Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR)

NCT00405704 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: DK074059 (IND)U01DK074059
• Study Type: interventional
• Target: 607
• Locations: 1 country
• Sites: 19

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.

Conditions

Vesicoureteral Reflux; Urinary Tract Infections

Keywords

Vesicoureteral Reflux; Urinary Tract Infections; Renal Scarring; Antibiotic Resistance; Controlled Clinical Trial; Trimethoprim-Sulfamethoxazole; Children

Outcome Measures

Primary Outcomes (1)

• Recurrent Febrile or Symptomatic Urinary Tract Infection During 2-year Follow-up

  2 years

Secondary Outcomes (7)

• Outcome Renal Scarring

  2 years

• Severe Renal Scarring on Outcome Scan

  2 years

• New Renal Scarring on Outcome Scan

  2 years

• Treatment Failure Composite

  2 years

• Presence of E.Coli Resistant to Trimethoprim-Sulfamethoxazole (TMP-SMZ) (Based on Rectal Swab)

  2 years

Study Arms (2)

Trimethoprim-Sulfamethoxazole

ACTIVE COMPARATOR

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

Drug: Trimethoprim-Sulfamethoxazole

Placebo

PLACEBO COMPARATOR

Cherry-flavored liquid suspension matched to active comparator.

Drug: Placebo

Interventions

Trimethoprim-Sulfamethoxazole DRUG

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

Also known as: Sulfatrim, Bactrim

Trimethoprim-Sulfamethoxazole

Placebo DRUG

Cherry flavored liquid suspension matched to active comparator.

Placebo

Eligibility Criteria

• Age: 2 Months - 71 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead
• University of North Carolina, Chapel Hill: collaborator

Study Sites (19)

University of Alabama

Birmingham, Alabama, 35233, United States

Location

Alfred I. duPont Hospital for Children

Wilmington, Delaware, 19803, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Ann & Robert Lurie Children's Hospital of Chicago

Chicago, Illinois, 60614, United States

Location

Johns Hopkins School of Medicine

Baltimore, Maryland, 21287, United States

Location

Children's Hospital of Boston

Boston, Massachusetts, 02115, United States

Location

Children's Hospital of Michigan

Detroit, Michigan, 48201, United States

Location

Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

Women and Children's Hospital of Buffalo

Buffalo, New York, 14222, United States

Location

Wake Forest University Baptist Medical Center

Winston-Salem, North Carolina, 27157, United States

Location

Akron Children's Hospital

Akron, Ohio, 44308, United States

Location

Cincinnati Children's Hospital

Cincinnati, Ohio, 45229, United States

Location

University of Oklahoma

Oklahoma City, Oklahoma, 73104, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Penn State Hershey Medical Center

Hershey, Pennsylvania, 17033, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

University of Wisconsin Children's Hospital

Madison, Wisconsin, 53792, United States

Location

Related Publications (14)

• 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.

  PMID: 19450818 BACKGROUND

• 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.

  PMID: 19570724 BACKGROUND

• 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.

  PMID: 19018048 BACKGROUND

• 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.

  PMID: 18076937 BACKGROUND

• 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.

  PMID: 19018047 BACKGROUND

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

  PMID: 19086141 BACKGROUND

• 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.

  PMID: 22910235 BACKGROUND

• 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.

  PMID: 23546617 BACKGROUND

• 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.

  PMID: 24151147 BACKGROUND

• 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.

  PMID: 23044377 BACKGROUND

• Carpenter MA, Hoberman A, Mattoo TK, Mathews R, Keren R, Chesney RW, Moxey-Mims M, Greenfield SP; RIVUR Trial Investigators. The RIVUR trial: profile and baseline clinical associations of children with vesicoureteral reflux. Pediatrics. 2013 Jul;132(1):e34-45. doi: 10.1542/peds.2012-2301. Epub 2013 Jun 10.

  PMID: 23753091 RESULT

• RIVUR Trial Investigators; Hoberman A, Greenfield SP, Mattoo TK, Keren R, Mathews R, Pohl HG, Kropp BP, Skoog SJ, Nelson CP, Moxey-Mims M, Chesney RW, Carpenter MA. Antimicrobial prophylaxis for children with vesicoureteral reflux. N Engl J Med. 2014 Jun 19;370(25):2367-76. doi: 10.1056/NEJMoa1401811. Epub 2014 May 4.

  PMID: 24795142 RESULT

• 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.

  PMID: 28967387 DERIVED

• 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.

  PMID: 26055855 DERIVED

Related Links

• RIVUR trial web site

MeSH Terms

Conditions

Vesico-Ureteral Reflux; Urinary Tract Infections

Interventions

Trimethoprim, Sulfamethoxazole Drug Combination

Condition Hierarchy (Ancestors)

Urinary Bladder Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Infections

Intervention Hierarchy (Ancestors)

Sulfamethoxazole; Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfanilamides; Aniline Compounds; Amines; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Trimethoprim; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Limitations and Caveats

Results may not apply to children with different demographic or clinical characteristics or in locales where choice of TMP-SMZ may be limited by susceptibility patterns or clinical acceptability. Some subgroup analyses had limited statistical power.

Results Point of Contact

• Title: Dr. Myra Carpenter, Senior Investigator
• Organization: UNC Chapel Hill

myra_carpenter@unc.edu

919-962-3245

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

• Russell W Chesney, MD

  Le Bonheur Children's Medical Center, Memphis, TN

  STUDY CHAIR

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 29, 2006
• First Posted: November 30, 2006
• Study Start: May 1, 2007
• Primary Completion: June 1, 2013
• Study Completion: May 1, 2014
• Last Updated: April 21, 2020
• Results First Posted: April 16, 2015

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will share

Locations

US (19)