Clinical Trial Study Synopsis This file is posted on the Bayer HealthCare Clinical Trials Registry and Results website and is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labeling information approved for the patient's country or region. Data on this website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer HealthCare AG. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer HealthCare AG. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayerhealthcare.com apply to the contents of this file.
2. Study synopsis Title of the study: A randomized, open-label, multi-center, parallel-group study to investigate the efficacy and safety of vardenafil (, taken one hour prior to sexual activity) in comparison to tadalafil (, taken 24 h prior to sexual activity) in males with erectile dysfunction and a diagnosis of diabetes mellitus and/or hypertension and/or hyperlipidemia Investigators: Multicenter, principal investigator Mariano Sotomayor Zavaleta, MD Instituto Nacional de Ciencias Médicas y de la Nutrition SalvadorZubirán, Servicio de Urologia Vasco de Qurioga no. 15, Col Sección XVI 1400 Mexico D.F., Mexico Study centers: 59 centers: Germany 14, South Africa 9, Italy 6, Spain 6, Colombia 4, the Netherlands 4, Israel 4, Norway 3, Peru 3, Mexico 3, Belgium 3. Publications (references): None Period of study: 03 Dec 2003 02 Jun 2004 Clinical phase: Phase IIIb Objectives: Efficacy, safety, and tolerability of vardenafil (taken approximately 1 h prior to sexual activity) vs tadalafil (taken approximately 24 h prior to sexual activity) in men with ED. Methodology (design of study): Multicenter, randomized, open-label study. Subjects received on vardenafil or tadalafil as needed for a treatment period of 4 weeks after a 4-week run-in period.
Number of subjects: 734 men were screened at 59 centers in 11 countries. 611 subjects were valid for safety analysis (median age 56 years, age range 29-64 years; most frequent concomitant diseases hypertension 67%, diabetes mellitus 50%, and hyperlipidemia 31%; mean duration of erectile dysfunction 4.4 years; organic etiology in 55%, psychogenic in 4%, and mixed in 41%; 43% had used sildenafil in the past). 598 subjects were included in the ITT analysis. The total number of premature terminations was 26. Diagnosis and main criteria for inclusion: Test product, dose and mode of administration, batch number: Duration of treatment: Reference therapy, dose and mode of administration, batch number: Men with erectile dysfunction for >6 months according to the definition of the National Institute of Health (NIH) Consensus Statement with a diagnosis of diabetes mellitus, hypertension, or hyperlipidemia. Vardenafil, tablet, oral administration, single dose as needed. Batch number: BX006ES. 4 weeks, maximum of 4 administrations. Tadalafil, tablet, oral administration, single dose as needed. Batch number: BX01D2W. Criteria of evaluation: Efficacy: The primary efficacy variable was the number of attempts (successful/unsuccessful) in terms of responses to question 3 of the Sexual Encounter Profile (SEP#3): Did your erection last long enough for you to have successful intercourse? observed within 15 min to 4 h and 22 to 26 h after drug intake in the vardenafil and tadalafil treatment groups, respectively. Secondary efficacy variables included Ability to insert penis according to question 2 of the Sexual Encounter Profile (SEP#2) as obtained from the subject diary according to the question ( Were you able to insert your penis into the partner s vagina? ). Tumescense of the penis (as obtained from the subject s diary according to the question Were you able to achieve at least some erection (some enlargement of the penis? ).
Hardness of erection (as obtained from the subject s diary according to the question Were you satisfied with the hardness of your erection? ). Intercourse satisfaction (as obtained from the subject s diary according to the 3 of the Sexual Encounter Profile (SEP#5): Were you satisfied overall with this sexual experience? ). Ejaculation (as obtained from the subject s diary according to the question Did you ejaculate? ). Other responses to questions in the Subject Diary. Number of responders per treatment group defined as those subjects with at least 2 successful sexual attempts (SEP#3) within the observational window. Number of successful attempts (rates) per subject irrespective of the observational window: SEP#2. Number of successful attempts (rates) per subject irrespective of the observational window: SEP#3. IIEF-EF domain score at Visit 3 or at Premature Termination (PT) Visit. Safety: Measures of safety included laboratory evaluation (hematology, blood chemistry), physical examination, body weight, supine and standing blood pressure and heart rate, 12-lead ECG, adverse events at all visits and additionally for serious adverse events 24 h after the last dose of study medication. Statistical methods: Efficacy: The primary efficacy analysis was based on the variable with a valid entry in the Sexual Encounter Profile (SEP#3): Did your erection last long enough for you to have successful intercourse?. The diary entry was defined to be valid for if the sexual attempt was made between 22 to 26 h for the tadalafil group and between 15 min to 4 h in the vardenafil group after dosing of study medication. All randomized subjects were eligible for the efficacy analysis. The primary efficacy analysis was based on a modified ITT population defined as those randomized subjects having taken at least 1 dose of study medication and having had at least 1 post-baseline valid sexual attempt as defined above.
