Webposting Clinical Trial Results Synopsis

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1 Study Summary This summary information is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This summary information is not intended to replace the advice of a healthcare professional and should not be considered as a treatment recommendation or prescribing advice. Patients should always seek medical advice before making any decisions on their treatment. This study may involve approved and non-approved formulations or treatment regimens. Healthcare Professionals should always refer to the specific labeling information approved for the patient's country or region. Patients and professionals may want to refer to published or presented data in addition to the limited summary information provided herein. 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 Webposting Clinical Trial Results Synopsis Study Sponsor: Bayer HealthCare Pharmaceuticals Study Number: NCT Study Phase: IV Study Title: Prospective, open-label, noncomparative, multicenter study to evaluate the efficacy and safety of ciprofloxacin extended-release (Cipro XR) 1000 mg tablets given once daily for 7 to 14 days in the treatment of patients 18 years or older with complicated urinary tract infections caused by Pseudomonas aeruginosa and other common uropathogens Therapeutic Area: Infectious Disease Name of Test Product: Ciprofloxacin modified release [Cipro MR] Active Ingredient: Ciprofloxacin Ciprofloxacin: Chemical Description: (1) 3-Quinolinecarboxylic acid, 1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-7-(1piperazinyl)-; (2) 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl)-3-quinolinecarboxylic acid. CAS No: Other Aliases: BAY Q3939; ATC codes: J01MA02, S01AX02, S02AA15, S03AA07 Route of Administration: Oral Dosage: 1000 mg tablets once daily Reference Therapy: None Treatment Duration: 7 to 14 days Study Period: Date of first subject s first visit: 21 May 2004 Date of last subject s last visit: 01 September 2005 Methodology: Prospective, open-label, multicenter. Study Sites: United States (36 sites) Main Inclusion Criteria: Primary diagnosis for inclusion: complicated UTI caused by P. aeruginosa and other urinary pathogens in men or nonpregnant women aged 18 years. Typical subjects: subjects with spinal cord injury or trauma; indwelling urinary catheters (including transurethral and suprapubic); quadraplegia or paraplegia; multiple sclerosis and associated urological conditions; other risk factors for complicated UTI; and a previous history of a UTI or asymptomatic bacteruria with P. aeruginosa that was susceptible to fluoroquinolones. Onset of symptoms 72 hours before study entry. Eligible subjects also presented with at least 1 sign or symptom of a lower UTI or for spinal cord injury subjects if such symptoms were not present, at least 1 of the following: new or increased urinary incontinence (for subjects usually continent on an intermittent catheterization regimen), increased spasticity, autonomic hyperreflexia, increased sweating, malaise, or cloudy and odorous urine. In addition, subjects had at least 1 of the following underlying conditions: indwelling urinary catheter or intermittent catheterization; at least 100 ml of residual urine after voiding; neurogenic bladder; obstruction due to nephrolithiasis, tumor, or fibrosis; urinary retention due to benign prostatic hypertrophy (BPH), bladder cancer, or other urological anatomic abnormalities. Subjects had pyuria (defined as at least 1+ leukocyte esterase by dipstick of unspun urine or > 10 leukocytes/high-power field ([HPF] on urinalysis) within 48 hours before enrollment.

3 Study Objectives: The objectives of this study were to evaluate the safety and efficacy of ciprofloxacin MR 1000 mg orally (PO) given once daily for 7 to 14 days for the treatment of subjects with complicated urinary tract infection (UTI) caused by P. aeruginosa and other urinary pathogens. Evaluation Criteria: Efficacy: Primary parameter: Bacteriological outcome at the Test for Cure (TOC [Day +5 to +9]) visit. The TOC window was changed to +5 to +11 for validity. Secondary parameter: Was clinical response at the TOC visit. In addition, a secondary clinical efficacy parameter was clinical response at the Late Post-treatment visit (Day +28 to +42). This Late Post-treatment visit was only required for subjects with P. aeruginosa infections. Safety: Safety was assessed based on physical examination findings (including vital signs determinations), monitoring for adverse events and clinical laboratory testing. Statistical Methods: Per Protocol (PP) population (primary efficacy population): All efficacy analysis and tabulation of efficacy data Primary microbiological efficacy analyses Secondary analysis of clinical response Clinical and bacteriological responses were performed as success versus failure (missing and indeterminate outcomes were to be excluded from analysis). Intent to treat (ITT) population (secondary efficacy population): All efficacy analysis and tabulation of efficacy data Supportive primary and secondary efficacy analysis Comparisons of success versus non-success were performed Clinical efficacy population (all subjects fulfilling the PP criteria, except those for bacteriological outcome): Primary efficacy parameter: a 95% confidence interval was calculated. Secondary efficacy analyses were summarized descriptively. Demographic variables and baseline characteristics were summarized using the mean and standard deviation, median, quartiles, and minima/maxima (quantitative data) or frequency counts (qualitative/categorical data). As safety analyses and urine laboratory abnormalities were summarized descriptively. Number of Subjects: Enrolled: 237 subjects Invalidated from all analyses because of significant deficiencies found on site audit: 33 subjects Valid for safety analyses: 204 subjects Valid for the per-protocol (PP) analysis: 56 subjects Included in the clinical efficacy analyses: 130 subjects. Subjects Included in Each Analysis Population Ciprofloxacin MR 1000 mg Subject Population N % Enrolled 237 Valid for safety analysis Valid for per-protocol (PP) analysis Valid for clinical efficacy Results Summary Efficacy Bacteriological Outcome at the Test of Cure (Day +5 to +11 Post-treatment) Visit (Subjects Valid Per Protocol [PP]) Bacteriological Ciprofloxacin MR 1000 mg (N=56)

