Urinary Tract Infections, Vesicoureteral Reflux
Conditions
Keywords
Vesicoureteral Reflux, Urinary Tract Infections, Renal Scarring, Antibiotic Resistance, Controlled Clinical Trial, Trimethoprim-Sulfamethoxazole, Children
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.
Interventions
DRUGTrimethoprim-Sulfamethoxazole
Cherry-flavored liquid suspension with 3 mg of trimethoprim plus 15 mg sulfamethoxazole per kilogram of body weight, taken once daily.
DRUGPlacebo
Cherry flavored liquid suspension matched to active comparator.
Sponsors
University of North Carolina, Chapel Hill
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Months to 71 Months
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Recurrent Febrile or Symptomatic Urinary Tract Infection During 2-year Follow-up | 2 years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Outcome Renal Scarring | 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 | 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 | 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. |
| Recurrent Febrile or Symptomatic UTI With Any Resistant Pathogen | 2 years | — |
| Presence of E.Coli Resistant to Trimethoprim-Sulfamethoxazole (TMP-SMZ) (Based on Rectal Swab) | 2 years | — |
| Recurrent Febrile or Symptomatic UTI With Resistant E. Coli | 2 years | — |
| Treatment Failure Composite | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Trimethoprim-Sulfamethoxazole Trimethoprim-Sulfamethoxazole: Cherry-flavored liquid suspension with 3 mg of trimethoprim plus 15 mg sulfamethoxazole per kilogram of body weight, taken once daily. | 302 |
| Placebo Placebo: Cherry flavored liquid suspension matched to active comparator. | 305 |
| Total | 607 |
Baseline characteristics
| Characteristic | Trimethoprim-Sulfamethoxazole | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 12 months | 12 months | 12 months |
| Region of Enrollment United States | 302 participants | 305 participants | 607 participants |
| Sex: Female, Male Female | 277 Participants | 281 Participants | 558 Participants |
| Sex: Female, Male Male | 25 Participants | 24 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 79 / 302 | 105 / 305 |
| serious Total, serious adverse events | 0 / 302 | 0 / 305 |
Outcome results
Primary
Recurrent Febrile or Symptomatic Urinary Tract Infection During 2-year Follow-up
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trimethoprim-Sulfamethoxazole | Recurrent Febrile or Symptomatic Urinary Tract Infection During 2-year Follow-up | 39 participants |
| Placebo | Recurrent Febrile or Symptomatic Urinary Tract Infection During 2-year Follow-up | 72 participants |
p-value: <0.001Log Rank
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.
Time frame: 2 years
Population: The analysis population excluded 82 subjects in the trimethoprim-sulfamethoxazole group and 78 subjects in the placebo group who did not have an outcome dimercaptosuccinic acid scan.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trimethoprim-Sulfamethoxazole | New Renal Scarring on Outcome Scan | 18 participants |
| Placebo | New Renal Scarring on Outcome Scan | 19 participants |
p-value: 0.94Cochran-Mantel-Haenszel
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.
Time frame: 2 years
Population: The analysis population excluded 75 subjects in the trimethoprim-sulfamethoxazole group and 70 subjects in the placebo group who did not have an outcome dimercaptosuccinic acid scan.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trimethoprim-Sulfamethoxazole | Outcome Renal Scarring | 27 participants |
| Placebo | Outcome Renal Scarring | 24 participants |
p-value: 0.55Cochran-Mantel-Haenszel
Secondary
Presence of E.Coli Resistant to Trimethoprim-Sulfamethoxazole (TMP-SMZ) (Based on Rectal Swab)
Time frame: 2 years
Population: The analysis population excluded 99 subjects in the trimethoprim-sulfamethoxazole group and 95 subjects in the placebo group who did not have stool analyzed at the outcome visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trimethoprim-Sulfamethoxazole | Presence of E.Coli Resistant to Trimethoprim-Sulfamethoxazole (TMP-SMZ) (Based on Rectal Swab) | 56 participants |
| Placebo | Presence of E.Coli Resistant to Trimethoprim-Sulfamethoxazole (TMP-SMZ) (Based on Rectal Swab) | 41 participants |
p-value: 0.065Cochran-Mantel-Haenszel
Secondary
Recurrent Febrile or Symptomatic UTI With Any Resistant Pathogen
Time frame: 2 years
Population: The analysis population is restricted to the 38 subjects in the trimethoprim-sulfamethoxazole (TMP-SMZ) group and 69 subjects in the placebo group who had a recurrent UTI with an organism for which sensitivity to TMP-SMZ was assessed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trimethoprim-Sulfamethoxazole | Recurrent Febrile or Symptomatic UTI With Any Resistant Pathogen | 26 participants |
| Placebo | Recurrent Febrile or Symptomatic UTI With Any Resistant Pathogen | 17 participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Recurrent Febrile or Symptomatic UTI With Resistant E. Coli
Time frame: 2 years
Population: The analysis population is restricted to the 30 subjects in the trimethoprim-sulfamethoxazole (TMP-SMZ) group and 57 subjects in the placebo group who had a recurrent UTI with E. coli for which sensitivity to TMP-SMZ was assessed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trimethoprim-Sulfamethoxazole | Recurrent Febrile or Symptomatic UTI With Resistant E. Coli | 19 participants |
| Placebo | Recurrent Febrile or Symptomatic UTI With Resistant E. Coli | 11 participants |
p-value: <0.001Cochran-Mantel-Haenszel
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.
Time frame: 2 years
Population: The analysis population excluded 75 subjects in the trimethoprim-sulfamethoxazole group and 70 subjects in the placebo group who did not have an outcome dimercaptosuccinic acid scan.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trimethoprim-Sulfamethoxazole | Severe Renal Scarring on Outcome Scan | 9 participants |
| Placebo | Severe Renal Scarring on Outcome Scan | 6 participants |
p-value: 0.37Cochran-Mantel-Haenszel
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.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trimethoprim-Sulfamethoxazole | Treatment Failure Composite | 14 participants |
| Placebo | Treatment Failure Composite | 27 participants |
p-value: 0.04Log Rank