| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated Urinary Tract Infections |
|
| E.1.1.1 | Medical condition in easily understood language |
| Complicated Urinary Tract Infections or pyelonephritis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10046571 |
| E.1.2 | Term | Urinary tract infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 (complicated Urinary Tract Infection). |
|
| 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 (Test Of Cure) 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 |
1- Have evidence of pyuria as demonstrated by either of the following:
o A urine specimen that is positive for leukocyte esterase via urine dipstick or urinalysis
o A urine specimen with ≥10 WBCs per microliter from an unspun sample or ≥5 WBCs per high power field from a centrifuged specimen.
2- Have a current documented or suspected cUTI or pyelonephritis as indicated by the following clinical signs or symptoms:
COMPLICATED URINARY TRACT INFECTION
o Symptomatic cUTI
Children 3 months to <2 years of age
Must have at least ONE of the following signs or symptoms:
– Vomiting
– Recent weight loss or failure to thrive
– Abdominal pain
– Irritability
– Poor feeding
– Decrease in normal level of activity
AND
– have at least ONE complicating factor (see below)
Children 2 to <18 years of age
Must have at least ONE of the following signs or symptoms:
– Dysuria
– Increased urinary frequency
– Urgency
– Suprapubic or abdominal pain
– Secondary urinary incontinence
AND
– have at least ONE complicating factor (see below)
o Asymptomatic cUTI
Children 3 months to <18 years of age
Must be unable to perceive symptoms of UTI due to congenital or acquired spinal cord injury or abnormality
AND
have at least ONE complicating factor (see below)
Complicating Factors for All Age Categories (3 months to <18 years of age): All subjects enrolled with a diagnosis of complicated UTI must have at least ONE of the following complicating factors:
- Indwelling urinary catheter or other indwelling urinary tract instrumentation that is anticipated to be removed during the course of IV study drug therapy
- Use of intermittent urinary 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 where the obstruction is likely to resolve or be relieved during the course of IV study drug therapy administration
- Previously documented vesicoureteral reflux
- Neurogenic disturbances of micturition with significant impact on bladder emptying with bladder residual volume ≥50 mL for children weighing <40 kg and ≥100 mL for children weighing ≥40 kg as previously determined by voiding cystourethrogram (VCUG) or ultrasound or urinary catheterization immediately post void. (Chang 2009)
- Recurrent UTI (defined as 2 or more previous UTIs within a 12-month period)
- Evidence that the current UTI may be caused by a resistant uropathogen including a suspected breakthrough infection in a child receiving chronic antimicrobial prophylaxis for the prevention of UTI
- Prior documentation of congenital structural or functional urologic
abnormality including but not limited to findings from prenatal or postnatal ultrasound or postnatal VCUG
PYELONEPHRITIS
Subjects in all age categories (3 months to <18 years of age) enrolled with a diagnosis of pyelonephritis must have both:
Evidence of systemic inflammatory response as demonstrated by at least ONE of the following:
o Fever (oral temperature >38.0C, tympanic temperature >38.3C, or rectal or core temperature >38.8C) or hypothermia (rectal or core temperature <35.0C)
o Have leukocytosis defined as WBC >or=15,000 cells/microL OR >or=15% immature neutrophils, regardless of the total peripheral white cell count
AND
Have at least ONE of the following signs or symptoms:
Children 3 months to <2 years of age
– Vomiting
– Recent weight loss or failure to thrive
– Abdominal pain
– Irritability
– Poor feeding
– Decrease in normal level of activity
Children 2 to <18 years of age
– Nausea
– Vomiting
– Chills
– Dysuria
– Increased urinary frequency
– Urgency
– Lower back or flank pain or costovertebral angle tenderness
3- Must, based on the judgment of the investigator, require hospitalization initially and 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 |
1 - 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.
2 - Concomitant infection including but not limited to suspected or confirmed meningitis or other central nervous system infection requiring systemic antibiotic or antifungal therapy at the time of randomization. (Clarification: possible bacteremia with the presumed same urinary pathogen is acceptable).
3 - Received any amount systemic antibiotic therapy within 96 hours (4 days) before obtaining the pretreatment baseline urine culture specimen. (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 baseline urine culture specimen).
4 - Have received more than 24 hours of systemic antibiotic therapy after obtaining the pretreatment baseline urine culture specimen
5 - 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 do not 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.
6 - Have a history of uncontrolled epilepsy defined as at least 1 seizure within the 6 months before randomization |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Adverse events, Clinical laboratory tests and Vital signs measurements |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline up to 42 days after the last dose of study drug |
|
| E.5.2 | Secondary end point(s) |
1 - To determine the clinical cure rate and favorable microbiological response rate of doripenem compared with that of cefepime at
the test of cure (TOC) visit
2 - To determine the clinical improvement rate and favorable microbiological response rate of doripenem compared with that of
cefepime at the end of treatment with iv study drug therapy (EIV) visit
3 - To determine the sustained clinical cure rate and favorable microbiological response rate of doripenem compared with that of cefepime at the late follow-up (LFU) visit
4 - To characterize the pharmacokinetics of doripenem in hospitalized children with cUTI on the basis of a sparse pharmacokinetic sampling scheme |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 - 7 to 14 days after the last dose of iv study drug including oral antibiotic therapy
2 - Within 24 hours after completion of the last dose of iv study drug
3 - 28 to 42 days after the last dose of iv study drug including oral antibiotic therapy
4 - 1, 2, 4 and 6 hours after the 4th, 5th, 6th, or 7th dose administrations of doripenem/doripenem placebo |
|
| 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 | No |
| 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 | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Argentina |
| Brazil |
| Colombia |
| Czech Republic |
| Germany |
| India |
| Latvia |
| Lithuania |
| Mexico |
| Panama |
| Poland |
| Uganda |
| Ukraine |
| United States |
|
| 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) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 17 |
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