This study was a multicenter, randomized, double-blind, parallel, placebo-controlled study that evaluated the efficacy and safety of on-demand dosing of orally administered 20mg tadalafil or placebo for 12 weeks to Korean men with erectile dysfunction (ED). The local ethics committees of each medical center reviewed and approved the study protocol. Written informed consent was obtained from each patient prior to randomization.

The study consisted of 2 periods. The first period was a 4-week screening and run-in-period that began once the patient signed an informed consent document. The second period was a 12-week double-blind treatment period of three 4-week visits. The patients were randomly assigned to receive placebo or tadalafil 20mg in a 1:2 ratio according to a computer-generated randomization table. The patients were instructed to take study medication as needed prior to expected sexual activity, but not more than once daily. Food intake and timing thereof were unrestricted.

The patients eligible for inclusion in the study were men at least 18 years of age who were in a monogamous relationship with a female partner and who had at least a 3 month history of ED of psychogenic, organic or mixed etiologies. Erectile dysfunction was defined as an inability to attain and/or maintain a penile erection sufficient for satisfactory sexual performance.4 For purposes of this study, ED severity was classified based on baseline IIEF Erectile Function Domain score into mild (≥17), moderate (11-16) and severe (0-10). Severity groups defined by Cappelleri et al11 as mild to moderate, mild and no ED were combined in this study to form the mild ED severity group.

The etiology of ED was determined by the study investigator based on the patient history, physical and laboratory examination findings, and any previous diagnostic testing.

Exclusions to study participation included history of radical prostatectomy (with the exception of bilateral nerve-sparing prostatectomy) or other pelvic surgery with subsequent failure to achieve erection; clinically significant renal insufficiency within the last 6 months; clinically significant hepatobiliary disease; angina occurring during sexual intercourse in the last 6 months; unstable angina within 6 months prior to the first visit; history of myocardial infarction or coronary artery bypass graft surgery or percutaneous coronary intervention (e.g. angioplasty or stent placement) within 90 days prior to the first visit; history of HIV infection or current infection with any sexually transmitted disease; or current treatment with nitrates, cancer chemotherapy, or antiandrogens.

The efficacy of tadalafil was assessed using the self-administered IIEF questionnaire that assesses five domains of male sexual function, including erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction,10 SEP diary and Global Assessment Questions (GAQ). The patients completed the IIEF at the conclusion of the run-in period (baseline) and after 4, 8, 12 weeks of double-blind therapy. They completed the SEP diary after each sexual encounter and reviewed the diary with the physician at each visit. The patients completed the GAQ at the final visit (study end or early discontinuation).

The primary efficacy endpoints were changes from baseline to endpoint in the IIEF EF domain and changes from baseline to postbaseline on SEP2 and SEP3. The IIEF erectile function domain is the sum of Questions 1-5 and 15, with a maximum score of 30. The mean per patient percentage of 'yes' responses were determined for SEP2 (Were you able to insert your penis into your partner's vagina?) and SEP3 (Did your erection last long enough for you to have successful intercourse?). The baseline and endpoint score for each SEP question was the patient's percentages of 'yes' responses to that question during the run-in period and post baseline period, respectively.

The secondary efficacy endpoints included the change from baseline in intercourse satisfaction domain score of the IIEF; overall satisfaction domain score of the IIEF; Questions 3 and 4 of the IIEF; SEP4 and SEP5 of the patient SEP diary; and the percentage of 'yes' responses to two Global Assessment Questions [GAQ 1 ("Has the treatment you have been taking during this study improved your erections?"), and GAQ 2 ("If yes, has the treatment improved your ability to engage in sexual activity?") asked of the patients at the end of the treatment period or at the discontinuation visit. The IIEF Intercourse Satisfaction was defined as the sum of Questions 6, 7, and 8 (possible total score 0 through 15), IIEF Overall Satisfaction was defined as the sum of Questions 13 and 14 (possible total score 2 through 10) and for Question 3 [penetration ability: "Over the past 4 weeks, when you attempted sexual intercourse, how often were you able to penetrate (enter) your partner?"] and Question 4 [erection maintenance: "Over the past 4 weeks, during sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner?"] of the IIEF questionnaire scores were graded on scale of 1 to 5.

