Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier:
NCT00405704
First received: November 29, 2006
Last updated: April 15, 2015
Last verified: April 2015
  Purpose

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.


Condition Intervention Phase
Vesicoureteral Reflux
Urinary Tract Infections
Drug: Trimethoprim-Sulfamethoxazole
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR)

Resource links provided by NLM:


Further study details as provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Primary Outcome Measures:
  • Recurrent Febrile or Symptomatic Urinary Tract Infection During 2-year Follow-up [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Outcome Renal Scarring [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    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.

  • Severe Renal Scarring on Outcome Scan [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    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.

  • New Renal Scarring on Outcome Scan [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    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.

  • Treatment Failure Composite [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    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.

  • Presence of E.Coli Resistant to Trimethoprim-Sulfamethoxazole (TMP-SMZ) (Based on Rectal Swab) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Recurrent Febrile or Symptomatic UTI With Resistant E. Coli [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • Recurrent Febrile or Symptomatic UTI With Any Resistant Pathogen [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Enrollment: 607
Study Start Date: May 2007
Study Completion Date: May 2014
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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:
  • Sulfatrim
  • Bactrim
Placebo Comparator: Placebo
Cherry-flavored liquid suspension matched to active comparator.
Drug: Placebo
Cherry flavored liquid suspension matched to active comparator.

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.

  Eligibility

Ages Eligible for Study:   2 Months to 71 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00405704

  Show 19 Study Locations
Sponsors and Collaborators
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 Research Institute
Principal Investigator: Mary Ann Queen, MD Children's Mercy Hospital-Kansas City, MO
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
  More Information

Additional Information:
Publications:

Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT00405704     History of Changes
Other Study ID Numbers: DK074059 (IND), U01 DK074059
Study First Received: November 29, 2006
Results First Received: December 4, 2014
Last Updated: April 15, 2015
Health Authority: United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):
Vesicoureteral Reflux
Urinary Tract Infections
Renal Scarring
Antibiotic Resistance
Controlled Clinical Trial
Trimethoprim-Sulfamethoxazole
Children

Additional relevant MeSH terms:
Gastroesophageal Reflux
Urinary Tract Infections
Vesico-Ureteral Reflux
Deglutition Disorders
Digestive System Diseases
Esophageal Diseases
Esophageal Motility Disorders
Gastrointestinal Diseases
Infection
Urinary Bladder Diseases
Urologic Diseases
Sulfamethoxazole
Trimethoprim
Trimethoprim-Sulfamethoxazole Combination
Anti-Infective Agents
Anti-Infective Agents, Urinary
Antimalarials
Antiparasitic Agents
Antiprotozoal Agents
Enzyme Inhibitors
Folic Acid Antagonists
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Renal Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on May 21, 2015