Presepsin to Safely Reduce Antibiotics in Preterm Infants (PRESAFE)

Presepsin to Safely Reduce Antibiotics in Preterm Infants: a Randomized Controlled Trial

In the Netherlands, more than 85% of the preterm infants born <32 weeks gestational age get antibiotics directly after birth because of the risk of infection with a bacteria. However, only 1 in 70 of these preterm babies actually has a bacterial infection. The use of antibiotics after birth can lead to problems on short term (bowel infection, infection with a bacteria later on or death) or long term (asthma, allergy, obesity).

The goal of the PRESAFE trial is to investigate whether addition of a biomarker (presepsin) to the Dutch early-onset neonatal sepsis (EOS) guideline safely reduces unnecessary empirical antibiotic exposure after birth in preterm infants born before 32 weeks gestational age. In this 874-subject multicenter, randomized clinical trial with a concurrent observational cohort, the hypothesis to be tested is that by adding presepsin to the national guideline the amount of unnecessary empirical antibiotic exposure after birth will be reduced with at least 30% without increase in infants with untreated sepsis. The study targets a population of clinical stable very preterm infants with risk factors for eary-onset neonatal sepsis. Antibiotic administration after birth is started to pre-emptively treat EOS.

By adding a presepsin-guided step to the Dutch EOS guideline for those infants qualifying for antibiotic treatment, it is assumed that the rate of antibiotic administration can be reduced. However, it is imperative that this reduction in antibiotics is not outweighed by an increase in (culture proven) EOS. Therefore, the co-primary outcomes of the study are: 1) the incidence of culture-proven EOS (non-inferiority) and 2) unnecessary antibiotics prescription i.e. antibiotic administration for ≤ 3 days when started within the first 72 hours after birth (superiority). Secondary outcomes include sepsis-related severity of illness, total number of antibiotic days when started < 72 hours after birth, and the composite outcome of necrotizing enterocolitis (NEC), late-onset sepsis (LOS), or death until discharge from the initial hospital.

Study Overview

• Status: Recruiting
• Conditions: Early-Onset Neonatal Sepsis
• Intervention / Treatment: Diagnostic test: Presepsin; Diagnostic test: Standard Care

Detailed Description

STUDY POPULATION

All infants born at a gestational age of 24+0 to 31 6/7 weeks are eligible for enrollment. As part of standard care all infants will be screened and classified according to the Dutch EOS guideline for the indication of starting empirical antibiotics:

i. Infants at low risk of EOS who do not have an indication for empirical antibiotics according to the Dutch EOS guideline;

ii. Infants at high risk of EOS defined as: 1) suspected or confirmed diagnosis of maternal sepsis; 2) suspected or proven EOS in other infants (in case of multiple births) or infants born to mothers with previous infant with GBS disease/infection; 3) unexplained respiratory insufficiency requiring invasive mechanical ventilation and FiO2>0.40 or non-invasive ventilation with FiO2 >0.60 at time of randomization; 4) ongoing hemodynamic instability requiring inotrope medication or more than one 10 ml/kg fluid bolus at time of randomization; 5) strong clinical concern for sepsis due to physical exam findings (i.e. minimal responsiveness, poor tone).

iii. Infants at moderate risk of EOS who should be treated with empirical antibiotics based on the Dutch EOS guideline. In this group of infants the risks and benefits of receiving empiric antibiotics remain unclear and clinical equipoise is suggested.

Infants in category i. and ii. will be excluded for randomization and included in the observational part of the study; these patients will be further treated according to the Dutch EOS guideline. Infants in category iii. are eligible to be included in the RCT-part of the study.

RANDOMIZATION

Included category iii infants will be evaluated for EOS with blood culture and randomly assigned (1:1) to one of the following study groups:

Intervention-group, presepsin-guided therapy: The decision to start empirical antibiotics in this group will be based on presepsin measurement within four hours after birth. When the presepsin value is above the cut-off value of 645 pg/ml, antibiotics will be ordered and administered within 4 hours of life and discontinued following the criteria of the Dutch EOS guideline. Cessation of antibiotic treatment typically occurs when blood culture results remain sterile within 3 days after birth.

When the presepsin level is below the cut-off value of 645 pg/ml, the treating physician will not start antibiotic treatment. These infants will be closely observed for at least 72 hours. In case of deterioration of the clinical condition within this observation period, the clinician can decide to perform a sepsis evaluation and start with antibiotic treatment. Investigators anticipate that <5% of infant subjects will experience worsening of conditions. When the initial blood culture in this group turns back positive without clinical signs and symptoms of EOS sepsis, a new blood culture and antibiotic treatment will be advised.

Comparator-group, standard care: Standard care according to the Dutch EOS guideline. Presepsin will be determined with the treating physician blinded for the test result. In the Dutch EOS guideline maternal and neonatal risk factors for EOS are categorized as red flags or minor criteria. In the presence of 1 red flag or ≥ 2 minor criteria it is advised to perform a blood culture (= sepsis evaluation) and start empirical antibiotics for EOS suspicion.2 Antibiotic treatment will be advised to discontinue when blood culture turns back negative, reassuring the infants clinical condition with no other indicators of possible infection (e.g. CRP).

