Clinical trial NCT05274776: Safely Reduce Newborn Antibiotic Exposure With the Early-onset Sepsis Calculator
Official title: Safely Reduce Newborn Antibiotic Exposure With the Early-onset Sepsis Calculator: a Cluster Randomized Study (EOS Calculator RCT)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Early-Onset Sepsis, Neonatal
EOS
Keywords: early-onset sepsis
neonatal
EOS calculator
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: Dutch Society of Pediatrics
name: Zorgevaluatie Nederland
name: Care4Neo
name: everywhereIM
First posted: 2022-03-10
Enrollment: 1830
Sex: ALL
Maximum age (years): 24
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A prospective, cluster-randomized trial will be conducted; five hospitals will be randomized to NVK guidelines use, five hospitals will be randomized to EOS calculator use. After randomization, the assigned protocol is considered standard care for newborns with suspected EOS within 0-24 hours after birth during the study period in that hospital. This means that the NVK guidelines or the EOS calculator (depending on randomization) will be used for all newborns at risk for EOS (within 0-24 hours after birth) in the assigned hospital, independent of study participation. It is noteworthy that attending physicians have the option to choose for clinical management according to another protocol instead of the assigned protocol.
Primary purpose: TREATMENT

Brief summary: Newborns are at risk for early-onset sepsis (EOS), which occurs within 72 hours after birth. The incidence of proven EOS is 0.5-2.0 per 1000 live births. The annual birth rate in the Netherlands is around 170.000, consequently the number of EOS cases varies between 85 to 340. However, about 5%, thus 8500, of late preterm and term newborns receive empiric antibiotic therapy in compliance with the current Dutch guideline. An alternative is the CE certified EOS calculator application, which calculates an individual EOS risk with treatment advice. In this prospective cluster-randomized multicenter trial the current Dutch guideline will be compared with the EOS calculator in newborns at risk for EOS.

The primary objectives of this study are:

1. To investigate whether the use of the EOS calculator reduces antibiotic exposure in newborns with suspected EOS in the first 24 hours after birth.
2. To investigate the presence of one or more of the following four predefined safety criteria, namely 1) the need for any respiratory support, and/or 2) the need for an intravascular fluid bolus for hemodynamic instability due to sepsis, and/or 3) referral to a Neonatal Intensive Care Unit for sepsis treatment, and/or 4) proven EOS.

Secondary objectives of the study are:

1. To investigate if the use of the EOS calculator decreases the total duration of antibiotic therapy in newborns with suspected EOS.
2. To investigate if the use of the EOS calculator decreases the percentage of antibiotic therapy started for suspected and, or proven EOS if symptoms started between 24-72 hours after birth.
3. To study the impact of (suspected) EOS on parents/guardians.

Detailed description: Suspicion of EOS is often based on risk factors and nonspecific clinical symptoms, such as maternal fever during labor or rapid breathing in the newborn. The combination of the difficulty to recognize EOS in time and the risk of serious consequences of EOS not treated timely has resulted in a low threshold for the start of empirical antibiotic therapy. This has led to significant overtreatment.

The current standard of care in the Netherlands is the Dutch Society of the Nederlands (NVK) guideline "Prevention and treatment of early-onset neonatal infections", which is an adaptation of the 2012 version of the National Institute for Health and Care Excellence (NICE) guideline "Antibiotics for early-onset neonatal infection: antibiotics for the prevention and treatment of early-onset neonatal infection". The NVK guideline uses risk factors and symptoms to categorically indicate which newborns need antibiotic therapy. Evaluating its use in 9 Dutch hospitals, limited adherence was found, especially when antibiotics were recommended by the guideline but withheld by the clinicians. This limited adherence indicates that it is desirable to amend the current guideline or to investigate the use of an alternative method.

A new method for determining which newborns need antibiotic therapy is the "EOS calculator". Developed in the United States, this method uses a combination of detailed information about 5 maternal risk factors and the presence of clinical neonatal symptoms to calculate an individual EOS risk and treatment advice.

For the Dutch situation, equipoise between the current NVK guideline and the EOS calculator can be established given balance of risk for both over- and undertreatment of EOS for both strategies. A large body of evidence now supports the safety of the EOS calculator approach, but validation outside of the North-American setting is limited, especially for safety outcomes.

A prospective cluster-randomized Dutch validation study of the EOS calculator is needed before implementation because of the following reasons:

1. Multicenter validation of actual EOS calculator use has not been performed in the Netherlands.
2. To date, no randomized prospective study of EOS calculator use with safety as an outcome measure has been performed. Specifically, there are no studies that take into account the potential effects of a treatment delay due to EOS calculator use. This especially holds true for cases that are clinically suspect for EOS, but not culture-confirmed.

Eligibility criteria: Inclusion Criteria:

* postmenstrual age of 34 weeks or more;
* age between 0-24 hours;
* at least one EOS risk factor or clinical sign of infection (suspected of EOS) present within the first 24 hours of life;
* parental/guardian consent.

Exclusion Criteria:

* major congenital anomalies;
* language barrier (lack of effective communication or whenever it hinders understanding).

Primary outcomes:
measure: Co-primary superiority outcome: antibiotic therapy started within 24 hours after birth
timeFrame: 0-24 hours after birth
measure: First co-primary non-inferiority outcome (safety): proportion of patients with respiratory support
timeFrame: 0-14 days after birth
measure: Second co-primary non-inferiority outcome (safety): proportion of patients with hemodynamic support
timeFrame: 0-14 days after birth
measure: Third co-primary non-inferiority outcome (safety): proportion of patients referred to a NICU for sepsis treatment
timeFrame: 0-14 days after birth
measure: Fourth co-primary non-inferiority outcome (safety): proportion of patients with proven EOS
timeFrame: 0-14 days after birth
Secondary outcomes:
measure: Duration of antibiotic therapy
timeFrame: 0-14 days after birth
measure: Antibiotic therapy started between 24-72 hours after birth
timeFrame: 24-72 hours after birth
measure: Questionnaire: quality of life
timeFrame: 14-28 days after birth
Other outcomes:
Locations:
city: Alkmaar
country: Netherlands
facility: Northwest Clinics
city: Almere
country: Netherlands
facility: FlevoHospital
city: Amstelveen
country: Netherlands
facility: Amstelland Hospital
city: Amsterdam
country: Netherlands
facility: OLVG
city: Groningen
country: Netherlands
facility: Martini Hospital
city: Haarlem
country: Netherlands
facility: Spaarne Hospital
city: Hoorn
country: Netherlands
facility: Dijklander Hospital
city: Nijmegen
country: Netherlands
facility: Canisius-Wilhelmina Hospital
city: Veldhoven
country: Netherlands
facility: Máxima Medical Center
city: Zaandam
country: Netherlands
facility: Zaans Medical Centre
Study officials:
affiliation: Amsterdam UMC, Tergooi Ziekenhuizen
name: Frans B. Plötz, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Erasmus Medical Center
name: Niek B. Achten, MD, PhD
role: STUDY_DIRECTOR
affiliation: Amsterdam UMC, Tergooi Ziekenhuizen
name: Bo M. van der Weijden, MD
role: STUDY_DIRECTOR
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