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Reduction of Intravenous Antibiotics In Neonates (RAIN)

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ClinicalTrials.gov Identifier: NCT03247920
Recruitment Status : Recruiting
First Posted : August 14, 2017
Last Update Posted : January 30, 2019
Sponsor:
Collaborator:
Erasmus Medical Center
Information provided by (Responsible Party):
Gerdien Tramper, Franciscus Gasthuis

Brief 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

Condition or disease Intervention/treatment Phase
Neonatal Infection Neonatal SEPSIS Drug: Amoxicillin Clavulanate Drug: Antibiotics Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 550 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Multicenter prospective randomized controlled non-inferiority trial
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Intravenous to Oral Antibiotic Switch Therapy for Probable Neonatal Bacterial Infections: Clinical Efficacy, Safety and Cost-effectiveness
Actual Study Start Date : November 4, 2017
Estimated Primary Completion Date : January 1, 2020
Estimated Study Completion Date : January 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antibiotics

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




Primary Outcome Measures :
  1. Bacterial re-infection within 28 days after cessation of antibiotic treatment (within 35 days after initial presentation) [ Time Frame: 0-35 days ]

Secondary Outcome Measures :
  1. Duration of hospitalization [ Time Frame: 0-35 days after birth ]
  2. Percentage of re-admission [ Time Frame: 0-35 days after birth ]
  3. 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

  4. Quality of life [ Time Frame: At day 7 & day 35 post partum ]
    Quality of life will be assessed using a questionnaire on day 7 and 21 after admission, filled in by both parents.

  5. 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.


  6. 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.




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Ages Eligible for Study:   up to 28 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  • Reassuring levels of inflammatory parameters 48-72 hours after initiation of therapy
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03247920


Contacts
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Contact: Fleur Keij, MD (0)655805452 ext +31 rainstudie@erasmusmc.nl
Contact: Gerdien Tramper, MD, PhD g.tramper@franciscus.nl

Locations
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Netherlands
IJsselland Ziekenhuis Recruiting
Capelle Aan Den IJssel, Netherlands
Contact: Arianne v Driel, MD         
Sint Antonius Ziekenhuis Recruiting
Nieuwegein, Netherlands
Contact: Jojanneke Heidema, MD/PhD         
Erasmus MC-Sophia Children's Hospital Recruiting
Rotterdam, Netherlands
Contact: René Kornelisse, MD/PhD         
Franciscus Gasthuis Recruiting
Rotterdam, Netherlands
Contact: A. Kamerbeek, MD         
Principal Investigator: Gerdien Tramper, MD/PhD         
Ikazia Ziekenhuis Recruiting
Rotterdam, Netherlands
Contact: Paul den Butter, MD         
Franciscus Vlietland Recruiting
Schiedam, Netherlands
Contact: Sandra Kenter, MD         
Maxima Medisch Centrum Recruiting
Veldhoven, Netherlands
Contact: Jacqueline vd Sluijs, MD         
Sponsors and Collaborators
Franciscus Gasthuis
Erasmus Medical Center

Additional Information:
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Responsible Party: Gerdien Tramper, Principal investigator, MD, PhD, Franciscus Gasthuis
ClinicalTrials.gov Identifier: NCT03247920     History of Changes
Other Study ID Numbers: RAIN
First Posted: August 14, 2017    Key Record Dates
Last Update Posted: January 30, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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

Keywords provided by Gerdien Tramper, Franciscus Gasthuis:
Antibiotic switch therapy
Amoxicillin/clavulanic acid

Additional relevant MeSH terms:
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Anti-Bacterial Agents
Antibiotics, Antitubercular
Infection
Neonatal Sepsis
Sepsis
Infant, Newborn, Diseases
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Amoxicillin
Clavulanic Acid
Clavulanic Acids
Amoxicillin-Potassium Clavulanate Combination
Anti-Infective Agents
Antitubercular Agents
beta-Lactamase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action