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Hyperhydration in Children With Shiga Toxin-Producing E. Coli Infection (HIKO-STEC)

Primary Purpose

Shiga Toxin-Producing Escherichia Coli (E. Coli) Infection, Hemolytic-Uremic Syndrome

Status
Recruiting
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Infusion of 200% maintenance fluids as balanced crystalloid IV solution
Oral fluids; infusion of up to 110% maintenance fluids as balanced crystalloid IV solution
Sponsored by
University of Calgary
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Shiga Toxin-Producing Escherichia Coli (E. Coli) Infection focused on measuring Child, Hemolytic Uremic Syndrome, Shiga-Toxigenic Escherichia coli, Renal Replacement Therapy, Acute Kidney Injury, Ambulatory Care, Emergency Department

Eligibility Criteria

9 Months - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Alabama at BirminghamRecruiting
  • Arkansas Children's HospitalRecruiting
  • University of California, San DiegoRecruiting
  • University of California, DavisRecruiting
  • University of Colorado DenverRecruiting
  • Children's Research InstituteRecruiting
  • Emory UniversityRecruiting
  • Indiana University Children's HospitalRecruiting
  • University of KentuckyRecruiting
  • Norton Children's HospitalRecruiting
  • Children's Minnesota HospitalRecruiting
  • Washington UniversityRecruiting
  • Children's Hospital Medical CenterRecruiting
  • University Hospitals Rainbow Babies & Children's HospitalRecruiting
  • Nationwide Children's HospitalRecruiting
  • University of Oklahoma Health Sciences CenterRecruiting
  • Oregon Health & Science UniversityRecruiting
  • Medical University of South CarolinaRecruiting
  • Vanderbilt Children's HospitalRecruiting
  • Baylor College of MedicineRecruiting
  • University of UtahRecruiting
  • Seattle Children's HospitalRecruiting
  • Alberta Children's HospitalRecruiting
  • University of AlbertaRecruiting
  • McMaster UniversityRecruiting
  • The Hospital for Sick ChildrenRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Hyperhydration

Conservative Fluid Management

Arm Description

In this study arm, all eligible children are admitted for the administration of intravenous fluids. The following specifics will form the basis of the fluid management protocol: Reversal of dehydration: Initial ED rehydration strategies should focus on rapidly reversing dehydration. Infusion of 200% of maintenance fluids x 24 hours If hematocrit reduction < 20% from initial value, repeat step #2 [infusion of 200% maintenance fluids x 24 hours]. Oral fluids permitted ad lib. Once the target hematocrit reduction is achieved (20% decrement in initial HCT) AND a 10% weight gain, adjust total IV fluid volume to maintain targeted weight gain: insensible plus output (i.e., urine plus stool).

The conservative fluid management arm has been designed to align and integrate into existing local practice patterns. Implementation of this approach will allow institutions and their practitioners to choose their management of protocol eligible children. All children will undergo a protocolized baseline evaluation that includes reversal of dehydration (if present) and follow-up plan (see Pre-Pathway care). The fluid management decision in the ED (i.e., to treat dehydration) will be at the discretion of the clinical care team. In the absence of evidence of microangiopathy (i.e., normal urinalysis, LDH, hemoglobin and platelet counts, and creatinine concentrations), the decision to admit the child to hospital or discharge the child to home will be at the discretion of the clinical care team. If microangiopathy is present (i.e., abnormal urinalysis, LDH, hemoglobin or platelet counts, or creatinine concentrations) admission for monitoring will be required.

Outcomes

Primary Outcome Measures

Major Adverse Kidney Events by 30 days (MAKE30)
Death due to any cause censored at 30 days after enrollment OR Provision of RRT, any modality, within 30 days of trial enrollment OR Sustained loss of kidney function (100% increase of serum sCr from baseline at 30±7 days)

Secondary Outcome Measures

Number of Participants with Significant Extrarenal Complications (life-threatening):
a. Neurologic: i. Seizures requiring anticonvulsant therapy ii. Coma iii. Thrombotic or hemorrhagic stroke confirmed by neuroimaging b. Cardiac: i. Myocardial infarction ii. Myocarditis iii. Myocardial dysfunction iv. Arrhythmias requiring cardioversion or pharmacological anti-arrhythmic therapy c. Respiratory: i. Respiratory failure ii. Pleural effusions d. Gastrointestinal: i. Hyperglycemia requiring prolonged insulin therapy ii. Bowel obstruction/perforation requiring surgical repair iii. Intussusception requiring reduction iv. Acute cholecystitis v. Pancreatitis vi. Hepatitis/ liver failure vii. Ascites requiring paracentesis e. Infectious complications i. Bacteremia ii. Peritonitis
Number of Participants who Develop HUS among those without it at randomization
Anemia (hematocrit level <30%) AND Thrombocytopenia (platelet count <150 X 103/mm3) AND Renal azotemia (serum creatinine concentration >upper limit of reference range for age)

