Trial Outcomes & Findings for Pharmacokinetic (PK) and Safety Study of Meropenem in Young Infants With Intra-abdominal Infections (NCT NCT00621192)

Last Updated: 2023-04-25

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

200 participants

Primary outcome timeframe

Average of 12 days (3 to 21 days)

Results posted on

2023-04-25

Participant Flow

Enrollment Period - June 19, 2008 to October 6, 2009 Locations - Hospitals including University Hospitals Total number of sites - 24 Total number of participants - 200

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.

Participant milestones

Participant milestones
Measure	1. GA <32 Wks; PNA<2 Wks Group 1: GA at birth below 32 weeks - PNA \< 2 weeks;	2. GA <32 Wks; PNA 91days ≥ 2Wks Group 2: GA at birth below 32 weeks - PNA ≥ 2 weeks and \< 91 days	3. GA ≥ 32 Wks; PNA <2 Wks Group 3: GA at birth 32 weeks or older - PNA \< 2 weeks;	4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks Group 4: GA at birth 32 weeks or older - PNA ≥ 2 weeks and \< 91 days.
Overall Study STARTED	39	103	31	27
Overall Study Safety Population	39	103	31	27
Overall Study Efficacy Population	39	101	28	27
Overall Study COMPLETED	35	94	26	24
Overall Study NOT COMPLETED	4	9	5	3

Reasons for withdrawal

Reasons for withdrawal
Measure	1. GA <32 Wks; PNA<2 Wks Group 1: GA at birth below 32 weeks - PNA \< 2 weeks;	2. GA <32 Wks; PNA 91days ≥ 2Wks Group 2: GA at birth below 32 weeks - PNA ≥ 2 weeks and \< 91 days	3. GA ≥ 32 Wks; PNA <2 Wks Group 3: GA at birth 32 weeks or older - PNA \< 2 weeks;	4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks Group 4: GA at birth 32 weeks or older - PNA ≥ 2 weeks and \< 91 days.
Overall Study Withdrawal by Subject	0	0	2	0
Overall Study Physician Decision	1	3	0	0
Overall Study Protocol Violation	1	0	0	1
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

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	1. GA <32 Wks; PNA<2 Wks n=39 Participants Group 1: GA at birth below 32 weeks - PNA \< 2 weeks;	2. GA <32 Wks; PNA 91days ≥ 2Wks n=103 Participants Group 2: GA at birth below 32 weeks - PNA ≥ 2 weeks and \< 91 days	3. GA ≥ 32 Wks; PNA <2 Wks n=31 Participants Group 3: GA at birth 32 weeks or older - PNA \< 2 weeks;	4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks n=27 Participants Group 4: GA at birth 32 weeks or older - PNA ≥ 2 weeks and \< 91 days.	Total n=200 Participants Total of all reporting groups
Age, Continuous Mean Postnatal Age	8.5 Days STANDARD_DEVIATION 3.3 • n=5 Participants	38.3 Days STANDARD_DEVIATION 19.3 • n=7 Participants	6.5 Days STANDARD_DEVIATION 3.5 • n=5 Participants	36.0 Days STANDARD_DEVIATION 22.0 • n=4 Participants	27.3 Days STANDARD_DEVIATION 21.6 • n=21 Participants
Sex: Female, Male Female	15 Participants n=5 Participants	47 Participants n=7 Participants	9 Participants n=5 Participants	11 Participants n=4 Participants	82 Participants n=21 Participants
Sex: Female, Male Male	24 Participants n=5 Participants	56 Participants n=7 Participants	22 Participants n=5 Participants	16 Participants n=4 Participants	118 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=5 Participants	16 Participants n=7 Participants	4 Participants n=5 Participants	3 Participants n=4 Participants	28 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	32 Participants n=5 Participants	81 Participants n=7 Participants	27 Participants n=5 Participants	24 Participants n=4 Participants	164 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	6 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	8 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	2 Participants n=21 Participants
Race (NIH/OMB) Black or African American	12 Participants n=5 Participants	33 Participants n=7 Participants	8 Participants n=5 Participants	5 Participants n=4 Participants	58 Participants n=21 Participants
Race (NIH/OMB) White	25 Participants n=5 Participants	65 Participants n=7 Participants	21 Participants n=5 Participants	18 Participants n=4 Participants	129 Participants n=21 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants	5 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	4 Participants n=21 Participants

