SEARCH

SEARCH BY CITATION

Keywords:

  • erectile dysfunction;
  • phosphodiesterase type 5 inhibitor;
  • vardenafil

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgment
  9. References
  10. Appendix

Abstract  Aim:  Vardenafil is a selective and highly potent phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), with improved selectivity for PDE5 and demonstrated efficacy for improving sexual function in men with ED. The current study investigated the safety and efficacy of this new PDE5 inhibitor in Japanese men with ED.

Methods:  This was a prospective, double blind, randomized clinical trial designed to evaluate the efficacy and safety of vardenafil. Following a 4-week treatment-free observation period, 283 eligible patients were randomized to 12 weeks treatment with vardenafil 5 mg, 10 mg, 20 mg, or placebo. Primary efficacy responses were assessed using the scores of Q3 and Q4 of the international index of erectile function (IIEF).

Results:  All three vardenafil doses showed significantly better improvement than the placebo group in Q3 and Q4 scores of the IIEF questionnaire, either at 12 weeks or at the ‘last observation carried forward’ (LOCF, P < 0.0001). Q3 scores were improved to 4.06 with vardenafil 5 mg, 4.53 with vardenafil 10 mg, and 4.64 with vardenafil 20 mg, versus 3.17 with placebo. Comparable scores for Q4 were 3.47, 4.15 and 4.31 versus 2.31 for placebo. Up to 86% of patients achieved improved erections as assessed by the global assessment question (GAQ). Reported adverse event rates were 35.3%, 45.3% and 54.5% with vardenafil 5 mg, 10 mg and 20 mg, respectively, versus 21.1% in the placebo group. No serious adverse drug reactions were reported. The most common treatment-emergent adverse events were transient headache, flushing and rhinitis, which were mostly mild.

Conclusion:  Vardenafil is an effective and well-tolerated treatment for ED and provides improvement in key indices of erectile function among Japanese men with ED. The results of our trial show that up to nearly 90% of patients achieve improved erections with the administration of vardenafil.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgment
  9. References
  10. Appendix

The NIH Consensus Development Panel on Impotence has defined male erectile dysfunction (ED) as the inability to achieve and maintain an erection of the penis sufficiently to complete satisfactory sexual intercourse, a definition that gained worldwide acceptance. Based on epidemiological surveys, it has been estimated that close to 30 million men in the United States and 2–4 million men in Japan, suffer from ED.1,2 However, the Investigative Committee on ‘Health and Sex of Adult Men’ reported that among Japanese men aged 31–70 years, 1.74 million had complete ED, 8 million had moderate ED, and 9.8 million had mild ED.3 Additional studies conducted in the USA, Europe and Japan have established that ED is a common disease, and have found a male prevalence ranging from 10% to 52%.4–6

Until recently, standard treatment of ED involved counselling, injectable agents, and physical interventions (vacuum devices and penile prostheses) that induce erections in the absence of sexual stimulation. The introduction of sildenafil, an orally administered phosphodiesterase type 5 (PDE5) inhibitor, was a significant improvement over earlier therapies for most ED patients.7 With sexual stimulation, nitric oxide (NO) is released and diffuses into corporal cavernosal smooth muscle cells where it activates guanylate cyclase. This enzyme catalyzes the synthesis of cyclic guanosine monophosphate (cGMP) that mediates smooth muscle cell relaxation, and results in the filling and expansion of the sinusoidal space, facilitating the development of an erection. PDE5 is the most prominent phosphodiesterase (PDE) within the corpora cavernosa and provides the natural termination signal to this cascade by hydrolyzing cGMP. Thus, inhibition of PDE5 prevents the breakdown of cGMP, thereby enhancing and prolonging the erectile response.

Vardenafil (Levitra), a highly selective and potent PDE5 inhibitor, has been evaluated in a comprehensive series of animal and in vitro studies, indicating that vardenafil is up to 10 times more potent than sildenafil and shows greater selectivity for PDE5, relative to other phosphodiesterases, especially PDE1 and PDE6.8 In a rabbit model, orally administered vardenafil facilitated penile erection.9–11 Additional clinical trials have demonstrated that vardenafil is an efficacious agent in improvement of erectile function.12–16 In the present study, we report the results of a Phase IIb trial, which investigated safety and efficacy of vardenafil in Japanese ED patients. This trial used the same protocol as previously described by Porst et al.,12 and was positioned as a bridging study in order to compare the efficacy and safety of vardenafil in Japanese with that in Caucasians.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgment
  9. References
  10. Appendix

Patients

Three hundred and seventy-five patients were enrolled in this trial, which involved 33 investigation centers, and occurred between October 2000 and March 2001. At the first visit, patients were registered for participation in the trial and all provided written informed consent. They then entered a 4-week unmedicated run-in period in which they could not use sildenafil, or any other mechanical, oral or injectable therapy for ED. Patients not in accordance with inclusion and exclusion criteria were withdrawn at this stage.