Randomization will be performed centrally, using web-based block randomization stratified by study site with random permuted blocks within the strata. Randomization sequence is generated using Castor EDC, which is regulatory compliant software, ensuring allocation concealment. Multiples (i.e. siblings) will be randomized to the same treatment arm.

• Study Type: Interventional
• Enrollment (Estimated): 900
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Douwe Visser, MD PhD; Phone Number: +31205669111; Email: d.h.visser@amsterdamumc.nl
• Study Contact Backup: Name: Charlotte Nusman, MD PhD; Phone Number: +31205669111; Email: c.m.nusman@amsterdamumc.nl

Study Locations

• Netherlands
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1105 AZ
      • Recruiting
      • Amsterdam UMC
      • Contact: Douwe Visser, MD PhD; Phone Number: 0031205669111; Email: d.h.visser@amsterdamumc.nl
      • Contact: Charlotte Nusman, MD PhD; Phone Number: 0031205669111; Email: c.m.nusman@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Infants born at a gestational age of 24+0 to 31 6/7 weeks
• Moderate risk of early-onset neonatal sepsis, i.e. infants who should be treated with empirical antibiotics based on the Dutch EOS guideline.

Exclusion Criteria:

• low risk of early-onset neonatal sepsis who do not have an indication for empirical antibiotics according to the Dutch EOS guideline;

• high risk of early-onset neonatal sepsis defined as:

  1. suspected or confirmed diagnosis of maternal sepsis;
  2. suspected or proven EOS in other infants (in case of multiple births) or infants born to mothers with previous infant with GBS disease/infection;
  3. unexplained respiratory insufficiency requiring invasive mechanical ventilation and FiO2>0.40 or non-invasive ventilation with FiO2 >0.60 at time of randomization;
  4. ongoing hemodynamic instability requiring inotrope medication or more than one 10 ml/kg fluid bolus at time of randomization;
  5. strong clinical concern for sepsis due to physical exam findings (i.e. minimal responsiveness, poor tone).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Presepsin-guided therapy; The decision to start empirical antibiotics in this group will be based on presepsin measurement within four hours after birth. When the presepsin value is above the cut-off value of 645 pg/ml, antibiotics will be ordered and administered within 4 hours of life and discontinued following the criteria of the Dutch EOS guideline. When the presepsin level is below the cut-off value of 645 pg/ml, the treating physician will not start antibiotic treatment. These infants will be closely observed for at least 72 hours. In case of deterioration of the clinical condition within this observation period, the clinician can decide to perform a sepsis evaluation and start with antibiotic treatment.	Diagnostic test: Presepsin; Umbilical cord blood or blood from the first routine venous puncture within four hours after birth will be used for presepsin determination. Presepsin measurement can be performed in 100 μl plasma with "PATHFAST™ Presepsin" which is a rapid chemiluminescent enzyme immunoassay (Mitsubishi Chemical Medience corporation, Tokyo, Japan) with results available within 15 minutes.
Active Comparator: Standard care; Standard care according to the Dutch EOS guideline. Presepsin will be determined with the treating physician blinded for the test result. In the Dutch EOS guideline maternal and neonatal risk factors for EOS are categorized as red flags or minor criteria. In the presence of 1 red flag or ≥ 2 minor criteria it is advised to perform a blood culture (= sepsis evaluation) and start empirical antibiotics for EOS suspicion. Antibiotic treatment will be advised to discontinue when blood culture turns back negative, reassuring the infants clinical condition with no other indicators of possible infection (e.g. CRP).	Diagnostic test: Standard Care; Standard care according to the Dutch EOS guideline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the incidence of culture-proven early-onset sepsis	non-inferiority	72 hours after birth
presence of unnecessary antibiotics prescription	antibiotic administration for ≤3 days when started within the first 72 hours after birth (superiority)	72 hours after birth

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
sepsis-associated severity of illness (nSOFA)	Sepsis-associated severity of illness will be evaluated with the nSOFA score (a combination of respiratory, cardiovascular and hematologic dysfunction)	from birth until discharge from initial hospital (up to 6 months)
sepsis-associated severity of illness (meningitis)	Sepsis-associated severity of illness will be evaluated with the incidence of meningitis within seven days after disease onset.	from birth until discharge from initial hospital (up to 6 months)
sepsis-associated severity of illness (death)	Sepsis-associated severity of illness will be evaluated with the incidence of death within seven days after disease onset.	from birth until discharge from initial hospital (up to 6 months)
total number of antibiotic days when started < 72 hours after birth		from birth until discharge from initial hospital (up to 6 months)
Presence of necrotizing enterocolitis and/or late-onset sepsis and/or death	NEC is defined by Bell's stages II or III. LOS is defined as a positive blood culture obtained after 72 hours of life and intent to treat with antibiotics for 5 days or more. Death is defined as death during the index hospitalization.	from birth until discharge from initial hospital (up to 6 months)

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: Douwe Visser, MD PhD, Amsterdam UMC

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2024
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: October 15, 2023
• First Submitted That Met QC Criteria: October 20, 2023
• First Posted (Actual): October 25, 2023

Study Record Updates

• Last Update Posted (Estimated): October 2, 2025
• Last Update Submitted That Met QC Criteria: September 30, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: preterm infants; antibiotics; presepsin
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Neonatal Sepsis
• Other Study ID Numbers: 10140022210043

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: Data will become available after publication of the main article in peer-reviewed journal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No