Intra-abdominal Infection, Necrotizing Enterocolitis
Conditions
Keywords
meropenem, infants, intra-abdominal infection, pharmacokinetics, safety
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.
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.
Interventions
DRUGmeropenem
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
Sponsors
The Emmes Company, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 90 Days
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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. |
| Deaths | Up to 51 days (Recorded from the time of informed consent until 72 hours following the last dose of study drug) | — |
| Meropenem Clearance | 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. |
| Key Safety Endpoints | 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 |
Countries
United States
Participant flow
Recruitment details
Enrollment Period - June 19, 2008 to October 6, 2009 Locations - Hospitals including University Hospitals Total number of sites - 24 Total number of participants - 200
Pre-assignment details
Other antimicrobials in addition to meropenem was used in the study due to concerns regarding the safety and ethics of using monotherapy in this patient population.The study was designed as an open-label, dose escalation study because sufficient data regarding the feasibility of a randomized, active controlled efficacy study was unavailable.
Participants by arm
| Arm | Count |
|---|---|
| 1. GA <32 Wks; PNA<2 Wks Group 1: GA at birth below 32 weeks - PNA \< 2 weeks; | 39 |
| 2. GA <32 Wks; PNA 91days ≥ 2Wks Group 2: GA at birth below 32 weeks - PNA ≥ 2 weeks and \< 91 days | 103 |
| 3. GA ≥ 32 Wks; PNA <2 Wks Group 3: GA at birth 32 weeks or older - PNA \< 2 weeks; | 31 |
| 4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks Group 4: GA at birth 32 weeks or older - PNA ≥ 2 weeks and \< 91 days. | 27 |
| Total | 200 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 1 |
| Overall Study | Death | 2 | 5 | 0 | 0 |
| Overall Study | Final Assessments not Completed | 0 | 0 | 3 | 1 |
| Overall Study | Physician Decision | 1 | 3 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | 1. GA <32 Wks; PNA<2 Wks | 2. GA <32 Wks; PNA 91days ≥ 2Wks | 3. GA ≥ 32 Wks; PNA <2 Wks | 4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks | Total |
|---|---|---|---|---|---|
| Age, Continuous Mean Postnatal Age | 8.5 Days STANDARD_DEVIATION 3.3 | 38.3 Days STANDARD_DEVIATION 19.3 | 6.5 Days STANDARD_DEVIATION 3.5 | 36.0 Days STANDARD_DEVIATION 22 | 27.3 Days STANDARD_DEVIATION 21.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 16 Participants | 4 Participants | 3 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 81 Participants | 27 Participants | 24 Participants | 164 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 6 Participants | 0 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 33 Participants | 8 Participants | 5 Participants | 58 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) White | 25 Participants | 65 Participants | 21 Participants | 18 Participants | 129 Participants |
| Sex: Female, Male Female | 15 Participants | 47 Participants | 9 Participants | 11 Participants | 82 Participants |
| Sex: Female, Male Male | 24 Participants | 56 Participants | 22 Participants | 16 Participants | 118 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 39 | 8 / 103 | 2 / 31 | 3 / 27 |
| serious Total, serious adverse events | 9 / 39 | 18 / 103 | 2 / 31 | 5 / 27 |
Outcome results
Primary
Deaths
Time frame: Up to 51 days (Recorded from the time of informed consent until 72 hours following the last dose of study drug)
Population: The Safety Population includes all patients who receive any amount of meropenem.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1. GA <32 Wks; PNA<2 Wks | Deaths | 3 Participants |
| 2. GA <32 Wks; PNA 91days ≥ 2Wks | Deaths | 8 Participants |
| 3. GA ≥ 32 Wks; PNA <2 Wks | Deaths | 0 Participants |
| 4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks | Deaths | 0 Participants |
Primary
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)
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.
Time frame: Average of 12 days (3 to 21 days)
Population: The Efficacy Population includes all patients who have efficacy assessment (Clinical Signs) at Pre-Dose and Study Day 28 (or the day that the Day 28 assessments were taken).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1. GA <32 Wks; PNA<2 Wks | 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) | 29 Participants |
| 2. GA <32 Wks; PNA 91days ≥ 2Wks | 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) | 82 Participants |
| 3. GA ≥ 32 Wks; PNA <2 Wks | 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) | 26 Participants |
| 4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks | 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) | 25 Participants |
Primary
Key Safety Endpoints
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
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)
Population: Safety Population - The Safety Population includes all patients who receive any amount of meropenem.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1. GA <32 Wks; PNA<2 Wks | Key Safety Endpoints | Death | 3 Participants |
| 1. GA <32 Wks; PNA<2 Wks | Key Safety Endpoints | Antimicrobial Therapy Failure | 7 Participants |
| 1. GA <32 Wks; PNA<2 Wks | Key Safety Endpoints | Development of Candidiasis | 5 Participants |
| 1. GA <32 Wks; PNA<2 Wks | Key Safety Endpoints | Seizure | 4 Participants |
| 1. GA <32 Wks; PNA<2 Wks | Key Safety Endpoints | Perforation | 2 Participants |
| 1. GA <32 Wks; PNA<2 Wks | Key Safety Endpoints | Strictures | 0 Participants |
| 1. GA <32 Wks; PNA<2 Wks | Key Safety Endpoints | Wound Dehiscence | 1 Participants |
| 2. GA <32 Wks; PNA 91days ≥ 2Wks | Key Safety Endpoints | Development of Candidiasis | 3 Participants |
| 2. GA <32 Wks; PNA 91days ≥ 2Wks | Key Safety Endpoints | Antimicrobial Therapy Failure | 12 Participants |
| 2. GA <32 Wks; PNA 91days ≥ 2Wks | Key Safety Endpoints | Wound Dehiscence | 1 Participants |
| 2. GA <32 Wks; PNA 91days ≥ 2Wks | Key Safety Endpoints | Death | 8 Participants |
| 2. GA <32 Wks; PNA 91days ≥ 2Wks | Key Safety Endpoints | Seizure | 3 Participants |
| 2. GA <32 Wks; PNA 91days ≥ 2Wks | Key Safety Endpoints | Strictures | 0 Participants |
| 2. GA <32 Wks; PNA 91days ≥ 2Wks | Key Safety Endpoints | Perforation | 2 Participants |
| 3. GA ≥ 32 Wks; PNA <2 Wks | Key Safety Endpoints | Death | 0 Participants |
| 3. GA ≥ 32 Wks; PNA <2 Wks | Key Safety Endpoints | Antimicrobial Therapy Failure | 2 Participants |
| 3. GA ≥ 32 Wks; PNA <2 Wks | Key Safety Endpoints | Development of Candidiasis | 0 Participants |
| 3. GA ≥ 32 Wks; PNA <2 Wks | Key Safety Endpoints | Strictures | 0 Participants |
| 3. GA ≥ 32 Wks; PNA <2 Wks | Key Safety Endpoints | Wound Dehiscence | 1 Participants |
| 3. GA ≥ 32 Wks; PNA <2 Wks | Key Safety Endpoints | Perforation | 0 Participants |
| 3. GA ≥ 32 Wks; PNA <2 Wks | Key Safety Endpoints | Seizure | 1 Participants |
| 4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks | Key Safety Endpoints | Antimicrobial Therapy Failure | 2 Participants |
| 4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks | Key Safety Endpoints | Wound Dehiscence | 1 Participants |
| 4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks | Key Safety Endpoints | Perforation | 0 Participants |
| 4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks | Key Safety Endpoints | Death | 0 Participants |
| 4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks | Key Safety Endpoints | Seizure | 2 Participants |
| 4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks | Key Safety Endpoints | Strictures | 0 Participants |
| 4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks | Key Safety Endpoints | Development of Candidiasis | 0 Participants |
Primary
Meropenem Clearance
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.
Time frame: Up to 7-8hrs post drug administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1. GA <32 Wks; PNA<2 Wks | Meropenem Clearance | 0.089 L/h/kg | Standard Deviation 0.027 |
| 2. GA <32 Wks; PNA 91days ≥ 2Wks | Meropenem Clearance | 0.122 L/h/kg | Standard Deviation 0.037 |
| 3. GA ≥ 32 Wks; PNA <2 Wks | Meropenem Clearance | 0.135 L/h/kg | Standard Deviation 0.04 |
| 4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks | Meropenem Clearance | 0.202 L/h/kg | Standard Deviation 0.061 |