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Efficacy of Once-Daily Administration of Udenafil for 24 Weeks on Erectile Dysfunction: Results from a Randomized Multicenter Placebo-Controlled Clinical Trial Ki Hak Moon, MD, PhD,* Young Hwii Ko, MD, PhD,* Sae Woong Kim, MD, PhD,† Du Geon Moon, MD, PhD,‡ Je Jong Kim, MD, PhD,‡ Nam Cheol Park, MD, PhD,§ Sung Won Lee, MD, PhD,¶ Jae-Seung Paick, MD, PhD,** Tae Young Ahn, MD, PhD,†† Woo Sik Chung, MD, PhD,‡‡ Kwon Sik Min, MD, PhD,§§ Jong Kwan Park, MD, PhD,¶¶ Dae Yul Yang, MD, PhD,*** and Kwangsung Park, MD, PhD††† *Department of Urology, College of Medicine, Yeungnam University, Daegu, Korea; †Department of Urology, The Catholic University of Korea College of Medicine, Seoul, Korea; ‡Department of Urology, College of Medicine, Korea University, Seoul, Korea; §Department of Urology, Pusan National University School of Medicine, Busan, Korea; ¶ Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; **Department of Urology, Seoul National University Medical School, Seoul, Korea; ††Department of Urology, Asan Medical Center, Ulsan University School of Medicine, Seoul, Korea; ‡‡Department of the Urology, Ewha Womans University School of Medicine, Seoul, Korea; §§Department of Urology, College of Medicine, Inje University, Pusan, Korea; ¶¶Department of Urology, Chonbuk National University Medical School, Jeonju, Korea; ***Department of Urology, College of Medicine, Hallym University, Seoul, Korea; †††Department of Urology, Chonnam National University Medical School, Gwangju, Korea DOI: 10.1111/jsm.12862
ABSTRACT
Introduction. The method of administration of oral phosphodiesterase-5 inhibitors has been expanded to once-daily repeated administration with lower initial dosage than on-demand administration. Aim. The aim of this study was to evaluate the efficacy and safety of once-daily udenafil as a treatment for erectile dysfunction (ED) for intermediate-term period. Methods. This multicenter, randomized, double-blind clinical trial included 346 ED patients (placebo, udenafil 50 mg, udenafil 75 mg). Subjects were treated with each medication once daily for 24 weeks. Main Outcome Measures. Subjects were asked to complete the International Index of Erectile Function (IIEF)erectile function (EF) domain at baseline, 12 weeks, and 24 weeks and the development of adverse drug reactions (ADRs) was inspected. Results. Both dosages of udenafil induced a significant increase in IIEF-EF compared with placebo at both 12 and 24 weeks. When patients were divided according to the severity of baseline EF score, significant improvement was observed only with udenafil 75 mg regardless of the degree of ED. At 24 weeks, the proportions of patients who reported a return to normal EF (IIEF-EF over 26) were 39.1% for udenafil 50 mg and 47.0% for udenafil 75 mg. In terms of safety, ADRs were observed in 6.1%, 12.9%, and 17.9% for placebo, udenafil 50 mg, and 75 mg, respectively. Although a statistically higher rate of ADRs was observed in the udenafil 75 mg group (P = 0.024), the majority were mild and recovered without treatment. Conclusions. Once-daily administration of udenafil 50 mg and 75 mg for 24 weeks resulted in improvement of EF. In particular, udenafil 75 mg improves EF regardless of the baseline degree of ED. Moon KH, Ko YH, Kim SW, Moon DG, Kim JJ, Park NC, Lee SW, Paick J-S, Ahn TY, Chung WS, Min KS, Park JK, Yang DY, and Park K. Efficacy of once-daily administration of udenafil for 24 weeks on erectile dysfunction: Results from a randomized multicenter placebo-controlled clinical trial. J Sex Med **;**:**–**. Key Words. Udenafil; Phosphodiesterase 5 Inhibitors; Clinical Trial; Erectile Dysfunction
© 2015 International Society for Sexual Medicine
J Sex Med **;**:**–**
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Moon et al.
