Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR)

NCT ID: NCT00405704

Last Updated: 2020-04-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 607 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-05-31
• Study Completion Date: 2014-05-31

Brief 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.

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.

Conditions

Vesicoureteral Reflux; Urinary Tract Infections

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Trimethoprim-Sulfamethoxazole

Cherry-flavored liquid suspension with 3 mg of trimethoprim plus 15 mg sulfamethoxazole per kilogram of body weight, taken once daily.

Group Type: ACTIVE_COMPARATOR

Trimethoprim-Sulfamethoxazole

Intervention Type: DRUG

Cherry-flavored liquid suspension with 3 mg of trimethoprim plus 15 mg sulfamethoxazole per kilogram of body weight, taken once daily.

Placebo

Cherry-flavored liquid suspension matched to active comparator.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Cherry flavored liquid suspension matched to active comparator.

Interventions

Trimethoprim-Sulfamethoxazole

Cherry-flavored liquid suspension with 3 mg of trimethoprim plus 15 mg sulfamethoxazole per kilogram of body weight, taken once daily.

Intervention Type: DRUG

Placebo

Cherry flavored liquid suspension matched to active comparator.

Intervention Type: DRUG

Other Intervention Names

Sulfatrim; Bactrim

Eligibility 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

• Minimum Eligible Age: 2 Months
• Maximum Eligible Age: 71 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: collaborator

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

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sahar Fathallah, MD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama, Birmingham, AL

Myra A Carpenter, PhD

Role: PRINCIPAL_INVESTIGATOR

University of NC at Chapel Hill, Chapel Hill, NC

Caleb P. Nelson, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Boston, Boston, MA

Eileen Brewer, MD

Role: PRINCIPAL_INVESTIGATOR

Texas Children's Hospital, Houston, TX

Saul P Greenfield, MD

Role: PRINCIPAL_INVESTIGATOR

Women and Children's Hospital of Buffalo, Buffalo, NY

Alejandro Hoberman, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Pittsburgh, Pittsburgh, PA

Ron Keren, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Philadelphia, Philadelphia, PA

Bradley P Kropp, MD

Role: PRINCIPAL_INVESTIGATOR

University of Oklahoma, Oklahoma City, OK

Ranjiv Mathews, MD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Tej K Mattoo, MD,DCH, FRCP

Role: PRINCIPAL_INVESTIGATOR

Wayne State University School of Medicine, Detroit, MI

H. Gil Rushton, MD, FAAP

Role: PRINCIPAL_INVESTIGATOR

Children's National Research Institute

Mary Ann Queen, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Mercy Hospital Kansas City

Russell W Chesney, MD

Role: STUDY_CHAIR

Le Bonheur Children's Medical Center, Memphis, TN

Steven J Skoog, MD FACS,FAAP

Role: PRINCIPAL_INVESTIGATOR

Oregon Health & Science University, Portland, OR

Amy Renwick, MD

Role: PRINCIPAL_INVESTIGATOR

Alfred I. duPont Hospital for Children, Wilmington, DE

Earl Y. Cheng, MD

Role: PRINCIPAL_INVESTIGATOR

Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL

Milan Nadkarni, MD

Role: PRINCIPAL_INVESTIGATOR

Wake Forest University Baptist Medical Center, Winston-Salem, NC

Caleb P Nelson, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Boston, Boston, MA

William R DeFoor, Jr, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

Cincinnati Children's Hospital, Cincinnati, OH

Dan McMahon, MD

Role: PRINCIPAL_INVESTIGATOR

Akron Children's Hospital, Akron, OH

Ross Decter, MD

Role: PRINCIPAL_INVESTIGATOR

Penn State Hershey Medical Center, Hershey, PA

Sharon M Bartosh, MD

Role: PRINCIPAL_INVESTIGATOR

University of Wisconsin, Madison

Locations

University of Alabama

Birmingham, Alabama, United States

Alfred I. duPont Hospital for Children

Wilmington, Delaware, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Ann & Robert Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

Johns Hopkins School of Medicine

Baltimore, Maryland, United States

Children's Hospital of Boston

Boston, Massachusetts, United States

Children's Hospital of Michigan

Detroit, Michigan, United States

Children's Mercy Hospital

Kansas City, Missouri, United States

Women and Children's Hospital of Buffalo

Buffalo, New York, United States

Wake Forest University Baptist Medical Center

Winston-Salem, North Carolina, United States

Akron Children's Hospital

Akron, Ohio, United States

Cincinnati Children's Hospital

Cincinnati, Ohio, United States

University of Oklahoma

Oklahoma City, Oklahoma, United States

Oregon Health & Science University

Portland, Oregon, United States

Penn State Hershey Medical Center

Hershey, Pennsylvania, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

Texas Children's Hospital

Houston, Texas, United States

University of Wisconsin Children's Hospital

Madison, Wisconsin, United States

Countries

United States

References

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Reference Type: BACKGROUND

PMID: 19450818 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19570724 (View on PubMed)

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(Suppl 5):S240-50. doi: 10.1542/peds.2008-1285d.

Reference Type: BACKGROUND

PMID: 19018048 (View on PubMed)

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. doi: 10.1016/j.juro.2007.10.100. No abstract available.

Reference Type: BACKGROUND

PMID: 18076937 (View on PubMed)

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(0 5):S233-9. doi: 10.1542/peds.2008-1285c.

Reference Type: BACKGROUND

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Keren R. Pediatrics. RIVUR trial. Introduction. Pediatrics. 2008 Dec;122 Suppl 5:S231-2. doi: 10.1542/peds.2008-1285b. No abstract available.

Reference Type: BACKGROUND

PMID: 19086141 (View on PubMed)

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.

Reference Type: BACKGROUND

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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.

Reference Type: BACKGROUND

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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.

Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: RESULT

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Reference Type: RESULT

PMID: 24795142 (View on PubMed)

Primack W, Bukowski T, Sutherland R, Gravens-Mueller L, Carpenter M. What Urinary Colony Count Indicates a Urinary Tract Infection in Children? J Pediatr. 2017 Dec;191:259-261.e1. doi: 10.1016/j.jpeds.2017.08.012. Epub 2017 Sep 28.

Reference Type: DERIVED

PMID: 28967387 (View on PubMed)

Keren R, Shaikh N, Pohl H, Gravens-Mueller L, Ivanova A, Zaoutis L, Patel M, deBerardinis R, Parker A, Bhatnagar S, Haralam MA, Pope M, Kearney D, Sprague B, Barrera R, Viteri B, Egigueron M, Shah N, Hoberman A. Risk Factors for Recurrent Urinary Tract Infection and Renal Scarring. Pediatrics. 2015 Jul;136(1):e13-21. doi: 10.1542/peds.2015-0409. Epub 2015 Jun 8.

Reference Type: DERIVED

PMID: 26055855 (View on PubMed)

Related Links

http://www.rivur.net

RIVUR trial web site

Other Identifiers

U01DK074059

Identifier Type: NIH

Identifier Source: secondary_id

View Link

DK074059 (IND)

Identifier Type: -

Identifier Source: org_study_id