A complete medical history and a 12- lead ECG of the patients was performed at the first visit. A physical examination was conducted at both the first and the final visits. During the study, adverse events were collected at each visit. In addition, concomitant medication use was recorded and blood pressure and heart rate were measured at each visit. The clinical laboratory tests were performed at the screening visit and the end of the treatment.

Patient baseline characteristics were summarized for each treatment group using descriptive statistics. All efficacy analysis was performed on an intent-to-treat basis and included all patients with baseline and post baseline observations. Last observation carried forward (LOCF) was used to impute missing IIEF EF Domain data. The baseline and endpoint score for each SEP question was the patient's percentages of 'yes' responses to the question during the run-in period and the treatment period respectively. The percentage of 'yes' responses to each SEP question was treated as a continuous variable.

Analysis of covariance (ANCOVA) models for the change from baseline in the IIEF domains and the SEP variables included terms for the baseline value of the efficacy variable, treatment group, pooled investigator site, and baseline-by-treatment group interaction (if significant at p<0.10). Logistic regression models were used to evaluate the GAQ at endpoint and to evaluate the percentage of patients who attained normal erectile function at the endpoint. The logistic regression models included the same covariate terms as in the ANCOVA models, but the baseline IIEF erectile function domain score was used as the baseline efficacy value.

Safety analyses included all randomized patients. Safety was assessed by evaluating all reported adverse events and the change in vital signs, clinical laboratory values and physical examination findings. Adverse events entered by the investigators were coded using the Medical Dictionary for Regulatory Activities (MedDRA Version 5) preferred terms. The investigator recorded the severity of the adverse events and their relationship to the study drug. Change in continuous laboratory analytes and vital signs were evaluated by a ranked ANOVA model with a term for treatment group. The statistical analyses were conducted using Statistical Analysis Software version 8.1 (SAS®, SAS Institute Inc., Cary, USA).

Tadalafil 20mg was superior to placebo on all primary efficacy measures (Table 2). The mean change from baseline in the IIEF EF domain score for the tadalafil group was 7.8 vs. 0.1 for the placebo group (p<0.001).

Similarly, improvement from 17.7% at baseline to 71.2% at endpoint in the mean per-patient success rate for intercourse attempts (SEP3) for the tadalafil group, were significantly greater than the 10.1% mean change, for the placebo group (p<0.001).

Patients of all ED severities (mild, moderate or severe at baseline) demonstrated significantly greater mean changes (baseline to endpoint) in the IIEF EF domain score in the tadalafil 20mg group compared with placebo (Fig. 2). Additionally, 44.2% of patients treated with tadalafil 20mg had IIEF EF Domain score ≥26 ("return to normal") compared to 5.0% treated with placebo (p<0.001).

The secondary endpoint efficacy variables are also summarized in Table 2. Tadalafil therapy significantly improved erectile function and patient satisfaction compared with placebo in all secondary efficacy variables (p<0.001). In addition, a significantly greater proportion of patients treated with tadalafil (80%) reported improved erections at endpoint than those treated with placebo (44%; GAQ, p<0.001).

Tadalafil was generally well-tolerated. No deaths or serious adverse events were reported. Headache (tadalafil 16.3%, placebo 4.9%, p=0.086), flushing (tadalafil 5%, placebo 4.9%, p=1.00) and eye pain (tadalafil 5%, placebo 0%, p=0.298) were the 3 most commonly reported adverse events in the tadalafil group (Table 3). Four patients reported Eye Pain, 3 of them mild and transient and 1 as moderate. One patient in the tadalafil treatment group reported a severe adverse event (intervertebral disc herniation) which was not considered to be related to study drug. One patient in the tadalafil group discontinued from the study because of an adverse event (headache). There were no statistically significant differences between treatment groups in the mean change from baseline to endpoint in any laboratory parameter. No clinically relevant changes occurred in vital signs.