A double-blind, randomised- placebo, controlled, parallel group, multicentre, flexible-dose escalation study to assess the efficacy and safety of sildenafil administered as required to male outpatients with erectile dysfunction in Korea

Abstract

The efficacy and safety of sildenafil was evaluated in a randomiSed, double-blind, placebo-controlled, flexible-dose study in Korean men aged 28–78 y with erectile dysfunction (ED) of broad-spectrum aetiology and more than 6 months duration. A total of 133 patients were randomised at six centres in Korea to receive either sildenafil (50 mg initially, increased if necessary to l00 mg or decreased to 25 mg depending on efficacy and tolerance) (n=66) or matching placebo (n=67) taken on an ‘as needed’ basis l h prior to anticipated sexual activity for a period of 8 weeks. At the end of this time, the primary efficacy variables relating to the achievement and maintenance of erections sufficient for sexual intercourse, and the secondary efficacy variables, which included: (1) the five separate domains of sexual functioning of the International Index of Erectile Function (IIEF) scale, (2) the percentage of successful intercourse attempts, and (3) a global assessment of erections, were all statistically significantly improved by sildenafil in comparison with placebo (P<0.0001). Treatment-related adverse events occurred in 56.1% of patients receiving sildenafil and 20.9% receiving placebo. The most common adverse events with sildenafil were vasodilatation (flushing), headache and abnormalities in colour vision (31.8, 22.7 and 6.1% of patients, respectively), and most were mild in nature. The efficacy and safety of sildenafil in this population of Korean men appears similar to that reported in other studies in western populations.

Introduction

Clinical studies have shown sildenafil, an orally active inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5,1 to be effective in improving erectile dysfunctioin (ED) of various aetiologies.2,3,4,5,6,7 In addition, its effectiveness has also been demonstrated in various subsets of ED patients, including those with diabetes mellitus,8 spinal cord injury,9 antidepressant-induced dysfunction,10 and following nerve-sparing radical prostatectomy.11 We therefore investigated the efficacy and safety of sildenafil in Korean men. The Asian Sildenafil Efficacy and Safety Study in Korea (ASSESS-K) trial was a randomised, double-blind, placebo-controlled, flexible-dose study carried out at six different centres.

Materials and methods

Study population

The ASSESS-K study was conducted during the period from November 1998 to March 1999 in 133 Korean men aged 28–67 y who had a well-documented history (>6 months) of ED (NIH definition12) of organic, psychogenic or mixed aetiology. To ensure adequate distribution of patients between young and elderly population (infulfilment of Korean FDA requirements), the subjects were stratified into two groups by ages: the subjects who were born before and on or after 1 January 1947 and allocated to placebo or sildenafil with the same ratio. The patients were required to be in a stable heterosexual relationship for at least the previous 6 months, and not to have any of the following: ED caused by genital anatomical abnormalities or spinal cord injury; other coexisting sexual disorders (eg hypoactive sexual desire); raised serum prolactin levels (> 3 × upper limit of normal) or a low free testosterone level (>20% below the lower limit of the normal range at 0900–1100 h); a major psychiatric disorder or a history of alcohol or substance abuse; major haematological, renal or hepatic diseases; diabetes mellitus that is poorly controlled or associated with untreated proliferative retinopathy; a history of stroke or myocardial infarction within the previous 6 months; hypotension or any other significant cardiovascular disease; or a history of retinitis pigmentosa. Patients were also excluded if they were receiving drugs known to be causally associated with ED androgen therapy, trazodone, nitrates or nitiric oxide donor compounds (in any form), and if they were using vacuum devices or any other treatments for ED. Patients gave their informed consent to participate in the study, which was conducted in accordance with the Institutional Review Board regulations at each site.

