Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR)

Urinary Tract Infections Clinical Trial

— RIVUR  

Official title:

Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00405704
• Other study ID #: DK074059 (IND)
• Secondary ID: U01DK074059
• Status: Completed
• Phase: Phase 3
• Start date: May 2007
• Est. completion date: May 2014

Study information

• Verified date: April 2020
• Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 607
• Est. completion date: May 2014
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Months to 71 Months

Eligibility

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

Related Conditions & MeSH terms

• Gastroesophageal Reflux
• Urinary Tract Infections
• Vesico-Ureteral Reflux
• Vesicoureteral Reflux

Intervention

Drug:
• Trimethoprim-Sulfamethoxazole
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.

Locations

Country	Name	City	State
United States	Akron Children's Hospital	Akron	Ohio
United States	Johns Hopkins School of Medicine	Baltimore	Maryland
United States	University of Alabama	Birmingham	Alabama
United States	Children's Hospital of Boston	Boston	Massachusetts
United States	Women and Children's Hospital of Buffalo	Buffalo	New York
United States	Ann & Robert Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital	Cincinnati	Ohio
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Penn State Hershey Medical Center	Hershey	Pennsylvania
United States	Texas Children's Hospital	Houston	Texas
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	University of Wisconsin Children's Hospital	Madison	Wisconsin
United States	University of Oklahoma	Oklahoma City	Oklahoma
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Children's National Medical Center	Washington	District of Columbia
United States	Alfred I. duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	University of North Carolina, Chapel Hill

Country where clinical trial is conducted

United States, 

References & Publications (12)

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. — View 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):e3 — View 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:S233-9. doi: 10.1542/peds.2008-1285c. — View 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. Review. — View 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. — View 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. — View 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. — View 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:S240-50. doi: 10.1542/peds.2008-1285d. — View Citation

Keren R. Pediatrics. RIVUR trial. Introduction. Pediatrics. 2008 Dec;122 Suppl 5:S231-2. — View 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. Review. — View 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 — View 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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Recurrent Febrile or Symptomatic Urinary Tract Infection During 2-year Follow-up		2 years
Secondary	Outcome Renal Scarring	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.	2 years
Secondary	Severe Renal Scarring on Outcome Scan	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.	2 years
Secondary	New Renal Scarring on Outcome Scan	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.	2 years
Secondary	Treatment Failure Composite	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.	2 years
Secondary	Presence of E.Coli Resistant to Trimethoprim-Sulfamethoxazole (TMP-SMZ) (Based on Rectal Swab)		2 years
Secondary	Recurrent Febrile or Symptomatic UTI With Resistant E. Coli		2 years
Secondary	Recurrent Febrile or Symptomatic UTI With Any Resistant Pathogen		2 years

External Links

•   RIVUR trial web site