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Presepsin to Safely Reduce Antibiotics in Preterm Infants (PRESAFE)

Primary Purpose

Early-Onset Neonatal Sepsis

Status
Not yet recruiting
Phase
Not Applicable
Locations
Study Type
Interventional
Intervention
Presepsin
Standard Care
Sponsored by
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Early-Onset Neonatal Sepsis focused on measuring preterm infants, antibiotics, presepsin

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Active Comparator

    Arm Label

    Presepsin-guided therapy

    Standard care

    Arm Description

    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.

    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).

    Outcomes

    Primary Outcome Measures

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

    Secondary Outcome Measures

    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)
    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.
    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.
    total number of antibiotic days when started < 72 hours after birth
    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.

    Full Information

    First Posted
    October 15, 2023
    Last Updated
    October 20, 2023
    Sponsor
    Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
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    1. Study Identification

    Unique Protocol Identification Number
    NCT06100614
    Brief Title
    Presepsin to Safely Reduce Antibiotics in Preterm Infants
    Acronym
    PRESAFE
    Official Title
    Presepsin to Safely Reduce Antibiotics in Preterm Infants: a Randomized Controlled Trial
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    October 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    January 1, 2024 (Anticipated)
    Primary Completion Date
    January 1, 2026 (Anticipated)
    Study Completion Date
    January 1, 2026 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    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.
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Early-Onset Neonatal Sepsis
    Keywords
    preterm infants, antibiotics, presepsin

    7. Study Design

    Primary Purpose
    Diagnostic
    Study Phase
    Not Applicable
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    900 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Presepsin-guided therapy
    Arm Type
    Experimental
    Arm Description
    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.
    Arm Title
    Standard care
    Arm Type
    Active Comparator
    Arm Description
    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).
    Intervention Type
    Diagnostic Test
    Intervention Name(s)
    Presepsin
    Intervention Description
    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.
    Intervention Type
    Diagnostic Test
    Intervention Name(s)
    Standard Care
    Intervention Description
    Standard care according to the Dutch EOS guideline
    Primary Outcome Measure Information:
    Title
    the incidence of culture-proven early-onset sepsis
    Description
    non-inferiority
    Time Frame
    72 hours after birth
    Title
    presence of unnecessary antibiotics prescription
    Description
    antibiotic administration for ≤3 days when started within the first 72 hours after birth (superiority)
    Time Frame
    72 hours after birth
    Secondary Outcome Measure Information:
    Title
    sepsis-associated severity of illness (nSOFA)
    Description
    Sepsis-associated severity of illness will be evaluated with the nSOFA score (a combination of respiratory, cardiovascular and hematologic dysfunction)
    Time Frame
    from birth until discharge from initial hospital (up to 6 months)
    Title
    sepsis-associated severity of illness (meningitis)
    Description
    Sepsis-associated severity of illness will be evaluated with the incidence of meningitis within seven days after disease onset.
    Time Frame
    from birth until discharge from initial hospital (up to 6 months)
    Title
    sepsis-associated severity of illness (death)
    Description
    Sepsis-associated severity of illness will be evaluated with the incidence of death within seven days after disease onset.
    Time Frame
    from birth until discharge from initial hospital (up to 6 months)
    Title
    total number of antibiotic days when started < 72 hours after birth
    Time Frame
    from birth until discharge from initial hospital (up to 6 months)
    Title
    Presence of necrotizing enterocolitis and/or late-onset sepsis and/or death
    Description
    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.
    Time Frame
    from birth until discharge from initial hospital (up to 6 months)

    10. Eligibility

    Sex
    All
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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: suspected or confirmed diagnosis of maternal sepsis; suspected or proven EOS in other infants (in case of multiple births) or infants born to mothers with previous infant with GBS disease/infection; unexplained respiratory insufficiency requiring invasive mechanical ventilation and FiO2>0.40 or non-invasive ventilation with FiO2 >0.60 at time of randomization; ongoing hemodynamic instability requiring inotrope medication or more than one 10 ml/kg fluid bolus at time of randomization; strong clinical concern for sepsis due to physical exam findings (i.e. minimal responsiveness, poor tone).
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Douwe Visser, MD PhD
    Phone
    +31205669111
    Email
    d.h.visser@amsterdamumc.nl
    First Name & Middle Initial & Last Name or Official Title & Degree
    Charlotte Nusman, MD PhD
    Phone
    +31205669111
    Email
    c.m.nusman@amsterdamumc.nl

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Time Frame
    Data will become available after publication of the main article in peer-reviewed journal.

    Learn more about this trial

    Presepsin to Safely Reduce Antibiotics in Preterm Infants

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