E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Complicated Urinary Tract Infections |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10046571 |
E.1.2 | Term | Urinary tract infection |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to establish the safety and tolerability profile of doripenem compared with that of cefepime in hospitalized children 3 months to <18 years of age with cUTI. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives are: •To determine the clinical cure rate of doripenem compared with that of cefepime at the TOC visit •To determine the favorable microbiological response rate of doripenem compared with that of cefepime at the TOC visit •To determine the clinical improvement rate of doripenem compared with that of cefepime at the end of treatment with IV study drug therapy (EIV) visit •To determine the favorable microbiological response rate of doripenem compared with that of cefepime at the EIV visit •To determine the sustained clinical cure rate of doripenem compared with that of cefepime at the late follow-up (LFU) visit •To determine the favorable microbiological response rate of doripenem compared with that of cefepime at the LFU visit •To characterize the pharmacokinetics of doripenem in hospitalized children with cUTI based on a sparse pharmacokinetic sampling scheme |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Boy or girl 3 months to <18 years of age, inclusive •Have a current episode of cUTI as indicated by the following clinical signs or symptoms: –Complicated UTI Infants 3 months to <2 years of age –Presenting with at least one of the following signs or symptoms: Recent weight loss Failure to thrive Abdominal pain Vomiting Diarrhea Irritability Poor feeding Lack of normal level of activity Jaundice, or Fever (oral temperature >=38.0 degrees C or equivalent by an alternative method). Refer to Attachment 1, Oral Temperature Conversion Table for oral temperature equivalents by alternative methods –AND has at least 1 complicating factor (see below) Children 2 to <18 years of age –Presenting with at least one of the following signs or symptoms: Dysuria Urinary frequency Urgency Suprapubic or abdominal pain Secondary urinary incontinence, or Fever (oral temperature >=38.0 degrees C or equivalent by an alternative method). Refer to Attachment 1, Oral Temperature Conversion Table for oral temperature equivalents by alternative methods –Note: subjects who are not able to perceive dysuria, urinary frequency, urgency, or suprapubic or abdominal pain due to congenital or acquired spinal cord injury will be allowed to enroll with the diagnosis of “asymptomatic cUTI” but are required to provide 2 study-qualifying baseline urine cultures from urine specimens obtained at least 1 hour apart (see Section 9.4, Criteria for Study Qualifying Pretreatment Baseline Urine Culture for further details) –AND have at least 1 complicating factor (see below) Complicating Factors for All Age Categories (3 months to <18 years of age) –Include at least one of the following complicating factors: Current bladder instrumentation or presence of an indwelling catheter that is anticipated to be removed during the course of IV study drug therapy Use of intermittent catheterization Urogenital surgery within the 7 days before administration of the first dose of IV study drug Known functional or anatomic abnormality of the urogenital tract Obstructive uropathy Vesicoureteral reflux Neurogenic disturbances of micturation with significant impact on bladder emptying Recurrent UTI (defined as 2 or more previous UTIs within a 12-month period), or Evidence that the current UTI may be caused by a resistant uropathogen (including evidence that the current episode is a breakthrough infection or in a child on chronic antimicrobial suppression with unresolved vesicoureteral reflux), or If this is the initial UTI episode in a child 3 months to <2 years of age, the child is suspected of having an acquired or congenital structural or functional urologic abnormality –Pyelonephritis: Children >2 years of age –Presenting with at least one of the following signs or symptoms: Fever (oral temperature >=38.0 degrees C or equivalent by an alternative method). Refer to Attachment 1, Oral Temperature Conversion Table for oral temperature equivalents by alternative methods); and at least one of the following: nausea or vomiting costovertebral angle tenderness or flank pain •Have a positive urinalysis (urine specimen positive for nitrite and leukocyte esterase via urine dipstick or urinalysis) •Have a study-qualifying pretreatment “baseline” urine culture specimen obtained by an acceptable method including SPA, clean urethral catheterization, indwelling urethral catheter, or mid-stream clean catch (urine specimens obtained from urine bags will not be allowed) (see Section 9.5, Urine Collection Procedures) within 48 hours before the start of the administration of the first dose of IV study drug therapy from which a bacterial uropathogen is isolated with a growth of >=10^5 CFU/mL (see Section 9.4, Criteria for Study Qualifying Pretreatment Baseline Urine Culture). (Note: Subjects may be enrolled into the study before the results of the pretreatment urine culture are known. However, if the baseline urine culture results do not meet the definition of a study-qualifying pretreatment baseline urine specimen as described in Section 9.4, Criteria for Study-Qualifying Pretreatment Baseline Urine Culture, the subject must discontinue study drug therapy although he or she will remain in the study for safety follow up). •Must, based on the judgment of the investigator, require 10 to 14 days of antibacterial therapy for the treatment of the presumed cUTI. (Note that the subject must require at least 3 days of IV antibiotic therapy initially). |
