<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/NCT03275792</url>
  </required_header>
  <id_info>
    <org_study_id>CHREB-12345</org_study_id>
    <nct_id>NCT03275792</nct_id>
  </id_info>
  <brief_title>Shiga Toxin Producing Escherichia Coli (STEC) Volume Expansion</brief_title>
  <official_title>Inpatient Volume Expansion in Children With Shiga Toxin-Producing Escherichia Coli (STEC) Infection to Prevent Hemolytic Uremic Syndrome (HUS)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Calgary</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Calgary</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will provide feasibility data regarding the conduct of a clinical trail evaluating&#xD;
      the use of early aggressive inpatient intravenous rehydration in children with Shiga Toxin&#xD;
      producing E. coli infection.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background: Shiga toxin-producing Escherichia coli (STEC) cause a spectrum of disease,&#xD;
      ranging from asymptomatic carriage to bloody diarrhea and the hemolytic uremic syndrome&#xD;
      (HUS). HUS is caused by a toxin that destroys red blood cells, consumes platelets and impairs&#xD;
      kidney function. HUS results in morbidity and even death in otherwise healthy children. Over&#xD;
      the last 30 years however, there has been extremely limited progress in preventing acute and&#xD;
      long-term complications in children with STEC infection. However, it is believed that Shiga&#xD;
      toxins generate clots or blockages in the kidneys that damage it much the way strokes cause&#xD;
      brain damage. There is emerging evidence that if children with STEC infection are recognized&#xD;
      early, then the interval between diarrhea onset and the presence of HUS could be exploited to&#xD;
      preserve kidney function through the use of intravenous rehydration.&#xD;
&#xD;
      Study Design: The investigators propose to conduct the first randomized clinical trial of&#xD;
      volume expansion therapy in children with STEC infection. Employing Alberta's unique&#xD;
      province-wide microbiology network and its only two pediatric tertiary care centres, the&#xD;
      investigators will conduct a proof of principal feasibility study that evaluates novel&#xD;
      technologies to identify STEC infected children and those at risk for HUS.&#xD;
&#xD;
      Objectives: The primary outcome will be process: number of children recruited. Secondary&#xD;
      outcomes will include: 1) resources: retention; refusal; compliance; eligibility criteria;&#xD;
      questionnaires; data collection tools; and time requirements; 2) management: capacity and&#xD;
      impact on clinical services; 3) scientific: utility of point-of-care STEC diagnostics; use of&#xD;
      urine biomarkers to identify high risk children, monitoring of kidney injury and response to&#xD;
      therapy; and safety.&#xD;
&#xD;
      Significance: This pilot will provide the necessary data to integrate novel technologies into&#xD;
      the design and conduct of a multicentre, multinational, clinical trial that will reduce&#xD;
      morbidity and mortality from STEC infection.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Funding not obtained.&#xD;
  </why_stopped>
  <start_date type="Anticipated">May 2020</start_date>
  <completion_date type="Anticipated">April 2021</completion_date>
  <primary_completion_date type="Anticipated">April 2021</primary_completion_date>
  <phase>Phase 1</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>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of children enrolled in the study protocol</measure>
    <time_frame>at the end of the 24 month study recruiting period</time_frame>
    <description>The number of children recruited per month per site will be calculated and will be related to the number screened, number eligible, and number consented.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The proportion of children enrolled in each study arm who develop adverse events</measure>
    <time_frame>at the end of the 24 month study recruiting period</time_frame>
    <description>For participants enrolled in each study arm we will quantify the proportion that are admitted to Intensive Care Units, the proportion requiring respiratory support (CPAP, BiPAP, endotracheal intubation), hypoxia defined by the administration of supplemental oxygen, and evidence of congestive heart failure defined by blinded independent reviewers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Retention</measure>
    <time_frame>at the end of the 24 month study recruiting period</time_frame>
    <description>The proportion of children who complete the study protocol</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time requirements</measure>
    <time_frame>at the end of the 24 month study recruiting period</time_frame>
    <description>We will quantify the number of hours children remain admitted and to which clinical units</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Child/family perspectives</measure>
    <time_frame>at the end of the 24 month study recruiting period</time_frame>
