Clinical Study Synopsis

Transcription

1 Clinical Study Synopsis This file is posted on the Bayer HealthCare Clinical Trials Registry and Results website or on the website hosted by the Pharmaceutical Research and Manufacturers of America (PhRMA). It 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 in this document or on the related 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 BAY / Title page Title: Test drug: Indication: REALISE Levitra Real Life Safety and Efficacy of Levitra BAY /vardenafil HCI/Levitra Erectile dysfunction Study number: Sponsor s name: Bayer Vital GmbH Phase: IV Date:

3 BAY / Study synopsis Title of the study: REALISE Levitra Real Life Safety and Efficacy of Levitra Investigator(s): Principal/Coordinating Investigator (For details see Section ): Eric, Cheng, MD, 3309 Church Avenue, Brooklyn, New York, Study center(s): This study was conducted at 4284 active centers in the United States and in Puerto Rico. Publications (references): None Period of study: 14 Oct 2003 to 30 Sep 2004 (first subject s first visit to last subject s last visit) Clinical phase: Phase IV Objectives: To collect data on safety, efficacy, and subject acceptance of vardenafil treatment under daily life conditions in a large number of subjects with erectile dysfunction (ED) Methodology (design of study): This study was an open-label, multi-center, prospective, non-controlled, observational study. The observation and assessment period of the study consisted of an initial subject visit and 1 or 2 follow-up visits within 2 months after the first dose of vardenafil. This study was conducted in an outpatient setting by urologists, internists, and general practitioners. Number of subjects: The planned number of subjects to be treated was 30,000 in the United States (US). Actually 30,964 subjects were enrolled, of which 30,010 were included in safety/intent-to-treat analysis. The main reason for 954 subjects not being included in the safety/itt analysis was that these patients did not take study drug (n=924). Further 16 subjects (0.05%) were lost to followup and could not be assessed for dose administration, safety or efficacy, and in addition for 14 patients implausible or inconsistent data resulted in exclusion from safety/itt analysis. Of those patients excluded from the safety/itt population (30,010 subjects) to form the adjusted safety/itt population (26,043 subjects), 3813 subject had no documentation of

4 BAY / efficacy or vardenafil intake and in addition 154 subjects did not have visit one information. Patient questionnaires were available for 17,477 and 17,333 subjects of safety/itt and adjusted safety/itt population, respectively. Diagnosis and main criteria for inclusion: Male outpatients 18 years of age with a diagnosis of ED according to the 1992 US National Institutes of Health (NIH) Consensus Statement (the inability to achieve and maintain penile erection sufficient to complete satisfactory intercourse), and independent of any previous ED treatment. Exclusion criteria adhered to the US Prescribing Information (PI), i.e. concomitant treatment with nitrates or nitric oxide donors as well as alpha-blockers was contraindicated. Test product, dose, and mode of administration, batch number: Vardenafil was supplied by the sponsor in 5 mg, 10 mg, and 20 mg oral doses. Study medication was dispensed to subjects according to best medical practice and approved Prescribing Information (PI). Batch numbers: 5 mg tablets: 25N mg tablets: 25007X0 and BXA mg tablets: BXB9L41 and BXA085L Duration of treatment: Reference therapy, dose, and mode of administration, batch number: Study medication was dosed as needed (PRN) by subjects who were instructed not to exceed 1 dose in a calendar day. The planned observation period of the study was the time between the initial visit and the last follow-up visit within the 2 months after the first dose of vardenafil. Not applicable. Criteria of evaluation: Safety: Adverse events, including - Events of special interest (special events committee assessment and adjudication) - WHO critical events - Serious unlisted related events Global assessment of tolerability

5 BAY / Efficacy: Case report form (CRF) for physician: - Improvement of ED and number of tablets taken to achieve improvement - Minimum time interval between intake and start of sexual activity - Second successful intercourse within 24 hours of intake - Overall assessment of efficacy - Preference of Levitra treatment in comparison with last ED treatment Patient Questionnaire (PQ): - Assessment of individual attempts - Improvement of ED and number of tablets taken to achieve improvement - Second successful intercourse within 24 hours of intake - Overall assessment of efficacy - Preference of Levitra treatment with last ED treatment Utilization parameters: - Number of tablets dispensed by dose and visit - Number of tablets taken by dose and visit Statistical methods: Safety analysis was based on safety/itt population including all subjects with safety follow-up data. Efficacy analysis was based on adjusted safety/itt population including patients which either had intake data, efficacy data or an AE reported. Descriptive analysis of the data were performed using summary statistics for categorical and quantitative data. Continuous data were described by mean, SD, minimum, 1, 5, 25, 75, 95, 99 percentiles, median, maximum, number of nonmissing values. In addition, continuous data were categorized in a clinically meaningful way. Categorical data including categories of continuous data were presented in frequency tables. Stratified frequency tables contain column percent and row percent if applicable. Number of patients with missing data were presented as a separate category. Percentages were calculated as a proportion of each category including the category missing values. In some subgroup analyses percentages were calculated based on non-missing values (adjusted frequencies). In summary tables of the report (sections 11 and 12) the category missing was in general not displayed in order to make tables better readable.

