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

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ClinicalTrials.gov Identifier: NCT05219110

Recruitment Status : Recruiting

First Posted : February 1, 2022

Last Update Posted : May 10, 2023

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View this study on Beta.ClinicalTrials.gov

Sponsor:

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

Information provided by (Responsible Party):

University of Calgary

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).

Condition or disease	Intervention/treatment	Phase
Shiga Toxin-Producing Escherichia Coli (E. Coli) Infection Hemolytic-Uremic Syndrome	Other: Infusion of 200% maintenance fluids as balanced crystalloid IV solution Other: Oral fluids; infusion of up to 110% maintenance fluids as balanced crystalloid IV solution	Phase 3

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	1040 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Intervention Model Description:	Cluster crossover
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Hyperhydration to Improve Kidney Outcomes in Children With Shiga Toxin-Producing E. Coli Infection: A Multinational Embedded Cluster Crossover Randomized Trial
Actual Study Start Date :	September 19, 2022
Estimated Primary Completion Date :	August 31, 2026
Estimated Study Completion Date :	August 31, 2027

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Atypical hemolytic-uremic syndrome

MedlinePlus related topics: E. Coli Infections

Drug Information available for: Shiga toxin

Genetic and Rare Diseases Information Center resources: Hemolytic Uremic Syndrome Acute Graft Versus Host Disease

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Hyperhydration 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).	Other: Infusion of 200% maintenance fluids as balanced crystalloid IV solution 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.
Active Comparator: Conservative Fluid Management 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.	Other: Oral fluids; infusion of up to 110% maintenance fluids as balanced crystalloid IV solution Administration of less than or equal to 110% of maintenance fluids as oral or balanced crystalloid IV solution.

Arm

Intervention/treatment

Experimental: Hyperhydration

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).

Other: Infusion of 200% maintenance fluids as balanced crystalloid IV solution

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.

Active Comparator: Conservative Fluid Management

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.

Other: Oral fluids; infusion of up to 110% maintenance fluids as balanced crystalloid IV solution

Administration of less than or equal to 110% of maintenance fluids as oral or balanced crystalloid IV solution.

Outcome Measures

Primary Outcome Measures :

Major Adverse Kidney Events by 30 days (MAKE30) [ Time Frame: 30 days ]
1. Death due to any cause censored at 30 days after enrollment OR
2. Provision of RRT, any modality, within 30 days of trial enrollment OR
3. 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): [ Time Frame: 30 days ]
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 [ Time Frame: 30 days ]
1. Anemia (hematocrit level <30%) AND
2. Thrombocytopenia (platelet count <150 X 103/mm3) AND
3. Renal azotemia (serum creatinine concentration >upper limit of reference range for age)

Other Outcome Measures:

Length of Stay [ Time Frame: 30 days ]
1. Number of days as an inpatient
2. Number of days in an intensive care unit (a unit capable of providing mechanical ventilation)
3. 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.
4. Score each hospital day
  - # days with HUS with RRT
  - # days with HUS without RRT
  - # days in hospital - no HUS
Number of Participants who Receive Transfusion Therapy [ Time Frame: 30 days ]
1. Red Blood Cell
2. Platelets
Number of Participants who Receive Invasive Medical Procedures [ Time Frame: 30 days ]
1. Mechanical ventilation
2. Endotracheal intubation
3. Thoracentesis, thoracotomy, ARDS
4. Central venous catheter insertion
5. Dialysis catheter insertion
6. Therapeutic plasma exchange
7. Other operative room surgical interventions

Eligibility Criteria

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Ages Eligible for Study:	9 Months to 21 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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:
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.

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.
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.

Contacts and Locations