Introduction
Materials and Methods
A
Study Design This randomized, double-blind, placebocontrolled study was conducted at 13 centers located in Korea, according to the guidelines of the Good Clinical Practice and International Conference on Harmonization and adhering to the ethical principles of the Declaration of Helsinki. The duration of the study was 28 weeks, consisting of a treatment-free run-in period of 4 weeks followed by a treatment period of 24 weeks (Figure 1). After approval of the local institutional review board, patients were independently assigned randomly to receive placebo or udenafil 50 mg or 75 mg at a ratio of 1:1:1 using the block randomization method at each clinical trial site. Enrolled patients took a pill once per day at the same time for 24 consecutive weeks. Considering about 15% of dropout rate, the target enrollment for this trial was 336 subjects (112 subjects per group). The statistically and clinically significant difference in EF domain between udenafil group and placebo group was set as “3.45” from the previous placebo-controlled study [10]. The sample size was determined assuming a level of significance of α = 0.05 (two-sided) and a 90% statistical power of test.
n optimal outcome in the treatment of erectile dysfunction (ED) is to enable a return to normal erectile function (EF) [1]. To achieve this goal, the method of administration and dosage of oral phosphodiesterase-5 inhibitors (PDE-5Is) have been expanded to once-daily repeated administration with lower dosage than that required for on-demand administration [2–4]. Several clinical trials on once-daily administration of PDE-5I demonstrated an improvement in ED [2,5,6]. Udenafil (Zydena®; Dong-A, Seoul, Korea), a recently developed selective PDE-5I, showed promising pharmacokinetic characteristics for use in a once-daily strategy with a peak plasma concentration at 0.8–1.3 hours, which then declines monoexponentially with a half-life (T1/2) ranging from 9.9 to 12.1 hours [7–9]. During regular repeated administration, udenafil reaches steady state by day 5, without significant drug accumulation [8]. We previously reported the outcomes of a placebo-controlled, randomized controlled trial on once-daily dosing of udenafil 25 mg, 50 mg, and 75 mg for 12 weeks. In that study, we demonstrated improved EF with safety with administration of udenafil at a dose of 50 mg or 75 mg once daily, in comparison with placebo [10]. Based on these prior findings, we now focused on and evaluated the efficacy and safety of two different doses of udenafil (50 mg and 75 mg) once per day for a longer term period of 24 weeks as a treatment for ED, particularly from the viewpoint of assessing the recovery of normal EF by use of a patientreported questionnaire in comparison with a placebo.
Subjects
The inclusion criteria were subjects with a history of ED for a minimum of 6 months, which was defined as over 50% failure on sexual intercourse (minimum of four attempts during the run-in period), and below 25 on the International Index
Figure 1 Study design and data collection schedule
J Sex Med **;**:**–**
Efficacy of Once-Daily Udenafil for 24 Weeks on ED of Erectile Function (IIEF)-EF domain, which was estimated from baseline (week 0). Inclusion criteria were also adult men 20 years of age or older with ED for more than 6 months, who have a fixed relationship with one sexual intercourse partner and who understood the objective of this clinical trial and provided written consent after deciding to participate voluntarily. The same protocol used in our previous study was used for exclusion criteria [10]: penile anatomic defects; spinal cord injury; prior radical prostatectomy or radical pelvic surgery; hyperprolactinemia; low level of total testosterone; poorly controlled diabetes (glycosylated hemoglobin >12%) or proliferative diabetic retinopathy; major uncontrolled psychiatric disorder; history of active peptic ulcer disease within 1 year of screening; history of major hematologic, renal or hepatic abnormalities; recent (within the previous 6 months) history of cardiovascular disease, stroke, myocardial infarction, cardiac failure, unstable angina, or a lifethreatening arrhythmia; or history of alcoholism or substance abuse. Also excluded were persons taking androgens (e.g., testosterone) or anti-androgens. Prior use of other PDE-5Is was allowed; however, patients who reported not responding to other PDE-5Is were excluded from this study.