6 BAY / The safety analysis was based on treatment-emergent signs and symptoms (TESS). A conservative approach was used for the definition of TESS: An AE was considered a TESS in case: a) the AE started on or after the first visit date (CRF) or first documented intake (PQ) (what ever was first) and b) the AE started before or at the last visit date (CRF) or last signature date on the CRF or last intake (PQ) (what ever was the latest date). Safety analysis included tabulation of type (using MedDRA coding) and frequency of all adverse events. The seriousness, start of AE related to time of Levitra intake and sexual activity, action taken and outcome of events were described. The incidence rates of AEs, ADRs, SAEs, SADRs, special events (myocardial infarction, torsades de pointes, ventricular arrhythmias, sudden death, cerebral vascular accident, syncope, hospitalization due to abnormal ECG; in addition, any occurrences of 22 MedDRA terms potentially related to QT prolongation and torsades de pointes were reviewed), WHO critical and serious unlisted related events were calculated. Incidence rate was defined as number of events / number of subjects at risk, where number of events = number of subjects reporting the event and number at risk = all subjects valid for safety/itt population. For multiple occurrences of an event within a subject, the event was counted only once. Summary and conclusions: Summary of efficacy: Levitra was generally effective in the treatment of ED. At the end of the observation period, erections had improved in 78.3% of the subjects. For 18.0% no improvement could be observed. Correspondingly in 75.2% of all subjects the overall efficacy was rated satisfying (35.0%) or very satisfying (40.2%); for 20.7% the efficacy was documented as unsatisfying. Efficacy varied depending on severity, etiology and duration of the disorder as well as on the age of the patient. Patients aged <65 years and suffering from mild to moderate ED, more often had a benefit from Levitra treatment than older patients or patients with severe ED. As well for patients suffering from

7 BAY / solely psychogenic etiology of ED or with a maximum of 3 years duration of disease, comparably higher improvement and satisfaction rates were observed. In the subgroup of patients with a history of radical prostatectomy (n=872) lower rates for improvement and satisfaction were observed (52.2% improved, 47.5% satisfied/very satisfied). Results as assessed by physicians were confirmed by responses from patients questionnaires. No clinically significant differences in overall efficacy assessments for the total sample as well as the subgroup analyses were observed. For 89.5% of all sexual attempts documented in patients questionnaires, penetration was possible; in 81.3% of attempts the erection could be maintained long enough to complete intercourse and for 80.0% of the attempts, subjects considered were satisfied or very satisfied with their erections. Summary of safety: In general, Levitra treatment was well tolerated, with a rating of satisfied / very satisfied in 75.0% of all cases in the overall tolerability assessment of the attending physician (16.8% missing values). The percentage of subjects with treatment-emergent AEs were 8.74% and of treatment-emergent ADRs 7.16%. The most frequent adverse events were headache, flushing and nasal congestion, which are consistent with the known safety profile of vardenafil. The number of patients experiencing treatment-emergent SAEs and SADRs was 113 (0.38%) and 16 (0.05%), respectively. Within the observation period 21 deaths were reported. With exception of one subject (unknown relation to Levitra ) all deaths were considered not to be drug-related. Twenty-one of 39 candidate special events were judged as events of special interest by a special event committee. For ten of these subjects the event was evaluated as possibly related to Levitra (8 syncopes, 1 loss of consciousness, 1 myocardial infarction) and for three subjects the relation to Levitra was not assessable (1 unspecified death, 1 myocardial infarction, 1 arrhythmia). The events of 8 cases were adjudicated as not or unlikely related to Levitra therapy. (3 myocardial infarctions,

8 BAY / syncopes, 2 cardio-respiratory arrests, 1 cerebrovascular accident). WHO critical events occurred in 96 subjects (0.32%) and serious related adverse events not listed in the Company Core Data Sheet occurred in 1 subject (Prinzmetal angina, arterial spasm). No events signaling an effect of vardenafil on the male reproductive system were reported. In 645 subjects (2.48%) Levitra intake was stopped permanently due to adverse events. Main reasons for discontinuation due to AE were headache (n=322), flushing (n=86), dizziness (n=48), nasal congestion (n=40) and nausea (n=39). Hundred and thirty-nine subjects (0.46%) suffered from events which were assigned to the primary or secondary System Organ Class of Eye disorders and which were with few exceptions also classified as ADRs (0.43%). Symptoms such as blurred vision, cyanopsia and eye redness were predominant among eye disorder events. For one of these subjects the symptom (eye swelling) was assessed as SADR since it was a medically important event. No case of nonarteritic ischemic optic neuropathy (NAION) was reported. The clinical safety profile of 316 patients concomitantly treated with alpha-blockers was similar to the population without alpha-blocker treatment. Events of interest related to concomitant use of alpha-blockers and PDE5 inhibitors including SAEs occurred in 5 of 316 patients (3 dizziness, 1 loss of consciousness, 1 blood pressure decreased). Summary of pharmacokinetics: Not applicable. Conclusions: In this observational study, vardenafil was generally well tolerated and was highly effective in the treatment of mild, moderate and severe ED of varying etiology. Considering all adverse events it can be concluded that in this study vardenafil s clinical safety profile was consistent with the current Company Core Data Sheet (CCDS). Of the 21 events of special interest, there were no cases of sudden death or ventricular torsades de pointes.

9 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