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Synopsis Document Number: HM2004/00378/00 Study Number: VAR100447 NAME OF COMPANY: The data for this study are being reported in an abbreviated clinical study report because the study is not planned to be used in a regulatory submission. Investigators: This was a multicentre study. Study centres: 38 centres in 10 countries. Publications: None at the time of this report. Study period: 19 April 2004-19 July 2004 Clinical phase: IIIB Objective: To determine if 10mg vardenafil therapy demonstrates superior efficacy when compared to 10mg tadalafil in erectile dysfunction (ED) subjects of mild/moderate to severe aetiology when sexual intercourse (penetration) is attempted at any time in the first 45 minutes following dosing. Methodology: This was a randomised, double-blind, double-dummy, parallel-group, active-controlled study evaluating the efficacy of 10mg vardenafil versus 10mg tadalafil in the first 45 minutes post-dosing, in an as-required regimen for 4 weeks in subjects with mild/moderate to severe ED. The study comprised a 4-week, treatment-free, run-in period followed by a 4-week double-blind treatment phase (10mg vardenafil or 10mg tadalafil). Subjects were given a diary in which to record study medication use, the date and time sexual activity was attempted, the time from start of sexual activity until his erection was sufficient for penetration, and answered questions about erections and attempts at sexual activity. 2
Number of subjects: It was planned that approximately 940 subjects would be screened and entered into the run-in period to ensure that 752 subjects (376 per arm) were randomised, to obtain 676 completers. A total of 946 subjects were screened, of whom 759 subjects were randomised (381 to the vardenafil group and 378 to the tadalafil group). A total of 364 subjects (96%) in the vardenafil group and 359 subjects (95%) in the tadalafil group completed the study. The main reason for withdrawal was that the subject was lost to follow-up (eight subjects [2%] in each group). Diagnosis and criteria for inclusion: Heterosexual males, between 18 and 64 years old with ED for more than 6 months. Subjects must have made at least four attempts at sexual intercourse on four separate days during the 4-week untreated run-in period, of which at least 50% must have been unsuccessful. At the end of the run-in period subjects were to have a score of 5 and 21 on the International Index of Erectile Function (IIEF)-EF domain. Subjects were excluded from the study if they had penile anatomical abnormalities, primary hypoactive sexual desire, retinitis pigmentosa, spinal cord injury or a history of surgical prostatectomy (excluding transurethral resection of the prostate). Test product, dose and mode of administration, batch numbers: Subjects randomised to the vardenafil group took vardenafil 10mg on an as-required basis, and were to attempt sexual intercourse (penetration) in the first 45 minutes post-dosing. The tablet dose was administered orally. Subjects were not to take more than one dose every 3 days, and a maximum of eight doses during the 4-week treatment phase. As this was a double-dummy study, subjects also took matching placebo tablets for tadalafil. batch number: BX006ES; tadalafil placebo batch number: BX01FWC. Duration of treatment: 4 weeks. 3
Reference therapy, dose and mode of administration, batch numbers: Subjects randomised to the tadalafil group took tadalafil 10mg on an as-required basis, and were to attempt sexual intercourse (penetration) in the first 45 minutes post-dosing. The tablet dose was administered orally. Subjects were not to take more than one dose every 3 days, and a maximum of eight doses during the 4-week treatment phase. As this was a double-dummy study, subjects also took matching placebo tablets for vardenafil. Tadalafil batch number: A031784; vardenafil placebo batch number: 530214E. Criteria for evaluation: The primary endpoint was the success of maintenance, based on subject s diary response from 0-4 weeks, or to premature discontinuation, to the Sexual Encounter Profile Question 3 (SEP-3) [Did your erection last long enough for you to have successful intercourse? (Y/N)], assessed after each dose (based only on attempts 0-45 minutes after dosing). Statistical methods: The study was designed to detect a clinically meaningful treatment difference on success of SEP-3 of 10% (standard deviation [SD]=40%) in the mean proportion of successes at 4 weeks with 90% power and an alpha level of 0.05. Mean per-subject success rates for each treatment were compared using analysis of covariance (ANCOVA) adjusting for baseline values and centre. Secondary efficacy variables