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 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.

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.