<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03247920</url>
  </required_header>
  <id_info>
    <org_study_id>RAIN</org_study_id>
    <nct_id>NCT03247920</nct_id>
  </id_info>
  <brief_title>Reduction of Intravenous Antibiotics In Neonates</brief_title>
  <acronym>RAIN</acronym>
  <official_title>Intravenous to Oral Antibiotic Switch Therapy for Probable Neonatal Bacterial Infections: Clinical Efficacy, Safety and Cost-effectiveness</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Franciscus Gasthuis</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Erasmus Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Franciscus Gasthuis</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Randomized controlled open-label non-inferiority trial comparing complete intravenous&#xD;
      antibiotic treatment with a short iv. course followed by oral antibiotics in neonates (0-28&#xD;
      days) with probable bacterial infection.&#xD;
&#xD;
      Primary outcome:&#xD;
&#xD;
      - Bacterial re-infection within 28 days after finishing of antibacterial therapy.&#xD;
&#xD;
      Secondary outcome(s):&#xD;
&#xD;
        -  Pharmacokinetic profile of oral amoxicillin/clavulanic acid&#xD;
&#xD;
        -  Quality of life&#xD;
&#xD;
        -  Cost-effectiveness&#xD;
&#xD;
        -  Alterations in gut microbiome&#xD;
&#xD;
        -  Use of molecular techniques for better detection of bacterial pathogens&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Neonates have a high antibiotic consumption because of their susceptibility for bacterial&#xD;
      infections. Since the early diagnosis of bacterial infection in neonates is difficult,&#xD;
      intravenous broad-spectrum antimicrobial therapy is usually started promptly after subtle&#xD;
      symptoms. The majority of neonates become asymptomatic shortly after initiation; when&#xD;
      infection is probable or proven by elevated inflammatory markers and/or a positive blood&#xD;
      culture, intravenous antibiotics are administered for at least 7 days.&#xD;
&#xD;
      However, for neonates blood culture has a limited sensitivity. Therefore, the majority of&#xD;
      neonates with probable infection are treated for a prolonged time with intravenous&#xD;
      broad-spectrum antimicrobial therapy. In older children, intravenous antibiotics are often&#xD;
      changed to oral antibiotics after cessation of symptoms and decreasing inflammatory&#xD;
      parameters. This is not yet widely practised in neonates because of uncertainties in&#xD;
      pharmacokinetics. Two explorative small studies from France and Italy into neonatal&#xD;
      antibiotic switch therapy suggest that follow-up treatment with an oral antibiotic is&#xD;
      promising; but the non-inferiority and safety was not yet properly addressed. Neonatal switch&#xD;
      therapy, if proven to be safe and efficacious, would have a major impact on neonatal&#xD;
      well-being, mother-to-child bonding and moreover costs.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 4, 2017</start_date>
  <completion_date type="Actual">July 15, 2021</completion_date>
  <primary_completion_date type="Actual">June 15, 2021</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Multicenter prospective randomized controlled non-inferiority trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Bacterial re-infection within 28 days after cessation of antibiotic treatment (within 35 days after initial presentation)</measure>
    <time_frame>0-35 days</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of hospitalization</measure>
    <time_frame>0-35 days after birth</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of re-admission</measure>
    <time_frame>0-35 days after birth</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total costs and cost-effectiveness</measure>
    <time_frame>0-35 days after birth</time_frame>
    <description>Cost-effectiveness of intravenous to oral switch compared to a full course of antibiotics + possible extra costs due to early antibiotic switch</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difference in Quality of Life between oral and intravenous antibiotic treatment</measure>
    <time_frame>0-35 days after birth</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time above MIC (T&gt;MIC) of oral amoxicillin.</measure>
    <time_frame>0-7 days</time_frame>
    <description>2 blood samples after administration of antibiotic suspension at different time points will be taken.&#xD;
Time above MIC (T&gt;MIC) will be defined. Target MIC is 8 mg/liter.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time above MIC (T&gt;MIC) of oral clavulanic acid.</measure>
    <time_frame>0-7 days</time_frame>
    <description>2 blood samples after administration of antibiotic suspension at different time points will be taken.&#xD;
Time above MIC (T&gt;MIC) will be defined. Target MIC is 8 mg/liter.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">510</enrollment>
  <condition>Neonatal Infection</condition>
  <condition>Neonatal SEPSIS</condition>
  <arm_group>
    <arm_group_label>Oral group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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.&#xD;
In order to investigate the pharmacokinetic profile of oral amoxicillin/clavulanic acid serum levels will be measured.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intravenous group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Neonates will complete the full course of antibiotics of 7 days intravenously in hospital following local protocol.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Amoxicillin Clavulanate</intervention_name>
    <description>Dose 75 mg/kg/day, (3dd 25 mg/kg). Concentration amoxicillin/clavulanic acid: 4:1</description>
    <arm_group_label>Oral group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Antibiotics</intervention_name>
    <description>Intravenous antibiotic therapy following local protocol</description>
    <arm_group_label>Intravenous group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Neonates (≥ 35+0 weeks, 0-28 days old, ≥ 2 kg)&#xD;
&#xD;
          -  Probable bacterial infection defined as clinical symptoms and/or maternal risk factors&#xD;
             and elevated inflammatory markers for which empiric broad-spectrum antibiotic&#xD;
             treatment was initiated and needs to be continued for &gt; 48 hours&#xD;
&#xD;
          -  Clinically well&#xD;
&#xD;
          -  Toleration of oral feeding without overt vomiting&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Proven bloodstream infection&#xD;
&#xD;
          -  Absence of blood culture&#xD;
&#xD;
          -  Severe localized infection (meningitis, osteomyelitis, necrotizing enterocolitis)&#xD;
&#xD;
          -  Severe clinical sepsis (compromised circulation, need for mechanical ventilation)&#xD;
&#xD;
          -  Continuous need for a central venous line&#xD;
&#xD;