|
E.4 | Principal exclusion criteria |
•Have a history of hypersensitivity reactions to carbapenems, cephalosporins, penicillins, or other beta-lactam antibiotics. Note: Subjects with a history of mild non urticarial skin rash temporally related to but considered not associated with the previous use of beta-lactam antibiotics are permitted to enroll in the study. For such subjects, there must be a description of the rash and documentation by the investigator that upon review of the history it is his/her opinion that the rash was unlikely due to any of the above-mentioned classes of drugs for the subject to qualify for inclusion in the study. •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. (Clarification: possible bacteremia with the presumed same urinary pathogen is acceptable). •Receipt of any amount of potentially therapeutic antibiotic for the treatment of the current UTI within 96 hours before obtaining the study-qualifying pretreatment baseline urine. (Exception: Subjects receiving oral antibiotics for UTI prophylaxis and are suspected to have a breakthrough UTI are eligible to enroll if all other eligibility criteria are met including obtaining a study-qualifying pretreatment baseline urine culture). •Have received systemic antibiotic therapy for more than 24 hours since obtaining the study-qualifying pretreatment baseline urine specimen •Intractable UTI/pyelonephritis infection anticipated to require more than 14 days of study drug therapy •Have a permanent indwelling bladder catheter or instrumentation including nephrostomy •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. (Clarification: Intermittent straight catheterization after the IV study drug therapy administration period is acceptable). •Complete, permanent obstruction of the urinary tract •Confirmed fungal UTI with a colony count >=10^3 CFU/mL •Suspected or confirmed perinephric or intrarenal abscess •Suspected or confirmed prostatitis •Known ileal loops •Girls who are pregnant or are nursing a child or are menarchal, and, if sexually active, are not practicing a highly effective method of birth control (eg, prescription hormonal contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method, eg, condoms, diaphragm, or cervical cap, with spermicidal foam, cream, or gel, male partner sterilization) as local regulations permit, before screening and agree to continue using a highly effective method of birth control (as previously described) for 30 days after administration of the last dose of study drug therapy. Note: for all menarchal girls, confirm a negative urine or serum pregnancy test (beta-human chorionic gonadotropin [beta-hCG]) at screening, before enrolling the subject into the study. •Have any rapidly progressing disease or immediately life-threatening illness including acute hepatic failure, respiratory failure, or septic shock, or require vasopressor therapy if hemodynamically unstable (volume repletion for support of blood pressure without the use of pressers is allowed), or are considered unlikely to survive for the duration of the study for any other reason (approximately 7 to 8 weeks) •The subject has any of the following clinically significant laboratory abnormalities: –Absolute neutrophil count (ANC) <500 cells/microlitre –Platelet count <40,000 cells/microlitre –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 CLcr <60 mL per minute or requires dialysis therapy for any reason. •Are profoundly immunodeficient and require prophylactic antimicrobial therapy for Pneumocystis jirovicei, Toxoplasma gondii, or herpes viruses, and/or chronic or intermittent inmunoglobin replacement therapy •Are receiving chemotherapy for current malignancy •Have received an organ or bone marrow transplant and are treated with chronic immunosuppressive therapy for prevention of organ transplantation rejection •Are receiving imuran, methotrexate, or chronic corticosteroid therapy equivalent to >=1 mg/kg of prednisone daily for the 30 days before randomization •Have a history of uncontrolled epilepsy •Are currently receiving probenecid or valproic acid |
|
E.5 End points |
E.5.1 | Primary end point(s) |
A subject will be considered to have completed the study if he or she has received at least a partial dose of study drug therapy and completed the LFU visit. Subjects who prematurely discontinue study treatment will also be considered to have completed the study after the LFU visit. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of trial is last visit of the last subject (Late Follow Up visit (LFU) |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 11 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 18 |