Inclusion criteria

Inclusion criteria were as follows: (i) males with a history of ED of at least 6 months duration; (ii) men willing to make at least four attempts at sexual intercourse during the 4-week unmedicated period; (iii) men in a stable, heterosexual relationship for at least the previous 6 months; (iv) men aged between 20 and 70 years; and (v) absence of significant cardiac disease as determined from a 12-lead electrocardiogram (ECG) taken during the first visit.

Exclusion criteria

Exclusion criteria were as follows: (i) any medical, psychiatric or substance abuse disorder that, in the opinion of the investigator, would be likely to preclude the patient's participation in the study or affect the patient's ability to complete the study; (ii) uncontrolled diabetes mellitus (fasting plasma glucose: ≥126 mg/dL, postprandial plasma glucose: ≥200 mg/dL, or HbA1c: ≥6.5%); (iii) erectile dysfunction subsequent to spinal cord injury; (iv) history of radical prostatectomy; (v) diagnosis of retinitis pigmentosa; (vi) history of positive test for hepatitis B surface antigen (HbsAg) or hepatitis C antibody; (vii) presence of significant penile anatomical abnormalities (e.g. penile fibrosis); (viii) clinically significant chronic heart disease or cardiac failure, or a history of myocardial infarction, stroke, angina, electrocardiographic ischemia, or life-threatening arrhythmia; (ix) history of risk factors for coronary disease (such as smoking history or family history) that, in the opinion of investigator, rendered the patient a high risk for undiagnosed coronary disease; (x) severe chronic liver disease or liver function abnormalities (GOT or GPT > 3× the upper limit of normal); (xi) chronic hematologic disease; (xii) history of significant peptic ulcer or peptic ulcer bleeding within the previous year, or bleeding disorder; (xiii) resting hypotension (a resting systolic blood pressure of <90/50 mmHg) or hypertension (a resting systolic blood pressure >170/100 mmHg); (xiv) symptomatic postural hypotension within 6 months of Visit 1; (xv) current use of nitrates or nitric oxide donors; (xvi) current use of beta-blockers for angina; (xvii) controlled hypertension but unable to maintain a relatively constant dose of antihypertensive medication; (xviii) current use of cimetidine, erythromycin, ketoconazole, or rifampicin; (xix) current use of anticoagulants other than low dose aspirin (≤325 mg/day); (xx) current use of antiandrogens, androgens (e.g. testosterone), or trazodone; (xxi) current use of digoxin derivatives or digitoxin antiarrhythmics; (xxii) use of any investigational drug (including placebo) in the previous 3 months; (xxiii) use of sildenafil or other therapy for ED within 7 days of the first visit; (xxiv) any significant laboratory abnormality apparent at the time of screening, especially if suggesting risk for cardiovascular diseases; (xxv) low serum total testosterone (<300 ng/dL); (xxvi) elevated serum creatinine (>2.0 mg/dL); (xxvii) serum free thyroxine (T4) outside the normal range, or free thyroid stimulating hormone (TSH) level below the normal range, or free TSH level more than 4 mU/L above the upper limit of normal (patients on thyroid replacement therapy were acceptable if their blood tests were within the defined ranges); (xxviii) patients with a known hypersensitivity to sildenafil or to three or more other drugs; (xxix) history within the past 6 months of severe migraine headaches of at least once-monthly frequency (well controlled migraine was not an exclusion criterion); (xxx) primary hypoactive sexual desire; and (xxxi) history of unresponsiveness to sildenafil.

Premature discontinuation

Premature discontinuation was permitted for the following reasons: (i) a patient's own request for any reason (including withdrawal of consent); (ii) difficulty in continuing the trial owing to adverse events; (iii) gross patient non-compliance with the study medication (including discrepancy between diary records and the returned medication); (iv) any significant protocol violation; (v) new occurrence of angina or severe cardiovascular disease; (vi) spontaneous cure or improvement so that medication was no longer needed; (vii) worsened symptoms or lack of efficacy; and (viii) death during the study. The reason for all discontinuations was investigated as thoroughly as possible, for any possible influence on safety, tolerability or efficacy.