          -  Severe hyperbilirubinemia exceeding the exchange level&#xD;
&#xD;
          -  Parents inability to administer medication&#xD;
&#xD;
          -  Major congenital or syndromic anomalies&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Day</minimum_age>
    <maximum_age>28 Days</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gerdien Tramper</last_name>
    <role>Principal Investigator</role>
    <affiliation>Franciscus Gasthuis &amp; Vlietland</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Meander Medical Center</name>
      <address>
        <city>Amersfoort</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rijnstate Hospital</name>
      <address>
        <city>Arnhem</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Amphia Hospital</name>
      <address>
        <city>Breda</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IJsselland Ziekenhuis</name>
      <address>
        <city>Capelle Aan Den IJssel</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Reinier de Graaf Gasthuis</name>
      <address>
        <city>Delft</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Haaglanden Medical Center</name>
      <address>
        <city>Den Haag</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Juliana Kinderziekenhuis-Haga Hospital</name>
      <address>
        <city>Den Haag</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Catharina Hospital</name>
      <address>
        <city>Eindhoven</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medisch Spectrum Twente</name>
      <address>
        <city>Enschede</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Groene Hart Ziekenhuis</name>
      <address>
        <city>Gouda</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sint Antonius Ziekenhuis</name>
      <address>
        <city>Nieuwegein</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Erasmus MC-Sophia Children's Hospital</name>
      <address>
        <city>Rotterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Franciscus Gasthuis</name>
      <address>
        <city>Rotterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ikazia Ziekenhuis</name>
      <address>
        <city>Rotterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Maasstad Hospital</name>
      <address>
        <city>Rotterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Franciscus Vlietland</name>
      <address>
        <city>Schiedam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Maxima Medisch Centrum</name>
      <address>
        <city>Veldhoven</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isala</name>
      <address>
        <city>Zwolle</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <link>
    <url>http://www.rainstudie.nl</url>
    <description>Study website (in dutch)</description>
  </link>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>July 3, 2017</study_first_submitted>
  <study_first_submitted_qc>August 9, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 14, 2017</study_first_posted>
  <last_update_submitted>August 23, 2021</last_update_submitted>
  <last_update_submitted_qc>August 23, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 24, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Franciscus Gasthuis</investigator_affiliation>
    <investigator_full_name>Gerdien Tramper</investigator_full_name>
    <investigator_title>Principal investigator, MD, PhD</investigator_title>
  </responsible_party>
  <keyword>Antibiotic switch therapy</keyword>
  <keyword>Amoxicillin/clavulanic acid</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Neonatal Sepsis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anti-Bacterial Agents</mesh_term>
    <mesh_term>Amoxicillin</mesh_term>
    <mesh_term>Clavulanic Acid</mesh_term>
    <mesh_term>Clavulanic Acids</mesh_term>
    <mesh_term>Amoxicillin-Potassium Clavulanate Combination</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Data will be made available on request through a repository and shared after consent of the principal investigator.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03247920
org study id: RAIN
nct id: NCT03247920
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
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
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Multicenter prospective randomized controlled non-inferiority trial
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Bacterial re-infection within 28 days after cessation of antibiotic treatment (within 35 days after initial presentation)
time frame: 0-35 days
measure: Duration of hospitalization
time frame: 0-35 days after birth
measure: Percentage of re-admission
time frame: 0-35 days after birth
measure: Total costs and cost-effectiveness
time frame: 0-35 days after birth
description: Cost-effectiveness of intravenous to oral switch compared to a full course of antibiotics + possible extra costs due to early antibiotic switch
measure: Difference in Quality of Life between oral and intravenous antibiotic treatment
time frame: 0-35 days after birth
description: 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.
measure: Time above MIC (T>MIC) of oral amoxicillin.
time frame: 0-7 days
description: 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.
measure: Time above MIC (T>MIC) of oral clavulanic acid.
time frame: 0-7 days
description: 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.
arm group label: Oral group
arm group type: Active Comparator
description: 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.
arm group label: Intravenous group
arm group type: Active Comparator
description: Neonates will complete the full course of antibiotics of 7 days intravenously in hospital following local protocol.
intervention type: Drug
intervention name: Amoxicillin Clavulanate
description: Dose 75 mg/kg/day, (3dd 25 mg/kg). Concentration amoxicillin/clavulanic acid: 4:1
arm group label: Oral group
intervention type: Drug
intervention name: Antibiotics
description: Intravenous antibiotic therapy following local protocol
arm group label: Intravenous group
criteria: 
gender: All
minimum age: 1 Day
maximum age: 28 Days
healthy volunteers: No
last name: Gerdien Tramper
role: Principal Investigator
affiliation: Franciscus Gasthuis & Vlietland
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Netherlands
url: http://www.rainstudie.nl
description: Study website (in dutch)
responsible party type: Principal Investigator
investigator affiliation: Franciscus Gasthuis
investigator full name: Gerdien Tramper
investigator title: Principal investigator, MD, PhD
mesh term: Infections
mesh term: Neonatal Sepsis
mesh term: Anti-Bacterial Agents
mesh term: Amoxicillin
mesh term: Clavulanic Acid
mesh term: Clavulanic Acids
mesh term: Amoxicillin-Potassium Clavulanate Combination
sharing ipd: Yes
ipd description: Data will be made available on request through a repository and shared after consent of the principal investigator.