<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/NCT01732250</url>
  </required_header>
  <id_info>
    <org_study_id>0276-12-RMC</org_study_id>
    <nct_id>NCT01732250</nct_id>
  </id_info>
  <brief_title>Multicenter Open-label Randomized Controlled Trial (RCT) to Compare Colistin Alone Versus Colistin Plus Meropenem</brief_title>
  <official_title>Multicenter Open-label RCT to Compare Colistin Alone vs. Colistin Plus Meropenem</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mical Paul</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>European Commission</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Rabin Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine whether the addition of meropenem to colistin is&#xD;
      better than colistin alone in the treatment of clinically significant infections caused by&#xD;
      multi-drug resistant bacteria&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 2013</start_date>
  <completion_date type="Actual">February 28, 2017</completion_date>
  <primary_completion_date type="Actual">January 31, 2017</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical success</measure>
    <time_frame>14 days</time_frame>
    <description>defined as a composite of all of the following, all measured at 14 days:&#xD;
Patient alive&#xD;
Systolic blood pressure &gt;90 mmHg without need for vasopressor support&#xD;
Stable or improved SOFA score, define as:&#xD;
for baseline SOFA ≥ 3: a decrease of at least 30%;&#xD;
for baseline SOFA &lt;3: stable or decreased SOFA score&#xD;
For patients with HAP/ VAP, PaO2/FiO2 ratio stable or improved&#xD;
For patients with bacteremia, no growth of the initial isolate in blood cultures taken on day 14 if patient still febrile</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Secondary outcomes and adverse events</measure>
    <time_frame>14 and 28 days</time_frame>
    <description>14 and 28-day all-cause mortality.&#xD;
If patients are discharged or death occurs before end of follow-up (day 28), we will end data collection at that date. We will attempt to determine survival status at day 28 for all patients (central registry in Israel; re-admissions, rehabilitation centers, hospital transfers in Greece and Italy).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical success with modification</measure>
    <time_frame>14 days</time_frame>
    <description>Clinical success, but with modification to the antibiotic treatment not permitted by protocol</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to defervescence</measure>
    <time_frame>28 days</time_frame>
    <description>defined as time to reach a temperature of &lt;38°C with no recurrence for 3 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to weaning</measure>
    <time_frame>28 days</time_frame>
    <description>Time to weaning from mechanical ventilation in VAP for patients weaned alive</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to hospital discharge</measure>
    <time_frame>28 days</time_frame>
    <description>Time to hospital discharge for patient discharged alive</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Microbiological failure</measure>
    <time_frame>28 days</time_frame>
    <description>Microbiological failure, defined as isolation of the initial isolate (phenotypically identical) in a clinical sample (blood or other) 7 days or more after start of treatment or its identification in respiratory samples.&#xD;
For all patients with VAP/ HAP sputum or tracheal aspirates will be obtained on day 7, regardless of clinical response&#xD;
For all patients with UTI, a repeat urine culture will be obtained on day 7, regardless of clinical response&#xD;
For patients with bacteremia, blood cultures will be repeated on day 7 and 14, only if the patient is febrile at that time</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Superinfections</measure>
    <time_frame>28 days</time_frame>
    <description>Defined as a new clinically or microbiologically-documented infections by CDC criteria within 28 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New resistant infection</measure>
    <time_frame>28 days</time_frame>
    <description>Colonization or infection by newly-acquired (other species than the initial infection) carbapenem-resistant or colistin-resistant Gram-negative bacteria. Colonization will be assessed by rectal surveillance</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CDAD</measure>
    <time_frame>28 days</time_frame>
    <description>Clostridium-difficile-associated diarrhea, defined by diarrhea with a positive C. difficile toxin test</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">406</enrollment>
  <condition>Gram-Negative Bacterial Infections</condition>
  <arm_group>
    <arm_group_label>Colistin and Meropenem</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>IV meropenem, 2 gram q8h, adjusted for renal function IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Colistin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Colistin</intervention_name>
    <description>IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function, for 10 days.</description>
    <arm_group_label>Colistin</arm_group_label>
    <arm_group_label>Colistin and Meropenem</arm_group_label>
    <other_name>Colistimethate Sodium</other_name>
    <other_name>Coliracin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Meropenem</intervention_name>
    <description>IV meropenem, 2 gram q8h, adjusted for renal function, for up to 10 days.</description>
    <arm_group_label>Colistin and Meropenem</arm_group_label>
    <other_name>Meronem</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult inpatients&#xD;
&#xD;
          -  Clinically significant, microbiological-documented infection caused by&#xD;
             carbapenem-resistant and colistin-susceptible Gram-negative bacteria and identified&#xD;
             according to CDC criteria- blood stream infections, hospital acquired pneumonia,&#xD;
             ventilator associated pneumonia, and urinary tract infections&#xD;
&#xD;
          -  Patient recruitment will occur only after microbiological documentation and&#xD;
             susceptibility testing. Patients will be included within 96 hours of the time the&#xD;
             index culture was taken (typically within 48 hours of isolate identification),&#xD;
             regardless of the antibiotic treatment administered during this time period.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous inclusion in the trial. Patients will be included in the RCT only once for&#xD;
             the first identified episode of infection&#xD;
&#xD;
          -  Pregnant women&#xD;
&#xD;
          -  Epilepsy or prior seizures&#xD;
&#xD;
