 6 sessions. It would be conducted as a day procedure.<br>|
| Sham Comparator: Sham ESWT<br>Sham therapy would be given with a modified probe which no shockwave would be emitted. A working noise would still be generated which mimicked active treatment. | Device: Sham Therapy<br>* Same device as the active treatment arm would be used, with the addition of sham probe which block all shockwaves.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in International Index of Erectile Function - Erectile Function Domain (IIEF-EF) score | Validated questionnaire in assessing the erectile function over the past 4 weeks Minimum value - 1 Maximum values - 30 Higher scores represent a better outcome | One month after treatment, compared with pre-op level | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Erection Hardness Score (EHS) | Hardness score of penis. Minimum value is 1, maximum is 4. Higher score represents better erection hardness. | At week 4, 26 and 52 after treatment | 
| Percentage of patients with 5-points International Index of Erectile Function - Erectile Function Domain improvement | The percentage(%) of patients with 5 points or more International Index of Erectile Function - Erectile Function improvement compared with pre-study baseline level. | At week 4, 26 and 52 after treatment | 
| Percentage of patients with Erection Hardness Score improved to 3 or above | The percentage(%) of patients with Erection Hardness Score improved to 3 or above. | At week 4, 26 and 52 after treatment | 
| Frequency of nocturnal erections | A non-invasive ambulatory diagnostic machine Rigiscan would be used to provide an objective measure of the frequency of nocturnal erections at night. (number of erections during sleeping) | At week 4 and 52 after treatment | 
| Duration of nocturnal erections | A non-invasive ambulatory diagnostic machine Rigiscan would be used to provide an objective measure of the duration of nocturnal erections.(Time in seconds) | At week 4 and 52 after treatment | 
| Change in nocturnal penile tumescence | A non-invasive ambulatory diagnostic machine Rigiscan would be used to provide an objective measure of the change in penile girth at penile base and penile tip during nocturnal erections.(in cm) | At week 4 and 52 after treatment | 
| Complications after the procedure | Number of participants reported penile pain or urethral bleeding during treatment or within 4 weeks after the treatment. | Within 4 weeks after treatment |