Efficacy End Point The primary objective was the changes from baseline IIEF-EF scores at 24 weeks in total or subgroups of patients, classified according to the severity of ED. Based on this, the proportions of patients who achieved a return to normal EF as measured by an IIEF-EF domain score over 26 were determined. Safety and Adverse Events After obtaining consent from the subjects for their participation in this clinical trial, all adverse events (AEs) and adverse drug reactions (ADRs) were monitored. Vital signs were checked at each visit. Laboratory parameters from blood (total blood count, glucose, creatinine, and electrolytes) and urine samples (pH, protein, glucose, nitrate, and occult blood) and 12-lead electrocardiograms were evaluated at baseline, 12 weeks, and 24 weeks after administration of the drug. Prolactin, testosterone, and HbA1C were checked at screening only. Statistical Analysis For assessment of the primary and secondary objective, analysis of variance (anova) was performed on
3
the mean difference in the IIEF-EF domain score at baseline and final visit (Week 24) between the dose groups, and statistical significance was determined. Changes within a dose group were tested by performance of repeated measures anova for each dose group with determination of statistical significance. For assessment of shift to normal EF, chi-square test was used for comparison of the ratio of subjects who showed an improvement to normal erection (IIEF-EF domain score ≥ 26) at 12 weeks and 24 weeks between the dose groups and to determine the statistical significance. All statistical analyses were performed using SAS (Ver. 9.2, SAS Institute, Cary, NC, USA), using two-sided tests with a significance level of 5%. If a significant difference was observed between dose groups, Dunnett’s method was used with the placebo group as a control for continuous variables, and the step-down Bonferroni method was used for analysis of categorical data. Results
Subjects A total of 378 subjects were screened in this trial, and 349 subjects (92.3%) were enrolled (116 subjects in the placebo group, 116 subjects in the group administered with udenafil 50 mg, and 117 subjects in the group administered with udenafil 75 mg). Two subjects in the placebo group who did not continue with follow-up after randomization were excluded from the analysis; therefore, 347 subjects were analyzed for safety. A summary of the baseline characteristics of each group is shown in Table 1. The severity of ED using the IIEF-EF domain score was similar across three dose groups (P = 0.7148). The mean duration of ED was 5.28 years, and approximately 78% of subjects had experiences of taking other PDE-5Is. Efficacy Outcomes Regardless of dosage of udenafil, it induced a significant increase in IIEF-EF, compared with placebo at both 12 and 24 weeks. The difference (change from baseline ± standard deviation) in the EF domain score at 24 weeks after drug administration compared with baseline was 2.56 ± 5.78 in the placebo group, 7.9 ± 6.15 in the udenafil 50 mg group, and 8.83 ± 6.45 in the udenafil 75 mg group, and statistically significant differences were observed between the dose groups (P < 0.0001). When dividing subjects based on the baseline severity of ED, a significant increase was J Sex Med **;**:**–**
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Moon et al.
Table 1 Demographics of study subjects Udenafil
Age, year Height, cm Weight, kg Etiology: n (%) Organic Psychogenic Mixed Severity of ED (EF domain score); n (%) Severe (
Efficacy of Once-Daily Administration of Udenafil for 24 Weeks on Erectile Dysfunction: Results from a Randomized Multicenter Placebo-Controlled Clinical Trial Ki Hak Moon, MD, PhD,* Young Hwii Ko, MD, PhD,* Sae Woong Kim, MD, PhD,† Du Geon Moon, MD, PhD,‡ Je Jong Kim, MD, PhD,‡ Nam Cheol Park, MD, PhD,§ Sung Won Lee, MD, PhD,¶ Jae-Seung Paick, MD, PhD,** Tae Young Ahn, MD, PhD,†† Woo Sik Chung, MD, PhD,‡‡ Kwon Sik Min, MD, PhD,§§ Jong Kwan Park, MD, PhD,¶¶ Dae Yul Yang, MD, PhD,*** and Kwangsung Park, MD, PhD††† *Department of Urology, College of Medicine, Yeungnam University, Daegu, Korea; †Department of Urology, The Catholic University of Korea College of Medicine, Seoul, Korea; ‡Department of Urology, College of Medicine, Korea University, Seoul, Korea; §Department of Urology, Pusan National University School of Medicine, Busan, Korea; ¶ Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; **Department of Urology, Seoul National University Medical School, Seoul, Korea; ††Department of Urology, Asan Medical Center, Ulsan University School of Medicine, Seoul, Korea; ‡‡Department of the Urology, Ewha Womans University School of Medicine, Seoul, Korea; §§Department of Urology, College of Medicine, Inje University, Pusan, Korea; ¶¶Department of Urology, Chonbuk National University Medical School, Jeonju, Korea; ***Department of Urology, College of Medicine, Hallym University, Seoul, Korea; †††Department of Urology, Chonnam National University Medical School, Gwangju, Korea DOI: 10.1111/jsm.12862
