A Safety and Tolerability Study of Doripenem Compared With Cefepime in Children Hospitalized With Complicated Urinary Tract Infections

A Prospective, Randomized, Double-Blind, Multicenter Study to Establish the Safety and Tolerability of Doripenem Compared With Cefepime in Hospitalized Children With Complicated Urinary Tract Infections

The purpose of this study is to evaluate the safety and tolerability of doripenem compared to cefepime in children hospitalized with complicated urinary tract infections.

This is a randomized (study assigned by chance), double-blind (neither physician nor patient knows the name of the assigned study drugs), double-dummy (all patients are given both a placebo [salt solution] and study drug in alternating periods of time during the study), active comparator-controlled (compare the 'test' treatment to standard-of-care therapy), multinational, multicenter study to establish the safety and tolerability of the antibiotic doripenem compared with the antibiotic cefepime administered by intravenous (iv) infusion (slow injection of drug solution into the vein over a period of time) in children ages 3 months to less than 18 years hospitalized with a complicated urinary tract infection (cUTI). The study includes 3 periods: a pretreatment (screening) period that will occur within 2 days prior to randomization (assignment of study drug); a treatment period of 10 to 14 days where the patients will receive study drug treatment, and a posttreatment period consisting of 2 study visits. The maximum duration of study drug therapy is 14 days. The total duration of the study is approximately 7 to 8 weeks for each patient. Safety and tolerability will be evaluated by examining the incidence, severity, and type of adverse events, changes in clinical laboratory tests, vital sign measurements, and findings from physical examinations that are recorded as adverse events during treatment and at each posttreatment visit. An independent monitoring committee (IDMC) will be established for this study to ensure that the safety of patients is not compromised. The IDMC will consist of individuals who are not associated with the conduct of the study, and will include but will not be limited to individuals with expertise relevant to the care of pediatric patients, and including at least one infectious disease physician and at least one statistician. IV study drug therapy (Cefepime [50mg/kg up to 2g/dose] and doripenem placebo or doripenem [20mg/kg up to 500mg/dose] and cefepime placebo will be administered once every 8 hours for up to 14 days. After receiving a minimum of 3 days of IV study drug therapy, patients may be discharged from the hospital and continue PO antibiotic therapy with amoxicillin/clavulanate potassium, ciprofloxacin, or alternative antibiotic therapy.

Inclusion Criteria:

• Patients who are eligible for the study must have a current episode of cUTI or pyelonephritis
• Have evidence of pyuria that meets criteria specified in the study protocol
• Have a study-qualifying pretreatment "baseline" urine culture specimen obtained by an acceptable method within 48 hours before the start of the administration of the first dose of iv study drug from which a bacterial pathogen is isolated with a growth of >= 100000 colony forming units (CFU)/mL
• Require hospitalization initially and 10 to 14 days of antibacterial therapy [of which at least 72 hours should be iv therapy] for the treatment of the presumed UTI
• Have a signed informed consent form completed by the patient's parent or legal representative (and a signed assent form obtained from patients who are capable of providing assent, typically, children 7 years of age or older)

Exclusion Criteria:

• Have a history of hypersensitivity reactions to carbapenems, cephalosporins, penicillins, or other beta-lactam antibiotics
• concomitant infection including but not limited to suspected or confirmed meningitis or central nervous system infection requiring systemic antibiotic or antifungal therapy in addition to the iv study drug therapy at the time of randomization
• Receipt of any amount of systemic antibiotic within 96 hours before obtaining the study-qualifying pretreatment baseline urine or systemic antibiotic therapy for more than 24 hours after obtaining the study-qualifying pretreatment baseline urine specimen
• Have a diagnosis of intractable UTI/pyelonephritis infection anticipated to require more than 14 days of study drug therapy, a permanent indwelling bladder catheter or instrumentation including nephrostomy or current urinary catheter that will not be removed or anticipation of urinary catheter placement that will not be removed during the course of iv study drug therapy administration, complete and permanent obstruction of the urinary tract, confirmed fungal UTI, suspected or confirmed perinephric or intrarenal abscess, suspected or confirmed prostatitis, known ileal loops, or any of the following clinically significant laboratory abnormalities: absolute neutrophil count (ANC) <500 cells/µL, platelet count <40,000 cells/µL, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin >5x the age-specific upper limit of normal (ULN), acute or chronic renal insufficiency with a baseline creatinine clearance <60 mL per minute or requires dialysis therapy for any reason
• Have a history of uncontrolled epilepsy defined as at least 1 seizure within the 6 months before randomization