The primary analysis was repeated on the per protocol (PP) population. Secondary efficacy analyses based on the other diary data were performed similar to that of the primary efficacy analysis. Safety: All subjects to whom drug had been dispensed were included in the safety analysis. The safety analysis presents all adverse events (events reported after drug dispense or those reported in the medical history with dates later than or equal to screening examination), treatment-emergent adverse events (TEAEs), drug-related TEAEs, and serious adverse events. All adverse events are presented in terms of MedDRA classification.
Summary and conclusions Summary of efficacy: of vardenafil taken within the time window of 15 min to 4 h prior to intended intercourse was superior to tadalafil (time window 22 to 26 h) in maintaining erections (SEP Question #3; primary variable; ITT population) (Table 2-1). Success rates were 79% vs 69% in subjects receiving vardenafil and tadalafil, respectively, and the difference was statistically significant. Similar results were achieved when analyzing the PP population. However, only 55% of all sexual attempts made by subjects receiving tadalafil occurred during the intended time period between 22 and 26 h compared with 93% of those in the vardenafil group. Table 2-1: SEP Question #3 ( Did your erection last long enough for you to have successful intercourse? ) success rates using GEE analyses; time windows 15 min 4 h (vardenafil) and 22 26 h (tadalafil) Population Vardenafil Tadalafil Treatment Odds ratio 95% CI parameter effect ITT population Number of subjects 306 292 Success rate 78.83% 68.93% P = 0.004 1.68 1.18 2.39 PP population Number of subjects 278 266 Success rate 77.63% 67.76% P = 0.006 1.65 1.15 2.37 When comparing observational time windows of 0 to 12 h (vardenafil) and 0 to 36 h (tadalafil), the treatment difference in favor of vardenafil remained statistically significant for SEP#3 (79% vs 71%) (Table 2-3). Of the secondary efficacy variables, vardenafil was superior to tadalafil concerning diary questions hardness of erection (67% vs 59%), overall satisfaction (74% vs 66%), and ejaculation (89% vs 82%) with treatment differences reaching statistical significance in time-window 15 min to 4 h prior to intended intercourse (vardenafil) vs 2 to 26 h (tadalafil) as well as for 0 to 12 h vs 0 to 36 h (Table 2-3). For these parameters, treatment effects of tadalafil were inferior to vardenafil for the comparison of the main time windows of interest in this study (15 min to 4 h vs 22 to 26 h) as well as for 0 to 12 h and 0 to 36 h. Difference of success rates concerning SEP#1 ( erection ) and SEP#2 ( penetration ) were not statistically significant between treatments neither for the limited nor for the broadened time window.
Table 2-2: Diary questions - success rates using GEE analyses (ITT population); time windows 15 min 4 h (vardenafil) and 22 26 h (tadalafil) Diary question Vardenafil Tadalafil Treatment effect Odds ratio 95% CI SEP#1: "Were you able to achieve at least some erection?" Success rate 91.91% 93.31% P = 0.452 0.81 0.48 1.39 SEP#2: "Were you able to insert your penis into the partner's vagina?" Success rate 92.70% 89.29% P = 0.073 1.52 0.96 2.41 "Were you satisfied with the hardness of your erection?" Success rate 66.82% 58.57% P = 0.039 1.42 1.02 2.00 SEP#5: "Were you satisfied overall with this sexual experience?" Success rate 74.03% 64.54% P = 0.012 1.57 1.10 2.22 "Did you ejaculate?" Success rate 88.46% 81.83% P = 0.010 1.70 1.14 2.55 Table 2-3: Diary questions - success rates using GEE analyses; time windows 0 12 h (vardenafil) and 0 36 h (tadalafil) Diary question Vardenafil Tadalafil Treatment effect Odds ratio 95% CI SEP#3: "Did your erection last long enough for you to have successful intercourse?" (ITT) Success rate 78.72% 71.24% P = 0.015 1.49 1.08 2.06 SEP#3: "Did your erection last long enough for you to have successful intercourse?" (PP) Success rate 77.57% 70.23% P = 0.022 1.47 1.06 2.03 SEP#1: "Were you able to achieve at least some erection?" (ITT) Success rate 91.92% 91.88% P = 0.980 1.01 0.64 1.58 SEP#2: "Were you able to insert your penis into the partner's vagina?" (ITT) Success rate 92.75% 91.42% P = 0.413 1.20 0.78 1.85 "Were you satisfied with the hardness of your erection?" (ITT) Success rate 67.45% 59.68% P = 0.029 1.40 1.03 1.90 SEP#5: "Were you satisfied overall with this sexual experience?" (ITT) Success rate 74.26% 64.97% P = 0.005 1.56 1.14 2.11 "Did you ejaculate?" (ITT) Success rate 88.72% 83.28% P = 0.013 1.58 1.10 2.27
