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Early-Onset Sepsis, NeonatalNCT05274776

Safely Reduce Newborn Antibiotic Exposure With the Early-onset Sepsis Calculator

A study testing EOS calculator in people with Early-Onset Sepsis, Neonatal and EOS, run by prof. dr. Frans B. Plötz at 10 sites in Netherlands.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages Up to 24 hours
Conditions the study is for
Early-Onset Sepsis, Neonatal, EOS
What is being tested?
EOS calculator
Type of treatment
Medical device
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,830 participants
Where
10 sitesNetherlands
Study dates
12 Apr 2022to Oct 2024
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 24 hours
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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.

Who cannot join

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

Trial locations and contacts

10 sites in 1 country.

Prof. Frans B. Plötz, MD, PhD contact

+31(0)887531753

fbplotz@tergooi.nl

Bo M. van der Weijden, MD contact

b.m.vanderweijden@amsterdamumc.nl

10 sites in 1 country

Netherlands10 sites, 10 recruiting

  • Northwest Clinics

    Alkmaar

    Recruiting

  • FlevoHospital

    Almere Stad

    Recruiting

  • Amstelland Hospital

    Amstelveen

    Recruiting

  • OLVG

    Amsterdam

    Recruiting

  • Martini Hospital

    Groningen

    Recruiting

  • Spaarne Hospital

    Haarlem

    Recruiting

  • Dijklander Hospital

    Hoorn

    Recruiting

  • Canisius-Wilhelmina Hospital

    Nijmegen

    Recruiting

  • Máxima Medical Center

    Veldhoven

    Recruiting

  • Zaans Medical Centre

    Zaandam

    Recruiting

Other trials in Netherlands

About this study

Official title: Safely Reduce Newborn Antibiotic Exposure With the Early-onset Sepsis Calculator: a Cluster Randomized Study (EOS Calculator RCT)

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:

Read more
  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.
Read the 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.
Being tested
EOS calculator
Keywords
early-onset sepsis, neonatal, EOS calculator
Medical subject headings
Neonatal Sepsis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EOS calculatorDevice

    Also called early-onset sepsis calculator, neonatal early-onset sepsis calculator, sepsis risk calculator (SRC), newborn sepsis calculator

    For this study the EOS calculator was developed as a mobile application (by everywhereIM), including CE marking. It is concerned a medical device for health care professionals.

Study groups in NCT05274776
Study groupRoleWhat they receive
NVK GuidelinesNo interventionThe NVK guidelines use 8 maternal and 15 neonatal risk factors, each categorized as either red flag or non-red flag. These criteria guide clinicians on the management in case of suspected EOS. Briefly, antibiotic treatment is recommended if at least one red flag and, or, two or more non-red flags are present. An observation period of at least 12 hours is recommended if one non-red flag is present. Antibiotics are recommended when an infection is suspected during this observation. Newborns without EOS risk factors, with a good clinical condition, and a gestational age of more than 36 weeks will be discharged. If the guidelines recommend an observation period, the newborn with a good clinical condition is discharged after repeating physical examination. In case antibiotic treatment is started, discharge depends on the duration of treatment and the clinical course. At discharge, parents are instructed to call the hospital in case of signs of infection within the first 14 days of life.
EOS CalculatorExperimentalUsing the EOS calculator application between 0-24 hours after birth, maternal EOS risk factors combined with the physical examination of the newborn are used to assign a risk category and accompanying clinical recommendation based on estimated EOS incidence for each newborn at-risk for an infection. The EOS calculator results are used to guide clinical management on performing either a diagnostic work-up and start of antibiotics for (suspected) EOS, or a conservative approach with routine controls of vital parameters every 3 hours. In case of routine controls, re-evaluation of physical appearance by a pediatric resident or pediatrician will take place within 24 hours postpartum. Newborns will be observed for at least 24 hours. In case antibiotics are started, the need for further treatment is depending on blood culture results, infection parameters, and clinical condition of the newborn. Discontinuation of antibiotics and discharge is at the discretion of the treating physician.
Receives: Device: EOS calculator

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Co-primary superiority outcome: antibiotic therapy started within 24 hours after birth

    The proportion of patients that started antibiotic therapy for suspected and, or proven EOS in the first 24 hours after birth.

    Measured: 0-24 hours after birth

  2. First co-primary non-inferiority outcome (safety): proportion of patients with respiratory support

    A composite non-inferiority outcome regarding 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 (NICU) for sepsis treatment, and/or 4) proven EOS.

