The SCOUT Study: Short Course Therapy for Urinary Tract Infections in Children

Study Overview
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Brief Summary
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The SCOUT study is a multi-center, centrally randomized, double-blind, placebo-controlled non-inferiority clinical trial. 746 participants will be enrolled over a 4.5 year period. 672 will be evaluated for the study's primary outcome measure. After the first 5 days of primary care physician initiated antimicrobial therapy, patients who are afebrile and asymptomatic will then be randomized (1:1) to the standard course therapy arm of 5 more days of the same antibiotic therapy or the short course therapy arm of a placebo for 5 more days (for 10 days total). The primary objective of this study is to determine if halting antimicrobial therapy in subjects who have exhibited clinical improvement 5 days after starting antibiotic therapy (short course therapy) have the same failure rate (symptomatic UTI) through visit Day 11-14 as subjects who continue to take antibiotics for an additional 5 days (standard course therapy).

Detailed Description
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The SCOUT Study is a multi-center, centrally randomized, double-blind, placebo-controlled non-inferiority clinical trial of 746 children ages two months (at least 36 weeks gestation from birth for subjects < two years of age) to 10 years with a confirmed diagnosis of a urinary tract infection (UTI) to evaluate 672 for the study's primary outcome measure. UTI is one of the most common serious bacterial infections during childhood. Escherichia coli (E. coli) isolates account for 80-90 percent of all outpatient UTIs in children. Although antibiotics are the first treatment choice for urinary tract infections, antibiotic-resistant strains of E. coli, the most common cause of UTIs, are increasing worldwide. The study will enroll 746 children who have demonstrated clinical improvement five days after starting the originally prescribed antibiotic (afebrile and asymptomatic) and they will be randomized either to the standard-course arm or the short-course arm at a 1:1 ratio. Subjects will be enrolled over approximately a four and a half year period. Study duration for each individual subject will be approximately five weeks. The study product will consist of trimethoprim-sulfamethoxazole (TMP-SMX), cefixime, cefdinir, cephalexin and the corresponding placebos. The primary objective of this study is to determine if halting antimicrobial therapy in subjects who have exhibited clinical improvement 5 days after starting antibiotic therapy (short course therapy) have the same failure rate (symptomatic UTI) through visit Day 11-14 as subjects who continue to take antibiotics for an additional 5 days (standard course therapy). The secondary objectives are: 1) to determine if short-course therapy compared to standard course therapy results in similar numbers of children experiencing a recurrent urinary tract infection (relapse and reinfection; 2) to determine if short-course therapy compared to standard course therapy results in similar numbers of children with asymptomatic bacteriuria; 3) to determine if short-course therapy compared to standard course therapy results in similar numbers of children with gastrointestinal colonization of antimicrobial resistant Escherichia coli (E. coli) and Klebsiella pneumonia (K. pneumoniae); 4) to determine if short-course therapy compared to standard course therapy results in similar numbers of subjects presenting with clinical symptoms that may be related to UTI; 5) to determine if the number of subjects with positive urine culture prior to or at visit Day 11-14 is similar after short-course therapy compared to standard course therapy.

Official Title
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Targeted Clinical Trials to Reduce the Risk of Antimicrobial Resistance The SCOUT Study: Short Course Therapy for Urinary Tract Infections in Children

Conditions
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Urinary Tract Infection