Initially, the patients underwent a 4-week run-in period during which baseline data on their sexual activities were collected, a full medical/drug history, physical examination. A 12-lead ECG and standard laboratory safety tests were performed, and sitting blood pressure and heart rate were measured. Then the patients were referred to a cardiologist for treadmill test. The patients were also instructed in the use of event logs to record information on their erections, the sexual activity that took place, and medication details (number of tablets and when taken). In addition to the initial screening visit, they were required to undergo a further four clinic visits—at the start of treatment (week 0) and thereafter at weeks 2, 4 and 8.

Study medication

Following the run-in period, eligible patients were randomised to receive either sildenafil (Viagra™) or a matching placebo in a double-blind manner for a period of 8 weeks. For the first 2 weeks of the study, patients were instructed to take a 50 mg sildenafil tablet (or a matching placebo) as required 1 h prior to anticipated sexual activity and not more than once daily. At subsequent visits and at the discretion of the investigator, either an increase to 100 mg (if the response was not adequate) or a decrease to 25 mg (if higher doses were not well tolerated) was allowed.

Assessment of efficacy

The 15-question International Index of Erectile Function (IIEF)13 was used to assess clinical efficacy. Patients completed this validated, multidimensional, self-administered questionnaire at the end of the run-in period and at the scheduled end of treatment (week 8) or at the time of discontinuation. In addition, efficacy was also assessed via patients' event logs of sexual activity and medication taken, which were reviewed at each visit, and via a global efficacy assessment of erections at the end of treatment or discontinuation. The investigators also assessed patients at each visit to determine whether the dose taken was optimal and whether they should continue in the trial.

The primary efficacy variables were the responses to questions 3 and 4 of the IIEF questionnaire, which assess the patients' ability to penetrate their partners during sexual intercourse and to maintain the erection after penetration. The secondary efficacy variables were: (1) the responses to the five separate domains of sexual function assessed by the IIEF questionaire, that is, erectile function (questions 1–5 and 15), intercourse satisfaction (questions 6–8), orgasmic function (questions 9 and 10), sexual desire (questions 11 and 12) and overall satisfaction (questions 13 and 14);13 (2) event log responses regarding the success of attempts at sexual intercourse; and (3) a global efficacy assessment in response to the question: ‘Has the treatment you have been taking over the past four weeks improved your erections?’

Assessment of safety

Patients were assessed for adverse events at each visit and all observed or reported events were recorded regardless of a suspected causal relationship to the study medication. Sitting blood pressure, heart rate details of concomitant medications were also recorded at each visit and a 12-lead ECG and standard laboratory tests of haematological and blood chemistry parameters were repeated at the end of treatment of visit (week 8).

Statistical analyses

The treatment groups were checked for similarity with respect to demographic and event log variables using descriptive statistics. Primary efficacy variables were analysed for both the intent-to-treat population (patients who took at least one dose of the study medication and had at least one postrandomisation evaluation) and the evaluable population (patients who either completed the study, or did not complete it but had efficacy data available in defined windows and did not violate the protocol in any fundamental way). The secondary efficacy variables were analysed for the intent-to-treat population only. Each of the two primary efficacy variables was analysed separately using univariate analysis of covariance (ANCOVA). Responses to the five domains of the IIEF sexual function questionnaire were also analysed using ANCOVA, as were the percentages of successful intercourse attempts derived from patients' event logs. Responses to the global efficacy assessment question were analysed using logistic regression. In all ANCOVA analyses, the model included terms for treatment, centre, baseline value of the efficacy variables, and two-factor interactions between treatment group and other model terms. Covariates modelled in all analyses included the duration of the disease, patient age, history of smoking, and disease aetiology. All tests of hypotheses were performed at the 5% significance level using two-sided tests of significance.

Results

Of the 133 patients who entered the trial, two did not complete the IIEF for final evaluation and were not included in the analyses. Baseline characteristics of the 133 patients who were randomised and took the study medication are shown in Table 1. The mean ages and body weights of the two groups were similar, as was the mean duration of erectile dysfunction (approximately 5 y) and the distribution of the primary diagnosis (ie organic, psychogenic or mixed aetiology). Among other diseases present at baseline, unspecified disorder of the eyes was the most common reported (21 sildenafil group, 14 placebo); this included primarily presbyopia, myopia, hypermetropia and, less commonly, cataracts and visual abnormalities.

