Clinical trial NCT00405704: Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR)
Official title: Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Vesicoureteral Reflux
Urinary Tract Infections
Keywords: Vesicoureteral Reflux
Urinary Tract Infections
Renal Scarring
Antibiotic Resistance
Controlled Clinical Trial
Trimethoprim-Sulfamethoxazole
Children
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
Collaborators: name: University of North Carolina, Chapel Hill
First posted: 2006-11-30
Enrollment: 607
Sex: ALL
Minimum age (years): 2
Maximum age (years): 71
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Recurrent Febrile or Symptomatic Urinary Tract Infection During 2-year Follow-up
timeFrame: 2 years
Secondary outcomes:
measure: Outcome Renal Scarring
timeFrame: 2 years
measure: Severe Renal Scarring on Outcome Scan
timeFrame: 2 years
measure: New Renal Scarring on Outcome Scan
timeFrame: 2 years
measure: Treatment Failure Composite
timeFrame: 2 years
measure: Presence of E.Coli Resistant to Trimethoprim-Sulfamethoxazole (TMP-SMZ) (Based on Rectal Swab)
timeFrame: 2 years
measure: Recurrent Febrile or Symptomatic UTI With Resistant E. Coli
timeFrame: 2 years
measure: Recurrent Febrile or Symptomatic UTI With Any Resistant Pathogen
timeFrame: 2 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Wilmington
country: United States
facility: Alfred I. duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Ann & Robert Lurie Children's Hospital of Chicago
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins School of Medicine
state: Maryland
city: Boston
country: United States
facility: Children's Hospital of Boston
state: Massachusetts
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Buffalo
country: United States
facility: Women and Children's Hospital of Buffalo
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University Baptist Medical Center
state: North Carolina
city: Akron
country: United States
facility: Akron Children's Hospital
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Hershey
country: United States
facility: Penn State Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Madison
country: United States
facility: University of Wisconsin Children's Hospital
state: Wisconsin
Study officials:
affiliation: University of Alabama, Birmingham, AL
name: Sahar Fathallah, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of NC at Chapel Hill, Chapel Hill, NC
name: Myra A Carpenter, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital of Boston, Boston, MA
name: Caleb P. Nelson, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Texas Children's Hospital, Houston, TX
name: Eileen Brewer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Women and Children's Hospital of Buffalo, Buffalo, NY
name: Saul P Greenfield, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital of Pittsburgh, Pittsburgh, PA
name: Alejandro Hoberman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital of Philadelphia, Philadelphia, PA
name: Ron Keren, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Oklahoma, Oklahoma City, OK
name: Bradley P Kropp, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins University
name: Ranjiv Mathews, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wayne State University School of Medicine, Detroit, MI
name: Tej K Mattoo, MD,DCH, FRCP
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's National Research Institute
name: H. Gil Rushton, MD, FAAP
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Mercy Hospital Kansas City
name: Mary Ann Queen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Le Bonheur Children's Medical Center, Memphis, TN
name: Russell W Chesney, MD
role: STUDY_CHAIR
affiliation: Oregon Health & Science University, Portland, OR
name: Steven J Skoog, MD FACS,FAAP
role: PRINCIPAL_INVESTIGATOR
affiliation: Alfred I. duPont Hospital for Children, Wilmington, DE
name: Amy Renwick, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
name: Earl Y. Cheng, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wake Forest University Baptist Medical Center, Winston-Salem, NC
name: Milan Nadkarni, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital of Boston, Boston, MA
name: Caleb P Nelson, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Cincinnati Children's Hospital, Cincinnati, OH
name: William R DeFoor, Jr, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Akron Children's Hospital, Akron, OH
name: Dan McMahon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Penn State Hershey Medical Center, Hershey, PA
name: Ross Decter, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Wisconsin, Madison
name: Sharon M Bartosh, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
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citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
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