Introduction. A Benchekroun 1 *, M Faik 1, S Benjelloun 2, S Bennani 2, M El Mrini 2 and A Smires 3

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1 (2003) 15, Suppl 1, S19 S24 & 2003 Nature Publishing Group All rights reserved /03 $ A baseline-controlled, open-label, flexible dose-escalation study to assess the safety and efficacy of sildenafil citrate (Viagra s )in patients with erectile dysfunction A Benchekroun 1 *, M Faik 1, S Benjelloun 2, S Bennani 2, M El Mrini 2 and A Smires 3 1 Department of Urology, Ibn Sina University Hospital, Rabat, Morocco; 2 Department of Urology, Ibn Rochd University Hospital, Casablanca, Morocco; and 3 Urology & Andrology Center, Abou Abdellah Nafii, Casablanca, Morocco Although sildenafil citrate (Viagra s ) has demonstrated effectiveness in the treatment of erectile dysfunction (ED), the dosing regimens often used in clinical trials may not always match those employed in clinical practice. This study was undertaken to further assess the efficacy and safety of sildenafil taken as required in male outpatients 18 years of age and older with ED (n ¼ 71). It was conducted as a placebo-baseline controlled, open-label, flexible dose-escalation study, with sildenafil (25,50, or 100 mg) administered for 8 weeks following a 4-week placebo run-in. Efficacy variables included questions 3 and 4 of the International Index of Erectile Function (IIEF), other IIEF domains, patient event logs, and quality-of-life (QOL) assessments. Treatment with sildenafil resulted in improvements from baseline in all IIEF domains analyzed (all Po0.0001), as well as overall QOL and amelioration of specific sexual and social relationships (all Po0.0001). Sildenafil was well tolerated. One participant discontinued treatment because of adverse events. Results suggest that flexible dosing with oral sildenafil is safe and has beneficial effects on all indices of erectile function and QOL. (2003) 15, Suppl 1, S19 S24. doi: /sj.ijir Keywords: erectile function; International Index of Erectile Function; quality of life; sildenafil Introduction Erectile dysfunction (ED) is a very common disorder reported to affect as many as 152 million men worldwide. 1 3 Results of one recent global projection suggest that as many as 322 million men will experience ED by Risk for ED increases progressively with age. The results of the Massachusetts Male Aging Study showed that prevalence rates for all degrees of ED were 40% at age 40, 48% at 50 years, 57% at age 60, and 67% in men 70 years of age. 1 As noted in epidemiologic studies, ED is commonly associated with other conditions that are prevalent in ageing men, namely, depressive symptomatology, hypertension, ischemic heart disease, peripheral vascular disease, hyperlipidemia, and diabetes mellitus. 4,5 The link between cardiovascular disease and ED is strongly supported by recent study results, which showed a significant correlation between ED severity and the number of obstructed coronary vessels. 6 ED has also been shown to be predictive of undiagnosed ischemic *Correspondence: Dr A Benchekroun, Department of Urology, Ibn Sina University Hospital, Rabat, Morocco. heart disease. 7 Moreover, increased risk for ED has been associated with treatment for prostate cancer and the presence of benign prostatic hyperplasia Whereas ED may be considered a benign disease, it has significant effects on quality of life (QOL) for both patients and their partners. 2 It is well established that ED may be associated with depression, loss of self-esteem, poor self-image, and increased anxiety and stress in interactions with one s sexual partner; 2 indeed, marital discord and even violence 11 have been noted. Although the greatest impairment in QOL for men with ED is in the emotional domains, physical domains are also significantly affected. 12 Thus, sexual health plays a critical role in the overall QOL. One recent poll indicated that 94% of respondents thought that sexual enjoyment added to QOL at any age, and 90% indicated that sexual problems caused depression, emotional distress, and significant marital difficulties. 13 ED is now recognized as the second most common sexual problem among men (after premature ejaculation); nonetheless, it is still underdiagnosed and undertreated. 14 Underdiagnosis of ED results primarily from poor communication because of fear, concern about the lack of adequate treatments, embarrassment, or a multitude of reasons between physician and patient. Many patients do not believe

