Ateş Kadıoğlu, Department of Urology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34390, Turkey. E-mail: firstname.lastname@example.org
Udenafil is a potent phosphodiesterase type-5 inhibitor (PDE5) previously shown in studies conducted in populations of Eastern-Asian ethnicity, to significantly improve sexual function, in addition to a favourable safety profile. The purpose of this study was to evaluate the efficacy and safety of udenafil for the treatment of erectile dysfunction (ED), for the first time in a non-Eastern-Asian population. In this multicentre, randomized, double-blind, parallel, placebo-controlled study conducted in five centres in Turkey, 118 eligible subjects were randomized to receive udenafil 100 mg taken as on-demand or matching placebo for an 8-week treatment period. The primary efficacy variable was the change from baseline of the International Index of Erectile Function Questionnaire–Erectile Function Domain (IIEF–EFD) score, secondary efficacy variables were changes from baseline in IIEF Questionnaire Domains' 2–5 scores (Intercourse Satisfaction, Orgasmic Function, Sexual Desire, Overall Sexual Satisfaction) and IIEF Questionnaire Grand Total score, changes from baseline in penetration success rates (SEP2) and intercourse completion rates (SEP3) and evaluation of responses to the global assessment question (GAQ). Patients treated with udenafil demonstrated significantly higher increase in the IIEF–EFD scores compared with placebo-treated subjects [4.0 (95% CI: 1.3–6.6; p = 0.003)]. Similarly, greater improvements were observed in the scores for SEP2 [0.65 (95% CI: 0.02–1.3, p = 0.043)], SEP3 [0.9 (95% CI: 0.3–1.5, p = 0.003)] and two other IIEF Questionnaire Domains (Domain 4: Sexual Desire, Domain 5: Overall Sexual Satisfaction). The proportion of positive responses to the GAQ was greater in the udenafil compared to the placebo group (72.2% vs. 49.1%, p = 0.014). The most frequent treatment-emergent adverse events were headache, flushing and rhinorrhea, all of mild or moderate severity. This is the first study to demonstrate in a non-Eastern-Asian population that udenafil 100 mg taken as on-demand can effectively improve erectile function and is well tolerated.
Erectile dysfunction (ED) is a common condition that results from a variety of medical, psychological and lifestyle causes and greatly affects sexual function and quality of life of men and their partners worldwide (McKinlay, 2000; Mallis et al., 2006). Although not life-threatening, men with ED often experience a significant degree of frustration and anxiety resulting in withdrawal from sexual intimacy, reduced working productivity and increased use of health care resources (Litwin et al., 1998). By 2025, men to have experienced ED are expected to reach 322 million from 152 million worldwide in 1995 (Ayta et al., 1999; McKinlay, 2000). The areas with the greatest anticipated projected increases are Asia, Africa and South America (Ayta et al., 1999). Currently, phosphodiesterase type-5 inhibitors (PDE5) are widely used as the first line oral treatment for ED, owing to their ability to promote the natural erectile function in the presence of a sexual stimulus (Hatzimouratidis et al., 2010). Although, both efficacious and well tolerated, the first generation of PDE5 inhibitors has on occasion been attributed with slow onset and short duration of action (Bell & Palmer, 2010).
Udenafil (Zydena; Dong–A Pharmaceutical Co., Seoul, Korea) is a newly developed potent PDE5 inhibitor administered orally to patients experiencing ED. It is rapidly absorbed reaching maximal concentration within 1–1.5 h and has a relatively long half-life (T1/2) of 11–13 h (Salem et al., 2006). This distinct pharmacokinetic profile accounts for its unique pharmacological properties of rapid onset and long duration of action, comprising thus a good alternative to already existing ED treatments. In previous clinical trials, udenafil has proven efficacious in treating ED of organic, psychogenic or mixed aetiology (Paick et al., 2009; Park et al., 2010; Zhao et al., 2011), including patients suffering from diabetes mellitus (Moon du et al., 2011). Moreover, ascribable to its low selectivity for PDE11 and PDE6 (Salem et al., 2006; Kouvelas et al., 2009), udenafil exhibits a favourable safety and tolerability profile (Kim et al., 2008; Porst et al., 2008). A previous study showed that the age-adjusted overall prevalence of ED in Turkey is 69.2%, increasing from 49.9% in men between 40 and 49 years to 94.7% in men of older age (>70 years) (Akkus et al., 2002). The age-adjusted percentage for patients diagnosed with mild or severe ED is 36.0%, also markedly increased with age from 7.6% to 90.1.
