Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR)
Information source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Vesicoureteral Reflux; Urinary Tract Infections
Intervention: Trimethoprim-Sulfamethoxazole (Drug); Placebo (Drug)
Phase: Phase 3
Status: Completed
Sponsored by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Official(s) and/or principal investigator(s): Sahar Fathallah, MD, Principal Investigator, Affiliation: University of Alabama, Birmingham, AL Myra A Carpenter, PhD, Principal Investigator, Affiliation: University of NC at Chapel Hill, Chapel Hill, NC Caleb P. Nelson, MD, MPH, Principal Investigator, Affiliation: Children's Hospital of Boston, Boston, MA Eileen Brewer, MD, Principal Investigator, Affiliation: Texas Children's Hospital, Houston, TX Saul P Greenfield, MD, Principal Investigator, Affiliation: Women and Children's Hospital of Buffalo, Buffalo, NY Alejandro Hoberman, MD, Principal Investigator, Affiliation: Children's Hospital of Pittsburgh, Pittsburgh, PA Ron Keren, MD, MPH, Principal Investigator, Affiliation: Children's Hospital of Philadelphia, Philadelphia, PA Bradley P Kropp, MD, Principal Investigator, Affiliation: University of Oklahoma, Oklahoma City, OK Ranjiv Mathews, MD, Principal Investigator, Affiliation: Johns Hopkins University Tej K Mattoo, MD,DCH, FRCP, Principal Investigator, Affiliation: Wayne State University School of Medicine, Detroit, MI H. Gil Rushton, MD, FAAP, Principal Investigator, Affiliation: Children's Research Institute Mary Ann Queen, MD, Principal Investigator, Affiliation: Children's Mercy Hospital-Kansas City, MO Russell W Chesney, MD, Study Chair, Affiliation: Le Bonheur Children's Medical Center, Memphis, TN Steven J Skoog, MD FACS,FAAP, Principal Investigator, Affiliation: Oregon Health & Science University, Portland, OR Amy Renwick, MD, Principal Investigator, Affiliation: Alfred I. duPont Hospital for Children, Wilmington, DE Earl Y. Cheng, MD, Principal Investigator, Affiliation: Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL Milan Nadkarni, MD, Principal Investigator, Affiliation: Wake Forest University Baptist Medical Center, Winston-Salem, NC Caleb P Nelson, MD, MPH, Principal Investigator, Affiliation: Children's Hospital of Boston, Boston, MA William R DeFoor, Jr, MD, MPH, Principal Investigator, Affiliation: Cincinnati Children's Hospital, Cincinnati, OH Dan McMahon, MD, Principal Investigator, Affiliation: Akron Children's Hospital, Akron, OH Ross Decter, MD, Principal Investigator, Affiliation: Penn State Hershey Medical Center, Hershey, PA Sharon M Bartosh, MD, Principal Investigator, Affiliation: University of Wisconsin, Madison
Summary
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.
Clinical Details
Official title: Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR)
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
Primary outcome: Recurrent Febrile or Symptomatic Urinary Tract Infection During 2-year Follow-up
Secondary outcome: Outcome Renal ScarringSevere Renal Scarring on Outcome Scan New Renal Scarring on Outcome Scan Treatment Failure Composite Presence of E.Coli Resistant to Trimethoprim-Sulfamethoxazole (TMP-SMZ) (Based on Rectal Swab) Recurrent Febrile or Symptomatic UTI With Resistant E. Coli Recurrent Febrile or Symptomatic UTI With Any Resistant Pathogen
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
Minimum age: 2 Months.
Maximum age: 71 Months.
Gender(s): Both.