Table 1 Baseline characteristics of the 236 patients randomised to treatment with either sildenafil or placebo

Two patients in placebo group had their medication discontinued because of lack of efficacy and withdrawn consent and were excluded from the intent-to-treat population, which therefore comprised 131 patients (66 sildenafil, 65 placebo). The evaluable patient comprised 129 patients (64 sildenafil, 65 placebo), two being excluded because of violation of an inclusion criterion.

The mean duration of treatment was 53.17 days in the sildenafil group and 51.31 days in the placebo group and the median number of doses taken was 24.52 and 22.07, respectively. The initial 50 mg dose (sildenafil or matching placebo) was increased in most patients during the trial and at the week 8 end point, 43 (65.2%) of the sildenafil group were taking the highest dose (100 mg), 22 (33.3%) the medium dose (50 mg), and 1 (1.5%) the lowest dose (25 mg). In the placebo group, the high dose was taken by all 65 patients. Three patients receiving sildenafil had dose reductions or temporary discontinuation because of adverse events.

Primary efficacy variables

Mean scores for IIEF questions 3 and 4 at baseline and at the end of treatment for the intent-to-treat populations of the sildenafil and placebo groups are shown in Table 2. These two questions assess the frequency with which penetration was achieved during attempts at sexual intercourse and the frequency with which erections were able to be maintained after penetration, both questions having maximum scores of 5 (almost always or always) and minimum scores of 0 (did not attempt intercourse). The mean scores obtained in the two groups expressed as percentages of the maximum score for each question are shown in Figure 1. For both efficacy variables, sildenafil was statistically significantly more effective than placebo (P<0.0001). Similar results were obtained in the evaluable population analysis (data not shown).

Table 2 Mean scores for the primary and secondary efficacy variables in men receiving sildenafil or placebo for 8 weeks (intent-to-treat analysis)
Figure 1
figure1

Mean scores, as percentages of the maximum IIEF scores, at baseline and following 12 weeks of sildenafil or placebo administration for the primary efficacy variables: (1) frequency of penetration (IIEF question 3) and (2) frequency of maintained erection after penetration (IIEF question 4). For both questions, scores were available for 110 patients receiving sildenafil and for 111 receiving placebo. *P<0.0001 versus placebo.

Secondary efficacy variables

The mean scores at baseline and at the end of treatment for the five IIEF domains of sexual functioning (ie erectile function, intercourse satisfaction, orgasmic function, sexual desire and overall satisfaction) for the intent-to-treat populations of the two groups are shown in Table 2, and the scores expressed as percentages of the maximum scores in Figure 2. For all five domains, sildenafil was statistically significantly more effective than placebo (P<0.0001).

Figure 2
figure2

Mean scores, as percentages of the maximum IIEF domain scores, at baseline and following 12 weeks of sildenafil or placebo administration for: (1) erectile function (IIEF questions 1–5 and 15); (2) intercourse satisfaction (IIEF questions 6–8); (3) orgasmic function (IIEF questions 9 and 10); (4) sexual desire (IIEF questions 11 and 12); and (5) overall satisfaction (IIEF questions 13 and 14). For all domains, scores were available for 110 patients receiving sildenafil and for 111 receiving placebo, except for the erectile function and overall satisfaction domains for which scores in the placebo group were available for 110 and 109 patients, respectively. * P<0.0001 versus placebo.

Data from the patients' event logs showed that the mean percentage of successful attempts at sexual intercourse was significantly greater with sildenafil than with placebo (62.0% vs 25.9%, respectively; P<0.0001) (Table 2 and Figure 3). Similarly, responses to the global assessment question regarding erections at week 8 also elicited a statistically significantly greater treatment effect with sildenafil, 81.2% of patients describing their erections as improved as compared with 27.6% of patients receiving placebo (P<0.0001) (Figure 3).