Despite its high overall prevalence of 69.2%, few studies have been conducted regarding treatment of ED with PDE5 inhibitors in the Turkish population. Moreover, previous clinical trials investigating the efficacy and safety of udenafil in patients with ED have been conducted in populations of Eastern-Asian ethnicity (Paick et al., 2008, 2009; Kim et al., 2009; Park et al., 2010; Moon du et al., 2011; Zhao et al., 2011). The aim of the present trial was to evaluate the efficacy and safety of 100 mg udenafil taken on-demand over 8 weeks, for the treatment of ED in a population of men from Turkey.
Materials and methods
This multicentre, randomized, double-blind, parallel, placebo-controlled study was conducted in five centres located in Turkey, in accordance with the Good Clinical Practice guidelines of the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use, and the principles of the Declaration of Helsinki and applicable Turkish law. All patients provided written consent before inclusion into the study. The study was approved by the Central Ethical Committee of the Turkish Ministry of Health.
Study duration was 10 weeks, including an initial 2 weeks run-in period. Patient screening was followed by an 8-week treatment period during which eligible patients were randomized in a 1 : 1 ratio to either receive udenafil (100 mg) or matching placebo, taken once daily as on-demand, 30 min to 1 h before anticipated sexual intercourse. Randomization codes were generated by a centralized computer.
Male patients from Turkey, between 18 and 60 years without uncontrolled diabetes and with an established diagnosis of mild, moderate or severe ED of organic, psychogenic or mixed aetiology at least 3 months prior to entering the study and willing to attempt at least one sexual intercourse each week for the entire study period, were enrolled. Participating subjects were eligible patients visiting the study centres enrolled into the trial by the study investigators. Recruitment was not performed by referral or self selection. Eligible patients were expected to have been in a heterosexual monogamous relationship for at least 6 months prior to randomization and were asked to maintain this relationship for the duration of the study.
The major exclusion criteria were as follows: patients with total erectile failure (i.e. complete inability to achieve an erection) or any other sexual disorder; patients with a significant penile deformity or trauma; history of major psychiatric disorder; history of significant pathological cardiovascular conditions (e.g. congestive heart failure, life-threatening arrhythmia or ischaemic heart disease) within the past 6 months or central nervous system disorders, such as stroke, transient ischemic attacks or spinal cord injury; radical prostatectomy or radical pelvic surgery; previous failure to respond to treatment with PDE5 inhibitors or other ED therapies within 14 days prior to entering the study or known hypersensitivity to PDE5 inhibitors; uncontrolled hypertension (>170/100) or hypotension (<90/50); clinically significant renal or hepatic insufficiency or haematological disorder; a history of retinitis pigmentosa, proliferative diabetic retinopathy or non-arteritic anterior ischaemic optic neuropathy; history of sickle cell disease, multiple myeloma, leukaemia or any other disorders that may cause priapism; known diagnosis of AIDS or positive HIV status; history of alcoholism and/or drug abuse.
The medications that were contraindicated were as follows: any drugs or herbal preparations for the treatment of ED including PDE5 inhibitors, nitrates/nitrites (NO) donors and CYP3A4 inhibitors and/or inducers. If patients were taking alpha-blockers (except tamsulosin) attributable to benign prostate hyperplasia or hypertension, they were advised to only use them 6–8 h before or after the administration of the study medication. CYP450 3A4 inhibitors were taken only after careful consideration.
