Clinical Trial Study Synopsis

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1 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 2. Study synopsis Title of the study: Randomized, double-blind, multi-center, parallel-group study to investigate the efficacy and safety of 3 doses of BAY (5 mg, 10 mg and 20 mg) versus placebo in the treatment of subjects with erectile dysfunction (Study 10690). Investigator(s): Principal/Coordinating Investigator (for details see Section ): Prof Guo Ying-Lu, Peking University Institute of Clinical Pharmacology, Beijing, China. Study center(s): This study was conducted at 7 centers in China. Publications (references): None Period of study: 23 Dec 2002 to 20 Sep 2003 (first subject s first visit to last subject s last visit) Clinical phase: Phase III Objectives: The primary objective of the study was to compare the efficacy and safety of 3 doses of vardenafil, 5 mg, 10 mg and 20 mg, with placebo in Asian men with erectile dysfunction (ED). Subjects were to be treated for a maximum period of 12 weeks. Methodology (design of study): This was a randomized, double-blind, multi-center, parallelgroup study. The overall design comprised a Pretreatment period (unmedicated 4-week baseline period), a Treatment period (consisting of 12 weeks of treatment) and a Posttreatment period (24 hours post-dosing). Number of subjects: A total of 624 subjects were screened, enrolled and randomized at the 7 study centers in China. Twenty-two subjects, although randomized at Visit 2 (Week 0), were lost to follow-up. The overall mean age was 51 years for the 4 treatment groups. A total of 540 (86.5%) subjects completed the study. Diagnosis and main criteria for inclusion: Subjects who met all of the following criteria, were included in the study: Men with ED for more than 6 months. ED is defined according to the National Institute of Health consensus statement, as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance.

3 The subject had to make at least 4 attempts at sexual intercourse, on 4 separate days during the unmedicated 4-week baseline period. This was determined by the subject diary question: Was sexual intercourse attempted? At least 50% of attempts during the unmedicated 4-week baseline period had to be unsuccessful. This was determined by the following 3 subject diary questions of which at least 1 question had to be answered No : a. Were you able to achieve at least some erection (some enlargement of the penis)? b. Were you able to insert your penis into your partner s vagina? c. Did your erection last long enough for you to have successful intercourse? Stable heterosexual relationship for more than 6 months Aged 22 years or older Documented written, informed consent Test product, dose, and mode of administration, batch number: BAY (vardenafil), 5 mg, 10 mg and 20 mg tablets. Subjects were randomized to receive either vardenafil 5 mg, 10 mg, 20 mg or placebo. Subjects were instructed to take a maximum of 1 dose of study medication, within a 24-hour period, with a glass of water about 1 hour prior to intended sexual intercourse. Bulk batch numbers (vardenafil): 5 mg tablet: S, BX0050D 10 mg tablet: T 20 mg tablet: L Duration of treatment: Reference therapy, dose, and mode of administration, batch number: All subjects received study medication for a maximum 12-week period. Placebo matching BAY (vardenafil), 5 mg, 10 mg, and 20 mg tablets. Bulk batch numbers (placebo): 5 mg tablet: K 10 mg tablet: L, E 20 mg tablet: K, D

4 Criteria of evaluation: Efficacy: Primary efficacy parameters Assessment of the erectile function (EF) domain score of the International Index of Erectile Function (IIEF) questionnaire, calculated as the sum of scores from Questions 1 to 5 and 15 at Visit 5 (Week 12) using the last observation carried forward (LOCF) method The success rate of penetration (Question 5: Were you able to insert your penis into your partner s vagina? ), as recorded in the subject s diary, was assessed overall from randomization (Visit 2 [Week 0]) to Visit 5 (Week 12). All subjects who had completed the study as well as subjects who had prematurely discontinued their participation were included in the determination of the success rate. The success rate in maintaining an erection during intercourse (Question 7: Did your erection last long enough for you to have successful intercourse? ), as recorded in the subject s diary, was assessed overall from randomization (Visit 2 [Week 0]) to Visit 5 (Week 12) Secondary efficacy parameters The Global Assessment Question (GAQ) was assessed at Visit 5 (Week 12), as observed and using the LOCF method The EF domain score of the IIEF questionnaire was assessed at Visit 3 (Week 4), Visit 4 (Week 8) and Visit 5 (Week 12), as observed at each visit The success rate of penetration and maintenance of erection (Question 5: Were you able to insert your penis into your partner s vagina? and Question 7: Did your erection last long enough for you to have successful intercourse? ) as recorded in the subject s diary was assessed, as observed and using the LOCF method, for the following visit periods: a. Randomization (Visit 2 [Week 0]) to Visit 3 (Week 4) b. Visit 3 (Week 4) to Visit 4 (Week 8) c. Visit 4 (Week 8) to Visit 5 (Week 12) The orgasmic function (OF), sexual desire, intercourse satisfaction (IS) and overall satisfaction (OS) domain scores of the IIEF questionnaire were assessed at Visit 3 (Week 4),