ABSTRACT
Introduction. The method of administration of oral phosphodiesterase-5 inhibitors has been expanded to once-daily repeated administration with lower initial dosage than on-demand administration. Aim. The aim of this study was to evaluate the efficacy and safety of once-daily udenafil as a treatment for erectile dysfunction (ED) for intermediate-term period. Methods. This multicenter, randomized, double-blind clinical trial included 346 ED patients (placebo, udenafil 50 mg, udenafil 75 mg). Subjects were treated with each medication once daily for 24 weeks. Main Outcome Measures. Subjects were asked to complete the International Index of Erectile Function (IIEF)erectile function (EF) domain at baseline, 12 weeks, and 24 weeks and the development of adverse drug reactions (ADRs) was inspected. Results. Both dosages of udenafil induced a significant increase in IIEF-EF compared with placebo at both 12 and 24 weeks. When patients were divided according to the severity of baseline EF score, significant improvement was observed only with udenafil 75 mg regardless of the degree of ED. At 24 weeks, the proportions of patients who reported a return to normal EF (IIEF-EF over 26) were 39.1% for udenafil 50 mg and 47.0% for udenafil 75 mg. In terms of safety, ADRs were observed in 6.1%, 12.9%, and 17.9% for placebo, udenafil 50 mg, and 75 mg, respectively. Although a statistically higher rate of ADRs was observed in the udenafil 75 mg group (P = 0.024), the majority were mild and recovered without treatment. Conclusions. Once-daily administration of udenafil 50 mg and 75 mg for 24 weeks resulted in improvement of EF. In particular, udenafil 75 mg improves EF regardless of the baseline degree of ED. Moon KH, Ko YH, Kim SW, Moon DG, Kim JJ, Park NC, Lee SW, Paick J-S, Ahn TY, Chung WS, Min KS, Park JK, Yang DY, and Park K. Efficacy of once-daily administration of udenafil for 24 weeks on erectile dysfunction: Results from a randomized multicenter placebo-controlled clinical trial. J Sex Med **;**:**–**. Key Words. Udenafil; Phosphodiesterase 5 Inhibitors; Clinical Trial; Erectile Dysfunction
© 2015 International Society for Sexual Medicine
J Sex Med **;**:**–**
2
Moon et al.
Introduction
Materials and Methods
A
Study Design This randomized, double-blind, placebocontrolled study was conducted at 13 centers located in Korea, according to the guidelines of the Good Clinical Practice and International Conference on Harmonization and adhering to the ethical principles of the Declaration of Helsinki. The duration of the study was 28 weeks, consisting of a treatment-free run-in period of 4 weeks followed by a treatment period of 24 weeks (Figure 1). After approval of the local institutional review board, patients were independently assigned randomly to receive placebo or udenafil 50 mg or 75 mg at a ratio of 1:1:1 using the block randomization method at each clinical trial site. Enrolled patients took a pill once per day at the same time for 24 consecutive weeks. Considering about 15% of dropout rate, the target enrollment for this trial was 336 subjects (112 subjects per group). The statistically and clinically significant difference in EF domain between udenafil group and placebo group was set as “3.45” from the previous placebo-controlled study [10]. The sample size was determined assuming a level of significance of α = 0.05 (two-sided) and a 90% statistical power of test.
n optimal outcome in the treatment of erectile dysfunction (ED) is to enable a return to normal erectile function (EF) [1]. To achieve this goal, the method of administration and dosage of oral phosphodiesterase-5 inhibitors (PDE-5Is) have been expanded to once-daily repeated administration with lower dosage than that required for on-demand administration [2–4]. Several clinical trials on once-daily administration of PDE-5I demonstrated an improvement in ED [2,5,6]. Udenafil (Zydena®; Dong-A, Seoul, Korea), a recently developed selective PDE-5I, showed promising pharmacokinetic characteristics for use in a once-daily strategy with a peak plasma concentration at 0.8–1.3 hours, which then declines monoexponentially with a half-life (T1/2) ranging from 9.9 to 12.1 hours [7–9]. During regular repeated administration, udenafil reaches steady state by day 5, without significant drug accumulation [8]. We previously reported the outcomes of a placebo-controlled, randomized controlled trial on once-daily dosing of udenafil 25 mg, 50 mg, and 75 mg for 12 weeks. In that study, we demonstrated improved EF with safety with administration of udenafil at a dose of 50 mg or 75 mg once daily, in comparison with placebo [10]. Based on these prior findings, we now focused on and evaluated the efficacy and safety of two different doses of udenafil (50 mg and 75 mg) once per day for a longer term period of 24 weeks as a treatment for ED, particularly from the viewpoint of assessing the recovery of normal EF by use of a patientreported questionnaire in comparison with a placebo.