    <description>7-item likert scales will be employed to evaluate perspectives of parents and participants as appropriate related to study protocols, procedures and participation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>compliance/adherence</measure>
    <time_frame>at the end of the 24 month study recruiting period</time_frame>
    <description>The proportion of children enrolled in each study arm who comply with the key interventions of the respective study arms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>data collection tool performance</measure>
    <time_frame>at the end of the 24 month study recruiting period</time_frame>
    <description>Individual data fields will be audited with respect to data quality, reliability, completeness, timeliness of completion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact on clinical services</measure>
    <time_frame>at the end of the 24 month study recruiting period</time_frame>
    <description>We will qualitatively explore with the department leads at the respective institutions if the study protocol had any impact on clinical care provided either to the admitted patients or to other patients on their services</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cost</measure>
    <time_frame>at the end of the 24 month study recruiting period</time_frame>
    <description>We will quantify the costs per child in each study arm</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Point-of-Care STEC diagnosis</measure>
    <time_frame>at the end of the 24 month study recruiting period</time_frame>
    <description>diagnostic accuracy compared with standard culture</description>
  </other_outcome>
  <other_outcome>
    <measure>Urine biomarkers</measure>
    <time_frame>at the end of the 24 month study recruiting period</time_frame>
    <description>ability to predict progression to AKI and HUS</description>
  </other_outcome>
  <other_outcome>
    <measure>Point-of-Care STEC diagnosis</measure>
    <time_frame>at the end of the 24 month study recruiting period</time_frame>
    <description>turnaround time</description>
  </other_outcome>
  <other_outcome>
    <measure>Point-of-Care STEC diagnosis</measure>
    <time_frame>at the end of the 24 month study recruiting period</time_frame>
    <description>proportion O157 vs other STEC</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Hemolytic-Uremic Syndrome</condition>
  <arm_group>
    <arm_group_label>Admission/Intravascular Volume Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Infusion of 40 mL/kg of 0.9% normal saline (NS) IV over 60 minutes&#xD;
0.9% NS with 5% dextrose at 150% of standard maintenance volume&#xD;
If urine output is &lt;0.5 ml/kg/hr over a 12-hour period (AKI Stage 2), repeat 20 mL/kg bolus or boluses of 0.9% NS will be infused as long as there are no signs of central volume overload&#xD;
Oral fluids ad lib along with strict input/output documentation&#xD;
Fluids will be restricted if: A) Anuria for 12 hours OR B) Evidence of fluid overload&#xD;
Daily laboratory tests and in-person assessment until inpatient discharge criteria reached:&#xD;
A) 2 - 4 days since symptom onset AND rising platelet count (&gt;5% increase) documented over 48 hours in a clinically well child B) ≥5 days since symptom onset AND stable platelet count (&lt;5% decrease) documented over 48 hours in a clinically well child&#xD;
Repeat hematocrit, platelet, renal function 24 and 72-hours post-discharge.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Outpatient Observation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Following standard emergency department (ED) care [volume status assessed; dehydration corrected employing oral rehydration in children with mild to moderate dehydration (most common); IV if severe (rarely)], children are discharged with saline lock IV (routine procedure across Canadian pediatric EDs).&#xD;
Oral fluids (preferably electrolyte maintenance solutions) ad lib following ED discharge&#xD;
Additional health assessments as required&#xD;
Daily blood tests at a local laboratory with results conveyed daily to the site-investigator until outpatient discharge criteria achieved; no in-person assessment given logistics (i.e. distance), impact on family, and mirroring of standard practice A) 2 - 4 days since symptom onset AND rising platelet count (&gt;5% increase) documented over 48 hours in a clinically well child B) ≥5 days since symptom onset AND stable platelet count (&lt;5% decrease) documented over 48 hours in a clinically well child</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>D5-0.9%NS</intervention_name>
    <description>Admission for intravascular volume expansion</description>
    <arm_group_label>Admission/Intravascular Volume Expansion</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Routine home oral rehydration</intervention_name>
    <description>Routine oral fluids as is given at home to all children with acute diarrheal disease</description>
    <arm_group_label>Outpatient Observation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age &lt;18.0 years;&#xD;
&#xD;
          2. STEC infection [positive culture OR antigen OR polymerase chain reaction test for&#xD;
             Stx/gene];&#xD;
&#xD;
