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

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

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).

Study Overview

• Status: Completed
• Conditions: Urinary Tract Infection
• Intervention / Treatment: Drug: Cefixime; Drug: Cephalexin; Drug: Trimethoprim/Sulfamethoxazole; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 717
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213-3205
      • Children's Hospital of Pittsburgh of UPMC - General Academic Pediatric

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months to 10 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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).
2. Confirmed UTI (Urinary Tract Infection) diagnosis.

3. Documented Clinical Improvement at Randomization.

   1. Afebrile: No documented temperature > / = 100.4 degrees Fahrenheit or 38 degrees Celsius (measured anywhere on the body) 24 hours prior to the enrollment visit

   2. 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

4. 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)
5. Parental or guardian permission (informed consent) and if appropriate, child assent (if > / = seven years of age).

Exclusion Criteria:

1. 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.
2. A child hospitalized with a UTI that has the following: concomitant bacteremia associated with the UTI, urosepsis, or is in intensive care.
3. A child whose urine culture reveals an organism that is resistant to the initially prescribed antibiotic.
4. A child with a catheter-associated UTI.
5. A child with known anaphylactic allergies to the study products.
6. A child with phenylketonuria (PKU).
7. A child diagnosed with congenital anomalies of the genitourinary tract.
8. UTI in children with known anatomic abnormalities of the genitourinary tract other than VUR (Vesicoureteral reflux), duplicated collection systems, and hydronephrosis.
9. A child that is not able to take oral medications.
10. Previous surgery of the genitourinary tract (except circumcision in male children).
11. Presence of an immunocompromising condition (e.g., HIV, malignancy, solid-organ transplant recipients, use of chronic corticosteroids or other immunosuppressive agents).
12. Unlikely to complete follow-up (e.g. not available for the two follow-up study visits and the follow-up phone call).
13. A child with a known history of type I hypersensitivity of the study antibiotics to be prescribed .
14. Enrollment in another antibiotic study less than 30 days prior to enrollment visit.
15. Previous enrollment of individuals in this study.
16. Planned enrollment during this study coincides with enrollment in another therapeutic drug study (excluding vaccine).
17. A child with a history of UTI within the past 30 days.
18. A child with known Grade III-V VUR.
19. A child taking antibiotic prophylaxis for any reason.
20. A child who has started Day 6 of the originally prescribed antibiotic treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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: SymptomsSymptoms 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) ,dysuriaAdditional 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: SymptomsSymptoms 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) ,dysuriaAdditional 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)dysuriaAdditional symptoms for children > 2 years of age:suprapubic, abdominal, or flank pain or tenderness ORurinary 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 ORvomiting AND; A positive urine culture5 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)dysuriaAdditional symptoms for children > 2 years of age:suprapubic, abdominal, or flank pain or tenderness ORurinary 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 ORvomiting AND; A positive urine culture5 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

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2012
• Primary Completion (Actual): June 30, 2019
• Study Completion (Actual): August 12, 2019

Study Registration Dates

• First Submitted: May 8, 2012
• First Submitted That Met QC Criteria: May 8, 2012
• First Posted (Estimate): May 10, 2012

Study Record Updates

• Last Update Posted (Actual): August 6, 2020
• Last Update Submitted That Met QC Criteria: July 23, 2020
• Last Verified: October 22, 2013

More Information

Terms related to this study

• Keywords: children; urinary tract infections; antibiotic therapy; antimicrobial resistance; E.coli; K.pneumoniae; parent study; SCOUT Study; spectrum stool bacteria; stool culture
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Disease Attributes; Infections; Communicable Diseases; Urinary Tract Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Folic Acid Antagonists; Anti-Dyskinesia Agents; Anti-Infective Agents, Urinary; Renal Agents; Cytochrome P-450 CYP2C8 Inhibitors; Cephalexin; Trimethoprim; Sulfamethoxazole; Cefixime
• Other Study ID Numbers: 09-0103

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No