Of the 1378 men screened, 390 were randomized to treatment, with 129 receiving avanafil, 100 mg, 131 receiving avanafil, 200 mg, and 130 receiving placebo (). Exclusionary laboratory test results accounted for most of the screening failures. Patient baseline characteristics were similar for all 3 treatment groups (). Most of the patients had type 2 diabetes (349/390 [89.5%]; randomized set) and presented with moderate or severe ED (365/390 [78.2%]; randomized set). Overall, patients had been diagnosed as having diabetes for approximately 11.3 years (randomized set). Most patients (239/388 [61.6%]; safety set) were taking concomitant medications to control blood pressure (BP), and 24 (6.2%; safety set) reported use of α-blockers (). In total, 224 patients (57.4%; randomized set) had dyslipidemia (including hypercholesterolemia, hyperlipidemia, and hypertriglyceridemia) at baseline. Most patients (292/388 [75.3%]; safety set) reported previous use of oral ED therapies.
Patient disposition in the study. In total, 1378 patients were enrolled in the study and 390 were assigned randomly to treatment. Of the 390 randomized patients, 333 completed the study and 57 discontinued participation. tx = treatment.
Demographic and Baseline Characteristics of the Randomized Populationa
From baseline to the treatment period, the percentage of sexual attempts in which patients were able to maintain an erection of sufficient duration for successful intercourse (SEP 3) was significantly improved after treatment with avanafil (100 and 200 mg; LS mean change for both doses, P<.001 vs placebo). On average, 20.5% of sexual attempts in patients receiving placebo resulted in successful intercourse compared with 34.4% and 40.0% of attempts in patients treated with avanafil, 100 and 200 mg, respectively. Patients receiving placebo experienced a LS mean increase from baseline to the treatment period of 13.6% in the percentage of successful intercourse attempts compared with increases of 28.7% and 34.0% for avanafil, 100 and 200 mg, respectively (P<.001 for both doses vs placebo and P<.001 for all 3 treatment arms vs baseline; , A). The difference in SEP 3 efficacy observed between the avanafil, 100 and 200 mg, groups was not significant.
FIGURE 2 Effect of treatment between baseline and the treatment period on Sexual Encounter Profile (SEP) 3 (intent-to-treat [ITT] population) (A) and SEP 2 (ITT population) (B) and from baseline to the end of treatment on International Index of Erectile Function (more ...)
Avanafil treatment also resulted in a significant improvement between baseline and the treatment period in the percentage of sexual attempts in which patients were able to insert their penis into the partner's vagina (SEP 2). Patients taking avanafil, 100 and 200 mg, experienced a 21.5% and 25.9% LS mean increase in sexual attempts with successful vaginal penetration, respectively, whereas there was a 7.5% LS mean increase in successful penetration attempts in the placebo group (P<.001 and P<.001 for avanafil, 100 and 200 mg, vs placebo, respectively). Both avanafil treatment arms (P<.001) and the placebo arm (P=.009) were also significant vs baseline for the treatment period (, B). As before, the difference between treatment with avanafil, 100 and 200 mg, was not significant.
At end of treatment, the IIEF-EF domain scores were 13.2, 15.8, and 17.3 for placebo, avanafil, 100 mg, and avanafil, 200 mg, respectively. The LS mean change in IIEF-EF domain scores between baseline and end of treatment averaged 1.8, 4.5, and 5.4 for placebo, avanafil, 100 mg, and avanafil, 200 mg, respectively, with avanafil treatments providing significantly greater improvement when compared with placebo (P=.002 and P<.001 for avanafil, 100 and 200 mg, respectively; , C). Consistent with other end points, the change in IIEF-EF domain score was not significantly different between the 2 avanafil treatment groups (P=.34). At the end of treatment, a numerically higher proportion of men who were receiving avanafil vs placebo had normalized IIEF-EF domain scores (≥26) for all baseline severity groups (, D). In addition, significant improvements in the individual IIEF domain scores of orgasmic function (P=.003 and P=.002 for avanafil, 100 and 200 mg, vs placebo, respectively), intercourse satisfaction (P=.02 and P=.001 for avanafil, 100 and 200 mg, vs placebo, respectively), and overall satisfaction (P=.001 and P<.001 for avanafil, 100 and 200 mg, vs placebo, respectively) were observed for both avanafil treatment groups compared with placebo.
