Neonatal InfectionPhase 4RAINNCT03247920
Reduction of Intravenous Antibiotics In Neonates
A Phase 4 study testing Amoxicillin Clavulanate and Antibiotics in people with Neonatal Infection and Neonatal SEPSIS, run by Franciscus Gasthuis at 18 sites in Netherlands.
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. Read more about this study
- Who is it for?
- Ages 1 day to 28 days
- Conditions the study is for
- Neonatal Infection, Neonatal SEPSIS
- What is being tested?
- Amoxicillin Clavulanate and Antibiotics
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 510 participants
- Where
- 18 sitesNetherlands
- Study dates
- 4 Nov 2017to 15 Jul 2021
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 day to 28 days
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
18 sites in 1 country.
18 sites in 1 country
Netherlands18 sites
Meander Medical Center
Amersfoort
Rijnstate Hospital
Arnhem
Amphia Hospital
Breda
IJsselland Ziekenhuis
Capelle aan den IJssel
Reinier de Graaf Gasthuis
Delft
Catharina Hospital
Eindhoven
Medisch Spectrum Twente
Enschede
Groene Hart Ziekenhuis
Gouda
Sint Antonius Ziekenhuis
Nieuwegein
Erasmus MC-Sophia Children's Hospital
Rotterdam
Franciscus Gasthuis
Rotterdam
Ikazia Ziekenhuis
Rotterdam
Maasstad Hospital
Rotterdam
Franciscus Vlietland
Schiedam
Haaglanden Medical Center
The Hague
Juliana Kinderziekenhuis-Haga Hospital
The Hague
Maxima Medisch Centrum
Veldhoven
Isala
Zwolle
About this study
Official title: 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
Read the 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.
- Conditions
- Neonatal Infection, Neonatal SEPSIS
- Being tested
- Amoxicillin Clavulanate, Antibiotics
- Keywords
- Antibiotic switch therapy, Amoxicillin/clavulanic acid
- Medical subject headings
- Neonatal Sepsis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Amoxicillin ClavulanateDrug
Dose 75 mg/kg/day, (3dd 25 mg/kg). Concentration amoxicillin/clavulanic acid: 4:1
AntibioticsDrug
Intravenous antibiotic therapy following local protocol
| Study group | Role | What they receive |
|---|---|---|
| Oral group | Active comparator | 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. Receives: Drug: Amoxicillin Clavulanate |
| Intravenous group | Active comparator | Neonates will complete the full course of antibiotics of 7 days intravenously in hospital following local protocol. Receives: Drug: Antibiotics |
What is being measured
The primary outcome is the main question the study is designed to answer.
Bacterial re-infection within 28 days after cessation of antibiotic treatment (within 35 days after initial presentation)
Measured: 0-35 days
Secondary outcomes (6)
Duration of hospitalization
Measured: 0-35 days after birth
Percentage of re-admission
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 0-7 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Aug 2017
- Study start4 Nov 2017
- Primary completion15 Jun 2021
- Study completion15 Jul 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Neonatal InfectionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Multicenter prospective randomized controlled non-inferiority trial
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 510 participants (actual)
Sponsor and investigators
- Lead sponsor
- Franciscus Gasthuis
- Sponsor type
- University, hospital or other
- Collaborators
- Erasmus Medical Center
- Responsible party
- Principal investigator, Gerdien Tramper, Franciscus Gasthuis
- Investigators
- Gerdien Tramper, Principal investigator, Franciscus Gasthuis & Vlietland
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03247920
- Sponsor's protocol ID
- RAIN
- Acronym
- RAIN
- Status last verified
- Aug 2021
- First submitted
- 3 Jul 2017
- Last updated
- 24 Aug 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data will be made available on request through a repository and shared after consent of the principal investigator.
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.
PubMed 36088952Keij 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.
PubMed 31289068
Study at a glance
From the registry record, last updated by the sponsor on 24 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Intravenous to Oral Antibiotic Switch Therapy for Probable Neonatal Bacterial Infections: Clinical Efficacy, Safety and Cost-effectiveness
- ClinicalTrials.gov ID
- NCT03247920
- Acronym / sponsor ID
- RAIN / RAIN
- Conditions
- Neonatal Infection, Neonatal SEPSIS
- Keywords
- Antibiotic switch therapy, Amoxicillin/clavulanic acid
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 510 participants (actual)
- Lead sponsor
- Franciscus GasthuisUniversity, hospital or other
- Collaborators
- Erasmus Medical Center
- Study start
- 4 Nov 2017 (actual)
- Primary completion
- 15 Jun 2021 (actual)
- Study completion
- 15 Jul 2021 (actual)
- First posted
- 14 Aug 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- Model description
- Multicenter prospective randomized controlled non-inferiority trial
| Arm | Type | Receives |
|---|---|---|
| Oral group | Active comparator | Drug: Amoxicillin ClavulanateAfter 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. |
| Intravenous group | Active comparator | Drug: AntibioticsNeonates will complete the full course of antibiotics of 7 days intravenously in hospital following local protocol. |
Who may qualify
- Ages
- 1 day to 28 days
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Amoxicillin ClavulanateDose 75 mg/kg/day, (3dd 25 mg/kg). Concentration amoxicillin/clavulanic acid: 4:1 | Drug | Oral group |
| AntibioticsIntravenous antibiotic therapy following local protocol | Drug | Intravenous group |
Primary outcome
Bacterial re-infection within 28 days after cessation of antibiotic treatment (within 35 days after initial presentation)
Time frame: 0-35 days
6 secondary outcomes
Duration of hospitalization
Time frame: 0-35 days after birth
Percentage of re-admission
Time frame: 0-35 days after birth
Total costs and cost-effectiveness
Time frame: 0-35 days after birth
Difference in Quality of Life between oral and intravenous antibiotic treatment
Time frame: 0-35 days after birth
Time above MIC (T>MIC) of oral amoxicillin.
Time frame: 0-7 days
Time above MIC (T>MIC) of oral clavulanic acid.
Time frame: 0-7 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Aug 2021.
- Derived from this study: PubMed 36088952Keij 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.
- Derived from this study: PubMed 31289068Keij 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.
- Individual participant dataSharing planned: Yes. Data will be made available on request through a repository and shared after consent of the principal investigator.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gerdien Tramper principal investigator
Franciscus Gasthuis & Vlietland
18 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Amoxicillin Clavulanate and Antibiotics in people with Neonatal Infection and Neonatal SEPSIS, run by Franciscus Gasthuis at 18 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 18 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Bacterial re-infection within 28 days after cessation of antibiotic treatment (within 35 days after initial presentation) (time frame: 0-35 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03247920, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Aug 2021.