Full Information

First Posted
January 20, 2022
Last Updated
July 21, 2023
Sponsor
University of Calgary
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID), Children's Hospital Medical Center, Cincinnati, Washington University School of Medicine, University of Utah, Seattle Children's Hospital, University of Colorado, Denver, Emory University, University of California, Davis, Baylor College of Medicine, Indiana University School of Medicine, University of Alabama at Birmingham, Arkansas Children's Hospital Research Institute, Children's National Research Institute, Children's Hospitals and Clinics of Minnesota, Medical University of South Carolina, University of Louisville, University of Oklahoma, Oregon Health and Science University, University of California, San Diego, McMaster University, The Hospital for Sick Children, University of Alberta, University of Kentucky, Case Western Reserve University, Nationwide Children's Hospital, Vanderbilt University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT05219110
Brief Title
Hyperhydration in Children With Shiga Toxin-Producing E. Coli Infection
Acronym
HIKO-STEC
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

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 29, 2022 (Actual)
Primary Completion Date
August 31, 2026 (Anticipated)
Study Completion Date
August 31, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Calgary
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID), Children's Hospital Medical Center, Cincinnati, Washington University School of Medicine, University of Utah, Seattle Children's Hospital, University of Colorado, Denver, Emory University, University of California, Davis, Baylor College of Medicine, Indiana University School of Medicine, University of Alabama at Birmingham, Arkansas Children's Hospital Research Institute, Children's National Research Institute, Children's Hospitals and Clinics of Minnesota, Medical University of South Carolina, University of Louisville, University of Oklahoma, Oregon Health and Science University, University of California, San Diego, McMaster University, The Hospital for Sick Children, University of Alberta, University of Kentucky, Case Western Reserve University, Nationwide Children's Hospital, Vanderbilt University Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Crossover Assignment
Model Description
Cluster crossover
Masking
None (Open Label)
Allocation
Randomized
Enrollment
1040 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Hyperhydration
Arm Type
Experimental
Arm Description
In this study arm, all eligible children are admitted for the administration of intravenous fluids. The following specifics will form the basis of the fluid management protocol: Reversal of dehydration: Initial ED rehydration strategies should focus on rapidly reversing dehydration. Infusion of 200% of maintenance fluids x 24 hours If hematocrit reduction < 20% from initial value, repeat step #2 [infusion of 200% maintenance fluids x 24 hours]. Oral fluids permitted ad lib. Once the target hematocrit reduction is achieved (20% decrement in initial HCT) AND a 10% weight gain, adjust total IV fluid volume to maintain targeted weight gain: insensible plus output (i.e., urine plus stool).
Arm Title
Conservative Fluid Management
Arm Type
Active Comparator
Arm Description
The conservative fluid management arm has been designed to align and integrate into existing local practice patterns. Implementation of this approach will allow institutions and their practitioners to choose their management of protocol eligible children. All children will undergo a protocolized baseline evaluation that includes reversal of dehydration (if present) and follow-up plan (see Pre-Pathway care). The fluid management decision in the ED (i.e., to treat dehydration) will be at the discretion of the clinical care team. In the absence of evidence of microangiopathy (i.e., normal urinalysis, LDH, hemoglobin and platelet counts, and creatinine concentrations), the decision to admit the child to hospital or discharge the child to home will be at the discretion of the clinical care team. If microangiopathy is present (i.e., abnormal urinalysis, LDH, hemoglobin or platelet counts, or creatinine concentrations) admission for monitoring will be required.
Intervention Type
Other
Intervention Name(s)
Infusion of 200% maintenance fluids as balanced crystalloid IV solution
Intervention Description
Infusion of 200% of maintenance fluids x 24 hours provided, ideally, as a balanced crystalloid (PlasmaLyteTM, Ringer's Lactate) IV solution. Electrolytes and dextrose may be administered as required and desired by the clinical care team; customized solutions are permitted if so desired. Intravenous fluid solutions containing < 130 mEq/L sodium may increase risk for hyponatremia and may be less effective in achieving intravascular volume expansion and should be avoided.
Intervention Type
Other
Intervention Name(s)
Oral fluids; infusion of up to 110% maintenance fluids as balanced crystalloid IV solution
Intervention Description
Administration of less than or equal to 110% of maintenance fluids as oral or balanced crystalloid IV solution.
Primary Outcome Measure Information:
Title
Major Adverse Kidney Events by 30 days (MAKE30)
Description
Death due to any cause censored at 30 days after enrollment OR Provision of RRT, any modality, within 30 days of trial enrollment OR Sustained loss of kidney function (100% increase of serum sCr from baseline at 30±7 days)
Time Frame
30 days
Secondary Outcome Measure Information:
Title
Number of Participants with Significant Extrarenal Complications (life-threatening):
Description
a. Neurologic: i. Seizures requiring anticonvulsant therapy ii. Coma iii. Thrombotic or hemorrhagic stroke confirmed by neuroimaging b. Cardiac: i. Myocardial infarction ii. Myocarditis iii. Myocardial dysfunction iv. Arrhythmias requiring cardioversion or pharmacological anti-arrhythmic therapy c. Respiratory: i. Respiratory failure ii. Pleural effusions d. Gastrointestinal: i. Hyperglycemia requiring prolonged insulin therapy ii. Bowel obstruction/perforation requiring surgical repair iii. Intussusception requiring reduction iv. Acute cholecystitis v. Pancreatitis vi. Hepatitis/ liver failure vii. Ascites requiring paracentesis e. Infectious complications i. Bacteremia ii. Peritonitis