Figure 3
figure3

Percentages of attempts at intercourse rated as successful (from data recorded in patients' event logs) and percentages of patients rating their erections as improved (as assessed via the global efficacy question) following administration of sildenafil or placebo for 12 weeks. * P<0.0001 versus placebo.

Adverse events

All 133 patients who were randomised to treatment were included in the adverse event analysis, but laboratory test data were only available for 131 patients (66 receiving sildenafil and 65 placebo). Adverse events recorded during the trial, regardless of causality, are shown in Table 3. Adverse events considered by the investigators to be treatment-related occurred in 37 (56.1%) patients receiving sildenafil and 14 (20.9%) receiving placebo. In the sildenafil group, the most commonly encountered adverse event was vasodilatation (flushing), which was considered treatment-related in 21 (31.8%) patients, followed by headache (15 patients; 22.7%), abnormalities in colour vision (four patients; 6.1%), and blurred vision and nasal congestion (each in three patients; 4.5%). Most adverse events with sildenafil were mild in nature, and only one patient had a severe event (flushing) that was considered treatment-related, which resolved without treatment.

Table 3 Numbers of patients (%) receiving sildenafil and placebo who experienced adverse events during the 8-week study period (all-cause and treatment-related events)a

Serious adverse events occurred in two patients in the placebo group but none was considered treatment-related.

Laboratory results

Among the 131 patients for whom laboratory test results were available, five of 66 (7.6%) receiving sildenafil showed a clinically significant laboratory abnormality as compared with two of 65 (3.1%) receiving placebo. Three patients on sildenafil had elevated eosinophils. One patient was considered by the investigator to be because of the underlying disease (urticaria), and two patients were not clinically significant. Two patients with elevated glucose had concomitant medical history of diabetes. One with elevated creatinine had values within normal range specified as acceptable by protocol on repeat test. There were no abnormalities occurring in more than one patient in either treatment group for patients with normal baselines.

Discussion

As a result of misinformation and the numerous myths that surround the condition, many Korean men with ED do not seek treatment for their condition for fear of personal embarrassment or try to find a way for enhancing their energy using traditional oriental medicine. The lack of experience on the part of doctors who are consulted about it or, in some cases, reluctance to deal with the problem has led to disappointment for the sufferer and perpetuated the myth that there are no effective treatments for ED. This situation highlights the need for more open discussion and better education about ED and its origins, and for an effective therapy that is both simple and safe to use and does not interfere with the natural sexual relationship. In view of the reported efficacy of sildenafil in improving the sexual functioning of western men with ED of various different aetiologies,5,6,7,8,9,10,11 its effectiveness and safety in Korean men is of considerable interest and underlines its expanding role in the management of ED. This study in Korean men has shown that a flexible dose regimen of sildenafil ranging from 25 to 100 mg taken 1 h prior to anticipated sexual activity is effective in improving ED of organic, psychogenic and mixed origin, as evaluated by the patients' own assessments in their own environments. The assessment methods used were the IIEF questionnaire, patient-completed event logs of sexual activity and a global efficacy question regarding erections. The IIEF questionnaire provides a broad measure of sexual functioning across five domains and has adequate sensitivity for detecting treatment-related changes in erectile function, although it has some limitations, for example, the sole focus on sexual functioning and limited assessments of nonerectile components of the sexual response and the partner relationship. Despite this, the IIEF questionnaire has been widely used in studies evaluating the efficacy of therapies for ED in English, its adaptation to Korean languages has not been found to be associated with cross-cultural problems of comprehension.14

Both the primary and secondary efficacy variables used in this study showed significantly greater treatment effects for sildenafil in comparison with placebo (P<0.0001). The only IIEF parameter that did not show a significant difference between the two groups was the number of attempts at sexual intercourse (ie the responses to question 6: ‘How many times have you attempted sexual intercourse over the past 4 weeks?’), but data from the patients' event logs showed that the mean proportion of successful attempts at intercourse was more than doubled by sildenafil in comparison with placebo (62.0% of attempts vs 25.9%; P<0.0001).