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
Locations and Contacts
University of Alabama, Birmingham, Alabama 35233, United States
Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803, United States
Children's National Medical Center, Washington, District of Columbia 20010, United States
Ann & Robert Lurie Children's Hospital of Chicago, Chicago, Illinois 60614, United States
Johns Hopkins School of Medicine, Baltimore, Maryland 21287, United States
Children's Hospital of Boston, Boston, Massachusetts 02115, United States
Children's Hospital of Michigan, Detroit, Michigan 48201, United States
Children's Mercy Hospital, Kansas City, Missouri 64108, United States
Women and Children's Hospital of Buffalo, Buffalo, New York 14222, United States
Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157, United States
Akron Children's Hospital, Akron, Ohio 44308, United States
Cincinnati Children's Hospital, Cincinnati, Ohio 45229, United States
University of Oklahoma, Oklahoma City, Oklahoma 73104, United States
Oregon Health & Science University, Portland, Oregon 97239, United States
Penn State Hershey Medical Center, Hershey, Pennsylvania 17033, United States
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States
Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States
Texas Children's Hospital, Houston, Texas 77030, United States
University of Wisconsin Children's Hospital, Madison, Wisconsin 53792, United States
Additional Information
RIVUR trial web site
Related publications: Ziessman HA, Majd M. Importance of methodology on (99m)technetium dimercapto-succinic acid scintigraphic image quality: imaging pilot study for RIVUR (Randomized Intervention for Children With Vesicoureteral Reflux) multicenter investigation. J Urol. 2009 Jul;182(1):272-9. doi: 10.1016/j.juro.2009.02.144. Epub 2009 May 17. Mathews R, Carpenter M, Chesney R, Hoberman A, Keren R, Mattoo T, Moxey-Mims M, Nyberg L, Greenfield S. Controversies in the management of vesicoureteral reflux: the rationale for the RIVUR study. J Pediatr Urol. 2009 Oct;5(5):336-41. doi: 10.1016/j.jpurol.2009.05.010. Epub 2009 Jul 1. Review. Keren R, Carpenter MA, Hoberman A, Shaikh N, Matoo TK, Chesney RW, Matthews R, Gerson AC, Greenfield SP, Fivush B, McLurie GA, Rushton HG, Canning D, Nelson CP, Greenbaum L, Bukowski T, Primack W, Sutherland R, Hosking J, Stewart D, Elder J, Moxey-Mims M, Nyberg L. Rationale and design issues of the Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) study. Pediatrics. 2008 Dec;122 Suppl 5:S240-50. doi: 10.1542/peds.2008-1285d. Greenfield SP, Chesney RW, Carpenter M, Moxey-Mims M, Nyberg L, Hoberman A, Keren R, Matthews R, Mattoo T. Vesicoureteral reflux: the RIVUR study and the way forward. J Urol. 2008 Feb;179(2):405-7. Chesney RW, Carpenter MA, Moxey-Mims M, Nyberg L, Greenfield SP, Hoberman A, Keren R, Matthews R, Matoo TK; members of the RIVUR Steering Committee. Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR): background commentary of RIVUR investigators. Pediatrics. 2008 Dec;122 Suppl 5:S233-9. doi: 10.1542/peds.2008-1285c. Keren R. Pediatrics. RIVUR trial. Introduction. Pediatrics. 2008 Dec;122 Suppl 5:S231-2. Greenfield SP, Carpenter MA, Chesney RW, Zerin JM, Chow J. The RIVUR voiding cystourethrogram pilot study: experience with radiologic reading concordance. J Urol. 2012 Oct;188(4 Suppl):1608-12. doi: 10.1016/j.juro.2012.06.032. Epub 2012 Aug 19. Hoberman A, Shaikh N, Bhatnagar S, Haralam MA, Kearney DH, Colborn DK, Kienholz ML, Wang L, Bunker CH, Keren R, Carpenter MA, Greenfield SP, Pohl HG, Mathews R, Moxey-Mims M, Chesney RW. Factors that influence parental decisions to participate in clinical research: consenters vs nonconsenters. JAMA Pediatr. 2013 Jun;167(6):561-6. doi: 10.1001/jamapediatrics.2013.1050. Bhatnagar S, Hoberman A, Kearney DH, Shaikh N, Moxey-Mims MM, Chesney RW, Carpenter MA, Greenfield SP, Keren R, Mattoo TK, Mathews R, Gravens-Mueller L, Ivanova A. Development and impact of an intervention to boost recruitment in a multicenter pediatric randomized clinical trial. Clin Pediatr (Phila). 2014 Feb;53(2):151-7. doi: 10.1177/0009922813506961. Epub 2013 Oct 22. Chesney RW, Patters AB. Childhood vesicoureteral reflux studies: registries and repositories sources and nosology. J Pediatr Urol. 2013 Dec;9(6 Pt A):731-7. doi: 10.1016/j.jpurol.2012.09.003. Epub 2012 Oct 5. Review.
Starting date: May 2007
Last updated: April 15, 2015
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