2 S20 that ED is considered a medical problem, and a large majority also think that discussing such problems would be embarrassing or awkward. 13,14 Physicians are also reluctant to initiate conversations with their patients regarding sexual function. 14 Improved communication between physician and patient is important, and beneficial to both parties, but will need more education and media efforts. Sildenafil citrate (Viagra s ) has been used effectively to treat ED in a wide range of patients, including the elderly, those who have undergone treatment for prostate cancer, and patients with cardiovascular disease, spinal cord damage, or Parkinson s disease The dosing regimens used in clinical trials (eg, fixed-dose or forced-dose escalation) may not always match those in clinical practice, however. Moreover, clinical efficacy trials do not always evaluate the effects of therapy on QOL. The current flexible-dose study was undertaken to assess the efficacy and safety of sildenafil taken as required prior to anticipated sexual activity in male outpatients with ED. Effects of therapy on QOL were also assessed. Patients and methods Study design This was a placebo-baseline controlled, multicenter, single-group, open-label, flexible dose-escalation study in which sildenafil (25, 50, or 100 mg) was administered during an 8-week period. The study included a 4-week placebo treatment run-in and an 8- week flexible dose-escalation treatment phase. Conducted in compliance with the ethical principles from the revised Declaration of Helsinki (Revised South Africa, 1996) and local laws and regulations relevant to the conduct of clinical research in Morocco, this study had its protocol and all amendments evaluated and approved by an Independent Ethics Committee (IEC) as required by Moroccan authorities. Written informed consent was obtained from each subject participant prior to study entry. The study enrolled male subjects 18 years of age with a clinical diagnosis of ED (defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance) for longer than 6 months who were in a stable relationship for at least the prior 6 months. Excluded were individuals with genital anatomical deformities that would significantly impair erection (eg, severe penile fibrosis); other sexual disorders (eg, hypoactive sexual desire) considered the primary diagnosis along with a coexisting diagnosis of ED; major psychiatric disorders (including major depression or schizophrenia) not well controlled with treatment; history of alcoholism or substance abuse; or those with major hematologic, renal, or hepatic abnormalities. Also excluded were patients with ED following spinal cord injury; those with poorly controlled diabetes mellitus; history of stroke or myocardial infarction within the previous 6 months; significant cardiovascular disease including cardiac failure, unstable angina, or life-threatening arrhythmia within the previous 6 months; hypotension; or a history of malignant hypertension, and/or a resting systolic blood pressure 4180 mmhg, and/or a resting diastolic blood pressure 4110 mmhg. Subjects who had been prescribed (for the first time) any medication known to be causally associated with ED (eg, beta blockers, thiazide diuretics, digoxin, tricyclic antidepressants, finasteride) within 2 weeks prior to screening, or who were likely to require changes in such therapy during the study, were also excluded, as were those currently prescribed and/or taking nitrates or nitric oxide donors in any form. Individuals with any medical or psychological condition or social circumstance that would impair their ability to participate reliably in the study, and those with a history of retinitis pigmentosa or proliferative retinopathy, were excluded. Participants were required to discontinue use of any other treatments for ED throughout the study. This was an open-label dose titration study, in which titration was based on efficacy and tolerability. Individuals entering the active treatment phase were given sildenafil 50 mg as required during the first 2 weeks. Thereafter, the dose could be increased or decreased according to efficacy and tolerability. Subjects were instructed to take a dose when required for anticipated sexual activity. Subjects could be withdrawn if unacceptable side effects occurred and if they had derived no benefit from a lower dose. Efficacy assessments Participants completed the validated International Index of Erectile Function (IIEF) questionnaire, which recorded various domains of sexual function at baseline and at week 8, or if they were discontinued prior to week 8. An event log was completed for each attempt at sexual activity. The following questions were asked: (1) Was the study medication taken? (2) Did you have any sexual stimulation? and (3) Did you have successful sexual intercourse? If not, was it because the erection was not hard enough or did not last long enough, or was it due to other reasons? A global efficacy assessment was asked at the end of treatment or at the time of discontinuation: Has the treatment you have been taking over the past 4 weeks improved your erections? A Life Satisfaction Checklist was also completed at baseline and at the end of treatment.