During the treatment period, no participating member (Investigators, Patients, Study Monitors, Data Managers or Statisticians) was aware of the treatment being administered to each subject. At the screening visit and after confirmation of eligibility, patients were assigned a subject randomization number. Subsequently, at the baseline visit, each patient was assigned a treatment box labelled with the same randomization number. To achieve the blind design, the double dummy technique was applied. The placebo tablets were manufactured so as to be identical to the test drug tablets. No codes or signs printed on the tablets, blisters or treatment boxes per visit could reveal the nature (study drug or placebo) of the product.
For the purposes of the study, a version of the International Index of Erectile Function Questionnaire (IIEF) validated for the Turkish language by the Turkish Society of Andrology was utilized.
The primary efficacy variable was the change from baseline of the International Index of Erectile Function Questionnaire–Erectile Function Domain (IIEF–EFD) score calculated as the sum of scores for questions 1–5 and 15 (Rosen et al., 1997; Cappelleri et al., 1999), with a change from baseline of 2, 5, 7 in the domain score, considered as the minimum clinically important difference (MCID) for patients diagnosed with mild, moderate and severe ED, respectively (Rosen et al., 2011).
Secondary efficacy variables were as follows: changes in IIEF Questionnaire Domains' 2–5 scores (Intercourse Satisfaction, Orgasmic Function, Sexual Desire and Overall Sexual Satisfaction) and IIEF Questionnaire Grand Total score at the end of the treatment period as compared with baseline. In addition, changes in penetration success rates (SEP2) (Over the last 4 weeks, when you attempted intercourse, how often were you able to penetrate your partner?) and intercourse completion rates (SEP3) (Over the last 4 weeks, during sexual intercourse, how often were you able to maintain your erection after you had penetrated your partner?) were assessed at the end of the treatment period as compared with baseline. A minimum increase in SEP2 of >0, 16.7, 27.3% for patients diagnosed with mild, moderate and severe ED, respectively, was regarded as the MCID (Araujo et al., 2012). The MCID for SEP3 was a minimum increase of 5, 23.3, 17.0% for patients diagnosed with mild, moderate and severe ED respectively (Araujo et al., 2012). Last, the global assessment question (GAQ) ‘Has the treatment you have been taking over the past study period improved your erections?’ was evaluated at the end of the study.
Safety assessments included the presence of all reported adverse events (AEs) regardless of relationship to the study drug, clinically significant changes in laboratory results (haematological, biochemical, viral/HIV test), monitoring of vital signs (heart rate and blood pressure) and complete physical examination, during the treatment period. Analysis of safety included all patients that received at least one dose of study drug (safety population). In this article, treatment-emergent adverse events (TEAEs), defined as all AEs appearing in the safety population, are shown.
The analysis of subjects' demographic and other disease specific characteristics was conducted by descriptive statistical methods. Continuous variables are presented by measures of central tendency and dispersion and categorical variables by frequency distribution tables. Between-group comparison of continuous variables was performed by a two-sample t-test or Wilcoxon's rank sum test, in the cases where deviation from Normality was exhibited. Between-group comparison of categorical variables was performed by Pearson's chi-square test of independence or Fisher's exact test.
Difference between groups regarding the changes of IIEF questionnaire (domain scores and total scores) from baseline was assessed by a two-sample t-test. Pearson's chi-square test of independence was used to test the difference in positive responses to patient's GAQ and MCID achievement rates (IIEF-EFD, SEP2, SEP3), between the two groups.
All efficacy analyses were performed using the data from intention-to-treat population, which included all randomized patients who received at least one dose of the study drug and at least one valid post-baseline evaluation.
Significance level was set at 5%. Statistical analysis was implemented by sas v9.2 statistical software (SAS Institute Inc., Cary, NC, USA).