An exploratory analysis conducted to assess the number of successful intercourse attempts during various postdose periods revealed a numerically higher success rate for each interval tested in the avanafil treatment groups vs placebo (, E). In total, 5634 of 6979 attempts (80.7%) were made within 1 hour of study drug dosing. For attempts initiated at 15 minutes or less after dosing, 33 of 53 (62.3%) and 16 of 45 (35.6%) were successful in men treated with avanafil, 100 and 200 mg, respectively, compared with 12 of 46 placebo-treated men (26.1%). When intercourse was attempted more than 6 hours after dosing, 6 of 12 attempts (50.0%) and 21 of 31 attempts (67.7%) were successful after treatment with avanafil, 100 and 200 mg, respectively, compared with 1 of 21 attempts (4.8%) in the placebo group. Similar results were observed for SEP 2 and for responses to diary questions regarding satisfaction with sexual experience.
The beneficial effects of avanafil treatment on all 3 coprimary efficacy end points were consistently observed regardless of diabetes type, diabetes duration, baseline ED severity, and duration of ED. However, the subgroup of men with type 1 diabetes was of insufficient sample size to make meaningful comparisons with the type 2 diabetes subgroup. The magnitude of the treatment effect was numerically greater in men with a longer duration of ED (≥60 months) than in those with a shorter duration of ED (<60 months) for SEP 2 and IIEF-EF scores. Although treatment with avanafil, 200 mg, resulted in similar improvements in the percentage of successful intercourse attempts for both white and black subgroups (34.9% and 29.3%, respectively; both P<.001 vs baseline), the small sample size of black men does not allow for definitive conclusions about potential differences in treatment effect between these groups.
Treatment with avanafil was safe and generally well tolerated. Overall, 86 of the 258 men (33.3%) treated with avanafil and 31 of the 130 men (23.8%) treated with placebo reported 1 or more treatment-emergent AEs (). Events that occurred in 2% or more of any treatment group included headache, nasopharyngitis, flushing, sinus congestion, back pain, sinusitis, dyspepsia, and influenza (). All drug-related AEs were mild to moderate in severity. Of the 57 men (14.6%) who discontinued participation in the study, 4 (1.0%) discontinued because of AEs. There were no reports of priapism, hemodynamic changes, or major cardiac events. One patient discontinued because of unstable angina; however, the investigators determined the event to be unrelated to study drug. One patient in the avanafil, 200 mg, group reported blurred vision. Eight patients reported serious AEs, which included spinal compression fracture (placebo), deep vein thrombosis, urinary tract infection, localized infection (avanafil, 100 mg), left arm pain and weakness, unstable angina, pneumonia, and bladder cancer (avanafil, 200 mg), none of which was deemed to be drug related. No deaths were reported during the study.
Overview of Adverse Events in the Safety Population
No notable changes were found in vital signs, laboratory values, or physical examination results related to study treatment. For each treatment group, mean systolic BP, mean diastolic BP, and mean heart rate at the end of treatment were similar to those at randomization. Rates of abnormal systolic BP (systolic BP >140 mm Hg and an increase from baseline >20 mm Hg on 2 or more occasions or systolic BP >180 mm Hg at any time during the study) were consistent across all treatment groups (4 in the placebo group, 3 in the avanafil, 100 mg, group, and 3 in the avanafil, 200 mg, group). Three patients receiving avanafil, 100 mg, and 1 patient receiving placebo experienced an increase in diastolic BP of 15 mm Hg or greater from baseline on 2 or more occasions or diastolic BP greater than 110 mm Hg at any time during the study; no patients treated with avanafil, 200 mg, experienced abnormal diastolic BP values. No drug-drug interactions were reported with antidiabetic medications.