This randomised, double-blind, parallel, placebo-controlled study was conducted at seven sites in two countries. The ethical review board for each investigative site approved the protocol and informed consent document. The study was conducted in accordance with the protocol and ethical principles stated in the Declaration of Helsinki 2002 and applicable local laws of each country.
The study objectives were to evaluate the efficacy and safety of ‘as needed’ dosing of 20 mg tadalafil administered for 12 weeks to men with ED. ‘As needed’ dosing in this study refers to the administration of tadalafil prior to the potential for sexual activity, but at a maximum frequency of one dose per day. Thirty doses, to be available ‘as needed’, were dispensed to patients at visits.
The study consisted of two periods. The first period was the screening period of approximately 4 weeks’ duration starting from time when the eligible patients signed the informed consent document till the end of the fourth week at visit 2. Screened patients were stratified at randomisation by the International Index of Erectile Function (IIEF) Erectile Function domain scores in the following category: mild ED = a score higher or equal to 17, moderate ED = 11–16, and severe ED = 1–10. Patients were randomly assigned to treatment groups in a 1:3 (placebo:20 mg tadalafil) fashion. This was followed by a treatment period that lasted approximately 12 weeks.
The International Index of Erectile Function and the Sexual Encounter Profile (SEP) diary were administered through the treatment period. Global Assessment Questions (GAQ) were asked at the end of treatment period or at the early discontinuation visit.
Study participants were male patients at least 18 years of age who anticipated having the same female sexual partner during the study and had symptoms of ED (defined as the consistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance) with any kind of severity and any aetiological reasons for at least 3 months. Major exclusion criteria were: ED caused by premature ejaculation or untreated endocrine disease; failure to achieve erection after pelvic surgery including radical prostatectomy (except bilateral nerve-sparing) or patients receiving nitrates, anti-androgens or chemotherapy; significant penile deformity or penile implant; clinically significant renal or hepatic insufficiency; poorly controlled diabetes (haemoglobin A1c >13%); a recent history of stroke or spinal cord trauma; unstable cardiovascular diseases (e.g. unstable angina, recent myocardial infarction or coronary intervention, history of sudden cardiac arrest despite medical or device therapy, evidence of congestive heart failure, new significant conduction defect or uncontrolled hypertension). Patients with prior ineffective treatment with sildenafil citrate, in the opinion of the investigator, could have been excluded from the study. Concomitant use of other therapies for ED was not allowed during the study. Although the study was originally planned to be performed in three countries with 189 patients, 139 patients from Egypt and Turkey participated in the study. The study remained sufficiently (>90%) powered for all co-primary end point analyses.
The first co-primary efficacy measure was the IIEF Erectile Function domain, defined as the sum of questions 1–5 and 15 of the IIEF. The IIEF was administered at the end of the treatment-free run-in period, and at the end of 4, 8 and 12 weeks of treatment. Further co-primary efficacy measures were the mean per patient percent of ‘yes’ responses to SEP question 2 ]SEP2: Were you able to insert your penis into your partner's vagina? (yes/no)[ and SEP3 ]Did your erection last long enough for you to have successful intercourse? (yes/no)[.
Secondary efficacy measures of the study include: IIEF Intercourse Satisfaction and Overall Satisfaction Domain scores, IIEF questions 3 and 4, mean per patient percent of ‘yes’ responses to SEP4 (Were you satisfied with the hardness of your erection?) and SEP5 (Were you satisfied overall with this sexual experience?) and responses to two GAQ questions (GAQ1-Has the treatment you have been taking during this study improved your erections? GAQ2-If yes, has the treatment improved your ability to engage in sexual activity?).
Safety was assessed by evaluating the incidence of treatment-emergent adverse events and any changes in laboratory results or vital signs. At the screening and last study visit a full physical examination and clinical laboratory tests were performed. A 12-lead ECG was also performed at the first visit. Study personnel recorded concomitant medication use, blood pressure and pulse at every visit. The date of onset or resolution of any adverse event was recorded at each study visit. Treatment-emergent adverse events (events that first occurred or worsened after baseline) were summarised by the Medical Dictionary for Regulatory Activities (MedDRA) version 5.0, and severity and possible relationship to study drug were noted.
The co-primary efficacy variables were mean change from baseline to end point in the IIEF EF domain score and mean changes from baseline to the post-baseline period in the mean per patient percent of ‘yes’ responses to SEP2 and SEP3.
The null hypothesis was that tadalafil and placebo did not differ on each of the three co-primary efficacy end points. To reject the null hypothesis a significance of 0.05 was required (two-tailed). The study had 90% power to detect a significant treatment effect in each of the three co-primary efficacy variables at the 0.05 alpha level.
The efficacy analyses were conducted on an intent-to-treat basis. Efficacy analyses included all patients who had a baseline measurement and at least one post-baseline measurement. The scores on the IIEF domains and questions were analysed using the last observation carried forward convention. For each SEP question the baseline and post-baseline scores were analysed as the mean per patient percent of ‘yes’ responses (number of yes responses relative to the number of sexual encounters during the run-in and treatment periods respectively).
The efficacy variables were analysed using analysis of covariance (ancova) models, including terms for baseline efficacy value, treatment group, pooled site and baseline-by-treatment group interaction (if p < 0.10). Logistic regression was performed to evaluate the GAQ using the same terms as in the ancova model except that the baseline IIEF EF domain value was used in the model as a covariate. Only patients who responded to the GAQ were included in the model. An additional analysis of the percentage of patients who returned to normal erectile function (as defined by an IIEF Erectile Function Domain score of ≥26) by baseline severity after treatment was performed.
Safety analyses included all randomised patients. The incidence of treatment-emergent adverse events between treatment groups was compared. The statistical analyses in this study were conducted using the SAS statistical package version 8.2 for windows (SAS Institute, Cary, NC, USA).