Patient demographics and disposition
Of the total 141 consecutive men screened for eligibility, 118 were randomized for treatment (59 in the udenafil group, 59 in the placebo group). These patients also comprised the Safety and ITT population. Four patients prematurely discontinued participation in the study (one in the udenafil and three in the placebo group) (Fig. 1).
Patients' demographic characteristics and relevant medical history at baseline are presented in Table 1. Patients with ED of organic, psychogenic and mixed aetiology were 18.6, 61.0 and 20.3%, respectively in the udenafil group and 13.6, 62.7 and 23.7%, respectively, in the placebo group. Sixty-two patients (52.5%) had used PDE5 inhibitors before entering the study. Overall, baseline demographic characteristics and clinical variables were balanced between the two treatment groups. In addition, no significant differences in the mean baseline IIEF Questionnaire Domains' scores, including IIEF–EFD and Grand Total Score were observed between the two treatment groups (data not shown).
Table 1. Demographic characteristics and medical history of study subjects at baselinea
Placebo (n = 59)
Udenafil (n = 59)
No significant differences between treatment groups (p > 0.05).
Mean ± SD
42.9 ± 8.66
43.8 ± 8.77
Mean ± SD
80.3 ± 10.35
79.8 ± 10.20
Mean ± SD
173.1 ± 5.72
173.1 ± 7.26
Mean ± SD
26.8 ± 3.32
26.6 ± 3.07
Smoking status, n (%)
Diagnosis, n (%)
Aetiology, n (%)
Duration of illness, months
Previous use of PDE5 inhibitor, n (%)
Hypertension, n (%)
Diabetes mellitus, n (%)
Primary efficacy results
Following 8 weeks of treatment, udenafil was superior to placebo in the primary efficacy endpoint by 4.0 (95% CI: 1.3–6.6; p = 0.003; Table 2, Fig. 2). The mean change from baseline on the IIEF–EFD was 3.8 (95% CI: 1.8–5.7) for the placebo and 7.7 (95% CI: 5.9–9.5) for the udenafil group (Table 2). The per cent of patients that achieved the MCID at the end of the treatment period (week 8) was higher for udenafil-treated (79.6%) compared with placebo-treated (52.0%) patients (p = 0.009).
Table 2. IIEF Questionnaire Domains' scores at baseline and after 4 and 8 weeks of treatment given as mean ± SD (N = 118)
Difference udenafil-placebo (95% CI)
Difference expressed as odds ratio (OR).
MCID was defined as 2, 5, 7 change in the EF domain score from baseline for patients diagnosed with mild, moderate and severe ED, respectively.
Significant improvement from baseline until the end of the treatment period was observed in the remaining IIEF Questionnaire Domains' scores (Domains 2–5), with the exception of satisfaction with intercourse (Domain 2) and orgasmic function (Domain 3) (Table 2, Fig. 3). In addition, change in the IIEF Questionnaire Grand Total score was greater by 7.7 (95% CI: 2.2–13.3, p = 0.007) among the udenafil-treated [17.7 (95% CI: 13.9–21.5)] than the placebo-treated [10.0(95% CI: 5.8–14.2)] patients (Table 2, Fig. 3).
Udenafil was also associated with successful outcomes for SEP2 and SEP3. Mean difference in the increases for SEP2 between the udenafil vs. the placebo group baseline was 0.65 (95% CI: 0.02–1.3, p = 0.043) from baseline to the end of the 8-week treatment period, with 66.0% reaching the MCID in the former vs. 46.0% in the latter group (p = 0.040). Likewise, mean change in the increases for SEP3 between the udenafil vs. the placebo group baseline was 0.9 (95% CI: 0.3–1.5, p = 0.003), with 69.8% reaching the MCID in the former vs. 42.0% in the latter group (p = 0.005). Lastly, following 8 weeks of treatment the proportion of positive responses (‘yes’) to the GAQ was significantly higher in the udenafil compared with the placebo group (72.2% vs. 49.1%, p = 0.014; Table 3, Fig. 4).
