Official Title: “Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR)”

The purpose of this study is to learn whether all children with vesicoureteral reflux (VUR) should be treated with antibiotics. The study will tell us if prophylactic antibiotic treatment prevents urinary tract infections and renal scarring in children with VUR.

Study Type: Interventional

Study Design: Prevention, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: June 2011

This multicenter, randomized, double-blind, placebo-controlled trial is 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 will be randomly assigned to treatment for 2 years with daily antimicrobial prophylaxis (trimethoprim-sulfamethoxazole) or placebo. The study is designed to recruit 600 children (approximately 300 in each treatment group) over a 24 month period. The protocol will encourage prompt evaluation of children with UTI symptoms and early therapy of culture-proven UTIs. It is 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%.

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 will be assessed periodically throughout the study.

Intervention(s) in this Clinical Trial

• Drug: Trimethoprim-Sulfamethoxazole
  • Cherry-flavored liquid suspension in which each 5 mL contains 200 mg sulfamethoxazole and 40 mg trimethoprim. Prophylactic dose is based on trimethoprim component: 3 mg per kg body weight taken once daily.
• Drug: Placebo
  • Cherry flavored liquid suspension matched to active comparator.

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
• Placebo Comparator: 2

Primary Measures

• Recurrent febrile or symptomatic urinary tract infection during 2-year follow-up
  • Time Frame: 2 years
    Safety Issue?: Yes

Secondary Measures

• Renal scarring based on DMSA scan performed 1 and 2 years after enrollment
  • Time Frame: 2 years
    Safety Issue?: Yes
• Severe renal scarring on outcome scan
  • Time Frame: 2 years
    Safety Issue?: Yes
• Treatment failure composite based on multiple recurrent UTIs or, in children with baseline scarring of grade 3 or higher, new renal scarring at 12-months or further scarring at any time following recurrent febrile UTI
  • Time Frame: 2 years
    Safety Issue?: Yes
• Presence of E.coli resistant to TMP/SMZ (based on rectal swab)
  • Time Frame: 2 years
    Safety Issue?: No
• Recurrent febrile or symptomatic UTI caused by TMP/SMZ-resistant organism
  • Time Frame: 2 years
    Safety Issue?: Yes

Inclusion Criteria:

• Age at randomization: at least 2 months, but less than 6 years of age. Note that children as young as 1 month may be 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 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, G6PD 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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 2 Months

Maximum Age for this Clinical Trial: 71 Months

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Overall Clinical Trial Officials and Contacts

Mark Benfield, MD Principal Investigator University of Alabama, Birmingham, AL  

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00405704

Study ID Number: DK074059

ClinicalTrials.gov Identifier: NCT00405704

Health Authority: United States: Federal Government

RIVUR trial web site