Time Frame
30 days
Title
Number of Participants who Develop HUS among those without it at randomization
Description
Anemia (hematocrit level <30%) AND Thrombocytopenia (platelet count <150 X 103/mm3) AND Renal azotemia (serum creatinine concentration >upper limit of reference range for age)
Time Frame
30 days
Other Pre-specified Outcome Measures:
Title
Length of Stay
Description
Number of days as an inpatient Number of days in an intensive care unit (a unit capable of providing mechanical ventilation) Hospital-Free Days: Measured as the number of calendar days alive and out of the hospital between randomization (day 0) and day 30. Patients who die prior to hospital discharge will be recorded as zero hospital-free days. Score each hospital day # days with HUS with RRT # days with HUS without RRT # days in hospital - no HUS
Time Frame
30 days
Title
Number of Participants who Receive Transfusion Therapy
Description
Red Blood Cell Platelets
Time Frame
30 days
Title
Number of Participants who Receive Invasive Medical Procedures
Description
Mechanical ventilation Endotracheal intubation Thoracentesis, thoracotomy, ARDS Central venous catheter insertion Dialysis catheter insertion Therapeutic plasma exchange Other operative room surgical interventions
Time Frame
30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
9 Months
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
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: Aged 9.0 months to <21 years at the time of informed consent. Evidence of high-risk STEC infecting pathogen defined by any of the following: 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 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 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. Presence of Advanced HUS defined by: Hematocrit <30% AND Platelet count <150 x 103/mm3 AND 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. Prior episode of HUS or diagnosis of atypical HUS. Chronic disease limiting fluid volumes administered (e.g. impaired renal, liver, or cardiac function, chronic lung disease). Evidence of anuria (i.e., no urine output for > 24 hours). Hypoxemia requiring oxygen therapy Hypertensive emergency Greater than or equal to 10 days since onset of diarrhea or if no diarrhea then the onset of other symptoms. Patients with known pregnancy Patients or caregivers with language barriers impairing appropriate conduct of the study protocol.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Study Manager
Phone
(801) 581-6410
Email
hikostec@hsc.utah.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephen Freedman, MDCM
Organizational Affiliation
University of Calgary
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Individual Site Status
Recruiting
Facility Name
Arkansas Children's Hospital
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72202
Country
United States
Individual Site Status
Recruiting
Facility Name
University of California, San Diego
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States
Individual Site Status
Recruiting
Facility Name
University of California, Davis
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Individual Site Status
Recruiting
Facility Name
University of Colorado Denver
City
Denver
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Individual Site Status
Recruiting
Facility Name
Children's Research Institute
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Individual Site Status
Recruiting
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Individual Site Status
Recruiting
Facility Name
Indiana University Children's Hospital
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
47401
Country
United States
Individual Site Status
Recruiting
Facility Name
University of Kentucky
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40526
Country
United States
Individual Site Status
Recruiting
Facility Name
Norton Children's Hospital
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
Individual Site Status
Recruiting
Facility Name
Children's Minnesota Hospital
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55404
Country
United States
Individual Site Status
Recruiting
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Individual Site Status
Recruiting
Facility Name
Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229-3039
Country
United States
Individual Site Status
Recruiting
Facility Name
University Hospitals Rainbow Babies & Children's Hospital
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Individual Site Status
Recruiting
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Individual Site Status
Recruiting
Facility Name
University of Oklahoma Health Sciences Center
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Individual Site Status
Recruiting
Facility Name
Oregon Health & Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Individual Site Status
Recruiting
Facility Name
Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Individual Site Status
Recruiting
Facility Name
Vanderbilt Children's Hospital
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
43205
Country
United States
Individual Site Status
Recruiting
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Individual Site Status
Recruiting
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Individual Site Status
Recruiting
Facility Name
Alberta Children's Hospital
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T2N 1N4
Country
Canada
Individual Site Status
Recruiting
Facility Name
University of Alberta
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T5J 4P6
Country
Canada
Individual Site Status
Recruiting
Facility Name
McMaster University
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8S 4K1
Country
Canada
Individual Site Status
Recruiting
Facility Name
The Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Individual Site Status
Recruiting

12. IPD Sharing Statement

Learn more about this trial

Hyperhydration in Children With Shiga Toxin-Producing E. Coli Infection

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