Intervention / Treatment
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* Drug: Cefixime
* Drug: Cephalexin
* Other: Placebo
* Drug: Trimethoprim/Sulfamethoxazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age at randomization: at least two months (at least 36 weeks gestational age for subjects less than two years of age) to 10 years of age (120 months). Confirmed UTI (Urinary Tract Infection) diagnosis. Documented Clinical Improvement at Randomization. Afebrile: No documented temperature > / = 100.4 degrees Fahrenheit or 38 degrees Celsius (measured anywhere on the body) 24 hours prior to the enrollment visit Asymptomatic: report NONE of the following symptoms: Symptoms for all children (ages two months to 10 years): Fever (a documented temperature of at least 100.4 degrees Fahrenheit OR 38 degrees Celsius measured anywhere on the body) dysuria Additional symptoms for children > 2 years of age: suprapubic, abdominal, or flank pain or tenderness OR urinary urgency, frequency, or hesitancy (defined as an increase in these symptoms from pre-diagnosis conditions) Additional symptoms for children > / = 2 months to 2 years of age: poor feeding OR vomiting Only children who have been prescribed one of the four antibiotics for which a placebo is available will be eligible to participate. TMP-SMX; Cefixime; Cefdinir or Cephalexin. (Note a child that received a one-time dose of I.M. or I.V. medication (i.e. in ER or clinic) prior to starting on the one of the four oral medications is eligible for enrollment) Parental or guardian permission (informed consent) and if appropriate, child assent (if > / = seven years of age). Exclusion Criteria: A urine culture proven infection with a second uropathogen > 10,000 CFU/mL collected via suprapubic aspiration or catheter or > 50,000 CFU/mL collected via clean void. A child hospitalized with a UTI that has the following: concomitant bacteremia associated with the UTI, urosepsis, or is in intensive care. A child whose urine culture reveals an organism that is resistant to the initially prescribed antibiotic. A child with a catheter-associated UTI. A child with known anaphylactic allergies to the study products. A child with phenylketonuria (PKU). A child diagnosed with congenital anomalies of the genitourinary tract. UTI in children with known anatomic abnormalities of the genitourinary tract other than VUR (Vesicoureteral reflux), duplicated collection systems, and hydronephrosis. A child that is not able to take oral medications. Previous surgery of the genitourinary tract (except circumcision in male children). Presence of an immunocompromising condition (e.g., HIV, malignancy, solid-organ transplant recipients, use of chronic corticosteroids or other immunosuppressive agents). Unlikely to complete follow-up (e.g. not available for the two follow-up study visits and the follow-up phone call). A child with a known history of type I hypersensitivity of the study antibiotics to be prescribed . Enrollment in another antibiotic study less than 30 days prior to enrollment visit. Previous enrollment of individuals in this study. Planned enrollment during this study coincides with enrollment in another therapeutic drug study (excluding vaccine). A child with a history of UTI within the past 30 days. A child with known Grade III-V VUR. A child taking antibiotic prophylaxis for any reason. A child who has started Day 6 of the originally prescribed antibiotic treatment.

