Efficacy of Intracavernosal as add-on Therapy to Sildenafil 100 mg on Demand Compared to Sildenafil 100 mg on Demand for the Treatment of Erectile Dysfunction (ED) Not Sufficiently Responsive to Standard Therapy With Phosphodiesterase Type 5 Inhibitors

Efficacy of Intracavernosal (Xeomin®) 100U as add-on Therapy to Sildenafil 100 mg on Demand Compared to Sildenafil 100 mg on Demand for the Treatment of Erectile Dysfunction (ED) Not Sufficiently Responsive to Standard Therapy With Phosphodiesterase Type 5 Inhibitors

The primary objective of this study is to investigate the efficacy of intracavernosal (Xeomin®) (100U) as add-on therapy to sildenafil 100 mg on demand in men with ED and insufficient response to standard therapy with 100 mg sildenafil on demand during the 4-week open-label run-in phase.

The secondary objectives are to further describe the efficacy and safety of (Xeomin®) 100U IC as add-on therapy to sildenafil 100 mg on demand:

1. to further assess efficacy using.

   • i) a log diary five-item questionnaire completed after each sexual attempt (Sexual Encounter Profile);
   • ii) a self-reporting measure that scores erection hardness on a 4 point scale completed after each sexual attempt;
   • iii) The Global Assessment Question.

2. to assess effect persistence at month 6 and month 9.

3. to assess safety of (Xeomin®) 100U IC in combination with sildenafil 100 mg on demand.

This randomized, double-blind, placebo-controlled study will be conducted in 9 centers, study participants will be adult men with ED and insufficient response to standard therapy with 100 mg sildenafil on demand during the 4-week open label run-in-phase, follow-up in the study will be 10±2 months.

This is a standard procedure to use placebo as control in studies assessing the efficacy of pharmacological treatment of ED. Furthermore the placebo group provides a benchmark for an objective analysis of safety and tolerability findings. The open-label run-in phase assures that only subjects who are true non-responders i.e. with insufficient response to standard therapy with 100 mg sildenafil prn during the 4-week open-label run-in phase are randomized and participate in the double-blind treatment phase.

Participants distributed between groups at a ratio of 1:1.

Inclusion Criteria:

Subjects have to fulfill all of the following criteria before being included in the open-label run-in phase:

• Written informed consent obtained from the subject
• History of ED for at least 6 months prior to screening, defined as "the inability to achieve and maintain an erection of the penis sufficient to complete satisfactory sexual intercourse" (NIH), the diagnosis of ED has to be confirmed by a physician
• Understanding of study procedures and willingness to abide by all procedures during the course of the study
• Male subject aged ≥18 to ≤ 80 years at visit 1
• Have a monogamous relationship with a female sexual partner (vaginal penetration required for several of the primary efficacy variables) for at least 6 months prior to screening
• Highly motivated to obtain treatment for ED
• History of previous use of at least 1 marketed PDE5 inhibitor and insufficient therapeutic efficacy despite use of the highest approved dose

Subjects have to fulfill all of the following criteria before being included in the double blind treatment phase:

• At least 4 attempts at sexual intercourse during the open-label run-in phase with use of 100 mg sildenafil approximately 1 hour before attempting intercourse
• IIEF-EF score <17
• At least 50% of attempts at sexual intercourse during the open-label run-in phase had been unsuccessful i.e. the following question in the Subject Diary had to be answered with "No":

"Did your erection last long enough for you to have successful intercourse?" (SEP3: success in maintenance of erection)

• Highly motivated to obtain treatment for ED according to the investigator judgment
• Ability to understand and follow study-related instructions

Exclusion Criteria:

• Hypersensitivity to the active substance (Clostridium Botulinum neurotoxin type A) or to any of the excipients (Human albumin, sucrose)
• BW <50 kg
• ED caused by other primary sexual disorders including premature ejaculation or ED caused by untreated endocrine disease (eg, hypopituitarism, hypothyroidism, or hypogonadism)
• History of penile implant.
• The presence of clinically significant penile deformity in the opinion of the investigator.
• Patients with chronic stable angina treated with long-acting nitrates, or patients with chronic stable angina who have required short-acting nitrates in the last 90 days, or angina occurring during sexual intercourse in the last 6 months.
• Patients having met the criteria for unstable angina within 6 months prior to Visit 1, history of myocardial infarction or coronary artery bypass graft surgery within 90 days prior to Visit 1, or percutaneous coronary intervention (eg, angioplasty or stent placement) within 90 days prior to Visit 1.
• Any supraventricular arrhythmia with an uncontrolled ventricular response (mean heart rate >100 bpm) at rest despite medical or device therapy, or any history of spontaneous or induced sustained ventricular tachycardia (heart rate >100 bpm for 30 sec) despite medical or device therapy, or the presence of an automatic internal cardioverter-defibrillator.
• A history of sudden cardiac death (arrest) despite medical or device therapy.
• Any evidence of congestive heart failure within 6 months prior to Visit 1.
• A significant conduction defect within 90 days prior to Visit 1.
• Systolic blood pressure >170 or <90 mm Hg or diastolic blood pressure >100 or <50 mm Hg at screening (if stress is suspected, retest under basal conditions), or patients with malignant hypertension.
• <12 weeks since most recent injection of BTX-A/B into any body region for any indication
• Neurological disorder associated with neuro muscular dysfunction of any kind in medical history.
• Planned concomitant treatment with BTX -A/B of any body region during the study.
• Known hypersensitivity to human serum albumin, sucrose, or the active substance BTX-A.
• Generalized disorders of muscles activity (e.g. myasthenia gravis, Lambert-Eaton-Syndrome, amyotrophic lateral sclerosis) or any other significant peripheral neuromuscular dysfunction which might interfere with the study.
• Any condition that would interfere with the patient's ability to provide informed consent or comply with study instructions, would place patient at increased risk, or might confound the interpretation of the study results.
• Current treatment with nitrates (as outlined in previous Exclusion Criterion, cancer chemotherapy, or anti-androgens.
• History of drug, alcohol, or substance abuse within the past 6 months.
• Investigators, site personnel directly affiliated with this study, and their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted.
• Treatment within the last 30 days with a drug or device that has not received regulatory approval at the time of study entry.
• Ongoing severe or uncontrolled systemic disease, current malignancy, haemophilia, or HIV infection in medical history.
• Severe or uncontrolled respiratory disease in medical history.
• Evidence or suspicion that the subject is not willing or unable (e.g.due to severe cognitive communication impairment) to understand the information that is given to him as part of the informed consent, in particular regarding the risks and discomfort which he would agree to be exposed to.
• Any reason which in the investigator's opinion is likely to compromise the subject's ability to participate in the study.
• Subject who is imprisoned or is lawfully kept in an institution
• Participation in a clinical study within 12 weeks prior to screening or planned participation during this study.
• Previous participation in this clinical study.