Background:
Erectile dysfunction (ED)effects up to 20% of men, and an increasing problem with advancing age. There are many contributing causes of ED, including concomitant use of prescribed medications for health problems including hypertension, or causal diseases such as diabetes. The current treatment includes improved diet, exercise, stress reduction and sleep, but also the use of drugs that stimulate Phosphodiesterase pathway which leads to vasodilation in the venous system of the penis to induce erections. These drugs have significant long-term side effects and are very expensive prohibiting their use by a large percentage of men with ED.
There are a number of electrical fields in the body, with the electrocardiogram (EKG) and brain encephalogram (EEG) being examples. Nearly all tissues in the body have an electrical field across their surface. Bioelectric stimulation (BES) utilizes precise microcurrents targeted to specific proteins in the target tissue that causes upregulation or increased local tissue expression of the protein(s) of interest. The identification of the precise signal has taken decades to define using quantitative measurements from tissues that were stimulated at various frequencies until the optimal signal was identified. The use of BES has been shown to be very safe, and in fact is being tested as a treatment for cancer. It has been used to induce organ and tissue repair and regeneration in many diseases and conditions, varying from accelerating tooth movement, reversing heart failure, traumatic brain injury and stroke.
This study follows the very successful demonstration of the absolute safety and remarkable efficacy of using functional bioelectric stimulation to treat ED by Carboni and colleagues1. Dr Carboni will also serve as the Principal Investigator. of this new study. The previous study was a very well designed randomized, sham and placebo-controlled trial demonstrated 100 % success in reversing ED with no other treatment, while none of the control subjects experienced reversal of ED during the 4-week study period. The study targeted only a single protein, vascular endothelial growth factor (VEGF), which has been shown to be one of the most potent inducers of inducing the formation of new blood vessels and improved blood flow.
The goal of this study will be to examine the potentially additive effect of adding a third arm to the previous protocol to include the addition of 3 new target proteins including endothelial nitric oxide (eNOS), which regulated endothelial vasoreactivity and should enhance venous vasodilation, follistatin, which is a potent stimulator of muscle function and contractile leading to enhanced erection, and platelet derived growth factor (PDGF), which also enhances blood flow, all leading to improved blood flow and reversal of ED.
Study Design: Randomized, single blind, sham and placebo controlled
Randomization will be carried out in two steps: generation of random numbers in each group, using the RANDOM subroutine of the PEPI software suite (computer programs for epidemiologists); and allocation concealment, which will ensure by placing numbers in letter-sized manila envelopes.
Number of Study Subjects: 30, with 10 subjects in each of 3 groups
Number of Sites: one
Department of Health Science and Rehabilitation, Federal University of Health Sciences of Porto Alegre–UFCSPA, Porto Alegre, Rio Grande do Sul, Brazil
Principal Investigator: Cristiane Carboni, Msc, Physiotherapy
Study Enrollment: No subject will receive treatment until they have had all possible risks and benefits explained by the PI and the Consent Form signed.
Expected Duration of Enrollment: 3 months
Study Arms: 3
Gp I: Control. To receive the same duration of BES in a blinded manner for the same duration as the other two groups, but no BES delivered. (the same procedure for the same time, but the electric appliance switches itself off after the first impulse keeping the working light on).
Gp II: BES at the same current, duration, and frequency as the previous study targeted to only VEGF. (Transcutaneous penile electrostimulation will be applied for 20 minutes using frequency 50Hz and 500us with intensity up (mA) to the motor threshold in the intervention group, a 4s up ramp, 4s time off, 1s decay ramp and 4s off time)
Gp III: BES targeted to 3 additional proteins (eNOS, Follistatin, and PDGF) in the penis during the same length of treatment as in the other groups.
Inclusion criteria
From 40 to 70 years old male patient with a stable marital relationship (6 months); diagnosis of erectile dysfunction (IIEF5 score less than 22); clinical history of ED for at least 6 months
Exclusion criteria: neurogenic ED (due to spinal cord injury, Parkinson’s disease, multiple sclerosis, prostatectomy); hypogonadism (total testosterone < 300 ng/ dl); decompensated diabetes mellitus (fasting blood glucose > 200 mg/dl and/or glycated hemoglobin > 8%); decompensated systemic arterial hypertension (SBP > 160 and/or DBP > 100); morbid obesity; diagnosis of coronary heart disease and/or cerebrovascular disease; and inability to understand the study objectives/technique or to provide informed consent.
Note: If patients were previously taking any commercially available drug or non-drug treatment for ED (e.g., injection therapy, topical applications, herbal, or alternative medicines, vacuum-assisted erection devices), such treatments should terminate at, or before, the screening
visit and should not be used at any time during the study until the final evaluation. Patients who are on PDE5 inhibitors will be asked to complete a 4-week wash-out period before enrollment in the trial and not to use it until the last evaluation after finishing the treatment.
Treatment:
Number of total treatments: 8
Frequency: twice/week for 4 weeks
Duration of treatment: 20 minutes/treatment
Method of Delivery of stimulation: Simple self-adhesive patch electrodes (3cm) applied to the dorsum of the penis and connected to the bioelectric stimulator. The current will be slowly increased from zero to the specific current for each protein to be stimulated.
End Points:
1. Reversal of self-assessed ED compared to baseline. Erectile function will be assessed by the validated International Index of Erectile Function (IIEF-5) and Erection Hardness Score (EHS) instruments. Quality of life (QoL) will be assessed with the validated WHOQOL-BREF questionnaire. All of the questionnaires will be applied before and immediately after the treatment. The instruments will be completed by a blinded investigator, according to the protocol to which the patient had been randomized. Only the physiotherapist who applied the technique will be aware of group allocation.
2. Adverse events including pain or skin irritation or difficulty with urination
3. Serum Testosterone levels will be measured in 3 randomly selected subjects in each of the three treatment groups at baseline, one hour after a treatment following 2 weeks of study, and at the end of the study. These blood levels are to examine the potential role of BES in stimulating increased testosterone production.
Data Analysis:
Patients will be seen by the PI or sub-investigator at the time of study enrollment, and at the midpoint (2 weeks) and end of the study (4 weeks) to assess response to therapy including degree of reversal of ED and any adverse events. Each subject will have a self-assessment of the degree of reversal of ED collected by a person blinded to treatment assignment to prevent bias in data analysis.