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	1. GA <32 Wks; PNA<2 Wks n=39 Participants Group 1: GA at birth below 32 weeks - PNA \< 2 weeks;	2. GA <32 Wks; PNA 91days ≥ 2Wks n=98 Participants Group 2: GA at birth below 32 weeks - PNA ≥ 2 weeks and \< 91 days	3. GA ≥ 32 Wks; PNA <2 Wks n=28 Participants Group 3: GA at birth 32 weeks or older - PNA \< 2 weeks;	4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks n=27 Participants Group 4: GA at birth 32 weeks or older - PNA ≥ 2 weeks and \< 91 days.
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	82 Participants	26 Participants	25 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	1. GA <32 Wks; PNA<2 Wks n=39 Participants Group 1: GA at birth below 32 weeks - PNA \< 2 weeks;	2. GA <32 Wks; PNA 91days ≥ 2Wks n=103 Participants Group 2: GA at birth below 32 weeks - PNA ≥ 2 weeks and \< 91 days	3. GA ≥ 32 Wks; PNA <2 Wks n=31 Participants Group 3: GA at birth 32 weeks or older - PNA \< 2 weeks;	4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks n=27 Participants Group 4: GA at birth 32 weeks or older - PNA ≥ 2 weeks and \< 91 days.
Deaths	3 Participants	8 Participants	0 Participants	0 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	1. GA <32 Wks; PNA<2 Wks n=39 Participants Group 1: GA at birth below 32 weeks - PNA \< 2 weeks;	2. GA <32 Wks; PNA 91days ≥ 2Wks n=98 Participants Group 2: GA at birth below 32 weeks - PNA ≥ 2 weeks and \< 91 days	3. GA ≥ 32 Wks; PNA <2 Wks n=28 Participants Group 3: GA at birth 32 weeks or older - PNA \< 2 weeks;	4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks n=27 Participants Group 4: GA at birth 32 weeks or older - PNA ≥ 2 weeks and \< 91 days.
Meropenem Clearance	0.089 L/h/kg Standard Deviation 0.027	0.122 L/h/kg Standard Deviation 0.037	0.135 L/h/kg Standard Deviation 0.040	0.202 L/h/kg Standard Deviation 0.061

PRIMARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	1. GA <32 Wks; PNA<2 Wks n=39 Participants Group 1: GA at birth below 32 weeks - PNA \< 2 weeks;	2. GA <32 Wks; PNA 91days ≥ 2Wks n=103 Participants Group 2: GA at birth below 32 weeks - PNA ≥ 2 weeks and \< 91 days	3. GA ≥ 32 Wks; PNA <2 Wks n=31 Participants Group 3: GA at birth 32 weeks or older - PNA \< 2 weeks;	4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks n=27 Participants Group 4: GA at birth 32 weeks or older - PNA ≥ 2 weeks and \< 91 days.
Key Safety Endpoints Death	3 Participants	8 Participants	0 Participants	0 Participants
Key Safety Endpoints Seizure	4 Participants	3 Participants	1 Participants	2 Participants
Key Safety Endpoints Strictures	0 Participants	0 Participants	0 Participants	0 Participants
Key Safety Endpoints Perforation	2 Participants	2 Participants	0 Participants	0 Participants
Key Safety Endpoints Wound Dehiscence	1 Participants	1 Participants	1 Participants	1 Participants
Key Safety Endpoints Development of Candidiasis	5 Participants	3 Participants	0 Participants	0 Participants
Key Safety Endpoints Antimicrobial Therapy Failure	7 Participants	12 Participants	2 Participants	2 Participants

