Reduction of Intravenous Antibiotics In Neonates

Neonatal SEPSIS Clinical Trial

— RAIN  

Official title:

Intravenous to Oral Antibiotic Switch Therapy for Probable Neonatal Bacterial Infections: Clinical Efficacy, Safety and Cost-effectiveness

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03247920
• Other study ID #: RAIN
• Status: Completed
• Phase: Phase 4
• Start date: November 4, 2017
• Est. completion date: July 15, 2021

Study information

• Verified date: August 2021
• Source: Franciscus Gasthuis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Randomized controlled open-label non-inferiority trial comparing complete intravenous antibiotic treatment with a short iv. course followed by oral antibiotics in neonates (0-28 days) with probable bacterial infection.

Primary outcome:

• Bacterial re-infection within 28 days after finishing of antibacterial therapy.

Secondary outcome(s):

• Pharmacokinetic profile of oral amoxicillin/clavulanic acid

• Quality of life

• Cost-effectiveness

• Alterations in gut microbiome

• Use of molecular techniques for better detection of bacterial pathogens

Description:

Neonates have a high antibiotic consumption because of their susceptibility for bacterial infections. Since the early diagnosis of bacterial infection in neonates is difficult, intravenous broad-spectrum antimicrobial therapy is usually started promptly after subtle symptoms. The majority of neonates become asymptomatic shortly after initiation; when infection is probable or proven by elevated inflammatory markers and/or a positive blood culture, intravenous antibiotics are administered for at least 7 days.

However, for neonates blood culture has a limited sensitivity. Therefore, the majority of neonates with probable infection are treated for a prolonged time with intravenous broad-spectrum antimicrobial therapy. In older children, intravenous antibiotics are often changed to oral antibiotics after cessation of symptoms and decreasing inflammatory parameters. This is not yet widely practised in neonates because of uncertainties in pharmacokinetics. Two explorative small studies from France and Italy into neonatal antibiotic switch therapy suggest that follow-up treatment with an oral antibiotic is promising; but the non-inferiority and safety was not yet properly addressed. Neonatal switch therapy, if proven to be safe and efficacious, would have a major impact on neonatal well-being, mother-to-child bonding and moreover costs.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 510
• Est. completion date: July 15, 2021
• Est. primary completion date: June 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 28 Days

Eligibility

Inclusion Criteria:

• Neonates (= 35+0 weeks, 0-28 days old, = 2 kg)

• Probable bacterial infection defined as clinical symptoms and/or maternal risk factors and elevated inflammatory markers for which empiric broad-spectrum antibiotic treatment was initiated and needs to be continued for > 48 hours

• Clinically well

• Toleration of oral feeding without overt vomiting

• Signed informed consent

Exclusion Criteria:

• Proven bloodstream infection

• Absence of blood culture

• Severe localized infection (meningitis, osteomyelitis, necrotizing enterocolitis)

• Severe clinical sepsis (compromised circulation, need for mechanical ventilation)

• Continuous need for a central venous line

• Severe hyperbilirubinemia exceeding the exchange level

• Parents inability to administer medication

• Major congenital or syndromic anomalies

Related Conditions & MeSH terms

• Infection
• Neonatal Infection
• Neonatal SEPSIS

Intervention

Drug:
• Amoxicillin Clavulanate
Dose 75 mg/kg/day, (3dd 25 mg/kg). Concentration amoxicillin/clavulanic acid: 4:1
• Antibiotics
Intravenous antibiotic therapy following local protocol

Locations

Country	Name	City	State
Netherlands	Meander Medical Center	Amersfoort
Netherlands	Rijnstate Hospital	Arnhem
Netherlands	Amphia Hospital	Breda
Netherlands	IJsselland Ziekenhuis	Capelle Aan Den IJssel
Netherlands	Reinier de Graaf Gasthuis	Delft
Netherlands	Haaglanden Medical Center	Den Haag
Netherlands	Juliana Kinderziekenhuis-Haga Hospital	Den Haag
Netherlands	Catharina Hospital	Eindhoven
Netherlands	Medisch Spectrum Twente	Enschede
Netherlands	Groene Hart Ziekenhuis	Gouda
Netherlands	Sint Antonius Ziekenhuis	Nieuwegein
Netherlands	Erasmus MC-Sophia Children's Hospital	Rotterdam
Netherlands	Franciscus Gasthuis	Rotterdam
Netherlands	Ikazia Ziekenhuis	Rotterdam
Netherlands	Maasstad Hospital	Rotterdam
Netherlands	Franciscus Vlietland	Schiedam
Netherlands	Maxima Medisch Centrum	Veldhoven
Netherlands	Isala	Zwolle

Sponsors (2)

Lead Sponsor	Collaborator
Franciscus Gasthuis	Erasmus Medical Center

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Bacterial re-infection within 28 days after cessation of antibiotic treatment (within 35 days after initial presentation)		0-35 days
Secondary	Duration of hospitalization		0-35 days after birth
Secondary	Percentage of re-admission		0-35 days after birth
Secondary	Total costs and cost-effectiveness	Cost-effectiveness of intravenous to oral switch compared to a full course of antibiotics + possible extra costs due to early antibiotic switch	0-35 days after birth
Secondary	Difference in Quality of Life between oral and intravenous antibiotic treatment	Two questionnaires on day 7 and 21 after admission, filled in by both parents. Data will be provided in a descriptive manner as no validated QoL questionnaires exist for neonates.	0-35 days after birth
Secondary	Time above MIC (T>MIC) of oral amoxicillin.	2 blood samples after administration of antibiotic suspension at different time points will be taken.; Time above MIC (T>MIC) will be defined. Target MIC is 8 mg/liter.	0-7 days
Secondary	Time above MIC (T>MIC) of oral clavulanic acid.	2 blood samples after administration of antibiotic suspension at different time points will be taken.; Time above MIC (T>MIC) will be defined. Target MIC is 8 mg/liter.	0-7 days

External Links

•   Study website (in dutch)