<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/NCT01687543</url>
  </required_header>
  <id_info>
    <org_study_id>ProENT11</org_study_id>
    <nct_id>NCT01687543</nct_id>
  </id_info>
  <brief_title>Probiotics for Reduction of Infections With Clostridium Difficile in Critically Ill Patients</brief_title>
  <acronym>ProbiEnt</acronym>
  <official_title>Probiotics for Reduction of Colonisation With Clostridium Difficile in Antibiotic Treated Intensive Care Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Region Skane</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Lund University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Region Skane</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Symptoms of Clostridium difficile infection is almost always induced as a complication to the&#xD;
      use of antibiotics. Most ICU patients are given antibiotics.&#xD;
&#xD;
      Probiotics has the ability to improve conditions in the gut and it has been shown in some&#xD;
      smaller studies that overgrowth of C. difficile can be reduced or prevented.&#xD;
&#xD;
      In this study the intention is to show with sufficient statistical power that a mixture of&#xD;
      two otherwise well studied probiotic strains reduces or prevents the incidence of emerging&#xD;
      colonisation with C. difficile in critical ill patients on antibiotics.&#xD;
&#xD;
      Half of the patients will be given a mixture of Lactobacillus plantarum 299 and Lactobacillus&#xD;
      plantarum 299v twice daily and the rest a placebo mixture.&#xD;
&#xD;
      Rectal swabs or faeces will be analysed for C.difficile and its toxins and the incidence of&#xD;
      new cases will be compared for the two groups.&#xD;
&#xD;
      White blood cells (WBC´s), C reactive protein (CRP), lactate, urea, and creatinine will be&#xD;
      followed daily as well as antibiotics, corticosteroids and all acid reducing medication.&#xD;
&#xD;
      Nutrition, enteral and total, and bowel habits will be recorded.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Infections with Clostridium difficile is considered to be the most frequent health care&#xD;
      associated bacterial infection. Almost all cases are connected to the use of antibiotics.&#xD;
&#xD;
      The spectra of symptoms of infection reaches from loose stools to sepsis and death. It is&#xD;
      estimated that about 5% of the population are carriers without symptoms.&#xD;
&#xD;
      Elderly people are more likely to be diagnosed with C. difficile infections and as about 50 %&#xD;
      of ICU admissions (at least in Sweden) are patients aged 64 years or older C. difficile is&#xD;
      also an ICU issue.&#xD;
&#xD;
      Probiotic bacteria given to antibiotic treated patients results in fever cases of infection&#xD;
      with C. difficile as we and others have shown in some small studies. Due to a low statistical&#xD;
      power in our former study this multicentre study is calculated to be large enough to fulfil&#xD;
      statistical requirements.&#xD;
&#xD;
      Adult patients with an expected length of stay in intensive care for three days or more can&#xD;
      be included.&#xD;
&#xD;
      Primary objective is to find emerging cases of colonisation with C. difficile and consequent&#xD;
      symptoms of infection such as diarrhoea.&#xD;
&#xD;
      Cultures and toxin analyses will be taken at inclusion and every second day till day 13 and&#xD;
      then every third or fourth day depending on length of ICU stay. Positive cases will be given&#xD;
      antibiotics according to normal routines.&#xD;
&#xD;
      No other cultures are collected per protocol but all cultures will be recorded and results&#xD;
      will be analysed in order to find any connection between treatment and reduction of secondary&#xD;
      infections.&#xD;
&#xD;
      In our earlier small study we found an improved and normalised gut barrier function for those&#xD;
      patients that were given probiotic bacteria compared to a worsened, scattered pattern for the&#xD;
      placebo group. This is probably why we found that inflammatory parameters improved for the&#xD;
      probiotics group while those parameters remained elevated for the control patients. The same&#xD;
      goes for creatinine, urea and lactate. This is why we will record those parameters together&#xD;
      with blood gas analyses in this expanded study.&#xD;
&#xD;
      Antibiotics and medication with corticosteroids, proton pump inhibitors or other acid&#xD;
      reducing preparations, All nutritive prescriptions (enteral formulas and IV solutions as well&#xD;
      as medical preparations containing glucose or fat) will be recorded and compared to actually&#xD;
      given nutrients.&#xD;
&#xD;
      Bowel movements frequency and consistency will be recorded and compared between groups.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Too low inclusion rate and several sites did not comply&#xD;
  </why_stopped>
  <start_date>June 2012</start_date>
  <completion_date type="Actual">October 1, 2017</completion_date>
  <primary_completion_date type="Actual">June 2017</primary_completion_date>
  <phase>N/A</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>Prevention</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Differences in emerging cases of Clostridium difficile</measure>
    <time_frame>Throughout the ICU stay, expected mean LOS 10 days</time_frame>
    <description>Emerging cases of Clostridium difficile, identified as positive cultures and/or toxin tests</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>White blood cells</measure>
    <time_frame>Throughout the ICU , expected mean LOS 10 days</time_frame>
    <description>Samples taken at admission or inclusion and then daily</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>C Reactive Protein</measure>
    <time_frame>Throughout the ICU , expected mean LOS 10 days</time_frame>
    <description>Samples taken at admission or inclusion and then daily</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Creatinine</measure>
    <time_frame>Throughout the ICU , expected mean LOS 10 days</time_frame>
    <description>Samples taken at admission or inclusion and then daily</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urea</measure>
    <time_frame>Throughout the ICU , expected mean LOS 10 days</time_frame>
    <description>Samples taken at admission or inclusion and then daily</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lactate</measure>
    <time_frame>Throughout the ICU , expected mean LOS 10 days</time_frame>
    <description>Samples taken at admission or inclusion and then daily</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ventilator days</measure>
    <time_frame>Throughout the ICU stay, expected mean LOS 10 days</time_frame>
    <description>Records are held for how long the patients require mechanical ventilation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of stay ICU</measure>
    <time_frame>Length of ICU stay, about 10 days in accordance with a prior similar study</time_frame>
    <description>Length of stay is recorded for the ICU as well as for the Hospital stay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of Hospital stay</measure>
    <time_frame>Within six months from date of ICU admission</time_frame>
    <description>Length of stay is recorded for the Hospital as well as for the ICU stay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Survival</measure>
    <time_frame>Six months</time_frame>
    <description>For participating patients the status of survival or non survival at days 28 and 180 (six months) will be recorded</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diarrhea and obstipation</measure>
    <time_frame>Throughout the ICU stay, expected mean LOS 10 days</time_frame>
    <description>As ICU patients tend to display diarrhea as well as obstipation the frequency and consistency of stools will be recorded.&#xD;
Probiotics are anticipated to stabilise bowel function</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>Clostridium Difficile Colonisation</condition>
  <condition>Impact of Enteral Probiotics on Certain Lab Parameters</condition>
  <arm_group>
    <arm_group_label>Probiotics</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will be given a mixture of maltodextrin ( a starch product often used i alimentary products) and two strains of probiotic bacteria ( L. plantarum 299 and L. plantarum 299v ) dissolved in water through a nasogastric tube. Patients randomized 1:1 between groups</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients will be given only the dissolved maltodextrin in water through the nasogastric tube. Patients randomized 1:1 between groups</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>L. plantarum 299 and L. plantarum 299v (+maltodextrin)</intervention_name>
    <description>A suspension of Lactobacillus plantarum 299 and Lactobacillus plantarum 299v together with maltodextrin is distributed to the patients twice a day.</description>
    <arm_group_label>Probiotics</arm_group_label>
    <other_name>Lactobacillus plantarum 299</other_name>
    <other_name>Lactobacillus plantarum 299v</other_name>
    <other_name>Maltodextrin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Maltodextrin</intervention_name>
    <description>A suspension of maltodextrin (as placebo control) is distributed to the patients twice a day.</description>
    <arm_group_label>Control</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Anticipated need for intensive care 3 days or longer&#xD;
&#xD;
          -  Patients condition allowing enteral nutrition to be started within 24 h from ICU&#xD;
             admission&#xD;
&#xD;
          -  Antibiotics on-going or planned&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known positive test for Clostridium difficile within the last week&#xD;
&#xD;
          -  Known ulcers in the mouth, oropharynx, esophagus and stomach&#xD;
&#xD;
          -  Known immune deficiencies&#xD;
&#xD;
          -  Enteral nutrition contra indicated&#xD;
&#xD;
          -  Pancreatitis as admission diagnosis at the hospital or at the ICU&#xD;
&#xD;
          -  ICU admission earlier during this period of illness Patient being moribund&#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>Bengt Klarin, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Lund University, Lund, Sweden</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Intensive Care Unit, Helsingborg Hospital</name>
      <address>
        <city>Helsingborg</city>
        <zip>SE 251 87</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Intensive Care Unit, Kristianstad Central hospital</name>
      <address>
        <city>Kristianstad</city>
        <zip>SE 291 85</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lund University Hospital</name>
      <address>
        <city>Lund</city>
        <zip>SE 22185</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dept of Anesthesia &amp; Intensive Care, University Hospital of Norrland</name>
      <address>
        <city>Umeå</city>
        <zip>SE-901 85</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <link>
    <url>http://www.probi.se</url>
    <description>Producers of the study products</description>
  </link>
  <reference>
    <citation>Klarin B, Wullt M, Palmquist I, Molin G, Larsson A, Jeppsson B. Lactobacillus plantarum 299v reduces colonisation of Clostridium difficile in critically ill patients treated with antibiotics. Acta Anaesthesiol Scand. 2008 Sep;52(8):1096-102. doi: 10.1111/j.1399-6576.2008.01748.x.</citation>
    <PMID>18840110</PMID>
  </reference>
  <verification_date>October 2017</verification_date>
  <study_first_submitted>August 28, 2012</study_first_submitted>
  <study_first_submitted_qc>September 13, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 19, 2012</study_first_posted>
  <last_update_submitted>October 3, 2017</last_update_submitted>
  <last_update_submitted_qc>October 3, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">October 5, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Clostridium difficile</keyword>
  <keyword>WBC</keyword>
  <keyword>CRP</keyword>
  <keyword>Lactate</keyword>
  <keyword>Urea</keyword>
  <keyword>Creatinine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Clostridium Infections</mesh_term>
  </condition_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/NCT01687543
org study id: ProENT11
nct id: NCT01687543
lead sponsor: 
collaborator: 
has dmc: No
Symptoms of Clostridium difficile infection is almost always induced as a complication to the
      use of antibiotics. Most ICU patients are given antibiotics.

      Probiotics has the ability to improve conditions in the gut and it has been shown in some
      smaller studies that overgrowth of C. difficile can be reduced or prevented.

      In this study the intention is to show with sufficient statistical power that a mixture of
      two otherwise well studied probiotic strains reduces or prevents the incidence of emerging
      colonisation with C. difficile in critical ill patients on antibiotics.

      Half of the patients will be given a mixture of Lactobacillus plantarum 299 and Lactobacillus
      plantarum 299v twice daily and the rest a placebo mixture.

      Rectal swabs or faeces will be analysed for C.difficile and its toxins and the incidence of
      new cases will be compared for the two groups.

      White blood cells (WBC´s), C reactive protein (CRP), lactate, urea, and creatinine will be
      followed daily as well as antibiotics, corticosteroids and all acid reducing medication.

      Nutrition, enteral and total, and bowel habits will be recorded.
Infections with Clostridium difficile is considered to be the most frequent health care
      associated bacterial infection. Almost all cases are connected to the use of antibiotics.

      The spectra of symptoms of infection reaches from loose stools to sepsis and death. It is
      estimated that about 5% of the population are carriers without symptoms.

      Elderly people are more likely to be diagnosed with C. difficile infections and as about 50 %
      of ICU admissions (at least in Sweden) are patients aged 64 years or older C. difficile is
      also an ICU issue.

      Probiotic bacteria given to antibiotic treated patients results in fever cases of infection
      with C. difficile as we and others have shown in some small studies. Due to a low statistical
      power in our former study this multicentre study is calculated to be large enough to fulfil
      statistical requirements.

      Adult patients with an expected length of stay in intensive care for three days or more can
      be included.

      Primary objective is to find emerging cases of colonisation with C. difficile and consequent
      symptoms of infection such as diarrhoea.

      Cultures and toxin analyses will be taken at inclusion and every second day till day 13 and
      then every third or fourth day depending on length of ICU stay. Positive cases will be given
      antibiotics according to normal routines.

      No other cultures are collected per protocol but all cultures will be recorded and results
      will be analysed in order to find any connection between treatment and reduction of secondary
      infections.

      In our earlier small study we found an improved and normalised gut barrier function for those
      patients that were given probiotic bacteria compared to a worsened, scattered pattern for the
      placebo group. This is probably why we found that inflammatory parameters improved for the
      probiotics group while those parameters remained elevated for the control patients. The same
      goes for creatinine, urea and lactate. This is why we will record those parameters together
      with blood gas analyses in this expanded study.

      Antibiotics and medication with corticosteroids, proton pump inhibitors or other acid
      reducing preparations, All nutritive prescriptions (enteral formulas and IV solutions as well
      as medical preparations containing glucose or fat) will be recorded and compared to actually
      given nutrients.

      Bowel movements frequency and consistency will be recorded and compared between groups.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Triple (Participant, Care Provider, Investigator)
measure: Differences in emerging cases of Clostridium difficile
time frame: Throughout the ICU stay, expected mean LOS 10 days
description: Emerging cases of Clostridium difficile, identified as positive cultures and/or toxin tests
measure: White blood cells
time frame: Throughout the ICU , expected mean LOS 10 days
description: Samples taken at admission or inclusion and then daily
measure: C Reactive Protein
time frame: Throughout the ICU , expected mean LOS 10 days
description: Samples taken at admission or inclusion and then daily
measure: Creatinine
time frame: Throughout the ICU , expected mean LOS 10 days
description: Samples taken at admission or inclusion and then daily
measure: Urea
time frame: Throughout the ICU , expected mean LOS 10 days
description: Samples taken at admission or inclusion and then daily
measure: Lactate
time frame: Throughout the ICU , expected mean LOS 10 days
description: Samples taken at admission or inclusion and then daily
measure: Ventilator days
time frame: Throughout the ICU stay, expected mean LOS 10 days
description: Records are held for how long the patients require mechanical ventilation
measure: Length of stay ICU
time frame: Length of ICU stay, about 10 days in accordance with a prior similar study
description: Length of stay is recorded for the ICU as well as for the Hospital stay
measure: Length of Hospital stay
time frame: Within six months from date of ICU admission
description: Length of stay is recorded for the Hospital as well as for the ICU stay
measure: Survival
time frame: Six months
description: For participating patients the status of survival or non survival at days 28 and 180 (six months) will be recorded
measure: Diarrhea and obstipation
time frame: Throughout the ICU stay, expected mean LOS 10 days
description: As ICU patients tend to display diarrhea as well as obstipation the frequency and consistency of stools will be recorded.
Probiotics are anticipated to stabilise bowel function
arm group label: Probiotics
arm group type: Experimental
description: Patients will be given a mixture of maltodextrin ( a starch product often used i alimentary products) and two strains of probiotic bacteria ( L. plantarum 299 and L. plantarum 299v ) dissolved in water through a nasogastric tube. Patients randomized 1:1 between groups
arm group label: Control
arm group type: Placebo Comparator
description: Patients will be given only the dissolved maltodextrin in water through the nasogastric tube. Patients randomized 1:1 between groups
intervention type: Dietary Supplement
intervention name: L. plantarum 299 and L. plantarum 299v (+maltodextrin)
description: A suspension of Lactobacillus plantarum 299 and Lactobacillus plantarum 299v together with maltodextrin is distributed to the patients twice a day.
arm group label: Probiotics
other name: Lactobacillus plantarum 299
other name: Lactobacillus plantarum 299v
other name: Maltodextrin
intervention type: Other
intervention name: Maltodextrin
description: A suspension of maltodextrin (as placebo control) is distributed to the patients twice a day.
arm group label: Control
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Bengt Klarin, MD, PhD
role: Principal Investigator
affiliation: Lund University, Lund, Sweden
facility: 
facility: 
facility: 
facility: 
country: Sweden
url: http://www.probi.se
description: Producers of the study products
citation: Klarin B, Wullt M, Palmquist I, Molin G, Larsson A, Jeppsson B. Lactobacillus plantarum 299v reduces colonisation of Clostridium difficile in critically ill patients treated with antibiotics. Acta Anaesthesiol Scand. 2008 Sep;52(8):1096-102. doi: 10.1111/j.1399-6576.2008.01748.x.
PMID: 18840110
responsible party type: Sponsor
mesh term: Clostridium Infections