5 Visit 4 (Week 8) and Visit 5 (Week 12), as observed at each visit and using the LOCF method The scores for Questions 3, 4 and 15 of the IIEF questionnaire were assessed at Visit 3 (Week 4), Visit 4 (Week 8), and Visit 5 (Week 12), as observed at each visit and using the LOCF method Subject s diary responses, regarding partial erection, hardness of erection, overall satisfaction with the sexual experience and ejaculation (Question 4 Were you able to achieve at least some erection (some enlargement of the penis)? Question 8 Were you satisfied with the hardness of your erection? ; Question 9 Were you overall satisfied with this sexual experience?, and Question 10 Did you ejaculate? ) were assessed at randomization (Visit 2 [Week 0]), Visit 3 (Week 4), Visit 4 (Week 8), and at Visit 5 (Week 12), as observed at each visit and using the LOCF method. The diary responses were also assessed overall from randomization (Visit 2 [Week 0]) to Visit 5 (Week 12). Scores for the IIEF questions (Questions 1, 2 and 5 to 14) were assessed at Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 12), as observed at each visit and using the LOCF method and were summarized for exploratory reasons only Safety: Safety variables included the following: all laboratory evaluations (hematology, clinical chemistry, urinalysis), physical examination, vital signs (blood pressure [systolic and diastolic], heart rate, body height, body weight, body mass index, adverse events and 12-lead electrocardiogram. Statistical methods: The efficacy of vardenafil in the treatment of ED was only to be considered proven if all 3 primary efficacy measurements are significantly greater for vardenafil, 5 mg, 10 mg and 20 mg as compared to placebo. The primary comparisons were performed between each of the 3 active vardenafil treatment groups and the placebo treatment group and an alpha adjustment according to Bonferroni was performed. All pairwise comparisons were done with a significance level of 1.66% to warrant an overall alpha level of 5%. The primary analysis of each of these efficacy variables was based on the intention to treat (ITT) population, using the LOCF method, if appropriate. The analyses were repeated for the per

6 Summary and conclusions: protocol (PP) population as a secondary analysis to check for the consistency of results. The 3 parameters, EF domain score, success rate of penetration (Question 5 of subject diary) and success rate of maintaining an erection during intercourse (Question 7 of subject diary) were analyzed using an analysis of covariance (ANCOVA) with a treatment and center effect. The ANCOVA included the baseline value as a covariate applied to endpoint. The baseline value was calculated from the subject s diary as completed during the unmedicated 4-week baseline period (Visit 1 [Week -4] to Visit 2 [Week 0]). The difference in success rates between treatment groups was also analyzed descriptively. Supportive summary statistics included, for each treatment group, the observed total number of attempts and successes and the associated rate of success in percentage. Other categorical efficacy variables, such as, the proportion of subjects who answered Yes to the GAQ ( Has the treatment you have been taking over the past 4 weeks improved your erections ) were to be analyzed using logistic regression with a term for treatment by specifying a Bernoulli distribution and logit link function. Analysis of the primary and secondary efficacy parameters was performed for all centers combined and, where appropriate, the mean and sexual desire was plotted against time. Summary of efficacy: The primary efficacy objective of the study was to compare the efficacy of 3 doses of vardenafil, 5 mg, 10 mg and 20 mg, with placebo in Asian men with ED, treated for a maximum of 12 weeks. For both the ITT and PP populations the EF domain score, of the IIEF questionnaire, of subjects in each of the 3 vardenafil treatment groups, 5 mg, 10 mg and 20 mg, improved significantly (P value [treatment] < ) from Baseline (Visit 2 [Week 0]) to Visit 5 (Week 12) as compared to subjects in the placebo treatment group. The LS means of IIEF EF domain scores from the ANCOVA models (LOCF values, subjects valid for ITT analysis) were as follows: placebo: 16.4, vardenafil 5 mg: 22.3 (P < versus placebo), vardenafil 10 mg: 22.5 (P < versus placebo), vardenafil 20 mg: 23.5 (P < versus placebo)

