Reduction of Intravenous Antibiotics In Neonates (RAIN)

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

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

Study Overview

• Status: Completed
• Conditions: Neonatal Infection; Neonatal SEPSIS
• Intervention / Treatment: Drug: Amoxicillin Clavulanate; Drug: Antibiotics

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 510
• Phase: Phase 4

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 4 weeks (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Oral group; After 48 hours of intravenous antibiotics eligible neonates will switch to amoxicillin/clavulanic acid suspension for the remaining 5 days. When the oral suspension is well tolerated neonates can be discharged from hospital. In order to investigate the pharmacokinetic profile of oral amoxicillin/clavulanic acid serum levels will be measured.	Drug: Amoxicillin Clavulanate; Dose 75 mg/kg/day, (3dd 25 mg/kg). Concentration amoxicillin/clavulanic acid: 4:1
Active Comparator: Intravenous group; Neonates will complete the full course of antibiotics of 7 days intravenously in hospital following local protocol.	Drug: Antibiotics; Intravenous antibiotic therapy following local protocol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Bacterial re-infection within 28 days after cessation of antibiotic treatment (within 35 days after initial presentation)	0-35 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of hospitalization		0-35 days after birth
Percentage of re-admission		0-35 days after birth
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
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
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
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

Collaborators and Investigators

• Sponsor: Franciscus Gasthuis
• Collaborators: Erasmus Medical Center
• Investigators: Principal Investigator: Gerdien Tramper, Franciscus Gasthuis & Vlietland

Publications and helpful links

General Publications

• Keij FM, Kornelisse RF, Hartwig NG, van der Sluijs-Bens J, van Beek RHT, van Driel A, van Rooij LGM, van Dalen-Vink I, Driessen GJA, Kenter S, von Lindern JS, Eijkemans M, Stam-Stigter GM, Qi H, van den Berg MM, Baartmans MGA, van der Meer-Kappelle LH, Meijssen CB, Norbruis OF, Heidema J, van Rossem MC, den Butter PCP, Allegaert K, Reiss IKM, Tramper-Stranders GA. Efficacy and safety of switching from intravenous to oral antibiotics (amoxicillin-clavulanic acid) versus a full course of intravenous antibiotics in neonates with probable bacterial infection (RAIN): a multicentre, randomised, open-label, non-inferiority trial. Lancet Child Adolesc Health. 2022 Nov;6(11):799-809. doi: 10.1016/S2352-4642(22)00245-0. Epub 2022 Sep 9.
• Keij FM, Kornelisse RF, Hartwig NG, Mauff K, Poley MJ, Allegaert K, Reiss IKM, Tramper-Stranders GA. RAIN study: a protocol for a randomised controlled trial evaluating efficacy, safety and cost-effectiveness of intravenous-to-oral antibiotic switch therapy in neonates with a probable bacterial infection. BMJ Open. 2019 Jul 9;9(7):e026688. doi: 10.1136/bmjopen-2018-026688.

Helpful Links

• Study website (in dutch)

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2017
• Primary Completion (Actual): June 15, 2021
• Study Completion (Actual): July 15, 2021

Study Registration Dates

• First Submitted: July 3, 2017
• First Submitted That Met QC Criteria: August 9, 2017
• First Posted (Actual): August 14, 2017

Study Record Updates

• Last Update Posted (Actual): August 24, 2021
• Last Update Submitted That Met QC Criteria: August 23, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Antibiotic switch therapy; Amoxicillin/clavulanic acid
• Additional Relevant MeSH Terms: Pathologic Processes; Systemic Inflammatory Response Syndrome; Inflammation; Infant, Newborn, Diseases; Sepsis; Infections; Neonatal Sepsis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; beta-Lactamase Inhibitors; Anti-Bacterial Agents; Amoxicillin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination
• Other Study ID Numbers: RAIN

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Data will be made available on request through a repository and shared after consent of the principal investigator.

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