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

Hemolytic-Uremic Syndrome Clinical Trial

— 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05219110
• Other study ID #: DMID 21-0042
• Secondary ID: R01AI165327
• Status: Recruiting
• Phase: Phase 3
• Start date: September 29, 2022
• Est. completion date: August 31, 2027

Study information

• Verified date: May 2023
• Source: University of Calgary
• Contact: Study Manager
• Phone: (801) 581-6410
• Email: hikostec[@]hsc.utah.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1040
• Est. completion date: August 31, 2027
• Est. primary completion date: August 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 9 Months to 21 Years

Eligibility

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.

Related Conditions & MeSH terms

• Communicable Diseases
• Escherichia coli Infections
• Hemolysis
• Hemolytic-Uremic Syndrome
• Infections
• Water Intoxication

Intervention

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.
• 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.

Locations

Country	Name	City	State
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	University of Alberta	Edmonton	Alberta
Canada	McMaster University	Hamilton	Ontario
Canada	The Hospital for Sick Children	Toronto	Ontario
United States	Emory University	Atlanta	Georgia
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Children's Hospital Medical Center	Cincinnati	Ohio
United States	University Hospitals Rainbow Babies & Children's Hospital	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	University of Colorado Denver	Denver	Colorado
United States	Baylor College of Medicine	Houston	Texas
United States	Indiana University Children's Hospital	Indianapolis	Indiana
United States	University of California, San Diego	La Jolla	California
United States	University of Kentucky	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Norton Children's Hospital	Louisville	Kentucky
United States	Children's Minnesota Hospital	Minneapolis	Minnesota
United States	Vanderbilt Children's Hospital	Nashville	Tennessee
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Oregon Health & Science University	Portland	Oregon
United States	University of California, Davis	Sacramento	California
United States	Washington University	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's Research Institute	Washington	District of Columbia

Sponsors (27)

Lead Sponsor

Collaborator

University of Calgary

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

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Length of Stay	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	30 days
Other	Number of Participants who Receive Transfusion Therapy	Red Blood Cell; Platelets	30 days
Other	Number of Participants who Receive Invasive Medical Procedures	Mechanical ventilation; Endotracheal intubation; Thoracentesis, thoracotomy, ARDS; Central venous catheter insertion; Dialysis catheter insertion; Therapeutic plasma exchange; Other operative room surgical interventions	30 days
Primary	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)	30 days
Secondary	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	30 days
Secondary	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)	30 days