Table 3. Changes of secondary efficacy variables from baseline to the end of the study
Difference udenafil-placebo (95% CI)
SEP: Sexual encounter profile; GAQ: Global assessment question.
Difference expressed as odds ratio (OR).
MCID was defined as >0, 16.7, 27.3% change in SEP2 score from baseline for mild, moderate and severe ED categories respectively.
MCID was defined as 5, 23.3, 17.0% change in SEP3 score from baseline for mild, moderate and severe ED categories respectively.
In general, udenafil was well tolerated as the overall incidence of TEAEs was low. In total, 10 (16.9%) TEAEs and 8 (13.6%) were reported in the udenafil group and the placebo group respectively. As a result of the AEs, one patient (0.02%) temporarily discontinued treatment in the udenafil group. The most frequently reported (≥3%) TEAEs in the udenafil-treated patients were headache (5.1%) and flushing (3.4%). All treatment-emergent AEs were mild or moderate and the majority resolved completely. No serious AEs were reported.
In this study, the efficacy and safety of administration of 100 mg udenafil was assessed in a population of men from Turkey. Udenafil has been shown to be efficacious and well tolerated in a number of previous trials (Kim et al., 2008; Paick et al., 2009; Park et al., 2010; Moon du et al., 2011; Zhao et al., 2011). These, however, have mainly included subjects of Eastern-Asian ethnicity. To our knowledge, this is the first study examining the above-mentioned endpoints conducted in a population of non-Eastern-Asian ethnicity. This is of clinical significance as this ethnic population has been shown to differ genetically from Eastern-Asians with regard to certain hepatic enzymes that participate in drug metabolism (Kim et al., 2004), including those responsible for the metabolism of udenafil (Shim et al., 2003). Moreover, attitudes, perceptions of ED and percentages of patients seeking treatment for ED differ among populations of different ethnic backgrounds (Nicolosi et al., 2003; Perelman et al., 2005).
For the purposes of this study, a population of Turkish patients with ED of organic, psychogenic or mixed aetiology was recruited to receive udenafil 100 mg taken as on-demand. At the end of the study period, patients treated with udenafil showed a statistically significant improvement in erectile function, recorded as an increase of 7.7 in the IIEF–EFD score, from 16.0 to 23.7. This indicates a shift from moderate to milder pathologies (Cappelleri et al., 1999). The clinical significance of this result was also confirmed by the significantly higher percent of patients accomplishing MCID in the udenafil vs. the placebo group, at the end of the observation period. Results of this study are comparable to a previous 12-week, randomized controlled study showing a 7.5 increase in the IIEF–EFD score in patients with ED of various aetiologies treated with the same dose of udenafil (100 mg) (Paick et al., 2008). Similarly, an increase of 8.4 in the IIEF–EFD score was observed in the 100 mg udenafil dose group in a randomized controlled trial that included patients with ED receiving concomitant antihypertensive agents (Paick et al., 2009).
Further confirmation of the efficacy of udenafil in treating ED was achieved by simultaneous improvements in secondary study endpoints. Specifically, scores in the Sexual Desire Domain scores (Domain 4) and the Overall Sexual Satisfaction Domain (Domain 5) exhibited an increase by 1.6 (placebo: 0.7) and 2.2 (placebo: 1.2), respectively. Such increases verify, according to the ‘Description and scoring rules of the IIEF Questionnaire’ (Rosen et al., 2002), a decrease in the overall sexual dysfunction experienced by patients. In agreement with our results, increases of 2.86 and 1.23 in Domain 4 and Domain 5, respectively, were also observed in a previous study by (Paick et al., 2008). In contrast, we were not able to observe a significant difference in the Satisfaction with Intercourse Domain's (Domain: 2) and Orgasmic Function Domain's (Domain: 3) scores between treatment groups. This may be justified by the fact that changes in the Satisfaction with Intercourse Domain score and Orgasmic Function score are not only related to improvement of the erectile function (such as penile rigidity etc.), but also to other factors including relationship with the partner, intimacy, fatigue, illness, etc. (Hawton et al., 1992). However, the IIEF Questionnaire Grand Total score also exhibited a significant improvement in the udenafil group compared with the placebo group (udenafil: 17.7, placebo: 10.0).
