Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) (RIVUR)
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| ClinicalTrials.gov Identifier: NCT00405704 |
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Recruitment Status :
Completed
First Posted : November 30, 2006
Results First Posted : April 16, 2015
Last Update Posted : April 16, 2015
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Sponsor:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Vesicoureteral Reflux Urinary Tract Infections | Drug: Trimethoprim-Sulfamethoxazole Drug: Placebo | Phase 3 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 607 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Prevention |
| Official Title: | Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) |
| Study Start Date : | May 2007 |
| Actual Primary Completion Date : | June 2013 |
| Actual Study Completion Date : | May 2014 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: Trimethoprim-Sulfamethoxazole
Cherry-flavored liquid suspension with 3 mg of trimethoprim plus 15 mg sulfamethoxazole per kilogram of body weight, taken once daily.
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Drug: Trimethoprim-Sulfamethoxazole
Cherry-flavored liquid suspension with 3 mg of trimethoprim plus 15 mg sulfamethoxazole per kilogram of body weight, taken once daily.
Other Names:
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Placebo Comparator: Placebo
Cherry-flavored liquid suspension matched to active comparator.
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Drug: Placebo
Cherry flavored liquid suspension matched to active comparator. |
Primary Outcome Measures :
- Recurrent Febrile or Symptomatic Urinary Tract Infection During 2-year Follow-up [ Time Frame: 2 years ]
Secondary Outcome Measures :
- Outcome Renal Scarring [ Time Frame: 2 years ]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.
- Severe Renal Scarring on Outcome Scan [ Time Frame: 2 years ]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.
- New Renal Scarring on Outcome Scan [ Time Frame: 2 years ]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.
- Treatment Failure Composite [ Time Frame: 2 years ]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.
- Presence of E.Coli Resistant to Trimethoprim-Sulfamethoxazole (TMP-SMZ) (Based on Rectal Swab) [ Time Frame: 2 years ]
- Recurrent Febrile or Symptomatic UTI With Resistant E. Coli [ Time Frame: 2 years ]
- Recurrent Febrile or Symptomatic UTI With Any Resistant Pathogen [ Time Frame: 2 years ]
Information from the National Library of Medicine
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| Ages Eligible for Study: | 2 Months to 71 Months (Child) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00405704
Show 19 Study Locations
Sponsors and Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
| Principal Investigator: | 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 Research Institute | |
| Principal Investigator: | Mary Ann Queen, MD | Children's Mercy Hospital Kansas City | |
| Study Chair: | Russell W Chesney, MD | Le Bonheur Children's Medical Center, Memphis, TN | |
| Principal Investigator: | 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 |
Additional Information:
Publications of Results:
Other Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) |
| ClinicalTrials.gov Identifier: | NCT00405704 History of Changes |
| Other Study ID Numbers: |
DK074059 (IND) U01DK074059 ( U.S. NIH Grant/Contract ) |
| First Posted: | November 30, 2006 Key Record Dates |
| Results First Posted: | April 16, 2015 |
| Last Update Posted: | April 16, 2015 |
| Last Verified: | April 2015 |
Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):
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Vesicoureteral Reflux Urinary Tract Infections Renal Scarring Antibiotic Resistance |
Controlled Clinical Trial Trimethoprim-Sulfamethoxazole Children |
Additional relevant MeSH terms:
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Gastroesophageal Reflux Urinary Tract Infections Vesico-Ureteral Reflux Esophageal Motility Disorders Deglutition Disorders Esophageal Diseases Gastrointestinal Diseases Digestive System Diseases Infection Urologic Diseases Urinary Bladder Diseases Trimethoprim Trimethoprim, Sulfamethoxazole Drug Combination Sulfamethoxazole |
Anti-Infective Agents, Urinary Anti-Infective Agents Renal Agents Antimalarials Antiprotozoal Agents Antiparasitic Agents Folic Acid Antagonists Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-Dyskinesia Agents Cytochrome P-450 CYP2C8 Inhibitors Cytochrome P-450 Enzyme Inhibitors Anti-Bacterial Agents |