Study design

This was a prospective double blind, placebo controlled, parallel group trial to investigate the safety and efficacy of three doses of vardenafil. At the end of the 4-week observation period, 283 eligible patients, who satisfied all inclusion and exclusion criteria, were randomized to vardenafil 5 mg, 10 mg, 20 mg, or placebo. Patients received a supply of study medication during the second visit. Randomization was organized centrally, and vardenafil and placebo tablets were of similar appearance. Patients were instructed to take a single dose 1 hour before sexual intercourse and not to take more than one dose per day, with at least 24 h elapsing between doses. Patients were instructed that there were no restrictions on food, although alcohol was not allowed within 2 h before taking study medication.

Efficacy parameters

The intent-to-treat (ITT) population was used for the analysis. The primary, predefined outcome variables were the scores of Questions 3 and 4 of the international index of erectile function (IIEF),17 as assessed at Week 12 of the study (last observation carried forward, LOCF). Question 3 asks ‘When you attempted sexual intercourse (vaginal penetration) how often were you able to penetrate your partner?’ Question 4 asks ‘During sexual intercourse (vaginal penetration) how often were you able to maintain your erection after you had penetrated (entered) your partner?’. Scores were graded on a scale of 1–5, with one for never or almost never, and five for always or almost always, with no intercourse noted as zero. In addition, the IIEF-erectile function (IIEF-EF) domain was also evaluated (the sum of Questions 1–5 plus Question 15), which ranges from severe (≤10), to moderate (11–16), to mild-moderate (17–21), to mild (22–25), to normal (>25). The 12-week LOCF score was used.

The following variables were also evaluated:

  • 1
    Responses on the patient's diary concerning ‘success in penetration’, ‘success in maintaining erection during intercourse’, ‘success of intercourse attempts’ and ‘overall satisfaction with sexual experience’.
  • 2
    The global assessment question (GAQ), ‘has the treatment you have been taking over the past 4 weeks improved your erection?’ (assessed at Week 12, as observed and LOCF).
  • 3
    The Fugl-Meyer quality of life questionnaire, ‘How satisfactory are these different aspects of your life? (i) Life as a whole is; (ii) my sexual life is; (iii) my partnership relation is; (iv) my contacts with friends and acquaintances are; (v) my leisure situation is; (vi) my vocational situation is; and (vii) my financial situation is’).18

Fugl-Meyer QOL scores were graded on a scale of 1–6, with one for very unsatisfying, and six for very satisfying.

Safety parameters

Safety was evaluated by recording adverse events, and from physical examination, vital sign determination (including 12-lead ECG) and standard laboratory tests.

Observations

The schedule of observations made during the study are summarized in Table 1. Patients were requested to complete diary entries at the time of each dose and met with the investigator every 4 weeks during the study to assess the IIEF questionnaire. At the first visit (registration) and second visit (randomization), and at the last visit (Week 12) (or at the time of premature withdrawal), heart rate, blood pressure, 12-lead ECG and laboratory tests were performed. Laboratory tests were also performed at Week 4.

Table 1.  Observation/tests and time schedule
 Run-in periodTreatment period (12 weeks)Follow up (telephone)
  • Total cholesterol, triglyceride, FT4, TSH, and testosterone are included.

  • Total cholesterol, triglyceride, FT4 and TSH are included.

  • BP, blood pressure; ECG, electrocardiogram; IIEF, international index of erectile function; QOL, quality of life; TSH, thyroid stimulating hormone; Y, yes.

Visit 1234 5
Week–4048121316
Informed consentY
Patient characteristicsY
Preliminary eligibility judgment (preliminary registration)Y
Eligibility judgment (main registration)Y
Concomitant treatment/concomitant therapyYYYY
Body weightY
Prescription of study drugYYY
Collection of study drugYYY
Efficacy
 Record of IIEF questionnaireYYYY
 Global assessment questionYY
 Fugl-Meyer and QOL questionnaireYY
 Dispense of patient diaryYYYY
 Collection of patient diaryYYYY
Safety
 Laboratory exam (hematology and urinalysis)YYYY
 Vital sign (BP and pulses)YYY
 12-lead ECGYYY
 Adverse eventsYYYYYYY

Statistics

The number of patients required for this study was calculated a priori in order to detect statistically significant differences between the placebo and the three vardenafil groups in the Q3 and Q4 scores at Week 12 (LOCF). Using a predefined, ordered test procedure, the following null hypotheses were tested at a two-sided alpha level of 0.05: (i) vardenafil 20 mg was not superior to placebo; (ii) vardenafil 10 mg was not superior to placebo; and (iii) vardenafil 5 mg was not superior to placebo. Only if a hypothesis was rejected, was the next hypothesis in sequence tested.

The ITT population was the primary analysis population of this study and comprised all patients who took at least one dose of study drug and who had both baseline and post-baseline efficacy data. Only protocol-compliant patients were included in a secondary analysis population, named the per-protocol analysis. All patients who took at least one dose of study drug were included in the safety analysis.