3 Safety Results S21 Safety assessments included recording of adverse events, clinical laboratory tests (hematology, blood chemistry, urinalysis), physical examinations, and recording of vital signs (sitting blood pressure and heart rate). An electrocardiogram (ECG) was also carried out at screening. Data analysis All efficacy variables were analyzed using the intent-to-treat (ITT) population. These measures were assessed at baseline and at the end of therapy or at the time of discontinuation for individuals who discontinued treatment before week 8. The lastobservation-carried-forward (LOCF) algorithm was used to fill any missing values. Analyses were performed using SAS s version 6.12 (SAS Institute, Cary, NC, USA). All hypothesis tests were two-sided and conducted at the 5% level of significance. The two primary efficacy variables were question 3 of the IIEFFability to penetrate partner during sexual intercoursefand question 4 of the IIEFFability to maintain erection after the penetration. Changes from baseline for questions 3 and 4 of the IIEF were analyzed separately using single sample t-tests. The intragroup P-value was computed from the t-test for the null hypothesis (mean change from baseline ¼ 0). Secondary efficacy variables The secondary efficacy variables consisted of IIEF questions (excluding questions 3 and 4), IIEF domains, event logs, Life Satisfaction Checklist, and the global efficacy assessment. The response variable based on the event logs was the proportion of successful attempts at sexual intercourse during the analysis periods. The proportion of successful sexual intercourse attempts (the intercourse success rate) was summarized using mean data. Event-log data were not subjected to formal statistical hypothesis testing. The change from baseline to end point was analyzed for each item of the Life Satisfaction Checklist using single sample t-tests. The intragroup P-value was computed from the t-test for the null hypothesis (mean change from baseline ¼ 0). The proportion of participants reporting an improvement in the quality of their erections based on the global efficacy assessment was summarized with 95% confidence intervals (CI). Responses to the global efficacy assessment were not subjected to formal statistical hypothesis testing. Safety analyses were performed on all participants who received at least one dose of sildenafil. In all, 71 subjects were screened and assigned to treatment at nine centers across Morocco; all 71 received treatment with sildenafil. Of these, 61 (85.9%) completed the study and 10 (14.1%) discontinued treatment. One participant discontinued because of an adverse event, one because of lack of efficacy; seven were lost to follow-up, and one individual violated the study protocol. Demographic and clinical characteristics of study participants are summarized in Table 1. Sildenafil dosing The median duration of treatment for sildenafil was 56.0 days and the median number of doses taken was Overall, 68 men started sildenafil treatment at the 50-mg dose, two began treatment at 25 mg, and one started at 100 mg. At treatment end, 44 (62%) remained on the 50-mg dose, 22 (31%) were taking 100 mg, and five (7%) were taking 25 mg. Efficacy Sildenafil significantly improved erectile function as indicated by answers to questions 3 and 4 of the IIEF (Figure 1). At baseline, the mean score for question 3 was 1.38 compared to 4.11 at the end of treatment (Po0.0001). Respective values for question 4 (frequency of maintained erection) were 1.28 and 4.08 (Po0.0001). Sildenafil treatment resulted in significant improvements from baseline in all IIEF domains (Table 2), including erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction (all Po0.0001). The mean proportion of successful attempts at sexual intercourse, as evidenced by the event log, Table 1 subjects Characteristic Demographic and clinical characteristics for treated Mean (range) Age 46.3 y (27 67) Weight 77.2 kg (57 102) Duration of ED 2.6 y ( ) Comorbid conditions n (%) Diabetes mellitus 3 (4.2%) Chronic obstructive pulmonary disease 2 (2.8%) Radical prostatectomy 2 (2.8%) Transurethral prostatectomy 1 (1.4%) Prostate cancer 1 (1.4%) Bladder cancer 1 (1.4%)

4 S22 Table 3 Adverse events n(%) Adverse event All causalities Treatment-related Headache 5 (7.0) 5 (7.0) Flushing 3 (4.2) 3 (4.2) Palpitations 1 (1.4) 1 (1.4) Abdominal pain 1 (1.4) 1 (1.4) Abnormal vision 1 (1.4) 1 (1.4) Back pain 1 (1.4) 0 Pain 1 (1.4) 0 Safety Figure 1 Baseline and end-of-treatment scores for IIEF questions 3 and 4. *Po vs baseline computed from the t-test for the null hypothesis (mean change from baseline=0). Table 2 IIEF domain Effects of sildenafil therapy on IIEF domains Baseline Last observation P-value* Erectile function n Mean o s.d Orgasmic function n Mean o s.d Sexual desire n Mean o s.d Intercourse satisfaction n Mean o s.d Overall satisfaction n Mean o s.d s.d.=standard deviation. *Intragroup P-value was computed from the t-test for the null hypothesis (mean change from baseline=0). was markedly improved with sildenafil treatment (83.9%, compared to baseline, 18.3%). There were significant improvements between mean scores from baseline to the last observation for QOL as a whole, quality of sexual life, quality of partner relationship, quality of family life, quality of contacts with friends and acquaintances, quality of leisure situation, and vocational situation (all Po0.0001). The mean proportion of participants reporting an improvement in the quality of erections based on the global assessment question was 93.6% after treatment with sildenafil (95% CI %). Sildenafil was well tolerated. One individual discontinued treatment because of adverse events (headache, palpitations, and transient blurred vision) considered by the investigator to be related to study medication. An additional five men (7.0%) had their sildenafil doses reduced because of adverse events. Events leading to dose reductions included back and leg pain (1 participant); headache