Clinical Study Synopsis

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1 Clinical Study Synopsis 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 Study Sponsor: Study Number: Study Phase: Official Study Title: Clinical Trial Results Synopsis Study Design Description Bayer Healthcare Pharmaceuticals Inc. IIIb Therapeutic Area: Anti-Infectives NCT A prospective, randomized study to compare ciprofloxacin (either as oral suspension or as IV or sequential IV oral suspension therapy) versus control regimens (either trimethoprim/sulfamethoxazole (TMP/SMX) oral suspension, cefixime oral suspension, IV ceftazidime, sequential IV ceftazidime trimethoprim/sulfamethoxazole oral suspension therapy or sequential IV ceftazidime PO cefixime) in the treatment of pediatric subjects with complicated urinary tract infections (UTI) or pyelonephritis Test Product Name of Test Product: Name of Active Ingredient: Dose and Mode of Administration: Ciprofloxacin (BAYO9867) Stratum I: Ciprofloxacin oral suspension Stratum II: Ciprofloxacin intravenous (IV) - 10 to 20 mg/kg every 12 hrs, maximum dose of 750 mg bid; orally (ie, total oral daily dose 1500 mg) - 6 to 10 mg/kg every 8 hrs, maximum dose of 400 mg tid; IV (ie, total IV daily dose 1200 mg). The dosage was not exceeded, even in children weighing over 51 kg. Reference Therapy/Placebo Reference Therapy: Stratum I: Cefixime oral suspension and Trimethoprim/sulfamethoxazole (TMP/SMX) (Canada only) Dose and Mode of Administration: Stratum II: Ceftazidime IV - 8 mg/kg/day cefixime, given in 2 divided doses of 4 mg/kg q12h; orally and 4 mg/kg TMP and 20 mg/kg SMX every 12 hours. The maximum daily dose was not to exceed 320 mg TMP and 1600 mg SMX. Children who weighed more than 50 kg or who were older than 12 years of age were treated with the recommended adult dose of cefixime of 200 mg q12h. -Ceftazidime mg/kg q8h; IV. The maximum dose was not to exceed 6 g per day. Duration of Treatment: The total duration of therapy for each age group, ranged between 10 and 21 days. Studied period: Date of first subjects first visit: 09 Sep 1999 Date of last subjects last visit: 26 Jun 2003 Study Center(s): Sixty one investigational sites enrolled 689 subjects in eight countries: 27 centers in US, 4 centers in Canada, 5 centers in South Africa, 9 centers in Argentina, 3 centers in Peru, 6 centers in Germany, one Page 1 of 5

3 center in Costa Rica and 6 centers in Mexico. Methodology: This trial was a prospective, randomized, double-blind, activecontrolled, parallel group, multinational, pediatric clinical protocol. Enrolled subjects were stratified prior to randomization based on whether IV therapy was initially warranted and were then randomized to receive either ciprofloxacin or control antibiotics (1:1 randomization). In the first stratum, ciprofloxacin oral suspension was compared to control regimens (cefixime and TMP/SMX oral suspension) and in the second stratum, IV ciprofloxacin and IV ciprofloxacin followed by ciprofloxacin oral suspension was compared to control regimens (IV ceftazidime, sequential IV ceftazidime followed by PO cefixime and sequential IV ceftazidime PO TMP/SMX). Subjects with a history of Pseudomonas infections or those in whom Pseudomonas was isolated on pretherapy culture were to remain on IV therapy for the entire course of study, regardless of assigned regimen, to ensure adequate antimicrobial coverage for this organism. The clinical evaluation was based on serial examinations to determine the effect of study drug therapy on the signs and symptoms of infection and was determined on Day 2 to 5 during therapy, on Day +5 to +9 following therapy (Test-of-Cure), and on Day +28 to +42 following therapy (first follow-up). Indication/ Main Inclusion Criteria: Study Objectives: Evaluation Criteria: Complicated UTI or pyelonephritis in older infants, younger and older children and adolescents. For assessing subject eligibility for fluoroquinolone therapy, following factors were considered: whether subjects had multiple recent bouts of complicated UTI (ie, >2 treated episodes within the past 6 months), the clinical and bacteriological response patterns to other classes of antimicrobial agents, subjects known to have persistent or recurrent complicated UTI caused by resistant bacterial pathogens and current infection classified as a postsurgical infection. Overall: To determine the musculoskeletal safety, i.e. joint, articular cartilage, tendon and ligament, of purely IV, sequential (IV PO) and purely oral ciprofloxacin in comparison to IV ceftazidime, sequential (IV ceftazidime PO TMP/SMX or IV ceftazidime PO cefixime) and purely PO TMP/SMX or PO cefixime) therapy among pediatric subjects with complicated UTI or pyelonephritis. Secondary: To assess the neurological safety of these dosage regimens among subjects with complicated UTI or pyelonephritis. To collect blood specimens for determination of serum ciprofloxacin concentration. Ciprofloxacin concentration data from this study were pooled with those from other studies in a pediatric population pharmacokinetic analysis. Efficacy (Primary): - The clinical success (resolution) rate at the Test-of-Cure visit (Day +5 to +9 after the end of therapy). - Clinical Efficacy: comparison between the proportion of subjects treated and evaluable with purely IV, sequential (IV PO) and purely oral regimens of ciprofloxacin, who experienced clinical success versus Page 2 of 5