Subjects
The inclusion criteria were subjects with a history of ED for a minimum of 6 months, which was defined as over 50% failure on sexual intercourse (minimum of four attempts during the run-in period), and below 25 on the International Index
Figure 1 Study design and data collection schedule
J Sex Med **;**:**–**
Efficacy of Once-Daily Udenafil for 24 Weeks on ED of Erectile Function (IIEF)-EF domain, which was estimated from baseline (week 0). Inclusion criteria were also adult men 20 years of age or older with ED for more than 6 months, who have a fixed relationship with one sexual intercourse partner and who understood the objective of this clinical trial and provided written consent after deciding to participate voluntarily. The same protocol used in our previous study was used for exclusion criteria [10]: penile anatomic defects; spinal cord injury; prior radical prostatectomy or radical pelvic surgery; hyperprolactinemia; low level of total testosterone; poorly controlled diabetes (glycosylated hemoglobin >12%) or proliferative diabetic retinopathy; major uncontrolled psychiatric disorder; history of active peptic ulcer disease within 1 year of screening; history of major hematologic, renal or hepatic abnormalities; recent (within the previous 6 months) history of cardiovascular disease, stroke, myocardial infarction, cardiac failure, unstable angina, or a lifethreatening arrhythmia; or history of alcoholism or substance abuse. Also excluded were persons taking androgens (e.g., testosterone) or anti-androgens. Prior use of other PDE-5Is was allowed; however, patients who reported not responding to other PDE-5Is were excluded from this study.
Efficacy End Point The primary objective was the changes from baseline IIEF-EF scores at 24 weeks in total or subgroups of patients, classified according to the severity of ED. Based on this, the proportions of patients who achieved a return to normal EF as measured by an IIEF-EF domain score over 26 were determined. Safety and Adverse Events After obtaining consent from the subjects for their participation in this clinical trial, all adverse events (AEs) and adverse drug reactions (ADRs) were monitored. Vital signs were checked at each visit. Laboratory parameters from blood (total blood count, glucose, creatinine, and electrolytes) and urine samples (pH, protein, glucose, nitrate, and occult blood) and 12-lead electrocardiograms were evaluated at baseline, 12 weeks, and 24 weeks after administration of the drug. Prolactin, testosterone, and HbA1C were checked at screening only. Statistical Analysis For assessment of the primary and secondary objective, analysis of variance (anova) was performed on
3
the mean difference in the IIEF-EF domain score at baseline and final visit (Week 24) between the dose groups, and statistical significance was determined. Changes within a dose group were tested by performance of repeated measures anova for each dose group with determination of statistical significance. For assessment of shift to normal EF, chi-square test was used for comparison of the ratio of subjects who showed an improvement to normal erection (IIEF-EF domain score ≥ 26) at 12 weeks and 24 weeks between the dose groups and to determine the statistical significance. All statistical analyses were performed using SAS (Ver. 9.2, SAS Institute, Cary, NC, USA), using two-sided tests with a significance level of 5%. If a significant difference was observed between dose groups, Dunnett’s method was used with the placebo group as a control for continuous variables, and the step-down Bonferroni method was used for analysis of categorical data. Results
Subjects A total of 378 subjects were screened in this trial, and 349 subjects (92.3%) were enrolled (116 subjects in the placebo group, 116 subjects in the group administered with udenafil 50 mg, and 117 subjects in the group administered with udenafil 75 mg). Two subjects in the placebo group who did not continue with follow-up after randomization were excluded from the analysis; therefore, 347 subjects were analyzed for safety. A summary of the baseline characteristics of each group is shown in Table 1. The severity of ED using the IIEF-EF domain score was similar across three dose groups (P = 0.7148). The mean duration of ED was 5.28 years, and approximately 78% of subjects had experiences of taking other PDE-5Is. Efficacy Outcomes Regardless of dosage of udenafil, it induced a significant increase in IIEF-EF, compared with placebo at both 12 and 24 weeks. The difference (change from baseline ± standard deviation) in the EF domain score at 24 weeks after drug administration compared with baseline was 2.56 ± 5.78 in the placebo group, 7.9 ± 6.15 in the udenafil 50 mg group, and 8.83 ± 6.45 in the udenafil 75 mg group, and statistically significant differences were observed between the dose groups (P < 0.0001). When dividing subjects based on the baseline severity of ED, a significant increase was J Sex Med **;**:**–**
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Moon et al.
Table 1 Demographics of study subjects Udenafil
Age, year Height, cm Weight, kg Etiology: n (%) Organic Psychogenic Mixed Severity of ED (EF domain score); n (%) Severe (