Scores at Week 12 (end of treatment period) were used as the final score (LOCF in prematurely withdrawn patients). These final scores from the IIEF questionnaire were analyzed using analysis of covariance (ANCOVA), including treatment group as the main effect and baseline score as a covariate. For each treatment group, least-squares mean (LS mean) from the ANCOVA model are presented.

Ethics

The protocol of this clinical trial was approved by the appropriate institutional review boards. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, and the protocol complied with the requirements specified in Item 3 of Article 14 and Item 2 of Article 80 in the Pharmaceutical Affairs Law in Japan, and the Good Clinical Practice (GCP) issued on April 1, 1997.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgment
  9. References
  10. Appendix

Patients

Efficacy was evaluated in 279 patients, and safety in 280 patients. The four treatment groups had similar baseline characteristics (Table 2). There were no significant differences  between  treatment  groups  with  regard  to age (P = 0.2711), frequency of alcohol consumption (P = 0.5623), smoking (P = 0.8855), duration of ED (P = 0.8762), etiology of ED (P = 0.4205) and baseline IIEF-EF domain score (P = 0.8880). There were no significant differences in height, weight, BMI, medication, or comorbidity. Duration of ED for most patients was shorter than 3 years after diagnosis of ED (Table 2), although they had realized their ED before the diagnosis (2.3 years before diagnosis as the median, ranging from 0.5 to 27.1 years).

Table 2.  Patients’ background (ITT population)
 PlaceboVardenafil
5 mg10 mg20 mg
  1. ED, erectile dysfunction; IIEF-EF, erectile function domain score of international index of erectile function; ITT, intent-to-treat.

Number of patients71677566
Age (mean, range; years)51.9 (23–68)52.5 (31–70)51.5 (30–70)49.8 (21–66)
Weight (kg)66.269.768.366.6
Duration of ED after diagnosis (year) 0.3 0.2 0.2 0.3
Etiology: n (%)
 Organic 4 (5.6) 2 (3.9) 4 (5.3) 4 (6.1)
 Psychogenic62 (87.3)63 (94.0)66 (88.0)54 (81.8)
 Mixed 5 (7.0) 2 (3.0) 4 (5.3) 4 (6.1)
Sildenafil user: n (%) 4 (5.6) 9 (13.2) 6 (8.0)10 (15.2)
Baseline IIEF-EF
 Domain score (mean ± SD)13.6 ± 5.214.0 ± 5.113.8 ± 5.313.4 ± 4.9
 Domain score n (%)
  <1025 (35.2)19 (28.4)23 (30.721 (31.8)
  11–1618 (25.4)26 (38.8)27 (36.0)26 (39.4)
  17–2124 (33.8)15 (22.4)19 (25.3)17 (25.8)
  22–25 4 (5.6) 7 (10.4) 6 (8.0) 2 (3.0)

A total of 238 patients completed 12 weeks treatment and 45 others withdrew before 12 weeks. Reasons for withdrawal included adverse events, withdrawal of consent, lost to follow-up, and protocol violation. The disposition of patients is shown in Fig. 1.

image

Figure 1. Disposition of patients.

Download figure to PowerPoint

Efficacy

Primary efficacy parameters

All three vardenafil dosages were statistically significantly superior to placebo in improving Q3 and Q4 scores from the IIEF questionnaire at Week 12 (or LOCF) (P < 0.0001). The LS mean Q3 score at Week 12 was 4.06 with vardenafil 5 mg, 4.53 with vardenafil 10 mg, and 4.64 with vardenafil 20 mg. The LS mean Q3 score was 3.17 with placebo (Fig. 2a). The LS mean Q4 score at Week 12 was also improved to 3.47 with vardenafil 5 mg, 4.15 with vardenafil 10 mg and 4.31 with vardenafil 20 mg. The LS mean Q4 score with placebo was 2.31 (Fig. 2b). There were also statistically significant differences between vardenafil 5 mg and the two higher dosages. The LS mean Q3 scores were statistically significantly higher in the vardenafil 20-mg and 10-mg groups than in the 5-mg group (P = 0.0033 and P = 0.0146, respectively) (Fig. 2a). Likewise the LS mean Q4 scores were statistically significantly higher in the vardenafil 20-mg and 10-mg groups than in the 5-mg group (P = 0.0003 and P = 0.0025, respectively) (Fig. 2b).