In addition to the aforementioned findings, assessment of further secondary efficacy variables also established a better outcome for patients with ED treated with udenafil, demonstrated as increases in the penetration ability (SEP2) (udenafil: 1.3, placebo: 0.7) and penile rigidity (SEP3) (udenafil: 1.5, placebo: 0.6), combined to higher per cent of patients accomplishing minimum clinical significance in the udenafil compared with the placebo group for both variables (SEP2: 66.0% vs. 46.0%, SEP3: 69.8% vs. 42.0%). Furthermore, positive answers to the GAQ were provided by a higher proportion of patients in the udenafil (72.2%) compared with the placebo (49.1%) group. These results are consistent with observations from previous trials reporting enhanced rates for SEP2, SEP3 and GAQ for the same dose of udenafil (Paick et al., 2009; Park et al., 2010; Moon du et al., 2011).
The main limitation of the study was that the placebo responses were relatively higher compared with previous studies. It might be argued that this can be attributed to a relatively high proportion of patients with a diagnosis of mild-to-moderate ED of psychogenic aetiology (62.7%) included, in comparison with recruited patients with ED of mixed or organic aetiology. However, even this subgroup of patients can benefit from treatment with PDE5, as increased erection hardness ensured by PDE5 inhibitors can improve confidence and therefore effectively reduce performance anxiety (Althof et al., 2010).
In this study, the favourable tolerability profile of udenafil, already established in populations of Eastern-Asian ethnicity, was also confirmed (Kim et al., 2008; Paick et al., 2008; Park et al., 2010). In total, 16.9% TEAEs of mild or moderate severity were reported in the study drug group. None of the patients receiving udenafil discontinued study participation referable to an AE. Our results agree with previous trials conducted evaluating the safety of the same dose of udenafil (100 mg) exhibiting a similarly low incidence of AEs of 11.3% (Park et al., 2010) and 15.8% (Moon du et al., 2011), the majority of which were mild or moderate in severity.
The most frequent AEs recorded in the udenafil group were headache (5.1%) and flushing (3.4%). These were also described in previous trials as the most commonly occurring AEs of the 100 mg udenafil dose (Paick et al., 2008, 2009; Moon du et al., 2011). In addition, reporting of mild vasodilatory effects like headache, flushing, dyspepsia and nasal congestion or rhinitis is commonly recorded for all PDE5 inhibitors (Markou et al., 2004; Seftel, 2004; Kim et al., 2008; Tsertsvadze et al., 2009). However, abnormalities of vision or myalgias that are often experienced by patients receiving tadalafil or sildenafil (Makhlouf et al., 2006) were not reported in this study, confirming udenafil's high selectivity for PDE5.
This study has demonstrated that administration of udenafil 100 mg, taken as on-demand, is an effective and well-tolerated treatment in a population of men with mild-to-moderate ED from Turkey. As the prevalence of ED in Turkey remains high (Akkus et al., 2002) and treatment with other PDE5 inhibitor regimens has shown limited success (Carson et al., 2004; Ozgur et al., 2009), there is added need for further investigation into new therapeutic options. The unique pharmacokinetic profile and clinical efficacy and safety of udenafil present a promising alternative.
This work was supported by a grant from Abdi Ibrahim Ilac San. Ve Tic. A.S., Turkey. The authors thank the study participants and study investigators Erdem Ozturk, Ziya Akbulut and Serkan Altinova for their efforts and contributions.
Conflict of interest
Drs M.O., S.Ç., M.K.Ç., M.Ö.Y., T.M.O., M.B.S., A.B.A., M.D.B., M.F.Ö., A.K. have received research grants from Abdi Ibrahim Ilac San. Ve Tic. A.S., Turkey.