          3. Day of illness 1-10: Children who develop HUS will do so by day #14 of illness;8&#xD;
             restricting enrolment to the first 10 days will ensure all participants are at risk of&#xD;
             HUS.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Evidence of evolving HUS: A) Hematocrit &lt;30% OR B) Platelet count &lt;150 x 109/L;&#xD;
&#xD;
          2. Responsible physician desires patient admission (therefore unable to randomize);&#xD;
&#xD;
          3. Unable to contact family within 48 hours of positive stool test;&#xD;
&#xD;
          4. Patient with history of atypical HUS;&#xD;
&#xD;
          5. Chronic disease limiting fluid volumes administered (e.g. impaired cardiac function)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Months</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stephen Freedman, MDCM, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Calgary</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Alberta Children's Hospital</name>
      <address>
        <city>Calgary</city>
        <state>Alberta</state>
        <zip>T3B 6A8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>September 2019</verification_date>
  <study_first_submitted>August 29, 2017</study_first_submitted>
  <study_first_submitted_qc>September 5, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 8, 2017</study_first_posted>
  <last_update_submitted>November 5, 2020</last_update_submitted>
  <last_update_submitted_qc>November 5, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 9, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Shiga-Toxigenic Escherichia coli</keyword>
  <keyword>Child</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Escherichia coli Infections</mesh_term>
    <mesh_term>Hemolytic-Uremic Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
    <mesh_term>Hemolysis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03275792
org study id: CHREB-12345
nct id: NCT03275792
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This study will provide feasibility data regarding the conduct of a clinical trail evaluating
      the use of early aggressive inpatient intravenous rehydration in children with Shiga Toxin
      producing E. coli infection.
Background: Shiga toxin-producing Escherichia coli (STEC) cause a spectrum of disease,
      ranging from asymptomatic carriage to bloody diarrhea and the hemolytic uremic syndrome
      (HUS). HUS is caused by a toxin that destroys red blood cells, consumes platelets and impairs
      kidney function. HUS results in morbidity and even death in otherwise healthy children. Over
      the last 30 years however, there has been extremely limited progress in preventing acute and
      long-term complications in children with STEC infection. However, it is believed that Shiga
      toxins generate clots or blockages in the kidneys that damage it much the way strokes cause
      brain damage. There is emerging evidence that if children with STEC infection are recognized
      early, then the interval between diarrhea onset and the presence of HUS could be exploited to
      preserve kidney function through the use of intravenous rehydration.

      Study Design: The investigators propose to conduct the first randomized clinical trial of
      volume expansion therapy in children with STEC infection. Employing Alberta's unique
      province-wide microbiology network and its only two pediatric tertiary care centres, the
      investigators will conduct a proof of principal feasibility study that evaluates novel
      technologies to identify STEC infected children and those at risk for HUS.

      Objectives: The primary outcome will be process: number of children recruited. Secondary
      outcomes will include: 1) resources: retention; refusal; compliance; eligibility criteria;
      questionnaires; data collection tools; and time requirements; 2) management: capacity and
      impact on clinical services; 3) scientific: utility of point-of-care STEC diagnostics; use of
      urine biomarkers to identify high risk children, monitoring of kidney injury and response to
      therapy; and safety.

      Significance: This pilot will provide the necessary data to integrate novel technologies into
      the design and conduct of a multicentre, multinational, clinical trial that will reduce
      morbidity and mortality from STEC infection.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Number of children enrolled in the study protocol
time frame: at the end of the 24 month study recruiting period
description: The number of children recruited per month per site will be calculated and will be related to the number screened, number eligible, and number consented.
measure: The proportion of children enrolled in each study arm who develop adverse events
time frame: at the end of the 24 month study recruiting period
description: For participants enrolled in each study arm we will quantify the proportion that are admitted to Intensive Care Units, the proportion requiring respiratory support (CPAP, BiPAP, endotracheal intubation), hypoxia defined by the administration of supplemental oxygen, and evidence of congestive heart failure defined by blinded independent reviewers.