image

Figure 2. (a) Each study arm receiving vardenafil showed significantly better improvement in the Q3 score of the international index of erectile function (IIEF) questionnaire at Week 12 (last observation carried forward, LOCF) in comparison with the placebo arm. These scores were graded on a scale of 1–5, with one for never or almost never, and five for always or almost always, with no intercourse noted as zero. (b) Each study arm receiving vardenafil showed significantly better improvement in the Q4 score of the IIEF questionnaire at Week 12 (LOCF) in comparison with the placebo arm. These scores were graded on a scale of 1–5, with one for never or almost never, and five for always or almost always, with no intercourse noted as zero. (c) All three doses of vardenafil demonstrated significant improvement of IIEF-erectile function domain score at Week 12 (LOCF) compared to placebo. These scores provide the range of severity of ED (severe, ≤10; moderate, 11–16; mild-moderate, 17–21; mild, 22–25; normal, ≥26). bsl00022, baseline; ▪, 3 months. *, P < 0.0001 versus placebo; **, P = 0.0017 versus 5 mg; ***, P = 0.0009 versus 5 mg.

Download figure to PowerPoint

Secondary efficacy parameters

Vardenafil demonstrated statistically significantly superior efficacy to placebo for Q3 and Q4 scores at weeks 4, 8 and 12 (P < 0.0001). At all three vardenafil dosages, vardenafil led to a greater improvement in the IIEF-EF domain score (sum of Q1–Q5 and Q15) at Week 12 (LOCF) than was attained with placebo (P < 0.0001 for all three vardenafil dosages) (Fig. 2c). Furthermore, vardenafil 10 mg and 20 mg were statistically significantly superior to vardenafil 5 mg for improvement in the IIEF-EF domain score (P = 0.0017 and P = 0.0009, respectively).

Significantly higher percentages of patients in the three vardenafil groups answered ‘yes’ to the question, ‘Do you consider that this was a successful attempt at sexual intercourse?’ in the patient diary, relative to patients in the placebo group (P < 0.0001) (Fig. 3).

image

Figure 3. Results of patients’ diaries: A greater percentage of patients in the vardenafil arms answered ‘Yes’ to the question, ‘Do you consider that this was a successful attempt at sexual intercourse?’ compared to placebo arm. bsl00022, baseline; ▪, 3 months. *, P < 0.0001 versus placebo.

Download figure to PowerPoint

The percentage of patients at Week 12 (LOCF) who answered ‘yes’ to the question of ‘Is your erectile function improved?’ (the GAQ) was up to 86% in the vardenafil groups versus 35% in the placebo group (P < 0.0001 all dosages vs placebo) (Fig. 4).

image

Figure 4. Results of global assessment question. Higher improvement rates were obtained in all of the vardenafil groups than in the placebo group (P < 0.0001).

Download figure to PowerPoint

The score at Week 12 (LOCF) for ‘sexual life’ in the Fugl-Meyer QOL survey was significantly increased in all three vardenafil groups. The LS mean score was 3.95 with vardenafil 5 mg, 4.13 with vardenafil 10 mg, and 4.33 with vardenafil 20 mg, compared to an LS mean score of 2.98 with placebo (P < 0.0001, all vardenafil dosages vs placebo).

Safety

The per-patient incidence of any adverse events was 57% (39 patients) with vardenafil 5 mg, 63% (47 patients) with vardenafil 10 mg, 74% (49 patients) with vardenafil 20 mg, and 52% (37 patients) with placebo (Table 3). Most cases were mild, except for 10 instances in which the adverse event was reported as moderate.

Table 3.  Drug-related adverse events (>2%)
 PlaceboVardenafil
n = 715 mg n = 6710 mg n = 7520 mg n = 66
  1. CK, creatine kinase.

Overall15 (21%)24 (35%)34 (45%)36 (55%)
Flushing 4 (6%)14 (21%)22 (29%)24 (36%)
Headache 4 (6%) 5 (7%) 9 (12%) 7 (11%)
Rhinitis 0 (0%) 3 (4%) 5 (7%) 6 (9%)
Palpitation 0 (0%) 3 (4%) 4 (5%) 2 (3%)
CK increase 0 (0%) 0 (0%) 1 (1%) 2 (3%)
Dyspepsia 0 (0%) 1 (1%) 0 (0%) 2 (3%)
Flatulence 1 (1%) 0 (0%) 0 (0%) 2 (3%)

Adverse events believed by the investigator to be treatment-related were reported in 35% (24 patients) of the vardenafil 5-mg group, 45% (34 patients) of the vardenafil 10-mg group, 55% (36 patients) of the vardenafil 20-mg group and 21% (15 patients) of the placebo group. No serious treatment-related adverse events were reported.