and flushing (2); abdominal pain, headache, and flushing (1); and headache (1). All these events occurred with sildenafil 50 mg, and all but the back and leg pains were considered related to study medication. Of the 71 safety-evaluable participants, six (8.5%) experienced treatment-emergent adverse events (Table 3), of which five (7.0%) were considered related to sildenafil therapy. The most common adverse events were headache and flushing. All but one of these events were rated mild or moderate in severity. There were no clinically significant changes in either laboratory data or vital signs. Discussion Results indicate that sildenafil is safe and effective for the treatment of patients with ED when administered according to a flexible dosing schedule similar to one that may be used in clinical practice. Analysis of both primary and secondary efficacy variables indicated significant improvements versus baseline with sildenafil therapy. Frequency of penetration and frequency of maintained erection (the two primary efficacy variables), as well as erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction (secondary efficacy variable domains), all improved with sildenafil use. The QOL questionnaire also indicated significant improvements from baseline to end point in many aspects of each patient s life after

5 treatment with sildenafil. The safety results support the tolerability of flexible dosing with sildenafil. Only one subject discontinued therapy because of an adverse event, and only five required dose reductions. The incidence of all treatment-emergent adverse events was low. The most frequently reported adverse events were headache and flushing, most of which were assessed as mild or moderate in intensity. Results of the present trial are consistent with those of several studies that have shown that sildenafil is effective in patients with ED and a wide range of comorbid conditions, including hypertension, diabetes, spinal cord injury, Parkinson s disease, and history of prostatectomy or radiotherapy as treatment for prostate cancer Based on the study s flexible dose-escalation design, the present results suggest that most men are effectively treated with sildenafil 50 mg, with a number benefiting from a higher dose. This result is consistent with clinical trial data indicating that many patients are titrated to 100 mg. For example, Meuleman et al 22 assessed the effectiveness of sildenafil in 315 patients who received a starting dose of 25 mg of active drug or matching placebo. Dosing could be increased to 50 mg and then to 100 mg of sildenafil, based on efficacy and tolerability. After 12 weeks of treatment, 26%, 32%, and 42% of patients were taking 25, 50, and 100 mg of sildenafil, respectively. A similar distribution of doses was reported after 26 weeks of treatment. As in the present study, sildenafil significantly improved IIEF domain scores and patients ability to achieve and maintain erections. Goldstein et al 23 also reported that many patients increased their sildenafil dose in a 12-week dose-escalation study that included 329 men with ED. At the end of 12 weeks of treatment, 23% of men were taking 50 mg and 74% were on 100 mg. Similar results have been reported in other flexible dosing studies of sildenafil. 15,24 As in the present study, all sildenafil doses were effective and well tolerated in these trials. Thus, the results of this trial and those of previous flexible-dose studies indicate that, barring significant side effects, patients may be titrated to 100 mg if initial treatment with sildenafil 50 mg is ineffective. Normal sexual functioning is an important determinant of QOL for patients and partners, 2,12 and the present results are consistent with previous findings indicating significant beneficial effects of sildenafil on QOL. Hussain et al 21 evaluated the effects of sildenafil therapy on QOL in 24 patients with either Parkinson s disease or multiple-system atrophy and reported significant positive effects of therapy on the quality of patients sexual lives. Hultling et al 25 also reported that sildenafil therapy had significant positive effects on QOL in 178 men with ED secondary to spinal cord injury. The investigators noted significant improvements in mental health, well-being, depression, and anxiety in these pa- tients. Briceno Mayz et al 26 reviewed the clinical histories of 144 consecutive patients with ED who received sildenafil 50 mg and assessed response to treatment based on patient evaluations of QOL before and after therapy. Of the 144 patients evaluated, 67% experienced positive effects of treatment on QOL. In the present report, safety results indicated that sildenafil was very well tolerated. This is consistent with prior findings that only 2% of patients who received sildenafil in open trials withdrew because of adverse events, and that the most common side effects are mild-to-moderate headache and flushing. 27 No significant cardiovascular events were noted for patients who received sildenafil in the present study. This result is also consistent with previously demonstrated cardiovascular safety of sildenafil when dosed according to prescribing information and current treatment guidelines. Olsson and Persson 20 specifically assessed the efficacy and safety of sildenafil for the treatment of ED in men with cardiovascular disease concurrently receiving antihypertensive medications excluding nitrates. Their results indicated that sildenafil therapy was associated with significant increases in mean end-of-treatment scores for IIEF questions 3 and 4. These investigators also noted that there were no treatment-related cardiovascular adverse events in any of their patients. In conclusion, the results of this placebo-baseline controlled, flexible dose-escalation study indicate that oral sildenafil is an effective and well-tolerated treatment for ED. Sildenafil has beneficial effects on all indices of erectile function and QOL. 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