Individualized Duration of Antibiotic Treatment in Early Onset Infection in Newborns. (DurATi-n)

Individualized Duration of Antibiotic Treatment in Culture Negative Early Onset Infection in Term Born Newborns: A Nationwide Randomized Controlled Non-inferiority Trial.

A nationwide multicenter open label randomized controlled non-inferiority trial, including 18 departments. The study aims to compare an individualized antibiotic treatment duration with standard seven days of antibiotic treatment for culture negative early-onset infection in term newborns.

Study Overview

• Status: Recruiting
• Conditions: Antibiotic Side Effect; Early-Onset Neonatal Sepsis
• Intervention / Treatment: Other: Individualized treatment duration strategy

Detailed Description

There is a documented antibiotic overuse in newborns, and a lack of evidence for the optimal duration of antibiotic therapy in culture-negative infection. The study aims to evaluate the effect of individualized treatment duration in early-onset infection.

The study aims to compare an individualized treatment duration with seven days of treatment for culture negative early-onset infection. The investigators hypothesize that the individualized treatment duration, based on structured clinical assessment of symptoms and level of CRP is non-inferior to the standard care being seven days of treatment. In the experimental treatment arm, antibiotics will be stopped when the participant had 24 hours without symptoms and at same time point have decreasing level of CRP, with an absolute threshold of CRP ≤ 30 mg/l. The investigators hypothesize that individualized treatment will shorten the duration of antibiotic therapy in newborns with early onset infection with very little risk of relapse. Newborns who fulfill criteria to stop antibiotics within 48 hours will not be eligible for inclusion.

• Study Type: Interventional
• Enrollment (Anticipated): 488
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Emma Malchau Carlsen, MD,PhD; Phone Number: +4527380508; Email: emma.louise.malchau.carlsen@regionh.dk
• Study Contact Backup: Name: Ulrikka Nygaard, MD,PhD; Email: ulrikka.nygaard@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Ulrikka Nygaard

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 hour to 3 days (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Gestational age ≥ 35 weeks
• Birth weight ≥ 2000
• Probable or possible infection according to the structured infection risk assessment
• Sufficient size blood culture, preferably 0.5-1 ml, but at least 0.2 ml, drawn after onset of symptoms but before start of antibiotic treatment
• Negative blood culture after 48 hours

Exclusion Criteria:

• Infants with positive blood culture
• Blood culture volume prior to antibiotics of < 0.2 ml
• Site-specific infection as for example, meningitis or osteomyelitis
• Infant fulfill current recommendation to stop antibiotic treatment at 36-48 hours; Low suspicion of sepsis initially including few and vague symptoms, CRP maximum 35-50 mg/l, negative blood culture and no symptoms after 48 hours of treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Individualized treatment duration; Antibiotic treatment will be discontinued when both of the following two criteria are fulfilled: The infant has had 24 hours without clinical symptoms of infection, after systematic clinical evaluation by a neonatologist. Clinical symptoms specified in Table 1.; CRP is < 30 mg/l. If CRP is > 30 at the time when the infant has been symptom-free for 24 hours, CRP will be assessed once every 24 -48 hours and antibiotics will be stopped when CRP < 30.	Other: Individualized treatment duration strategy; As listed under arm description.
NO_INTERVENTION: Standard treatment duration; Standard treatment duration is seven days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Readmission due to infection.	Readmission due to infection, defined as symptoms, affected biomarkers and antibiotic treatment > 72 hours	From 1-21 days after end of first course of antibiotic treatment.
Death	Death of any cause	From 1-21 days after end of first course of antibiotic treatment.
Total use of antibiotics	Use of antibiotics (in hours)	From initiation of antibiotics and the next 28 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
C-reactive protein (CRP)	CRP (mg/l) levels at follow-up	CRP measured at follow-up 2 days after initial antibiotic treatment ended
Readmission due to infection within 3 months	Readmission due to infection, defined as symptoms, affected biomarkers and antibiotic treatment > 72 hours	From 1-100 days after first course of antibiotics ended.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital stay	Length of hospital stay within 28 days after initial antibiotic treatment started	From initiation of antibiotics and the next 28 days.
Positive blood cultures	Numbers of culture positive infections	From 1-21 days after end of first course of antibiotic treatment.
Serious adverse events (SAE)	Any serious adverse events related to the study intervention	From initiation of antibiotics and the next 100 days.
Total use of antibiotics	Use of antibiotics (in hours)	From initiation of antibiotics and the next 100 days.
Breastfeeding	Exclusive and partial breastfeeding rates	At 2 day and 21 day follow up, after end of initial antibiotic treatment.

Collaborators and Investigators

• Sponsor: Ulrikka Nygaard
• Collaborators: University of Copenhagen; Innovation Fund Denmark
• Investigators: Principal Investigator: Emma Malchau Carlsen, MD, PhD, Department of Neonatology, Rigshospitalet, Copenhagen, Denmark; Study Director: Tine Brink Henriksen, MD, Prof, Department of Neonatology, Skejby Sygehus, Aarhus, Denmark

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 22, 2022
• Primary Completion (ANTICIPATED): April 18, 2025
• Study Completion (ANTICIPATED): April 18, 2028

Study Registration Dates

• First Submitted: April 7, 2022
• First Submitted That Met QC Criteria: April 13, 2022
• First Posted (ACTUAL): April 15, 2022

Study Record Updates

• Last Update Posted (ACTUAL): June 30, 2022
• Last Update Submitted That Met QC Criteria: June 26, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: infection; antibiotic; neonatal; early-onset
• Additional Relevant MeSH Terms: Pathologic Processes; Systemic Inflammatory Response Syndrome; Inflammation; Infant, Newborn, Diseases; Sepsis; Infections; Neonatal Sepsis
• Other Study ID Numbers: H-21004823

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Researchers who provide a methodologically sound proposal will be granted access to a full copy of individual deidentified data.
• IPD Sharing Time Frame: The data will be available from 3 months after the publication of the study, ending 5 years after publication.
• IPD Sharing Access Criteria: Proposals should be directed to the corresponding author of this article, and access can be granted after the proposal is approved by the trial steering committee. Data will be available at a third party website after a data access agreement is signed (link to website will be shared after request is approved).
• 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