Clinical trial NCT05219110: Hyperhydration in Children With Shiga Toxin-Producing E. Coli Infection
Official title: Hyperhydration to Improve Kidney Outcomes in Children With Shiga Toxin-Producing E. Coli Infection: A Multinational Embedded Cluster Crossover Randomized Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Shiga Toxin-Producing Escherichia Coli (E. Coli) Infection
Hemolytic-Uremic Syndrome
Keywords: Child
Hemolytic Uremic Syndrome
Shiga-Toxigenic Escherichia coli
Renal Replacement Therapy
Acute Kidney Injury
Ambulatory Care
Emergency Department
Lead sponsor: University of Calgary
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Children's Hospital Medical Center, Cincinnati
name: Washington University School of Medicine
name: University of Utah
name: Seattle Children's Hospital
name: University of Colorado, Denver
name: Emory University
name: University of California, Davis
name: Baylor College of Medicine
name: Indiana University School of Medicine
name: University of Alabama at Birmingham
name: Arkansas Children's Hospital Research Institute
name: Children's National Research Institute
name: Children's Hospitals and Clinics of Minnesota
name: Medical University of South Carolina
name: University of Louisville
name: University of Oklahoma
name: Oregon Health and Science University
name: University of California, San Diego
name: McMaster University
name: The Hospital for Sick Children
name: University of Alberta
name: University of Kentucky
name: Case Western Reserve University
name: Nationwide Children's Hospital
name: Vanderbilt University Medical Center
First posted: 2022-02-01
Enrollment: 1040
Sex: ALL
Minimum age (years): 9
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Cluster crossover
Primary purpose: TREATMENT

Brief summary: The objective of this study is to determine if early high volume intravenous fluid administration (hyperhydration) may be effective in mitigating or preventing complications of shiga toxin-producing E. coli (STEC) infection in children and adolescents when compared with traditional approaches (conservative fluid management).

Detailed description: The hemolytic uremic syndrome (HUS) is the most serious complication of high-risk Shiga toxin-producing Escherichia coli (STEC) infection and the most common cause of acquired acute kidney injury in otherwise healthy children. HUS develops in up to 20% of children following STEC infection, 60% of whom require temporary renal replacement therapy (RRT); an additional 50% develop serious extrarenal complications. Although mortality from acute HUS is low (1-3%), it has remained constant for three decades and approximately 30% of HUS survivors experience long-term sequelae, chiefly chronic kidney disease, hypertension, and diabetes. There have been only three relatively small, randomized trials to prevent progression to HUS and/or to reduce kidney injury once HUS is established; none have demonstrated benefits, and none have been performed since 1999.

Recent cohort studies suggest that early intravascular volume expansion (hyperhydration) in STEC infected children could be nephroprotective if and when HUS occurs. However, more evidence is needed before hyperhydration supplants traditional 'wait and see' (i.e., conservative fluid management) reactive care approaches which focus on outpatient care and minimizing intravenous fluid administration to avoid fluid overload in children who do develop HUS. Here, we will confirm or refute the hypothesis that aggressive volume expansion, administered early in STEC infected children, is associated with better renal outcomes and fewer adverse events than conservative management by accomplishing three Specific Aims: (1) Determine the effectiveness of hyperhydration in decreasing the prevalence of Major Adverse Kidney Events by 30 days (defined as death, RRT, or sustained loss of kidney function at 30 days) in STEC-infected children versus conservative fluid management; (2) Determine the effectiveness and safety of hyperhydration in decreasing HUS and life-threatening, extrarenal complications in STEC-infected children versus conservative fluid management; (3) Create a biorepository that will be linked to our clinical data to identify prognostic biomarkers and therapeutic targets in STEC-infected children.

Eligibility criteria: Inclusion Criteria:

In order to be eligible to participate in this study (i.e., to be enrolled in the relevant institutional clinical care pathway), an individual must meet all of the following criteria:

1. Aged 9.0 months to \<21 years at the time of informed consent.
2. Evidence of high-risk STEC infecting pathogen defined by any of the following:

   1. Bloody diarrhea within the preceding 7 days

      * Positive STEC culture OR
      * Positive antigen/polymerase chain reaction test for toxin/gene type not otherwise specified OR
   2. Bloody or Non-bloody diarrhea within the preceding 7 days

      •Presumptive diagnosis of HUS
      * (meeting all 3 HUS criteria - anemia, thrombocytopenia, and renal insufficiency) OR
   3. Non-bloody or no diarrhea

      * Positive STEC culture for high-risk strain (i.e., O103, O104, O111, O113, O121, O145 or O157) OR
      * Positive antigen/polymerase chain reaction test Stx2 toxin/gene

Exclusion Criteria:

All individuals meeting any of the exclusion criteria at baseline will be excluded from study participation.

1. Presence of Advanced HUS defined by:

   1. Hematocrit \<30% AND
   2. Platelet count \<150 x 103/mm3 AND
   3. Creatinine \> 2.0 mg/dL (177 µmol/L)

      * The presence of only 1 or 2 of these criteria will not result in patient exclusion, regardless of how close the 3rd criterion is to meeting the exclusion criteria.
2. Prior episode of HUS or diagnosis of atypical HUS.
3. Chronic disease limiting fluid volumes administered (e.g. impaired renal, liver, or cardiac function, chronic lung disease).
4. Evidence of anuria (i.e., no urine output for \> 24 hours).
5. Hypoxemia requiring oxygen therapy
6. Hypertensive emergency
7. Greater than or equal to 10 days since onset of diarrhea or if no diarrhea then the onset of other symptoms.
8. Patients with known pregnancy
9. Patients or caregivers with language barriers impairing appropriate conduct of the study protocol.

Primary outcomes:
measure: Major Adverse Kidney Events by 30 days (MAKE30)
timeFrame: 30 days
Secondary outcomes:
measure: Number of Participants with Significant Extrarenal Complications (life-threatening):
timeFrame: 30 days
measure: Number of Participants who Develop HUS among those without it at randomization
timeFrame: 30 days
Other outcomes:
measure: Length of Stay
timeFrame: 30 days
measure: Number of Participants who Receive Transfusion Therapy
timeFrame: 30 days
measure: Number of Participants who Receive Invasive Medical Procedures
timeFrame: 30 days
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: La Jolla
country: United States
facility: University of California, San Diego
state: California
city: Sacramento
country: United States
facility: University of California, Davis
state: California
city: Denver
country: United States
facility: University of Colorado Denver
state: Colorado
city: Washington
country: United States
facility: Children's Research Institute
state: District of Columbia
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University Children's Hospital
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Louisville
country: United States
facility: Norton Children's Hospital
state: Kentucky
city: Minneapolis
country: United States
facility: Children's Minnesota Hospital
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Cincinnati
country: United States
facility: Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Rainbow Babies & Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt Children's Hospital
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Hamilton
country: Canada
facility: McMaster University
state: Ontario
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: University of Calgary
name: Stephen Freedman, MDCM
role: PRINCIPAL_INVESTIGATOR
References: