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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05219110
Other study ID # DMID 21-0042
Secondary ID R01AI165327
Status Recruiting
Phase Phase 3
First received
Last updated
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
Health authority
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.

Study Design


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
See also
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Not yet recruiting NCT06389474 - Efficacy of INM004 in Children With STEC-HUS Phase 3
Completed NCT01406288 - Outbreak of Hemolytic Uremic Syndrome Linked to Escherichia Coli of Serotype O104:H4 N/A
Terminated NCT04132375 - Phase 2/3 Study to Evaluate PK, Safety & Efficacy of INM004 in STEC Positive Pediatric Patients for Prevention of HUS Phase 2/Phase 3
Completed NCT03776851 - Erythropoietin in Hemolytic Uremic Syndrome Phase 4
Completed NCT01666548 - Haemolytic Uraemic Syndrome in Childhood: Clinical, Cognitive and Psychological Aspects N/A
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