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

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the safety and tolerability of doripenem compared with meropenem in children hospitalized with complicated intra-abdominal infections.

Detailed Description
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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.

Official Title
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A Prospective, Randomized, Double-Blind, Multicenter Study to Establish the Safety and Tolerability of Doripenem Compared With Meropenem in Hospitalized Children With Complicated Intra-Abdominal Infections

Conditions
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Abscess, Intra-Abdominal, Abdominal Abscess, Abdomen, Acute, Abdominal Pain, Appendicitis, Rupture, Infection, Intestinal Perforation, Peritonitis, Ileus

Intervention / Treatment
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* Drug: Doripenem
* Drug: Meropenem placebo
* Drug: Meropenem
* Drug: Doripenem placebo
* Drug: Amoxicillin/clavulanate potassium


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doripenem<br>Doripenem 20 mg/kg per dose (up to 500 mg/dose)will be administered every 8 hours as 60-minutes IV (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium). Total duration of treatment 5 to 14 days. | Drug: Doripenem<br>* Type=once every 8 hours infused over 60 minutes, Unit=mg, Number=20mg/kg up to 500mg/dose, Form=solution for infusion, Route-intravenous use. At least 3 days of iv doripenem administered every 8 hours immediately after meropenem placebo for up to 14 days<br>Drug: Meropenem placebo<br>* Form=solution for infusion, Route=intravenous use, administered once every 8 hours infused over 30 minutes immediately before each iv infusion of doripenem for up to 14 days.<br>Drug: Amoxicillin/clavulanate potassium<br>* Form=suspension or tablets, Route=oral (by mouth), may be administered at the discretion of the investigator once every 12 hours for up to 14 days following IV therapy with doripenem or meropenem.<br>|
| Experimental: Meropenem<br>Meropenem 20 mg/kg per dose (up to 1 g/dose) will be administered every 8 hours as 30-minutes IV (at least 3 days of IV meropenem only or IV meropenem followed by oral amoxicillin/clavulanate potassium). Total duration of treatment 5 to 14 days. | Drug: Meropenem<br>* Type=once every 8 hours infused over 30 minutes, Unit=mg, Number=20 mg/kg to 1 gram per dose, Form=solution for infusion, Route=intravenous use. At least 3 days of iv meropenem administered every 8 hours immediately before doripenem placebo for up to 14 days<br>Drug: Doripenem placebo<br>* Form=solution for infusion, Route=intravenous use, administered once every 8 hours infused over 60 minutes immediately after each iv infusion of meropenem for up to 14 days<br>Drug: Amoxicillin/clavulanate potassium<br>* Form=suspension or tablets, Route=oral (by mouth), may be administered at the discretion of the investigator once every 12 hours for up to 14 days following IV therapy with doripenem or meropenem.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants With Clinical Cure Rate at Test Of Cure (TOC) Visit | The participants were considered as clinical cure if they had clinical improvement in signs and symptoms of the intra-abdominal infection such that no additional antibacterial therapy or surgical or percutaneous intervention is/was required for the treatment of the index infection, no fever, and a favorable response at End of IV visit. | TOC (7 to 14 days after the last dose of study medication therapy) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants With Clinical Improvement Rate at End of IV (EIV) Visit | The participants were considered as clinical improved if they had clinical improvement in signs and symptoms of the intra-abdominal infection, no fever, decrease in WBC, and not received any nonstudy antibiotics for the treatment of intra-abdominal infection after IV study drug therapy had begun. | EIV (within 24 hours after completion of the last dose of IV study medication therapy) | 
| The Number of Participants With Clinical Cure Rate at Late Follow-Up (LFU) Visit | The participants were considered as clinical cure if they had clinical improvement in signs and symptoms of the intra-abdominal infection such that no additional antibacterial therapy or surgical or percutaneous intervention is/was required for the treatment of the index infection, no fever, and a favorable response at End of IV visit. | LFU (28 to 42 days after the last dose of study medication therapy) | 
| The Number of Participants With Favorable Per-participant Microbiological Response | Favorable per-participant microbiological response rate was evaluated at the at End of IV (EIV) visit, Test Of Cure (TOC) visit, and Late Follow-Up (LFU) visit. The favorable per-participant microbiological response was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment). | EIV (within 24 hours after completion of the last dose of IV study medication therapy), TOC (7 to 14 days after the last dose of study medication therapy), and LFU (28 to 42 days after the last dose of study medication therapy) | 
| Number of Participants With Favorable Per-pathogen Microbiological Outcome Rate at End of IV (EIV) Visit | A total of 24 pathogens in the doripenem group and 6 pathogens in the meropenem group were isolated at baseline from the intra-abdominal culture and were susceptible to the study drug received. The most common pathogens isolated from the intra-abdominal culture are listed in the table below; the numbers in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem and meropenem treatment groups, respectively. The favorable per-pathogen microbiological outcome was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment). | EIV (within 24 hours after completion of the last dose of IV study medication therapy) | 
| Number of Participants With Favorable Per-pathogen Microbiological Outcome Rate at Test Of Cure (TOC) Visit | A total of 24 pathogens in the doripenem group and 6 pathogens in the meropenem group were isolated at baseline from the intra-abdominal culture and were susceptible to the study drug received. The most common pathogens isolated from the intra-abdominal culture are listed in the table below; the numbers in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem and meropenem treatment groups, respectively. The favorable per-pathogen microbiological outcome was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment). | TOC (7 to 14 days after the last dose of study medication therapy) | 
| Number of Participants With Favorable Per-pathogen Microbiological Outcome Rate at Late Follow-Up (LFU) Visit | A total of 24 pathogens in the doripenem group and 6 pathogens in the meropenem group were isolated at baseline from the intra-abdominal culture and were susceptible to the study drug received. The most common pathogens isolated at baseline from the intra-abdominal culture are listed in the table below; the numbers in parenthesis next to each pathogen represent the number of participants with the pathogen isolated in the doripenem and meropenem treatment groups, respectively. The favorable per-pathogen microbiological outcome was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment). | LFU (28 to 42 days after the last dose of study medication therapy) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-Infective Agents, Doripenem, Meropenem, Child, Hospitalized, Complicated Intra-Abdominal Infections