Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) (RIVUR)

April 13, 2020 updated by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
In this 2-year, multisite, randomized, placebo-controlled trial involving 607 children with vesicoureteral reflux that was diagnosed after a first or second febrile or symptomatic urinary tract infecton, we evaluated the efficacy of Trimethoprim-Sulfamethoxazole (TMP-SMZ) prophylaxis in preventing recurrences (primary outcome). Secondary outcomes were renal scarring, treatment failure (a composite of recurrences and scarring), and antimicrobial resistance.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This multicenter, randomized, double-blind, placebo-controlled trial was designed to determine whether daily antimicrobial prophylaxis is superior to placebo in preventing recurrence of urinary tract infection (UTI) in children with vesicoureteral reflux (VUR). Eligibility criteria are described elsewhere. Patients were randomly assigned to treatment for 2 years with daily antimicrobial prophylaxis (trimethoprim-sulfamethoxazole) or placebo. The study was designed to recruit 600 children (approximately 300 in each treatment group). The protocol encouraged prompt evaluation of children with UTI symptoms and early therapy of culture-proven UTIs. It was expected that approximately 10% of children will have to discontinue study medication due to allergic reactions. Assuming a 20% placebo event rate and 10% non-compliance rate, the study has 83% power to detect an absolute 10% event rate in the antimicrobial prophylaxis group. If the placebo event rate is instead 25%, power is 97% to detect an absolute 10% event rate in the treated group, even if non-compliance is as high as 15%. The primary analysis is intention-to-treat with missing outcome data analyzed as UTI.

In addition to collecting follow-up data on urinary tract infections, renal scarring and antimicrobial resistance, quality of life, compliance, safety parameters, utilization of health resources, and change in VUR were assessed periodically throughout the study.

Study Type

Interventional

Enrollment (Actual)

607

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35233
        • University of Alabama
    • Delaware
      • Wilmington, Delaware, United States, 19803
        • Alfred I. DuPont Hospital for Children
    • District of Columbia
      • Washington, District of Columbia, United States, 20010
        • Children's National Medical Center
    • Illinois
      • Chicago, Illinois, United States, 60614
        • Ann & Robert Lurie Children's Hospital of Chicago
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins School of Medicine
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
        • Children's Hospital of Boston
    • Michigan
      • Detroit, Michigan, United States, 48201
        • Children's Hospital of Michigan
    • Missouri
      • Kansas City, Missouri, United States, 64108
        • Children's Mercy Hospital
    • New York
      • Buffalo, New York, United States, 14222
        • Women and Children's Hospital of Buffalo
    • North Carolina
      • Winston-Salem, North Carolina, United States, 27157
        • Wake Forest University Baptist Medical Center
    • Ohio
      • Akron, Ohio, United States, 44308
        • Akron Children's Hospital
      • Cincinnati, Ohio, United States, 45229
        • Cincinnati Children's Hospital
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • University of Oklahoma
    • Oregon
      • Portland, Oregon, United States, 97239
        • Oregon Health & Science University
    • Pennsylvania
      • Hershey, Pennsylvania, United States, 17033
        • Penn State Hershey Medical Center
      • Philadelphia, Pennsylvania, United States, 19104
        • Children's Hospital of Philadelphia
      • Pittsburgh, Pennsylvania, United States, 15213
        • Children's Hospital of Pittsburgh
    • Texas
      • Houston, Texas, United States, 77030
        • Texas Children's Hospital
    • Wisconsin
      • Madison, Wisconsin, United States, 53792
        • University of Wisconsin Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 months to 5 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age at randomization: at least 2 months, but less than 6 years of age. Note that children as young as 1 month were screened for the study.
  • Diagnosed first or second febrile or symptomatic UTI within 112 days prior to randomization
  • Presence of Grade I- IV VUR based on radiographic voiding cystourethrogram (VCUG) performed within 112 days of diagnosis of index UTI.
  • Appropriately treated index febrile or symptomatic UTI

Exclusion Criteria:

  • Index UTI diagnosis more than 112 days prior to randomization
  • History of more than two UTIs prior to randomization
  • For patients less than 6 months of age at randomization, gestational age less than 34 weeks
  • Co-morbid urologic anomalies
  • Hydronephrosis, SFU Grade 4
  • Ureterocele
  • Urethral valve
  • Solitary kidney
  • Profoundly decreased renal size unilaterally on ultrasound (based on 2 standard deviations below the mean for age and length) performed within 112 days after diagnosis of index UTI
  • Multicystic dysplastic kidney
  • Neurogenic bladder
  • Pelvic kidney or fused kidney
  • Known sulfa allergy, inadequate renal or hepatic function, Glucose-6-phosphate dehydrogenase deficiency or other conditions that are contraindications for use of TMP-SMZ
  • History of other renal injury/disease
  • Unable to complete the study protocol
  • Congenital or acquired immunodeficiency
  • Underlying anomalies or chronic diseases that could potentially interfere with response to therapy such as chronic gastrointestinal conditions (i.e., malabsorption, inflammatory bowel disease), liver or kidney failure, or malignancy.
  • Complex cardiac disease as defined in the Manual of Procedures.
  • Any known syndromes associated with VUR or bladder dysfunction
  • Index UTI not successfully treated
  • Unlikely to complete follow-up
  • Family history of anaphylactic reaction to sulfa medications

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Trimethoprim-Sulfamethoxazole
Cherry-flavored liquid suspension with 3 mg of trimethoprim plus 15 mg sulfamethoxazole per kilogram of body weight, taken once daily.
Drug: Trimethoprim-Sulfamethoxazole
Cherry-flavored liquid suspension with 3 mg of trimethoprim plus 15 mg sulfamethoxazole per kilogram of body weight, taken once daily.
Other Names:
  • Bactrim
  • Sulfatrim
Placebo Comparator: Placebo
Cherry-flavored liquid suspension matched to active comparator.
Drug: Placebo
Cherry flavored liquid suspension matched to active comparator.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Recurrent Febrile or Symptomatic Urinary Tract Infection During 2-year Follow-up
Time Frame: 2 years
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Outcome Renal Scarring
Time Frame: 2 years
Renal scarring was defined as a decreased uptake of tracer that was associated with loss of contours or the presence of cortical thinning. Outcome dimercaptosuccinic acid (DMSA) scan was performed at 2 years after enrollment or 3-4 months after the child had met treatment failure criteria.
2 years
Severe Renal Scarring on Outcome Scan
Time Frame: 2 years
Severe renal scarring was defined as scarring in more than 4 of 12 segments in at least one kidney or global atrophy characterized by diffusely scarred and shrunken kidney. Outcome DMSA scan performed at 2 years after enrollment or 3-4 months after the child had met treatment failure criteria.
2 years
New Renal Scarring on Outcome Scan
Time Frame: 2 years
New renal scarring was defined as scarring on the outcome renal scan with technetium -99m-labeled dimercaptosuccinic acid that was not present at baseline. Outcome DMSA scan performed at 2 years after enrollment or 3-4 months after the child had met treatment failure criteria.
2 years
Treatment Failure Composite
Time Frame: 2 years
Treatment failure was defined as the occurrence of two febrile urinary tract infections (UTIs), one febrile UTI and three symptomatic UTIs, four symptomatic UTIs, or new or worsening renal scarring on an interim scan (e.g,, the 12-month visit); renal scans from the 2-year visit are NOT considered in the treatment failure criteria.
2 years
Presence of E.Coli Resistant to Trimethoprim-Sulfamethoxazole (TMP-SMZ) (Based on Rectal Swab)
Time Frame: 2 years
2 years
Recurrent Febrile or Symptomatic UTI With Resistant E. Coli
Time Frame: 2 years
2 years
Recurrent Febrile or Symptomatic UTI With Any Resistant Pathogen
Time Frame: 2 years
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborators

University of North Carolina, Chapel Hill

Investigators

  • Principal Investigator: Sahar Fathallah, MD, University of Alabama, Birmingham, AL
  • Principal Investigator: Myra A Carpenter, PhD, University of NC at Chapel Hill, Chapel Hill, NC
  • Principal Investigator: Caleb P. Nelson, MD, MPH, Children's Hospital of Boston, Boston, MA
  • Principal Investigator: Eileen Brewer, MD, Texas Children's Hospital, Houston, TX
  • Principal Investigator: Saul P Greenfield, MD, Women and Children's Hospital of Buffalo, Buffalo, NY
  • Principal Investigator: Alejandro Hoberman, MD, Children's Hospital of Pittsburgh, Pittsburgh, PA
  • Principal Investigator: Ron Keren, MD, MPH, Children's Hospital of Philadelphia, Philadelphia, PA
  • Principal Investigator: Bradley P Kropp, MD, University of Oklahoma, Oklahoma City, OK
  • Principal Investigator: Ranjiv Mathews, MD, Johns Hopkins University
  • Principal Investigator: Tej K Mattoo, MD,DCH, FRCP, Wayne State University School of Medicine, Detroit, MI
  • Principal Investigator: H. Gil Rushton, MD, FAAP, Children's National Research Institute
  • Principal Investigator: Mary Ann Queen, MD, Children's Mercy Hospital Kansas City
  • Study Chair: Russell W Chesney, MD, Le Bonheur Children's Medical Center, Memphis, TN
  • Principal Investigator: Steven J Skoog, MD FACS,FAAP, Oregon Health & Science University, Portland, OR
  • Principal Investigator: Amy Renwick, MD, Alfred I. duPont Hospital for Children, Wilmington, DE
  • Principal Investigator: Earl Y. Cheng, MD, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
  • Principal Investigator: Milan Nadkarni, MD, Wake Forest University Baptist Medical Center, Winston-Salem, NC
  • Principal Investigator: Caleb P Nelson, MD, MPH, Children's Hospital of Boston, Boston, MA
  • Principal Investigator: William R DeFoor, Jr, MD, MPH, Cincinnati Children's Hospital, Cincinnati, OH
  • Principal Investigator: Dan McMahon, MD, Akron Children's Hospital, Akron, OH
  • Principal Investigator: Ross Decter, MD, Penn State Hershey Medical Center, Hershey, PA
  • Principal Investigator: Sharon M Bartosh, MD, University of Wisconsin, Madison

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2007

Primary Completion (Actual)

June 1, 2013

Study Completion (Actual)

May 1, 2014

Study Registration Dates

First Submitted

November 29, 2006

First Submitted That Met QC Criteria

November 29, 2006

First Posted (Estimate)

November 30, 2006

Study Record Updates

Last Update Posted (Actual)

April 21, 2020

Last Update Submitted That Met QC Criteria

April 13, 2020

Last Verified

April 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DK074059 (IND)
  • U01DK074059 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Data are available at the NIDDK Central Repository: https://repository.niddk.nih.gov/studies/rivur/?query=rivur

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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