were analysed using ANCOVA or by logistic regression. The primary population for the efficacy analysis was the intent-to-treat (ITT) population (at least one dose of vardenafil or tadalafil and any post-randomisation safety data and baseline and post-baseline efficacy data). The primary population for the assessment of safety was the safety population (at least one dose of vardenafil or tadalafil and any post-randomisation safety data). Summary: Demography The demographic and baseline disease characteristics of the subjects were similar between the treatment groups. Overall, the mean age of the subjects was 53 years and the mean weight was 82kg. Most subjects were Caucasian (80%) or Asian (18%). Most subjects had a baseline ED severity category of moderate (vardenafil: 41%, tadalafil: 45%) or mild-moderate (vardenafil: 34%, tadalafil: 30%). The mean EF domain score was similar between the vardenafil group (14.1) and the tadalafil group (13.8). Over half of the subjects in both treatment groups had ED of mixed 4
Demography (continued) aetiology (vardenafil: 53%, tadalafil: 51%). Overall, the mean time since diagnosis of ED was 3.4 years and the mean time since it was first noticed by the subject was 5.7 years. At baseline (i.e., based on attempts during the treatment-free run-in period), the success of insertion (SEP-2) was 50% in the vardenafil group and 45% in the tadalafil group, and the success of maintenance to completion of intercourse (SEP-3) was 16% for both treatment groups. Efficacy For the primary endpoint (success of maintenance [SEP-3] in the early window of opportunity [0-45 minutes after dosing]) over weeks 0-4, the licensed start dose of vardenafil showed a statistically significant (p<0.001) superiority to that of tadalafil, demonstrating that on average, subjects have successful completion of intercourse (SEP-3) with 29.71% of vardenafil 10mg doses versus 20.45% with tadalafil 10mg (all valid doses). Although this did not reach the pre-defined 10% difference, this represents a real clinical advantage for vardenafil in some patients. Therefore, the licensed start dose of vardenafil (10mg) demonstrated a 45% greater intercourse completion rate (SEP-3) relative to that of tadalafil (10mg) in the early window of opportunity. The clinically and statistically significant superiority of vardenafil versus tadalafil for SEP-3 success rate in the early window of opportunity was further confirmed when considering only doses with a valid attempt in the early window of opportunity, demonstrating that on average, subjects have successful completion of intercourse (SEP-3) with 63.64% of vardenafil doses versus 50.77% of tadalafil doses (post-hoc subset analysis). Subjects also responded more favourably to vardenafil than tadalafil in terms of SEP-3 success rate regardless of race, age, BMI, diabetic status, duration of ED, baseline EF domain score or ED aetiology. The secondary SEP-3 endpoints success of maintenance by dose (based on attempts 0-60 minutes after dosing) and by attempt (overall) both showed a clinically and statistically (p<0.001) superiority of vardenafil compared to tadalafil over 4 weeks of treatment. There was a statistically significant (p=0.003) superiority of vardenafil in the reliability of maintenance based on dose (0-45 minute window). This statistically significant difference in reliability rates was also seen for attempts (overall) for the vardenafil group compared to the tadalafil group over 4 weeks of treatment. 5
Efficacy (continued) For the secondary SEP-2 endpoints, there was a statistically significant treatment difference in favour of vardenafil for success of insertion by dose (based on attempts 0-45 minutes after dosing, p<0.001) and by attempt (overall, p=0.003). When considering only doses with a valid attempt in the early window of opportunity, on average subjects had successful vaginal penetration (SEP-2) with 73.63% of vardenafil doses versus 62.07% of tadalafil doses (post-hoc subset analysis). This treatment difference was clinically and statistically significant (p<0.001). The reliability of insertion was statistically significantly superior for vardenafil compared to tadalafil over 4 weeks of treatment when analysed by dose (based on attempts 0-45 minutes after dosing, p=0.023) and attempt (overall, p=0.029). The core and exploratory secondary SEP-2 and SEP-3 endpoints therefore support the findings from the primary endpoint. The treatment groups had similar LS mean IIEF EF domain scores at baseline. There was a statistically significant (p=0.002) difference between vardenafil and tadalafil at Week 4. Subjects in the vardenafil group had a LS mean EF domain score of 23 (i.e., mild severity) and subjects in the tadalafil group had a LS mean EF domain score of 21 (i.e., mild-moderate severity). In addition, a larger proportion of subjects in the vardenafil group (46%) had an EF domain score returning to the normal range compared to the tadalafil group (38%) at Week 4 (p=0.024). At Week 4, the proportion of subjects responding positively to the Global Assessment Question (GAQ) was slightly but not statistically significantly greater for the vardenafil group (77%) compared to the tadalafil group (71%). Mean baseline scores for the Global Confidence Question (GCQ), the Erection Quality Scale (EQS) and each of the Treatment Satisfaction Scale (TSS) subscales were similar for the two treatment groups. There were small differences between the treatment groups in favour of vardenafil for the mean scores for the GCQ, the EQS, and each of the TSS subscales at Week 4. These differences reached statistical significance (p<0.05) for the GCQ, the EQS, and four of the six TSS subscales. 6
Safety Overall, vardenafil and tadalafil were well-tolerated with the majority of reported adverse events (AEs) being mild and transient in nature. There were no deaths during the course of the study and two serious adverse events (both reported by subjects in the tadalafil group). These were fractured radius and malignant lung neoplasm, which were not considered by the investigator to be related to the study medication. More subjects in the vardenafil group (76, 20.6%) than in the tadalafil group (63, 17.2%) reported at least one treatment-emergent AE. The most frequently reported AEs ( 2% in either group) were headache, flushing and nasal congestion, which were reported more frequently in the vardenafil group (vardenafil: 8%, 8%, and 4%, respectively; tadalafil: 4%, 3% and 1%, respectively). More subjects in the vardenafil group (64, 17.3%) than in the tadalafil group (42, 11.5%) experienced an AE considered by the investigator to be related to the study medication. One subject (0.3%) in the vardenafil group and three subjects (0.8%) in the tadalafil group had an AE that resulted in a discontinuation from the study. Only one subject (0.3%) in the vardenafil group and two subjects (0.5%) in the tadalafil group reported treatment-emergent back pain, and three subjects (0.8%) in the tadalafil group reported myalgia. No clinically significant trends in laboratory abnormalities, vital signs or electrocardiograms were observed during the study. Conclusions The results of this first well-controlled study comparing vardenafil and tadalafil support the conclusion that the licensed start dose of vardenafil is clinically and statistically superior to that of tadalafil in the early window of opportunity: The licensed start dose of 10mg vardenafil demonstrated a 45% greater intercourse completion rate (SEP-3) relative to that of 10mg tadalafil in the early window of opportunity (0-45 minutes after dosing) (mean per-subject SEP-3 success rate 29.71% versus 20.45%; p<0.001). Although this did not reach the pre-defined 10% difference, this represents a real clinical advantage for vardenafil in some patients. The clinically and statistically significant (p<0.001) superiority of vardenafil versus tadalafil for success of maintenance (SEP-3) in the early window of opportunity was further confirmed when considering only doses with a valid attempt in the early window of opportunity, demonstrating that on average, subjects have successful completion of intercourse (SEP-3) with 63.64% of vardenafil doses versus 50.77% of tadalafil doses. 7
Conclusions (continued) Subjects responded more favourably to vardenafil than tadalafil for all of the subgroups summarised for the primary endpoint. The primary endpoint was generally supported by the core and exploratory secondary endpoints. and tadalafil were well-tolerated. The majority of AEs were mild, transient in nature and consistent with those anticipated for phosphodiesterase type 5 (PDE5) inhibitors. In both treatment groups the frequencies of the most common AEs (headache, flushing and nasal congestion) were lower than those described in the EU Summary of Product Characteristics (SPC) and the US package insert (PI) for vardenafil and tadalafil. AE rates were numerically higher for vardenafil; this comparison should be interpreted with caution due to the relatively low number of events. Date of Report: 01 December 2004 8
Appendix to Clinical Study Synopsis Product Identification Information US Trade Name(s) All Trade names (worldwide) Generic names Levitra Levitra Company code(s) Bay 38-9456 Chemical description Aliases : 1-[[3-(3,4-Dihydro-5-methyl-4-oxo- 7propylimidazo[5,1-f]-as-triazin-2-yl)-4- ethoxyphenyl]sulfony]-4-ethylpiperazine