Pharmacokinetic (PK) and Safety Study of Meropenem in Young Infants With Intra-abdominal Infections

Study Description

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Brief Summary:

Meropenem is an antibiotic that is commonly used to treat serious infections. Although it is used in premature and young infants, the correct dose is not known. The purpose of this study is to determine the correct dose and the safety of meropenem for the treatment of complicated intra-abdominal infections in these young babies.

Condition or disease	Intervention/treatment	Phase
Necrotizing Enterocolitis; Intra-abdominal Infection	Drug: meropenem	Phase 1; Phase 2

Detailed Description:

This study will evaluate the safety, tolerability and Pharmacokinetics - Pharmacodynamics (PK-PD) of meropenem in infants <91 days of age with suspected and complicated intra-abdominal infections.

The specific aims of this trial are:

1. To characterize meropenem single-dose and multiple-dose PK in subjects with suspected and complicated intra-abdominal infections.
2. To characterize the safety profile of meropenem in the treatment of suspected and complicated intra-abdominal infections.
3. To assess collected efficacy data for meropenem for the treatment of suspected and complicated intra-abdominal infections.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	200 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Multiple Dose Pharmacokinetic Study of Meropenem in Young Infants (<91 Days) With Suspected or Complicated Intra-abdominal Infections
Study Start Date :	June 2008
Actual Primary Completion Date :	October 2009
Actual Study Completion Date :	October 2009

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Meropenem; These Participants were subdivided into the following four groups based on Gestational Age (GA) and Postnatal Age (PNA): Group 1: GA at birth below 32 weeks - PNA <2 weeks; Group 2: GA at birth below 32 weeks - PNA ≥2 weeks and <91 days; Group 3: GA at birth 32 weeks or older - PNA <2 weeks; Group 4: GA at birth 32 weeks or older - PNA ≥2 weeks and <91 days.

Drug: meropenem; Meropenem was administered concomitantly with compatible medications. Because an in-line filter is not appropriate due to drug binding, the 30 minute infusion was rate controlled by using appropriate infusion (syringe) pumps. Dosing and administration of other antimicrobial therapy (e.g., an aminoglycoside) was administered per local standard of care at the discretion of the infant's neonatologist. If there was a delay in the study drug shipment, sites were to use open-label meropenem to protect the safety of the participant. 20 mg/kg every 12 hours in infants <32 weeks GA and PNA < 2 weeks 20 mg/kg every 8 hours in infants <32 weeks GA and PNA ≥ 2 weeks 20 mg/kg every 8 hours in infants ≥32 weeks GA and PNA < 2 weeks 30 mg/kg every 8 hours in infants ≥32 weeks GA and PNA ≥ 2 weeks; Other Name: Merrem

Outcome Measures

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Primary Outcome Measures :

1. Efficacy Success (Alive at Efficacy Visit,Last Culture (if Obtained) From Sterile Body Fluid is Negative for Bacteria (Except Staphylococcus Species) From Start of Study Drug Until Efficacy Visit,Presumptive Clinical Cure Score(PCCS) >7 at Efficacy Visit) [ Time Frame: Average of 12 days (3 to 21 days) ]

   The PCCS was derived by comparing clinical signs and symptoms prior to administration of the first dose of study drug and study Day 28.The elements of the PCCS include Mean BP,Temp,PaO2(mmHg)/FiO2,Lowest serum pH,seizures,Urine output,Cardiovascular inotrope support,C-reactive protein (CRP)and Abdominal girth.

   Score - Asymptomatic to Asymptomatic 1;Asymptomatic to Worsening 0;Symptomatic to Worsening 0;Symptomatic to No change 0;Symptomatic to Improved 1;Symptomatic to Asymptomatic 1

   If 7 or more of 10 signs received a score of 1, then the infant was considered a presumptive clinical cure.

   GA stands for Gestational Age and PNA stands for Postnatal Age.

2. Deaths [ Time Frame: Up to 51 days (Recorded from the time of informed consent until 72 hours following the last dose of study drug) ]
3. Meropenem Clearance [ Time Frame: Up to 7-8hrs post drug administration ]
   Given the limited availability of blood for Pharmacokinetic (PK) assessments in this population a sparse sampling approach was utilized. Subjects were assigned to one of two Dose 1 sample collection schedules, "PK-odd" and "PK-even" based on birth date to ensure collection of PK data throughout the dose interval. In addition, PK samples were collected around approximately the 5th dose. Subjects that did not have Dose 1 PK samples could have steady-state (Dose 5) using the Dose 5 PK collection schedule.
4. Key Safety Endpoints [ Time Frame: Up to 51 days (Adverse Events (AEs) were recorded from the time of informed consent until 72 hours following the last dose of study drug) ]
   Safety assessments included death, seizure documentation (including correlation of serum meropenem level and seizures), strictures, perforation, wound dehiscence, short gut, development of extended beta lactamase infection, development of candidiasis, antimicrobial therapy failure

Eligibility Criteria

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Ages Eligible for Study:	up to 90 Days (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Written permission from parent or legal guardian
2. Age younger than 91 days
3. Likely to survive beyond the first 48 hours after enrollment

4. Sufficient intravascular access (either peripheral or central) to receive study drug.

   AND ONE OF THE FOLLOWING

5. 1) Physical, radiological, and/or bacteriological findings of a complicated intra-abdominal infection. These include peritonitis, NEC (Necrotizing Enterocolitis) Grade II or higher by Bell's criteria, Hirschsprung's disease with perforation, spontaneous perforation, meconium ileus with perforation, bowel obstruction with perforation, as evidenced by free peritoneal air on abdominal radiograph, intestinal pneumatosis or portal venous gas on abdominal radiographic examination.