    • Respiratory support is defined as any form of respiratory support (invasive ventilation, continuous positive airway pressure (CPAP), high flow nasal cannula (HFNC), low flow oxygen) during the first week of life.

    Measured: 0-14 days after birth

  3. Second co-primary non-inferiority outcome (safety): proportion of patients with hemodynamic support

    • Intravascular fluid bolus is defined as the intravenous administration of a fluid bolus of 10ml/kg within 15-30 minutes. It is the first step in the treatment of hemodynamically unstable newborns due to sepsis.

    Measured: 0-14 days after birth

  4. Third co-primary non-inferiority outcome (safety): proportion of patients referred to a NICU for sepsis treatment

    Measured: 0-14 days after birth

  5. Fourth co-primary non-inferiority outcome (safety): proportion of patients with proven EOS

    • Proven EOS is defined as a blood or cerebrospinal fluid (CSF) culture obtained within 72 hours after birth growing a pathogenic bacterial species.

    Measured: 0-14 days after birth

Secondary outcomes (3)

  1. Duration of antibiotic therapy

    The total duration of antibiotic therapy: date and time of first administration of intravenous antibiotic therapy, and date and time of the last administration of intravenous antibiotic therapy.

    Measured: 0-14 days after birth

  2. Antibiotic therapy started between 24-72 hours after birth

    The proportion of antibiotic therapy started for suspected and, or proven EOS if symptoms started between 24-72 hours after birth.

    Measured: 24-72 hours after birth

  3. Questionnaire: quality of life

    To get an impression of the impact of (suspected) early-onset sepsis on the quality of life (QoL) of both parents/guardians and their child, parents/guardians will be asked to fill in a questionnaire on day 14 after birth. The first part collects information on medical factors after hospitalization (side effects, number of medical visits, readmission, and medication use) and basic needs of the newborn (sleep quality of the patient, (breast)feeding success rate). The second part addresses the subjective parental/guardian evaluation of the impact of newborns' admission, and parental/guardian projection of future QoL of their newborn. Statements with six possible answers will be used: 'not at all, a little, on average, more than average, a lot, not applicable' or 'poor, fair, good, very good, excellent, not applicable'. Participants will not score on a numbered scale but tick the answer (in text) that apply best. The last part of the questionnaire collects demographic data.

    Measured: 14-28 days after birth

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Mar 2022
  2. Study start12 Apr 2022
  3. Primary completionApr 2024 (estimated)
  4. Study completionOct 2024 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
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.
Masking
None (open label)
Enrolment
1,830 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05274776
Sponsor's protocol ID
NL78203.018.21
Status last verified
Jan 2024
First submitted
28 Feb 2022
Last updated
1 Feb 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Data will be made available on request through a repository and shared after consent of the principal investigator.

Publications

  • Shane AL, Sanchez PJ, Stoll BJ. Neonatal sepsis. Lancet. 2017 Oct 14;390(10104):1770-1780. doi: 10.1016/S0140-6736(17)31002-4. Epub 2017 Apr 20.

    PubMed 28434651

  • Sagori Mukhopadhyay, Karen M. Puopolo; Neonatal Early-Onset Sepsis: Epidemiology and Risk Assessment. Neoreviews April 2015; 16 (4): e221-e230.

  • Simonsen KA, Anderson-Berry AL, Delair SF, Davies HD. Early-onset neonatal sepsis. Clin Microbiol Rev. 2014 Jan;27(1):21-47. doi: 10.1128/CMR.00031-13.

    PubMed 24396135

  • Klingenberg C, Kornelisse RF, Buonocore G, Maier RF, Stocker M. Culture-Negative Early-Onset Neonatal Sepsis - At the Crossroad Between Efficient Sepsis Care and Antimicrobial Stewardship. Front Pediatr. 2018 Oct 9;6:285. doi: 10.3389/fped.2018.00285. eCollection 2018.

    PubMed 30356671

  • Cantey JB, Wozniak PS, Pruszynski JE, Sanchez PJ. Reducing unnecessary antibiotic use in the neonatal intensive care unit (SCOUT): a prospective interrupted time-series study. Lancet Infect Dis. 2016 Oct;16(10):1178-1184. doi: 10.1016/S1473-3099(16)30205-5. Epub 2016 Jul 22.

