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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). A minimum of 120 patients will be enrolled in this study and randomly assigned to 1 of 2 treatment groups in a 3:1 ratio: a minimum of 90 patients will be assigned to the doripenem group and 30 patients will be assigned to the cefepime group. 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. During the pretreatment period, the patient's eligibility for the study will be determined by review of specific entry criteria. After a signed informed consent form explaining the details about the study has been obtained from the patient's parent or legal representative (and a signed assent form has been obtained from patients who are capable of providing assent, typically, children 7 years of age and older), screening procedures will be performed. Screening procedures will include the collection of information about the patient's medical history, demographics (age and race), therapies (including medications) taken within the last 30 days, and any preplanned surgeries or procedures. If a patient is receiving treatment for any chronic pre-existing diseases at the time of study entry, the type and dosage of medications taken should not be changed during the study, if medically appropriate. During screening, a physical examination will be performed; vital signs (heart rate, respiratory rate, and blood pressure) and body temperature obtained; height/length and body weight measured; and signs and symptoms of UTI will be assessed. Within 48 hours before treatment assignment, blood and urine samples will be obtained from patients for laboratory testing (urinalysis, serum chemistry, hematology, and calculated creatinine clearance) and for culture to test for the presence of bacteria. In addition, a urine (or serum) pregnancy test will be performed on all girls who have had their first menstrual period. After all screening procedures have been completed, the patient will be assigned to receive iv study drug (doripenem or cefepime) which will be considered Day 1 of the study. Patients will begin treatment with doripenem or cefepime by iv infusion within the following 24 hours. Because doripenem will be administered over a 60-minute period and cefepime will be administered over a shorter 30-minute period there is the potential for the patient and study staff to know which study drug is being administered. To prevent this, patients will be administered study drug along with (or paired with) a placebo as follows: patients randomized to receive a 60-minute iv infusion of doripenem will first receive a 30-minute iv infusion of a placebo identical in appearance to cefepime, and patients who are randomized to receive cefepime will receive a 60-minute IV infusion of placebo identical in appearance to doripenem. The 30-minute infusions of cefepime/cefepime placebo will be always administered first. During the study, patients will receive 10 to 14 days of antibiotic therapy (either iv study drug alone or iv study drug for approximately 72 hours [minimum of 9 paired doses] followed by other iv or oral [PO] antibiotic therapies). Patients will remain hospitalized for the duration of treatment with iv study drug. During the treatment period, patients who develop renal impairment with a calculated creatinine clearance (measure of the level of the waste product creatinine in your blood and urine) of less than 60 mL per minute or require dialysis for any reason will discontinue treatment with iv study drug but continue to be monitored in the study for safety. If the patient's cUTI symptoms improve after 72 hours of treatment with iv study drug, the investigator may choose to stop iv study drug and switch the patient to an orally administered antibiotic (amoxicillin/clavulanate potassium) 3 times a day to complete a 10 to 14-day antibiotic course of therapy. No patient will receive more than 14 days of treatment with doripenem or cefepime during the study. Patients may be switched to another oral antibiotic (ciprofloxacin) if they are 1 or more years of age and have Pseudomonas aeruginosa (specific bacteria) isolated at baseline (prior to study drug therapy) from their urine. An alternative PO antibiotic may be considered in cases of intolerance or bacterial resistance to amoxicillin/clavulanate potassium or ciprofloxacin. No other therapy for the treatment of UTI will be permitted. Patients who require other therapy for their cUTI (or for another infection) will discontinue study drug therapy and be followed for safety. If after 72 hours of treatment with iv study drug, no improvement in signs and symptoms of the patient's UTI is observed, or if the patient continues to have a fever that is not resolving without an alternative explanation, or continues to have positive urine cultures and requires treatment with alternative antibiotic therapy, the patient will be considered a "treatment failure" and be discontinued from iv study drug but will continue to be monitored in the study for safety. Throughout the study, all patients will be monitored daily for safety, signs and symptoms of UTI, and occurrence of adverse events. In addition, blood samples for serum chemistry and hematology laboratory assessments, and pharmacokinetic (determination of doripenem plasma concentrations), and calculated creatinine clearance will be performed on selected days. Within 24 hours of the last dose of study drug (and before discharge from the hospital), patients will have end of treatment (EIV) clinical outcome assessment performed. Patients will be rated with a clinical outcome of "clinical improvement", "clinical failure", or "indeterminate" on the basis of their response to treatment. After the EIV, patients will return for 2 posttreatment study visits conducted 7 to 14 days and 28 to 42 days, respectively, after the last dose of study drug and follow up safety procedures performed. Any patients withdrawn from the study at any time will return to have posttreatment visit procedures performed. The primary outcome measure in the study is safety and tolerability. 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 observed 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.
Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Urinary Tract Infections
doripenem/ cefepime placebo, cefepime/ doripenem placebo
Not yet recruiting
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Published on BioPortfolio: 2014-07-23T21:09:26-0400
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