RAIN: Reduction of Intravenous Antibiotics In Neonates

Sponsor

Franciscus Gasthuis (Other)

Overall Status

Completed

CT.gov ID

NCT03247920

Collaborator

Erasmus Medical Center (Other)

510

Enrollment

Locations

Arms

44.3

Actual Duration (Months)

28.3

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

510 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Multicenter prospective randomized controlled non-inferiority trialMulticenter 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 :

Nov 4, 2017

Actual Primary Completion Date :

Jun 15, 2021

Actual Study Completion Date :

Jul 15, 2021

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Bacterial re-infection within 28 days after cessation of antibiotic treatment (within 35 days after initial presentation) [0-35 days]

Secondary Outcome Measures

Duration of hospitalization [0-35 days after birth]
Percentage of re-admission [0-35 days after birth]
Total costs and cost-effectiveness [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
Difference in Quality of Life between oral and intravenous antibiotic treatment [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.
Time above MIC (T>MIC) of oral amoxicillin. [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.
Time above MIC (T>MIC) of oral clavulanic acid. [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Day to 28 Days

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country
1	Meander Medical Center	Amersfoort	Netherlands
2	Rijnstate Hospital	Arnhem	Netherlands
3	Amphia Hospital	Breda	Netherlands
4	IJsselland Ziekenhuis	Capelle Aan Den IJssel	Netherlands
5	Reinier de Graaf Gasthuis	Delft	Netherlands
6	Haaglanden Medical Center	Den Haag	Netherlands
7	Juliana Kinderziekenhuis-Haga Hospital	Den Haag	Netherlands
8	Catharina Hospital	Eindhoven	Netherlands
9	Medisch Spectrum Twente	Enschede	Netherlands
10	Groene Hart Ziekenhuis	Gouda	Netherlands
11	Sint Antonius Ziekenhuis	Nieuwegein	Netherlands
12	Erasmus MC-Sophia Children's Hospital	Rotterdam	Netherlands
13	Franciscus Gasthuis	Rotterdam	Netherlands
14	Ikazia Ziekenhuis	Rotterdam	Netherlands
15	Maasstad Hospital	Rotterdam	Netherlands
16	Franciscus Vlietland	Schiedam	Netherlands
17	Maxima Medisch Centrum	Veldhoven	Netherlands
18	Isala	Zwolle	Netherlands