          -  Known allergy to colistin or a carbapenem&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Johan Mouton, MD PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Radboud University Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Mical Paul, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Rambam Health Care Centre</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Atikkon Hospital</name>
      <address>
        <city>Athens</city>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Laikon Hosptial</name>
      <address>
        <city>Athens</city>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rambam Health Care Center</name>
      <address>
        <city>Haifa</city>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rabin Medical Center</name>
      <address>
        <city>Petach-Tikvah</city>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tel-Aviv Sourasky Medical Center</name>
      <address>
        <city>Tel-Aviv</city>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Monaldi Hospital, University of Naples S.U.N.</name>
      <address>
        <city>Naples</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Agostino Gemelli Hospital</name>
      <address>
        <city>Rome</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Greece</country>
    <country>Israel</country>
    <country>Italy</country>
  </location_countries>
  <verification_date>April 2017</verification_date>
  <study_first_submitted>November 19, 2012</study_first_submitted>
  <study_first_submitted_qc>November 21, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 22, 2012</study_first_posted>
  <last_update_submitted>April 10, 2017</last_update_submitted>
  <last_update_submitted_qc>April 10, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">April 12, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Rabin Medical Center</investigator_affiliation>
    <investigator_full_name>Mical Paul</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <keyword>Gram-Negative Bacterial Infections</keyword>
  <keyword>Resistant Bacteria</keyword>
  <keyword>Drug Resistance, Bacterial</keyword>
  <keyword>Colistin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bacterial Infections</mesh_term>
    <mesh_term>Gram-Negative Bacterial Infections</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Meropenem</mesh_term>
    <mesh_term>Colistin</mesh_term>
  </intervention_browse>
  <!-- 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/NCT01732250
org study id: 0276-12-RMC
nct id: NCT01732250
lead sponsor: 
collaborator: 
has dmc: No
The purpose of this study is to determine whether the addition of meropenem to colistin is
      better than colistin alone in the treatment of clinically significant infections caused by
      multi-drug resistant bacteria
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Clinical success
time frame: 14 days
description: defined as a composite of all of the following, all measured at 14 days:
Patient alive
Systolic blood pressure >90 mmHg without need for vasopressor support
Stable or improved SOFA score, define as:
for baseline SOFA ≥ 3: a decrease of at least 30%;
for baseline SOFA <3: stable or decreased SOFA score
For patients with HAP/ VAP, PaO2/FiO2 ratio stable or improved
For patients with bacteremia, no growth of the initial isolate in blood cultures taken on day 14 if patient still febrile
measure: Secondary outcomes and adverse events
time frame: 14 and 28 days
description: 14 and 28-day all-cause mortality.
If patients are discharged or death occurs before end of follow-up (day 28), we will end data collection at that date. We will attempt to determine survival status at day 28 for all patients (central registry in Israel; re-admissions, rehabilitation centers, hospital transfers in Greece and Italy).
measure: Clinical success with modification
time frame: 14 days
description: Clinical success, but with modification to the antibiotic treatment not permitted by protocol
measure: Time to defervescence
time frame: 28 days
description: defined as time to reach a temperature of <38°C with no recurrence for 3 days
measure: Time to weaning
time frame: 28 days
description: Time to weaning from mechanical ventilation in VAP for patients weaned alive
measure: Time to hospital discharge
time frame: 28 days
description: Time to hospital discharge for patient discharged alive
measure: Microbiological failure
time frame: 28 days
description: Microbiological failure, defined as isolation of the initial isolate (phenotypically identical) in a clinical sample (blood or other) 7 days or more after start of treatment or its identification in respiratory samples.
For all patients with VAP/ HAP sputum or tracheal aspirates will be obtained on day 7, regardless of clinical response
For all patients with UTI, a repeat urine culture will be obtained on day 7, regardless of clinical response
For patients with bacteremia, blood cultures will be repeated on day 7 and 14, only if the patient is febrile at that time
measure: Superinfections
time frame: 28 days
description: Defined as a new clinically or microbiologically-documented infections by CDC criteria within 28 days
measure: New resistant infection
time frame: 28 days
description: Colonization or infection by newly-acquired (other species than the initial infection) carbapenem-resistant or colistin-resistant Gram-negative bacteria. Colonization will be assessed by rectal surveillance
measure: CDAD
time frame: 28 days
description: Clostridium-difficile-associated diarrhea, defined by diarrhea with a positive C. difficile toxin test
arm group label: Colistin and Meropenem
arm group type: Experimental
description: IV meropenem, 2 gram q8h, adjusted for renal function IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function
arm group label: Colistin
arm group type: Active Comparator
description: IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function
intervention type: Drug
intervention name: Colistin
description: IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function, for 10 days.
arm group label: Colistin
arm group label: Colistin and Meropenem
other name: Colistimethate Sodium
other name: Coliracin
intervention type: Drug
intervention name: Meropenem
description: IV meropenem, 2 gram q8h, adjusted for renal function, for up to 10 days.
arm group label: Colistin and Meropenem
other name: Meronem
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Johan Mouton, MD PhD
role: Study Chair
affiliation: Radboud University Medical Center
last name: Mical Paul, MD
role: Principal Investigator
affiliation: Rambam Health Care Centre
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Greece
country: Israel
country: Italy
responsible party type: Sponsor-Investigator
investigator affiliation: Rabin Medical Center
investigator full name: Mical Paul
investigator title: MD
mesh term: Bacterial Infections
mesh term: Gram-Negative Bacterial Infections
mesh term: Meropenem
mesh term: Colistin