OR 2) Possible NEC OR 3) Otherwise receiving meropenem per local standard of care

Exclusion criteria:

1. Renal dysfunction evidenced by urine output <0.5 mL/hr/kg over the prior 24 hours
2. Serum creatinine >1.7 mg/dL
3. History of clinical seizures or EEG (Electroencephalogram) confirmed seizures
4. Concomitant treatment with another carbapenem (ertapenem or imipenem) at the time of informed consent
5. Any condition which would make the subject or the caregiver, in the opinion of the investigator, unsuitable for the study

Contacts and Locations

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Locations

United States, Alabama
University of Alabama
Birmingham, Alabama, United States, 35233
United States, California
Children's Hospital of Oakland
Oakland, California, United States, 94609
Children's Hospital of Orange County
Orange, California, United States, 92868
University of California Medical Center
San Diego, California, United States, 92117
Sharp-Mary Birch Hospital for Women
San Diego, California, United States, 92123
United States, Connecticut
Yale New Haven Hospital
New Haven, Connecticut, United States
United States, District of Columbia
Children's National Medical Center
Washington DC, District of Columbia, United States, 20010
United States, Florida
University of Florida
Gainesville, Florida, United States, 32610
United States, Hawaii
Kapiolani Medical Center for Women and Children
Honolulu, Hawaii, United States, 96826
United States, Illinois
Evanston Northwestern Healthcare
Evanston, Illinois, United States, 60056
United States, Indiana
Indiana University - Riley Hospital for Children
Indianapolis, Indiana, United States, 46202
United States, Kentucky
University of Louisville
Louisville, Kentucky, United States, 40202
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Missouri
Kansas City Children's Mercy Hospital
Kansas City, Missouri, United States, 64108
United States, New York
Albany Medical Center
Albany, New York, United States, 12208
Suny Downstate Medical Center
Brooklyn, New York, United States, 11203
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27708
Duke University
Durham, North Carolina, United States, 27715
United States, Ohio
Akron Children's Hospital
Akron, Ohio, United States, 44308
Case Western Reserve, RB&C, UHCMC
Cleveland, Ohio, United States, 44106
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Magee Women's Hospital
Pittsburg, Pennsylvania, United States, 15213
United States, Tennessee
Vanderbilt Children's Hospital
Nashville, Tennessee, United States, 37232
United States, Texas
University of Texas Southwestern Medical Center
Dallas, Texas, United States
Baylor College of Medicine
Houston, Texas, United States, 77030
United States, Utah
University of Utah medical Center
Salt lake City, Utah, United States, 84108

Sponsors and Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

The EMMES Corporation

Investigators

Principal Investigator:	Danny Benjamin, MD, PhD, MPH	Duke University

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Cohen-Wolkowiez M, Poindexter B, Bidegain M, Weitkamp JH, Schelonka RL, Randolph DA, Ward RM, Wade K, Valencia G, Burchfield D, Arrieta A, Mehta V, Walsh M, Kantak A, Rasmussen M, Sullivan JE, Finer N, Rich W, Brozanski BS, van den Anker J, Blumer J, Laughon M, Watt KM, Kearns GL, Capparelli EV, Martz K, Berezny K, Benjamin DK Jr, Smith PB; Meropenem Study Team. Safety and effectiveness of meropenem in infants with suspected or complicated intra-abdominal infections. Clin Infect Dis. 2012 Dec;55(11):1495-502. doi: 10.1093/cid/cis758. Epub 2012 Sep 5.

Responsible Party:	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier:	NCT00621192 History of Changes
Other Study ID Numbers:	HHSN267200700051C; HHSN267200700051C ( Other Identifier: NICHD )
First Posted:	February 22, 2008
Results First Posted:	November 29, 2011
Last Update Posted:	April 17, 2015
Last Verified:	March 2015

Keywords provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):

meropenem; infants; intra-abdominal infection; pharmacokinetics; safety

Additional relevant MeSH terms:

Infection; Communicable Diseases; Enterocolitis; Enterocolitis, Necrotizing; Intraabdominal Infections; Gastroenteritis; Gastrointestinal Diseases	Digestive System Diseases; Intestinal Diseases; Meropenem; Thienamycins; Anti-Bacterial Agents; Anti-Infective Agents