Adverse Events

1. GA <32 Wks; PNA<2 Wks

Serious events: 9 serious events

Other events: 9 other events

Deaths: 0 deaths

2. GA <32 Wks; PNA 91days ≥ 2Wks

Serious events: 18 serious events

Other events: 8 other events

Deaths: 0 deaths

3. GA ≥ 32 Wks; PNA <2 Wks

Serious events: 2 serious events

Other events: 2 other events

Deaths: 0 deaths

4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks

Serious events: 5 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	1. GA <32 Wks; PNA<2 Wks n=39 participants at risk Group 1: GA at birth below 32 weeks - PNA \< 2 weeks;	2. GA <32 Wks; PNA 91days ≥ 2Wks n=103 participants at risk Group 2: GA at birth below 32 weeks - PNA ≥ 2 weeks and \< 91 days	3. GA ≥ 32 Wks; PNA <2 Wks n=31 participants at risk Group 3: GA at birth 32 weeks or older - PNA \< 2 weeks;	4. GA ≥32 Wks; PNA 91 Days ≥ 2 Wks n=27 participants at risk Group 4: GA at birth 32 weeks or older - PNA ≥ 2 weeks and \< 91 days.
Infections and infestations Sepsis	12.8% 5/39 • Number of events 12 • Adverse Events (AEs) were recorded from the time of informed consent until 72 hours following the last dose of study drug for non-Serious Adverse Events (SAEs) and until 30 days after the last dose of study drug for SAEs. Any AE that occurred between the time informed consent was obtained and the initial dose of study, that was considered related to a protocol specified procedure, were reported. The Investigator was responsible for assessing relationship of AE to study medication using the following definitions:Not related, possibly, probably or definitely related.	4.9% 5/103 • Number of events 12 • Adverse Events (AEs) were recorded from the time of informed consent until 72 hours following the last dose of study drug for non-Serious Adverse Events (SAEs) and until 30 days after the last dose of study drug for SAEs. Any AE that occurred between the time informed consent was obtained and the initial dose of study, that was considered related to a protocol specified procedure, were reported. The Investigator was responsible for assessing relationship of AE to study medication using the following definitions:Not related, possibly, probably or definitely related.	3.2% 1/31 • Number of events 12 • Adverse Events (AEs) were recorded from the time of informed consent until 72 hours following the last dose of study drug for non-Serious Adverse Events (SAEs) and until 30 days after the last dose of study drug for SAEs. Any AE that occurred between the time informed consent was obtained and the initial dose of study, that was considered related to a protocol specified procedure, were reported. The Investigator was responsible for assessing relationship of AE to study medication using the following definitions:Not related, possibly, probably or definitely related.	3.7% 1/27 • Number of events 12 • Adverse Events (AEs) were recorded from the time of informed consent until 72 hours following the last dose of study drug for non-Serious Adverse Events (SAEs) and until 30 days after the last dose of study drug for SAEs. Any AE that occurred between the time informed consent was obtained and the initial dose of study, that was considered related to a protocol specified procedure, were reported. The Investigator was responsible for assessing relationship of AE to study medication using the following definitions:Not related, possibly, probably or definitely related.
Nervous system disorders Convulsion	10.3% 4/39 • Number of events 10 • Adverse Events (AEs) were recorded from the time of informed consent until 72 hours following the last dose of study drug for non-Serious Adverse Events (SAEs) and until 30 days after the last dose of study drug for SAEs. Any AE that occurred between the time informed consent was obtained and the initial dose of study, that was considered related to a protocol specified procedure, were reported. The Investigator was responsible for assessing relationship of AE to study medication using the following definitions:Not related, possibly, probably or definitely related.	2.9% 3/103 • Number of events 10 • Adverse Events (AEs) were recorded from the time of informed consent until 72 hours following the last dose of study drug for non-Serious Adverse Events (SAEs) and until 30 days after the last dose of study drug for SAEs. Any AE that occurred between the time informed consent was obtained and the initial dose of study, that was considered related to a protocol specified procedure, were reported. The Investigator was responsible for assessing relationship of AE to study medication using the following definitions:Not related, possibly, probably or definitely related.	3.2% 1/31 • Number of events 10 • Adverse Events (AEs) were recorded from the time of informed consent until 72 hours following the last dose of study drug for non-Serious Adverse Events (SAEs) and until 30 days after the last dose of study drug for SAEs. Any AE that occurred between the time informed consent was obtained and the initial dose of study, that was considered related to a protocol specified procedure, were reported. The Investigator was responsible for assessing relationship of AE to study medication using the following definitions:Not related, possibly, probably or definitely related.	7.4% 2/27 • Number of events 10 • Adverse Events (AEs) were recorded from the time of informed consent until 72 hours following the last dose of study drug for non-Serious Adverse Events (SAEs) and until 30 days after the last dose of study drug for SAEs. Any AE that occurred between the time informed consent was obtained and the initial dose of study, that was considered related to a protocol specified procedure, were reported. The Investigator was responsible for assessing relationship of AE to study medication using the following definitions:Not related, possibly, probably or definitely related.

Additional Information

David Siegel, MD

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Phone: 301-595-8670

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place