A Safety and Tolerability Study of Doripenem Compared With Meropenem in Children Hospitalized With Complicated Intra-abdominal Infections

This is a randomized (study drug 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 evaluate the safety of the study drugs
(doripenem and meropenem) administered by intravenous (iv) infusion (slow injection of drug
solution into the vein over a period of time) in children aged 3 months to less than 18
years who are hospitalized with complicated intra abdominal infections (cIAI). Complicated
intra abdominal infections include but are not limited to appendicitis with rupture and/or
abscess (local collection of pus), acute (severe or intense) gastric, duodenal (beginning
section of the small intestine), or gall bladder perforation (a hole in the wall of the
stomach, small intestine, or gallbladder), and secondary peritonitis. The study will include
3 periods: a pretreatment (screening) period that will occur within 2 days prior to
randomization (assignment of study drug), a treatment period of 5 to 14 days where patients
will receive iv study drug treatment only or IV study therapy and a switch to oral
antibiotic therapy, and a posttreatment period consisting of 2 study visits. The max
duration of study drug therapy is 14 days. The total duration of the study is approximately
7 to 8 weeks. Safety and tolerability will be evaluated by examining the incidence,
severity, and type of adverse events, changes in clinical laboratory tests, vital signs
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. Patients
will receive IV Doripenem (20 mg/kg to 500 mg/dose) and meropenem placebo OR meropenem (20
mg/kg to 1 gram/dose) and doripenem placebo once every 8 hours for up to 14 days. If the
patient's cIAI 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 postassium) to complete the 5- to 14 day
course of antibiotic therapy.

Inclusion Criteria:

- Patients who are eligible for the study must have clinical evidence of cIAI

- Require surgical intervention (eg, laparotomy, laparoscopic surgery, or percutaneous
drainage) to manage the cIAI

- Require antibacterial therapy for 5 to 14 days in addition to the surgical
intervention

- Must, based on the judgment of the investigator, require hospitalization initially
and antibacterial therapy for 5 to 14 days in addition to surgical intervention for
the treatment of the current cIAI. (Note that the patient must require at least 3
days of IV antibiotic therapy initially)

- 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 and 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 nonstudy systemic antibiotic therapy for cIAI for more than 24 hours
immediately preceding the start of the infusion of the first dose of iv study drug
therapy

- Have a diagnosis of abdominal wall abscess confined to musculature of the abdominal
wall, small bowel obstruction or ischemic bowel disease without perforation,
traumatic bowel perforation requiring surgery within 12 hours of perforation, or
perforation of gastroduodenal ulcers requiring surgery within 24 hours of perforation
(these are considered situations of peritoneal soiling before the infection has
become established)

- Have simple (noncomplicated), nonperforated appendicitis or gangrenous appendicitis
without rupture into the peritoneal cavity identified during a surgical procedure OR
presence of spontaneous bacterial peritonitis or peritonitis associated with
cirrhosis or chronic ascites

- Known at the time of randomization to have a cIAI caused by at least one pathogen
that is nonsusceptible to doripenem or meropenem

- Presence of any of the following clinically significant laboratory abnormalities:
Hematocrit of less than 20%, absolute neutrophil count (ANC) <500 cells/µL, platelet
count <40,000 cells/µL, serum alanine aminotransferase or aspartate aminotransferase
(AST) or total bilirubin 5 times or greater the age-specific upper limit of normal
(ULN) or acute/chronic renal insufficiency with a baseline creatinine clearance <50
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