Brief Summary:

Background and pathophysiology: Erectile dysfunction (ED) is defined as the recurrent inability to achieve and maintain an erection satisfactory for sexual intercourse.

ED is not in itself a "serious" disease, but its impact on quality of life is extremely important, affecting the family and interpersonal relationships.

Male erection is a complex mechanism that involves neuro-vascular tissue responses with several phases including arterial dilatation, smooth muscle cells relaxation and ultimately veno-occlusive activation.

Vasculogenic erectile dysfunction can be divided in arteriogenic (when there is insufficiency of arterial component of erection due to atherosclerotic plaque encroachment of the penile arteries) or venogenic (where there is insufficiency of the venous component of erection for venous endoleak) Standard treatment Erectile dysfunction is commonly treated by oral phosphodiesterase-5-inhibitor (PDE5i) administration. However, up to 50% of men have a suboptimal response to PDE5-i therapy with the need of additional therapies. New treatment Only recently several studies have been published on percutaneous treatment of ED using plain old balloon angioplasty (POBA), Drug eluting balloons (both paclitaxel and sirolimus, PEB and SES) and drug eluting stents (DES).

Aim of the study: Evaluation of the safety and feasibility of sirolimus drug eluting balloon treatment in focal atherosclerotic lesions of the internal pudendal arteries among men with erectile dysfunction (ED) and a no response to phosphodiesterase-5 inhibitors.

Erectile dysfunction (ED) is defined as the recurrent inability to achieve and maintain an erection satisfactory for sexual intercourse ED is not in itself a "serious" disease, but its impact on quality of life is extremely important, affecting the family and interpersonal relationships. Depression, shame, decreased self-esteem and relationship problems are commonly reported symptoms and experiences to people suffering from ED.

Therefore, successful treatment of ED has a strong impact on quality of life. More than 150 million men worldwide have ED, and 52% of men in the United States 40 to 70 years of age report some degree of ED.

The male erection is a complex mechanism that involves neuro-vascular-tissue responses. In particular, the erection mechanism includes a phase of arterial dilation, the relaxation of the musculature of the trabecular smooth muscle cells at the level of the cavernous bodies and, ultimately, the activation of a veno-occlusive at the level of the same mechanism.

Restoring adequate arterial inflow in patients with penile arterial insufficiency can improve erectile function. Surgical re-vascularization has been used successfully in younger men after blunt perineal trauma or pelvic fracture. Older subjects can have obstructive atherosclerotic disease identified by angiography in the iliac, internal pudendal, and cavernosal arteries. Although endovascular revascularization with balloon angioplasty has resulted in at least short-term improvement of erectile function, there have been no prior reports on the feasibility of Sirolimus eluting balloon treatment for ED.

ED counts various causes including psychological factors, neurological hormonal, iatrogenic and to particular lifestyle. A careful collection of the clinical history is essential to identify risk factors for ED: present diseases, drug therapies, previous surgery, smoking and use of drugs.

Clinical examination should aim to assess the secondary sexual characteristics, size and consistency of the testes, perianal sensation, tone of the anal sphincter associated to digital rectal examination and the bulb-cavernous reflection. Palpation of the penis is important to detect the presence of penile plaques indicative of induration penis plastica (Peyronie's disease) and the digital rectal examination provides an opportunity to perform a prostate exam.

The cardiovascular examination should include, in addition to measuring blood pressure and heart rate, the evaluation of peripheral arterial pulses. It has been shown that a good anamnestic collection and a correct clinical examination have a sensitivity of 95% (specificity but much less: about 50%) for a diagnosis of ED of organic origin. For this reason, a definitive diagnosis also requires a diagnostic-instrumental study and laboratory Drug Eluting Balloons (DEBs) represent an attractive and novel treatment modality that offers numerous theoretical advantages over standard angioplasty and stent technologies. Among these benefits: homogenous distribution of an anti-proliferative drug to the vessel wall (not just to segments of the wall in direct contact with stent struts); immediate drug release without the use of a polymer that could trigger late thrombosis; no prolonged, direct drug contact with the arterial wall, allowing better re-endothelialization of the vessel if a bare metal stent (BMS) is used in conjunction; no foreign object left in the body, which is especially important in peripheral applications where stents have been used with suboptimal results; maintenance of original vessel anatomy and flexibility, important during superficial femoral artery re-vascularization especially; and finally, lower restenosis rates in some indications.

The objective of this study is to evaluate of the safety and feasibility of sirolimus drug eluting balloon treatment in focal atherosclerotic lesions of the internal pudendal arteries among men with erectile dysfunction (ED) and no-response to phosphodiesterase-5 inhibitors for at least 6 months before enrollment.

Currently available Drug Coated Balloons (DCBs) in the market are Paclitaxel Eluting Balloon (PEB) - in which paclitaxel is delivered using various drug carriers - and, very recently, Sirolimus Eluting Balloon (SEB). Paclitaxel is cytotoxic drug and can lead to toxicity whereas cytostatic properties of Limus drugs not prone to toxicity as safety margin of sirolimus is higher multiple-folds compared to paclitaxel.