measure: Retention
time frame: at the end of the 24 month study recruiting period
description: The proportion of children who complete the study protocol
measure: Time requirements
time frame: at the end of the 24 month study recruiting period
description: We will quantify the number of hours children remain admitted and to which clinical units
measure: Child/family perspectives
time frame: at the end of the 24 month study recruiting period
description: 7-item likert scales will be employed to evaluate perspectives of parents and participants as appropriate related to study protocols, procedures and participation
measure: compliance/adherence
time frame: at the end of the 24 month study recruiting period
description: The proportion of children enrolled in each study arm who comply with the key interventions of the respective study arms
measure: data collection tool performance
time frame: at the end of the 24 month study recruiting period
description: Individual data fields will be audited with respect to data quality, reliability, completeness, timeliness of completion
measure: Impact on clinical services
time frame: at the end of the 24 month study recruiting period
description: We will qualitatively explore with the department leads at the respective institutions if the study protocol had any impact on clinical care provided either to the admitted patients or to other patients on their services
measure: Cost
time frame: at the end of the 24 month study recruiting period
description: We will quantify the costs per child in each study arm
measure: Point-of-Care STEC diagnosis
time frame: at the end of the 24 month study recruiting period
description: diagnostic accuracy compared with standard culture
measure: Urine biomarkers
time frame: at the end of the 24 month study recruiting period
description: ability to predict progression to AKI and HUS
measure: Point-of-Care STEC diagnosis
time frame: at the end of the 24 month study recruiting period
description: turnaround time
measure: Point-of-Care STEC diagnosis
time frame: at the end of the 24 month study recruiting period
description: proportion O157 vs other STEC
arm group label: Admission/Intravascular Volume Expansion
arm group type: Experimental
description: Infusion of 40 mL/kg of 0.9% normal saline (NS) IV over 60 minutes
0.9% NS with 5% dextrose at 150% of standard maintenance volume
If urine output is <0.5 ml/kg/hr over a 12-hour period (AKI Stage 2), repeat 20 mL/kg bolus or boluses of 0.9% NS will be infused as long as there are no signs of central volume overload
Oral fluids ad lib along with strict input/output documentation
Fluids will be restricted if: A) Anuria for 12 hours OR B) Evidence of fluid overload
Daily laboratory tests and in-person assessment until inpatient discharge criteria reached:
A) 2 - 4 days since symptom onset AND rising platelet count (>5% increase) documented over 48 hours in a clinically well child B) ≥5 days since symptom onset AND stable platelet count (<5% decrease) documented over 48 hours in a clinically well child
Repeat hematocrit, platelet, renal function 24 and 72-hours post-discharge.
arm group label: Outpatient Observation
arm group type: Active Comparator
description: Following standard emergency department (ED) care [volume status assessed; dehydration corrected employing oral rehydration in children with mild to moderate dehydration (most common); IV if severe (rarely)], children are discharged with saline lock IV (routine procedure across Canadian pediatric EDs).
Oral fluids (preferably electrolyte maintenance solutions) ad lib following ED discharge
Additional health assessments as required
Daily blood tests at a local laboratory with results conveyed daily to the site-investigator until outpatient discharge criteria achieved; no in-person assessment given logistics (i.e. distance), impact on family, and mirroring of standard practice A) 2 - 4 days since symptom onset AND rising platelet count (>5% increase) documented over 48 hours in a clinically well child B) ≥5 days since symptom onset AND stable platelet count (<5% decrease) documented over 48 hours in a clinically well child
intervention type: Drug
intervention name: D5-0.9%NS
description: Admission for intravascular volume expansion
arm group label: Admission/Intravascular Volume Expansion
intervention type: Drug
intervention name: Routine home oral rehydration
description: Routine oral fluids as is given at home to all children with acute diarrheal disease
arm group label: Outpatient Observation
criteria: 
gender: All
minimum age: 6 Months
maximum age: 18 Years
healthy volunteers: No
last name: Stephen Freedman, MDCM, MSc
role: Principal Investigator
affiliation: University of Calgary
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Escherichia coli Infections
mesh term: Hemolytic-Uremic Syndrome
mesh term: Syndrome
mesh term: Hemolysis
sharing ipd: Undecided