Clinical Trial of Topically-applied Glyceryl Trinitrate (GTN) for the Treatment of Erectile Dysfunction (ED)

This randomised, double-blind, placebo-controlled cross-over study is designed to evaluate the efficacy and safety of MED2005, a topically applied glyceryl trinitrate (GTN) gel administered to the penis of male subjects immediately before sexual intercourse. Subjects will be male aged between 18 and 70 years of age self-diagnosed with ED. Treatment requires the topical application of a pea sized volume (approximately 300 mg) of a 0.2% (w/w) gel to deliver a dose of 0.6 mg GTN to the glans of the penis. A total of 192 eligible subjects are planned to be enrolled into the study. Subjects will be screened for eligibility during the screening period (Day -45 to Day -2), provide a history of their ED treatments and those deemed eligible and who have a female consenting partner will participate in a run-in-period and two treatment periods (treatment period 1 and 2). The International Index for Erectile Function (IIEF) question 1 -5 and 15 will be used to determine pre-screening eligibility for the subject online. A score of 25 or less will be acceptable for inclusion to the run-in-period. Screening (visit 1) will be conducted over 1 day or may be divided into more than 1 day if wash-out of prior medications is needed. The screening period is applicable for visit 1 Informed consent will be signed by both partners before a couple can be admitted to the study. There will also be a subject and partner training requirement to ensure that the product is applied in an appropriate manner. After refraining from using other ED treatments for at least a period of a week, in the run-in-period (visit 2), subjects and their female partners will make at least 4 intercourse attempts (with a minimum of 1 attempt per week) during a 4 week (± 1 week) period. The subjects and their partners will be asked to complete questionnaires online to record their experiences after each sexual intercourse attempt and at the end of the run-in period. Subjects who cannot comply with the minimum number of sexual attempts verified by completed Sexual Event Profile (SEP) or exceed 25 on the IIEF question 1 -5 and 15 will be excluded from the study. Scores generated from the run-in period will be used as an established baseline in the planned analyses. The run-in period will be completed prior to randomisation and dosing.

In treatment period 1 (visit 3 and visit 4), subjects will be allocated to receive either placebo or MED2005 (0.6 mg GTN) according to a pre-defined randomisation schedule. After refraining from using other ED treatments for at least a period of a week, subjects and their female partner will be trained in the application of the test article and asked to apply the test article immediately prior to sexual intercourse, and to make at least 4 intercourse attempts during a 4 week (± 1 week) period. The subjects and their partners will be asked to complete questionnaires online to record their experiences after each sexual intercourse attempt, and again at the end of each treatment period. Subjects will be asked to return to the Clinical Pharmacology Unit (CPU) after 4 weeks' (± 1 week) to return used and unused test article from the first treatment period, to enable the clinical staff to check compliance and to assess their health status, including assessment of any Adverse Event (AE). At the end of treatment period 1 (visit 4), tubes will be weighed to ensure subject compliance.

Following a 1 week treatment-free cross-over period, the subjects will enter into treatment period 2.

In treatment period 2 (visit 5 and visit 6), subjects will be issued with the alternative test article, either placebo or MED2005 (0.6 mg GTN) according to the pre-defined randomisation code. Training on the application of the test article will be reinforced / repeated and the subject or their female partner will be asked to apply the test article immediately prior to sexual intercourse on at least 4 separate occasions during a 4-week period. After each intercourse attempt the subjects and their partners will be asked to complete questionnaires online to record their experiences after each sexual intercourse attempt, and again at the end of each treatment period.. Subjects will be asked to return to the CPU after 4 weeks' (± 1 week) time to return used and unused test article from the second treatment period, to enable the clinical staff to check compliance and to assess their health status, including assessment of any AEs. At the end of treatment period 2 (visit 6), tubes will be weighed to ensure subject compliance.

Subjects and their female partners will be followed up at 7 day's ± 2 days (visit 7) after the outpatient visit on week 4 of treatment period 2, as necessary, to follow up any on-going AEs.

Inclusion criteria

• Male aged between 18 and 70 years of age inclusive.
• Confirmed self-diagnosis of ED for more than 3 months.
• IIEF question 1 -5 and 15 score of 25 or less will be acceptable for inclusion to the run-in period.
• Subject answers "yes" to the question "At home over the past 3 months, have you experienced at least some growth of your penis in response to: (1) mechanical stimulation, or (2) visual stimulation?"
• In a continuous heterosexual relationship for at least 6 months prior to screening.
• Documented written informed consent from both subject and his female partner.
• Both partners must agree to use one of the acceptable methods of contraception listed below:

• Occlusive cap (diaphragm or cervical/vault caps).
• Surgical sterilisation (vasectomy with documentation of azoospermia).
• The female partner uses oral contraceptives, injectable progesterone or subdermal implants.
• The female partner uses medically prescribed topically-applied transdermal contraceptive patch.
• The female partner has undergone documented tubal ligation (female sterilisation).
• The female partner has undergone documented placement of an Intra Uterine Device (IUD).
• Both partners are capable of understanding and complying with the requirements of the protocol and must have signed the informed consent form.

Exclusion criteria

• Any significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, haematological, endocrinological, metabolic, neurological, psychiatric, or other disease.
• Any history of an unstable medical or psychiatric condition or using any medication that, in the opinion of the PI, is likely to affect the subject's ability to complete the study or precludes the subject's participation in the study.
• Any presence of a symptomatic, active urinary tract infection diagnosed by the PI or delegate at screening.
• Any presence of chronic indwelling urethral catheterization or penile anatomical abnormalities (e.g. penile fibrosis) that would significantly impair erectile function.
• Any history of operations for Peyronie's disease.
• Primary hypoactive sexual desire or any history of hypogonadism
• Any history of radical prostatectomy.
• Any history of severe / uncontrolled diabetes.
• Subjects taking two or more anti-hypertensives for the treatment of blood pressure.
• Subjects with nursing partners, known pregnant partners or wish to become pregnant during the course of the study.
• Confirmed positive results from urine drug screen or from the alcohol breath test at screening and on admission (Day -1).
• Subject has recent (last 12 months) clinical evidence of alcoholism or drug abuse.
• Subject has a positive screen for hepatitis B consisting of Hepatitis B surface antigen (HBsAG), hepatitis C antibody, and human immunodeficiency virus (HIV).
• Any clinically significant abnormal laboratory, vital signs or other safety findings at screening or on admission.
• Subjects unwilling to cease use of vacuum devices, intracavernosal injection, Viagra ® or other therapy for ED.
• Unwillingness of the subject to agree to make four attempts at sexual intercourse on four separate days during each treatment period.
• Any history of unresponsiveness to Viagra ® treatment due to lack of efficacy with sexual stimulation after multiple attempts of sexual intercourse, or significant side effects excluding visual disturbances of Viagra ®.
• Less than 4 attempts at sexual intercourse or high IIEF scores (> 25) during the run-in period.
• Any known hypersensitivity to any component of the investigational product.
• Subjects who are illiterate or are unable to understand the language in which the online questionnaires are available.
• Subject has received any investigational product during the 90 days prior to dosing for this study.
• Subject or their partner cannot communicate reliably with the Investigator.