However, due to lipophilic properties of Sirolimus, short term delivery of the drug is thought to be a major challenge. Recently, nanotechnology has being applied to drug eluting balloon. Nanotechnology may offer the advantages of a larger surface area, higher bio-availability, less dose, higher in tissue uptake, and finally good adhesion properties on balloon. With this technology, sirolimus delivery from balloon has been reported to be successful.

Magic Touch™ is a sirolimus nanocarrier coated balloon catheter currently approved for coronary use in Europe. Nanocarriers of sirolimus are encapsulated with a unique phospholipid drug carrier. The drug dose is 180 µg on 3.00 X 15mm (1.27 µg/mm2). The drug carrier has unique cell mimicking properties as well as a phospholipid bi-layer allowing drug retention at higher levels even at very low dose of sirolimus.

This is an observational, retrospective-prospective multicenter registry in patients evaluating the use of Sirolimus Eluting Balloon for the treatment of de novo stenosis in native internal pudendal arteries.

The study population will include 100 patients (10% estimated dropout) affected by vasculogenic ED non responder to PDE5i with up to 2 de novo atherosclerotic artery lesions requiring treatment.

After visual examination, the device must be selected in accordance with the instruction for use (IFU), provided with the device.

The total population in this study will be 100 patients. All patients who meet all the eligibility criteria will be asked to participate. This study will be conducted as a retrospective-prospective "hybrid" study. Two different and specific informed consent forms are provided for patients to be enrolled.

• Prospective patients are informed of the objectives of the study and what their participation in the study will entail.
• Retrospective-prospective patients already underwent angioplasty with the DCB in study consistently with all the eligibility criteria will be informed that their participation will involve the collection of data on their previous angioplasty and participation in the follow-up visits foreseen by the protocol.

Once the patient's eligibility has been determined and the attending physician agrees, a member of the Research Team will approach the patient to initiate the informed consent process The background of the proposed study and the benefits and risks of the procedures and of the study will be explained to the patient.

In both forms the patient is informed that his private data will be protected in accordance with current legislation. The patient must sign the informed consent form prior to enrolment. Failure to obtain a signed informed consent renders the patient ineligible for the study.

• Male able to understand and sign a witnessed informed consent for the procedure
• Age >18 years
• Eligibility for percutaneous peripheral intervention
• Patients with ED evaluated by International Index of Erectile Function- (IIEF)-5 score < 15, positive dynamic doppler (PSV <25 cm/sec) and/or evidence at basal CT angiography of single or multiple atherosclerotic lesions in the pudendal arteries
• Hemodynamic conditions must be stable (systolic BP > 100 heart rate (HR) > 40 < 100).
• Left ventricular ejection fraction (LVEF) ≥40% as measured prior to enrollment.
• No response to any dosage of PDE5i for more than 6 mos before enrollment (either chronic or on-demanding).

Angiographic inclusion criteria

• Target lesions must be de novo lesions located in at least one native pudendal artery with a visually estimated reference vessel diameter (RVD) 1.5 mm and 2.5 mm.
• If two lesions in the same vessel are treated, overlapping balloon treatment is allowed.
• Target lesion must be in the pudendal arteries or dorsalis penis with visually estimated stenosis >70% and <100%.

Exclusion Criteria:

• Ejection Fraction below 40%
• Hemodynamic instability (systolic blood pressure <100 mm Hg; heart rate <40 bpm or >100 bpm; complex ventricular arrhythmias; AtrioVentricular (AV) block) requiring balloon counterpulsation or inotropic support.
• Patient was never treated with PDE5i
• Patient has not performed a basal and dynamic pelvic Doppler
• Patient has a platelet count <100,000 cells/mm3 or >700,000 cells/mm3
• Patient has a white blood cell (WBC) count <3,000 cells/mm3
• Patient is on dialysis or has known renal insufficiency (serum creatinine > 2 mg/dl, or Glomerular Filtration Rate (GFR) <40)
• Patient has had a cerebrovascular accident (CVA) or transient ischemic attack (TIA) within the past 6 months, or has any permanent neurologic defect that may cause non-compliance with the protocol
• Patient has a known allergy to Sirolimus or protocol required concomitant medications (clopidogrel, thienopyridines, aspirin, contrast) that cannot be adequately premedicated
• Patient has an active peptic ulcer or active gastrointestinal (GI) bleeding
• Patient has a history of coagulopathy
• Patient has other serious medical illness (eg, cancer, congestive heart failure) that may reduce life expectancy to less than 24 months
• Patient is participating in another investigational drug or device clinical trial that has not reached its primary endpoint

Angiographic exclusion criteria

• Vessel size < 1.5 mm by visual estimation.
• Lesion length > 80 mm by visual estimation.
• Restenosis from previous intervention
• Thrombus, or possible thrombus, present in the target vessel
• Previous implantation of a bare/DES in the target vessel

Patients with erectile dysfunction (ED) and no-response to phosphodiesterase-5 inhibitors for at least 6 months before enrollment