Reduction of Intravenous Antibiotics In Neonates (RAIN)

August 23, 2021 updated by: Gerdien Tramper, Franciscus Gasthuis

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

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
510

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

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

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Bacterial re-infection within 28 days after cessation of antibiotic treatment (within 35 days after initial presentation)
Time Frame: 0-35 days
0-35 days

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Duration of hospitalization
Time Frame: 0-35 days after birth
0-35 days after birth
Percentage of re-admission
Time Frame: 0-35 days after birth
0-35 days after birth
Total costs and cost-effectiveness
Time Frame: 0-35 days after birth
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
Time Frame: 0-35 days after birth
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.
Time Frame: 0-7 days

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.
Time Frame: 0-7 days

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

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Franciscus Gasthuis

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Erasmus Medical Center

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Gerdien Tramper, Franciscus Gasthuis & Vlietland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 4, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 15, 2021

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 15, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 3, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 9, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 14, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 24, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 23, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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