4 Outcome n % 95% Confidence Interval for Eradication Rate Eradication % % Persistence New infection Bacteriological Eradication Rate by Causative Organism at the Test of Cure (Day +5 to +11 Post-treatment) Visit (Subjects Valid Per-Protocol) Ciprofloxacin MR 1000 mg Organism (most commonly isolated) Eradication Rate n/n % Escherichia coli 23/ Klebsiella pneumoniae 9/10 90 Pseudomonas aeruginosa 7/7 100 For the 7 PP subjects with P. aeruginosa complicated UTI, 3 (42.9%) had continued eradication at the Late Posttreatment visit. The eradication rates generally were consistent across demographic and baseline subgroups and underlying conditions. Fifty-three of the 56 PP subjects (94.6%) had an outcome of clinical success Response rates and bacteriological eradication: Results for the valid for safety population were consistent with those for the PP population. Response rates were lower because of the large number of indeterminate or missing responses. Fifty-one of the 121 subjects (42.1%) valid for safety with causative organisms, had an outcome of bacteriological eradication. When the indeterminate evaluations were excluded, the bacteriological eradication rate was 68.9%. Seven of 12 subjects (58.3%) with P. aeruginosa complicated UTI achieved bacteriological eradication at the TOC visit. Three subjects (25.0%) had continued eradication at the Late Post-treatment visit. A total of 114 subjects (55.9%) had a clinical response of cure at the TOC visit. Three subjects (25.0%) had continued cure at the Late Post-treatment visit. As observed for the PP population, all subjects who had a bacteriological response of eradication had a clinical response of cure. Clinical efficacy: Of the 130 subjects valid for clinical efficacy, 104 subjects (80.0%) had an outcome of clinical success at the TOC visit. Subjects with causative organisms isolated at pre-therapy had a somewhat higher clinical cure rate (83.1%) as compared with subjects who had no causative organisms isolated at pre-therapy (74.5%). Results Summary Safety: Summary of Adverse Events (Subjects Valid for Safety) Ciprofloxacin MR 1000 mg (N=204) n % Any adverse event Any drug-related adverse event Any serious adverse event Any drug-related serious adverse event 0 0 Discontinued because of adverse event Deaths 0 0 Adverse Events in at Least 3 Subjects (Subjects Valid for Safety) Ciprofloxacin MR 1000mg (N=204) n % n % Nausea Fatigue Diarrhoea Headache Vomiting Dizziness Vulvovaginal mycotic infection Severity: Number of subjects with AEs that were: (as Mild Moderate Severe assessed by investigator) 23/58 (39.7%) 32/58 (55.2%) 3/58 (5.2%) Discontinuations due to AEs:

5 Four subjects, 2 of whom experienced serious adverse events, discontinued study drug therapy early because of adverse events. Adverse events leading to discontinuation included: Diarrhea and nausea in 1 subject; Diarrhea in 1 subject; Identification of bacteria in the urine in 1 subject; Vomiting, hydronephrosis, and syncope in 1 subject. SAEs: Vomiting, nausea, and diarrhea in 1 subject; Anemia in 1 subject; Hydronephrosis and syncope in 1 subject. Safety Laboratory tests: Three subjects had treatment-emergent increases in serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT) > 3 x the upper limit of normal (ULN); however, none was considered to be related to the study drug. Safety Laboratory results Parameter Proportion of subjects Most common high clinical laboratory test abnormality Serum glucose 24.5% Most common low clinical laboratory test abnormality Hemoglobin 10.2% Urine WBC count Most common qualitative/categorical laboratory abnormality 28.0% Leukocyte esterase Increase of 0.5 mg/dl Most common specified abnormality 3.7% in creatinine Vital Signs: No clinically relevant changes in vital sign measurements were observed. Conclusion(s) Ciprofloxacin MR 1000 mg for 7 to 14 days was effective in eradicating the causative pathogen in 82% (46/56) of subjects. The eradication rate also was high when presented for subjects with the 3 most common causative organisms: 100% (23/23) for E. coli, 90% (9/10) for, K. pneumoniae, and 100% (7/7) for P. aeruginosa. The clinical response rate at the TOC visit was high overall (94.6%; 53/56) and when limited to the subjects with the 3 most common causative organisms (95.7% [22/23] for E. coli, 100% (10/10) for K. pneumoniae, and 100% (7/7) for P. aeruginosa). All of the valid PP subjects with a response of bacteriological eradication also had a response of clinical cure. In this prospective, open-label, noncomparative, multicenter, phase IV study, ciprofloxacin MR was effective, safe, and well tolerated when administered in a dosage of 1000 mg PO once daily for 7 to 14 days to adult subjects with complicated UTI caused by P. aeruginosa and other common uropathogens. Updated

6 Appendix to Clinical Study Synopsis Product Identification Information US Trade Name(s) All Trade names (worldwide) Generic names Cipro Baycip Cipro Ciproxin Ciproxina Ciprobay Ciprofloxacin Company code(s) Bay q 3939 Chemical description Aliases Ciprofloxacin: (2) 1-Cyclopropyl-6-fluoro-1,4-dihydro-4- oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid