<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/NCT03011151</url>
  </required_header>
  <id_info>
    <org_study_id>IRB-P00024070</org_study_id>
    <nct_id>NCT03011151</nct_id>
  </id_info>
  <brief_title>Protease Activated Receptor-2 and Gastrointestinal Dysfunction in Critical Illness</brief_title>
  <official_title>Examining the Role of Protease-activated Receptor 2 Agonists in Gastrointestinal Dysfunction in Pediatric Surgical Critical Illness</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boston Children's Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boston Children's Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Gastrointestinal (GI) dysfunction affects up to 50% of medical and surgical critically ill&#xD;
      children. GI dysfunction, specifically gastric dysmotility and loss of epithelial barrier&#xD;
      integrity, is associated with significant morbidity in critical illness. The mechanisms&#xD;
      underlying GI dysfunction in critical illness are not well understood. GI dysfunction in&#xD;
      surgery and critical illness has been associated with inflammation. There is evidence to&#xD;
      suggest the protease-activated receptor 2 (PAR2) is a link between inflammation and GI&#xD;
      dysfunction. PAR2 is a G-coupled receptor present throughout the GI tract. PAR2 mediates GI&#xD;
      motility and epithelial barrier integrity. PAR2 is activated by PAR2 agonists, specifically&#xD;
      GI serine proteases and zonulin, released under conditions of inflammation. In this study the&#xD;
      investigators will examine the relationship between inflammation and PAR2 activation by PAR2&#xD;
      agonists and subsequent GI dysfunction in pediatric critically ill surgical patients. The&#xD;
      overall hypothesis of this study is that PAR2 activation by PAR2 agonists, GI serine&#xD;
      proteases and zonulin, released due to inflammation results in gastric dysmotility and loss&#xD;
      of epithelial barrier integrity. In this study, the investigators will examine whether PAR2&#xD;
      agonist expression is increased and correlates with GI dysfunction in critically ill surgical&#xD;
      pediatric patients. This proposal fills a knowledge gap in the understanding of mechanisms&#xD;
      for GI dysfunction in critical illness, and will be applicable to all surgical and medical&#xD;
      critically ill children.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators in this study aim to examine a plausible mechanism by which&#xD;
      gastrointestinal dysfunction, gastric dysmotility and loss of epithelial barrier integrity,&#xD;
      occur in critical illness. Specifically, the investigators will examine whether an increase&#xD;
      in PAR2 agonist levels, zonulin and serine proteases, are associated with gastric dysmotility&#xD;
      and loss of epithelial barrier integrity in critical surgical illness in children. The&#xD;
      investigators will examine GI function, gastric motility and epithelial barrier integrity,&#xD;
      and PAR2 agonist levels, zonulin and serine protease, in participants before surgery and&#xD;
      after surgery. Specifically, children undergoing posterior spinal fusion, a known significant&#xD;
      inflammatory trigger, and with planned admissions to the intensive care unit will be&#xD;
      enrolled. Gastrointestinal function and PAR2 agonist levels will be tested non-invasively in&#xD;
      blood and stool.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 1, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>PAR2 agonist activity- serum zonulin</measure>
    <time_frame>Immediately pre-operative versus post-operative day 1</time_frame>
    <description>PAR2 agonist activity will be measured by serum zonulin levels (ng/mL)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>PAR2 agonist activity- fecal protease activity</measure>
    <time_frame>Immediately pre-operative versus post-operative day 1</time_frame>
    <description>PAR2 agonist activity will be measured by fecal serine protease activity (trypsin units/gm protein)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Gastric motility by the acetaminophen absorption test- AUC</measure>
    <time_frame>Immediately pre-operative versus post-operative day 1</time_frame>
    <description>Pharmacokinetic parameters of acetaminophen will be used to determined gastric motility including the concentration of acetaminophen at 60 minutes (mcg/mL).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gastric motility by the acetaminophen absorption test- Tmax</measure>
    <time_frame>Immediately pre-operative versus post-operative day 1</time_frame>
    <description>Pharmacokinetic parameters of acetaminophen will be used to determined gastric motility including the time to maximum concentration of acetaminophen (minutes).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gastric motility by the acetaminophen absorption test- Cmax</measure>
    <time_frame>Immediately pre-operative versus post-operative day 1</time_frame>
    <description>Pharmacokinetic parameters of acetaminophen will be used to determined gastric motility including area under the curve at 60 minutes (mcg*min/mL).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Epithelial barrier integrity by serum biomarkers</measure>
    <time_frame>Immediately pre-operative versus post-operative day 1</time_frame>
    <description>Epithelial barrier integrity by serum biomarkers, specifically serum zonulin (ng/mL) and lipopolysaccharide binding protein levels (ng/mL).</description>
  </secondary_outcome>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Gastroparesis</condition>
  <condition>Gastrointestinal Disorder, Functional</condition>
  <condition>Critical Illness</condition>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood, Stool&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Children undergoing posterior spinal fusion and admitted to the pediatric intensive care&#xD;
        unit&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  2 years and older&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Liver dysfunction&#xD;
&#xD;
          -  Renal dysfunction&#xD;
&#xD;
          -  Pre-diagnosed gastroparesis/ delayed gastric emptying&#xD;
&#xD;
          -  Pre-diagnosed gastrointestinal malabsorption&#xD;
&#xD;
          -  Contraindication to acetaminophen administration&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Years</minimum_age>
    <maximum_age>30 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Enid Martinez, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Boston Children's Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Enid Martinez, MD</last_name>
    <phone>6173557327</phone>
    <email>enid.martinez@childrens.harvard.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Boston Children's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Enid Martinez, MD</last_name>
      <phone>617-355-7327</phone>
      <email>enid.martinez@childrens.harvard.edu</email>
    </contact>
    <contact_backup>
      <last_name>Brooke Sens, RN</last_name>
      <phone>6173556185</phone>
      <email>brooke.sens@childrens.harvard.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>January 2, 2017</study_first_submitted>
  <study_first_submitted_qc>January 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 5, 2017</study_first_posted>
  <last_update_submitted>March 13, 2023</last_update_submitted>
  <last_update_submitted_qc>March 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Boston Children's Hospital</investigator_affiliation>
    <investigator_full_name>Enid Martinez</investigator_full_name>
    <investigator_title>Assistant in Critical Care Medicine</investigator_title>
  </responsible_party>
  <keyword>pediatric</keyword>
  <keyword>critical illness</keyword>
  <keyword>surgery</keyword>
  <keyword>gastrointestinal dysfunction</keyword>
  <keyword>gastric emptying</keyword>
  <keyword>epithelial barrier</keyword>
  <keyword>nutrition</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gastroparesis</mesh_term>
    <mesh_term>Gastrointestinal Diseases</mesh_term>
    <mesh_term>Digestive System Diseases</mesh_term>
    <mesh_term>Critical Illness</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT03011151
org study id: IRB-P00024070
nct id: NCT03011151
lead sponsor: 
has dmc: No
Gastrointestinal (GI) dysfunction affects up to 50% of medical and surgical critically ill
      children. GI dysfunction, specifically gastric dysmotility and loss of epithelial barrier
      integrity, is associated with significant morbidity in critical illness. The mechanisms
      underlying GI dysfunction in critical illness are not well understood. GI dysfunction in
      surgery and critical illness has been associated with inflammation. There is evidence to
      suggest the protease-activated receptor 2 (PAR2) is a link between inflammation and GI
      dysfunction. PAR2 is a G-coupled receptor present throughout the GI tract. PAR2 mediates GI
      motility and epithelial barrier integrity. PAR2 is activated by PAR2 agonists, specifically
      GI serine proteases and zonulin, released under conditions of inflammation. In this study the
      investigators will examine the relationship between inflammation and PAR2 activation by PAR2
      agonists and subsequent GI dysfunction in pediatric critically ill surgical patients. The
      overall hypothesis of this study is that PAR2 activation by PAR2 agonists, GI serine
      proteases and zonulin, released due to inflammation results in gastric dysmotility and loss
      of epithelial barrier integrity. In this study, the investigators will examine whether PAR2
      agonist expression is increased and correlates with GI dysfunction in critically ill surgical
      pediatric patients. This proposal fills a knowledge gap in the understanding of mechanisms
      for GI dysfunction in critical illness, and will be applicable to all surgical and medical
      critically ill children.
The investigators in this study aim to examine a plausible mechanism by which
      gastrointestinal dysfunction, gastric dysmotility and loss of epithelial barrier integrity,
      occur in critical illness. Specifically, the investigators will examine whether an increase
      in PAR2 agonist levels, zonulin and serine proteases, are associated with gastric dysmotility
      and loss of epithelial barrier integrity in critical surgical illness in children. The
      investigators will examine GI function, gastric motility and epithelial barrier integrity,
      and PAR2 agonist levels, zonulin and serine protease, in participants before surgery and
      after surgery. Specifically, children undergoing posterior spinal fusion, a known significant
      inflammatory trigger, and with planned admissions to the intensive care unit will be
      enrolled. Gastrointestinal function and PAR2 agonist levels will be tested non-invasively in
      blood and stool.
observational model: Cohort
time perspective: Prospective
measure: PAR2 agonist activity- serum zonulin
time frame: Immediately pre-operative versus post-operative day 1
description: PAR2 agonist activity will be measured by serum zonulin levels (ng/mL)
measure: PAR2 agonist activity- fecal protease activity
time frame: Immediately pre-operative versus post-operative day 1
description: PAR2 agonist activity will be measured by fecal serine protease activity (trypsin units/gm protein)
measure: Gastric motility by the acetaminophen absorption test- AUC
time frame: Immediately pre-operative versus post-operative day 1
description: Pharmacokinetic parameters of acetaminophen will be used to determined gastric motility including the concentration of acetaminophen at 60 minutes (mcg/mL).
measure: Gastric motility by the acetaminophen absorption test- Tmax
time frame: Immediately pre-operative versus post-operative day 1
description: Pharmacokinetic parameters of acetaminophen will be used to determined gastric motility including the time to maximum concentration of acetaminophen (minutes).
measure: Gastric motility by the acetaminophen absorption test- Cmax
time frame: Immediately pre-operative versus post-operative day 1
description: Pharmacokinetic parameters of acetaminophen will be used to determined gastric motility including area under the curve at 60 minutes (mcg*min/mL).
measure: Epithelial barrier integrity by serum biomarkers
time frame: Immediately pre-operative versus post-operative day 1
description: Epithelial barrier integrity by serum biomarkers, specifically serum zonulin (ng/mL) and lipopolysaccharide binding protein levels (ng/mL).
Blood, Stool
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 2 Years
maximum age: 30 Years
healthy volunteers: No
last name: Enid Martinez, MD
role: Principal Investigator
affiliation: Boston Children's Hospital
last name: Enid Martinez, MD
phone: 6173557327
email: enid.martinez@childrens.harvard.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Boston Children's Hospital
investigator full name: Enid Martinez
investigator title: Assistant in Critical Care Medicine
mesh term: Gastroparesis
mesh term: Gastrointestinal Diseases
mesh term: Digestive System Diseases
mesh term: Critical Illness
sharing ipd: No