4 Statistical Methods: the analogous proportion of subjects treated and evaluable within the control regimens. Efficacy (Secondary): Overall clinical outcome assessed at Day +5 to +9 post-therapy and at Day +28 to +42 post-therapy (cure, failure, indeterminate). - The bacteriological response on Day +5 to +9 and on Day +28 to +42 following therapy. Safety: - The primary safety variable was the arthropathy event rate at the first follow-up visit (Day +28 to +42). - To assess the neurological safety of ciprofloxacin versus the comparators in pediatric subjects with complicated UTI or pyelonephritis. - To assess the musculoskeletal safety of ciprofloxacin versus the comparators in pediatric subjects with complicated UTI or pyelonephritis up to one-year post-treatment. - Medical history and physical examination findings (including vital signs), reports of clinical adverse events, results of blood chemistry and hematology, urinalysis, theophylline levels and prothrombin time (when applicable) and pregnancy test results. Pharmacokinetics: Serum concentrations of ciprofloxacin. Efficacy (Primary): - A two-sided 95% confidence interval for the weighted difference between treatment groups in clinical success rates was constructed using Mantel-Haenszel weights based on disease stratum. The difference was constructed as P(e) minus P(s), where P(e) was the clinical success rate for the experimental ciprofloxacin arm and P(s) was the clinical success rate for the control regimens. Equivalence was defined statistically in this case as the lower limit of a two-sided 95% confidence interval for the weighted difference in clinical success rates being greater than -12%. Efficacy (Secondary): Microbiological success rates were examined and weighted confidence intervals calculated. The effect of disease stratum (either oral or sequential and purely intravenous therapy) was taken into account in the statistical analyses. Safety: - A two-sided 95% confidence interval for the weighted difference between treatment groups in arthropathy incidence rates was constructed using Mantel-Haenszel weights reflecting disease stratum. The difference was constructed as P(e) minus P(s), where P(e) was the arthropathy incidence rate for the experimental ciprofloxacin arm and P(s) was the arthropathy incidence rate for the control regimens. Equivalence was defined statistically in this case as the upper limit of a two-sided 95% confidence interval for the weighted difference in arthropathy incidence rates being less than 6%. - Comparison of incidence rates of adverse events was done in a descriptive manner across the 4 age groups. Page 3 of 5

5 Pharmacokinetics: The statistical analyses pooled the comparator drugs from the US with Canada due to the use of a different oral comparator drug at Canadian sites. Descriptive consistency checks were performed between the Canadian and US sites to examine any differences in treatment group comparisons. Number of Subjects: A total of 689 subjects were enrolled into the trial, out of which 337 were in ciprofloxacin group and 352 in comparator group. Results Summary Subject Disposition and Baseline Study Results Of the 689 subjects enrolled into the trial, majority of subjects valid for efficacy analysis in both treatment groups were females (85% ciprofloxacin and 86% comparator). Four hundred and forty two subjects were valid for efficacy analysis (211 in ciprofloxacin group and 231 in comparator group). Following race groups contributed the vast majority of subjects: Caucasian, Black, Asian, Hispanic and uncodable. Fifty-six percent of ciprofloxacin subjects were treated for pyelonephritis and the remaining 44% for complicated UTI. The corresponding numbers were similar for the comparator group (59% pyelonephritis and 41% complicated UTI). The distribution of demographic variables was similar in the 2 treatment groups for the valid for safety population as well. The majority of subjects enrolled on comparator therapy took oral cefixime (208/231=90%). The remaining 3 subjects (1%) on oral therapy received TMP/SMX. These subjects were from Canada where cefixime is not currently approved for complicated UTIs. Twenty subjects (9%) who received IV therapy were given ceftazidime either IV only or were given IV and then were switched to oral therapy. Results Summary Efficacy The clinical cure rate at the Test-of-Cure visit in subjects valid for efficacy analysis was 96% in the ciprofloxacin group and 93% in the comparator group. The 95% confidence interval for the treatment difference in clinical cure rate (-1.3%, 7.3%) indicated that ciprofloxacin in the treatment of pediatric subjects with complicated UTI or pyelonephritis was at least as effective as the comparator. The clinical cure rates for the pyelonephritis subjects were 97% and 93% for the ciprofloxacin and comparator groups, respectively. The clinical cure rates for the complicated UTI subjects were 95% and 92% for the ciprofloxacin and comparator groups, respectively. The eradication rates for the pyelonephritis subjects were 93% for the ciprofloxacin group and 89% for the comparator group. The eradication rates were 78% versus 68% in the ciprofloxacin and comparator groups, respectively, for subjects with complicated UTIs. Table1: Clinical Response at Test-of-Cure for Subjects Valid for Efficacy Ciprofloxacin (N=211) Comparator (N=231) Cure 202 (95.7%) 214 (92.6%) Failure 9 (4.3%) 17 (7.3%) 95% Confidence Interval (-1.3%, 7.3%) The bacteriological eradication rate at the Test-of-Cure visit in subjects valid for efficacy analysis, was 86% in the ciprofloxacin group and 81% in the comparator group. The 95% confidence interval for the treatment difference in eradication rate (-1.4%, 12.6%) indicated that ciprofloxacin is at least as effective as the comparator in the treatment of pediatric subjects with complicated UTI or pyelonephritis. Page 4 of 5