Summary of safety: Vardenafil and tadalafil were generally well tolerated. Treatment-emergent adverse events were slightly more frequent with vardenafil (19.9%) than with tadalafil (15.7%). The incidence rate of drug-related treatment-emergent adverse events was also slightly higher in subjects receiving vardenafil (13.8%) compared with 10.3% in the tadalafil group. 4 subjects in the vardenafil and 2 subjects in the tadalafil group reported serious adverse events. With the exception of 1 case of syncope, none of the serious adverse events was considered drug-related. 3 subjects in each of the 2 treatment groups discontinued study participation because of adverse events. 5 subjects (vardenafil 2, tadalafil 3) reported other clinically significant events, of which all included increases of creatine kinase. The most frequent adverse events were those being typical for the class of PDE5 inhibitors and related to the pharmacodynamic mode of action: headache (5 % in both treatment groups), flushing (vardenafil 3%, tadalafil 1%), and nasal congestion (2 % in both treatment groups). CPK elevations occurred in 10% of subjects and were obviously not associated with cardiac events or rhabdomyolysis. No deaths were reported. Table 2-4: Incidence rates of adverse events (safety population) Adverse event type Vardenafil n = 311 Tadalafil n = 300 Adverse events 80 (25.7%) 65 (21.7%) TEAEs 62 (19.9%) 47 (15.7%) Drug-related TEAEs 43 (13.8%) 31 (10.3%) Adverse events leading to study 3 (1.0%) 3 (1.0%) discontinuation Serious adverse events 4 (1.3%) 2 (0.7%) Serious TEAEs 3 (1.0%) 1 (0.3%) Summary of pharmacokinetics: Not applicable.
Conclusions: Within the respective time windows, vardenafil was superior to tadalafil in maintaining erections, which was the primary efficacy parameter. Success rates were higher by 10% (limited time window) and 7% (broadened time window), respectively, and the differences between treatments were statistically significant in favor of vardenafil. With regard to secondary efficacy variables, vardenafil was superior to tadalafil concerning diary questions hardness of erection, overall satisfaction with sexual experience SEP#5, and ejaculation with treatment differences reaching statistical significance. Differences of success rates between treatments concerning SEP#1 ( erection ) and SEP#2 ( penetration ) were neither clinically relevant nor statistically significant. The differences of success rates between the 2 treatment groups narrowed only slightly when the broadened-time-window analysis was applied. Both drugs were generally well tolerated. Treatment-emergent adverse events occurred more often with vardenafil (19.9%) than with tadalafil (15.7%). The incidence rate of drug-related treatment-emergent adverse events was also slightly higher in subjects receiving vardenafil (13.8%) compared with 10.3% in the tadalafil group. Headache, flushing, and nasal congestion were the most frequent adverse events, which were typical for the class of PDE5 inhibitors and related to their pharmacodynamic mode of action. CPK elevations occurred in 10% of subjects and were not associated with cardiac events or with rhabdomyolysis. 4 subjects in the vardenafil and 2 subjects in the tadalafil group reported serious adverse events. With the exception of 1 case of syncope, none of the serious adverse events was considered drug-related. No deaths were reported. Both vardenafil and tadalafil were clinically efficacious in this population of subjects with ED and additional cardiovascular risk factors. On average, the baseline score of the EF domain indicated a mild-to-moderate degree of ED. Despite clinically relevant improvements in EF domain score with both treatments, the results of this study indicate superiority of vardenafil compared with tadalafil with regard to most diary questions. For these parameters, treatment effects of tadalafil were inferior to vardenafil for the comparison of the main time windows of interest in this study (15 min to 4 h vs 22 to 26 h) as well as for 0 to 12 h vs 0 to 36 h.
Appendix to Clinical Study Synopsis Product Identification Information US Trade Name(s) All Trade names (worldwide) Generic names Levitra Levitra Vardenafil Company code(s) Bay 38-9456 Chemical description Aliases Vardenafil: 1-[[3-(3,4-Dihydro-5-methyl-4-oxo- 7propylimidazo[5,1-f]-as-triazin-2-yl)-4- ethoxyphenyl]sulfony]-4-ethylpiperazine