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active treatment<br>5 days of active therapy to match the physician-initiated therapy, Trimethoprim sulfamethoxazole, Cefixime or Cefdinir or Cephalexin (subjects originally receiving Cefdinir will receive Cefixime) | Drug: Cefixime<br>* Cefixime 8 mg/kg/day orally, in 1 dose, with a maximum of 400 mg. Subjects originally receiving Cefdinir will receive Cefixime.<br>Drug: Cephalexin<br>* Cephalexin 50mg/kg/day in 3 divided doses<br>Drug: Trimethoprim/Sulfamethoxazole<br>* 8 mg/kg/day of Trimethoprim-sulfamethoxazole (TMP-SMX) orally in 2 divided doses, with a maximum dose of 160 mg twice a day.<br>|
| Placebo Comparator: Placebo treatment<br>5 days of placebo treatment to match physician-initiated therapy | Other: Placebo<br>* Placebo to match the other four active treatments<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of Efficacy Based on Symptomatic Urinary Tract Infection (UTI) Between Short-course and Standard-course of Antibiotics. | A subject will be categorized as a treatment failure, if he/she has a symptomatic UTI in period between Day 6 through the Day 11 - 14 Test of Cure (TOC) Visit: Symptoms Symptoms for all subjects (ages two months to 10 years): fever (a documented temperature of at least 100.4 °F OR 38°C measured anywhere on the body) ,dysuria Additional symptoms for subjects > 2 years of age: suprapubic, abdominal, or flank pain or tenderness OR urinary urgency, frequency, or hesitancy (defined as an increase in these symptoms from pre-diagnosis conditions) Additional symptoms for subjects = 2 months to 2 years of age: poor feeding OR vomiting AND Pyuria on urinalysis AND Culture proven infection with a single uropathogen NOTE: As per the above criteria, asymptomatic subjects (including subjects assessed as having asymptomatic bacteriuria) at the Day 11-14 TOC visit will NOT be considered a treatment failure for the primary outcome measure. | Day 11 through Day 14 | 
| Comparison of Efficacy Based on Symptomatic Urinary Tract Infection (UTI) Between Short-course and Standard-course of Antibiotics. Per-protocol Population. | A subject will be categorized as a treatment failure, if he/she has a symptomatic UTI in period between Day 6 through the Day 11 - 14 Test of Cure (TOC) Visit: Symptoms Symptoms for all subjects (ages two months to 10 years): fever (a documented temperature of at least 100.4 °F OR 38°C measured anywhere on the body) ,dysuria Additional symptoms for subjects > 2 years of age: suprapubic, abdominal, or flank pain or tenderness OR urinary urgency, frequency, or hesitancy (defined as an increase in these symptoms from pre-diagnosis conditions) Additional symptoms for subjects = 2 months to 2 years of age: poor feeding OR vomiting AND Pyuria on urinalysis AND Culture proven infection with a single uropathogen NOTE: As per the above criteria, asymptomatic subjects (including subjects assessed as having asymptomatic bacteriuria) at the Day 11-14 TOC visit will NOT be considered a treatment failure for the primary outcome measure. | Day 11 through Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of Number of Subjects That Have a Recurrent Infection (Includes a Relapse UTI or a Reinfection) Following Short-course Versus Standard-course of Antibiotics. |  | Day 11 through Day 44 | 
| Comparison of Number of Subjects That Have a Recurrent Infection (Includes a Relapse UTI or a Reinfection) Following Short-course Versus Standard-course of Antibiotics. Per-protocol Population. |  | Day 11 through Day 44 | 
| Comparison of the Number of Subjects That Become Colonized With Antimicrobial Resistant Escherichia Coli (E. Coli) and Klebsiella Pneumoniae (K. Pneumoniae) in the Gastrointestinal Tract Following Short-course Versus Standard Course of Antibiotics. | A child would have emergent antibiotic resistance if they: Had no antibiotic-resistant E.coli or K.pneumoniae at enrollment but one or both are now present. OR Had either antibiotic-resistant E.coli or K.pneumoniae at enrollment but now the other antibiotic-resistant organism is present OR Had antibiotic-resistant E.coli and/or K.pneumoniae at enrollment, but have now developed resistance to new antibiotics in either organism. | Day 11 through Day 30 | 
| Comparison of the Number of Subjects That Become Colonized With Antimicrobial Resistant E. Coli and K. Pneumoniae in the Gastrointestinal Tract Following Short-course Versus Standard Course of Antibiotics. Per-protocol Population. | A child would have emergent antibiotic resistance if they: Had no antibiotic-resistant E.coli or K.pneumoniae at enrollment but one or both are now present. OR Had either antibiotic-resistant E.coli or K.pneumoniae at enrollment but now the other antibiotic-resistant organism is present OR Had antibiotic-resistant E.coli and/or K.pneumoniae at enrollment, but have now developed resistance to new antibiotics in either organism. | Day 11 through Day 30 | 
| Comparison of the Number of Subjects With Asymptomatic Bacteriuria Following Short-course Versus Standard-course of Antibiotics. | Asymptomatic Bacteriuria is defined in any SCOUT subject by: Absence of symptoms attributable to UTI including fever AND/OR the following: Symptoms for all children (ages two months to 10 years): fever (a documented temperature of at least 100.4 °F OR 38°C measured anywhere on the body) dysuria Additional symptoms for children > 2 years of age: suprapubic, abdominal, or flank pain or tenderness OR urinary urgency, frequency, or hesitancy (defined as an increase in these symptoms from pre-diagnosis conditions) Additional symptoms for children = 2 months to 2 years of age: poor feeding OR vomiting AND A positive urine culture 5 x 104 CFU/mL (catheterized or suprapubic aspiration urine specimen) OR >105 CFU/mL (clean void specimen). | Day 11 through Day 14 | 
| Comparison of the Number of Subjects With Asymptomatic Bacteriuria Following Short-course Versus Standard-course of Antibiotics. Per-protocol Population. | Asymptomatic Bacteriuria is defined in any SCOUT subject by: Absence of symptoms attributable to UTI including fever AND/OR the following: Symptoms for all children (ages two months to 10 years): fever (a documented temperature of at least 100.4 °F OR 38°C measured anywhere on the body) dysuria Additional symptoms for children > 2 years of age: suprapubic, abdominal, or flank pain or tenderness OR urinary urgency, frequency, or hesitancy (defined as an increase in these symptoms from pre-diagnosis conditions) Additional symptoms for children = 2 months to 2 years of age: poor feeding OR vomiting AND A positive urine culture 5 x 104 CFU/mL (catheterized or suprapubic aspiration urine specimen) OR >105 CFU/mL (clean void specimen). | Day 11 through Day 14 | 
| Comparison of the Number of Subjects With Clinical Symptoms That May be Related to a UTI Following Short-course Versus Standard-course of Antibiotics. |  | Up to Day 14 | 
| Comparison of the Number of Subjects With Clinical Symptoms That May be Related to a UTI Following Short-course Versus Standard-course of Antibiotics. Per-protocol Population |  | Up to Day 14 | 
| Comparison of the Number of Subjects With Positive Urine Cultures Following Short-course Versus Standard-course of Antibiotics. |  | Up to Day 14 | 
| Comparison of the Number of Subjects With Positive Urine Cultures Following Short-course Versus Standard-course of Antibiotics. Per-protocol Population. |  | Up to Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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antibiotic therapy, antimicrobial resistance, children, E.coli, K.pneumoniae, parent study, SCOUT Study, spectrum stool bacteria, stool culture, urinary tract infections