6 Results Summary Safety In the ciprofloxacin group, 12 (3.6%) subjects experienced adverse events with the study drug permanently discontinued and 25 (7.5%) subjects experienced serious adverse events. All serious adverse events reported in the ciprofloxacin group were judged to be unlikely or not related to study drug. The most common adverse events leading to premature discontinuation of ciprofloxacin therapy were vomiting (3 subjects), nausea (2 subjects) and moniliasis (2 subjects). No subject discontinued due to a musculoskeletal adverse event. The incidence of premature discontinuation due to an adverse event and serious adverse events in the comparator group was 6 (1.7%) and 20 (5.7%), respectively. The incidence of musculoskeletal adverse events at any time up to 1 year was 10.7% in the ciprofloxacin group and 7.2% in the comparator group. Arthralgia was reported in 7.5% of the ciprofloxacin subjects and 4.6% in the comparator subjects. Arthrosis occurred in 1.2% of ciprofloxacin and 0.3% of the comparator subjects. Myalgia occurred in 0.9% of the ciprofloxacin subjects and in 2.3% of the comparator subjects. Tendon disorder was reported in only one (0.3%) of the comparator subjects and was not observed in the ciprofloxacin group. All other musculoskeletal events occurred in <1% of either treatment group. Arthralgia was considered by the investigator(s) to be drug-related in 1.5% of ciprofloxacin subjects and 0.9% of the comparator group. The incidence of neurological events, up to one-year posttreatment follow-up, was 5.1% in the ciprofloxacin group and 3.7% in the comparator group. Convulsions occurred in 0.9% of ciprofloxacin subjects and 1.1% of comparator subjects. Neuropathy (0.3%) and hypesthesia (0.3%) were reported at the same incidence in both groups. All other neurological events were reported in <1% of subjects in either group. No clear evidence of neurological sequelae was observed in this study. Two subject deaths were reported during the study; in both cases judged to be of no relationship to the study drug. The incidence of laboratory test abnormalities was comparable between the 2 treatment groups. No clinically meaningful treatment differences were observed in mean diastolic blood pressure, systolic blood pressure, or heart rate (HR). Results Summary Pharmacokinetics Serum concentrations of ciprofloxacin were assayed using a high performance liquid chromatography method. A population pharmacokinetic analysis was performed, which is reported separately. Conclusion(s) In this study, the clinical cure rate at the Test-of-Cure visit in pediatric subjects was 96% in the ciprofloxacin group (compared to 93% in the comparator group). The bacteriological eradication rate at the Test-of Cure visit was 86% in the ciprofloxacin group and 81% in the comparator group. Therefore, ciprofloxacin was considered to be an effective antimicrobial agent in pediatric subjects with complicated UTI or pyelonephritis. Based on the efficacy and safety profile of ciprofloxacin in this pivotal study and the extensive clinical experience (adult and pediatric populations) with ciprofloxacin, it was concluded that ciprofloxacin in oral doses of 10 to 20 mg/kg q12h and intravenous doses of 6 to 10 mg/kg q8h was appropriate for use in the treatment of pediatric subjects with complicated UTI or pyelonephritis when prescribed for a 10 to 21 day treatment duration. Although a lack of equivalence between groups, using a clinically meaningful difference of 6%, was observed for cases of arthropathy, any drugrelated events appeared to be self-limited without sequelae. Date Created or Date Last Updated: 25 Aug 2011 Page 5 of 5