The most frequently reported treatment-related adverse events were reported in the vardenafil 5 mg, vardenafil 10 mg, vardenafil 20 mg, and placebo groups, respectively: flushing 21% (14 patients), 29% (22 patients), 36% (24 patients), and 6% (4 patients); headache 7% (5 patients), 12% (9 patients), 11% (7 patients), and 6% (4 patients); and rhinitis 4% (3 patients), 7% (5 patients), 9% (6 patients) and 0% (0 patient). Reported cardiovascular adverse events included one instance each of tachycardia, atrial flutter, paroxysmal supraventricular contraction and migraine in the vardenafil arms of the study, and one instance of tachycardia in the placebo arm. Adverse events affecting the visual system comprised one instance of ‘sensory disturbance of the eye’ with vardenafil 5 mg and one instance of ‘abnormal vision and brightening’ with vardenafil 20 mg.

Elevated creatine kinase (greater than upper limit of normal) was occasionally observed in the study; there was one instance of this with vardenafil 10 mg, and two instances with vardenafil 20 mg.

Most adverse events were mild and transient and were consistent with the pharmacological effects of PDE5 inhibitors. A few patients discontinued due to adverse events. These comprised 3% of the vardenafil 5 mg group, 3% of the vardenafil 10 mg group, 4% of the vardenafil 20 mg group and 6% of the placebo group.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgment
  9. References
  10. Appendix

The introduction of PDE5 inhibitors has enabled a safe and efficacious ED treatment, and surveys have consistently indicated that the oral form of ED treatment is preferred by the majority of patients. Numerous studies have reported good efficacy in a variety of Asian populations treated with PDE5 inhibitors; for example, the ASSESS trial included patients from Malaysia, Singapore, and the Philippines.19,20 However, the present study is the first to investigate the safety and efficacy of a PDE5 inhibitor in an exclusively Japanese population. We have demonstrated that vardenafil taken orally 1 h before sexual intercourse improves key aspects of erectile function in a manner similar to that previously observed in studies in Europe and North America. The LS mean Q3 score at Week 12 (LOCF) was improved to 4.53 and 4.64 in patients receiving vardenafil 10 mg and 20 mg, respectively. The LS mean Q4 score at Week 12 (LOCF) was also improved to 4.15 and 4.31 in patients receiving vardenafil 10 mg and 20 mg, respectively (Fig. 2a,b). The LS mean scores of 4.53 and 4.64 in Q3 at vardenafil 10 and 20 mg dosages indicate that the greater majority of subjects with ED were able to enter their partners almost always or always. Similarly, the Q4 scores reveal that the majority of subjects were able to sustain their erections for the duration of sexual intercourse. Importantly, the LS mean IIEF-EF domain scores, 25.62 and 25.96 at vardenafil 10 and 20 mg (Fig. 2c), respectively, were indicative of the restoration of normal erectile function (EF domain score >25).

In other countries, Phase II and Phase III clinical trials have demonstrated high efficacy of vardenafil in a broad range of ED patients. Goldfischer and Donatucci et al. reported the results of pooled data from two placebo-controlled double-blinded randomized vardenafil clinical trials involving 1385 ED patients.13,14 These clinical trials included a high percentage of patients with hypertension, hyperlipidemia and diabetes; thus allowing for sub-analysis of patients with these comorbidities. Vardenafil led to clinically meaningful increases in EF domain scores for all three subgroups (P < 0.01), including diabetic patients (P < 0.001).13 Likewise, subgroup analyses by etiology (organic, psychogenic, mixed) or by severity (mild, moderate, severe) showed that, for all categories of ED patients, vardenafil improved LS mean IIEF domain scores, irrespective of etiology or severity.14 Furthermore, the results for Q3 of this sub-analysis indicated that the higher vardenafil dosage gave greater improvement from baseline in the moderate or severe ED patient groups compared to those in the mild to moderate ED patient groups. Adverse events were mild or moderate in intensity.13,14

Goldstein described a randomized, placebo-controlled Phase III clinical trial that examined the efficacy of vardenafil in men with ED accompanying diabetes mellitus.15 The EF domain score in the 10 mg and 20 mg vardenafil groups improved significantly to 17.1 and 19.0, respectively (P < 0.0001) from the baseline of 11, whereas the LS mean EF domain score was 12.6 in the placebo arm of the study. In the GAQ, 57% of patients treated with vardenafil 10 mg and 72% of those treated with 20 mg reported improvement of erection, whereas only 13% in the placebo arm reported improvement (P < 0.0001). No serious adverse events were reported in this clinical trial. In addition, this trial was extended to 6 months for the patients who wished to continue to participate in the trial. Men suffering from ED responded to vardenafil for the entire 6 month period, maintaining the improved erectile function that was observed at 3 months. Newly initiated vardenafil treatment after 3 months of placebo treatment produced efficacy responses similar to those on 6 months of treatment.21,22 Adverse events were typical of PDE5 inhibitors,23 and the rate of adverse events declined over time.21,22

Brock et al. conducted a Phase III clinical trial targeting 440 men aged 44–77 years with ED following radical prostatectomy for prostate cancer; men included in this study had experienced ED for at least 6 months (1.7 years after surgery on average, bilateral nerve sparing was performed in 70%).16 Patients were randomly assigned to placebo or vardenafil (10 mg or 20 mg) for 12 weeks. The EF domain score of both vardenafil 10 mg and 20 mg at Week 12 (LOCF) significantly improved to 15.3 (P < 0.0001) from 9.1 at the baseline EF domain scores, whereas the EF domain score of the placebo arm was 9.2 at Week 12 (LOCF). In the GAQ, 59% of patients showed improvement in the vardenafil 10 mg arm and 65% in the vardenafil 20 mg arm (P < 0.0001): only 13% of placebo-treated patients reported improvement. Furthermore, vardenafil 20 mg significantly decreased depressive symptoms among a small subset of post-prostatectomy patients who exhibited elevated depressive symptomatology at baseline.16 The finding that vardenafil significantly improved erectile function in post-prostatectomy patients is important because men who suffer from ED following prostatectomy are among the most difficult to treat because their ED is typically severe.

These pivotal efficacy studies demonstrated that the three studied doses of vardenafil (5 mg, 10 mg and 20 mg) were always statistically superior to placebo on the EF domain score, and on diary questions regarding success in penetration and the maintenance of erection. This finding also applies to studies performed in the general ED population. In the trials that included a vardenafil 5 mg arm, vardenafil 10 and 20 mg were generally shown to be statistically significantly superior to vardenafil 5 mg.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgment
  9. References
  10. Appendix

The results of the present trial demonstrate that vardenafil is a well-tolerated medicine in Japanese men, and that up to 86% of Japanese men with ED achieve improved erections when treated with vardenafil. In conclusion, vardenafil is a new therapy that improves key measures of erectile function in a broad population of Japanese men with ED.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgment
  9. References
  10. Appendix
  • 1
    NIH Consensus Development Panel on Impotence. NIH Consensus Conference: impotence. JAMA 1993; 270: 8390.
  • 2
    Shirai M, Takanami M, Tanaka T. A stochastic survey of impotence population in Japan. Impotence 1987; 2: 6793.
  • 3
    Shirai M. Trend of erectile dysfunction patients in Japan. Modern Physician 1999; 19: 10813.
  • 4
    Levine LA. Diagnosis and treatment of erectile dysfunction. Am. J. Med. 2000; 109 (Suppl. 1): 312.
  • 5
    Feldman HA, Johannes CB, Derby CA et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study. Prev. Med. 2000; 30: 32838.
  • 6
    Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999; 281: 53744.
  • 7
    Nagao K. Erectile dysfunction. Jpn Clin. Endocrinol. 2002; 50: 518.
  • 8
    Bischoff E, Niewoehner U, Haning H, Es Sayed M, Schenke T, Schlemmer KH. Vardenafil a potent and selective inhibitor of phosphodiesterase type 5 increase cGMP in rabbit corpus cavernosum. Int. J. Impot. Res. 2001; 13 (Suppl. 1): S25.
  • 9
    Bischoff E, Niewoehner U, Haning H, Es Sayed M, Schenke T, Schlemmer KH. The oral efficacy of vardenafil hydrochloride in a conscious rabbit model. J. Urol. 2001; 165: 131628.
  • 10
    Bischoff E, Schneider K. A conscious-rabbit model to study vardenafil hydrochloride and other agents that influence penile erection. Int. J. Impot. Res. 2001; 13: 2305.
  • 11
    Pryor J. Vardenafil: update on clinical experience. Int. J. Impot. Res. 2002; 14 (Suppl. 1): S65S69.
  • 12
    Porst H, Rosen R, Padma-Nathan H et al. The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction: the first at-home clinical trial. Int. J. Impot. Res. 2001; 13: 1929.
  • 13
    Goldfischer E, Eardley I, Segerson T. Vardenafil improves erectile function in men with significant comorbidities associated with erectile dysfunction (ED) (Abstract). J. Urol. 2002; 167 (Suppl. 4): 178.
  • 14
    Donatucci C, Eardley I, McVary KT, Thibonnier M. Vardenafil improves erectile function regardless of etiology or baseline severity in men with erectile dysfunction (Abstract). J. Urol. 2002; 167 (Suppl. 4): 178.
  • 15
    Goldstein I, Young JM, Fischer J, Bangerter K, Segerson T, Taylor T. Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: a multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care 2003; 26 (3): 77783.
  • 16
    Brock G, Taylor T, Seger M. Efficacy and tolerability of vardenafil in males with erectile dysfunction following radical prostatectomy. Eur. Urol. 2002; 1 (Suppl. 1): 152.
  • 17
    Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49: 82230.
  • 18
    Fugl-Meyer AR, Lodnert G, Branholm IB, Fugl-Meyer KS. On life satisfaction in male erectile dysfunction. Int. J. Impot. Res. 1997; 9: 1418.
  • 19
    Tan HM, Moh CL, Mendoza JB et al. Asian sildenafil efficacy and safety study (ASSESS-1): a double-blind, placebo-controlled, flexible-dose study of oral sildenafil in Malaysian, Singaporean, and Filipino men with erectile dysfunction. Urology 2000; 56: 63540.
  • 20
    Lim PH, Ng FC, Cheng CW et al. Clinical safety profile of sildenafil in Singaporean men with erectile dysfunction: pre-marketing experience (ASSESS-I evaluation). J. Int. Med. Res. 2002; 30: 13743.
  • 21
    Goldstein I, Young J, Segerson T, Thibonnier M. Influence of HbA1c on the efficacy and safety of vardenafil for the treatment of erectile dysfunction in men with diabetes (Abstract). Diabetes 2002; 51 (Suppl. 2): A98.
  • 22
    Goldstein I, Young J, Segerson T, Thibonnier M. Long-term efficacy and safety of diabetic men with erectile dysfunction (Abstract). Diabetes 2002; 51 (Suppl. 2): A98.
  • 23
    Fink HA, MacDonald R, Rutks IR, Nelson DB, Wilt TJ. Sildenafil for male erectile dysfunction: a systematic review and meta-analysis. Arch. Intern. Med. 2002; 162: 134960.