Our results in Korean men are similar to those reported in Western populations, the improvements in the ability to achieve and maintain erections sufficient for penetration and/or for the five IIEF domains being comparable to those achieved in double-blind, placebo-controlled studies conducted in the US and UK.3,4,5,6,7 We employed a flexible-dose schedule of sildenafil, allowing for increases up to 100 mg for lack of efficacy or reductions to 25 mg for lack of tolerance. At the end of the 8-week study period, 65.2% of patients receiving sildenafil were found to be taking a 100 mg dose, while 33.3% were taking a 50 mg dose and 1.5% a 25 mg dose (Figure 4). This finding is very similar to that reported by Goldstein et al,2 who noted that 74% of patients in the flexible-dose arm of their study were taking a 100 mg dose after 12 weeks of therapy, while 23% were taking a 50 mg dose and 2% were taking a 25 mg dose.

Figure 4
figure4

Percentages of patients taking each dose of sidenafil or placebo at baseline (week 0) and at weeks 2, 4, 8, and 12. All patients took a 50 mg dose (sidenafil or matching placebo) during the first 2 weeks, after which their doses were either increased up to 100 mg if the response was insufficient, or decreased to 25 mg if higher doses were not well tolerated.

As regards safety, again we have confirmed the findings of studies in Western populations in demonstrating that sildenafil is well tolerated in Korean men, with no serious adverse events related to its use and no instances of priapism. The most common adverse events experienced by our patients were vasodilatation (flushing) (31.8% of patients), headache (22.7%) and abnormalities in colour vision (6.1%), which reflect the drug's pharmacological activity. In most cases, the adverse events were mild in nature and only one patient experienced a severe event (flushing), which was resolved without treatment. Adverse events led to a dose reduction or a temporary discontinuation in three patients in sildenafil group. However, there were no withdrawals because of laboratory abnormalities.

The absence of serious safety concerns in our patients confirms the findings of a clinical safety overview of 28 phase II or III studies with sildenafil conducted in Western populations.15 Although 25% of our patients were receiving antihypertensive drugs (principally α-adrenoceptor blockers or calcium channel blockers) and 33% of patients in the placebo-controlled studies included in the overview analysis15 were receiving antihypertensive treatment, the tolerability of sildenafil in these men was no different to that in patients not receiving antihypertensive drugs. However, in other studies, coadministration of sildenafil with nitrate drugs has been reported to result in clinically significant decreases in blood pressure, and the use of sildenafil is clearly contraindicated in patients receiving organic nitrates in any form. A recent ACC/AHA consensus document in the US has also advised caution, depending on an individual clinical assessment, in: (1) patients with active coronary ischaemia not taking nitrates (eg those with a positive exercise test for ischaemia); (2) patients with congestive heart failure and borderline low blood pressure and borderline low volume status; (3) patients receiving complicated, multidrug antihypertensive regimens; and (4) patients receiving other drugs that may affect the clearance of sildenafil (eg agents that inhibit cytochrome P450 3A4 such as erythromycin or cimetidine).16

Conclusions

The results of this randomised, double-blind, placebo-controlled, flexible-dose study conducted at six centres in Korea have indicated that sildenafil is effective in improving the sexual functioning of Korean men with ED of organic, psychogenic and mixed aetiologies.

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Acknowledgements

This paper is supported by grants from Pfizer.

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Correspondence to H K Choi.

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Choi, H., Ahn, T., Kim, J. et al. A double-blind, randomised- placebo, controlled, parallel group, multicentre, flexible-dose escalation study to assess the efficacy and safety of sildenafil administered as required to male outpatients with erectile dysfunction in Korea. Int J Impot Res 15, 80–86 (2003). https://doi.org/10.1038/sj.ijir.3900944

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Keywords

  • erectile dysfunction: sildenafil
  • efficacy
  • safety

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