7 Similar results were obtained in those subjects valid for the PP population. In subjects valid for the ITT population, a statistically significant difference (P value [treatment] Visit 5 [Week 12]: < and LOCF: < ) in the success rate of penetration (rate of Yes responses to the subject diary Question 5 Were you able to insert your penis into your partner s vagina? ), was observed between treatment groups, overall from randomization (Visit 2 [Week 0]) to Visit 5 [Week 12] and using the LOCF method: The LS means of the per subject rates (%) of Yes response to the diary question Were you able to insert your penis into your partner s vagina? from the ANCOVA models (overall values, subjects valid for ITT analysis) were as follows: placebo: 54.6, vardenafil 5 mg: 79.3 (P < versus placebo), vardenafil 10 mg: 81.5 (P < versus placebo), vardenafil 20 mg: 86.0 (P < versus placebo). Similar results were obtained in those subjects valid for the PP population. In subjects valid for the ITT population, a statistically significant difference (P value [treatment] Visit 5 [Week 12]: < and LOCF: < ) was also observed in the success rate of maintaining an erection during intercourse (rate of Yes responses to the subject diary Question 7 Did your erection last long enough for you to have successful intercourse? ), between treatment groups, overall from randomization (Visit 2 [Week 0]) to Visit 5 [Week 12] and using the LOCF method. The LS means of the per subject rates (%) of Yes response to the diary question Did your erection last long enough for you to have successful intercourse? from the ANCOVA models (overall values, subjects valid for ITT analysis) were as follows: placebo: 32.2, vardenafil 5 mg: 58.4 (P < versus placebo), vardenafil 10 mg: 67.7 (P < versus placebo), vardenafil 20 mg: 71.3 (P < versus placebo). Similar results were obtained in those subjects valid for the PP population. Vardenafil, 5 mg, 10 mg and 20 mg, was proven to be more effective than placebo in the treatment of ED, as the statistical

8 models for all 3 primary efficacy variables resulted in significant differences between vardenafil and placebo (using Bonferroni adjustment). The same result was observed at all scheduled post-baseline visits (Visit 3 [Week 4] to Visit 5 [Week 12]) and no heterogeneity in treatment effect was observed across centers. A significantly greater proportion of subjects in each of the 3 vardenafil treatment groups, 5 mg, 10 mg and 20 mg, as compared to placebo, were of the opinion that the treatment improved their erections and answered Yes to the GAQ Has the treatment you have been taking over the past 4 weeks improved your erections?. This result was observed at Visit 5 (Week 12) and using LOCF. Similar results were obtained in those subjects valid for the PP population. A statistically significant difference was observed in the LS mean value of the OF, sexual desire, IS and OS domain scores, of the IIEF questionnaire, between the placebo treatment group and each of the 3 vardenafil treatment groups, 5 mg, 10 mg and 20 mg, at each visit and using the LOCF method. It can therefore be concluded that the OF, sexual desire, IS and OS domain scores of subjects in the 3 vardenafil treatment groups, 5 mg, 10 mg and 20 mg, improved statistically significantly from Baseline (Visit 2 [Week 0]) as compared to subjects in the placebo treatment group. With the exception of the sexual desire domain score, in all comparisons of vardenafil by dose group, 5 mg, 10 mg or 20 mg, to placebo, a statistically significant difference in the calculated point estimate and subsequent 98.33% confidence interval was also observed (Bonferroni adjustment), providing further confirmation of the aforementioned primary efficacy results. This implies that the improvement in the OF, IS and OS domain scores of subjects randomized to vardenafil, 5 mg, 10 mg and 20 mg, from Baseline (Visit 2 [Week 0]) to each visit and LOCF was significantly greater than that of subjects in the placebo treatment group. Vardenafil 5 mg did not effect a significantly greater improvement in the sexual desire domain score from Baseline (Visit 2 [Week 0]) to LOCF as compared to the placebo treatment group. However, both vardenafil 10 mg and 20 mg effected a statistically significant improvement in the sexual

9 desire domain score from Baseline (Visit 2 [Week 0]) to LOCF. This difference was not clinically significant however. Similar results were obtained in the PP population. No formal statistical comparison of the IIEF scores for Questions 3, 4 and 15 was performed. It would appear, however, that a greater change from Baseline (Visit 2 [Week 0]) to LOCF was observed for subjects randomized to vardenafil, 5 mg, 10 mg and 20 mg, as compared to subjects in the placebo treatment group. No formal statistical comparison of the success rate (responses as Yes ) for Questions 4, 8, 9 and 10 of the subject diary was performed. It would appear, however, that a greater change from Baseline (Visit 2 [Week 0]) to LOCF was observed for subjects randomized to vardenafil, 5 mg, 10 mg and 20 mg, as compared to subjects in the placebo treatment group. Although no formal statistical comparison was made, it was observed, that the mean scores for the IIEF Questions 1, 2 and 5 to 14, of subjects in the placebo treatment group were noticeably less than that of subjects in the 3 vardenafil treatment groups, 5 mg, 10 mg and 20 mg, at each of the visits and LOCF. Vardenafil consistently performed better than placebo for all the primary and secondary efficacy variables. In conclusion, vardenafil 5 mg, 10 mg and 20 mg, showed statistically and clinically significant improvements in various efficacy variables after 12 weeks of treatment compared to placebo in the treatment of Asian men with ED. Summary of safety: Placebo, vardenafil, 5 mg, 10 mg and 20 mg, were generally well tolerated. The incidence of treatment-emergent adverse events was, as expected, greater in the 3 vardenafil treatment groups, 5 mg, 10 mg and 20 mg, as compared to the placebo treatment group. A total number of 152 (25.2%) subjects presented with at least 1 treatment-emergent adverse event (placebo 23 [15.5%] subjects; vardenafil 5 mg 34 [22.5%] subjects, vardenafil 10 mg 42 [28.0%] subjects; vardenafil 20 mg 53 [34.6%] subjects). At least 1 drug-related treatment-emergent adverse event was reported by 129 (21.4%) subjects (placebo 11 [7.4%] subjects; vardenafil 5 mg 30 [19.9 %] subjects; vardenafil 10 mg 39 [26.0%] subjects; vardenafil 20 mg 49 [32.0%] subjects).

10 The most frequently reported drug-related treatment-emergent adverse events were Flushing (placebo 3 [2.0%] subjects; vardenafil 5 mg 12 [7.9%] subjects; vardenafil 10 mg 20 [13.3%] subjects), Headache (placebo 3 [2.0%] subjects; vardenafil 5 mg 8 [5.3%] subjects; vardenafil 10 mg 6 [4.0%] subjects; vardenafil 20 mg 15 [9.8%] subjects), Nasal congestion (placebo 0 [0.0%] subjects; vardenafil 5 mg 6 [4.0%] subjects; vardenafil 10 mg 2 [1.3%] subjects; vardenafil 20 mg 4 [2.6%] subjects). The profile of drug-related treatment-emergent adverse events was as expected considering the known pharmacological effects of PDE5 inhibitors. The majority of adverse events were mild in severity, usually transient in nature and resolved at the end of the study. No deaths occurred during the course of the study. One serious treatment-emergent adverse event was reported by Subject , randomized to the placebo treatment group. The subject, aged 66 years, suffered a severe acute myocardial infarction. The event was not considered to be related to the study medication and reported as improved by the end of the study. The overall clinical and laboratory safety profile of the 3 vardenafil treatment groups, 5 mg, 10 mg and 20 mg, was favorable and the incidence of abnormal laboratory tests was similar between treatment groups. There was no evidence of relevant differences between the treatment groups in vital signs and 12-lead electrocardiogram (ECG) assessments. In conclusion, the 3 doses of vardenafil, 5 mg, 10 mg and 20 mg, proved to be generally safe and well tolerated in Asian men presenting with ED. Summary of pharmacokinetics: Not applicable. Conclusions: The 3 doses of vardenafil, 5 mg, 10 mg and 20 mg, proved to be effective, generally safe and well tolerated in Asian men presenting with ED.

11 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 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