Appendix

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgment
  9. References
  10. Appendix

Appendix I

Sites of investigation
SiteInvestigator
Sapporo Medical University HospitalTaiji Tsukamoto
Yoshikazu Sato
Hokkaido Social Insurance HospitalTakaoki Hirose
Takumi Sasao
Ryoji Furuya
Otaru Hokusei HospitalHiroki Horita
Chiba University HospitalTomohiko Ichikawa
Keio University HospitalMasaru Murai
Ken Marumo
Toho University Omori HospitalNobuhisa Ishii
Kazukiyo Miura
Koichi Nagao
St. Marianna University School of Medicine HospitalTeruaki Iwamoto
Michitaka Yajima
Kitasato University School of Medicine HospitalShin Egawa
Satoru Shimura
Chubu-Rosai HospitalToshikazu Otani
Nagano Red Cross HospitalToshiyasu Amano
University Hospital, Kyoto Prefectural University of MedicineTsuneharu Miki
Jintetsu So
Yoshio Naya
Osaka City University HospitalTaketoshi Kishimoto
Tatsuya Nakatani
Osaka University HospitalAkihiko Okuyama
Kiyomi Matsumiya
Akira Tsujimura
Kinki University HospitalTakashi Kurita
Takahide Sugiyama
Kobe University HospitalSadao Kamidono
Soichi Arakawa
Masato Fujisawa
Yoshinobu Akao
Sansei HospitalSogo Saito
Yasuyuki Okamoto
Koji Sawada
Kurashiki Medical CenterHitoshi Takamoto
Tokushima University HospitalYasushi Kurokawa
Takushi Naroda
Takamatsu Red Cross HospitalYasuo Kawanishi
Yoshihiro Li
Ryoichi Nakanishi
University of Occupational and Environmental Health HospitalTetsuro Matsumoto
Hisato Inatomi
Harasanshin HospitalAkito Yamaguchi
Mineo Takei
Kiyoshi Komatsu
Hiroyuki Nomura
Osaka City Juso HospitalRyoji Yasumoto
Osaka Chuo HospitalMasami Takeyama
Minoru Koga
Nihon Red Cross Hospital Wakayama Medical CenterTadashi Hayashi
Toshio Kanaoka
Tsukuba University HospitalHideyuki Akaza
Hitoshi Takeshima
Sanjukai Urological HospitalHitoshi Tanda
Saka Urological HospitalTaketoshi Saka
Hideki Wada
Iwasawa ClinicAkihiko Iwasawa
Teine Urological ClinicNobukazu Suzuki
Koichi Takeda
Nagakubo ClinicIchiro Nagakubo
Masaki Horiba
Takamitsu Morikawa
Sumiya ClinicHidenori Sumiya
Moriguchi ClinicRyuichiro Moriguchi
Niiza Shiki Central General Hospital Urology/Clinical Pharmacology CentreMichio Takase
Masao Tateno
Akira Mitaniyama