Ignite Creation Date:
2026-03-26 @ 3:19 PM
Ignite Modification Date:
2026-03-31 @ 12:38 PM
Study NCT ID:
NCT07484633
Status:
NOT_YET_RECRUITING
Last Update Posted:
2026-03-20
First Post:
2026-03-03
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
A Randomised Study to Compare the Efficacy and Safety of Extended and Intermittent Infusion of Beta-lactams in Critically Ill Paediatric Patients.
Sponsor:
Semmelweis University
Organization:
Study Overview
Official Title:
A Protocol of a Randomised, Two-arm Superiority Study to Compare the Efficacy and Safety of Extended and Intermittent Infusion of Beta-lactams in Critically Ill Paediatric Patients.
Status:
NOT_YET_RECRUITING
Status Verified Date:
2026-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PEBBLE
Brief Summary:
The goal of this clinical trial is to examine the success and safety of administering certain antibiotics (beta-lactams) given in a longer 3-hour infusion to children (0-17 years) who are critically ill and have severe infection.
The main question it aims to answer is:
Is the longer infusion more effective than the conventional short-term (0.5-hour-long) infusion? Researchers will compare the 3-hour-long infusion group to the 0.5-hour-long infusion group to determine whether the longer infusion can cure the infection earlier and whether it is equally safe. The doses are the same in the two groups. Only the duration differs until the patient receives the antibiotic.
Participants will:
* be given the required antibiotic drug in a 3-hour-long or in a 0.5 hour-long infusion.
* be examined to make sure their blood drug levels are correct. This will require two blood tests.
* be treated according to routine care and have examinations and blood tests performed.
The main question it aims to answer is:
Is the longer infusion more effective than the conventional short-term (0.5-hour-long) infusion? Researchers will compare the 3-hour-long infusion group to the 0.5-hour-long infusion group to determine whether the longer infusion can cure the infection earlier and whether it is equally safe. The doses are the same in the two groups. Only the duration differs until the patient receives the antibiotic.
Participants will:
* be given the required antibiotic drug in a 3-hour-long or in a 0.5 hour-long infusion.
* be examined to make sure their blood drug levels are correct. This will require two blood tests.
* be treated according to routine care and have examinations and blood tests performed.
Detailed Description:
Treatment begins with a short, intermittent infusion of antibiotics. If the patient meets study criteria, randomisation must occur within 24 hours. Prior to enrolment, written informed consent or a declaration of contribution must be signed by the legal guardian and, where age-appropriate, the patient.
Plans for the collection and laboratory evaluation of biological samples:
Per protocol:
This study involves collecting blood samples (200 µl per sample) to monitor drug levels, with each sample identified by the patient's assigned PIN. To ensure measurements reflect steady-state conditions, samples must be collected at least 48 hours after the first post-allocation dose and immediately prior to the next scheduled dose (trough or minimum level). Analysis of free (unbound) drug concentrations is performed via High-Performance Liquid Chromatography (HPLC) with specific absorbance detection for meropenem (290 nm), piperacillin (252 nm), tazobactam (210 nm), and cefepime (263 nm); ceftriaxone is measured using liquid chromatography-mass spectrometry (LC-MS).
For evaluating the drug levels:
Pathogen MIC values will be sourced directly from the microbiology laboratory when available; otherwise, values will be retrieved from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) database. In place of a measured MIC, the epidemiological cut-off value (ECOFF)-representing the upper MIC limit for wild-type, non-resistant bacteria-may be used. For empirical dosing where no specific pathogen is identified, the highest MIC for antibiotic-susceptible bacteria will be applied to account for a worst-case scenario.
Standard care:
Routine laboratory assessments-including a complete blood count (CBC) and blood chemistry tests-will be conducted at enrolment and daily thereafter. To ensure accuracy, samples must be analysed within 1-2 hours of collection. Baseline data will include inflammatory markers (C-reactive protein \[CRP\], procalcitonin \[PCT\]), hematological parameters (white blood cell count \[WBC\], platelet count), liver function (liver enzymes and total/direct bilirubin), and serum creatinine. Additionally, clinical severity will be assessed using Paediatric Index of Mortality 3 (PIM-3), Paediatric Risk of Mortality III (PRISM III), and Paediatric Logistic Organ Dysfunction 2 (PELOD 2) scores. While all patients require a pre-antibiotic blood culture, those with negative cultures will be excluded from the microbiological eradication analysis.
In cases where microbiological cultures are negative, the clinician will diagnose infection based on clinical signs and symptoms. These signs and symptoms will also be examined when assessing the clinical response outcome.
Signs of infection may include elevated acute phase proteins (CRP \> 10 mg/L or PCT \> 0.5 µg/L or WBC \> 10,000 /µL), or infection/inflammation confirmed by imaging and any clinical signs (fever \> 37.5 °C core temperature or haemodynamic instability - need for inotropic or vasopressor therapy or abnormal blood gas values (normal arterial blood gas values: pH=7.35-7.45, PaO2=80-100 mmHg, PCO2=35-45 mmHg, \[HCO3-\]=22-28 mEq/L and lactate\<3 mmol/L; normal venous blood gas values: pH=7.31-7.41, PvO2=35-45 mmHg, PCO2=41-51 mmHg, \[HCO3-\]=22-28 mEq/L and lactate\<3 mmol/L; normal capillary blood gas values: pH=7.35-7.45, PCO2=35-45 mmHg, \[HCO3-\]=22-28 mEq/L) or respiratory failure or neurological signs or enteral feeding intolerance.