    PubMed 27452782

  • Korpela K, Zijlmans MA, Kuitunen M, Kukkonen K, Savilahti E, Salonen A, de Weerth C, de Vos WM. Childhood BMI in relation to microbiota in infancy and lifetime antibiotic use. Microbiome. 2017 Mar 3;5(1):26. doi: 10.1186/s40168-017-0245-y.

    PubMed 28253911

  • Low JSY, Soh SE, Lee YK, Kwek KYC, Holbrook JD, Van der Beek EM, Shek LP, Goh AEN, Teoh OH, Godfrey KM, Chong YS, Knol J, Lay C. Ratio of Klebsiella/Bifidobacterium in early life correlates with later development of paediatric allergy. Benef Microbes. 2017 Oct 13;8(5):681-695. doi: 10.3920/BM2017.0020. Epub 2017 Oct 12.

    PubMed 29022383

  • NVOG (Nederlandse Vereniging voor Obstetrie en Gynaecologie), NVK (Nederlandse Vereniging Kindergeneeskunde). Preventie en behandeling van early-onset neonatale infecties (Adaptatie van de NICE-richtlijn). 2017 p. 1-94.

  • Neonatal infection: antibiotics for prevention and treatment. London: National Institute for Health and Care Excellence (NICE); 2024 Mar 19. Available from http://www.ncbi.nlm.nih.gov/books/NBK571222/

    PubMed 34133110

  • van der Weijden BM, Achten NB, Bekhof J, Evers EE, Berk M, Kamps AWA, Rijpert M, Ten Tusscher GW, van Houten MA, Plotz FB. Multicentre study found that adherence to national antibiotic recommendations for neonatal early-onset sepsis was low. Acta Paediatr. 2021 Mar;110(3):791-798. doi: 10.1111/apa.15488. Epub 2020 Aug 10.

    PubMed 32686180

  • Escobar GJ, Puopolo KM, Wi S, Turk BJ, Kuzniewicz MW, Walsh EM, Newman TB, Zupancic J, Lieberman E, Draper D. Stratification of risk of early-onset sepsis in newborns >/= 34 weeks' gestation. Pediatrics. 2014 Jan;133(1):30-6. doi: 10.1542/peds.2013-1689. Epub 2013 Dec 23.

    PubMed 24366992

  • Puopolo KM, Draper D, Wi S, Newman TB, Zupancic J, Lieberman E, Smith M, Escobar GJ. Estimating the probability of neonatal early-onset infection on the basis of maternal risk factors. Pediatrics. 2011 Nov;128(5):e1155-63. doi: 10.1542/peds.2010-3464. Epub 2011 Oct 24.

    PubMed 22025590

  • Kuzniewicz MW, Puopolo KM, Fischer A, Walsh EM, Li S, Newman TB, Kipnis P, Escobar GJ. A Quantitative, Risk-Based Approach to the Management of Neonatal Early-Onset Sepsis. JAMA Pediatr. 2017 Apr 1;171(4):365-371. doi: 10.1001/jamapediatrics.2016.4678.

    PubMed 28241253

  • Achten NB, Klingenberg C, Benitz WE, Stocker M, Schlapbach LJ, Giannoni E, Bokelaar R, Driessen GJA, Brodin P, Uthaya S, van Rossum AMC, Plotz FB. Association of Use of the Neonatal Early-Onset Sepsis Calculator With Reduction in Antibiotic Therapy and Safety: A Systematic Review and Meta-analysis. JAMA Pediatr. 2019 Nov 1;173(11):1032-1040. doi: 10.1001/jamapediatrics.2019.2825.

    PubMed 31479103

  • Achten NB, Dorigo-Zetsma JW, van der Linden PD, van Brakel M, Plotz FB. Sepsis calculator implementation reduces empiric antibiotics for suspected early-onset sepsis. Eur J Pediatr. 2018 May;177(5):741-746. doi: 10.1007/s00431-018-3113-2. Epub 2018 Feb 18.

    PubMed 29455368

Questions about this trial

What is this clinical trial studying?

A study testing EOS calculator in people with Early-Onset Sepsis, Neonatal and EOS, run by prof. dr. Frans B. Plötz at 10 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 1 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Prof. Frans B. Plötz, MD, PhD (+31(0)887531753, fbplotz@tergooi.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Co-primary superiority outcome: antibiotic therapy started within 24 hours after birth (time frame: 0-24 hours after birth). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05274776, which also lists 35 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2024.

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