Criteria for discontinuation or modification of designated interventions:
If blood samples reveal sub-therapeutic antibiotic levels (underexposure), dosing must be adjusted by increasing the dose or the frequency of administration. All adjustments must be documented. Patients requiring these changes will remain in their originally assigned study arm for analysis under the modified intention-to-treat (mITT) population; crossover between study arms is strictly prohibited. In the event of clinician-reported adverse events, the Steering Committee (SC) will determine whether the antibiotic should be discontinued.
If β-lactam therapy must be changed due to clinical deterioration or antibiotic resistance, and the new antibiotic is also a study β-lactam (meropenem, piperacillin/tazobactam, cefepime, or ceftriaxone), the patient remains in the assigned arm (EI or SI) and is not excluded.
All patients are followed for 30 days post-allocation or until discharge or death. For patients discharged before the 30-day mark, a telephone follow-up will be conducted on day 30 to evaluate their clinical status.
Plans for the collection and laboratory evaluation of biological samples:
Per protocol:
This study involves collecting blood samples (200 µl per sample) to monitor drug levels, with each sample identified by the patient's assigned PIN. To ensure measurements reflect steady-state conditions, samples must be collected at least 48 hours after the first post-allocation dose and immediately prior to the next scheduled dose (trough or minimum level). Analysis of free (unbound) drug concentrations is performed via High-Performance Liquid Chromatography (HPLC) with specific absorbance detection for meropenem (290 nm), piperacillin (252 nm), tazobactam (210 nm), and cefepime (263 nm); ceftriaxone is measured using liquid chromatography-mass spectrometry (LC-MS).
For evaluating the drug levels:
Pathogen MIC values will be sourced directly from the microbiology laboratory when available; otherwise, values will be retrieved from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) database. In place of a measured MIC, the epidemiological cut-off value (ECOFF)-representing the upper MIC limit for wild-type, non-resistant bacteria-may be used. For empirical dosing where no specific pathogen is identified, the highest MIC for antibiotic-susceptible bacteria will be applied to account for a worst-case scenario.
Standard care:
Routine laboratory assessments-including a complete blood count (CBC) and blood chemistry tests-will be conducted at enrolment and daily thereafter. To ensure accuracy, samples must be analysed within 1-2 hours of collection. Baseline data will include inflammatory markers (C-reactive protein \[CRP\], procalcitonin \[PCT\]), hematological parameters (white blood cell count \[WBC\], platelet count), liver function (liver enzymes and total/direct bilirubin), and serum creatinine. Additionally, clinical severity will be assessed using Paediatric Index of Mortality 3 (PIM-3), Paediatric Risk of Mortality III (PRISM III), and Paediatric Logistic Organ Dysfunction 2 (PELOD 2) scores. While all patients require a pre-antibiotic blood culture, those with negative cultures will be excluded from the microbiological eradication analysis.
In cases where microbiological cultures are negative, the clinician will diagnose infection based on clinical signs and symptoms. These signs and symptoms will also be examined when assessing the clinical response outcome.
Signs of infection may include elevated acute phase proteins (CRP \> 10 mg/L or PCT \> 0.5 µg/L or WBC \> 10,000 /µL), or infection/inflammation confirmed by imaging and any clinical signs (fever \> 37.5 °C core temperature or haemodynamic instability - need for inotropic or vasopressor therapy or abnormal blood gas values (normal arterial blood gas values: pH=7.35-7.45, PaO2=80-100 mmHg, PCO2=35-45 mmHg, \[HCO3-\]=22-28 mEq/L and lactate\<3 mmol/L; normal venous blood gas values: pH=7.31-7.41, PvO2=35-45 mmHg, PCO2=41-51 mmHg, \[HCO3-\]=22-28 mEq/L and lactate\<3 mmol/L; normal capillary blood gas values: pH=7.35-7.45, PCO2=35-45 mmHg, \[HCO3-\]=22-28 mEq/L) or respiratory failure or neurological signs or enteral feeding intolerance.
Criteria for discontinuation or modification of designated interventions:
If blood samples reveal sub-therapeutic antibiotic levels (underexposure), dosing must be adjusted by increasing the dose or the frequency of administration. All adjustments must be documented. Patients requiring these changes will remain in their originally assigned study arm for analysis under the modified intention-to-treat (mITT) population; crossover between study arms is strictly prohibited. In the event of clinician-reported adverse events, the Steering Committee (SC) will determine whether the antibiotic should be discontinued.
If β-lactam therapy must be changed due to clinical deterioration or antibiotic resistance, and the new antibiotic is also a study β-lactam (meropenem, piperacillin/tazobactam, cefepime, or ceftriaxone), the patient remains in the assigned arm (EI or SI) and is not excluded.
All patients are followed for 30 days post-allocation or until discharge or death. For patients discharged before the 30-day mark, a telephone follow-up will be conducted on day 30 to evaluate their clinical status.
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?: